Cyclic coronary flow: defining preinfarction angina at the crossroads of unstable angina and myocardial infarction
Mitchell W. Krucoff, M.D., F.A.C.C., F.C.C.P.

Dr. Krucoff is associate professor of medicine, Duke University Medical Center, and director, Ischemia Monitoring Laboratory, Duke Clinical Research Institute.

From unstable angina as coronary insufficiency to preinfarction angina as cyclic coronary occlusion

Many of the clinical terms widely used to depict unstable coronary syndromes such as accelerated angina, unstable anigina, preinfarction angina, and even myocardial infarction (MI), have come into common usage without precise pathophysiolgic understanding or definition. Recent pathologic, angiographic, and rheological observations have begun to elucidate both the shared and the unique features of mechanisms underlying unstable coronary syndromes. These insights taken together suggest that the unstable coronary syndromes broadly represent an acute phase in the chronic process of atherosclerosis that is characterized by lipid-laden plaque rapture with concomitant coronary spasm, platelet activation and aggregation, and thrombus formation. The mechanical effects of these "acute-on-chronic" changes superimpose nonatheromatous obstruction onto the already existing plaque, producing sudden severe reductions of coronary flow and clinical symptoms that are independent of exertion (ie, angina with minimal exertion or at rest).

Endogenous responses to these acute processes frequently include localized secretion of metabolic by-products with vasodilator antioxidant and thrombolytic substances that act to reverse spasm and dissolve thrombus. The interaction between these responses and the initial acute-on-chronic insults produce a highly dynamic syndrome characterized by intermittent severe coronary narrowing, clinically expressed as "waxing and waning" or "stuttering" rest angina.

The progression from the dynamic coronary narrowing that produces unstable angina to the sustained total coronary occlusion that characterizes MI is intuitively perceived by many clinicians as a two-stage sequence of events. MI is diagnosed by ST-segment elevation on a static electrocardiogram (ECG), while rest pain with any other ECG findings is considered unstable angina. Similarly, interruption of infarction is widely perceived as a single-index event, reperfusion, that either happens or doesn't. This perception developed historically from early angiographic observations of total coronary occlusion and the restoration of antegrade coronary flow, or reperfusion, with the use of intracoronary thrombolytic agents.1,2 However, even reports at that time observed that about 20% of patients presenting with ST elevation and chest pain had TIMI 3 flow with resolution of their ECG changes and their pain by the time the coronary catheter was in place.1-3 This suggested to us that even in the presence of myocardial necrosis, a dynamic, endogenous battle between platelet, thrombus, and spasm-inducing factors, and endogenous, vasodilating, and clot-dissolving factors appeared to be in evidence in a nontrivial cohort of patients. With a greater understanding of this dynamic component, both diagnostic and therapeutic implications emerge.

Even as the MI diagnosed by ST elevation on a static ECG and imaged briefly during coronary angiography led to the dichotomous vision of an occluded or reperfused infarct artery, the response to therapy and relationships between infarct artery patency, ventricular function recovery, and clinical outcome were also simplistically conceived. However, the data produced relative to such questions were anything but simple. As time from onset of chest pain to diagnosis and treatment has been reduced with the advent of intravenous thrombolytic therapy and dedicated chest pain centers (CPCs), the relationships between the use of lytic therapy and clinical outcomes has strengthened. Paradoxically, the relationships between drug therapy, coronary patency, ventricular function, and clinical outcome seemed to grow more complex over that same literature.

Continuous ST-segment monitoring, first performed on uncalibrated bedside monitors4,5 and later with dedicated ischemia-monitoring technologies,3,6-8 has provided a unique tool from which observations have begun to shed light on the divergence between earlier thrombolytic therapy, infarct artery patency, and clinical outcome. These insights include two general areas: recognizing the differences in ECG patterns as coronary flow reduction progresses to complete coronary flow obstruction; and documenting the dynamic behavior of the infarct artery, or cyclic coronary flow, prior to the evolution of persistent coronary occlusion. Together these two genres of observation could be considered a more precise means with which to define the transition from unstable angina to MI through the bridge that we propose defines true preinfarction angina Ñ a transition that is ambiguous or virtually transparent when assessed clinically or with static tools like the ECG or angiography.

ECG behavior with reduced coronary flow versus transient coronary occlusion: recognizing preinfarction angina

In Figure 1 continuously monitored 12-lead patterns of ischemia from an elective coronary angioplasty of a single coronary site in an individual are shown.9 With inflation of a standard balloon in the left anterior descending coronary, for even periods of 40 to 60 seconds, anterolateral ST-segment elevation is produced. When the standard balloon is changed to a perfusion balloon, which allows some antegrade flow even when the balloon is inflated, the ischemia in the same individual from the same coronary site is manifest on the ECG by inferolateral ST-segment depression. This ECG difference between insufficient flow and no-flow states provides an objective means of discriminating patients with significant reduction in coronary flow, which produces angina at rest and ST-segment depression on ECG, that is, patients with unstable angina from patients with transient total interruption of coronary flow, which also produces angina at rest but in association with transient ST-segment elevation on ECG, that is, patients with preinfarction angina.

Describing patients who present with cyclic coronary flow as having preinfarction angina may itself be a misnomer, as frequently the cumulative insult and duration of these occlusions when they occur spontaneously is sufficient to produce some myocardial necrosis. Such a patient is illustrated in Figure 2 with rapid oscillating ST-segment elevation in the inferior leads, suggesting cyclic changes in coronary flow. The earliest changes in this recording were spontaneous. The later, labeled changes were the result of balloon angioplasty inflations after initial angiography showed an occluded right coronary artery. All the changes shared the identical precordial ECG pattern or "fingerprint"10 of occlusion in the one site in the right coronary. While no occlusion period was longer than 10 minutes, serum CPK enzymes were elevated. These patients may also be more vulnerable to progression from intermittent to sustained coronary occlusion, as illustrated by the patient in Figure 3. Earlier diagnosis and treatment, more cyclic flow presentations

Continuous ST-segment recording suggesting cyclic coronary flow in MI patients was realtively rare in the era of intracoronary thrombolytic therapy, occurring in 10% to 20% of MI patients. More recent reports have observed this kind of ST-segment oscillation in 30% to 50% of MI patients.7,11,12 Over the time period of these observations the route of delivery of thrombolytic agents changed from intracoronary to intravenous and emergency departments began developing dedicated CPCs. Combined, these two developments significantly reduced the time from chest pain onset to diagnosis and treatment of patients with unstable coronary syndromes. We consider it more than coincidental that as the time to diagnosis and therapy drop, the incidence of cyclic coronary flow observed rises. From our observations it would seem likely that cyclic coronary flow or preinfarction anginal syndrome is in fact the earliest stage of the more irreversible insults that characterize MI: sustained coronary thrombosis and myocardial necrosis. Clinically, this is evidenced by the frequency with which early presentations are associated with waxing and waning or stuttering chest pain symptoms.

Imputing the mechanisms of cyclic coronary flow and therapeutic implications

While the continuously monitored ECG in patients with angina at rest may identify those who have dynamic ST elevations from transient coronary occlusion, the ECG changes are nonspecific when it comes to mechanism per se. Coronary occlusion, whether by balloon inflation, platelet thrombus, fibrin rich thrombus, or coronary spasm, produces ST-segment elevation.

As nonspecific as such changes may intrinsically be, demonstration of their disappearance in association with a mechanistically specific agent provides important mechanistic insights. Early evidence that transient coronary occlusion sometimes responded or failed to respond to intracoronary infusion of nitrates or of streptokinase when dynamic ST-segment activity was observed suggested that both local coronary spasm and local thrombosis play a role in the earliest stages of MI.4,5 The early use of nitrates and of thrombolytic agents for patients with ST elevation and chest pain has since become a standard of clinical practice. Interestingly, in the more modern era of early diagnosis and therapy of MI patients, cyclic flow continues to be demonstrated in about 30% of patients treated with both nitrates and thrombolytics.11-13 In the context of prospective randomized clinical trials we have seen a significant further reduction of such dynamic activity with the use of highly potent parenteral antiplatelet data,14,15 suggesting that platelet activity is a unique and powerful element in the transition from unstable angina to MI.

Thus, the definition of true preinfarction angina with the use of continuous ECG characterization may provide the means to differentiate a subgroup of patients with chest pain at rest who are at very high risk of going on to persistent coronary occlusion and MI.

Theoretically, based on recent observations, the treatment of such patients might focus first on the use of nitrates and intensive antiplatelet therapy, reserving the more risk-laden thrombolytic agents for more persistent coronary occlusions. Optimal application of such theory will need to be defined by well-designed clinical trials in the future.

References

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