ABSTRACT: The diagnosis coronary artery disease is classically based on patient’s symptoms and morphology, as analyzed by angiography. The importance of risk factors for the development of coronary atherosclerosis and disturbance of coronary vasomotion is clearly established. However, microembolization of the coronary circulation has also to be taken into account. Microembolization may occur as a single or as multiple, repetitive events, and it may induce inflammatory responses. Spontaneous microembolization may occur, when the fibrous cap of an atheroma or fibroatheroma (Stary IV and Va) ruptures and the lipid pool with or without additional thrombus formation is washed out of the atheroma into the microcirculation. Such events with progressive thrombus formation are known as cyclic flow variations. Plaque rupture occurs more frequently than previously assumed, i.e., in 9% of patients without known heart disease suffering a traffic accident and in 22% of patients with hypertension and diabetes. Also, in patients dying from sudden death, microembolization is frequently found. Patients with stable and unstable angina show not only signs of coronary plaque rupture and thrombus formation, but also microemboli and microinfarcts, the only difference between those with stable and unstable angina being the number of events. Appreciation of microembolization may help to better understand the pathogenesis of ischemic cardiomyopathy, diabetic cardiomyopathy and acute coronary syndromes, in particular in patients with normal coronary angiograms, but plaque rupture detected by intravascular ultrasound. Also, the benefit from glycoprotein IIb/IIIa receptor antagonist is better understood, when not only the prevention of thrombus formation in the epicardial atherosclerotic plaque, but also that of microemboli, is taken into account. Microembolization also occurs during PTCA, inducing elevations of troponin T and I and elevations of the ST segment in the electrocardiogram. Elevated baseline coronary blood flow velocity, as a potential consequence of reactive hyperemia in myocardium surrounding areas of microembolization, is more frequent in patients with high-frequency rotablation than in patients with stenting and in patients with PTCA. The hypothesis of iatrogenic microembolization during coronary interventions is now supported by the use of aspiration and filtration devices, where particles with a size of up to 700 µm have been retrieved. In the experiment, microembolization is characterized by perfusion-contraction mismatch, as the proportionate reduction of flow and function seen with an epicardial stenosis is lost and replaced by contractile dysfunction in the absence of reduced flow. The analysis of the coronary microcirculation, in addition to that of the morphology and function of epicardial coronary arteries, and in particular appreciation of the concept of microembolization will further improve the understanding of the pathophysiology and clinical symptoms of coronary artery disease. Microembolization into the coronary microcirculation as a result of dislodgement of thrombi from injured epicardial arteries has previously been described.113,124,125 In patients with fatal ischemic heart disease, post mortem coronary angiography and autopsy procedures provided evidence of recurrent mural thrombus formation with peripheral embolization.64,143 Until recently, clinical cardiology was unable to verify the source and consequences of microembolization. New methods for the measurement of coronary20,131 and myocardial perfusion48,96,141,233,234,255 as well as for the assessment of coronary morphology59,81,157,163,168,245,254 have largely extended our knowledge. It became evident that spontaneous and induced microembolization plays an important role in the development of ischemic heart disease. This review attempts to describe the evidence from pathology for the role of plaque rupture and microembolization, its pathophysiological consequences and the clinical evidence for spontaneous and interventionally induced microembolization. Atherosclerotic lesions Plaque rupture. Plaque fissuring and plaque rupture are the causes of acute coronary syndromes — unstable angina, acute myocardial infarction, sudden death.41,42,44,75,76,185,212 Lesions with plaque fissuring and plaque ruptures are classified according to the American Heart Association (AHA) and American College of Cardiology (ACC) recommendations as Type VI lesions.212 Apparently, healthy people undergoing autopsy after cardiac death have experienced plaque rupture in 9% even at a young age,63 and in patients with diabetes plaque rupture is found in up to 22%.41 In careful pathologic-anatomic studies, ruptured plaques are usually found in more than one area.42,63 Recently, coronary angiography in acute myocardial infarction confirmed these findings; in 21% of patients, more than 1 lesion with signs of occlusion, ulceration, fissuring or filling defects could be detected, so that the authors suggested that plaque instability is not a vascular accident but a generalized coronary process.205 Complex lesions are subdivided: Type VIa: plaque ulceration; Type VIb: intramural hematoma; and Type VIc: incomplete or complete thrombus formation.212 Plaque ulceration. Type VIa is often misinterpreted by coronary angiography as coronary aneurysm,84,176,256 but represents a typical phenomenon, which has been described by Ambrose et al.12,13 Overhanging edges and scalloped borders are classified as Ambrose Type II eccentric lesions and are found in two-thirds of patients with unstable angina.12,13 Pathologic-anatomic studies confirmed that these lesions are mainly eccentric and have irregular borders,41,42,63 whereas angiography cannot visualize the intimal structure or biological features characteristic of the unstable lesion.144 Using intracoronary ultrasound, plaque rupture (Figure 1) can now be imaged.80,84,256 These studies demonstrated plaque ulcerations (Type VIa) with tears in the fibrous cap located in the center in 26% or the outer edges in 55% of patients.80 Richardson et al.185 described in their pathologic-anatomic studies centrally and eccentrically located tears in 29% and 49%, respectively. The incidence was only underestimated in superficially distributed lesions (9% versus 22%), possible due to the limited resolution of intravascular ultrasound.185 The ulcerated plaques may contain free-floating structures indicating thrombus formation.122 The exposed tissue of the plaque ulcer is a strong promoter of coronary thrombosis and contains high levels of tissue factors.16,66,229,249 Shed membrane microparticles with procoagulant potential are found, and apoptosis was suggested as a critical determinant of plaque thrombogenicity after plaque rupture.151 Of utmost importance is the finding that such plaque ruptures occur in the absence of a flow-limiting stenosis, and can even be present when coronary angiography is negative or suggestive of a normal anatomy.21 The calculated volume of plaque ulcera is in the range of 30–60 mm2, but may be as much as 1 ml in single patients.80 After washout, the plaque material is microembolized into the distal coronary circulation. Since plaque rupture appears to be truly a continuously ongoing process, multiple episodes of microembolization at different sites may occur. In pathology, multiple layering of atherosclerotic plaques is frequent, suggesting an ongoing process of rupturing and healing64 as one mechanism of progression of coronary atherosclerosis. Follow-up studies using intravascular ultrasound demonstrated healing with attachment of the fibrous cap to the vessel wall, resulting in wall thickening even within 10 days after onset of symptoms.21,83 Intermittently, the plaque ulcer may be filled up with thrombi, as illustrated recently.122 Intramural hematomas. Such hematomas are classified as Type VIb lesions.212 Hemorrhage into the plaque may be extensive and disruptive and may induce significant luminal narrowing.33,34,64 Intramural hematoma is regarded as the missing link (Figure 2) between morphology, atherosclerosis and function (spasm).11,64 Using coronary angiography, such lesions can only be detected indirectly. They may induce coronary luminal narrowing, which cannot be distinguished from coronary atherosclerotic lesions. Using intravascular ultrasound, few cases of intramural hematoma have been described.80 The sensitivity and accuracy are dependent on the resolution of intravascular ultrasound and may not be high enough to demonstrate all Type VIb lesions. According to pathologic-anatomic studies, Type VIb lesions are very common, and they may be another form of progression of coronary lesions.33,34 Occlusive or non-occlusive thrombus formation. Fissuring or rupturing of atherosclerotic plaques with thrombus formation is classified as a Type VIc lesion. This phenomenon was first described by Sinapius210 in a pathologic-anatomic study. He demonstrated ruptured plaques containing thrombus within the plaque but also protruding into the vascular lumen. Since atherosclerotic plaques are highly thrombogenic, the exposure of subintimal tissue after plaque fissure and rupture induces thrombus formation.151 Thrombi are found within the lumen of the plaque when plaque material has been washed out, and they may fill it completely. Protruding thrombi are visualized by coronary angiography as filling defects.12,13 In patients with episodes of chest pain within 24 hours of coronary angiography, an incidence of thrombosis of up to 100% has been found. In two-thirds of patients, thrombi are also present distal to the lesions, possibly as a result of turbulent blood flow, as suggested by Ambrose et al.11 Using intracoronary ultrasound, single and multiple layering of the lesion has been described and interpreted as mural thrombus formation.129 A fine granular speckled appearance and/or difference in reflectivity from surrounding tissues is typical.246 Such lesion types are predominantly seen in unstable lesions, can be explained by a closely apposed layer of thrombus, and are also found in experimental studies.129 In addition, a rough inner surface with small floating structures can be seen. Similarly, thrombus formation has been demonstrated in acute myocardial infarction, resulting in a typical speckled character when using intravascular ultrasound.27 Intravascular ultrasound has a low sensitivity but high specificity of up to 100% for the detection of mural thrombus formation.71 Mural thrombus formation may be overlooked, particularly when the ruptured plaques are completely filled with thrombi and no thrombus is protruding. Mural thrombus formation and plaque disruption can also be visualized using coronary angioscopy. In patients with recent onset angina an incidence of 100% is found, whereas in patients with a lower class of unstable angina, mural thrombus formation is less frequent.7,46,145,164,217,248 However, mural thrombus formation is even present when coronary angiography is negative.248 Coronary angioscopy appears to be more sensitive than intracoronary ultrasound and angiography for visualizing intracoronary thrombus formation.71 Peripheral coronary microembolization Previous experimental studies have demonstrated that coronary lesions in epicardial arteries can induce microembolization, resulting in severe myocardial ischemia and lethal arrhythmias.113,124,125 Microembolization has been found at autopsy in patients with acute coronary syndromes who died of sudden death.64,143 Even multiple episodes of microinfarcts secondary to atherosclerotic thromboemboli were found. Atherosclerotic material containing cholesterol crystals formed the source for thrombus formation in the microcirculation.64 Such microemboli were also detected in patients with stable angina pectoris.64 The major difference between these clinical situations was only the number of episodes. More than one episode was present in unstable angina in 87% and in stable angina in 71%, with microemboli in 53% and 43% and microinfarcts in 47% and 29% of cases, respectively,64 possibly resulting from intermittent thrombus fragmentation (Figure 2), which may be as frequent as recurrent thrombus formation.64 Recurrent embolization due to remodeling of the platelet thrombus has also been found,113,124,125 and platelet-rich thromboemboli have been demonstrated in up to 79% of patients with unstable angina and sudden death.43,73,145 In a recent study,143 thromboemboli were found at autopsy in 20% of patients with out-of-hospital death due to ischemic heart disease, and all patients in this study had an acute thrombus in the coronary artery supplying the area of myocardium containing the thromboemboli.143 Pathophysiology of microembolization With acute coronary arterial inflow reduction by an epicardial coronary artery stenosis, contractile function in the dependent myocardium is rapidly reduced.225 Within a few minutes, a new steady state of perfusion-contraction matching191 develops where regional myocardial function (demand) is reduced in proportion to regional myocardial blood flow (supply),78 and such perfusion-contraction matching can be maintained over several hours154 and may be the pathophysiologic substrate of hibernating myocardium.107 Experimental microvascular obstruction by intracoronary injection of inert particles with a diameter of 15 or 100 µm also induces regional contractile dysfunction, and the amount of dysfunction is proportionate to the number of injected particles.115,116 In contrast to an epicardial coronary arterial inflow reduction, baseline blood flow into the microembolized area is not reduced, but may actually even be enhanced secondary to an adenosine-related hyperemia of the myocardium surrounding the embolized microregions.116 Comparing an epicardial stenosis to microembolization with microspheres of 45 µm diameter at identical degrees of contractile dysfunction, we have recently demonstrated perfusion-contraction mismatch secondary to microvascular obstruction, with severe contractile dysfunction and no decrease in regional blood flow.53,188 The profound contractile dysfunction could not be related to the amount of infarcted myocardium. Therefore, the mechanical disadvantage from multiple microinfarcts (Figures 3–5) with multiple border zones to nonischemic myocardium appears to be greater than that of a single infarct of the same volume. Importantly, the inflammatory response to microembolization is also greater than the response to inflow reduction, and inflammatory mediators may contribute to the observed contractile dysfunction. Clinical scenarios with microembolization in acute coronary syndromes Unstable angina pectoris. Unstable angina is classified by Braunwald29 according to its time course and extracardiac factors. He also provided an etiological approach to management. In unstable angina, analysis of wall motion by angiography, echocardiography and nuclear medicine techniques revealed significant, transient wall motion abnormalities as signs of myocardial ischemia.10,74,91,127,182,198 Nuclear medicine studies in patients with unstable angina also demonstrated perfusion defects as well as areas with redistribution, indicating maintained viability.74,91,127,198 New markers for the detection of myocardial necrosis were recently introduced.17,98,128,175,182,187 An increase of troponin T and troponin I was found in a higher percentage than the elevation of CK and CK-MB in unstable angina, and these marker elevations are now regarded as indicators of micronecrosis.187 Positive troponin T and troponin I levels in unstable angina indicate a reduced prognosis.175,187,236 Angiographic signs of unstable angina include occlusive filling defects, irregular coronary artery contours and aneurysms. The prevalence of these signs depends on the time between start of symptoms and angiography.11,12 The degree of coronary luminal narrowing is below 50% in the majority of patients, so that a flow reduction due to coronary luminal narrowing cannot explain the onset of ischemic symptoms. In up to 15% of patients, no coronary luminal narrowing is detected.51 However, the prognosis of those with minor or no luminal narrowing has been as poor as the prognosis of those with significant luminal narrowing.51 Since significant coronary luminal narrowing cannot explain the symptoms and signs of myocardial ischemia, different pathophysiologic mechanisms must be discussed: 1. Intermittent coronary spasm enhanced by plaque rupture with activation of platelets and leukocytes and release of vasoactive mediators, such as serotonin and endothelin.9,30,70,90,162,171,213 2. Imbalance of vasoconstriction and vasodilation due to endothelial damage and dysfunction,19,88,161,171,213 which may be enhanced by plaque hemorrhage (Type VIb lesion).33,34 3. Cyclic flow variations with recurrent platelet aggregation and thrombus formation and washout.19,213 4. Thrombus formation after plaque fissuring or rupture (Type VIc lesion) which is not totally blocking the coronary artery, but may or may not embolize, as demonstrated by angioscopy and intravascular ultrasound.7,46,88,129,163,164,248 5. Plaque rupture and ulceration with microembolization of plaque debris (Type VIa lesions).21,80 All these factors are certainly involved, but according to pathologic-anatomic studies and the evidence of plaque ulceration obtained by intracoronary ultrasound, microembolization plays an important role. The development of thromboemboli after microembolization of plaque debris helps to explain why patients with acute coronary syndromes respond to treatment with glycoprotein IIb/IIIa receptor antagonists and experience a reduction of adverse cardiac events.218,222,223 The efficacy of this treatment can be explained by the reduction of thrombus formation induced by atherosclerotic material from ruptured plaques both at the site of the epicardial artery but also of the embolizing plaque particles in the microcirculation. In patients with unstable angina, elevated levels of C-reactive protein were found at discharge.22,24,148,153,159,186,230 C-reactive protein is a non-specific but sensitive marker of inflammation (Figure 3) and was observed for up to 3 months in patients admitted with severe unstable angina.148 Whereas a chlamydia pneumoniae or helicobacter infection as the source of inflammation has been proposed,24 inflammatory reactions such as an increase of eosinophiles have also been reported after microvascular embolization.40,178 Continued on next page
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