The effects of norepinephrine on myocardial biology: Implications for the therapy of heart failure

Increased sympathetic nervous system (SNS) activity in patients with heart failure may help to support cardiovascular function. However, increased SNS activity, particularly if prolonged, may exert deleterious effects on cardiovascular structure and function by stimulating pathologic myocardial remodeling. In vitro, norepinephrine mimics many features of myocardial remodeling, including hypertrophy of individual myocytes and reinduction of fetal genes. Furthermore, stimulation of the beta-adrenergic pathway has been shown to stimulate apoptosis of cardiac myocytes in vitro, in rats infused with isoproterenol, and in mice that overexpress the stimulatory G-protein, Gs. Thus, increased SNS activity, acting via beta-adrenergic receptors, may play an important role in the progression of myocardial failure by acting directly on myocytes and other cell types in the heart to regulate fundamental biologic properties such as growth, apoptosis, and the composition of the extracellular matrix. This thesis provides a mechanism by which beta-adrenergic antagonists may inhibit or reverse pathologic remodeling, improve myocardial structure and function, and prolong patient survival.