Project 3 will test the overarching hypothesis that variation in the gene (ADRA2A) encoding the a2A- adrenergic receptor (a2A-AR) is an important determinant of platelet aggregation and insulin secretion in pathological and physiological conditions that occur in the setting of sympathetic activation. Recent independent lines of evidence, including our own studies, implicate a2A-AR genetic variation, particularly haplotype 4 (characterized by rs553668, a variant present in 16-24% of people), as a mediator of important differences in adrenergically-mediated responses. However, the clinical consequences of such variability, which are most likely to be manifest under conditions of sympathetic activation, are not known. Platelet aggregation in response to epinephrine is mediated by a2A-ARs;there is increased aggregation and increased risk of myocardial infarction concurrent with the early morning diurnal peak in sympathetic activity. The contribution of genetic variability to adrenergically-mediated diurnal platelet responses is not known. Accordingly, Specific Aim 1 will test the hypothesis that ADRA2A haplotype affects diurnal platelet aggregation responses. Sympathetic activation, in addition to increasing platelet aggregation, also inhibits insulin secretion;this response is mediated by a2A-ARs and is affected by ADRA2A genetic variation, in particular, haplotype 4. Two conditions characterized by hyperglycemia in the setting of sympathetic activation are stress-induced hyperglycemia, such as commonly occurs in patients with serious illness, and gestational diabetes. Thus, we will test the hypothesis that ADRA2A haplotype is associated with increased risk of stress-induced hyperglycemia in patients with myocardial infarction (Specific Aim 2), and gestational diabetes (Specific Aim 3). The proposed studies will translate basic science findings and previous genetic discovery studies into fundamental mechanistic information that is clinically relevant. This will allow, on the basis of genetic information, the future targeting for interventions those individuals at increased risk of specific adverse outcomes that occur under conditions characterized by increased sympathetic drive.

Public Health Relevance

Sympathetic activation is important in the pathogenesis of many diseases. The ability to identify patients at high risk of complications mediated by increased sympathetic activity would allow the eariy identification of disease and targeted interventions to prevent complications in this group.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL056693-16
Application #
8293465
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
16
Fiscal Year
2012
Total Cost
$303,030
Indirect Cost
$103,485
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Kawai, Vivian K; Chung, Cecilia P; Solus, Joseph F et al. (2015) The ability of the 2013 American College of Cardiology/American Heart Association cardiovascular risk score to identify rheumatoid arthritis patients with high coronary artery calcification scores. Arthritis Rheumatol 67:381-5
Bestawros, Michael; Darbar, Dawood; Arain, Amir et al. (2015) Ictal asystole and ictal syncope: insights into clinical management. Circ Arrhythm Electrophysiol 8:159-64
Adefurin, A; Ghimire, L V; Kohli, U et al. (2015) Genetic variation in the ?1A-adrenergic receptor and phenylephrine-mediated venoconstriction. Pharmacogenomics J 15:310-5
Mar, Philip L; Raj, Vidya; Black, Bonnie K et al. (2014) Acute hemodynamic effects of a selective serotonin reuptake inhibitor in postural tachycardia syndrome: a randomized, crossover trial. J Psychopharmacol 28:155-61
Mai, Tu H; Wu, Jing; Diedrich, André et al. (2014) Calcitonin gene-related peptide (CGRP) in autonomic cardiovascular regulation and vascular structure. J Am Soc Hypertens 8:286-96
Gamboa, Alfredo; Okamoto, Luis E; Arnold, Amy C et al. (2014) Autonomic blockade improves insulin sensitivity in obese subjects. Hypertension 64:867-74
Ramirez, Claudia E; Okamoto, Luis E; Arnold, Amy C et al. (2014) Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension 64:1235-40
Jeff, Janina M; Donahue, Brian S; Brown-Gentry, Kristin et al. (2014) Genetic variation in the *1-adrenergic receptor is associated with the risk of atrial fibrillation after cardiac surgery. Am Heart J 167:101-108.e1
Biaggioni, Italo (2014) New developments in the management of neurogenic orthostatic hypotension. Curr Cardiol Rep 16:542
Raj, Satish R (2014) Highlights in clinical autonomic neurosciences: Insights into the roles of the carotid body and carotid baroreceptor. Auton Neurosci 183:80-2

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