Systemic microvascular response to insulin is associated with risk of heart failure with preserved ejection fraction in women with type 2 diabetes
Authors: Dal Canto E , Van Deursen L , Elders P , Hoek A , Den Ruijter H M , Van Empel V , Eringa E C , Beulens J W J 
Published: October 2022

Abstract

Background
Endothelial microvascular dysfunction (MD) is a key pathophysiologic mechanism for heart failure with preserved ejection fraction (HFpEF). Comorbidities such as type 2 diabetes (T2D) indeed can affect the endothelium of both peripheral and coronary microcirculation, thereby triggering systemic derangements as well as left ventricular diastolic dysfunction (LVDD). Altered microvascular response to insulin is common in T2D but its clinical relevance and association with cardiovascular risk and particularly HFpEF remains unclear. Likewise, the involvement of systemic MD in early HFpEF and LVDD is uncertain. Finally, the influence of sex on MD and on its association with HFpEF needs further investigation to help understand the female predominance in HFpEF.

Purpose
We aimed to characterize systemic MD in T2D, and investigate its association with clinical and echocardiographic markers of LVDD/HFpEF. Further, we aimed to test for effect modification by sex in the association between MD and LVDD/HFpEF.

Methods
152 prospectively enrolled participants (77 men, 75 women) from the Hoorn Diabetes Care System Cohort underwent in vivo evaluation of MD, echocardiography and blood sampling. MD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin (Ins), acetylcholine (ACh) and sodium nitroprusside (SNP). The association between indices of MD and markers of LVDD/HFpEF was assessed by multivariable linear regression analysis adjusted for confounders. LVDD was defined as presence of cardiac structural and functional abnormalities, according to current recommendation. Probability of HFpEF was estimated with the H2PEFF score.

Results
Mean age was 65±6y, mean HbA1c 7.5±1.2%, 70.6% were asymptomatic. Comorbidity burden and biomarkers did not significantly differ between the sexes. Women had smaller LV mass index (82.8±18.1 vs 99.2±20.3 g/m2) and higher E/E' (13.4±4.4 vs 11.3±2.8) compared to men. Skin perfusion plateau after application of each substance was higher in women than men but no significant differences between sexes were observed in terms of relative perfusion change, calculated as 100% × ([Perfusion plateau − Baseline flow] / Baseline flow) for any of the substances. The relative perfusion change due to Ins was associated with the H2PEFF score, independently of cardiovascular risk factors and cardiovascular drug use (1% increase in perfusion associated to 0.07% decrease of the H2PEFF score). Stratified by sex, this association was present only in women (1% increase in perfusion associated to 0.10% decrease of the H2PEFF score). No significant associations were observed between perfusion change after ACh and SNP and H2PEFF score or between any MD indices and LVDD markers.

Conclusions
Impaired endothelial-mediated vasodilation in response to insulin confers a higher risk of HFpEF in women with T2D. In vivo measures of systemic MD could represent novel cardiovascular risk markers, for refined risk prediction of HFpEF.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Young Investigator award grant, Early HFpEF and ShePredicts programs, Hartstichting, The Netherlands.