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Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects

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Abstract

Cardiac hypertrophy is promoted by adrenergic over-activation and represents an independent risk factor for cardiovascular morbidity and mortality. The basic knowledge about mechanisms by which sustained adrenergic activation promotes myocardial growth, as well as understanding how structural changes in hypertrophied myocardium could affect myocardial function has been acquired from studies using an animal model of chronic systemic β-adrenoreceptor agonist administration. Sustained β-adrenoreceptor activation was shown to enhance the synthesis of myocardial proteins, an effect mediated via stimulation of myocardial growth factors, up-regulation of nuclear proto-oncogenes, induction of cardiac oxidative stress, as well as activation of mitogen-activated protein kinases and phosphatidylinositol 3-kinase. Sustained β-adrenoreceptor activation contributes to impaired cardiac autonomic regulation as evidenced by blunted parasympathetically-mediated cardiovascular reflexes as well as abnormal storage of myocardial catecholamines. Catecholamine-induced cardiac hypertrophy is associated with reduced contractile responses to adrenergic agonists, an effect attributed to downregulation of myocardial β-adrenoreceptors, uncoupling of β-adrenoreceptors and adenylate cyclase, as well as modifications of downstream cAMP-mediated signaling. In compensated cardiac hypertrophy, these changes are associated with preserved or even enhanced basal ventricular systolic function due to increased sarcoplasmic reticulum Ca2+ content and Ca2+-induced sarcoplasmic reticulum Ca2+ release. The increased availability of Ca2+ to maintain cardiomyocyte contraction is attributed to prolongation of the action potential due to inhibition of the transient outward potassium current as well as stimulation of the reverse mode of the Na+–Ca2+ exchange. Further progression of cardiac hypertrophy towards heart failure is due to abnormalities in Ca2+ handling, necrotic myocardial injury, and increased myocardial stiffness due to interstitial fibrosis.

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Acknowledgments

Editorial comments suggested by Prof. D. Paul Thomas (University of Wyoming, USA) are greatly appreciated.

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  1. Cardiology Group, School of Clinical Sciences, University Clinical Departments, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK

    Oleg E. Osadchii

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Correspondence to Oleg E. Osadchii.

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Osadchii, O.E. Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev 12, 66–86 (2007). https://doi.org/10.1007/s10741-007-9007-4

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  • DOI: https://doi.org/10.1007/s10741-007-9007-4

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