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Changes in cellular Ca 2+ and Na + regulation during the progression towards heart failure in the guinea pig
Author(s) -
Ke H.Y.,
Yang H.Y.,
Francis A. J.,
Collins T. P.,
Surendran H.,
AlvarezLaviada A.,
Firth J. M.,
MacLeod K. T.
Publication year - 2019
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp277038
Subject(s) - heart failure , muscle hypertrophy , medicine , chemistry , pressure overload , in vivo , endocrinology , biophysics , cardiac hypertrophy , biology , microbiology and biotechnology
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 μ m 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.