RESUMEN
BACKGROUND: Atrial fibrillation (AF) is present in a significant number of patients with congestive heart failure (CHF) caused by left ventricular dysfunction and is associated with significant morbidity and increased mortality rates. Thus it is necessary to establish therapy to improve the outcome in this high-risk population. METHODS: We conducted a retrospective analysis of data from the US Carvedilol Heart Failure Trials Program and identified patients with AF at the time of enrollment. In these trials, 1094 patients with at least 3 months of heart failure symptoms and an ejection fraction < or = 0.35 were randomly assigned to receive carvedilol or placebo in a double-blind, stratified program according to performance on an exercise test. RESULTS: One hundred thirty-six patients with concomitant AF and CHF were identified during the screening visit (84 assigned to carvedilol and 52 to placebo). Therapy with carvedilol resulted in a significant improvement in left ventricular ejection fraction (from 23% to 33% with carvedilol and from 24% to 27% with placebo, P =.001). The physician global assessment improved in a greater number of patients treated with carvedilol than in those treated with placebo (71% vs 48%, P =.025). A trend toward a reduction in the combined end point of death or CHF hospitalization was also observed (19% in patients treated with placebo and 7% in patients on carvedilol; relative risk, 0.35; 95% confidence interval, 0.12, 1.02; P =.055). CONCLUSIONS: In patients with AF complicating CHF, carvedilol significantly improves left ventricular ejection fraction and physician global assessment and probably reduces the combined end point of CHF hospitalizations or death.
Asunto(s)
Antagonistas Adrenérgicos alfa/farmacología , Fibrilación Atrial/tratamiento farmacológico , Carbazoles/farmacología , Propanolaminas/farmacología , Disfunción Ventricular Izquierda/tratamiento farmacológico , Anciano , Fibrilación Atrial/patología , Carvedilol , Método Doble Ciego , Prueba de Esfuerzo , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Disfunción Ventricular Izquierda/patología , Función Ventricular IzquierdaRESUMEN
BACKGROUND: The purpose of our study was to define the incidence and mechanisms of atypical right atrial flutter. METHODS AND RESULTS: A total of 28 (8%) of 372 consecutive patients with atrial flutter (AFL) had 36 episodes of sustained atypical right AFL. Among 24 (67%) of 36 episodes of lower loop reentry (LLR), 13 (54%) of 24 episodes had early breakthrough at the lower lateral tricuspid annulus, whereas 11 (46%) of 24 episodes had early breakthrough at the high lateral tricuspid annulus, and 9 (38%) of 24 episodes showed multiple annular breaks. Bidirectional isthmus block resulted in elimination of LLR. A pattern of posterior breakthrough from the eustachian ridge to the septum was observed in 4 (14%) of 28 patients. Upper loop reentry was observed in 8 (22%) of 36 episodes and was defined as showing a clockwise orientation with early annular break and wave-front collision over the isthmus. Two patients had atypical right AFL around low voltage areas ("scars") in the posterolateral right atrium. CONCLUSIONS: Atypical right AFL is most commonly associated with an isthmus-dependent mechanism (ie, LLR or subeustachian isthmus breaks). Non-isthmus-dependent circuits include upper loop reentry or scar-related circuits.
Asunto(s)
Aleteo Atrial/fisiopatología , Atrios Cardíacos/fisiopatología , Anciano , Estudios de Cohortes , Electrocardiografía , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Persona de Mediana Edad , Taquicardia/fisiopatologíaRESUMEN
We describe a patient whose presentation of ICD generator failure was excruciating shoulder pain lasting 3 hours. This painful episode prompted evaluation and subsequent generator replacement. Destructive analysis of the explanted device revealed a short circuit of three battery filter capacitors, which resulted in the battery "dumping" its full energy very rapidly, since the impedance across the battery terminal was < 1 ohm. The duration of the painful episode was equal to the estimated ICD battery life under this low impedance condition.
Asunto(s)
Desfibriladores Implantables/efectos adversos , Dolor/etiología , Adulto , Axila , Falla de Equipo , Femenino , Humanos , HombroRESUMEN
BACKGROUND: Passengers who have ventricular fibrillation aboard commercial aircraft rarely survive, owing to the delay in obtaining emergency care and defibrillation. METHODS: In 1997, a major U.S. airline began equipping its aircraft with automated external defibrillators. Flight attendants were trained in the use of the defibrillator and applied the device when passengers had a lack of consciousness, pulse, or respiration. The automated external defibrillator was also used as a monitor for other medical emergencies, generally at the direction of a passenger who was a physician. The electrocardiogram that was obtained during each use of the device was analyzed by two arrhythmia specialists for appropriateness of use. We analyzed data on all 200 instances in which the defibrillators were used between June 1, 1997, and July 15, 1999. RESULTS: Automated external defibrillators were used for 200 patients (191 on the aircraft and 9 in the terminal), including 99 with documented loss of consciousness. Electrocardiographic data were available for 185 patients. The administration of shock was advised in all 14 patients who had electrocardiographically documented ventricular fibrillation, and no shock was advised in the remaining patients (sensitivity and specificity of the defibrillator in identifying ventricular fibrillation, 100 percent). The first shock successfully defibrillated the heart in 13 patients (defibrillation was withheld in 1 case at the family's request). The rate of survival to discharge from the hospital after shock with the automated external defibrillator was 40 percent. A total of 36 patients either died or were resuscitated after cardiac arrest. No complications arose from use of the automated external defibrillator as a monitor in conscious passengers. CONCLUSIONS: The use of the automated external defibrillator aboard commercial aircraft is effective, with an excellent rate of survival to discharge from the hospital after conversion of ventricular fibrillation. There are not likely to be complications when the device is used as a monitor in the absence of ventricular fibrillation.
Asunto(s)
Aeronaves , Cardioversión Eléctrica , Paro Cardíaco/terapia , Anciano , Cardioversión Eléctrica/instrumentación , Electrocardiografía , Femenino , Paro Cardíaco/diagnóstico , Paro Cardíaco/mortalidad , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Resucitación/educación , Tasa de Supervivencia , Voluntarios/educaciónRESUMEN
A hallmark of vascular lesions is the phenotypic modulation of vascular smooth muscle cells (VSMCs) from a quiescent, contractile state to a more primitive, proliferative phenotype with a more fetal pattern of gene expression. Using subtraction hybridization to identify genes that may regulate this transition, we cloned a novel gene named EVEC, an acronym for its expression in the embryonic vasculature and the presence of Ca2+ binding epidermal growth factor-like repeats contained in the predicted protein structure. Although these repeats are characteristic of the extracellular matrix proteins, fibrillin, fibulin, and the latent transforming growth factor-beta binding proteins, EVEC most closely resembles the H411 and T16/S1-5 gene products, the latter of which are believed to regulate DNA synthesis in quiescent fibroblasts. Using in situ hybridization, we demonstrated that EVEC is expressed predominantly in the VSMCs of developing arteries in E11.5 through E16.5 mouse embryos. Lower levels of expression are also observed in endothelial cells, perichondrium, intestine, and mesenchyme of the face and kidney. EVEC mRNA expression is dramatically downregulated in adult arteries, except in the uterus, where cyclic angiogenesis continues; however, EVEC expression is reactivated in 2 independent rodent models of vascular injury. EVEC mRNA is observed in cellular elements of atherosclerotic plaques of LDL receptor-deficient, human apolipoprotein B transgenic mice and in VSMCs of the media and neointima of balloon-injured rat carotid arteries. These data suggest that EVEC may play an important role in the regulation of vascular growth and maturation during development and in lesions of injured vessels.
Asunto(s)
Factor de Crecimiento Epidérmico/genética , Proteínas de la Matriz Extracelular , Regulación del Desarrollo de la Expresión Génica , Músculo Liso Vascular/química , Proteínas Recombinantes , Factores de Edad , Animales , Arteriosclerosis/genética , Arteriosclerosis/metabolismo , Northern Blotting , Células COS , Células Cultivadas , Clonación Molecular , Gránulos Citoplasmáticos/metabolismo , Elastina/análisis , Factor de Crecimiento Epidérmico/metabolismo , Feto/química , Feto/fisiología , Hibridación in Situ , Ratones , Microsomas/química , Microsomas/metabolismo , Datos de Secuencia Molecular , Músculo Liso Vascular/citología , Músculo Liso Vascular/fisiología , Fenotipo , ARN Mensajero/análisis , Ratas , Secuencias Repetitivas de Ácidos Nucleicos , Homología de Secuencia de Aminoácido , Túnica Íntima/química , Túnica Íntima/citología , Túnica Íntima/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg. kg-1. d-1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg. kg-1. d-1) or even higher doses of CsA (10 and 20 mg. kg-1. d-1) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressure-overload hypertrophy can arise through calcineurin-independent pathways.
Asunto(s)
Inhibidores de la Calcineurina , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Hipertrofia Ventricular Izquierda/fisiopatología , Animales , Aorta Torácica/fisiología , Calcineurina/fisiología , Ciclosporina/farmacología , Modelos Animales de Enfermedad , Hipertensión/genética , Hipertensión/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Ligadura , Masculino , Complicaciones Posoperatorias/mortalidad , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Tacrolimus/farmacologíaRESUMEN
Monoclonal antibodies that bound to the external domain of the rabbit low density lipoprotein receptor-related protein (LRP) were taken into rabbit fibroblasts by receptor-mediated endocytosis. Uptake occurred in fibroblasts from Watanabe-heritable hyperlipidemic rabbits, which lack low density lipoprotein receptors, as well as in normal rabbit fibroblasts. The fate of the internalized antibodies differed, depending on the domain of LRP that was recognized. LRP is synthesized as a single polypeptide chain that is cleaved to form a heterodimer of two noncovalently bound proteins, 1) a 515-kDa subunit that contains the binding domain, and 2) an 85-kDa subunit that contains the membrane-spanning region and cytoplasmic tail. A monoclonal antibody directed against the 515-kDa subunit (anti-LRP 515) rapidly dissociated from LRP at pH 5.2. After uptake by cells this antibody dissociated from the receptor and was degraded in lysosomes. A second antibody directed against the external portion of the 85-kDa subunit (anti-LRP 85) failed to dissociate at acid pH. After uptake by cells this antibody was not degraded, but instead was released from the cells in an acid-precipitable form. When administered intravenously to rabbits, both 125I-labeled antibodies were rapidly cleared from the circulation, 75-95% of the uptake occurring in the liver. The anti-LRP 515 antibody was degraded and acid-soluble products appeared in the plasma. No significant acid-soluble products appeared when the anti-LRP-85 antibody was infused. We conclude that LRP can carry out receptor-mediated endocytosis and that its ligand-binding domain, like the similar domain of the low density lipoprotein receptor, undergoes an acid-dependent conformational change that ejects ligands within the endosome. We also conclude that in the body this endocytotic function is expressed primarily in the liver. Both of these conclusions lend support to the hypothesis that LRP may function in humans and animals as a receptor for apolipoprotein E-enriched lipoproteins, such as chylomicron remnants.
Asunto(s)
Anticuerpos Monoclonales , Endocitosis , Hígado/metabolismo , Receptores de LDL/metabolismo , Animales , Células Cultivadas , Fibroblastos/metabolismo , Concentración de Iones de Hidrógeno , Cinética , Hígado/inmunología , Sustancias Macromoleculares , Masculino , Modelos Moleculares , Conformación Proteica , Conejos , Receptores de LDL/inmunologíaRESUMEN
The binding of native rabbit beta-very low density lipoproteins (beta-VLDL) to the low density lipoprotein receptor-related protein (LRP) requires incubation with exogenous apolipoprotein (apo) E. Inclusion of a mixture of the C apolipoproteins in the incubation inhibits this binding. In the present study, the ability of the individual C apolipoproteins (C-I, C-II, and C-III) to block binding of beta-VLDL to the LRP was examined by measuring cholesteryl ester formation in mutant fibroblasts that lack low density lipoprotein receptors or by measuring binding to the LRP using ligand blotting. In each assay, both apoC-I and apoC-II inhibited binding; apoC-I was the more effective inhibitor. Apolipoprotein C-III had no effect on binding activity, regardless of its sialylation level. Binding of human apoE to rabbit beta-VLDL in the absence or presence of human apoC-I, apoC-II, and monosialo-apoC-III was also determined, by gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The results of these studies are consistent with a mechanism in which exogenous human apoE displaces the endogenous apoE and the beta-VLDL particle becomes enriched with apoE (by 4.2-fold in this study). At this higher apoE content, the beta-VLDL bound to the LRP. Inclusion of apoC-I, apoC-II, or apoC-III in the incubation mixture resulted in a differential displacement of apoE from the beta-VLDL; however, at the concentrations examined, only apoC-I and apoC-II were capable of displacing sufficient apoE to abolish binding to LRP.
Asunto(s)
Apolipoproteínas C/farmacología , Apolipoproteínas E/metabolismo , Lipoproteínas VLDL/metabolismo , Receptores de LDL/metabolismo , Secuencia de Aminoácidos , Animales , Apolipoproteína C-I , Unión Competitiva , Línea Celular , Ésteres del Colesterol/biosíntesis , Humanos , Cinética , Datos de Secuencia Molecular , Neuraminidasa/farmacología , Conejos , Homología de Secuencia de Ácido NucleicoRESUMEN
The low density lipoprotein receptor-related protein (LRP) from rat liver membranes binds apoprotein E (apoE)-enriched rabbit beta-migrating very low density lipoproteins (beta-VLDL) in a ligand blotting assay on nitrocellulose membranes. Binding was markedly activated when the beta-VLDL was preincubated with recombinant human apoE-3, native human apoE-3 or E-4, or native rabbit apoE. Human apoE-2, which binds poorly (1-2% of apo E-3 binding) to low density lipoprotein receptors, was approximately 40% as effective as apoE-3 or apoE-4 in binding to LRP. Stimulation of apoE-dependent binding to LRP was blocked by the inclusion of a mixture of human apoC proteins, but not apoA-I or A-II, in the preincubation reaction. High concentrations of apoE did not overcome the apoC inhibition. The effects of apoE and apoC on the ligand blotting assay were paralleled by similar effects in the ability of beta-VLDL to stimulate cholesteryl ester synthesis in mutant human fibroblasts that lack low density lipoprotein receptors. These properties of LRP are consistent with the known effects of apoE and apoC on uptake of chylomicron and very low density lipoprotein remnants in the liver and raise the possibility that LRP functions as a receptor for apoE-enriched forms of these lipoproteins in intact animals.
Asunto(s)
Apolipoproteínas E/farmacología , Lipoproteínas VLDL/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Apolipoproteínas A/farmacología , Células Cultivadas , Ésteres del Colesterol/biosíntesis , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Cinética , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Masculino , Unión Proteica , Conejos , Receptores de LDL/metabolismo , Proteínas Recombinantes/farmacología , Piel/metabolismoRESUMEN
The low density lipoprotein receptor-related protein (LRP) is a cell surface glycoprotein that binds and transports plasma lipoproteins enriched in apolipoprotein E. It is synthesized in the endoplasmic reticulum as a transmembrane glycosylated precursor that migrates with an apparent molecular mass of about 600 kd on SDS-polyacrylamide gels. After it reaches the Golgi complex, the protein is cleaved to generate two subunits with apparent molecular masses of approximately 515 and 85 kd respectively. The larger NH2-terminal alpha-subunit lacks a membrane-spanning region. It remains attached to the membrane through noncovalent association with the smaller COOH-terminal beta-subunit. Proteolysis occurs at the sequence RHRR, which resembles the sequence RKRR at the proteolytic site in the receptors for insulin and insulin-like growth factor-1 (IGF-1), the only other cell surface receptors known to undergo proteolytic processing. Proteolysis of LRP occurs coincident with the conversion of the N-linked carbohydrates to the mature endoglycosidase H-resistant, neuraminidase-sensitive form. Proteolysis is prevented by brefeldin A, which blocks transport to the Golgi complex. These data raise the possibility that LRP and the receptors for insulin and IGF-1 are processed by a specific endoprotease that recognizes protein with extended basic sequences and resides in the trans-Golgi complex or in post-Golgi vesicles of the constitutive secretory pathway.
Asunto(s)
Aparato de Golgi/metabolismo , Receptores Inmunológicos/metabolismo , Acetilglucosaminidasa , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales , Brefeldino A , Células Cultivadas , Ciclopentanos/farmacología , Técnica del Anticuerpo Fluorescente , Glicósido Hidrolasas , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/inmunología , Humanos , Hígado/inmunología , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidasa , Ratones , Datos de Secuencia Molecular , Peso Molecular , Neuraminidasa , Conformación Proteica , Conejos , Ratas , Receptores Inmunológicos/inmunologíaRESUMEN
Low density lipoprotein receptor-related protein (LRP) is a recently described cell-surface protein of 4544 amino acids that contains reiterated sequences found in the 839-amino acid receptor for low density lipoprotein (LDL). In the current studies, we purified LRP from rat liver, prepared polyclonal antibodies that recognize the extracellular domain, and demonstrated an immunoreactive protein of approximately 600 kDa in human fibroblasts. The function of this LRP was studied in mutant human fibroblasts that do not produce LDL receptors. The mutant cells were incubated with beta-migrating very low density lipoprotein (beta-VLDL) that was isolated from cholesterol-fed rabbits and artificially enriched with apoprotein (apo) E by incubation in vitro with human apo E produced in a bacterial expression system. The apo E-enriched beta-VLDL, but not unincubated beta-VLDL, stimulated incorporation of [14C]-oleate into cholesteryl [14C]oleate 20- to 40-fold in the mutant cells. This stimulation was blocked by chloroquine, suggesting that such stimulation resulted from receptor-mediated uptake and lysosomal hydrolysis of the cholesteryl esters in apo E-enriched beta-VLDL. Stimulation of cholesterol esterification was blocked by the antibody against LRP, but not by an antibody against the LDL receptor. Unlike the LDL receptor, the amount of LRP was not reduced when cells were incubated with oxygenated sterols. We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E.
Asunto(s)
Apolipoproteínas E/metabolismo , Ésteres del Colesterol/metabolismo , Hígado/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de LDL/metabolismo , Animales , Células Cultivadas , Cloroquina/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Lipoproteínas VLDL/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Peso Molecular , Mutación , Ácido Oléico , Ácidos Oléicos/metabolismo , Ratas , Receptores Inmunológicos/biosíntesis , Receptores Inmunológicos/aislamiento & purificación , Receptores de LDL/biosíntesis , Piel/metabolismo , Triglicéridos/biosíntesisRESUMEN
The 5'-flanking region of the gene for hamster 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) is shown to contain promoter sequences that drive transcription in vitro in the presence of a HeLa whole-cell extract. DNase I protection studies revealed at least six different regions within the 277-base-pair (bp) promoter that bind nuclear proteins and produce "footprints." The functional significance of these sequences was determined through transcriptional analysis of a series of substitution mutations that scrambled short sequences throughout this region. Two of the footprint sequences were crucial for transcription in vitro; one of these contains a match in 6 of 6 bp, with a sequence in the adenovirus type 2 major late promoter that is known to be required for transcription. Scrambling a 26-bp sequence in a third footprint led to a consistent 2-fold increase in transcription, suggesting that this sequence might be a site for negative regulation. These studies define three regions that play a role in regulating transcription of the gene for HMG-CoA reductase, a negatively regulated enzyme in the cholesterol biosynthetic pathway.