Abstract
Endothelial dysfunction, associated with depressed nitric oxide (NO) bioavailability, is a well-recognized contributor to both accelerated atherogenesis and microvascular complications in type 2 diabetes (DM). However, growing evidence points to the comorbidities-driven endothelial dysfunction 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 diastolic dysfunction and hypertrophy; (2) hemodynamic consequences and prognostic effects of restrictive LV remodeling and combined diastolic and mild systolic LV dysfunction on cardiovascular outcomes 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, beyond associations with accelerated atherogenesis and microvascular complications, endothelial dysfunction supplements the multiple interwoven pathways affecting cardiomyocytes, endothelial cells and the extracellular matrix with consequent LV dysfunction in DM patients. The association amongst impaired endothelial function, reduced coronary flow reserve, combined LV diastolic and discrete systolic dysfunction, and low LV stroke volume and preload reserve—all of which are adverse outcome predictors—is a dangerous constellation of inter-related abnormalities, underlying the development of heart failure. Nevertheless, the relevance of endothelial effects of novel drugs in terms of their ability to attenuate cardiovascular remodeling and delay heart failure onset in DM patients remains to be investigated.
Highlights
Endothelial dysfunction entails depressed bioavailability of nitric oxide (NO), a short-living mediator generated from L-arginine by endothelial NO synthase in response to blood flow-induced shear stress and multiple chemical stimuli [1]
DM is associated with increased activity and expression of endothelial arginase I, which decreases the availability of L-arginine to endothelial NO synthase (eNOS) [25]
The relevance of the complex estimation of left ventricular (LV) function could be concluded from an earlier work by Andersson et al [58]. They demonstrated a selective impairment of longitudinal LV systolic and diastolic function in DM patients free of coronary artery disease (CAD) in comparison with controls matched for age, gender and presence of hypertension despite no identifiable changes in EF and other conventional measures of LV function [58]
Summary
Endothelial dysfunction entails depressed bioavailability of nitric oxide (NO), a short-living mediator generated from L-arginine by endothelial NO synthase (eNOS) in response to blood flow-induced shear stress and multiple chemical stimuli [1]. DM is associated with increased activity and expression of endothelial arginase I, which decreases the availability of L-arginine to eNOS [25] The latter mechanism might involve a cross-talk between the endothelium and red blood cells (RBC), where DM—via arginase I up-regulation and eNOS uncoupling—impairs an export of NO bioactivity with consequent endothelial dysfunction [26,27,28]. It is not implausible to assume that the most prevalent causes of HF in DM appear to be mechanisms other than myocardial infarction These mechanisms are likely to account for an increased risk of HF in DM patients in population-based cohorts [35,41,42,43,48]. This review is focused on the clinical importance of endothelial dysfunction in DM patients for restrictive left ventricular (LV) remodeling and diastolic dysfunction, predisposing to subsequent development of HFpEF
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