|Year : 2020 | Volume
| Issue : 2 | Page : 56-62
Transesophageal echocardiography for aortic arch atheromas in patients with cryptogenic stroke/transient ischemic attack – An underutilized entity
Raghuram Palaparti, Sudarshan Palaparthi, PS S Chowdary, Gopala Krishna Koduru, Prasad Maganti, Purnachandra Rao Kondru, Somasekhar Ghanta, Boochi Babu Mannuva, Sasidhar Yendapalli
Department of Cardiology, Aayush Hospitals, Vijayawada, Andhra Pradesh, India
|Date of Submission||08-Dec-2019|
|Date of Decision||17-Jan-2020|
|Date of Acceptance||27-Apr-2020|
|Date of Web Publication||4-Aug-2020|
Dr. Raghuram Palaparti
Aayush Hospitals, Ramachandra Nagar, Vijayawada - 520 008, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: Large aortic arch atheromas (≥4 mm) and complex and mobile aortic atheromas have been associated with ischemic brain stroke in various previous studies. Transesophageal echocardiography (TEE) is the imaging modality of choice, however, is an underutilized investigation in routine clinical practice. We sought out to find the prevalence and severity of aortic arch atheromas in patients with cryptogenic stroke/transient ischemic attack (TIA) at a tertiary care center.
Patients and Methods: One hundred and eighty-eight consecutive stroke patients were screened for stroke risk factors. Sixty-one patients were found to have stroke without obvious cause (cryptogenic), 52 patients underwent TEE, four patients were further excluded after evidence of potential cardioembolic source in TEE, and finally, data of 48 patients with cryptogenic stroke were analyzed.
Results: We found that one-third of the patients (n = 16, 33.3%) had aortic atheromas and half of them (n = 8, 16.4%) had atheromas ≥4 mm. Diabetes, dyslipidemia, and smoking status were individually associated with a higher prevalence of aortic plaques in our study (P = 0.03). The frequency of aortic plaques was significantly higher in patients with ischemic brain infarction than in TIA (P = 0.01). Large atheromas (≥4 mm) were significantly associated with more severe clinical illness as assessed by the National Institute of Health Stroke Scale, longer hospital stay, and death (P < 0.001).
Conclusions: In the present observational study at a tertiary care center, we found that the relevant aortic atheromas in patients with cryptogenic stroke are fairly common and are associated with adverse clinical events. The diagnosis of aortic atheromas should be sought actively by TEE in patients with cryptogenic stroke or in patients with recurrent embolic events and multiple risk factors. Antiplatelet agents and statins are the mainstay of therapy. Anticoagulation is reasonable in selected high-risk patients. Future randomized trials of direct oral anticoagulants compared to antiplatelet therapy in patients with complex aortic atheromas are anticipated to guide the clinicians.
Keywords: Aortic arch atheromas, cryptogenic stroke, transesophageal echocardiography, underutilized entity
|How to cite this article:|
Palaparti R, Palaparthi S, S Chowdary P S, Koduru GK, Maganti P, Kondru PR, Ghanta S, Mannuva BB, Yendapalli S. Transesophageal echocardiography for aortic arch atheromas in patients with cryptogenic stroke/transient ischemic attack – An underutilized entity. Heart India 2020;8:56-62
|How to cite this URL:|
Palaparti R, Palaparthi S, S Chowdary P S, Koduru GK, Maganti P, Kondru PR, Ghanta S, Mannuva BB, Yendapalli S. Transesophageal echocardiography for aortic arch atheromas in patients with cryptogenic stroke/transient ischemic attack – An underutilized entity. Heart India [serial online] 2020 [cited 2020 Sep 19];8:56-62. Available from: http://www.heartindia.net/text.asp?2020/8/2/56/291359
| Introduction|| |
Aortic arch atheromas are the second most prevalent cardioembolic risk factor for stroke after atrial fibrillation (AF) and are found in 16%–20% of all patients with stroke or transient ischemic attack (TIA) in various studies. Many studies utilizing transesophageal echocardiography (TEE) reported that large atheromas (≥4 mm), ulcerated plaques, and complex and mobile aortic arch atheromas were associated with ischemic brain stroke. Although it is not recommended in all patients, TEE is an invaluable investigation in patients with cryptogenic ischemic stroke. Unfortunately, it is underutilized in routine clinical practice.
Aims and objectives
In this present observational study, we planned to study the prevalence and severity of the aortic arch atherosclerotic disease in patients with either cryptogenic ischemic stroke or TIA at a tertiary care center.
| Patients and Methods|| |
Stroke was defined according to the World Health Organization criteria. The severity of stroke was categorized as mild (0–4), moderate (5–15), or severe (16–42) by the National Institute of Health Stroke Scale (NIHSS)., Cryptogenic stroke is defined according to the Trial of Org 10172 in Acute Stroke Treatment. After screening 188 consecutive patients at our institute, we enrolled 48 consecutive patients with cryptogenic ischemic stroke/TIA. Patients were included either from the outpatient department or from inpatients. Exclusion criteria were age ≤18 years, intracranial hemorrhage, poor Glasgow Coma Scale (GCS) (≤8), and refusal to give consent. Almost all the patients had computed tomography/magnetic resonance imaging (MRI) of the brain to confirm stroke and had their risk factors assessed. All patients had complete blood count, blood glucose, renal function test, serum electrolytes, lipid profile, electrocardiography, transthoracic echocardiography, and carotid Doppler as part of their initial stroke risk assessment. Patients with cardioembolic stroke, significant carotid atherosclerosis (>50%), and small-vessel stroke were excluded from the study. Cardioembolic stroke was diagnosed in the following conditions: mechanical prosthetic valve, mitral stenosis with or without AF, isolated AF or atrial flutter, left atrial appendage thrombus, left ventricular (LV) thrombus, recent myocardial infarction (≤6 weeks), dilated cardiomyopathy, akinetic/hypokinetic LV segment/congestive heart failure with <40% of ejection fraction, atrial myxoma, infective endocarditis and nonbacterial thrombotic endocarditis, patent foramen ovale (PFO), dense echo contrast, and interatrial septal aneurysm. All the patients received appropriate therapy including antiplatelets, statins and anticoagulation according to the clinical indication. Outcomes such as duration of hospital stay, severity of stroke (NIHSS), and death were recorded during the index hospitalization.
A comprehensive TEE with detailed imaging of the aorta was performed with a commercially available Philips CX 50 portable ultrasound imaging system and Philips X7-2t 2D TEE transducer. The proximal and mid-ascending aortas were imaged at a probe depth of 30 cm with a multiplane angle of 100°–150° to view the vessel in the long axis. The descending thoracic aorta was examined by advancing the probe to the distal esophagus, imaging the aorta in cross-section (at 0°), and then, slowly withdrawing the probe to image proximal segments. As the transducer reached the AA, the multiplane angle was rotated to between 0° and 90° to acquire sequential short-axis views. Plaque thickness was measured as the maximal thickness of the intimal and medial layers and graded as mild (<1 mm), moderate (1–3.99 mm), or severe (≥4 mm) with the criteria of Amarenco et al. Plaques were also assessed for morphological features, including heteroechogenicity, mobility, and ulceration that have been specifically linked to cerebral embolism. Heteroechogenicity of the plaque was defined as focal increase in echocardiographic density within the aortic plaque combined with a broad acoustic shadow that indicated the presence of calcifications. A complex atheroma is defined as a lesion with a base ulcer, mobile nature, or size larger than ≥4 mm. TEE was also used to assess morphology of interatrial septum (atrial septal defect/PFO) or for left atrium (LA) appendage clot.
| Results|| |
One hundred and eighty-eight consecutive patients visiting the outpatient department or admitted in our institute with a diagnosis of acute stroke were screened. 61 patients (38 male) with cryptogenic stroke were enrolled in the study. The mean age of the cohort is 58.2 ± 13.8. TEE was successfully carried out in 52 patients. Seven patients were in poor general condition with lower GCS scores and TEE could not be performed. Two patients could not tolerate the procedure and were abandoned. Four more patients with LA appendage clot (n = 1) or PFO (n = 2) or atrial septal aneurysm (n = 1) on TEE were excluded from the study group, as a possible cardioembolic source is found. Finally, a total of 48 patients' data were analyzed. The baseline characteristics and TEE findings of the study group are shown in [Table 1]. Of the 48 patients, 39 patients had imaging-proven ischemic cerebrovascular accident (CVA) and rest of the nine patients had TIA. Aortic atheromas were observed in 16 patients (33.3%). Plaques were ≥4 mm thick in eight patients, and in other eight patients, they were <4 mm thick. We found that the advanced age (≥65) was associated with a higher prevalence of plaques (P < 0.001). Males more commonly had larger aortic plaques and severe clinical illness when compared to females (P = 0.04). About 31.2% (n = 15) of the patients were diabetics, 35.4% (n = 17) of the patients were hypertensives, and 14.5% (n = 7) of the patients had smoking habit. Dyslipidemia was seen in 22.9% (n = 11) of the patients. Plaques were found in the ascending aorta in two patients, in the aortic arch in nine patients, and in the proximal descending aorta in five patients [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6] and Videos 1-7]
|Table 1: Baseline characteristics, transesophageal echocardiography findings and outcomes of patients with cryptogenic stroke/ transient ischemic attack|
Click here to view
|Figure 1: Transesophageal echocardiography image showing a plaque in the ascending aorta close to the sinotubular junction|
Click here to view
|Figure 2: Diffusion weighted magnetic resonance imaging brain images of a patient with showing foci of restricted diffusion in the left thalamus and the left frontoparietal regions involving both the left middle cerebral artery and posterior cerebral artery territories. This patient developed on table stroke while undergoing coronary bypass graft angiography. Cine fluroscopy and transesophageal echocardiography showed a large mobile atheroma in the ascending aorta|
Click here to view
|Figure 3: Transesophageal echocardiography showing atheroma in the aortic arch|
Click here to view
|Figure 4: Transesophageal echocardiography still image showing mobile atheroma in the aortic arch|
Click here to view
|Figure 5: Another representative patients' transesophageal echocardiography showing Grade III atheroma|
Click here to view
|Figure 6: One of the patients with large heterogenous and mobile atheroma. This patient presented with recurrent cerebrovascular accident. Found to have aortic atheroma on transesophageal echocardiography as a probable embolic source during her second admission|
Click here to view
Large mobile atheromas were found in two of our patients. Both the atheromas were found in the region of ascending aorta. One patient, a 58-year-old-female, had 9 mm plaque in the ascending aorta, developed recurrent CVA and was identified to have severe aortic atherosclerosis during her second hospital admission [Figure 6] and Video 6]. Another patient had 12 mm mobile calcific plaque. He was a diabetic, hypertensive presented with unstable angina and preserved LV function. He underwent graft angiography and developed embolic stroke on table. MRI showed a multiple bilateral cerebellar thalamic infarcts suggestive of a shower of atheroembolism [Figure 2]. TEE showed a large atheroma in the ascending aorta. Retrospectively, fluoroscopy also identified a mobile calcified atheroma which probably embolized during invasive procedure [Video 7]. He succumbed to sepsis later during a hospital stay.
Diabetes, dyslipidemia, and smoking status were associated individually with a higher prevalence of aortic plaques in our study (P < 0.05). The prevalence of aortic plaques was not significantly different in patients with hypertension and without hypertension. The frequency of aortic plaques was significantly higher in patients with ischemic brain infarction rather than in TIA (P = 0.01). Low-grade atherosclerotic lesions (stenosis <50%) were noted in 43.7% (7/16) of the patients with aortic atherosclerotic plaques and only in 15.6% (5/32) of the patients without atherosclerotic aortic arch plaques. Six patients died in our study group during the hospital stay. Large atheromas, defined as 4 mm or higher, were significantly associated with more severe illness as assessed by the NIHSS, longer hospital stay, and death (P < 0.001).
| Discussion|| |
In their autopsy and clinical studies of individuals older than 60, Amarenco et al. found that a higher prevalence of atheromas in the aortic arch in patients with cryptogenic stroke. In their study, 28% of the patients showed plaques ≥4 mm thick, as compared with 16.6% of the patients in our study. A lower frequency of larger atheromas in our study group may be due to nonselected population with all age groups and exclusion of patients with carotid atherosclerosis. Aortic atheromas have been classified according to the size by Amarenco et al. (described above) and are widely accepted. Aortic atheromas were also classified by Katz et al. as follows: Grade 1, normal-appearing intima of the aorta; Grade 2, extensive intimal thickening; Grade 3, sessile atheroma protruding <5 mm into the aorta; Grade 4, atheroma protruding >5 mm; and Grade 5, mobile atheroma.
The initial imaging modality of choice for the diagnosis of aortic atheromas is TEE. TEE allows an adequate visualization of the proximal ascending aorta and thoracic descending aorta. However, visualization of the distal ascending aorta and its branches is hampered by the so-called blind spot caused by the air-filled trachea which interposes the esophagus and aorta. A meta-analysis of diagnostic accuracy studies showed that the sensitivity of TEE in the diagnosis of severe atherosclerosis of aortic arch was a mere 21%. Aortic view technique has been developed to eliminate this blind spot to be used as an additional diagnostic tool prior to cardiac surgery. A balloon is positioned in the trachea, which provides an echocardiographic window to the aorta after inflation with saline. The method allows also visualization of the aortic arch and the origins of the cerebral arteries. This modified TEE had a good overall diagnostic accuracy (area under the receiver operating curve of 0.89) for aortic atherosclerosis with a positive predictive value of 67% and negative predictive value of 97%. The main advantage of TEE is its easy availability and still remains the first imaging modality of choice. The diagnostic accuracy of computed tomography compared to TEE appears to be lower for the presence of aortic atherosclerosis. MRI can also used to diagnose aortic atherosclerosis. The advantage of MRI lies in its ability to characterize the tissue including the fibrous cap, lipid core, and thrombus. Several studies compared the diagnosis of aortic atheroma with MRI to TEE and found that MRI is superior compared to TEE in the ascending aorta and aortic arch, although TEE quality was superior for the descending aorta. Despite the advantages of MRI, its use in general practice is limited because of several limitations, including current imaging times, availability, costs, and the lack of intraoperative imaging and expertise in imaging interpretation.
Aortic atheromas are found in various regions of the aorta, while in the ascending aorta and arch, it is uncommon. In our small study population, we found aortic atheromas more commonly in the aortic arch. The presence of large plaques in the ascending aorta, arch, or in the proximal descending aorta is a definite risk factor of stroke, and studies have shown that it can result in a 2.5- to 4-fold increased risk of stroke. The mechanism of atheroma formation is similar to atherosclerosis; however, thormbus formation due to hypercoagulable states has also been proposed as a mechanism in some of the patients. We did not evaluate our patients for any hypercoagulable states as most of our patients with aortic atheromas had atleast one of the traditional atherosclerosis risk factors such as diabetes, hypertensions, dyslipidemia, and smoking habit. However, thromboembolism is still possible from aortic atheromas secondary to plaque erosion or rupture. The overall prevalence and characteristics of aortic atheromas and demographic profile of our study population are in agreement with various previous studies.,
The diagnosis of aortic atherosclerosis if at all made is generally after embolic stroke or rarely after peripheral embolism. In routine clinical practice, TEE is underutilized to evaluate for aortic atheromas in patients presenting with stroke. The causes for this are manifold in the Indian scenario. First, the atherosclerotic aortic pathology is less often considered by the primary physicians as a cause for acute ischemic stroke. Second, TEE being a semi-invasive investigation is less often utilized in stroke patients with poor general condition. Third, TEE may not change the management pathway acutely and hence is less driven in the diagnostic pathway, thereby likely to be missed altogether in follow-up. It is also relatively technically challenging. Our observational study shows that almost one-third of the patients with cryptogenic stroke/TIA had aortic atheromas, but should all the patients with ischemic stroke should undergo TEE for evaluation of aortic arch atherosclerosis is an alluring inquest. This has been answered in few studies. Harloff et al. in their prospective study enrolled 301 patients with acute cerebral ischemia and found that the routine use of TEE to exclude aortic plaques in patients with normal carotid ultrasound is not beneficial. They concluded that TEE should however, be performed in patients with carotid atherosclerosis, particularly in those with internal carotid artery stenosis ≥50%.
The identification of atheromas helped us to intensify the medical therapy in our patients with dual antiplatelets and high-dose statins. We did not use oral anticoagulant therapy in any of our patients. Aortic Arch Related Cerebral Hazard (ARCH) trial randomized patients to aspirin plus clopidogrel or warfarin in patients with an aortic arch plaque >4 mm and found that ischemic stroke occurred less frequently in the aspirin plus clopidogrel group; however, these results were statistically insignificant. However, several other studies found no significant benefit to single antiplatelet therapy over dual antiplatelet therapy. The 2014 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend antiplatelet therapy and statin treatment for patients with an ischemic stroke and with evidence for an aortic arch atheroma. Endovascular therapy and angioplasty have also been reported as isolated reports; however, these procedures are also associated with higher incidence of periprocedural stroke. In fact, one of our patients developed severe ischemic stroke after coronary and bypass graft vessel angiography. Aortic arch atherectomy has also been advocated as a treatment modality but may be limited to patients who are young, suffered recurrent embolic events from aortic plaques, and refractory to medical therapy. However, the surgical risk is higher and is in itself associated with intraoperative stroke. The AHA/ASA recommends against routine surgical endarterectomy of aortic arch plaque for the purposes of secondary stroke prevention.
According to a recent major trial, in patients with a recent history of embolic stroke of undetermined source, dabigatran was found not to be superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group (RE-SPECT ESUS trial). Similarly, rivaroxaban was also found not to be superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding (NAVIGATE ESUS trial). Further randomized trials are necessary to resolve this equipoise. Limiting the oral anticoagulation therapy to the selected high-risk population with lower bleeding risk rather than as a generalized one for all strategy may yield clinical benefits.
Stroke risk from aortic arch atheromas may be decreased prophylactically with anticoagulation therapy. In a prospective cohort study by Ferrari et al., they found that patients with complex aortic atheromas treated with antiplatelet therapy had significantly more embolic events and a ninefold higher mortality compared to those on anticoagulation therapy with warfarin. A narrative review published by Capmany et al. illustrated various studies showing anticoagulation's superiority to antiplatelet therapy in patients with stroke and complex aortic atheromas. They also concluded that statin therapy may reduce the relative risk of new vascular events. However, majority of the studies are observational and randomized clinical trials exist. Currently, there exist no studies for direct oral anticoagulants (DOACs) in the management of complex aortic arch atheromas or aortic thrombus. With the emerging data showing the superiority or noninferiority with lesser bleeding risk of DOACs over Vitamin K antagonists (VKA) in almost every clinical scenario, it will be interesting to see the role of DOACs in this high-risk subset of patients particularly in patients with high bleeding risk. As of now, a short duration of VKA therapy appears reasonable in patients with aortic thrombosis or in patients with complex, mobile atheromas and recurrent embolic events as a secondary prophylaxis.
| Conclusions|| |
TEE is an underutilized investigation for timely diagnosis of aortic atheromas in routine clinical practice. In the present observational study at a tertiary care center, we found that the relevant aortic atheromas in patients with cryptogenic stroke are fairly common and are associated with adverse clinical events. The diagnosis of aortic atheromas should be sought actively by TEE in patients with cryptogenic stroke or in patients with recurrent embolic events and multiple risk factors. Management of symptomatic complex aortic atheromas is still an unresolved enigma and the management should be individualized. Patients with cryptogenic stroke in which a complex aortic arch atheroma is identified remain at high risk of subsequent cerebrovascular events despite optimal therapy with antiplatelets and statins. Anticoagulants should be considered in selected high-risk patients. Future randomized trials of DOACs compared to antiplatelet therapy in these high-risk patients are anticipated to guide the clinicians toward best practices.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Institutional ethics committee approval has been obtained for the study.
| References|| |
Sen S, Hinderliter A, Sen PK, Simmons J, Beck J, Offenbacher S, et al
. Aortic arch atheroma progression and recurrent vascular events in patients with stroke or transient ischemic attack. Circulation 2007;116:928-35.
Capmany RP, Ibañez MO, Pesquer XJ. Complex atheromatosis of the aortic arch in cerebral infarction. Curr Cardiol Rev 2010;6:184-93.
Coupland AP, Thapar A, Qureshi MI, Jenkins H, Davies AH. The definition of stroke. J R Soc Med 2017;110:9-12.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N
Engl J Med 1995;333:1581-7.
Lyden P. Using the National Institutes of Health Stroke Scale: A cautionary tale. Stroke 2017;48:513-9.
Adams HP Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al
. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41.
Patil TA, Nierich A. Transesophageal echocardiography evaluation of the thoracic aorta. Ann Card Anaesth 2016;19:S44-55.
Amarenco P, Bogousslavsky J, Caplan LR, Donnan GA, Hennerici MG. Classification of stroke subtypes. Cerebrovasc Dis 2009;27:493-501.
Katz ES, Tunick PA, Rusinek H, Ribakove G, Spencer FC, Kronzon I. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992;20:70-7.
Tunick PA, Krinsky GA, Lee VS, Kronzon I. Diagnostic imaging of thoracic aortic atherosclerosis. AJR Am J Roentgenol 2000;174:1119-25.
Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, et al
. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N
Engl J Med 1994;331:1474-9.
Roth M, Schönburg M, Kloevekorn WP, Bauer EP. Thrombotic formations within the aortic arch as source of embolization in patients with coagulopathia. Eur J Cardiothorac Surg 2001;19:534-6.
Di Tullio MR, Sacco RL, Gersony D, Nayak H, Weslow RG, Kargman DE, et al
. Aortic atheromas and acute ischemic stroke: A transesophageal echocardiographic study in an ethnically mixed population. Neurology 1996;46:1560-6.
Tunick PA, Rosenzweig BP, Katz ES, Freedberg RS, Perez JL, Kronzon I. High risk for vascular events in patients with protruding aortic atheromas: A prospective study. J Am Coll Cardiol 1994;23:1085-90.
Lee JS, Chandraratna PA. Peripheral embolism from an aortic-arch atheroma. N
Engl J Med 2003;349:e23.
Harloff A, Handke M, Geibel A, Oehm E, Guschlbauer B, Olschewski M, et al
. Do stroke patients with normal carotid arteries require TEE for exclusion of relevant aortic plaques?. J Neurol Neurosurg Psychiatry 2005;76:1654-8.
Amarenco P, Davis S, Jones EF, Cohen AA, Heiss WD, Kaste M, et al
. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke 2014;45:1248-57.
2018 Guidelines for the Early Management of Patients with Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke 2018;49:e46-110.
Khaki A, Ravichandran PS, Kelly S, Gately HL, Starr A, Floten HS. Extended aortic arch atherectomy. Ann Thoracic Surg 1998;65:255-7.
Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al
. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N
Engl J Med 2019;380:1906-17.
Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al
. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N
Engl J Med 2018;378:2191-201.
Ferrari E, Vidal R, Chevallier T, Baudouy M. Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: Benefit of oral anticoagulants. J Am Coll Cardiol 1999;33:1317-22.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]