Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes

State-of-the-art Review

Milton Packer, MD

Disclosures

JACC Heart Fail. 2021;9(7):535-549. 

In This Article

Activation of Sodium Hydrogen Exchanger in the Diabetic Heart and Kidney

The exchange of sodium for hydrogen ions across cell membranes is mediated by a family of evolutionarily conserved antiporters, of which the sodium-hydrogen exchanger isoform 1 (NHE1) and sodium-hydrogen exchanger isoform 3 (NHE3) are most pertinent to the pathogenesis of heart failure in diabetes. The NHE1 isoform is expressed in all organs, but it is the predominant isoform in the heart, where it regulates cellular volume and pH. In contrast, the expression of the NHE3 isoform is limited to the apical surface of renal and gastrointestinal epithelial cells, where it mediates sodium reabsorption. NHE3 mediates the majority of the sodium reuptake that follows glomerular filtration.[45] It is therefore noteworthy that insulin stimulates the activity of NHE1 in the heart as well as NHE3 in the kidneys.[46,47]

Increased expression of NHE1 and NHE3 has been implicated in the development of organ injury in states of glucose intolerance. Up-regulation of NHE1 may contribute to the vascular abnormalities of diabetes mellitus, including endothelial dysfunction, medial hypertrophy, and neointimal proliferation,[48,49] which may contribute to the microvascular and macrovascular disease of diabetes mellitus.[50–52] Increased renal NHE1 and NHE3 activity (stimulated by hyperglycemia and hyperinsulinemia) contribute to glomerular hyperfiltration and mesangial proliferation,[53,54] the hallmarks of diabetic nephropathy.

Up-regulation of both NHE1 and NHE3 plays a particular role in the genesis of heart failure in patients with type 2 diabetes (Figure 2). Increased activity of NHE1 contributes directly to the cardiac hypertrophy and dysfunction in experimental diabetes mellitus, may enhance the dysfunction caused by other etiologies in diabetic patients, and is sufficient to precipitate heart failure.[55–57] The rise in intracellular sodium after NHE1 activation leads to abnormal calcium transients, cardiomyocyte injury, and cardiomyopathy.[57,58] Inhibition of NHE1 decreases cardiac necrosis and infarct size and reduces the development of cardiac hypertrophy, fibrosis, remodeling, and systolic dysfunction.[58,59] Furthermore, up-regulation of the NHE3 isoform in the kidneys mediates enhanced sodium reabsorption in the proximal tubule and has been implicated in the pathogenesis of fluid retention as well as resistance to diuretic agents and endogenous natriuretic peptides.[60,61]

Figure 2.

Type 2 Diabetes Causes Up-Regulation of Sodium-Hydrogen Exchanger Isoform 1 in Heart and Isoform 3 in the Kidneys
Type 2 diabetes leads to up-regulation of sodium-hydrogen exchanger mechanisms in both the heart and the kidney, the former leading to cardiac injury and cardiomyopathy, and the latter leading to sodium hyper-reabsorption in the proximal renal tubule. NHE1 = sodium-hydrogen exchanger isoform 1; NHE3 = sodium-hydrogen exchanger isoform 3. Adapted with permission from Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017;2(9):1025–1029.

These observations, taken together, suggest that diabetes may promote the development of both HFrEF and HFpEF by virtue of the actions of hyperinsulinemia to activate NHE1 in cardiomyocytes (leading to injury and loss) and NHE3 in the proximal renal tubules (leading to sodium retention and plasma volume expansion).

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