In HFrEF, chronic neurohumoral activation stimulates the activation of cardiac NHE-1 and renal NHE-3, leading to enhanced sodium retention that contributes to the physiological and clinical progression of HFrEF associated with fluid retention (edema) and increased sodium influx and intracellular calcium linked to cardiac hypertrophy, cell injury and fibrosis [90,92,93]. Here, SLC9A1 is linked to cardiac hypertrophy.