BRIEF REVIEW
Coronary microembolization
Raimund Erbel, MD, FESC, FACC* and
Gerd Heusch, MD, FESC, FACC
* Departments of Cardiology, University of Essen Medical School, Essen, Germany
Pathophysiology, University of Essen Medical School, Essen, Germany
Reprint requests and correspondence: Prof. Dr. Gerd Heusch, Abteilung fuer Pathophysiologie, Zentrum fuer Innere Medizin, Universitaetsklinikum Essen, Hufelandstr. 55, 45122 Essen, Germany
gerd.heusch{at}uni-essen.de
A series of recent studies identified coronary microembolization as a potential cause of regional myocardial contractile dysfunction in the absence of an atherosclerotic obstruction of an epicardial coronary artery that could account for such dysfunction. This review attempts to provide evidence for coronary microembolization and analyzes its sources and consequences.
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Evidence from postmortem histology
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Experimental platelet and coagulation thrombi with embolization into the coronary microcirculation and subsequent microinfarction and lethal arrhythmias in the laboratory animal were described more than three decades ago (1). Subsequently, microembolization and microinfarcts were also identified at autopsy of patients with acute coronary syndromes who had died of sudden cardiac death (2,3). Atherosclerotic material, including cholesterol crystals, formed the core and source of thrombi in the microcirculation. Often there was evidence for multiple, recurrent microinfarcts secondary to atherosclerotic thrombemboli, particularly in patients with prodromal unstable angina (2,4,5). Intramyocardial thrombemboli were identified at autopsy in 15% of patients with ischemic heart disease who died out of the hospital (3).
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Experimental pathophysiology of microembolization
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With acute coronary arterial inflow reduction by an epicardial coronary artery stenosis, contractile function in the dependent myocardium is rapidly reduced (6). Within a few minutes, a new steady state of perfusion-contraction matching (7,8) develops in which regional myocardial function is reduced in proportion to regional myocardial blood flow, and such perfusion-contraction matching can be maintained over several hours (9) and may be the pathophysiological substrate of hibernating myocardium (10). Experimental microvascular obstruction by intracoronary injection of inert particles also induces regional contractile dysfunction, and the amount of dysfunction is proportionate to the number of injected particles (11,12). In contrast to an epicardial coronary arterial inflow reduction, baseline blood flow into the microembolized area is not reduced, but may actually be enhanced, secondary to an adenosine-related hyperemia of the myocardium surrounding the embolized microregions (11,12). Comparing an epicardial stenosis to microembolization with microspheres of 42 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 detectable decrease in regional blood flow (13,14). The profound contractile dysfunction could not be related to the amount of infarcted myocardium. Therefore, the mechanical disadvantage from multiple microinfarcts (Fig. 1) 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 that to inflow reduction, and inflammatory mediators may contribute to the observed contractile dysfunction.
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Figure 1 Experimental microinfarct with inflammatory response in a myocardial area perfused by a small artery that has been embolized with microspheres of 42 µm in diameter. Calibration 50 µm.
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Cyclic flow variations are a typical phenomenon in severely stenotic coronary arteries, with the progressive flow reduction reflecting the formation of platelet aggregates and its rapid restoration, reflecting dislodgement of platelet emboli into the microcirculation (15,16).
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Clinical evidence
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New imaging techniques, in particular coronary angioscopy and intravascular ultrasound, have facilitated the detection of epicardial coronary plaque rupture and ulceration (17–21). Plaque ulceration, previously often misinterpreted as coronary aneurysm (17), is frequently found in patients with unstable and stable angina (22,23) but also occasionally in patients with a normal coronary angiogram (24). Apparently, plaque rupture and ulceration are frequent events and part of the general atherosclerotic process, as confirmed at autopsy (22,23). The material that is washed out of the plaque cannot only induce local thrombus formation in the immediate coronary arterial segment but is also dislodged into the microcirculation and can cause thrombemboli there (2). The elevations in creatine kinase (CK), troponin T and I, which are regarded as signs of micronecrosis in patients with unstable angina, may just be the consequences of such microembolization (25,26). Conversely, the efficacy of glycoprotein IIb/IIIa receptor antagonists in this scenario and in acute myocardial infarction (26) may not only reflect resolution of the thrombus overlying the ruptured epicardial plaque but also that of the thrombemboli in the microcirculation (27). Interestingly, as in the above experimental studies, inflammatory responses are also found in patients with unstable angina (28), in patients with successful percutaneous transluminal coronary angioplasty (29) and in documented cases of microembolization (30).
Not only in spontaneous plaque rupture and ulceration, but also during coronary interventions, microembolization is, in fact, induced, again leading to myocardial micronecrosis, as reflected by elevated CK and troponin (31,32) as well as by electrocardiogram changes (32) and to reduced coronary reserve, as documented with myocardial perfusion measurements (33). The incidence of such "infarctlets" is higher in those undergoing rotational atherectomy/revascularization than it is in those undergoing balloon angioplasty (34,35). Cyclic flow variations, as seen in animal experiments (15,16), are a sign predicting immediate complications after angioplasty (36). Interestingly, patients without normalization of coronary reserve after balloon angioplasty often have elevated baseline coronary flow velocity (33,37,38), reminiscent of the reactive hyperemia seen with experimental microembolization (11,12).
The best available clinical evidence for microembolization is probably from use of aspiration and filtration devices, that is, "ex iuvantibus," which can retrieve surprisingly large pieces of plaque debris and thrombotic material and prevent it from being embolized into the microcirculation (39,40).
In conclusion, putting the available pathologic "anatomic, experimental" pathophysiologic and clinical evidence together, we propose the following scheme (Fig. 2) of plaque rupture/thrombosis/microembolization, that ultimately induces the clinical consequences of arrhythmias "up to sudden death" and, most notably, contractile dysfunction.
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Figure 2 Schematic presentation of epicardial plaque fissuring/plaque rupture/thrombosis inducing embolization of atherosclerotic and thrombotic material into the microcirculation, resulting in arrhythmias, micronecrosis, contractile dysfunction and reduced coronary reserve (modified from reference 41).
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Footnotes
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The author’s studies were supported by the German Research Foundation (E 155/4-2) and the IFORES grant 107509-0 of the University of Essen Medical School, Essen, Germany.
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Top
Evidence from postmortem...
Experimental pathophysiology of...