Thomas E. Raya

Importance of venodilatation in prevention of left ventricular dilatation after chronic large myocardial infarction in rats: a comparison of captopril and hydralazine.

In rats with large myocardial infarctions, we compared the effects of captopril, a presumed arterial and venous vasodilator, with hydralazine, which is thought primarily to be an arterial vasodilator. To determine if the effects of captopril were dependent on the pathophysiological consequences of heart failure, we also studied a group of noninfarcted rats treated with captopril. In noninfarcted rats treated with captopril, left ventricular (LV) systolic and mean aortic pressures decreased from 132±12 to 107±15 mm Hg and 122±1 to 100±2, respectively (p<0.01). In noninfarcted rats, captopril decreased LV weight, LV weight/body weight, and total heart weight/body weight but produced no effects on the peripheral venous circulation. Rats subjected to coronary artery ligation were selected by ECG criteria to have large myocardial infarctions and were treated for 4 weeks with captopril (n=8), hydralazine (n=5), or placebo (n=9). In infarcted rats treated with captopril, LV systolic, mean aortic pressures and LV end-diastolic pressure (LVEDP) decreased (p<0.01) from 115±4 to 86±3 mm Hg, 106±4 to 74±3 mm Hg, and 23±2 to 11±2 mm Hg, respectively. Mean circulatory filling pressure decreased (p<0.05) from 11.2±0.6 to 8.7±0.8 mm Hg and venous compliance increased (p<0.05) from 2.04±0.07 to 2.70±0.20 ml/mm Hg/kg. Blood volume decreased (p<0.05) from 67.3±0.9 to 58.2±1.8 ml/kg. At LVEDP recorded during the hemodynamic study, LV end-diastolic volume (“operating” LV end-diastolic volume) decreased (p<0.01) from 2.64±0.15 to 1.88±0.12 ml/kg. Hydralazine treatment decreased (p<0.01) LV systolic (91±3 mm Hg) and mean aortic (86±2 mm Hg) pressures, increased (p<0.05) LVEDP (27±2 nun Hg) but did not change mean circulatory filling pressure, venous compliance, blood volume, or operating LV end-diastolic volume. We conclude that in rats with heart failure, captopril, in addition to being an arterial vasodilator, produced venodilatation and decreased blood volume. Operating LV end-diastolic volume and LVEDP were decreased. These changes appear to be caused by the decrease in blood volume and venodilatation in combination with afterload reduction because hydralazine which has no effect on the venous circulation did not alter LVEDP or operating LV end-diastolic volume.

Contractility and stiffness of noninfarcted myocardium after coronary ligation in rats. Effects of chronic angiotensin converting enzyme inhibition.

BackgroundPrevious studies have shown that global left ventricular function is depressed after myocardial infarction. However, little is known about the effects of myocardial infarction on contractility and the passive-elastic properties of residual myocardium. Methods and ResultsWe evaluated isometric function and passive myocardial stiffness in isolated, noninfarcted left ventricular papillary muscle from rats 6 weeks after sham operation or myocardial infarction. Maximal developed tension and peak rate of tension rise (+dT/dt) were significantly decreased in untreated rats with large myocardial infarction compared with controls 3.3 + 1.1 versus 43 + 0.6 g/mm2 and 49.5 ± f17.5 versus 72.5 ± +10.5 g/mm2/sec, respectively). Time to peak tension was prolonged (120 ± 8 versus 102 ± 4 msec) and myocardial stiffness was increased in untreated myocardial infarction rats compared with controls (35.2 ± 4.9 versus 24.2 ± 3.7). Rats with smaller myocardial infarctions differed from controls only with respect to a prolongation of time to peak tension. Papillary muscle myocyte cross-sectional area was increased by 44% (p<0.05), and myocardial hydroxyproline content was increased by 160% (p<0.05) in rats with large myocardial infarctions compared with controls. To determine whether treatment that improves left ventricular function after myocardial infarction also improves myocardial function, rats were treated with captopril beginning 3 weeks after myocardial infarction and continuing for 3 weeks. Treatment with captopril attenuated the prolongation in time to peak tension in the myocardial infarction rats; however, developed tension, +dT/dt, and muscle stiffness remained abnormal. Compared with untreated myocardial infarction rats, captopril-treated myocardial infarction rats had a 9% decrease in myocyte cross-sectional area (p = 0.1) but a persistent increase in myocardial collagen content. In summary, large myocardial infarction in rats causes contractile dysfunction, increased stiffness, myocyte hypertrophy, and increased collagen content in the residual noninfarcted myocardium. Treatment with captopril alters the process of cardiac remodeling and hypertrophy and improves one parameter of contractility in noninfarcted myocardium; however, myocardial collagen content and myocardial stiffness remain abnormal. ConclusionsThese findings suggest that angiotensin converting enzyme inhibition in the ratinfarct model of heart failure improves global cardiac performance via combined effects on myocardial function and the peripheral circulation. (Circulation 1991;83:1028–1037)

Alterations in left ventricular relaxation during atrioventricular pacing in humans.

To determine whether the asynchronous left ventricular contraction-relaxation sequence that exists during right ventricular pacing alters left ventricular relaxation, measurements of both the maximal rate of decline of left ventricular pressure (peak negative dP/dt) and the time constant of left ventricular relaxation were obtained during atrial and atrioventricular (AV) pacing in 25 patients referred for diagnostic cardiac catheterization. Heart rate was maintained at 10 to 15 beats/min above the sinus rate at rest, and relaxation was assessed during atrial pacing, AV pacing and repeat atrial pacing. The patients were classified into two groups. Group 1 included 10 patients with normal left ventricular systolic function at rest (ejection fraction greater than 0.55) and without evidence of prior myocardial infarction. Group 2 included 15 patients with a depressed left ventricular ejection fraction or akinesia of one or more left ventricular segments on the contrast ventriculogram, or both. Heart rate, peak left ventricular systolic pressure, end-systolic pressure and end-diastolic pressure remained constant during atrial, AV pacing and repeat atrial pacing in all patients. In group 1 patients, the decrease in peak negative dP/dt (1,507 +/- 200 versus 1,424 +/- 187 mm Hg/s) and the increase in the time constant of left ventricular relaxation (48 +/- 11 versus 51 +/- 11 ms) during AV pacing was not significantly different when compared with values during atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial changes in left ventricular relaxation and chamber stiffness after large myocardial infarction in rats.

To determine the time course of changes in left ventricular diastolic properties after a large myocardial infarction, we serially measured left ventricular relaxation, chamber stiffness, and the ratio of left ventricular cavity to wall volume (V/VW) after coronary artery ligation in rats. Left ventricular relaxation was measured during the occlusion and then both relaxation and chamber stiffness were measured at 3 hr, 24 hr, and 3, 5, and more than 22 days after infarction. Left ventricular pressures and left ventricular dP/dt were recorded with micromanometer-tipped catheters. Left ventricular relaxation was measured by computer digitization of the left ventricular pressure tracings and averaged over 100 to 150 cardiac cycles. Five chamber stiffness constants were calculated from pressure-volume curves that were obtained ex vivo. We found ventricular relaxation prolonged for the first hour after coronary occlusion; relaxation was maximally prolonged at 10 to 15 min after onset of occlusion. After 1 hr relaxation returned to normal. However, by 5 days ventricular relaxation was again prolonged. Left ventricular stiffness constants were increased at 3 and 24 hr, resulting in a shift of the left ventricular pressure-volume relation to the left. At 3 days after coronary artery ligation, all stiffness constants and the pressure-volume relation returned to normal. At more than 22 days the pressure-volume relation was shifted to the right and the stiffness constant for low filling pressures was decreased. V/VW was significantly decreased from 0.603 +/- 0.021 at 3 and 24 hr to 0.379 +/- 0.024 and 0.362 +/- 0.032, respectively. V/VW was significantly increased at more than 22 days (0.921 +/- 0.094).(ABSTRACT TRUNCATED AT 250 WORDS)

Left Ventricular Performance and Remodeling in Rabbits After Myocardial Infarction Effects of a Thyroid Hormone Analogue

BACKGROUND Because the rat postinfarction model differs from human heart failure with respect to the composition of myosin heavy chain (MHC) isoforms and other contractile proteins, alternative animal models are needed for the development of new treatments for human heart failure. The purpose of this study was threefold: (1) to test the feasibility of using the V3(beta,beta) rabbit postinfarction model for the study of heart failure by characterizing the effects of chronic coronary artery occlusion on the left ventricle; (2) to determine whether the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) produces improvements in left ventricular function; and (3) to determine the effects of myocardial infarction and treatment with DITPA on MHC protein isoforms. METHODS AND RESULTS Male New Zealand White rabbits underwent proximal circumflex coronary artery ligation. After infarction, rabbits were treated with DITPA (3.75 mg/kg body wt) or placebo for 21 days and then underwent conscious and open-chest hemodynamic studies. In separate groups of rabbits, beta- and alpha-MHC isoforms were separated, and relative proportions were measured using gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis and laser densitometry. Infarction resulted in increased left ventricular end-diastolic pressure and prolonged left ventricular relaxation (tau) (P = .001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and tau (P = .002 and P = .001, respectively) and increased maximum positive and negative dP/dt (P = .002 and P = .016, respectively). Infarcted rabbits treated with DITPA had no significant changes in heart rate or left ventricular systolic pressure compared with untreated rabbits with infarction. There were no significant differences in heart rate, positive dP/dt, peak systolic pressure, or tau between sham-operated rabbits and sham-operated rabbits treated with DITPA. Although infarction resulted in increased left ventricular diameter, there were no effects of DITPA on left ventricular remodeling. Neither myocardial infarction nor treatment with DITPA altered the ratio of MHC isoforms. CONCLUSIONS Rabbits that survive occlusion of the circumflex artery will develop myocardial dysfunction and left ventricular remodeling. Therapy with DITPA, a thyroid hormone analogue, produces improvement in ventricular performance and reduces end-diastolic pressure. The hemodynamic effects of DITPA were not associated with alterations of MHC isoforms. Whether DITPA represents the prototype of a previously undescribed class of agents for the treatment of heart failure will need to be determined by clinical trials.

Left ventricular function and remodeling after myocardial infarction in aging rats.

- Adaptations of the aging left ventricle (LV) to hemodynamic overload are functionally and structurally distinct from those of the young organism. This study describes the influence of aging on LV hemodynamics and remodeling late after myocardial infarction (MI) in Fischer 344 Brown Norway rats. In sham rats at 23 mo, LV weight, myocyte cross-sectional area (CSA), and myocardial fibrosis were increased, whereas LV dP/d t, LV relaxation, and maximal LV systolic function declined with respect to younger rats (7, 12, and 18 mo of age). Isometric myocardial function was evaluated in papillary muscles of 12- and 23-mo-old sham rats. Myocardial systolic function was decreased in older rats. To determine how aging affects LV function and remodeling after MI, rats were infarcted at 7 and 18 mo of age and were studied 5 mo later. Infarct size was similar in each group. Right ventricular weight, LV end-diastolic pressure, and volume index were increased, whereas LV dP/d t, peak cardiac index, and peak developed LV pressure declined after MI. However, there were no significant differences between young and older rats in any variable of LV systolic function or remodeling after MI. Myocyte CSA increased in younger rats after MI but was unchanged in 23-mo-old rats. After MI, myocardial fibrosis was significantly increased from baseline only in younger rats. The negative interaction of aging and MI on myocyte hypertrophy and fibrosis was highly significant. The findings indicate that baseline LV and myocardial function decline with age. In the aging rat after MI, despite limited compensatory hypertrophy and more advanced baseline myocardial fibrosis, the long-term functional and structural adaptations to MI are similar to those of the mature adult heart.Adaptations of the aging left ventricle (LV) to hemodynamic overload are functionally and structurally distinct from those of the young organism. This study describes the influence of aging on LV hemodynamics and remodeling late after myocardial infarction (MI) in Fischer 344 Brown Norway rats. In sham rats at 23 mo, LV weight, myocyte cross-sectional area (CSA), and myocardial fibrosis were increased, whereas LV dP/dt, LV relaxation, and maximal LV systolic function declined with respect to younger rats (7, 12, and 18 mo of age). Isometric myocardial function was evaluated in papillary muscles of 12- and 23-mo-old sham rats. Myocardial systolic function was decreased in older rats. To determine how aging affects LV function and remodeling after MI, rats were infarcted at 7 and 18 mo of age and were studied 5 mo later. Infarct size was similar in each group. Right ventricular weight, LV end-diastolic pressure, and volume index were increased, whereas LV dP/dt, peak cardiac index, and peak developed LV pressure declined after MI. However, there were no significant differences between young and older rats in any variable of LV systolic function or remodeling after MI. Myocyte CSA increased in younger rats after MI but was unchanged in 23-mo-old rats. After MI, myocardial fibrosis was significantly increased from baseline only in younger rats. The negative interaction of aging and MI on myocyte hypertrophy and fibrosis was highly significant. The findings indicate that baseline LV and myocradial function decline with age. In the aging rat after MI, despite limited compensatory hypertrophy and more advanced baseline myocardial fibrosis, the long-term functional and structural adaptations to MI are similar to those of the mature adult heart.

Combination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid. A new approach to improving left ventricular performance in heart failure.

BACKGROUND An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. METHODS AND RESULTS To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 micrograms/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21 +/- 2 and 26 +/- 2 mm Hg, respectively, vs 34 +/- 3 mm Hg, P < .05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P < .05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in tau, the time constant of LV pressure decline (17.5 +/- 1.0 vs 22.2 +/- 1.7 milliseconds, P < .05) and a larger absolute value for -dP/dtmax (-4561 +/- 361 vs -3346 +/- 232 mm Hg/s, P < .05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P > .05). CONCLUSIONS The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.

Effects of endothelial and inducible nitric oxide synthases inhibition on circulatory function in rats after myocardial infarction

OBJECTIVES To examine the relative roles of eNOS and iNOS (endothelial and inducible nitric oxide synthases) on basal and beta-adrenergic receptor (beta-AR)-stimulated arterial hemodynamic responses after myocardial infarction (MI). METHODS Left ventricular (LV) pressures and steady-state and pulsatile arterial hemodynamics were measured at baseline, and after acute NOS inhibition with either NG-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg) or iNOS inhibition with aminoguanidine (AG, 75 mg/kg) in sham-operated and MI Sprague-Dawley rats. RESULTS In sham rats, L-NAME decreased (P < 0.05) peak positive LV dP/dt and aortic blood velocity by 19% and 53%, respectively, and increased (P < 0.05) mean arterial pressure (MAP); systemic vascular resistance, and LV end-diastolic pressure (EDP) by 20, 189 and 89%, respectively. The frequency-dependent components of hemodynamics including aortic input impedance modulus, characteristic impedance, and phase shift were increased (P < 0.05) with L-NAME, while pulsatile power was decreased (P < 0.05). AG increased (P < 0.05) aortic input impedance modulus and characteristic impedance but had no effect on any other hemodynamic variable. In MI rats, L-NAME decreased (P < 0.05) LV dP/dt and aortic blood velocity by 22 and 55%, respectively, and increased (P < 0.05) SVR by 108%. There was no effect of L-NAME on MAP or LV EDP in MI rats. After MI, AG increased (P < 0.05) heart rate and LV dP/dt but had no effect on other LV or pulsatile hemodynamic variables. Compared to sham rats, heart rate, LV dP/dt, and blood velocity-isoproterenol dose responses were shifted downward (P < 0.05), while SVR-isoproterenol dose response was shifted upward (P < 0.05) in MI rats. In sham rats, L-NAME potentiated (P < 0.05, at > 10(-2) micrograms/kg) the isoproterenol-induced increase in LV dP/dt and aortic blood velocity, and potentiated (P < 0.05) the isoproterenol-induced decline in SVR. As expected, AG had no effects on isoproterenol-stimulated hemodynamics in sham rats. After MI, there was no effect of L-NAME or AG on isoproterenol-stimulated hemodynamics. CONCLUSIONS (1) Circulatory and cardiac responses to inhibition of NO by L-NAME suggest that eNOS, but not iNOS, is the principal regulator of integrated arterial hemodynamic function in rats. (2) Both basal and beta-AR-stimulated NO regulation of hemodynamic are attenuated after MI. (3) The attenuation of arterial hemodynamic effects after isoproterenol is mediated, in part, by alterations in the beta-AR-activation of eNOS system after MI.

Studies on the use of thyroid hormone and a thyroid hormone analogue in the treatment of congestive heart failure

In heart failure, cardiac output is insufficient to meet the needs of the body for oxygen delivery. Available data suggest that alterations in thyroid hormone metabolism may contribute to defective myocardial performance. Accordingly, thyroid hormone or a thyroid hormone analogue that improves cardiac performance might be useful in the treatment of heart failure and has been studied. Experimental and theoretical results of these studies are reviewed and indicate that thyroid hormone increases cardiac output by a combination of effects on the heart and peripheral circulation, specifically by increasing myocardial contractile performance and decreasing venous compliance. In the rat postinfarction model of heart failure, treatment with low doses of thyroxine (1.5 micrograms/100 g) for 3 days produced a positive inotropic response, including an increase in rate of change of left ventricular pressure and a decrease in left ventricular end-diastolic pressure. These changes could be attributed to conversion to triiodothyronine, the active intracellular form of thyroid hormone. When treatment with thyroxine was continued at the same or higher doses (3 to 15 micrograms/100 g) for 10 to 12 days, heart rate increased and improvement in left ventricular end-diastolic pressure was not sustained. More favorable results were obtained with 3,5-diiodothyropropionic acid, a cardiotonic thyroid hormone analogue administered at doses of 375 microgram/100 g, given in combination with captopril. Thus, triiodothyronine or a thyroid hormone analogue may be a useful adjunct to other measures in the treatment of heart failure.

Captopril restores hemodynamic responsiveness to atrial natriuretic peptide in rats with heart failure.

Atrial natriuretic peptide levels are elevated in heart failure. However, the hemodynamic responses to exogenous atrial natriuretic peptide infusion in heart failure are blunted. To determine if captopril can restore hemodynamic responsiveness to atrial natriuretic peptide infusion in rats with heart failure, studies were performed in a rat model of heart failure after coronary artery ligation. Rats with heart failure received either captopril (2 g/l drinking water) or placebo for 4 weeks and then were treated with an infusion of atrial natriuretic peptide (0.3 microgram/kg/min). Captopril treatment alone improved hemodynamics. Left ventricular end-diastolic pressure, mean aortic pressure, and mean circulatory filling pressure decreased from 22 +/- 2 to 14 +/- 1, from 106 +/- 4 to 76 +/- 3, and from 10.5 +/- 0.6 to 8.8 +/- 0.4 mm Hg, respectively. Heart rate, right atrial pressure, and hematocrit were unchanged. Total blood volume decreased from 66.0 +/- 1.0 to 60.0 +/- 1.0 ml/kg; venous compliance increased from 2.1 +/- 0.1 to 2.7 +/- 0.1 ml/kg/mm Hg. Atrial natriuretic peptide alone had minimal hemodynamic effects on rats with heart failure. There was no change in right atrial pressure, mean aortic pressure, left ventricular end-diastolic pressure, mean circulatory filling pressure, and total blood volume. However, atrial natriuretic peptide infusion increased venous compliance from 2.1 +/- 0.1 to 2.4 +/- 0.1 ml/kg/mm Hg. Heart rate and hematocrit increased from 323 +/- 5 to 359 +/- 8 beats/min and from 48 +/- 1% to 51 +/- 1%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)