Changes in cellular Ca2+ 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 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 follow 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) remains constant despite HW:BW ratio increasing by 39% (CH) until HF develops 150 days post‐TAC when FS decreases from 70% to 39%. Using live and fixed fluorescent imaging and electrophysiological techniques we found an increase in I _{Na late} from –0.34 A.F⁻¹ to –0.59 A.F⁻¹ and a decrease in Na⁺/K⁺ ATPase current from 1.09 AF⁻¹ to 0.54 A.F⁻¹ during CH. These changes persist as HF develops (I _{Na late} increases to –0.82 A.F⁻¹ and Na⁺/K⁺ ATPase current decreases to 0.51 A.F⁻¹). SR Ca²⁺ content increases during CH then decreases in HF (from 32 μm.l⁻¹ 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 show, 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 changes from 6.3.s⁻¹ to 3.0.s⁻¹) in HF. In HF there is 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.

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