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

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 beta-adrenoreceptor agonist administration. Sustained beta-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 beta-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 beta-adrenoreceptors, uncoupling of beta-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 Ca(2+) content and Ca(2+)-induced sarcoplasmic reticulum Ca(2+) release. The increased availability of Ca(2+) 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(+)-Ca(2+) exchange. Further progression of cardiac hypertrophy towards heart failure is due to abnormalities in Ca(2+) handling, necrotic myocardial injury, and increased myocardial stiffness due to interstitial fibrosis.

Removal of the Cardiac Troponin I N-terminal Extension Improves Cardiac Function in Aged Mice

“…It is worth noting that this mechanism functions without an overall chronic activation of ␤-adrenergic pathways, that has proven detrimental to cardiac function (see Ref. 41 for review). Thus the cTnI N-terminal extension serves as a mechanism to modulate cardiac Ca 2ϩ sensitivity and cross-bridge cycling by ␤-adrenergic induced phosphorylation at Ser-23/24 or through its removal, both resulting from an alteration of its interaction with TnC to favor the closed conformation.…”

β2-Adrenergic and M2-muscarinic receptors decrease basal t-tubular L-type Ca2+ channel activity and suppress ventricular contractility in heart failure

“…In experiments, transgenic overexpression of 1-adrenergic receptors in the murine heart causes dilated cardiomyopathy (Engelhardt et al, 1999). We also found that metoprolol, a selective 1-adrenergic antagonist, almost completely prevented cardiac hypertrophy and failure of isoproterenol-treated mice (data not shown), indicating that excessive stimulation of 1-adrenergic receptors is the primary cause of myocardial remodeling in isoproterenol-treated mice (Osadchii, 2007;Xiao et al, 2006).…”

“…In heart failure, chronic and excessive -adrenergic receptor stimulation causes remodeling of the myocardium and aggravates cardiac function (Osadchii, 2007;Rockman et al, 2002). This concept is the theoretical basis for the treatment of heart failure with -adrenergic antagonists.…”

“…Thus, development of medical treatment based on further understanding of the pathophysiology of heart failure is required to improve the quality of life of patients with heart failure. Maladaptive remodeling of ventricular excitation-contraction (EC) coupling caused by such as chronic -adrenergic receptor stimulation, and activation of the reninangiotensin-aldosterone system plays a predominant role in an impaired cardiac function in heart failure (Mann, 2008;Osadchii, 2007;Rockman et al, 2002). The underlying primary defect is a decrease in sarcoplasmic reticulum (SR) Ca 2+ content due to decreased activity and/or expression of SR Ca 2+ -ATPase 2, increased expression of sarcolemmal Na + /Ca 2+ exchangers and diastolic Ca 2+ leak from the SR via ryanodine receptors (Bers, 2008).…”

Combined blockade of β- and α1-adrenoceptors in left ventricular remodeling induced by hypertension: Beneficial or not?

“…1,3 Chronic AR stimulation promotes pathological remodeling, leading to hypertrophy and/or heart failure. 2,7,8 b 1 -AR signaling shows strong down-regulation in pathophysiological conditions, whereas a 1 -AR expression does not change. 5 Relative increases in a 1 -AR expression levels raise this receptor subtype to a more important role in the regulation of cardiac function in pathophysiological conditions.…”