De novo immunosuppression with sirolimus and tacrolimus in heart transplant recipients compared with cyclosporine and mycophenolate mofetil: a one-year follow-up analysis.

BACKGROUND: Limited data exist regarding the safety and efficacy of sirolimus in combination with a calcineurin inhibitor in heart transplant recipients. METHODS: From January 2001 to June 2002, 31 de novo heart transplant recipients (treatment group) received a combination of sirolimus, tacrolimus, low-dose rabbit antithymocyte globulin, and glucocorticoids. Outcomes, such as actuarial survival, rate of rejection, incidence of infection, probability of developing diabetes mellitus, renal function, platelet and white blood cell counts, and incidence of coronary artery disease at 1 year, were compared with a cohort of 25 patients (control group) who underwent transplantation primarily in 2000 and in early 2002 treated with cyclosporine, mycophenolate mofetil, and glucocorticoids. All patients were followed up for at least 12 months. RESULTS: Kaplan-Meier actuarial 1-year survival rates were equivalent between groups (97% for the treatment group and 88% for the control group), as was freedom from allograft rejection (48% and 42% for treatment and control groups, respectively). No cases of transplant arteriopathy were noted within the first posttransplantation year. Renal function was not significantly affected in either group. There was a striking increased incidence of mediastinitis in the treatment group (19%) versus 0% in the control group (P = .02). Tacrolimus-sirolimus therapy was associated with a nearly 11-fold increased incidence of new-onset diabetes mellitus as well (P = .004). CONCLUSION: Tacrolimus, sirolimus, and steroids (following low-dose rabbit antithymocyte globulin) were associated with an increased incidence of mediastinitis and posttransplantation diabetes mellitus. No obvious long-term benefit on survival, arteriopathy, or renal function was noted.

Cardiac transplantation in New Jersey.

Heart transplantation is an effective treatment for end-stage congestive heart failure resulting in a one-year survival of 80 percent and a return to normal function in 90 percent of survivors. Refinements in the pre- and postoperative medical management of transplant recipients portend further benefits.

Effects of once-daily benazepril therapy on exercise tolerance and manifestations of chronic congestive heart failure. The Benazepril Heart Failure Study Group.

The effects of the long-acting angiotensin-converting enzyme inhibitor benazepril hydrochloride on exercise tolerance and signs and symptoms of congestive heart failure (CHF) were evaluated in a double-blind, multicenter, placebo-controlled clinical trial. Patients with chronic New York Heart Association class II to IV symptoms of CHF and an ejection fraction by radionuclide scanning of less than or equal to 35% were randomized in a 2:1 ratio to treatment with ascending doses of oral benazepril (n = 114) or placebo (n = 58) once daily, while continuing to receive background therapy with digoxin and diuretics. After randomization, patients were evaluated clinically every 2 weeks during a 12-week, double-blind treatment period. Maximal exercise tolerance was measured before and at specified time points after randomization by graded treadmill exercise testing. At week 12, mean exercise time increased 95 +/- 12 (SEM) seconds in the group receiving benazepril, whereas the increase was 37 +/- 18 seconds in the group receiving placebo (p less than 0.01 for the difference between the groups). There was also greater improvement in overall clinical status and in the signs and symptoms of CHF in benazepril-treated patients than in control subjects. There were 3 deaths in placebo-treated patients and none in benazepril-treated patients (p less than 0.05); the overall incidence of adverse effects was identical in the 2 groups. Benazepril is a well-tolerated angiotensin-converting enzyme inhibitor that provides clinically important improvement in exercise tolerance and in signs and symptoms when given once daily to patients with CHF receiving background therapy with digoxin and a diuretic.

2-Hydroxydesipramine and desipramine plasma levels and electrocardiographic effects in depressed younger adults.

Desipramine was given to 34 outpatients aged 20 to 51 years who had primary major depressive disorder but who were otherwise in good health. Daily dosage at bedtime was constant for the final 3 weeks of the 5-week study (mean, [SD] 169.1 [46.1] mg). Electrocardiograms done predrug and after 5 weeks were read by a cardiologist blind to the order in which they were performed. Plasma samples drawn 14 hours after the final study dose were assayed by high performance liquid chromatography; mean (SD) levels were 140.2 (140.0) ng/ml for desipramine and 56.5 (29.4) ng/ml for 2-hydroxydesipramine (2-OH-DMI). Heart rate and PR, QRS and QTc intervals were significantly greater at the end of the study than at baseline, while QT intervals were significantly less. Changes in heart rate and PR, QT and QTc intervals were significantly negatively correlated with the value of the respective cardiac parameters at baseline. Changes in PR interval were significantly positively correlated with log desipramine, log 2-OH-DMI and log (desipramine + 2-OH-DMI). Stepwise multiple regression analyses showed that, for PR interval, each of the three plasma level variables showed a significant ability to improve R2 over that obtained from baseline PR alone. These findings suggest that both 2-OH-DMI and desipramine plasma levels predict a prolongation of intracardiac conduction in younger adults and that monitoring both levels may be useful in the clinical management of certain younger adult patients.

Long-term therapy with benazepril in patients with congestive heart failure: effects on clinical status and exercise tolerance.

Benazepril hydrochloride (CGS 14824A) is an orally active, nonsulfhydryl compound that is transformed in vivo to a long-acting inhibitor of angiotensin-converting enzyme (ACE). Previous studies have shown benazepril to lower blood pressure in hypertensive patients and to confer acute hemodynamic benefits in patients with congestive heart failure (CHF). In the current multicenter investigation, 16 patients with chronic CHF due to left ventricular systolic dysfunction (ejection fraction less than 0.40 at rest) whose symptoms corresponded to New York Heart Association classes II to IV were given open-label benazepril once daily in ascending doses of 2 to 20 mg and followed biweekly for 12 weeks. Evaluation of the 15 subjects who completed the trial showed a progressive increase in treadmill exercise duration (from 7.65 +/- 3.64 [SD] minutes at baseline to 9.74 +/- 3.66 minutes at 12 weeks, P less than .001); augmentation of the mean left ventricular ejection fraction (from 0.266 +/- 0.133 at baseline to 0.292 +/- 0.136 at 12 weeks, P less than .025); relief of exertional dyspnea in 7 of the 15 patients (P less than .02); and improvement in global symptomatic status in 10 of the patients (P less than .01). These responses were accompanied by a reduction in serum ACE activity of 75% (from 27.2 +/- 10.5 IU/L at baseline to 6.7 +/- 1.9 IU/L at 12 weeks, P less than .001), which was independent of dose and duration of treatment. The magnitude of ACE inhibition did not correlate with changes in the efficacy variables. Aside from two instances of symptomatic hypotension (one of which was complicated by volume depletion), the drug was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilators as first-line therapy for congestive heart failure: a comparative hemodynamic study of hydralazine, digoxin, and their combination.

Although digitalis and vasodilators both enhance cardiac performance in patients with congestive heart failure, their relative efficacy is unknown. Accordingly, the acute hemodynamic effects of intravenous hydralazine (0.15 mg/kg), digoxin (1.0 mg), and the hydralazine-digoxin combination were evaluated in 14 normotensive heart failure patients at sitting rest, nine of whom were also studied during submaximal upright bicycle exercise. Hemodynamic responses at rest and exercise were similar. Cardiac output and stroke volume rose with both agents, the increase in cardiac output with hydralazine exceeding that with digoxin at rest. Left and right ventricular filling pressures declined equally. Systemic arterial mean pressure and total systemic vascular resistance fell with hydralazine, while, with digoxin, systemic arterial mean pressure increased and total systemic vascular resistance was unchanged. The hydralazine-digoxin combination produced increases in cardiac output and stroke volume that were greater than with either drug alone, and that equalled the sum of the drugs' individual effects; reductions in ventricular filling pressures were similar to the single-drug interventions. Thus, hydralazine is at least as effective as digoxin in improving cardiac function over the short term. Vasodilators may constitute an acceptable alternative to digitalis as initial therapy for congestive heart failure, except where a reduction in systemic arterial pressure is potentially deleterious. Use of combined treatment produces greater increases in cardiac output than with either drug alone, but requires risking the toxicities of two agents.

Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study.

The effects of the digitalis glycosides on systemic vascular resistance (SVR) in patients with congestive heart failure (CHF) are controversial. Most investigators report a reduction in total SVR, an action that has been attributed primarily to withdrawal of elevated sympathetic tone. Direct proof of this hypothesis is lacking, however, and the roles played by the renin-angiotensin-aldosterone and vasopressin systems have not been fully explored. Moreover, in several studies of patients with CHF, SVR did not decrease after the administration of digitalis. To clarify these issues, the hemodynamic and hormonal effects of digoxin were correlated in 11 normotensive men in sinus rhythm with CHF due to dilated cardiomyopathy. Patients were evaluated at rest and during submaximal exercise before and 6 hours after the intravenous infusion of 1.0 mg of digoxin (mean serum concentration 1.7 ng/ml). With digoxin therapy, heart rate, pulmonary wedge pressure and right atrial pressure declined and cardiac output increased. Although vasopressin was unchanged, both plasma norepinephrine concentrations and plasma renin activity decreased, the reduction in norepinephrine correlating with the increase in cardiac output. Despite these hemodynamic and hormonal effects, there was no change in total SVR at rest or during exercise. It is concluded that the improvement in cardiac function with digoxin in this patient group was a result of the inotropic properties of the drug, without an associated reduction in impedance. The failure of total SVR to decrease despite decreases in plasma norepinephrine levels and plasma renin activity might be explained by concomitant digitalis-induced vasoconstriction, impaired ability of arterioles to dilate in CHF, or offsetting alterations in other vasoactive hormone systems.

Effect of acute changes in serum digoxin concentration on renal digoxin clearance.

The effect of acute alterations of serum digoxin concentration (S DIG) on the renal clearance of digoxin (C DIG) was studied in six normal subjects undergoing water diuresis. Digoxin in a 5% dextrose and water solution was infused at a rate of 0.01 microgram/kg/min (low dose). One hour after the infusion began, three 20-min urine samples for clearance determination were taken. The digoxin infusion rate was then increased to 0.05 microgram/kg/min (high dose) and three additional urine samples were taken an hour later. With low doses of digoxin, the S DIG was (means +/- SD) 0.63 +/- 0.08 ng/ml, C DIG was 252.3 +/- 65.1 ml/min, inulin clearance (C IN) was 96.8 +/- 15.7 ml/min, the ratio C DIG/C IN was 2.59 +/- 0.38, and renal blood flow (C PAH) was 516 +/- 90 ml/min. With the high-dose infusion, S DIG rose to 3.23 +/- 0.44 ng/ml; C IN, C DIG, C DIG/C IN, and C PAH remained stable. C DIG correlated strongly with both C IN and C PAH. We conclude that in normal subjects undergoing water diuresis, C DIG/C IN is not altered by acutely increasing S DIG, digoxin is extensively secreted by the nephron, and C DIG is linearly related to renal plasma flow.

Prospective study comparing different echocardiographic measurements of pulmonary capillary wedge pressure in patients with organic heart disease other than mitral stenosis.

In 25 patients with cardiac disease, but free of left ventricular inflow obstruction, the electrocardiogram and M-mode echocardiogram of the aortic root, left atrium and both the mitral and the aortic valves were obtained simultaneously with the pulmonary artery wedge pressure (PAWP) during right heart catheterization. The echocardiographic measurements of the left atrial size, PR-AC interval, left atrial emptying index and the ratio between the electrocardiographic Q wave to mitral valve closure (Q-MVC) and between aortic valve closure to the mitral E point (AVC-E) were correlated to the pulmonary artery wedge pressure by means of linear regression analysis. A formula in which PAWP = 36.6 (Q-MVC/AVC-E)-- 2 was prospectively used to study the measured pressure in the current group of patients. The pulmonary artery wedge pressure derived from these latter measurements correlated well with the invasive measurement of this pressure (r = 0.91). The pulmonary artery wedge pressure calculated by echocardiography differed from the pulmonary artery wedge pressure measured by catheterization by 3 mm Hg or less in 19 of the 25 patients, by 4 mm Hg or less in 22 patients and by 6 mm Hg or less in 24 patients. Although the correlation between the (Q-MVC/AVC-E) ratio and measured pulmonary artery wedge pressure was highly significant (r = 0.91, probability [p] less than 0.001, n = 25), the left atrial emptying index, PR-AC and left atrial size revealed poor correlation coefficients (r = 0.45, r = 0.45 and r = 0.56 [p less than 0.05]), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of captopril in patients with severe chronic heart failure.

The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25 mg dose, the cardiac index increased from 1.82 +/- 0.14 to 2.28 +/- 0.30 liters/min/m2 (p less than 0.05) while pulmonary capillary wedge pressure decreased from 22.7 +/- 2.0 to 14.7 +/- 4.7 mm Hg (p less than 0.05). Mean blood pressure and systemic vascular resistance decreased from 85.7 +/- 6.7 to 71.2 +/- 12.0 mm Hg (p less than 0.001) and from 1,909 +/- 246 to 1,362 +/- 347 dynes-s-cm5 (p less than 0.001), respectively. Heart rate did not change significantly. There was an inverse relation between maximal augmentation in cardiac index and maximal reduction in pulmonary capillary wedge pressure (r = -0.82, p less than 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic heart failure whose plasma renin activity was within normal range (1.1 to 7.3 ng/ml/hour).

Dobutamine therapy in acute myocardial infarction.

The short-term response of combined dopamine hydrochloride-sodium nitroprusside therapy was compared with administration of dobutamine in eight patients with acute myocardial infarction complicated by hypotension and severe left ventricular dysfunction. All patients were receiving dopamine before the study began. The addition of sodium nitroprusside increased cardiac index (Cl) from 1.94 +/- 0.490 to 2.22 +/- 0.48 L/min/sq m; decreased left ventricular filling pressure (LVFP) from 28.9 +/- 3.5 to 19.9 +/- 3.3 mm Hg and mean systemic arterial pressure (MAP) from 82.1 +/- 5.1 to 71.5 +/- 6.0 mm Hg. During dobutamine infusion, Cl, LVFP, and MAP were 2.33 +/- 0.31 L/min/sq m, 20.8 +/- 4.8 mm Hg, and 74.1 +/- 8.1 mm Hg, respectively. There was no statistical difference between short-term hemodynamic benefits produced by dobutamine or combined dopamine-sodium nitroprusside therapy. Dobutamine, a synthetic cathecholamine, provides a substitute for dopamine-sodium nitroprusside therapy in acute myocardial infarction. Dobutamine has the advantage of being a single agent and is therefore easier to administer.

Effects of combined dopamine and nitroprusside therapy in patients with severe pump failure and hypotension complicating acute myocardial infarction.

In severe pump failure with hypotension complicating acute myocardial infarction, dopamine has been useful in raising arterial pressure by increasing myocardial performance and augmenting peripheral resistance. Once adequate blood pressure are obtained, vasodilators may be used to reduce peripheral resistance and thus enhance pump performance. Accordingly, the hemodynamic effects of dopamine and nitroprusside administration were monitored in eight patients who developed hypotension following an acute myocardial infarction. With dopamine therapy alone, mean arterial pressure averaged 84 +/- 3.6 mm Hg and mean left ventricular filling pressure 32 +/-7.9 mm Hg. The addition of nitroprusside, at doses ranging from 0.5 to 1.6 micrograms/kg/min, resulted in a decrease in arterial pressure to 75 +/- 2.4 mm Hg (p less than 0.01) and in left ventricular filling pressure to 23 +/- 7.2 mm Hg (p less than 0.001). Cardiac index increased modestly from 1.81 +/- 0.61 to 2.01 +/- 0.60 liters/min/m2 (p less than 0.05), while systemic vascular resistance fell from 1,967 +/- 707 to 1,586 +/- 634 dynes-sec-cm-5 (p less than 0.01). Heart rate did not change significantly. Seven of eight patients died in the hospital within 4 days of admission. It appears that despite a beneficial hemodynamic response effected by combined dopamine-nitroprusside administration, the prognosis of this group of patients may not be favorably altered because of the extensive destruction of myocardium.

Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensin-converting enzyme.

The renin-angiotensin system is thought to maintain elevated systemic vascular resistance in heart failure. The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with stable congestive heart failure poorly controlled by digitalis and diuretics. At single daily doses of 25 to 150 mg, the cardiac index rose from 1.75 +/- 0.18 to 2.27 +/- 0.39 (mean +/- S.D.) liters per minute per square meter (P less than 0.001), and pulmonary-wedge pressure fell from 26.5 +/- 7.5 to 17.3 +/- 6.1 mm Hg (P less than 0.01). Systemic vascular resistance decreased from 2006 +/- 300 to 1393 +/- 238 dyne seconds per centimeter (P less than 0.001), and mean arterial pressure fell from 83.7 +/- 7.0 to 70.3 +/- 9.9 mm Hg (P less than 0.001) (mean +/- S.D.). Heart rate did not change appreciably. Hemodynamic alterations peaked at 90 minutes and persisted for three to four hours. Control plasma renin activity ranged from 1.1 to 7.3 ng per milliliter per hour and did not correlate with changes in hemodynamic values. Three patients on long-term treatment maintained clinical improvement. Although its mechanism of action has not been completely elucidated, captopril may prove useful in the treatment of chronic congestive heart failure.

Anticoagulation in myocardial infarction: modern approach to an old problem.

The role of routine anticogulation in acute myocardial infarction continues to be a source of controversy. There is currently strong evidence to suggest that conventional anticoagulation will prevent the formation of most deep vein thrombi and subsequent pulmonary embolization. Anticoagulant agents also appear to reduce the incidence of emboli from cardiac mural thrombi to peripheral arteries. Patients without a predisposition to bleeding are unlikely to have hemorrhagic complications in the hospital after usual doses of anticoagulant drugs. In patients with severe hypertension, prior gastrointestinal bleeding, carcinoma or advanced age, small dose heparin therapy appears to reduce the incidence of venous thrombosis and probably of pulmonary emboli as well. Its value in preventing peripheral arterial embolization has not been defined. Anticoagulation with standard "large" doses is an effective means of preventing the risks of pulmonary and peripheral emboli during the in-patient phase of acute myocardial infarction. Small dose heparin therapy provides an excellent alternative to conventional anticoagulation when there is more than a negligible risk of hemorrhage. There is little evidence at this time to support the use of long-term anticoagulation beyond the acute phase of myocardial infarction.

Amrinone: a new non-glycosidic, non-adrenergic cardiotonic agent effective in the treatment of intractable myocardial failure in man.

Chronic congestive heart failure not controlled by conventional therapy was treated with intravenous amrinone, a new non-glycosidic, non-catecholamine cardiotonic agent. Eight patients with New York Heart Association functional class III-IV symptoms were hemodynamically monitored. At peak effect, cardiac index (CI) increased from 1.84 +/- 0.32 to 2.74 +/- 0.44 l/min/m2 (mean +/- SD) (p less than 0.001) and left ventricular filling pressure (LVFP) decreased from 25.8 +/- 6.2 to 19.5 +/- 6.8 mm Hg (p less than 0.05), while heart rate and mean aortic blood pressure did not change significantly. Mean endocardial circumferential fiber shortening (mean Vcf), determined by echocardiography, increased from 0.61 +/- 0.27 to 0.89 +/- 0.34 cir/sec (p less than 0.05). The duration of action after bolus infusion varied from 60--90 minutes. During continuous infusion of amrinone, sustained increases in CI and reductions in LVFP, similar to those at the time of peak effect after bolus administration, were maintained for 180 minutes. These marked cardiotonic effects of amrinone in patients already taking digitalis for severe heart failure occurred without side effects of arrhythmias or altered arterial pressures. The fact that the drug is orally active makes amrinone a v:ry promising inotropic agent for the treatment of chronic heart failure in man.