Coronary Artery Ectasias: Too Large to Miss?

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Citation
European Cardiovascular Disease 2006 - Issue 2;2006:2(2):1-6
DOI
http://dx.doi.org/10.15420/ecr.2006.0.2.1e

Coronary artery ectasia (CAE) is a relatively common entity causing inappropriate dilatation of the coronary vasculature. The exact mechanism of its development is unknown, but evidence suggests a combination of genetic predisposition, common risk factors for coronary artery disease (CAD) and abnormal vessel wall metabolism. It frequently co-exists with aneurysms elsewhere, mostly involving the aorta. In this review, we describe the flow disturbances that are associated with this condition and the imaging modalities, which can be used for diagnosis and prospective follow-up. The prognosis of coronary ectasias is not benign and prospective studies focusing on conservative or invasive strategies to prevent cardiac complications are lacking.

Since its first description by Morgagni in 1761, CAE has puzzled physicians regarding its cause, clinical sequelae and treatment.1 The incidence of CAE during coronary angiography is 1-5%, but this figure may underrepresent the true frequency in the general population.2-8 In the largest series from the CASS registry, CAE was documented in 4.9% in more than 20,000 coronary angiograms2 and in an Indian patient cohort with ischaemic heart disease has been reported to exceed 10%.9 The most commonly used angiographic definition of CAE is the diameter of the ectatic segment being more than 1.5 times larger compared with an adjacent healthy reference segment.2-3 More than half of CAE cases are ascribed to coronary atherosclerosis, but occasionally they are related to other pathological entities.10 CAE have also been observed in association with connective tissue disorders such as scleroderma,11 Ehler-Danlos syndrome12 and polyarteritis nodosa,13 but also with bacterial infections14 and Kawasaki disease.15 In a small percentage of patients CAE can be congenital in origin.16 Acquired CAE should also be differentiated from large ulcerated coronary plaques and, more importantly, coronary aneurysms following percutaneous interventions, a distinction necessitating imaging with intravascular ultra-sound.17 These include true or pseudo-aneurysms during coronary balloon angioplasty, or following coronary stent placement, atherectomy and brachytherapy.18-20

CAE may be associated with aneurysms in other vascular beds as well. They are seen more frequently in patients with aneurysms of the abdominal and ascending aorta, the popliteal arteries, veins and the pulmonary artery.21

In a retrospective study by Stajduhar et al., 20.8% of patients operated on for abdominal aortic aneurysm had CAE, compared with 2.9% of patients who were operated on for occlusive peripheral vascular disease.22 Similar findings have been reported by most,23-25 but not all investigators.2,5 A five-fold increase in the frequency of angiographically detected CAE has been documented in patients operated on for aneurysm of the ascending aorta by our group.26

Pathophysiology of CAE

Although the specific mechanisms of abnormal luminar dilatation in CAE remain unclear, the histopathological similarities to coronary atherosclerosis have led to hypotheses involving the vascular endothelium and the biological properties of the vascular wall. Virmani and other investigators have provided detailed pathological characterisation of CAE, including lipid deposition with foam cells, fibrous caps and significant loss of musculoelastic vascular wall components as main histological abnormalities.4,23-24 It is interesting that in a minority of cases, CAE are present in the absence of significant atheromatous burden. Despite the intact intima, extensive media degeneration and hyalinisation have been reported in this setting, serving as a possible common denominator in all cases with CAE.27

On a pathophysiological basis, chronic over-stimulation of endothelium by Nitric Oxide (NO) or NO donors has been identified by many investigators in epidemiological studies including munition workers and subjects exposed to herbicide sprays,28-31 suggesting a possible link between NO and medial thinning leading to CAE. Furthermore, ectatic coronary segments may undergo intense coronary spasm, in response to exogenous administration of vasoreactive medications, such as ergonovine and acetylcholine.32-33 This phenomenon may, at least in part, contribute to the rare development of acute coronary syndromes in patients with CAE without coronary stenoses ('dilated coronaropathyÔÇÖ).10

Lamblin et al., focused on the system of metallo-proteinases, which are actively involved in the proteolysis of the extracellular matrix proteins.25 The investigators found that patients with CAE, compared with patients with obstructive coronary lesions, had a higher percentage of the 5A/5A polymorphism of the metalloproteinase-3 (MMP-3) implicating over-expression of MMP-3 and enhanced vessel wall degradation of various matrix proteins, such as proteoglycans, laminin, fibronectin and collagen types III, IV, V and IX.34-35

These results are in line with recent evidence suggesting the presence of higher MMP-3 levels and an imbalance of MMP/TIMP in patients with generalised CAE.36 The contribution of vascular inflammation is further strengthened by observations linking the presence of CAE with elevated plasma levels of high sensitivity C-reactive protein (hsCRP),37-38 interleukin (Il)-639 and vascular cell adhesion molecule (V-CAM), intracellular adhesion molecule (I-CAM) and E-selectin.40 In one recent study, more than a 2.5-fold increase in vascular endothelial growth factor (VEGF) levels was found in patients with diffuse CAE, compared with patients with or without CAD.41

CAE Imaging

Coronary angiography still remains the gold standard for the assessment of CAE. Three decades ago Markis et al. proposed a classification of CAE based on the extent of ectatic involvement. In decreasing order of severity, diffuse ectasia of two or three vessels was classified as type I, diffuse disease in one vessel and localised disease in another vessel as type II, diffuse ectasia of one vessel only as type III and localised or segmental ectasia as type IV.4 In addition, CAE have been classified according to the anatomical shape of the ectatic segment in fusiform or saccular types.21 All three coronary vessels can be affected by CAE, but in approximately 75% of patients in a unilateral form.3 The proximal and mid segments of the right coronary artery are the most frequently involved, followed by the left anterior descending artery and the circumflex artery.2-3 The aetiology for the higher right coronary artery predisposition to CAE is not well understood, but may be flow-related. Compared with discrete saccular type CAE, diffuse fusiform type CAE tend to have more frequently bilateral distribution and association with abdominal aortic aneurysms, but they less frequently co-exist with obstructive coronary lesions.3,10,22 In a small percentage of patients, CAE do not co-exist with coronary stenoses; rather they involve part or the whole length of the artery in a diffuse form (dilated coronaropathy).10 To date there are no systematic studies examining the anatomical changes that may occur in CAE over time.42

Intravascular ultrasound (IVUS) provides an excellent tool to assess luminal size and characterise arterial wall changes. Ruptured and emptied plaque cavities may appear angiographically as CAE and the distinction is of clinical importance, since these false aneurysms may be associated with acute coronary syndromes.43 Ge et al. observed atheromatous burden in the majority of CAE, with plaque areas evenly distributed between proximal and distal reference segments, as well as within the aneurysmal segment.17 Of importance, IVUS was also able to correctly differentiate true from false aneurysms caused by plaque rupture.44

Recently, MRI has been successfully used by our group to assess coronary anatomy in patients with Kawasaki syndrome and patients with CAE (see Figure 1).45-46 This modality, together with electron beam computerised tomography (CT), may prove to be of particular value for the non-invasive prospective evaluation of CAE.

Flow Alterations Caused by CAE

Disturbances in blood flow filling and washout are an inherent characteristic of CAE, representing the direct result of inappropriate coronary dilatation and are clearly associated with the severity of CAE.10 Most notably they include angiographic signs of turbulent and stagnant flow, delayed antegrade dye filling, a segmental back flow phenomenon and local deposition of dye (stasis) in the dilated coronary segment.4,10

In a detailed study, Akyurek et al. used the Doppler wire (Flowire) to measure blood-flow velocity and coronary flow reserve in patients with isolated CAE and in a control group.47 They reported within the CAE, compared with the control group, a trend for lower resting blood flow velocity. The estimated resting absolute volumetric flow within the CAE was approximately three times higher and following intracoronary administration of papaverine, a potent hyperaemic stimulus, the coronary flow reserve was 1.51 in the CAE compared with 2.67 in the control arteries (p<0.001). This report confirmed findings using the TIMI frame count method (TFC), an invasive index of coronary flow velocity along the entire epicardial coronary artery48 and was subsequently documented non-invasively using magnetic resonance angiography.49

Interestingly, in comparison with coronary artery patients, CAE patients exhibit significantly less nitrate-mediated brachial artery dilatation, but similar flow-mediated dilatation in an ultrasonographic study.50

Prognosis in Patients with CAE

CAE accompanies atherosclerotic coronary disease in the vast majority of cases.2-4,6 Thus, the clinical presentation and the long-term cardiac complications are typical of CAD. In this patient cohort, it has been repeatedly shown that CAE do not confer an additional risk to that attributed to co-existing coronary stenoses.2-4 In the largest series from the CASS study, the presence of CAE did not affect the adjusted five-year survival of patients with CAD (75% versus 81%).2 In a more recent report corresponding to a better medical management, the two-year survival in the two groups was also similar (96.7% versus 94.8%).3

In patients with isolated CAE (with no or non-significant coronary stenoses) previous studies convincingly documented the presence of angina, positive exercise stress test and pacing-induced myocardial ischaemia.10,51 In addition, unstable coronary syndromes may occur despite the absence of stenoses. In one study, 38.7% of patients with isolated CAE reported having history of myocardial infarction (MI) in the corresponding myocardial territory.3 Cardiac event rate in this patient group appears to be low and clinical follow-up suggests a relatively favourable prognosis. As previously reported, mortality approximates 2% per year.2

Treatment

To date there are no randomised studies specifically addressing the medical management of patients with CAE. Based on the significant flow disturbances within the ectatic segments, chronic anticoagulation has been previously proposed as the main therapy.28,52 This treatment, however, has not been prospectively tested, and cannot be routinely recommended unless supported by future studies,27 although the use of anticoagulants in patients with CAE and recurrent thromboses may be reasonable. Heparin infusion as well as fibrinolysis, have been successfully used for recanalisation of acute thrombotic occlusions in CAE, occasionally revealing absence of flow-limiting stenoses.53-54

The overwhelming co-existence of CAE with obstructive coronary lesions and the observed incidence of MI, even in patients with isolated coronary ectasias, have led to the generalised administration of aspirin in all patients with CAE.2,55 The role of combined anti-platelet therapy, with the addition of ADP inhibitors, has not yet been evaluated. Medications with vasodilating properties against coronary spasm have also been proposed.28 Nitrates, presumably by causing further coronary epicardial dilation, have been shown to exacerbate myocardial ischaemia and should be avoided in patients with isolated CAE.10 It is obvious that, since CAE represent a form of atherosclerotic heart disease, intense risk factor modification for primary and secondary prevention is necessary, especially in patients with familial hypercholesterolemia.56

Percutaneous and/or surgical coronary vascularisation can safely and effectively improve myocardial perfusion in patients with co-existing obstructive lesions and symptoms or signs of significant ischaemia despite medical therapy. Ochiai et al. reported excellent acute and long-term results of balloon angioplasty in lesions adjacent to coronary aneurysms57 and these findings also agree with our clinical observations. One point of special consideration is the need for adequate stent expansion and wall apposition. This at times can be accomplished only with IVUS (see Figure 2). Although we did not encounter acute complications using the IVUS, extra care is recommended during introduction and withdrawal of the device, in order to avoid stent dislocation. The implantation of covered versus bare metal stents offers superior acute angiographic result excluding the ectatic segment, but long term benefit has not been adequately proven.58 During coronary artery bypass grafting, proximal and distal ligation, aneurysmorrhectomy and even aneurysm resection have been used to remove thrombus and to exclude large aneurysms, with uniformly good outcome.59-60 However, no prospective evaluation with control series for comparison has been carried out. From the above it can be seen that for this not so infrequent entity, diagnostic evaluation and treatment modalities are surprisingly inadequate. Ôûá

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