92 Chapter 5 Table 2. Overview of stressors used to test the regulation of MBV Agents Mechanism Outcome Dobutamine Stimulating myocardial β1-receptor → ↑ contractile force and heartrate (i.e. positive inotropic and chronotropic effect) Increased MVO2 Insulin Healthy: Binding to insulin receptors on vascular endothelium → increased eNOS phosphorylation → ↑ NO release Microvascular dilatation, ↑ MBV Obesity/type 2 diabetes: Binding to insulin receptor on vascular endothelium → activation mitogen-activated protein kinase pathway → ↑ production of ET-1 Vasoconstriction, ↓ MBV Adenosine Binding to A1, A2A, A2B, and A3 receptors on smooth muscle cells and endothelial cells → ↑ NO release Microvascular dilatation, ↑ MBF Acetylcholine Healthy: Binding to muscarinic (M3) receptors on vascular endothelium → ↑ Ca2+ binding to eNOS → ↑ NO release Vasodilatation Endothelial dysfunction: Binding to muscarinic (M2 and M3) receptors on smooth muscle → ↑ Ca2+ in smooth muscle Vasoconstriction Abbreviations: MVO2: Myocardial Oxygen Consumption, NO: Nitric Oxide; MBV: Myocardial Blood Volume; ET1: Endotelin-1; MBF: Myocardial Blood Flow These microvascular effects of insulin are impaired in insulin-resistance, diabetes mellitus, obesity and hypertension, all common comorbidities in INOCA patients.25 Moreover, resistance to insulin’s microvascular action can be a hidden phenomenon since it can occur before hyperglycemia, and thus overt metabolic defects.26 The effects of hyperinsulinemia on MBV and MBF have never been studied in INOCA patients, while the blunted effect of insulin on the coronary microcirculation can be an additional factor leading to endothelial dysfunction in INOCA. Myocardial contrast echocardiography (MCE) allows real-time, non-invasive quantitative assessment of myocardial perfusion, using continuous infusion of gas-filled microbubbles.27, 28 MBV can be derived from the ratio between contrast intensity in the myocardium and in the left ventricle cavity. Although MCE is the gold standard to quantify MBV, this imaging technique is not routinely performed in clinical practice.29 Recent studies have provided evidence for a new and noninvasive diagnostic technique in INOCA patients to examine myocardial perfusion, namely cardiac magnetic resonance (CMR). CMR can be used to detect abnormalities in perfusion in INOCA patients, using the quantitative myocardial perfusion reserve index (MPRi) as diagnostic tool for INOCA, and a reduced MPRi in INOCA patients as an independent imaging marker to predict MACE.30, 31 Furthermore, CMR can also be used to provide information on the myocardial water content. T1-mapping
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