Adrenergic overload and apoptosis in heart failure: implications for therapy.

Colucci WS, Sawyer DB, Singh K, Communal C
J Card Fail. 2000 6 (2 Suppl 1): 1-7

PMID: 10908092

Sympathetic nervous system activity to the myocardium is increased in patients with heart failure. It is now appreciated that norepinephrine (NE), the primary sympathetic neurotransmitter, can exert direct adverse effects on cardiac myocytes and might thereby contribute to pathological remodeling, a chronic process which leads to progressive left ventricular (LV) chamber dilation and loss of contractile function. The demonstration of apoptosis in failing human hearts has led to the thesis that continuing loss of viable myocytes is a mechanism for progressive myocardial failure. For many years it has been appreciated that chronic exposure to catecholamines can exert a toxic effect on the myocardium. In vitro studies in cultured cardiac myocytes show that tonic exposure to NE increases the number of apoptotic myocytes via stimulation of the beta-adrenergic receptor (beta-AR) pathway. Interestingly, a beta1-AR selective antagonist completely prevented NE-stimulated apoptosis, whereas a beta2-AR selective antagonist increased the amount of apoptosis, suggesting that beta1- versus beta2-AR may couple to different signaling pathways. In rats, isoproterenol infusion for as little as 12 hours increased the frequency of terminal deoxynucleotidyltransferase-mediated nick end-labeling (TUNEL)-positive myocytes. Likewise, mice that overexpress beta1-AR or G alpha s in the myocardium develop left ventricular dilation, contractile dysfunction and apoptosis. Although the link between apoptosis and myocardial failure remains to be proven, these in vitro and in vivo observations provide a rational mechanism by which beta-AR antagonists may help to prevent or slow LV remodeling and failure in patients.

MeSH Terms (15)

Adrenergic beta-Agonists Animals Animals, Newborn Apoptosis Gene Expression Regulation Heart Failure Humans Isoproterenol Mice Mice, Transgenic Norepinephrine Rats Receptors, Adrenergic, beta Ventricular Dysfunction, Left Ventricular Remodeling

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