Heart failure predominantly affects individuals of advanced age, and is currently reaching epidemic proportions. Nearly half the patients with symptoms of heart failure have preserved systolic ejection fraction (EF>50 percent), and are generally thought to suffer from ventricular diastolic dysfunction. However, most of these same individuals are over 65 years of age and have systolic hypertension, both factors that can themselves adversely impact on diastolic function. An additional mechanism that may prominently contribute to failure symptoms despite preservation of EF is ventricular-arterial stiffening. Vascular stiffening is common with aging, and results in increased arterial pulse pressure and systolic hypertension, both dominant risk factors for the development of coronary artery disease and heart failure. We have shown that ventricular systolic stiffening with or without cardiac hypertrophy accompanies progressive vascular stiffening with age. When combined, these changes can limit cardiac reserve capacity, enhance blood pressure fluctuations with daily activities of living, and limit coronary flow reserve. The studies in this proposal test the novel hypothesis that ventricular-vascular stiffening is a potent contributor to cardiac failure with preserved EF by reducing exercise capacity due to limited systolic reserve, enhancing blood pressure lability, and inducing abnormal coronary flow and myocardial energy balance with increased stress. The studies employ new methods for non-invasive quantitation of ventricular/vascular stiffening recently developed and validated in the P.I.'s laboratory. The first two specific aims test whether ventricular-vascular stiffening is greater in patients with """"""""non-systolic"""""""" heart failure versus a control group of similar age, blood pressure, hypertrophy, and sex, and tests its impact on blood pressure lability, reduced systolic reserve, and exercise performance.
The third aim focuses on the impact of ventricular/vascular stiffening on coronary flow regulation and high energy phosphate metabolism. These studies test the influence of combined stiffening on cardiac supply/demand balance with stress. This research should provide major new insights regarding the pathophysiology of heart failure with preserved EF and specifically the importance of ventricular-vascular stiffening. This could lead to new therapeutic approaches to this difficult clinical problem that affects a growing aged patient population.
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