O'Connell Jb

Long-term β-Blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: A double-blind, randomized study of bucindolol versus placebo☆

PURPOSEnBucindolol is a potent nonselective beta-blocking agent with vasodilatory properties. In this study, we evaluated the effects of long-term bucindolol therapy in the treatment of heart failure from idiopathic dilated cardiomyopathy.nnnPATIENTS AND METHODSnPatients were eligible for enrollment if they had symptomatic heart failure, idiopathic dilated cardiomyopathy, and left ventricular ejection fraction less than 0.40. All patients received an initial test dose of 12.5 mg bucindolol orally every 12 hours for two or three doses. Patients tolerating the test dose were randomly assigned (double-blind) to receive bucindolol or placebo in a 3:2 ratio. Study medication was begun at a dose of 12.5 mg orally every 12 hours and gradually increased over a 1-month period until either a maximum tolerated dose or a target dose of 100 mg every 12 hours was reached. Study medication was then continued for an additional 2 months.nnnRESULTSnA total of 24 patients were enrolled into the study. Twenty-three patients tolerated bucindolol test challenge; 14 were randomized to receive bucindolol, and nine were randomly assigned to receive placebo. The placebo group (age 56 +/- 2 years) was significantly older than the bucindolol group (46 +/- 3 years), but by all other clinical and hemodynamic parameters the two groups were comparable. Twenty-two of 23 patients completed the study. Patients treated with bucindolol had significant improvements in clinical heart failure symptoms and in resting hemodynamic function, including an increase of left ventricular ejection fraction (0.26 +/- 0.02 to 0.35 +/- 0.09, p = 0.003), cardiac index (2.2 +/- 0.1 to 2.5 +/- 0.4 L/minute/m2, p = 0.014), and left ventricular stroke work index (25 +/- 3 to 35 +/- 7 g.m/m2, p = 0.002) and a decrease in pulmonary artery wedge pressure (17 +/- 3 to 10 +/- 5 mm Hg, p = 0.005) and heart rate (86 +/- 3 to 75 +/- 9 beats/minute, p = 0.012). Patients treated with bucindolol also had a significant increase in exercise left ventricular ejection fraction (0.26 +/- 0.03 to 0.32 +/- 0.14, p = 0.015) and reduction in questionnaire-measured symptoms (p = 0.007) and New York Heart Association functional class (p less than 0.001). However, total treadmill exercise duration and maximal oxygen consumption with exercise did not change. No changes in rest or exercise parameters were observed in the placebo-treated group. Central venous plasma norepinephrine concentration decreased significantly in the bucindolol-treated group (423 +/- 79 to 212 +/- 101 pg/mL, p = 0.010), but was unchanged in the placebo-treated group.nnnCONCLUSIONnBucindolol is well tolerated in patients with idiopathic dilated cardiomyopathy and congestive heart failure, and therapy for 3 months is associated with improved resting cardiac function, improved heart failure symptoms, and a reduction in venous norepinephrine concentration.

Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy.

BACKGROUNDnWe measured the content and activities of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex and adrenergic neurotransmitter levels in left and right ventricular myocardial preparations derived from 77 end-stage failing human hearts from patients with idiopathic dilated cardiomyopathy (IDC) or ischemic dilated cardiomyopathy (ISCDC).nnnMETHODS AND RESULTSnThe results were compared with data obtained in 21 nonfailing hearts removed from organ donors. Compared with ISCDC ventricles, IDC left and right ventricles exhibited a greater degree of total beta- or beta 1-receptor downregulation. In contrast, compared with IDC right ventricles, isolated tissue preparations of ISCDC right ventricles exhibited a greater degree of subsensitivity to the inotropic effect of isoproterenol, indicating a relatively greater degree of functional uncoupling of right ventricular ISCDC beta-receptors from mechanical response. In addition, relative to IDC left ventricles, preparations of ISCDC left ventricle exhibited greater subsensitivity to beta-agonist-mediated adenylate cyclase stimulation, indicating functional uncoupling of left ventricular ISCDC beta-receptors from cyclic AMP generation. The uncoupling of beta-receptors in ISCDC left and right ventricles may have been a result of abnormalities in G protein activation of adenylate cyclase; compared with age- and cardiac function-matched respective left or right IDC ventricles, ISCDC left ventricles exhibited less stimulation of adenylate cyclase by NaF or forskolin but no change in Mn2+ stimulation, whereas ISCDC right ventricles exhibited less stimulation by the nonhydrolyzable guanine nucleotide Gpp (NH)p. Also, IDC right ventricles exhibited a selective (not present in IDC left ventricles or ISCDC ventricles) decrease in stimulation of adenylate cyclase by Mn2+. Tissue neurotransmitter levels and pertussis toxin-catalyzed ADP ribosylation were altered to similar extents in IDC and ISCDC:nnnCONCLUSIONSnThese data indicate that potentially important differences exist in the regulatory behavior of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex in IDC versus ISCDC, differences that presumably relate to the distinct pathophysiologies of these two types of heart muscle disease.

Beta-blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy

BACKGROUNDnWe investigated the effects of bucindolol, a nonselective, non-ISA beta-blocker with mild-vasodilatory properties, in patients with congestive heart failure from ischemic dilated cardiomyopathy (ISCDC, n = 27) and compared the results with those in subjects with heart failure from idiopathic dilated cardiomyopathy (IDC, n = 22).nnnMETHODS AND RESULTSnPatients were randomized in a double-blind fashion to receive 12 weeks treatment with either bucindolol or placebo, with randomization stratified for IDC or ISCDC: Invasive (right heart catheterization) and noninvasive (echo, MUGA, central venous norepinephrine, exercise treadmill studies, and symptom scores) tests of heart failure severity were determined at baseline and end of the study. For all subjects (ISCDC plus IDC), relative to placebo treatment, bucindolol-treated patients had significant improvement in ejection fraction, left ventricular size and filling pressure, stroke work index, symptom score, and central venous norepinephrine. However, most of these differences could be attributed to improvement in the IDC subgroup, as the only parameter with a statistically significant degree of improvement in the bucindolol-treated ISCDC subgroup was left ventricular size.nnnCONCLUSIONSnWe conclude that beta-blockade may produce quantitatively different degrees of response in different kinds of heart muscle disease.

The use of mycophenolate mofetil (RS-61443) in human heart transplant recipients.

Mycophenolate mofetil is a potent inhibitor of de novo guanine nucleotide synthesis that selectively blocks lymphocyte proliferative responses. In animal models, mycophenolate mofetil has been shown to prolong allograft survival, reverse ongoing rejection, and induce strainspecific tolerance. To assess the safety and efficacy of mycophenolate mofetil in cardiac transplantation, 30 recipients with mild rejection were enrolled in an 8-week phase I trial. Mycophenolate mofetil in doses from 500 to 3000 mg/day orally was substituted for azathioprine, while baseline cyclosporine levels and corticosteroid doses were maintained. Rejection resolved in the majority of patients, with a significant decrease in mean biopsy score. By protocol, mycophenolate mofetil was discontinued in 4 patients due to persistent mild rejection, and in 4 patients due to progression to moderate rejection. The rate of progression to moderate rejection compared favorably with that observed in patients with mild rejection maintained on azathioprine without augmentation of immunosuppression. Significant increases were observed in hematocrit, total white blood cell count, and absolute neutrophil count. Absolute lymphocyte count remained unchanged. No nephrotoxicity or hepatotoxicity was observed. Gastrointestinal side effects prompted discontinuation of mycophenolate mofetil in one patient. Two major infections occurred. Mycophenolate mofetil remained well tolerated during long-term maintenance immunosuppression, with a rate of rejection similar to that in patients receiving azathioprine. We conclude that mycophenolate mofetil is safe and well tolerated in cardiac transplant recipients, is less myelosuppressive than azathioprine, and appears to be at least equipotent to azathioprine.

Clinical merit of endomyocardial biopsy.

At this time, endomyocardial biopsy has proven validity as a diagnostic method in few circumstances. However, it is overused. In the near term, the extent of its use should be modified by knowledge of its therapeutic relevance in patients with myocarditis. In the long term, numerous new techniques for studying pathophysiology at the subcellular and molecular levels will demand a central role for endomyocardial biopsy in the diagnosis, treatment and fundamental understanding of myocardial diseases. We believe that endomyocardial biopsy will serve as an indispensible link between basic scientists and clinicians in the effort to describe disease mechanisms.

HLA class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy. Validation study and meta-analysis of published HLA association studies.

We previously reported antigen frequency differences for HLA-DR4 and HLA-DRw6 between idiopathic dilated cardiomyopathy (IDC) patients and healthy controls in a pilot study. To confirm these findings, we undertook an independent study with a prospective hypothesis regarding the frequencies of DR4 and DRw6; typing for a second family of class II antigens (HLA-DQ) was included because of the proximity of the DQ loci to the DR loci and the strong linkage disequilibrium between some of the DR and DQ alleles. Comparing a new consecutive series of IDC patients (n = 41) and healthy blood bank controls (n = 53), we confirmed an increase of DR4 antigen frequency in patients (49% versus 21%, p less than 0.005). A trend toward decreased expression of DRw6 among patients was also noted (10% of patients versus 23% of controls). HLA-DQw4 was significantly elevated in patients compared with controls (27% versus 6%, p less than 0.005; relative risk, 6.1; etiologic fraction, 0.22). We identified the combined DR4-DQw4 haplotype in five of 41 Caucasian IDC patients (12%) and none of 53 controls (p less than 0.007). A comparison of specific antigen frequencies between the preliminary and validation studies did not reveal significant differences; therefore, the data from the two studies were examined in combination. For the combined studies, DR4 was elevated (51% versus 27% in controls, p less than 0.001), and DRw6 was decreased (9% versus 24% in controls, p less than 0.01). The relative risk for DR4 was 2.8, and the etiologic fraction was 0.33.(ABSTRACT TRUNCATED AT 250 WORDS)

Lisinopril lowers cardiac adrenergic drive and increases beta-receptor density in the failing human heart.

BackgroundIn subjects with heart failure, angiotensin converting enzyme inhibitors exhibit mild systemic antiadrenergic effects, as deduced from treatment-related lowering of systemic venous norepinephrine levels. The effects of angiotensin converting enzyme inhibitors on cardiac adrenergic drive in subjects with heart failure has not previously been investigated. Methods and Resuls. In a placebo-controlled, double-blind crossover study of 14 patients, we measured cardiac and systemic adrenergic drive, myocardial and lymphocyte 1-adrenergic receptors, and hemodynamic changes at baseline and after 12 weeks of therapy. Relative to placebo, lisinopril therapy was associated with only minimal, statistically insignificant changes in hemodynamics, a significant increase in myocardial P-receptor density, no significant (P<.05) changes in cardiac or systemic adrenergic drive, and no detectable change in lymphocyte P-receptor density. When subjects were rank ordered into groups with the highest and lowest coronary sinus norepinephrine levels, those with the highest norepinephrine levels exhibited significant decreases in central venous norepinephrine, coronary sinus norepinephrine, and an increase in myocardial 1receptor density relative to changes in placebo or relative to baseline values. Subjects with lower cardiac adrenergic drive exhibited no significant changes in coronary sinus or systemic norepinephrine levels or in myocardial 1-receptor density. ConclusionThe angiotensin converting enzyme inhibitor lisinopril lowered cardiac adrenergic drive and increased 1-receptor density in subjects with increased cardiac adrenergic drive but had no effects on these parameters in subjects with normal cardiac adrenergic drive. These data suggest that cardiac antiadrenergic properties contribute to the efficacy of angiotensin converting enzyme inhibitor in subjects with heart failure.

PREVENTION OF Pneumocystis carinii PNEUMONIA IN CARDIAC TRANSPLANT RECIPIENTS BY TRIMETHOPRIM SULFAMETHOXAZOLE

Pneumocystis carinii pneumonia (PCP) continues to cause significant morbidity in recipients of solid-organ transplants. While some programs administer trimethoprim-sulfamethoxazole (TMP-SMX) prophylactically following transplantation, a prospective determination of the safety and efficacy of TMP-SMX in cardiac transplant recipients has not previously been reported. We therefore prospectively randomized 58 cardiac transplant recipients to receive TMP (160 mg)-SMX (800 mg) twice daily either three days per week (group B), or seven days per week (group C), or to receive no treatment (group A). Treatment began 14 days after transplantation and continued for four months. Age, sex, preexisting pulmonary pathology and immunosuppressive protocols did not differ among the groups. Of 17 patients in the control group (A), 7 developed a clinical syndrome compatible with PCP, with the diagnosis histologically confirmed by bronchoalveolar lavage during the first four months following transplantation. In contrast, no patients in either the daily or intermittent therapy groups developed PCP during the study period (P<0.005). Both doses of TMP-SMX were well tolerated, and discontinuation of therapy was not necessary in any patient. Total white blood cell count, azathioprine dose, and number of treated episodes of rejection per patient did not differ among the three groups. We conclude that TMP-SMX can safely and effectively be administered to prevent the occurrence of P carinii pneumonia during the first four months following cardiac transplantation.

The repetitive histologic pattern of vascular cardiac allograft rejection. Increased incidence associated with longer exposure to prophylactic murine monoclonal anti-CD3 antibody (OKT3).

While vascular cardiac allograft rejection increases morbidity and mortality following transplantation, factors predisposing to its development have not been completely elucidated. To evaluate the influence of the duration of early rejection prophylaxis with the murine monoclonal anti-CD3 antibody (OKT3) on the development of a repetitive histologic pattern of vascular cardiac allograft rejection, endomyocardial biopsies from 344 heart transplant recipients were prospectively evaluated. The influence of clinical characteristics was assessed. Eighty-three patients (24%) developed and 261 patients (76%) did not develop a repetitive histologic pattern of vascular cardiac allograft rejection. The vascular rejection pattern was more common in patients with a positive crossmatch (89% versus 11%, P<0.0001) and OKT3 sensitization (73% versus 27%, P<0.0001), and was positively correlated with the duration of OKT3 treatment (P<0.0001). The correlation persists even after excluding patients with a positive crossmatch or OKT3 sensitization. Patients developing a repetitive histologic pattern of vascular cardiac allograft rejection early after transplantation had decreased allograft survival (P=0.0008). The development of a repetitive histologic pattern of vascular cardiac allograft rejection is positively correlated with the duration of OKT3 treatment. Judicious use of OKT3 in early rejection prophylaxis in cardiac transplantation is warranted.

METHOTREXATE AS AN ADJUNCT IN THE TREATMENT OF PERSISTENT MILD CARDIAC ALLOGRAFT REJECTION

Because methotrexate arrests inflammation in autoimmune disease, we studied its efficacy in persistent low-grade cardiac allograft rejection. Seventeen patients aged 39.5 +/- 0.9 years (mean +/- SE) had persistent rejection despite previous therapy with high dose corticosteroids. Maintenance immunosuppression consisted of prednisone, azathioprine, and cyclosporine. The rejection episode treated with methotrexate occurred 180 +/- 55.4 days posttransplantation. Patients had incurred 2.7 +/- 0.3 previous episodes of rejection with the first episode occurring 30.6 +/- 6.2 days post transplant. Methotrexate was administered orally in 3 doses to an average weekly dose of 12.8 +/- 0.8 mg. The duration of methotrexate therapy was 9.0 +/- 1.1 weeks. Sixteen of the seventeen persistent rejection episodes resolved by 22.8 +/- 3.2 days of methotrexate therapy. Using methotrexate, the prednisone dose was decreased from 22.4 +/- 4.8 mg/day at initiation of methotrexate to 9.7 +/- 1.4 mg/day at the completion of methotrexate therapy (P less than 0.01). Over a 306 +/- 35-day follow-up, 9 of 17 patients (53%) have remained rejection-free. Leukopenia, necessitating reduction in azathioprine occurred in 10 patients. One patient developed herpes zoster during therapy. These data indicate that methotrexate is effective in resolving persistent cardiac allograft rejection with minimal morbidity. In addition, the use of methotrexate for treatment of rejection allows reduction in maintenance corticosteroid doses.