Coronary artery ectasia (CAE) is frequently considered an incidental finding during coronary angiography, however, several reports have shown an association with myocardial ischemia and infarction. When acute myocardial infarction (AMI) occurs in cases of CAE, current reperfusion therapies, due to the large arterial size and the massive intracoronary thrombus, when used alone are limited in preventing the development of distal embolization and ‘no reflow phenomenon.’ In this article, we described the case of a multiple sclerosis (MS) patient with diffuse CAE and ST elevation AMI, treated by coronary dethrombosis multistrategy (mechanical and pharmacologic) during a transradial primary angioplasty. The higher thrombotic burden in MS with CAE was analyzed and possible common pathophysiologic pathways were discovered in the imbalance between proteolytic activities of metalloproteinases and endogenous tissue inhibitor, with subsequent increased proteolysis leading to a risk for coronary plaque rupture. The one-year clinical and angiographic follow-up with coronary computed tomography (CT) angiography, together with long-term antiplatelet therapy, was also evaluated.
Coronary thrombosis is the leading cause of ST elevation acute myocardial infarction (AMI). Related to a more frequent platelets abnormalities and ‘floating’ growing thrombi, distal embolization often occur during primary percutaneous coronary intervention (PCI) stenting1,2 especially in coronary artery ectasia (CAE), causing a large variability in coronary flow pattern. This variability is related to a wide spectrum of coronary flow encountered from thrombolysis in myocardial infarction 3 (TIMI 3) to ‘no reflow phenomenon’ resulting in different degrees of myocardial perfusion impairment and/or recovery. In fact, in order to minimize the distal embolization pharmacologic and mechanical coronary dethrombosis strategy are used differently, alone or in association, in the setting of primary PCI.3 Moreover, no data are found about the best strategy of revascularization and the safety and efficacy in the concomitant use of different dethrombosis especially in this particular subset of patients with coronary ectasia during primary transradial PCI.4–7
The most commonly used angiographic definition of CAE, albeit arbitrary, is the diameter of the ectatic segment being more than 1.5 times larger, compared with an adjacent healthy reference segment. However, as the distribution of CAE is quite variable and not always focal, normal reference segments may not be readily apparent, and this definition potentially underestimates the true incidence of the disease.8 Moreover, there is an overlap between CAE and coronary aneurysm, likely expressions of the same pathologic process. Owing to a lack of a uniform definition, the terms ‘ectasia’ and ‘aneurysm’ have been used inaccurately and regardless of coincident coronary artery stenosis, suggesting the difference in the incidence of CAE reported. The right coronary artery is the most commonly affected, followed by the left circumflex or left anterior descending artery. Three-vessel or left main involvement is rare.8
Current knowledge on the epidemiology and natural history of coronary ectasia derives from several large angiographic series, where patients have been divided according to the presence or absence of the atherosclerotic lesion. Although the clinical presentation and the long-term cardiac complications are mostly associated with the severity of the co-existing coronary lesions, in the subset of CAE patients without coronary stenosis the mechanisms that are likely related to acute coronary syndromes are spasm occurrence within the CAE or at its borders, thrombus formation in ectatic segment in the presence of flow disturbances together with possible distal microembolization. In CAE, MI is caused by repeated distal dissemination of microemboli or by in situ thrombosis of the dilated vessel.
Recent studies have also suggested that the ectatic wall may be a source of thrombogenic substances;9 also an increased prevalence of circulating anti-endothelial cell antibodies provides the evidence of a possible role of autoimmunity in certain cases of CAE.10 Flow alterations in particular ‘slow flow’ are an inherent characteristic of CAE and this has been directly evaluated,11 using the Doppler wire to measure blood flow velocity and coronary flow reserve in patients with isolated CAE. Moreover, several studies12 demonstrated that presence of CAE was associated with higher TIMI frame count, indicating slower coronary flow. It is interesting that a significantly lower myocardial blush grade was observed in patients with CAE despite brisk epicardial flow, thereby suggesting a significant microvascular impairment.13 The main histologic features of CAE are lipid deposition with foam cells, fibrous caps, and extensive destruction of musculoelastic elements of the media; these findings are similar to those described for aortic aneurysms but the two forms of disease are not always associated.
Although the molecular mechanism underlying coronary ectasia has yet to be elucidated, several studies suggest the pivotal role of the increased level of metalloproteinases (MMPs), which are actively involved in the proteolysis of the extracellular matrix proteins. In fact, differing from patients with obstructive coronary lesions, CAE patients have a higher percentage of the 5A/5A polymorphism of the metalloproteinase-3 (MMP-3) causing an imbalance between MMPs and their endogenous tissue inhibitors.14
Matrix MMPs are also implicated in blood–brain barrier (BBB) disruption, and in degradation of extracellular matrix proteins and myelin components that are the major finding of the pathogenesis of multiple sclerosis (MS). In particular an imbalance in levels of MMPs and tissue inhibitors of MMP (TIMP) has been implicated in the pathogenesis of MS, an inflammatory, demyelinating disease of the central nervous system (CNS), with BBB breakdown. Since monocytes form a major cell population in acute MS lesions and may facilitate their entrance into the CNS by secretion of MMP. In fact, previous studies show that MS is associated with elevated levels of MMP and TIMP expressing blood monocytes that may contribute to MS pathogenesis.15–17 This increased proteolysis could theoretically predispose to an increased risk for plaque rupture and a subsequent acute coronary event with a diagnosis made at the time of urgent angiography. However, when AMI occurs in a case of CAE, current reperfusion therapies (thrombolysis, primary stenting, manual thrombectomy) due to the large arterial size and a massive intracoronary thrombus, when used alone, are limited in terms of preventing the development of distal embolization and the ‘no reflow phenomenon.’
A 45-year-old man, with hypercholesterolemia and MS was admitted to our emergency department for a chest pain lasting two hours and ST segment elevation on D2-D3-aVF-V5-V6 D1- and aVL leads. After a loading dose of 300 mg of aspirin, 600 mg of clopidogrel, and a 5,000 IU bolus dose of unfractioned heparin (UFH) the patient was transferred in the catheterization laboratory in order to perform an urgent coronary angiography. The coronary angiography showed: left main, normal without significant narrowing; anterior descending and circumflex arteries, large vessels with diffuse ectasia without significant narrowing (see Figure 1); right coronary artery (RCA), dominant vessel: diffuse ectasia with large thrombotic endoluminal involvement in the middle segment (TIMI 1, Thrombus Score 2); and occlusion of a large acute lateral branch (TIMI 0) (see Figure 2A).
Engagement of the right coronary artery was performed using a Judkins Right 4 (6 French-Mach1 Boston Scientific) guiding catheter via transradial left approach. A Balance Middle Weight 0.014 inch (Abbott) guidewire was used to cross the occlusion of acute lateral branch persisting after distal positioning of the wire. An embolic protection device (Filter Wire EZ-Boston Scientific Corp., 2011 Stierlin Court, Mountain View, CA 94043-4655 US) was positioned in the distal segment of the right coronary artery to minimize distal embolization (see Figure 2B). In order to manage the high thrombotic burden in a very large and ectatic coronary vessel (quantitative coronary angiography [QCA] of proximal segment: 7.1 mm), multiple thrombus aspirations were performed (total = 4) with Export XT Catheter (Medtronic Inc., 710 Medtronic Parkway Minneapolis, US) (see Figure 2B) followed by an intracoronary locally delivered injection of a 10 ml abciximab (ReoPro, Eli Lilly) bolus across a rapid exchange therapeutic perfusion catheter (Clear Way RX, Atrium Medical Corp, New Hampshire, US) (see Figure 2C). Considering the thrombotic burden and vessel size, we decided to perform a plain old balloon angioplasty (POBA) with simultaneous inflation (kissing-balloon) of 4.0 x 15 mm balloon (Apex, Boston) in coronary artery and 3.0 x 15 mm (Riujin Plus, Terumo) in the acute marginal branch (see Figure 2D).
After filter removing, the angiograms showed a final TIMI 3 flow/myocardial blush grade 3/Thrombus Score 1 (see Figure 3A). A large amount of thrombus was found in the basket of the filter. Ninety minutes after the procedure the electrocardiogram (ECG) showed a complete ST resolution with a T-wave inversion on D2-D3-aVF and V5-V6 leads. A 12-hour abciximab endovenous infusion was performed, followed by clopidogrel 75 mg per day and aspirin 100 mg per day.
The creatine kinase-MB (CK-MB) and troponin I (TnI) peak was reached six hours after procedure (CK-MB = 110 UI; TnI = 11 ngr/l). At day three, an angiographic control was performed in order to exclude thrombus persistence after mechanical and pharmacologic dethrombosis, it showed an excellent angiographic result. In hospital, the clinical outcome was uncomplicated, an echocardiogram before discharge showed an inferior ipokinesia and 0.53 ejection fraction. The patient was discharged on double antiplatelet regimen (aspirin 100 mg plus clopidogrel 75 mg). One year later, after one month of clopidogrel discontinuation, an angiographic follow-up with multislice-computed tomography scan was performed confirming the excellent long-term angiographic result (see Figure 3B).
Thrombus distal embolization is not an infrequent complication during primary PCI1 and it more relevant in patients with CAE more frequently presenting platelets reactivity abnormalities and large thrombus burden. Actually, there are different pharmacologic and mechanical dethrombosis strategies, in order to minimize distal embolization, these can be used alone or in association in the setting of primary PCI. Moreover, no data are found about the best strategy in terms of microcirculatory preservation, safety, and efficacy in cases of concomitant use of different dethrombosis strategy, especially in the subset of patients with CAE.
The elevation of many serologic markers (hsCRP, Il-6, V-CAM, I-CAM, and E-selectin) is described in association with CAE suggesting a pathophysiologic role of inflammation. In particular, although the molecular mechanism underlying CAE has not yet been elucidated, several studies suggest the pivotal role of increased level of MMPs. In fact, compared with patients with obstructive coronary lesions, CAE patients have a higher percentage of the 5A/5A polymorphism of the MMP-3 causing an imbalance between MMPs and their endogenous tissue inhibitors (TIMP). Matrix MMPs are also implicated in BBB disruption, and in degradation of extracellular matrix proteins and myelin components that are the major findings in the pathogenesis of MS. In particular an imbalance in levels of MMPs/TIMP of derived-by blood monocytes has been implicated in the pathogenesis of MS. We speculate that in our patients CAE and MS share possible common pathophysiologic pathways in the imbalance between MMPs and TIMP with increased proteolysis leading to a risk for plaque rupture and subsequent acute coronary event.
Although patients with aneurysms and atherosclerotic disease were much more likely to undergo percutaneous transluminal coronary angioplasty with successful stent implantation,18 the patients with CAE are less frequently treated with stent implantation. The principal reason is related to difficulties in determining the real extent of coronary involvement. In fact, even if large, the focal localization of the aneurysm, is more suitable for stent implantation with effective aneurismal lumen exclusion: many case series have reported the feasibility and safety of a graft-coated stent for the treatment of coronary aneurysm during a primary PCI.19 Conversely, the presence of diffuse CAE, despite intravascular ultrasound (IVUS) guidance, is related to an inability to detect a healthy/normal segment in which a stent can be safely implanted;20 for this reason we decided to perform a plain old balloon angioplasty with ‘kissing’ technique (double-balloon inflation) to provide a better thrombus remodeling at the bifurcation carena.
Owing to the large arterial size and to the massive intracoronary thrombosis, current reperfusion therapies (thrombolysis, primary stenting, manual thrombectomy), if used alone, cannot prevent the development of distal embolization and the ‘no reflow phenomenon.’ Therefore, a dethrombosis multistrategy is needed, as demonstrated in this case report. The transradial approach, as known, is associated with a lower rate of bleeding complications affecting the prognosis in patients with an acute coronary syndrome. This case report demonstrates the feasibility and efficacy of a sequential dethrombosis multistrategy (thrombus aspiration, filter wire, abciximab intracoronary infusion) with a 6 French guiding catheter transradial approach. Contrary to atherosclerotic coronary artery disease, there are poor data adequately addressing the medical management of coronary artery ectasia, the viewpoints about use of long-term anticoagulation are contradictory and optimal antithrombotic treatment guidelines have not been well established. The use of post-procedural dual antiplatelet regimen (aspirin plus clopidogrel) for a follow-up period of one year was clinically and angiographically effective confirming in this case report the anti-thrombotic preventive role of antiplatelet therapy alone. As with patients with other coronary anomalies or coronary artery bypass grafts, the coronary CT angiography is a valid and suitable alternative to coronary angiography, for performing the angiographic follow-up of patients with coronary ectasia.
- Henriques JP, Zijlstra F, Ottervanger JO, et al., Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction, Eur Heart J, 2001;141:353–9.
- Grines CL, Cox DA, Stone GW, et al., Coronary angioplasty with or without stent implantation for acute myocardial infarction, N Engl J Med, 1999;341:1949–56.
- Petronio AS, Rovai D, Musumeci G, et al., Effects of abiciximab on microvascular integrity and left ventricular functional recovery in patients with acute infarction treated by primary coronary angioplasty, Eur Heart J, 2003;24:67–76.
- Burzotta F, Testa L, Giannico F, et al., Adjunctive devices in primary or rescue PCI: a meta-analysis of randomized trials, Int J Cardiol, 2008;123:313–21.
- Svilaas T, Vlaar PJ, van der Horst IC, et al., Thrombus aspiration during primary percutaneous coronary intervention, N Engl J Med, 2008;358:557–67.
- Vlaar PJ, Svilaas T, Vlaar PJ, et al., Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study. (TAPAS): a 1 year follow-up study, Lancet, 2008;371:1915–20.
- Burzotta F, Trani C, Romagnoli E, et al., Feasibility of sequential thrombus aspiration and filter distal protection in the management of very high thrombus burden lesions, J Invasive Cardiol, 2007;19(8):317–23.
- Markis JE, Joffe CD, Cohn PF, et al., Clinical significance of coronary arterial ectasia, Am J Cardiol, 1976;37(2):217–22.
- Bernard F, Revel F, Monsegu J, et al., Coronary vessel ectasia: Coronary artery disease with high tromboembolic risk, Ann Cardiol Angiol, 1998:47(3):160–4.
- Katritsis DG, Zografos T, Korovesis S, et al., Antiendothelial cell antibodies in patients with coronary artery ectasia, Coron Artery Dis, 2010;21(6):352–6.
- Akyurek O, Berkalp B, Sayin T, et al., Oral D. Altered coronary flow properties in diffuse coronary artery ectasia, Am Heart J, 2003;145:66–72.
- Papadakis MC, Manginas A, Cotileas P, et al., Documentation of slow coronary flow by the TIMI frame count in patients with coronary ectasia, Am J Cardiol, 2001;88(9):1030–2.
- Gulec S, Atmaca Y, Kilickap M, et al., Angiographic assessment of myocardial perfusion in patients with isolated coronary artery ectasia, Am J Cardiol, 2003;91(8):996–9.
- Lamblin N, Bauters C, Hermant X, et al., Polymorphisms in the promoter regions of MMP-2, MMP-3, MMP-9 and MMP-12 genes as determinants of aneurysmal coronary artery disease, J Am Coll Cardiol, 2002;40(1):43–8.
- Kermode AG, Thompson AJ, Tofts P, et al., Breakdown of the blood brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis, Brain, 1990;113:1477–89.
- Clements JM, Cossins JA, Wells GM, et al., Matrix metalloproteinase expression during experimental autoimmune encephalomyelitis and effects of a combined matrix metalloproteinase and tumor necrosis factor-alpha inhibitor, J Neuroimmunol, 1997;74:85–94.
- Chandler S, Miller KM, Lury J, et al., Matrixmetalloproteinases, tumor necrosis factor and multiple sclerosis: an overview, J Neuroimmunol, 1997;72:155–61.
- Yip HK, Chen MC, Wu CJ, et al., Clinical features and outcome of coronary artery aneurysm in patients with acute myocardial infarction undergoing a primary percutaneous coronary intervention, Cardiology, 2002;98(3):132–40.
- Burzotta F, Trani C, Romagnoli E, et al., Percutaneous treatment of a large coronary aneurysm using the self-expandable symbiot PTFE-covered stent, Chest, 2004;126(2):644–5.
- Ochiai M, Yamagushi T, Tagushi J, et al., Angioplasty of stenoses adjacent to aneurysmal coronary artery disease, Jpn Heart J, 1990;31:749–57.