A B S T R A C T The hemodynamic determinants of the time-course of fall in isovolumic left ventricular pressure were assessed in isolated canine left ventricular preparations. Pressure fall was studied in isovolumic beats or during prolonged isovolumic diastole after ejection. Pressure fall from the time of maximum negative dP/dt was found to be exponential during isovolumic relaxation for isovolumic and ejecting beats (r > 0.98) and was therefore characterized by a time constant, T.Higher heart rates shortened T slightly from 52.6 ±4.5 ms at 110/min to 48.2±6.0 ms at 160/min (P < 0.01, ) = 8): Higher ventricular volumes under isovolumic conditions resulted in higher peak left ventricular pressure but no significant change in T. T did shorten from 67.1+5.0 ms in isovolumic beats to 45.8+ 2.9 ms in the ejecting beats (P < 0.001, n = 14). In the ejecting beats, peak systolic pressure was lower, and end-systolic volume smaller. To differentiate the effects of sy-stolic shortening during ejection from those of lower systolic pressure and smaller end-systolic volume, beats with large end-diastolic volumes were compared -to beats with smaller end-diastolic volumes. The beats with smaller end-diastolic volumes exhibited less shortening but similar end-systolic volumes and peak systolic pressure. T again shortened to a greater extent in the beats with greater systolic shortening.Calcium chloride and acetylstrophanthidin resulted in no significant change in T, but norepinephrine, which accelerates active relaxation, resulted in a significant shortening of T (65.6±13.4 vs. 46.3+7.0 ms, P < 0.02).

Echocardiograms were performed on 105 male participants in the National Institutes on Aging's volunteer Longitudinal Study Program. All subjects (25--84 years of age) were physically active and had no evidence of hypertension or cardiovascular disease. Measurements were made of the initial diastolic (E-F) slope of the anterior mitral valve leaflet, the aortic and left ventricular cavity dimensions, and the thickness of the posterior left ventricular wall. Fractional shortening of the minor semi-axis of the left ventricle and the velocity of circumferential fiber shortening were also determined. It was found that increasing age correlated with a decrease mitral valve E-F slope and increased aortic root diameter and left ventricular wall thickness. Aging did not affect left ventricular cavity dimension, fractional shortening of the minor semi-axis, and velocity of circumferential fiber shortening. These findings suggest that aging in the normal male is associated with altered left ventricular diastolic filling, increased aortic root diameter and left ventricle hypertrophy but little change in contractile ability in the resting state.

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Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.