Changes in cellular Ca(2+) and Na(+) regulation during the progression towards heart failure in the guinea pig

KEY POINTS: During compensated hypertrophy in vivo fractional shortening (FS) remains constant until heart failure (HF) develops, when FS decreases from 70% to 39%. Compensated hypertrophy is accompanied by an increase in I (Na,late) and a decrease in Na(+),K(+)‐ATPase current. These changes persist as HF develops. SR Ca(2+) content increases during compensated hypertrophy then decreases in HF. In healthy cells, increases in SR Ca(2+) content and Ca(2+) transients can be achieved by the same amount of inhibition of the Na(+),K(+)‐ATPase as measured in the diseased cells. SERCA function remains constant during compensated hypertrophy then decreases in HF, when there is also an increase in spark frequency and spark‐mediated Ca(2+) leak. We suggest an increase in I (Na,late) and a decrease in Na(+),K(+)‐ATPase current and function alters the balance of Ca(2+) flux mediated by the Na(+)/Ca(2+) exchange that limits early contractile impairment. ABSTRACT: We followed changes in cardiac myocyte Ca(2+) and Na(+) regulation from the formation of compensated hypertrophy (CH) until signs of heart failure (HF) are apparent using a trans‐aortic pressure overload (TAC) model. In this model, in vivo fractional shortening (FS) remained constant despite HW:BW ratio increasing by 39% (CH) until HF developed 150 days post‐TAC when FS decreased from 70% to 39%. Using live and fixed fluorescence imaging and electrophysiological techniques, we found an increase in I (Na,late) from –0.34 to –0.59 A F(−1) and a decrease in Na(+),K(+)‐ATPase current from 1.09 A F(−1) to 0.54 A F(−1) during CH. These changes persisted as HF developed (I (Na,late) increased to –0.82 A F(−1) and Na(+),K(+)‐ATPase current decreased to 0.51 A F(−1)). Sarcoplasmic reticulum (SR) Ca(2+) content increased during CH then decreased in HF (from 32 to 15 μm l(−1)) potentially supporting the maintenance of FS in the whole heart and Ca(2+) transients in single myocytes during the former stage. We showed using glycoside blockade in healthy myocytes that increases in SR Ca(2+) content and Ca(2+) transients can be driven by the same amount of inhibition of the Na(+),K(+)‐ATPase as measured in the diseased cells. SERCA function remains constant in CH but decreases (τ for SERCA‐mediated Ca(2+) removal changed from 6.3 to 3.0 s(−1)) in HF. In HF there was an increase in spark frequency and spark‐mediated Ca(2+) leak. We suggest an increase in I (Na,late) and a decrease in Na(+),K(+)‐ATPase current and function alters the balance of Ca(2+) flux mediated by the Na(+)/Ca(2+) exchange that limits early contractile impairment.