The term “coronary instability” commonly refers to the sequence of events that lead from plaque erosion or rupture to the occurrence of acute coronary syndromes (ACS). However, evidence indicates that coronary microvascular dysfunction plays a relevant pathophysiologic and prognostic role in the setting of ACS, both in ST-segment elevation myocardial infarction and in non–ST-segment elevation ACS. Our group have recently demonstrated that Tako-Tsubo syndrome, which clinically mimics ACS, is sustained by a common pathophysiologic mechanism represented by reversible coronary microvascular dysfunction. Given this evidence, we propose a reappraisal of the concept of coronary instability, extending this notion from the dramatic event represented by plaque erosion or rupture to a more diffuse process that can acutely affect each segment of the coronary circulation.
The term “coronary instability” usually refers to the sequence of events that lead to acute coronary syndromes (ACS). At a certain unpredictable moment of its life span, an atherosclerotic plaque becomes unstable. This definition commonly implies the mechanical disruption of the fibrous cap of the plaque, a process driven mainly by inflammatory cell activation and degranulation and the consequent exposure of prothrombotic substances to circulating blood. ACS ultimately take place when the superimposition of coronary thrombosis reduces coronary blood flow at rest. The paradigm of the coronary arteries as passive conduit pipelines was first challenged by the demonstration of epicardial coronary artery vasospasm. In the past few years, however, the dynamic behavior of coronary circulation has been extended to the microcirculatory district. Specifically, coronary microvascular dysfunction (CMD) has been found to be involved in several cardiac diseases, ranging from those with chronic clinical presentations, such as microvascular angina, hypertensive cardiomyopathy and dilated and hypertrophic cardiomyopathy, to those with sudden unstable clinical onset, from ACS, with their wide spectrum of presentations, to takotsubo syndrome (TTS). The aim of this editorial is to reappraise the concept of coronary instability, extending this notion from the dramatic event represented by plaque instability to a more diffuse process in which coronary microcirculation may play a primary pathogenetic role.
Microvascular Dysfunction in ST-Segment Elevation Myocardial Infarction
ST-segment elevation myocardial infarction (STEMI) represents the most dramatic clinical presentation of coronary instability. The sequence of events that takes place in epicardial coronary arteries has been extensively investigated. Prothrombotic stimuli are unleashed by the unstable plaque, leading to platelet activation and aggregation, together with the consequent activation of coagulation cascade. The tight mesh of aggregated platelets and fibrin then traps circulating cells, mainly red cells, to completely occlude the coronary lumen. As consequence, the persistent lack of nutritive flow to downstream myocardium causes transmural ischemia and necrosis.
In the setting of STEMI, however, the event of coronary thrombosis is part of a more complex pathophysiologic scenario in which CMD plays a key pathogenetic and prognostic role. This notion is clearly demonstrated by the observation that although primary percutaneous coronary intervention (PCI) can restore anterograde flow in the infarct-related coronary artery, such recanalization is not necessarily followed by effective myocardial perfusion. This condition, known as the “no-reflow” phenomenon, occurs in about 40% of patients with STEMI who undergo successful primary PCI, is the result of microvascular obstruction and is associated with worse outcomes. The underlying mechanisms are complex and probably multifactorial, including distal embolization of fibrin or platelets, leukocyte intravascular plugging, tissue edema, and microvascular spasm.
The status of coronary microcirculation can be invasively assessed at the time of primary PCI and elevated microvascular resistance soon after the recanalization of the culprit vessel has recently been found to predict final infarct size. However, microvascular obstruction is dynamic, since the sequential assessment of myocardial perfusion by myocardial contrast echocardiography has allowed to show that myocardial perfusion detected 24 hours after successful PCI spontaneously improves in approximately 50% of patients. Given this observation, microvascular obstruction has been categorized as “sustained” or “reversible.” The former is the result of the anatomic irreversible damage of coronary microvessels, whereas the latter is mainly attributable to functional changes in the microcirculation. Among functional alterations, vasoconstriction is likely to play a key role. Indeed, experimental models have shown that the rupture of atherosclerotic lesions leads to a rapid and marked increase in distal vascular resistance as consequence of severe microvascular vasoconstriction. Coronary plaques can release potent vasoconstrictors, including endothelin-1 and tissue factor. Of note, endothelin antagonists administered at the time of reperfusion has been shown to significantly decrease postischemic microvascular no-reflow and increase myocardial thickness in the canine model.
In the setting of STEMI, CMD is not limited to the territory of the infarct-related artery but also involves the remote myocardium. Using positron emission tomography in a group of patients with STEMI and single-vessel disease, Uren et al documented that coronary microvascular response to dipyridamole was impaired soon after the episode, showing a progressive improvement over time also in myocardial regions not supplied by culprit coronary arteries.
Finally, transient ST-segment elevation during spontaneous or provoked angina has been reported in Japanese patients with normal coronary arteries and angina attacks at rest. Although the simultaneous occurrence of episodes of vasospastic and microvascular angina has been reported, intracoronary acetylcholine in these patients reproduced angina and ST-segment changes in the absence of epicardial spasm, thus suggesting coronary microvascular spasm leading to transmural ischemia.
Microvascular Dysfunction in Non–ST-Segment Elevation Acute Coronary Syndromes
The involvement of CMD is important also in the setting of non–ST-segment elevation ACS. The finding of normal or near normal coronary arteries in case of suspected non–ST-segment elevation ACS is relatively frequent, ranging from 5% to 30%. In the absence of other causes, such as coronary spasm, spontaneously recanalized coronary thrombosis and myocarditis, primary CMD may play a key pathogenetic role. For instance, Beltrame et al found that non–ST-segment elevation ACS were the admission diagnoses in almost 3/4 of patients showing slow coronary flow on angiography. The involvement of CMD in non–ST-segment elevation ACS is also suggested by experimental and clinical findings where, challenging the traditional model of coronary blood flow control, severe microcirculatory vasoconstriction rather than vasodilation during spontaneous or demand-induced ischemia has been demonstrated. To separate the pathogenetic role of epicardial arteries and of coronary microcirculation in patients with unstable angina, Marzilli et al found that episodes of transient myocardial ischemia at rest were associated with a marked increase in coronary microvascular resistance and that this increase was prevented by the administration of antiplatelet drugs.
Inflammation may play a primary role in increasing coronary microvascular resistance. In patients with unstable angina, Neri Serneri et al elegantly demonstrated an acute inflammatory process involving the coronary microvessels but not the cardiomyocytes. Again, CMD is not limited to the region supplied by the culprit coronary vessel. Indeed, challenging the traditional construct that CMD might be a consequence of the downstream spread of immunogenic material or vasoactive substances from ruptured plaques, it has been convincingly shown that CMD is widespread, and its degree is proportional to systemic levels of C-reactive protein, a prototypical marker of inflammation, independently of traditional coronary risk factors.
Microvascular Dysfunction in Non–ST-Segment Elevation Acute Coronary Syndromes
The involvement of CMD is important also in the setting of non–ST-segment elevation ACS. The finding of normal or near normal coronary arteries in case of suspected non–ST-segment elevation ACS is relatively frequent, ranging from 5% to 30%. In the absence of other causes, such as coronary spasm, spontaneously recanalized coronary thrombosis and myocarditis, primary CMD may play a key pathogenetic role. For instance, Beltrame et al found that non–ST-segment elevation ACS were the admission diagnoses in almost 3/4 of patients showing slow coronary flow on angiography. The involvement of CMD in non–ST-segment elevation ACS is also suggested by experimental and clinical findings where, challenging the traditional model of coronary blood flow control, severe microcirculatory vasoconstriction rather than vasodilation during spontaneous or demand-induced ischemia has been demonstrated. To separate the pathogenetic role of epicardial arteries and of coronary microcirculation in patients with unstable angina, Marzilli et al found that episodes of transient myocardial ischemia at rest were associated with a marked increase in coronary microvascular resistance and that this increase was prevented by the administration of antiplatelet drugs.
Inflammation may play a primary role in increasing coronary microvascular resistance. In patients with unstable angina, Neri Serneri et al elegantly demonstrated an acute inflammatory process involving the coronary microvessels but not the cardiomyocytes. Again, CMD is not limited to the region supplied by the culprit coronary vessel. Indeed, challenging the traditional construct that CMD might be a consequence of the downstream spread of immunogenic material or vasoactive substances from ruptured plaques, it has been convincingly shown that CMD is widespread, and its degree is proportional to systemic levels of C-reactive protein, a prototypical marker of inflammation, independently of traditional coronary risk factors.
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