112 Chapter 6 INTRODUCTION Angina with non-obstructed coronary arteries (ANOCA) is increasingly recognized as an important clinical syndrome in the setting of chronic coronary syndromes. The pathophysiology of ANOCA is complex and multifactorial, but coronary vasomotor disorders are considered a central element. Such vasomotor disorders include vasospasm of the epicardial vessels or the microvasculature, as well as coronary microvascular dysfunction (CMD).1 The diagnosis can be made through coronary function testing (CFT). CFT includes measurement of the vasodilator reserve capacity of the coronary circulation in response to pharmacological vasodilatation (typically adenosine) to evaluate the presence of CMD, as well as the evaluation of abnormal vasoconstrictor responses during acetylcholine provocation testing to diagnose coronary vasospasm.2, 3, 4 Coronary function testing aims to link angina(-equivalent) symptoms in ANOCA to inducible vasomotor disorders and myocardial ischemia. In short, myocardial ischemia occurs when oxygen delivery is insufficient to meet metabolic demand. Oxygen delivery, in turn, is determined by myocardial blood flow (MBF) and myocardial blood volume (MBV). MBF and MBV are independently regulated by large and small arterioles, respectively. The current diagnostic approach focuses on reduced MBF as a cause of reduced oxygen supply. MBV, encompassing the total blood content within the microcirculation, determines extraction of nutrients and oxygen from blood but remains an uninvestigated aspect of microvascular integrity in ANOCA. Myocardial contrast echocardiography (MCE) enables non-invasive, real-time assessment of myocardial microvascular perfusion using microbubble contrast infusion, and is the most sensitive technique for MBV quantification.5, 6, 7 The regulation of MBV can therefore be evaluated using MCE in combination with physiological stimuli like dobutamine and hyperinsulinemia. In skeletal muscle, both MBF and MBV increase in response to increased oxygen consumption (MVO2), and these responses are impaired in insulin resistance.8 Similarly, in a healthy coronary circulation, an increase in MBV occurs in response to stress, exercise, and hyperinsulinemia.9 ANOCA is associated with hypertension, dyslipidemia, diabetes, and obesity.1 These cardiometabolic risk factors are collectively known as the metabolic syndrome, of which insulin resistance is considered the joint underlying factor [10]. In young, healthy people, hyperinsulinemia induces vasodilatation via nitric oxide (NO) synthesis. However, in peripheral microvascular networks of obese and type 2 diabetic subjects insulin-induced vasoconstriction and microvascular rarefaction (i.e. a reduced microvascular density) have been demonstrated, and reduce muscle metabolism and function.11, 12, 13 We hypothesized that reduced MBV contributes to ANOCA, and that insulin resistance influences MBV regulation.14 Understanding the role of MBV in ANOCA could provide valuable insights into the pathophysiology of this condition. To explore this, we evaluated
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