Changes in cellular Ca2+ and Na+ regulation during the progression towards heart failure in the guinea pig. (18th March 2019)

• Record Type: Journal Article
• Authors: Ke, H.‐Y.; Yang, H.‐Y.; Francis, A. J.; Collins, T. P.; Surendran, H.; Alvarez‐Laviada, A.; Firth, J. M.; MacLeod, K. T.
• Is Part Of: Journal of physiology. Volume 598:Number 7(2020)
• Page Start: 1339
• Page End: 1359
• Publication Date: 2019-03-18
• Subjects: cardiac hypertrophy -- heart failure -- sodium -- calcium -- Na+/K+ ATPase; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP277038
• Languages: English
• ISSNs: 0022-3751

Abstract

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 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. 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.