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

Abstract

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 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.

Abstract: 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 μm 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.

Keywords: Na+/K+ ATPase; calcium; cardiac hypertrophy; heart failure; sodium.