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Calcium mishandling impairs contraction in right ventricular hypertrophy prior to overt heart failure

  • Muscle physiology
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Abstract

Currently, there are no tailored therapies available for the treatment of right ventricular (RV) hypertrophy, and the cellular mechanisms that underlie the disease are poorly understood. We investigated the cellular changes that occur early in the progression of the disease, when RV hypertrophy is evident, but prior to the onset of heart failure. Intracellular Ca2+ ([Ca2+]i) handling was examined in a rat model of monocrotaline (MCT)-induced pulmonary hypertension and subsequent RV hypertrophy. [Ca2+]i and stress production were measured in isolated RV trabeculae under baseline conditions (1-Hz stimulation, 1.5 mM [Ca2+]o, 37 °C), and in response to inotropic interventions (5-Hz stimulation or 1-μM isoproterenol). Under baseline conditions, MCT trabeculae had impaired Ca2+ release in response to stimulation with a 45% delay in the time-to-peak Ca2+, but there was no difference in the amplitude and decay of the Ca2+ transient, or active stress relative to RV trabeculae from normotensive hearts (CON). Increasing stimulation frequency from 1 to 5 Hz increased stress in CON, but not MCT trabeculae. Similarly, β-adrenergic stimulation with isoproterenol increased Ca2+ transient amplitude and active stress in CON, but not in MCT trabeculae, despite accelerating Ca2+ transient decay in trabeculae from both groups. During isoproterenol treatment, MCT trabeculae showed increased diastolic Ca2+ leak, which may explain the blunted inotropic response to β-adrenergic stimulation. Confocal imaging of trabeculae fixed following functional measurements showed that myocytes were on average wider, and transverse-tubule organisation was disrupted in MCT which provides a mechanism to explain the observed slower release of Ca2+.

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Acknowledgments

We would like to thank Linley Nisbet for the animal husbandry.

Funding

This work was funded by the Project Grant No. 1601 from the National Heart Foundation of New Zealand. Amelia Power was the recipient of the Patricia Mary Carroll Estate Doctoral Scholarship.

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Authors and Affiliations

  1. Department of Physiology, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, 1023, New Zealand

    Amelia S. Power, David J. Crossman, Denis S. Loiselle & Marie-Louise Ward

  2. School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland, 1023, New Zealand

    Anthony J. Hickey

  3. Auckland Bioengineering Institute, University of Auckland, Private Bag 92019, Auckland, 1023, New Zealand

    Denis S. Loiselle

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  1. Amelia S. Power
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  2. Anthony J. Hickey
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Correspondence to Marie-Louise Ward.

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The experimental protocol was approved by the Animal Ethics Committee of The University of Auckland (permit number AEC 1403).

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Power, A.S., Hickey, A.J., Crossman, D.J. et al. Calcium mishandling impairs contraction in right ventricular hypertrophy prior to overt heart failure. Pflugers Arch - Eur J Physiol 470, 1115–1126 (2018). https://doi.org/10.1007/s00424-018-2125-0

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