Early Detection of Vulnerable Atherosclerotic Plaque for Risk Reduction of Acute Aortic Rupture and Thromboemboli and Atheroemboli Using Non-Obstructive Angioscopy

Abstract

The mortality rate due to rupture of aortic dissection and aortic aneurysm is approximately 90%. Acute aortic rupture can be fatal prior to hospitalization and has proven difficult to diagnose correctly or predict. The in-hospital mortality rate of ruptured aortic aneurysm ranges from 53 to 66%. Emergency surgical and endovascular treatments are the only options for ruptured aortic dissection and aortic aneurysm. No method of systematic early detection or inspection of vessel injury is available at the prevention stage. Regardless of the improvement in many imaging modalities, aortic diameter has remained a major criterion for recommending surgery in diagnosed patients. Previous reports have suggested a relationship between vulnerable plaque and atherosclerotic aortic aneurysm. Non-obstructive angioscopy is a new method for evaluating intimal injury over the whole aorta. It has been used to identify many advanced atherosclerotic plaques that were missed on traditional imaging modalities before aneurysm formation. Non-obstructive angioscopy has shown that atherosclerosis of the aorta begins before that of the coronary artery, which had been noted on autopsy “in vivo”. Strong or repetitive aortic injuries might cause sudden aortic disruption. Aortic atheroma is also a risk factor of stroke and perivascular embolism. Detecting aortic vulnerable atherosclerotic plaque on non-obstructive angioscopy may not only clarify the pathogenesis of acute aortic rupture and “aortogenic” thromboemboli and atheroemboli but also play a role in the pre-emptive medicine. (Circ J 2015; 79: 742–750)

Still Silent But Virulent: High Mortality of Ruptured Aortic Aneurysm and Dissection

Disruption of the aortic wall causes aneurysm and dissection, which can be rapidly fatal if they rupture. In general, aneurysms remain silent until rupture. Death from a ruptured aneurysm and dissection prior to hospitalization might be erroneously attributed to another cause unless an autopsy is performed.¹ The Hisayama study, in which approximately 80% of deceased subjects enrolled in the study underwent autopsy, showed that the prevalence of aortic aneurysm and dissection among sudden unexpected deaths has increased threefold over 30 years in Japan.² The mortality rate of ruptured abdominal aortic aneurysm (AAA) is approximately 90%.^3–5 Of the approximately 75% of patients with ruptured AAA who reach an emergency department alive, 40% die immediately, 1% per hour dying thereafter, and between 5% and 20% dying during or shortly after surgery.^6–8 In-hospital mortality of ruptured AAA was reported to range from 53% to 66% in England and the USA.⁹

The indications for endovascular repair (EVAR) are rapidly increasing,¹⁰ but the superiority of EVAR is controversial. The EVAR trial 2 showed no benefit from stent grafting compared with no therapy for AAA. The DREAM trial compared EVAR with traditional surgical therapy.¹¹ The midterm follow-up in the DREAM trial found that at 2 years, the survival curves cross, and, from that point on, stent-treated patients had poorer survival than surgically treated patients with AAA.⁹

Even if patients are admitted to the emergency department, ruptured aortic dissection is also difficult to promptly diagnose.¹² Only 15–43% of patients are initially diagnosed correctly.^13–15 Approximately 1–2% of patients per hour die after onset.¹⁶ Combining pre-hospital with in-hospital mortality rates indicates that 93% of deaths from aortic dissection occur within 24 h after onset.¹⁷ Reported survival rates of aortic dissection have ranged from 52% to 94% at 1 year and from 45% to 88% at 5 years.^18–22 Survival for patients with type A acute aortic dissection treated surgically was 96.1±2.4% and 90.5±3.9% at 1 and 3 years vs. 88.6±12.2% and 68.7±19.8% for those treated without surgery.²³ Others have reported that patients with type A dissection who survive surgery have survival rates of approximately 75% at 5 years and 54% at 10 years.¹ Three-year survival for patients with type B acute aortic dissection treated medically, surgically, or with endovascular therapy was 77.6±6.6%, 82.8±18.9%, and 76.2±25.2%, respectively.²⁴ Even in type B aortic dissection, which has a better prognosis than type A, medication does not necessarily avoid an aortic event. Some patients with type B aortic dissection may develop type A dissection or recurrent type B dissection or progress to rupture.^24,25 Thus, pre-emptive medicine is therefore important to prevent ruptured aortic aneurysm and dissection regardless of improvements in the outcomes of surgery and EVAR.

Limitation of Size-Based Indication for Treatment

The indication of aortic aneurysm for surgery or EVAR is determined based on dimensions and growth rates of the aneurysm. The incidence of rupture increased with the dimensions and growth rate of aneurysms.^26,27 There is a hinge point for rupture according to size: these hinge points are thought to be 6 cm in the ascending aorta and 7 cm in the descending aorta. There is a limitation, however, to the size-based determination of indications for treatment. Computed tomography (CT), magnetic resonance imaging (MRI), and echocardiography are used for the measurement for the aorta, and estimating its true size is difficult.²⁸ There is no consensus on whether the aortic wall should be included or excluded in the aortic diameter, leading to a difference of several millimeters in the calculated measurements.²⁹

Initially detected aneurysms smaller than indicated for surgery must be periodically monitored until they grow to the critical size or exhibit a growth rate >0.5 cm/year. Among patients screened for AAA, 5.1% had AAA ≥3.0 cm in size: 83% of the aneurysms were 3.0–4.4 cm, 13% were 4.5–5.5 cm, and 4.1% were >5.5 cm.³⁰ There is a sex difference in rupture risk. Women had the same growth rates but a fourfold increased risk of rupture compared with men.²⁹ Moreover, dissections can occur at small aortic size.^28,29 The growth rate of aneurysm is variable even within an individual. Aneurysms in the descending aorta grow faster than aneurysms in the ascending aorta.²⁹ Large aneurysms grow more rapidly than small aneurysm.³¹

Some previous reports have suggested that aortic atherosclerotic plaque might cause progression of aneurysm and rupture. Repeated intraplaque hemorrhages play a major role in the evolution of thrombotic occlusive disease, similar to the role of intraluminal thrombus in the progression of AAA toward rupture.³² Ruptured atherosclerotic plaque may cause spontaneous rupture of the aorta.³³ Fibrous cap, lipid pool, and thrombus have been detected inside AAA on MRI.³⁴ There are few modalities, however, that can visualize advanced or vulnerable plaques inside the aorta. Recently, aortic fluorine 19 (¹⁹F) MRI and ¹⁸F-fluoromisonidazole positron emission tomography have been used in attempts to detect vulnerable plaque,^35,36 although this use remains experimental. These modalities have the essential limitation of poor spatial resolution.

“Swirling Storm Inside”: Intra-Arterial Live Imaging With Non-Obstructive Angioscopy In Vivo

Angioscopy provides a full-color, 3-D perspective of the vessel surface morphology and reasonably accurate information regarding factors such as coronary plaque rupture,³⁷ yellow plaque,³⁸ plaque regression,³⁹ dissection,⁴⁰ thrombus,⁴¹ and intimal stent coverage.⁴² By the 1980 s, coronary angioscopy had been used in patients at the time of peripheral or coronary bypass surgery, in addition to its use in experimental models.^43,44 After the completion of trials aimed at developing the system,⁴⁵ two types of angioscopy became available: non-obstructive angioscopy, which was developed in Japan (Figure 1),³⁸ and occlusion-type angioscopy, which was developed in the USA.⁴⁶ Occlusion-type angioscopy has one key limitation: occlusion by balloon catheter for the removal of blood and to clarify the visual field may cause myocardial ischemia.⁴⁷

Figure 1.

(A) The conventional non-obstructive angioscopy system. Low-molecular-weight dextran is infused from the probing catheter to obtain a visual field. (B) The dual-infusion system for non-obstructive angioscopy. Low-molecular-weight dextran is infused both from the probing catheter and the guiding catheter to obtain a visual field. CCD, charge-coupled device.

The main methodology in the original non-obstructive angioscopy was to obtain a visual field by injecting low-molecular-weight dextran into the space between the 4-Fr probing catheter and the fiber (Figure 1A). Consequently, the blood is diluted, and the field of vision is widened. Non-obstructive angioscopy is relatively safe, because adequate blood flow is maintained throughout the process of image acquisition. Initially this method was used in the coronary artery, and it has since been applied to other larger arteries such as the renal artery⁴⁸ and pulmonary artery.⁴⁹

When low-molecular-weight dextran is dual-infused from the 4-Fr probing catheter along with a 6-Fr guiding catheter (Figure 1B), the visual field can be obtained more clearly than with a single infusion, and the application of non-obstructive angioscopy can be expanded to vessels larger than coronary arteries, including thoracic and abdominal aorta. Angioscopic observation of the aorta is performed continuously while a 6-Fr guiding catheter is slowly pulled back and rotated for vessel-wide screening. The approach can be either by femoral artery, pulling back from the ascending aorta to iliac artery, or by left brachial artery, pulling back initially from the ascending aorta to aortic arch, then directing the guiding catheter to the common iliac artery with a guidewire, and finally pulling back from the common iliac artery to aortic arch. A representative case is shown in Figure 2. Twenty-six yellow plaques including 5 ruptured plaques and 3 erosions were identified in an aorta without significant ectasia or dissection. Waves of thrombi on the vulnerable plaque spontaneously ripple, and they are torn and scatter like cotton or dandelion fuzz (Figure 3).

Figure 2.

A representative case of abundant aortic plaque. A 49-year-old man with hypertension, hyperlipidemia, and diabetes mellitus was admitted due to atypical chest pain. Coronary angiography of (A) left coronary artery and (B) right coronary artery did not show significant stenosis. (C,D) Location of plaques on non-obstructive angioscopy projected onto a volume-rendered contrast-enhanced computed tomography image for (C) anterior and (D) posterior projection. No ectasia, dissection, or aneurysm was observed in the aorta. (E) Non-obstructive angioscopy of the aorta showed 26 plaques including ruptured plaque with mixed thrombi (panels 18–26), small fissure (panels 5,11), and white thrombus (panels 15,18).

Figure 3.

Serial images of aortic vulnerable plaque. Three waves of thrombi (blue, black, and white arrows) ripple, one by one. These waves move from the right side to the left side through the center of the visual field and then scatter like cotton or dandelion fuzz. The movement implies that infusion of low-molecular-weight dextran to obtain a visual field in the non-obstructive angioscopy system does not influence plaque rupture. If the current of low-molecular-weight dextran injured vulnerable plaque, thrombi should move from the center to the surroundings.

The preliminary data from ascending aorta to iliac artery in 75 consecutive patients who had or were susspected to have coronary artery disease and no previous detection of aortic aneurysm indicate that atherosclerosis of the aorta is more advanced than atherosclerosis of the coronary artery (Figure 4). Surprisingly, plaque rupture or erosion was found in 86.7% of patients, and the number of plaque ruptures and erosions averaged 5.3±5.0 per patient (Figure 5). These findings are consistent with a previous pathological study reporting that the percentage area affected with fatty streaks and raised lesions was greater in the aorta than in the coronary artery.⁵⁰

Figure 4.

Number of yellow plaques in the aorta vs. the number of coronary artery yellow plaques on non-obstructive angioscopy in 75 consecutive patients with or suspected of having coronary artery disease. The aorta was screened from ascending aorta to common iliac artery, and the coronary artery with the most progressed stenosis was observed as distally as possible.

Figure 5.

Number of aortic vulnerable plaques from ascending aorta to iliac artery determined on non-obstructive angioscopy in 75 consecutive patients who had or were suspected to have coronary artery disease and no previous detection of aortic aneurysm.

With non-obstructive angioscopy, vascular surgeons can view the surface of the aneurysm at the location where operation is required. While pathologists can thoroughly evaluate a formalin-fixed aorta, there has been no systematic early detection or inspection of vessel injury at the prevention stage. Non-obstructive angioscopy can provide intra-arterial live imaging in vivo. Even inside a normal-sized aorta (Figure 6), spontaneous plaque ruptures and intimal injury appear as a swirling storm. For instance, white thrombi (Figure 6C, panels 6,25,29), mixed thrombi (Figure 6C, panels 3,8,10,17), subintimal hematoma (Figure 6C, panels 5,11,22,23,26–28), and small intimal fissures that might cause aortic fragileness were observed (Figure 6C, panels 8,21,23,26–28). Using non-obstructive angioscopy, many types of advanced atherosclerotic plaque were clearly demonstrated that were missed on traditional imaging modalities (Figure 6D).

Figure 6.

Representative case of abundant aortic plaque with coronary artery disease. An asymptomatic 78-year-old man with a history of percutaneous coronary intervention to the middle left circumflex coronary artery, hypertension, and hyperlipidemia. (A,B) Location of plaques on non-obstructive angioscopy projected onto aortography for the (A) thoracic aorta and (B) abdominal aorta. (C) Non-obstructive angioscopy of the aorta showed 32 plaques including ruptured plaque with mixed thrombi (panels 3,8,17,26), small fissure (panels 8,11,13,21,23,27,28), and white thrombus (panels 6,19,29). (D) Comparison of non-obstructive angioscopy, aortography, contrast-enhanced computed tomography, and 10-MHz intravascular ultrasound of the aorta.

Intramural hematoma,⁵¹ penetrating atherosclerotic ulcer,⁵² and ulcer-like projection⁵³ detected on CT may represent important signs for increased rupture risk. CT, however, seems to visualize intimal injury less clearly compared with non-obstructive angioscopy (Figure 7). Diagnosis at an earlier stage of aortic injury might play a role in preventing unexpected rupture of aneurysm and dissection. Intramural hemorrhage and aortic aneurysm smaller than is indicated for surgery should not be ignored if observed on non-obstructive angioscopy, because intimal injury does exist.

Figure 7.

A 73-year-old man, who had a history of hypertension and hyperlipidemia, who presented to hospital with severe chest and back pain for 15 min, 2 days previously. Electrocardiogram did not indicate any abnormality. (A) Chest X-ray showed enlargement and protrusion of the left first aortic arch. Cardiothoracic ratio was 48.8%. Coronary angiography did not show any stenosis (data not shown). (B) Volume-rendered, (C) coronal, and (D) sagittal images of thoracic aorta, and (E) coronal image of abdominal aorta from contrast-enhanced computed tomography. Aortic arch aneurysm of 52×47 mm, infrarenal abdominal aortic aneurysm of 40×29 mm, and left common iliac artery aneurysm of 28×25 mm were detected. Arterial wall thickening and intimal protrusion were suspected in the greater curvature of the aortic arch aneurysm. Aortography of the (F) anterior and (G) left 50º oblique projection. Only slight irregularity was demonstrated in the greater curvature of the aortic arch aneurysm. Non-obstructive angioscopy of the aorta (H, panels 1–4) correspond to the same numbers in (D,E), respectively. The inner surface of the aortic arch aneurysm was rough and erosive, probably due to intramural hemorrhage (1). Yellow plaque and mixed thrombi were also detected (2). No flap that could have caused dissection was found. Salmon-pink intramural hemorrhage was detected in the infrarenal abdominal aortic aneurysm (3). A cave-like formation filled with red thrombi was detected in the right common iliac artery aneurysm (4). The patient had not had chest X-ray or CT previously. One speculation is that the patient’s chest and back pain was thought to be related to acute injury including intramural hematoma in the aortic arch. In future, non-obstructive angioscopy might be able to be used to determine whether intimal injury is new or old.

Two New Paradigm Shifts in Acute Aortic Rupture and Embolism

No existing method allows observation of intimal injury in vivo more precisely than non-obstructive angioscopy. Thus, non-obstructive angioscopy of the aorta may produce two paradigm shifts. The first is that direct evaluation of intimal injury might enable pre-emptive therapies for aortic rupture or dissection. The change in aortic size resulting from atherosclerotic dilation is only the reflection of aortic injury. A new risk stratification for rupture or dissection might be possible if angioscopic findings can predict aortic events such as aortic death, aortic rupture, or dissection. A prospective registration trial concerning the relationship between angioscopic findings and prognosis is ongoing. Recently, it was reported that treatment with doxycycline, which inhibits matrix metalloproteinases, suppressed the development of AAA in the experimental elastase-induced rodent model of AAA.⁵⁴ Novel approaches to intimal repair by drug,⁵⁵ stenting, and regenerative therapies⁵⁶ in the prevention stage might be more effective under guidance with non-obstructive angioscopy.

Second, non-obstructive angioscopy could aid in the early detection and prevention of thromboemboli and atheroemboli (also called cholesterol embolization syndrome).⁵⁷ Both types of emboli may differ in composition and clinical manifestations. Thromboemboli, which are 20–45-fold more common than atheroemboli,^58,59 are reported to be fragmented pieces of thrombi from the surface of an ulcerated plaque.⁶⁰ In addition to causing local mechanical obstruction, these cholesterol crystal emboli also induce an inflammatory reaction that contributes to tissue ischemia and end-organ damage.^59,61–64 No imaging modality has demonstrated rupture of aortic vulnerable plaque and ruptured plaque in vivo. A preliminary angioscopic study demonstrated that thrombi and advanced atherosclerotic plaques were spontaneously ruptured. Complex atheromatous plaques in the aortic arch and descending aorta detected on transesophageal echocardiography (TEE) have been reported to increase the risk of stroke or transient ischemic attack.^65,66 Embolization from the abdominal aorta may cause lower extremity ischemia.⁶² CT may underestimate the atheromatous plaque burden in the aorta compared with 2-D TEE.⁶⁷ Complex plaque, defined as plaque at least 4 mm thick or having a mobile component detected on TEE, has been considered more likely to cause embolic events.⁶⁸ Detection of thromboemboli and atheroemboli and distinguishing between them might play a role in risk stratification. Moreover, detection of aortic ruptured plaque might predict the risk of thrombotic complication of coronary or the need for aortic catheterization procedures such as intra-aortic balloon pump and transcatheter aortic valve implantation.^69–71

Conclusions

Non-obstructive angiography of the aorta is a novel method that may have important implications for the diagnosis and management of vulnerable atherosclerotic plaque. The use of non-obstructive angioscopy, as well as the invasive method, in the diagnosis of aortic disease, the significance of its use in screening, in safety for acute aortic dissection and aneurysm, and in the widening of the field of view should be explored. The significance of “vulnerable plaque” may differ between coronary artery and aorta. The difference may be clarified on non-obstructive angioscopy. Further research on the applications and clinicopathological correlates of non-obstructive angiographic findings will be valuable in establishing the full potential of the approach for pre-emptive medicine in preventing acute aortic rupture and “aortogenic” thromboemboli and atheroemboli.

Acknowledgments

We thank Hiroki Fujiwara, Yui Morimoto, and Koichi Nishiuchi for technical assistance.

Disclosures

K.K. is the president of Inter-tec Medicals and the person who developed non-obstructive angioscopy. S.K. is a technical consultant for Nemoto Kyorin-do.

Funding Source

None.

References

• 1.    Krüger  T,  Conzelmann  LO,  Bonser  RS,  Borger  MA,  Czerny  M,  Wildhirt  S, et al. Acute aortic dissection type A. Br J Surg 2012; 799: 1331–1344.
• 2.    Nagata  M,  Ninomiya  T,  Doi  Y,  Hata  J,  Ikeda  F,  Mukai  N, et al. Temporal trends in sudden unexpected death in a general population: The Hisayama study. Am Heart J 2013; 165: 932–938.
• 3.    Rutledge  R,  Oller  DW,  Meyer  AA,  Johnson  GJ Jr. A statewide population-based time-series analysis of the outcome of ruptured abdominal aortic aneurysm. Ann Surg 1996; 223: 492–505.
• 4.    Ashton  HA,  Buxton  MJ,  Day  NE,  Kim  LG,  Marteau  TM,  Scott  RA, et al; Multicentre Aneurysm Screening Study Group. The Multicenter Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: A randomized controlled trial. Lancet 2002; 360: 1531–1539.
• 5.    Brown  LC,  Powell  JT. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance: UK small aneurysm trial participants. Ann Surg 1999; 230: 289–296.
• 6.    Anagnostopoulos  CE,  Prabhakar  MJ,  Kittle  CF. Aortic dissections and dissecting aneurysms. Am J Cardiol 1972; 30: 263–273.
• 7.    HIirst  AE Jr,  Johns  VJ Jr,  Kime  SW Jr. Dissecting aneurysm of the aorta: A review of 505 cases. Medicine (Baltimore) 1958; 37: 217–279.
• 8.    Masuda  Y,  Yamada  Z,  Morooka  N,  Watanabe  S,  Inagaki  Y. Prognosis of patients with medically treated aortic dissections. Circulation 1991; 84: III7–III13.
• 9.    Karthikesalingam  A,  Holt  PJ,  Vidal-Diez  A,  Ozdemir  BA,  Poloniecki  JD,  Hinchliffe  RJ, et al. Mortality from ruptured abdominal aortic aneurysms: Clinical lessons from a comparison of outcomes in England and the USA. Lancet 2014; 383: 963–969.
• 10.    Handa  N,  Yamashita  M,  Takahashi  T,  Onohara  T,  Okamoto  M,  Yamamoto  T, et al. Impact of introducing endovascular aneurysm repair on treatment strategy for repair of abdominal aortic aneurysm: National Hospital Organization network study in Japan. Circ J 2014; 78: 1104–1111.
• 11.   EVAR Trial Participants. Endovascular aneurysm repair and outcome in patients unfit for open repair of abdominal aortic aneurysm (EVAR trial 2): Randomised controlled trial. Lancet 2005; 365: 2187–2192.
• 12.    Hansen  MS,  Nogareda  GJ,  Hutchison  SJ. Frequency of and inappropriate treatment of misdiagnosis of acute aortic dissection. Am J Cardiol 2007; 99: 852–856.
• 13.    Mészáros  I,  Mórocz  J,  Szlávi  J,  Schmidt  J,  Tornóci  L,  Nagy  L, et al. Epidemiology and clinicopathology of aortic dissection. Chest 2000; 117: 1271–1278.
• 14.    Sullivan  PR,  Wolfson  AB,  Leckey  RD,  Burke  JL. Diagnosis of acute thoracic aortic dissection in the emergency department. Am J Emerg Med 2000; 18: 46–50.
• 15.    Sullivan  PR,  Wolfson  AB,  Leckey  RD,  Burke  JL. Frequency of and inappropriate treatment of misdiagnosis of acute aortic dissection. Am J Cardiol 2007; 99: 852–856.
• 16.    Hagan  PG,  Nienaber  CA,  Isselbacher  EM,  Bruckman  D,  Karavite  DJ,  Russman  PL, et al. The International Registry of Acute Aortic Dissection (IRAD): New insights into an old disease. JAMA 2000; 283: 897–903.
• 17.   JCS Joint Working Group. Guidelines for diagnosis and treatment of aortic aneurysm and aortic dissection (JCS 2011): Digest version. Circ J 2013; 77: 789–828.
• 18.    Haverich  A,  Miller  DC,  Scott  WC,  Mitchell  RS,  Oyer  PE,  Stinson  EB, et al. Acute and chronic aortic dissections: Determinants of long-term outcome for operative survivors. Circulation 1985; 72: II22–II34.
• 19.    Pansini  S,  Gagliardotto  PV,  Pompei  E,  Parisi  F,  Bardi  G,  Castenetto  E, et al. Early and late risk factors in surgical treatment of acute type A aortic dissection. Ann Thorac Surg 1998; 66: 779–784.
• 20.    Chiappini  B,  Schepens  M,  Tan  E,  Dell’Amore  A,  Morshuis  W,  Dossche  K, et al. Early and late outcomes of acute type A aortic dissection: Analysis of risk factors in 487 consecutive patients. Eur Heart J 2005; 26: 180–186.
• 21.    Lai  DT,  Robbins  RC,  Mitchell  RS,  Moore  KA,  Oyer  PE,  Shumway  NE, et al. Does profound hypothermic circulatory arrest improve survival in patients with acute type A aortic dissection? Circulation 2002; 106: I218–I228.
• 22.    Sabik  JF,  Lytle  BW,  Blackstone  EH,  McCarthy  PM,  Loop  FD,  Cosgrove  DM. Long-term effectiveness of operations for ascending aortic dissections. J Thorac Cardiovasc Surg 2000; 119: 946–962.
• 23.    Tsai  TT,  Evangelista  A,  Nienaber  CA,  Trimarchi  S,  Sechtem  U,  Fattori  R, et al. Long-term survival in patients presenting with type A acute aortic dissection: Insights from the International Registry of Acute Aortic Dissection (IRAD). Circulation 2006; 114(1 Suppl): I350–I356.
• 24.    Tsai  TT,  Fattori  R,  Trimarchi  S,  Isselbacher  E,  Myrmel  T,  Evangelista  A, et al. Long-term survival in patients presenting with type B acute aortic dissection: Insights from the International Registry of Acute Aortic Dissection. Circulation 2006; 114: 2226–2231.
• 25.    Minami  T,  Imoto  K,  Uchida  K,  Yasuda  S,  Karube  N,  Suzuki  S, et al. Mid-term outcomes of acute type B aortic dissection in Japan single center. Ann Thorac Cardiovasc Surg 2013; 19: 461–467.
• 26.    Elefteriades  JA. Natural history of thoracic aortic aneurysms: Indications for surgery, and surgical versus nonsurgical risks. Ann Thorac Surg 2002; 74: S1877–S1880.
• 27.    Brewster  DC,  Cronenwett  JL,  Hallett  JW Jr,  Johnston  KW,  Krupski  WC,  Matsumura  JS, et al. Guidelines for the treatment of abdominal aortic aneurysms: Report of a subcommittee of the Joint Council of the American Association for Vascular Surgery and Society for Vascular Surgery. J Vasc Surg 2003; 37: 1106–1117.
• 28.    Coady  MA,  Rizzo  JA,  Hammond  GL,  Mandapati  D,  Darr  U,  Kopf  GS, et al. What is the appropriate size criterion for resection of thoracic aortic aneurysms? J Thorac Cardiovasc Surg 1997; 113: 476–491.
• 29.    Elefteriades  JA,  Farkas  EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Cardiol 2010; 55: 841–857.
• 30.    Lee  ES,  Pickett  E,  Hedayati  N,  Dawson  DL,  Pevec  WC. Implementation of an aortic screening program in clinical practice: Implications for the Screen For Abdominal Aortic Aneurysms Very Efficiently (SAAAVE) Act. J Vasc Surg 2009; 49: 1107–1111.
• 31.    Hollier  LH,  Taylor  LM,  Ochsner  J. Recommended indications for operative treatment of abdominal aortic aneurysms: Report of a subcommittee of the Joint Council of the Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery. J Vasc Surg 1992; 15: 1046–1056.
• 32.    Michel  JB,  Delbosc  S,  Ho-Tin-Noé  B,  Leseche  G,  Nicoletti  A,  Meilhac  O, et al. From intraplaque haemorrhages to plaque vulnerability: Biological consequences of intraplaque haemorrhages. J Cardiovasc Med (Hagerstown) 2012; 13: 628–634.
• 33.    Komanapalli  CB,  Tripathy  U,  Ravichandran  PS,  Slater  MS. Spontaneous rupture of the thoracic aorta. Eur J Cardiothorac Surg 2006; 29: 616–618.
• 34.    Kramer  CM,  Cerilli  LA,  Hagspiel  K,  DiMaria  JM,  Epstein  FH,  Kern  JA. Magnetic resonance imaging identifies the fibrous cap in atherosclerotic abdominal aortic aneurysm. Circulation 2004; 109: 1016–1021.
• 35.    van Heeswijk  RB,  Pellegrin  M,  Flögel  U,  Gonzales  C,  Aubert  JF,  Mazzolai  L, et al. Fluorine MR imaging of inflammation in atherosclerotic plaque in vivo. Radiology 2014 December 12, doi:10.1148/radiol.14141371.
• 36.    Mateo  J,  Izquierdo-Garcia  D,  Badimon  JJ,  Fayad  ZA,  Fuster  V. Noninvasive assessment of hypoxia in rabbit advanced atherosclerosis using ¹⁸F-fluoromisonidazole positron emission tomographic imaging. Circ Cardiovasc Imaging 2014; 7: 312–320.
• 37.    Kodama  K,  Asakura  M,  Ueda  Y,  Yamaguchi  O,  Hirayama  A. The role of plaque rupture in the development of acute coronary syndrome evaluated by the coronary angioscope. Intern Med 2000; 39: 333–335.
• 38.    Asakura  M,  Ueda  Y,  Yamaguchi  O,  Adachi  T,  Hirayama  A,  Hori  M, et al. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: An angioscopic study. J Am Coll Cardiol 2001; 37: 1284–1288.
• 39.    Hirayama  A,  Saito  S,  Ueda  Y,  Takayama  T,  Honye  J,  Komatsu  S, et al. Qualitative and quantitative changes in coronary plaque associated with atorvastatin therapy. Circ J 2009; 73: 718–725.
• 40.    Komatsu  S,  Hirayama  A,  Ueda  Y,  Okuyama  Y,  Ogasawara  N,  Kashiwase  K, et al. Coronary ruptured plaque mimicking spontaneous coronary dissection in a young woman. Int J Cardiol 2006; 113: 288–289.
• 41.    Komatsu  S,  Sato  Y,  Ueda  Y,  Achenbach  S,  Ebihara  Y,  Hirayama  A, et al. Thrombotic occlusion proximal to plaque rupture in acute myocardial infarction: Evaluation by intravascular ultrasound and coronary angioscopy. Int J Cardiol 2007; 123: e12–e14, doi:10.1016/j.ijcard.2006.11.106.
• 42.    Ueda  Y,  Nanto  S,  Komamura  K,  Kodama  K. Neointimal coverage of stents in human coronary arteries observed by angioscopy. J Am Coll Cardiol 1994; 23: 341–346.
• 43.    Spears  JR,  Marais  HJ,  Serur  J,  Pomerantzeff  O,  Geyer  RP,  Sipzener  RS, et al. In vivo coronary angioscopy. J Am Coll Cardiol 1983; 1: 1311–1314.
• 44.    Litvack  F,  Grundfest  WS,  Lee  ME,  Carroll  RM,  Foran  R,  Chaux  A, et al. Angioscopic visualization of blood vessel interior in animals and humans. Clin Cardiol 1985; 8: 65–70.
• 45.    Nanto  S,  Ohara  T,  Mishima  M,  Hirayama  A,  Komamura  K,  Matsumura  Y, et al. Coronary angioscopy: A monorail angioscope with movable guide wire. Am J Card Imaging 1991; 5: 1–5.
• 46.    Mizuno  K,  Arai  T,  Satomura  K,  Shibuya  T,  Arakawa  K,  Okamoto  Y, et al. New percutaneous transluminal coronary angioscope. J Am Coll Cardiol 1989; 13: 363–368.
• 47.    Emanuelsson  H. Future challenges to coronary angioplasty: Perspectives on intracoronary imaging and physiology. J Intern Med 1995; 238: 111–119.
• 48.    Komatsu  S,  Ohara  T,  Takewa  M,  Takahashi  S,  Nomamoto  T,  Kamata  T, et al. Nonobstructive angioscopy in patient with atherosclerotic renal artery stenosis. J Cardiol Cases 2014; 9: 18–21.
• 49.    Nakanishi  N,  Nakamura  T,  Yamano  T,  Shiraishi  H,  Matoba  S,  Matsumuro  A, et al. Angioscopic observation in chronic thromboembolic pulmonary hypertension before and after balloon pulmonary angioplasty. J Cardiovasc Med (Hagerstown) 2014 August 1, doi:10.2459/JCM.0000000000000166.
• 50.    Strong  JP,  Malcom  GT,  McMahan  CA,  Tracy  RE,  Newman  WP 3rd,  Herderick  EE, et al. Prevalence and extent of atherosclerosis in adolescents and young adults: Implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 1999; 281: 727–735.
• 51.    Vilacosta  I,  San Roman  JA,  Ferreiros  J,  Aragoncillo  P,  Méndez  R,  Castillo  JA, et al. Natural history and serial morphology of aortic intramural hematoma: A novel variant of aortic dissection. Am Heart J 1997; 134: 495–507.
• 52.    Stanson  AW,  Kazmier  FJ,  Hollier  LH,  Edwards  WD,  Pairolero  PC,  Sheedy  PF, et al. Penetrating atherosclerotic ulcers of the thoracic aorta: Natural history and clinicopathologic correlations. Ann Vasc Surg 1986; 1: 15–23.
• 53.    Kaji  S,  Akasaka  T,  Katayama  M,  Yamamuro  A,  Yamabe  K,  Tamita  K, et al. Long-term prognosis of patients with type B aortic intramural hematoma. Circulation 2003; 108(Suppl): II307–II311.
• 54.    Petrinec  D,  Liao  S,  Holmes  DR,  Reilly  JM,  Parks  WC,  Thompson  RW. Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: Preservation of aortic elastin associated with suppressed production of 92 kD gelatinase. J Vasc Surg 1996; 23: 336–346.
• 55.    Kurosawa  K,  Matsumura  JS,  Yamanouchi  D. Current status of medical treatment for abdominal aortic aneurysm. Circ J 2013; 77: 2860–2866.
• 56.    Bashur  CA,  Rao  RR,  Ramamurthi  A. Perspectives on stem cell-based elastic matrix regenerative therapies for abdominal aortic aneurysms. Stem Cells Transl Med 2013; 2: 401–408.
• 57.    Saric  M,  Kronzon  I. Cholesterol embolization syndrome. Curr Opin Cardiol 2011; 26: 472–479.
• 58.    Saric  M,  Kronzon  I. Aortic atherosclerosis and embolic events. Curr Cardiol Rep 2012; 14: 342–349.
• 59.    Kronzon  I,  Tunick  PA. Aortic atherosclerotic disease and stroke. Circulation 2006; 114: 63–75.
• 60.    Tunick  PA,  Kronzon  I. Atheromas of the thoracic aorta: Clinical and therapeutic update. J Am Coll Cardiol 2000; 35: 545–554.
• 61.    Flory  C. Arterial occlusions produced by emboli from eroded aortic atheromatous plaques. Am J Pathol 1945; 21: 549–565.
• 62.    Liew  YP,  Bartholomew  JR. Atheromatous embolization. Vasc Med 2005; 10: 309–326.
• 63.    Yutani  C,  Imakita  M,  Ishibashi-Ueda  H,  Hatanaka  K,  Waki  R,  Ogawa  M, et al. Cerebro-spinal infarction caused by atheromatous emboli. Acta Pathol Jpn 1985; 35: 789–801.
• 64.    Masuda  J,  Yutani  C,  Ogata  J,  Kuriyama  J,  Yamaguchi  T. Atheromatous embolism in the brain: A clinicopathologic analysis of 15 autopsy cases. Neurology 1994; 44: 1231–1237.
• 65.    Guidoux  C,  Mazighi  M,  Lavallée  P,  Labreuche  J,  Meseguer  E,  Cabrejo  L, et al. Aortic arch atheroma in transient ischemic attack patients. Atherosclerosis 2013; 231: 124–128.
• 66.    Katsanos  AH,  Spence  JD,  Bogiatzi  C,  Parissis  J,  Giannopoulos  S,  Frogoudaki  A, et al. Recurrent stroke and patent foramen ovale: A systematic review and meta-analysis. Stroke 2014; 45: 3352–3359.
• 67.    Molisse  TA,  Tunick  PA,  Kronzon  I. Complications of aortic atherosclerosis: Atheroemboli and thromboemboli. Curr Treat Options Cardiovasc Med 2007; 9: 137–147.
• 68.    Stern  A,  Tunick  PA,  Culliford  AT,  Lachmann  J,  Baumann  FG,  Kanchuger  MS, et al. Protruding aortic arch atheromas: Risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J 1999; 138: 746–752.
• 69.    Yutani  C,  Imakita  M,  Ueda-Ishibashi  H,  Katsuragi  M,  Fujita  H. Coronary artery embolism with special reference to invasive procedure as the source. Mod Pathol 1992; 5: 244–249.
• 70.    Karalis  DG,  Quinn  V,  Victor  MF,  Ross  JJ,  Polansky  M,  Spratt  KA, et al. Risk of catheter-related emboli in patients with atherosclerotic debris in the thoracic aorta. Am Heart J 1996; 131: 1149–1155.
• 71.    Van Mieghem  NM,  Schipper  ME,  Ladich  E,  Faqiri  E,  van der Boon  R,  Randjgari  A, et al. Histopathology of embolic debris captured during transcatheter aortic valve replacement. Circulation 2013; 127: 2194–2201.