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(Circulation Research. 2005;97:847.)
© 2005 American Heart Association, Inc.

Editorials

Targeted Uptake-1 Carrier to Rescue the Failing Heart

Fabio A. Recchia, Mauro Giacca

From the Department of Physiology (F.A.R.), New York Medical College, Valhalla, NY; Scuola Superiore Sant’Anna (F.A.R.), Sector of Medicine, Pisa, Italy; and the Molecular Medicine Laboratory (M.G.), International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.

Correspondence to Fabio A. Recchia, MD, PhD, Department of Physiology, New York Medical College, Valhalla, NY 10595. E-mail fabio_recchia@nymc.edu

See related article, pages 928–936

Key Words: norepinephrine • gene transfer • heart failure

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Heart failure is characterized by sympathetic nervous system activation with consequent increase in cardiac and systemic norepinephrine (NE) release. Sympathetic hyperactivity preferentially targets the heart during early stages of failure and subsequently involves other organs. A landmark study published in 1984 by Cohn et al showed that plasma NE concentration in venous blood sampled at rest provides a better guide to the prognosis of chronic congestive heart failure than other indexes of cardiac performance.¹

Although the augmented adrenergic drive in the failing heart is initially a compensatory mechanism to preserve contractility and cardiac output, in the long term it leads to very complex maladaptive phenomena (Figure). In particular, two deleterious effects must be mentioned, both caused by excessive catecholamine release: cardiomyocyte injury and functional denervation. NE is indeed markedly toxic for cardiomyocytes at concentrations typically found in the failing heart. Sustained ß-adrenergic stimulation leads to cAMP-mediated calcium overload of the cardiac cell, with a resulting decrease in synthetic activity and/or viability² and contractile impairment. It can also trigger myocyte apoptosis mediated by protein kinase A and calcium entry via voltage-dependent calcium channels.³ On the other hand, functional denervation of the failing heart is responsible for reduced inotropic support, especially during exercise, and can be attributed to at least three mechanisms: depletion of NE stores in cardiac nerve endings,^4–5 selective downregulation of ß₁-adrenoceptors,⁶ and desensitization of the intracellular ß-adrenergic signaling cascade, mainly mediated by ß-adrenergic receptor kinase and ß-arrestin.⁷ The excessive NE release in myocardial interstitial space is . . . [Full Text of this Article]

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