Mitochondrial dysfunction, expressed by the decline of the organelle membrane potential, plays a key role in myocyte senescence, and may contribute to impaired cardiac function and to the increased age-related incidence of heart failure. At the molecular and cellular levels, mitochondrial dysfunction is the best-documented mechanism of cellular senescence, yet its role in myocardial aging at the organ level has largely been neglected. Noninvasive monitoring of mitochondrial decay using a targeted probe would enable the elucidation of the dynamic and spatial processes of myocardial aging in the intact organ, as well as further the understanding of the molecular basis of the functional impairment in the aged heart. Accordingly, our long-term goal is to facilitate the design of a novel noninvasive imaging technology targeting membrane potential for the characterization of the evolution of mitochondrial dysfunction in time, space and magnitude in the intact aging heart. Specifically, we hypothesize that the voltage sensor 18F-fluorobenzyltriphenyl phosphonium (18F-FBnTP) and PET constitute an effective noninvasive technology to detect and quantify the extent and localization of mitochondrial dysfunction in the aging heart. This hypothesis is supported by PET observation of well-delineated area-specific decreases of 18F-FBnTP uptake in the heart of old vs. young rats, which strongly correlated with the extent and localization of key aspects of mitochondrial dysfunction: mtDNA damage and apoptosis. In this proposal we will characterize the age-dependent temporal and spatial kinetics of change in FBnTP myocardial distribution, correlate it with MR strain maps and molecular markers of mitochondrial dysfunction. Accordingly, the specific aims of the current proposal are Aim 1: To quantify the magnitude and spatial distribution of 18F-FBnTP myocardial uptake in Brown Norway rats by repeated PET imaging within the same animal every 6 months from the age of 6 to 24 months.
Aim 2 : To correlate 3-dimensional myocardial maps acquired by 18F-FBnTP PET and magnetic resonance strain imaging within the same rat every 6 months from age 6 to 24 months.
Aim 3 : To characterize the composition of myocardial cellular volume as a function of severity of regional decrease of FBnTP PET uptake in 6, 12, 18 and 24-month-old rats, with immunostaining as a gold standard.
Our population is aging at an accelerated pace, and associated diseases, particularly heart disease, are rapidly becoming a major public health problem. In 2004, 12.4% of the population was aged 65 yrs or over and that number will double in next 20 yrs. This exploratory proposal aimed at facilitating the design of a novel and highly sensitive technology for an early and accurate non-invasive detection of a key mechanism of cellular senescence - mitochondrial dysfunction - using F-18-FBnTP and PET imaging.
