The goal of this proposal is to obtain mechanistic insights into the role of cardiac mitochondria in defining the substrate for atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice. With a projected 6-fold increase in the prevalence and a cost exceeding $15 billion per year, AF remains a major national health problem. Despite the recognition that aging increases susceptibility of the atria to fibrillation, with a 100 fold higher prevalence in the older-elderly compared to young adults, the molecular bases for this remains unknown. Changes in hemodynamic, vascular, and metabolic factors that accompany aging or associated disease contribute to functional and structural atrial remodeling promoting cardiomyocytes loss and fibrosis that increases susceptibility to fibrillation, however, the molecular bases for such alterations contributing to the progression of atrial dysfunction are not well defined. In our preliminary studies, using human atrial tissue, a distinct transcriptional downregulation of genes regulating mitochondrial energetics and signaling pathways involved in energy production and utilization, cell loss and fibrosis was demonstrated with aging and AF. Additionally, functional defects with impaired capacity to maintain cellular energetics and ionic homeostasis under stress were demonstrated in senescent mitochondria that can be ameliorated by modulating mitochondrial membrane permeability. Based on these, we hypothesize that susceptibility to AF in the elderly results from diminished mitochondrial functional reserves in the atria that promote cardiomyocyte loss and fibrosis due to enhanced sensitivity of the myocardium to energetic failure, calcium overload and oxidative injury during stress, thus facilitating development and progression of the substrate for AF. We propose 1) to identify differences in atrial structure and function, energetics and mitochondrial susceptibility to stress in patients with low or high risk for the development of AF and those with paroxysmal, persistent or permanent AF;2) to identify mechanisms underlying atrial energetic deficits and mitochondrial dysfunction predisposing to enhanced cell loss and fibrosis;and 3) to determine the protective role of mitochondrial modulation against mitochondrial and cellular injury during metabolic stress in patients at risk for or with AF.
These aims will be achieved using atrial tissue obtained from patients undergoing coronary artery bypass surgery without or with risk factors for AF (heart failure, hypertension, or mitral regurgitation) or a history of paroxysmal, persistent or permanent AF. An integrative approach combining clinical information with in vivo and in vitro atrial structural and functional data obtained by imaging with comprehensive cellular and mitochondrial studies assessing differences in ultrastructural, functional, molecular, genetic and proteomic changes in atrial tissue between those at risk of AF, who develops AF following surgery and those with AF, not only is highly innovative but also of high clinical significance. The results will provide new insights into the role of mitochondria priming the substrate for AF and identify novel targets for the development of therapeutics toward prevention of AF.

Public Health Relevance

This study will identify the role of mitochondrial dysfunction in aging-associated susceptibility to atrial fibrillation. A comprehensive multiparametric approach will be used to integrate expertise from clinical cardiology, cardiac electrophysiology, cardiac surgery, imaging, mitochondrial physiology, aging, genomics and proteomics for analysis of atrial structural and functional changes with aging, development of risk factors for AF and with atrial fibrillation. These studies ranging from in vivo, in vitro, cellular and mitochondrial levels with direct correlation with the changes in expression of genes and proteins regulating mitochondrial function will provide novel insights into the role of mitochondria in predisposition of the senescent heart to arrhythmogenesis and may lead to recognition of new targets to prevent atrial remodeling that predispose to atrial fibrillation. This information is of high public health interest, since the growing epidemic of atrial fibrillation in the elderly continues to contribute to increased risk for stroke, disability and death in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101240-04
Application #
8241932
Study Section
Special Emphasis Panel (ZHL1-CSR-N (F1))
Program Officer
Schwartz, Lisa
Project Start
2010-04-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$509,165
Indirect Cost
$105,066
Name
Aurora Health Care, Inc.
Department
Type
DUNS #
130185960
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
Mirza, Mahek; Shen, Win-Kuang; Sofi, Aamir et al. (2013) Frequent periodic leg movement during sleep is associated with left ventricular hypertrophy and adverse cardiovascular outcomes. J Am Soc Echocardiogr 26:783-90
Mirza, Mahek; Shen, Win-Kuang; Sofi, Aamir et al. (2013) Frequent periodic leg movement during sleep is an unrecognized risk factor for progression of atrial fibrillation. PLoS One 8:e78359
Strunets, Anton; Mirza, Mahek; Sra, Jasbir et al. (2013) Novel anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly. Expert Rev Clin Pharmacol 6:677-89
Holmuhamedov, Ekhson L; Czerny, Christoph; Beeson, Craig C et al. (2012) Ethanol suppresses ureagenesis in rat hepatocytes: role of acetaldehyde. J Biol Chem 287:7692-700
Mirza, Mahek; Caracciolo, Giuseppe; Khan, Uzma et al. (2011) Left atrial reservoir function predicts atrial fibrillation recurrence after catheter ablation: a two-dimensional speckle strain study. J Interv Card Electrophysiol 31:197-206