Coronary microvascular dysfunction: pathophysiology, diagnosis, and therapeutic strategies across cardiovascular diseases

Abstract

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide, presenting with acute and chronic coronary syndromes. Although coronary atherosclerosis is a major cause of IHD, many patients with angina or myocardial ischemia do not have obstructive coronary heart disease and impairment of the coronary microcirculation has been increasingly implicated as a relevant cause of IHD. Therefore, coronary microvascular dysfunction (CMD) refers to a term covering a wide spectrum of structural and functional alterations which affect the coronary microcirculation leading to myocardial ischemia and angina. The advent of non-invasive and invasive functional tests has exponentially broadened the ability to recognize CMD and delineate related clinical and biochemical features. Despite major advances in diagnosing and stratifying this condition, therapeutic strategies remain limited and poorly defined. In this review, we will provide an overview of the pathophysiology and the diagnostic evaluation of CMD across the spectrum of cardiovascular diseases. Furthermore, we will discuss the novel therapeutic strategies available for these patients in the perspective of a personalized medicine approach.

Keywords: ANOCA; INOCA; coronary microvascular dysfunction; coronary spasm; precision medicine.

Table 1. Non-invasive techniques for the diagnosis of CMD

Table 2. Current therapeutic strategies for microvascular dysfunction

Figure 1. Pathophysiology of coronary microvascular dysfunction

(Abbreviations: CMD: coronary microvascular dysfunction; VSMC: vascular smooth muscle cells)

Figure 2. Molecular pathways involved in coronary microvascular dysfunction

Abbreviations. AP-1: Activator Protein 1; ERK1/2: Extracellular Signal-Regulated Kinases 1 and 2; ET1: Endothelin 1; HIF-1: Hypoxia-Inducible Factor 1; JNK: c-Jun N-terminal Kinase; MAPK: Mitogen-Activated Protein Kinase; NF-κB: Nuclear Factor Kappa B; NO: Nitric Oxide; NOS: Nitric Oxide Synthase; NOX: NADPH Oxidase; ONOO⁻: Peroxynitrite; p38MAPK: p38 Mitogen-Activated Protein Kinase; p66shc: SHC Adaptor Protein 1; Rho Kinase: Rho-Associated Protein Kinase; RhoA: Ras Homolog Family Member A; ROS: Reactive Oxygen Species; SIRT1: Sirtuin 1; XO: Xanthine Oxidase; XDH: Xanthine Dehydrogenase.

Figure 3. Epigenetic modifications involved in coronary microvascular dysfunction

Abbreviations. TNFα: Tumor necrosis factor; VSMC: vascular smooth muscle cells

Figure 4. The role of CMD across cardiovascular diseases

Abbreviations. CAD: coronary artery disease; HFpEF: Heart failure with preserved ejection fraction; MINOCA: myocardial infarction and non-obstructive coronary arteries; MVA: microvascular angina; MVO: microvascular obstruction.