Our previous investigations have shown that many elderly people develop falls and syncope due to the hypotensive effects of nitrate medications taken for coronary artery disease (CAD). Furthermore, some elderly people develop profound blood pressure reduction in response to nitroglycerine, while others do not. Pilot data from our laboratory show a relationship between impaired diastolic filling of the heart and a hypotensive response to preload reduction during upright posture. Therefore, we hypothesize the following: 1) Elderly people with impaired diastolic function who take nitrate medications are particularly susceptible to hypotension, due to the preload-reducing effects of this class of drugs. 2) Further reduction in preload due to diuretics, orthostasis, or meal digestion may compound the risk of hypotension. 3) Calcium-channel blockers which have less of an effect on cardiac preload may be a safer alternative for the treatment of coronary artery disease in these people. To test these hypotheses we propose a 3-part study of cardiovascular responses to orthostasis and a meal, in defined groups of elderly CAD patients taking either isosorbide dinitrate, with or without a diuretic; diltiazem, with or without a diuretic; a diuretic alone; or no medication. Doppler echocardiography will be used to characterize baseline diastolic function. In Part I, blood pressure (BP), heart rate (HR), stroke volume (by impedance cardiography), systemic vascular resistance, forearm vascular resistance, and venous tone will be measured supine and during 60 degree head-up tilt, then BP and HR will be determined before and after a meal. In Part II, subjects with 20 mm Hg or greater systolic BP declines in response to these stimuli, will be switched to alternate medication regimens (e.g., discontinue isosorbide and begin diltiazem or D/C all medications), then rechallenged with repeated tilt and meal studies. In part III, unmedicated controls with and without CAD will be randomized to sequential 2 week double-blind treatments with isosorbide, diltiazem, or placebo, then cardiovascular responses to tilt and a meal on each of these regimens will be compared. Multivariate analyses will be performed to determine clinical, echocardiographic, and hemodynamic variables associated with the development of nitrate-induced hypotension.
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