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Regular Research

Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity

Joshua D. Lovelock, Michelle M. Monasky, Euy-Myoung Jeong, Harvey A. Lardin, Hong Liu, Bindiya G. Patel, Domenico M. Taglieri, Lianzhi Gu, Praveen Kumar, Narayan Pokhrel, Dewan Zeng, Luiz Belardinelli, Dan Sorescu, R.John Solaro, Samuel C. Dudley
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https://doi.org/10.1161/CIRCRESAHA.111.258251
Circulation Research. 2012;CIRCRESAHA.111.258251
Originally published February 16, 2012
Joshua D. Lovelock
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Michelle M. Monasky
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Euy-Myoung Jeong
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Harvey A. Lardin
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Hong Liu
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Bindiya G. Patel
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Domenico M. Taglieri
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Lianzhi Gu
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Praveen Kumar
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Narayan Pokhrel
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Dewan Zeng
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Luiz Belardinelli
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Dan Sorescu
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R.John Solaro
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Samuel C. Dudley
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Abstract

Rationale: Previously, we demonstrated that a deoxycorticosterone acetate (DOCA)-salt hypertensive mouse model produces cardiac oxidative stress and diastolic dysfunction with preserved systolic function. Oxidative stress has been shown to increase late inward sodium current (INa), reducing the net cytosolic Ca2+ efflux.

Objective: Oxidative stress in the DOCA-salt model may increase late INa, resulting in diastolic dysfunction amenable to treatment with ranolazine.

Methods and Results: Echocardiography detected evidence of diastolic dysfunction in hypertensive mice that improved after treatment with ranolazine (E/E': sham, 31.9±2.8, sham+ranolazine, 30.2±1.9, DOCA-salt, 41.8±2.6, and DOCA-salt+ranolazine, 31.9±2.6; P=0.018). The end-diastolic pressure-volume relationship slope was elevated in DOCA-salt mice, improving to sham levels with treatment (sham, 0.16±0.01 versus sham+ranolazine, 0.18±0.01 versus DOCA-salt, 0.23±0.2 versus DOCA-salt+ranolazine, 0.17±0.0 1 mm Hg/L; P<0.005). DOCA-salt myocytes demonstrated impaired relaxation, τ, improving with ranolazine (DOCA-salt, 0.18±0.02, DOCA-salt+ranolazine, 0.13±0.01, sham, 0.11±0.01, sham+ranolazine, 0.09±0.02 seconds; P=0.0004). Neither late INa nor the Ca2+ transients were different from sham myocytes. Detergent extracted fiber bundles from DOCA-salt hearts demonstrated increased myofilament response to Ca2+ with glutathionylation of myosin binding protein C. Treatment with ranolazine ameliorated the Ca2+ response and cross-bridge kinetics.

Conclusions: Diastolic dysfunction could be reversed by ranolazine, probably resulting from a direct effect on myofilaments, indicating that cardiac oxidative stress may mediate diastolic dysfunction through altering the contractile apparatus.

  • diastole
  • ranolazine
  • oxidative stress
  • myofilaments
  • Received October 6, 2011.
  • Revision received February 3, 2012.
  • Accepted February 9, 2012.
  • © 2012 American Heart Association, Inc.
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    Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity
    Joshua D. Lovelock, Michelle M. Monasky, Euy-Myoung Jeong, Harvey A. Lardin, Hong Liu, Bindiya G. Patel, Domenico M. Taglieri, Lianzhi Gu, Praveen Kumar, Narayan Pokhrel, Dewan Zeng, Luiz Belardinelli, Dan Sorescu, R.John Solaro and Samuel C. Dudley
    Circulation Research. 2012;CIRCRESAHA.111.258251, originally published February 16, 2012
    https://doi.org/10.1161/CIRCRESAHA.111.258251

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    Ranolazine Improves Cardiac Diastolic Dysfunction Through Modulation of Myofilament Calcium Sensitivity
    Joshua D. Lovelock, Michelle M. Monasky, Euy-Myoung Jeong, Harvey A. Lardin, Hong Liu, Bindiya G. Patel, Domenico M. Taglieri, Lianzhi Gu, Praveen Kumar, Narayan Pokhrel, Dewan Zeng, Luiz Belardinelli, Dan Sorescu, R.John Solaro and Samuel C. Dudley
    Circulation Research. 2012;CIRCRESAHA.111.258251, originally published February 16, 2012
    https://doi.org/10.1161/CIRCRESAHA.111.258251
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