Changes in cellular Ca²⁺ and Na⁺ regulation during the progression towards heart failure in the guinea pig

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 Ca²⁺ content increases during compensated hypertrophy then decreases in HF. In healthy cells, increases in SR Ca²⁺ content and Ca²⁺ 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 Ca²⁺ leak. We suggest an increase in I_Na,late and a decrease in Na⁺ ,K⁺ -ATPase current and function alters the balance of Ca²⁺ flux mediated by the Na⁺ /Ca²⁺ exchange that limits early contractile impairment.

We followed changes in cardiac myocyte Ca²⁺ 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) Ca²⁺ content increased during CH then decreased in HF (from 32 to 15 microm l^-1 ) potentially supporting the maintenance of FS in the whole heart and Ca²⁺ transients in single myocytes during the former stage. We showed using glycoside blockade in healthy myocytes that increases in SR Ca²⁺ content and Ca²⁺ 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 Ca²⁺ removal changed from 6.3 to 3.0 s^-1 ) in HF. In HF there was an increase in spark frequency and spark-mediated Ca²⁺ leak. We suggest an increase in I_Na,late and a decrease in Na⁺ ,K⁺ -ATPase current and function alters the balance of Ca²⁺ flux mediated by the Na⁺ /Ca²⁺ exchange that limits early contractile impairment.