Background: Systemic hypertension and aortic valve stenosis can lead to left ventricular hypertrophy (LVH), which is a leading cause of death and morbidity in the US. Myocardial hypertrophy is initially an adaptive response to stress. Hypertrophy becomes maladaptive with ongoing stress. A hypothesis was proposed by Taegtmeyer et al in 2004, that metabolic remodeling precede LV remodeling in pressure overload LVH and induces the fetal gene program. However, this hypothesis has not been completely tested due to the limited available technologies. Identifying metabolic mechanisms that occur during the progression to heart failure with LVH from pressure overload is now possible due to recent technological advances in non-invasive imaging of the mouse heart using dedicated small animal scanners. Accordingly, we will utilize a mouse model of LV pressure-overload myocardial hypertrophy and state-of-the-art Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) to address the following aims:
Aim 1 : Develop and optimize quantitative PET imaging techniques in-vivo to evaluate the hypothesis that metabolic changes lead to LV remodeling in LVH: Quantitative PET-MR measurements early on in the disease progression will enable evaluation of the hypothesis, that metabolic remodeling precedes structural and functional changes in pressure overload LVH in-vivo. Serial imaging over a course of 8 weeks will enable determination of the time at which the adaptive response becomes maladaptive in LVH.
Aim 2 : Evaluate the effect of pharmacologic interventions on glucose metabolism and structure and function in LVH: The effect of standard of care treatments such as Ace-inhibitors (AI) and beta-blockers (BB) or a combination of AI+BB on cardiac metabolism and structure and function will be evaluated in-vivo in LVH.
This aim will evaluate whether noninvasive imaging of myocardial metabolism can provide an early indication of the beneficial effect of therapy, which could possibly be used to tailor therapy to the individual to improve outcome. Sample size and statistical considerations: The PET-MRI imaging protocols will utilize approximately 10 mice in each group (untreated TAC, shams and treated TAC) at each time point based on a sample size calculation of 25% difference between the groups with a power of 0.8 and 95% confidence level. Image analysis: Glucose SUV measurements, tracer kinetics in a compartment model approach and pixel-by- pixel glucose influx map will be used to study metabolic alterations using PET. Ejection fractions, heart weight to body weight ratios, wall thickness measurements and PCr/ATP ratios will be used for functional, structural and metabolic changes using MRI-MRS. End-point: Ultimately, the goal is to test the hypothesis that metabolic remodeling precedes, triggers and sustains LV remodeling in LVH by developing and optimizing effective imaging strategies in-vivo. Time line: Hypothesis testing in the first 12-14 months and the effect of AI and BB in the next 10-12 months.
Patients with pressure-overload diseases such as systemic hypertension and aortic valve stenosis exhibit left ventricular hypertrophy (LVH), a major determinant of mortality and morbidity in cardiovascular diseases in the United States. This project would quantitatively evaluate and test the hypothesis that alterations in glucose metabolism precede structural and functional changes in pressure overload LVH. This is very important as it may lead to the development of treatment strategies targeting metabolism early on to prevent adverse structural and functional changes and thereby improve patient outcomes. Also the clinically relevant question of the adaptive response in LVH becoming maladaptive with ongoing stress may be answered. The studies to be carried out in this proposal by improved non-invasive nuclear medicine and magnetic resonance imaging techniques may contribute to the development of novel strategies and tools for the prevention and treatment of myocardial hypertrophy, which is a significant clinical problem.
