BackgroundSmall artery pathophysiology is frequently invoked as a cause of obesity‐related diastolic heart failure. However, evidence to support this hypothesis is scant, particularly in humans.Methods and ResultsTo address this, we studied human small artery structure and function in obesity and looked for correlations between vascular parameters and diastolic function. Seventeen obese patients with metabolic syndrome and 5 control participants underwent echocardiography and subcutaneous gluteal fat biopsy. Small arteries were isolated from the biopsy and pressure myography was used to study endothelial function and wall structure. In comparison with the control group, small arteries from obese participants exhibited significant endothelial dysfunction, assessed as the vasodilatory response to acetylcholine and also pathological growth of the wall. For the obese participants, multiple regression analysis revealed an association between left atrial volume and both the small artery wall thickness (β=0.718, P=0.02) and wall‐to‐lumen ratio (β=0.605, P=0.02). Furthermore, the E:E′ ratio was associated with wall‐to‐lumen ratio (β=0.596, P=0.02) and inversely associated with interleukin‐6 (β=−0.868, P=0.03). By contrast, endothelial function did not correlate with any of the echocardiographic parameters studied.ConclusionsAlthough the small arteries studied were not cardiac in origin, our results support a role for small artery remodeling in the development of diastolic dysfunction in humans. Further direct examination of the structure and function of the myocardial resistance vasculature is now warranted, to elucidate the temporal association between metabolic risk factors, small artery injury, and diastolic impairment.