Aging increases cardiovascular disability, yet the molecular basis for increased stress susceptibility of the senescent human myocardium remains unknown. Particularly little is known about the atria, despite the exponential increase in the prevalence of atrial electrical and structural abnormalities with advancing age. Our preliminary studies in aging rodents demonstrate an age-associated loss of endogenous cardioprotection associated with reduction in mitochondrial energetic reserves and disruption of myocardial capacity for transduction of stress signals into protective responses. Deficient in defense mechanisms, the aging rodent heart can however be protected by modulation of mitochondrial membrane potential and activation of the ATP- sensitive potassium (KATP) channel. Whether aging-associated loss of endogenous cardioprotective responses also occurs in aged human atria is not clear. In pilot studies, using atrial tissue from adult and aged patients, a distinct transcriptional downregulation of genes regulating mitochondrial energetics and cardioprotective pathways, including the human KATP channel metabolic decoder subunit, was demonstrated in aging heart. We hypothesize that the increased vulnerability of the senescent human atria to injury results from an aging- associated attenuation in energetic homeostasis that sensitizes the myocardium to energetic failure, calcium overload and increased oxidants during stress. We propose to define age-related i) changes in energetic homeostasis in human atria and its functional consequences on tolerance to stress; ii) mechanisms that underlie age-related changes in energetics with focus on pathways that link energy production with energy sensing and utilization pathways; and iii) rescue senescent human atrial myocytes and mitochondria from stress-induced injury by modulation of stress responsive homeostatic pathways.
These aims will be achieved using human right atrial appendage obtained during surgery from adult (35-55 years) and elderly (65-85 years) patients. The novelty of the proposed studies is to obtain functional, molecular, genetic and proteomic information from the same human atrial tissue to characterize age-related changes in cardiac energetics, metabolic and cardioprotective signaling, protein-protein interactions and cellular physiology under baseline and stress conditions. Information on the sensitivity of human aged and adult atria to stress and cardioprotective responsiveness to KATP channel activation, mitochondrial membrane potential modulation and inhibition of mitochondrial permeability transition pore will also be determined. This comprehensive analysis of the effect of aging on atrial biology is of high clinical significance. Recognition of aging-associated specific functional defects and its rectification by homeostatic pathway modulation will identify targets that can be selected to reinstate the lost protective responsiveness of the senescent heart and thereby development of strategies to limit adverse atrial structural and electrical remodeling with stress and disability with aging. Public Health Relevance: This study will identify specific defects that underlie loss of cardioprotection in the elderly and identify therapeutic targets to prevent, slow or reverse changes that increase vulnerability of the aging atria to injury. This information is of high public health interest, since cardiovascular diseases continue to be the leading cause of disability in the elderly. ? ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Special Emphasis Panel (ZRG1-CVS-D (03))
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Schwartz, Lisa
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Mayo Clinic, Rochester
United States
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Emelyanova, Larisa; Preston, Claudia; Gupta, Anu et al. (2018) Effect of Aging on Mitochondrial Energetics in the Human Atria. J Gerontol A Biol Sci Med Sci 73:608-616
Jahangir, A; Mirza, M; Shahreyar, M et al. (2018) Presence of obesity is associated with lower mortality in elderly patients with implantable cardioverter defibrillator. Int J Obes (Lond) 42:169-174
Ross, Gracious R; Bajwa Jr, Tanvir; Edwards, Stacie et al. (2017) Enhanced store-operated Ca2+ influx and ORAI1 expression in ventricular fibroblasts from human failing heart. Biol Open 6:326-332
Ortiz, Daniel; Singh, Maharaj; Jahangir, Arshad et al. (2017) Bivalirudin versus unfractionated heparin during peripheral vascular interventions: A Propensity-matched Study. Catheter Cardiovasc Interv 89:408-413
Emelyanova, Larisa; Ashary, Zain; Cosic, Milanka et al. (2016) Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation. Am J Physiol Heart Circ Physiol 311:H54-63
Turagam, Mohit K; Mirza, Mahek; Werner, Paul H et al. (2016) Circulating Biomarkers Predictive of Postoperative Atrial Fibrillation. Cardiol Rev 24:76-87
Rizvi, Farhan; DeFranco, Alessandra; Siddiqui, Ramail et al. (2016) Chamber-specific differences in human cardiac fibroblast proliferation and responsiveness toward simvastatin. Am J Physiol Cell Physiol 311:C330-9
Negmadjanov, Ulugbek; Godic, Zarko; Rizvi, Farhan et al. (2015) TGF-?1-mediated differentiation of fibroblasts is associated with increased mitochondrial content and cellular respiration. PLoS One 10:e0123046
Jahangir, Arshad; Jain, Renuka (2015) Strain Echocardiography and LQTS Subtypes: Mechanical Alterations in an Electrical Disorder. JACC Cardiovasc Imaging 8:511-513
Shahreyar, Muhammad; Mupiddi, Vijayadershan; Choudhuri, Indrajit et al. (2015) Implantable cardioverter defibrillators in diabetics: efficacy and safety in patients at risk of sudden cardiac death. Expert Rev Cardiovasc Ther 13:897-906

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