JCS/JSCVS/JATS/JSVS 2021 Guideline on Implantable Left Ventricular Assist Device for Patients With Advanced Heart Failure

Abbreviations

ACE	angiotensin-converting enzyme
AI	aortic insufficiency
ARB	angiotensin II receptor blocker
ARNI	angiotensin-receptor neprilysin inhibitor
BiVAD	biventricular assist device
BTB	bridge to bridge
BTC	bridge to candidacy
BTD	bridge to decision
BTR	bridge to recovery
BTT	bridge to transplantation
CHD	Congenital heart disease
CRT	cardiac resynchronization therapy
DT	destination therapy
ECMO	extracorporeal membrane oxygenation
EUROMACS	European Registry for Patients with Mechanical Circulatory Support
HM-II	HeartMate II
IABP	intra-aortic balloon pump
ICD	implantable cardioverter defibrillator
INTERMACS	Interagency Registry for Mechanically Assisted Circulatory Support
J-MACS	Japanese Registry for Mechanically Assisted Circulatory Support
JOT	Japan Organ Transplant Network
LVAD	left ventricular assist device
LVEF	left ventricular ejection fraction
MCS	mechanical circulatory support
MRA	mineralocorticoid receptor antagonist
NYHA	New York Heart Association
PCWP	pulmonary capillary wedge pressure
PDE	phosphodiesterase
QOL	quality of life
RVAD	right ventricular assist device
SGLT2	sodium-glucose co-transporter 2
VAD	ventricular assist device
VA-ECMO	veno-arterial extracorporeal membrane oxygenation

Introduction

1. Background

More than 20 years have passed since heart transplantation began to be performed under the Organ Transplant Law enacted in 1997. The Law was amended to include the Organ Transplant Act in 2010; the number of organ donations has been slowly, but steadily increasing. However, it has not kept pace with the increase in the number of patients on the heart transplant waiting list; in fact, the waiting period exceeded 1,500 days in 2019. Novacor was first approved as an implantable ventricular assist device (VAD) for a bridge to transplantation (BTT) in 2004, but 2 years later it was withdrawn from the Japanese market due to insufficient social infrastructure. In response to the need for long-term durable BTT devices for heart transplantation, in 2005–2006, the “Next-generation Medical Device Evaluation Index” and the “Japanese Guidance for Ventricular Assist Devices/Total Artificial Hearts” were developed in cooperation with the Ministry of Health, Labor and Welfare (MHLW) and the Ministry of Economy, Trade and Industry (METI), respectively. These were designed to focus on the clinical introduction of smaller, continuous-flow implantable left ventricular assist devices (LVADs), which had already become mainstream in Europe and the United States.¹

In 2010, the Ad hoc Committee for establishing requirements for practicing implantable LVAD treatment, consisting of related academic societies, submitted the Practice Standards for “Implantable VADs” to the MHLW, and proposed “Safety management standards for home care”. Included in this proposal were “Systems necessary for fulfilling the safety management standards for home care” and “Standards for outpatient management”. To ensure safety management of home care, certification for VAD management specialists was newly started in 2009. With the approval of EVAHEART and DuraHeart for health insurance reimbursement in 2011, the Council for Clinical Use of Ventricular Assist Device Related Academic Societies (9 academic societies at that time) began certification of facilities and physicians performing implantable LVADs. In Europe and the USA, implantable LVADs had already been approved in the mid-2000s and guidelines were developed accordingly. In Japan, the “Guidelines for device therapy: Implantable left ventricular assist device for patients with severe heart failure” (JCS/JSCVS2013) were published in 2013 with the aim of establishing appropriate use and standardization of treatment, and yielding treatment benefits equivalent to or greater than those in Europe and the USA.²

The real-world clinical outcomes of implantable LVAD for BTT in Japan are superior to those reported by the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)³ in the USA, and the European Registry for Patients with Mechanical Circulatory Support (EUROMACS)⁴ in Europe.⁵ Since the 2013 guidelines, various new implantable LVADs have been developed and introduced into clinical practice. Outcomes after implantation of these new devices in the USA and Europe have shown improved survival rates and a significant reduction in the incidence of many serious complications. In Japan, HVAD and HeartMate3 (HM-3) were successively approved for health insurance reimbursement in 2019, only for BTT.

In terms of the therapeutic purpose of implantable LVADs, destination therapy (DT) is essential, along with BTT. In the USA, the proportion of implantable LVADs used for DT rapidly increased with the introduction of a new organ allocation policy for heart transplantation in October 2018. In Japan, clinical trials are underway for the approval of implantable LVADs for DT. With the introduction of new and improved implantable LVAD devices and the worldwide spread of DT, accordingly it is essential to revise the guidelines in a timely fashion, before DT becomes a treatment option for severe heart failure in Japan.

The goal of LVAD implantation for BTT is to bridge the patient to heart transplantation. In contrast, the final destination of DT without heart transplantation is death. Discussion among the multidisciplinary team members involved in the treatment is essential to develop an understanding not only among patients and caregivers, but also society on how to maintain and improve quality of life (QOL) as the intended purpose of DT, and how to prepare for and accept death as the endpoint of treatment.

2. Purpose of the Revision

Based on the building of an appropriate safety management system and a significant reduction in complications as a result of the improved and newly introduced devices in Japan, the guidelines have been revised to improve treatment outcomes, further expand the use of implantable LVADs, and to introduce DT. Although more than 24,000 implantable LVADs patients have been registered with INTERMACS in the USA,³ just over 1,000 have been registered with the Japanese Registry for Mechanically Assisted Circulatory Support (J-MACS).⁵ Therefore, most of the knowledge in Japan is not from evidence-based medicine, but rather it is based on annual reports from INTERMACS and analyses of single-center studies with small numbers of patients. The J-MACS report in 2019, which evaluated 945 Japanese patients with continuous-flow devices such as EVAHEART, DuraHeart, HeartMate II (HM-II), and Jarvik2000, showed better clinical outcomes than in patients in Europe and the USA.⁵ Clinical outcomes of LVAD implantation rely on long-term team care. It is our hope that the guideline will be shared among physicians, surgeons, nurses, administrators, and clinical engineers (including certified VAD management specialists and coordinators), physical therapists, pharmacists, and other related professionals, and thereby contribute to the establishment of a new social infrastructure for implantable LVAD therapy including the coming DT.

Currently, it may be difficult to describe a sufficiently sophisticated content of the guideline, because DT with implantable LVADs has not been initiated in Japan. However, we strongly hope that the guideline will be widely used by many implantable LVAD therapy professionals, patients, and caregivers, and it will be continuously revised in the future.

3. General Principles for Developing Guidelines

The American College of Cardiology/American Heart Association guidelines are designed to be applicable to the care of patients with the most common cardiovascular diseases under a wide range of conditions and are essentially based on a literature review of the results of randomized, prospective, multicenter clinical trials to justify diagnostic procedures and therapeutic measures. The current consensus on the efficacy of each diagnostic and therapeutic modality is classified into classes I–III to assist clinicians in their daily practice.

However, randomized, prospective, multicenter, large-scale clinical trials of implantable LVAD therapy are limited to the following 6 trials: REMATCH, the HeartMate VE DT trial (2001);⁶ HM-II BTT trial (2007);⁷ HM-II DT trial (2009);⁸ ADVANCE, the HVAD BTT trial (2012);⁹ ENDURANCE, the HVAD DT trial (2018);¹⁰ and MOMENTUM 3, the largest trial of implantable LVADs in BTT and DT using HM-3 with short-term results¹¹ (2018) and long-term results¹² (2019). Each clinical trial was a single device trial limited to BTT or DT. The introduction of improved next-generation devices has led to improvements in clinical trial results and the frequency of complications, thereby leading to changes in indications, such as the severity of heart failure. Therefore, the trial results cannot be interpreted in the same manner as large clinical trials of drug therapy.

As real-world evidence, the INTERMACS Registry for post-approval devices in the USA,³ the J-MACS Registry in Japan,⁵ and the EUROMACS Registry in Europe⁴ are available. Although the registries have a larger number of cases than clinical trials, the data’s completeness and reliability are inferior. Due to the poor prognosis of the disease in these studies, it is not morally acceptable to conduct a randomized trial of implantable LVAD in comparison with medical therapy that was already used as a control in previous clinical trials. The only randomized prospective trial of DT in the USA was the REMATCH study, but the device used is no longer commercially available. As with many surgical treatments, guidelines for implantable LVADs are based largely on evidence from observational and retrospective studies or from analyses using historical controls.

There is no experience with DT in Japan, and therefore, the guidelines should provide a certain path to the end-of-life issues that have not been discussed to date, including withholding treatment or stopping devices according to advance directives, which are being promoted in Europe and the USA, when improvement of QOL, the original purpose of DT, cannot be expected. This guideline should be considered as a compilation of expert opinions based on the current treatment strategies adopted by individual experts and data obtained from clinical trials conducted by device manufacturers, with the assumption of continuous revision in the future. Efforts should be continued to eliminate personal bias of each expert involved in the guideline development, and thus we welcome criticism.

The following classes of recommendations (Table 1) and levels of evidence (Table 2) are used as criteria for recommendations on the diagnosis and indications for treatment.

Table 1. Classes of Recommendations

Class I	There is evidence or general agreement that the procedure or treatment is effective or useful
Class IIa	Likely to be effective and useful based on evidence and opinion
Class IIb	Efficacy and usefulness are not so well established based on evidence and opinions
Class III (No benefit)	There is evidence or general agreement that the procedure or treatment is not effective or useful
Class III (Harm)	There is evidence or general agreement that the procedure or treatment is harmful

Table 2. Levels of Evidence

Level A	Demonstrated by randomized interventional clinical trials or meta-analyses
Level B	Demonstrated in a single randomized interventional clinical trial or in a large non-randomized interventional clinical trial
Level C	Consensus of experts and/or small clinical trials (including retrospective studies and registries)

I. Indications

1. Indications for Left Ventricular Assist Devices (LVADs)

1.1 Institutional Eligibility Judgment System and Eligibility Review Committee for Heart Transplantation and Implantable LVADs

As of the end of August 2020, the implantable LVAD is only approved for health insurance reimbursement for use in bridge to transplantation (BTT). Prior to LVAD implantation, the eligibility for heart transplantation has to be approved by the Institutional Review Committee of the transplant center. In addition, LVAD implantation should be only performed after approval by the Eligibility Review Committee for Heart Transplantation of the Japanese Circulation Society (JCS) through WEB application and registration on the waiting list of the Japan Organ Transplant Network (JOT). Since May 2015, institutions that have performed >50 heart transplants and are certified by the JCS Heart Transplantation Committee (appropriateness of their eligibility review process and medical practices for heart transplantation) have been able to register directly with the JOT if determined as eligible by the institutional Eligibility Review Committee. As of December 2020, there are 3 such institutions: the National Cerebral and Cardiovascular Center, Osaka University, and the University of Tokyo.

Patients who become INTERMACS Profile 2 before JCS approval for heart transplantation and require immediate LVAD implantation to save their lives may undergo implantation after obtaining written approval from the collaborating heart transplant center. However, in this case, a web report to JCS is required within 1 month after implantation, and the Post-implantation Validation Subcommittee will verify it. Participation of an experienced collaborating heart transplant center is required for LVAD implantation at facilities with <3 LVAD implantations in the past 2 years.

J-MACS defines the status of patients prior to VAD implantation as follows: registered with JOT (BTT), applied for JCS eligibility review for heart transplantation or judged eligible for heart transplant at transplant center (possible BTT), planned for long-term home care due to ineligibility for transplant (destination therapy [DT]), having a history of acute decompensated heart failure (ADHF) and planned weaning (bridge to recovery: BTR), and those without ADHF and planned weaning (rescue therapy).

1.2 Bridge to Transplantation (BTT)

Currently, in Japan, implantable LVADs are approved for health insurance reimbursement only for the purpose of BTT, and the criteria for implantable LVAD therapy are based on the heart transplant listing criteria. In principle, implantable LVAD therapy is performed after approval by the JCS committee (BTT listed) or after approval by the Institutional Review Board in high-volume transplant centers (BTT inhouse approval). However, implantation for BTT may even be performed during eligibility review for heart transplantation by the JCS committee if it is judged to be transplant eligible within the institution and approved by the collaborating transplant center. In this case, the post-implantation verification of appropriateness for implantable LVADs must be applied for from the JCS within 1 month after implantation (BTT applied). The number of implantations for each of the above 3 types of BTT (BTT listed, BTT inhouse approval, BTT applied) has been reported in J-MACS.⁵

1.3 Bridge to Candidacy (BTC)

Impaired renal and hepatic function due to hemodynamic deterioration may preclude the decision for transplantation before LVAD implantation.¹³ In many cases, after hemodynamic support by LVAD, the organ disorder improves and the patient can be listed for transplantation.¹⁴ In addition, some conditions that do not meet the requirements for transplantation may be resolved during a certain period of circulatory support. LVAD implantation with the goal of future listing of such patients is called BTC, and the eligibility for transplantation can be reevaluated after a certain period of LVAD therapy. BTC with implantable VAD is approved for health insurance reimbursement in Japan as of May 2021, albeit the reimbursement is limited in several facilities.

INTERMACS classifies BTC into 3 categories: “likely”, with a high likelihood of future listing; “moderately likely”, with a 50-50 likelihood; and “unlikely”, with a low likelihood. A scoring system has also been proposed to predict the degree of improvement in renal and hepatic function after LVAD implantation based on preoperative bilirubin and creatinine levels, as well as the patient’s age.¹⁵

1.4 Bridge to Decision (BTD)

Hemodynamic stabilization is the top priority for patients with severe heart failure who have or are going into cardiogenic shock, and the use of a paracorporeal (extracorporeal) VAD (including centrifugal pump for extracorporeal circulation) primarily for life saving in such patients is called BTD. However, there are many cases in which the patient’s family background or their own intentions are unknown, or possible post-resuscitation encephalopathy cannot be ruled out. In such cases, the use of catheter-based transaortic microaxial pumps (IMPELLA), central extracorporeal membrane oxygenation (ECMO), or other temporary mechanical support (percutaneous or open chest) may also be included in BTD.¹⁶ In contrast, the use of conventional intra-aortic balloon pump (IABP) or veno-arterial (VA)-ECMO (percutaneous cardiopulmonary support [PCPS]) is not considered as BTD status.

1.5 Bridge to Bridge (BTB)

BTB refers to the use of a paracorporeal VAD (including centrifugal pump for extracorporeal circulation) or central ECMO for BTD or BTC, followed by replacement with an implantable LVAD upon approval for heart transplantation. In the latest J-MACS, patients with BTB who bridged from paracorporeal VADs (including centrifugal pumps for extracorporeal circulation) to implantable LVADs were analyzed.⁵ As a rule, bridging with IMPELLA, IABP, or VA-ECMO (PCPS) that does not involve thoracotomy is not included as BTB.

1.6 Bridge to Recovery (BTR)

In patients with severe heart failure, the use of VAD may restore cardiac function as a result of myocardial reverse remodeling, leading to weaning from the VAD.¹⁷ In addition, in patients with cardiogenic shock due to fulminant myocarditis or peripartum cardiomyopathy, the use of paracorporeal VAD may restore the patient from the underlying disease. Such cases are referred to as BTR. It is not easy to predict which patients are likely to recover,^18,19 and there is no consensus as to which therapy will accelerate recovery after VAD implantation.^20,21

To estimate the degree of cardiac recovery or to consider weaning from the device, an off-pump test is performed for paracorporeal pulsatile-flow VADs, and cardiopulmonary function tests have also been proposed to determine cardiac reserve.²² With continuous-flow LVADs, in order to avoid the backflow that occurs when the pump is completely stopped, hemodynamic stability is evaluated at a reduced rotational speed without backflow to determine weaning (pseudo-off test).²³

1.7 Bridge by IMPELLA

IMPELLA is a percutaneously inserted catheter-based temporary VAD that pumps blood from the left ventricle to the aorta by an axial flow pump. In Japan, the IMPELLA 2.5, CP, and 5.0, which have different assist flow rates and catheter sizes, are available only for patients with cardiogenic shock. Just as with other extracorporeal VADs, IMPELLA can be used for BTR, BTD, or BTT in patients with INTERMACS/J-MACS Profile 1 or 2, such as acute myocardial infarction, fulminant myocarditis, or acute exacerbation of chronic heart failure that leads to cardiogenic shock.

According to reports from the USA and Europe, IMPELLA 2.5 is mainly used in acute myocardial infarction, and in about 50% of the cases it is used for BTR, and in only about 3% of cases is there conversion to an implantable LVAD.²⁴ IMPELLA 2.5 and CP are thought to be effective in preoperative stabilization of patients with INTERMACS/J-MACS Profile 2 due to exacerbation of chronic heart failure, though there are no studies to date. IMPELLA 5.0 is used for severe heart failure due to acute myocardial infarction or cardiomyopathy; it has a survival discharge rate of about 60–70% (mean support period of 6–7 days), with 30% for BTR, 20% for BTT, and 30% for conversion to an implantable LVAD.^24,25 Although in-hospital complications, such as hemorrhage, hemolysis, infection, hematoma, lower extremity ischemia, vascular injury, aortic valve injury, and equipment failure can occur,^25,26 even with cardiogenic shock about 60–70% of patients can be switched to another therapy, indicating its usefulness as a bridge therapy.^24,25 Small observational studies have reported the efficacy of prolonged IMPELLA support for unloading in patients with fulminant myocarditis (PROPELLA), IMPELLA RP for right heart failure (not approved in Japan), and use in combination with VA-ECMO (BIPELLA or ECPELLA).²⁷

2. Indications for Bridge to Transplantation (BTT)

The indications of implantable LVADs for BTT are shown in Table 3. Patients indicated for BTT should be <65 years old in accordance with the indication for heart transplantation. Eligibility for BTT must be determined by considering 3 inclusion criteria: (1) irreversible cardiac dysfunction that does not improve from NYHA functional class IV despite standard therapy, (2) physical status that can tolerate heart transplantation, and (3) appropriate social environment.

Table 3. Indications for Implantable LVADs in BTT Therapy

Indications
Eligible	Clinical condition	Endstage severe heart failure according to criteria for heart transplantation, NYHA functional class IV, and stage D heart failure with progressive symptoms despite adequate standard therapy recommended by the guidelines
	Age	<65 years old
	Body surface area	Defined for each device
	Severity	Dependent on inotropes such as dobutamine, dopamine, norepinephrine, and PDE III inhibitors (INTERMACS Profile 2 or 3); dependent on IABP, circulatory support pump catheters, and extracorporeal LVADs; modifier A (especially for INTERMACS Profile 4)
	Social conditions	Patient and caregivers understand the circumstances of long-term home care and the patient can expect to return to society
	Pharmacotherapy	Maximum pharmacotherapy, including ACE inhibitors, ARBs, β-blockers, MRAs, SGLT2 inhibitors, ARNI, ivabradine, and diuretics, has been tried
	Non-pharmacotherapy	CRT, interventions for mitral regurgitation, and revascularization for ischemic cardiomyopathy have been well considered
Ineligible	Systemic disorders	Difficult-to-treat systemic diseases with poor prognosis, such as malignant tumors and collagen diseases
	Organ damage	Irreversible hepatic and renal dysfunction, insulin-dependent severe diabetes mellitus, severe bleeding tendency, dialysis due to chronic renal failure
	Respiratory illness	Severe respiratory failure
		Irreversible pulmonary hypertension (PVR >6 Wood units despite the use of vasodilators)
	Cardiovascular diseases	Difficult-to-treat aortic aneurysm, moderate or severe aortic valve insufficiency that cannot be treated, mechanical aortic valve unable to be replaced by a biological valve, severe peripheral vascular diseases
	Neurological disorders	Severe central nervous system disorder
		Drug or alcohol addiction
		Neuropsychiatric disorders affecting ability to follow or understand the protocol
	Infectious diseases	Active serious infections
	Pregnancy	Pregnant or planning to become pregnant
	Others	Patients considered unsuitable by the Institutional Eligibility Review Committee, such as those with significant obesity

ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ARNI, angiotensin-receptor neprilysin inhibitor; BTT, Bridge to Transplantation; CRT, cardiac resynchronization therapy; IABP, intra-aortic balloon pump; INTERMACS, interagency registry for mechanically assisted circulatory support; LVAD, left ventricular assist device; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; PDE, phosphodiesterase; PVR, pulmonary vascular resistance; SGLT2, sodium-glucose co-transporter 2.

The first criterion assumes that the patient does not improve from severe endstage heart failure (NYHA functional class IV) despite adequate application of standard therapy (Table 3), including pharmacotherapy with β-blockers, angiotensin-converting enzyme (ACE) inhibitors, mineralocorticoid receptor antagonists (MRAs), sodium-glucose co-transporter 2 (SGLT2) inhibitors, angiotensin-receptor neprilysin inhibitor (ARNI), ivabradine, or diuretics, and non-pharmacologic therapy such as cardiac resynchronization therapy (CRT). Such patients may be dependent on intravenous inotropes (i.e., INTERMACS Profile 2 or 3, or J-MACS Level 2 or 3) or on IABP, IMPELLA, or extracorporeal VADs. Patients with ventricular arrhythmias refractory to pharmacotherapy that require frequent implantable cardioverter defibrillator (ICD) activation (modifier A) may be eligible for an implantable LVAD even if they are INTERMACS Profile 4 or J-MACS Level 4.

For the second criterion, the physical status represents absence of the following: (1) difficult-to-treat diseases with poor prognosis, such as malignant tumors and collagen diseases, (2) severe respiratory failure and irreversible pulmonary hypertension, (3) irreversible hepatic and renal dysfunction and insulin-dependent severe diabetes mellitus, (4) difficult-to-treat aortic aneurysm, moderate or severe aortic valve insufficiency that cannot be treated, mechanical aortic valve non-replaceable with a biological valve, severe peripheral vascular diseases, (5) pregnancy or plan to become pregnant and (6) significant obesity. The reversibility of pulmonary vascular resistance (PVR) should be assessed by performing oxygen loading, if PVR is between 3 and 6 Wood units. The recovery of renal function after LVAD implantation is transient and worsens over time, so the creatinine clearance level before LVAD implantation should be ≥30 mL/min.²⁸ In addition, there are numerous prognostic factors following implantation (age, level of emergency, preoperative albumin level, serum creatinine level, and right heart failure) and the eligibility for implantation needs to be carefully determined even if the exclusion criteria shown in Table 3 are not relevant.²⁹

As for the social environment, the waiting time for heart transplantation is >4 years as of 2020 in Japan, so patients need to fully understand the long-term management of implantable LVADs, and caregivers (who preferably live with the patient) need to be familiar with the device operation.

Shared decision making based on participation and dialog between the patient and healthcare providers is the foundation for considering LVAD implantation. The optimal LVAD implant stage is INTERMACS Profile 3 (J-MACS Level 3), which is “inotropic dependent but without progressive organ damage”. For patients with INTERMACS Profile 4 (J-MACS Level 4) and repeated hospitalizations, care should be taken to avoid organ damage so that implantation can be performed at the appropriate time. For patients with status 2 who are on the waiting list for heart transplantation, the criteria for the timing of LVAD implantation should be thoroughly discussed by the multidisciplinary team, including the attending physician, and should be well understood by the patient and caregivers.

3. Indications for Destination Therapy (DT)

In patients with severe heart failure who are NYHA functional class IV and are not eligible for heart transplantation, medical therapy alone has a poor prognosis, with a 1-year survival rate of 25%, but left ventricular assist device (LVAD) therapy has been shown to improve the prognosis.⁶ LVAD therapy without the goal of transplantation is termed DT. In the USA, the use of HM-II in DT (approved in 2010) has rapidly spread, accounting for about half of all cases of implantable LVADs and improved long-term prognosis has been documented.³⁰ In the both the USA and Europe, DT is recommended for stage D heart failure with reduced ejection fraction (HFrEF) patients not eligible for transplantation. In addition, patients will be able to be discharged home and have a social life, and their quality of life (QOL) will improve.³¹

As of August 2021, HM-3 has been approved for use as DT in Japan. The indications and implementation of DT in Japan are based on the guidance of the Council for Clinical Use of Ventricular Assist Device Related Academic Societies, which consists of 10 academic societies (Table 4).³² The recommendations and level of evidence for implantable LVAD therapy in patients with HFrEF who are not eligible for heart transplantation are listed in Table 5.

Table 4. Selection Criteria for DT

Eligible

• In accordance with the indications for implantable LVADs for severe heart failure

• Adults (≥18 years) who need a heart transplant but are not eligible for noncardiac reasons

• Must be INTERMACS Profile 2–4

• Low risk by adequate risk assessment for age, renal function, liver function, etc., such as the J-HeartMate Risk Score*

• Life expectancy of ≥5 years as defined by factors other than cardiac disease

• Have a supportive caregiver living with the patient for 6 months after discharge (preferably, the caregiver or a public service can continue to provide care for the patient after that)

• Patients and caregivers understand and accept the end-of-life care in DT

Ineligible

• Maintenance dialysis

• Liver cirrhosis

• Severe infectious diseases

• Predicted difficulty in discharge due to postoperative right heart failure

• Predicted difficulty in device self-management due to brain damage or neuromuscular disease

• Determined by a physician to be excluded for other reasons

*Japan-VAD risk score = 0.0274 × age − 0.723 × alb (g/dL) + 0.74 × Crn (mg/dL) + 1.136 × INR + 0.807 × (0 or 1) (0 if the institution has had ≥3 cases of implantable LVAD in 2 years) (Source: based on the Council for Clinical Use of Ventricular Assist Device Related Academic Societies. 2014.³²) DT, destination therapy; INTERMACS, interagency registry for mechanically assisted circulatory support; LVAD, left ventricular assist device.

Table 5. COR and LOE for Implantable LVAD Therapy to Improve Prognosis and QOL in Patients With HFrEF Not Eligible for Heart Transplantation

	COR	LOE	GOR (MINDS)**	LOE (MINDS)**
Implantable LVAD therapy* should be considered to improve prognosis and QOL for patients with stage D HFrEF who are not eligible for heart transplantation.	IIa	B	B	II

*Based on clinical trials in the USA and Europe. **Classifications proposed by the MINDS of the Japan Council for Quality Health Care. GOR B refers to “recommended with scientific evidence”, and LOE II “one or more randomized controlled trials”. COR, class of recommendation; GOR, grade of recommendations; HFrEF, heart failure with reduced ejection fraction; LOE, level of evidence; LVAD, left ventricular assist device; MINDS, Medical Information Network Distribution Service; QOL, quality of life.

In the USA and Europe, reasons for transplant ineligibility in patients with DT include advanced age, renal dysfunction, pulmonary hypertension, illicit drug use, and noncompliance.³³ There are also cases of shifting from BTT to substantial DT with the onset of malignancy, and from DT to BTT due to improvement of organ failure.³⁴ Thus, the difference between DT and BTT is whether or not the patient eventually undergoes transplantation. Recently, in the USA and Europe, BTT and DT have not been distinguished in the indications for LVAD therapy. In fact, HM-3 has been studied with no distinction between BTT and DT,^35,36 and approved by the Food and Drug Administration and the same is true for the European approval (CE mark).

4. Indications for Ventricular Assist Devices (VADs) in Children

In recent years, VAD therapy has been applied to pediatric patients in Japan and in other countries;^29,37–39 the introduction of new VADs has markedly changed the landscape of treatment for severe heart failure. As reported by Nakatani et al,³⁷ in the J-MACS registry, no patients under the age of 10 years with continuous-flow LVAD implantation were registered and only 7 patients aged 10-17 years were registered up to April 2015. However, in the monthly J-MACS registry report as of June 2019, the number of patients under 19 years increased to 58. The use of the Berlin Heart EXCOR VAD (Berlin Heart, The Woodland, TX, USA), an extracorporeal VAD for pediatric patients, has also increased rapidly since 2015,^40,41 and 54 patients had received implants by June 2019, 25 of whom underwent heart transplantation (12 in Japan). A nationwide survey by the Japanese Society for Heart Transplantation showed that prior to heart transplantation, 27 of 33 recipients under the age of 18 years at the end of 2018 had been using a VAD, including 8 Nipro VADs, 7 EXCORs, 6 Jarvik2000, 2 HVADs (one was a biventricular HVAD), 2 EVAHEARTs (one was a right ventricular assist device [RVAD] co-implanted with Nipro VAD), and 1 HeartMate (HM)-II.^42,43

To date, unlike adults, there is no standardized VAD treatment system in children, and indications and treatment strategies depend on age, body size, and primary disease. In this section, the indications for VAD in children are described, focusing on specific strategies.

4.1 Patient Selection

Although the outcome of pediatric VAD therapy has been improving, it depends greatly on the experience of individual institutions; unfortunately, to date there is no standardized criteria for patient selection. Timeliness of VAD implantation is critical to avoid multiple organ failure, various postoperative complications, and the need for right heart assistance. On the other hand, premature implantation should be avoided because of various risks associated with VAD therapy. For pediatric indications for VAD, the “Standards of practice and appropriate use of pediatric assistive devices” have been issued.⁴⁴

First, the need for VAD must be evaluated in all pediatric patients who are dependent on inotropic therapy. VAD should be considered in patients who require artificial respiratory management due to heart failure. The off-label use of a centrifugal pump is currently the only choice in bridge to decision (BTD), because unlike in Europe and the USA, neither EXCOR nor continuous-flow implantable VAD can be implanted without an indication for heart transplantation.^45–47 Expansion of the indications for VADs or obtaining approval of long-term durable centrifugal pumps in BTD through physician-led trials is a critical necessity.^48,49 In children aged ≥10 years, who rarely present with respiratory failure, VAD therapy should be considered if signs of multiple organ failure such as hepatic and renal dysfunction, eating difficulty, and malnutrition progress under inotropic therapy.

In congenital heart disease, morphological assessment is necessary to determine the suitability of a VAD. Morphology, size, and connection status of the ventricles and large vessels and surgical history (e.g., systemic-to-pulmonary artery shunt, Glenn procedure, Fontan operation) are evaluated to determine the VAD model, pump location, method of attaching the inflow and outflow cannulas, and drive line routing.³⁹

VAD therapy is contraindicated in extremely premature infants, low body weight <2.5 kg (EXCOR is generally indicated for >3.0 kg), severe neurological disorders, contraindication to anticoagulation, and congenital diseases, metabolic diseases, and chromosomal abnormalities with a poor prognosis.³⁹ Currently, both EXCOR and implantable VADs require the patient to be eligible for heart transplantation, which means that the following must be confirmed: (1) the disease cannot be treated by conventional medical or surgical therapy (e.g., no correctable disease such as abnormal origin of coronary artery), (2) there is no organ failure other than the heart, (3) there is no systemic infection, and (4) the caregivers have a good understanding of transplant medicine and are compliant with the treatment.^37,42

4.2 Model Selection

The model of VAD is selected based on VAD placement reason (bridge to recovery [BTR], bridge to decision [BTD], bridge to transplantation [BTT], etc.), body size, need for RVAD, expected duration of assistance, and availability of insurance coverage. Percutaneous extracorporeal membrane oxygenation (ECMO) without opening the chest is useful in cases of acute cardiogenic shock where the primary disease, neurological complications, indications for heart transplantation, and family intentions are unknown.^47,50,51 However, if the left ventricle is dilated without aortic valve opening under ECMO assistance, left ventricular decompression is necessary, and central ECMO with open chest or LVAD or biventricular assist device (BiVAD) combined with ECMO should be used.⁴⁷ Oxygenators should be avoided as much as possible because they promote inflammation and coagulation. Off-label centrifugal pumps for extracorporeal circulatory devices are currently used as short-term VAD pumps in Japan and other countries, but complications such as thrombus and hemolysis are common due to low blood volume delivered in small children; the development of long-term durable, safe centrifugal pumps^48,49 is underway. IMPELLA⁵² and TandemHeart⁵³ will be used for larger stature children in the future.

If long-term circulatory support is required, an extracorporeal EXCOR or a continuous-flow implantable VAD such as HM-II,⁵⁴ HeartWare HVAD,^55,56 Jarvik2000, or HM-3 should be selected. The EXCOR is available in a variety of pump sizes (10, 15, 25, 30, 50, and 60 mL) and delivery cannula sizes (5, 6, 9, and 12 mm), to allow the appropriate size choice for individual patients.^38,39,57 In contrast, a growing number of institutions are choosing continuous-flow implantable VADs for larger children with the expectation of durability and improvement in activities of daily living. In children with various ventricular morphologies, it is important to insert the bleeding cannula parallel to the ventricular septum.^56–58

5. Diseases Indicated for Ventricular Assist Device (VAD)

5.1 Acquired Heart Disease

The indications for an implantable left ventricular assist device (LVAD) include: dilated and dilated-phase hypertrophic cardiomyopathy, ischemic myocardial disease, valvular disease, congenital heart disease, and post-myocarditis cardiomyopathy.^59,60 An implantable LVAD should be considered in patients with progressive symptomatic stage D heart failure, despite adequate standard therapy as recommended in the guidelines.

However, implantable LVADs may not be indicated or may be ineffective due to comorbidities, such as moderate or severe aortic valve insufficiency that is difficult to treat, cardiac shunt, mechanical aortic valve, severe right ventricular dysfunction, or small left ventricular cavity or diameter;⁶¹ therefore careful consideration is necessary.

5.1.1 Idiopathic Cardiomyopathy

a. Dilated Cardiomyopathy

Dilated cardiomyopathy, defined as “a group of diseases characterized by (1) diffuse left ventricular contractile impairment and (2) left ventricular enlargement”,⁶² is classified by morphology and function. Clinically, it is necessary to differentiate it from secondary cardiomyopathies with similar features, including those with the following causes: hypertensive heart disease, ischemic heart disease, valvular heart disease, anemia, endocrine heart disease, alcoholic heart disease, peripartum cardiomyopathy, left ventricular noncompaction, myocarditis, neuromuscular disease, Fabry disease, hemochromatosis, metabolic disease, sarcoidosis, and amyloidosis.⁶² As some of these secondary cardiomyopathies are not amenable to implantable LVADs, identification of the causative disease is important.

b. Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is defined as a group of diseases characterized by (1) hypertrophy of the left or right ventricular myocardium and (2) left ventricular diastolic dysfunction based on cardiac hypertrophy.⁶² It is important to differentiate from secondary cardiomyopathy associated with systemic diseases with extracardiac lesions or with other storage diseases, such as Fabry disease and amyloidosis, for which disease-specific treatments are available.

Although an implantable LVAD may not be indicated in hypertrophic cardiomyopathy with an extremely narrow cavity, it may be indicated for endstage patients with heart failure symptoms refractory to medical therapy in the dilated phase and for patients with refractory lethal arrhythmias without left ventricular outflow or with mid-ventricular obstruction.

c. Other Idiopathic Cardiomyopathies

The pathophysiology of restrictive cardiomyopathy is left ventricular diastolic dysfunction, and any of the following 4 conditions are criteria for its diagnosis: (1) presence of a stiff left ventricle, (2) absence of left ventricular enlargement or hypertrophy, (3) normal or near-normal left ventricular systolic function, and (4) unknown cause (underlying cardiac disease).⁶³ Constrictive pericarditis and cardiac amyloidosis are underlying diseases that must be differentiated; neither is an indication for an implantable LVAD.⁶⁵ Other idiopathic cardiomyopathies to be considered are: cardiac hemochromatosis, endomyocardial fibrosis, and radiation myocardial damage. Arrhythmogenic right ventricular cardiomyopathy is based on fatty infiltration of the myocardium primarily in the right ventricle, resulting in right ventricular dilatation and ventricular arrhythmias of right ventricular origin.⁶⁵ The prognosis is poor for complicated left ventricular dysfunction, as right heart failure is often in the foreground; thus careful evaluation is necessary for each individual patient to determine whether an implantable LVAD will truly improve the hemodynamics and symptoms.

5.1.2 Secondary Cardiomyopathy

The causes of secondary cardiomyopathy are diverse but often associated with systemic disease, and serious consideration should be given to whether cardiac function can be improved with treatment other than heart transplantation or VADs, and whether aggressive treatment is available.

a. Ischemic Cardiomyopathy

Ischemic cardiomyopathy is a severe ischemic heart disease characterized by left ventricular enlargement and wall motion abnormalities similar to those of dilated cardiomyopathy, caused by chronic ischemia from extensive myocardial infarction or multivessel disease. Before considering a VAD, it is important to evaluate the coronary artery lesions and residual ischemia, and to perform as much revascularization as possible, and finally, provide adequate medical treatment for heart failure. Control of risk factors, such as diabetes mellitus and hypertension, are important, as well as confirming good patient adherence.

b. Myocarditis

Implantable LVADs are indicated when lymphocytic myocarditis is followed by prolonged cardiac dysfunction resembling dilated cardiomyopathy, or when chronic myocarditis progresses to a condition analogous to dilated cardiomyopathy. Eosinophilic myocarditis and giant cell myocarditis may also be indicated when steroid therapy is unsuccessful.

c. Cardiac Sarcoidosis

The diagnosis of cardiac sarcoidosis can be complicated, as differentiation from dilated cardiomyopathy, chronic myocarditis, and giant cell myocarditis is necessary. Sometimes patients are diagnosed only after histological examination of the myocardium obtained during heart transplantation or left ventriculoplasty or based on a sample taken at autopsy.⁶⁶ Although steroids, which are specific treatment for this disease, have been reported to improve exercise tolerance even in patients with severe cardiac dysfunction,⁶⁷ some reports have shown no improvement in cardiac function and a poor prognosis.^68,69 Implantable LVADs are indicated for (1) systemic sarcoidosis in which cardiac function does not improve despite controlled inflammatory activity using low-dose steroids, or (2) cardiac sarcoidosis in which cardiac function does not improve regardless of steroid administration. However, the indications should be carefully assessed, with particular consideration given to steroid-related infections.

d. Drug-Induced Cardiomyopathy

In patients treated with anthracyclines, cardiomyopathy may develop ≥1 year after the end of treatment and it can be severe. Indications of VAD should be considered with special reference to the duration of complete remission of the primary malignant tumor, the possibility of recurrence, and the effect on prognosis.

e. Muscular Dystrophy

In patients with cardiomyopathy associated with muscular dystrophy, VADs are indicated when the progression of systemic myopathy is slow, such as in Becker muscular dystrophy, and the patient’s prognosis is determined by the cardiac disease.⁷⁰ VADs may not be indicated in patients with pre-existing skeletal muscle disorders; collaboration with a neurologist is critical.

f. Other Secondary Cardiomyopathies

Among other secondary cardiomyopathies, cardiomyopathy associated with Danon disease, mitochondrial cardiomyopathy, and congenital metabolic disorder require careful evaluation of the indications, giving appropriate consideration to the various accompanying symptoms and complications in other organs.

g. Fatal Arrhythmia

Patients with INTERMACS Profile 4–6 who are not dependent on inotropic therapy may be eligible for implantable LVADs as modifier A if they have hemodynamic compromise due to ≥2 fatal arrhythmias or proper activation of an implantable cardioverter defibrillator (ICD) within 1 week.

5.2 Congenital Heart Disease (CHD)

In recent years, the VAD has become established as a therapeutic strategy for CHD, but its indications, contraindications, and timing remain controversial.^71,72 In general, heart transplantation and VADs are effective for the treatment of systemic ventricular failure, but many issues remain regarding the indications for a single ventricle, especially in failing Fontan patients with hepatic and cardiac dysfunction due to chronic heart failure, congenital malformations (pulmonary artery and vein stenosis), and protein-losing enteropathy (PLE).⁷¹ Therefore, when considering the indications for a VAD, it is important to carefully consider the systolic and diastolic functions of the systemic ventricles, the degree of atrioventricular regurgitation, and any complications specific to the disease. Although the procedure is often performed in adulthood, it is essential to have detailed knowledge specific to the particular CHD (e.g., situs inversus, pulmonary arteriovenous abnormalities, and aortic abnormalities). Therefore, it is recommended that the procedure be performed at a facility with experience in heart transplantation and VADs, as well as extensive experience in surgery and long-term management of CHD, especially complex congenital heart disease such as Fontan.⁷²

According to the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) 2018,⁷³ of the 423 pediatric VADs, 86 were for CHD with an age of 5.7±5.8 years and a weight of 21.7±23.5 kg at the time of placement, and 52 (61%) were cases of single ventricle. There were 52 cases of placement as bridge to transplantation (BTT), 22 cases of bridge to candidacy (BTC), 1 case of destination therapy (DT), 7 cases of bridge to recovery (BTR), and 4 other cases; 66 cases of LVAD, 11 cases of right ventricular assist device, 7 cases of biventricular assist device, and 2 cases of total artificial heart (TAH). INTERMACS Profile 1 is more common in CHD (24.6%), and especially in patients with a single ventricle, extracorporeal VADs tend to be more commonly placed than in patients with 2 ventricles (Table 6).⁷³ The prognosis of CHD is poorer than that of other cardiac diseases due to the high prevalence of multiple organ failure; thus it is important to consider the appropriate timing of VAD placement. Noteworthy is that the use of VADs in CHD has been reported to improve the prognosis and quality of life (QOL), as well as the outcome of heart transplantation after BTT.

Table 6. Percentage of CHD According to INTERMACS Profile and Type of VAD

	INTERMACS Profile		Extracorporeal pulsatile VAD	Extracorporeal non-pulsatile VAD	Implantable non-pulsatile VAD
	1	2
Single ventricle	20	26	15	22	13
Biventricular	14	14	10	8	10
Total	34 (24.6)*	40 (17.2)*	25 (20.7)**	30 (38.7)**	23 (11.7)**

*Percentage of CHD in each INTERMACS Profile (%). **Percentage of CHD in each VAD (%). (Source: based on Morales et al, 2019.⁷³) CHD, congenital heart disease; VAD, ventricular assist device.

5.2.1 Selection of Implantable VAD Models

For implantable VADs, continuous-flow implantable VADs, such as the HeartMate (HM)-II, HVAD, Jarvik2000, and HM-3, are selected based on body size, thorax shape, size and shape of the heart, and the location of the ventricles and large vessels. An analysis of adult patients on the US heart transplantation waiting list showed that 1,800 of 30,925 patients with medical urgency level 1 had CHD, of whom 37 were BTT; HVAD was used in 20 patients, HM-II in 14 patients, Jarvik2000 in 2 patients, and HM-XVE in 1 patient.^74,75

By the end of December 2019, there were 3 CHD patients who underwent heart transplantation in Japan, of whom 2 were BTT: 1 underwent transplantation at 1,257 days after EVAHEART placement,⁵⁸ and the other at 149 days after EXCOR placement. In contrast, in J-MACS, 16 of 945 patients with implantable VADs as of April 30, 2019 had CHD, all with primary LVADs; unfortunately, however, the diseases and LVAD models are unknown. To date, EVAHEART,^58,76 Jarvik2000,^77,78 HM-II, and HVAD have been used, but the use of HVAD and HM-3 is expected to increase in the future.

5.2.2 VAD for Failing Fontan Patients

Due to the aging of Fontan patients and the shortage of donors for heart transplantation, the role of mechanical circulatory support (MCS) as a treatment for single ventricle is becoming increasingly important in Europe and the USA, but its indications remain controversial.^72,73 The current MCS devices have been developed to provide circulatory support for the failing systemic ventricle in patients with a biventricular heart. To date no Fontan-specific MCS device has been developed; the use of MCS for Fontan circulation has only been reported in some case reports. Failing Fontan includes various disease groups. VADs are effective for systemic ventricular failure, but less effective in the absence of pulmonary ventricles, congenital malformations (pulmonary artery and vein stenosis), and cases of PLE. When a VAD is placed in the systemic ventricle, the pulmonary artery wedge pressure decreases, resulting in a decrease in pulmonary artery pressure, which improves congestion in the systemic venous system. However, it is extremely difficult to develop a VAD specifically for the right ventricular system that can remove blood from the low pressure venous system, and it has not yet been achieved; ECMO is currently used only temporarily. Therefore, the use of VADs for failing Fontan has only been reported in case reports, which include VADs for BTT^79–81 and TAH,^82,83 but there are no reports of such VAD use in DT. HM-3 has also been reported.⁸⁴

In recent years, even though VADs for failing Fontan (attached to the Glenn anastomosis and pumping blood from the superior and inferior venae cavae to the bilateral pulmonary arteries) have been studied,⁸⁵ it will take time for clinical application.

5.3 Eligibility/Ineligibility Criteria for Implantable LVADs

The severity of heart failure should be evaluated first when considering an implantable LVAD, then the indications for LVAD implantation should be evaluated considering the risk of coexisting cardiac disease requiring surgical intervention, the surgical risk of LVAD implantation, the risk of complications after implantation, the patient’s and caregiver’s willingness and ability to manage the implantable LVAD, and the management system.⁸⁶

5.3.1 Severity

The INTERMACS Profile classification was proposed to further subdivide severe heart failure (NYHA functional class III–IV) according to the patient’s condition and disease course, and the expected time until further intervention such as mechanical assisted circulation or heart transplantation is required.⁸⁷ In Japan, the J-MACS classification is used as a similar classification (Table 7).⁸⁸

Table 7. INTERMACS and J-MACS Classifications and Options of Device Therapy

Profile	INTERMACS	Status	Options of device therapy
	J-MACS
1	Critical cardiogenic shock “crash and burn”	Patients with compromised hemodynamics and peripheral hypoperfusion despite rapid escalation of intravenous inotropes and/or introduction of mechanical circulatory support	IABP, peripheral VA-ECMO, percutaneous VAD, centrifugal pumps for extracorporeal circulation, and paracorporeal VADs
2	Progressive decline despite inotropic support “sliding on inotropes”	Patients with declining renal function, nutritional status, and signs of congestion despite intravenous inotropes and required incremental doses	IABP, peripheral VA-ECMO, percutaneous VAD, centrifugal pumps for extracorporeal circulation, paracorporeal VADs, implantable LVADs
3	Stable but inotrope-dependent “dependent stability”	Patients with stable hemodynamics on intravenous inotropes at relatively low doses, but physicians are not able to discontinue the intravenous treatment because of the risk of hypotension, worsening symptoms of heart failure, or worsening renal function	Implantable LVADs
4	Resting symptoms “frequent flyer”	Patients who can be weaned from intravenous inotropic support temporarily and can be discharged from hospital, but may soon repeat hospitalization for worsening heart failure	Consider implantable LVADs (especially patients with modifier A*)
5	Exertion intolerant “house- bound”	Patients who can do daily routines in the home, but have significant limitations in activities of daily living, and can barely go out	Consider implantable LVADs for patients with modifier A*
6	Exertion limited “walking wounded”	Patients who can go out, but have difficulty in doing anything other than light activities, and have symptoms while walking <100 m
7	Advanced NYHA classification class III “placeholder”	Patients can walk >100 m without fatigue, and have had no hospitalizations in the recent 6 months

*Recurrent appropriate ICD shocks due to life-threatening ventricular arrhythmias. (Adapted from 2021 JCS/JHFS “Guideline focus update for the treatment of acute and chronic heart failure” 2021.⁸⁸) IABP, intra-aortic balloon pump; ICD, implantable cardioverter defibrillator; INTERMACS, interagency registry for mechanically assisted circulatory support; LVAD, left ventricular assist device; NYHA, New York Heart Association; VAD, ventricular assist device; VA-ECMO, veno-arterial extracorporeal membrane oxygenation.

Implantable LVADs are indicated for INTERMACS (J-MACS) Profile 2 and 3 patients who are dependent on intravenous inotropic drugs, despite the use of adequate guideline-recommended standard therapy. Profile 3 includes hemodynamically and clinically stable patients under relatively low-dose intravenous inotropic drugs but dose reduction or withdrawal is not possible due to hypotension, worsening of heart failure symptoms, dysfunction of kidneys and other parenchymal organs, and worsening of the nutritional status. Profile 2 includes patients with worsening renal function, nutritional status, and signs of congestion even under intravenous inotropic therapy, requiring increased doses of such drugs. Although both Profile 2 and 3 patients are inotropic drug dependent and eligible for implantable LVADs, the prognosis after LVAD implantation in Profile 2 is poorer than that in Profile 3. It has been reported that the INTERMACS Profile classification may differ among evaluators.⁹¹ In order to implant the LVAD at the appropriate time, it is important to distinguish between Profile 2 and 3, and between Profile 3 and 4, and it is recommended to involve multiple healthcare providers in the patient evaluation. It is also important not to miss any possible transition from Profile 3 to Profile 2, and to highly consider implantation in Profile 3.

INTERMACS (J-MACS) Profile 1 defines the condition as “compromised hemodynamics and peripheral hypoperfusion despite rapid escalation of intravenous inotropes and/or introduction of mechanical circulatory support”.⁶⁰ Peripheral hypoperfusion should be determined by physical examination as well as by elevated blood lactate level (2 mmol/L, 18 mg/dL) and progressive acidosis. Patients with Profile 1 are often not eligible for implantable LVADs because of complicated multiple organ damage, such as hepatic and renal disease and malnutrition, and would likely have a poor prognosis after LVAD implantation. Indications for implantable LVADs should be reconsidered after multiple organ function and nutritional status are improved by hemodynamic stabilization with other mechanical assist devices such as intra-aortic balloon pump (IABP), veno-arterial extracorporeal membrane oxygenation (VA-ECMO), IMPELLA, or extracorporeal VAD. If the patient is hemodynamically stable with these mechanical assist devices, has no organ dysfunction, such as the liver or kidneys, and has stable respiratory condition, the patient should be considered as INTERMACS (J-MACS) Profile 2 or 3. However, it is also important to confirm whether their neurological function, cognitive ability, and higher functions are preserved.

On the other hand, for INTERMACS (J-MACS) Profile 4 patients, a better prognosis has been reported after LVAD implantation compared with medical therapy.⁹² Though implantable LVADs may be considered in such cases, it is critical to evaluate not only the benefits of implantable LVADs in terms of improved prognosis and QOL, but also the risks of surgery and postoperative complications, the risk of reduced QOL in the event of complications, and the health economic benefits. Patients may be considered eligible if they qualify for modifier A, which refers to frequent and appropriate ICD activation due to drug-refractory fatal ventricular arrhythmias.⁸⁷ Patients with mild INTERMACS Profile 5–7 are not eligible for implantable LVADs unless they meet modifier A.

5.3.2 Age

Although the eligibility criteria for implantable LVADs include the preferable age of ≤65 years (though older age may be eligible depending on physical ability), there are no clear age ineligibility criteria. Aging is a well-known independent prognostic factor for implantable LVADs.^93,94 For the purpose of BTT, LVAD implantation may be considered even after the age of 65 years if the patient was registered on the heart transplant waiting list when younger than age 65, or if implantation for DT becomes feasible. In such cases, eligibility for an implantable LVAD should be evaluated by a multidisciplinary team, with reference to the Japan-VAD risk score and considering factors that are likely to affect the prognosis after implantation, such as comorbidities, nutritional status, sarcopenia, frailty, and cognitive function, as well as the postoperative management needed for the implantable LVAD and care system for the patient.

5.3.3 Body Size

Implantable LVADs are becoming smaller, with the recommended body surface area for implantation of 1.3 m², 1.1–1.2 m², and 1.2 m² for the HM-II, Jarvik2000, and for both the HM-3 and HVAD, respectively, although there have been reports of implantation in patients with smaller body surface areas. An experienced physician should be involved in making a comprehensive determination of implantation eligibility based on the patient’s body size, body surface area, and the specific anatomy of the planned implantation site. For children who are too small for these implantable LVADs, the pediatric Berlin Heart EXCOR may be considered.

5.3.4 Obesity

Obesity itself is not an ineligible criterion for implantable LVADs.^86,95 Although many reports have shown no significant difference in long-term life expectancy in very obese patients with body mass index ≥35 kg/m², caution should be exercised due to the reported early postoperative risk and higher incidence of pump thrombosis and driveline infections.^96–99

5.3.5 Pharmacologic and Nonpharmacologic Therapy

In the consideration of implantable LVAD eligibility, it is assumed that the standard medical therapy of the heart failure guidelines (beta-blockers, ACE inhibitors/ARBs, MRAs, ivabradine, ARNI, and SGLT2 inhibitors) is in use and intensified when possible, and that CRT and mitral valve interventions are in use when indicated.

Despite the above standard therapies, patients with the following should be considered for MCS, such as with an implantable LVAD: persistent NYHA functional class III–IV status, poor prognosis within 2 years (predicted by maximal oxygen uptake and prognostic score for heart failure) or inotropic dependence. It should be noted, however, that some reports indicate a lack of efficacy of CRT in patients with NYHA functional class IV with inotropic dependence.¹⁰⁰ Even though difficult for patients with new onset, severely decompensated heart failure (acute myocardial infarction or fulminant myocarditis), cardiac function must be assessed before possible improvement by the introduction of standard therapies after revascularization, surgical intervention, and circulatory support with intravenous inotropic drugs, and percutaneous or extracorporeal VADs. Also, cardiac rehabilitation, including exercise therapy, should be performed whenever possible.

5.3.6 Circulatory Support (IABP, VA-ECMO, IMPELLA, Extracorporeal VADs)

Current eligibility criteria for implantable LVADs in patients with circulatory support include dependence on IABP and extracorporeal VADs, as well as inotropic drugs. Implantable LVADs are indicated for IABP-dependent patients with stable circulation during IABP support but that worsens upon weaning. The same patient status (stable during support, but worsening upon weaning) is true for the indication for extracorporeal VADs.⁵ After long-term support with an extracorporeal VAD, infection at the skin penetration site of the inflow and outflow cannulas is often observed, and care must be taken to avoid pump pocket infection after replacement.¹⁰¹ In patients with left ventricular bypass using a centrifugal pump for temporary support, replacement with implantable LVAD is indicated as BTD in Europe and the USA,¹⁰² and the development of such a BTD protocol is urgently needed in Japan as well.⁴⁹ IMPELLA, a pump catheter for assisted circulation, is also used for temporary circulatory support until LVAD implantation.¹⁰³

Because VA-ECMO uses an artificial lung, coagulation factors and platelets are consumed, and bleeding complications often occur. Conversely, ischemic complications such as thromboembolism and ischemia of the lower extremities on the inflow side may also occur. In addition, assessment of right heart function and pulmonary vascular resistance (PVR) are difficult when the pulmonary circulation is reduced by VA-ECMO; right heart failure and pulmonary hypertension may become apparent after LVAD placement. Although patients with VA-ECMO who are generally unstable are not clearly ineligible for implantable LVADs, eligibility must be carefully considered for each patient.

5.3.7 Eligibility/Ineligibility Criteria for VAD in CHD

Although the outcome of VAD therapy for CHD has improved, the results are largely dependent on the experience of the individual institutions, and there is still no standardized indication for VAD in CHD. It is important not to miss the opportunity to use a VAD to avoid multiple organ failure, various postoperative complications, and the need for right heart assistance. In contrast, there are various risks associated with VAD therapy, and premature implantation should be avoided.^71,72

First, the need for a VAD should be evaluated in all patients who are inotropic therapy-dependent. VAD should be considered in patients with heart failure requiring artificial respiratory support, but in Japan, unlike in Europe and the USA, an implantable VAD cannot be used unless the patient is judged to be a candidate for heart transplantation. Therefore, circulatory support in BTD can only be provided by a centrifugal pump for extracorporeal circulation or a Nipro VAD. Because respiratory failure is rare in teenagers and adults, a VAD should be considered if signs of multiple organ failure, such as hepatic and renal dysfunction, eating difficulty and malnutrition, worsen under inotropic therapy.

In CHD, morphologic assessment is important. The morphology, size, and connecting status of the ventricles and large vessels and surgical history (e.g., systemic-to-pulmonary artery shunt, Glenn procedure, Fontan operation) are evaluated to determine the VAD model, pump location, method of attaching the inflow and outflow cannulas, and drive line routing.

Most common CHDs for which VADs are indicated are corrected transposition of the great arteries or post-atrial switch for complete transposition of the great arteries^104–106 and failing Fontan.^71–73

As with other cardiac diseases, ineligibility criteria for VAD treatment include the following: (1) irreversible disorders of vital organs, (2) uncontrolled systemic infection, (3) uncontrolled coagulation disorders, (4) malignant diseases, (5) severe psychoneurologic and motor developmental disorders, (6) abnormalities of the pulmonary arteriovenous system (e.g., PVR ≥6 Wood units, severe systemic-to-pulmonary artery collaterals), and (7) complicated congenital diseases, metabolic diseases, and chromosomal abnormalities with a poor prognosis.

Regarding (1) above, hepatic complications associated with Fontan circulation and PLE are of particular concern. A liver biopsy may be necessary to determine if the hepatic damage is irreversible. Percutaneous liver biopsy is often not possible due to ascites or coagulation abnormalities; in such patients a transvenous liver biopsy should be considered. It has been reported that PLE is not a prognostic factor after heart transplantation,¹⁰⁷ and may basically be reversible, but it is necessary to carefully determine the status of each patient. As for PVR, many reports have shown that pulmonary hypertension improves in children who successfully undergo LVAD implantation, and thus the indication may be expanded in the future.

5.3.8 Eligibility/Ineligibility Criteria in the Presence of Comorbidities

Implantable LVADs are associated with various early- and late-onset postoperative complications. In addition, if the patient’s QOL is not sufficiently improved by LVAD treatment and worsens to require repeated hospitalization, then the cost and caregiver’s burden may become significant issues. Therefore, it is necessary to meaningfully evaluate the specific conditions involved in short- and long-term outcomes.

Severe irreversible liver disease, such as cirrhosis, and severe chronic renal failure requiring dialysis¹⁰⁸ are contraindications; however, hepatic or renal dysfunction in severe heart failure is not an ineligible criterion if sufficient functional improvement can be achieved with improvement of heart failure, although such determination is often difficult. If organ specialists’ evaluations determine that the patient has potential for recovery, despite severe laboratory abnormalities, IABP and extracorporeal VADs are used to improve hemodynamics.^109–111 In such cases, if functional improvement is achieved, then an implantable VAD is indicated. Residual functional impairment, despite treatment optimization, is a poor prognostic factor, especially estimated glomerular filtration rate <30 mL/min/1.73 m², total bilirubin >3 g/dL,¹¹² and Model for End-stage Liver Disease (MELD) score >17,¹¹³ which are reported as high-risk criteria.

Pulmonary hypertension associated with left heart failure often improves after LVAD placement, even with a high PVR (>6 Wood units), which is not indicated for transplantation.^114,115 However, data on the upper limit are scarce, and persistent high levels despite appropriate treatment should be carefully noted because of the increased risk of right heart failure.

Because chronic lung disease also has a significant effect on postoperative outcomes, respiratory function tests are important. To avoid the effects of pulmonary congestion associated with heart failure, evaluation should be performed during controlled pulmonary congestion. Advanced chronic obstructive pulmonary disease with forced expiratory volume 1.0% <50% and chronic restrictive lung disease with %VC (Vital Capacity) <50% are ineligible criteria.¹¹

Although diabetes mellitus has been reported as a risk factor for infection and brain complications after VAD placement,¹¹⁶ it has also been reported not to affect prognosis,¹¹⁷ and is not a contraindication. However, insulin-dependent diabetes mellitus with severe end-organ damage, and diabetes mellitus with poor glycemic control, despite the appropriate treatment, require careful evaluation.

Uncontrolled active infection,¹¹⁸ severe bleeding tendency, and severe peripheral vascular disease with rest pain or ulceration¹¹² are contraindications because of the high surgical risk. Severe central nervous system disorders, psychiatric disorders, drug addiction, and alcoholism may interfere with VAD management and medication, and thus are also contraindications. Malignancy is a contraindication if life expectancy is not expected to exceed 5 years.

Even in conditions that are not contraindications alone, the accumulation of these factors may worsen the long-term outcome. Therefore, it is critical to refer to a risk score that predicts survival after LVAD implantation.^119,120

Among the complications of valvular heart disease, aortic insufficiency (AI) requires particular attention. In patients with AI, much of the blood flow to the ascending aorta is regurgitated into the left ventricle, increasing LVAD flow but decreasing systemic blood flow, ultimately resulting in symptoms of left heart failure. Worsening of AI after LVAD implantation has been reported,^121–123 and moderate or severe AI has been considered as ineligible. Interestingly, however, favorable results have recently been reported with the addition of aortic valve surgery (bioprosthetic valve replacement, valvuloplasty, or patch closure) during LVAD surgery.^124–126 Other valvular diseases, such as tricuspid regurgitation and mitral valve disease, are not ineligible, but concomitant surgery is a controversial topic.

Previous prosthetic valve replacement is not a contraindication if a bioprosthetic valve is used, but it is generally ineligible if a mechanical aortic valve is used because of the high risk of thrombus formation due to low blood flow through the valve, leading to embolization during valve release.¹²⁷ However, in recent years, positive results have been reported for conversion to a bioprosthetic valve and valve closure with a patch.^128–130 Mechanical mitral valves are not contraindications, but they require rigorous anticoagulation.^131,132

In acute myocardial infarction, LVAD with cannulation of the left ventricular apex as the outflow renders a higher risk as the left ventricular wall is fragile and the lumen is not expanded. In particular, patients with ventricular septal perforation are contraindicated. In postinfarction ventricular aneurysm, simultaneous left ventriculoplasty and LVAD placement is relatively easy.^133,134 There has been a report of aortic surgery performed simultaneously with LVAD placement in patients with thoracic aortic aneurysms, but the treated lesions were limited to the ascending aorta.¹³⁵ Patients with severe atherosclerotic lesions in the ascending and aortic arch are ineligible because of the high risk of intraoperative and postoperative cerebral infarction.

5.3.9 Support From Caregivers

Support from caregivers is important for patients with implantable LVADs; likewise mental and financial support from spouse, parents, siblings, or children is beneficial for continued treatment. Generally, it is also important for caregivers to be within the range of the alarm. Caregivers are often, but not always, live-in family members. The primary caregivers should be adults. The use of social resources, such as social workers and counselors, may also be effective.

6. Indications for Right Ventricular Assist Device (RVAD) and Biventricular Assist Devices (BiVAD)

In general, few patients with right heart failure alone require a RVAD, and the INTERMACS report shows that RVAD implantation alone is <0.2%.³⁰

If sufficient LVAD flow cannot be maintained even with inotropic therapy and pulmonary vasodilators after LVAD implantation and right heart failure occurs, RVAD implantation is necessary; ≈3.5% of such patients need RVAD for severe right heart failure.^30,136 In a multicenter study of BTT patients in Japan, <1% of patients with HM-II required a RVAD,¹³⁷ suggesting a device selection bias. In addition, there are no reports on the effect of devices on the right heart.

Although there have been reports of patients who were able to wait until heart transplantation with BiVADs,^138,139 only extracorporeal devices are currently available as RVADs in Japan.

In general, the prognosis of patients requiring RVADs is poorer than that of patients with LVADs alone.^136,140,141 More than half of patients can be weaned from the RVAD within 1–2 weeks after LVAD placement, and it has been reported that the prognosis of patients weaned from RVADs is not poorer than that with LVADs alone.¹⁴²

II. Perioperative Management

1. Preoperative Management

Prior to left ventricular assist device (LVAD) implantation various issues must be considered regarding preoperative management (Table 8).

Table 8. Points of Consideration Regarding Management Before LVAD Implantation

Issues to be considered	Points of preoperative management
INTERMACS	Maintain INTERMACS Profile 3 or higher, whenever possible
Liver dysfunction	Optimization of hemodynamics and fluid status will lead to improvement of organ function. Mechanical circulatory support such as IABP, IMPELLA, VA-ECMO, and ultrafiltration should be considered if necessary
Kidney dysfunction
Right heart failure
Arrhythmia	Aggressive intervention, including catheter ablation, should be considered
Infection (bacteremia, sepsis)	Infection control with antimicrobial drugs, intervention by infection control teams and appropriate antimicrobial use support teams
Electrolyte disturbance	Correct aggressively. Consider use of appropriate diuretics
Bleeding/thrombotic tendency	Understanding coagulation function and searching for predisposition to thrombosis. Control the risk of bleeding. Blood transfusion should be considered if necessary
Diabetes mellitus	Aggressive glycemic control
Obesity	Aggressive weight control
Malnutrition	Assessment of nutritional status, intervention by a nutritional support team, and occasionally enteral or intravenous nutrition should be considered
Muscle weakness	Introduction of cardiac rehabilitation
Gastrointestinal complications	Identify and treat hemorrhagic lesions

IABP, intra-aortic balloon pump; INTERMACS, interagency registry for mechanically assisted circulatory support; LVAD, left ventricular assist device; VA-ECMO, veno-arterial extracorporeal membrane oxygenation.

1.1 Heart Failure and Arrhythmia

Patients who undergo LVAD placement after circulatory collapse due to advanced heart failure or ventricular tachyarrhythmia have a high postoperative mortality rate.¹⁴³ The use of mechanical circulatory support (MCS), such as intra-aortic balloon pump (IABP) or IMPELLA, should be considered in patients with refractory organ failure. Patients who had IABP placed before LVAD surgery have a similar postoperative prognosis despite more severe condition than those without IABP, suggesting a risk reduction by IABP.^109,144 Preoperative evaluation and management of right ventricular function is also essential, and the use of diuretics, renal replacement therapy, inotropic agents, and MCS, including IABP, IMPELLA, and veno-arterial extracorporeal membrane oxygenation (VA-ECMO), should be considered to improve right ventricular failure.^95,145 Catheter ablation can be considered for drug-refractory atrial tachyarrhythmias, and BiVAD should be considered for refractory ventricular tachycardia and ventricular fibrillation.^95,145

1.2 Respiratory Dysfunction and Pulmonary Hypertension

As with conventional cardiovascular surgery, smoking cessation and respiratory physical therapy are important to prevent postoperative complications of LVAD surgery. Pulmonary hypertension due to left heart disease can generally be improved after LVAD implantation,¹⁴⁶ but patients with severe pulmonary hypertension are ineligible for LVAD implantation because of the high probability of irreversibility. The reversibility of pulmonary vascular resistance should be assessed during preoperative right heart catheterization. There is no clinical evidence that preoperative administration of oral pulmonary vasodilators such as PDE5 inhibitors and endothelin-receptor antagonists can prevent post-LVAD right heart failure; rather, it might be harmful.^146–148

1.3 Renal Dysfunction

Although renal dysfunction associated with heart failure is expected to recover to some extent after LVAD implantation, patients with irreversible renal dysfunction are currently ineligible for heart transplantation. When patients have renal dysfunction, urinalysis, renal ultrasonography, and evaluation of renal artery disease should be performed to confirm the absence of primary renal diseases. It has been reported that estimated glomerular filtration rate <30 mL/min/1.73 m² could be considered as irreversible renal insufficiency.¹⁴⁹ Renal failure due to low cardiac output should be treated preoperatively with inotropes or MCS; fluid retention due to renal insufficiency should be treated with aggressive diuresis or ultrafiltration.⁹⁵ The JCS 2017/JHFS 2017 “Guideline on diagnosis and treatment of acute and chronic heart failure” recommend the use of vasopressin V₂ receptor antagonists (e.g., tolvaptan) and loop diuretics.⁶⁰ Administration of tolvaptan before LVAD implantation surgery has been reported to be effective in the management of heart failure;¹⁵⁰ however, the clinical evidence of efficacy of tolvaptan in the perioperative period has not been established.

1.4 Liver Dysfunction

Liver dysfunction associated with heart failure is mainly caused by hepatic ischemia due to hypoperfusion and hepatic congestion due to increased right atrial pressure. The more severe the liver dysfunction, the greater the risk of postoperative bleeding and death.¹⁵¹ A total bilirubin level >5 mg/dL is reported to have a poor post-LVAD prognosis.¹⁵² In patients with a history of liver disease or chronic right heart failure, liver cirrhosis should be screened and consultation with a hepatologist before LVAD implantation is recommended.⁹⁵ When liver dysfunction is refractory, implementation of inotropes and MCS should be considered.⁹⁵

1.5 Electrolyte Abnormalities

With the progression of heart failure, dilutional hyponatremia may occur due to increased blood vasopressin levels caused by low cardiac output and increased water reabsorption in the renal collecting ducts.¹⁵³ Implantation of a LVAD during hyponatremic status may result in central pontine myelinolysis due to rapid correction of serum sodium levels caused by the increased cardiac output and decreased blood vasopressin levels.¹⁵⁰ Therefore, it is advisable to normalize the serum sodium levels as much as possible before surgery.

Correction of serum sodium levels in patients with severe heart failure and hyponatremia is difficult by fluid restriction alone; often tolvaptan, a vasopressin V₂ receptor antagonist, is required.^154,155 To avoid hemodynamic disruption due to excessive aquaresis, it is recommended to start with a low dose and gradually correct the serum sodium levels.¹⁵⁶

1.6 Bacteremia and Sepsis

Patients undergoing LVAD implantation are at higher risk of postoperative infections than those undergoing conventional open-heart surgery because of the possibility of immunodeficiency due to heart failure and/or the implantation of devices.^157,158 Bacteremia after LVAD implantation has also been reported to be associated with cerebrovascular disease in patients with LVAD.^159–161

Screening by laboratory analyses (general blood tests, blood C-reactive protein level, chest X-ray) and/or bacterial culture (sputum, nasal cavity, pharynx) should be carried out. As well, preoperative patient hygiene should be carried out, including whole body skin cleansing, gargling, hand washing, and prevention of tooth decay.

1.7 Gastrointestinal Complications

In LVAD therapy requiring anticoagulant and antiplatelet therapy, prevention of preoperative gastrointestinal complications is critical not only for intra- and perioperative management, but also for long-term postoperative management.^162,163 Gastrointestinal hemorrhage is reported to be more frequent in elderly LVAD patients,¹⁶⁴ so special attention should be paid to both the middle-aged and elderly. Multiple preoperative fecal occult blood tests should be performed to screen for gastrointestinal bleeding; if suspected, the source of bleeding must be identified by a gastroenterologist and aggressive treatment should be started. Patients with an active peptic ulcer or uncontrolled gastrointestinal bleeding are not indicated for implantable LVAD.

1.8 Peripheral Arterial Disease

It is important to provide appropriate rehabilitation and to consider and implement reperfusion therapy before LVAD implantation. Unfortunately, acute artery hypoperfusion due to thrombosis of the extremities can occur as a complication of implantable LVADs, so thorough assessment of the peripheral arteries of the extremities is important.

1.9 Diabetes, Obesity, and Nutritional Disorders

Insulin-dependent diabetes mellitus complicating diabetes-related comorbidity and uncontrolled diabetes mellitus, despite appropriate treatment, are contraindications to heart transplantation; patients with these diseases might need discussion to decide the indication for an implantable LVAD. However, patients with diabetes mellitus are not always ineligible. Although some reports have suggested that diabetes mellitus does not affect the prognosis after implantable LVAD surgery,^165,166 and others have reported that diabetes mellitus improves after LVAD implantation.^165,167 However, a high incidence of infectious complications and hemolysis after LVAD implantation with diabetes mellitus have also been reported.^165,168 Therefore, preoperative diabetic management is extremely important. Aggressive treatment for diabetes mellitus should be given and patients and their caregivers must understand the necessity of diabetic management. Likewise, diabetic retinopathy must be appropriately treated by an ophthalmologist before surgery, as postoperative retinal hemorrhage could occur due to anticoagulation therapy after LVAD implantation. Furthermore, visual impairment caused by diabetic retinopathy may affect the patient’s ability to manage the LVAD equipment and daily care. In such cases, support from caregivers is necessary.

Obesity has been reported to have no effect on the prognosis after implantable LVAD surgery,^169–171 although it has been reported to increase the risk of pump thrombosis and rehospitalization for heart failure;^170,171 therefore, preoperative improvement of obesity is advised.

The nutritional management of patients with severe heart failure influences both the peri- and postoperative course.¹⁷² It has been reported that cardiac cachexia occurs in 35–55% of patients with severe heart failure.^173–175 Because the energy needs of patients with severe heart failure increase by 30–50%, based on the increased energy needs of the heart,^173,176 those heart failure patients who need an implantable VAD have a high rate of nutritional disorders. Pre- and postoperative malnutrition is associated with a poor prognosis.^177–181 It is important to appropriately evaluate nutritional assessments using the Mini Nutritional Assessment (MNA), the Controlling Nutrition Status (CONUT) score, or the prognostic nutritional index (PNI). If the nutritional requirements cannot be met orally, central venous nutrition or tube feeding may be indicated.

1.10 Neuropsychiatric Function

Decreased sleep quality, increased daytime sleepiness, and decreased self-care ability are often observed before LVAD implantation,^182,183 and may persist even after surgery.¹⁸³ Patients may become mentally unstable and depressed due to disease-related anxiety, uncertainty about the future and a sense of loss; sometimes they express their frustration and dissatisfaction to others. Psychiatric management and counseling by specialists are necessary. It is also known that patients and caregivers endure various stresses from the perioperative to late postoperative period.^184,185 Therefore, proactive interventions, such as setting up a place where patients and caregivers can easily consult with psychiatrists, clinical psychologists, and liaison nurses prior to surgery, can contribute to maintaining a good psychological quality of life (QOL) after surgery.

Because neurologic dysfunction due to cerebrovascular disease is one of the complications of implantable LVADs, preoperative neurologic assessment is essential to determine the preoperative status, which facilitates the differentiation of whether such dysfunction is new onset or not. Standard neurologic function tests should be performed by a neurologist with the appropriate diagnostic testing and consultation.

1.11 Advance Care Planning (ACP)

Although palliative care has been developed for cancer and acquired immune deficiency syndrome, according to a 2014 World Health Organization report cardiovascular disease is the top category among those requiring palliative care.¹⁸⁶ It is often difficult to determine when to introduce palliative care in severe heart failure, and it is important to conduct ACP at an early stage to prepare for future changes in the patient’s condition, including end of life. ACP is the entire process of planning for patient care achieved by early dialog (patients, caregivers, and medical professionals) before the patient’s decision-making ability declines; the goal is for the patient to lead a satisfied life to the end of life. ACP has been shown to reflect patients’ wishes at the end of life, reduce rates of depression and anxiety, and increase satisfaction.¹⁸⁷

One part of ACP is the advance directives. A multidisciplinary team assists the patient in making decisions about whether or not to resuscitate or prolong life at the end of life, and prepares an advance directive. The main purpose of ACP is to share the patient’s views on values, life, and death with caregivers and medical professionals, and it is not to make decisions about treatment.

Palliative care, ACP, and advance directives are not specific to implantable LVAD therapy and should be initiated at the start of treatment for stage D severe heart failure;⁶⁰ ACP regarding endstage treatment should be implemented again when an implantable LVAD becomes necessary, because the LVAD is a life support device. During ACP discussions with patients and caregivers, the patient’s wishes regarding analgesia, sedation, nutritional support through gastrostomy tube or intravenous infusion, artificial respiration, dialysis, implantable cardioverter defibrillator/pacemaker, and assisted circulation therapy, including implantable LVAD, should be confirmed in the advance directives, assuming that at that time patients will be unable to communicate their wishes.

The 2016 ESC guidelines define the “end of life” as the following: (1) progressive decline in physical and mental functioning that requires assistance with most activities of daily living, (2) a significant decline in QOL despite appropriate pharmacologic and nonpharmacologic treatments, (3) frequent hospitalization or severe deterioration without indication for heart transplantation or VAD, and (4) clinical condition that is considered to be close to the end of life due to cardiac cachexia.¹⁸⁸ With reference to the above, a multidisciplinary medical team, consisting of physicians, nurses, clinical psychologists, social workers, certified artificial heart management technicians, recipient transplant coordinators, VAD coordinators, etc., certifies the end-of-life. In end-of-life care, the first priority is to alleviate the patient’s pain, general malaise, and depression,⁶⁰ and then the decision on which treatment to discontinue or continue should be made based on the patient’s own wishes or in consultation with caregivers based on the advance directives indicating the patient’s intentions.

Regarding the withdrawal of life-prolonging treatment at the end of life, “Guidelines for device therapy: implantable left ventricular assist device for patients with severe heart failure (JCS/JSCVS2013)”,² “Guidelines for end-of-life care in emergency and intensive care” (JAAM/JSICM/JCS in 2014¹⁸⁹), and JCS 2017/JHFS 2017 “Guideline on diagnosis and treatment of acute and chronic heart failure”⁶⁰ note that decisions should be made by a multidisciplinary team through a process of discussion with the patient and caregivers based on the patient’s wishes or advance directives. In cases where the medical team is unable to make decisions, such as when the patient or caregiver strongly desires to discontinue the implantable LVAD despite not being at the end of life, it is recommended that the institutional ethics committee review the appropriateness of the decision.

It must be clearly indicated in the patient’s medical record that the decisions on end-of-life care were made by consensus of the multidisciplinary team, not solely by the judgment of the attending physician. The process of policy making and medical treatment by the team (explanation of surgery, acceptance, confirmation of advance directives, determination of the end of life, palliative care, explanation of discontinuation of life-prolonging treatment, consent, care of caregivers, etc.) should be included in the description. In particular, it is important to describe details of the diagnosis of the end of life and its rationale, the explanation to the caregivers and their understanding of the situation, the patient’s own intentions, including advance directives, the caregiver’s intentions, and changes in circumstances.

1.12 Preoperative Treatment Optimization

Prognostic factors after LVAD placement include the urgency of LVAD placement, preoperative hepatic and renal dysfunction, and concomitant right ventricular dysfunction.²⁹ Optimizing treatment from the preoperative stage and maintaining a favorable status (INTERMACS Profile 3 or higher, if possible) will ensure a good postoperative prognosis.

Hepatic and renal dysfunction in patients with severe heart failure is often attributable to hemodynamic abnormalities. Fluid retention and low cardiac output should be evaluated, and hemodynamic optimization should be achieved by diuretic dose adjustment, inotropic drug administration, and assisted circulation, such as IABP, VA-ECMO, and IMPELLA.¹⁴ Preoperative evaluation of right heart function is also important. If the right ventricular function is impaired, diuretics, continuous hemofiltration, inotropic drugs, and assisted circulation should be used to optimize hemodynamics.¹⁹⁰ For arrhythmias, pharmacologic treatment should be considered before surgery. In particular, ventricular tachycardia is a potential cause of right heart failure after LVAD implantation and should be treated aggressively before surgery. Catheter ablation and cryoablation at the time of surgery should also be considered if necessary.

The risk of infection should be assessed and minimized; accordingly, unnecessary intravenous lines and catheters should be removed as much as possible before surgery. Preoperative oral infection control is important, and if intervention is necessary, oral care and dental treatment should be considered. If the patient has bacteremia, the appropriate antimicrobial agents should be used for at least 1 week before LVAD placement, and no relapse should be observed for >5 days after a negative blood culture. Bleeding or thrombotic tendencies should be controlled.⁹⁵

Obesity is a risk factor for surgery, and weight control is essential. In diabetic patients, preoperative glycemic control is also important. If the disease is difficult to manage, consultation with a specialist should be considered. Nutritional status, according to levels such as albumin and prealbumin, should be assessed, and if malnutrition is revealed, refer to the nutrition support team for intervention. Enteral nutrition or central venous nutrition may be considered. Preoperative cardiac rehabilitation is recommended to maintain muscle strength, but careful gradual introduction is advisable in severely affected patients.¹⁹¹

2. Timing of Implantation

2.1 Initial Implantation Surgery

Left ventricular assist device (LVAD) implantation should be performed before the progression of organ damage such as renal dysfunction, hepatic dysfunction, and increased pulmonary vascular resistance.^{95,188,192–194} INTERMACS Profile 3 is the most suitable timing for implantation;^95,192 Profile 2 is considered to be the latest timing for implantation. To improve implantation outcomes, nutritional status should be improved, pulmonary vascular resistance should be decreased, hepatic congestion should be reduced, renal function should be optimized, coagulation function should be improved, and treatment and prevention of infections should be promoted if the heart failure condition permits.^95,192 Though LVAD implantation in Profile 1 has been reported to be acceptable,¹⁹⁵ it is not recommended, because of the generally poor outcomes.^188,192 In patients with Profile 1, temporary VAD treatment is used to improve their general condition and prevent organ damage so that an implantable LVAD can be indicated.^196,197 In Japan, the use of extracorporeal membrane oxygenation (ECMO), which is a typical condition of Profile 1, was not originally indicated for implantable LVADs, but this is not necessarily the case currently, because there are cases in which little or no organ damage is observed or recovery is highly probable even on ECMO. In patients with moderate renal or hepatic impairment equivalent to Profile 2, prompt LVAD implantation should be considered if organ function is highly likely to recover with improved circulation. The use of implantable LVADs in Profile 4 is increasing in Europe and the USA;¹⁹⁸ likewise, in Japan it has also been increasingly considered, thanks to device improvements. In particular, in patients with frequent severe ventricular arrhythmias, an implantable LVAD should be considered, regardless of the severity of heart failure.¹⁹⁹

As for the timing of LVAD implantation for destination therapy (DT), Profile 3 is optimal according to the INTERMACS report.³³ Implantation in Profile 4 is also increasing. Just as with implantation for bridge to transplantation (BTT), implantation in Profile 1 for DT is not recommended. According to the risk analysis of DT in INTERMACS,³³ the prognosis is better in younger patients, those without a history of open-heart surgery, low blood urea nitrogen levels, and non-severe right heart failure.

2.2 Bridge From Extracorporeal VADs to Implantable VADs¹⁹⁷

Extracorporeal VADs are used as a bridge to decision (BTD) for severe cardiogenic shock (Profile 1) and as bridge to candidacy (BTC) for moderate or severe renal or hepatic dysfunction, concomitant infection, or high pulmonary vascular resistance (Profile 2). The strategy of bridging from an extracorporeal VAD to an implantable LVAD is called bridge to bridge (BTB). Recently, central ECMO has been used as a bridging device as well as an extracorporeal VAD (air-driven pulsatile type and centrifugal pump continuous-flow type).

The ideal timing for conversion to implantable LVADs is when all of the following 4 conditions are met: the patient (1) is capable of self-determination, (2) has no or minimal organ damage other than cardiac damage, (3) is expected to be independent and return to society after discharge, and (4) has no obvious infection, including at the cannula skin exit sites. Depending on the patient’s general condition prior to extracorporeal VAD placement, BTB may be performed within a few days after extracorporeal VAD placement, or it may take several months or more.

BTB is a strategy that has been uniquely developed in Japan to obtain an indication for implantable LVADs; to date there are no corresponding reports from Europe or the USA. The first report on the results of BTB in Japan was published in 2020 in the 2nd J-MACS Report.⁵

III. Home Therapy and Long-Term Management

1. Management of Late Phase and Complication Control

1.1 Brain Complications (Cerebral Infarction and Cerebral Hemorrhage)

The incidence of cerebral infarction after left ventricular assist device (LVAD) implantation is bimodal, with the highest incidence immediately post-implantation and increasing again in the chronic phase.²⁰⁰ In acute cerebral infarction, perioperative low cardiac output has been reported as a risk factor, thus it is important to maintain appropriate cardiac output.²⁰¹ In contrast, the presence of bloodstream infection has been suggested to be a risk factor for chronic cerebral infarction,¹⁶¹ and careful management is necessary in patients with infection. To prevent chronic-phase thromboembolism, the prothrombin time-international normalized ratio (PT-INR) control with warfarin is advised and self-measurement of PT-INR using a coagulation analyzer (e.g., CoaguChek XS Personal) may achieve stabilization of PT-INR values.²⁰² Because dehydration can give rise to cerebral infarction, particular care should be taken if the daily weight fluctuation is large.¹⁹² Although there have been reports of intracerebrovascular thrombolysis for incident cerebral infarction,²⁰³ the risk of postinfarction hemorrhage is high, and anticoagulation after cerebral infarction should be performed with caution.¹⁹² As for endovascular therapy, a recent multicenter study reported that reperfusion was possible in 75% of cases, but careful attention to the onset of postoperative cerebral hemorrhage is necessary.²⁰⁴

Cerebral hemorrhage is often fatal; an urgent head CT scan is recommended when symptoms such as headache, nausea, neurological symptoms, and change in consciousness level are observed. If cerebral hemorrhage is confirmed, immediate neutralization of anticoagulation, depending on the extent of the hemorrhage, is important to prevent progression of hemorrhagic lesions.²⁰⁵ Intravenous prothrombin complex concentrate is effective in rapidly lowering the PT-INR; it has been reported to reduce the progression of intracerebral hemorrhage more than vitamin K and fresh frozen plasma.²⁰⁶ If the PT-INR is lowered and maintained, thromboembolism may be a concern, to be noted, it can be recommended to open the autologous valve without increasing the pump speed too much to prevent peri-aortic thrombosis. However, caution must be taken as the decreased auxiliary flow rate increases the risk of pump thrombosis.

1.2 Infections (Driveline Infections, Bacteremia, and Pocket Infections)

1.2.1 Driveline Infections and Bacteremia

Steps can be taken to prevent driveline infections; the entire fiber-covered portion of the driveline should be placed through muscle as much as possible within a subcutaneous tunnel.¹⁹² The driveline must be fixed because any movement of the line can lead to damage and subsequently infection at the skin penetration site. The driveline exit can be stabilized by suturing the line to the skin using 1 or 2 stitches at the time of surgery and then fixing the site for 2–3 weeks.²⁰⁷ It should be noted however, that the fixed site may cause skin ulceration, leading to infection; thus, disinfection of the driveline exit site should be performed daily until the wound is stabilized. Silver ion-containing wound dressings with antibacterial activity may be used to prevent infection.²⁰⁸

Patient education on wound fixation and disinfection is also important, as well as promptly notifying medical institutions of any abnormalities at the exit site.¹⁹²

If redness, tenderness, and signs of systemic infection are observed around the driveline exit sites, a diagnosis of bacteremia should be made and the causative pathogens must be identified based on the JAID/JSC “Guide to clinical management of infectious diseases” 2019;²⁰⁹ subsequent antibiotic administration should be determined based on the culture results. The most common causative pathogens are Staphylococcus aureus and Pseudomonas aeruginosa;¹¹⁸ antimicrobials with activity against these pathogens should be selected for empiric therapy. Infections caused by fungi or gram-negative rods have a poorer prognosis than those caused by gram-positive cocci. Antibiotic therapy for gram-positive cocci requires attention to microbial substitution.^210,211 Furthermore, if the infection progresses along the driveline tunnel, surgical debridement should be considered.²⁰⁸ Gallium-scintigraphy or FDG-PET/CT may be useful to identify the extent of infection^212,213 Negative pressure wound therapy (NPWT) after debridement may be used to enhance wound healing.

1.2.2 Pump Pocket Infections

Abnormalities such as tenderness at the pump implantation site or suspected pump pocket infection on imaging tests are difficult to definitively diagnose and may require an open wound examination.²⁰⁸ Infection, if any, should be washed out with drainage. Infection of the blood pump itself (pump endocarditis) is rare in small implantable LVADs, but infection caused by the inflow and outflow cannulas may occur. In both cases, long-term systemic administration of appropriate antibiotics is necessary. Infection control by using NPWT or by device replacement²¹⁴ may be required. In such cases, if there is dead space around the blood pump, filling the space with a musculocutaneous or omental flap can be considered.^215,216 Device removal or semi-urgent heart transplantation²¹⁷ may also be considered. If heart transplantation is undertaken, the prognosis can be good despite the history of bacteremia.²¹⁸

1.3 Right Heart Failure

With the widespread use of implantable LVADs, it has become recognized that there are some patients who preoperatively do not present obvious signs of right heart failure but they become apparent weeks or more after implantation. This is referred to as late-onset right ventricular failure (RVF), and it is currently a major concern as a late complication of implantable LVADs. The pathogenesis suggests that LVAD-induced left ventricular aspiration may cause a shift of the septum toward the left ventricle and thereby alter the morphology of the right ventricle, resulting in right heart dysfunction. Right ventricular dysfunction can occur in both diastolic and systolic states. Late-onset RVF is associated with impaired exercise tolerance, and inotropic infusion may be required despite the use of an LVAD.

Reported predictors of late-onset RVF include the following: left ventricular end-diastolic diameter (LVDd) <64 mm before LVAD implantation,⁶¹ tricuspid annular diameter ≥41 mm,²¹⁹ elevated blood urea nitrogen, and elevated right atrial pressure/pulmonary artery wedge pressure.²²⁰ Some reports, however, have suggested that there is no clear predictor,^221,222 and to date, nothing has been established as a confirmed predictor. Although there is no specific treatment for right heart failure, as tricuspid regurgitation (TR) often worsens, tricuspid valve replacement or tricuspid annuloplasty may be performed for severe TR.

1.4 Gastrointestinal (GI) Bleeding

GI bleeding has been recognized as one of the continuous-flow pump diseases that are characteristic complications of continuous-flow VADs currently used as implantable VADs. The pathogenic mechanisms include anticoagulation, acquired von Willebrand syndrome associated with changes in von Willebrand factor, changes in peripheral circulation associated with decreased pulse pressure, and suppression of platelet function. Outside Japan, 18–40% of patients are reported to have GI bleeding.^{163,223–227} According to the J-MACS statistical report published in September 2019, the 1- and 2-year GI bleeding-free rates in patients with primary LVADs were 95% and 93%, respectively, which were higher than in other countries.⁸⁸

Endoscopy should be considered when clinical symptoms are evident, such as hemorrhage or hematemesis, or when GI bleeding cannot be ruled out for unexplained anemia. When possible, the target PT-INR value should be reduced with consideration given to a reduction in or withdrawal of antiplatelet agents, taking into account the VAD model being used and the patient’s sensitivity to anticoagulation and antiplatelet therapy. During this period, the patient’s general condition (presence of embolism) and device parameters should be carefully monitored.^228–230 Angiodysplasia is a relatively common pathological finding of the bleeding source, but in view of the relationship with shear stress, lowering the LVAD rotation speed should be considered if the hemodynamics permit. Endoscopic hemostasis is the first choice of treatment for GI bleeding, but surgical resection of the bleeding site, though rare, may be required.

As for pharmacotherapy, more evidence is needed, but small studies and case reports have reported the efficacy of the following: octreotide,²³¹ thalidomide,²³² angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor blockers,²³³ doxycycline,²²⁹ desmopressin,²³⁴ bevacizumab,²³⁵ digoxin,²³⁶ and omega acid.²³⁷

1.5 Aortic Insufficiency (AI)

Implantable LVADs are not indicated for patients with moderate or severe AI, because of the known worsening of AI following implantable LVAD surgery,^122,238 but it may be possible by using concomitant aortic valve replacement with a bioprosthetic valve. It is also known that patients without AI preoperatively may newly develop AI after LVAD implantation.^239,240 Such AI is usually characterized by regurgitation not only in diastole but also in systole, and aortic valve dysfunction due to degeneration of the aortic root or aortic valve. In addition, the degree of AI is often exacerbated by persistence of specific hemodynamic changes under LVAD assistanc.²³⁸

Conventional color Doppler underestimates the severity of AI, but recently, Doppler echocardiography of the outlet of the inflow cannula has been proposed as a more accurate quantification of AI.^241,242 The occurrence of AI has been shown to increase pulmonary artery wedge pressure and central venous pressure despite LVAD support.²⁴¹ Increasing the LVAD rotational speed can temporarily increase the cardiac output, but may exacerbate AI in the long term.²⁴³

It has been postulated that decreased pulse pressure under LVAD support (especially in continuous flow) and turbulence formation at the aortic root due to the outflow of the LVAD, may cause thinning of the vessel wall and enlargement of the aortic root, which results in aortic regurgitation. Aortic regurgitation can also occur due to degeneration of the aortic valve by persistent aortic valve closure in cases of severely impaired native left ventricular function.^123,244 Known risk factors include female sex, large body surface area, use of continuous-flow LVADs (to decrease pulse pressure),²⁴⁵ and high rotational speed (to decrease left ventricular pressure and, conversely, to increase aortic root pressure).²⁴³ As mentioned above, persistent aortic valve closure is a well-known postoperative risk factor.^122,123,244 AI seems to occur less frequently in some patients whose aortic valves are closed at rest but open during exercise.²⁴⁶

Although no definite conclusions can be drawn on the relationship between AI and prognosis, it is certain that AI increases rehospitalization due to worsening heart failure and decreases exercise tolerance.^122,123,247 For mild AI, the following treatment attempts have been made: setting a lower LVAD rotational speed to open the aortic valve, adjusting antihypertensive drugs to reduce afterload, and increasing the dose of β-blockers to promote reverse remodeling of the native heart. Unfortunately however, none these are unlikely to become fundamental treatments.¹⁹² For severe AI, valve replacement,¹²⁴ valvuloplasty,²⁴⁸ valve patch closure,²⁴⁹ and valve closure with ASD closure devices²⁵⁰ have been tried, and in recent years, transcatheter aortic valve implantation has also been tried.²⁵¹ Heart transplantation is the best solution, but that depends on the waiting time.

1.6 Arrhythmias

Late-onset sustained ventricular tachycardia or ventricular fibrillation are common after VAD placement. Because implantable cardioverter defibrillators (ICDs) are likely to be activated while awake, they are often set up to avoid shock delivery even if a lethal arrhythmia occurs. Ventricular fibrillation cannot be immediately fatal if the VAD is working properly, but cardiac output may decrease due to reduced right heart function. Defibrillation should be performed under sedation, and antiarrhythmic drugs such as amiodarone should be administered. Arrhythmias may be caused by a type of mechanical stimulation due to physical contact between the outflow cannula and left ventricle wall. In such cases, adjusting the rotational speed or preload may be effective. Some patients remain in chronic ventricular fibrillation without improvement despite various treatments, and for some their hemodynamic status can be maintained, yet not for others, but the reason for the difference remains unclear.

Predictive factors for ventricular arrhythmias after VAD placement include a history of ventricular arrhythmias prior to implantation,^252–254 long duration of heart failure (time from onset of heart failure to VAD implantation >84 months²⁵² or duration of heart failure >12 months²⁵³), history of atrial fibrillation prior to implantation, underlying dilated cardiomyopathy,²⁵³ early onset (within 30 days) of ventricular arrhythmias,²⁵³ and no treatment with ACE inhibitors.²⁵³

1.7 Implantable LVAD Pump Malfunction and Pump Replacement Surgery

Although the durability of continuous-flow VADs, which have become the mainstream VADs, has been greatly improved compared with conventional pulsatile-flow VADs, there are still reports of device failure.^8,255 However, because continuous-flow VADs do not have a backflow prevention valve, blood flows back into the left ventricle from the aortic outflow cannula through the pump body if the blood pump stops, causing circulatory failure. One of the most common causes of blood pump dysfunction is driveline disconnection, which has been reported to occur in 3% of patients after HeartMate (HM)-II implantation; it accounts for 46% of all pump replacements.²⁵⁶ However, the HM-3, a centrifugal pump with full magnetic levitation, has decreased the incidence of device failure and resulting pump replacement.³⁵

The most common cause of pump malfunction is pump thrombosis and its incidence has been reported to vary from 1% over 2 years to 8% over 6 months, and account for 29–50% of all pump replacements,¹² Although the factors that contribute to pump thrombosis are not fully understood, multiple factors are likely involved. Device-related factors include rotor-generated heat, high shear stress leading to platelet aggregation, thrombus formation around the outflow cannula, malpositioning of the inflow cannula, and outflow stenosis. Patient factors include preoperative Intra-atrial or ventricular thrombus, atrial fibrillation, presence of artifacts in the left ventricular system, and dehydration. Poor patient management factors may include low PT-INR, inadequate antiplatelet medication, concomitant infections, and low pump speed.

Pump malfunction due to malfunction of the blood pump or driveline often requires urgent pump replacement.^257,258 The same is true for pump malfunction caused by thrombus in the blood pump. Malfunctions of external parts, such as controllers, may be resolved by replacing the parts.

Pump replacement surgery can be performed through repeat median sternotomy or through a subcostal incision.^259–261 In the latter case, the inflow and outflow of the cardiopulmonary bypass are inserted through peripheral vessels such as the femoral artery and vein. In recent years, the latter method of pump replacement has been increasingly used, but the approach should be determined according to the experience of each institution and the extent of debridement associated with the infection. For urgent pump replacement surgery, it is necessary to administer intravenous human prothrombin complex or vitamin K and to perform adequate hemostasis because the patient is still on anticoagulant therapy.²⁶¹

1.8 Blood Pressure (BP) Control (Table 9)

Table 9. COR and LOE for Chronic Blood Pressure Control in Patients With Implantable LVADs

	COR	LOE
Target blood pressure
Proactive use of medications, mainly cardioprotective antihypertensive agents, should be considered to achieve a mean blood pressure <90 mmHg (<80 mmHg if tolerated)	IIa	C
Self-management of blood pressure
Patients should be encouraged and educated to measure their blood pressure at home and to record it as a daily self-management goal	IIa	C

Note: The above recommendations are based on reports mainly on axial flow LVADs. As the currently available implantable LVADs in Japan are all the centrifugal pump type, the blood pressure findings in future may differ. COR, class of recommendation; LOE, level of evidence; LVAD, left ventricular assist device.

All implantable LVADs currently in use in Japan are driven by continuous-flow pumps. It is known that the flow rate of a continuous-flow pump is highly dependent on the preload and afterload of the pump. At a constant preload, the flow rate decreases as the patient’s systemic BP, afterload of the pump, increases; in contrast, at low BP, the flow rate increases as afterload decreases. Therefore, from the viewpoint of treatment of heart failure and circulatory failure as the main purpose for LVAD implantation, it is necessary to maintain low BP to ensure a sufficient flow rate. However, excessive BP lowering may lead to subjective patient symptoms such as fatigue, and orthostatic hypotension due to decreased organ perfusion pressure, which may result in peripheral organ damage. In contrast, from the viewpoint of LVAD complications, it has been reported that elevated BP can cause stroke, pump thrombosis, and aortic valve dysfunction; therefore, adequate BP control is one of the most important issues in the long-term management of patients with implantable LVADs.

1.8.1 Patient Education and BP Monitoring

Patients with an implantable LVAD should be educated prior to discharge on the following: (1) the importance of BP measurement, (2) the necessity to develop a daily routine to measure and record BP at home, and (3) how to monitor other healthcare indicators (e.g., weight, pulse rate). However, patients with an implantable LVAD generally have low pulse pressures that are difficult to measure with home cuff BP monitors because the LVAD itself is a continuous-flow system and native cardiac output is often low. Therefore, patients should try out BP monitors to determine a suitable type. If it is still difficult to measure BP with a home BP monitor, medical professionals can measure the patient’s BP by Doppler ultrasound in the clinic and provide the results to the patient. In a study of 60 patients with an axial flow LVAD, the Elemano BP monitor (Terumo Corp.), an upper arm cuff BP monitor that uses double-cuff oscillometric slow deflation technology, yielded accurate BP measurements in >90% of patients, compared with ultrasound Doppler as the standard.²⁶²

1.8.2 Target BP

Although the target BP of patients with implantable LVADs should be considered in the context of the patient’s condition, previous reports recommend maintaining BP below certain levels. A report that stratified 123 ambulatory patients with implantable LVADs (111 with axial flow pumps) into 3 groups according to BP measured by ultrasound Doppler (<80 mmHg in the control group, 80–89 mmHg in the moderately high group, and ≥90 mmHg in the high group) and evaluated subsequent complications and prognosis showed that complications occurred more frequently in the high BP group.²⁶³ In particular, cerebral hemorrhage was significantly more common in the high BP group, and a similar trend was observed for aortic valve insufficiency, but thromboembolism was not associated with BP. Similarly, another study showed that more strokes occurred in the ambulatory mean BP >90 mmHg group, and discussed an association with pump thrombosis.²⁶⁴ These results suggest that the recommended target BP for patients with implantable LVADs should be <90 mmHg, and if well tolerated, <80 mmHg should be considered.

1.8.3 Antihypertensive Drugs

A study using INTERMACS Registry data has reported that BP increases temporarily after LVAD implantation, but then tends to decrease.²⁶⁵ In the chronic phase, about 90% of patients received antihypertensive drugs such as β-blockers, ACE inhibitors, and aldosterone antagonists, including those who received combination therapy with 2 or 3 agents. [It should be noted that INTERMACS did not collect data on calcium-channel blockers, and not all of the drugs administered were used for lowering BP, as such drugs are also used for cardioprotection, renal protection, and arrhythmia prevention after implantable LVAD implantation.]

1.9 Shared Care

Care is shared^266,267 to provide advanced and specialized care, such as VAD therapy and heart transplantation, in cooperation with a team of specialized centers and core hospitals. In recent years, the need for shared care has increased due to the uneven regional distribution of VAD implantation centers, longer treatment periods, and an increase in the number of patients to beyond the capacity of each center.²⁶⁸

The care to be shared via multidisciplinary involvement includes: daily education and care of patients and caregivers, equipment management, response to patients’ illnesses, emergency response to VAD-related complications, and education of community facilities, such as fire departments and schools.¹⁴⁵ The extent of responsibility shared by the implantation center, the management center, and the core hospital varies depending on the content, geographical distance, and other factors. The European and USA guidelines recommend that obvious equipment malfunctions should be addressed by an experienced facility, but patients with unstable conditions should be stabilized at the nearest hospital.¹⁹³ In Japan as well, when a patient’s condition suddenly changes, prompt response at a management facility or core hospital in the patient’s surrounding residential area is desirable.

The advantage of shared care is not only the shortening of the initial response time to events with a prognostic impact of time elapsed, such as brain complications or device problems, but also for the continuation of care and communication provided before implantation and to reduce the patient’s physical and financial burden of hospital visits.²⁶⁹ Unfortunately however, to date no studies have shown evidence of the benefits of shared care, including the effects on prognosis and frequency of complications.

The experience of VAD treatment by referring physicians and community healthcare providers through shared care is expected to enhance the understanding of VAD treatment and to provide more appropriate treatment choices for patients and care givers.

2. Late Surgery

2.1 Heart Transplantation in Patients With Implantable LVADs as a Form of Bridging

Because heart transplantation in patients with an implantable LVAD is a repeat thoracotomy, it is important to predict the time required for dissection. After confirmation of donor heart integrity in the final evaluation, surgery can be started. The femoral artery is exposed to prepare for emergency extracorporeal circulation. It is important to confirm that the inflow cannula, which often runs adjacent to the median mediastinum, is covered by a Gore-Tex® sheet; next the position of the cannula in relation to the sternum is confirmed by chest CT. Dissection should be undertaken with care to avoid injury of the LVAD inflow and outflow cannulas. Cardiopulmonary bypass should be started in sequence with the time of arrival of the donor heart. After systemic heparinization, the inflow cannula is inserted into the distal ascending aorta and the outflow cannula into the superior and inferior venae cavae. The inflow cannula is cut off midway, and extracorporeal circulation is started. The LVAD is usually removed together with the heart, but if dissection is difficult, the apex is removed at the time of heart removal, the donor heart is anastomosed, and then the LVAD is removed. During LVAD removal, the driveline is separated in the pocket, and it is important to disinfect, clean and cover the unclean driveline ends.

Regarding the surgical technique, compared with the Lower-Shumway method (biatrial method),²⁷⁰ the bicaval method²⁷¹ is widely used because of the high prevalence of sinus node dysfunction and tricuspid regurgitation; the modified bicaval method²⁷² is used in ≈70% of patients in Japan. In cardiac resection, after blocking the aorta, the LVAD anastomosis is resected, the aorta is transversely cut, and the pulmonary artery is transversely cut on the valve. After incising the upper left atrium while elevating the heart, the bicaval technique involves a transverse incision of the superior and inferior venae cavae and an incision of the lower left atrium to complete the heart removal. In contrast, the modified bicaval method involves an incision of the anterior half of the superior vena cava, leaving the posterior wall continuous with the similarly incised inferior vena cava.

After removal of the heart, the donor heart should be anastomosed immediately. The left atrial anastomosis can be followed by the pulmonary artery, aorta, inferior vena cava right atrial anastomosis, and superior vena cava anastomosis, although any order is possible. If the ischemic time is lengthy, the left atrial anastomosis may be followed by aortic anastomosis to initiate reperfusion, and then the other anastomoses would follow. Finally, warm blood cardioplegia is injected, the aortic blockade is released to allow sufficient time for reperfusion until cardiac function is restored, and then the patient is weaned from the extracorporeal circulation. Due to the shortage of donors, many of the patients who received heart transplantation in Japan were bridged with an implantable LVAD, but the United Network for Organ Sharing (UNOS) data suggest that the early outcome of heart transplantation is poorer in patients with implantable LVAD bridges than in those who are managed with medical therapy until heart transplantation, and particular caution is warranted in patients with impaired renal function.²⁷³

2.2 Weaning From Implantable LVADs

LVADs restore left ventricular function in patients with severe heart failure by reducing left ventricular volume and pressure load, which is termed reverse remodeling; sufficient cardiac function recovery to allow weaning from the LVAD support has been reported with preservation of cardiac function for several years after the weaning.²⁷⁴ The proposed mechanism of reverse remodeling includes improvement of cardiomyocyte hypertrophy²⁷⁵ and increased adrenaline β-receptor responsiveness.²⁷⁶ The LVAD weaning rate associated with reverse remodeling varies from 1% to 13%.^277–281 Recovery of cardiac function is often observed within 3 months after LVAD implantation, and factors associated with recovery include young age (<50 years), nonischemic cardiomyopathy, short duration of heart failure (<2 years) before LVAD implantation, no history of implantable cardioverter defibrillator, serum creatinine <1.2 mg/dL, and left ventricular end-diastolic diameter (LVEDD) <6.5 cm.²⁷⁹ In patients with an implantable LVAD, β-blockers,²⁰ angiotensin-converting enzyme inhibitors, and spironolactone are administered for cardioprotection, and there is also a Harefield recovery protocol that adds the β-1 agonist clenbuterol.²¹

The standard criteria for LVAD weaning are the “Berlin” criteria of Dandel et al,²⁸⁰ and weaning might be safely possible with off-pump echocardiographic left ventricular ejection fraction (LVEF) ≥45% and LVEDD ≤55 mm. Even if these criteria are not met, expanded criteria have been proposed, which include echocardiographic LVEF ≥30% and LVEDD ≤65 mm, as well as no decrease in LVEF or increase in pulmonary capillary wedge pressure (PCWP) under an off-pump.²⁸¹ However, most of the reports are regarding pulsatile-flow LVADs; reports of continuous-flow LVADs are scarce because of the difficulty in evaluating under off-pump due to the backflow through the pump when the blood pump is stopped. Of the 1,108 patients enrolled in the HM-II destination therapy (DT) trial, only 1.8% were weaned from LVAD based on cardiac improvement.²⁸² Weaning because of reverse remodeling is less common in patients with continuous-flow LVADs than in those with pulsatile-flow LVADs.²⁸³ One of the reasons for the low weaning rate is that continuous-flow LVADs are more prone to late aortic regurgitation (AR) than pulsatile-flow LVADs,²³⁹ and the volume load caused by the late AR may prevent reverse remodeling.¹²²

Of the 15,138 adult patients with LVAD implantation enrolled in INTERMACS between March 2006 and June 2015, 192 (1.3%) were weaned from the LVAD.²⁷⁹ The reason for LVAD implantation was cardiac function improvement (bridge to recovery; BTR) in 14 patients (11.2%, 7.3 times/100 patient-years), whose weaning rate was significantly higher than that of 178 patients (1.2%, 0.9 times/100 person-years) implanted for heart transplantation, eligibility evaluation of heart transplantation, or DT (non-BTR). Interestingly, of the 7,084 patients who were followed up for left ventricular systolic function, 892 (12.6%) had an effective improvement in cardiac function, 97% of whom were non-BTR patients. These results indicate that the frequency of weaning from LVAD varies greatly depending on the purpose of LVAD implantation.

During pump removal surgery, the apical inflow cuff is left in place and sutured if it is soft, but it may cause late infection. If the cuff is too hard to close, it is removed under cardiopulmonary bypass; however, there is a method of inserting a plug into the cuff,²⁸⁴ which allows the cuff to be used in case heart failure worsens again. As much of the infected inflow cuff as possible should be removed, and if the infection is severe, omental filling can be considered.

2.3 Off-Pump Test

Patients aiming to wean from the Nipro VAD should have the off-pump test. Prior to the test, the frequency of assistance is gradually reduced at a rate of ≈5 times/min per week to ≈60 times/min. If the patient has good echocardiographic native aortic valve patency, B-type natriuretic peptide <100 pg/mL, and maximal oxygen uptake (peak V̇O₂) ≥16 mL/kg/min or ≥60% of normal control on cardiopulmonary function test (CPXT), then the VAD should be stopped to assess hemodynamics and exercise tolerance.

In the off-pump test, hemodynamic evaluations and exercise load tests are performed under off-pump while manually pushing the air pump (“hand pump”), which is prepared for emergency use, ≈10 times/min to prevent thrombosis and maintain a minimum flow rate. During the initial hemodynamic assessment, if there is a clear decrease in LVEF on echocardiography, a marked increase in PCWP, or a marked decrease in body blood pressure, weaning should be considered to be difficult and the test should be stopped. If this can be passed, then a so-called “water (saline) load” of 10 mL/kg of saline over 15 min is performed. If the PCWP increases >10 mmHg and/or the cardiac output is decreased, weaning should be considered to be difficult. Weaning can be expected in patients with an elevated PCWP of <10 mmHg and unchanged or elevated cardiac output; however, the decision should be carefully made together with the results of echocardiography and cardiopulmonary function tests. The off-pump exercise stress test is associated with certain risks, and extreme care should be taken in its implementation. However, if the off-pump peak V̇O₂ is ≥16 mL/kg/min, the possibility of weaning is high; if it is ≤12 mL/kg/min, it is considered difficult to wean. It should be noted that the weaning protocol and interpretation of the test results have not been established and remain at the level of expert opinion.

Because implantable LVADs usually cannot be completely deactivated, more careful assessment for weaning is needed. Just as with the Nipro VAD, echocardiographic findings, hemodynamic assessment, and exercise tolerance are important. Based on the echocardiographic findings and CPXT test results at the lowest possible VAD rotation, it has been reported that patients with the following can be weaned: left ventricular end-systolic diameter (LVDs) <60 mm, LVDs <50 mm, LVEF >45%, PCWP <15 mmHg, cardiac index >2.4 L/min/m², and peak V̇O₂ >16 mL/kg/min on CPXT.²⁷⁹

As for exercise tolerance, Japanese patients with heart failure often fail to meet the peak V̇O₂ >16 mL/kg/min because of the delay in improvement of muscle strength, which is the result of advanced disuse during the long-term morbidity despite sufficient cardiac improvement by the VAD. In CPXT about 3 months after VAD implantation, it was reported that 86% of patients could be weaned from the VAD if the load was ≥51 watts, peak V̇O₂ ≥12.8 mL/kg/min, and the V̇E/V̇CO₂ slope ≤34, and in such patients, the test for weaning should be considered.²²

3. End-of-Life Care

3.1 End-of-Life Care in Implantable LVAD Therapy

In Japan, implantable LVADs have been mainly used as bridge to transplantation (BTT), and some BTT patients show improved cardiac function and can be weaned from LVAD (BTR). In recent years, LVADs have been used in Europe and the USA as DT in patients with expected long-term survival but no indication for heart transplantation, or as bridge to decision (BTD) in patients with uncertainty of the indication for heart transplantation,⁸ and their use as DT was also approved for health insurance reimbursement in Japan in 2021. Guidelines for end-of-life care in DT are described in Section 4 of “Appropriate indication of implantable VADs in Japan: About destination therapy”.²⁸⁵ When the systemic circulation is maintained by an implantable LVAD and BTT, BTR, BTD, or DT is the aim, continued support with an implantable LVAD is justified. However, the following conditions are considered to be end-of-life: (1) severe organ (e.g., liver) dysfunction deemed irreversible, (2) severe cerebral neuropathy, (3) respiratory failure (excluding those associated with circulatory failure), (4) severe blood disorder (e.g., bleeding tendency), or (5) severe infection.

In addition, the following conditions are also applicable: (1) indication for BTT but no longer indicated for heart transplantation (except when the condition is temporary and may be indicated again), (2) indication for BTD (when BTT, BTR or DT is not indicated), and (3) indication for DT and unable to provide home care (except when the condition is temporary and treatment allows for continuation of home treatment).

3.2 Continuation of Implantable LVAD Assistance at End of Life

The purpose of circulatory support with an implantable LVAD is to assist or substitute for the pumping function of the heart to allow time for BTT, BTR, or BTD and to move on to the next procedure, or to achieve long-term survival at home as DT. If the purpose cannot be achieved due to noncardiac organ dysfunction including the brain, additional treatment should not be considered and discontinuation of the implantable LVAD will be considered.²⁸⁶

Informed consent must be obtained for the implantable LVAD therapy. In this process, patients, their caregivers, and family members should be given sufficient explanation and then they should consent not to add another therapy and to discontinue the implantable LVAD if the patient is diagnosed as end-of-life. It is essential to keep adequate records of these explanations and consent. If the above conditions are met, it is not desirable to be held civilly or criminally liable for discontinuing life-prolonging measures at the end of life.

When the patient is diagnosed as end-of-life by a multidisciplinary team (if necessary, by a committee consisting of third parties and other experts), the patient, caregivers, and patient’s family members (or only caregivers and family members if the patient’s will cannot be confirmed) should be fully informed of the patient’s condition, and the implantable LVAD should be discontinued when they accept it. Even if the caregiver and/or family members wish to continue the implantable LVAD therapy, it is reasonable not to provide additional treatment unless there is a medical indication for it. For patients who are expected to reach the end of life, it is desirable to discuss with the patient, caregivers, and family members in advance and determine the method of response and a representative decision-maker.^287,288 Advance care planning (ACP), a process that maximizes the patient’s will, is emphasized. In this process, healthcare providers are required to provide the necessary information and options. Because a patient’s wishes can change, it is necessary to confirm them when there are changes in the patient’s condition. It should be noted, however, that ACP is not mandatory or compulsory.

If a patient, caregivers or family members strongly request discontinuation of the implantable LVAD even though the patient is not end-of-life, the multidisciplinary team should discuss the situation and, if necessary, the institutional ethics committee should be consulted. However, such a procedure should not be undertaken if it is considered as an active euthanasia or assisted suicide.

As a rule, if a patient with an implanted LVAD dies, the device should be removed. After the patient is pronounced dead, the LVAD should be removed and the manufacturer should be asked to collect it. Unlike pacemakers, implantable LVADs do not contain batteries, such as lithium batteries, and are therefore not likely to rupture during cremation.

Appendix 1. JCS/JSCVS/JATS/JSVS Joint Working Group

Chairs:

• Minoru Ono, Department of Cardiac Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo

• Osamu Yamaguchi, Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine

Members:

• Norihide Fukushima, Department of Transplant Medicine, National Cerebral and Cardiovascular Center

• Koichiro Kinugawa, Second Department of Internal Medicine, Faculty of Medicine, University of Toyama

• Goro Matsumiya, Department of Cardiovascular Surgery, Chiba University Graduate School of Medicine

• Tomohito Ohtani, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine

• Yoshikatsu Saiki, Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine

• Yoshiki Sawa, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine

• Akira Shiose, Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kyushu University

• Hiroyuki Tsutsui, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University

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

• Kenji Yamazaki, Advanced Medical Research Institute, Hokkaido Cardiovascular Hospital

• Masanobu Yanase, Department of Transplant Medicine, National Cerebral and Cardiovascular Center

Collaborators:

• Masatoshi Akiyama, Department of Cardiovascular Surgery, Tohoku University Graduate School of Medicine

• Miyoko Endo, Department of Nursing, The University of Tokyo Hospital

• Takeo Fujino, Department of Cardiovascular Medicine, Kyushu University Hospital

• Toru Hashimoto, Department of Cardiovascular Medicine, Kyushu University Hospital

• Masaru Hatano, Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo

• Haruhiko Higashi, Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine

• Taiki Higo, Department of Cardiovascular Medicine, Kyushu University Hospital

• Yumiko Hori, Department of Nursing and Transplant Medicine, National Cerebral and Cardiovascular Center

• Teruhiko Imamura, Second Department of Internal Medicine, Faculty of Medicine, University of Toyama

• Kiyotaka Iwasaki, Cooperative Major in Advanced Biomedical Sciences, Graduate School of Advanced Science and Engineering, Waseda University

• Koichi Kashiwa, Department of Medical Engineering, The University of Tokyo Hospital

• Osamu Kinoshita, Department of Cardiac Surgery, The University of Tokyo Hospital

• Kaori Kubota, Department of Transplantation Medicine, Osaka University Graduate School of Medicine

• Toru Miyoshi, Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine

• Takashi Nishimura, Department of Cardiovascular and Thoracic Surgery, Ehime University Hospital

• Tomohiro Nishinaka, Department of Artificial Organs, National Cerebral and Cardiovascular Center

• Hiroshi Nishioka, Department of Clinical Engineering, National Cerebral and Cardiovascular Center

• Yoshihiko Ohnishi, Department of Anesthesiology, National Cerebral and Cardiovascular Center

• Takahiro Okumura, Department of Cardiology, Nagoya University Graduate School of Medicine

• Osamu Seguchi, Department of Transplant Medicine, National Cerebral and Cardiovascular Center

• Koichi Toda, Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine

• Motoharu Yamanaka, Department of Nursing, Tokyo Women’s Medical University Hospital

Independent Assessment Committee:

• Takeshi Kimura, Department of Cardiovascular Medicine, Graduate School of Medicine and Faculty of Medicine, Kyoto University

• Shunei Kyo, Tokyo Metropolitan Geriatric Hospital

• Takeshi Nakatani, Maki Hospital

• Takayuki Ohno, Department of Cardiovascular Surgery, Mitsui Memorial Hospital

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

(Listed in alphabetical order; affiliations as of November 2020)

Appendix 2. Disclosure of Potential Conflicts of Interest (COI): JCS/JSCVS/JATS/JSVS 2021 Guideline on Implantable Left Ventricular Assist Device for Patients With Advanced Heart Failure (2018/01/01–2020/12/31)

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
Chairs: Minoru Ono				Sun Medical Technology Research Corp. Medtronic Japan Co., Ltd. Century Medical, Inc. Nipro Corporation		Kono Seisakusho Co., Ltd.	Astellas Pharma Inc. Sun Medical Technology Research Corp. NIKON CORPORATION Nissan Chemical Corporation
Chairs: Osamu Yamaguchi				Daiichi Sankyo Company, Limited Takeda Pharmaceutical Company Limited Bayer Yakuhin, Ltd. Otsuka Pharmaceutical Co., Ltd. Medtronic Japan Co., Ltd. AstraZeneca K.K. Ono Pharmaceutical Co., Ltd. Novartis Pharma K.K.		CANON MEDICAL SYSTEMS CORPORATION	Takeda Pharmaceutical Company Limited Edwards Lifesciences Corporation Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Astellas Pharma Inc. Bayer Yakuhin, Ltd. Sumitomo Dainippon Pharma Co., Ltd. Abbott Vascular Japan Co., Ltd. Nippon Boehringer Ingelheim Co., Ltd. Teijin Pharma Limited							Astellas Pharma Inc. Teijin Pharma Limited Takeda Pharmaceutical Company Limited
Members: Koichiro Kinugawa				Otsuka Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited AstraZeneca K.K. Nippon Boehringer Ingelheim Co., Ltd. Mitsubishi Tanabe Pharma Corporation Nipro Corporation	Otsuka Pharmaceutical Co., Ltd.	Ono Pharmaceutical Co., Ltd.	Otsuka Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd.
Members: Goro Matsumiya							Edwards Lifesciences Corporation Century Medical, Inc. TERUMO CORPORATION Otsuka Pharmaceutical Co., Ltd.
Members: Tomohito Ohtani	Takeda Pharmaceutical Company Limited
Members: Yoshikatsu Saiki							Century Medical, Inc. Nipro Corporation Sun Medical Technology Research Corp.
Members: Yoshiki Sawa						Edwards Lifesciences Corporation Cuorips Inc. JTEC Corporation Century Medical, Inc. DAIKIN INDUSTRIES, LTD. TERUMO CORPORATION Nacalai Tesque, Inc. Nipro Corporation HeartLab,Inc. LivaNova Japan K.K. ROHTO Pharmaceutical Co., Ltd. Sun Medical Technology Research Corp. Mediplus Pharma, Inc. Sumitomo Riko Company Limited Ono Pharmaceutical Co., Ltd. Taki Chemical Co., Ltd. Dai Nippon Printing Co., Ltd. Sumitomo Dainippon Pharma Co., Ltd. Daiichi Sankyo Company, Limited Teijin Pharma Limited Medtronic Japan Co., Ltd.	Abbott Medical Japan L.L.C Edwards Lifesciences Corporation Smith & Nephew KK Century Medical, Inc. TERUMO CORPORATION Nipro Corporation Paramedic Japan Co., Ltd. JMS Co., Ltd. Myoridge Co., Ltd. Konishi Medical Instruments Co., Ltd. Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Abiomed Japan K.K. Medtronic Japan Co., Ltd.	Medtronic Japan Co., Ltd.
Members: Akira Shiose				Abbott Medical Japan L.L.C TERUMO CORPORATION Otsuka Pharmaceutical Co., Ltd. Abiomed Japan K.K. Medtronic Japan Co., Ltd. Japan Lifeline Co.,Ltd.		AIR WATER INC. Edwards Lifesciences Corporation Century Medical, Inc.	USCI Japan Ltd. Astellas Pharma Inc. Abbott Medical Japan L.L.C Eisai Co., Ltd. Edwards Lifesciences Corporation Kanaya Ikakikai, Co., Ltd Sun Medical Technology Research Corp. TERUMO CORPORATION Fukuda Denshi Seibu-kita hanbai Co., Ltd LivaNova Japan K.K. Cardio Incorporated KISHIYA Inc. SENKO MEDICAL INSTRUMENT Mfg. Co., Ltd. Medtronic Japan Co., Ltd. Japan Lifeline Co.,Ltd. HEIWA BUSSAN Co., Ltd.
Members: Hiroyuki Tsutsui				AstraZeneca K.K. Novartis Pharma K.K. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Kowa Company, Ltd. Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd.	nippon rinsho Co.,Ltd.	IQVIA Services Japan K.K. OMRON HEALTHCARE Co., Ltd. Medical Innovation Kyushu MEDINET Co., Ltd. Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Japan Tobacco Inc. Nippon Boehringer Ingelheim Co., Ltd.	St.Mary's Hospital. Daiichi Sankyo Company, Limited Teijin Pharma Limited Teijin Healthcare Limited Mitsubishi Tanabe Pharma Corporation Nippon Boehringer Ingelheim Co., Ltd.	Actelion Pharmaceuticals Japan 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 L.L.C 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: Kenji Yamazaki	Sun Medical Technology Research Corp.
Collaborators: Toru Hashimoto								Abbott Medical Japan L.L.C Medtronic Japan Co., Ltd. Nipro Corporation
Collaborators: Masaru Hatano								Century Medical, Inc. Nipro Corporation TERUMO CORPORATION
Collaborators: Haruhiko Higashi														Astellas Pharma Inc. Teijin Pharma Limited Takeda Pharmaceutical Company Limited
Collaborators: Toru Miyoshi														Astellas Pharma Inc. Teijin Pharma Limited Takeda Pharmaceutical Company Limited
Collaborators: Tomohiro Nishinaka						Nipro Corporation TERUMO CORPORATION Sun Medical Technology Research Corp. EVI JAPAN.INC.		Ain Pharmaciez Inc. Edwards Lifesciences Corporation Sun Medical Technology Research Corp. JMS Co., Ltd. Century Medical, Inc. TERUMO CORPORATION Nipro Corporation Medtronic Japan Co., Ltd.
Collaborators: Takahiro Okumura				AstraZeneca K.K. Novartis Pharma K.K. Medtronic Japan Co., Ltd. Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd.										Astellas Pharma Inc. Daiichi Sankyo Company, Limited
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: Shunei Kyo		TOBU RAILWAY CO.,LTD.								Daiko Jitsugyo, Ltd	TOBU RAILWAY CO.,LTD.
Independent Assessment Committee: 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 Bristol-Myers Squibb Actelion Pharmaceuticals Japan Ltd. Amgen Astellas BioPharma K.K. Abbott Medical Japan L.L.C Sony Corporation Nipro Corporation 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 L.L.C 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

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

Members: Norihide Fukushima, none

Members: Masanobu Yanase, none

Collaborators: Masatoshi Akiyama, none

Collaborators: Miyoko Endo, none

Collaborators: Takeo Fujino, none

Collaborators: Taiki Higo, none

Collaborators: Yumiko Hori, none

Collaborators: Teruhiko Imamura, none

Collaborators: Kiyotaka Iwasaki, none

Collaborators: Koichi Kashiwa, none

Collaborators: Osamu Kinoshita, none

Collaborators: Kaori Kubota, none

Collaborators: Takashi Nishimura, none

Collaborators: Hiroshi Nishioka, none

Collaborators: Yoshihiko Ohnishi, none

Collaborators: Osamu Seguchi, none

Collaborators: Koichi Toda, none

Collaborators: Motoharu Yamanaka, none

Independent Assessment Committee: Takeshi Nakatani, none

Independent Assessment Committee: Takayuki Ohno, none

References

• 1.  　 Yamane T, Kyo S, Matsuda H, Abe Y, Imachi K, Masuzawa T, et al. Japanese guidance for ventricular assist devices/total artificial hearts. Artif Organs 2010; 34: 699–702.
• 2.  　 Kyo S, Isobe M, Ono M, Kinugawa K, Saiki Y, Sawa Y, et al; Japanese Circulation Society, Japanese Society for Cardiovascular Surgery. Guidelines for device therapy: Implantable left ventricular assist device for patients with severe heart failure (JCS/JSCVS2013) [in Japanese]. https://www.j-circ.or.jp/old/guideline/pdf/JCS2013_kyo_h.pdf [accessed March, 2021].
• 3.  　 Teuteberg JJ, Cleveland JC Jr, Cowger J, Higgins RS, Goldstein DJ, Keebler M, et al. The Society of Thoracic Surgeons Intermacs 2019 Annual Report: The changing landscape of devices and indications. Ann Thorac Surg 2020; 109: 649–660.
• 4.  　 de By TMMH, Mohacsi P, Gahl B, Zittermann A, Krabatsch T, Gustafsson F, et al; EUROMACS members. The European Registry for Patients with Mechanical Circulatory Support (EUROMACS) of the European Association for Cardio-Thoracic Surgery (EACTS): Second report. Eur J Cardiothorac Surg 2018; 53: 309–316.
• 5.  　 Kinugawa K, Nishimura T, Toda K, Saiki Y, Niinami H, Nunoda S, et al; J-MACS investigators. The second official report from Japanese registry for mechanical assisted circulatory support (J-MACS): First results of bridge to bridge strategy. Gen Thorac Cardiovasc Surg 2020; 68: 102–111.
• 6.  　 Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, et al; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 2001; 345: 1435–1443.
• 7.  　 Miller LW, Pagani FD, Russell SD, John R, Boyle AJ, Aaronson KD, et al; HeartMate II Clinical Investigators. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007; 357: 885–896.
• 8.  　 Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D, et al; HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009; 361: 2241–2251.
• 9.  　 Aaronson KD, Slaughter MS, Miller LW, McGee EC, Cotts WG, Acker MA, et al; HeartWare Ventricular Assist Device (HVAD) Bridge to Transplant ADVANCE Trial Investigators. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012; 125: 3191–3200.
• 10.  　 Milano CA, Rogers JG, Tatooles AJ, Bhat G, Slaughter MS, Birks EJ, et al; ENDURANCE Investigators. HVAD: The ENDURANCE supplemental trial. JACC Heart Fail 2018; 6: 792–802.
• 11.  　 Goldstein DJ, Mehra MR, Naka Y, Salerno C, Uriel N, Dean D, et al; MOMENTUM 3 Investigators. Impact of age, sex, therapeutic intent, race and severity of advanced heart failure on short-term principal outcomes in the MOMENTUM 3 trial. J Heart Lung Transplant 2018; 37: 7–14.
• 12.  　 Mehra MR, Uriel N, Naka Y, Cleveland JC Jr, Yuzefpolskaya M, Salerno CT, et al; MOMENTUM 3 Investigators. A fully magnetically levitated left ventricular assist device: Final report. N Engl J Med 2019; 380: 1618–1627.
• 13.  　 Imamura T, Kinugawa K, Shiga T, Endo M, Kato N, Inaba T, et al. Novel risk scoring system with preoperative objective parameters gives a good prediction of 1-year mortality in patients with a left ventricular assist device. Circ J 2012; 76: 1895–1903.
• 14.  　 Russell SD, Rogers JG, Milano CA, Dyke DB, Pagani FD, Aranda JM, et al; HeartMate II Clinical Investigators. Renal and hepatic function improve in advanced heart failure patients during continuous-flow support with the HeartMate II left ventricular assist device. Circulation 2009; 120: 2352–2357.
• 15.  　 Imamura T, Kinugawa K, Shiga T, Endo M, Kato N, Inaba T, et al. Preoperative levels of bilirubin or creatinine adjusted by age can predict their reversibility after implantation of left ventricular assist device. Circ J 2013; 77: 96–104.
• 16.  　 Kashiwa K, Nishimura T, Saito A, Kubo H, Fukaya A, Tamai H, et al. Left heart bypass support with the Rotaflow Centrifugal Pump^® as a bridge to decision and recovery in an adult. J Artif Organs 2012; 15: 207–210.
• 17.  　 Drakos SG, Kfoury AG, Stehlik J, Selzman CH, Reid BB, Terrovitis JV, et al. Bridge to recovery: Understanding the disconnect between clinical and biological outcomes. Circulation 2012; 126: 230–241.
• 18.  　 Imamura T, Kinugawa K, Hatano M, Fujino T, Muraoka H, Inaba T, et al. Preoperative beta-blocker treatment is a key for deciding left ventricular assist device implantation strategy as a bridge to recovery. J Artif Organs 2014; 17: 23–32.
• 19.  　 Matsumiya G, Monta O, Fukushima N, Sawa Y, Funatsu T, Toda K, et al. Who would be a candidate for bridge to recovery during prolonged mechanical left ventricular support in idiopathic dilated cardiomyopathy? J Thorac Cardiovasc Surg 2005; 130: 699–704.
• 20.  　 Nishimura T, Kyo S. High-dose carvedilol therapy for mechanical circulatory assisted patients. J Artif Organs 2010; 13: 88–91.
• 21.  　 Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006; 355: 1873–1884.
• 22.  　 Imamura T, Kinugawa K, Nitta D, Fujino T, Inaba T, Maki H, et al. Novel scoring system using postoperative cardiopulmonary exercise testing predicts future explantation of left ventricular assist device. Circ J 2015; 79: 560–566.
• 23.  　 Holzhauser L, Lang RM, Raikhelkar J, Sayer G, Uriel N. Reverse ramp testing in left ventricular assist device support and myocardial recovery. ASAIO J 2020; 66: e1–e4.
• 24.  　 den Uil CA, Akin S, Jewbali LS, Dos Reis Miranda D, Brugts JJ, Constantinescu AA, et al. Short-term mechanical circulatory support as a bridge to durable left ventricular assist device implantation in refractory cardiogenic shock: A systematic review and meta-analysis. Eur J Cardiothorac Surg 2017; 52: 14–25.
• 25.  　 Hall SA, Uriel N, Carey SA, Edens M, Gong G, Esposito M, et al. Use of a percutaneous temporary circulatory support device as a bridge to decision during acute decompensation of advanced heart failure. J Heart Lung Transplant 2018; 37: 100–106.
• 26.  　 Lima B, Kale P, Gonzalez-Stawinski GV, Kuiper JJ, Carey S, Hall SA. Effectiveness and safety of the Impella 5.0 as a bridge to cardiac transplantation or durable left ventricular assist device. Am J Cardiol 2016; 117: 1622–1628.
• 27.  　 Patel SM, Lipinski J, Al-Kindi SG, Patel T, Saric P, Li J, et al. Simultaneous venoarterial extracorporeal membrane oxygenation and percutaneous left ventricular decompression therapy with Impella is associated with improved outcomes in refractory cardiogenic shock. ASAIO J 2019; 65: 21–28.
• 28.  　 Yoshioka D, Takayama H, Colombo PC, Yuzefpolskaya M, Garan AR, Topkara VK, et al. Changes in end-organ function in patients with prolonged continuous-flow left ventricular assist device support. Ann Thorac Surg 2017; 103: 717–724.
• 29.  　 Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson LW, Blume ED, et al. Seventh INTERMACS annual report: 15,000 patients and counting. J Heart Lung Transplant 2015; 34: 1495–1504.
• 30.  　 Kirklin JK, Pagani FD, Kormos RL, Stevenson LW, Blume ED, Myers SL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36: 1080–1086.
• 31.  　 Adams EE, Wrightson ML. Quality of life with an LVAD: A misunderstood concept. Heart Lung 2018; 47: 177–183.
• 32.  　補助人工心臓治療関連学会協議会, Destination Therapy (DT) 研究会. 我が国における植込型補助人工心臓適応適正化の考え方：Destination Therapyについて. 2014. https://www.jacvas.com/view-dt/ [accessed March, 2021].
• 33.  　 Kirklin JK, Naftel DC, Pagani FD, Kormos RL, Stevenson L, Miller M, et al. Long-term mechanical circulatory support (destination therapy): On track to compete with heart transplantation? J Thorac Cardiovasc Surg 2012; 144: 584–603.
• 34.  　 Khot UN, Mishra M, Yamani MH, Smedira NG, Paganini E, Yeager M, et al. Severe renal dysfunction complicating cardiogenic shock is not a contraindication to mechanical support as a bridge to cardiac transplantation. J Am Coll Cardiol 2003; 41: 381–385.
• 35.  　 Mehra MR, Naka Y, Uriel N, Goldstein DJ, Cleveland JC Jr, Colombo PC, et al; MOMENTUM 3 Investigators. A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med 2017; 376: 440–450.
• 36.  　 Mehra MR, Goldstein DJ, Uriel N, Cleveland JC Jr, Yuzefpolskaya M, Salerno C, et al; MOMENTUM 3 Investigators. Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med 2018; 378: 1386–1395.
• 37.  　 Nakatani T, Sase K, Oshiyama H, Akiyama M, Horie M, Nawata K, et al; J-MACS investigators. Japanese registry for Mechanically Assisted Circulatory Support: First report. J Heart Lung Transplant 2017; 36: 1087–1096.
• 38.  　 Almond CS, Morales DL, Blackstone EH, Turrentine MW, Imamura M, Massicotte MP, et al. Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children. Circulation 2013; 127: 1702–1711.
• 39.  　 Adachi I, Burki S, Fraser CD Jr. Current status of pediatric ventricular assist device support. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2017; 20: 2–8.
• 40.  　 Kanaya T, Ueno T, Taira M, Kido T, Okuda N, Araki K, et al. Impact of long-term support with Berlin Heart EXCOR® in pediatric patients with severe heart failure. Pediatr Cardiol 2019; 40: 1126–1133.
• 41.  　 Kakuta T, Hoashi T, Sakaguchi H, Kagisaki K, Negishi J, Shimada M, et al. Early single institutional experience of Berlin Heart EXCOR^® pediatric ventricular assist device in Japan. Circ J 2016; 80: 2552–2554.
• 42.  　 Fukushima N, Ono M, Saiki Y, Sawa Y, Nunoda S, Isobe M. Registry report on heart transplantation in Japan (June 2016). Circ J 2017; 81: 298–303.
• 43.  　 Japanese Society for Heart Transplantation. The Registry Report of Japanese Heart Transplantation [in Japanese]. http://www.jsht.jp/registry/japan/ [accessed March, 2021].
• 44.  　補助人工心臓治療関連学会協議会. 小児用補助人工心臓実施基準及び適正使用基準. 2015. https://www.jacvas.com/application/1/j-standard/ [accessed March, 2021].
• 45.  　 Thuys CA, Mullaly RJ, Horton SB, O’Connor EB, Cochrane AD, Brizard CP, et al. Centrifugal ventricular assist in children under 6 kg. Eur J Cardiothorac Surg 1998; 13: 130–134.
• 46.  　 Duncan BW, Bohn DJ, Atz AM, French JW, Laussen PC, Wessel DL. Mechanical circulatory support for the treatment of children with acute fulminant myocarditis. J Thorac Cardiovasc Surg 2001; 122: 440–448.
• 47.  　 Haines NM, Rycus PT, Zwischenberger JB, Bartlett RH, Undar A. Extracorporeal Life Support Registry Report 2008: Neonatal and pediatric cardiac cases. ASAIO J 2009; 55: 111–116.
• 48.  　 Fukushima N, Tatsumi E, Seguchi O, Takewa Y, Hamasaki T, Onda K, et al. Assessment of safety and effectiveness of the extracorporeal continuous-flow ventricular assist device (BR16010) use as a bridge-to-decision therapy for severe heart failure or refractory cardiogenic shock: Study protocol for single-arm non-randomized, uncontrolled, and investigator-initiated clinical trial. Cardiovasc Drugs Ther 2018; 32: 373–379.
• 49.  　 Seguchi O, Fujita T, Kitahata N, Iwasaki K, Kuroda K, Nakajima S, et al. A novel extracorporeal continuous-flow ventricular assist system for patients with advanced heart failure: Initial clinical experience. Circ J 2020; 84: 1090–1096.
• 50.  　 Teele SA, Allan CK, Laussen PC, Newburger JW, Gauvreau K, Thiagarajan RR. Management and outcomes in pediatric patients presenting with acute fulminant myocarditis. J Pediatr 2011; 158: 638–643.e1.
• 51.  　 Okada N, Murayama H, Hasegawa H, Kawai S, Mori H, Yasuda K. Peripheral veno-arterial extracorporeal membrane oxygenation as a bridge to decision for pediatric fulminant myocarditis. Artif Organs 2016; 40: 793–798.
• 52.  　 Andrade JG, Al-Saloos H, Jeewa A, Sandor GG, Cheung A. Facilitated cardiac recovery in fulminant myocarditis: Pediatric use of the Impella LP 5.0 pump. J Heart Lung Transplant 2010; 29: 96–97.
• 53.  　 Ricci M, Gaughan CB, Rossi M, Andreopoulos FM, Novello C, Salerno TA, et al. Initial experience with the TandemHeart circulatory support system in children. ASAIO J 2008; 54: 542–545.
• 54.  　 Cabrera AG, Sundareswaran KS, Samayoa AX, Jeewa A, McKenzie ED, Rossano JW, et al. Outcomes of pediatric patients supported by the HeartMate II left ventricular assist device in the United States. J Heart Lung Transplant 2013; 32: 1107–1113.
• 55.  　 Conway J, Miera O, Adachi I, Maeda K, Eghtesady P, Henderson HT, et al; Pediatric VAD Investigators. Worldwide experience of a durable centrifugal flow pump in pediatric patients. Semin Thorac Cardiovasc Surg 2018; 30: 327–335.
• 56.  　 Adachi I, Guzmán-Pruneda FA, Jeewa A, Fraser CD Jr, Dean McKenzie E. A modified implantation technique of the HeartWare ventricular assist device for pediatric patients. J Heart Lung Transplant 2015; 34: 134–136.
• 57.  　 Weinstein S, Bello R, Pizarro C, Fynn-Thompson F, Kirklin J, Guleserian K, et al. The use of the Berlin Heart EXCOR in patients with functional single ventricle. J Thorac Cardiovasc Surg 2014; 147: 697–704; discussion 704–705.
• 58.  　 Fujita T, Fukushima S, Fukushima N, Shiraishi I, Kobayashi J. Three-dimensional replica of corrected transposition of the great arteries for successful heart transplantation. J Artif Organs 2017; 20: 289–291.
• 59.  　 Japanese Association for Clinical Ventricular Assist Systems (JACVAS). https://www.jacvas.com/ [accessed March, 2021].
• 60.  　 Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, et al; Japanese Circulation Society and the Japanese Heart Failure Society Joint Working Group. JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure: Digest version. Circ J 2019; 83: 2084–2184.
• 61.  　 Imamura T, Kinugawa K, Kato N, Muraoka H, Fujino T, Inaba T, et al. Late-onset right ventricular failure in patients with preoperative small left ventricle after implantation of continuous flow left ventricular assist device. Circ J 2014; 78: 625–633.
• 62.  　 Tsutsui H, Kitaoka H, Isobe M, Ide T, Ishibashi-Ueda H, Ono M, et al; Japanese Circulation Society, Japan Heart Failure Society. JCS 2018 guideline on diagnosis and treatment of cardiomyopathies [in Japanese]. http://www.j-circ.or.jp/guideline/pdf/JCS2018_tsutsui_kitaoka.pdf [accessed March, 2021].
• 63.  　 Matsumori A, Furukawa Y, Hasegawa K, Sato Y, Nakagawa H, Morikawa Y, et al; Co-research workers. Epidemiologic and clinical characteristics of cardiomyopathies in Japan: Results from nationwide surveys. Circ J 2002; 66: 323–336.
• 64.  　 Ha JW, Ommen SR, Tajik AJ, Barnes ME, Ammash NM, Gertz MA, et al. Differentiation of constrictive pericarditis from restrictive cardiomyopathy using mitral annular velocity by tissue Doppler echocardiography. Am J Cardiol 2004; 94: 316–319.
• 65.  　 Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: Proposed modification of the task force criteria. Circulation 2010; 121: 1533–1541.
• 66.  　 Terasaki F, Azuma A, Anzai T, Ishizaka N, Ishida Y, Isobe M, et al; Japanese Circulation Society Joint Working Group. JCS 2016 guideline on diagnosis and treatment of cardiac sarcoidosis: Digest version. Circ J 2019; 83: 2329–2388.
• 67.  　 Isobe M, Tezuka D. Isolated cardiac sarcoidosis: Clinical characteristics, diagnosis and treatment. Int J Cardiol 2015; 182: 132–140.
• 68.  　 Yazaki Y, Isobe M, Hiroe M, Morimoto S, Hiramitsu S, Nakano T, et al; Central Japan Heart Study Group. Prognostic determinants of long-term survival in Japanese patients with cardiac sarcoidosis treated with prednisone. Am J Cardiol 2001; 88: 1006–1010.
• 69.  　 Chiu CZ, Nakatani S, Zhang G, Tachibana T, Ohmori F, Yamagishi M, et al. Prevention of left ventricular remodeling by long-term corticosteroid therapy in patients with cardiac sarcoidosis. Am J Cardiol 2005; 95: 143–146.
• 70.  　 Seguchi O, Kuroda K, Fujita T, Fukushima N, Nakatani T. Advanced heart failure secondary to muscular dystrophy: Clinical outcomes after left ventricular assist device implantation. J Heart Lung Transplant 2016; 35: 831–834.
• 71.  　 Rychik J, Atz AM, Celermajer DS, Deal BJ, Gatzoulis MA, Gewillig MH, et al. American Heart Association Council on Cardiovascular Disease in the Young and Council on Cardiovascular and Stroke Nursing. Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement from the American Heart Association. Circulation 2019; 140: e234–e284.
• 72.  　 Miller JR, Lancaster TS, Callahan C, Abarbanell AM, Eghtesady P. An overview of mechanical circulatory support in single-ventricle patients. Transl Pediatr 2018; 7: 151–161.
• 73.  　 Morales DLS, Rossano JW, VanderPluym C, Lorts A, Cantor R, St Louis JD, et al; Pedimacs Investigators. Third Annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) report: Preimplant characteristics and outcomes. Ann Thorac Surg 2019; 107: 993–1004.
• 74.  　 Cedars A, Tecson KM, Zaidi AN, Lorts A, McCullough PA. Impact of durable ventricular assist device support on outcomes of patients with congenital heart disease waiting for heart transplant. ASAIO J 2020; 66: 513–519.
• 75.  　 SRTR: Scientific Registry of Transplant Recipients. https://www.srtr.org/ [accessed November 11, 2018].
• 76.  　 Komagamine M, Nishinaka T, Ichihara Y, Nagashima M, Shimizu M, Shinohara T, et al. Ventricular assist device implantation late after double switch operation for L-transposition of the great arteries. Ann Thorac Surg 2014; 98: e109–e111.
• 77.  　 Tanoue Y, Fujino T, Tatewaki H, Shiose A. Jarvik 2000 axial flow ventricular assist device in right single ventricle after Fontan operation. J Artif Organs 2019; 22: 338–340.
• 78.  　 Tanoue Y, Jinzai Y, Tominaga R. Jarvik 2000 axial-flow ventricular assist device placement to a systemic morphologic right ventricle in congenitally corrected transposition of the great arteries. J Artif Organs 2016; 19: 97–99.
• 79.  　 Carlo WF, Villa CR, Lal AK, Morales DL. Ventricular assist device use in single ventricle congenital heart disease. Pediatr Transplant, doi:10.1111/petr.13031.
• 80.  　 Chen S, Rosenthal DN, Murray J, Dykes JC, Almond CS, Yarlagadda VV, et al. Bridge to transplant with ventricular assist device support in pediatric patients with single ventricle heart disease. ASAIO J 2020; 66: 205–211.
• 81.  　 Buratto E, Shi WY, Ye XT, Konstantinov IE. Ventricular assist devices for the failing univentricular circulation. Expert Rev Med Devices 2017; 14: 449–459.
• 82.  　 Villa CR, Morales DLS. The Total Artificial Heart in end-stage congenital heart disease. Front Physiol 2017; 8: 131.
• 83.  　 Wells D, Villa CR, Simón Morales DL. The 50/50 cc Total Artificial Heart Trial: Extending the benefits of the Total Artificial Heart to underserved populations. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2017; 20: 16–19.
• 84.  　 Lorts A, Villa C, Riggs KW, Broderick J, Morales DLS. First use of HeartMate 3 in a failing Fontan circulation. Ann Thorac Surg 2018; 106: e233–e234.
• 85.  　 Granegger M, Thamsen B, Hubmann EJ, Choi Y, Beck D, Valsangiacomo Buechel E, et al. A long-term mechanical cavopulmonary support device for patients with Fontan circulation. Med Eng Phys 2019; 70: 9–18.
• 86.  　 Peura JL, Colvin-Adams M, Francis GS, Grady KL, Hoffman TM, Jessup M, et al. Recommendations for the use of mechanical circulatory support: Device strategies and patient selection: A Scientific Statement from the American Heart Association. Circulation 2012; 126: 2648–2667.
• 87.  　 Stevenson LW, Pagani FD, Young JB, Jessup M, Miller L, Kormos RL, et al. INTERMACS profiles of advanced heart failure: The current picture. J Heart Lung Transplant 2009; 28: 535–541.
• 88.  　 Tsutsui H, Ide T, Ito H, Kinugawa K, Kinugawa S, Kihara Y, et al; Japanese Circulation Society and Japanese Heart Failure Society. JCS/JHFS 2021 guideline focused update on diagnosis and treatment of acute and chronic heart failure [in Japanese]. https://www.j-circ.or.jp/cms/wp-content/uploads/2021/03/JCS2021_Tsutsui.pdf [accessed March, 2021].
• 89.  　deleted in proof.
• 90.  　 Kormos RL, Cowger J, Pagani FD, Teuteberg JJ, Goldstein DJ, Jacobs JP, et al. The Society of Thoracic Surgeons Intermacs Database Annual Report: Evolving indications, outcomes, and scientific partnerships. Ann Thorac Surg 2019; 107: 341–353.
• 91.  　 Cowger J, Shah P, Stulak J, Maltais S, Aaronson KD, Kirklin JK, et al. INTERMACS profiles and modifiers: Heterogeneity of patient classification and the impact of modifiers on predicting patient outcome. J Heart Lung Transplant 2016; 35: 440–448.
• 92.  　 Estep JD, Starling RC, Horstmanshof DA, Milano CA, Selzman CH, Shah KB, et al; ROADMAP Study Investigators. Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: Results from the ROADMAP Study. J Am Coll Cardiol 2015; 66: 1747–1761.
• 93.  　 Holman WL, Kormos RL, Naftel DC, Miller MA, Pagani FD, Blume E, et al. Predictors of death and transplant in patients with a mechanical circulatory support device: A multi-institutional study. J Heart Lung Transplant 2009; 28: 44–50.
• 94.  　 Adamson RM, Stahovich M, Chillcott S, Baradarian S, Chammas J, Jaski B, et al. Clinical strategies and outcomes in advanced heart failure patients older than 70 years of age receiving the HeartMate II left ventricular assist device: A community hospital experience. J Am Coll Cardiol 2011; 57: 2487–2495.
• 95.  　 Feldman D, Pamboukian SV, Teuteberg JJ, Birks E, Lietz K, Moore SA, et al. The 2013 International Society for Heart and Lung Transplantation guidelines for mechanical circulatory support: Executive summary. J Heart Lung Transplant 2013; 32: 157–187.
• 96.  　 Clerkin KJ, Naka Y, Mancini DM, Colombo PC, Topkara VK. The impact of obesity on patients bridged to transplantation with continuous-flow left ventricular assist devices. JACC Heart Fail 2016; 4: 761–768.
• 97.  　 Yost G, Coyle L, Gallagher C, Graney N, Siemeck R, Tatooles A, et al. The impact of extreme obesity on outcomes after left ventricular assist device implantation. J Thorac Dis 2017; 9: 4441–4446.
• 98.  　 Raymond AL, Kfoury AG, Bishop CJ, Davis ES, Goebel KM, Stoker S, et al. Obesity and left ventricular assist device driveline exit site infection. ASAIO J 2010; 56: 57–60.
• 99.  　 Akay MH, Nathan SS, Radovancevic R, Poglajen G, Jezovnik MK, Candelaria IN, et al. Obesity is associated with driveline infection of left ventricular assist devices. ASAIO J 2019; 65: 678–682.
• 100.  　 Lindenfeld J, Feldman AM, Saxon L, Boehmer J, Carson P, Ghali JK, et al. Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure. Circulation 2007; 115: 204–212.
• 101.  　 Yoshioka D, Sakaguchi T, Saito S, Miyagawa S, Nishi H, Yoshikawa Y, et al. Initial experience of conversion of Toyobo paracorporeal left ventricular assist device to DuraHeart left ventricular assist device. Circ J 2012; 76: 372–376.
• 102.  　 Worku B, Pak SW, van Patten D, Housman B, Uriel N, Colombo P, et al. The CentriMag ventricular assist device in acute heart failure refractory to medical management. J Heart Lung Transplant 2012; 31: 611–617.
• 103.  　 Yoshida S, Toda K, Miyagawa S, Yoshikawa Y, Hata H, Torikai K, et al. Impella 5.0 as a bridge to implantable left ventricular assist device: First clinical case in Japan. Circ J 2018; 82: 2923–2924.
• 104.  　 Riggs KW, Fukushima S, Fujita T, Rizwan R, Morales DLS. Mechanical support for patients with congenitally corrected transposition of the great arteries and end-stage ventricular dysfunction. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2019; 22: 66–73.
• 105.  　 Michel E, Orozco Hernandez E, Enter D, Monge M, Nakano J, Rich J, et al. Bridge to transplantation with long-term mechanical assist devices in adults with transposition of the great arteries. Artif Organs 2019; 43: 90–96.
• 106.  　 Peng DM, Koehl DA, Cantor RS, McMillan KN, Barnes AP, McConnell PI, et al. Outcomes of children with congenital heart disease implanted with ventricular assist devices: An analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs). J Heart Lung Transplant 2019; 38: 420–430.
• 107.  　 Schumacher KR, Gossett J, Guleserian K, Naftel DC, Pruitt E, Dodd D, et al. Fontan-associated protein-losing enteropathy and heart transplant: A pediatric heart transplant study analysis. J Heart Lung Transplant 2015; 34: 1169–1176.
• 108.  　 Gustafsson F, Rogers JG. Left ventricular assist device therapy in advanced heart failure: Patient selection and outcomes. Eur J Heart Fail 2017; 19: 595–602.
• 109.  　 Imamura T, Kinugawa K, Nitta D, Hatano M, Kinoshita O, Nawata K, et al. Prophylactic intra-aortic balloon pump before ventricular assist device implantation reduces perioperative medical expenses and improves postoperative clinical course in INTERMACS profile 2 patients. Circ J 2015; 79: 1963–1969.
• 110.  　 Kirklin JK, Naftel DC, Kormos RL, Pagani FD, Myers SL, Stevenson LW, et al. Quantifying the effect of cardiorenal syndrome on mortality after left ventricular assist device implant. J Heart Lung Transplant 2013; 32: 1205–1213.
• 111.  　 Maltais S, Stulak JM. Right and left ventricular assist devices support and liver dysfunction: Prognostic and therapeutic implications. Curr Opin Cardiol 2016; 31: 287–291.
• 112.  　 Kirklin JK, Pagani FD, Goldstein DJ, John R, Rogers JG, et al, Editors. American Association for Thoracic Surgery/International Society for Heart and Lung Transplantation guidelines on selected topics in mechanical circulatory support. J Heart Lung Transplant 2020; 39: 187–219.
• 113.  　 Yang JA, Kato TS, Shulman BP, Takayama H, Farr M, Jorde UP, et al. Liver dysfunction as a predictor of outcomes in patients with advanced heart failure requiring ventricular assist device support: Use of the Model of End-stage Liver Disease (MELD) and MELD eXcluding INR (MELD-XI) scoring system. J Heart Lung Transplant 2012; 31: 601–610.
• 114.  　 Mikus E, Stepanenko A, Krabatsch T, Loforte A, Dandel M, Lehmkuhl HB, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg 2011; 40: 971–977.
• 115.  　 Mikus E, Stepanenko A, Krabatsch T, Dandel M, Lehmkuhl HB, Loforte A, et al. Left ventricular assist device or heart transplantation: Impact of transpulmonary gradient and pulmonary vascular resistance on decision making. Eur J Cardiothorac Surg 2011; 39: 310–316.
• 116.  　 Asleh R, Briasoulis A, Schettle SD, Tchantchaleishvili V, Pereira NL, Edwards BS, et al. Impact of diabetes mellitus on outcomes in patients supported with left ventricular assist devices: A single institutional 9-year experience. Circ Heart Fail 2017; 10: e004213.
• 117.  　 Yassin AS, Subahi A, Adegbala O, Abubakar H, Akintoye E, Ahmed A, et al. Clinical impact of diabetes mellitus on short-term outcomes and in-hospital mortality of cardiac mechanical support with left ventricular assist device (LVAD): A retrospective study from a National Database. Cardiovasc Revasc Med 2019; 20: 883–886.
• 118.  　 Kusne S, Mooney M, Danziger-Isakov L, Kaan A, Lund LH, Lyster H, et al. An ISHLT consensus document for prevention and management strategies for mechanical circulatory support infection. J Heart Lung Transplant 2017; 36: 1137–1153.
• 119.  　 Cowger J, Sundareswaran K, Rogers JG, Park SJ, Pagani FD, Bhat G, et al. Predicting survival in patients receiving continuous flow left ventricular assist devices: The HeartMate II risk score. J Am Coll Cardiol 2013; 61: 313–321.
• 120.  　 Michaels A, Cowger J. Patient selection for destination LVAD therapy: Predicting success in the short and long term. Curr Heart Fail Rep 2019; 16: 140–149.
• 121.  　 Truby LK, Garan AR, Givens RC, Wayda B, Takeda K, Yuzefpolskaya M, et al. Aortic insufficiency during contemporary left ventricular assist device support: Analysis of the INTERMACS Registry. JACC Heart Fail 2018; 6: 951–960.
• 122.  　 Toda K, Fujita T, Domae K, Shimahara Y, Kobayashi J, Nakatani T. Late aortic insufficiency related to poor prognosis during left ventricular assist device support. Ann Thorac Surg 2011; 92: 929–934.
• 123.  　 Imamura T, Kinugawa K, Fujino T, Inaba T, Maki H, Hatano M, et al. Aortic insufficiency in patients with sustained left ventricular systolic dysfunction after axial flow assist device implantation. Circ J 2015; 79: 104–111.
• 124.  　 Feldman CM, Silver MA, Sobieski MA, Slaughter MS. Management of aortic insufficiency with continuous flow left ventricular assist devices: Bioprosthetic valve replacement. J Heart Lung Transplant 2006; 25: 1410–1412.
• 125.  　 Fukuhara S, Takeda K, Chiuzan C, Han J, Polanco AR, Yuzefpolskaya M, et al. Concomitant aortic valve repair with continuous-flow left ventricular assist devices: Results and implications. J Thorac Cardiovasc Surg 2016; 151: 201–209, 210.e1–e2.
• 126.  　 Robertson JO, Naftel DC, Myers SL, Prasad S, Mertz GD, Itoh A, et al. Concomitant aortic valve procedures in patients undergoing implantation of continuous-flow left ventricular assist devices: An INTERMACS database analysis. J Heart Lung Transplant 2015; 34: 797–805.
• 127.  　 Rao V, Slater JP, Edwards NM, Naka Y, Oz MC. Surgical management of valvular disease in patients requiring left ventricular assist device support. Ann Thorac Surg 2001; 71: 1448–1453.
• 128.  　 Goda A, Takayama H, Pak SW, Uriel N, Mancini D, Naka Y, et al. Aortic valve procedures at the time of ventricular assist device placement. Ann Thorac Surg 2011; 91: 750–754.
• 129.  　 Tasset MR, Kavarana MN, Gray LA, Dowling RD. Simple mechanical aortic valve closure in ventricular assist device recipients. Ann Thorac Surg 2006; 82: 316–318.
• 130.  　 Adamson RM, Dembitsky WP, Baradarian S, Chammas J, May-Newman K, Chillcott S, et al. Aortic valve closure associated with HeartMate left ventricular device support: Technical considerations and long-term results. J Heart Lung Transplant 2011; 30: 576–582.
• 131.  　 Tisol WB, Mueller DK, Hoy FB, Gomez RC, Clemson BS, Hussain SM. Ventricular assist device use with mechanical heart valves: An outcome series and literature review. Ann Thorac Surg 2001; 72: 2051–2054; discussion 2055.
• 132.  　 Swartz MT, Lowdermilk GA, Moroney DA, McBride LR. Ventricular assist device support in patients with mechanical heart valves. Ann Thorac Surg 1999; 68: 2248–2251.
• 133.  　 Matsumiya G, Miyamoto Y, Monta O, Takano H, Sawa Y, Matsuda H. Left ventricular restoration for ischemic cardiomyopathy and simultaneous implantation of left ventricular assist system actively aiming at bridge to recovery. J Thorac Cardiovasc Surg 2005; 130: 219–220.
• 134.  　 Osaki S, Edwards NM, Kohmoto T. Strategies for left ventricular assist device insertion after the Dor procedure. J Heart Lung Transplant 2009; 28: 520–522.
• 135.  　 Takeda K, Ahmad U, Malaisrie SC, Lee R, McCarthy PM, McGee EC Jr. Successful implantation of HeartWare HVAD left ventricular assist device with concomitant ascending and sinus of valsalva aneurysms repair. J Artif Organs 2012; 15: 204–206.
• 136.  　 Kiernan MS, Grandin EW, Brinkley M Jr, Kapur NK, Pham DT, Ruthazer R, et al. Early right ventricular assist device use in patients undergoing continuous-flow left ventricular assist device implantation: Incidence and risk factors from the Interagency Registry for Mechanically Assisted Circulatory Support. Circ Heart Fail 2017; 10: e003863.
• 137.  　 Yoshioka D, Toda K, Ono M, Nakatani T, Shiose A, Matsui Y, et al; Japanese HeartMateII Investigators. Clinical results, adverse events, and change in end-organ function in elderly patients with HeartMateII left ventricular assist device: Japanese Multicenter Study. Circ J 2018; 82: 409–418.
• 138.  　 Sakaguchi T, Saito S, Yoshioka D, Sawa Y. Long-term biventricular support with rotary blood pumps in a patient with a noncontractile heart. J Thorac Cardiovasc Surg 2013; 146: e29–e30.
• 139.  　 Yoshioka D, Toda K, Yoshikawa Y, Sawa Y. Over 1200-day support with dual Jarvik 2000 biventricular assist device. Interact Cardiovasc Thorac Surg 2014; 19: 1083–1084.
• 140.  　 Saito S, Toda K, Nakamura T, Miyagawa S, Yoshikawa Y, Hata H, et al. Rescuing patients with severe biventricular failure in the era of continuous-flow left ventricular assist device. Circ J 2019; 83: 379–385.
• 141.  　 Takeda K, Naka Y, Yang JA, Uriel N, Colombo PC, Jorde UP, et al. Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion. J Heart Lung Transplant 2014; 33: 141–148.
• 142.  　 Yoshioka D, Takayama H, Garan RA, Topkara VK, Han J, Kurlansky P, et al. Contemporary outcome of unplanned right ventricular assist device for severe right heart failure after continuous-flow left ventricular assist device insertion. Interact Cardiovasc Thorac Surg 2017; 24: 828–834.
• 143.  　 Kormos RL, Cowger J, Pagani FD, Teuteberg JJ, Goldstein DJ, Jacobs JP, et al. The Society of Thoracic Surgeons Intermacs database annual report: Evolving indications, outcomes, and scientific partnerships. J Heart Lung Transplant 2019; 38: 114–126.
• 144.  　 DeVore AD, Hammill BG, Patel CB, Patel MR, Rogers JG, Milano CA, et al. Intra-aortic balloon pump use before left ventricular assist device implantation: Insights from the INTERMACS Registry. ASAIO J 2018; 64: 218–224.
• 145.  　 Crespo-Leiro MG, Metra M, Lund LH, Milicic D, Costanzo MR, Filippatos G, et al. Advanced heart failure: A Position Statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018; 20: 1505–1535.
• 146.  　 Krishnamurthy Y, Cooper LB, Parikh KS, Felker GM, Milano CA, Rogers JG, et al. Pulmonary hypertension in the era of mechanical circulatory support. ASAIO J 2016; 62: 505–512.
• 147.  　 Lampert BC, Teuteberg JJ. Right ventricular failure after left ventricular assist devices. J Heart Lung Transplant 2015; 34: 1123–1130.
• 148.  　 Gulati G, Grandin EW, Kennedy K, Cabezas F, DeNofrio DD, Kociol R, et al. Preimplant phosphodiesterase-5 inhibitor use is associated with higher rates of severe early right heart failure after left ventricular assist device implantation. Circ Heart Fail 2019; 12: e005537.
• 149.  　 Mehra MR, Canter CE, Hannan MM, Semigran MJ, Uber PA, Baran DA, et al; ISHLT Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 2016; 35: 1–23.
• 150.  　 Imamura T, Kinugawa K, Shiga T, Kato N, Endo M, Inaba T, et al. Correction of hyponatremia by tolvaptan before left ventricular assist device implantation. Int Heart J 2012; 53: 391–393.
• 151.  　 Matthews JC, Pagani FD, Haft JW, Koelling TM, Naftel DC, Aaronson KD. Model for end-stage liver disease score predicts left ventricular assist device operative transfusion requirements, morbidity, and mortality. Circulation 2010; 121: 214–220.
• 152.  　 Shiga T, Kinugawa K, Hatano M, Yao A, Nishimura T, Endo M, et al. Age and preoperative total bilirubin level can stratify prognosis after extracorporeal pulsatile left ventricular assist device implantation. Circ J 2011; 75: 121–128.
• 153.  　 Imamura T, Kinugawa K, Hatano M, Fujino T, Inaba T, Maki H, et al. Low cardiac output stimulates vasopressin release in patients with stage d heart failure: Its relevance to poor prognosis and reversal by surgical treatment. Circ J 2014; 78: 2259–2267.
• 154.  　 Imamura T, Kinugawa K, Minatsuki S, Muraoka H, Kato N, Inaba T, et al. Urine osmolality estimated using urine urea nitrogen, sodium and creatinine can effectively predict response to tolvaptan in decompensated heart failure patients. Circ J 2013; 77: 1208–1213.
• 155.  　 Imamura T. Aquaporin-2-guided tolvaptan therapy in patients with congestive heart failure accompanied by chronic kidney disease. Int Heart J 2014; 55: 482–483.
• 156.  　 Imamura T, Kinugawa K. Update of acute and long-term tolvaptan therapy. J Cardiol 2019; 73: 102–107.
• 157.  　 Lietz K, Long JW, Kfoury AG, Slaughter MS, Silver MA, Milano CA, et al. Outcomes of left ventricular assist device implantation as destination therapy in the post-REMATCH era: Implications for patient selection. Circulation 2007; 116: 497–505.
• 158.  　 Topkara VK, Dang NC, Barili F, Cheema FH, Martens TP, George I, et al. Predictors and outcomes of continuous veno-venous hemodialysis use after implantation of a left ventricular assist device. J Heart Lung Transplant 2006; 25: 404–408.
• 159.  　 Pawar M, Mehta Y, Kapoor P, Sharma J, Gupta A, Trehan N. Central venous catheter-related blood stream infections: Incidence, risk factors, outcome, and associated pathogens. J Cardiothorac Vasc Anesth 2004; 18: 304–308.
• 160.  　 Kanjanahattakij N, Horn B, Abdulhadi B, Wongjarupong N, Mezue K, Rattanawong P. Blood stream infection is associated with cerebrovascular accident in patients with left ventricular assist device: A systematic review and meta-analysis. J Artif Organs 2018; 21: 271–277.
• 161.  　 Yoshioka D, Sakaniwa R, Toda K, Samura T, Saito S, Kashiyama N, et al. Relationship between bacteremia and hemorrhagic stroke in patients with continuous-flow left ventricular assist device. Circ J 2018; 82: 448–456.
• 162.  　 Barbara DW, Olsen DA, Pulido JN, Boilson BA, Bruining DH, Stulak JM, et al. Periprocedural management of 172 gastrointestinal endoscopies in patients with left ventricular assist devices. ASAIO J 2015; 61: 670–675.
• 163.  　 Stern DR, Kazam J, Edwards P, Maybaum S, Bello RA, D’Alessandro DA, et al. Increased incidence of gastrointestinal bleeding following implantation of the HeartMate II LVAD. J Card Surg 2010; 25: 352–356.
• 164.  　 Kawabori M, Kurihara C, Critsinelis AC, Sugiura T, Kaku Y, Civitello AB, et al. Gastrointestinal bleeding after HeartMate II or HVAD implantation: Incidence, location, etiology, and effect on survival. ASAIO J 2020; 66: 283–290.
• 165.  　 Mohamedali B, Yost G, Bhat G. Is diabetes mellitus a risk factor for poor outcomes after left ventricular assist device placement? Tex Heart Inst J 2017; 44: 115–119.
• 166.  　 Siméon S, Flécher E, Revest M, Niculescu M, Roussel JC, Michel M, et al. Left ventricular assist device-related infections: A multicentric study. Clin Microbiol Infect 2017; 23: 748–751.
• 167.  　 Yen DC, Watson MH, Burgess LD, Kuchibhatla M, Patel CB, Campbell KB, et al. Positive impact of continuous-flow left ventricular assist device implantation on glycemic control in patients with type 2 diabetes mellitus and advanced chronic systolic heart failure. Pharmacotherapy 2016; 36: 1210–1216.
• 168.  　 Vest AR, Mistak SM, Hachamovitch R, Mountis MM, Moazami N, Young JB. Outcomes for patients with diabetes after continuous-flow left ventricular assist device implantation. J Card Fail 2016; 22: 789–796.
• 169.  　 Volkovicher N, Kurihara C, Critsinelis A, Kawabori M, Sugiura T, Manon M 2nd, et al. Effect of obesity on outcomes in patients undergoing implantation of continuous-flow left ventricular assist devices. J Artif Organs 2018; 21: 180–187.
• 170.  　 Lee AY, Tecson KM, Lima B, Shaikh AF, Collier J, Still S, et al. Durable left ventricular assist device implantation in extremely obese heart failure patients. Artif Organs 2019; 43: 234–241.
• 171.  　 Mohamedali B, Yost G, Bhat G. Obesity as a risk factor for consideration for left ventricular assist devices. J Card Fail 2015; 21: 800–805.
• 172.  　 Munoz E, Lonquist JL, Radovancevic B, Baldwin RT, Ford S, Duncan JM, et al. Long-term results in diabetic patients undergoing heart transplantation. J Heart Lung Transplant 1992; 11: 943–949.
• 173.  　 Carr JG, Stevenson LW, Walden JA, Heber D. Prevalence and hemodynamic correlates of malnutrition in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1989; 63: 709–713.
• 174.  　 Mancini DM, Walter G, Reichek N, Lenkinski R, McCully KK, Mullen JL, et al. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992; 85: 1364–1373.
• 175.  　 Freeman LM, Roubenoff R. The nutrition implications of cardiac cachexia. Nutr Rev 1994; 52: 340–347.
• 176.  　 Schwengel RH, Gottlieb SS, Fisher ML. Protein-energy malnutrition in patients with ischemic and nonischemic dilated cardiomyopathy and congestive heart failure. Am J Cardiol 1994; 73: 908–910.
• 177.  　 Mano A, Fujita K, Uenomachi K, Kazama K, Katabuchi M, Wada K, et al. Body mass index is a useful predictor of prognosis after left ventricular assist system implantation. J Heart Lung Transplant 2009; 28: 428–433.
• 178.  　 Saito A, Amiya E, Hatano M, Shiraishi Y, Nitta D, Minatsuki S, et al. Controlling nutritional status score as a predictive marker for patients with implantable left ventricular assist device. ASAIO J 2020; 66: 166–172.
• 179.  　 Uribarri A, Rojas SV, Hanke JS, Dogan G, Siemeni T, Kaufeld T, et al. Prognostic value of the nutritional risk index in candidates for continuous flow left ventricular assist device therapy. Rev Esp Cardiol (Engl Ed) 2019; 72: 608–615.
• 180.  　 Critsinelis AC, Kurihara C, Kawabori M, Sugiura T, Civitello AB, Morgan JA. Preoperative prealbumin level as a predictor of outcomes in patients who underwent left ventricular assist device implantation. Am J Cardiol 2017; 120: 1998–2002.
• 181.  　 Yost G, Tatooles A, Bhat G. Preoperative nutritional assessment with the prognostic nutrition index in patients undergoing left ventricular assist device implantation. ASAIO J 2018; 64: 52–55.
• 182.  　 Casida JM, Davis JE, Pagani FD, Aikens JE, Williams C, Yang JJ. Sleep and self-care correlates before and after implantation of a left-ventricular assist device (LVAD). J Artif Organs 2018; 21: 278–284.
• 183.  　 Casida JM, Brewer RJ, Smith C, Davis JE. An exploratory study of sleep quality, daytime function, and quality of life in patients with mechanical circulatory support. Int J Artif Organs 2012; 35: 531–537.
• 184.  　 Yamanaka M, Inoue T. Living with ventricular assist device: The life experience of patients awaiting heart transplantation and suggestions for their nursing practice [in Japanese]. J Jpn Acad Crit Care Nurs 2014; 10: 28–40.
• 185.  　 Yamanaka M. Experiences of transitioning to home care in patients with implantable ventricular assist devices and their caregivers [in Japanese]. J Jpn Acad Crit Care Nurs 2016; 12: 25–37.
• 186.  　 World Health Organization. Global atlas of palliative care at the end of life. 2014. https://www.who.int/nmh/Global_Atlas_of_Palliative_Care.pdf [accessed March, 2021].
• 187.  　 Detering KM, Hancock AD, Reade MC, Silvester W. The impact of advance care planning on end of life care in elderly patients: Randomised controlled trial. BMJ 2010; 340: C1345.
• 188.  　 Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129–2200.
• 189.  　日本救急医学会, 日本集中治療医学会, 日本循環器学会. 救急・集中治療における終末期医療に関するガイドライン～3 学会からの提言～. 2014. https://www.jaam.jp/info/2014/pdf/info-20141104_02_01_02.pdf [accessed March, 2021].
• 190.  　 Kavarana MN, Pessin-Minsley MS, Urtecho J, Catanese KA, Flannery M, Oz MC, et al. Right ventricular dysfunction and organ failure in left ventricular assist device recipients: A continuing problem. Ann Thorac Surg 2002; 73: 745–750.
• 191.  　 Japanese Association of Cardiac Rehabilitation. Cardiac rehabilitation standard program for acute myocardial infarction (2017) [in Japanese]. http://www.jacr.jp/web/wp-content/uploads/2015/04/shinfuzen2017_2.pdf [accessed March, 2021].
• 192.  　 Slaughter MS, Pagani FD, Rogers JG, Miller LW, Sun B, Russell SD, et al; HeartMate II Clinical Investigators. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010; 29: S1–S39.
• 193.  　 Cook JL, Colvin M, Francis GS, Grady KL, Hoffman TM, Jessup M, et al; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Radiology and Intervention; and Council on Cardiovascular Surgery and Anesthesia. Recommendations for the use of mechanical circulatory support: Ambulatory and community patient care: A Scientific Statement from the American Heart Association. Circulation 2017; 135: e1145–e1158.
• 194.  　 Heart Failure Society of America. Surgical approaches to the treatment of heart failure. J Card Fail 2006; 12: e76–e79.
• 195.  　 Pawale A, Schwartz Y, Itagaki S, Pinney S, Adams DH, Anyanwu AC. Selective implantation of durable left ventricular assist devices as primary therapy for refractory cardiogenic shock. J Thorac Cardiovasc Surg 2018; 155: 1059–1068.
• 196.  　 Seguchi O, Fujita T, Watanabe T, Kuroda K, Hisamatsu E, Nakajima S, et al. Temporary biventricular support with extracorporeal membrane oxygenation: A feasible therapeutic approach for cardiogenic shock with multiple organ failure. J Artif Organs 2017; 20: 206–214.
• 197.  　 Yoshitake S, Kinoshita O, Nawata K, Hoshino Y, Itoda Y, Kimura M, et al. Single-center experience of the bridge-to-bridge strategy using the Nipro paracorporeal ventricular assist device. J Artif Organs 2018; 21: 405–411.
• 198.  　 Kirklin JK, Naftel DC, Kormos RL, Stevenson LW, Pagani FD, Miller MA, et al. The Fourth INTERMACS Annual Report: 4,000 implants and counting. J Heart Lung Transplant 2012; 31: 117–126.
• 199.  　 Imamura T, Kinugawa K, Shiga T, Endo M, Inaba T, Maki H, et al. Early decision for a left ventricular assist device implantation is necessary for patients with modifier A. J Artif Organs 2012; 15: 301–304.
• 200.  　 Frontera JA, Starling R, Cho SM, Nowacki AS, Uchino K, Hussain MS, et al. Risk factors, mortality, and timing of ischemic and hemorrhagic stroke with left ventricular assist devices. J Heart Lung Transplant 2017; 36: 673–683.
• 201.  　 Samura T, Yoshioka D, Toda K, Sakaniwa R, Shimizu M, Miyagawa S, et al. Risk of stroke early after implantation of a left ventricular assist device. J Thorac Cardiovasc Surg 2019; 157: 259–267.e1.
• 202.  　 Teuteberg J, Lockard K. Chapter 14: Predischarge and outpatient management. In: Kormos RL, Miller LW, editors. Mechanical circulatory support: A companion to Braunwald’s heart disease. Elsevier/Saunders, 2012; 183–193.
• 203.  　 Moazami N, Smedira NG, McCarthy PM, Katzan I, Sila CA, Lytle BW, et al. Safety and efficacy of intraarterial thrombolysis for perioperative stroke after cardiac operation. Ann Thorac Surg 2001; 72: 1933–1939.
• 204.  　 Kitano T, Sakaguchi M, Yamagami H, Ishikawa T, Ishibashi-Ueda H, Tanaka K, et al. Mechanical thrombectomy in acute ischemic stroke patients with left ventricular assist device. J Neurol Sci 2020; 418: 117142.
• 205.  　 Masotti L, Di Napoli M, Godoy DA, Rafanelli D, Liumbruno G, Koumpouros N, et al. The practical management of intracerebral hemorrhage associated with oral anticoagulant therapy. Int J Stroke 2011; 6: 228–240.
• 206.  　 Huttner HB, Schellinger PD, Hartmann M, Köhrmann M, Juettler E, Wikner J, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: Comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006; 37: 1465–1470.
• 207.  　 Yarboro LT, Bergin JD, Kennedy JL, Ballew CC, Benton EM, Ailawadi G, et al. Technique for minimizing and treating driveline infections. Ann Cardiothorac Surg 2014; 3: 557–562.
• 208.  　 Kormos L, Holman W. Chapter 13: Adverse events and complications of mechanical circulatory support. In: Kormos RL, Miller LW, editors. Mechanical circulatory support: A companion to Braunwald’s heart disease. Elsevier/Saunders, 2012; 166–182.
• 209.  　 Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16: 128–140.
• 210.  　 Gordon SM, Schmitt SK, Jacobs M, Smedira NM, Goormastic M, Banbury MK, et al. Nosocomial bloodstream infections in patients with implantable left ventricular assist devices. Ann Thorac Surg 2001; 72: 725–730.
• 211.  　 Toda K, Yonemoto Y, Fujita T, Shimahara Y, Sato S, Nakatani T, et al. Risk analysis of bloodstream infection during long-term left ventricular assist device support. Ann Thorac Surg 2012; 94: 1387–1393.
• 212.  　 Kimura Y, Seguchi O, Mochizuki H, Iwasaki K, Toda K, Kumai Y, et al. Role of Gallium-SPECT-CT in the management of patients with ventricular assist device-specific percutaneous driveline infection. J Card Fail 2019; 25: 795–802.
• 213.  　 Dell’Aquila AM, Mastrobuoni S, Alles S, Wenning C, Henryk W, Schneider SR, et al. Contributory role of fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis and clinical management of infections in patients supported with a continuous-flow left ventricular assist device. Ann Thorac Surg 2016; 101: 87–94.
• 214.  　 Nurozler F, Argenziano M, Oz MC, Naka Y. Fungal left ventricular assist device endocarditis. Ann Thorac Surg 2001; 71: 614–618.
• 215.  　 Kimura M, Nishimura T, Kinoshita O, Okada S, Inafuku H, Kyo S, et al. Successful treatment of pump pocket infection after left ventricular assist device implantation by negative pressure wound therapy and omental transposition. Ann Thorac Cardiovasc Surg 2014; 20(Suppl): 842–845.
• 216.  　 Matsumiya G, Nishimura M, Miyamoto Y, Sawa Y, Matsuda H. Successful treatment of Novacor pump pocket infection by omental transposition. Ann Thorac Surg 2003; 75: 287–288.
• 217.  　 Poston RS, Husain S, Sorce D, Stanford E, Kusne S, Wagener M, et al. LVAD bloodstream infections: Therapeutic rationale for transplantation after LVAD infection. J Heart Lung Transplant 2003; 22: 914–921.
• 218.  　 Schulman AR, Martens TP, Russo MJ, Christos PJ, Gordon RJ, Lowy FD, et al. Effect of left ventricular assist device infection on post-transplant outcomes. J Heart Lung Transplant 2009; 28: 237–242.
• 219.  　 Nakanishi K, Homma S, Han J, Takayama H, Colombo PC, Yuzefpolskaya M, et al. Usefulness of tricuspid annular diameter to predict late right sided heart failure in patients with left ventricular assist device. Am J Cardiol 2018; 122: 115–120.
• 220.  　 Rich JD, Gosev I, Patel CB, Joseph S, Katz JN, Eckman PM, et al; Evolving Mechanical Support Research Group (EMERG) Investigators. The incidence, risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow left ventricular assist device. J Heart Lung Transplant 2017; 36: 50–58.
• 221.  　 Kapelios CJ, Charitos C, Kaldara E, Malliaras K, Nana E, Pantsios C, et al. Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device. J Heart Lung Transplant 2015; 34: 1604–1610.
• 222.  　 Kurihara C, Critsinelis AC, Kawabori M, Sugiura T, Loor G, Civitello AB, et al. Frequency and consequences of right-sided heart failure after continuous-flow left ventricular assist device implantation. Am J Cardiol 2018; 121: 336–342.
• 223.  　 John R, Kamdar F, Eckman P, Colvin-Adams M, Boyle A, Shumway S, et al. Lessons learned from experience with over 100 consecutive HeartMate II left ventricular assist devices. Ann Thorac Surg 2011; 92: 1593–1600.
• 224.  　 Morgan JA, Paone G, Nemeh HW, Henry SE, Patel R, Vavra J, et al. Gastrointestinal bleeding with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2012; 31: 715–718.
• 225.  　 Demirozu ZT, Radovancevic R, Hochman LF, Gregoric ID, Letsou GV, Kar B, et al. Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. J Heart Lung Transplant 2011; 30: 849–853.
• 226.  　 Aggarwal A, Pant R, Kumar S, Sharma P, Gallagher C, Tatooles AJ, et al. Incidence and management of gastrointestinal bleeding with continuous flow assist devices. Ann Thorac Surg 2012; 93: 1534–1540.
• 227.  　 Kushnir VM, Sharma S, Ewald GA, Seccombe J, Novak E, Wang IW, et al. Evaluation of GI bleeding after implantation of left ventricular assist device. Gastrointest Endosc 2012; 75: 973–979.
• 228.  　 Bartoli CR, Kang J, Restle DJ, Zhang DM, Shabahang C, Acker MA, et al. Inhibition of ADAMTS-13 by doxycycline reduces von Willebrand factor degradation during supraphysiological shear stress: Therapeutic implications for left ventricular assist device-associated bleeding. JACC Heart Fail 2015; 3: 860–869.
• 229.  　 Bartoli CR, Zhang DM, Hennessy-Strahs S, Kang J, Restle DJ, Bermudez C, et al. Clinical and in vitro evidence that left ventricular assist device-induced von Willebrand factor degradation alters angiogenesis. Circ Heart Fail 2018; 11: e004638.
• 230.  　 Fraser KH, Zhang T, Taskin ME, Griffith BP, Wu ZJ. A quantitative comparison of mechanical blood damage parameters in rotary ventricular assist devices: Shear stress, exposure time and hemolysis index. J Biomech Eng 2012; 134: 081002.
• 231.  　 Molina TL, Krisl JC, Donahue KR, Varnado S. Gastrointestinal bleeding in left ventricular assist device: Octreotide and other treatment modalities. ASAIO J 2018; 64: 433–439.
• 232.  　 Namdaran P, Zikos TA, Pan JY, Banerjee D. Thalidomide use reduces risk of refractory gastrointestinal bleeding in patients with continuous flow left ventricular assist devices. ASAIO J 2020; 66: 645–651.
• 233.  　 Houston BA, Schneider AL, Vaishnav J, Cromwell DM, Miller PE, Faridi KF, et al. Angiotensin II antagonism is associated with reduced risk for gastrointestinal bleeding caused by arteriovenous malformations in patients with left ventricular assist devices. J Heart Lung Transplant 2017; 36: 380–385.
• 234.  　 Cushing M, Kawaguchi K, Friedman KD, Mark T. Factor VIII/von Willebrand factor concentrate therapy for ventricular assist device-associated acquired von Willebrand disease. Transfusion 2012; 52: 1535–1541.
• 235.  　 Asleh R, Albitar HAH, Schettle SD, Kushwaha SS, Pereira NL, Behfar A, et al. Intravenous bevacizumab as a novel treatment for refractory left ventricular assist device-related gastrointestinal bleeding. J Heart Lung Transplant 2020; 39: 492–495.
• 236.  　 Vukelic S, Vlismas PP, Patel SR, Xue X, Shitole SG, Saeed O, et al. Digoxin is associated with a decreased incidence of angiodysplasia-related gastrointestinal bleeding in patients with continuous-flow left ventricular assist devices. Circ Heart Fail 2018; 11: e004899.
• 237.  　 Imamura T, Nguyen A, Rodgers D, Kim G, Raikhelkar J, Sarswat N, et al. Omega-3 therapy is associated with reduced gastrointestinal bleeding in patients with continuous-flow left ventricular assist device. Circ Heart Fail 2018; 11: e005082.
• 238.  　 Cowger J, Pagani FD, Haft JW, Romano MA, Aaronson KD, Kolias TJ. The development of aortic insufficiency in left ventricular assist device-supported patients. Circ Heart Fail 2010; 3: 668–674.
• 239.  　 Pak SW, Uriel N, Takayama H, Cappleman S, Song R, Colombo PC, et al. Prevalence of de novo aortic insufficiency during long-term support with left ventricular assist devices. J Heart Lung Transplant 2010; 29: 1172–1176.
• 240.  　 Hatano M, Kinugawa K, Shiga T, Kato N, Endo M, Hisagi M, et al. Less frequent opening of the aortic valve and a continuous flow pump are risk factors for postoperative onset of aortic insufficiency in patients with a left ventricular assist device. Circ J 2011; 75: 1147–1155.
• 241.  　 Grinstein J, Kruse E, Sayer G, Fedson S, Kim GH, Jorde UP, et al. Accurate quantification methods for aortic insufficiency severity in patients with LVAD: Role of diastolic flow acceleration and systolic-to-diastolic peak velocity ratio of outflow cannula. JACC Cardiovasc Imaging 2016; 9: 641–651.
• 242.  　 Grinstein J, Kruse E, Sayer G, Fedson S, Kim GH, Sarswat N, et al. Novel echocardiographic parameters of aortic insufficiency in continuous-flow left ventricular assist devices and clinical outcome. J Heart Lung Transplant 2016; 35: 976–985.
• 243.  　 Sayer G, Sarswat N, Kim GH, Adatya S, Medvedofsky D, Rodgers D, et al. The hemodynamic effects of aortic insufficiency in patients supported with continuous-flow left ventricular assist devices. J Card Fail 2017; 23: 545–551.
• 244.  　 Letsou GV, Connelly JH, Delgado RM 3rd, Myers TJ, Gregoric ID, Smart FW, et al. Is native aortic valve commissural fusion in patients with long-term left ventricular assist devices associated with clinically important aortic insufficiency? J Heart Lung Transplant 2006; 25: 395–399.
• 245.  　 Imamura T, Kinugawa K, Nitta D, Hatano M, Kinoshita O, Nawata K, et al. Advantage of pulsatility in left ventricular reverse remodeling and aortic insufficiency prevention during left ventricular assist device treatment. Circ J 2015; 79: 1994–1999.
• 246.  　 Imamura T, Kinugawa K, Nitta D, Hatano M, Ono M. Opening of aortic valve during exercise is key to preventing development of aortic insufficiency during ventricular assist device treatment. ASAIO J 2015; 61: 514–519.
• 247.  　 Jorde UP, Uriel N, Nahumi N, Bejar D, Gonzalez-Costello J, Thomas SS, et al. Prevalence, significance, and management of aortic insufficiency in continuous flow left ventricular assist device recipients. Circ Heart Fail 2014; 7: 310–319.
• 248.  　 McKellar SH, Deo S, Daly RC, Durham LA 3rd, Joyce LD, Stulak JM, et al. Durability of central aortic valve closure in patients with continuous flow left ventricular assist devices. J Thorac Cardiovasc Surg 2014; 147: 344–348.
• 249.  　 Fujita T, Kobayashi J, Hata H, Seguchi O, Sato T, Yanase M, et al. Aortic valve closure for rapidly deteriorated aortic insufficiency after continuous flow left ventricular assist device implantation. J Artif Organs 2013; 16: 98–100.
• 250.  　 Parikh KS, Mehrotra AK, Russo MJ, Lang RM, Anderson A, Jeevanandam V, et al. Percutaneous transcatheter aortic valve closure successfully treats left ventricular assist device-associated aortic insufficiency and improves cardiac hemodynamics. JACC Cardiovasc Interv 2013; 6: 84–89.
• 251.  　 Yehya A, Rajagopal V, Meduri C, Kauten J, Brown M, Dean L, et al. Short-term results with transcatheter aortic valve replacement for treatment of left ventricular assist device patients with symptomatic aortic insufficiency. J Heart Lung Transplant 2019; 38: 920–926.
• 252.  　 Martins RP, Leclercq C, Bourenane H, Auffret V, Boulé S, Loobuyck V, et al. Incidence, predictors, and clinical impact of electrical storm in patients with left ventricular assist devices: New insights from the ASSIST-ICD study. Heart Rhythm 2019; 16: 1506–1512.
• 253.  　 Galand V, Flécher E, Auffret V, Boulé S, Vincentelli A, Dambrin C, et al; ASSIST-ICD Investigators. Predictors and clinical impact of late ventricular arrhythmias in patients with continuous-flow left ventricular assist devices. JACC Clin Electrophysiol 2018; 4: 1166–1175.
• 254.  　 Makki N, Mesubi O, Steyers C, Olshansky B, Abraham WT. Meta-analysis of the relation of ventricular arrhythmias to all-cause mortality after implantation of a left ventricular assist device. Am J Cardiol 2015; 116: 1385–1390.
• 255.  　 Kashiwa K, Nishimura T, Kubo H, Tamai H, Baba A, Ono M, et al. Study of device malfunctions in patients with implantable ventricular assist devices living at home. J Artif Organs 2010; 13: 134–138.
• 256.  　 Moazami N, Milano CA, John R, Sun B, Adamson RM, Pagani FD, et al; HeartMate II Investigators. Pump replacement for left ventricular assist device failure can be done safely and is associated with low mortality. Ann Thorac Surg 2013; 95: 500–505.
• 257.  　 Birks EJ, Tansley PD, Yacoub MH, Bowles CT, Hipkin M, Hardy J, et al. Incidence and clinical management of life-threatening left ventricular assist device failure. J Heart Lung Transplant 2004; 23: 964–969.
• 258.  　 Jafar M, Gregoric ID, Radovancevic R, Cohn WE, McGuire N, Frazier OH. Urgent exchange of a HeartMate II left ventricular assist device after percutaneous lead fracture. ASAIO J 2009; 55: 523–524.
• 259.  　 Gregoric ID, Bruckner BA, Jacob L, Kar B, Cohn WE, La Francesca S, et al. Clinical experience with sternotomy versus subcostal approach for exchange of the HeartMate XVE to the HeartMate II ventricular assist device. Ann Thorac Surg 2008; 85: 1646–1649.
• 260.  　 Adamson RM, Dembitsky WP, Baradarian S, Chammas J, Jaski B, Hoagland P, et al. HeartMate left ventricular assist system exchange: Results and technical considerations. ASAIO J 2009; 55: 598–601.
• 261.  　 Stulak JM, Cowger J, Haft JW, Romano MA, Aaronson KD, Pagani FD. Device exchange after primary left ventricular assist device implantation: Indications and outcomes. Ann Thorac Surg 2013; 95: 1262–1268.
• 262.  　 Lanier GM, Orlanes K, Hayashi Y, Murphy J, Flannery M, Te-Frey R, et al. Validity and reliability of a novel slow cuff-deflation system for noninvasive blood pressure monitoring in patients with continuous-flow left ventricular assist device. Circ Heart Fail 2013; 6: 1005–1012.
• 263.  　 Saeed O, Jermyn R, Kargoli F, Madan S, Mannem S, Gunda S, et al. Blood pressure and adverse events during continuous flow left ventricular assist device support. Circ Heart Fail 2015; 8: 551–556.
• 264.  　 Pinsino A, Castagna F, Zuver AM, Royzman EA, Nasiri M, Stöhr EJ, et al. Prognostic implications of serial outpatient blood pressure measurements in patients with an axial continuous-flow left ventricular assist device. J Heart Lung Transplant 2019; 38: 396–405.
• 265.  　 Elmously A, de Biasi AR, Risucci DA, Worku B, Horn EM, Salemi A. Systemic blood pressure trends and antihypertensive utilization following continuous-flow left ventricular assist device implantation: An analysis of the interagency registry for mechanically assisted circulatory support. J Thorac Dis 2018; 10: 2866–2875.
• 266.  　 Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant 2010; 29: 914–956.
• 267.  　 Doull I. Shared care: Is it worth it for the patient? J R Soc Med 2012; 105(Suppl): S25–S29.
• 268.  　 Kiernan MS, Joseph SM, Katz JN, Kilic A, Rich JD, Tallman MP, et al; Evolving Mechanical Support Research Group (EMERG) Investigators. Sharing the care of mechanical circulatory support: Collaborative efforts of patients/caregivers, shared-care sites, and left ventricular assist device implanting centers. Circ Heart Fail 2015; 8: 629–635.
• 269.  　 Estep JD, Trachtenberg BH, Loza LP, Bruckner BA. Continuous flow left ventricular assist devices: Shared care goals of monitoring and treating patients. Methodist Debakey Cardiovasc J 2015; 11: 33–44.
• 270.  　 Kitamura S, Nakatani T, Bando K, Sasako Y, Kobayashi J, Yagihara T. Modification of bicaval anastomosis technique for orthotopic heart transplantation. Ann Thorac Surg 2001; 72: 1405–1406.
• 271.  　 Aziz T, Burgess M, Khafagy R, Wynn Hann A, Campbell C, Rahman A, et al. Bicaval and standard techniques in orthotopic heart transplantation: Medium-term experience in cardiac performance and survival. J Thorac Cardiovasc Surg 1999; 118: 115–122.
• 272.  　 Kitamura S, Nakatani T, Kato T, Yanase M, Kobayashi J, Nakajima H, et al. Hemodynamic and echocardiographic evaluation of orthotopic heart transplantation with the modified bicaval anastomosis technique. Circ J 2009; 73: 1235–1239.
• 273.  　 Truby LK, Farr MA, Garan AR, Givens R, Restaino SW, Latif F, et al. Impact of bridge to transplantation with continuous-flow left ventricular assist devices on posttransplantation mortality. Circulation 2019; 140: 459–469.
• 274.  　 Levin HR, Oz MC, Chen JM, Packer M, Rose EA, Burkhoff D. Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading. Circulation 1995; 91: 2717–2720.
• 275.  　 Frazier OH, Myers TJ. Left ventricular assist system as a bridge to myocardial recovery. Ann Thorac Surg 1999; 68: 734–741.
• 276.  　 Klotz S, Barbone A, Reiken S, Holmes JW, Naka Y, Oz MC, et al. Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties. J Am Coll Cardiol 2005; 45: 668–676.
• 277.  　 Mancini DM, Beniaminovitz A, Levin H, Catanese K, Flannery M, DiTullio M, et al. Low incidence of myocardial recovery after left ventricular assist device implantation in patients with chronic heart failure. Circulation 1998; 98: 2383–2389.
• 278.  　 Maybaum S, Mancini D, Xydas S, Starling RC, Aaronson K, Pagani FD, et al. Cardiac improvement during mechanical circulatory support: A prospective multicenter study of the LVAD Working Group. Circulation 2007; 115: 2497–2505.
• 279.  　 Wever-Pinzon O, Drakos SG, McKellar SH, Horne BD, Caine WT, Kfoury AG, et al. Cardiac recovery during long-term left ventricular assist device support. J Am Coll Cardiol 2016; 68: 1540–1553.
• 280.  　 Dandel M, Weng Y, Siniawski H, Potapov E, Lehmkuhl HB, Hetzer R. Long-term results in patients with idiopathic dilated cardiomyopathy after weaning from left ventricular assist devices. Circulation 2005; 112(Suppl): I37–I45.
• 281.  　 Matsumiya G, Saitoh S, Sakata Y, Sawa Y. Myocardial recovery by mechanical unloading with left ventricular assist system. Circ J 2009; 73: 1386–1392.
• 282.  　 Goldstein DJ, Maybaum S, MacGillivray TE, Moore SA, Bogaev R, Farrar DJ, et al; HeartMate II Clinical Investigators. Young patients with nonischemic cardiomyopathy have higher likelihood of left ventricular recovery during left ventricular assist device support. J Card Fail 2012; 18: 392–395.
• 283.  　 Krabatsch T, Schweiger M, Dandel M, Stepanenko A, Drews T, Potapov E, et al. Is bridge to recovery more likely with pulsatile left ventricular assist devices than with nonpulsatile-flow systems? Ann Thorac Surg 2011; 91: 1335–1340.
• 284.  　 Cohn WE, Gregoric ID, Radovancevic B, Frazier OH. A felt plug simplifies left ventricular assist device removal after successful bridge to recovery. J Heart Lung Transplant 2007; 26: 1209–1211.
• 285.  　補助人工心臓治療関連学会協議会, Destination therapy (DT) 研究会. 4. DT患者管理ガイドライン：DT終末期医療のガイドライン. 我が国における植込型補助人工心臓適応適正化の考え方：Destination Therapyについて. 2014. https://www.jacvas.com/view-dt/ [accessed March, 2021].
• 286.  　 Brush S, Budge D, Alharethi R, McCormick AJ, MacPherson JE, Reid BB, et al. End-of-life decision making and implementation in recipients of a destination left ventricular assist device. J Heart Lung Transplant 2010; 29: 1337–1341.
• 287.  　 Nonogi H, Ueda Y, Kamakura S, Sakamoto T, Tada K, Tanaka K, et al; Japanese Circulation Society. Statement for end-stage cardiovascular care (JCS 2010) [in Japanese]. Circ J 2011; 75(Suppl I): 81–128.
• 288.  　 Ministry of Health, Labour and Welfare. 人生の最終段階における医療・ケアの決定プロセスに関するガイドライン 解説編. 2018.