Systemic Microvascular Endothelial Dysfunction in Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a systemic disorder featuring microvascular dysfunction and metabolic comorbidities such as type 2 diabetes (T2D). However, the extent to which systemic microvascular abnormalities reflect HFpEF or coexisting T2D remains incompletely understood. The aim of this study was to characterize systemic microvascular dysfunction in patients with HFpEF and to evaluate the contribution of comorbid T2D. Systemic microvascular function, defined as flow responses expressed as cutaneous vascular conductance, was assessed using laser speckle contrast analysis with iontophoresis of acetylcholine, insulin, and sodium nitroprusside. Analysis adjusted for age and sex were performed across healthy controls (n = 23), T2D (n = 138), HFpEF without T2D (n = 63), and HFpEF with T2D (n = 27). Insulin-mediated microvascular perfusion was reduced in participants with T2D (-0.30 arbitrary perfusion units [APU]/mm Hg; P < 0.001) and in HFpEF with T2D (-0.32 APU/mm Hg; P = 0.004) compared with controls, whereas responses in HFpEF without T2D were not different from controls. Perfusion responses to sodium nitroprusside were reduced in T2D and HFpEF with T2D, while responses to acetylcholine were preserved. No statistically detectable interaction between HFpEF and T2D was observed. Sex did not modify the relationship between HFpEF and microvascular dysfunction, but exploratory sex-stratified analyses showed reduced insulin-mediated microvascular perfusion in T2D (mean difference: -0.30 APU/mm Hg; P = 0.020) and HFpEF + T2D (mean difference: -0.51 APU/mm Hg; P = 0.002) compared with controls. Systemic microvascular dysfunction, particularly impaired insulin-mediated vasodilation, was observed in HFpEF. The observed abnormalities were predominantly present in participants with comorbid type 2 diabetes.