Exertional disability, dyspnea, and fatigue are common symptoms in elderly individuals with impaired left ventricular contractile function. However, there is often a poor correlation between conventional measures of systolic function, such as ejection fraction and cardiac output, and the extent of """"""""fragility"""""""". The studies outlined in this proposal test the hypothesis that an important link, and therefore potentially treatable contributor, to such frailty is age-related stiffening of the arterial system and of the left ventricular chamber in both systole and diastole. We propose that the coupling of a stiff ventricle with non-compliant arteries will impede the adaptability of the cardiovascular system to exercise and ischemia stress. Furthermore, this stiffening will modify hemodynamic effects of vasoactive and inotropic medications, and therefore influence the selection of optimal heart failure treatments. Lastly, the studies test whether specific drug therapies designed to reduce ventricular and vascular stiffening improve exercise performance. Studies are conducted in intact human subjects aged 50-85 yrs, spanning a range of baseline systolic and/or diastolic ventricular dysfunction and level of disability. Ventricular stiffening is quantified by pressure- volume and stress-strain relations obtained by state-of-the-art catheter- based techniques during cardiac catheterization. Arterial stiffening is measured by analysis of the arterial pressure and flow waveforms and by effective arterial elastance. Exertional disability is quantified by treadmill or bicycle exercise testing with oxygen consumption measurements. Hemodynamic reserve during exercise or ischemic stress (in subjects with coronary disease) will be measured to test an inverse relation between reserve capacity and ventricular-arterial stiffening. Specific drug interventions which alter systolic and/or diastolic ventricular stiffness (beta-receptor blocker and agonist, Ca2+-receptor blocker) or arterial stiffness (vasodilator and alpha-agonist) will be studied to determine how age-dependent stiffening modifies the cardiovascular response to these interventions. Lastly, non-invasive exercise studies will test whether exertional capacity can be improved by acute drug interventions which reduce stiffnesses of vascular, ventricular, or both systems. These latter studies employ novel methods to characterize ventricular systolic properties by maxim power, as well as pulsatile arterial loads. The data obtained from these studies will likely yield important new insights regarding the mechanisms of exertional disability in elderly patients and the specific role of ventricular- vascular stiffening. They will also test how changes in stiffening of both systems influences exertional capacity, and thus provide critical groundwork for improved chronic treatment strategies.
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