| Summary: | Endothelial dysfunction, associated with depressed nitric oxide (NO) bioavailability, is a<br />well-recognized contributor to both accelerated atherogenesis and microvascular complications in<br />type 2 diabetes (DM). However, growing evidence points to the comorbidities-driven endothelial<br />dysfunction within coronary microvessels as a key player responsible for left ventricular (LV)<br />diastolic dysfunction, restrictive LV remodeling and heart failure with preserved ejection fraction<br />(HFpEF), the most common form of heart failure in DM. In this review we have described: (1)<br />multiple cellular pathways which may link depressed NO bioavailability to LV diastolic<br />dysfunction and hypertrophy; (2) hemodynamic consequences and prognostic effects of restrictive<br />LV remodeling and combined diastolic and mild systolic LV dysfunction on cardiovascular<br />outcomes in DM and HFpEF, with a focus on the clinical relevance of endothelial dysfunction; (3)<br />novel therapeutic strategies to improve endothelial function in DM. In summary, beyond<br />associations with accelerated atherogenesis and microvascular complications, endothelial<br />dysfunction supplements the multiple interwoven pathways affecting cardiomyocytes, endothelial<br />cells and the extracellular matrix with consequent LV dysfunction in DM patients. The association<br />amongst impaired endothelial function, reduced coronary flow reserve, combined LV diastolic and<br />discrete systolic dysfunction, and low LV stroke volume and preload reserve—all of which are<br />adverse outcome predictors—is a dangerous constellation of inter-related abnormalities, underlying<br />the development of heart failure. Nevertheless, the relevance of endothelial effects of novel drugs<br />in terms of their ability to attenuate cardiovascular remodeling and delay heart failure onset in DM<br />patients remains to be investigated
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