Loss of the AE3 anion exchanger in a hypertrophic cardiomyopathy model causes rapid decompensation and heart failure

► Loss of AE3 Cl−/HCO3− exchanger increased death rate in hypertrophic cardiomyopathy. ► Loss of AE3 had no effect on cardiac hypertrophy or NHE1 Na+/H+ exchanger levels. ► Increased death rate was due to more rapid decompensation and heart failure. ► Decompensation was due to impaired Ca2+ handling and β-adrenergic responses. ► Impaired Ca2+ handling and β-adrenergic responses led to reduced cardiac reserve.