Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Left ventricular hypertrophy (LVH) due to hypertension is an important risk factor for the development of systolic and diastolic HF. Prevention of hypertrophy by improving energy generation and use has recently received renewed interest as a therapeutic target to improve patient outcomes. In response to pressure overload the heart switches from fatty-acid to glucose metabolism for energy production. This initially beneficial metabolic response becomes maladaptive when sustained and may trigger the onset of functional and structural remodeling of the heart leading to LVH. Recent FDG PET imaging data from our laboratory in transverse aortic constriction (TAC)-induced pressure overload LVH in mice and hypertension-induced LVH in humans have identified glucose metabolism as a possible therapeutic target. We hypothesize that alterations in glucose metabolism in the pressure-overloaded heart precede the development of impaired cardiac function that eventually lead to LVH and HF. The temporal and causal relationship between metabolic remodeling and impaired cardiac function and the development of LVH is, however, unknown. The TAC mouse model lacks some of the key features of the human disease, most importantly the slow progressive development of pressure overload. This makes it impossible to distinguish the maladaptive from the adaptive metabolic response and to identify the window for aggressive therapeutic strategies that could be used to improve clinical outcome in human hypertension. We thus propose to characterize the myocardial metabolic changes and consequences on cardiac structure and function in the spontaneously hypertensive rat (SHR) model that is widely used as a model for transition from stable compensated LVH to systolic HF. In this proposal, we will test our central hypothesis that changes in myocardial metabolism, specifically the switch to glucose as a major energy source, although initially beneficial to maintaining cardiac function, becomes maladaptive and plays a major role in the development of contractile dysfunction in the pressure overloaded heart. To test this hypothesis, we will under Aim 1 evaluate the temporal relationship between myocardial glucose metabolism and the progression of the disease to LVH and HF by serial FDG PET and MR imaging in vivo, hemodynamic measurements and ex vivo molecular and metabolic analysis of SHR and control Wistar-Kyoto (WKY) rat hearts over the 20-24 month life cycle of the rats.
Under Aim 2 we will then test whether intervention with metformin, a FDA-approved drug that improves glucose metabolism, can prevent impairments in the contractile function and cardiac structure of the SHR heart using serial FDG PET and MR imaging in vivo, hemodynamic studies and ex vivo analysis. These studies will provide basic knowledge for future translational research using human FDG PET imaging to define a window for metabolic intervention for prevention of LVH and thus improve patient outcomes.
The proposed research is relevant to public health because the knowledge gained may change the current clinical paradigm of treating patients with hypertension-induced left ventricular hypertrophy (LVH) in that metabolic imaging will become a diagnostic tool to identify hypertensive patients who are at high risk for progression to LVH or heart failure, and thus would benefit from aggressive treatment strategies to prevent cardiac dysfunction. The project is relevant to NHLBI's mission in that it pertains to the development and application of non-invasive imaging methods for in vivo monitoring of disease progression and of effects of therapeutic intervention in hypertension-induced LVH in the spontaneously hypertensive rat that can be readily translated to clinical practice.
| Li, Yinlin; Kundu, Bijoy K (2018) An improved optimization algorithm of the three-compartment model with spillover and partial volume corrections for dynamic FDG PET images of small animal hearts in vivo. Phys Med Biol 63:055003 |
