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Genetic variants on top of traditional cardiovascular risk factors associated with coronary microvascular disease

Commented by ESC Working Group on Coronary Pathophysiology & Microcirculation

Pathophysiology and Mechanisms

Ischemic heart disease remains the most frequent cause of death worldwide, having atherosclerotic disease the leading pathophysiologic mechanism. However, nearly 75 years ago, in 1951, the first case of myocardial infarction without acute coronary occlusion (nowadays known as MINOCA) was described by Miller et al. on a pathological study(1). Later on, DeWood, and nowadays many authors report a prevalence of MINOCA between 5%-15%. However, these data may be biased due to discrepancy between the population enrolled in the clinical studies and the population affected in clinical practice.(2)

Severino et al., divided pathophysiological mechanisms of MINOCA in two groups:  atherosclerotic (that include plaque rupture, plaque erosion and calcified nodules), and non-atherosclerotic (more heterogenous ) causes including: epicardial coronary vasospasm, coronary microvascular dysfunction (CMD), coronary embolism/thrombosis, spontaneous coronary dissection and supply/demand mismatch.
CMD is a pathophysiological mechanism of MINOCA, that rises great interest in the resent years, partly due to the improved diagnostic possibilities with the development of many different non-invasive and invasive diagnostic procedures. Coronary microvascular disease leading to dysfunction can be due to Structural mechanisms, such as abnormal vascular remodeling, capillary rarefaction, luminal obstruction, vascular wall infiltration, and extrinsic vascular compression (e.g., edema, fat infiltration, amyloidosis, and perivascular fibrosis); and Functional mechanisms, such as endothelial dysfunction and vascular smooth muscle cell hyperreactivity. These two mechanisms usually coexist, and net results of these mechanisms are impaired vasodilatation and/or enhanced vasoconstriction.

Risk factors attributable to MINOCA include some traditional risk factors such as arterial hypertension and diabetes associated with a significantly reduced endothelial-dependent and endothelial-independent coronary vasodilator function and chronic inflammation. However, it does aper at younger age, female gender and platelet disorders, pointing to the involvement of non-traditional risk factors as well. (3)

A more basic inside to the pathophysiology of MINOCA point to the primary genetic and molecular mechanisms. Genetic variants (single-nucleotide polymorphisms (SNPs) may predispose, particularly affecting proteins involved in coronary blood flow (CBF) regulation, to CMD and, to MINOCA. This is associated with CBF imbalance and myocardial ischemia. Multiple gene loci are associated with alterations of the molecular pathways and with the development of microcirculatory dysfunction. (4) Molecular pathways associated with an increased risk of CFR alterations have been identified in intronic sequences of the vascular endothelial growth factor-A (VEGF-A) and cyclin-dependent kinase inhibitor 2B-AS1 (CDKN2B-AS1) genes, leading to decreased expression of VEGF. This is correlated with vascular dysfunction and lower survival of endothelial cells, due to apoptotic processes and repairing mechanisms abnormalities. Hemeoxygenase1 (HMOX1) is a stress-induced enzyme with a protective role against myocardial ischemia, including ischemic injury. Its’ polymorphisms are found to be associated with CMD. Endotelin-1 (ET-1) is a potent promotor of vaso proliferative activities, endothelial dysfunction and inflammation. A gene locus on chromosome 6p24 regulates ET-1 gene expression and the allelic variant rs9349379-G is associated with the increased plasma concentrations of ET-1. Nitric oxide (NO) has important role on vascular tone, and the allelic variants of eNOS, such as rs1799983_G/T, are associated with impaired NO, that affect both epicardial arteries and microcirculation. Of note, there are gene polymorphisms that demonstrates protective role against CMD as well. Finally, gender differences in SNPs are under analysis, as it is recognized that males and females over their lifetime are exposed to different hormonal changes and risk factors, develop different vessel diseases, and are burdened with different outcomes. (4)

In conclusion, MINOCA has heterogenous pathophysiological mechanisms that make the treatment particularly challenging. CMD is one of the mechanisms, consisting of structural and functional alterations of microcirculation, which hamper the cross-talk between coronary circulation and myocardial metabolism. With this respect, genetic susceptibility may have a primary role, affecting proteins involved in the regulation of vasomotor tone, endothelial function, cell proliferation, and atherosclerotic plaque stability. Further identification of genetic variants associated with CMD may improve the curent knowledge regarding the pathophysiology of MINOCA, and offer possible innovative treatment targets of these patients.



  1. Miller RD, Burchell HB, Edwards JE. Myocardial infarction with and without acute coronary occlusion: a pathologic study. AMA Arch Intern Med. 1951; 88:597–604.
  2. Tamis-Holland JE, Jneid H, Reynolds HR, Agewall S, Brilakis ES, Brown TM, Lerman A, Cushman M, Kumbhani DJ, Arslanian-Engoren C, Bolger AF, Beltrame JF; American Heart Association Interventional Cardiovascular Care Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Quality of Care and Outcomes Research. Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation. 2019 Apr 30;139(18):e891-e908. doi: 10.1161/CIR.0000000000000670. PMID: 30913893.
  3. Hansen B., Holtzman J.N., Juszczynski C., Khan N., Kaur G., Varma B., Gulati M. Ischemia with No Obstructive Arteries (INOCA): A Review of the Prevalence, Diagnosis and Management. Curr. Probl. Cardiol. 2023;48:101420. doi: 10.1016/j.cpcardiol.2022.101420.
  4. Kessler T., Vilne B., Schunkert H. The impact of genome-wide association studies on the pathophysiology and therapy of cardiovascular disease. EMBO Mol. Med. 2016;8:688–701. doi: 10.15252/emmm.201506174.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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