SPECIAL MEDICAL EDITORIAL
Why should we study the coronary microcirculation?

Consiglio Nazionale delle Ricerche Institute of Clinical Physiology, 56100 Pisa, Italy

	INTRODUCTION

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THE QUESTION we are posing to the readers is why should we study the microcirculation of the heart. First, let us define who are "we." In this issue of the American Journal of Physiology: Heart and Circulatory Physiology, a collection of papers are included as part of a Special Call on "Emerging Concepts in the Control of the Coronary Microcirculation." It is obvious why the coronary microcirculation should be studied from a basic perspective; even the most seminal reactions, autoregulation and metabolic dilation, are incompletely understood. Our editorial will not highlight basic problems but rather discuss the clinical importance of the coronary microcirculation. Our opinion is that the "we" who should study the coronary microcirculation are both basic scientists and clinicians, so that a much clearer understanding of the role of coronary microvessels in the etiology of ischemic heart disease may be elucidated.

Most cardiologists believe that coronary artery disease is only a disease of large vessels, and there is little microvascular involvement in this pathology. We believe otherwise! In our opinion, abnormal coronary microvascular reactions to many stimuli contribute and possibly cause cardiac pathologies. To put our view in perspective, a case history from our institute provides a useful example (2). Several years ago we were treating a patient with angina pectoris who had rapidly decreasing tolerance to exercise. Coronary angiography documented a single subocclusive stenosis of the left anterior descending coronary artery, which was characterized by a complex morphology. Because of the presence of ischemia, the lesion was thought to be significant, and an angioplasty procedure was performed. Two minutes following successful dilation of the lesion, the patient complained of chest pain while the electrocardiogram monitoring the patient showed S-T segment elevation on the anterior leads. Another angiogram was immediately performed and showed a patent, nonstenotic left coronary artery characterized by a slow antegrade flow of the contrast medium. Measurement of coronary pressure by the balloon catheter did not show significant pressure gradients along the coronary artery, indicating that the resistance to flow was located distally to the epicardial vessel, i.e., in the coronary microcirculation. Despite intracoronary administration of nitrates, the transmural anterior ischemia persisted. The patient underwent emergency bypass grafting; however, at discharge, an anterior infarction was diagnosed with a severe impairment in left ventricular function that required cardiac transplantation in the follow-up. This case history and numerous others (28) with remarkable similarity have been published in the literature. These histories have promulgated the hypothesis that, at least in some patients, the basis for myocardial ischemia could be also due to abnormalities in the control of coronary resistance vessels rather than the more generally accepted view that the disease is exclusive to stenotic, epicardial coronary arteries (13).

Difficulty in the clinical evaluation of coronary microvascular function has prevented a complete identification of the role of the coronary microcirculation as a cause of ischemic heart disease. In fact, in patients in whom coronary microvascular dysfunction was initially advocated, these uncertainties led to the naming of this condition syndrome X. The difficulty of diagnosing syndrome X has led to an alternative view; namely, that it does not exist! This opposing view to syndrome X and a culprit role for the coronary microcirculation credits many of the pathophysiological manifestations to alterations in the myocardium and even psychosomatic disorders.

The goal of this review is to cite cogent literature that supports the hypothesis that coronary microvascular dysfunction can produce pathological manifestations in patients with coronary artery disease. Clearly, the potential for the coronary microcirculation to produce cardiac abnormalities exists. For example, intracoronary infusion of the potent constrictor endothelin-1 in a normal experimental animal without coronary disease can produce such severe constriction that ischemia ensues, followed by myocardial dysfunction and often fibrillation (W. Chilian, personal communications; see also Ref. 9). Thus constriction in some circumstances has the potential to override ischemia-induced dilation. Within the context of this editorial, we will review some situations of ischemic heart disease in which coronary microvascular dysfunction seems to cause the malady. We will also summarize how current understanding of basic coronary physiology appears to support our hypothesis for a microvascular role in certain types of ischemic heart disease.

	A MICROVASCULAR ROLE IN CORONARY ARTERY DISEASE?

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It is well known that stable coronary disease is characterized by the appearance of symptoms during effort. The pathophysiology of this condition has been accurately characterized by a number of experimental and clinical studies. In animal experiments, it is well known that the severity of epicardial obstruction, usually obtained by external constriction of an otherwise normal coronary artery, is strictly correlated with the degree of impairment in maximal flow capacity, which is the increase in flow obtained with pharmacological vasodilation (5). Because autoregulation and metabolic regulation of blood flow maintain constant rates of myocardial perfusion under baseline conditions, the degree of epicardial stenosis is also correlated with the reduction in the ratio between maximal and baseline blood flow, i.e., in coronary reserve. This concept has been accurately documented in a number of experiments and to date represents an intuitive explanation of the occurrence of ischemia on effort in patients with coronary artery disease. Nevertheless, this clinical convention (a stenosis is the only culprit in lessening reserve) is challenged by a large number of observations. First, the tolerance to effort markedly varies over time according to the presence of various, often unpredictable, factors. Second, when tested in the clinical setting, the relationship between stenosis severity and coronary flow reserve is characterized by large scatter (25, 26). This variance has been attributed to the presence of diffuse atherosclerosis, which might prevent a correct angiographic estimation of stenosis severity (1). Third, in regions perfused by nonstenotic vessels in patients, several studies documented an abnormal flow response to many vasodilators: serotonin (4), acetylcholine (15, 29), dipyridamole (17, 24), or atrial pacing (15, 17). From a clinical standpoint, these findings strongly suggest the presence of a microvascular abnormality in patients with coronary artery disease and point to an important clinical implication; that is to say, it calls into question the definition of critical stenosis (refer to the case from our institute described previously). This phenomenon might explain the limited sensitivity of myocardial perfusion scintigraphy in the detection of single vessel coronary artery disease (17).

A major question is whether endothelial dysfunction, in the absence of coronary disease, could cause improper regulation of coronary resistance vessels to such an extent that ischemia could result. To this end, several basic observations provide insight into this possibility. It is well known that stimuli most active on distal vascular segments, such as oxygen consumption, ischemia, or adenosine, primarily exert their vasodilation independently from the endothelium. However, distal vasodilation also affects proximal tone: it lowers the distal microvascular resistance and increases shear stress in the more proximal segments. This increase in shear stress causes flow-dependent dilation of these segments (6, 8, 14, 20, 21). This pathway offers some theoretical benefits during changes in flow. Dilation of the proximal segment would allow better transmission of pressure into the microcirculation to facilitate water and solute exchange. Also, this mechanism would prevent excessive dilation of the distal segment (3), thus preserving vasodilator reserve of small coronary arterioles. Importantly, atherosclerosis impairs endothelial production of nitric oxide and other endothelium-dependent dilators in response to shear stress (6, 8). From the preceding discussion, it is not unreasonable to propose that coronary atherosclerosis might hamper the regulation of vasomotor tone and thus myocardial perfusion via mechanisms besides the hydraulics of epicardial obstruction.

In agreement with the hypothesis based on basic observations, some observations in the literature challenge the current dogma of coronary disease: that large vessel disease is a prerequisite. Recently, Sambuceti et al. (18) observed that, in patients with single vessel coronary artery disease, progressive increases in heart rate were associated with paradoxical increases in coronary resistance leading to angina and S-T segment depression. Intracoronary administration of adenosine markedly decreased coronary resistance in all patients and eliminated, in some cases, the electrocardiographic signs of ischemia.

The hypothesis of an abnormal microvascular function has been corroborated by the measurement of coronary reserve following revascularization. After coronary angioplasty, Wilson et al. (27) showed that an abnormally low coronary flow reserve can persist following angioplasty in a significant fraction of patients. More recent studies (7) showed that even the optimization of revascularization by stent deployment does not always result in the restoration of a normal vasodilating capability. Although it is well known that coronary angioplasty might per se affect microvascular function, abnormal recovery of coronary-vasodilating capability following revascularization is more frequently observed in those patients who have evidence of an improper coronary microvascular funcion already before the procedure. In fact, preliminary data obtained in our institute indicate that patients with low values of coronary reserve following revascularization show high minimal resistance also before angioplasty as measured by monitoring of coronary blood flow and distal coronary pressure following administration of adenosine (12). These data indicate that regulation of coronary microvascular function might be profoundly altered in patients with coronary artery disease and that this disorder might contribute to the precipitation of ischemia in these patients.

The study of coronary microvascular function in patients with acute coronary syndromes is particularly difficult because of their unpredictable presentation. Only recently the study of microvascular resistance has been possible in patients with unstable angina by the continuous monitoring of coronary blood flow and transstenotic pressure gradient. With this methodology, it has been possible to separate the contribution of atherosclerotic plaque and distal coronary microcirculation during transient ischemia in patients with unstable angina. Marzilli and co-workers (11) documented that transient ischemia was associated with a marked increase in coronary microvascular resistance in patients with unstable angina. Importantly, adenosine caused dramatic dilation of the coronary microcirculation. Furthermore, preliminary data (19) indicate that the beneficial effect of the glycoprotein IIB/IIIA antagonists might also be due to the effect of this molecule on microvascular function. In fact, in patients with unstable angina, administration of abciximab induced an early reduction in baseline and minimal resistance at the level of coronary microvasculature without any significant effect at the level of coronary plaque.

	A MICROVASCULAR ROLE IN MYOCARDIAL INFARCTION?

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Traditionally, myocardial infarction is thought to be exclusively related to large vessel disease (critical stenosis, spasm, or thrombus). However, as we mentioned in our first case report, there may be the possibility that inappropriate microvascular constriction may cause myocardial infarction. Several studies suggest the presence of a coronary microvascular involvment in patients with acute myocardial infarction. In this setting, of course, the study of a pathophysiological role for this vascular compartment is particularly difficult because patients undergo diagnostic evaluation after the precipitation of ischemia. Under this condition, ischemia and reperfusion can affect per se coronary microvascular function, and this has been extensively documented both in the clinical setting and in experimental models (22). However, some observations suggest a peculiarity of the clinical model of myocardial infarction with respect to microvascular function. In fact, Uren and co-workers (23) studied, by positron emission tomography, a group of patients with acute myocardial infarction and single vessel disease, paying attention to myocardial regions remote to infarction and supplied by nonstenotic coronary arteries (23). Using this methodology, these authors documented that microvascular response to dipyridamole is particularly impaired soon after the episode and shows a progressive improvement over time. The mechanisms of these phenomena have not been conclusively investigated; however, they strongly suggest the presence of a microvascular abnormality at least in the early days following acute infarction. In agreement with this hypothesis, Neumann and co-workers (16) documented that the administration abciximab can improve microvascular function following primary angioplasty for acute myocardial infarction. Moreoever, Marzilli and co-workers (10) treated the ischemic myocardium with adenosine before primary percutaneous transluminal coronary angioplasty for acute myocardial infarction, and they observed a marked beneficial effect of this maneuver on mortality in a small group of patients. The result of this pilot study strongly suggests that administration of drugs that "target" the coronary microcirculation of the ischemic myocardium can improve the results of therapies in the setting of acute ischemic syndromes.

In summary, from the above discourse, we can summarize three important concepts. First, paradoxical coronary microvascular constriction occurs in some patients during increases in oxygen consumption and during attacks of unstable angina. Second, dilation of the microcirculation reduces the severity of ischemia in many patients with the above symptoms. Finally, interventions aimed at treating the coronary microvasculature can improve outcomes of many patients with coronary artery disease. Thus the answer to why should we study the coronary microcirculation hopefully has become even more obvious: to further our understanding of both coronary physiology and the pathophysiology of ischemic heart disease.

	FOOTNOTES

Address for reprint requests and other correspondence: G. Sambuceti, CNR Institute of Clinical Physiology, 56100 Pisa, Italy (E-mail: battesto{at}po.ifc.pi.cnr.it).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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