Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort

BACKGROUND: Microvascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association. METHODS: We recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified. RESULTS: Mean age was 67?±?6y, mean HbA1c 7.6?±?1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34-165 vs. 46, 27-117 pg/ml) and E/E'(13.3?±?4.3 vs. 11.4?±?3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers. CONCLUSIONS: Impaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.