Cellular mechanisms of altered contractility in the hypertrophied heart: Big hearts, big sparks

Stephen R. Shorofsky, Rajesh Aggarwal, Mary Corretti, Jeanne M. Baffa, Judy M. Strum, Badr A. Al-Seikhan, Yvonne M. Kobayashi, Larry Jones, W. Gil Wier, C. William Balke

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

To investigate the cellular mechanisms for altered Ca2+ homeostasis and contractility in cardiac hypertrophy, we measured whole-cell L-type Ca2+ currents (I(Ca,L)), whole-cell Ca2+ transients ([Ca2+](i)), and Ca2+ sparks in ventricular cells from 6-month-old spontaneously hypertensive rats (SHRs) and from age- and sex-matched Wistar-Kyoto and Sprague-Dawley control rats. By echocardiography, SHR hearts had cardiac hypertrophy and enhanced contractility (increased fractional shortening) and no signs of heart failure. SHR cells had a voltage-dependent increase in peak [Ca2+](i) amplitude (at 0 mV, 1330 ± 62 nmol/L [SHRs] versus 836 ± 48 nmol/L [controls], P < 0.05) that was not associated with changes in I(Ca,L) density or kinetics, resting [Ca2+](i), or Ca2+ content of the sarcoplasmic reticulum (SR). SHR cells had increased time of relaxation. Ca2+ sparks from SHR cells had larger average amplitudes (173 ± 192 nmol/L [SHRs] versus 109 ± 64 nmol/L [control]; P < 0.05), which was due to redistribution of Ca2+ sparks to a larger amplitude population. This change in Ca2+ spark amplitude distribution was not associated with any change in the density of ryanodine receptors, calsequestrin, junctin, triadin 1, Ca2+-ATPase, or phospholamban. Therefore, SHRs with cardiac hypertrophy have increased contractility, [Ca2+](i) amplitude, time to relaxation, and average Ca2+ spark amplitude ('big sparks'). Importantly, big sparks occurred without alteration in the trigger for SR Ca2+ release (I(Ca.L)), SR Ca2+ content, or the expression of several SR Ca2+-cycling proteins. Thus, cardiac hypertrophy in SHRs is linked with an alteration in the coupling of Ca2+ entry through L-type Ca2+ channels and the release of Ca2+ from the SR, leading to big sparks and enhanced contractility. Alterations in the microdomain between L-type Ca2+ channels and SR Ca2+ release channels may underlie the changes in Ca2+ homeostasis observed in cardiac hypertrophy. Modulation of SR Ca2+ release may provide a new therapeutic strategy for cardiac hypertrophy and for its progression to heart failure and sudden death.

Original languageEnglish
Pages (from-to)424-434
Number of pages11
JournalCirculation Research
Volume84
Issue number4
StatePublished - Mar 5 1999

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Inbred SHR Rats
Sarcoplasmic Reticulum
Cardiomegaly
Homeostasis
Heart Failure
Calsequestrin
Ryanodine Receptor Calcium Release Channel
Calcium-Transporting ATPases
Sudden Death
Sprague Dawley Rats
Echocardiography

Keywords

  • Ca spark
  • Ca transient
  • Cardiac hypertrophy
  • Spontaneously hypertensive rat

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Shorofsky, S. R., Aggarwal, R., Corretti, M., Baffa, J. M., Strum, J. M., Al-Seikhan, B. A., ... Balke, C. W. (1999). Cellular mechanisms of altered contractility in the hypertrophied heart: Big hearts, big sparks. Circulation Research, 84(4), 424-434.

Cellular mechanisms of altered contractility in the hypertrophied heart : Big hearts, big sparks. / Shorofsky, Stephen R.; Aggarwal, Rajesh; Corretti, Mary; Baffa, Jeanne M.; Strum, Judy M.; Al-Seikhan, Badr A.; Kobayashi, Yvonne M.; Jones, Larry; Wier, W. Gil; Balke, C. William.

In: Circulation Research, Vol. 84, No. 4, 05.03.1999, p. 424-434.

Research output: Contribution to journalArticle

Shorofsky, SR, Aggarwal, R, Corretti, M, Baffa, JM, Strum, JM, Al-Seikhan, BA, Kobayashi, YM, Jones, L, Wier, WG & Balke, CW 1999, 'Cellular mechanisms of altered contractility in the hypertrophied heart: Big hearts, big sparks', Circulation Research, vol. 84, no. 4, pp. 424-434.
Shorofsky SR, Aggarwal R, Corretti M, Baffa JM, Strum JM, Al-Seikhan BA et al. Cellular mechanisms of altered contractility in the hypertrophied heart: Big hearts, big sparks. Circulation Research. 1999 Mar 5;84(4):424-434.
Shorofsky, Stephen R. ; Aggarwal, Rajesh ; Corretti, Mary ; Baffa, Jeanne M. ; Strum, Judy M. ; Al-Seikhan, Badr A. ; Kobayashi, Yvonne M. ; Jones, Larry ; Wier, W. Gil ; Balke, C. William. / Cellular mechanisms of altered contractility in the hypertrophied heart : Big hearts, big sparks. In: Circulation Research. 1999 ; Vol. 84, No. 4. pp. 424-434.
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