Editorials
Exploring Deep Into the Coronary Microcirculation of Patients With Microvascular Angina
2018 Volume 82 Issue 4 Pages 951-953
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2018 Volume 82 Issue 4 Pages 951-953
Myocardial ischemia and angina have traditionally been thought to be caused by obstructive coronary artery disease (CAD). However, a substantial number of patients with angina and documented myocardial ischemia have no significant CAD, suggesting coronary microvascular angina (CMVA). Because of rather limited methodology for evaluating coronary microvascular dysfunction (CMVD) in clinical settings, the pathogenesis, epidemiology, prognosis, prevention, and therapy of CMVA are less well understood than those of CAD. On the other hand, a growing body of experimental research has revealed the mechanisms of blood flow regulation in the coronary microcirculation under physiological and pathophysiological conditions. The coronary microcirculation is regulated mutually by myocardial contraction and relaxation, and CMVD causes myocardial underperfusion, especially in the subendocardial myocardial layers.1
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Recent advancements in methodologies (e.g., Doppler guide wire, cardiovascular magnetic resonance, positron emission tomography, echocardiography) are opening the door to a new era of understanding CMVD in the clinical setting.2,3 In this issue of the Journal, Lanza et al4 report the long-term (range 5–31 years) outcome of exercise stress testing (EST) in patients with CMVA. They show persistence of exercise-induced ST-segment depression in 58% of the patients, but negative results for myocardial ischemia in 42%. Their report is valuable not only for recognizing that EST-induced myocardial ischemia improves over time in a sizeable proportion of the patients with CMVA, but also for planning future research based on the variability of the prognosis of patients with CMVA. The variable outcome of EST-induced myocardial ischemia in long-term follow-up of patients with CMVA poses following questions. First, factors that changed the prognosis of exercise-induced myocardial ischemia need to be clarified. Second, whether the factors affecting the outcome of myocardial ischemia in patients with CMVA are modifiable should be asked from a wide range of biomedical approaches, including lifestyle changes and medical therapy. Third, will appropriate control of such factors contribute to a better outcome of the patient with CMVA is the question that needs long-term clinical investigation.
To approach these questions, it seems reasonable to revisit coronary physiology, especially of the subendocardial myocardial layers.1 In both CAD and CMVD, the subendocardial myocardial layers are the most vulnerable to ischemia (Figure).5 Perfusion of the subendocardial layers depends on the interaction between myocardial contraction and intramyocardial vascular functions. Cardiac contraction is known to squeeze the intramyocardial vessels and impede coronary arterial flow, particularly in the subendocardium.6 In response to the phasic mechanical effects on the subendocardial vessels, resistance vessels dilate by endothelium-dependent and -independent, but vascular smooth muscle tone-dependent, mechanisms.7–9 Accordingly, failure of the vasodilatory mechanisms in the subendocardial resistance vessels may cause underperfusion and ischemia, leading to cardiac dysfunction. Indeed, a growing body of evidence is accumulating to indicate that both coronary endothelial-dependent and -independent dysfunction predicts adverse prognosis, including heart failure, in patients with CMVA.10,11 Lanza et al reported that a substantial portion of the patients diagnosed with CMVA experienced exercise-induced dyspnea,4 suggesting that CMVD is complicated by cardiac dysfunction. Because the coronary microcirculation is closely coupled with cardiac function, patients with CMVA may be in the process of progression of heart failure. Paulus and Tschöpe proposed the pivotal effect of coronary microvascular endothelial dysfunction (i.e., limited bioavailability of nitric oxide (NO) on myocardial remodeling and dysfunction in heart failure.12 Indeed, in patients with dilated cardiomyopathy, diminished bioavailability of endothelium-derived NO from the coronary microcirculation has been documented by intravascular NO measurement.13 Therefore, integrity of the coronary microvascular endothelial function may affect the prognosis of patients with CMVA. It seems reasonable to investigate the mechanisms and preventive and therapeutic interventions of CMVA and CMVD integratively with myocardial remodeling and dysfunction by focusing on endothelial function.12
Differences in myocardial ischemia caused by a significant coronary stenosis (A) or by coronary microvascular dysfunction (B). In the case of an epicardial (Epi) stenosis, myocardial ischemia diffusely involves the whole myocardial (usually subendocardial) territory supplied by the vessel (gray area), thus resulting in regional contractile dysfunction. In the case of microvascular alterations, myocardial ischemia is likely localized in small, patchily diffuse areas of myocardium (small circles); this may not result in detectable contractile abnormalities because of the presence of normal contractile myocardial cells in the same territory. Also in this case, ischemia more easily occurs in subendocardial regions (more intense gray color of the small ischemic areas). Endo indicates endocardial. a and b, dysfunctional microvessels; P1 and P2, blood pressure proximal and distal to obstructive vessels. (Reproduced with permission from Lanza and Crea.5)
Lanza et al do not report a significant association between changes in EST results and symptomatic status.4 Several factors may affect the ECG signs of myocardial ischemia and anginal symptoms in patients with CMVD. Heterogeneity of coronary microvascular blood flow distribution increases from the subepicardium to the subendocardium.14 In the case of CMVD, myocardial ischemia may be localized to small areas of the subendocardial myocardium (Figure).5 Such a distribution of perfusion abnormalities may explain the difficulties in obtaining objective evidence of myocardial ischemia in patients with CMVD. Furthermore, the sparse distribution of myocardial ischemia, although sufficient to produce ECG changes, may not result in anginal symptoms. As Lanza et al discuss, a different role of cardiac nociception, as compared with myocardial ischemia, may contribute to the symptomatic outcome in individual patients with CMVD.4 Also, a coronary microvascular spasm may cause an anginal episode in the patients with and without positive EST.15 Finally, future study is warranted to establish the preventive and therapeutic interventions that can contribute to improving coronary microvascular function and cardiac function, and thus lead to better outcomes for patients with CMVA.
M.G. has no conflicts of interest to disclose.
