The investigators will study in vivo global and regional cardiac beta-adrenergic responsiveness and cardiac sympathetic nervous system (SNS) function using positron emission tomographic (PET) imaging in groups of healthy young and older subjects to define the effects of aging on the cardiac SNS. The PET measures of cardiac SNS will be related to left ventricular contractile responses to beta agonist stimulation with isoproterenol and to contractile responses to exercise stress. Whether beta-adrenergic responsiveness and cardiac SNS function improve with exercise training, which is known to improve exercise left ventricular function, will also be determined. The general hypothesis is that changes in cardiac SNS function contribute to declines in beta-adrenergic responsiveness with aging in humans, that the deficits occur in both genders, and that the SNS function deficits and decreased responsiveness can be ameliorated by exercise training.
Aim 1 will determine the effects of normal aging on global and regional cardiac SNS function measured by PET imaging and the effects of aging on left ventricular beta-adrenergic responsiveness measured during isoproterenol infusions and exercise stress. Pre-synaptic SNS cardiac function will be assessed by PET imaging of the norepinephrine analog, 11C-MHED, and post synaptic SNS cardiac function (beta receptor density) will be measured by imaging of the beta receptor antagonist, 11C-CGP 12177. The hypothesis is that cardiac beta receptor down regulation and pre synaptic up-regulation occur with aging in vivo and that the SNS changes correlate with the magnitude of reduced beta-adrenergic responsiveness of the left ventricle. It is further hypothesized that there are no gender differences in reduced beta-adrenergic responsiveness or in the cardiac SNS defects.
Aim 2 will determine beta-adrenergic responsiveness and cardiac SNS function before and after six months of endurance training in groups of healthy young and older subjects. The investigators hypothesize that training will improve cardiac beta-adrenergic responsiveness by alterations in the cardiac SNS measured by PET.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015462-04
Application #
6372196
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Dutta, Chhanda
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
2001
Total Cost
$339,770
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bahrainy, Samira; Levy, Wayne C; Busey, Janet M et al. (2016) Exercise training bradycardia is largely explained by reduced intrinsic heart rate. Int J Cardiol 222:213-216
Caldwell, James H; Link, Jeanne M; Levy, Wayne C et al. (2008) Evidence for pre- to postsynaptic mismatch of the cardiac sympathetic nervous system in ischemic congestive heart failure. J Nucl Med 49:234-41
Woo, J Susie; Derleth, Christina; Stratton, John R et al. (2006) The influence of age, gender, and training on exercise efficiency. J Am Coll Cardiol 47:1049-57
Madden, Kenneth M; Levy, Wayne C; Stratton, John K (2006) Exercise training and heart rate variability in older adult female subjects. Clin Invest Med 29:20-8
Madden, Kenneth M; Levy, Wayne C; Stratton, John R (2006) Normal aging impairs upregulation of the beta-adrenergic but not the alpha-adrenergic response: aging and adrenergic upregulation. J Cardiovasc Pharmacol 48:153-9
Link, Jeanne M; Stratton, John R; Levy, Wayne et al. (2003) PET measures of pre- and post-synaptic cardiac beta adrenergic function. Nucl Med Biol 30:795-803
Stratton, John R; Levy, Wayne C; Caldwell, James H et al. (2003) Effects of aging on cardiovascular responses to parasympathetic withdrawal. J Am Coll Cardiol 41:2077-83
Tseng, H; Link, J M; Stratton, J R et al. (2001) Cardiac receptor physiology and its application to clinical imaging: present and future. J Nucl Cardiol 8:390-409
Stratton, J R (1999) Effects of age and gender on the cardiovascular responses to isoproterenol. J Gerontol A Biol Sci Med Sci 54:B401-3