124 Chapter 6 increase in myocardial work load or hyperinsulinemia remains unaffected. These findings occurred even though ANOCA patients had significantly lower insulin-sensitivity compared with healthy controls (36.8 mol/kg/min vs 69.1 mol/kg/min, p < 0.001), and ANOCA patients had a significantly reduced heart rate reserve in ANOCA patients (54.8 ± 21.6 BPM) compared to healthy controls (67.1 ± 11.9 BPM). Prior studies have noted contraction-induced MVR between groups, which we didn’t observe in our study. An explanation for this discrepancy might be aging of the microvasculature as we included age-matched participants with a mean age of 57 years, while other studies reporting differences in MVR included a mean age ranging from 26 years27 to 46 years28. Aging of the microvasculature involves a gradual decline in capillary numbers and density due to the accumulation of waste products and CO2, and a decline in NO activity.29, 30 Endothelial NO synthase (eNOS) activity, i.e. NO-production, is lower in older women compared to younger women.31 Additionally, aging is linked to increased endothelin-1 (ET-1), leading to vasoconstriction.32 Consequently, microvasculature aging may contribute to impaired capillary recruitment, reducing MBV regulation. An important finding in our study is that MBV is diminished under all physiologically relevant conditions. The regulation of MBV during acute stimulation, such as hyperinsulinemia and increased cardiac work, is not the driving factor of reduced MBV. The extraction of oxygen is high under all circumstances, even at rest9, where a decrease in myocardial blood volume lead to angina. Myocardial blood flow The coronary microvasculature plays a key role in regulating flow and oxygen delivery to the myocardium.33 An increase in myocardial oxygen demand is mostly met by enhancing myocardial blood flow, since oxygen extraction is already up to almost 70–80% at rest.9 Consequently, current guidelines focus on a reduced coronary flow as a potential cause of ANOCA. Besides MBV, comprehensive MCE also allows non-invasive assessment of absolute myocardial blood flow.5 Notably, we identified a significantly lower MBF during dobutamine-induced stress between ANOCA patients and matched healthy controls (Supplemental Figure 3A), as well as a significantly reduced MBF response to dobutamineinduced stress (Supplemental Figure 3C). Dobutamine is a strong adrenergic α1 agonist and acts as a catecholamine by enhancing heart rate, the contractile force of the myocardium, and atrioventricular conduction, inducing stress.34 Moreover, it is important to emphasize that part of the participants were not able to complete the dobutamine induced stress-test due to undesired effects. These patients probably experienced the most severe outcomes during increased myocardial oxygen demand, suggesting our study may underestimate the observed effect difference.
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