125 The MICORDIS study Clinical perspectives Our study showed that ANOCA patients are characterized by a higher BMI and a higher prevalence of hypertension, higher prevalence of hyperlipidemia and insulin resistance compared to matched healthy controls, suggesting metabolic disruptions are linked to ANOCA pathophysiology. Risk factors like obesity, hypertension, and dyslipidemia have been associated with reduced myocardial perfusion and inflammatory processes that disrupt endothelial function.35, 36 This indicates ANOCA may resemble a syndrome where multiple comorbidities contribute to reduced insulin sensitivity and impaired endothelial function, leading to a decreased MBV. Quantification of myocardial capillary blood volume can complement CFT, as flow responses determined during CFT are determined by arteriolar dilatation rather than capillary density. As such CFT may not adequately diagnose all ANOCA patients, especially those with metabolic syndrome. This approach could enable personalized clinical management and facilitate improved risk stratification, including targeted medication and management plans. Unfortunately, MCE is a laborious technique. However, new imaging modalities, such as CMR, might contribute further insights. Further research should provide evidence regarding the pathophysiological mechanisms reducing MBV in ANOCA and explore the possibilities to alter these pathways with medication to benefit ANOCA patients. A better understanding of this condition could lead to potential new therapies, providing a step towards a tailored treatment to reduce angina burden and improve quality of life.37 Limitations Certain limitations need to be considered. Firstly, conducting MCE can be challenging due to participants’ poor acoustic window or inability to hold their breath for 10 s. This affects echo-quality and hampers MCE analysis. Secondly, technical difficulties in MCE analysis include variation in intravenous infusion rate of microbubbles. However, to overcome these difficulties regarding MCE, recordings were duplicated in various views, and over 10.000 ROIs were analyzed by two independent readers to enhance reliability. Furthermore, due to ethical reasons, the healthy control group could not be tested invasively for the presence of CMD or vasospasm. However, this group was extensively screened for heart diseases with different imaging techniques. Lastly, our study’s relatively small sample size restricts statistical power. This limitation is enhanced by the inability of a minority of participants to complete all tests, especially the dobutamine test. Despite these limitations, we extensively characterized macro- and microvascular function. Due to a small proportion of male ANOCA patients in our clinic, our ability to detect sex differences is limited, but the distribution of the sexes in our study corresponds with the described prevalence of ANOCA.38 6
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