Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development

NHE-1 is a Na⁺/H⁺ exchanger that receives phosphorylation signals, binds calmodulin and responds to neurohormonal input from angiotensin II, endothelin-1, and adrenergic pathways. In cardiac myocytes, NHE-1 maintains pH homeostasis and couples to Na⁺/Ca²⁺ exchange and mitochondrial ion handling. During heart disease sustained activation drives intracellular Na⁺ accumulation, promoting Ca²⁺ overload and mitochondrial dysfunction. Oxidative stress then creates amplifying cycles that activate signaling pathways resulting to arrhythmias and fibrosis. Clinical trials failed despite preclinical promise, due to a variety of false experimental factors. SGLT2 inhibitors appear to modulate NHE-1 indirectly through metabolic reprogramming and hemodynamic effects rather than direct blockade. Current approaches use structural data to target regulatory sites and phosphorylation-dependent conformational states instead of the transport pore. Translation to patients will require biomarkers identifying pathological hyperactivity and better patient stratification methods. Here, we try to review NHE-1 structure, regulation, and physiology that may influence research on future drug development.