RESUMEN
BACKGROUND: Carvedilol has improved the symptomatic status of patients with moderate to severe heart failure in single-center studies, but its clinical effects have not been evaluated in large, multicenter trials. METHODS AND RESULTS: We enrolled 278 patients with moderate to severe heart failure (6-minute walk distance, 150 to 450 m) and a left ventricular ejection fraction < or = 0.35 at 31 centers. After an open-label, run-in period, each patient was randomly assigned (double-blind) to either placebo (n = 145) or carvedilol (n = 133; target dose, 25 to 50 mg BID) for 6 months, while background therapy with digoxin, diuretics, and an ACE inhibitor remained constant. Compared with placebo, patients in the carvedilol group had a greater frequency of symptomatic improvement and lower risk of clinical deterioration, as evaluated by changes in the NYHA functional class (P = .014) or by a global assessment of progress judged either by the patient (P = .002) or by the physician (P < .001). In addition, treatment with carvedilol was associated with a significant increase in ejection fraction (P < .001) and a significant decrease in the combined risk of morbidity and mortality (P = .029). In contrast, carvedilol therapy had little effect on indirect measures of patient benefit, including changes in exercise tolerance or quality-of-life scores. The effects of the drug were similar in patients with ischemic heart disease or idiopathic dilated cardiomyopathy as the cause of heart failure. CONCLUSIONS: These findings indicate that, in addition to its favorable effects on survival, carvedilol produces important clinical benefits in patients with moderate to severe heart failure treated with digoxin, diuretics, and an ACE inhibitor.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Carbazoles/uso terapéutico , Gasto Cardíaco Bajo/tratamiento farmacológico , Propanolaminas/uso terapéutico , Antagonistas Adrenérgicos beta/efectos adversos , Anciano , Carbazoles/efectos adversos , Gasto Cardíaco Bajo/mortalidad , Gasto Cardíaco Bajo/fisiopatología , Carvedilol , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Morbilidad , Placebos , Propanolaminas/efectos adversos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Volumen Sistólico/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Small-scale clinical investigations have demonstrated that single doses of beta-blocking agents can improve left ventricular function in heart failure from idiopathic dilated cardiomyopathy (IDC). The purpose of this multicenter clinical trial was to determine the dose-effect characteristics of beta-blockade in a heart failure population that includes ischemic dilated cardiomyopathy (ISCD). METHODS AND RESULTS: Bucindolol is a nonselective beta-blocking agent with mild vasodilatory properties. One hundred forty-one subjects with class II or III heart failure, left ventricular ejection fraction (LVEF) < or = 0.40, and background therapy of angiotensin-converting enzyme inhibitors, digoxin, and diuretics were given an initial challenge dose of bucindolol 12.5 mg. One hundred thirty-nine subjects (99 with IDC, 40 with ISCDC) tolerated challenge and were randomized to treatment with placebo or bucindolol 12.5 mg/d (low dose), 50 mg/d (medium dose), or 200 mg/d (high dose). At the end of 12 weeks, left ventricular function and other parameters were measured and compared with baseline values. There was a dose-related improvement in left ventricular function in bucindolol-treated subjects. In the high-dose bucindolol group, radionuclide-measured LVEF improved by 7.8 EF units (%) compared with 1.8 units in the placebo group (P < .05), and compared with the placebo group, a greater percentage of subjects had an increase in LVEF by > or = 5 units. In contrast, all three bucindolol doses prevented deterioration of myocardial function as defined by an LVEF decline of > or = 5 units. CONCLUSIONS: In heart failure from systolic dysfunction, beta-blockade with bucindolol produces a dose-related improvement in and prevents deterioration of left ventricular function.
Asunto(s)
Antagonistas Adrenérgicos beta/administración & dosificación , Cardiomiopatía Dilatada/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Propanolaminas/administración & dosificación , Antagonistas Adrenérgicos beta/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Propanolaminas/uso terapéutico , Estudios Prospectivos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Administration of histamine to rabbits may result in myocardial damage similar to that produced by catecholamines and the anthracycline antibiotics. To explore the mechanisms involved in histamine-mediated myocardial damage, conscious New Zealand white rabbits were pretreated with H1 and H2 receptor blocking agents, alone and in combination, and then administered histamine. Coronary artery blood flow was measured with radiolabeled microspheres in rabbits that received histamine alone, and in those that received an H1 blocking agent and histamine. Rabbits that received an H1 blocking agent had a significant reduction in morphological injury which was scored as follows: grade 1, minimal or no injury; grade 2, moderate; and grade 3, severe injury (mean pathology score = 1.1 +/- 0.28 for histamine alone vs. 0.06 +/- 0.06 with H1 receptor blockade, p less than 0.05). Animals pretreated with H2 receptor blockade (mean pathology score = 1.2 +/- 0.49) were not protected against morphological injury. Coronary blood flow decreased in animals that received histamine alone: control = 2.61 +/- 0.38 vs. 1.80 +/- 0.30 ml/min/g (p less than 0.05), and in animals pretreated with H1 blockade; control = 3.29 +/- 0.34 vs. 1.91 +/- 0.28 ml/min/g (p less than 0.01). We conclude that histamine-mediated myocardial damage appears to be mediated by the H1 receptor system and that this appears to be independent of initial changes in global coronary blood flow.
Asunto(s)
Circulación Coronaria/efectos de los fármacos , Cardiopatías/fisiopatología , Antagonistas de los Receptores Histamínicos H1/farmacología , Histamina/fisiología , Animales , Difenhidramina/farmacología , Femenino , Histamina/farmacología , Microesferas , ConejosRESUMEN
Using data derived from clinical and experimental observations, we examine the role of the myocardial beta-adrenergic receptor system in pathophysiologic processes involved in heart muscle disease and heart failure. The available data suggest that the sympathetic nervous system exerts important influences on myocardial structure and function. As such the beta-adrenergic pathways represents an obvious locus for therapeutic intervention in evolving cardiomyopathic states.
Asunto(s)
Cardiomiopatías/fisiopatología , Catecolaminas/fisiología , Insuficiencia Cardíaca/fisiopatología , Receptores Adrenérgicos beta/fisiología , Adenilil Ciclasas/metabolismo , Agonistas Adrenérgicos beta/efectos adversos , Agonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Animales , Calcio/metabolismo , Cardiomiopatías/metabolismo , Cardiotónicos/uso terapéutico , Catecolaminas/farmacología , Catecolaminas/toxicidad , AMP Cíclico/fisiología , Interacciones Farmacológicas , Tolerancia a Medicamentos , Cobayas , Insuficiencia Cardíaca/metabolismo , Humanos , Contracción Miocárdica/efectos de los fármacos , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Conejos , Receptores Adrenérgicos beta/metabolismo , Sarcolema/metabolismoAsunto(s)
Antineoplásicos/efectos adversos , Cardiomiopatías/inducido químicamente , Corazón/efectos de los fármacos , Animales , Antibióticos Antineoplásicos , Biopsia , Cardiomiopatías/prevención & control , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Electrocardiografía , Fluorouracilo/efectos adversos , Humanos , Miocardio/patología , Naftacenos/efectos adversos , Neoplasias/tratamiento farmacológicoRESUMEN
We tested the hypothesis that cardiac histamine release mediates subacute doxorubicin (DXR) cardiotoxicity in rabbits. New Zealand white rabbits given DXR 20 mg/kg i.v. over 30 min developed myocardial damage 24 h later that was similar to that observed in humans. In isolated heart preparations, DXR produced dose-related cardiac histamine release at DXR concentrations of 1, 5, and 25 micrograms/ml given as 1-min exposures. Prior exposure of isolated hearts to 10 microM cromolyn sodium completely prevented histamine release from 5 micrograms/ml DXR. Pretreatment of animals with cromolyn produced significant protection against DXR-mediated subacute cardiotoxicity. We conclude that the release of cardiac histamine may be involved in the pathogenesis of anthracycline cardiotoxicity.
Asunto(s)
Cardiopatías/inducido químicamente , Liberación de Histamina/efectos de los fármacos , Animales , Antibióticos Antineoplásicos , Cromolin Sódico/farmacología , Doxorrubicina/sangre , Doxorrubicina/toxicidad , Femenino , Cardiopatías/metabolismo , Naftacenos/toxicidad , Conejos , Factores de TiempoRESUMEN
A new system for rapidly quantitating left ventricular volume using two-dimensional echocardiography is tested. This system relies on a microprocessor built into a sector scanner that immediately calculates the length, area, and volume of the chamber being imaged using the mathematical model of an ellipsoid of revolution. The calculations are made after the observer superimposes a smooth calibrated ellipse outline on the endocardium imaged with the sector scanner. We report our experience with this system in 50 patients with a variety of cardiac disorders and compare the left ventricular volumes measured with those obtained using cineangiography, M-mode, and more detailed light pen tracing techniques. Correlations between volumes measured with the elliptical calipers and angiography were good (r = 0.820, SEE +/- 38.8 ml) (n = 100), but not as good as that between light pen tracing of the echo images and angiography (r = 0.847, SEE +/- 27.8 ml) (n = 22). M-mode correlated less well with angiography (r = 0.789; SEE +/- 42.1 ml) (n = 90). We conclude that the calibrated ellipse system is rapid and simple to use, while its accuracy matches previous studies using two-dimensional echocardiography to quantitate left ventricular volume.
Asunto(s)
Ecocardiografía/métodos , Ventrículos Cardíacos/anatomía & histología , Enfermedades Cardiovasculares/patología , Cineangiografía , Humanos , MicrocomputadoresAsunto(s)
Volumen Cardíaco , Cineangiografía , Ecocardiografía , Adolescente , Adulto , Femenino , Fluoroscopía , Ventrículos Cardíacos , Humanos , Masculino , Persona de Mediana Edad , Volumen Sistólico , Tantalio , TransductoresRESUMEN
Recent investigations suggest that the vasoactive substances, histamine, prostaglandin E2, and thromboxane A2 are mediators of coronary artery spasm. These substances may be released during a episode of urticaria. We report here a case of coronary artery spasm associated with an episode of acute urticaria. The coronary spasm may have been mediated by the vasoactive substances released from basophils and secondary platelet aggregation, known to occur with urticaria.