Mitochondrial Dysfunction and Susceptibility to Atrial Fibrillation in the Elderly

Dr. Arshad Jahangir of the Division of Cardiovascular Diseases at Mayo Clinic Arizona studies aging and its effect on the heart’s response to stress. Dr. Jahangir and co-investigators were recently awarded  a 4-year grant from the National Heart, Lung and Blood Institute of the National Institutes of Health to study mechanistic insights into the role of cardiac mitochondria in defining the substrate for atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice.

Summary:
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 basis for this susceptibility 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. The molecular bases for such alterations contributing to the progression of atrial dysfunction, however, are not well defined.

In 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. The defects can be ameliorated by modulating mitochondrial membrane permeability.

Based on these findings, Dr. Jahangir and his co-investigators hypothesize that susceptibility to AF in the elderly results from diminished mitochondrial functional reserves in the atria. The diminished reserves promote cardiomyocyte loss and fibrosis due to enhanced sensitivity of the myocardium to energetic failure, calcium overload and oxidative injury during stress, facilitating development and progression of the substrate for AF.

The study proposes:

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
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. To assess those at risk of AF, those who develop AF following surgery and those with AF, investigators will use an  integrative approach that combines:

• clinical information
• in vivo and in vitro atrial structural and functional data obtained by imaging
• comprehensive cellular and mitochondrial studies assessing differences in ultrastructural, functional, molecular, genetic and proteomic changes in atrial tissue

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.

Co-investigators:
Francisco A. Arabia, M.D., Louis A. Lanza, M.D., Marek Belohlavek, M.D., Ph.D.