RESUMEN
Recent evidence has shown that improvement in left ventricular (LV) systolic function in patients with New York Heart Association class II to III heart failure occurs with beta-adrenergic blocking agents. However the specific effects on LV diastolic function have been subjected to only limited examination. This study investigated the effects of the combined beta blocker/vasodilator, carvedilol, on systolic and diastolic LV performance in dilated cardiomyopathy. Thirty-six patients with New York Heart Association II to III heart failure and LV ejection fraction < or = 0.35 were entered into either arm of this placebo-controlled, double-blind 4-month trial. Twenty-one subjects were entered into the carvedilol treatment arm and 15 patients were entered into the placebo arm in a 3:2 ratio. Carvedilol therapy resulted in a significant improvement in LV ejection fraction, from 0.22 +/- 0.02 to 0.30 +/- 0.02 when compared with the placebo group (0.19 +/- 0.02 to 0.21 +/- 0.02 at baseline and after 4 months of therapy, respectively; p = 0.0001). However, no significant change in radionuclide parameters of LV diastolic function, including peak filling rate or time to peak filling rate, was observed. LV end-diastolic volume index did not change with carvedilol therapy, whereas end-diastolic volume index increased in the placebo group, although the difference between groups at 4 months was significant (p = 0.02). In conjunction with these changes, end-systolic volume index was smaller at 4 months after carvedilol treatment compared with that of the placebo group (p = 0.04). Thus, these results demonstrate that in moderate chronic heart failure, systolic LV performance improves but diastolic LV function does not improve when compared with placebo after treatment with carvedilol.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Carbazoles/uso terapéutico , Cardiomiopatía Dilatada/tratamiento farmacológico , Isquemia Miocárdica/tratamiento farmacológico , Propanolaminas/uso terapéutico , Función Ventricular Izquierda/efectos de los fármacos , Antagonistas Adrenérgicos beta/farmacología , Cateterismo Cardíaco , Volumen Cardíaco/efectos de los fármacos , Carvedilol , Diástole/efectos de los fármacos , Método Doble Ciego , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Volumen Sistólico/efectos de los fármacos , Sístole/efectos de los fármacosRESUMEN
BACKGROUND: We 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). METHODS AND RESULTS: Patients 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. CONCLUSIONS: We conclude that beta-blockade may produce quantitatively different degrees of response in different kinds of heart muscle disease.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Cardiomiopatía Dilatada/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Propanolaminas/uso terapéutico , Adulto , Factores de Edad , Método Doble Ciego , Ejercicio Físico , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
During a 3-year period we administered enoximone, a phosphodiesterase inhibitor with positive inotropic and vasodilator properties, to 73 pretransplantation patients with end-stage heart failure who exhibited a clinical requirement for additional inotropic support. The clinical course and myocardial beta-adrenergic receptor status in the explanted hearts of these 73 patients was compared with results in 113 concurrently listed pretransplantation patients not requiring additional inotropic support. Only three patients required cessation of enoximone because of adverse effects, all from exacerbation of ventricular arrhythmias. Sixty-six of 73 (90.4%) enoximone-treated patients ultimately underwent cardiac transplantation a mean of 39.2 +/- 6.6 days (range 1 to 221 days) after starting enoximone, whereas seven patients (9.6%) died awaiting cardiac transplantation. The respective 1-, 3-, and 6-month pretransplantation survival rates of patients treated with enoximone calculated from their time on the waiting list for transplantation were 88.0%, 82.5%, and 82.5% compared with 92.1%, 83.8%, and 76.2% in control patients not receiving enoximone (all p = not significant). In 25 patients who received enoximone, ventricular myocardial beta-adrenergic receptors were measured at the time of transplantation and compared with values in failing ventricles from 52 pretransplantation patients not exposed to enoximone. Compared with ventricular myocardium of patients not given enoximone or intravenous beta-adrenergic agonists, total beta-adrenergic receptor (beta 1 plus beta 2) density was not decreased in patients treated with enoximone or enoximone plus intravenous beta-adrenergic agonists, but was decreased by 31% (p less than 0.05) in patients given intravenous beta-adrenergic agonists alone. Additionally, patients treated with enoximone had higher myocardial beta 2-adrenergic receptor densities than respective subgroups treated without (28% higher, p less than 0.01) or with (65% higher, p less than 0.01) intravenous beta-adrenergic agonists. Finally, isoproterenol- or calcium-mediated contractile responses in isolated right ventricular preparations from 14 patients treated with enoximone were similar to values in control patients not exposed to enoximone or intravenous beta-adrenergic agonists, suggesting that enoximone-related beta-adrenergic subsensitivity or damage to the contractile apparatus does not occur.
Asunto(s)
Cardiotónicos/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Imidazoles/uso terapéutico , Contracción Miocárdica/efectos de los fármacos , Receptores Adrenérgicos beta/efectos de los fármacos , Adulto , Calcio/farmacología , Cardiomiopatía Dilatada/tratamiento farmacológico , Cardiomiopatía Dilatada/fisiopatología , Cardiotónicos/efectos adversos , Cardiotónicos/farmacología , Catecolaminas/análisis , Enoximona , Femenino , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Trasplante de Corazón , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacología , Isoproterenol/farmacología , Masculino , Persona de Mediana Edad , Miocardio/química , Receptores Adrenérgicos beta/análisis , Tasa de SupervivenciaRESUMEN
PURPOSE: Bucindolol 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. PATIENTS AND METHODS: Patients 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. RESULTS: A 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. CONCLUSION: Bucindolol 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.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Cardiomiopatía Dilatada/tratamiento farmacológico , Propanolaminas/uso terapéutico , Vasodilatadores/uso terapéutico , Adulto , Anciano , Cardiomiopatía Dilatada/fisiopatología , Método Doble Ciego , Femenino , Pruebas de Función Cardíaca , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Pruebas de Función RespiratoriaRESUMEN
An increase in cardiac beta-adrenergic sensitivity or beta-receptor density or both has been described in several animal species after denervating the heart. The transplanted human heart is also denervated and, therefore, may exhibit supersensitivity to beta-adrenergic agonists and an increase in beta-adrenergic receptor density. In 16 patients examined 1-3 months after orthotopic cardiac transplantation, beta-adrenergic receptor density measured by [125I]iodocyanopindolol binding in endomyocardial biopsy specimens was not significantly different in transplant recipients compared with normal controls (transplant = 1,429 +/- 199, control = 1,728 +/- 263 fmol/g wet wt; p = NS). However, when normalized to Lowry protein, the [125I]iodocyanopindolol in beta-adrenergic receptor density in biopsy tissue from transplant recipients was significantly lower than in tissue from controls (transplant = 58.1 +/- 6.2, control = 93.5 +/- 13.4 fmol/g Lowry protein; p = 0.011). Atrial sinus node activity of the denervated donor heart and the innervated atrial cuff of the native recipient heart could be detected on the surface electrocardiogram in six patients. In these six patients, the heart rate response to graded infusions of epinephrine (taken up by the adrenergic nerve terminals) and isoproterenol (not taken up by the adrenergic nerve terminals) was measured. The epinephrine dose-response curve in transplanted donor atria was significantly to the left of the native recipient atrial dose-response curve (p less than 0.0001). The isoproterenol dose-response curves for native and transplanted atria were not different. We conclude that myocardial beta-adrenergic receptors are not increased in human orthotopic cardiac allografts and that there is no evidence for beta-receptor-mediated supersensitivity of postsynaptic origin.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Trasplante de Corazón , Miocardio/metabolismo , Receptores Adrenérgicos beta/fisiología , Sinapsis/fisiología , Adulto , Catecolaminas/sangre , Epinefrina/farmacología , Atrios Cardíacos/efectos de los fármacos , Humanos , Isoproterenol/farmacología , Receptores Adrenérgicos beta/metabolismo , Sinapsis/metabolismoRESUMEN
Murine monoclonal CD-3 antibody (OKT3) is a significant new addition to the immunosuppressant armamentarium for treatment of heart transplant rejection. In the Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program, Salt Lake City, a broad experience with OKT3 has been acquired. Fifteen patients were treated for refractory rejection, whereas 68 patients were treated for early rejection prophylaxis therapy utilizing either 10- or 14-day protocols. To facilitate early hospital discharge, 12 patients were able to complete OKT3 therapy as outpatients. A retrospective review of length of initial hospital stay and clinical results revealed that patients who received OKT3 had an average hospital stay (+ standard deviation) of 17.1 days, and their 12-month survival was 96%. Patients who received antithymocyte globulin and/or steroids had an average stay of 27.4 days (p less than 0.05) and a 12-month survival of 93%. In conclusion, the possibility for reduced hospital stay and consequent cost reduction exists with the use of OKT3, especially when completion of therapy can be managed in an outpatient setting.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Superficie/inmunología , Rechazo de Injerto , Trasplante de Corazón , Tiempo de Internación , Atención Ambulatoria/economía , Animales , Anticuerpos Monoclonales/efectos adversos , Suero Antilinfocítico/efectos adversos , Suero Antilinfocítico/uso terapéutico , Evaluación de Medicamentos , Humanos , Terapia de Inmunosupresión/métodos , Tiempo de Internación/economía , Ratones , Persona de Mediana Edad , Estudios Retrospectivos , Linfocitos T/inmunologíaRESUMEN
Compliance, motivation, and strong family support have been identified as important factors to the success of heart transplantation. Approaches to psychosocial evaluations determining suitability of candidates vary among transplant centers. Although testing, interviewing, and retrospective analyses of patient profiles are valuable, they do not allow for longitudinal evaluation of patients who have been denied transplantation under these standard methods of assessment. The Utah Cardiac Transplant Program (UCTP) combines heart failure and transplant services to provide maximum conventional and experimental therapy to patients with end-stage cardiac dysfunction. A single medical team provides care to all patients. From March 8, 1985 to November 1, 1986, UCTP evaluated 170 patients, assigning 57 to conventional medication therapy, 72 to experimental medication therapy, and 41 directly to heart transplantation. Of the 72 patients assigned to experimental therapy, 21 were subsequently assigned to heart transplantation. In the initial evaluation of four patients, it was determined that they did not have adequate family support or emotional stability to undergo transplantation. After monitoring these four patients through a drug study, it was found that the initial evaluation was incorrect, as the patients demonstrated the ability to adhere to a complex regimen involving multiple diagnostic tests, clinic visits, and medication therapy. Three of these patients subsequently underwent successful transplantations and are alive with a mean follow-up time of 212 days. In conclusion, combining all modalities of treatment for end-stage heart disease into one unified program has definite advantages that include longitudinal evaluation of patients previously denied transplantation.