The vascular compartment in the myocardium comprises the great arteries, arterioles, capillary network and smaller intra-myocardial veins. The coronary microcirculation is characteristically composed of vessels smaller than 200 µm in diameter. The microcirculation not only serves as a passive channel through which blood is transported into the myocardium, but rather an active site of blood flow control with complex metabolic and myogenic regulatory mechanisms. Currently, early mechanical reperfusion of the epicardial coronary artery by PCI is the recommended therapy for STEMI. Successful restoration of epicardial coronary blood flow is achieved in over 95% of PCI procedures, but complete restoration of perfusion of the distal coronary microvasculature is not achieved, even though angiographic culprit blood flow is reperfused to TIMI 3 grade in approximately half of the patients, leading to CMD . Several mechanisms are involved in the development of CMD after STEMI, including ischemia-related injury, reperfusion-related injury, distal embolization, intramyocardial inflammation, and individual susceptibility of the microcirculation to injury [6, 13]. Therefore, evaluation of CMD is necessary since it may affect the prognosis of STEMI.
Various diagnostic modalities can be used for the assessment of CMD, including both non-invasive and invasive techniques. Each methods has its own strengths and weaknesses . Studies have shown that the index of microcirculatory resistance (IMR) and hyperemic microvascular resistance (HMR) are useful for the early identification of severe CMD in patients with STEMI after PCI, which are associated with a higher risk of long-term MACEs in patients with STEMI . However, both IMR and HMR are invasive. The systemic inflammation marker, i.e., the ratio of serum C-reactive protein to albumin, has been proven to predict imperfect reperfusion that can worsen the prognosis of STEMI . Several studies have frequently used CMR as a non-invasive tool for detecting CMD . Nevertheless, CMR also has some limitations, such as prolonged offline post-processing, concerns over the safety of gadolinium-based contrast agents, and association with nephrogenic systemic fibrosis in patients with chronic kidney disease. In our study, MCE was chosen as a non-invasive tool to detect CMD in patients with STEMI. Moreover, MCE is a more convenient, economical, and safer method that can accurately identify patients who develop CMD after STEMI.
The principle underlying MCE entails the administration of microbubble contrast agents via the peripheral veins to improve the echocardiographic signal. Ultrasound-induced microbubble destruction can be used for the measurement of myocardial blood flow during continuous infusion of contrast agents. The relative agent concentration in different myocardial beds represents the capillary density or the sum of its cross-sectional area. The microbubble concentration in the microcirculation reflects the blood volume in the microvasculature. Thus, MCE facilitates effective assessment of the coronary microcirculation. Studies have shown that the incidence of CMD after STEMI is approximately 54.9–89% (10.12.13). Our study indicated that 62.9% of patients developed CMD, despite the success of PCI. We observed a similar incidence of CMD based on MCE examination. Thus, we can infer that MCE is a reliable tool to detect CMD, and that CMD is a common phenomenon that warrants attention.
In this study, patients with CMD exhibited significantly higher levels of TnI and BNP, poorer Killip class, and different culprit vessels. These results suggest that CMD may be associated with the degree of myocardial necrosis and cardiac function during the acute phase of STEMI. One study showed that the Killip classification can predict the risk of CMD in patients with STEMI undergoing PCI . Meanwhile, MCE revealed that the LVEF and GLS were lower and WM was worse in patients with CMD. Our previous study showed that CMD was independently associated with the global LV myocardial work index assessed by echocardiography (adjusted OR 0.997, 95% CI 0.994–1.000, P = 0.029) . Another of our previous studies found that CMD could lead to exacerbation in the LVEF and WM in patients with STEMI, after adjusting for culprit vessels . Moreover, CMD after acute MI increases the risk of acute HF during hospitalization . These results suggest that CMD after STEMI can result in a poor prognosis during hospitalization.
We found that CMD was an independent predictor of total MACEs at 13 months of follow-up, after adjusting for hypertension, peak TnI level, culprit vessel, and Killip classification. The risk of re-hospitalization-adjusted HF increased more than fourfold (OR, 5.184; P = 0.044), while that of repeat MI increased nearly two-fold (adjusted OR, 2.896; P = 0.030). Animal studies have demonstrated a direct association between persistent microvascular obstruction and adverse ventricular remodeling . The presence of microvascular obstruction is a powerful predictor of LV remodeling and HF events . Post-ischemic CMD is predictive of a greater than fourfold increase in the long-term risk of adverse outcomes, which is mainly driven by the occurrence of HF . In this study, MCE confirmed that the risk of HF could still increase in the presence of CMD, despite complete timely revascularization (the median revascularization time was 6.7 h in the CMD group). HF is a common complication of STEMI and is predictive of a poor prognosis . Although national door-to-balloon times have improved significantly over the last few years for patients undergoing primary PCI, several STEMI patients still develop HF in the long term. Identification and intervention of CMD may provide new concepts for the prevention of HF after STEMI. This study also found that patients with CMD were at a higher risk of repeat MI (adjusted OR, 2.896; P = 0.030). It is generally assumed that epicardial events precede and cause CMD. However, a novel concept of the pathogenic mechanism was posited, which states that transient or permanent microvascular dysfunction limits coronary blood flow, leads to alterations in shear stress (affecting endothelial function), and enhances thrombus formation at the epicardial level . This may explain the high risk of long-term repeat MI to some extent. However, the existence of other mechanisms requires further investigation. Subgroup analysis of the FOURIER study showed that patients with a history of repeat MI were at a higher risk of MACEs and a poor prognosis . These findings underscore the necessity of identifying CMD in patients with STEMI.
To date, no randomized trials have compared therapies for the reduction of adverse cardiac events in patients with CMD. Lifestyle changes and risk factor management should be considered essential in the management of CMD. Conventional pharmacotherapeutic strategies, such as beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), statins, antiplatelet therapy and nitrates are recommended . Research into novel treatment for CMD is an unmet clinical need. One novel strategy entails inhibiting Rho-kinase in order to ameliorate CMD . Therapeutic modalities targeting perivascular adipose tissue to stimulate the production of vasoactive and vasorelaxant factors such as adiponectin or hydrogen sulfide could be beneficial [25, 26]. All patients enrolled in our study had received standard conventional therapy for coronary heart disease. Further studies focusing on the treatment and management of patients with CMD remain a clinical requirement.
A previous study found that CMD was associated with long-term mortality in patients with STEMI . However, we did not find any difference in the risk of mortality between the CMD and non-CMD groups (P = 0.973). The sample size of our study was merely 167 patients, and the follow-up period was relatively short; only two patients died in the CMD group, and none died in the non-CMD group; thus, the mortality-related data did not converge in the Cox regression analysis. Moreover, we only analyzed the culprit vessels and multivessel disease, whereas the effect of other coronary anatomical data on perfusion was not compared. The sample size and short follow-up period were limitations of our study and may be responsible for the lack of significant differences in the mortality between the two groups. Future studies with larger samples and longer follow-up durations should be performed and more coronary anatomical data should be analyzed. Moreover, the change in coronary microcirculation perfusion is a dynamic process, but we only obtained MCE data at one period of time (within 7 days post-PCI). Imaging data at follow-up should be added to gain a more comprehensive understanding of the impact of CMD on STEMI.
We used MCE to detect CMD, which is a safer and more convenient method for patients with STEMI. Our findings revealed that CMD occurred in a significant proportion of patients with STEMI, which led to a poor prognosis. This study provides evidence of the feasibility of predicting MACEs using MCE in patients with STEMI and proved the importance of early identification of CMD in patients with STEMI.