EPIDEMIOLOGY AND NATURAL HISTORY
Based on several angiographic studies, the incidence of coronary artery aneurysms ranges widely from 0.3% to 5.3% of the population, and a pooled analysis reports a mean incidence of 1.65%.2 A study from India reported an incidence of 10–12%, the highest in the literature to date, perhaps reflecting a specific genetic and/or environmental predisposition.3 The right coronary artery is the most commonly affected (40–87% of aneurysms), followed by the left circumflex or left anterior descending artery, depending on the study.4 Three-vessel or left main involvement is rare.
Current knowledge on the epidemiology and natural history of coronary aneurysms derives from several large angiographic series, where patients have been divided into 3 groups defined by the presence of aneurysms alone, aneurysms and atherosclerotic coronary artery disease (ACAD), and ACAD alone. As part of the Coronary Artery Surgery Study (CASS) registry, consecutive angiograms from over 20,000 patients performed to evaluate suspected ACAD, revealed a 4.9% incidence of coronary aneurysms.5 Comparing nearly 1000 patients with aneurysms to those with coronary artery stenoses but no aneurysms, patients with aneurysms were more likely to have 3-vessel disease, a history of myocardial infarction, and to be male. Patients with aneurysms, however, were less likely to have a family history of ACAD and did not differ from patients without aneurysms in left ventricular ejection fraction (LVEF) or in the incidence of hypertension, diabetes, smoking, peripheral vascular disease, hyperlipidemia, or angina. Further analysis of patients with coronary artery aneurysms showed that the majority (957 of 978 patients) also had coronary stenoses, which were generally ≥70% in severity (888 patients). Patients with both aneurysms and ACAD had a reduced 5-year actuarial survival relative to patients with ACAD alone (74% vs. 83%). When the severity of angiographic disease and LVEF were accounted for, however, no difference in survival between patients with aneurysms and ACAD and those with ACAD alone was found. Patients with aneurysms alone or aneurysms and nonsignificant ACAD (<70% stenoses) had no survival difference compared with patients with ACAD alone. Nearly 500 patients with aneurysmal disease underwent coronary artery bypass graft (CABG) surgery, with no difference in 5-year actuarial survival relative to patients with ACAD alone undergoing CABG.
A group in the United Kingdom reviewed nearly 5000 consecutive patient coronary angiograms from a single institution.2 Seventy patients were found to have coronary ectasia, and 54 of these 70 patients also had significant ACAD. In this study, there was a significant gender difference in the incidence of aneurysms, with 0.5% of females and 2.2% of males with ACAD having concomitant ectasia. Of the 70 patients with ectasia, 26 were treated with CABG, 2 with angioplasty, with the remainder managed medically. At a mean of 3.2 years follow-up, mortality rates after surgery and medical management were 7.7% (2 of 26) and 13% (3 of 21 where follow-up was available), respectively. Similar mortality rates at 5 years were reported in the European Coronary Surgery Study for patients treated surgically or medically.6 At a mean follow-up of 13 months, the 2 patients who underwent angioplasty were well.
In another retrospective study from Greece, review of 3900 patient angiograms identified 203 patients (5.3%) with coronary aneurysms, with the majority having associated significant ACAD (173 of 203).7 Patients with aneurysms and CAD were compared with a group of patients with ACAD alone, matched by age and sex, and no significant difference in the incidence of hyperlipidemia, hypertension, diabetes, myocardial infarction, LVEF, smoking, or family history of CAD was noted. A third small group of patients with aneurysms and no ACAD had a lower incidence of myocardial infarction than patients with ACAD with or without aneurysmal disease. All 3 groups had a similar incidence of angina and positive exercise tolerance tests, but patients with aneurysms alone had a significantly increased exercise tolerance time. In patients with ACAD and aneurysms, 34% of stenoses were in the same vessels affected by ectasia, while 66% were in nonectatic vessels. On follow-up, no difference in cardiac death; a composite of cardiac death, unstable angina, and myocardial infarction; or in CABG was found between patients with aneurysms and ACAD relative to patients with ACAD alone, whereas all of these outcomes were significantly less frequent in patients with aneurysmal disease alone, without ACAD. Patients with aneurysms and ACAD were much less likely to undergo percutaneous transluminal coronary angioplasty, presumably reflecting a relative lack of experience in treating these lesions via this approach.
More recently over 30,000 angiograms done between 1995 and 2003 at Emory University were retrospectively analyzed, and characteristics of patients with aneurysms to controls matched for ACAD were compared.8 In this series, aneurysmal segments were defined more rigorously, as those with diameter ≥2 times normal, yielding a 0.9% incidence of aneurysms (276 patients), the majority being in patients over 50 years of age. Relative to matched controls, patients with aneurysms were significantly more likely to be male and to have hyperlipidemia and were significantly less likely to be former smokers or diabetic. Among patients with aneurysms, this study found no association between aneurysm size and a host of clinical variables including sex, age, survival rate, obstructive ACAD, hypertension, hyperlipidemia, or diabetes. Patients with aneurysms had a 5-year mortality rate of 29.1%, irrespective of concomitant ACAD, a notable difference from the studies described above, where survival was better for patients with aneurysms alone without obstructive ACAD. Multivariate analysis of this population found a statistically significant hazard ratio for mortality of 1.56 among patients with aneurysms, making it one of the strongest predictors of mortality. This discrepancy with previous natural history studies may in part be related to the more stringent size cutoff for aneurysms.
In the aggregate, these studies reveal several common features regarding the natural history of coronary artery aneurysms. Aneurysms are more common in males and are most often seen in association with ACAD, as would be expected among a population for whom manifestations of ACAD are the primary drivers of angiography. There are no consistent differences in the incidence of typical cardiac risk factors between patients with aneurysmal disease and ACAD and those with ACAD alone. These observations have led to the hypothesis that coronary aneurysms are a manifestation of atherosclerosis, with a similar pathophysiology. In support of this, patients with heterozygous familial hypercholesterolemia, who are at markedly increased risk for atherosclerosis, have a significantly increased incidence of coronary artery ectasia (15% vs. 2.5%).9 Patients with aneurysms in the absence of significant epicardial ACAD are identified much less commonly. Based on the above series, it is not clear whether these patients have similar or better outcomes than patients with associated ACAD. It is apparent, however, that they have worse outcomes than the general population, confirming that coronary aneurysms are not a benign finding.
PATHOPHYSIOLOGY AND ETIOLOGY
The pathophysiology of coronary artery aneurysms is thought to be similar to that for aneurysms of larger vessels, with destruction of the vessel media resulting in increased wall stress and subsequent dilation. Some studies have suggested that patients with coronary aneurysms may have an increased risk of aortic aneurysm. Table 1 lists the diverse etiologies for coronary aneurysms. Coronary aneurysms are frequently seen in association with atherosclerosis, suggesting an overlap in risk factors and pathogenesis. It has been estimated that 50% of coronary aneurysms are due to atherosclerosis. The next most common cause is congenital, accounting for 20–30% of coronary aneurysms. A host of inflammatory and connective tissue disorders have also been associated with coronary aneurysms. Most well known is the association with Kawasaki disease, but coronary aneurysms have also been reported in patients with Takayasu's arteritis, lupus, rheumatoid arthritis, Marfan syndrome, and Ehlers-Danlos syndrome. Coronary aneurysms have also been noted in conjunction with infection, drug use, trauma, and percutaneous coronary intervention. In the Taxus-V trial, coronary artery aneurysms were more prevalent after implantation of paclitaxel-eluting stents than bare metal stents (1.4% vs. 0.2%), though this trend did not quite achieve statistical significance (P = 0.07).10 This did not appear to be due to differences in pressure during deployment or stent size, suggesting that aneurysms may be the result of an inflammatory reaction to the drug-coated stent.11
Although the molecular mechanism underlying coronary aneurysms has yet to be elucidated, there is evidence that matrix metalloproteinases (MMPs) have a role. MMPs are a large family of molecules involved in tissue turnover and have been implicated in large vessel aneurysms. Analysis of several MMP genes has determined that certain MMP-3 genotypes, associated with higher levels of gene expression, are more common among patients with coronary aneurysms than matched controls.12 Interestingly, higher circulating MMP-3 levels have also been linked to coronary lesions in patients with Kawasaki disease. Linkage disequilibrium mapping has recently identified a functional polymorphism in the inositol 1,4,5-triphosphate 3-kinase C gene associated with increased susceptibility to Kawasaki disease and coronary artery lesions.13 This molecule acts as a negative regulator of T cell activation, and the disease-associated polymorphism seems to result in immune hyper-reactivity.
The impetus for treating coronary aneurysms is predicated on the host of complications associated with these lesions. These most commonly include angina, myocardial infarction, and sudden death. Other adverse events include thrombosis, thromboembolism, formation of arteriovenous fistulae, vasospasm, and rupture. These complications may, in part, be related to turbulent flow associated with aneurysms, though they could also be attendant features of ACAD that tend to be seen in association with aneurysms. It has also been postulated that patients with aneurysms and angina can experience a paradoxical worsening of ischemia after using nitroglycerin via a mechanism termed “dilated coronaropathy.”14
Treatment options consist of surgical, percutaneous, and medical approaches. A substantial literature exists regarding the management of pediatric patients with coronary aneurysms associated with Kawasaki disease. These guidelines are beyond the scope of this review, however, and their relevance to adult patients, with presumed differences in pathophysiology, is uncertain.15 The largest experience in adults has been with surgical management, which typically includes bypass grafting. Based on the CASS substudy described above, no difference in survival after CABG was noted between patients with ACAD and aneurysms (over 500 patients) and ACAD alone.5 Operative therapy may also include aneurysm ligation, resection, or marsupialization with interposition graft, and the ideal approach has not yet been formally studied.16–17 Percutaneous treatment is a newer option, with a markedly smaller data set, and includes stenting and coiling. One of the largest studies retrospectively compared outcomes in a series of patients treated with either surgery (n = 18) or polytetrafluoroethylene-covered stents (n = 24).18 Patients treated with stents tended to be older (60.5 vs. 47.7 years old) and to have smaller aneurysms (9.8 vs. 35.1 mm). No deaths were reported in either group. Only 5 of the 24 patients who received stents were found to have restenosis on follow-up angiography, and these patients tended to have larger aneurysms, >10 mm in diameter. Based on these limited data, the authors suggest that polytetrafluoroethylene-covered stents should be limited to patients whose aneurysms are <10 mm in diameter. Other important considerations associated with use of these stents include decreased flexibility, making implantation in tortuous vessels complex, and blocking access to side branches. There are few data regarding medical therapy for coronary aneurysms. Medical management generally includes antiplatelet and/or antithrombotic agents, the use of which has been anecdotal. No data are currently available to indicate the relative merits of either approach.
Although our knowledge of coronary artery aneurysms and their management has progressed, a great deal remains unknown. Aneurysms are most commonly associated with ACAD, but it is not clear which factors promote the development of aneurysms in these patients. With regard to outcome, there is a discrepancy in the published series in how patients with aneurysms alone fare. It will be important to determine if these patients do better than those with aneurysms and concomitant ACAD, to formulate an appropriate treatment plan. For physicians managing patients with coronary artery aneurysms, it remains unclear whether anticoagulation and/or antiplatelet therapy offers benefits. Certainly, patients with concomitant ACAD should be treated with standard antiplatelet and lipid-lowering therapies to recommended prevention targets. Answers to questions regarding optimal treatment may come from newer clinical series or the development of a multicenter registry, as older published reports included many patients who did not have access to the full array of medical, percutaneous, and surgical options available today. With the increase in angiography and the more widespread use of high resolution CT scans and MRI imaging, the diagnosis of coronary aneurysms is likely to become more frequent, and the need for evidence-based management strategies will grow. As our knowledge of the pathophysiology and natural history of these lesions expands, treatment and outcomes for patients with coronary artery aneurysms are likely to continue to improve.
The authors thank Dr. Frederick G. Welt for providing the coronary angiography images and Dr. Sharmila Dorbala for providing the CT angiography images.
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Keywords:© 2008 Lippincott Williams & Wilkins, Inc.
aneurysm; ectasia; atherosclerotic coronary artery disease