Search

BACKGROUND: The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying. MATERIALS AND METHODS: One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction. RESULTS: Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide. CONCLUSION: We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.

Carvedilol reduces disease progression in heart failure, but to our knowledge, its effects on hospitalizations and costs have not been evaluated.We examined the effects on hospitalization frequency and costs in the U.S. Carvedilol Heart Failure Trials Program. This program consisted of four concurrent, multicenter, double-blind, placebo-controlled studies involving 1,094 patients with New York Heart Association class II to IV heart failure, which treated patients with placebo or carvedilol for up to 15 months (median, 6.5 months).Detailed resource utilization data were collected for all hospitalizations occurring between randomization and the end of follow-up. In-patient care costs were estimated based on observed levels of resource use.Compared with placebo, carvedilol reduced the risk of hospitalization for any reason by 29% (p = 0.009), cardiovascular hospitalizations by 28% (p = 0.034) and heart failure hospitalizations by 38% (p = 0.041). Carvedilol also decreased the mean number of hospitalizations per patient (for cardiovascular reasons 30% [p = 0.02], for heart failure 53% [p = 0.03]). Among hospitalized patients, carvedilol reduced severity of illness during hospital admission, as reflected by shorter length of stay and less frequent use of intensive care. For heart failure hospital admissions, carvedilol decreased mean length of stay by 37% (p = 0.03) and mean number of intensive care unit/coronary care unit days by 83% (p = 0.001), with similar effects on cardiovascular admissions. As a result, estimated inpatient care costs with carvedilol were 57% lower for cardiovascular admissions (p = 0.016) and 81% lower for heart failure admissions (p = 0.022).Carvedilol added to angiotensin-converting enzyme inhibition reduces hospitalization risk as well as severity of illness and resource utilization during admission in patients with chronic heart failure.

Although pharmacological therapy has ameliorated symptoms and improved the survival of patients with chronic heart failure (CHF), this chronic syndrome remains a progressive disease causing incremental morbidity and early mortality. A new therapy for the treatment of CHF should ideally decrease mortality, alleviate symptoms, and improve functional capacity. A growing body of evidence suggests that the use of implantable devices to resynchronize ventricular contraction may be a beneficial adjunct in the treatment of CHF.The Comparison of Medical Therapy, Pacing, and Defibrillation in Chronic Heart Failure (COMPANION) trial is a randomized, open-label, 3-arm study of patients in New York Heart Association class III or IV with an ejection fraction of 35% or less and a QRS duration of 120 milliseconds or less. The COMPANION study objectives are to determine whether optimal pharmacological therapy used with (1) ventricular resynchronization therapy alone or (2) ventricular resynchronization therapy combined with cardioverter-defibrillator capability is superior to optimal pharmacological therapy alone in reducing combined all-cause mortality and hospitalizations; reducing cardiac morbidity; improving functional capacity, cardiac performance, and quality of life; and increasing total survival.

This study was designed to evaluate the effects of low-dose enoximone on exercise capacity.At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated.This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring.By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups.Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.

In the 1980s and early 1990s, evidence suggesting a pivotal role for chronic neurohormonal stimulation in the pathophysiology of heart failure began to emerge, which has now produced a dramatic change in the way heart failure is viewed and treated. Preclinical data and results from clinical trials revealed that blocking the actions or generation of norepinephrine or angiotensin II positively affected the course of left ventricular dysfunction and myocardial failure, despite the fact that this inhibition had minimal or negative effects on hemodynamics. Angiotensin-converting enzyme (ACE) inhibitors have been used for heart failure for many years, but only recently have beta-blockers been recommended as part of standard treatment for heart failure. The negative inotropic effects of beta-blockers are well known; these agents must be used with caution in patients with heart failure. However, after several months of treatment, left ventricular ejection fraction (LVEF) gradually increases, and a reversal of the pathological remodeling associated with chronic heart failure occurs: left ventricular mass decreases, chamber shape becomes more elliptical, and mitral regurgitation decreases. Data from clinical trials have shown that long-term beta-adrenergic blockade halts the progression of pump dysfunction, substantially improves left ventricular function, and reduces morbidity and mortality rates in patients with mild-to-moderate heart failure. This article provides a detailed rationale for the use of beta-blockers in patients with chronic heart failure, based on the current understanding of pathophysiology and recent clinical trial data.

Anti-adrenergic therapy with β-adrenergic blocking agents has proved to be effective in the medical treatment of various dilated cardiomyopathies, including idiopathic, valvular and ischemic subtypes. This report will summarize the effects of β-blocker treatment on the dilated cardiomyopathy phenotype, as well as on clinical parameters.

Many patients remain markedly symptomatic despite optimal current therapy for heart failure. Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function.One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had symptomatic, advanced heart failure while on standard triple therapy, as evidenced by a mean ejection fraction of 0.22, marked reduction in distance traveled in a 6-minute corridor walk test, and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Questionnaire. After a 2-week, open-label test of 6.25 mg twice daily carvedilol, 105 patients were randomized (2:1) to receive either carvedilol (up to 25 mg twice daily, n = 70) or matching placebo (n = 35) for 6 months while background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant. Ten patients (8%) did not complete the open-label period because of adverse events and 11.4% in both the carvedilol and placebo groups dropped out in the double-blind phase. The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved. Quality of life, which was the primary endpoint, improved similarly in the carvedilol and placebo groups, whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol (P.05). Hospitalization and mortality rate were too low to evaluate a difference, and exercise time and New York Heart Association classification did not change significantly in response to the drug. Left ventricular ejection fraction rose significantly (+0.09) in the carvedilol group compared with the placebo group (+0.02, P = .004).The beta-blocker carvedilol can be safely employed in patients with severe heart failure. Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity.

The left-ventricular (LV) functional, hemodynamic, and antiadrenergic effects of metoprolol, bucindolol, and carvedilol have been compared in three concurrent placebo-controlled clinical trials in patients with symptomatic idiopathic dilated cardiomyopathy. All three drugs were well tolerated, all produced at least moderate degrees of beta-blockade as assessed by reduction in exercise heart rate, and all increased the left-ventricular ejection fraction. Compared with the beta 1-selective, second-generation compound metoprolol, the third-generation compounds bucindolol and carvedilol lowered indices of adrenergic activity and tended to improve LV function to a greater extent. In patients with chronic heart failure there may be important therapeutic response differences between second- and third-generation beta-blocking agents.

Recent developments in the treatment of chronic heart failure have lead to the use of beta blockers to improve ventricular function and symptoms, and to reverse or slow pathologic remodeling of the failing heart. Little practical information exists in the literature on how to initiate this therapy and how to select the proper beta-blocking agent. This editorial examines which beta-blocking agents are best tolerated and why, and describes how best to initiate treatment with these agents.

We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction.Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF)or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated.Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a "third-generation" beta -blocking agent with vasodilator properties, in chronic heart failure.Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P.001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P.001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (P.001). Carvedilol also lowered the hospitalization rate (by 58% to 64%, P = .01) and was generally well tolerated.In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

Allograft rejection remains a major cause of morbidity and mortality. Cyclophosphamide, a nitrogen mustard, is a potent immunosuppressive agent with effects on both T- and B-lymphocytes, and thus may be effective in preventing further cellular and/or humoral rejection in cardiac transplant recipients with recurrent or recalcitrant rejection. We retrospectively reviewed the records of 320 surviving cardiac transplant recipients. Cyclophosphamide was substituted for azathioprine in 28 patients because of frequent allograft rejection. We then reviewed the rejection history of these 28 patients, specifically looking at rejection frequency, type (cellular, vascular or mixed), and treatment. Cyclophosphamide was substituted for azathioprine at an average of 8.4 +/- 2.8 months after transplantation. Despite a 56.0% reduction in prednisone dose (p0.001), at least a threefold reduction in rejection frequency (p0.001) was observed, while cyclosporine levels were unchanged. Twenty-eight percent of the patients did not experience even mild rejection after beginning therapy with cyclophosphamide, 55% had 1 or 2 subsequent mild or moderate rejection episodes, and only 17% had more than two subsequent episodes of mild or moderate rejection. Overall, the number of treated rejection episodes decreased from 0.37 episodes per patient month with azathioprine to 0.10 episodes per patient month on therapy with cyclophosphamide. Separating the patients into two groups based on the predominant rejection type (cellular vs. vascular) occurring at the time of cyclophosphamide substitution revealed a similar reduction in cellular and vascular rejection in each respective group. While white blood cell count decreased by 16%, cyclophosphamide was not discontinued in any patient due to leukopenia, and no change was noted in hematocrit. Cyclophosphamide appears to be safe and effective in maintenance immunosuppression and may reduce rejection frequency in some patients with frequently occurring allograft rejection without necessitating the augmentation of either corticosteroids or cyclosporine.

Short-term studies suggest that cardiac transplant immunosuppression without maintenance corticosteroids is feasible in selected patients. However, concern exists as to the long-term effects, specifically the possibility of increased morbidity and mortality because of late allograft rejection and allograft coronary artery disease.We retrospectively reviewed the records from 441 consecutive heart transplantation procedures done in 416 patients with use of an immunosuppressive protocol that attempted corticosteroid withdrawal within 2 months of transplantation. forty-two patients died or underwent retransplantation during the first 3 months and were excluded from further analysis. Analysis focused on demographic and long-term outcome variables (including death, rejection, retransplantation, and infection).Thirty percent (111) of eligible patients (374) met the definition of successful early steroid withdrawal. Only male gender independently predicted successful withdrawal. Mortality, both short and long term, was significantly lower in patients in whom successful early withdrawal from corticosteroids was achieved than in patients in whom the early attempts failed (1.7% per year versus 4.7% per year; p0.0001). The prevalence of late acute allograft rejection (more than 1 year after transplantation) was lower in patients successfully withdrawn from steroid therapy early after transplantation (0.07 pt-yr of follow-up versus 0.15 pt-yr; p = 0.002). Multivariate analysis of the entire group identified incidence of infection (p = 0.001), older age (p = 0.001), failed early steroid withdrawal (p = 0.006), and female gender (p = 0.016) as independent predictors of mortality.Successful early corticosteroid withdrawal identifies a subgroup of "immunologically privileged" patients with a low risk for long-term mortality and is not associated with an increased prevalence of late rejection or clinically significant coronary artery disease.

Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined.We enrolled 1094 patients with chronic heart failure in a double-blind, placebo-controlled, stratified program, in which patients were assigned to one of the four treatment protocols on the basis of their exercise capacity. Within each of the four protocols patients with mild, moderate, or severe heart failure with left ventricular ejection fractionsor = 0.35 were randomly assigned to receive either placebo (n = 398) or the beta-blocker carvedilol (n = 696); background therapy with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor remained constant. Patient were observed for the occurrence death or hospitalization for cardiovascular reasons during the following 6 months, after the beginning (12 months for the group with mild heart failure).The overall mortality rate was 7.8 percent in the placebo group and 3.2 percent in the carvedilol group; the reduction in risk attributable to carvedilol was 65 percent (95 percent confidence interval, 39 to 80 percent; P0.001). This finding led the Data and Safety Monitoring Board to recommend termination of the study before its scheduled completion. In addition, as compared with placebo, carvedilol therapy was accompanied by a 27 percent reduction in the risk of hospitalization for cardiovascular causes (19.6 percent vs. 14.1 percent, P = 0.036), as well as a 38 percent reduction in the combined risk of hospitalization or death (24.6 percent vs, 15.8 percent, P0.001). Worsening heart failure as an adverse reaction during treatment was less frequent in the carvedilol than in the placebo group.Carvedilol reduces the risk or death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor.

For incompletely understood reasons, cardiac transplant recipients achieve only 60% to 70% of predicted values for maximal exercise capacity. The objective was to determine the characteristics of cardiac transplant recipients that are predictive of exercise capacity.One hundred ten patients underwent maximal exercise testing using a modified Naughton protocol 26 +/- 1 months after transplantation. Recipient characteristics, resting hemodynamic variables and exercise parameters were compared using univariate and multivariate analyses.The average maximum heart rate was 85% of predicted, and the average peak oxygen consumption (Vo2) was 17.7 +/- 0.3 ml/kg/min (64% of predicted). Pretransplant status, etiology of heart failure, ischemic time, degree of HLA disparity, cumulative corticosteroid exposure, and number of rejection episodes failed to correlate with any exercise parameter. Older recipient age and female gender were associated with greater values for the proportion of the predicted peak Vo2 (p0.001 for age; p = 0.001 for gender). Older donor age was the strongest independent predictor of a decreased chronotropic response (p0.001) and was a weak predictor of decreased peak Vo2 (p = 0.014). Even in the multivariate analysis, maintenance prednisone dose negatively impacts exercise duration (p = 0.05), peak Vo2 (p = 0.035) and percent of predicted peak Vo2 (p = 0.032). Of all characteristics tested, pulmonary vascular resistance within 24 hours of exercise most powerfully predicts exercise duration (p = 0.002) and peak Vo2 (p = 0.001).Female recipients and older recipients have a lower absolute exercise capacity, but achieve a greater proportion of their predicted capacity. Recipients of older donor hearts and those receiving chronic corticosteroids have decreased exercise capacity. Pulmonary vascular resistance is inversely correlated with exercise capacity.

In order to evaluate the chronic in vivo effects of excessive catecholamine levels, and the potential for spontaneous reversibility of these effects, we employed a chronic two-week infusion of epinephrine in rats. Epinephrine infusion resulted in myocyte hypertrophy, left ventricular fibrotic degenerative changes, diminished response to adrenergic stimuli, and enhanced left ventricular papillary contractile responses to calcium. Two weeks after cessation of the epinephrine infusion, left ventricular fibrotic degenerative changes were reduced, and responses to adrenergic stimuli were partially restored. However, myocyte hypertrophy and the enhanced responses to calcium persisted in these animals. This study indicates the potential for spontaneous reversal of some of epinephrine's toxic effects, and further implies that the loss in adrenergic sensitivity in epinephrine-treated animals may be a desensitization phenomenon, while the alterations in calcium response are less readily reversed.

Several small studies have suggested beneficial effects of long-term beta-blocker treatment in idiopathic dilated cardiomyopathy. Our large multicentre study aimed to find out whether metoprolol improves overall survival and morbidity in this disorder. 383 subjects with heart failure from idiopathic dilated cardiomyopathy (ejection fraction0.40) were randomly assigned placebo or metoprolol. 94% were in New York Heart Association functional classes II and III, and 80% were receiving background treatment. A test dose of metoprolol (5 mg twice daily) was given for 2-7 days; those tolerating this dose (96%) entered randomisation. Study medication was increased slowly from 10 mg to 100-150 mg daily. There were 34% (95% CI -6 to 62%, p = 0.058) fewer primary endpoints in the metoprolol than the placebo group; 2 and 19 patients, respectively, deteriorated to the point of needing transplantation and 23 and 19 died. The change in ejection fraction from baseline to 12 months was significantly greater with metoprolol than with placebo (0.13 vs 0.06, p0.0001). Pulmonary capillary wedge pressure decreased more from baseline to 12 months with metoprolol than with placebo (5 vs 2 mm Hg, p = 0.06). Exercise time at 12 months was significantly greater (p = 0.046) in metoprolol-treated than in placebo-treated patients. In patients with idiopathic dilated cardiomyopathy, treatment with metoprolol prevented clinical deterioration, improved symptoms and cardiac function, and was well tolerated.

Inotropic therapy, other than with digitalis glycosides, has had limited success in patients with chronic congestive heart failure. We investigated whether vesnarinone, a new positive inotropic agent, reduces morbidity and mortality and improves the quality of life of patients with symptomatic heart failure.Patients receiving concomitant therapy with digoxin (87 percent) and an angiotensin-converting-enzyme inhibitor (90 percent) who had ejection fractions of 30 percent or less were randomly assigned to receive double-blinded therapy with 60 mg of vesnarinone per day, 120 mg of vesnarinone per day, or placebo. Afer 253 patients had been enrolled, randomization to the 120-mg vesnarinone group had to be stopped because of a significant increase in early mortality in this group. Thereafter, patients were randomly assigned only to 60 mg of vesnarinone per day (a total of 239 patients) or placebo (a total of 238 patients).Significantly fewer patients in the group receiving 60 mg of vesnarinone than in the group receiving placebo (26 vs. 50 patients; P = 0.003) died or had worsening heart failure during the six-month study period. The reduction in risk was 50 percent (95 percent confidence interval, 20 to 69 percent). Similarly, there was a 62 percent reduction (95 percent confidence interval, 28 to 80 percent) in the risk of dying from any cause among the patients receiving vesnarinone. Furthermore, quality of life improved to a greater extent in the vesnarinone group than in the placebo group over 12 weeks (P = 0.008). The principal side effect associated with vesnarinone was reversible neutropenia, which occurred in 2.5 percent of the patients.Six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure. However, a higher dose of vesnarinone (120 mg per day) increased mortality, suggesting that this drug has a narrow therapeutic range; the long-term effects of vesnarinone are unknown.

We investigated the effects of clentiazem, a 1,5-benzothiazepine calcium antagonist, on epinephrine-induced cardiomyopathy in rats. With 2-week chronic epinephrine infusion, 16 of 30 rats died within 4 days, and severe ischemic lesions and fibrosis of the left ventricles were observed. In epinephrine-treated rats, left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced, but responses to calcium were normal or enhanced compared to controls. Left ventricular alpha and beta adrenoceptor densities were also reduced compared to controls. Treatment with clentiazem prevented epinephrine-induced death (P.05), and attenuated the ventricular ischemic lesions and fibrosis, in a dose-dependent manner. Left atrial and left ventricular papillary muscle contractile responses to isoproterenol were reduced compared to controls in groups treated with clentiazem alone, but combined with epinephrine, clentiazem restored left atrial responses and enhanced left ventricular papillary responses to isoproterenol. On the other hand clentiazem did not prevent epinephrine-induced down-regulation of alpha and beta adrenoceptors. Interestingly, clentiazem, infused alone, resulted in decreased adrenergic receptor densities in the left ventricle. Clentiazem also did not prevent the enhanced responses to calcium seen in the epinephrine-treated animals, although the high dose of clentiazem partially attenuated the maximal response to calcium compared to epinephrine-treated animals. In conclusion, clentiazem attenuated epinephrine-induced cardiac injury, possibly through its effect on the adrenergic pathway.

In membrane preparations derived from primary cultures of chick myocardial cells, beta adrenergic receptors modeled for a single low-affinity site for both betaxolol (beta-1-selective) and ICI 118551 (beta-2-selective) displacement of [125I]iodocyanopindolol (ICYP), indicating that the chick beta receptor is pharmacologically distinct from both mammalian beta-1 and beta-2 adrenergic receptors with respect to these antagonists. However, the highly beta-1-selective compound CGP 20712A was able to distinguish two binding sites on ICYP competition curves, a high-affinity "beta-1 site" (75%) and a low-affinity "beta-2 site" (25%). Also, in chick heart cell membranes the relative ability of agonists to displace ICYP produced a profile typical of beta-1 adrenergic receptors with a rank order of potency or efficacy of: isoproterenol greater than epinephrine = norephinephrine. When agonist-mediated adenylyl cyclase stimulation was assessed the order of potency was slightly different, isoproterenol greater than epinephrine greater than or equal to norepinephrine. Additionally, antagonism of isoproterenol stimulation of adenylyl cyclase by CGP 20712A yielded a Kb value (1.16 +/- 0.35 x 10(-7) M) intermediate between the high and low-affinity binding sites of CGP 20712A, suggesting that the low-affinity site is coupled to adenylyl cyclase. In membrane preparations of frog myocardial cells, ICYP/antagonist competition curves modeled for a mixed population of receptors, with subtype percentages varying from 50:50 beta-1:beta-2 to 100% beta-2 depending on the specific antagonist used and the individual cell preparation. For ICYP/agonist competition binding experiments the relative ability to displace ICYP was isoproterenol greater than epinephrine = norepinephrine, a profile typical of beta-1 adrenergic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

We have prospectively monitored 268 patients by our previously described method of routine immunofluorescence of endomyocardial biopsy specimens. We have classified these patients according to their rejection pattern: cellular, vascular, and mixed. The criteria for these designations have been previously described. In this study we retrospectively reviewed coronary angiograms of these patients to assess the presence and time-course of developing allograft coronary artery disease. All available explanted hearts and postmortem hearts were also assessed by light microscopic examination for acute coronary vasculitis and allograft coronary artery disease and by immunofluorescent microscopy for vascular immune complex deposition in a manner identical to immunofluorescent microscopic examination of endomyocardial biopsy specimens. Patients were also monitored for sensitization to immunoprophylactically administered murine monoclonal CD3 antibody (OKT3) and those demonstrated to be sensitized were separately analyzed. Clinical features and treatment of patients were retrospectively reviewed. We found that 141 patients could be classified as having cellular rejection, 76 as having vascular rejection, and 52 as having a mixed rejection pattern. The allograft survival in vascular rejection patients was significantly worse than in allografts of patients with cellular or mixed rejection, confirming our earlier results. Most importantly, we found a significant difference in the time to the development of allograft coronary artery disease based on the rejection pattern. This difference existed whether or not patients sensitized to OKT3 were excluded from evaluation. Patients with mixed rejection had an intermediate time to the development of allograft coronary artery disease between that of patients with cellular and vascular rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanical circulatory assistance has become a necessary supplement to more conventional means of hemodynamic support as a shortage of donor organs and associated increase in waiting time have contributed to an increased incidence of hemodynamic deterioration in potential transplant recipients. This review summarizes the experience with circulatory support before and after transplantation of the Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program and draws conclusions on the efficacy of one program's use of mechanical circulatory support. Between March 1985 and October 1990, 401 patients were accepted for first-time heart transplantation by the UTAH program. One hundred and eighty patients (46%) were supported before transplantation with conventional hemodynamic therapies, 72 patients (18%) with oral enoximone, 96 patients (25%) with intravenous inotropes, and 34 patients (9%) with an intraaortic balloon; nine patients (2%) required centrifugal blood pump circulatory support. Not included in these statistics are 10 patients awaiting transplantation as of October 10, 1990. Thirty-eight candidates (10%) died awaiting transplantation, 329 (84%) received transplantation, and 24 (6%) were removed from the transplantation list for other reasons. Ten patients (3%) required mechanical circulatory support after transplantation with 38% of this group surviving 1 year after after transplantation. No single factor, including either hemodynamic support before transplantation or donor heart ischemic time, was found to be predictive of the need for mechanical circulatory support after transplantation. One-year survival rates after transplantation of patients requiring mechanical circulatory support before transplantation (86%) were not significantly different than for all transplant patients (88%). The experience of the UTAH Cardiac Transplant Program shows that with the judicious use of mechanical circulatory support transplant patients with advanced forms of hemodynamic support can have as equal a probability of survival as patients who undergo elective transplantation.

For the past several years, the UTAH Cardiac Transplant Program has been investigating the use of enoximone, a phosphodiesterase inhibitor with unique properties, as an oral pharmacologic adjunct to conventional management of severe congestive heart failure in patients awaiting heart transplantation. The goal of this approach is not long-term survival, but the ability to maintain patients comfortably with adequate tissue perfusion until the donor heart becomes available. Enoximone exhibits both positive inotropic and vasodilator characteristics. It appears to be the only agent that produces positive inotropic effects by phosphodiesterase inhibition alone, and its effects appear to last significantly longer than those of beta-adrenergic agonists. The results of the program's clinical experience with 281 patients suggest that inotropic support with low-dose enoximone may be a useful adjunct in the short-term management of patients with severe end-stage congestive heart failure. Almost 25% of patients who had been dependent on intravenous inotropic support were able to be weaned from intravenous therapy and switched to oral enoximone. No acceleration in mortality while patients awaited transplantation was observed. The data also showed an increase in the beta 2-adrenergic receptors and a difference in the beta 1:beta 2-receptor subtype ratio of 56:42 with enoximone, compared with 65:35 in a group of failing control patients who received no enoximone. In addition, the combination of enoximone and beta-adrenergic agonists was not associated with beta-receptor down-regulation.

Because administration of murine monoclonal anti-CD3 antibody (OKT3) may result in the formation of human antimouse antibody, which complexes with OKT3, we conducted this study to assess the incidence and effect of human antimouse antibody formation during prophylactic administration of OKT3 in heart transplantation. Human antimouse antibody developed in eight of 55 (14%) cardiac allograft recipients receiving OKT3 prophylaxis as measured by enzyme-linked immunosorbent assay. Additionally, two recipients had an inexplicable rise in CD3+ lymphocytes during therapy without detectable antibody. The outcome of these 10 sensitized recipients was compared with that of 45 nonsensitized recipients. Age, preoperative diagnosis, hemodynamics, and the need for intravenous inotropes or mechanical assistance before transplantation were similar in both groups. No female patients were in the sensitized group, whereas 33% of the nonsensitized group were female patients. A trend toward greater sensitization when prophylaxis was extended to 21 days (28%) compared with the more conventional 14-day administration (10%) was not statistically significant. Retransplantation because of rejection was required in a single patient in each group. Allograft survival was significantly lower by 3 months in the sensitized group, and allograft loss caused by rejection selectively accounted for that difference. In survivors, rejection frequency and infectious complications were similar. These findings suggest that sensitization to OKT3 occurs at low frequency after prophylactic administration in heart transplantation but is associated with an increased frequency of graft loss because of rejection.

Potent prophylactic immunosuppressive protocols promote the safe withdrawal of corticosteroid maintenance. The benefits of corticosteroid-free maintenance immunosuppression include the absence of the cushingoid habitus, fewer infections, less obesity, and lower serum cholesterol. The incidence of allograft coronary artery disease is not increased by corticosteroid-free maintenance. To assess the long-term effects of corticosteroid-free immunosuppression on allograft function, we compared results of hemodynamic study and noninvasive evaluation over the 2-year follow-up of 57 patients on corticosteroid-free maintenance to 40 patients who required corticosteroid. Age and pretransplantation diagnoses were similar, but a greater percentage of those who required corticosteroid maintenance were female (28% versus 2%, p less than 0.001). Indexes of allograft function were similar in both groups and these indexes included ejection fraction, right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index, left ventricular end-diastolic dimension, and posterior wall thickness. Patient survival was identical in the two groups (98%). These data indicate that corticosteroids can be safely withdrawn with the subsequent early benefits and without compromising long-term allograft function.

Although the etiology of allograft coronary artery disease, a major limiting factor in long-term survival after cardiac transplantation, is poorly understood, it is undoubtedly in part immune mediated and not detected by routine endomyocardial biopsy. Therefore it is possible that withdrawal of maintenance corticosteroids, although providing other short- and long-term benefits, could increase the prevalence of allograft coronary artery disease by permitting undetected immune-mediated vascular injury to occur. To assess whether corticosteroid-free maintenance immunosuppression increased the prevalence of allograft coronary artery disease, we reviewed serial angiograms of 102 patients (49% not receiving corticosteroid maintenance therapy) who underwent heart transplantation after March 7, 1985. Multiple variables including serum cholesterol, recipient and donor age, sex, blood pressure, rejection frequency and severity, early rejection prophylaxis protocol (polyclonal versus monoclonal T-cell agents), and corticosteroid use were examined in relation to allograft coronary artery disease by univariate and multivariate analyses. Allograft coronary artery disease was identified in 21 patients (seven severe, four moderate, and 10 mild). The prevalence by Kaplan-Meier life-table analysis was 17% at 1 year and 25% at 2 years. No further allograft coronary artery disease was detected among patients undergoing angiography at three years. Increased allograft coronary artery disease was not noted in patients withdrawn from maintenance corticosteroids when compared with their corticosteroid-requiring counterparts. In fact, with each 1 gm increment in cumulative corticosteroid use, a slightly increased risk (1.04, p less than 0.05) of allograft coronary artery disease was noted (Cox regression model). None of the other variables correlated with the prevalence of allograft coronary artery disease. Thus withdrawal of maintenance corticosteroids is not associated with an increased risk of early allograft coronary artery disease and minimization of corticosteroids may lead to a decreased long-term incidence of coronary artery disease in cardiac transplant recipients.

The murine monoclonal CD3 antibody (OKT3) is effective in the treatment of refractory renal and cardiac allograft rejection and holds promise for improving rejection prophylaxis in heart transplantation. Although the administration of OKT3 is associated with many side effects, arteritis has not been previously reported. We report the development of acute necrotizing temporal arteritis associated with the deposition of mouse immunoglobulin G in a heart transplant recipient receiving OKT3 treatment of refractory rejection.

Immunosuppression for cardiac transplantation, as currently practiced, is based to a large extent on clinical trials that can best be characterized as single-institutional, uncontrolled, or historically controlled studies. While these non-randomized, retrospective studies clearly advanced the science and art of cardiac transplantation to the point that survival rates approaching 90% at 1 year are achievable, the specific immunosuppressive protocols used at any given institution are likely based more on the individual transplant surgeon's or physician's training and experience, than on a firm scientific basis. Thus, a significant lack of uniformity exists among transplant centers in virtually all phases of immunosuppression. More clinical and basic research efforts are needed to unify immunosuppressive strategies following cardiac transplantation. In the future, greater individualization of therapy is likely to occur and more prospectively randomized, multi-center trials are likely to be carried out, particularly in the area of early rejection prophylaxis.

Immunosuppression following cardiac transplantation can be divided into early rejection prophylaxis, chronic maintenance, and the treatment of established episodes of allograft rejection. Early rejection prophylaxis is the immunosuppressive protocol administered in the first few weeks following transplantation and consists of cyclosporine, azathioprine, and corticosteroids with or without the addition of specific anti-T cell agents such as antithymocyte globulins, antilymphoblast globulins, or the murine monoclonal anti-CD3 antibody (OKT3). Most programs now use triple therapy (cyclosporine, azathioprine, and prednisone) as chronic maintenance immunosuppression, although the feasibility of corticosteroid-free maintenance has been demonstrated. The treatment of acute allograft rejection involves optimization of cyclosporine and azathioprine doses along with the augmentation in corticosteroids and with or without the addition of a specific anti-T cell agent, depending on the histological grade hemodynamic consequences of the rejection episode. Further individualization of immunosuppressive therapy is likely to occur in the future.

Significant alterations in both the receptor-G protein-adenylate cyclase (RGC) complex and cardiac adrenergic neurons occur in subjects with idiopathic dilated cardiomyopathy and heart failure. These alterations result in subsensitivity of the failing heart to β-adrenergic stimulation. These changes may also have an important influence on the natural history of heart failure. Certain therapeutic interventions such as β-blockade or angiotensin converting enzyme inhibition may alter key components of the RGC complex and partially restore the sensitivity of the β-adrenergic pathway. This paper will review the current information about the myocardial RGC complex in both nonfailing and failing human hearts and summarize recent findings about the effects of therapy of heart failure on the myocardial RGC complex.

Histamine is an impressive modulator of immune functions at least via its effects on lymphoid cells. Its in vivo effects will not be used practically as long as they produce the profound cardiovascular and pulmonary effects for which the drug is known. A series of 13 congener derivatives and conjugates of histamine was constructed and was tested to investigate whether chemical alterations would result in pharmacologic actions on leukocytes that were more potent and effect specific than histamine. The new compounds, which contained spacer groups of varying lengths between ligand and carrier and with various aromatic modifying groups, showed potencies widely different from histamine when tested in natural suppressor cells. Some compounds showed selective effects on natural suppressor cells in that they were inactive on myocardial tissue, whereas other compounds were selectively active on the myocardium. Some compounds augmented the suppressive capacity of natural suppressor cells in mixed leukocyte reactions via H1 receptors. Our scheme might be more widely extrapolated to other low m.w. immune modulators in an attempt to make them lymphocyte specific. The data also encourage the in vivo testing of selected histamine analogues as selective modulators of immunity. Some of these modulators might be experimentally useful in vivo because they may lack actions in other tissues.

A case of acute vascular rejection occurring in a cardiac allograft is presented. The rejection was characterized by prominent lymphocytic infiltration of the major coronary arteries in a pattern similar to that observed in acute vascular rejection occurring in renal allografts. Additionally, there was electron microscopic evidence of endothelial damage of smaller vessels. In addition to routine light microscopic evaluation of heart biopsies obtained in this case, immunofluorescent staining of biopsies for IgG, IgM, C3, Clq, fibrinogen, T cells, B cells, and Ia human leukocyte antigen (HLA-DR) was also performed. These studies suggest that antibodies may have been important in the terminal rejection episode described in this case. Furthermore, immunofluorescent staining detected continuing endothelial cell damage, reflected as Ia antigen positivity of allograft blood vessels, despite apparent improvement of rejection as judged by light microscopy.

We have previously reported that murine antihuman monoclonal antibody OKT3 (Orthoclone OKT3) given for 14 days after heart transplantation is effective as immunosuppressive prophylaxis. The optimal protocol for OKT3 prophylaxis in heart transplantation is unknown, particularly the duration of OKT3 therapy. We conducted a consecutively allocated overlapping 6-month study with 68 heart transplant patients, comparing 14-day OKT3 (n = 34) to 10-day OKT3 treatment (n = 34). Both protocols included OKT3 given beginning 24 to 48 hours after operation, cyclosporine beginning on postoperative day 3, low-dosage steroids and azathioprine to prevent antibody production to OKT3, and a steroid pulse plus randomization to plus or minus vincristine after stopping OKT3. Pretransplant characteristics including age, sex, cause of congestive heart failure, and absence of positive pretransplant crossmatch were similar between the two groups. Although the infection rate was not significantly different between the two groups and mortality (one patient in each group) did not differ, 14-day prophylaxis decreased the number of treated rejection episodes per patient for the 6-month study (1.59 +/- 0.18 versus 2.24 +/- 0.19, p = 0.016). A 14-day course of OKT3 also decreased the risk of rejection during the 6-month follow-up period (p less than 0.05). In addition to having a decreased number of rejection episodes, patients in the 14-day protocol were also more likely to be withdrawn from maintenance steroids (79% versus 53%, p = 0.02). In conclusion, a measurable dose response efficacy can be demonstrated for 14-day versus 10-day OKT3 prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine is an impressive modulator of immune functions at least via its effects on lymphoid cells. Its in vivo effects will not be used practically as long as they produce the profound cardiovascular and pulmonary effects for which the drug is known. A series of 13 congener derivatives and conjugates of histamine was constructed and was tested to investigate whether chemical alterations would result in pharmacologic actions on leukocytes that were more potent and effect specific than histamine. The new compounds, which contained spacer groups of varying lengths between ligand and carrier and with various aromatic modifying groups, showed potencies widely different from histamine when tested in natural suppressor cells. Some compounds showed selective effects on natural suppressor cells in that they were inactive on myocardial tissue, whereas other compounds were selectively active on the myocardium. Some compounds augmented the suppressive capacity of natural suppressor cells in mixed leukocyte reactions via H1 receptors. Our scheme might be more widely extrapolated to other low m.w. immune modulators in an attempt to make them lymphocyte specific. The data also encourage the in vivo testing of selected histamine analogues as selective modulators of immunity. Some of these modulators might be experimentally useful in vivo because they may lack actions in other tissues.