Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects

OBJECTIVES: We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure. BACKGROUND: Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF. METHODS: Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks. RESULTS: Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups. CONCLUSIONS: In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.     

The neurohumoral and hemodynamic response to orthostatic tilt in patients with congestive heart failure

Thirty-five patients with varying degrees of congestive heart failure were subjected to 60 degrees upright tilt. Eight of the patients with normal resting hemodynamics had elevated resting plasma norepinephrine levels (PNE) (p less than 0.001), but their response to upright tilt was similar to that in normal subjects: All had increases in heart rate, plasma norepinephrine (from 263 +/- 32 to 483 +/- 78 pg/mg, p less than 0.02) and plasma renin activity (from 4.8 +/- 0.9 to 13.7 +/- 7.6 ng/ml/hour, p less than 0.05). In 27 patients with high resting pulmonary wedge pressure and low cardiac index, resting PNE was higher (668 +/- 71 ng/ml), but PNE, plasma renin activity and heart rate did not increase significantly during tilt despite a fall in pulmonary capillary wedge pressure and cardiac index. In 18 of these patients, PNE rose during tilt, whereas in nine it did not change or fell; the resting hemodynamics and the hemodynamic response to tilt were not significantly different in these two groups. These data suggest that an abnormality of mechanoreceptor or baroreceptor function is common in patients with CHF. This abnormality corresponds in part to the severity of the resting hemodynamic abnormality, but among patients with severe CHF, the reflex neurohumoral abnormality may provide independent information about the severity of the disease.     

Systemic and coronary hemodynamic and neurohumoral effects of levodopa in chronic congestive heart failure

Systemic and neurohumoral effects of oral levodopa were evaluated in 17 patients with severe chronic heart failure. The maximum mean dopamine level achieved after 1.5 g of oral levodopa was 19.6 +/- 16.4 ng/ml. At peak dopamine level, cardiac index increased by 14% from baseline (1.95 +/- 0.55 to 2.27 +/- 0.45 liters/min/m2, p less than 0.05), stroke volume index increased by 14% (22.4 +/- 6.0 to 25.9 +/- 5.8 ml/min/m2, p less than 0.01). There was a trend toward reduced systemic vascular resistance of 13% (1,773 +/- 769 to 1,535 +/- 432 dynes.s.cm-5, p = 0.08). There was no significant change from baseline in heart rate, mean arterial pressure, right atrial pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance and rate-pressure product. In addition, as the arterial dopamine level increased there was a concomitant decrease in plasma norepinephrine level that was sustained for the period of observation. In a subgroup of 8 patients, there was no change in coronary sinus blood flow, myocardial oxygen consumption, myocardial oxygen extraction, lactate extraction and transmyocardial release of catecholamines after levodopa. These findings suggest that oral levodopa, 1.5 g, can improve left ventricular function without adversely affecting myocardial energetics and catecholamine balance.     

Clinical, hemodynamic and neurohumoral effects of long-term therapy of patients with severe chronic heart failure with beta-adrenoblocker bisoprolol

The use of beta-adrenoblockers in conjunction with angiotensin converting enzyme inhibitors improves quality of life and prognosis of patients with chronic heart failure. However basic mechanisms of these positive effects in severe heart failure remain to be elucidated. METHODS: Patients (n=54) with NYHA class III-IV heart failure and left ventricular ejection fraction < or =35% were randomized either to treatment with bisoprolol (1.25-10 mg/day) (n=30) or in control group (n=24) and were followed up for 12 months. RESULTS: The use of bisoprolol was associated with significant improvement of heart failure functional class, lowering of heart rate (by 14%, p<0.01), elevation of systolic blood pressure (by 7.2+/-12.3 mm Hg, p<0.01) and increase of walking distance (by 30.1+/-29.0 m, p<0.01). No significant changes of these parameters occurred in control group. After 12 months increases of left ventricular end diastolic and end systolic volumes (by 85+/-69.2 and 71+/-51.5 ml, respectively, p<0.001) and of ejection fraction (by 5.7+/-7.3%, p<0.01) took place in bisoprolol treated patients. These changes were significantly (p<0.001) higher than those in control group. After 6 months of treatment with bisoprolol noradrenaline concentration fell from 533 to 402 pg/ml (p<0.05) while in controls it rose from 369 to 474 pg/ml, p<0.01). Decreases of plasma renin activity (from 1.2 to 0.42 ng/ml/h), plasma concentrations of angiotensin II (from 17.1 to 13.1 pg/ml) and aldosterone (from 173 to 148 pg/ml, p<0.05) were also observed in bisoprolol group. No substantial dynamics of activity of main components of renin angiotensin system took place in controls. There were no significant changes of atrial natriuretic peptide in both groups. Significant positive dynamics of parameters of heart rate variability was registered only in bisoprolol group: SDNN increased by 25% (p<0.05), high frequency spectrum by 106% (p=0.03), LF/HF ratio from 2.18+/-1.41 to 1.82+/-0.7. CONCLUSION: Long term use of bisoprolol was associated with improved clinical and hemodynamic status, increased systolic BP, blocked processes of pathological left ventricular remodeling, lowered activity of not only sympathetic-adrenal but also of main components of renin-angiotensin system and improved heart rate variability.     

Effect of orally administered hydralazine on neurohumoral factors and hemodynamic response in aged patients with chronic congestive heart failure

We studied the hemodynamic response to orally administered hydralazine (30 mg) and examined the changes in neurohumoral factors in 16 aged patients with chronic congestive heart failure. After a single 30 mg dose, 9 patients (Group I) demonstrated a greater than 30% decrease in systemic vascular resistance (SVR) and a significant increase in the cardiac index (CI); 7 patients, whose SVR was decreased by less than 30% (Group II), showed a less marked increase in CI. After 3 days of drug administration (90 mg/day), the CI decreased in Group I (p less than 0.05) while it tended to increase further in Group II. Pretreatment plasma norepinephrine was lower in Group I than Group II (p less than 0.05). However, in Group I, it increased after 3 days of therapy, with a concomitant increase in plasma renin activity (p less than 0.01) and total plasma volume (P less than 0.025). We conclude that the higher pretreatment plasma norepinephrine level in Group II, suggestive of more severe derangement of left ventricular function, may be associated with a less pronounced dilatory response of the peripheral vasculature after a single dose of hydralazine, and that the increase in norepinephrine in Group I after 3 days of treatment may limit these patients' late hemodynamic responses to the drug.     

Haemodynamic and neurohumoral response to exercise in patients with congestive heart failure treated with captopril

The contribution of the renin-angiotensin system to the cardiovascular response to exercise was studied in 12 patients with congestive heart failure. The haemodynamic effects of captopril were measured at rest and during supine bicycle exercise. After captopril administration, resting systemic vascular resistance fell by 26.6% and mean blood pressure by 16.7% and cardiac index increased by 19.7%. During exercise, captopril decreased systemic vascular resistance by 25.6% and mean blood pressure by 8.2% and increased cardiac index by 24.4%. Pulmonary wedge pressure fell by 25% at rest but was not altered by captopril during exercise. Pretreatment plasma renin activity increased from 13.4(16.0) ng/ml/hr (10.3(12.3) mmol/l/hr) at rest to 20.0(27.8) ng/ml/hr (15.4(21.4) mmol/l/hr) during exercise. Pretreatment plasma noradrenaline concentration increased from 659(433) pg/ml (39(25.6) nmol/l) at rest to 2622(1486) pg/ml during exercise (155(88) nmol/l). Captopril favourably alters systemic vascular resistance and cardiac index during exercise in patients with congestive heart failure. This may reflect inhibition of the increased activity of the renin-angiotensin system during exercise in these patients and a subsequent reduction in systemic vasoconstriction.     

心力衰竭患者的运动康复

心力衰竭是多种心血管疾病终末期的共同转归,临床症状重,死亡率较高,给个人及社会造成重大负担.心脏康复可提供综合性干预治疗,其中运动锻炼部分日益受到重视.本文重点介绍运动锻炼产生效应的可能机制,并对其实施和评估作一综述.     

Effect of exercise training on autonomic derangement and neurohumoral activation in chronic heart failure

BackgroundIn chronic heart failure (CHF), persistent autonomic derangement and neurohumoral activation cause structural end-organ damage, decrease exercise capacity, and reduce quality of life. Beneficial effects of pharmacotherapy and of exercise training in CHF have been documented at various functional and structural levels. However, pharmacologic treatment can not yet reduce autonomic derangement and neurohumoral activation in CHF to a minimum. Various studies suggest that exercise training is effective in this respect.Methods and ResultsAfter reviewing the available evidence we conclude that exercise training increases baroreflex sensitivity and heart rate variability, and reduces sympathetic outflow, plasma levels of catecholamines, angiotensin II, vasopressin, and brain natriuretic peptides at rest.ConclusionsExercise training has direct and reflex sympathoinhibitory beneficial effects in CHF. The mechanism by which exercise training normalizes autonomic derangement and neurohumoral activation is to elucidate for further development of CHF-related training programs aimed at maximizing efficacy while minimizing workload.     

A comparative evaluation of hemodynamic and neurohumoral effects of nitroglycerin and nifedipine in congestive heart failure

Nitroglycerin and nifedipine have been suggested as useful agents in the therapy of congestive heart failure. Because of the rapid action and feasability for sublingual administration of both drugs, their comparative hemodynamic and neurohumoral effects were studied in 12 patients with congestive heart failure. After sublingual nitroglycerin, there was a significant decrease in mean arterial pressure (96 +/- 17 to 90 +/- 15 mm Hg, p less than 0.01), left ventricular (LV) filling pressure (30 +/- 12 to 22 +/- 10 mm Hg, p less than 0.01), right atrial pressure (15 +/- 6 to 10 +/- 5 mm Hg, p less than 0.01) and systemic vascular resistance (21.5 +/- 7.7 to 19.3 +/- 6.2 units, p less than 0.05) and an increase in cardiac index (2.2 +/- 0.6 to 2.4 +/- 0.7 liters/min/m2, p less than 0.05) and LV stroke work index (20.4 +/- 7.0 to 24.5 +/- 8.6 gm-m/m2, p less than 0.01). After sublingual nifedipine, there was also a significant decrease in mean arterial pressure (96 +/- 16 to 89 +/- 14 mm Hg, p less than 0.01) and systemic vascular resistance (22.1 +/- 7.1 to 18.0 +/- 6.1 units, p less than 0.01) and an increase in cardiac index (2.1 +/- 0.6 to 2.4 +/- 0.6 liters/min/m2, p less than 0.01); in contrast to nitroglycerin, this was unaccompanied by significant changes in right- or left-sided filling pressures or LV stroke work index.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enalapril in congestive heart failure: acute and chronic invasive hemodynamic evaluation

Following hemodynamic evaluation using invasive and noninvasive methods, 73 patients were treated in an open, uncontrolled, multicenter study with single oral doses of enalapril maleate 1.25 to 40 mg until the optimal dose for each patient (based upon hemodynamic response) was achieved. Diuretics were withheld and reinstituted only if necessary. Hemodynamic measurements were made at 0 (predrug), 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours postdrug. Patients were discharged on their optimal dose, treated 1 to 4 months and then rehospitalized for repeat hemodynamic measurements. The optimal enalapril single dose was associated with the following mean peak responses: increased cardiac index 42% (SE = 6) and decreased pulmonary capillary wedge pressure 40% (SE = 3), systemic vascular resistance 39% (SE = 2), and mean arterial pressure 23% (SE = 1.5). These changes persisted during chronic therapy. Chronic treatment with enalapril also improved exercise capacity 40% (P less than 0.01), ejection fraction 18% (P less than 0.05) and clinical status (N.Y.H.A. functional class, P less than 0.01). Ten and 20 mg/day, taken as once- or twice-daily regimens, were the most commonly effective doses.     

Haemodynamic and neurohumoral response to exercise in patients with congestive heart failure treated with captopril.

The contribution of the renin-angiotensin system to the cardiovascular response to exercise was studied in 12 patients with congestive heart failure. The haemodynamic effects of captopril were measured at rest and during supine bicycle exercise. After captopril administration, resting systemic vascular resistance fell by 26.6% and mean blood pressure by 16.7% and cardiac index increased by 19.7%. During exercise, captopril decreased systemic vascular resistance by 25.6% and mean blood pressure by 8.2% and increased cardiac index by 24.4%. Pulmonary wedge pressure fell by 25% at rest but was not altered by captopril during exercise. Pretreatment plasma renin activity increased from 13.4(16.0) ng/ml/hr (10.3(12.3) mmol/l/hr) at rest to 20.0(27.8) ng/ml/hr (15.4(21.4) mmol/l/hr) during exercise. Pretreatment plasma noradrenaline concentration increased from 659(433) pg/ml (39(25.6) nmol/l) at rest to 2622(1486) pg/ml during exercise (155(88) nmol/l). Captopril favourably alters systemic vascular resistance and cardiac index during exercise in patients with congestive heart failure. This may reflect inhibition of the increased activity of the renin-angiotensin system during exercise in these patients and a subsequent reduction in systemic vasoconstriction.     

Resting lung function and hemodynamic parameters as predictors of exercise capacity in patients with chronic heart failure

STUDY OBJECTIVES: The aim of this study was to examine the role of resting pulmonary function and hemodynamic parameters as predictors of exercise capacity in patients with chronic heart failure. MEASUREMENTS AND RESULTS: Fifty-one patients with chronic heart failure underwent resting pulmonary function testing, including inspiratory capacity (IC) and symptom-limited, treadmill cardiopulmonary exercise testing (CPET). Right-heart catheterization and radionuclide ventriculography were performed within 2 days of CPET. Mean (+/- SD) left ventricular ejection fraction was 31 +/- 12% and cardiac index was 2.34 +/- 0.77 L/min/m(2). Percentage of predicted FEV(1) was 92 +/- 14%, percentage of predicted FVC was 94 +/- 15%, FEV(1)/FVC was 81 +/- 4%, and percentage of predicted IC was 84 +/- 18%. Mean peak oxygen uptake (peak O(2)) was 17.9 +/- 5.4 mL/kg/min. Analysis of variance among the three functional Weber classes showed statistically significant differences for pulmonary capillary wedge pressure (PCWP) and IC. Specifically, the more severe the exercise intolerance, the lower was IC and the higher was PCWP. In a multivariate stepwise regression analysis, using peak O(2) (liters per minute) as the dependent variable and the pulmonary function test measurements as independent variables, the only significant predictor selected was IC (r = 0.71, p < 0.0001). In a final stepwise regression analysis including all the independent variables of the resting pulmonary function tests and hemodynamic measurements, the two predictors selected were IC and PCWP (r(2) = 0.58). CONCLUSIONS: In patients with chronic heart failure, IC is inversely related to PCWP and is a strong independent predictor of functional capacity.     

Acute hemodynamic effects of biventricular and left ventricular pacing in chronic pacemaker-dependent patients with advanced heart failure

The beneficial hemodynamic effects of cardiac resynchronization in patients with intraventricular conduction delay have been demonstrated. The potential hemodynamic effects of cardiac resynchronization to compensate the pacing-induced left ventricular conduction delay in chronically paced heart failure patients are not as well established. The aim of the study was to evaluate the acute hemodynamic effects of biventricular and left ventricular pacing in chronically paced patients with advanced heart failure.Fourteen consecutive pacemaker or defibrillator patients with permanent atrial fibrillation and AV block (11 male, 3 woman, mean age: 68 +/- 7 years) were enrolled in this study. There were 5 ischemic (36%) and 9 nonischemic (64%) patients (mean left ventricular ejection fraction: 19 +/- 5%; mean end-diastolic left ventricular diameter: 71 +/- 11 mm). In all patients a right ventricular and left ventricular (via coronary sinus) pacing lead was placed. The aortic and left ventricular hemodynamic measurements were performed using a two-channel micro-tip catheter. The measurements of the aortic pulse pressure (APP) and (dP/ dtmax) were performed during right ventricular apical pacing (RVP), left ventricular (LVP), and biventricular pacing (BVP) (70 bpm).Compared to RVP, LVP and BVP increased APP and dP/dtmax (35.8 +/- 4.2 vs 43.3 +/- 4.5 and 41.2 +/- 4 mmHg; p < 0.001) and (758 +/- 56 vs 967 +/- 60 and 961 +/- 62 mmHg/s; p < 0.001). LVP and BVP showed a comparable hemodynamic response. The hemodynamic effects were not related to the width of the paced QRS complex. Every patient showed improved hemodynamics during LVP and BVP unrelated to the underlying heart disease and to the baseline level of left ventricular dysfunction. BVP and LVP pacing acutely improve contractile left ventricular function in chronically paced patients with advanced heart failure.     

The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure

The hemodynamic parameters (right atrial pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index, heart rate, blood pressure) and neurohumoral responses (alpha-ANP, plasma renin activity, aldosterone, angiotensin II) of Captopril, oral ACE inhibitor, and Bunazosin, oral alpha 1-blocker, were investigated in 28 patients with congestive heart failure at rest and after exercise. These data were analysed in both acute and chronic phases. 1) Acute effect. Captopril produced significant improvement of neurohumoral factors at rest and also after exercise. Bunazosin reduced alpha-ANP, but other neurohumoral factors did not change. Bunazosin produced significant hemodynamic improvement both at rest and after exercise. 2) Chronic effect. Captopril produced significant hemodynamic improvement both at rest and after exercise. Improvement of neurohumoral factors in acute phase was also preserved at chronic phase. On Bunazosin, improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors.     

Effects of prostaglandin E1, dobutamine and placebo on hemodynamic, renal and neurohumoral variables in patients with advanced heart failure.

Excessive neurohumoral activity remains a major burden to the circulation of patients with advanced heart failure. Prostaglandin E1 (PGE1), a balanced i.v. vasodilator, was shown to elicit favorable hemodynamic and clinical effects in this cohort. A prospective randomized parallel group trial was performed to evaluate acute, intermediate and chronic changes in hemodynamic, neurohumoral and renal variables in response to PGE1, dobutamine and placebo. Thirty patients with class III and IV heart failure and low cardiac index (mean 1.9 l/min/m2) two hours after oral drugs including high dose enalapril were included. A 7-day-infusion of PGE1 (16.5 +/- 5 ng/kg/min, range 10 to 20 ng/kg/min, group A n = 10), dobutamine (4.5 +/- 1 micrograms/kg/min, range 2.5 to 5 micrograms/kg/min, group B n = 10) or placebo (saline, group C n = 10) was administered via a central venous access line after stepwise titration until intolerable side effects developed with PGE1 or a 20% increase in cardiac index occurred with dobutamine, which was continued on this dose throughout while PGE1 was maintained on 50% peak dose. Hemodynamic data were collected at baseline, at peak dosages, after 12 hours and after 7 days. Of neurohumoral variables plasma norepinephrine, big endothelin (Big ET) and atrial natriuretic peptide (ANP) were simultaneously evaluated using RIA methods. Renal plasma flow (by paraaminohippurate clearance) and glomerular filtration rate (by iothalamate clearance) was measured prior to and during the infusions (after 12 hours and after 7 days). At peak dose and at 12 hours significant drops from baseline of mean pulmonary artery pressure, pulmonary capillary wedge pressure and systemic vascular resistance were observed which were accompanied by a rise in cardiac output with both PGE1 and dobutamine. These changes were maintained through 7 days when pulmonary vascular resistance levels also fell with both active drugs. Blood pressure did not change throughout, but PGE1 increased heart rate slightly at 12 hrs. Both PGE1 and dobutamine enhanced renal plasma flow after 7 days, but only PGE1 decreased glomerular filtration fraction significantly. Glomerular filtration rate did not change with either drug. PGE1 decreased ANP levels at 12 hrs, and dobutamine increased big ET levels at peak, but decreased big ET at 7 days. Norepinephrine levels were unaffected throughout. Except a slight decrease in right atrial pressure after 7 days placebo did not change any measured variable significantly. Taken together, these data suggest that treatment with PGE1 is as efficacious as low-dose dobutamine in improving cardiac performance and renal perfusion in advanced heart failure. Of importance, no deleterious neurohumoral counterregulation was observed with PGE1.     

Isometric exercise for the evaluation of vasodilatory therapy in severe congestive heart failure

Summary There are few data avallable about the hemodynamic effects of isometric handgrip in severe congestive heart failure and its role in the evaluation of vasodilatory therapy. Therefore, we studied 20 patients with dilated cardiomyopathy at rest, during isometric handgrip, and during supine bicycle exercise before and after a single 25-mg dose of captopril. During handgrip, heart rate (p<0.001); systemic vascular resistance (p<0.01); systolic, mean, and diastolic pulmonary artery pressure (p<0.01) increased significantly; stroke volume index fell (p<0.05); wheras mean arterial pressure showed only a small increase, and cardiac index did not change. In contrast, mean arterial pressure and cardiac index increased during dynamic exercise (p<0.001), and peripheral resistance decreased (p<001). During both handgrip and bicycle exercise, captopril induced a decrease of arterial pressure (p<0.01 and p<0.001; respectively), peripheral resistance (p<0.001 and p<0.01; respectively), and systolic (p<0.01 and p<0.001, respectively) mean (p<0.001), and diastolic pulmonary artery pressure (p<0.001). Captopril induced and increase in stroke volume indes (p<0.01) and cardiac index (p<0.001 and p<0.01 respectively) during both types of exercise. The increase in heart rate (p<0.001), systolic (p<0.01), mean (p<0.001), and diastolic pulmonary artery pressure (p<0.01), as well as the increase in stroke volume index (p<0.05) and cardiae index (p<0.001) was significantly higher in dynamic exercise. In contrast, systemic vascular resistance was clearly higher in isometric than in dynamic exercise (p<0.001). After captopril, these changes were nearly the same. Isometric exercise induced—in contrast to dynamic exercise—vasoconstriction which was blunted by the application of captopril. From that it is concluded that because of the different changes in systemic vascular resistance, isometric exercise seems preferable to dynamic exercise in the evaluation of vasodilatory drugs in congestive heart failure.     

Physical exercise in older patients with chronic heart failure

Maximal exercise capacity undergoes a steady decline after the age of 30 by approximately 10 % per decade. As a consequence of this development older people > 65 years of age suffer from the exercise limitation caused by age-associated cardiac, vascular and skeletal muscle changes. These physiologic alterations make older people especially vulnerable for the cardiovascular and peripheral alterations associated with chronic heart failure (CHF). These changes are not phenomenologically different from age-associated changes. Physical activity plays an important role for regaining a considerable part of vasomotor function, skeletal muscle contractility, and cardiac reserve. Up to now there are no prospective trials comparing the effects of physical training between older and younger patients with CHF. However, smaller observational studies indicate that elderly patients benefit equally well from training interventions with regard to functional improvements in proportion to their lower baseline values. In an aging population training aims at maintaining skeletal muscle force and muscle mass as well as locomotor coordination. Ultimately, the goal is to reduce the substantial morbidity among elderly CHF patients which constitute 79 % of all hospital admissions for heart failure.     

Amrinone and exercise performance in patients with chronic heart failure

Whether cardiotonic agents can improve the ability of patients with chronic heart failure to exercise remains unknown. Accordingly, the circulatory and respiratory response of 11 patients with severe heart failure refractory to digitalis, diuretic drugs and vasodilators was assessed during upright treadmill exercise before, within 24 hours and after 4 weeks of therapy with amrinone. The purpose of this study was to determine the ability of amrinone therapy to improve exercise hemodynamics, effort tolerance and aerobic capacity of these patients. Acute intravenous administration of amrinone (1.8 ± 0.1 mg/kg body weight) produced the following changes (mean values ± standard error of the mean) in hemodynamic variables during supine rest; increased cardiac index (from 2.04 ± 0.39 to 2.99 ± 0.38 liters/min per m²; p <0.01) and reduced pulmonary wedge pressure (from 24 ± 6 to 14 ± 6 mm Hg; p <0.01) without altering heart rate or mean arterial pressure. Within 24 hours after administration of amrinone, wedge pressure decreased at the onset of (from 25 ± 7 to 14 ± 7 mm Hg) and throughout exercise (p <0.01), whereas the exercise response of cardiac output, arteriovenous oxygen difference, heart rate, pulmonary and systemic vascular resistances, maximal oxygen uptake and the pattern of ventilation remained similar to control values. However, after 4 weeks of amrinone therapy, exercise and aerobic capacities were increased 44 and 48 percent (p <0.03), respectively, whereas the ventilatory response was unchanged. Thus, amrinone is a potent cardiotonic agent that acutely improves the function of the failing heart at rest and during exercise; the maximal aerobic capacity was increased after 4 weeks of therapy. Amrinone therefore appears to hold promise for the management of patients with chronic heart failure.     

Milrinone in congestive heart failure: acute and chronic hemodynamic and clinical evaluation

Acute and chronic hemodynamic and clinical responses to milrinone, a new oral inotrope-vasodilator agent, were evaluated prospectively in 37 patients with severe congestive heart failure. The majority of patients (n = 31) had not responded to prior vasodilator therapy, with a substantial number (n = 8) requiring intravenous inotropic support at the time of initial study. All patients showed acute hemodynamic improvement with oral milrinone, and an optimal maintenance dose was chosen for each patient during dose-ranging studies (average dose 48 mg/day). Milrinone was discontinued before follow-up hemodynamic study in 12 patients (because of worsening congestive heart failure in 6 patients, sudden death in 3 patients, arrhythmia in 1 patient and refusal by 2 patients). Hemodynamic effects of milrinone both acutely and after chronic therapy (average 37 days) were compared in the remaining 25 patients. Acutely, mean cardiac index increased from 1.9 +/- 0.5 to 2.5 +/- 0.5 liters/min per m2 (p less than 0.001), and mean pulmonary capillary wedge pressure decreased from 28 +/- 9 to 18 +/- 8 mm Hg (p less than 0.001). When oral milrinone was readministered after chronic therapy, mean cardiac index increased from 1.9 +/- 0.5 to 2.5 +/- 1.7 liters/min per m2 (p less than 0.001), and pulmonary capillary wedge pressure decreased from 27 +/- 8 to 20 +/- 8 mm Hg (p less than 0.001) at 1 hour. New York Heart Association functional class improved in 18 of the 25 patients treated over a long-term period (mean 5.5 +/- 2.3 months).(ABSTRACT TRUNCATED AT 250 WORDS)