Heart failure afflicts greater than 5 million people in the U.S. Alarmingly, heart failure contributes to more than 300,000 deaths per year in the U.S., with a five-year mortality of approximately 50%. Heart failure is associated with reproducible cellular changes in calcium-dependent and beta-adrenergic (beta-AR) receptor-mediated signaling pathways, which occur as the body attempts to respond to the pathophysiologic changes occurring in the failing heart. Changes in beta-AR signaling and a decrease in functional coupling of remaining beta-ARs to regulatory G-proteins occurs in heart failure. However, the extent to which beta-2-AR signaling is protective or causative in chronic heart failure (HF) is unclear. Although much is known about mechanisms of pathological remodeling in HF (re-shaping of the heart), much of the information derives from small animal models with HF produced surgically, and then defined as "chronic" after several weeks. Alternatively, investigators utilize genomic perturbation models (deletion or overexpression). The objective of this application is to define the contribution of beta-2-adrenergic- receptor signaling in the development of progressive heart failure in a chronic (greater than a year), non- ischemic, large animal model. These chronic maladaptive beta-2-ARs changes affect sarcoplasmic calcium release and ryanodine receptors;and lead to a decrement in contractile function, and an increase in caspase signaling. These subsequent changes lead to pathological remodeling and heart failure. Innovative aspects of the study include the large animal model of heart failure greater than a year in duration;the capability to combine whole-animal physiology and molecular and genetic techniques;investigation of mechanisms of maladaptive isolated, chronic beta-2-AR signaling in HF;and an investigation, in part, targeted at elucidating mechanisms of reverse remodeling in cardiac resynchronization therapy. The scientific approach will be focused on an intensive cell and molecular approach that will be combined with systems physiology. In a prolonged model of HF, we will physiologically assess these animals using methodologies utilized to evaluate human patients with chronic HF;and thereafter will be able to recreate this same pathology in isolated myocytes (ex vivo). After, identifying beta-2-ARs mediated mechanisms of HF, therapeutic strategies including cardiac resynchronization therapy (CRT), beta-1 adrenergic blockade or nonspecific beta-1-and-2 blockade will be implemented. The goal will be to attenuate pathological remodeling, maladaptive signaling, and gene regulation by correcting abnormal adrenergic signaling and calcium regulation. These interventions should lead to a reversal of pathological remodeling, and facilitate recovery from progressive heart failure. The successful completion of this research will contribute to our understanding of beta-2-ARs signaling and reverse remodeling in chronic HF, and provide a better insight into the mechanisms of CRT and beta- blocker therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084498-05
Application #
8135914
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Adhikari, Bishow B
Project Start
2010-09-20
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$353,750
Indirect Cost
$103,750
Name
Morehouse School of Medicine
Department
None
Type
Schools of Medicine
DUNS #
102005451
City
Atlanta
State
GA
Country
United States
Zip Code
30310
Feldman, David; Elton, Terry S; Menachemi, Doron M et al. (2010) Heart rate control with adrenergic blockade: clinical outcomes in cardiovascular medicine. Vasc Health Risk Manag 6:387-97
Kuhn, Donald E; Nuovo, Gerard J; Terry Jr, Alvin V et al. (2010) Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human Down syndrome brains. J Biol Chem 285:1529-43
Feldman, David S (2009) Beyond the guidelines: where evidence ends and the frontier begins. Curr Opin Cardiol 24:221-2
Wexler, Randy; Elton, Terry; Pleister, Adam et al. (2009) You can do more to slow the progression of heart failure. J Fam Pract 58:122-8
Wexler, Randy; Feldman, David; Larson, Douglas et al. (2008) Adoption of exercise and readiness to change differ between Whites and African-Americans with hypertension: a report from the Ohio State University Primary Care Practice-Based Research Network (OSU-PCPBRN). J Am Board Fam Med 21:358-60
Wexler, Randy; Feldman, David (2008) Medication nonadherence for blood pressure control is primarily a physician-related factor. Arch Intern Med 168:1928-9;author reply 1929
Feldman, David; Menachemi, Doron M; Abraham, William T et al. (2008) Management strategies for stage-D patients with acute heart failure. Clin Cardiol 31:297-301
Wexler, Randy; Feldman, David (2008) Letter by Wexler and Feldman regarding article, "Socioeconomic position, race/ethnicity, and inflammation in the multi-ethnic study of atherosclerosis". Circulation 117:e344
Kuhn, Donald E; Martin, Mickey M; Feldman, David S et al. (2008) Experimental validation of miRNA targets. Methods 44:47-54
Feldman, David S; Elton, Terry S; Sun, Benjamin et al. (2008) Mechanisms of disease: detrimental adrenergic signaling in acute decompensated heart failure. Nat Clin Pract Cardiovasc Med 5:208-18

Showing the most recent 10 out of 15 publications