Acute Coronary Syndromes (ACS)-Unravelling Biology to Identify New Therapies-The Microcirculation as a Frontier for New Therapies in ACS

Abstract

In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these.

Keywords: acute coronary syndrome; index of microcirculatory resistance; microvascular obstruction; myocardial infarction; percutaneous coronary intervention.

Figure 1

Pathophysiology of MVO. Various genetic polymorphisms and the absence of ischaemic pre-conditioning predispose coronary microcirculation to injury. Plaque disruption, whether spontaneous or PCI-induced, results in distal microembolisation of cellular debris and augmentation of the inflammatory cascade, particularly neutrophil activation. Ischaemic injury to the microcirculation causes endothelial damage and extravasation of erythrocytes and inflammatory cells, resulting in myocardial oedema and luminal narrowing. Moreover, ischaemic injury promotes vasoconstriction by decreasing eNOS release and increasing endothelin-1 release, further limiting microvascular flow. Triggered by inflammatory debris, the NLRP3 inflammasome activates caspase-1 thereby mediating the cleavage of proIL-1b and proIL-18 into their active forms. Reperfusion after a prolonged ischaemic period further potentiates the inflammatory response by augmenting leukocyte recruitment, ROS generation, neutrophil-platelet aggregate formation, and calcium release. Ischaemia-reperfusion injury also induces pericyte contraction and intramyocardial haemorrhage which further limit microvascular flow. Increasing age, hypertension, diabetes mellitus, dyslipidaemia, and inflammation all predispose to CMD, which is characterised by perivascular fibrosis, smooth muscle cell and endothelial dysfunction, vascular remodelling, rarefaction, and sympathetic hyperactivity. These interdependent mechanisms form the underlying pathogenesis of MVO. Abbreviations: Ca²⁺, Calcium; CMD, Coronary microvascular dysfunction; eNOS, Endothelial nitric oxide synthase; MVO, Microvascular obstruction; ROS, Reactive oxygen species.