JCS 2021 Guideline on the Clinical Application of Echocardiography

Abbreviations

2D	two-dimensional
3D	three-dimensional
18F-FDG PET	18F-fluorodeoxyglucose positron emission tomography
ACS	acute coronary syndrome
AF	atrial fibrillation
AHA/ACC	American Heart Association/American College of cardiology
AR	aortic regurgitation
AS	aortic stenosis
ASD	atrial septal defect
ASE	American Society of Echocardiography
BMI	body mass index
COVID-19	coronavirus disease 2019
CO	cardiac output
CT	computed tomography
CTRCD	cancer therapeutics-related cardiac dysfunction
DcT	deceleration time
ECG	electrocardiogram
FoCUS	focused cardiac ultrasound
GLS	global longitudinal strain
HFpEF	heart failure with preserved ejection fraction
HFrEF	heart failure with reduced ejection fraction
IE	infectious endocarditis
IVC	inferior vena cava
JCS	Japanese Circulation Society
JSE	Japanese Society of Echocardiography
LAA	left atrial appendage
LAVI	left atrial volume index
LV	left ventricular
LVEF	left ventricular ejection fraction
MAPSE	mitral annular plane systolic excursion
MR	mitral regurgitation
MRI	magnetic resonance imagings
MS	mitral stenosis
PAP	pulmonary arterial pressure
PAH	pulmonary arterial hypertension
PDA	patent ductus arteriosus
POCUS	point-of-care ultrasonography
PISA	proximal isovelocity surface area
PTMC	percutaneous transvenous mitral commissurotomy
PV	pulmonary venous
RV	right ventricular
RIMP	right ventricular index of myocardial performance
SV	stroke volume
TAPSE	tricuspid annular plane systolic excursion
TAVI	transcatheter aortic valve implantation
TEE	transesophageal echocardiography
TR	tricuspid regurgitation
TTE	transthoracic echocardiography
VSD	ventricular septal defect

I. Introduction

1. Preface to the Revision

The “Guidelines for the clinical indications of echocardiography” of the Japanese Circulation Society (JCS) were first developed between 1993 and 1994, and the first revision¹ was published in 2010. In these newly revised guidelines (JCS 2020), we would like to discuss the differences from the previous edition. As we all know, echocardiographic technology has been constantly evolving. In the past 10 years, the quality of two-dimensional (2D) images has improved remarkably, and advances in software for cardiac function analysis, including automatic measurements, have been outstanding. Except for some cases, including those of pulmonary disease, echocardiography allows even less experienced physicians to diagnose valvular heart disease, cardiomyopathy, congenital heart disease, and other cardiac diseases and to measure cardiac function just by placing an ultrasound probe on the patient’s chest. Transthoracic echocardiography has been called “a stethoscope substitution” and is recognized as an indispensable tool for the initial diagnosis of cardiovascular disease, just like plain chest radiography and electrocardiography. Recently introduced innovative therapeutic techniques, including transcatheter closure of atrial septal defects, transcatheter aortic valve replacement, percutaneous mitral valve clipping, and percutaneous left atrial appendage closure, cannot be performed without the support of echocardiographic images, particularly of transesophageal and intracardiac views. Additionally, advances in three-dimensional (3D) (transesophageal and transthoracic) echocardiography have shed new light on the diagnosis and treatment of valvular and congenital heart disease. Thus, it is clear that over the past decade, echocardiography has increasingly become an important diagnostic imaging tool and is used intensively and extensively in the cardiovascular field from ambulatory care to advanced invasive treatments. This powerful diagnostic tool has now become familiar and readily available to physicians. To make full use of this imaging modality in cardiovascular practice, it is necessary to “translate” and reflect the acquired data into clinical practice based on correct knowledge, pathophysiological understanding, and consensus. We aimed to revise this 2021 edition from the viewpoint of sharing “the way to translation” by all physicians involved in echocardiography. We have added a new chapter of “II. Recent Advances in Echocardiography as a Diagnostic Tool”, which was not included in the 2010 edition. In it the roles of TEE as essential imaging modalities for structural heart disease are described. In the first part of Chapter III, cardiac function is described in more detail than in the previous edition because in recent years the echocardiographic assessment of cardiac function has become increasingly important for a significantly increasing number of patients with heart failure. Also in Chapter III, current topics, including the diagnosis of secondary cardiomyopathy and Takotsubo syndrome, cardiac function assessment during treatment with cardiotoxic drugs, and adult congenital heart disease, are also described with recommendation classes and levels of evidence for echocardiography. We hope these 2021 revised guidelines will contribute to frontline cardiovascular care by clarifying the role of echocardiography in daily practice and by providing a way to “translate echocardiographic data” based on the collection and understanding of correct knowledge and consensus.

This English version is a translated, abbreviated form of the Japanese version; the sections were selected based on their importance, with some parts omitted from the English version.

Finally, a team leader of the working group for this Guideline would like to express profound gratitude to the team members and all individuals who helped in the revision of the guidelines by taking time out of their busy schedules.

2. Recommendation Classes and Levels of Evidence

Following previous guidelines, the recommendation classes and levels of evidence are classified according to the ACC/AHA and ESC guidelines (Tables 1,2). Although Minds, a medical information service business operated by the Japan Council for Quality Health Care, has made different classifications of recommended grades and levels of evidence,² the same recommendation classes and levels of evidence have been adopted as described in the previous edition, primarily because these classifications are widely used in cardiovascular practice in Japan and can be easily made in line with similar guidelines in other countries. The recommended classes and levels of evidence were determined by the author responsible for each section based on papers published to that date inside and outside Japan and were finally decided by a consensus of the working group members and external reviewers.

Table 1. Classes of Recommendations

Class I	Evidence and/or general agreement that a given procedure or treatment is effective and useful
Class IIa	Weight of evidence/opinion is in favor of usefulness/efficacy
Class IIb	Usefulness/efficacy is less well established by evidence/opinion
Class IIIa (No benefit)	There is evidence and/or general agreement that a given procedure or treatment is not effective/useful
Class IIIb (Harm)	There is evidence and/or general agreement that a given procedure or treatment is harmful

There are 5 classes of recommendations, with 2 subclasses for each of Classes II and III. Based on the recommendations of the JCS Guideline Development Committee, these classes are not stated with a noun at the end of sentences but stated using the phrases “be indicated” for Class I, “is reasonable” for Class IIa, “may be considered” for Class IIb, “is not recommended” for Class IIIa (no benefit), and “should not be performed” for Class IIIb (harm).

Table 2. Level of Evidence

Level A	Data derived from multiple randomized clinical trials or meta-analyses
Level B	Data derived from a single randomized clinical trial or large-scale non-randomized studies
Level C	Consensus of opinion of the experts and/or small-size clinical studies, retrospective studies, and registries

Of note, transesophageal echocardiography (TEE) and cardiac contrast-enhanced computed tomography (CT) are commonly used to exclude thrombus in the left atrial appendage before catheter ablation of atrial fibrillation. The role of these imaging modalities has been changing in routine clinical practice. We reviewed from recent literature the role of TEE when preoperative contrast-enhanced cardiac CT was performed and have created a Clinical Question to define indications of TEE in catheter ablation of atrial fibrillation. Here, in addition to the conventional JCS recommendation classes and levels of evidence, we present the Minds recommendation classes and levels of evidence (Tables 3,4).²

Table 3. MINDS Grades of Recommendation

Grade A	Strongly recommended and supported by strong evidence
Grade B	Recommended with moderately strong supporting evidence
Grade C1	Recommended despite no strong supporting evidence
Grade C2	Not recommended because of the absence of strong supporting evidence
Grade D	Not recommended as evidence indicates that the treatment is ineffective or even harmful

Table 4. MINDS Levels of Evidence (Levels of Evidence in Literature on Treatment)

I	Systematic review/meta-analysis of randomized controlled trials
II	One or more randomized controlled trials
III	Non-randomized controlled trials
IVa	Analytical epidemiological studies (cohort studies)
IVb	Analytical epidemiological studies (case-control studies and cross-sectional studies)
V	Descriptive studies (case reports and case series)
VI	Not based on patient data, or based on opinions from a specialist committee or individual specialists

II. Recent Advances in Echocardiography as a Diagnostic Tool

1. Transesophageal Echocardiography (TEE)

1.1 Overview

TEE is mainly performed when transthoracic imaging is unsatisfactory. Because TEE is not affected by the chest wall, high-frequency ultrasound can be used to produce high-resolution images, which is particularly useful in diagnosing organic heart diseases such as valvular heart disease and congenital heart disease, infective endocarditis, left atrial thrombus, and acute aortic disease. TEE is also used extensively to monitor cardiac function during major cardiovascular surgeries when transthoracic echocardiography (TTE) cannot be performed. Currently, multiplanar TEE probes or matrix probes for three-dimensional (3D) imaging are available. The insertion of the probe into the esophagus may cause some discomfort to the patient and thus should be performed by, or under the guidance of, a physician with adequate experience and knowledge.

The reported complications include bronchospasm, laryngospasm, pulmonary edema, vomiting, tachycardia, atrioventricular block, hypoxemia, blood pressure fluctuations, angina attacks, laryngeal hemorrhage, and esophageal injury or perforation. In particular, injuries to the laryngopharynx or esophagus may require hospitalization or surgical treatment. Therefore, before performing TEE, the patient should be informed of the imaging procedure and complications and give written consent. The procedure can be performed under local anesthesia if the patient can tolerate and control the discomfort or under intravenous anesthesia and sedation if the patient seems unable to tolerate. The Valsalva maneuver, used to detect right-to-left shunts, is performed under conscious conditions to achieve adequate stress. Because of the inevitable risks associated with anesthesia and probe insertion, a record should be kept, including the name of the examiner, date and time of the examination, anesthetic procedure and agents, changes in vital signs, and any complications and adverse reactions.³ Moreover, care must be taken to prevent infections such as viral hepatitis, and most institutions perform a blood test to exclude infections before imaging. TEE is one of the examinations at high risk of droplet infection to the examiner, so standard precautions should be taken: a facial mask, medical gloves, and apron should be worn and due to the outbreak of novel Covid-19 infection, it is now recommended that a goggle and face shield should be also used to prevent adhesion of the pathogen to the examiner’s face, including the eyes.⁴

1.2 Imaging Techniques

1.2.1 Patient Preparation

Place the patient in the left lateral decubitus position. Imaging also can be done with the patient supine or seated if lying on the left side is not possible. Have the patient hold a local anesthetic, such as viscous lidocaine (Xylocaine Viscous), in the mouth to numb the surface of the posterior pharyngeal wall and tongue base. A local anesthetic spray may be added as needed. For patients who are unable to tolerate the discomfort associated with probe insertion or in whom an elevation of blood pressure or heart rate has to be avoided or the examination is expected to take a longer time to complete, a short-acting intravenous anesthetic, such as midazolam or propofol, may be used for sedation. However, because these agents tend to cause hypotension and respiratory depression, transcutaneous oxygen saturation and other vital signs should be measured over time. It is recommended that a physician or nurse, other than the examiner, be dedicated to monitoring the patient. Cardiopulmonary resuscitation, including endotracheal intubation, should be prepared in case of sudden changes in the patient’s condition. In patients who are allergic to lidocaine (Xylocaine), an intravenous anesthetic combined with lidocaine (Xylocaine)-free ultrasound jelly may be used instead.

1.2.2 Probe Insertion and Disposition of Used Probes

Have the patient hold a mouthpiece or bite block in the mouth and adjust the patient’s posture to prevent saliva accumulation in the mouth. Insert the probe “in a sniffing position,” in which the jaw is pulled slightly forward, keeping the trachea straight from the mouth. It is recommended that a plastic probe cover should be used during the examination. Once inserted into the oral cavity, the probe is anteflexed to prevent contact with the posterior pharyngeal wall and avoid the vomiting reflex. The probe should be advanced to approximately 16–18 cm from the incisors and held, close to the epiglottis, at the bifurcation of the trachea and esophagus. Ask the conscious patient to swallow while the probe is retroflexed to ensure smooth insertion. Coughing may be induced when the probe enters the trachea. If the tip of the probe hits the piriform fossa, resistance to advancement will be encountered. In such a case, withdraw the probe slightly and try to advance it again. Once reaching the esophagus, the probe can be advanced without resistance. Advance the probe through the upper to the middle esophagus to sequentially obtain standard views (described in detail next). While being withdrawn, the probe is rotated to obtain horizontal images of the descending thoracic aorta. As the aorta is being viewed, the probe is gradually withdrawn until the aortic arch is brought into view. After viewing the aortic arch, the probe is removed.

If a probe cover is not used, wash the used probe with running water and rub it with gauze to wash away mucus and other adherent matter. A protein remover for endoscopes may be used. If a probe cover is used, this process can be eliminated, but ensure that the cover has not been damaged. The probe is then immersed in a disinfectant solution, such as o-phthalaldehyde. After removal, the probe should be rinsed with plenty of tap water to remove the disinfectant and suspended vertically to dry. Although it is not necessary to sterilize the probe, it is recommended to use a storage cabinet to keep echoendoscopes clean.³ For details of TEE practice, including probe disinfection and sedation, please refer to the Japanese Society of Echocardiography (JSE) Practical Guidance of TEE (2018 edition) (in Japanese).⁵

1.2.3 Anatomy and Standard Views in TEE

The American Society of Echocardiography (ASE) and the Society of Cardiovascular Anesthesiologists recommend 28 standard views should be obtained.⁶ However, these are not sufficient for detailed examinations of the left atrial appendage (LAA), atrial septum, and mitral valve in adult patients. Some examinations, such as those to obtain upper esophageal and deep transgastric views, cause considerable discomfort if performed under conscious conditions. Figure 1 shows the standard views, including those suitable for detailed observation of the entrance to the end of the LAA, detection of patent foramen ovale using contrast TEE with Valsalva maneuver, and detailed observation of commissural lesions of the mitral valve.

Figure 1.

Standard views of transesophageal echocardiography. (A) Mid-esophageal views. (1) Mid-esophageal 4-chamber view (0°, horizontal plane). (2) Mid-esophageal 5-chamber view (0°, probe flexed anteriorly from the 4-chamber view). (3) Mid-esophageal mitral commissural view (45–60°, angle at which both commissures open symmetrically), also known as “true commissure view”. (4) Mitral AC–PC commissural view (45–60°, rotated clockwise from the commissural view) to show the AC and PC, showing a case of PC prolapse. (5) Mid-esophageal LV long-axis view (135–150°, 90° up from the mitral commissural view, longitudinal cross-section through the center of the ascending aorta and LV apex). (6) Mid-esophageal ascending aorta long-axis view (ascending aorta is extensively seen by withdrawing the probe from the LV long-axis view). (7) Mid-esophageal ascending aorta short-axis view (90° down from the long-axis view of the ascending aorta). (8) Mid-esophageal aortic valve short-axis view (90° down from the LV long-axis view, showing the 3 commissures of the aortic valve). (9) Mid-esophageal 2-chamber view (90°, vertical plane). (10) Mid-esophageal LAA view (90°, rotated counterclockwise from the 2-chamber view). (11) Mid-esophageal LAA basal view (120°). (12) Mid-esophageal LAA entrance view (60°). (13) Mid-esophageal left pulmonary vein view (90°, rotated counterclockwise from the LAA view). (14) Mid-esophageal atrial septum view (90°, rotated clockwise from the 2-chamber view). (15) Mid-esophageal tricuspid valve view (60°, rotated clockwise from the atrial septal view, angle decreased). (16) Mid-esophageal bicaval view (90–110°, rotated clockwise from the tricuspid valve view). (17) Mid-esophageal right pulmonary vein view (90°, rotated clockwise from the bicaval view). (18) Mid-esophageal right ventricular inflow–outflow view (50–80°, probe inserted into the depth from the aortic valve short-axis view). (19) Mid-esophageal pulmonary artery bifurcation view (angle gradually decreased from 80°, probe pulled forward from the RV inflow–outflow tract view). (B) Transgastric views. (20) Transgastric mitral valve short-axis view (10–30°, probe strongly anteflexed in the stomach). (21) Transgastric 2-chamber view (90°, angled up from the transgastric mitral valve short-axis view). (C) Descending aorta views. (22) Descending aorta short-axis view (0°, probe rotated counterclockwise from the mid-esophageal 4-chamber view). (23) Descending aorta long-axis view (90°, angle increased from the descending aorta short-axis view). (24) Upper esophageal aortic arch long-axis view (0°, probe withdrawn from the descending aorta short-axis view). Ao, aorta; Arch, aortic arch; AV, aortic valve; IVC, inferior vena cava; LA, left atrium; LAA, left atrial appendage; L-PV, left pulmonary vein; LV, left ventricle; LVOT, left ventricular outflow tract; MV, mitral valve; RA, right atrium; R-PV, right pulmonary vein; RV, right ventricle; PA, pulmonary artery; PC, posterior commissure leaflet; SVC, superior vena cava; TV, tricuspid valve.

1.3 Indications and Contraindications for TEE

In terms of invasiveness, examination time, and cost, TEE should not be performed in patients for whom TTE provides sufficient information.⁷ Table 5 summarizes the recommendations and levels of evidence for TEE. TEE has been used to detect thrombus in the left atrium as a preoperative examination for cardioversion or catheter ablation of atrial fibrillation (AF) because it is often challenging to detect a thrombus with TTE, particularly in the LAA. The ACUTE study⁸ was conducted to compare TEE-based cardioversion strategy with conventional treatment (warfarin therapy for 3 weeks before cardioversion) in patients with AF of >48 h duration. The results showed that the time to return to sinus rhythm was significantly shorter in the TEE group (mean 3.0 days vs. 30.6 days). No differences were observed in the defibrillation success rate or incidences of embolism and major hemorrhagic events at 8 weeks, concluding that both treatment strategies are satisfactory. Cardioversion strategy with the use of TEE is recognized as one of the acceptable strategies for cardioversion.^8–10 On the other hand, TEE is often omitted in patients with no allergy to contrast media who are undergoing catheter ablation when the existence of thrombi in the LAA is excluded by preoperative contrast-enhanced cardiac computed tomography (CT) (see Clinical Question). TEE should also be considered when searching for a cardiac embolic source in patients with cerebral embolism of unknown origin. When a paradoxical embolism is suspected, the presence or absence of a right-to-left shunt has to be determined. It is mandatory for the diagnosis of paradoxical embolism to demonstrate an interatrial shunt by transthoracic or transesophageal color Doppler echocardiography or bubble testing (Valsalva and cough maneuvers) on TTE or TEE. TEE should be performed if no evidence is found by TTE.¹¹ TEE can also help assess valve pathology and its severity in patients with mitral regurgitation or stenosis, and is essential in patients in whom mitral valve repair or transcatheter mitral valve therapy is being considered.¹² In aortic valve disease, TEE is used to evaluate valve pathology and its severity, measure the valvular orifice area, and examine the aortic root. TEE is an essential preoperative examination, particularly in patients in whom aortic valve repair is being considered. It is also useful in patients with suspected valvular heart disease that has not been confirmed by TTE. After valve replacement or valve repair, TTE is often inadequate for perivalvular observation. In addition to perioperative monitoring of valvular heart disease, TEE should be performed in patients with suspected residual regurgitation, perivalvular regurgitation, or valvular dysfunction. TEE is valuable for evaluating the function of both mechanical and bioprosthetic valves in patients undergoing prosthetic valve replacement. Prosthetic leaflet mobility and degeneration, thrombi, pannus, and vibrations of the valve housing can be detected.¹³ TEE should be performed in patients with suspected prosthetic valve dysfunction. In patients with suspected infective endocarditis, TEE should be performed to evaluate the extent of vegetations, ring abscesses, and valvular destruction. TEE is strongly recommended, particularly for the observation of the surrounding area of prostheses, such as prosthetic valves and rings and pacemaker leads. Congenital shunt heart disease can often be diagnosed by TTE alone. TEE can still be used to determine the location and size of an atrial septal defect (ASD) and to measure the rim width. TEE is useful particularly in diagnosing ASD of the sinus venous or coronary sinus type (coronary sinus septal defect or unroofed coronary sinus) and anomalous pulmonary venous return.

Table 5. Recommendations and Levels of Evidence for Transesophageal Echocardiography

		COR	LOE
Conditions in which TEE should be performed	TEE is indicated if the presence of a thrombus in the left atrial appendage cannot be ruled out by contrast-enhanced cardiac CT when catheter ablation of atrial fibrillation is scheduled	I	B
	Color Doppler TEE is indicated to detect an interatrial shunt when a paradoxical embolism is suspected (this is not the case when an interatrial shunt can be detected by color Doppler TTE)	I	B
	TEE bubble test with Valsalva maneuvers is indicated if paradoxical embolism is suspected, but the color Doppler test is negative for interatrial shunt (this is not the case when a right–left shunt is detected by TTE bubble test with Valsalva or cough maneuver)	I	B
	TEE is reasonable when cardioversion is performed without prior 3-week anticoagulation in paroxysmal atrial fibrillation lasting >48 h with unstable hemodynamics	IIa	B
Cases where TTE is inadequate or difficult for observation	TEE is indicated to search for the embolic source in patients with suspected cardiogenic embolism originating other than the left atrial appendage	I	B
	TEE is indicated when atrial (including the left atrial appendage), atrial septal or thoracic aortic involvement is suspected	I	B
	TEE is indicated when infective endocarditis is suspected	I	B
	TEE is indicated when the diagnosis of congenital heart disease is suspected but not confirmed	I	B
	TEE with 3D imaging is indicated in patients who are scheduled to undergo surgery (especially valve repair) or catheter treatment for valvular heart disease	I	B
	TEE with 3D imaging is indicated for intraoperative monitoring of cardiovascular surgery and intraoperative diagnosis during valvular surgery	I	B
	TEE is reasonable when valvular heart disease is suspected	IIa	B
	TEE is reasonable when abnormal intracardiac structures are suspected	IIa	B
	TEE is reasonable when acute aortic disease (including aortic dissection) is suspected	IIa	C
	TEE is reasonable when TTE is difficult to perform due to open chest surgery, thoracic trauma or other reasons	IIa	C
	Repeat TEE is not recommended when changes in clinical findings due to treatment or over time are not expected	IIIa (No benefit)	C
	TEE is not recommended when a confirmed diagnosis or treatment decision has been made by TTE	IIIa (No benefit)	C
	TEE should not be performed when the risks outweigh the benefits of the examination	IIIb (Harm)	C
	TEE should not be performed if the patient’s consent or cooperation cannot be obtained for the examination	IIIb (Harm)	C
Preoperative and intraoperative assessments in surgery and catheter treatment for cardiovascular diseases	TEE is indicated to determine the indication of reoperation and evaluate prosthetic valve dysfunction during and after valve replacement, valve repair, and catheter treatment for valvular heart disease	I	B
	TEE, including 3D imaging, is indicated for intraoperative guidance for catheter treatment (e.g., atrial septal defect closure, left atrial appendage closure, aortic valve replacement, mitral valve clipping)	I	B

3D, three-dimensional; COR, class of recommendation; CT, computed tomography; LOE, level of evidence; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

TEE also helps in diagnosing thoracic aortic lesions such as aortic aneurysms, aortic dissections, and atherosclerotic plaques. Unlike contrast-enhanced CT, TEE can be safely performed in patients with renal dysfunction or allergy to contrast media. In patients with acute aortic diseases at a high risk of rupture due to hemodynamic changes, TEE should be performed under intravenous anesthesia with frequent measurements of vital signs. In thoracic aortic dissection, information on the entry, the thrombus and blood flow of the false lumen can be obtained. It should be noted that the distal ascending aorta cannot be visualized by TEE in some cases.

The right ventricle and the apex of the left ventricle (LV) are often better visualized with TTE and thus TEE is not recommended except in situations where the TTE approach is challenging, such as during surgery or catheterization. In general, repeat TEE is not recommended in patients whose clinical findings are unlikely to change over time or with treatment. TEE is not recommended in patients considered unlikely to have infective endocarditis based on clinical findings. Diseases or pathological conditions in which TEE may be contraindicated include esophageal stenosis, esophageal varices (red color sign, RC ≥1), esophageal diverticulum, postoperative stomach and esophagus, esophageal cancer, gastroesophageal bleeding, ulcer, tumor, and previous cervical or mediastinal radiotherapy. Cervical spine injuries and other conditions with problems in cervical mobility are also contraindicated. In patients with sliding hiatal hernia, TEE can be performed safely with careful positioning of the probe. In patients with liver cirrhosis, upper gastrointestinal endoscopy should be performed to examine for the presence or absence of esophageal varices prior to TEE. TEE should not be performed unless patients can cooperate with the procedure. Prior to TEE, the patient should be interviewed about a history of any contraindicated conditions to avoid potential risks. It is also necessary to evaluate bleeding tendency and platelet and coagulation function before the examination. It should be carefully determined whether TEE should be indicated or performed in patients who have unstable angina or acute myocardial infarction within 3 days of onset, acute aortic dissection or abdominal aortic aneurysm with uncontrolled blood pressure, acute phase of cerebral hemorrhage or cerebral infarction, or a cerebral aneurysm with a high risk of rupture. A history of hypersensitivity to local anesthetics or sedatives is also a contraindication of the procedure.

1.3.1 Evaluation of LV Function and Wall Motion

TTE is more suitable for visualizing the entire LV, and TEE is less useful. TEE is indicated when transthoracic imaging is inadequate or it is difficult to delineate the LV or LV function is to be assessed intraoperatively during cardiac and major vascular surgery. It is necessary to visualize and evaluate not in single but multiple views, for which 3D echocardiography is available to concurrently evaluate multiple views. The echo window by TEE is limited in patients with LV dilatation, because of the degraded image quality of the anatomy far from the probe and the narrow angle of view. LV function and wall motion should be assessed, keeping in mind that anesthetics and sedatives may suppress LV systolic function.

1.4 3D TEE

3D echocardiography has become widely used in recent years. 3D TEE is indispensable for the diagnosis of valvular and congenital heart diseases, for the determination of indications for surgical or transcatheter interventions and for perioperative assessment of patients who undergo cardiac surgery and catheterization. 3D image data allow observations at any cross-section and quantitative analysis of the cardiac volume without the use of hypothetical formulas. 3D echocardiography is still incomparable to two-dimensional (2D) echocardiography in terms of spatial and temporal resolutions, although image quality and temporal resolution have improved with the advances in technology. Many pathological conditions can be observed only by the 2D method, but 3D echocardiography is essential for catheter closure of ASD and patent foramen ovale, percutaneous mitral valve clipping, percutaneous LAA closure, and other transcatheter procedures. A 3D zoomed or full-volume acquisition mode is mainly used for perioperative diagnosis and intraoperative guidance for these procedures. In the full-volume mode, multiple heartbeat images can be acquired to construct a 3D image of a broader region of interest, and the 3D zoomed mode can display a limited area of interest with higher temporal resolution. Other imaging modalities to gain depth perception, such as live 3D and multiplanar review modes, are used depending on the situation.

1.5 Intraoperative TEE

TEE is widely used during cardiac and major vascular surgery. Indications for intraoperative TEE include valve repair,^14–16 coronary artery bypass grafting,¹⁷ valve replacement,¹⁸ and endovascular aortic repair.¹⁹ TEE is also used in noncardiovascular surgery to monitor cardiac function and LV wall motion,¹⁶ and allows for early detection of complications such as cardiac tamponade, acute bleeding, and myocardial infarction.^20–22 TEE is an essential tool, particularly during small-incision cardiac surgery, including robotic surgery, where the view of the surgical field is limited. It is also used during percutaneous transluminal mitral valve commissurotomy, transcatheter ASD closure, transcatheter aortic valve implantation, transcatheter mitral valve clipping, and transcatheter LAA closure. Continuous intraoperative monitoring by conventional TEE combined with 3D TEE is important for optimal positioning of the device in percutaneous mitral valve clipping and transcatheter LAA occlusion.^23–26

Clinical Question

Is it necessary to perform TEE in patients with AF when cardiac contrast-enhanced CT does not show the presence of a thrombus in the LAA?

In patients with AF, this Guideline recommends that TEE should be performed when the presence of a thrombus in the LAA cannot be ruled out by contrast-enhanced CT (Recommended Class I, Level of Evidence B) (Table 5). In contrast, when the presence of a thrombus in the LAA is negative on contrast-enhanced cardiac CT, whether TEE is not recommended (Class IIIa no benefit) (Table 6), whether TEE should still be reasonable (Class IIa), or whether TEE may be considered (Class IIb) (Table 6) is questionable. Searching for thrombus in the LAA before ablation of AF is essential for preventing thromboembolism, which has clinically serious outcomes. In reviewing the literature concerned with this issue, Aimo et al performed a meta-analysis of 10 studies and reported that contrast-enhanced cardiac CT could detect LAA thrombus with a sensitivity of 100% in 5 of 10 studies when TEE diagnosis for LAA thrombus was the gold standard.²⁷ In those studies, regardless of the prevalence of thrombus, the negative predictive value for detecting LAA thrombus was 100%. In 4 of the other 5 studies, the negative predictive value was ≥98%, but in the remaining 1 study it was a little low at 92%. By adding an appropriately delayed image, several investigators recently have reported that the sensitivity, specificity, and the positive/negative predictive values for identifying LAA thrombus all reached 100%.^28–30 Thus, this Guideline does not recommend TEE examination for this purpose (Class IIIa, no benefit). However, it has been acknowledged that TEE has a false-negative finding regarding the detection of thrombus in the LAA.^31–34 Therefore, a comparison of the diagnostic accuracy between the 2 modalities alone does not reveal the true diagnostic accuracy of contrast-enhanced cardiac CT in detecting intracardiac thrombus. In addition, the 2011 ACCF/AHA/HRS “Guidelines for the treatment of atrial fibrillation” recommend TEE as the only modality for the evaluation of intracardiac thrombus.³⁵ At the time of revision (March 2021), we have not been able to identify any studies that prospectively compared the clinical outcomes of the presence or absence of LAA thrombus observed during open-heart surgery or the development of embolism after catheter ablation of AF by assigning the search for LAA thrombus to either contrast-enhanced cardiac CT or TEE. A large, prospective, multicenter clinical study is needed to reach a conclusion. By the Minds classification, which has a more stringent definition of the level of evidence from literature review, the recommendations and evidence classification are as shown in Table 7. It should be noted that the level of evidence for both the conventional and Minds recommendation grades is low.

Table 6. Recommendations and Evidence Levels for Transesophageal Echocardiography as a Preoperative Test for Catheter Ablation of Atrial Fibrillation

	COR	LOE
TEE is performed when the presence of a thrombus in the LAA cannot be ruled out by cardiac CT before ablation therapy for atrial fibrillation (restated from Table 5)	I	B
TEE may be considered in the absence of delayed contrast imaging, even if the CT scan is negative for LAA thrombus	IIb	C
Routine TEE is not recommended when the presence of a thrombus in the LAA is negative on contrast-enhance cardiac CT with delayed contrast images*	IIIa (No benefit)	C

*After delayed contrast-enhanced cardiac CT, consider performing TEE or repeat delayed contrast-enhanced CT (in subjects without renal dysfunction, if the benefit of repeat testing is determined to outweigh the risk of exposure) if it is determined that there is a risk of thrombus formation in the time leading up to catheter ablation therapy, or if appropriate anticoagulation is not continued (Class IIa). COR, class of recommendation; CT, computed tomography; LAA, left atrial appendage; LOE, level of evidence; TEE, transesophageal echocardiography.

Table 7. Recommendations and Level of Evidence for Transesophageal Echocardiography as a Preoperative Test for Catheter Ablation of Atrial Fibrillation (Minds Recommendation Grade, Minds Evidence Classification)

	GOR (MIND)	LOE (MIND)
TEE is recommended even if the presence of a thrombus in the LAA is negative on contrast- enhanced cardiac CT without delayed contrast images, although there is no scientific evidence to support this	C1	IVb
If the presence of a thrombus in the LAA is negative on cardiac contrast-enhanced CT with delayed contrast images, there is no scientific evidence that TEE improves the sensitivity of thrombus detection, and it is recommended that TEE not be performed	C2	IVb

CT, computed tomography; GOR, grade of recommendation; LAA, left atrial appendage; LOE, level of evidence; TEE, transesophageal echocardiography.

2. Stress Echocardiography

2.1 Indications

Stress echocardiography is indicated for a wide range of diseases, including ischemic heart disease, valvular heart disease, cardiomyopathy, and pulmonary hypertension.^36–38 Symptoms of these heart diseases often develop on exertion because exercise increases the demand for oxygen in skeletal muscle and other organs, and as a response, the heart increases cardiac output to increase oxygen supply. Increases in cardiac output, blood pressure, and heart rate associated with exercise lead to dynamic changes of the heart. Capturing these stress-induced changes can provide useful information for assessing cardiac reserve and determining treatment strategies.

The main stress echocardiographic methods used in clinical practice are exercise and pharmacological stress, each having its own characteristic features. Exercise stress is physiological and has the advantages of being less complicated and providing sufficient stress. It also provides secondary information such as exercise capacity and hemodynamics. However, it cannot be performed in patients who have difficulty exercising; stress-induced ischemia may be missed if images are not acquired within a short time after the completion of the stress; and in some cases, body movements and breathing can make the images difficult to evaluate. On the other hand, pharmacological stress testing can be performed even in patients who have difficulty in exercising, can induce sufficient stress regardless of the subject’s state of mind, and often provides better images at each stress stage. However, it is not a physiological stress test. In addition, secondary information cannot be obtained from stress-induced hemodynamic changes, and the dobutamine stress test is strongly affected by medications such as β-blockers.^39,40 Therefore, it is necessary to select the appropriate stress method for each patient from the basis of a good understanding of these advantages and disadvantages.

Specific exercise methods include isotonic exercise on a treadmill or supine ergometer exercise and isometric exercise using a handgrip. In isotonic exercise, cardiac output increases with increasing exercise stress, and blood pressure and heart rate increase in a linear fashion with exercise intensity.⁴¹ In addition, the ventricles become larger with increasing venous return. These dynamic changes are highly useful for detecting myocardial ischemia and assessing the severity of valvular heart diseases. Isotonic exercise testing is also used for the early diagnosis of heart failure with preserved ejection fraction (HFpEF)⁴² and the detection of subclinical LV outflow tract obstruction in hypertrophic cardiomyopathy.⁴³ In isometric exercises, an increase in blood pressure is significant compared with heart rate, increasing the wall stress in the LV.⁴⁴ Increased wall stress enhances the myocardial oxygen demand but cannot produce stress sufficient to induce myocardial ischemia in many cases. This is often used to assess changes in mitral regurgitant volume. The following is a protocol for exercise stress testing on a supine ergometer, a commonly used stress test (adapted from the JSE practical guidance for the implementation of stress echocardiography⁴⁵).

1. If the echo bed can be tilted laterally, place the patient in a slightly left lateral decubitus position and raise the upper body.

2. Record resting echocardiography, blood pressure, and ECG.

3. Instruct the patient to place the feet on the pedals, and commence the exercise. The pedaling rate should be set at 50–60 revolutions/min.

4. The workload is generally increased by 25 W every 3 min (Figure 2A).⁴⁵

Figure 2.

Exercise stress protocol (ergometer). (A) Multistage protocol: workload is increased in 25-Watt increments every 3 min. (B) Ramp protocol: 3-min warm-up at 10 Watts, followed by exercise with 10-W increment every 3 min. BP, blood pressure; Echo, echocardiography; HR, heart rate. (Modified from Suzuki K, et al. 2018.⁴⁵)

5. For the elderly with considerable leg muscle weakness, a protocol using a 3-min warm-up at 10 W followed by 10-W increments every 3 min may be used (Figure 2B).⁴⁵

6. Monitor the patient’s ST-T changes and arrhythmias throughout exercise using an ultrasound monitor and record an ECG and blood pressure every minute.

7. Terminate the exercise when the patient reaches the target heart rate or when any termination criterion is met; otherwise, continue up to the limit of patient tolerance.

8. With the supine ergometer exercise stress testing, echocardiographic assessment can be performed during exercise.

9. In the supine ergometer exercise stress testing, the images should be obtained in the left lateral decubitus position. It is necessary to obtain data in the same views as those acquired at baseline. Instruct the patient to exhale longer and inhale shorter than usual during the exercise testing, and the operator should record as many images as possible during exhalation.

Diastolic stress echocardiography, which can evaluate diastolic function during exercise, is helpful to determine whether subjective symptoms such as shortness of breath in patients with heart disease are due to noncardiac causes or diastolic dysfunction.^46,47 The peak velocities of the early diastolic wave (E) and atrial contraction wave (A), peak early diastolic mitral annular velocity (e’), and peak tricuspid regurgitation (TR) velocity are recorded at rest and during exercise. To avoid fusion of the E- and A-waves, it is acceptable to record the parameters immediately after peak exercise (i.e., at the start of recovery). An E/e’ >14 (mean of the septal and lateral segments) and >15 (septal segment) during exercise is suggestive of elevated LV filling pressure.⁴⁸

Dobutamine is commonly used in pharmacological stress testing. Dobutamine stress echocardiography is used to assess myocardial ischemia and myocardial viability in patients with ischemic heart disease.^49–52 This stress modality is also valuable to differentiate between true severe aortic stenosis (AS) and pseudo-severe AS due to reduced LV function associated with concomitant disease in patients with suspected classical low-flow, low-gradient severe AS with reduced LV ejection fraction (EF) and to assess LV contractile reserve in such patients.^53–55 The protocol for dobutamine stress testing for myocardial ischemia assessment is as follows (Figure 3):³⁷ Dobutamine is delivered at a starting dose of 5 μg/kg/min and increased every 3 min to 10, 20, 30 or 40 μg/kg/min. When the target heart rate cannot be achieved, or when none of the termination criteria are met with dobutamine up to 40 µg/kg/min, the dobutamine dose is increased up to 50 µg/kg/min, or atropine is delivered by 0.25-mg increments every 1 min up to 2 mg. It has also been reported that the addition of handgrip (1/3 of maximal grip strength) to the peak stress dose of dobutamine may be helpful.⁵⁶ In the most common protocol for low-dose dobutamine stress echocardiography used for evaluating myocardial viability and severity of AS, dobutamine infusion is initiated at 5 μg/kg/min and increased at 5-min intervals to 10, 15 or 20 μg/kg/min.

Figure 3.

Dobutamine stress echocardiography protocols. (A) Protocol for detecting ischemia: When the target heart rate cannot be achieved, or when no termination criteria are met with dobutamine up to 40 µg/kg/min, the dobutamine dose is increased up to 50 µg/kg/min, or atropine is delivered by 0.25-mg increments every 1 min up to 2 mg. (B) Low-dose dobutamine stress protocol for evaluating myocardial viability and severity of aortic stenosis: Typically, dobutamine infusion is initiated at 5 μg/kg/min and increased at 5-min intervals to 10, 15 or 20 μg/kg/min. BP, blood pressure; Echo, echocardiography; HR, heart rate.

Although exercise stress echocardiography is considered a test with a low incidence of complications, serious complications such as severe arrhythmias and myocardial infarction have been reported in up to 0.2% of patients.⁵⁷ It should be noted that dobutamine stress echocardiography has a slightly higher incidence of complications, particularly arrhythmias.^58,59 It is crucial to perform stress testing safely, and it is necessary to be familiar with the contraindications and termination criteria for exercise and pharmacological stress tests (Table 8).⁶⁰

Table 8. Contraindications and Termination Criteria for Stress Echocardiography

Contraindications

ACS within 48 h of onset

Poorly controlled heart failure and respiratory failure

Poorly controlled hypertension

Symptomatic severe aortic stenosis

Severe obstructive hypertrophic cardiomyopathy (pressure gradient >90 mmHg)

Patients with lethal arrhythmias

Acute phase of acute aortic dissection, impending rupture of aortic aneurysm

Patients who cannot exercise

Patients who do not give consent

Other patients deemed ineligible by the attending physician

Termination criteria

When the heart rate reaches the target heart rate ([220 − age] × 0.85) beats/min

Excessive increase in blood pressure (systolic blood pressure ≥220 mmHg, diastolic blood pressure ≥120 mmHg)

Decrease in blood pressure (fall of ≥10 mmHg during exercise or no increase during exercise)

Occurrence of sustained tachyarrhythmia

Appearance of akinetic wall motion or of decreased motion in the segments in the territory of ≥2 coronary arteries

ST segment depression of ≥0.2 mV on ECG

Development or exacerbation of chest pain

Leg exhaustion

Development of any other symptoms that make continuation of exercise impossible

Hypersensitivity to drugs used in pharmacological stress testing

ACS, acute coronary syndrome; ECG, electrocardiography. (Cited from Fletcher GF, et al. 2013.⁶⁰)

Table 9 summarizes the recommendations and levels of evidence for stress echocardiography for chronic ischemic heart disease.⁶¹ Table 10 lists the recommendations and levels of evidence for stress echocardiography for valvular heart disease.⁶²

Table 9. Recommendations and Levels of Evidence for Stress Echocardiography for Chronic Coronary Disease

		COR	LOE	GOR (MIND)	LOE (MIND)
Diagnosis of CAD
a) Evaluation of stable chest pain	Low possibility of CAD, ECG evaluation is possible, exercise stress test is possible	IIIa (No benefit)	C	D	IVa
	Possibility of CAD is moderate or more	I	B	B	IVa
b) Evaluation of acute chest pain*	Possibility of CAD is moderate, no temporal ECG ST-T changes in the absence of myocardial necrosis	I	A	B	II
	High possibility of CAD, ECG ST-elevation	IIIb (Harm)	C	D	IVb
Prediction of prognosis (risk evaluation)
Post unstable angina pectoris/non-STEMI without any ischemic symptoms, heart failure symptoms, or early schedule for cardiac catheterization*		I	B	B	III
ACS, post-PCI, no symptoms, predischarge evaluation		IIIa (No benefit)	C	D	IVb
Post-PCI, ischemic symptoms (+)		I	B	B	III
Post-PCI, no symptoms, <2 years since intervention		IIIa (No benefit)	C	C2	IVb
Evaluation of myocardial viability
Stenosis confirmed by CAG, suitable for revascularization		I	A	A	III

*Not chronic CAD. ACS, acute coronary syndrome; CAD, coronary artery disease; CAG, coronary angiography; COR, class of recommendation; ECG, electrocardiography; GOR, grade of recommendation; LOE, level of evidence; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction. (Modified from JCS 2018 Guideline on diagnosis of chronic coronary heart diseases. 2021.⁶¹)

Table 10. Recommendations and Levels of Evidence for Stress Echocardiography for Valvular Heart Disease

			COR	LOE
MR	Chronic primary MR	Exercise stress echocardiography is reasonable in asymptomatic patients with severe MR or symptomatic patients with moderate MR to confirm the absence/ presence of symptoms and to assess changes of pulmonary arterial systolic pressure and LV function with exercise	IIa	C
	Secondary MR	Exercise stress echocardiography is reasonable in asymptomatic patients with severe MR or symptomatic patients with moderate MR to confirm the symptoms, to evaluate the severity of exercise-induced MR and the increase in pulmonary arterial systolic pressure during exercise, and to determine the indications for mitral valve surgery	IIa	C
MS		In patients with discordance between symptoms and stenosis severity, exercise stress echocardiography is reasonable for assessing the changes in mean transmitral pressure gradient and pulmonary arterial systolic pressure during stress	IIa	C
AS	Asymptomatic severe AS	Exercise stress echocardiography is reasonable to confirm the absence of symptoms, to assess hemodynamic changes with exercise, and to stratify the risk of cardiovascular events	IIa	B
	Low-flow, low-gradient AS with LVEF <50%	Low-dose dobutamine stress echocardiography is reasonable to differentiate true AS from pseudo-severe AS and to assess LV contractile reserve	IIa	B
AR		In patients with discordance between symptoms and AR severity, exercise stress echocardiography may be considered to assess hemodynamic response and LV contractile reserve	IIb	C

AR, aortic regurgitation; AS, aortic stenosis; COR, class of recommendation; LOE, level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MS, mitral stenosis. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

2.2 Interpretation

2.2.1 Ischemic Heart Disease

Wall motion is assessed for each segment according to the 4 levels of normokinesis, hypokinesis, akinesis, and dyskinesis using the LV 16-segment model of the ASE.⁶³ Attention should be paid not only to endocardial displacement but also to incremental changes in wall thickness. The location and extent of the appearance of wall motion decrease should be determined by comparing resting images in order to make a diagnosis of myocardial ischemia and to estimate its severity. In patients with abnormal wall motion at rest, responses during dobutamine stress echocardiography are classified into 4 types, namely, (1) improvement (sustained improvement in wall motion at low and high doses), (2) biphasic (wall motion improves at low doses and worsens at high doses), (3) worsening (wall motion further deteriorates at low and high doses), and (4) fixed (the severity and extent of wall motion abnormality are unchanged during dobutamine stress).⁶⁴ Patients with an improvement response should be considered to not have myocardial ischemia and have myocardial viability. Patients with biphasic or worsening response should be considered to have myocardial ischemia with viability. Patients with a fixed response should be considered to have transmural myocardial infarction without viability. Patients with chronic ischemic heart disease who show biphasic responses are considered to have “hibernating myocardium” with viability, and cardiac function can be expected to improve with coronary revascularization.⁶⁵

2.2.2 Valvular Heart Disease

Common assessment items include changes in the severity of valvular heart disease and the presence or absence of exercise-induced pulmonary hypertension. In mitral stenosis (MS), mitral regurgitation (MR), and AS, exercise-induced pulmonary hypertension is defined as an estimated pulmonary systolic pressure ≥60 mmHg,²⁷ which is known as a significant predictor of cardiovascular events.^66,67

a. MS

In addition to symptoms and signs, the pressure gradient and the presence of pulmonary hypertension should be evaluated. The predictors of cardiovascular events include a mean pressure gradient ≥15 mmHg across the mitral valve during exercise, an estimated pulmonary systolic pressure of ≥60 mmHg, and ≥90% increase in estimated pulmonary systolic pressure during exercise.^68–71

b. MR

i) Primary MR

In addition to symptoms and signs, the severity of regurgitation, presence of exercise-induced pulmonary hypertension, and left and right ventricular contractile reserve should be evaluated. The severity of regurgitation is assessed using the proximal isovelocity surface area (PISA) method or volumetric method. An increase in regurgitation ≥15 mL during exercise is a predictor of cardiovascular events.⁷² Exercise-induced pulmonary hypertension with an estimated pulmonary systolic pressure of ≥60 mmHg is also a predictor of cardiovascular events.⁶³ Contractile reserve is assessed using LVEF, LV global longitudinal strain (GLS), and tricuspid annular plane systolic excursion (TAPSE). An increase in LVEF ≤5% and an increase in GLS ≤2% during exercise stress and of TAPSE <18 mm during exercise stress are predictors of cardiovascular events.^73–75

ii) Secondary MR

Disease severity varies greatly according to the hemodynamic conditions (preload or afterload). Exercise-induced MR is associated with prognosis, acute pulmonary edema, and reduced exercise tolerance.^75–77 The effective regurgitant orifice area ≥0.20 cm² during exercise and an increase in the effective regurgitant orifice area ≥0.13 cm² during exercise are poor prognostic factors.^76–79 Exercise-induced pulmonary hypertension with an estimated pulmonary systolic pressure ≥60 mmHg is a predictor of cardiovascular events.⁸⁰

c. AS

AS is assessed by 2 types of stress echocardiography, namely, exercise and low-dose dobutamine stress echocardiography. Exercise stress echocardiography is used primarily to reproduce symptoms and signs and predict cardiovascular events. Dobutamine stress echocardiography is performed primarily to evaluate the severity of classical low-flow, low-gradient AS with reduced LVEF and to predict postoperative prognosis. Elevated mean gradient (≥18 mmHg), exercise-induced pulmonary hypertension, and insufficient increase in transvalvular flow rate (i.e., stroke volume/ejection time) during exercise stress have been demonstrated as predictors of cardiovascular events.^67,81–83 In addition to the echocardiographic findings, attention should be paid to other prognostic factors, including the occurrence of symptoms and changes in blood pressure and ECG findings, during stress testing.^84,85 In the low-dose dobutamine stress echocardiography for classical low-flow, low-gradient severe AS, true severe AS is defined as a peak velocity ≥4 m/s and a mean gradient ≥40 mmHg at the stenotic orifice at the maximum dobutamine dose of 20 μg/kg/min; otherwise it is defined as pseudo (severe) AS.⁸⁶ LV systolic reserve is assessed by whether the stroke volume is increased by ≥20% on dobutamine stress test. Poor LV systolic reserve is associated with poor prognosis after aortic valve replacement.^87,88

d. AR

In addition to symptoms and signs, LV end-systolic volume index and left and right ventricular contractile reserve during exercise have prognostic value.^89,90 LV contractile reserve is a useful predictor of LV function after aortic valve replacement.⁹¹

e. Pulmonary Hypertension

The transtricuspid pressure gradient is measured at rest and during exercise. Estimated pulmonary artery systolic pressure >40–50 mmHg during exercise stress is an indication of exercise-induced pulmonary hypertension, although it depends on the type of exercise undertaken.⁹² However, because pulmonary arterial pressure depends on cardiac output (CO), pulmonary arterial pressure corrected for CO has recently been considered useful in predicting prognosis.^93,94

III. Indications by Pathophysiology

1. Cardiac Function Assessment and Applications

1.1 Evaluation of Left Ventricular Systolic Function

1.1.1 Indications

Evaluation of LV systolic function is indicated for all patients who are considered eligible for transthoracic echocardiography (TTE) evaluation of cardiac function (Table 11). The primary measure of LV systolic function is LV ejection fraction (EF). However, it would be appropriate to consider LVEF as only a good surrogate due to its load dependency, although it sensitively reflects LV systolic function. LV systolic function should be evaluated using multiple parameters including stroke volume (SV), cardiac output (CO), wall motion score index (WMSI), and global longitudinal strain (GLS).

Table 11. Recommendations and Levels of Evidence for Transthoracic Echocardiography for Evaluation of Left Ventricular Systolic Function

	COR	LOE
LV systolic function should be assessed in patients considered for cardiac function evaluation by TTE	I	A
LVEF should be measured in patients with suspected heart failure	I	A
SV and CO should be measured in patients with suspected heart failure	I	A
LVEF should be measured in patients with valvular heart disease	I	A
LVEF should be measured to determine whether cardiac resynchronization or an implantable cardioverter-defibrillator is indicated	I	A
WMSI should be evaluated in patients with LV regional wall motion abnormalities	I	A
LVEF should be measured at baseline and during treatment with cardiotoxic drugs	I	A
GLS measurement is reasonable at baseline and during treatment with cardiotoxic drugs	IIa	B
GLS measurement is reasonable to detect latent LV systolic dysfunction	IIa	B

CO, cardiac output; COR, class of recommendation; GLS, global longitudinal strain; LOE, level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; SV, stroke volume; TTE, transthoracic echocariography; WMSI, wall motion score index.

1.1.2 Interpretation

a. LVEF

M-mode echocardiography, which estimates the function of the entire LV based on information from 2 local points, has been traditionally used to measure LVEF. However, it is considered insufficiently accurate in patients with regional wall motion abnormalities or LV conduction disturbances which can cause measurement errors. Currently, the most recommended method for measuring LVEF is the disk summation method (or the modified Simpson method) based on the LV volume by two-dimensional (2D) echocardiography. The LV volume is obtained from 2 cross-sections of the apical 4- and 2-chamber views.⁶³ With this method, the LV volume is underestimated when a cross-sectional image of the LV is shortened in the long-axis direction. Three-dimensional (3D) echocardiography is reported to give a more accurate LV volume.⁹⁵ Acquisition of high-quality echocardiographic images is a prerequisite because 3D echocardiography has lower spatial resolution than 2D echocardiography. In clinical practice, LVEF is often assessed visually, and it has been reported that assessments by skilled observers are highly reliable.⁹⁶

In Japan, normal values of the LVEF are reported to be 64±5% in men and 66±5% in women.⁹⁷ LVEF of 30–40% is defined as moderately reduced and <30% as severely reduced.⁶³ Careful interpretation of measured values is required because of significant variability between examiners in echocardiographic quantification of LVEF.⁹⁸ Calculation of LVEF is essential for diagnosing heart failure with reduced EF (≤40%: HFrEF), heart failure with mid-range LVEF (40–49%) (or heart failure with mildly reduced EF: HFmrEF), and heart failure with preserved LVEF (≥50%: HFpEF). In patients with HFrEF, LVEF is not only useful for diagnosing heart failure, evaluating treatment effects, and predicting prognosis, but also necessary for determining the indications for cardiac resynchronization therapy and an implantable cardioverter-defibrillator.⁹⁹ In patients with severe aortic or mitral valve disease, the measurement of LVEF is essential to determine whether they are candidates for surgery.¹⁰⁰

b. SV and CO

CO (L/min) is calculated as the product of SV (mL) and heart rate (beats/min). Because SV and CO are strongly influenced by preload and afterload, they are not true measures of LV systolic function, but can be regarded as integrated indices of LV systolic function that allow evaluation of systemic organ perfusion. The SV index (SVI) and cardiac index, calculated by dividing the SV and CO by the body surface area may be used to correct for body size. The SV is calculated using the pulsed Doppler method as the product of flow velocity–time integral, obtained from the LV outflow velocity pattern, and the cross-sectional area of the LV outflow tract, derived from the LV outflow tract diameter under the assumption of a circular shape. Alternatively, this parameter is calculated from the difference between the LV end-diastolic and end-systolic volumes using the disk summation method. SV and CO are useful echocardiographic parameters for differentiation between low- and high-output heart failure and for the monitoring of changes in LV function during heart failure treatment. In patients with aortic stenosis (AS), SVI measurements are used to diagnose low-flow, low-gradient AS and to assess LV contractility reserve under dobutamine stress.¹⁰¹

c. LV Wall Motion Score Index

Patients with regional LV wall motion abnormalities require a segmental wall motion assessment. The LV is typically divided into 16 or 17 segments, for each of which the wall motion is scored and evaluated.⁶³ A 17-segment model includes the apical apex (apical cap), but it is difficult to assess wall motion in this region. It is recommended to use a 16-segment model in clinical practice. Wall motion is scored as normokinesis=1, hypokinesis=2, akinesis=3, or systolic wall thinning or stretching=4. The WMSI is the mean of wall motion scores, derived by dividing the sum of scores of all individual segments by the number of segments visualized; thus, WMSI is 1 in normal cases. It has been shown that high WMSI after the onset of acute myocardial infarction is associated with a poor prognosis in the chronic phase of the disease.¹⁰² The WMSI is also used to diagnose myocardial ischemia and myocardial viability from the difference in its score between rest and stress by stress echocardiography.

d. Measures of LV Longitudinal Function (GLS, s’, MAPSE)

Measures of LV longitudinal function are reported to be useful in predicting the prognosis of patients with cardiac disease, because they can detect earlier systolic dysfunction compared with LVEF.^103,104 GLS is calculated as the mean of the peak systolic strain in the apical 4-chamber, 2-chamber and long-axis views using speckle-tracking. The reported GLS (absolute value) in healthy adults is >20%, but this normal range is not definitive for the following reasons.⁶³ There are variations in the normal range of GLS between different ultrasound and strain analysis systems. Therefore, it is currently recommended that the same ultrasound and strain analysis systems should be used to compare GLS between patients and for follow-up of the same patient.¹⁰⁵ The use of GLS is not recommended when >1 segment is deemed to be poorly tracked in a single apex image. In such a case, LV long-axis systolic function should be assessed using the peak systolic mitral annular velocity (s’) or mitral annular plane systolic excursion (MAPSE). s’ is measured at the septal and lateral mitral annulus using pulsed tissue Doppler, with higher lateral values than septal values in normal hearts. In normal adults, the normal reference range of s’ has been reported to be 8.1±1.5 cm/s at the septal site and 10.2±2.4 cm/s at the lateral site.¹⁰⁶ MAPSE is measured at the septal and left lateral mitral annulus using M-mode echocardiography. Similar to s’, the lateral MAPSE values are higher than septal MAPSE values in normal hearts.^103,107

In patients with HFpEF, who have reduced regional myocardial contractility due to myocardial hypertrophy and interstitial fibrosis, GLS has been reported as useful for detecting latent LV systolic dysfunction.¹⁰⁸ The bull’s eye display of GLS is of value for the diagnosis of a relative apical sparing longitudinal strain pattern, indicative of cardiac amyloidosis.¹⁰⁹ GLS is used to diagnose cardiotoxic drug-induced cardiac dysfunction in addition to the LVEF.¹¹⁰

e. Rate of LV Pressure Rise (dP/dt)

Similar to LVEF, the rate of LV pressure rise (dP/dt, mmHg/s) during isovolumic contraction is a fundamental measure of LV systolic function. The dP/dt can be estimated from the continuous-wave Doppler spectrum of the mitral regurgitation (MR) jet: the time t (s) for the LV–left atrial pressure gradient to increase from 4 to 36 mmHg is measured, and the dP/dt is calculated as (36 − 4)/t (mmHg/s). This dP/dt value has been reported to correlate with that obtained with cardiac catheterization.^111,112 However, when MR becomes moderate to severe, the time (t) does not always correspond with isovolumic contraction, resulting in incorrect estimations. The normal dP/dt is ≥1,200 mmHg/s.

1.2 Evaluation of LV Diastolic Function

1.2.1 Indications

As well as evaluating LV systolic function, LV diastolic function should be evaluated in all patients deemed candidates for TTE to evaluate cardiac function (Table 12). In particular, evaluation of LV diastolic function is essential in patients with suspected heart failure, because dyspnea, a major symptom of heart failure, is caused by LV diastolic dysfunction. The severity of LV diastolic dysfunction correlates with the severity of chronic heart failure, and the response of diastolic function to treatment is associated with prognosis, so evaluation of LV diastolic function is essential to determine the severity of heart failure and treatment effect.

Table 12. Recommendations and Levels of Evidence for Transthoracic Echocardiography for Evaluation of Left Ventricular Diastolic Function

	COR	LOE
LV diastolic function should be graded to assess cardiovascular risk during TTE	I	A
LAVI measurement is indicated to predict prognosis in patients with heart disease	I	A
DcT measurement is indicated to predict prognosis in patients with LV systolic dysfunction	I	B
e’ should be used to detect impaired LV relaxation in patients with preserved LVEF	I	B
E/A, E-wave velocity, E/e’, LAVI, and TRV should be used to estimate LV filling pressure in patients with LV systolic dysfunction	I	C
E/e’, e’, LAVI, and TRV should be used to evaluate LV diastolic function in patients without organic abnormalities in the left ventricle	I	C
Use of E/A, E-wave velocity, E/e’, LAVI, and TRV is reasonable to estimate LV filling pressure in patients with LV diastolic dysfunction and preserved LVEF	IIa	C

A, peak LV inflow velocity during atrial contraction; COR, class of recommendation; DcT, deceleration time of early diastolic inflow velocity; E, peak early diastolic LV inflow velocity; e’, peak early diastolic mitral annulus velocity; LAVI, left atrial volume index; LOE, level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; TRV, tricuspid regurgitant velocity; TTE, transthoracic echocardiography.

1.2.2 Interpretation

LV diastolic function is defined by active relaxation and elastic recoil in early diastole and passive elastic properties (compliance) associated with ventricular filling. LV diastolic dysfunction is defined as an impairment of the described function as well as the resulting increase in LV filling pressure.¹⁰⁸ Evaluation of LV diastolic function by echocardiography includes assessments of LV inflow velocity pattern^113,114 and pulmonary venous flow velocity pattern^115,116 using pulsed Doppler, peak early diastolic mitral annulus velocity using tissue Doppler imaging,^117–119 and left atrial volume index (LAVI) using 2D echocardiography.¹²⁰

For the LV inflow velocity pattern, the peak velocities of the early diastolic wave (E-wave) and atrial contraction wave (A-wave), their ratio (E/A), and the deceleration time (DcT) of the E-wave are measured. In early diastole, active relaxation and elastic recoil of the LV myocardium cause a rapid decrease in the LV pressure below the left atrial pressure, resulting in opening of the mitral valve, by which the LV is filled according to the atrioventricular pressure gradient. These changes are reflected in the E-wave flow velocity. The LV pressure then begins to increase due to myocardial compliance and extracardiac constraint, and the atrioventricular pressure gradient eventually decreases. These changes are reflected in the DcT. During atrial contraction, the left atrial pressure rises rapidly. The atrioventricular pressure gradient rises again, allowing blood to flow from the left atrium to the LV, which forms the A-wave.

This LV inflow velocity pattern changes from the normal to impaired relaxation type with impaired relaxation of the LV. When diastolic function further deteriorates to the level that causes an increase in left atrial pressure, the pattern changes to the pseudo-normal or restrictive type. In healthy young people, most of the ventricular filling occurs early in diastole due to enhanced LV relaxation, and blood inflow by left atrial contraction is small, so the E/A is >1.5.¹²¹ As the LV relaxation impairs with age and the contribution of left atrial contraction increases, the E-wave decreases and consequently E/A decreases.¹²¹ In the impaired relaxation type, the E-wave is usually <50 cm/s, with E/A <0.8.¹²¹ Meanwhile, the DcT is prolonged due to the decreased atrioventricular pressure gradient resulting from delayed myocardial relaxation. Impaired LV relaxation and decreased LV compliance cause an increase in left atrial pressure, resulting in an increased atrioventricular pressure gradient and thus an increase in peak E-wave velocity. Under such conditions, the LV pressure immediately before atrial contraction is also elevated, and the LV inflow by atrial contraction decreases; thus, the A-wave decreases. Such a pattern is referred to as the restrictive type, where E/A is >2.0.¹²¹ In addition, due to decreased LV compliance, the early diastolic LV pressure increases faster and greater than normal and exceeds the left atrial pressure, causing a rapid decrease in blood flow and shortening of the DcT. DcT is <160 ms in LV diastolic dysfunction of the restrictive type. Pseudonormalization is a transition between the impaired relaxation and restrictive types. It is difficult to differentiate between normal and pseudo-normal patterns based on the LV inflow velocity pattern alone. In addition, changes in the LV inflow velocity pattern correlate less well with LV filling pressure in patients with coronary artery disease with preserved LVEF¹²² and hypertrophic cardiomyopathy.^123,124 Therefore, elevation of the LV filling pressure should be estimated using several indices, including abnormal LV morphology, pulmonary venous flow velocity pattern, peak early diastolic mitral annulus velocity (e’) by tissue Doppler echocardiography,^{117–119,125} LAVI,¹²⁰ and tricuspid regurgitant velocity (TRV).^126,127

Peak early diastolic mitral annulus velocity (e’) by tissue Doppler echocardiography is considered to be an index of LV relaxation. In the LV inflow velocity pattern, the E-wave alters in a biphasic manner under the influence of both left atrial pressure and LV relaxation. Because e’ unidirectionally correlates with LV relaxation and is relatively independent of left atrial pressure, the E/e’ correlates linearly with left atrial pressure and is used to estimate the mean left atrial pressure.^{117–119,125}

The pulmonary venous flow velocity pattern consists of peak forward velocity during ventricular systole (PV S-wave), peak forward velocity during early diastole (PV D-wave), and peak velocity during atrial contraction (PV A-wave) and is defined by the pressure gradient between the pulmonary vein and the left atrium in each cardiac phase. In healthy young people, the LV is well relaxed and rapidly filled in the early diastolic phase with a fast D-wave, and the pulmonary vein S/D ratio can be <1. As LV relaxation impairs with age, the peak D-wave peak velocity decreases, which is compensated by an increase in the S-wave peak velocity. Thus, the S/D ratio can be >1 in individuals aged ≥40 years.¹²⁸ When the left atrial pressure increases, the pulmonary vein–left atrial pressure gradient decreases during ventricular systole because of an elevation of the left atrial V-wave, resulting in a decrease in the S-wave. Meanwhile, the E-wave in the LV inflow and the D-wave increase, and the S/D ratio becomes <1. The PV A-wave velocity and duration are closely related to LV end-diastolic pressure. A deep PV A-wave and prolonged PV A-wave duration are indicative of increased LV end-diastolic pressure.¹²¹ The left atrial volume reflects the degree and duration of LV diastolic dysfunction, because left atrial enlargement progresses with prolonged elevation of LV filling pressure.¹²⁹

In recent years, lung ultrasonography has been used to diagnose elevated left atrial pressure and pulmonary congestion, especially in emergency settings. When extravascular lung water accumulates due to pulmonary congestion, multiple high echogenic laser-like signals, which are called B-lines, arise from the pleural surface. The number of B-lines increases with increasing extravascular lung water.¹³⁰ It has been reported that patients with a higher number of B-lines in the anterolateral chest are more likely to have pulmonary congestion, although measurement approaches vary among reports.¹³¹

1.2.3 Algorithm for Diagnosis of LV Diastolic Dysfunction in Patients With Preserved LVEF and No Significant Myocardial Disease

The septal and lateral e’ velocities, average E/e’ratio, TRV, and LAVI are measured. The patient is judged to have LV diastolic dysfunction when ≥3 of these 4 indices are abnormal. Conversely, LV diastolic function should be considered normal when ≥3 of the indices are normal (Figure 4).¹⁰⁸ If only 3 of the 4 indices are available, a diagnosis of LV diastolic dysfunction should be made when 2 have abnormal values, and that of normal LV diastolic function is made when 2 of the indices have normal values.¹⁰⁸ If 2 of the 4 indices are abnormal, the diagnosis is indeterminate.

Figure 4.

Algorithm for diagnosis of left ventricular diastolic dysfunction in patients with preserved left ventricular ejection fraction (LVEF) and no significant myocardial disease. E, peak early diastolic left ventricular inflow velocity; e’, peak early diastolic mitral annulus velocity; LA, left atrial; TR, tricuspid regurgitation. (Cited from Nagueh SF, et al. 2016.¹⁰⁸)

1.2.4 Algorithm for Estimation of LV Filling Pressures and Grading LV Diastolic Function in Patients With LV Systolic Dysfunction and Patients With LV Myocardial Disease

In patients with LV systolic dysfunction, old myocardial infarction or LV myocardial disease, estimating an elevation of left atrial pressure is important because LV relaxation is impaired in such patients. The algorithm presented in this section is also applied for the patients who have LV diastolic dysfunction in the section 1.2.3, above.¹²¹ The parameters that are helpful in diagnosing latent LV systolic dysfunction in patients with preserved LVEF include GLS, mitral annular systolic peak velocity (s’), and MAPSE.¹⁰⁸ If a significant decrease in these parameters is observed, the algorithm shown below can be applied even to patients with preserved LVEF. When the mitral inflow pattern shows an E/A ≤0.8 together with a peak E velocity ≤50 cm/s, the left arterial pressure is highly likely not to be elevated, and a diagnosis of Grade I (impaired relaxation type) is made. In contrast, an E/A >2.0 is suggestive of severe elevation of the left arterial pressure, and a diagnosis of Grade III (restricted type) is made. If none of these criteria is met, a diagnosis of Grade II (pseudo-normal) is made when ≥2 of the following criteria are positive: E/e’ >14 (average of the septal and lateral segments), TRV >2.8 m/s, and LAVI >34 mL/m². A diagnosis of Grade I (impaired relaxation type) is made when ≥2 of the criteria are negative. If only 2 indices are evaluated, and 1 is positive, a diagnosis cannot be determined. However, in patients with LV systolic dysfunction, a diagnosis of Grade II (pseudo-normal type) can be made if the S/D is <1 (Figure 5).¹⁰⁸

Figure 5.

Algorithm for estimation of left ventricular filling pressures and grading left ventricular diastolic function in patients with left ventricular systolic dysfunction and patients with left ventricular myocardial disease. A, peak left ventricular inflow velocity during atrial contraction; CAD, coronary artery disease; E, peak early diastolic left ventricular inflow velocity; e’, peak early diastolic mitral annulus velocity; LA, left atrial; LAP, left atrial pressure; TR, tricuspid regurgitation. (Cited from Nagueh SF, et al. 2016.¹⁰⁸)

1.2.5 Conditions for Which E/A and E/e’ Cannot Be Applied

The algorithms presented in Figures 4,5 cannot be used for conditions in which E/A and E/e’ cannot be applied. Table 13 summarizes these conditions.

Table 13. Conditions for Which E/A and E/e’ Cannot Be Applied for Evaluation of Left Ventricular Diastolic Function

Difficult to be applied for left ventricular inflow pattern

Atrial fibrillation (chronic and paroxysmal)

Less than 3 months after atrial defibrillation

Fusion of E-wave and A-wave (e.g., tachycardia, I degree atrioventricular block)

MS

Difficult to be applied for E/e’

Severe primary MR

Moderate or more severe mitral annular calcification

After mitral valve surgery

Ventricular pacing

Left bundle branch block

Constrictive pericarditis

Others

After heart transplantation

Pulmonary hypertension due to causes other than left heart failure

Athletes

A, peak left ventricular inflow velocity during atrial contraction; E, peak early diastolic left ventricular inflow velocity; e’, peak early diastolic mitral annulus velocity; MR, mitral regurgitation; MS, mitral stenosis.

Atrial fibrillation (AF) frequently occurs in patients with heart failure. The E/A cannot be used, because of the absence of A-wave, which often makes estimation of the LV filling pressure challenging. In patients with AF and LV systolic dysfunction, a shortened DcT can help predict an increase in LV filling pressure, and other useful indices include E-wave acceleration (≥1,900 cm/s²), isovolumic relaxation time (≤65 ms), and the DcT of the pulmonary venous D-wave (≤220 ms).¹⁰⁸ The data obtained during multiple heartbeats have to be averaged due to irregular cardiac cycle lengths. Averaging the measurements from 10 consecutive heart beats is recommended, but is difficult in daily practice. Measurements averaged from 3 consecutive heart beats with cycle lengths within 10–20% of the average heart rate are also useful.¹⁰⁸

In patients with hypertrophic cardiomyopathy, the E-wave velocity does not increase easily even if the LV filling pressure is elevated. Increased LV filling pressure cannot be ruled out even if the E/A is low. LV filling pressure is considered elevated when ≥3 of the following criteria are met: E/e’ (average of the septal and lateral segments: >14), the difference in A-wave duration between pulmonary venous flow and left ventricular inflow (≥30 ms), TRV (>2.8 m/s), and LAVI (>34 mL/m²). A diagnosis of restrictive-type diastolic dysfunction is made if E/A is >2 and e’ is low (<7 cm/s for septal, <10 cm/s for lateral).¹⁰⁸

In patients with moderate or more severe mitral annular calcification, the E-wave may be increased due to narrowing of the mitral orifice, and e’ may be decreased due to the limited mitral annular motion, which results in an increase in E/e’ even in the absence of an elevation of LV filling pressure. Therefore, it is not recommended to estimate LV filling pressure from the E/e’ in these patients.

1.2.6 Prognostic Prediction by LV Diastolic Function Index

Indices of LV diastolic function are associated with prognosis for various cardiac diseases. Especially in patients with reduced LV systolic function, such as post-myocardial infarction and dilated cardiomyopathy, shortening of the DcT of the E-wave in the LV inflow velocity pattern is a strong predictor of rehospitalization and death.^132–138 E/e’ is useful in estimating prognosis in conditions such as acute myocardial infarction,¹³⁹ LV systolic dysfunction,^140,141 AF,¹⁴² and HFpEF.¹⁴³ LAVI is associated with prognosis such as heart failure and death, not only in patients with dilated cardiomyopathy¹⁴⁴ and acute myocardial infarction,¹⁴⁵ but also in asymptomatic general populations.^146–148 Moreover, in an observational study of community residents in Olmsted County, Minnesota, USA, the severity of LV diastolic function graded by LV inflow velocity pattern, E/e’, and pulmonary venous flow velocity pattern, was associated with death independently of LVEF and age.¹²⁵

1.3 Evaluation of Pulmonary Hypertension

1.3.1 Overview

Pulmonary hypertension is a spectrum of diseases for which a definite diagnosis is made when the mean pulmonary arterial pressure (mPAP) is ≥25 mmHg based on right heart catheterization at rest. According to etiology, pulmonary hypertension is broadly classified into 5 groups: Group I, pulmonary arterial hypertension (PAH); Group II, pulmonary hypertension associated with left heart disease; Group III, pulmonary hypertension associated with lung disease and/or hypoxemia; Group IV, chronic thromboembolic pulmonary hypertension; and Group V, pulmonary hypertension associated with unclear multifactorial mechanisms. The most common pathology is left heart failure-related Group II pulmonary hypertension, resulting from LV systolic and diastolic dysfunction (defined as mPAP ≥25 mmHg and mean pulmonary artery wedge pressure >15 mmHg). Group I PAH is defined as mPAP ≥25 mmHg and mean pulmonary artery wedge pressure ≤15 mmHg; the condition does not fall into Group III, IV or V. It is important to differentiate between PAH and chronic thromboembolic pulmonary hypertension because specific drugs are available.¹⁴⁹

1.3.2 Indications

Typically, shortness of breath or dyspnea with light exertion is the clinical manifestation of pulmonary hypertension, but syncope and chest pain may occur. Echocardiography should be performed if pulmonary hypertension is suspected from the ECG findings (e.g., right-axis deviation, strain ST-T changes in V1–4, increased R wave in V1, and deep S-wave in V5 and V6.) or chest X-ray (e.g., cardiomegaly, especially expansion of the left second arch, and bilateral pleural effusions) (Table 14).

Table 14. Recommendations and Levels of Evidence for Transthoracic Echocardiography for Suspected Pulmonary Hypertension

	COR	LOE
TRV should be measured, and TTE findings* indicative of pulmonary hypertension should be obtained to diagnose the presence of pulmonary hypertension	I	B
TTE is indicated when pulmonary hypertension is suspected based on symptoms and ECG and chest X-ray findings	I	C
LV diastolic function should be evaluated to differentiate from left heart failure	I	C
Right atrial area and the presence or absence of pericardial effusion should be determined for risk assessment	I	C
TEE is reasonable to differentiate from shunt heart disease	IIa	C

*For TTE findings indicative of pulmonary hypertension, please refer to section 1.3.3 Interpretation. COR, class of recommendation; ECG, electrocardiography; LOE, level of evidence; LV, left ventricular; TEE, transesophageal echocardiography; TRV, tricuspid regurgitant velocity; TTE, transthoracic echocardiography.

1.3.3 Interpretation

In diagnosing pulmonary hypertension, a simplified Bernoulli equation is used to calculate the systolic right ventricular (RV)–right atrial pressure gradient from the peak TRV and, in turn, to estimate systolic pulmonary arterial pressure by adding right atrial pressure. The absence of pulmonary stenosis is a prerequisite. However, this method has problems, including increased errors due to squaring the TRV and inaccurate estimation of right atrial pressure. Thus, to address these problems, it is recommended that the TRV value itself be used for screening.¹⁴⁹ If the TRV is >3.4 m/s, pulmonary hypertension should be highly suspected. For a TRV of 2.9–3.4 m/s, pulmonary hypertension is suspected when there are other echocardiographic findings suggestive of pulmonary hypertension, including RV enlargement (ratio to LV diameter >1), interventricular septum compression by the RV, enlarged right atrium (>18 cm²), dilated inferior vena cava (>21 mm with reduced respiratory collapse), accumulation of pericardial effusion, shortened RV outflow tract systolic acceleration time (<105 ms), biphasic RV outflow waveform, increased early diastolic pulmonary regurgitation velocity (>2.2 m/s), and dilated pulmonary artery diameter (>25 mm).

Evaluation of underlying cardiac disease is important in differentiating the cause of pulmonary hypertension. In particular, differentiation from left heart failure and shunt heart disease is essential (Table 14). In the presence of hepatic insufficiency or any other clinical features suggestive of a pulmonary arteriovenous shunt, contrast-enhanced CT or MRI is required for a definitive diagnosis of a pulmonary arteriovenous shunt. With the awareness that HFpEF has recently been increasing among patients with pulmonary hypertension associated with left heart failure, echocardiography should be performed to evaluate LV diastolic function.¹⁴⁹

Patients with scleroderma, a collagen vascular disease refractory to immunosuppressive therapy, are at a high risk of PAH. Therefore, initial screening by TTE is recommended for patients with scleroderma (Table 15). Exercise stress echocardiography can be performed in patients with scleroderma who have subjective symptoms but no abnormal findings at rest, although there is insufficient evidence that subclinical pulmonary hypertension can be detected by exercise stress test (Table 15).^94,150 Right heart catheterization for reevaluation and annual follow-up echocardiography after therapeutic intervention, such as drugs for pulmonary hypertension or lung transplantation, are necessary and recommended to evaluate the patient’s condition and response to treatment (Table 15). Annual follow-up echocardiography in patients with scleroderma and other high-risk individuals may be indicated after consideration of accessibility to medical institutions and current disease status (Table 15).

Table 15. Recommendations and Levels of Evidence for Echocardiographic Screening and Follow-up of Pulmonary Hypertension

	COR	LOE
TTE is indicated as the initial screening in patients with scleroderma	I	B
Exercise stress echocardiography is reasonable in patients with scleroderma who have subjective symptoms but no abnormal findings at rest	IIa	C
Annual follow-up TTE is reasonable after therapeutic intervention for pulmonary hypertension	IIa	C
Annual TTE may be considered in patients with scleroderma	IIb	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

1.4 Evaluation of Right Heart Function

1.4.1 Overview

The clinical implication of right heart dysfunction has been widely recognized because it can affect the prognosis of not only pulmonary hypertension but also left heart diseases such as heart failure and valvular heart disease.^151–156 Doppler echocardiography is the first choice in the evaluation of RV function and right heart hemodynamics, and plays an important role in understanding the pathophysiology, decision-making of treatment, and follow-up of patients. In the evaluation of right heart function and hemodynamics, RV systolic pressure needs to be estimated, because RV systolic and diastolic function depend on the afterload on the RV. Right atrial pressure also needs to be estimated.

1.4.2 Indications and Interpretation

a. RV Systolic Function

i) Parameters

Measurement of the RV parameters by 2D echocardiography needs careful attention because the view images easily change according to the position of the ultrasonic probe due to the complexity of the RV shape (Figure 6). To improve reproducibility, it is important to use an RV-focused 4-chamber view.¹⁵⁷ The key points are to obtain a view of the RV at its largest size to avoid the underestimation of the RV diameter and, conversely, to obtain a long-axis view showing the LV apex through the center of the LV to avoid overestimation of the RV diameter. It should be noted that the lateral wall of the RV may appear shorter than it actually is in views showing the LV outflow tract.

Figure 6.

Comparison of apical 4-chamber views with different ultrasound beam directions. Short- and long-axis views were reconstructed from the 3D data. View (1) is optimal. In the short-axis views shown in (1) and (2), the ultrasound beam passes through the left ventricular apex (red line), but in view (2), the ultrasound beam captures the right ventricular anterior wall and thus the right ventricular diameter is underestimated. In view (3), the right ventricular diameter is overestimated, and the left ventricular apex is not visualized, which shortens the longitudinal distance of the right ventricle (RV). 3D, three dimensional.

The RV longitudinal systolic function can be assessed using tricuspid annular plane systolic excursion (TAPSE), peak tricuspid annular systolic velocity (s’) by tissue Doppler, and longitudinal strain of the RV free wall. Global RV systolic function can be estimated using RV fractional area change (FAC) and RVEF by 3D echocardiography. The Tei index or RV index of myocardial performance (RIMP) is an integrated index of RV function. Table 16 summarizes the normal and cutoff values of each index. For estimation of RV systolic pressure, please refer to the evaluation of pulmonary hypertension (see III.1.3 Evaluation of Pulmonary Hypertension).

Table 16. Summary of Right Ventricular Function Indices

Index	Normal	Abnormal
TAPSE (mm)	23±7	<17
s’ (cm/s)	15±5	<9.5
RV free wall strain (%)*	−29±4.5	−20<
FAC (%)	49±7	<35
Tei index or RIMP (pulse Doppler)	0.26±0.085	>0.43
Tei index or RIMP (tissue Doppler)	0.38±0.08	>0.54
3D RVEF (%)	58±13	<45
E-wave DcT (ms)	180±31	<119 or >242
E/A	1.4±0.3	<0.8 or >2.0
E/e’	4.0±1.0	>6.0

*Reference values due to variations between equipment. A, tricuspid inflow velocity during atrial contraction; DcT, deceleration time; E, early diastolic tricuspid inflow velocity; e’, peak early diastolic tricuspid annular velocity; FAC, functional area change; RIMP, right ventricular index of myocardial performance; RV, right ventricle; RVEF, right ventricular ejection fraction; s’, peak tricuspid annular systolic velocity; TAPSE, tricuspid annular plane systolic excursion. (Cited from Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. 2010.¹⁵⁸)

ii) Indications for Evaluation of RV Systolic Function

It is strongly recommended to incorporate at least one of TAPSE, s’, FAC, Tei index, and RV free wall strain into routine echocardiographic practice. However, because there is not a single established method for assessing RV function, it is preferable to combine more than 1 of the above indices.^157,158

(i) TAPSE: Recommended method for evaluating RV systolic function in routine examination. However, this index may be over- or underestimated because it is affected by displacement of the heart due to contractions.^158,159

(ii)  s’: Recommended method for evaluating RV systolic function in routine examinations. It is measured at the base of the RV free wall using pulsed tissue Doppler. Similar to TAPSE, this method is affected by movement of the entire heart.

(iii) RV free wall systolic strain: Recommended method for evaluating RV systolic function in facilities that are proficient in the examination in light of the increasing clinical applications and accumulating evidence.^{155,160–162} However, no cutoff value has been established.⁶³

(iv) FAC: Recommended method for evaluating RV systolic function in routine examination. Caution is needed with obtaining a view for the measurement.

(v)  Tei index: Recommended method for evaluating RV function in routine examinations. However, it is preferable to use it in combination with other indices.

(vi) 3D RVEF: Most reliable index of RV systolic function. However, it is not recommended in routine practice because an echo dropout in part of the RV often occurs with the current method.¹⁶³ This index should be measured and evaluated at facilities with adequate experience in 3D echocardiography of the RV and a solid understanding of its limitations.

Table 17 summarizes the recommendations and levels of evidence for echocardiographic evaluation of RV function.

Table 17. Recommendations and Levels of Evidence for Transthoracic Echocardiography for Evaluation of Right Ventricular Function

	COR	LOE
RV function should be graded for cardiovascular risk assessment during TTE	I	A
RV systolic function should be evaluated by TAPSE, s’ by tissue Doppler or FAC	I	A
RV function should be evaluated by the Tei index	I	A
RV diastolic function should be evaluated by RV inflow pattern	I	B
Right atrial pressure should be estimated using the maximum diameter of the inferior vena cava and percentage change in the diameter of the inferior vena cava with a sniff or a breath	I	B
It is reasonable to evaluate RV systolic function by RV free wall strain	IIa	B
It is reasonable to evaluate RV diastolic function using RV E/e’	IIa	B
It is reasonable to evaluate RV diastolic function by hepatic venous flow velocity pattern	IIa	B
Measurement of RVEF by 3D echocardiography may be considered	IIb	C

COR, class of recommendation; E, early diastolic tricuspid inflow velocity; e’, peak early diastolic tricuspid annular velocity; FAC, functional area change; LOE, level of evidence; RV, right ventricular; RVEF, right ventricular ejection fraction; S’, peak tricuspid annular systolic velocity; TAPSE, tricuspid annular plane systolic excursion; TTE, transesophageal echocardiography.

b. RV Diastolic Function

RV diastolic dysfunction is extensively affected by aging, RV pressure or volume overload disease, primary pulmonary disease, ischemic heart disease, congenital heart disease, cardiomyopathy, LV failure (due to interventricular interactions), and acute and chronic systemic diseases.

RV diastolic dysfunction is graded according to the E/A ratio in the RV inflow velocity pattern (Tables 16,18).¹⁵⁸ The following ancillary conditions should be used: E-wave DcT, ratio of E to e’ in tissue Doppler pattern at the tricuspid annulus of the RV free wall (E/e’), and the presence of diastolic predominance of hepatic venous flow (systolic velocity–time-integral fraction <0.55).^63,164 Right atrial pressure stratified by the findings for the inferior vena cava (see 1.4.4 below) should also be used as a reference for assessing RV diastolic function. Table 16 presents the classification of RV diastolic function.

Table 18. Classification of Patterns of Right Ventricular Diastolic Function

	Abnormal relaxation	Pseudo-normal	Restrictive
Right ventricular E/A	<0.8	0.8–2.0	>2.0
Ancillary conditions	–	Right heart E/e’ >6 or TVIs / (TVIs + TVId) <0.55	Tricuspid E-wave DcT <120 ms

A, tricuspid inflow velocity during atrial contraction; DcT, deceleration time; E, early diastolic tricuspid inflow velocity; e’, peak early diastolic tricuspid annular velocity; TVI, time velocity integral of hepatic venous Doppler flow; TVId, TVI of D-wave in hepatic venous Doppler flow; TVIs, TVI of S-wave in hepatic venous Doppler flow. (Cited from Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. 2010.¹⁵⁸)

It is recommended to evaluate RV diastolic function as an index of early or mild RV dysfunction in patients with suspected RV disease and as a prognostic factor in patients with RV dysfunction.

1.4.3 Estimation of Central Venous Pressure

Central venous pressure (right atrial pressure) is assessed by the diameter of the inferior vena cava (IVC) and the change in the diameter with a sniff. The IVC, running beneath the liver, is visualized in its long axis through an epigastric approach to measurement. At end-expiration, the maximum diameter of the IVC is measured just proximal to the junction of the hepatic veins that lie approximately 0.5–3.0 cm proximal to the ostium of the right atrium.¹⁵⁸ It is recommended to keep the patient in the left lateral decubitus position because the morphology of the IVC changes with posture.¹⁶⁵ Displacement of the IVC with a sniff may prevent precise measurement of the IVC diameter. Thus, it is desirable to confirm changes in the position of the IVC with a sniff in a short-axis view.

Figure 7 shows the algorithm for estimating right atrial pressure. Right atrial pressure is stratified into 3 levels of 0–5, 5–10, and 10–20 mmHg according to the percent change in the maximum IVC diameter with a sniff. The respective medians of 3, 8, and 15 mmHg are used in the determination of reference values rather than the range. Right atrial pressure is classified as 3 mmHg (range, 0–5 mmHg) if the maximal IVC diameter is ≤2.1 cm and collapses ≥50% with a sniff, and as 15 mmHg (range, 10–20 mmHg) if the maximal IVC diameter is >2.1 cm and collapses <50% with a sniff.¹⁵⁸ Right atrial pressure is classified as 8 mmHg (range, 5–10 mmHg) if any of the criteria are not met. If possible, right atrial pressure should be comprehensively evaluated using secondary indices of increased right atrial pressure. These secondary indices are identical to those used for RV diastolic function as described above. If any of the secondary indices do not meet the criteria, right atrial pressure may be lowered to the level of 3 mmHg. On the other hand, right atrial pressure may be increased to the level of 15 mmHg if the secondary indices are abnormal and the collapse rate with a sniff is <35%. Right atrial pressure should remain at the 8 mmHg level if the above secondary indices are difficult to evaluate or if the result is inconclusive after the addition of the secondary indices. If a sniff is difficult for the patient to perform, collapse with normal inspiration <20% is suggestive of increased right atrial pressure. The short-axis view of the IVC is also helpful to estimate right atrial pressure, and sphericity of the IVC in cross-section is a useful finding supporting increased right atrial pressure.^166,167 On the other hand, it should be noted that collapse of the IVC does not accurately reflect right atrial pressure in patients on mechanical ventilation.¹⁶⁸ Young athletes have a large IVC diameter, making it difficult to estimate an increase in right atrial pressure.

Figure 7.

Algorithm for estimating right atrial pressure. E, early diastolic tricuspid inflow velocity; e’, peak early diastolic tricuspid annular velocity; DcT, deceleration time of early diastolic right ventricular inflow; TVId, time velocity integral of D-wave in hepatic venous flow; TVIs, time velocity integral of S-wave in hepatic venous flow. (Modified from Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. 2010.¹⁵⁸)

2. Aortic Valve Disease

2.1 Aortic Stenosis (AS)

2.1.1 Overview

The roles of echocardiography in the evaluation of AS include assessing (1) severity, (2) morphology of the aortic valve and root, and (3) left ventricular function and hypertrophy. In patients suspected of AS, transthoracic echocardiography (TTE) should be performed for these evaluations.

2.1.2 Severity Assessment

The severity of AS is assessed by peak and mean transvalvular pressure gradient (PG), calculated from the transvalvular flow velocity by continuous-wave Doppler, and the aortic valve area, determined by the continuity equation. Although it is easy to calculate the transvalvular PG, it has the disadvantage of being affected by hemodynamics. Because the Doppler method is angle-dependent, it is also important to obtain the highest PG by careful approach from multiple acoustic windows. On the other hand, the valve area is not influenced by hemodynamics, but the measurement error of the LV outflow tract diameter has a significant effect on the calculated valve area. Therefore, great care must be taken with the measurement. The criteria for severe AS requiring therapeutic intervention include a valve area <1 cm², an indexed valve area <0.6 cm²/m² (valve area divided by body surface area), a maximum transvalvular flow velocity ≥4.0 m/s as recorded by Doppler, and a mean PG ≥40 mmHg (Table 19).^{53,62,169,170}

Table 19. Grading the Severity of Aortic Stenosis

	Aortic valve sclerosis	Mild AS	Moderate AS	Severe AS	Very severe AS
Vmax (m/s)	≤2.5	2.6–2.9	3.0–3.9	≥4.0	≥5.0
Mean PG (mmHg)	–	<20	20–39	≥40	≥60
AVA (cm2)	–	>1.5	1.0–1.5	<1.0	<0.6
Indexed AVA (cm2/m2)	–	>0.85	0.60–0.85	<0.6	–
Velocity ratio	–	>0.50	0.25–0.50	<0.25	–

AVA, aortic valve area; PG, pressure gradient; Velocity ratio, ratio of velocity at left ventricular outflow tract to maximum velocity; Vmax, maximum velocity. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

A maximum flow velocity (Vmax) ≥5.0 m/s and a mean pressure gradient (PG) ≥60 mmHg are associated with poor outcome, even in asymptomatic patients. AS that meets the above criteria is defined as very severe, and aortic valve replacement should be considered.^171,172 Patients with AS with reduced stroke volume (SV index ≤35 mL/m²) have reduced transvalvular PG even though the valve area satisfies the criteria for severe AS, leading to an underestimation of disease severity.^88,173–175 In such patients, the next step is to assess the LV ejection fraction (EF). In patients with LVEF <50% (classical low-flow, low-gradient severe AS), it is recommended to evaluate the PG by dobutamine stress echocardiography.^{87–89,173,176} In patients with preserved LVEF (≥50%, paradoxical low-flow, low-gradient severe AS), it is recommended to comprehensively assess disease severity by the reproducibility of symptoms and other diagnostic modalities (Table 20).^167–180

Table 20. Comprehensive Assessment of Paradoxical Low-Flow, Low-Gradient Severe Aortic Stenosis

Assessment	Criteria
Clinical	Typical symptoms
Qualitative imaging data	Reduced LV longitudinal function
Quantitative imaging data	Stroke volume index ≤35 mL/m2 by 3D echocardiography or MRI
	Aortic valve calcification score
	Severe AS likely: men ≥2,000, women ≥1,200
	Severe AS unlikely: men <1,600, women <800

AS, aortic stenosis; LV, left ventricular; MRI, magnetic resonance imaging.

2.1.3 Morphological Assessment

In AS, the restricted valve opening is seen in the long-axis and short-axis views. The short-axis view is suitable for observing the number of leaflets and the commissural status. Two leaflets will be seen in the bicuspid aortic valve and commissural fusion in rheumatic aortic valvular disease. Sclerotic and calcified leaflets are age-related degenerative findings. Bicuspid aortic valve disease is the most common congenital aortic valve disease, which is typically characterized by 2 leaflets of unequal size, with the larger leaflet having a residual commissure. The raphe is often seen as a remnant of the residual commissure. There are 2 types of raphes, namely, anteroposterior and right–left types. The anteroposterior type is more common than the right–left type. The Sievers classification is also commonly used, in which the bicuspid aortic valve is classified by the number of raphes as type 0, 1 or 2. Systolic doming can be seen in the long-axis view of the bicuspid aortic valve. The changes in the aortic valve can largely be considered rheumatic when the mitral valve has rheumatic changes. However, because degeneration progresses with age in any type of AS, the cause is often difficult to identify due to the markedly high echogenicity and calcification. The LV wall is symmetrically thickened. The proximal aorta is sometimes enlarged. A bicuspid valve can be suspected by the presence of proximal aortic enlargement. Regardless of stenosis or regurgitation, the bicuspid aortic valve may be accompanied by aortic aneurysm, aortic dissection or aortic coarctation, as well as ascending aortic enlargement due to weakening of the aortic tunica media.^181–185 Coexisting subvalvular stenosis increases the aortic valve flow velocity as assessed by continuous-wave Doppler imaging. Therefore, caution should be exercised for the coexistence of a LV apico-basal abnormal band, sigmoid septum, and systolic anterior motion of the mitral valve. Transesophageal echocardiography (TEE) is useful for morphological assessment when TTE does not provide sufficient information partly due to suboptimal image quality.

2.1.4 Cardiac Function

Measurements of LV systolic function include fractional shortening, obtained from LV end-diastolic and end-systolic diameters, and SV and LVEF, both obtained from the LV end-diastolic and end-systolic volumes. LVEF <50% is a critical criterion for determining a surgical indication in patients with asymptomatic severe AS. Global longitudinal strain (GLS), a measurement of LV systolic function in the longitudinal axis, can be used to detect LV myocardial damage and may predict prognosis in patients with preserved LVEF.^186–188 It should be noted that GLS measurements are affected by variations between equipment.^189,190

2.1.5 Stress Echocardiography (see also II.2 Stress Echocardiography)

Exercise and low-dose dobutamine stress echocardiography are used in patients with AS. Exercise is mainly used to reproduce symptoms and signs and predict cardiovascular events, whereas dobutamine is mainly used to diagnose disease severity and predict postoperative outcomes in patients with classical low-flow, low-gradient AS and reduced LVEF. Exercise stress is contraindicated in patients with symptomatic AS.

a. Exercise Stress Echocardiography

Elevated mean PG at the aortic valve (≥18 mmHg) and exercise-induced pulmonary hypertension (i.e., estimated pulmonary artery systolic pressure during exercise ≥60 mmHg) have been reported to be predictors of cardiovascular events.^67,81,84,85

b. Dobutamine Stress Echocardiography

With low-dose dobutamine stress echocardiography for classical low-flow, low-gradient AS with reduced LVEF, true severe AS is defined as a peak velocity >4 m/s and a mean PG >40 mmHg at the maximum dobutamine dose of 20 µg/kg/min; otherwise it is defined as pseudo-severe AS.⁸⁷ LV contractile reserve is assessed by whether the SV is increased by ≥20% with dobutamine stress. Decreased LV contractile reserve has been shown to be associated with poor prognosis after aortic valve replacement.^88,89

2.1.6 Information Needed for Transcatheter Intervention

Contrast-enhanced cardiac CT is the standard approach for evaluating stenotic valve morphology before transcatheter aortic valve implantation (TAVI).^191,192 3D TEE can also provide information on the morphology of the stenotic valve, the annulus and the Valsalva sinus to determine the transcatheter valve size, and the left main coronary height from the annulus to predict complications of coronary occlusion during TAVI.¹⁹³ This imaging modality is particularly useful for patients in whom contrast-enhanced cardiac CT is contraindicated due to reduced renal function. 3D TEE allows determination of the distribution of calcification in the aortic valve and LV outflow tract, which may cause aortic valve annulus rupture during TAVI. 3D TEE also allows assessment of the coexistence of an apico-basal abnormal band, a sigmoidal septum, and mitral subvalvular apparatus abnormalities, which may cause systolic anterior motion of the mitral valve after TAVI. In addition, preoperative aortic regurgitation and the SV index should be assessed because they are prognostic factors of TAVI.^194–196 Intraoperative monitoring by TTE or TEE is valuable for positioning of the guidewire and valve on the catheter and for post-procedural evaluation of paravalvular regurgitation, and enables early detection of serious complications such as cardiac tamponade.¹⁹³

The utility of low-dose dobutamine stress echocardiography in classical low-flow, low-gradient AS is described above. TAVI is a less-invasive procedure compared with surgical aortic valve replacement and has been reported to improve prognosis and restore cardiac function, irrespective of the LV contractile reserve on dobutamine stress echocardiography.¹⁹⁷ Therefore, the lack of LV contractile reserve on dobutamine stress echocardiography does not necessarily mean the indication of conservative medical treatment rather than TAVI.¹⁹⁸

Contrast-enhanced cardiac CT has better spatial resolution than echocardiography and can help determine the type and size of the TAVI valve and assess the risk of aortic annular rupture due to calcification. Thus, it is essential for preoperative TAVI evaluation.^191,192 In addition, the CT-derived aortic valve calcification score is useful for diagnosing paradoxical low-flow, low-gradient severe AS.^169,178,199 Cardiac MRI allows anatomical assessment simultaneously with myocardial tissue characterization using T1 mapping or gadolinium delayed imaging.²⁰⁰

2.1.7 Follow-up Echocardiography

Because AS is a progressive disease, periodic follow-up by TTE is mandatory even for moderate AS. Periodic TTE is also indispensable in patients with severe AS who are not candidates for intervention. Table 21 lists the recommendations and levels of indications for echocardiography for AS.

Table 21. Recommendations and Levels of Evidence for Echocardiography for AS

	COR	LOE
TTE is indicated for patients with known or suspected AS to evaluate severity and etiology of AS, LV size, and LV function	I	B
Periodic TTE is indicated for patients with moderate AS to evaluate disease progression and for monitoring asymptomatic patients with severe AS to decide the timing of intervention	I	B
Monitoring by TTE or TTE is indicated during TAVI	I	C
Low-dose dobutamine stress echocardiography is reasonable to differentiate true- from pseudo-severe AS and to evaluate contractile reserve for patients with low-flow/low-gradient AS and reduced LVEF	IIa	B
Exercise stress echocardiography is reasonable for asymptomatic patients with severe AS or for symptomatic patients with moderate AS to evaluate symptoms and hemodynamics during exercise	IIa	C
TEE is reasonable to evaluate aortic valve and aortic root if TTE assessment is inconclusive due to technical difficulty	IIa	C

AS, aortic stenosis; COR, class of recommendation; LOE, level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; TAVI, transcatheter aortic valve implantation; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography. (Modified from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

2.2 Aortic Regurgitation (AR)

2.2.1 Overview

AR is a condition characterized by regurgitation from the aorta to the LV during diastole due to leaflet malcoaptation. As presented in Table 22, the etiology of AR is diverse^12,62 and can be broadly divided into (1) organic abnormalities of the valve itself and (2) incomplete leaflet coaptation due to aortic root abnormalities (e.g., aortic annular dilatation, aortic dissection, etc.) in the absence of organic abnormalities in the valve itself (Table 23).^62,201 These classifications were developed by surgeons for selecting operative procedures, so should be recognized as a means to understand the pathogenesis of AR and to consider its surgical treatment.

Table 22. Etiology of Aortic Regurgitation

Mechanism	Etiology
Congenital abnormalities	Bicuspid, unicuspid or quadricuspid aortic valve
Acquired abnormalities	Senile degeneration
	Infective endocarditis
	Rheumatic disease
	Leaflet prolapse
	Leaflet herniation associated with ventricular septal defect
	Radiation-induced valvulopathy
	Drug-induced valvulopathy
	Carcinoid
	Trauma
Congenital/genetic aortic root abnormalities	Annuloaortic ectasia
	Connective tissue disease: Loeys Dietz syndrome, Ehlers-Danlos syndrome, Marfan’s syndrome, osteogenesis imperfecta
Acquired aortic root abnormalities	Idiopathic aortic root dilatation
	Systemic hypertension
	Autoimmune disease: systemic lupus erythematosis, ankylosing spondylitis, Reiter’s syndrome
	Aortitis: syphilis, Takayasu’s arteritis
	Aortic dissection
	Trauma

(Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

Table 23. Repair-Oriented Functional Classification of Aortic Regurgitation With Description of Disease Mechanisms and Repair Techniques Used

Type I Normal appearing cusp				Type II Prolapse	Type III Restriction
Aortic root dilatation			Perforation Id
STJ-AAo Ia	SoV-STJ Ib	VAJ Ic

AAo, ascending aorta; SoV, sinuses of Valsalva; STJ, sinotubular junction; VAJ, ventriculoaortic junction (annulus). (Cited from Boodhwani M, et al. 2009.²⁰¹)

Chronic AR is accompanied by LV dilatation and eccentric hypertrophy due to LV volume overload. The role of echocardiography in the evaluation of AR includes (1) diagnosis and evaluation of the severity of regurgitation, (2) identification of the cause of regurgitation (morphological evaluation), (3) evaluation of LV dilatation and function, and (4) evaluation of coexisting abnormalities in the perivalvular structures and aorta. In acute AR, unlike chronic AR, regurgitation occurs abruptly when the LV has not had the opportunity to increase its end-diastolic volume (LV dilatation) and increase its compliance, resulting in a rapid increase in LV end-diastolic pressure. Consequently, the LV pressure exceeds the left atrial pressure in the middle of diastole, causing early closure of the mitral valve and subsequent diastolic mitral regurgitation (MR) and, in turn, a remarkable reduction in CO, leading to acute severe pulmonary edema and cardiogenic shock. Thus, unlike chronic AR, acute AR is a serious condition that requires emergency surgery.

In patients with suspected AR, TTE is the first examination to be performed to determine the severity and etiology of regurgitation and LV size and function, as well as the timing of therapeutic intervention.

2.2.2 Severity Assessment

The diagnosis of AR is made using color Doppler imaging to examine the diastolic blood flow from the aorta back into the LV. Table 24 presents the main assessment methods and grading of the severity of AR. Qualitative parameters include the color jet length, pressure half-time by continuous-wave Doppler, and diastolic flow reversal in the descending aorta. However, of note, the color jet length shown by color Doppler may be underestimated in patients with elevated LV diastolic pressure and is underestimated for an eccentric regurgitation jet. It should also be noted that the pressure half-time is affected by LV diastolic pressure. Semiquantitative parameters include vena contracta width and the ratio of the regurgitant jet width to the LV outflow tract diameter. Vena contracta width is considered useful when the shape of the regurgitant orifice of the aortic valve is relatively close to a circle; otherwise, caution is advised because over- or underestimation may occur depending on the view used. Quantitative parameters include regurgitant volume, regurgitant fraction, and effective regurgitant orifice area, which are calculated using transaortic and transmitral flow volumes measured by the PISA method or pulse Doppler imaging.

Table 24. Grading the Severity of Aortic Regurgitation

			AR severity
			Mild	Moderate	Severe
Transthorathic echocardiography	Structual parameters	Aortic leaflets	Normal or mildly abnormal	Normal or mildly abnormal	Abnormal, flail, or wide coaptation
		LV size	Normal	Normal or enlarged	Enlarged (except acute AR)
	Qualitative parameters	AR jet width, (color flow)	Small in central jets	Intermediate	Large in central jets: variable in eccentric jets
		AR flow convergence, (color flow)	None or very small	Intermediate	Large
		Jet density (color wave Doppler)	Incomplete or faint	Dense
		Jet deceleration rate (color wave Doppler), PHT, ms	>500	500–200	<200
		Diastolic flow reversal (descending aorta) (pulse wave Doppler)	Brief, early diastolic reversal	Intermediate	Prominent holodiastolic reversal
	Semiquantitative parameters	Vena contracta width (cm)	<0.3	0.3–0.6	>0.6
		Jet width/LVOT width (%) (central jet only)	<25	25–64	≥65
		Jet area/LVOT area (short axis) (%) (central jet only)	<5	5–59	≥60
	Quantitive parameters	Rvol (mL/beat): volumetric or PISA	<30	30–59	≥60
		RF (%): volumetric	<30	30–49	≥50
		EROA (cm2): PISA	<0.10	0.10–0.29	≥0.30
Transesophageal echocardiography	Semiquantitative parameters	3D vena contracta width (cm)	<0.3	0.3–0.6	>0.6
Cardiac MRI		RF (%): phase contrast	<30	30–49	≥50
Cardiac catheterization	Aortography	Sellers criteria	I	II	III–IV

AR, aortic regurgitation; EROA, effective regurgitant orifice area; LV, left ventricular; LVOT, left ventricular outflow tract; PHT, pressure half-time; PISA, proximal isovelocity surface area; RF, regurgitant fraction. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

2.2.3 Morphological Assessment

To identify the cause of AR, the presence or absence of organic abnormalities is assessed in short- and long-axis views of the aortic valve. A severely eccentric jet may be seen in the presence of a congenital bicuspid valve, aortic valve prolapse, and aortic valve herniation associated with ventricular septal defect (VSD). Diastolic fluttering of the anterior leaflet of the mitral valve may be observed in the presence of a regurgitant jet oriented toward the mitral anterior leaflet. When no organic abnormalities are found in the aortic valve, images should be examined for any dilatation of the ascending aorta, Valsalva sinus and aortic annulus. The subvalvular portion should be observed closely for any evidence of aortic cusp prolapsing into the VSD. As far as possible, aortic images other than those of the ascending aorta are also evaluated. Especially in patients with congenital bicuspid valve or connective tissue disease, the presence or absence of aortic coarctation, aneurysm, and dissection should be evaluated. When aortic valve surgery is considered, the ascending aorta diameter should always be measured to determine whether simultaneous surgery of the ascending aorta is indicated.⁶² In recent years, aortic valve repair and valve-sparing root replacement have become available, and these techniques require a more thorough assessment of valve morphology. TEE is useful in assessing aortic valve morphology and associated abnormalities of the aorta. TEE is indicated especially when transthoracic imaging does not provide sufficient information. TTE often provides more information on disease severity, because with TEE, the regurgitant jet is often evaluated from the perpendicular direction, making it difficult to visualize the entire regurgitant jet.

In acute AR, both the length and time of the regurgitant jet decrease, as measured by color Doppler, due to an abrupt increase in LV end-diastolic pressure associated with severe AR. Evidence of the early closure of the mitral valve with subsequent diastolic MR is suggestive of severe acute AR.

2.2.4 Evaluation of Cardiac Function and Load

Because AR imposes volume load on the LV, dilatation and eccentric hypertrophy of the LV may occur in the chronic phase. Echocardiography is used to evaluate LV dilatation and function. Enlarged LV diameter and decreased LVEF inform the decision on surgery for AR, even in asymptomatic patients. Therefore, it is important to accurately evaluate LV end-diastolic and end-systolic diameters and LVEF (particularly to evaluate changes over time). Major guidelines have proposed different criteria for LV enlargement, and they are even now being updated as appropriate. The LV end-diastolic diameter index, a LV end-diastolic diameter corrected for body surface area, is sometimes used in patients with small body size.^202–204 According to the JCS “Guidelines on the management of valvular heart disease” (2020 revised version), surgery is indicated for patients with asymptomatic AR if the LVEF is <50%, LV end-systolic diameter is >45 mm, and LV end-diastolic diameter is >65 mm or LV end-systolic diameter index is >25 mm/m².⁶²

2.2.5 Stress Echocardiography (see also II.2 Stress Echocardiography)

Despite limited evidence of stress echocardiography in AR, it has been reported that changes in LVEF and LV morphology in response to exercise vary from patient to patient. Small increments of LVEF (∆LVEF <4%) and increased LV end-systolic volume index (≥40 mL/m²) during exercise predict poor prognosis of AR and decreased LV function after aortic valve replacement.^{91,92,205,206}

2.2.6 Follow-up Echocardiography

Periodic TTE is required to follow-up LV function and LV diameter in patients with severe AR who do not meet the criteria for surgery and to evaluate disease progression in patients with moderate AR. Table 25 summarizes the recommendations and levels of evidence of echocardiography for AR.

Table 25. Recommendations and Levels of Evidence of Echocardiography for AR

	COR	LOE
TTE is indicated for patients with suspected AR to evaluate the etiology and severity of regurgitation, LV size and function and to determine the timing of intervention	I	B
TTE is indicated for patients with dilated Valsalva sinus or ascending aorta or with a bicuspid aortic valve to evaluate the presence and severity of AR	I	B
TEE is indicated for patients with moderate or severe AR and suboptimal TTE images for the assessment of etiology or severity of AR	I	B
TTE is indicated for patients with a bicuspid aortic valve to evaluate valve morphology and the severity of AS and AR and the shape and diameter of the aortic root for prediction of clinical outcome and determination of the timing of intervention	I	B
Periodic TTE is indicated for patients with moderate AR to evaluate the progression of AR and to determine the timing of intervention in asymptomatic patients with severe AR	I	B

AR, aortic regurgitation; AS, aortic stenosis; COR, class of recommendation; LOE, level of evidence; LV, left ventricular; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography. (Modified from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

3. Mitral Valve Disease

3.1 Mitral Stenosis (MS)

3.1.1 Indications

MS is caused by narrowing of the mitral valve orifice, which results in left atrial pressure overload, leading to left atrial dilatation, pulmonary congestion, and reduced cardiac output. Patients with mild stenosis are asymptomatic, but those with moderate or greater stenosis complain of symptoms of left heart failure such as shortness of breath. Pulmonary hypertension may cause tricuspid regurgitation (TR) with the development of symptoms of right heart failure. Atrial fibrillation (AF) is a common complication, and patients often complain of palpitations. Left atrial enlargement and AF may cause blood flow stasis in the left atrium, leading to thrombus formation and, in turn, systemic embolism such as cerebral infarction. Characteristic features on auscultation include a loud first heart sound, mitral opening snap, and diastolic rumble at the apex. Chest X-rays reveal left atrial enlargement and pulmonary congestion. If these findings are present, mitral valve disease should be suspected and transthoracic echocardiography (TTE) is indicated for diagnosis and assessment of severity and etiology.²⁰⁷

3.1.2 Interpretation

MS is divided into 2 types, namely, rheumatic MS, which is caused by rheumatic fever in childhood, and nonrheumatic MS, which is caused by age-related calcification of the mitral annulus. The diagnosis is based on restricted opening of the mitral valve by 2D echocardiography. In cases of rheumatic MS, commissural fusion, thickening of the valve, and degeneration of the mitral subvalvular apparatus (thickening, shortening, and fusion) are observed. In many cases, anterior leaflet mobility is relatively preserved, with doming of the anterior leaflet into the left ventricle (LV) in diastole. The posterior leaflet lacks mobility from an early stage and appears to be upright against the posterior wall of the LV. As the disease progresses, the valve leaflets as well as the commissures show high echogenicity, and calcification is often seen. In advanced stages, calcification extends from the chordae tendineae to the papillary muscles. All this information is important for determining the indication for percutaneous transvenous mitral commissurotomy (PTMC).²⁰⁸ The severity can be determined by the mitral valve area, which is measured using the 2D (tracing) method, the continuity equation or the pressure half-time (PHT) method, mean pressure gradient (PG), PHT itself, and the mitral and left atrial morphologies (Table 26).⁶² Nonrheumatic MS is characterized by leaflet calcification that develops from the valve annulus, making it inaccurate to estimate the mitral valve area by the PHT method. MS is often complicated by AF, leading to thrombus formation in the left atrium. Transesophageal echocardiography (TEE) is suitable for detecting thrombus. Mitral valve disease is frequently complicated by secondary pulmonary hypertension. It is important to assess the presence or absence and severity of pulmonary hypertension from the peak TR velocity. Table 27 summarizes the recommendations and levels of evidence for echocardiography for MS.

Table 26. Grading the Severity of Mitral Stenosis

	Mild	Moderate	Severe
MVA	1.5–2 cm2	1.0–1.5 cm2	<1.0 cm2
mPG*	<5 mmHg	5–10 mmHg	>10 mmHg
Diastolic PHT*	<150 ms	150–220 ms	>220 ms

*mPG and diastolic PHT should be used only as a reference because of the influence of hemodynamics. mPG, mean pressure gradient; MVA, mitral valve area; PHT, pressure half-time. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

Table 27. Recommendations and Levels of Evidence for Echocardiography for Mitral Stenosis

	COR	LOE
TTE is indicated for patients with suspected MS to assess the severity of stenosis, etiology, the size and function of the LV and LA, and pulmonary hypertension and other valvular diseases	I	B
Periodic TTE is indicated for patients in the advanced stage of MS to evaluate disease progression or for asymptomatic patients with significant stenosis, to determine the timing of surgery or PTMC	I	B
TEE is indicated to evaluate the mitral valve and subvalvular apparatus in patients with suspected left atrial thrombus or for whom PTMC is being considered	I	B
Exercise stress echocardiography is reasonable for patients with MS if there is a discrepancy between clinical symptoms and severity of MS by echocardiography at rest	IIa	B
TEE is reasonable to evaluate the mitral valve and subvalvular apparatus when TTE is inadequate due to suboptimal imaging	IIa	C
Repeat TEE is not recommended in situations where changes in clinical findings due to treatment or over time are not expected	IIIa (No benefit)	C

COR, class of recommendation; LA, left atrium; LOE, level of evidence; LV, left ventricle; MS, mitral stenosis; PTMC, percutaneous transseptal mitral commissurotomy; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

3.1.3 Stress Echocardiography (see also II.2 Exercise Stress Echocardiography)

Exercise stress echocardiography is mainly used and indicated for patients whose clinical presentation does not match the disease severity on resting echocardiography; that is, asymptomatic patients with severe MS or symptomatic patients with mild to moderate MS.^209,210 The mean mitral PG is calculated from transmitral flow velocities at rest and during exercise. Mean PG ≥15 mmHg during exercise is suggestive of severe MS. Severe MS is suggested when the estimated pulmonary artery systolic pressure is >60 mmHg, calculated from the TR pressure gradient during exercise.

3.1.4 Interpretation for Treatment Selection

Patients with valvular heart disease other than MS usually remain asymptomatic until the disease progresses to a severe stage. Patients with a mitral valve area of 1.0–1.5 cm², which has been defined as moderate MS in the conventional grading of severity, can be symptomatic during tachycardia because the symptoms of MS are dependent on heart rate. Thus, in the 2020 AHA/ACC “Guidelines on the management of valvular heart disease”,²⁰⁷ severe MS is defined as a valve area <1.5 cm², asymptomatic severe MS is defined as Stage C, and symptomatic severe MS is defined as Stage D. According to this grading of severity, recommendations for treatment of MS are defined. The 2020 AHA/ACC guidelines are excellent because the recommendations for treatment are based mainly on symptoms, but objective assessment of symptoms remains challenging. Following conventional grading of severity, the present guidelines define severe MS as a valve area <1.0 cm² and moderate MS as a valve area of 1.0–1.5 cm² in accordance with the JCS 2020 “Guidelines on the management of valvular heart disease”.⁶² Mean PG and diastolic PHT are used only as reference because these measures are substantially dependent on transvalvular flow volume, left atrial and LV compliance, and heart rate. As MS progresses, periodic TTE follow-up is recommended every 3–5 years for mild MS, every 1–2 years for moderate MS, and every year for a valve area <1.0 cm². Generally, invasive treatment (surgery or PTMC) is indicated when a patient with a valve area ≤1.5 cm² (moderate or severe MS) has symptoms such as shortness of breath despite medical treatment.

PTMC is indicated in addition to mitral valve replacement and open mitral commissurotomy in symptomatic patients. Echocardiography is essential for selecting and decision-making for this treatment.²⁰⁷ Mitral valve leaflet mobility, mitral subvalvular apparatus, valve thickening and calcification, commissural fusion and calcification, and left atrial thrombus should be examined. Patients with rheumatic MS with severe commissural fusion and calcification should be considered candidates for mitral valve replacement because PTMC and open mitral commissurotomy are ineffective and may even cause excessive commissural splitting or leaflet tear, resulting in MR. It should be noted that in cases of unilateral severe commissural fusion or calcification, the contralateral commissure with relatively mild fusion may be excessively dehisced, resulting in MR. PTMC is also not indicated for patients with atrial thrombus, moderate to severe MR, or severe subvalvular apparatus degeneration. TEE is suitable for the detection of these conditions. Basically, patients with nonrheumatic MS are not candidates for PTMC or open mitral commissurotomy, and mitral valve replacement is difficult to perform because of the high risk of valve annular rupture. These patients are often elderly and are at high risk of cardiac surgery due to comorbidities and other factors.²¹¹ Thus, they should be assessed for frailty. In addition, the aortic valve should be assessed because aortic stenosis is a risk factor of mitral annular calcification.²¹²

3.2 Mitral Regurgitation (MR)

3.2.1 Indications

MR is often found on medical checkups as a heart murmur (blowing pansystolic murmur) and abnormal findings on ECG and chest X-rays. Patients with advanced MR are likely to have arrhythmia such as AF and show symptoms of heart failure, including shortness of breath. TTE should be performed if abnormalities in the above examinations or symptoms are observed. Prompt actions should be taken for acute MR due to chordae tendineae rupture, infective endocarditis or papillary muscle rupture because rapid pulmonary edema and often hypotension may occur. Table 28 presents the etiologies of MR.⁶² TTE is performed for all suspected patients to diagnose and assess the severity and etiology of MR. Periodic follow-up TTE is required for patients with a definitive diagnosis of MR but who are not candidates for early surgery. TTE should be repeated every 3–5 years for mild MR, 1–2 years for moderate MR, and 6 months to 1 year for severe MR. TTE evaluation at shorter intervals should be considered when subjective symptoms develop or if patients have marked left atrial and LV enlargement or reduced ejection fraction. TEE should be proactively performed when it is difficult to identify the cause and assess the severity with TTE or when a decision is made for surgical treatment. When the severity is difficult to assess by TEE, additional 3D color Doppler imaging and cardiac magnetic resonance imaging (MRI) should be considered.¹⁷⁰ Table 29 summarizes the recommendations and levels of evidence for echocardiography for MR.⁶²

Table 28. Etiologies of Mitral Regurgitation

Lesion	Etiology	Mitral leaflet	Carpentier type
LV	Tethering due to LV dilatation and/or systolic dysfunction*	Reduced mobility	IIIb
Papillary muscle	Rupture due to myocardial infarction	Prolapse	II
Chordae tendineae	Elongation or rupture due to degeneration (FED)	Prolapse	II
	Rupture due to infective endocarditis	Prolapse	II
Mitral leaflet	Myxomatous change due to Barlow’s disease	Prolapse	II
	Infective endocarditis	Perforation	I
Mitral leaflet and/or chordae tendineae	Senile or rheumatic sclerosis and/or calcification	Reduced mobility	IIIa
LA and mitral annulus	LA and mitral annular dilatation mainly due to atrial fibrillation†	Reduced coaptation (+reduced mobility‡)	I (+IIIb‡)

*^,†Etiologies of secondary (functional) mitral regurgitation. The others are etiologies of primary (degenerative) mitral regurgitation. ^‡Atriogenic tethering of the posterior mitral leaflet is also suggested as an etiology of functional mitral regurgitation occurring due to left atrial and mitral annular dilatation. FED, fibroelastic deficiency; LA, left atrium (atrial); LV, left ventricle (ventricular). (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

Table 29. Recommendations and Levels of Evidence for Echocardiography for Mitral Regurgitation

	COR	LOE
TTE is indicated for patients with suspected MR to assess the severity and mechanism of the regurgitation, the size and function of the LV and LA, the degree of pulmonary hypertension, and existence of other valvular diseases	I	B
Periodic TTE is indicated for asymptomatic patients with severe MR to determine the timing of surgery	I	B
TEE is indicated for patients with moderate or severe MR in whom TTE is suboptimal to assess the severity and mechanism of MR	I	B
2D/3D TEE is indicated for morphological assessment of the mitral valve before, during, and after surgery or catheter intervention	I	B
Exercise stress echocardiography is reasonable for asymptomatic patients with severe MR or symptomatic patients with moderate MR to reproduce symptoms and to evaluate changes in MR severity and hemodynamics	IIa	B
2D/3D TEE may be considered for patients with mitral valve prolapse who are not considered candidates for surgery or catheter intervention to identify the prolapse site	IIb	C
Repeat TEE is not recommended in situations where changes in clinical findings due to treatment or over time are not expected	IIIa (No benefit)	C

2D/3D, two-dimensional/three-dimensional; COR, class of recommendation; LA, left atrium; LOE, level of evidence; LV, left ventricle; MR, mitral regurgitation; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

3.2.2 Interpretation

The diagnosis of MR is mainly made by detecting the regurgitant jet on transthoracic color Doppler echocardiography. The diagnosis, cause, severity, and origin of the regurgitation are determined. The causes of MR can be divided into primary (organic) and secondary (functional). Primary MR is caused by organic abnormalities of the valve leaflets, chordae tendineae or papillary muscles and includes mitral valve prolapse as well as degenerative and rheumatic diseases. Secondary MR is caused by enlargement or dysfunction of the left ventricle or atrium without significant organic abnormalities in the valve leaflet or chordae tendineae. Particularly in primary MR, it is important to identify the origin of the regurgitation. 2D echocardiography combined with color Doppler imaging can help identify the origin by determining the location of proximal flow convergence and the direction of the regurgitant jet.

Severity assessment is not always easy. A comprehensive assessment is required using qualitative and semiquantitative color Doppler imaging, quantitative Doppler method, and measuring other parameters such as valve morphology and chamber size.²⁰⁹ It is also necessary to understand the pitfalls of each parameter and to individualize the assessment for each patient. It should also be noted that the severity of MR is not constant throughout systole and varies according to the hemodynamics (preload and afterload). Table 30 presents grading of severity and the pitfalls of each parameter.⁶² It is imperative to use vague grading, such as “mild to moderate” or “moderate to severe,” if an accurate assessment of severity is difficult; for example, in patients with a discrepancy in severity between parameters or those in whom the severity varies from beat to beat due to AF or other arrhythmias. In addition to the evaluation of regurgitation, left atrial and ventricular diameters and estimated pulmonary arterial pressure are important factors that contribute to the determination of surgical indication and thus require highly accurate measurements.

Table 30. Grading the Severity of Mitral Regurgitation by Echocardiography

	MR severity			Pitfalls
	Mild	Moderate	Severe
Structural
LV and LA size	Normal	–	Dilated	LV and LA size can be within the normal range for patients with acute severe MR. The grading of secondary MR cannot be estimated from LV and/or LA size
Qualitative Doppler
Color flow jet area	Small, central, narrow, often brief	–	Large central jet (>50% of LA)	Regurgitant grading tends to be underestimated from eccentric wall-impinging jet
Proximal flow convergence	Not visible, transient or small	–	Large throughout systole
Continuous wave Doppler	Faint or partial	–	Holosystolic and dense
Semiquantitative
Vena contracta width (cm)	<0.3	0.3–0.69	≥0.7	Vena contracta width measured from a single plane is not suitable for the grading of secondary MR
Pulmonary vein flow	–	–	Minimal to no systolic flow or systolic flow reversal
Transmitral flow	–	–	E wave velocity elevation (>1.2 m/s)
Quantitative
EROA derived from PISA method (cm2)	<0.20	0.20–0.39	≥0.40	PISA method is not suitable for the grading of secondary MR
Regurgitant volume (mL)	<30	30–59	≥60	Regurgitant volume may be lower in patients with low-flow conditions in secondary MR due to LV dysfunction
Regurgitant fraction (%)	<30	30–49	≥50	Doppler-derived volumetric method comparing LV inflow and outflow is not suitable for MR grading in patients with cocomitant significant aortic regurgitation

EROA, effective regurgitant orifice area; LA, left atrial; LV, left ventricular; MR, mitral regurgitation; PISA, proximal isovelocity surface area. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

3.2.3 Stress Echocardiography for MR (see also II.2 Stress Echocardiography)

Exercise stress echocardiography is mainly used to reproduce symptoms and predict prognosis.

a. Primary MR

In addition to confirming symptoms, the severity of regurgitation, the presence or absence of exercise-induced pulmonary hypertension, and left and right ventricular contractile reserve should be evaluated. The severity of regurgitation is assessed using the proximal isovelocity surface area method or the volumetric method. An increase in regurgitant volume of ≥15 mL during exercise is a predictor of cardiovascular events.⁷² In addition, exercise-induced pulmonary hypertension, an estimated pulmonary artery systolic pressure ≥60 mmHg during exercise, is a predictor of cardiovascular events.²¹²

b. Secondary MR

It is known that the severity of MR is greatly affected by hemodynamics (preload and afterload) and that exercise-induced secondary MR is associated with prognosis, acute pulmonary edema, and exercise intolerance.^66,76,77 Patients with an effective regurgitant orifice area ≥0.20 cm² during exercise or an increase of ≥0.13 cm² from rest have poor prognosis.^76–79 Exercise-induced pulmonary hypertension with an estimated pulmonary artery systolic pressure ≥60 mmHg during exercise is a predictor of cardiovascular events.⁸⁰ It has been reported that MR is aggravated not only during exercise on a supine ergometer or treadmill but also during handgrip stress.^213,214 Therefore, it is reasonable to perform handgrip stress echocardiography for assessing the severity of MR in institutions where exercise stress echocardiography is difficult to perform.

As described above, several clinical studies quantitatively evaluated exercise-induced changes in primary and secondary MR.^{66,76-80,213,214} However, quantitative assessment of MR is not easy, and its quantitation during exercise is highly challenging. For clinical decision-making, it is important to interpret the echocardiographic findings during exercise with an understanding of the limitations of quantitative evaluation.

3.2.4 Interpretation for Treatment Selection

To determine the treatment for chronic primary severe MR associated with mitral valve prolapse, in addition to symptoms, the important factors that must be considered include (1) LV internal diameter and systolic function, (2) presence of pulmonary hypertension (>50 mmHg), and (3) presence of AF.^215–222 Surgery is indicated, even if symptoms are minimal, in patients with LVEF ≤60% or LV end-systolic diameter ≥40 mm. Patients with a progressive reduction in LV systolic function who still do not meet these criteria are also potential candidates for surgery. Thus, echocardiography is required for accurate measurements of the LV diameter and EF.

Among the patients who do not meet the criteria for resting status, those with pulmonary hypertension (pulmonary arterial systolic pressure >60 mmHg) with exercise or left atrial enlargement (≥60 mL/m²) are potential candidates for early surgery.^66,223 In early surgery in asymptomatic patients with MR and preserved LV systolic function not complicated by pulmonary hypertension or AF, accurate identification of the location of prolapse by TTE and TEE is critical because the feasibility of valve repair, which depends on the shape of the prolapse, is an important determinant for surgery.^224–226 Early surgery is indicated after the “Heart Team” organized at each institution has discussed and assured that safe, reliable, and durable valve repair is feasible. Valve replacement is essentially indicated for rheumatic MR because valve repair is challenging due to organic valve changes. Accurate determination of the cause of MR by echocardiography is essential to make a proper decision for the treatment strategy. In functional ischemic MR, not associated with organic changes in the valve leaflets, regurgitation occurs due to mitral leaflet tethering by LV remodeling.^227,228 Echocardiography is very useful for evaluating the degree of tethering (measured as tenting height and area), valvular morphology, and the degree of valve annulus dilatation as well as LV function. Regurgitation often recurs after annuloplasty for functional MR, resulting in functional MS.²²⁹ In addition to annuloplasty, various interventions are performed on the papillary muscle and LV myocardium to reduce tethering by the subvalvular apparatus. However, differences in long-term outcomes between these operative procedures and valve replacement are not evident and thus the operative procedure is determined on an individual basis according to institutional capability. Percutaneous mitral valve repair (MitraClip^®) is also a therapeutic option for functional MR, and it is important to determine whether this procedure is indicated for individual patients.

In addition to functional MR due to reduced LV function, MR associated with left atrial and mitral annular dilatation in patients with AF is considered to be a new concept of functional MR (atrial functional MR),^230,231 and new insights have been gained into the efficacy of medical and ablation therapies and the surgical indications and procedures for AF. Examination of cardiac function and ventricular and valvular morphology by TTE and TEE is indispensable in the selection of treatment options for primary and secondary MR. A thorough preoperative assessment using 2D and 3D echocardiography plays a critical role.

4. Tricuspid Valve Disease

4.1 Overview and Indications

Tricuspid valve disease can be roughly divided into tricuspid regurgitation (TR) and tricuspid stenosis (TS), both of which increase right atrial pressure, leading to congestion of the right heart and right heart failure. Most cases of tricuspid valve disease encountered in daily clinical practice are TR, which is caused by incomplete leaflet coaptation from causes listed in Table 31.^12,53,62 Accordingly, blood flows backward from the right ventricle (RV) to the right atrium during systole. TR is more often seen in association with left-sided valvular heart disease than as a result of isolated abnormalities of the tricuspid valve. TS, less common than regurgitation, is a disease in which there is a pressure gradient (PG) between the right atrium and ventricle during diastole due to restricted tricuspid mobility.^12,53,62

Table 31. Etiologies of Tricuspid Regurgitation

	Disease
Primary	Infective endocarditis
	Rheumatic
	Carcinoid
	Traumatic
	Marfan syndrome
	Tricuspid prolapse
	Ebstein’s anomaly
	Iatrogenic (interference with pacemaker leads, right ventricular biopsy)
Secondary	Arrhythmogenic right ventricular cardiomyopathy
	Other cardiomyopathies
	Right ventricular infarction
	COPD, pulmonary hypertension
	Left–right shunt
	Right atrial and tricuspid annular dilatation associated with atrial fibrillation

COPD, chronic obstructive pulmonary disease. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

Echocardiography is indicated for patients with tricuspid valve disease for (1) diagnosis of regurgitation and stenosis and assessment of severity, (2) morphological evaluation (evaluation of the cause), and (3) evaluation of right heart function (RV systolic function) and right heart overload. In patients with suspected TR, transthoracic echocardiography (TTE) should be performed first for these assessments^12,53,62

4.2 Interpretation

4.2.1 Severity Assessment

The severity of TR is more often assessed qualitatively compared with regurgitation of the left atrioventricular (mitral) valve. The diagnosis of regurgitation is made by color Doppler imaging showing a jet flowing from the RV to the atrium during systole. However, the jet may not be seen in the most severe cases, in which the leaflets are detached, because the RV and atrium are at equal pressure. In patients with a markedly enlarged right atrium, the severity of regurgitation would be underestimated based on the regurgitant jet area alone. In patients with severe TR, a V-wave cutoff sign of the continuous-wave Doppler TR jet and the systolic hepatic vein flow reversal may be seen. These findings can help in assessing the severity, which should be comprehensively determined using quantitative indices such as the PISA method as needed (Table 32).^12,53,62 Many patients requiring surgical treatment for TR may be also candidates for surgery for left-sided valvular heart disease. Thus, the tricuspid annular diameter should always be measured, which is necessary to determine the indication for multivalve surgery.

Table 32. Grading the Severity of Tricuspid Regurgitation

	Mild TR	Moderate TR	Severe TR
Qualitative
Color flow regurgitant jet	1+	2+	3+
CW signal of regurgitant jet			Triangular with early peaking
Semiquantitative
Regurgitant jet area (cm2)	<5	5–10	>10
Jet area/RA area (%)			≥50
Vena contracta width (cm)	<0.3	0.3–0.69	≥0.7
PISA radius (cm)*	<0.6	0.6–0.9	>0.9
Hepatic venous flow			Systolic reverse flow
Quantitative
EROA (cm2) (PISA method)	<0.2	0.2–0.39	≥0.4
Regurgitant volume (mL)	<30	30–44	≥45

*Set the aliasing velocity to 28 cm/s. CW, continuous wave; EROA, effective regurgitant orifice area; PISA, proximal isovelocity surface area; RA, right atrium; TR, tricuspid regurgitation. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

The diagnosis of TS is made when doming and restricted opening of the tricuspid valve are present with a mean diastolic PG at the tricuspid valve of ≥2 mmHg. The mean diastolic tricuspid PG is the index of severity assessment, and treatment intervention should be considered when this index is ≥5 mmHg.^12,53,62

4.2.2 Morphological Assessment

The etiologies of TR (Table 31) can be divided into primary (organic abnormalities in the tricuspid valve) and secondary (secondary to right ventricular [RV] or atrial enlargement). Primary causes include infective endocarditis, traumatic injuries, Ebstein’s anomaly, and iatrogenic origin. Secondary causes include cardiomyopathy, RV infarction, pulmonary hypertension, and valve annular dilatation associated with atrial fibrillation. Secondary TR is much more common. Transesophageal echocardiography (TEE) is useful for morphological assessment of the tricuspid valve and may be considered when the information from TTE is insufficient. However, in TEE, the imaging angle is often larger for the tricuspid valve than for the mitral valve, and it is often difficult to evaluate using 3D TEE. The importance of TEE for the tricuspid valve is expected to increase as catheter treatment for tricuspid valve disease emerges in the future.

4.2.3 Cardiac Function/Cardiac Overload Assessment

TR is a condition that causes RV volume overload and requires evaluation of RV function. The RV surrounds the left ventricle in a crescent shape, making it difficult to evaluate its systolic and diastolic functions by visualizing the entire RV in a single view. Surgical intervention is considered in patients with TR but without severe RV dysfunction. However, there are no definitive criteria for grading the severity of RV dysfunction. Commonly used echocardiographic indices of RV systolic function include tricuspid annular plane systolic excursion (TAPSE) using the M-mode method, peak tricuspid annular systolic velocity (s’) by tissue Doppler, and RV fractional area change. More recently, the longitudinal strain of the RV free wall using speckle-tracking and RV ejection fraction, calculated using 3D echocardiography, have also been used (see III.1.4 Evaluation of Right Heart Function). On the other hand, RV afterload is reduced in TR, making it difficult to accurately assess RV function in the presence of severe regurgitation.

RV preload (right atrial pressure) is estimated from the diameter of the inferior vena cava and its respiratory variations. Because the right heart is more susceptible to deformation due to overload than the left heart, ventricular septal flattening is often observed during diastole in patients with TR with significant volume overload.

It is also important to estimate concomitant pulmonary hypertension from TR signals. Pulmonary hypertension can cause TR. The RV–right atrial systolic PG is calculated from the peak TR velocity (V) using the simplified Bernoulli formula (PG = 4 × V²) (equivalent to pulmonary artery systolic pressure in the absence of pulmonary stenosis). The RV systolic pressure can be estimated by adding the estimated right atrial pressure to the calculated PG. Of note, the simplified Bernoulli formula is invalid and should not be used to estimate the PG in cases of severe TR in the presence of leaflet malcoaptation.

4.2.4 Stress Echocardiography (see also II.2 Stress Echocardiography)

Although evidence is limited, exercise stress echocardiography may help make a decision for treatment when symptoms are not apparent despite severe TR. Table 33 presents the recommendation and levels of evidence for diagnostic testing for TR.^12,53,62

Table 33. Recommendation and Levels of Evidence for Diagnostic Testing for Tricuspid Regurgitation

	COR	LOE
TTE is indicated to evaluate the severity of TR, etiology, RV and RA, estimated PASP, and concomitant left-sided heart disease	I	C
Cardiac catheterization is reasonable for patients with TR to assess pulmonary arterial pressures, pulmonary vascular resistance and RA pressure if there is a discrepancy between clinical findings and noninvasive tests	IIa	C
TEE may be considered when TTE images are inadequate	IIb	C
CMR or 3D echocardiography may be considered to assess RV volume and systolic function	IIb	C
Exercise stress echocardiography or CPX may be considered for patients with severe TR with no or minimal symptoms to assess exercise capacity	IIb	C

CMR, cardiac magnetic resonance imaging; COR, class of recommendation; CPX, cardiopulmonary exercise testing; LOE, level of evidence; PASP, pulmonary artery systolic pressure; RA, right atrium; RV, right ventricle; TEE, transesophageal echocardiography; TR, tricuspid regurgitation; TTE, transthoracic echocardiography.

5. Prosthetic Valves

5.1 Overview

The development of prosthetic valve replacement has markedly improved the prognosis of patients with valvular heart disease. On the other hand, once patients have undergone prosthetic valve replacement, they will be at risk for prosthetic valve dysfunction throughout their lifetime. Echocardiography is a noninvasive, repeatable, and useful examination for the evaluation of prosthetic valve dysfunction. If prosthetic valve dysfunction is suspected based on clinical symptoms and physical findings, an echocardiographic examination should be performed immediately. There are various causes of prosthetic valve dysfunction: if it occurs immediately after surgery it is related to the intraoperative procedure, such as paravalvular regurgitation due to suture failure. Other causes include prosthetic valve thrombus and prosthetic valve infection, both of which may occur at any time after replacement, and restricted valve opening due to pannus and structural deterioration of the bioprosthetic valve late after surgery. The pathogenesis of valve dysfunction may partly differ between bioprosthetic and mechanical valves. When the prosthetic valve size is small compared with the patient’s body size, a condition called prosthesis–patient mismatch (PPM) occurs, which may increase the prosthetic valve pressure gradient (PG) immediately after surgery, and is associated with cardiac events.^232,233 Echocardiographers should perform the examination with an awareness of the type and size of prosthetic valve and the time of surgery and possible complications. Another important role of echocardiography is to evaluate left ventricular (LV) size and systolic function over time after prosthetic valve replacement. Clinical evidence is lacking regarding criteria for when and how often echocardiography should be performed in asymptomatic patients after prosthetic valve replacement. Based on the limited evidence and expert consensus, the indications and interpretation of echocardiography after prosthetic valve replacement are described next.

5.2 Indications for Transthoracic Echocardiography (TTE)

In patients with prosthetic valve stenosis or regurgitation, it is important to evaluate changes of stenosis and regurgitation over time to consider the need for reoperation. The changes in postoperative cardiac function are also an important predictor of the long-term patient prognosis. Medical therapy, such as renin–angiotensin system inhibitors and β-blockers, may be required in patients with reduced cardiac function after valve replacement. For this reason, it is recommended that baseline TTE should be recorded early after surgery (before discharge) for subsequent comparison. If there is any evidence of prosthetic valve dysfunction or LV dysfunction at that time, TTE should be performed repeatedly as needed. Immediate TTE is recommended when clinical symptoms or physical findings suggest prosthetic valve dysfunction during the postoperative course. In asymptomatic patients without prosthetic valve dysfunction, the timing and frequency of follow-up TTE vary, depending on the type of valve and the postoperative time.

5.2.1 Bioprosthetic Valves (Surgical Replacement)

The degradation of bioprosthetic valves, called “structural valve deterioration (SVD)”, occurs as calcified and fibrotic leaflets, leading to valve stenosis and/or regurgitation. Because stenosis and regurgitation due to bioprosthetic deterioration often progress slowly, the timing of reoperation should be determined by following up the patient over time. Although the durability of bioprosthetic valves after surgical replacement depends on the patient’s age and comorbidities, the valve position, the type of prosthetic valve, and other factors, the incidence of SVD increases gradually from 5 years after surgery, and reoperation is required 10–15 years after surgery in many cases.²³⁴ Fibrous tissue ingrowth (i.e., pannus) around the sewing cuff may restrict the opening of the prosthetic valve. Although periodic follow-up at the outpatient clinic is mandatory, annual transesophageal echocardiography (TEE) is not necessarily required for the first 5 years after surgery unless problems are found with the prosthetic valve or LV function on the immediate postoperative echocardiography. However, if clinical symptoms and auscultation findings suggest prosthetic valve dysfunction, TTE should be promptly performed. In accordance with the recommendations in the guidelines of the American Society of Echocardiography (ASE),¹³ annual TTE should be performed from 5 years after bioprosthetic valve replacement because the incidence of SVD increases from that time onwards. With bioprosthetic valves, cusp tears may occur, which can result in cusp prolapse, leading to rapid worsening of regurgitation, which requires an immediate operation. Immediate TTE and TEE should be performed in patients with suspected cusp tear to determine the timing of reoperation.

5.2.2 Bioprosthetic Valves (Transcatheter Implantation)

In recent years, echocardiography has been used increasingly to follow-up patients undergoing transcatheter aortic valve implantation (TAVI). As with the ASE guidelines,²⁰⁹ the present guidelines address this topic separately from follow-up echocardiography after surgical valve replacement. It is known that moderate or more severe paravalvular regurgitation after TAVI is associated with prognosis.²³⁵ In patients with even mild paravalvular regurgitation demonstrated immediately after TAVI, postoperative TTE should be performed with a frequency depending on the severity. Transcatheter heart valve thrombosis is reported in up to approximately 1% of patients after TAVI and occurs most frequently within the first 1 year.^236,237 It is also indicated that thrombosis-related abnormal valve opening may occur within the first few months after TAVI.²³⁸ Therefore, in addition to TTE immediately after TAVI, regular TTE is recommended at least once within the first 6 months and the annually thereafter in patients undergoing TAVI.

5.2.3 Mechanical Valves

Postoperative echocardiography is regularly performed in patients with paravalvular regurgitation demonstrated immediately after surgery. In patients without prosthetic valve dysfunction, such as paravalvular regurgitation, or PPM immediately after surgery, routine echocardiography is not necessary, whereas echocardiography is performed promptly for patients with suspected prosthetic valve dysfunction. The main causes of restricted prosthetic valve opening include valve thrombus, pannus formation, and prosthetic valve infections. Careful attention should be paid to any abnormal structures such as those around the prosthetic valve in patients with increased transvalvular PG after surgery. Meanwhile, the flow velocity may vary due to the flow pass way through which part of the mechanical valve orifice the flow passes. For example, it is known that the flow velocity through the gap between the leaflets in a mechanical bi-leaflet valve measured by continuous-wave Doppler method is faster than it actually is, and accordingly, the PG is overestimated as calculated using the simplified Bernoulli equation.¹³ Therefore, the clinical significance of the transvalvular flow velocity and the estimated PG measured by Doppler method should be determined considering the serial changes from immediately after surgery. Symptoms of restricted opening of the implanted valve caused by valve thrombus or infection tend to develop relatively rapidly, and abnormal opening angles are often seen on fluoroscopy. In contrast, because the restriction of prosthetic valve opening due to pannus occurs relatively slowly, significant abnormalities may not be observed in the opening angle on fluoroscopy. TTE may not be fully effective in evaluating the perivalvular area of the mechanical valve due to artifacts. Thus, in cases of suspected prosthetic valve dysfunction, TEE is recommended, as described next. Because echocardiographic imaging is often inadequate to assess mechanical valve mobility, it is important to perform valve fluoroscopy without hesitation if mechanical valve dysfunction is suspected. Table 34 summarizes the recommendations and levels of evidence for echocardiography for patients undergoing prosthetic valve replacement.

Table 34. Recommendations and Levels of Evidence for Transthoracic Echocardiography for Prosthetic Valve Replacement

	COR	LOE
TTE is indicated to assess prosthetic valve function in patients with suspected prosthetic valve dysfunction or infection based on clinical symptoms and physical findings	I	B
Annual TTE is indicated to assess prosthetic valve function in patients who underwent surgical bioprosthetic valve replacement at least 5 years ago	I	B
TTE is indicated to assess prosthetic valve function within the first 6 months after TAVI	I	B
Annual postoperative TTE is indicated to assess prosthetic valve function in patients undergoing TAVI	I	B
TTE is indicated to assess baseline prosthetic valve function and cardiac function early after surgery	I	C

COR, class of recommendation; LOE, level of evidence; TAVI, transcatheter aortic valve implantation; TTE, transthoracic echocardiography.

5.3 Indications for TEE (Table 35)

Table 35. Recommendations and Levels of Evidence for Transesophageal Echocardiography for Prosthetic Valve Replacement

	COR	LOE
TEE is indicated as intraoperative monitoring during prosthetic valve replacement	I	B
TEE is indicated in patients with suspected prosthetic valve dysfunction	I	B
3D TEE is reasonable in patients with suspected prosthetic valve dysfunction	IIa	C
TEE is not recommended as a routine examination in patients without clinical symptoms or TTE findings suggestive of postoperative prosthetic valve dysfunction	IIIa (No benefit)	C

COR, class of recommendation; LOE, level of evidence; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

Intraoperative TEE is a useful monitoring tool for the early detection of various complications of prosthetic valve replacement and is therefore recommended.

Postoperative TTE often cannot provide optimal images due to many artifacts caused by the bioprosthetic stent and mechanical valve leaflet. Particularly after mechanical mitral valve replacement, it is difficult to observe the left atrium, and TTE is often inadequate to assess the paravalvular regurgitation. TEE is useful for assessment of the prosthetic valve in such situations and is thus recommended in cases of suspected prosthetic valve dysfunction. 3D TEE is particularly helpful for assessing paravalvular regurgitation and valve mobility and should also be performed if possible. However, because there are areas not adequately visualized due to artifacts, even by TEE, it is important to concurrently perform TTE to evaluate the implanted prosthetic valve from different aspects. TEE is a semi-invasive examination with a risk of complications and thus is not recommended for postoperative examination in patients without either clinical symptoms or TTE findings suggestive of prosthetic valve dysfunction.

5.4 Interpretation

Paravalvular leak observed on the outer side of the prosthetic sewing cuff is an abnormal finding regardless of its severity or the type of prosthetic valve. Mild cases are kept under observation, but reoperation should be considered in cases of a severe, progressive leak that could be a possible cause of hemolysis. A leak observed inside the sewing cuff is referred to as a transvalvular leak, and differentiating it from a paravalvular leak is important. Mild transvalvular leak from the hinge of the valvular leaflet is an inherent structural problem in mechanical valves. In bioprosthetic valves, transvalvular leak increases with time due to progressive SVD. It should be determined whether or not the transvalvular leak is abnormal, taking into consideration the type of prosthetic valve and structural changes over time. Table 36 presents the grading of the severity of prosthetic valve regurgitation.⁶² Prosthetic stenosis is assessed by the transvalvular flow velocity measured by continuous-wave Doppler or the derived PG. Table 37 presents the grading of the severity of prosthetic valve stenosis.⁶² The causes of prosthetic valve dysfunction include thrombus, pannus, SVD over time, and infection. Implanted prosthetic valves are carefully examined for any abnormal or mobile structures around them that are suspected of being a cause, as well as valve leaflet mobility and the presence of paravalvular regurgitation.

Table 36. Grading the Severity of Prosthetic Valve Regurgitation

	Mild	Moderate	Severe
Aortic valve prosthesis
AR jet width	Small	Intermediate	Large (>65% of LVOT)
Pressure half-time of AR jet (ms)	>500	200–500	<200
Circumferential extent of PVL (%)	<10	10–29	≥30
Vena contracta width (cm)	<0.3	0.3–0.6	>0.6
EROA (cm2) (PISA method)	<0.10	0.1–0.29	≥0.3
RV vol (mL)	<30	30–59	≥60
Mitral valve prosthesis
Color flow MR jet	Small	Intermediate	Large
Pulmonary vein flow	Systolic dominance	Systolic blunting	Systolic flow reversal
Mitral inflow (m/s)	–	–	≥1.9
DVI (VTIprMV/VTILVOT)	<2.2	2.2–2.5	>2.5
VC width (cm)	<0.30	0.30–0.59	≥0.6
Circumferential extent of PVL (%)	<10	10–29	≥30
EROA (cm2)	<0.20	0.20–0.39	≥0.40
RV vol (mL) (volumetric or PISA method)	<30	30–59	≥60

AR, aortic regurgitation; DVI, Doppler velocity index; EROA, effective regurgitant orifice area; LVOT, left ventricular outflow tract; MR, mitral regurgitation; PISA, proximal isovelocity surface area; PVL, paravalvular leakage; RV, right ventricle; VC, vena contracta; VTI, velocity–time integral; VTIpr_MV, VTI of the transprosthetic flow at the mitral valve position. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

Table 37. Grading the Severity of Prosthetic Valve Stenosis

	Normal	Possible obstruction	Significant obstruction
Aortic valve prosthesis
Acceleration time (ms)	<80	80–99	≥100
Peak velocity (m/s)	<3.0	3.0–3.9	≥4.0
Mean PG (mmHg)	<20	20–34	≥35
Increase in mean PG during follow-up (mmHg)	<10	10–19	≥20
EOA (cm2)	>1.1	0.8–1.1	<0.8
Measured EOA vs normal reference value (cm2)	Reference±1SD	<Reference−1SD	<Reference−2SD
DVI (VTILVOT/VTIprAV)	≥0.30	0.25–0.30	<0.25
Mitral valve prosthesis
Pressure half-time (ms)	<130	130–200	>200
Peak velocity (m/s)	<1.9	1.9–2.5	>2.5
Mean gradient (mmHg)	≤5	6–10	>10
Increase in mean PG during follow-up (mmHg)	<5	5–12	>12
EOA (cm2)	>2.0	1.0–2.0	<1.0
Measured EOA vs normal reference value (cm2)	Reference±1SD	<Reference−1SD	<Reference−2SD
DVI (VTIMV/VTILVOT)	<2.2	2.2–2.5	>2.5

DVI, Doppler velocity index; EOA, effective [valve] orifice area; LVOT, left ventricular outflow tract; MV, mitral valve; PG, pressure gradient; VTI, velocity–time integral; VTIpr_AV, VTI of the transprostetic flow at the aortic valve position. (Cited from JCS/JSCS/JATS/JSVS 2020 Guidelines on the management of valvular heart disease. 2020.⁶²)

How to interpret PPM is described here. It is not related to valve failure itself but may occur when an undersized valve, compared with the patient’s body size, has been implanted. Therefore, PPM should be suspected when a relatively high transvalvular PG is recorded early after surgery. Moderate PPM is relatively common (20–70%), whereas severe PPM is rare (2–10%) and is defined as an effective orifice area (EOA) index <0.65 cm²/m² (for body mass index (BMI) <30 kg/m²) or <0.55 cm² (for BMI ≥30 kg/m²) at the aortic position and EOA index <0.90 cm²/m² (for BMI <30 kg/m²) or <0.75 cm²/m² (for BMI ≥30 kg/m²) at the mitral position.⁶²

6. Myocarditis

6.1 Indications

Myocarditis, an inflammatory condition mainly involving the myocardium, is classified into acute and chronic forms. Acute myocarditis that causes circulatory collapse in the early stage of the disease and requires mechanical support is referred to as fulminant myocarditis.²³⁹ The diagnosis of acute myocarditis requires ruling out acute myocardial infarction and pathological evidence, such as inflammatory cell infiltration in the myocardium, in an endomyocardial biopsy. To rule out other cardiac diseases, transthoracic echocardiography (TTE) is essential in patients with suspected acute myocarditis.²⁴⁰ It is difficult to predict the prognosis of the disease, including the development of fulminant disease, in the early stage of the disease.²⁴¹ Changes in left ventricular (LV) wall motion should be monitored over time.²⁴⁰ This disease requires careful follow-up even in mild cases, with TTE playing a role.²³⁹ Cardiac magnetic resonance imaging (MRI) and ⁶⁷Ga-myocardial scintigraphy are also useful diagnostic imaging modalities.²³⁹ Chronic myocarditis refers to myocarditis that persists for more than a few months²³⁹ and its echocardiographic findings are similar to those of dilated cardiomyopathy. Thus, it is difficult to differentiate chronic myocarditis and dilated cardiomyopathy by echocardiography alone. Table 38 summarizes the recommendations and levels of evidence of echocardiography for myocarditis.

Table 38. Recommendations and Levels of Evidence for Transthoracic Echocardiography for Myocarditis

	COR	LOE
TTE is reasonable for diagnosing acute myocarditis	IIa	C
TTE is reasonable for patients with acute myocarditis to diagnose fulminant disease and improvements in disease condition based on serial changes in TTE findings	IIa	C
Initial TTE is not recommended to predict fulminant disease in acute myocarditis	IIIa (No benefit)	C
TTE is not recommended for diagnosing chronic myocarditis	IIIa (No benefit)	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

6.2 Interpretation

Typical echocardiographic findings of acute and fulminant myocarditis include pericardial effusion,²⁴² inflammation-associated circumferential concentric wall thickening, and diffuse hypokinesis in the LV with no or minimal LV dilatation.²⁴³ The disease may be complicated by LV diastolic dysfunction²⁴⁴ and intracardiac thrombus.²⁴³ Patients with fulminant myocarditis often have severely impaired right ventricular function,²⁴⁵ affecting the subsequent course of treatment. In some patients with acute myocarditis that does not progress to fulminant disease, abnormalities in regional wall motion consistent with localization of inflammation are observed.²⁴⁶ Therefore, differentiating it from ischemic heart disease is required. The diagnosis of fulminant myocarditis should be made based on serial changes such as increased LV wall thickness,²⁴⁷ decrease in LV wall motion, and decreased cardiac output. Because fulminant myocarditis occasionally deteriorates rapidly,²⁴⁸ care should be taken not to miss the timing of mechanical circulatory support. When mechanical circulatory support (Impella^®; percutaneous cardiopulmonary support; intra-aortic balloon pumping) is introduced, echocardiography plays an important role not only in the serial evaluation of the disease state but also during the implantation of Impella^®.²⁴⁹ An improvement of wall motion in the left and right ventricles indicates an improvement of the disease condition.²⁴⁸ The condition should be evaluated by exercise tolerance test, Holter ECG, and echocardiography at 3–6 months after recovery from the acute phase.²⁴⁸

Patients with chronic myocarditis often have LV dilatation as well as diffuse wall hypokinesis,²⁴² with the dilated cardiomyopathy-like pattern on echocardiography.

7. Secondary Myocardial Disease

7.1 Cardiac Sarcoidosis

7.1.1 Indications

Cardiac lesions in sarcoidosis are an important factor that determines the prognosis for patients, necessitating early diagnosis. However, the diagnosis is often difficult due to the diverse pathophysiology of cardiac sarcoidosis and the lack of specific method of establishing the diagnosis other than endomyocardial biopsy findings. Even when performing endomyocardial biopsy, epithelioid cell granuloma/multinucleated giant cells without caseous necrosis, a characteristic finding in sarcoidosis, are reportedly detected at proportions <20%.²⁵⁰ In actual clinical settings, cardiac sarcoidosis is often diagnosed comprehensively on the basis of clinical findings, blood testing, and various diagnostic imaging techniques in accordance with clinical practice guidelines.²⁵¹

Echocardiography is a noninvasive examination to be performed firstly for screening of cardiac lesions in patients with systemic sarcoidosis or for screening of patients with undiagnosed cardiac sarcoidosis presenting with ECG abnormalities, ventricular arrhythmia, atrioventricular block, or other conditions.

7.1.2 Interpretation

Transthoracic echocardiography (TTE) is useful for delineating the characteristic features of cardiac sarcoidosis, including regional wall motion abnormalities not consistent with the coronary artery supply region, and wall thickening/ventricular aneurysm (often multiple), and can detect diffuse wall motion abnormalities and associated ventricular thrombus in advanced cases.²⁵² A characteristic finding in cardiac sarcoidosis is basal thinning of the ventricular septum. It is reported that noncaseating epithelioid granulomas occur anywhere in the myocardium in cardiac sarcoidosis and are distributed in a skipped and macular form, showing a wide range of shapes depending on the patient.²⁵³ Besides the base of the ventricular septum, the left ventricular (LV) basal inferior wall (posterior wall) and the apex are sites where regional wall motion abnormalities occur commonly, and thinning or aneurysm may not occur in the initial stage of the disease. Although cardiac sarcoidosis occurs also in the atrium, it is difficult to diagnose using echocardiography. Ventricular wall thinning and ventricular aneurysm in cardiac sarcoidosis are often localized and sometimes occur at multiple sites. When screening by TTE, great care should be paid not to overlook these localized lesions, not only by observation of the basic cross-sectional views but also by stereoscopic and continuous scanning on short- and long-axis sections from a parasternal approach and radial continuous scanning from an apical approach. These characteristic findings on TTE are important as a major sign for the diagnosis of cardiac sarcoidosis in the JCS 2016 “Guideline on diagnosis and treatment of cardiac sarcoidosis”.²⁵¹ In the case of isolated cardiac sarcoidosis without clinical findings of systemic sarcoidosis, the first diagnosis is often based on palpitations and arrhythmias, as well as nonspecific ECG abnormalities alone. In young patients with a chief complaint of ventricular arrhythmias or atrioventricular block, it is important to examine the presence of regional wall motion abnormalities suggestive of cardiac sarcoidosis using TTE. If a characteristic finding is obtained, together with the patient’s background and clinical findings, sarcoidosis should be strongly suspected. However, in many cases, it is difficult to diagnose cardiac sarcoidosis by echocardiographic images alone; it is desirable that other methods of noninvasive diagnostic imaging such as cardiac magnetic resonance imaging (MRI), ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET), and ⁶⁷Ga single photon emission computed tomography (SPECT) are used in combination. If any characteristic histological finding is found in the endomyocardial biopsy, the diagnosis will be established; however, because sarcoidosis lesions are distributed in a macular form, the diagnostic sensitivity of biopsy is low, and cardiac sarcoidosis cannot be ruled out even with negative pathologic findings. For details of multimodal diagnostic imaging, refer to the JCS 2016 Guideline.²⁵¹

The necessity of follow-up TTE in patients with confirmed cardiac sarcoidosis varies depending on the degree of myocardial damage, the degree of cardiac systolic and diastolic dysfunction, and the severity of associated heart failure in the individual patients, making a unified recommendation for the frequency of examination difficult. TTE for treatment effect determination and periodic follow-up monitoring after treatment is recommended as appropriate. Generally, follow-up monitoring early after the start of steroid treatment or early after electrophysiological treatment at intervals of 1 or 2–3 months should be performed as required. In the case of stable condition where the treatment strategy is unlikely to be changed because of examination results, then frequent and periodic echocardiography is not recommended; for patients in a stable condition, it is recommended that TTE may be considered at least annually. Table 39 summarizes the recommendations and evidence levels for echocardiography for cardiac sarcoidosis.

Table 39. Recommendations and Evidence Levels for Transthoracic Echocardiography in Cardiac Sarcoidosis

	COR	LOE
TTE is indicated for screening of cardiac sarcoidosis lesions for patients diagnosed as having sarcoidosis in other organs	I	B
TTE is indicated for screening of cardiac sarcoidosis lesions for patients presenting with ECG abnormalities, ventricular arrhythmia, and atrioventricular block	I	B
TTE is indicated for screening of cardiac sarcoidosis lesions for patients with suspected cardiac sarcoidosis by other diagnostic imaging	I	B
TTE is indicated for determination of treatment effect and for periodic follow-up after treatment in patients with confirmed cardiac sarcoidosis	I	C
Annual follow-up TTE may be considered if the condition is stable, and examination results (ECG, chest X rays, etc.) suggest a low likelihood of any change in the treatment strategy	IIb	C

COR, class of recommendation; ECG, electrocardiography; LOE, level of evidence; TTE, transthoracic echocardiography.

7.2 Cardiac Amyloidosis

7.2.1 Pathology

Cardiac amyloidosis is a disease characterized by a restrictive cardiomyopathy resulting from myocardial interstitial accumulation of amyloid protein that has a fibrous structure. Although >30 types of amyloid precursor protein have been identified as causing systemic amyloidosis, the amyloid protein that accumulates in the heart mainly causes immunoglobulin-free light chain-type (amyloid light chain, AL) amyloidosis and transthyretin (TTR)-type amyloidosis (ATTR).^252,253 In AL amyloidosis, the amyloid protein accumulates systemically, causing a wide variety of signs such as hepatosplenomegaly, subcutaneous nodules, and macroglossia. In ATTR amyloidosis, amyloid protein is likely to deposit on tendons and ligaments, which results in a high frequency of complications such as carpal tunnel syndrome. ATTR amyloidosis is classified into 2 types: hereditary TTR amyloidosis caused by a TTR gene mutation (ATTRv, traditionally known as familial amyloid polyneuropathy) and wild-type TTR with no TTR gene mutation (ATTRwt, traditionally known as senile systemic amyloidosis).^252,253 Although the main pathophysiology of cardiac amyloidosis is heart failure with preserved ejection fraction (HFpEF) due to amyloid protein accumulation, the heart failure is often exacerbated and intractable, and systolic heart failure occurs with the progression of disease stage. Particularly among elderly patients with HFpEF, the number of cases diagnosed as ATTRwt amyloidosis has been increasing.²⁵⁴

7.2.2 Indications and Interpretation

This disease is characterized by echocardiographic findings of diffuse myocardial hypertrophy due to amyloid protein accumulation. Amyloid protein deposits not only in the left ventricle but also in the right ventricle, atrial muscles, and valves, sometimes accompanied by valve thickening. Although a granular high-echo image in the LV myocardium (granular sparkling sign) is recognized as a characteristic finding of the disease, the sensitivity is low. Despite LV hypertrophy being detected by echocardiography, ECG findings such as a lack of LV hypertrophy or low voltage increase the suspicion of cardiac amyloidosis. In many cases, the LV is narrowed, whereas the left atrium is dilated, and atrial fibrillation sometimes occurs. Left atrial thrombus can be observed even in sinus rhythm; it is necessary to examine for the presence of thrombus, which requires transesophageal echocardiography. In distinguishing the condition from hypertension, hypertrophic cardiomyopathy, and LV hypertrophy associated with aortic stenosis, global longitudinal strain (GLS) using 2D speckle-tracking echocardiography has been reported as useful. An apical sparing pattern, preserved strain at the apex and reduction in strain at the base of LV are reportedly observed as a characteristic finding of cardiac amyroidosis.^109,255 Table 40 shows the recommendations and evidence levels for echocardiography in cardiac amyloidosis.²⁵⁶

Table 40. Recommendations and Evidence Levels for Transthoracic Echocardiography in Cardiac Amyloidosis

	COR	LOE
TTE (including M-mode echocardiography) is indicated for the assessment of LV hypertrophy, left atrial enlargement, pericardial effusion, LVEF, thickened papillary muscle, thickened RV wall, increased myocardial echogenicity, and voltage/mass ratio	I	B
TEE is indicated to detect intracardiac thrombus	I	B
Doppler echocardiography is indicated for the assessment of mitral inflow, pulmonary venous flow, and LV outflow tract flow and prognosis	I	B
Tissue Doppler echocardiography is indicated for the assessment of LV function	I	B
Speckle-tracking echocardiography is indicated for early detection of cardiac dysfunction, differentiation of cardiac amyloidosis from other causes of cardiac hypertrophy, and for prognosis	I	B

COR, class of recommendation; LOE, level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; RV, right ventricular; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

ATTR amyloidosis progresses relatively slowly, and it is recommended that follow-up by TTE should be performed every 6–12 months if the symptoms remain stable after diagnosis. After a change of medical treatment for heart failure, or if there is any change in the symptoms, TTE must be performed whenever appropriate, and LV systolic and diastolic function must be reevaluated. AL amyloidosis reportedly progresses rapidly with a poor prognosis; the 5-year survival rate without treatment is reportedly 13%. For this reason, even under treatment for the underlying disease, it is recommended that TTE follow-up should be performed every 3–6 months to monitor the pathologic condition. Table 41 shows the recommendations and evidence levels for follow-up TTE for cardiac amyloidosis.

Table 41. Recommendations and Evidence Levels for Follow-up Transthoracic Echocardiography for Cardiac Amyloidosis

	COR	LOE
TTE is indicated every 6–12 months in cases of diagnosed ATTR amyloidosis with stable symptoms	I	C
TTE is indicated every 3–6 months in cases of diagnosed AL amyloidosis with stable symptoms	I	C
TTE is indicated for the reevaluation in cases of diagnosed cardiac amyloidosis in which the symptoms have changed	I	C
TTE may be considered for screening of patients with a family history of ATTRv amyloidosis	IIb	C

AL, immunoglobulin-free light chain type; ATTR, transthyretin (TTR)-type amyloidosis; ATTRv, hereditary TTR amyroidosis; COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

7.3 Cardiac Fabry Disease

7.3.1 Pathology

Fabry disease is an X-linked hereditary metabolic disease in which sphingoglycolipid is not decomposed due to the lack of α-galactosidase activity (GLA), a lysosomal enzyme, and it accumulates in a wide variety of tissues and cells in all parts of the body, including the heart, kidneys, nerves, and skin.

7.3.2 Indications

In Fabry disease, male patients are hemizygous and begin to experience symptoms (anhidrosis, pain, angiokeratoma, hearing loss, gastrointestinal symptoms) during young childhood, complicated by renal dysfunction, heart failure, and stroke with aging. In contrast, female patients are heterozygotic carriers and only mildly affected by the disease; however, at middle and older ages, findings similar to those in male patients are manifested. In the presence of such clinical findings in the patient or his or her family, Fabry disease should be suspected, and echocardiography is required.

7.3.3 Interpretation

a. LV Hypertrophy

A characteristic finding of Fabry disease is progressive LV hypertrophy. Maximum wall thickness and the hypertrophy pattern should be evaluated by 2D TTE. The severity of hypertrophy ranges widely, from mild cases with a wall thickness ≤12 mm to severe cases with a wall thickness >20 mm. In male patients, hypertrophy often occurs in the ventricular septum or basal inferior wall (posterior wall). Female patients often show diffuse cardiac hypertrophy. It is also known that papillary muscle hypertrophy is common and that GLS in the basal posterior wall is reduced (Table 42).²⁵⁷

Table 42. Recommendations and Evidence Levels for Transthoracic Echocardiography in Patients With Cardiac Hypertrophy and Suspected Fabry Disease

	COR	LOE
TTE is indicated to accurately measure the LV maximum wall thickness	I	B
Cardiac MRI is indicated for the evaluation of cardiac hypertrophy in cases of inadequate TTE images	I	C
Annual follow-up TTE is indicated for patients with Fabry disease undergoing enzyme replacement therapy	I	C
TTE is reasonable for assessment of papillary muscle hypertrophy	IIa	B
TTE is reasonable for the assessment of wall motion in the basal posterior wall or the regional reduction in longitudinal strain	IIa	B

COR, class of recommendation; LOE, level of evidence; LV, left ventricular; MRI, magnetic resonance imaging; TTE, transthoracic echocardiography.

Of the parameters used in the Mainz severity score index (MSSI, a disease scoring system in which points are added for each of the systemic, nervous, cardiovascular, and renal systems),²⁵⁸ the degree of myocardial wall thickening is given the highest score, with 8 points added for a maximum wall thickness of 11.5–15 mm and 12 points for a greater maximum wall thickness; therefore, accurately measuring the maximum wall thickness is necessary. Cardiac MRI is recommended in cases where TTE provides inadequate images for the evaluation of maximum wall thickness (Table 42).

In addition, the LV myocardial mass is reported to decrease significantly with enzyme replacement therapy,²⁵⁹ so it is necessary to perform annual TTE to evaluate the treatment effect after enzyme replacement therapy (Table 40).

b. LV Dysfunction

Progression of LV diastolic dysfunction associated with hypertrophy is observed, and left heart failure such as left atrial dilatation and pulmonary hypertension are manifested. In addition, valve dysfunction can occur because sphingoglycolipids also deposit in the valves. The mitral valve is often affected and mitral regurgitation occurs.^260,261 As the disease progresses, LV systolic dysfunction manifests, and diffuse wall hypokinesis such as dilated cardiomyopathy occurs.

c. Differential Diagnosis

Fabry disease is the most common cause of secondary hypertrophic cardiomyopathy, with a reported incidence of 1–3% in Japanese patients with cardiac hypertrophy.²⁶² Measurement of GLA using dried blood spot method for males with hypertrophic cardiomyopathy may be considered as a screening test. In female patients, it is important that Fabry disease should be suspected based on family history and the presence of symptoms and signs specific to this disease, because identification of genetic mutation is the only available diagnostic method.

7.4 Idiopathic Restrictive Cardiomyopathy

7.4.1 Indications

In the World Health Organization’s Cardiovascular Diseases Unit & International Society and Federation of Cardiology (WHO/ISFC) report on the definition and classification of cardiomyopathy (1995), restrictive cardiomyopathy is roughly divided into idiopathic restrictive cardiomyopathy, in which belongs “cardiomyopathy,” and cardiac amyloidosis, Fabry disease, cardiac sarcoidosis, hemochromatosis, endocardial fibroelastosis, etc. are secondary cardiomyopathies.²⁶³ In the JCS/JHFS 2018 “Guideline on the diagnosis and treatment of cardiomyopathies”, it is stated that idiopathic restrictive cardiomyopathy should be diagnosed after evaluating cardiac morphological and functional abnormalities and the presence of family history of illness and genetic mutations, and ruling out secondary cardiomyopathy.²⁶⁴

The hallmark of restrictive cardiomyopathy is LV diastolic dysfunction, characterized by stiffened LV, lack of LV dilatation and hypertrophy, and relatively preserved LV systolic function.^265,266 Mildly affected patients may be asymptomatic. However, severely affected patients may have left heart failure symptoms such as exertional dyspnea and orthopnea and right heart failure symptoms such as jugular venous distention due to elevated right atrial pressure, congestive liver, ascites, and thigh edema. In addition, the disease can cause palpitations due to atrial fibrillation or supraventricular arrhythmias, as well as embolism and sudden death due to LV and atrial thrombi. On auscultation, the 4th sound is often heard, and in severely affected patients, the 3rd sound may be heard. In addition, mitral and tricuspid regurgitant murmurs may be heard. Chest X-ray shows normal findings in mildly affected cases. However, the left atrium is usually dilated, and as the disease progresses, the left atrium, right ventricle, and right atrium dilate (3-chamber enlargement). In cases of developing heart failure, pulmonary congestion and pleural effusion are observed. Although there is no specific ECG finding for the disease, abnormal findings such as P-wave abnormalities indicating left atrial overload, supraventricular premature contractions, atrial fibrillation, mild LV hypertrophy, and nonspecific ST-T changes may be observed. Table 43 presents the recommendations and evidence levels for TTE in restrictive cardiomyopathy.

Table 43. Recommendations and Evidence Levels for Transthoracic Echocardiography in Restrictive Cardiomyopathy

	COR	LOE
TTE is indicated for evaluation of LV systolic function in patients with suspected restrictive cardiomyopathy	I	B
TTE is indicated for measurement of LAVI in patients with suspected restrictive cardiomyopathy	I	B
TTE is indicated for measurement of mitral inflow velocity waveform (E-wave, A-wave, E-wave DcT) in patients with suspected restrictive cardiomyopathy	I	B
TTE is indicated for measurement of early diastolic mitral annular velocity (e’) and E/e’ in patients with suspected restrictive cardiomyopathy	I	B
TTE is reasonable for measurement of pulmonary venous flow waveform (S-wave, D-wave, and D-wave DcT) in patients with suspected restrictive cardiomyopathy	IIa	C
TTE may be considered for strain analysis by speckle-tracking in patients with suspected restrictive cardiomyopathy	IIb	C

A-wave, mitral inflow velocity during atrial contraction; COR, class of recommendation; DcT, deceleration time; D-wave, pulmonary venous flow velocity during eary diastole; E-wave, mitral inflow velocity during early diastole; LAVI, left atrial volume index; LOE, level of evidence; LV, left ventricular; S-wave, pulmonary venous flow velocity during systole; TTE, transthoracic echocardiography.

7.4.2 Interpretation (see also III.1.2 Evaluation of LV Diastolic Function)

In the LV inflow velocity pattern determined by pulsed Doppler echocardiography, increased early diastolic wave (E) flow, increased ratio of peak velocities of E to atrial contraction wave (A) (E/A >2), E-wave deceleration time (DcT) shortening (<160 ms), and isovolumic relaxation time shortening (<70 ms) are observed (restrictive pattern), reflecting LV end-diastolic pressure and left atrial pressure elevations due to LV filling abnormalities.^267,268 In the pulmonary venous flow velocity pattern determined by pulsed Doppler echocardiography, with increasing LV end-diastolic pressure and left atrial pressure, the ratio of systolic wave (S) to diastolic wave (D) decreases (S/D<1), the peak velocity of atrial flow reversal increases, and the duration is extended. If the duration of pulmonary atrial flow reversal is longer by ≥30 ms than the duration of LV inflow A, a significant elevation of LV end-diastolic pressure is suggested.

When using a tissue Doppler method, the early diastolic mitral annular velocity (e’) on the septal side decreases due to LV diastolic dysfunction in restrictive cardiomyopathy (<7 cm/s). In addition, the time difference between the onset of mitral inflow and the onset of the early diastolic mitral annulus velocity (T_E-e’) is prolonged. The ratio of the E-wave of LV inflow velocity and e’ on tissue Doppler echocardiography (E/e’) reflects the LV filling pressure, and an increase in E/e’ (average of the septal and lateral segments >14) suggests left atrial pressure elevation. Moreover, the left atrial volume index increases remarkably (>50 mL/m²).¹⁰⁸ However, although TTE has paramount utility in the diagnosis of restrictive cardiomyopathy, the final diagnosis requires a comprehensive assessment including cardiac catheter examination findings.

A pathophysiology similar to restrictive cardiomyopathy is also seen with constrictive pericarditis. Because the 2 diseases require different treatments, their distinction is clinically important.^269–271 In constrictive pericarditis, the ventricular septum shifts toward the LV side during inspiration and conversely shifts toward the right ventricular side during expiration (septal bounce); this phenomenon is referred to as interventricular dependence and is not seen in restrictive cardiomyopathy. In constrictive pericarditis, the E-wave in the LV inflow velocity increases during expiration compared with during inspiration, and the E-wave in the right ventricular inflow velocity decreases during expiration compared with during inspiration. In contrast, the respiratory variation is small in restrictive cardiomyopathy. In addition, in constrictive pericarditis, the diastolic flow velocity in the hepatic venous waveform increases during expiration, whereas it increases during inspiration in restrictive cardiomyopathy. On tissue Doppler echocardiography, e’ on the septal side remains constant or increases irrespective of the presence of LV filling pressure elevation in constrictive pericarditis (annulus paradoxus), whereas it decreases due to LV diastolic dysfunction in restrictive cardiomyopathy. In addition, the septal e’ is higher than the lateral e’ in constrictive pericarditis (annulus reversus), whereas the septal e’ is lower than the lateral e’ in restrictive cardiomyopathy.²⁷²

A study using strain analysis by speckle-tracking echocardiography has reported that the LV circumferential strain, torsion, and untwisting decrease, and longitudinal strain is relatively preserved in constrictive pericarditis, whereas the longitudinal strain decreases, and LV rotation is relatively preserved in restrictive cardiomyopathy.²⁷³ In restrictive cardiomyopathy, the GLS at the base of the LV decreases due to myocardial stiffening and fibrosis. If the disease progresses, the GLS decreases in the middle and apical segments of the LV.²⁷⁴

8. Takotsubo Syndrome

8.1 Overview

Despite the presentation being similar to that seen in acute coronary syndrome (ACS), including sudden chest pain and dyspnea, ECG changes, and left ventricular (LV) wall motion abnormalities, Takotsubo syndrome causes LV systolic dysfunction that cannot be explained by coronary artery disease.^275,276 This syndrome is relatively common among elderly women, with a male to female ratio of 1 : 9, and patients aged ≥50 years account for 90% of patients with this syndrome.^275,276 This syndrome occurs commonly after mental or physical stress, but develops in approximately 30% of patients without distinct stress. Takotsubo syndrome can occur secondarily as a complication of malignant tumors and respiratory diseases. It also occurs in a small percentage of patients developing subarachnoid hemorrhage.²⁷⁷ Although it is important to distinguish this syndrome from ACS, it has been reported that approximately 2% of patients with suspected ACS are diagnosed as this syndrome, and as high as approximately 10% of female patients with suspected ACS are diagnosed as this syndrome.²⁷⁸ ACS often occurs in the early morning, whereas Takotsubo syndrome reportedly often occurs in the daytime. There is no agreement on the seasonality of Takotsubo syndrome. ACS is sometimes complicated by Takotsubo syndrome.²⁷⁹

8.2 Indications

The significance of transthoracic echocardiography (TTE) in Takotsubo syndrome resides in distinguishing it from ACS, evaluation of wall motion abnormalities for the prediction of prognosis and complications, evaluation of the presence, severity, and mechanisms of LV outflow tract stenosis and mitral regurgitation (MR), and evaluation of the presence of intracardiac thrombus.²⁸⁰ It should be noted that cardiac rupture may occur in some patients. In addition, in many cases of Takotsubo syndrome, the wall motion abnormalities improve in several days to several months after the onset of the disease, with a relapse rate of approximately 10%. Thus, echocardiography is also the best examination to monitor the recovery process of Takotsubo syndrome.²⁸¹ Table 44 presents the recommendations and evidence levels for TTE for this disease.

Table 44. Recommendations and Evidence Levels for Transthoracic Echocardiography in Takotsubo Syndrome

	COR	LOE
TTE is indicated if Takotsubo syndrome is suspected	I	C
TTE is indicated to evaluate the pathophysiology and complications of Takotsubo syndrome over time	I	C
TTE is indicated to monitor recovery of wall motion abnormalities over time in Takotsubo syndrome	I	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

8.3 Interpretation

In typical cases of Takotsubo syndrome, akinesis in the LV apex and hyperkinesis in the basal segment of the LV are manifested. Such typical wall motion abnormalities are seen in 75–80% of patients with the disease.²⁷⁵ Although it is sometimes difficult to distinguish Takotsubo syndrome from ACS by TTE alone, the following findings help the differential diagnosis. The LV wall motion abnormalities in Takotsubo syndrome cannot be explained by coronary artery disease and occur in a left–right symmetry (as seen from the apex). However, there are some subtypes of wall motion abnormalities in Takotsubo syndrome; atypical cases include akinesis in the middle segment of the LV (14.6–18.6%), akinesis in the basal segment of the LV (the reverse pattern; 2.2%), and akinesis in only a portion of the anterior wall (1.5–6.9%).^275,280,282 In addition, about 18–34% of patients with Takotsubo syndrome have right ventricular wall motion abnormalities as a complication, and the prognosis of these patients is poor because the hemodynamics are likely to become instable.^283–285

LV outflow tract stenosis occurs as a complication in 18–25% of patients with Takotsubo syndrome.^286,287 The mechanisms of LV outflow tract stenosis comprise systolic anterior motion of the mitral valve associated with akinesis in the LV apex and hyperkinesis in the basal segment of the LV. The presence of a sigmoid septum is also likely to contribute to the LV outflow tract stenosis in some patients. Shock and heart failure due to LV outflow tract stenosis require an accurate diagnosis because the treatment strategy is completely different from that due to other causes. In addition, MR occurs as a complication in 14–25% of patients with Takotsubo syndrome^288,289 and can also cause shock and heart failure as with LV outflow tract stenosis. There are 2 patterns of MR in this disease: 1 associated with the aforementioned LV outflow tract stenosis and 1 caused by tethering of the mitral valve. Their distinction is important because different treatment strategies are required. When shock or pulseless electrical activity occurs, cardiac rupture should be considered in the differential diagnosis. The presence of pericardial effusion must be evaluated using TTE. Intracardiac thrombus occurs as a complication in 2–8% of patients with Takotsubo syndrome, which can cause systemic embolism.^290,291 The presence of intracardiac thrombus must be examined in the regions with wall motion abnormalities, particularly the apex. LV thrombus is likely to form in cases of akinesis in the LV apex, which are typical cases of this disease. Therefore, it is necessary to perform periodic TTE for evaluation.

9. Pericardial Disease

9.1 Indications

Pericardial diseases include pericarditis (acute, subacute, frequent, recurrent, chronic), pericardial effusion, cardiac tamponade, constrictive pericarditis, pericardial tumor, and pericardial defect. Of these, pericarditis, pericardial effusion, cardiac tamponade, and constrictive pericarditis are generically referred to as “pericardial syndromes”.²⁹² Transthoracic echocardiography (TTE) is the first-choice imaging examination to be performed for all patients with suspected pericardial diseases, providing a great deal of information, including myocardial lesions and cardiac hemodynamics.^292–294 On the other hand, contrast-enhanced cardiac computed tomography (CT) and cardiac magnetic resonance imaging (MRI) are suitable for evaluation of thickening and inflammation of pericardium;²⁹⁵ therefore, clinical practice using these diagnostic imaging techniques in combination should be implemented.^292,293

A diagnosis of acute pericarditis is made if 2 of 4 criteria are met: (i) characteristic chest pain suggestive of pericarditis, (ii) pericardial rub, (iii) extensive ST-elevation or P–R segment depression on ECG, and (iv) pericardial effusion.²⁹² TTE is performed within 24 h after attending hospital, and enhanced inflammatory reaction in blood laboratory tests and the findings of pericarditis on contrast-enhanced cardiac CT and cardiac MRI should be used for auxiliary diagnosis.^292,293 Cardiac MRI is reportedly useful when myocarditis is suspected as a complication of pericarditis even in the absence of cardiac dysfunction on echocardiography.^292,293 The treatment strategy is determined as follows: the patient is considered to be at high risk and must be hospitalized and needs treatment if ≥1 of the following conditions are seen: (i) fever >38℃, (ii) subacute onset, (iii) echo-free space behind the left ventricular (LV) posterior wall due to pericardial effusion is >20 mm, (iv) cardiac tamponade findings, and (v) ineffective response to anti-inflammatory therapy within 1 week. After confirming the disappearance of abnormal echocardiographic findings, exercise restriction is ceased.^292,296 On the other hand, in cases of viral or idiopathic acute pericarditis with no or little pericardial effusion and without complications, there is no need for follow-up TTE or other diagnostic imaging.²⁹⁵ Table 45 shows the recommendations and evidence levels for TTE in acute pericarditis.

Table 45. Recommendations and Evidence Levels for Transthoracic Echocardiography in Acute Pericarditis

	COR	LOE
TTE is indicated if acute pericarditis is suspected	I	C
TTE is indicated to determine treatment effect in patients hospitalized for acute pericarditis	I	C
TTE is reasonable to determine the cessation of exercise restriction in patients hospitalized for acute pericarditis	IIa	C
Periodic TTE is not recommended for patients with viral or idiopathic acute pericarditis and no or little pericardial effusion and without complications	IIIa (No benefit)	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

In the management of pericardial effusion, it is of paramount importance to assess not only the effusion volume but also the time course of the condition and the hemodynamic effect.²⁹² The causes of rapid pericardial effusion include acute pericarditis, myocardial infarction, ascending aortic dissection, trauma, open-heart surgery, and iatrogenic conditions due to catheter examination or treatment. If there is any change in the condition, such as cardiac shadow enlargement, hypotension, and chest pain, pericardial effusion should be suspected, and TTE must be performed. In the presence of cardiac tamponade, pericardial effusion due to bacterial infection, cancer, or systemic inflammatory disease is suspected. If it is necessary to evaluate the characteristics of the pericardial effusion, pericardiocentesis drainage should be performed under the guidance of TTE (and fluoroscopy).^{292,294,295,297,298} Post-drainage TTE is indispensable. In particular, TTE should be performed on continuous days just after drainage.^292,295 After discharge, periodic TTE should be performed to evaluate the risk of relapse.^292,295 For chronic idiopathic pericardial effusion, it is desirable that TTE should be performed every 6 months in cases of moderate volume of effusion and every 3–6 months in cases of a large volume of effusion;^292,294,296 in the latter cases, pericardiocentesis may be considered because cardiac tamponade can occur in 30–35% of cases.^292,297,298 Table 46 shows the recommendations and evidence levels for TTE in patients with pericardial effusion.

Table 46. Recommendations and Evidence Levels for Transthoracic Echocardiography in Patients With Pericardial Effusion

	COR	LOE
TTE is indicated to guide pericardiocentesis	I	B
TTE is indicated if pericardial effusion is suspected	I	C
TTE is indicated to determine the indications of pericardiocentesis	I	C
Follow-up TTE is indicated after drainage of pericardial effusion	I	C
Follow-up TTE is reasonable for patients with idiopathic pericardial effusion of a moderate or severe degree	IIa	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

The etiology of constrictive pericarditis is highly varied. The common causes in developed countries include idiopathic etiology, viruses, open-heart surgery, and radiotherapy. In Asian countries, tuberculosis is not a rare cause of constrictive pericarditis.²⁹² If constrictive pericarditis is suspected in right heart failure of unknown cause, TTE is mandatory. Constrictive pericarditis is diagnosed by demonstrating diastolic filling abnormalities due to pericardial restriction on imaging examinations, including TTE and cardiac catheterization. Constrictive pericarditis is generally divided into 3 forms: transient, effusive, and chronic. Each form requires a different treatment strategy. The transient form often develops after acute pericarditis and resolves with anti-inflammatory therapy within 2–3 months. Evaluation of pericardial inflammation by contrast-enhanced CT or cardiac MRI is useful in predicting the treatment effect.²⁹² Effusive constrictive pericarditis is defined as a condition observed in some patients with cardiac tamponade who are unable to obtain a 50% reduction in right atrial pressure or a right atrial pressure of <10 mmHg, even after pericardiocentesis.²⁹⁹ For this form of the disease, surgical resection of the pericardium (pericardiectomy) is the first-choice treatment. Pericardiectomy is also the first-choice treatment for chronic constrictive pericarditis. However, patients with the end stage of the disease, in whom decreased cardiac output (cardiac index <1.2 L/min/m²), hypoalbuminemia, and hepatic dysfunction are manifested, pose a high surgical risk and thus pericardiectomy is not sufficiently effective. For patients with constrictive pericarditis of any type, (transient, effusive or chronic), periodic TTE is essential over the course of treatment.²⁸⁶ Table 47 shows the recommendations and evidence levels for TTE in constrictive pericarditis.

Table 47. Recommendations and Evidence Levels for Transthoracic Echocardiography in Constrictive Pericarditis

	COR	LOE
TTE is indicated if constrictive pericarditis is suspected	I	C
Periodic TTE is indicated after drainage of pericardial effusion in patients with suspected effusive constrictive pericarditis	I	C
Periodic TTE is indicated during the treatment of constrictive pericarditis	I	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

9.2 Interpretation

If the pericardial effusion accumulates between the parietal and visceral pericardium, it appears as an echo-free space on echocardiography. The presence of pericardial effusion and its volume should be evaluated in multiple cross-sectional views. An echo-free space observed anteriorly to the descending aorta should represent pericardial effusion, whereas an echo-free space observed behind the descending aorta should be pleural effusion. Fat is relatively easy to be distinguished from pericardial effusion because the echogenicity of fat is higher than that of pericardial effusion and fat moves in concert with the myocardium during a cardiac cycle. If the volume of pericardial effusion is small, it appears below the LV posterior wall in the left lateral decubitus position. As the pericardial effusion increases, an echo-free space appears circumferentially.²⁹⁴ In addition, because the right atrium has the lowest pressure of the cardiac chambers, pericardial effusion is seen around the right atrium even in small amounts.²⁹⁴ After open-heart surgery, localized hematoma may compress a particular cardiac chamber and cause cardiac tamponade. This condition is sometimes difficult to diagnose by TTE. In such cases, transesophageal echocardiography is useful.²⁹³ Pericardial effusion is measured in the end-diastolic phase and its volume is classified into 3 grades by the width of the pericardial cavity containing pericardial effusion. When the width is <10 mm, the grade is “small”; when the width is 10–20 mm, the grade is “moderate”; when the width is >20 mm, the grade is “large”.^292,295,300 If pericardial effusion is observed only in systole, it is graded as “no significant pericardial effusion” or “very small”.²⁹³ When the amount of pericardial effusion is moderate or more, a circumferential echo-free space is seen and the heart has a pendular motion.

Key points for interpretation of echocardiography for the evaluation of cardiac tamponade include (i) stroke volume reductions and further reductions during inspiration, (ii) inferior vena cava dilatation (>21 mm) with reduced respiratory variation (<50%), (iii) LV cavity narrowing and ventricular septum shift to the LV side during inspiration, (iv) right atrial collapse in the end-diastolic phase to early systolic phase and right ventricular collapse in the early to mid-diastolic phase, and (v) respiratory variations in diastolic filling velocities in the LV (increase of ≥25–30% during expiration) and the right ventricle (an increase of ≥50–60% during inspiration).^{293,300–309} M-mode echocardiography is an excellent method for assessing the timing, duration, and respiratory variation in cardiac chamber collapse. Respiratory variation should be examined under spontaneous respiration.

In constrictive pericarditis, cardiac diastolic function is impaired by the fibrous thickening of the pericardium and pericardial adhesion. The following findings are observed on TTE: (i) dilatation of both atria and ventricular narrowing, (ii) inferior vena cava dilatation with reduced respiratory variation, (iii) a small shift of the ventricular septum toward the LV in the early diastolic phase (dip), (iv) flattening of the LV posterior wall in the diastolic phase, (v) increased early diastolic velocity (E-wave), shortening of the E-wave deceleration time, and decreased atrial contraction wave (A-wave) in the diastolic inflow velocity waveform of both ventricles (pseudonormalization), (vi) reduced LV inflow velocities (25–40%) and increased right ventricular inflow velocities (50–60%) soon after the onset of inspiration.^{292,293,305,308} Differentiation from restrictive cardiomyopathy is important. In constrictive pericarditis, the diastolic mitral annular velocity e’ at the septal site is >8 cm/s. The presence of mitral annulus reversus, a phenomenon in which the septal e’ is higher than the lateral e’, increases the likelihood of constrictive pericarditis. If the hepatic vein flow reversal ratio in diastole (diastolic reversal velocity/forward velocity) in expiration is ≥0.8, the diagnosis of constrictive pericarditis is highly likely.^108,309 It is also known that in constrictive pericarditis, strain in the LV free wall is decreased compared with that in the septal wall due to pericardial adhesion.³¹⁰

In left pericardial defects, the pericardium itself cannot be visualized by echocardiography; however, excessive motion of the LV posterior wall, paradoxical motion of the ventricular septum, and LV shape changes induced by postural change can help make the diagnosis.

10. Ischemic Heart Disease

10.1 Acute Coronary Syndrome (ACS)

10.1.1 Indications

Transthoracic echocardiography (TTE) is useful in the diagnosis of ACS because it can be performed noninvasively and quickly.³¹¹ In patients with suspected ACS, TTE can contribute to the diagnosis by detecting left ventricular (LV) wall motion abnormalities.^312,313 It is possible to estimate the responsible coronary artery and lesions from the region of wall motion abnormality in the left and right ventricles. In addition, TTE is essential to the diagnosis of mechanical complications associated with ACS, including LV wall rupture, cardiac tamponade, ventricular septal perforation, and papillary muscle rupture, as well as the diagnosis of ventricular aneurysm and thrombus in the LV.^314–323 Furthermore, it is also useful for the evaluation of LV remodeling, cardiac function, and hemodynamics after acute myocardial infarction,^{145,324–328} and is helpful in the differential diagnosis of acute chest pain such as acute aortic dissection, pulmonary thromboembolism, aortic stenosis, obstructive hypertrophic cardiomyopathy, Takotsubo syndrome, and pericarditis. In the acute stage, focused cardiac ultrasound (FoCUS) is useful for distinguishing between ACS and other fatal diseases that can cause chest pain.³²⁹ Therefore, TTE should be in routine use for patients with a complaint of chest pain, those with suspected ACS, and those with diagnosed ACS (Table 48).³¹¹

Table 48. Recommendations and Evidence Levels for Transthoracic Echocardiography in Acute Coronary Syndrome

	COR	LOE
TTE is indicated to evaluate wall motion for the diagnosis of ACS and the differential diagnosis	I	B
TTE is indicated to assess the infarction area in acute myocardial infarction	I	B
TTE is indicated to evaluate cardiac function in the acute stage of myocardial infarction	I	B
TTE is indicated to diagnose RV infarction in patients with inferior–posterior myocardial infarction	I	B
TTE is indicated to diagnose mechanical complications and LV mural thrombus in acute myocardial infarction	I	B
TTE is indicated to evaluate cardiac function and hemodynamics for the determination of treatment strategy	I	B
FoCUS is reasonable for the diagnosis of ACS and the differential diagnosis	IIa	B
TTE is reasonable to calculate the WMSI for the assessment of infarction area and the severity of wall motion abnormalities	IIa	B
TTE is reasonable to evaluate cardiac function and hemodynamics before hospital discharge for prediction of prognosis in acute myocardial infarction	IIa	B
Speckle-tracking TTE may be indicated for the diagnosis of ACS	IIb	C

ACS, acute coronary syndrome; COR, class of recommendation; FoCUS, focused cardiac ultrasound; LOE, level of evidence; LV, left ventricular; RV, right ventricular; TTE, transthoracic echocardiography; WMSI, wall motion score index.

10.1.2 Interpretation

a. Wall Motion Evaluation

If myocardial ischemia occurs due to myocardial perfusion insufficiency, LV wall motion abnormalities occur in advance of ECG changes and chest symptoms.³³⁰ Therefore, for the diagnosis of ACS by TTE, LV wall motion abnormalities are the most sensitive and important findings.^331–334 Wall motion abnormalities should be assessed visually based on a reduction or disappearance of inward motion of the endocardium and on a decrease or no change in the wall thickness.³³¹ Wall motion can be classified into normokinesis, hypokinesis, akinesis, and dyskinesis.⁶³ Regional wall motion abnormalities are evaluated using LV short-axis and long-axis cross-sections. Regional wall motion in the LV is evaluated in a total of 16 segments of the LV wall according to the coronary artery supply region: 6 segments in the base of the LV, 6 segments in the middle of the LV, and 4 segments in the apex.⁶³

In acute myocardial infarction, the degree of LV systolic dysfunction is associated with prognosis; therefore, the wall motion score index (WMSI), which quantifies the size of the infarction and the severity of the wall motion abnormalities, is useful in estimating complications and prognosis.^335–338 The WMSI is calculated as the mean of the 16 segments by scoring the wall motion in each segment in 4 grades: normal, 1; hypokinesis, 2; akinesis, 3; and systolic wall thinning or extension, 4.

Wall motion abnormalities basically occur in regions with insufficient myocardial perfusion. However, wall motion abnormalities are also observed in the ventricular wall close to the ischemic risk region, and thus it is likely that the ischemic myocardial regions and myocardial infarction area will be overestimated.^333,339,340 The presence of stunning, a phenomenon in which wall motion abnormalities are observed transiently after reperfusion therapy, can cause a discrepancy between the wall motion abnormalities observed by echocardiography in the acute stage and the myocardial infarction area seen on histological examination.^{334,341–343}

In recent years, quantitative evaluation of LV regional wall motion by speckle-tracking echocardiography has been clinically applied. Speckle-tracking echocardiography has enabled the detection of post-systolic shortening, LV contraction after the end of ejection, during acute myocardial ischemia.³⁴⁴ In addition, diastolic stunning, a phenomenon of prolonged LV relaxation due to delayed active contraction, has been proposed.³⁴⁵ These wall motion abnormalities are observed before wall motion is reduced or while reduced wall motion is not observed visually after transient ischemia. This technique can become a new diagnostic method for ACS. However, evidence for diagnostic accuracy is lacking at present.

b. Point-of-Care Ultrasonography for ACS Diagnosis

A method of ultrasonography that healthcare providers can use to make a bedside diagnosis in emergency settings is known as POCUS.³⁴⁶

TTE focusing on the differential diagnosis of ACS and other diseases presenting with chest pain, such as acute aortic dissection and pulmonary thromboembolism, is useful. FoCUS is a protocol for POCUS to evaluate cardiovascular diseases during shock or cardiopulmonary resuscitation.³⁴⁷ As a FoCUS protocol for the diagnosis of fatal diseases presenting with chest pain, EASY screening has been proposed:³²⁹ (i) pericardial effusion (E), (ii) aortic abnormality (A), (iii) ventricular size (S) and shape (S), and (iv) LV wall motion (asynergY) are evaluated (Figure 8).³²⁹

Figure 8.

FoCUS protocol as EASY screening. (1) Consider pericarditis, ventricular wall rupture due to ACS, and myocardial perforation due to devices in the differential diagnosis of diseases that cause cardiac tamponade. (2) If intimal flap, crescent aortic wall thickening, and aortic dilatation are observed in the parasternal long-axis view and from the supracostal approach, the condition is considered abnormal. ACS, acute coronary syndrome; FoCUS, focused cardiac ultrasound. (Cited from Nishigami K. 2015.³²⁹)

10.1.3 Evaluations After Acute Myocardial Infarction

a. Evaluation of Cardiac Structure and Function

i) Evaluation of LV Remodeling

Evaluation of LV volume and LV ejection fraction (LVEF) following acute myocardial infarction is useful for selecting a treatment and estimating the prognosis.^{145,324–328,348,349} These evaluations require measurements by the disc summation method.

ii) Hemodynamic Evaluation

Evaluations of LV diastolic function following acute myocardial infarction by Doppler echocardiography are useful for estimating the progression of LV remodeling and the prognosis.^{145,316–328}

b. Evaluation of Complications

After the onset of acute myocardial infarction, complications requiring urgent treatment can occur, and TTE is useful in the diagnosis of such complications.^314–323

i) LV Free Wall Rupture

LV free wall rupture can be divided into 2 types: oozing and blow-out. For the oozing type, pericardial effusion provides a clue to the diagnosis. To determine the treatment strategy, it is necessary to evaluate cardiac tamponade and the serial changes in effusion volume. Differential diagnoses of the oozing type include pericardial effusion due to pericardial disorders. Pericarditis resulting from acute myocardial infarction can occur in the acute stage. When it occurs in the subacute stage or thereafter, it is called Dressler syndrome. In addition, iatrogenic pericardial damage due to stenting and anticoagulation therapy can cause pericardial effusion.³¹⁴ The blow-out type often causes hemodynamic collapse just after the onset, leading to cardiac arrest. The presence of hematoma in the pericardial cavity provides a clue to the diagnosis. A differential diagnosis of the blow-out type free wall rupture is pericardial effusion due to aortic dissection, both of which are serious conditions.

ii) Ventricular Septal Perforation

Ventricular septal perforation is likely to occur in the apical septum in anteroseptal infarction and in the basal septum in inferoposterior infarction. A newly heard pansystolic murmur can provide a clue to the detection. On TTE, ventricular septal perforation is diagnosed by the presence of a shunt blood flow from the left ventricle to the right ventricle as detected using the color Doppler method. In addition, inferoposterior infarction is often complicated by right ventricular infarction, and right ventricular failure due to a left-to-right shunt worsens the prognosis. Therefore, evaluation of right ventricular function is important. Furthermore, perforation at the basal septum of the LV caused by inferoposterior infarction can be accompanied by complex conditions and thus extreme caution must be taken for associated complications such as myocardial dissection, intramyocardial hematoma, and ventricular pseudo-aneurysm.^315,316

iii) Papillary Muscle Rupture

Papillary muscle rupture often occurs in the posterior papillary muscle³¹⁷ and can cause acute pulmonary edema, which leads to shock. Because the papillary muscle is a subendocardial tissue, rupture can occur in non-ST-elevation acute myocardial infarction and in small infarctions.^318,319 On TTE, mitral valve prolapse and flail mitral leaflet as well as mitral regurgitation (MR) should be assessed. However, tachycardia due to shock and similar pressure in the left atrium and ventricle can make it difficult to assess mitral valve motion and MR by TTE; in such cases, transesophageal echocardiography is useful for the diagnosis.

iv) LV Thrombus

LV thrombus formed after myocardial infarction is a risk factor for embolism.^320–322 LV thrombus is often observed in apical ventricular aneurysms, and it is important to detect thrombus in patients at high risk of thrombus formation. In addition, because the risk of embolism varies according to thrombus location, shape, and mobility, it is necessary to characterize the nature of the thrombus.^338,339 However, the sensitivity of LV thrombus detection is lower with TTE than with cardiac magnetic resonance imaging (MRI); therefore, great attention should be given to ruling out the presence of thrombus.³²³

10.2 Chronic Ischemic Heart Disease

10.2.1 Indications

Resting TTE is recommended for evaluation of cardiac function as the first examination in patients with suspected chronic coronary artery disease such as prior myocardial infarction and stable angina pectoris and in those with newly developed or worsened chest pain and heart failure symptoms, or ECG changes during follow-up.^350–352 Because coronary artery disease has many complications, evaluation of the presence of systolic and diastolic dysfunction, valvular disease, myocardial or pericardial disease, and LV thrombus by TTE is useful for prognosis prediction and risk assessment.³⁵³ Table 49 presents the recommendations and evidence levels for resting TTE in patients with chronic ischemic heart disease.⁶¹

Table 49. Recommendations and Evidence Levels for Resting Transthoracic Echocardiography in Chronic Ischemic Heart Disease

	COR	LOE	GOR (MIND)	LOE (MIND)
Initial workup by echocardiography is recommended for patients suspected as coronary artery disease to detect regional wall motion abnormality, risk stratification with LVEF measurement, and evaluating LV diastolic function	I	B	B	IVa
Evaluating LV systolic/diastolic function and myocardial/pericardial abnormalities including Dopplar method is recommended in patients with coronary artery disease presenting abnormal Q waves, heart failure symptoms, complex ventricular arrhythmia or undiagnosed cardiac murmurs	I	B	B	IVa
Evaluating LVEF and regional wall motion abnormality by echocardiography are recommended for patients with new/worsened heart failure symptoms, or suspected myocardial infarction based on history or ECG during follow-up	I	C	B	IVa
Cardiac structural/functional assessment by echocardiography may be recommended for patients with hypertension or diabetes presenting abnormalities on ECG	IIb	C	C1	IVa
Echocardiography is not recommended for routine assessment of cardiac function in patients with normal ECG, no history of myocardial infarction, no symptoms suggesting heart failure, no complex ventricular arrhythmias, and no symptoms suggesting cardiac diseases	IIIa (No benefit)	C	C2	VI
Repeated evaluation of cardiac function by echocardiography is not recommended for patients without any changes in clinical status, for whom no change in therapy is planned, and with low risk for cardiovascular events	IIIa (No benefit)	C	C2	VI

COR, class of recommendation; ECG, electrocardiography; GOR, grade of recommendation; LOE, level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction. (Cited from JCS 2018 Guideline on diagnosis of chronic coronary heart diseases. 2021.⁶¹)

In coronary artery disease, abnormal findings such as regional wall motion abnormalities are not always observed on resting TTE;³⁵⁴ therefore, it is important to detect transient changes due to induced myocardial ischemia if not contraindicated. Stress TTE is used to diagnose myocardial ischemia for patients in whom the diagnosis by ECG is difficult due to resting ECG abnormalities such as left bundle branch block, ventricular pacing, Wolff-Parkinson-White syndrome, ST abnormalities, LV hypertrophy, and treatment with oral digitalis, and for those with symptoms after coronary revascularization and suspected coronary stenosis.³⁵¹ It is also useful for the assessment of myocardial viability to determine the indication of coronary revascularization,^355–357 as preoperative evaluation in major cardiovascular surgery³⁵⁸ and other major surgeries,^359,360 identification of ischemic regions in multivessel diseases,³⁶¹ and for evaluation of residual myocardial ischemia after coronary revascularization.^362,363 Selection of exercise stress (sensitivity 81%, specificity 79%) or dobutamine stress (sensitivity 81%, specificity 84%)³⁶⁴ should be determined by the patient’s acceptability of exercise stress, the presence of resting wall motion abnormalities, and the competence of the institution in performing stress echo or availability of equipment.^64,351 (For indications of stress echocardiography, see I.2 Exercise Echocardiography.)

10.2.2 Interpretation

On resting TTE, wall motion abnormalities consistent with coronary artery supply territories suggest coronary artery disease.^{352,353,365–367} In addition, reduced LVEF and increased LV volume, particularly increased end-systolic volume, are associated with the poor prognosis. LVEF is an index indispensable for the determination of treatment with an implantable defibrillator for ventricular arrhythmia.^{348,367–369} If heart failure symptoms appear, the presence and severity of systolic and diastolic LV dysfunction and MR, as well as the causes, should be evaluated to determine the treatment strategy. Even when the functional MR is mild, the prognosis can worsen; a therapeutic intervention is needed in moderate or more severely affected cases.^62,370 When a ventricular aneurysm is found, evaluation of systolic reserve in the regions other than where the aneurysm is located is important for determining whether to continue medical treatment or perform surgical treatment.³⁷¹

Stress echocardiography can evaluate the presence of myocardial ischemia by determining whether any new wall motion abnormality appears for each coronary artery supply region.³⁷² It is important to evaluate not only the inward motion of the wall but also the presence of wall thickness increase³⁷³ and a hinge point in the boundary between hyperkinetic and hypokinetic regions.

In nonischemic patients with normal LV systolic function, LV volume decreases, and wall motion become hyperkinetic during dobutamine stress, resulting in obstruction of the middle portion of the LV, which in turn can produce a pressure gradient between the apex and the base of the LV. Because the apex contraction can be delayed or decreased in such condition, even in the absence of abnormalities in the coronary artery, attention should be exercised not to misidentify such events as ischemia.³⁷⁴ An increased LV end-systolic volume under dobutamine stress is an important finding suggestive of the presence of multivessel disease or left main trunk disease.³⁷⁵ If wall motion abnormalities are observed at rest, whether they are derived from myocardial necrosis or myocardial hibernation, they can be determined by assessing the presence of a biphasic change in LV wall motion during dobutamine stress (see II.2 Stress Echocardiography).⁶⁴

Exercise stress testing is a physiological stress test and provides secondary information for the estimation of ischemia from the blood pressure and heart rate responses during stress testing. Decreased blood pressure during exercise stress is an important finding suggestive of left main trunk or multivessel disease,³⁷⁶ and decreased heart rate during exercise stress is considered a finding suggestive of lesions in the right coronary artery that perfuses the conduction system.⁶⁰ Because of its physiological nature, exercise stress testing is also useful to evaluate chronotropic incompetence, heart rate recovery, and exercise tolerance and to estimate prognosis.³⁷⁷

11. Infective Endocarditis

11.1 Overview

In infective endocarditis (IE), a vegetation containing bacteria forms on the valve leaflet, in the endocardium, and the intima of major vessels, and bacteremia, embolism, and a wide variety of clinical symptoms, including heart failure due to structural destruction of the valve leaflet, are manifested. Although this disease is likely to occur in intracardiac sites where turbulence is produced by high-velocity blood flows due to valve regurgitation or congenital cardiac disease, not a few patients do not have heart disease before having IE. In addition, the incidence of iatrogenic IE due to pacemakers, hemodialysis, and endovascular catheters has recently been increasing.^378,379 In the Duke diagnostic criteria for use in the diagnosis of IE,^380,381 positive findings on echocardiography are 1 of the 2 major criteria. Echocardiography plays a central role in the clinical practice of IE. In addition, it plays an important role not only in the diagnosis but also in the determination of treatment effect, follow-up, and prognosis evaluation. Detailed information on the roles of echocardiography in the diagnosis of IE is available in the “Guidelines for the prevention and diagnosis of infective endocarditis” by the Japanese Circulation Society.³⁷⁸

11.2 Indications

If IE is clinically suspected due to a fever of unknown cause or symptoms of embolism, transthoracic echocardiography (TTE) must be performed as early as possible (Table 50). Even when no positive findings are obtained by TTE, it is important to repeatedly perform TTE over time if IE cannot be ruled out due to positive blood culture test. TTE is a noninvasive examination that can be repeated as required, but the sensitivity for the detection of vegetation is approximately 70% for autologous valves and approximately 50% for prosthetic valves. The diagnostic performance of transesophageal echocardiography (TEE) is better than that of TTE; the sensitivity of TEE for the detection of vegetation is 90% for both autologous and prosthetic valves.^382,383 Therefore, TEE must be performed proactively in patients with clinical symptoms suggestive of IE but no vegetation found by TTE (Table 51). In particular, TEE is useful when a device infection is suspected due to the use of prosthetic valves or pacemaker, and to detect perivalvular abscess.³⁸³ In addition, even when IE is diagnosed using TTE, it is recommended that TEE should be performed to evaluate the risk of embolism or to diagnose the intracardiac comorbidity for determining indication of surgical treatment. Because TEE is a semi-invasive examination with possible complications, its indications must be determined on the basis of the risk–benefit balance.

Table 50. Recommendations and Evidence Levels for Transthoracic Echocardiography in Infective Endocarditis

	COR	LOE
TTE is indicated for all patients with suspected IE	I	B
Follow-up TTE is indicated when the onset of new complications is suspected	I	B
Follow-up TTE after 3–7 days is indicated in patients in whom IE is clinically suspected regardless of the negative result on initial echocardiography	I	C
Follow-up TTE is indicated for evaluating treatment effects	I	C
TTE is indicated at the end of treatment	I	C
TTE is reasonable for patients with staphylococcal bacteremia	IIa	B
Follow-up TTE is reasonable to evaluate the onset of asymptomatic intracardiac complications	IIa	B
TEE is reasonable for patients with positive result on TTE (except for cases of IE only in the right-sided heart valve)	IIa	C

COR, class of recommendation; IE, infectious endocarditis; LOE, level of evidence; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

Table 51. Recommendations and Evidence Levels for Transesophageal Echocardiography in Infective Endocarditis

	COR	LOE
TEE is indicated in patients in whom IE is suspected and optimal images cannot be obtained with TTE	I	B
TEE is indicated in patients in whom IE is suspected, and prosthetic valve or any cardiac device has been placed	I	B
TEE is reasonable in patients with suspected IE despite the negative result on TTE	IIa	B

COR, class of recommendation; IE, infectious endocarditis; LOE, level of evidence; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

11.3 Interpretation

Vegetation is defined as a periodically oscillating mass attached to the endocardium around the valve or intracardiac device. Vegetation size, shape, attachment site, and mobility must be examined by echocardiography. Echocardiographic findings that need to be distinguished from vegetation include thrombus, Lambl’s excrescences, prolapsed valve leaflet, myxomatous degeneration of the valves, chordal rupture, suture threads in prosthetic valves and the stent of the prosthetic valves, and cardiac tumors such as papillary fibroelastoma. It is often difficult to diagnose the condition as vegetation based on imaging findings alone; thus, the judgment should be made on a comprehensive evaluation including clinical findings such as fever and symptoms of embolism, inflammatory reactions such as elevation of C-reactive protein, and the results of blood culture. The risk of embolism can be predicted from vegetation size and appearance; for sizes >10 or 15 mm, high mobility, anterior mitral leaflet, staphylococcal or fungal origin, and increasing size during follow-up, the risk of embolism is considered high.³⁷⁸ However, risk evaluations based on echocardiographic findings alone are subject to limitations; there are some attempts to score the condition, including clinical findings.^384,385 In recent years, image quality and the temporal resolution of 3D echocardiography have been improving, making it possible to evaluate vegetation size and shape more accurately.³⁸⁶ 3D echocardiography is useful in evaluating findings other than vegetation suggestive of IE, including perivalvular abscess (including its extent), prosthetic valve tear and valve perforation.³⁸⁷ In patients with symptoms such as fever after prosthetic valve replacement, prosthetic valve IE should be suspected due to newly developed valvular regurgitation even if vegetation cannot clearly be identified.

11.4 Other Useful Diagnostic Modalities

11.4.1 Computed Tomography

On contrast-enhanced computed tomography (CT), vegetations are visualized as low-density masses attached to the valves or vessels, but small vegetations and highly mobile ones are difficult to diagnose. Prosthetic valves, calcified lesions, and perivalvular abnormalities, including abscess and mass, are difficult to evaluate by echocardiography. Thus, it is preferred to use in combination with contrast-enhanced CT to improve the diagnostic ability for these abnormalities.^388–390 CT is useful for evaluating not only cardiac lesions but also systemic embolism and is also useful for examining the presence of pulmonary embolism in right-sided IE.

11.4.2 ¹⁸F-FDG PET

¹⁸F-fluorodeoxyglucose positron emission tomography is a diagnostic technique based on the fact that glucose uptake in cells increases in malignant tumors and inflammatory disease, and its utility has been reported in cases of prosthetic valve and device infection where the condition is difficult to diagnose by echocardiography or contrast-enhanced CT.³⁹¹

11.5 Indications for Follow-up Echocardiography (see Table 50)

Follow-up TTE must be performed to evaluate the treatment effect 3–7 days after the treatment for IE has started. Because staphylococcal IE progresses rapidly, follow-up TTE should be performed earlier. If increased murmur or changes in clinical symptoms are found during follow-up, TTE should be performed as appropriate. Relapses are not rare in IE, so follow-up echocardiography after the end of treatment is also important. Valve morphology, status of residual vegetation, and degree of regurgitation should be evaluated by TTE at the end of treatment. In some cases, such as in patients with prosthetic valves, evaluation not only by TTE but also by TEE at the end of treatment should be considered. Relapses are often observed in the early stage; it is desirable that follow-up be performed within 3–6 months after the end of treatment. Thereafter, follow-up should be performed once a year for several years. During follow-up, relapse of IE, progression of valvular dysfunction, and changes in cardiac structure and function due to valvular dysfunction should be evaluated.

12. Intracardiac Masses or Cardiac Tumors

12.1 Overview

Intracardiac masses include cardiac tumors, thrombi, vegetations, congenital anomalies, and embryonic remnants. Cardiac tumors can be classified into primary cardiac tumors (benign and malignant) and metastatic cardiac tumors. Cardiac tumors are diagnosed incidentally by examination for other diseases or are manifested by a wide variety of clinical presentations including cardiac tamponade, heart failure symptoms, or sudden death. Approximately 75–85% of primary cardiac tumors are benign and include myxoma, lipoma, papillary fibroelastoma, rhabdomyoma, fibroma, angioma, and teratoma. Myxoma is the most common benign cardiac tumor, accounting for approximately 50% of adult cases of primary cardiac tumors.^392–394 Myxoma associated with Carney complex, an autosomal dominant hereditary disease complicated by skin pigmentation and peripheral endocrine neoplasia, often arises in multiple sites and also in rare sites other than the atrial septum and postoperative recurrence is common.^395,396 In 75% of cases, myxoma arises in the left atrium and often presents as a pedunculated tumor in the atrial septum, particularly in the fossa ovalis. However, it sometimes presents as a poorly mobile and nonpedunculated tumor, with 10–15% of cases found in the right atrium. Lipoma is the second most common benign cardiac tumor and is characterized by nonpedunculated polyp arising in all parts of the heart, including the endocardium (50%), epicardium (25%), and myocardium (25%). Lipoma commonly arises in the right atrium and left ventricle. When lipoma arises in the pericardium, it spreads widely. However, when lipoma arises in the myocardium, it is often encapsulated and small in size.³⁹⁷ Lipomatous hypertrophy of the atrial septum, which needs to be distinguished from lipoma, does not have a capsule, unlike lipoma. Papillary fibroelastoma is often pedunculated and mobile and arises in the valves and paravalvular endocardium in a multiple or solitary form.³⁹⁸ It is important to differentiate it from Lambl’s excrescences (a thin linear structure continuous from the cusp) and myxoma. Rhabdomyoma is the most common of cardiac tumors in infants and young children (50–60%), arises in the ventricular muscle in a multiple form, and occurs not infrequently as a complication of tuberous sclerosis (30–50% of cases of tuberous sclerosis).³⁹⁹

Primary malignant tumors account for 15–25% of cardiac tumors; most cases are sarcomas, such as angiosarcoma, rhabdomyosarcoma, and fibrosarcoma, with the exception of malignant lymphoma and pericardial mesothelioma.^392,393 Sarcomas occur with similar frequency in the left- and right-sided heart chambers. Angiosarcoma is the most common sarcoma.^400,401 Among tumors that arise in the pericardium, pericardial cyst is the most common. To distinguish it from diverticula, use of multiple modalities is necessary.⁴⁰²

Relatively common metastatic tumors include lung cancer (37%), hematological disorders such as malignant lymphoma (20%), breast cancer (7%), and esophageal cancer (6%).⁴⁰³

12.2 Indications

Conditions of suspected intracardiac masses or tumors include brain or systemic embolism, suspicion of intracardiac masses or pericardial effusion on other imaging, and detection of cardiac murmurs. First, noninvasive transthoracic echocardiography (TTE) is performed; however, TTE alone does not always provide sufficient information to rule out cardiac tumors. In cases where cardiac tumors cannot be ruled out, such as embolism of unknown cause, and in cases where cardiac tumors are suspected by TTE, transesophageal echocardiography (TEE) should be performed. TEE is useful in diagnosing tumoral lesions, particularly those in the left-sided heart chambers, such as the left atrium, mitral valve, and aortic valve. Recommendations and evidence levels for TTE (Table 52) and TEE (Table 53) in patients with suspected cardiac tumors are shown below.

Table 52. Recommendations and Evidence Levels for Transthoracic Echocardiography in Patients With Suspected Cardiac Tumors

	COR	LOE
TTE is indicated if brain or systemic embolism is observed	I	B
TTE is indicated if cardiac tumor is suspected from other examinations	I	B
Follow-up TTE is indicated for patients in whom recurrence can occur after surgery	I	B
TTE is indicated in patients in whom there are malignant tumors in other organs and cardiac involvement is suspected	I	B
TTE is reasonable in conditions that can form intracardiac masses but without clinical findings of the presence of the masses	IIa	B

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

Table 53. Recommendations and Evidence Levels for Transesophageal Echocardiography in Patients With Suspected Cardiac Tumors

	COR	LOE
TEE is indicated in patients with brain or systemic embolism and with negative result on TTE	I	B
TEE is indicated in patients with small masses that are difficult to evaluate by TTE or other examinations	I	B
TEE is indicated to determine the indications of surgery and anticoagulant therapy	I	B
TEE is reasonable in patients with suboptimal TTE images or limited echocardiographic windows	IIa	B

COR, class of recommendation; LOE, level of evidence; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

12.3 Interpretation

Conditions that should be distinguished from cardiac tumors include the following: intracardiac thrombus and vegetation (see III.11 Infective Endocarditis), structures with little pathological significance, such as Chiari network, Eustachian valve, and Thebesian valve in the right atrium, trabeculae carneae of the right ventricle (moderator band, etc.), the Coumadin ridge (the septum between the left atrial appendage and left superior pulmonary vein), embryonal remnants such as left ventricular (LV) false tendinous cord, and congenital anomalies. In addition, artifacts due to multiple reflection and mirror images are sometimes misidentified as masses. It is therefore necessary to make efforts, such as using multiple echocardiographic windows, checking for the presence of oscillations using M-mode method, to identify a cardiac tumor. Thrombus is likely to occur in sites where blood flow is congested, often accompanied by spontaneous echo contrast. Thrombus associated with mitral diseases or atrial fibrillation is commonly found in the left atrium, particularly the left appendage, whereas LV thrombus associated with ischemic heart disease or dilated cardiomyopathy is common in the apex of the LV. Although echocardiography allows evaluation of the tumor shape and attachment site, the presence of a stem, and its distribution, tissue characterization is limited to calcification and internal homogeneity. Contrast-enhanced computed tomography (CT) and cardiac magnetic resonance imaging (MRI) have excellent spatial resolution, so for tissue characterization, evaluation with such modalities in combination is useful.⁴⁰⁴ On the other hand, echocardiography has excellent temporal resolution and is suitable for the diagnosis of small mobile masses (vegetation, papillary fibroelastoma, etc.) that are difficult to detect by contrast-enhanced CT or cardiac MRI. In addition, it has the advantage that blood flow abnormalities and cardiac function can also be evaluated using a Doppler method.

It is also important to make an interpretation from the viewpoint of whether surgical treatment is indicated for intracardiac masses. Malignant tumors are indicated for surgical resection, and benign tumors posing a high risk of embolism are also indicated. Furthermore, large myxoma posing a risk of incarceration into the mitral valve is an indication of urgent surgery. In addition, large and mobile thrombus may be an indication of surgical resection because there is a high risk of embolism.

12.4 Other Useful Diagnostic Modalities

12.4.1 Computed Tomography

CT has excellent temporal and spatial resolutions, allowing for multiple cross-sectional views.⁴⁰⁵ Furthermore, because CT provides information on extracardiac organs such as the lung, mediastinum, and abdomen, it can be used to evaluate the association of cardiac tumors with the extracardiac organs and the extent of infiltration of the tumors. Tissue characterization such as fat, fluid, and calcification can be performed using CT density measurements; differentiation between benign tumors that are rich in blood vessels (myxoma and angioma) and malignant tumors is possible with contrast enhancement. In addition, preoperative evaluation of the arteries for coronary bypass surgery can be performed by ECG-gated contrast-enhanced coronary artery CT. Radiation exposure and renal toxicity due to contrast media are a drawback of CT examination.

12.4.2 Cardiac Magnetic Resonance Imaging

Although cardiac MRI is slightly inferior to CT in its spatial resolution, it is excellent for tissue characterization of soft tissue and for contrast resolution. Cardiac MRI is not subject to limited cross-sectional views, allowing evaluation of cardiac function and the tissues around the heart.⁴⁰⁶ T1- and T2-weighted MRI and gadolinium delayed enhancement allow tissue characterization. Adipose tissue shows high intensity on T1-weighted images, whereas water-rich myxoma and pericardial cyst show high intensity on T2-weighted images. Early imaging with gadolinium enhancement enables evaluation of blood flow volume in tumors and is useful in differentiating from thrombus with no blood flow.⁴⁰⁷ On delayed images with gadolinium enhancement, fibromas are enhanced homogeneously, whereas metastatic tumors and angiosarcomas are enhanced heterogeneously. Therefore, cardiac MRI is useful in differentiating between benign and malignant masses.⁴⁰⁸ In addition, a sunray pattern is a characteristic finding of angiosarcoma.⁴⁰⁹ Drawbacks of cardiac MRI include long imaging time, renal toxicity of gadolinium, limited choice of implantable cardiac devices that can be used during MRI scanning, and claustrophobia.

12.4.3 ¹⁸F-FDG PET

¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET), a method of evaluating glucose metabolism in the body, is useful in differentiating between benign and malignant tumors when used in combination with contrast-enhanced CT and cardiac MRI.⁴¹⁰ It is also useful for locating the primary lesions and in staging malignant diseases. Although ¹⁸F-FDG PET is inferior to MRI for tissue characterization, it is useful for distinguishing between recurrence of tumors and regional fibrosis, which are difficult to diagnose by delayed gadolinium enhancement MRI.⁴¹¹

13. Evaluation of Cardiac Function During Treatment With Cardiotoxic Drugs

13.1 Overview

In addition to classical antitumor drugs such as anthracyclines, cyclophosphamide, and 5-fluorouracil, other drugs have cardiac toxicities: monoclonal antibodies such as trastuzumab, bevacizumab, and nivolumab; tyrosine kinase inhibitors such as sunitinib and nilotinib; cytokines such as interferon α; antiviral drugs such as zidovudine; antidiabetic drugs such as pioglitazone, psychotropics such as tricyclic antidepressants; ergot alkaloids such as cabergoline; as well as alcohol and cocaine. In addition, β-blockers, and anti-arrhythmic drugs can adversely affect cardiac function, having cardiotoxicity in its broad sense. The pathophysiology of drug-induced cardiotoxicity includes not only heart failure due to left ventricular (LV) systolic dysfunction but also QT prolongation, arrhythmias, myocardial ischemia, pericarditis, myocarditis, hypertension, and thrombosis. Attention should be paid to the asymptomatic manifestation of myocardial damage; particularly in the early stage, LV diastolic dysfunction can occur.

13.2 Indications

Generally, in patients with a past history of cardiac dysfunction, cardiotoxicity is likely to occur; therefore, before the use of cardiotoxic drugs, echocardiography is helpful for risk stratification, and it is necessary to reconsider the use of the drugs depending on the examination results.^{110,412–414} During the use of cardiotoxic drugs, transthoracic echocardiography (TTE) is performed to diagnose cardiotoxicity in patients presenting with symptoms of heart failure. For the early diagnosis of asymptomatic cardiotoxicity, diagnostic imaging is indispensable, and TTE plays a central role. The cardiotoxicity of anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies such as trastuzumab develops irrespective of the dose. Therefore, periodic monitoring (usually every 3 months) during the drug treatment is needed. On the other hand, antitumor anthracyclines are known to exhibit cardiotoxicity in a dose-dependent manner. Because the influence is prolonged for several years to several decades after the end of treatment, TTE is also useful for the follow-up monitoring after the end of treatment.^110,414 Table 54 presents the recommendations and evidence levels for TTE during treatment with cardiotoxic drugs.

Table 54. Recommendations and Evidence Levels for Evaluation of Cardiac Function by Transthoracic Echocardiography During Treatment With Cardiotoxic Drugs

	COR	LOE
TTE is indicated to evaluate cardiac function in patients scheduled to receive cardiotoxic drugs	I	C
Periodic TTE is indicated to evaluate cardiac function in patients with no symptoms during or after treatment with cardiotoxic drugs	I	C
TTE is indicated for patients in whom heart failure symptoms are suspected or there is any change in the condition during treatment with cardiotoxic drugs	I	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

13.3 Interpretation

13.3.1 LV Systolic Function

Generally, LV systolic function is evaluated by the LV ejection fraction (EF) calculated using the biplane disc summation method. If the LVEF is lower than the normal lower limit, LV systolic function is considered to be reduced. A widely used range of normal values of LVEF calculated using the biplane disc summation method is 53–73%.⁶³ However, for the diagnosis of systolic dysfunction due to drug cardiotoxicity, the LVEF should be compared with the LVEF before drug administration.

The pathophysiology of LV systolic dysfunction due to antitumor drug cardiotoxicity is known as cancer therapeutics-related cardiac dysfunction (CTRCD), and the definition remains to be unified.⁴¹⁵ A commonly used definition for CTRCD is as: “a reduction of LVEF greater than 10% compared with baseline value and less than 53% of LVEF”.⁴⁰⁴ On the other hand, in a European Heart Journal (2016) position paper, CTRCD was defined as: “a reduction of LVEF greater than 10% compared with baseline value and less than 50% of LVEF”.¹¹⁰ However, given that 10% is equal to the measurement error of LVEF, if the patient has no symptoms, a reexamination should be performed 2 or 3 weeks after observation of the reduction in LVEF. In facilities where 3D echocardiography is available, it is recommended that the LVEF should be measured over time using this method, because it is superior to the 2D method in terms of reproducibility.⁴¹⁶

Global longitudinal strain (GLS), as obtained from 3 apical long-axis views using speckle-tracking echocardiography, is an index that reflects myocardial strain and can detect latent myocardial disorders. It has been reported that in patients receiving anthracyclines, the GLS is decreased in advance of a reduction in LVEF, and the onset of CTRCD can be predicted by a GLS reduction.⁴¹⁷ During treatment with antitumor drugs, a reduction of GLS ≥15% is considered to be a significant reduction and to indicate a high risk of the onset of CTRCD.^418,419 In facilities where GLS cannot be measured, mitral annular plane systolic excursion (MAPSE), as measured using M-mode echocardiography, and the systolic mitral annular maximum excursion velocity (s’), as measured using tissue-pulsed Doppler, can be used as surrogate indicators for GLS. However, no cutoff values have been established.

13.3.2 LV Diastolic Function

There are no established diastolic function indices to predict the onset of CTRCD. In patients scheduled to receive a cardiotoxic drug and in those receiving a cardiotoxic drug and at high risk of the CTRCD, the severity of LV diastolic dysfunction and the presence of left atrial pressure elevation are evaluated over time for the diagnosis of heart failure.⁴²⁰ Table 55 shows the recommendations and evidence levels for cardiac functional indices to be measured by TTE during treatment with cardiotoxic drugs.

Table 55. Recommendations and Evidence Levels for Cardiac Functional Indices Measured by Transthoracic Echocardiography During Treatment With Cardiotoxic Drugs

	COR	LOE
TTE is indicated to measure the LVEF	I	C
Speckle-tracking TTE is reasonable to evaluate the LV long-axis systolic function using GLS	IIa	C
TTE may be indicated for the evaluation of LV diastolic function and LV filling pressure	IIb	C

COR, class of recommendation; GLS, global longitudinal strain; LOE, level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; TTE, transthoracic echocardiography.

14. Congenital Heart Disease

14.1 Evaluation of Shunt Disease

14.1.1 Indications

Echocardiography is indicated in cases where shunt heart disease is suspected. Contrast echocardiography with agitated saline is useful in detecting right-to-left shunts.

14.1.2 Interpretation

The shunt site, the direction and volume of shunt flow, the cardiac cavity size, and the presence of pulmonary hypertension must be evaluated. Table 56 presents the methods of echocardiographic evaluation according to the shunt sites. The pulmonary-to-systemic flow ratio (Qp/Qs) is estimated from the flow volume calculated from the product of the outflow tract cross-sectional area and the flow velocity–time integral.⁴²¹ Flow volume estimations by 2D transthoracic echocardiography (TTE) are performed, assuming that the outflow tract cross-sectional area is circular and the blood flow is laminar. If these assumptions are not applicable, a measurement error is introduced. Thus, the Qp/Qs estimated by echocardiography is an index to be used for reference purposes only in treatment decision making. If the presence of shunt has been confirmed, and there is cardiac chamber dilatation due to volume overload, the shunt should be considered significant. In the detection of right-to-left shunts via a patent foramen ovale or arteriovenous fistula and the differential diagnosis of persistent left superior vena cava or partial anomalous pulmonary venous drainage, contrast echocardiography with agitated blood and saline is useful.^422–424 In particular, for inter-atrial shunts, a contrast method by transesophageal echocardiography (TEE) is useful in the semiquantitative evaluation of the shunt volume and the morphological diagnosis of the shunt.⁴²⁵

Table 56. Evaluation of Shunt Sites by Echocardiography

	ASD	VSD	PDA
Echo window for visualization of shunt site	Parasternal 4-chamber view Parasternal short-axis view Subcostal view Right lateral decubitus right parasternal view	Parasternal short-axis view Apical 4-chamber view Apical five-chamber view	High parasternal long-axis view (ductal view) Parasternal short-axis view Suprasternal notch short-axis view
Shunt phase	Entire cardiac phase	Entire systolic phase	Entire cardiac phase
Qp measurement site	RV outflow tract	RV outflow tract	LV outflow tract
Qs measurement site	LV outflow tract	LV outflow tract	RV outflow tract
Volume overload chambers	Right atrium, right ventricle	Left atrium, left ventricle	Left atrium, left ventricle
Comorbidities evaluated in echocardiography	MR TR Partial anomalous pulmonary venous drainage Pulmonary hypertension	Aortic right-coronary cusp prolapse AR Double-chambered right ventricle Pulmonary hypertension	Left heart failure Pulmonary hypertension

AR, aortic regurgitation; ASD, atrial septal defect; LV, left ventricular; MR, mitral regurgitation; PDA, patent ductus arteriosus; Qs, systemic blood flow; Qp, pulmonary blood flow; RV, right ventricular; TR, tricuspid regurgitation; VSD, ventricular septal defect.

14.2 Unoperated Congenital Heart Disease in Adults

The present guidelines focus on unoperated congenital heart diseases that may be diagnosed in adulthood, including corrected transposition of the great arteries, Ebstein’s disease, patent ductus arteriosus (PDA), and atrial septal defect (ASD).

14.2.1 Corrected Transposition of the Great Arteries

a. Indications

TTE is indicated if corrected transposition of the great arteries is suspected from atrioventricular block on ECG or dextrocardia or mesocardia on chest radiography. It is also indicated if there is any change in a patient’s condition such as a newly heard murmur and the development of heart failure symptoms after diagnosis. In patients with an established diagnosis of the disease, periodic TTE is indicated even in the absence of changes in condition; once every 2 years for the simple type and once a year for the complex type.

b. Interpretation

At first visit, this condition is diagnosed based on atrioventricular discordance and ventriculoarterial discordance using a segmental diagnosis.⁴²⁶ The prognosis of the complex type, which with ventricular septal defect (VSD) and pulmonary valve stenosis is poor compared with the simple type.⁴²⁷ Thus, it is necessary to differentiate these 2 types using echocardiography. Because the morphologic right ventricle (RV) supports the systemic circulation in this condition, attention must be paid to the development of RV dilatation and dysfunction and the progression of tricuspid regurgitation (TR) with aging. As an etiology of TR, organic abnormalities like Ebstein’s disease may be found in addition to functional abnormalities. Because echocardiography is limited on quantitation of RV volume and function in this condition, further evaluation by other imaging modalities such as cardiac magnetic resonance imaging (MRI) should be considered. Concomitant pulmonary valve stenosis has protective against systemic (tricuspid) atrioventricular valve regurgitation through ventricular septal flattening due to pressure overload on the sub-pulmonary left ventricle.⁴²⁸ Therefore, interventricular interactions such as deviation of the ventricular septum are important findings and should be evaluated. Because pacemaker rhythm in cases of atrioventricular block exaggerates systemic RV dysfunction due to cardiac dyssynchrony, evaluation of RV function is important in the choice of pacemaker device or cardiac reharmonaization therapy.⁴²⁸

14.2.2 Ebstein’s Disease

a. Indications

TTE is performed if TR is suspected from clinical findings such as leg edema, hepatomegaly, and ascites, due to venous congestion and right cardiac dilatation on chest radiography or signs of right cardiac overload on ECG.

b. Interpretation

For the diagnosis of Ebstein’s disease, it is necessary to assess not only tricuspid valve displacement in the apical 4-chamber view but also to confirm apical displacement of the posterior leaflet in the RV inflow view. Ebstein’s disease is a congenital anomaly of the RV as well as the tricuspid valve, and TTE findings should be interpreted with a focus on progressive RV dilatation and dysfunction. Ebstein’s disease is characterized by increased long-axis tricuspid annular motion compared with the RV ejection fraction. Thus, caution should be exerted in evaluating RV systolic function by tricuspid annular plane systolic excursion (TAPSE).⁴²⁹ It is recommended that the tricuspid leaflet and the RV wall characteristic should be evaluated to determine the indication of tricuspid valve repair (Cone procedure) in high-volume facilities.⁴³⁰

14.2.3 Patent Ductus Arteriosus

a. Indications

TTE is indicated in cases where PDA is suspected from increased pulse pressure, continuous murmurs, or left ventricular volume overload.

b. Interpretation

In PDA patients with continuous murmurs, irrespective of subjective symptoms, shunt volume, and Qp/Qs, the development of infective endocarditis and aneurysm formation of the ductus due to calcification with aging are of clinical concern and it is necessary to consider closure intervention; therefore, it is important to diagnose the presence of PDA by TTE. Patients with Eisenmenger syndrome where a reverse shunt is present show cyanosis in the lower part of the body. It is important to evaluate the presence of pulmonary hypertension and the flow rate of the PDA and the direction of the flow. In recent years, the indications of percutaneous treatment with closure devices for PDA have been expanded. Although the treatment is chosen on the basis of the morphology of the ductus, TTE has a limited role in the evaluation, and contrast-enhanced computed tomography (CT) is recommended.

14.2.4 Atrial Septal Defect

a. Indications

TTE is indicated if ASD is suspected from incomplete right bundle branch block, right-axis deviation, and RV hypertrophy on ECG; pulmonary arterial dilatation, RV dilatation, and increased pulmonary vascularity on chest radiography, as the differential diagnosis of pulmonary hypertension. TEE is indicated for the diagnosis of small defects and sinus venosus defects, which are difficult to be detected by TTE. It is also used for the indication judgement of transcatheter treatment of ASD and for intraoperative monitoring during transcatheter treatment. Periodic (once a year or so) TTE is indicated in patients undergoing closure surgery in adulthood and complicated with pulmonary hypertension, atrial arrhythmias, cardiac dysfunction, or atrioventricular valve regurgitation. TTE is also indicated for periodic follow-up monitoring after closure device treatment and for emergency evaluation of cardiac erosion and device migration, which can occur as rare complications of closure device treatment.⁴³¹

b. Interpretation

It is difficult to exclude ASD by TTE. TEE and other methods of diagnostic imaging should be used when the sinus venosus defect is suspected. In cases complicated with severe pulmonary hypertension, indications of defect closure surgery should be determined carefully. Therefore, RV pressure should be evaluated based on the maximum velocity of TR and ventricular septal flattening during systole. It should be noted that the maximum velocity of TR does not reflect the pulmonary arterial pressure when there are stenotic lesions in the RV outflow tract or the pulmonary artery. Qp/Qs ≥1.5 is an indicator of a significant left-to-right shunt in the ASD. However, because of measurement errors, the Qp/Qs estimated by echocardiography should be used only for reference purposes to determine treatment strategy. The examination should be performed while paying attention to comorbidities, including mitral regurgitation due to mitral valve prolapse and mitral valve cleft (common in ostium primum type) and pulmonary valve stenosis. It is difficult to exclude partial anomalous pulmonary venous drainage, which is a common complication of sinus venosus ASD, by echocardiography. Thus, it should be evaluated using other methods of diagnostic imaging. If cardiac erosion is suspected after closure device placement, pericardial effusion should be evaluated by echocardiography.

15. Ultrasound Diagnosis of Vascular Diseases

15.1 Aortic Lesions

15.1.1 Aortic Atheroma

Aortic atheroma detected by echocardiography has been reportedly associated with cerebral⁴³² and peripheral embolism.⁴³³ Furthermore, thoracic aortic atheroma is a strong predictor of coronary artery disease⁴³⁴ and has also been reported to be a predictor of increased mortality. Atherosclerotic lesions in the aorta are associated with cholesterol embolism, stroke following coronary bypass surgery, and embolism associated with cardiac catheterization or aortic balloon pumping.⁴³⁵ An aortic atheroma ≥2 mm is generally considered significant (Table 57).⁴³⁶ Furthermore, the severity of aortic atheroma is defined according to the size, morphological irregularity, presence of ulcerative lesions, and the presence of mobile lesions.⁴³⁶ Although aortic atheroma is evaluated by transesophageal echocardiography (TEE), the portions of the aorta visualized by transthoracic echocardiography (TTE) can also be evaluated. Echocardiography is not usually performed for evaluation of aortic atheroma. However, when performing TEE for valvular and other cardiac diseases, it is recommended that evaluation of aortic atheroma should be performed. In addition, it is not useless to perform rapid screening for aortic atheroma by TTE (Table 58).

Table 57. Grading System for Severity of Aortic Atherosclerosis

Grade	Severity (atheroma thickness)	Description
1	Normal	Intimal thickness <2 mm
2	Mild	Mild (focal or diffuse) intimal thickening of 2–3 mm
3	Moderate	Atheroma >3–5 mm (no mobile/ulcerated components)
4	Severe	Atheroma >5 mm (no mobile/ulcerated components)
5	Complex	Grade 2, 3, or 4 atheroma plus mobile or ulcerated components

(Cited from Goldstein SA, et al. 2015.⁴³⁶)

Table 58. Recommendations and Evidence Levels for Evaluation of Aortic Atheroma in Atherosclerotic Patients During Echocardiography

	COR	LOE
Evaluation of aortic atheroma is recommended during TEE	I	B
Evaluation of aortic atheroma may be considered during TTE	IIb	C

COR, class of recommendation; LOE, level of evidence; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

15.1.2 Aortic Aneurysm

Because some portions of the ascending aorta can be visualized using a supracostal approach in TTE, ascending aortic dilatation or ascending aortic aneurysm is often found by echocardiography. In patients with bicuspid aortic valve or Marfan syndrome, it is desirable that the aortic root and the ascending aorta should be examined during TTE (Table 59).^437,438 Although the aortic arch and the descending aorta can be visualized using a precordial or supraclavicular approach, detailed evaluation is difficult. TTE or abdominal echography can detect abdominal aneurysm and is useful for screening.^439–441 Table 60 shows the recommendations and evidence levels for echocardiographic screening for abdominal aneurysm. For follow-up monitoring and determination of treatment strategy, computed tomography (CT) is better because the diameter of the aneurysm can be measured accurately.

Table 59. Recommendations and Evidence Levels for Transthoracic Echocardiography to Evaluate Aortic Root and Ascending Aorta in Bicuspid Aortic Valve or Marfan Syndrome

	COR	LOE
Evaluation of the aorta is recommended at the time of first TTE	I	C
Annual evaluation of the aorta is recommended in patients with aortic dilatation on TTE	I	C

COR, class of recommendation; LOE, level of evidence; TTE, transthoracic echocardiography.

Table 60. Recommendations and Evidence Levels for Echocardiographic Screening for Abdominal Aneurysm

	COR	LOE
Echo screening is indicated for men aged ≥65 years	I	A
Echo screening is reasonable for the 1st-degree relatives of patients with abdominal aneurysm	IIa	B
Echo screening may be considered for women aged ≥65 years with a history of smoking	IIb	C
Echo screening is not recommended for women with no history of smoking or family history of illness	IIIa (No benefit)	C

COR, class of recommendation; LOE, level of evidence.

15.1.3 Acute Aortic Dissection

a. Pathology and Indications

Acute aortic dissection is a fatal disease that presents with the chief complaint of chest or back pain and should always be taken into account in the differential diagnosis of chest pain. One-quarter of untreated patients may die within 24 h after the onset of the disease.⁴⁴² Thus, accurate and early diagnosis is necessary (Table 61). Pathologically, it is characterized by 2 lumens in the aorta resulting from the dissected medial layer of the aortic wall. Although 70–80% of the patients present with the chief complaint of chest or back pain, some present with syncope due to cerebrovascular disorder or heart failure symptoms due to aortic regurgitation (AR).

Table 61. Recommendations and Evidence Levels for Echocardiography for Acute Aortic Dissection

	COR	LOE
TTE, D-dimer, and aortic dissection risk score should be used to diagnose acute aortic dissection in the emergency room	I	B
TTE is indicated to diagnose complications in type A dissection	I	B
TEE is reasonable if contrast-enhanced CT or cardiac MRI cannot be performed	IIa	B
TTE is not recommended for a definitive diagnosis	IIIa (No benefit)	C

COR, class of recommendation; CT, computed tomography; LOE, level of evidence; MRI, magnetic resonance imaging; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

The diagnosis of acute aortic dissection has 2 components: (i) diagnosis of the presence and location of dissection and (ii) diagnosis of the presence of complications. There are 2 classification systems for acute aortic disease based on the location of dissection: the DeBakey classification and the Stanford classification. The Stanford classification system, which classifies cases according to the location of dissection (whether in the ascending aorta or not), is commonly used for the determination of treatment strategy. In the Stanford classification system, cases are divided into 2 types: Stanford-A type, where the dissection affects the ascending aorta, and Stanford-B type, where the dissection does not affect the ascending aorta. Generally, in type A cases, emergency surgery (mainly graft replacement of the ascending aorta) is performed, whereas in type B cases, medical treatment (mainly blood pressure reduction) is performed, except in those with complications. Complications associated with aortic dissection include (i) cardiac tamponade, (ii) intrathoracic rupture, (iii) AR, (iv) cerebral blood flow disorders, (v) coronary circulation disorders, and (vi) renal and abdominal organ ischemia. It is essential to accurately diagnose the presence of dissection and its location, as well as the presence of complications to determine the treatment strategy.^443–445

b. Interpretation

i) Existence Diagnosis

CT scanning (plain and contrast-enhanced CT scanning) provides excellent sensitivity and specificity for the diagnosis of acute aortic dissection and thus is to be performed first. In Europe and the USA, a diagnostic algorithm used in the emergency room, including TTE, D-dimer, and the aortic dissection detection risk score (ADD-RS) (Table 62),⁴⁴⁶ has been proposed (Figure 9).⁴⁴⁷ Direct signs on TTE suggestive of aortic dissection include aortic flap, circular or crescent aortic wall thickening exceeding 5 mm, and caldera-like ulcerative lesions in the aortic wall, and indirect signs include thoracic aortic dilatation ≥4 cm, pericardial effusion, cardiac tamponade, and AR as detected by color Doppler method (Table 63). A rapid assessment of the aorta by focused cardiac ultrasound (FoCUS) is useful for the diagnosis of acute aortic dissection. The diagnostic sensitivity and specificity of direct signs of acute aortic dissection by FoCUS are reportedly 45.2% and 97.4%, respectively. When including indirect signs, the diagnostic sensitivity and specificity are reportedly 89% and 74.5%, respectively. If FoCUS is considered negative and the ADD-RS is ≤1, the negative predictive value is reportedly 93.8%, and when used in combination with D-dimer test, the negative predictive value is reportedly 100%.

Table 62. Acute Dissection Detection Risk Score (ADD-RS)

If any condition is met within any of the following 3 categories, a score of 1 point is given, and the rating is made at 4 levels of 0–3 points.
History of illness	Marfan syndrome, family history of aortic disease, known aortic valve disease, known thoracic aortic aneurysm, post-aortic surgery condition
Symptoms	Abrupt onset, severe pain, ripping or tearing pain
Physical findings	Perfusion deficit (pulse deficit, systolic blood pressure differential, focal neurological deficit), diastolic regurgitant murmur, hypotension/shock

ADD-RS, aortic dissection detection risk score.

Figure 9.

Diagnostic algorithm used in the emergency room combines transthoracic echocardiography, D-dimer, and acute aortic dissection risk factors. ADD-RS, aortic dissection detection risk score; CT, computed tomography; FoCUS, transthoracic focused cardiac ultrasound; MRI, magnetic resonance imaging; TEE, transesophageal ehocardiography. (Cited from Nazerian P, et al. 2019.⁴⁴⁷)

Table 63. Transthoracic FoCUS for Aortic Dissection

Direct signs	Aortic flap, circular or crescent wall thickening exceeding 5 mm, caldera-like ulcerative lesions in aortic wall
Indirect signs	Thoracic aortic dilatation ≥4 cm, pericardial effusion or cardiac tamponade, aortic regurgitation as detected by color Doppler method

FoCUS, transthoracic focused cardiac ultrasound.

A key point for the existence diagnosis of aortic dissection by TTE in echocardiography laboratories is finding a mobile flap dividing a true and a false lumen. It should be noted that artifacts due to mirror images and multiple reflection are often observed as a flap. The differentiation between a true flap and artifacts is possible because a true flap is observed from multiple windows and moves differently from surrounding structures. Evaluation of the blood flow in the true and false lumens using the color Doppler method is also useful in the differential diagnosis. In the case of type A dissection, the existence of dissection can be diagnosed by examining the ascending aorta just above the aortic valve (Figure 10). If present in the descending aorta, the dissection can be visualized using a suprasternal approach (Figure 11). In addition, visualization of the abdominal aorta using a TTE probe is also useful. The abdominal aorta is relatively easy to visualize; if a flap is present in the abdominal aorta, the condition can be diagnosed as abdominal aortic dissection. In such cases, it is likely that dissection is also present in the thoracic aorta, and confirmation by contrast-enhanced CT is needed (Figure 12).

Figure 10.

Transthoracic echocardiograms of a patient with Stanford type A acute aortic dissection. (Left) Parasternal long-axis view. A mobile flap (white arrow) is seen just above the aortic valve in the ascending aorta. (Right) Parasternal short-axis view. A mobile flap (white arrow) is seen in the ascending aorta.

Figure 11.

Transthoracic echocardiograms of a patient with Stanford type B acute aortic dissection. (Left) A flap (white arrows) is seen in the distal arch to the descending aorta from a suprasternal approach. (Right) A flap (yellow arrows) is seen in the distal arch to the descending aorta from a precordial approach. In this case, observation was possible from the right precordial approach (refer to the upper left scheme) due to the right aortic arch; however, in patients with a normal arch, a suprasternal approach should be used for visualization.

Figure 12.

Transthoracic echocardiograms of a patient with dissection in the abdominal aorta. A flap (white arrow) is seen in the abdominal aorta. This case was diagnosed as aortic dissection. (Left) Long-axis view of the abdominal aorta. (Right) Short-axis view of the abdominal aorta.

ii) Diagnosis of Complications

The mortality rate following the onset of acute aortic dissection is reported to be 1–2%/hour,⁴⁴⁸ and the main causes of deaths are complications of this serious disease. Of the aforementioned complications, cardiac tamponade, AR, and myocardial ischemia need to be diagnosed by TTE. In a case of type A dissection, urgent surgery (mainly graft replacement of the ascending aorta) is often required, and in patients with such complications, surgery should be performed much earlier. Patients complicated with cardiac tamponade or myocardial ischemia are likely to develop shock, leading to cardiac arrest. In such cases, urgent surgery should be performed to save their lives. In addition, in patients complicated with AR it is necessary to examine in detail the aortic valve by TTE for the determination of surgical procedures such as valve replacement or valve repair.

ii)-1 Cardiac Tamponade

Cardiac tamponade is the most common cause of death from acute aortic dissection and is reportedly the cause of death in 70% of autopsy cases of acute aortic dissection. It is caused by intrapericardial rupture or bloody exudate due to impending rupture of the dissected aorta. Cardiac tamponade can occur even with a small volume of pericardial effusion and is often associated with hematoma (Figure 13). In addition, the condition is likely to change over time. Thus, if there is any change in the vital signs, pericardial effusion should be re-examined using TTE. While waiting for surgery in the emergency room, intrapericardial rupture can occur, resulting in cardiac arrest. Conventionally, intrapericardial drainage has not been recommended because it is accompanied by a sudden blood pressure elevation, thereby increasing the risk of re-rupture; however, the risk of re-rupture could be reduced by adjusting drainage volume under monitoring blood pressure.⁴⁴⁹

Figure 13.

Transthoracic echocardiogram of cardiac tamponade as a complication of Stanford type A acute aortic dissection (4-chamber view). This is a case of noncommunicating aortic dissection complicated with cardiac tamponade, showing a mobile fibrin mass (white arrows) and pericardial effusion (yellow asterisk). A hematoma (red asterisk) is seen on the entire surface of the right ventricle. The right ventricle is compressed.

ii)-2 AR

The incidence of AR in patients with Stanford type A acute aortic dissection is 60–70% and about half of the patients complicated with AR need surgical valve treatment.⁴⁵⁰ To determine the indication of surgical treatment, it is important to evaluate the mechanism of the regurgitation. Proposed mechanisms include (i) incomplete leaflet closure due to dilatation of the sinotubular junction (Figures 14,15), (ii) aortic leaflet prolapse due to extension of the dissection into the aortic annulus, and (iii) incomplete leaflet closure due to prolapse of the dissecting flap into the aortic leaflets (Figure 16).⁴⁵¹ It should be noted that aortic valve prolapse due to aortic dissection occurs commonly in the noncoronary cusp. The degree of AR should be extensively evaluated before surgery because it is an important criterion for determining the surgical procedure.

Figure 14.

Transthoracic echocardiogram of aortic regurgitation (AR) as a complication of Stanford type A acute aortic dissection. AR is detected using the color Doppler method. In addition, a flap and a dilated ascending aorta are seen.

Figure 15.

Transesophageal echocardiograms of Stanford type A acute aortic dissection. (Left) A mobile flap is seen in the ascending aorta (white arrow), and pericardial effusion is seen posteriorly. This case was complicated with cardiac tamponade (white arrowheads). (Right) The dilated ascending aorta and aortic regurgitation are seen by the color Doppler method.

Figure 16.

Transesophageal echocardiograms of a patient with Stanford type A acute aortic dissection complicated with aortic regurgitation. (Left) Long-axis view: the flap is compressing the aortic valve. (Right) Accelerated blood flow and the regurgitation jet are seen at the aortic valve compressed by the flap on color Doppler.

iii)-3 Myocardial Ischemia

Myocardial ischemia has been reported to occur in 3–9% of patients with Stanford type A acute aortic dissection. Dissection often occurs along the right side of the aortic root and thus the right coronary artery is commonly involved.⁴⁵² In addition to chest pain, a wide variety of symptoms, such as atrioventricular block, are manifested. In Stanford type A aortic dissection, it is recommended that in addition to ECG, left ventricular wall motion should be evaluated by TTE to examine for the presence of myocardial ischemia. If it is possible to evaluate the origin of the coronary artery at the aortic root, it is necessary to determine whether the dissection extends into the coronary artery. In addition, acute aortic dissection often develops in patients with known ischemic heart disease. In such cases, even if the dissection does not affect the coronary artery, the surgical risk is increased, and the treatment course may be complicated. Thus, it is important that cardiac function, including wall motion abnormalities and the severity of valvular diseases, is evaluated sufficiently at the time of onset.

iv) Diagnosis by TEE

Because the esophagus lies in close contact with the thoracic aorta, TEE is suitable for evaluation of the aorta, particularly of the descending aorta.⁴⁵³ TEE, during which blood pressure can be elevated by the stimulation from the insertion of the probe, should be considered as a semi-invasive examination and sedation is generally needed during the procedure. It is also necessary to confirm the absence of esophageal disease before the procedure. Therefore, sufficient history taking and informed consent are required to perform this procedure in the emergency room. However, TEE has high diagnostic accuracy for aortic dissection, with a sensitivity of 98% and a specificity of 95%. Thus, it may be considered in patients with a contraindication to contrast-enhanced CT.⁴⁵⁴ In addition, intraoperative TEE is highly useful in visualizing the entry site in the ascending aorta and in assessing the conditions during surgery. It is also useful in visualizing the descending thoracic aorta and the branched vessels that are difficult to visualize by TTE and in evaluation of surgically-treated AR before chest closure. Generally, long-axis views at angles of 100–150 degrees or short-axis views at angles of 0–60 degrees are used to examine the ascending aorta, the aortic root, and the aortic valve (Figure 17). A segment of the aortic arch just after the brachiocephalic artery branch cannot be visualized due to the existence of the right bronchus and the tracheae. For examination of the descending aorta, short-axis views at angle of 0 degrees and long-axis views at angle of 90 degrees are useful and the aorta at the level of the celiac artery to the level of left subclavian artery branch can be visualized.⁴⁵³ In the examination of the dissection sites, the shape of the true and false lumens and the entry sites can be visualized (Figure 18). TEE is also useful in the diagnosis of noncommunicating aortic dissection.⁴⁵⁵ Noncommunicating aortic dissection is distinguished from mural thrombosis by displacement of calcified intima and smooth intima. In ulcer-like projection (ULP)-type dissection, blood flow from the entry site to the false lumen is seen in the aortic wall where ULP is observed by contrast-enhanced CT scanning. In penetrating atherosclerotic aortic ulcer, a subtype of aortic dissection, an aortic ulcer with irregular shape and intramural hematoma is observed and this finding is useful for the diagnosis.⁴⁵⁶

Figure 17.

Transesophageal echocardiograms of a patient with Stanford type A acute aortic dissection. (Left) Long-axis view. (Right) Short-axis view. A mobile flap (white arrow) is seen just above the aortic valve in the ascending aorta.

Figure 18.

Transesophageal echocardiograms of a patient with Stanford type B acute aortic dissection. (Left) Short-axis view of the descending aorta. A flap and an entry are visible. (Right) Color Doppler image. Blood flow from the true lumen to the false lumen is seen.

16. Echocardiography During the Coronavirus Disease 2019 (COVID-19) Pandemic

16.1 Indications

Echocardiography is generally performed in a closed space in a close-contact setting, which carries a high risk of transmission of COVID-19.⁴⁵⁷ Therefore, the indication of echocardiography should be discussed for patients with confirmed or suspected COVID-19. In particular, transesophageal echocardiography should be carefully discussed for its indications because this procedure carries a very high risk of transmission through droplets and aerosols generated during probe insertion.⁴⁵⁸ Appropriate infection control measures should be taken when echocardiography is performed in patients with confirmed or suspected COVID-19. During the COVID-19 pandemic, it was recommended that echocardiography should be performed with appropriate infection control measures, even if the patient was unlikely to be infected.^457–459

When transthoracic echocardiography is performed for patients with confirmed or suspected COVID-19, point-of-care ultrasonography is recommended to reduce the contact time.⁴⁶⁰ Table 64 summarizes the indications of echocardiography during the COVID-19 pandemic or endemic.

Table 64. Recommendations and Levels of Evidence for Echocardiography During the COVID-19 Pandemic

	COR	LOE
During the COVID-19 pandemic, TTE should be performed with appropriate infection control measures	I	C
During the COVID-19 pandemic, TEE should be performed with appropriate infection control measures	I	C
During the COVID-19 pandemic, the indications of TEE should be fully discussed	I	C
During the COVID-19 pandemic, TTE is reasonable after careful consideration of the indications	IIa	C
POCUS is reasonable when TTE is considered for patients with confirmed or suspected COVID-19	IIa	C

COR, class of recommendation; COVID-19, coronavirus disease 2019; LOE, level of evidence; POCUS, point-of-care ultrasound; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography.

Appendix 1. Details of Members

Chair

• Nobuyuki Ohte, Department of Cardiology, Nagoya City University Graduate School of Medical Sciences

Members

• Masao Daimon, The Department of Clinical Laboratory, The University of Tokyo Hospital

• Takeshi Hozumi, Department of Cardiovascular Medicine, Wakayama Medical University

• Tomoko Ishizu, Department of Cardiology, University of Tsukuba

• Hiroshi Itoh, Department of Cardiovascular Medicine, Okayama University Faculty of Medicine, Dentistry and Pharmaceutical Science

• Shiro Iwanaga, Department of Cardiology, Saitama Medical University International Medical Center

• Chisato Izumi, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center

• Satoshi Nakatani, Saiseikai Senri Hospital

• Masaki Nii, Department of Cardiology, Shizuoka Children’s Hospital

• Kazuhiro Nishigami, Division of Cardiovascular Medicine, Miyuki Hospital LTAC Heart Failure Center

• Hiroyuki Okura, Department of Cardiology, Gifu University Graduate School of Medicine

• Yutaka Otsuji, University of Occupational and Environmental Health

• Yasushi Sakata, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

• Yoshihiro Seo, Department of Cardiology, Nagoya City University Graduate School of Medical Sciences

• Toshihiko Shibata, Department of Cardiovascular Surgery, Osaka City University Graduate School of Medicine

• Toshiro Shinke, Division of Cardiology, Department of Medicine, Showa University School of Medicine

• Masaaki Takeuchi, Department of Laboratory and Transfusion Medicine, Hospital of University of Occupational and Environmental Health

• Kazuaki Tanabe, The Fourth Department of Internal Medicine, Shimane University Faculty of Medicine

• Hirotsugu Yamada, Department of Community Medicine for Cardiology, Tokushima University Graduate School of Biomedical Sciences

• Kazuhiro Yamamoto, Department of Cardiovascular Medicine and Endocrinology and Metabolism, Faculty of Medicine, Tottori University

• Satoshi Yasukochi, Department of Pediatric Cardiology, Heart Center, Nagano Children’s Hospital

Collaborators

• Kaoru Dohi, Department of Cardiology and Nephrology, Mie University Graduate School of Medicine

• Hidekatsu Fukuta, Core Laboratory, Nagoya City University Graduate School of Medical Sciences

• Akiko Goda, Department of Cardiovascular and Renal Medicine, Hyogo College of Medicine

• Hirotoshi Hamaguchi, Department of Neurology, Kita-harima Medical Center

• Katsuji Inoue, Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine

• Hiroyuki Iwano, Division of Cardiology, Hakodate Municipal Hospital

• Masaki Izumo, Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine

• Shuichiro Kaji, Department of Cardiovascular Medicine, Kansai Electric Power Hospital

• Akihisa Kataoka, Division of Cardiology, Teikyo University Hospital

• Kenya Kusunose, Department of Cardiovascular Medicine, Tokushima University Hospital

• Atsushi Okada, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center

• Yasuharu Takeda, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

• Hidekazu Tanaka, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine

• Nozomi Watanabe, Department of Cardiology, Miyazaki Medical Association Hospital Cardiovascular Center

• Satoshi Yamada, Department of Cardiology, Tokyo Medical University Hachioji Medical Center

Independent Assessment Committee

• Makoto Akaishi, Well-aging Cardiovascular Clinic

• Takashi Akasaka, Department of Cardiovascular Medicine, Wakayama Medical University

• Takeshi Kimura, Department of Cardiology, Kyoto University Graduate School of Medicine

• Masami Kosuge, Division of Cardiology, Yokohama City University Medical Center

• Tohru Masuyama, JCHO Hoshigaoka Medical Center

(Listed in alphabetical order; affiliations as of March 2021)

Appendix 2. Disclosure of Potential Conflicts of Interest (COI): JCS 2021 Guideline on the Clinical Application of Echocardiography (2018/1/1–2020/12/31)

Author	Member’s own declaration items									COI of the marital partner, first-degree family members, or those who share income and property			COI of the head of the organization/department to which the member belongs (if the member is in a position to collaborate with the head of the organization/department)
	Employer/ leadership position (private company)	Stakeholder	Patent royalty	Honorarium	Payment for manuscripts	Research grant	Scholarship (educational) grant	Endowed chair	Other rewards	Employer/ leadership position (private company)	Stakeholder	Patent royalty	Research grant	Scholarship (educational) grant
Chair: Nobuyuki Ohte				Daiichi Sankyo Company, Limited. Otsuka Pharmaceutical Co., Ltd. Bayer Yakuhin, Ltd.		Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Sanwa Kagaku Kenkyusho Co., Ltd. Bayer Yakuhin, Ltd. Daiichi Sankyo Company, Limited.	Daiichi Sankyo Company, Limited. Otsuka Pharmaceutical Co., Ltd. Kowa Pharmaceutical Co., Ltd. Takeda Pharmaceutical Company Limited Astellas Pharma Inc.
Members: Masao Daimon					Bunkodo Co., Ltd.
Members: Hiroshi Itoh				Ono Pharmaceutical Co., Ltd. Novartis Pharma K.K. AstraZeneca K.K. Mitsubishi Tanabe Pharma Corporation Daiichi Sankyo Company, Limited. Nippon Boehringer Ingelheim Co., Ltd.			Daiichi Sankyo Company, Limited. Novartis Pharma K.K. Mitsubishi Tanabe Pharma Corporation Ono Pharmaceutical Co., Ltd. Nippon Boehringer Ingelheim Co., Ltd.
Members: Chisato Izumi				Edwards Lifesciences Corporation Novartis Pharma K.K. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited.		Daiichi Sankyo Company, Limited.
Members: Satoshi Nakatani				Edwards Lifesciences Corporation
Members: Masaki Nii				Siemens Healthcare K.K.
Members: Hiroyuki Okura				Takeda Pharmaceutical Company Limited Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Bayer Yakuhin, Ltd.			Otsuka Pharmaceutical Co., Ltd. Taiho Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. TERUMO CORPORATION Boston Scientific Japan K.K. Abbott Vascular Japan Co., Ltd.	Gifu welfare agricultural cooperative association union meeting.
Members: Yutaka Otsuji						Fukuda Life Tech Co., Ltd.	Daiichi Sankyo Company, Limited. Takeda Pharmaceutical Company Limited
Members: Yasushi Sakata				AstraZeneca K.K. Novartis Pharma K.K. Bayer Yakuhin, Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Nippon Boehringer Ingelheim Co., Ltd. Medtronic Japan Co., Ltd. Mitsubishi Tanabe Pharma Corporation		Biosense Webster, Inc. Actelion Pharmaceuticals Japan Ltd. Amgen Astellas BioPharma K.K. Abbott Medical Japan LLC. Sony Corporation Nipro Corporation Bristol-Myers Squibb Roche Diagnostics K.K. Shionogi & Co., Ltd. JIMRO Co., Ltd. Integral Corporation REGiMMUNE Co., Ltd. Nippon Boehringer Ingelheim Co., Ltd. FUJIFILM RI Pharma Co., Ltd.	Cardinal Health Japan Astellas Pharma Inc. Abbott Medical Japan LLC. Edwards Lifesciences Corporation Johnson & Johnson K.K. St. Jude Medical Japan Co., Ltd. Novartis Pharma K.K. Bayer Yakuhin, Ltd. BIOTRONIK Japan, Inc. Boston Scientific Japan K.K. Kowa Company, Ltd. Kowa Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Taisho Biomed Instruments Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Biosensors Japan Co., Ltd. Nippon Boehringer Ingelheim Co., Ltd. Medtronic Japan Co., Ltd. Takeda Pharmaceutical Company Limited
Members: Yoshihiro Seo				Otsuka Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation Daiichi Sankyo Company, Limited. Nippon Boehringer Ingelheim Co., Ltd.
Members: Toshihiko Shibata				Daiichi Sankyo Company, Limited.			Edwards Lifesciences Corporation
Members: Toshiro Shinke				Abbott Medical Japan LLC. Daiichi Sankyo Company, Limited. Bayer Yakuhin, Ltd.		Abbott Medical Japan LLC.	Abbott Medical Japan LLC. Daiichi Sankyo Company, Limited. Nippon Boehringer Ingelheim Co., Ltd.						Abbott Medical Japan LLC.	Abbott Medical Japan LLC. Daiichi Sankyo Company, Limited. Nippon Boehringer Ingelheim Co., Ltd.
Members: Masaaki Takeuchi					GE Healthcare Japan Corporation	Philips Japan, Ltd. Roche Diagnostics K.K.	GE Healthcare Japan Corporation
Members: Kazuaki Tanabe							Otsuka Pharmaceutical Co., Ltd.
Members: Hirotsugu Yamada				Daiichi Sankyo Company, Limited. Bayer Yakuhin, Ltd. US-Lead,.co.LTD
Members: Kazuhiro Yamamoto				Otsuka Pharmaceutical Co., Ltd. Pfizer Japan Inc. Ono Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Novartis Pharma K.K.			Abbott Medical Japan LLC. Novartis Pharma K.K. Novo Nordisk Pharma Ltd. BIOTRONIK Japan, Inc. Fukuda Denshi Co., Ltd. Boston Scientific Japan K.K. Medtronic Japan Co., Ltd. LifeScan Japan K.K. Kowa Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Japan Lifeline Co.,Ltd. Nihon Kohden Corp. Takeda Pharmaceutical Company Limited
Members: Satoshi Yasukochi				Actelion Pharmaceuticals Japan Ltd.
Collaborators: Kaoru Dohi				Novartis Pharma K.K. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited			Shionogi & Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited.
Collaborators: Akiko Goda													Amgen K.K.	Ono Pharmaceutical Co., Ltd. Abbott Medical Japan LLC. Daiichi Sankyo Company, Limited.
Collaborators: Hirotoshi Hamaguchi				Daiichi Sankyo Company, Limited.
Collaborators: Masaki Izumo				Edwards Lifesciences Corporation Abbott Medical Japan LLC. Daiichi Sankyo Company, Limited.
Collaborators: Akihisa Kataoka				Abbott Medical Japan LLC.
Collaborators: Atsushi Okada						Pfizer Japan Inc.
Collaborators: Hidekazu Tanaka				AstraZeneca K.K. Daiichi Sankyo Company, Limited. Ono Pharmaceutical Co., Ltd.
Independent Assessment Committee: Takashi Akasaka				Abbott Vascular Japan Co., Ltd. Abbott Medical Japan LLC. Nipro Corporation Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Nihon Medi-Physics Co., Ltd.	Bunkodo Co., Ltd.	Daiichi Sankyo Company, Limited. Nihon Medi-Physics Co., Ltd.	Abbott Vascular Japan Co., Ltd. Bayer Yakuhin, Ltd.	Abbott Vascular Japan Co., Ltd. TERUMO CORPORATION Nipro Corporation
Independent Assessment Committee: Takeshi Kimura				Abbott Vascular Japan Co., Ltd. Sanofi K.K. Bristol-Myers Squibb Boston Scientific Japan K.K. Kowa Company, Ltd. Nippon Boehringer Ingelheim Co., Ltd.		Edwards Lifesciences Corporation EP-CRSU Co., Ltd. Pfizer Japan Inc. Kowa Company, Ltd. Daiichi Sankyo Company, Limited.	Astellas Pharma Inc. MID,Inc. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd. Takeda Pharmaceutical Company Limited
Independent Assessment Committee: Masami Kosuge				Daiichi Sankyo Company, Limited.										Abbott Medical Japan LLC. Abbott Vascular Japan Co., Ltd. Nipro Corporation
Independent Assessment Committee: Tohru Masuyama						Daiichi Sankyo Company, Limited.	MSD K.K. Otsuka Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Kowa Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited. Mitsubishi Tanabe Pharma Corporation Teijin Pharma Limited Bayer Yakuhin, Ltd.	Abbott Medical Japan LLC. Medtronic Japan Co., Ltd.

*Notation of corporation is omitted.

*The following persons have no conflict of interest to declare:

Members: Takeshi Hozumi

Members: Tomoko Ishizu

Members: Shiro Iwanaga

Members: Kazuhiro Nishigami

Collaborators: Hidekatsu Fukuta

Collaborators: Katsuji Inoue

Collaborators: Hiroyuki Iwano

Collaborators: Shuichiro Kaji

Collaborators: Kenya Kusunose

Collaborators: Yasuharu Takeda

Collaborators: Nozomi Watanabe

Collaborators: Satoshi Yamada

Independent Assessment Committee: Makoto Akaishi

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