11 General introduction myocardial blood flow (MBF) and myocardial blood volume (MBV). MBV refers to the total blood content within in the microcirculation including arterioles, capillaries and venules. In healthy individuals, the entire coronary circulation, including the large epicardial coronary arteries, contains about 12mL of blood per 100g of myocardium volume during diastole. The microcirculation contains about 90% of the myocardial blood flow (MBF), and most of the myocardial blood volume (MBV), predominantly within the capillaries.4 MBF and MBV independently regulate oxygen delivery by large and small arteriole, respectively. At rest, approximately half of myocardial capillaries are filled with blood.5 Stress, e.g. an increase in cardiac work, increases oxygen demand in the myocardium, triggering coronary vasodilation and augmenting MBF. Additionally, the fraction of simultaneously perfused capillaries in the myocardium increases, referred to as ‘microvascular recruitment’ (MVR). This regulatory process involves local arteriolar vasodilatation to redirect blood to capillary beds supplying larger areas of the myocardium. As more blood is in direct contact with capillary endothelial cells, tissue oxygenation becomes more efficient, and MBV increases.6, 7 The pathophysiology of ANOCA The typical ANOCA patient is more likely to be female, relatively young and has fewer traditional cardiac risk factors compared to patients with obstructive CAD. Consequently, patients with ANOCA are often classified as ‘low risk’ and discharged without a proper diagnosis or treatment.8 However, similar to patients with obstructive CAD, ANOCA is associated with a reduced quality of life in terms of physical, mental and social wellbeing.9 The pathophysiology of ANOCA is complex and multifactorial, involving abnormal vasomotor responses affecting the entire coronary circulation. These abnormal vasomotor responses involve enhanced vasoconstriction and impaired vasodilation, leading to coronary vasospasm and/or coronary microvascular dysfunction (CMD).10 In 2017, the Coronary Vasomotor Disorders International Study (COVADIS) group established the COVADIS criteria to develop global standards for diagnosing and differentiating between these abnormal vasomotor responses.11, 12 The endothelium plays a crucial role in regulation of the coronary vascular tone by releasing various vasodilators. An important vasodilator in physiological regulation of vascular tone and blood flow is Nitric Oxide (NO). The production of NO in endothelial cells depends on the activity of endothelial nitric oxidase synthase (eNOS), which converts L-arginine into L-citrulline and NO in vascular endothelial cells. In healthy endothelial cells, vasodilator agents such as acetylcholine, histamine or insulin increase intracellular calcium levels (acetylcholine) or phosphorylation of eNOS (insulin), increasing NO production, resulting in subsequent vasodilatation.13, 14 However, vasodilator agents such as acetylcholine and insulin can also have vasoconstriction effects. Insulin can activate the Ras/mitogen-activated protein kinase (MAPK) signaling pathway, resulting in the production of the vasoconstrictor endothelin-1 (ET-1). ET-1 can increase vascular tone, inducing vasoconstriction and counteracting NO-mediated vasodilation.15, 16 In the presence of endothelial dysfunction, acetylcholine directly increases calcium in vascular smooth muscle cells leading to vasoconstriction and vascular spasm. Other contributors 1
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