Endothelial Dysfunction: A Contributor to Adverse Cardiovascular Remodeling and Heart Failure Development in Type 2 Diabetes beyond Accelerated Atherogenesis

Endothelial dysfunction, associated with depressed nitric oxide (NO) bioavailability, is awell-recognized contributor to both accelerated atherogenesis and microvascular complications intype 2 diabetes (DM). However, growing evidence points to the comorbidities-driven endothelialdysfunction within coronary microvessels as a key player responsible for left ventricular (LV)diastolic dysfunction, restrictive LV remodeling and heart failure with preserved ejection fraction(HFpEF), the most common form of heart failure in DM. In this review we have described: (1)multiple cellular pathways which may link depressed NO bioavailability to LV diastolicdysfunction and hypertrophy; (2) hemodynamic consequences and prognostic effects of restrictiveLV remodeling and combined diastolic and mild systolic LV dysfunction on cardiovascularoutcomes in DM and HFpEF, with a focus on the clinical relevance of endothelial dysfunction; (3)novel therapeutic strategies to improve endothelial function in DM. In summary, beyondassociations with accelerated atherogenesis and microvascular complications, endothelialdysfunction supplements the multiple interwoven pathways affecting cardiomyocytes, endothelialcells and the extracellular matrix with consequent LV dysfunction in DM patients. The associationamongst impaired endothelial function, reduced coronary flow reserve, combined LV diastolic anddiscrete systolic dysfunction, and low LV stroke volume and preload reserve-all of which areadverse outcome predictors-is a dangerous constellation of inter-related abnormalities, underlyingthe development of heart failure. Nevertheless, the relevance of endothelial effects of novel drugsin terms of their ability to attenuate cardiovascular remodeling and delay heart failure onset in DMpatients remains to be investigated.