GENETIC ARCHITECTURE OF CORONARY MICROVASCULAR DYSFUNCTION: POLYMORPHISMS, SIGNALING PATHWAYS, AND MOLECULAR TARGETS

Highlights     

• Coronary microvascular dysfunction (CMD) is a pathophysiological condition characterized by impaired regulation of coronary microvascular tone and structure in the absence of obstructive epicardial artery disease. CMD is now recognized as a major contributor to myocardial ischemia, particularly in patients with angina and normal coronary angiograms (INOCA), as well as in cases of myocardial infarction with non-obstructive coronary arteries (MINOCA). The key mechanisms underlying CMD include impaired endothelium-dependent vasodilation, excessive vasoconstriction, inflammation, and capillary remodeling.
• The molecular regulation of coronary blood flow involves a complex network of signaling cascades, including ion channels, nitric oxide (NO), endothelin-1, cytokines, and regulatory non-coding RNAs. Single nucleotide polymorphisms (SNPs) in genes encoding these mediators and enzymes significantly affect microvascular function. Notably, SNPs in NOS3, KCNJ11, JAK2, HMOX1, VEGFA, and other genes have been associated with altered vasomotor reactivity, oxidative stress, inflammatory activation, and impaired angiogenesis.
• MicroRNAs (miRNAs) play a particularly important role in the pathogenesis of CMD by regulating gene expression at the post-transcriptional level. Dysregulation of miRNAs such as miR-126, miR-155, and miR-30 has been linked to endothelial dysfunction, reduced capillary density, and impaired myocardial energy metabolism. The interplay of molecular and genetic factors provides a mechanistic framework for CMD and offers new opportunities for personalized approaches in the diagnosis, prognosis, and treatment of microvascular forms of ischemic heart disease.

Abstract

Coronary microvascular dysfunction (CMD) has increasingly been recognized as an independent and clinically significant pathophysiological mechanism of myocardial ischemia, even in the absence of obstructive coronary artery disease. CMD is caused by both functional impairments, such as imbalance between vasodilation and vasoconstriction–and structural alterations of the microcirculatory network. Recent research highlights the crucial role of molecular and genetic factors in the development of CMD, including single nucleotide polymorphisms (SNPs) in genes encoding endothelial nitric oxide synthase (NOS3), ion channel subunits (KCNJ11, CACNA1C), inflammatory and angiogenic mediators (JAK2, VEGFA, HMOX1). In addition, the antioxidant system plays an important role in the pathogenesis of coronary microcirculatory dysfunction, which is involved in maintaining vascular homeostasis and protecting against oxidative stress. The main studied genes of the antioxidant system include SOD1–3, GPX1, CAT, HMOX1 and NOX2/NOX4, which provide a balance of production and utilization of reactive oxygen species and play a significant role in the pathophysiology of the vascular wall. Of particular interest are microRNAs that regulate the expression of genes involved in vascular reactivity, angiogenesis, oxidative stress, and inflammation. Dysregulation of microRNAs such as miR-126, miR-155, and miR-30 has been associated with endothelial dysfunction and capillary remodeling. This review explores key signaling pathways and molecular mechanisms underlying CMD, with a focus on their genetic and epigenetic modulation. A better understanding of these processes opens new perspectives for the development of personalized diagnostic and therapeutic approaches in microvascular forms of ischemic heart disease.

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