Preserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation

• Published in: American journal of physiology. Heart and circulatory physiology 2005-10, Vol.289 (4), p.H1359-H1365
• Main Authors: Kiriazis, Helen, Du, Xiao-Jun, Feng, Xinheng, Hotchkin, Elodie, Marshall, Tanneale, Finch, Samara, Gao, Xiao-Ming, Lambert, Gavin, Choate, Julia K, Kaye, David M
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - pharmacology; Animals; Echocardiography; Female; Gene Expression; Heart - innervation; Heart - physiology; Hypertrophy, Right Ventricular - diagnostic imaging; Hypertrophy, Right Ventricular - genetics; Hypertrophy, Right Ventricular - physiopathology; Isoproterenol - pharmacology; Male; Mice; Mice, Transgenic; Myocardium - pathology; Nerve Growth Factor - genetics; Norepinephrine - blood; Norepinephrine - pharmacokinetics; Sympathetic Nervous System - pathology; Sympathetic Nervous System - physiology; Tritium; Ventricular Function, Left
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01010.2004

1 Experimental Cardiology Laboratory, 2 Human Neurotransmitter Laboratory, and 3 Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, Melbourne; and 4 Department of Physiology, Monash University, Melbourne, Australia Submitted 4 October 2004 ; accepted in final form 9 May 2005 Cardiac-specific overexpression of nerve growth factor (NGF), a neurotrophin, leads to sympathetic hyperinnervation of heart. As a consequence, adverse functional changes that occur after chronically enhanced sympathoadrenergic stimulation of heart might develop in this model. However, NGF also facilitates synaptic transmission and norepinephrine uptake, effects that would be expected to restrain such deleterious outcomes. To test this, we examined 5- to 6-mo-old transgenic (TG) mice that overexpress NGF in heart and their wild-type (WT) littermates using echocardiography, invasive catheterization, histology, and catecholamine assays. In TG mice, hypertrophy of the right ventricle was evident (+67%), but the left ventricle was only mildly affected (+17%). Left ventricular (LV) fractional shortening and fractional area change values as indicated by echocardiography were similar between the two groups. Catheterization experiments revealed that LV ±dP/d t values were comparable between TG and WT mice and responded similarly upon isoproterenol stimulation, which indicates lack of -adrenergic receptor dysfunction. Although norepinephrine levels in TG LV tissue were approximately twofold those of WT tissue, TG plasma levels of the neuronal norepinephrine metabolite dihydroxyphenyglycol were fivefold those of WT plasma. A greater neuronal uptake activity was also observed in TG LV tissue. In conclusion, overexpression of NGF in heart leads to sympathetic hyperinnervation that is not associated with detrimental effects on LV performance and is likely due to concomitantly enhanced norepinephrine neuronal uptake. echocardiography; myocardial contraction; catecholamine; transgenic; nerve growth factor Address for reprint requests and other correspondence: D. M. Kaye, Wynn Dept. of Metabolic Cardiology, Baker Heart Research Institute, P.O. Box 6492 St. Kilda Road Central, Melbourne, Victoria 8008, Australia (E-mail: david.kaye{at}baker.edu.au )