RESUMEN
Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality. Timely diagnosis of the arrhythmia, particularly transient episodes, can be difficult since patients may be asymptomatic. In this study, we describe a robust algorithm for automatic detection of AF based on the randomness, variability and complexity of the heart beat interval (RR) time series. Specifically, we employ a new statistic, the Turning Points Ratio, in combination with the Root Mean Square of Successive RR Differences and Shannon Entropy to characterize this arrhythmia. The detection algorithm was tested on two databases, namely the MIT-BIH Atrial Fibrillation Database and the MIT-BIH Arrhythmia Database. These databases contain several long RR interval series from a multitude of patients with and without AF and some of the data contain various forms of ectopic beats. Using thresholds and data segment lengths determined by Receiver Operating Characteristic (ROC) curves we achieved a high sensitivity and specificity (94.4% and 95.1%, respectively, for the MIT-BIH Atrial Fibrillation Database). The algorithm performed well even when tested against AF mixed with several other potentially confounding arrhythmias in the MIT-BIH Arrhythmia Database (Sensitivity = 90.2%, Specificity = 91.2%).
Asunto(s)
Algoritmos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/fisiopatología , Electrocardiografía/métodos , Automatización/métodos , Bases de Datos Factuales , Femenino , Humanos , Masculino , Sensibilidad y EspecificidadRESUMEN
1. Are arterial blood pressure fluctuations buffered or reinforced by respiratory sinus arrhythmia (RSA)? There is still considerable debate about this simple question. Different results have been obtained, triggering a discussion as to whether or not the baroreflexes are responsible for RSA. We suspected that the measurements of different aspects of arterial pressure (mean arterial pressure (MAP) and systolic pressure (SP)) can explain the conflicting results. 2. Simultaneous recordings of beat-to-beat MAP, SP, left cardiac stroke volume (SV, pulsed ultrasound Doppler), heart rate (HR) and respiration (RE) were obtained in 10 healthy young adults during spontaneous respiration. In order to eliminate HR variations at respiratory frequency we used propranolol and atropine administration in the supine and tilted positions. Respiration-synchronous variation in the recorded variables was quantified by spectral analysis of the recordings of each of these variables, and the phase relations between them were determined by cross-spectral analysis. 3. MAP fluctuations increased after removing heart rate variations in both supine and tilted position, whereas SP fluctuations decreased in the supine position and increased in the head-up tilted position. 4. RSA buffers respiration-synchronous fluctuations in MAP in both positions. However, fluctuations in SP were reinforced by RSA in the supine and buffered in the tilted position.
Asunto(s)
Arritmia Sinusal/fisiopatología , Presión Sanguínea/fisiología , Respiración , Adulto , Antiarrítmicos/administración & dosificación , Atropina/administración & dosificación , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Propranolol/administración & dosificación , Volumen Sistólico/fisiología , Posición Supina , Pruebas de Mesa InclinadaRESUMEN
We investigated the requirement for Syk activation to initiate downstream signaling events during polymorphonuclear leukocyte (PMN) phagocytosis of Ab-coated erythrocytes (EIgG). When PMN were challenged with EIgG, Syk phosphorylation increased in a time-dependent manner, paralleling the response of PMN phagocytosis. Pretreatment of PMN with piceatannol, a Syk-selective inhibitor, blocked EIgG phagocytosis and Syk phosphorylation. We found that piceatannol inhibited protein kinase Cdelta (PKCdelta) and Raf-1 translocation from cytosol to plasma membrane by >90%. Extracellular signal-regulated protein kinase-1 and -2 (ERK1 and ERK2) phosphorylation was similarly blocked. We also investigated phosphatidylinositide 3-kinase (PI 3-kinase) activity and Syk phosphorylation using piceatannol, wortmannin, and LY294002, inhibitors of PI 3-kinase. The phosphorylation of Syk preceded the activation of PI 3-kinase. Both wortmannin and piceatannol inhibited PI 3-kinase, but only piceatannol inhibited Syk. In contrast to piceatannol, wortmannin did not inhibit PKCdelta and Raf-1 translocation. To elucidate signaling downstream of Syk activation, we assessed whether the cell-permeable diacylglycerol analogue didecanoylglycerol could normalize PMN phagocytosis, PKCdelta and Raf-1 translocation, and ERK1 and ERK2 phosphorylation inhibited by piceatannol. The addition of didecanoylglycerol to the Syk-inhibited phagocytosing PMN normalized all three without a concomitant effect on PI 3-kinase activity and Syk phosphorylation. We conclude that Syk activation following Fcgamma receptor engagement initiates downstream signaling events leading to mitogen-activated protein kinase activation independent of PI 3-kinase activation.
Asunto(s)
Precursores Enzimáticos/metabolismo , Neutrófilos/enzimología , Neutrófilos/inmunología , Fagocitosis/inmunología , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/inmunología , Androstadienos/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/inmunología , Membrana Celular/enzimología , Membrana Celular/inmunología , Inhibición de Migración Celular , Diglicéridos/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Inhibidores Enzimáticos/farmacología , Precursores Enzimáticos/antagonistas & inhibidores , Eritrocitos/inmunología , Humanos , Inmunoglobulina G/sangre , Péptidos y Proteínas de Señalización Intracelular , Isoenzimas/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Proteínas Opsoninas/sangre , Fagocitosis/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Fosfotirosina/metabolismo , Proteína Quinasa C/metabolismo , Proteína Quinasa C-delta , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de IgG/fisiología , Ovinos , Estilbenos/farmacología , Quinasa Syk , WortmaninaRESUMEN
In the present study, we investigated the mechanism by which sphingosine and its analogues, dihydrosphingosine and phytosphingosine, inhibit polymorphonuclear leukocyte (PMN) phagocytosis of IgG-opsonized erythrocytes (EIgG) and inhibit ERK1 and ERK2 phosphorylation. We used antibodies that recognized the phosphorylated forms of ERK1 (p44) and ERK2 (p42) (extracellular signal-regulated protein kinases 1 and 2). Sphingoid bases inhibited ERK1 and ERK2 activation and phagocytosis of EIgG in a concentration-dependent manner. Incubation with glycine, N,N'-[1, 2-ethanediylbis(oxy-2, 1-phenylene)]bis[N-[2-[(acetyloxy)methoxy]-2-oxoethyl]]-bis[ (acetylox y)methyl]ester (BAPTA,AM), an intracellular chelator of calcium, failed to block either phagocytosis or ERK1 and ERK2 phosphorylation, consistent with the absence of a role for a calcium-dependent protein kinase C (PKC) in ERK1 and ERK2 phosphorylations. Western blotting demonstrated that sphingosine inhibited the translocation of Raf-1 and PKCdelta from PMN cytosol to the plasma membrane during phagocytosis. These data are consistent with the interpretation that sphingosine regulates ERK1 and ERK2 phosphorylation through inhibition of PKCdelta, and this in turn leads to inhibition of Raf-1 translocation to the plasma membrane. Consistent with this interpretation, the sphingosine-mediated inhibition of phagocytosis, ERK2 activation, and PKCdelta translocation to the plasma membrane could be abrogated with a cell-permeable diacylglycerol analog. The increase in the diacylglycerol mass correlated with the translocation of PKCdelta and Raf-1 to the plasma membrane by 3 minutes after the initiation of phagocytosis. Additionally, the diacylglycerol analog enhanced phagocytosis by initiating activation of PKCdelta and its translocation to the plasma membrane. Because PMN generate sufficient levels of sphingosine by 30 minutes during phagocytosis of EIgG to inhibit phagocytosis, it appears that sphingosine can serve as an endogenous regulator of EIgG-mediated phagocytosis by downregulating ERK activation.
Asunto(s)
Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas Activadas por Mitógenos , Neutrófilos/fisiología , Fagocitosis/efectos de los fármacos , Esfingosina/farmacología , Transporte Biológico/efectos de los fármacos , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Membrana Celular/metabolismo , Diglicéridos/farmacología , Eritrocitos , Humanos , Inmunoglobulina G , Proteína Quinasa 1 Activada por Mitógenos , Proteína Quinasa 3 Activada por Mitógenos , N-Formilmetionina Leucil-Fenilalanina/farmacología , Proteínas Opsoninas , Fosforilación , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Receptores Fc/fisiologíaRESUMEN
BACKGROUND: In low doses, scopolamine paradoxically enhances parasympathetic outflow to the heart. The mechanisms which mediate this action are not fully understood. Moreover, there are conflicting data regarding the potential role of sympathetic activity. This study in 17 healthy individuals was designed to characterize the influence of low dose transdermal scopolamine on the gain of the baroreflex and respiratory heart rate reflex and to determine the role of sympathetic activity. METHODS: The effect of scopolamine was analyzed in the time and frequency domain by computing heart rate variability indices. The gains of the respiratory heart rate reflex and the baroreflex were estimated simultaneously by means of a cardiovascular system identification approach using an optimized autoregressive moving average algorithm. Measurements were repeated in the upright posture to assess the influence of enhanced sympathetic activity. In six subjects ambulatory ECGs were recorded to determine whether there are diurnal variations of the effect of scopolamine. RESULTS: Scopolamine enhances vagal modulation of heart rate through both the respiratory-heart rate reflex and the baroreflex, as the gains of both were augmented by the drug in the supine and in the upright postures. CONCLUSIONS: Scopolamine increases parasympathetic cardiac control by augmenting the gain of the respiratory-heart rate and baroreflex. This action is not attenuated in the upright posture when sympathetic tone is increased.
Asunto(s)
Barorreflejo/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Sistema Nervioso Parasimpático/efectos de los fármacos , Parasimpatolíticos/farmacología , Escopolamina/farmacología , Administración Cutánea , Adulto , Barorreflejo/fisiología , Presión Sanguínea/fisiología , Electrocardiografía Ambulatoria , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Masculino , Antagonistas Muscarínicos/administración & dosificación , Sistema Nervioso Parasimpático/fisiología , Parasimpatolíticos/administración & dosificación , Postura/fisiología , Fenómenos Fisiológicos Respiratorios , Escopolamina/administración & dosificación , Posición Supina/fisiologíaRESUMEN
INTRODUCTION: Beat-to-beat adaptation of ventricular repolarization duration to cardiac cycle length and autonomic activity has not been previously characterized in the spontaneously beating human heart. METHODS AND RESULTS: The ECG of 14 healthy subjects was recorded from the supine and upright positions. Autonomic blockade was accomplished by atropine and propranolol. RR and RT intervals were measured by a computer algorithm, and the impulse response (h) from RR to RT computed. In the supine position the maximal adjustment of the RT interval occurred in the first beat following a change in cycle length (hpeak = 17.8 +/- 1.6 msec/sec), but continued to be detectable for 3.8 seconds (2.9-4.7 sec). Propranolol attenuated the peak impulse response to 15.8 +/- 4.0 msec/sec (P = NS). In the standing position the peak impulse response was increased to 25.2 +/- 5.0 msec/sec (P = 0.004 vs supine), and the impulse response duration (hdur) shortened to 1.4 seconds (1.3-1.6). This was reversed by beta blockade (hpeak = 10.7 +/- 3.6 [P = 0.005 vs standing]; hdur = 5.5 sec [4.8-6.1]). Parasympathetic and combined autonomic blockade resulted in too little residual heart rate variability to estimate the impulse response accurately. The slope of the regression of delta RT and delta RR in the supine position was 0.0177 +/- 0.0016, which was closely correlated with the peak impulse response (r = 0.91). CONCLUSIONS: System identification techniques can assist in characterizing the cycle dependence of ventricular repolarization and may provide new insights into conditions associated with abnormal repolarization.
Asunto(s)
Bloqueo Nervioso Autónomo , Frecuencia Cardíaca/fisiología , Función Ventricular/fisiología , Adulto , Algoritmos , Atropina , Sistema Nervioso Autónomo/fisiología , Electrocardiografía , Humanos , Cinética , Masculino , Postura/fisiología , Propranolol , Programas Informáticos , Posición Supina/fisiologíaRESUMEN
To extend our studies about phenotypical and functional alterations of G-CSF-induced neutrophils we have evaluated their light-scatter profile, mobilization of intracellular calcium ([Ca2+]i) and membrane depolarization after stimulation. A significant increase in the forward scatter signals could be demonstrated in such neutrophils from patients with neutropenias of various origin and from healthy test subjects. This increase began 4 h and returned to normal 96 h after G-CSF injection in the latter group. We found an impairment of [Ca2+]i mobilization in neutrophils from patients with glycogen storage disease type IB after stimulation of these cells with fMLP. It was even more pronounced than in severe congenital neutropenia (SCN). However, [Ca2+]i fluxes were normal when ionomycin was used. Neutrophils from patients with cyclic neutropenia (cyNP) and chemotherapy-induced neutropenia (chNP) mobilized [Ca2+]i similar to those from healthy donors. Furthermore, we found a decreased percentage of neutrophils depolarizing after stimulation with fMLP and PMA in patients with SCN, whereas membrane depolarization was normal in patients with chNP and cyNP. All the alterations found here are suggested to be caused by a partial immaturity of the neutrophils, although in vivo activation and a direct effect of G-CSF on myeloid precursors might be involved.
Asunto(s)
Calcio/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Neutropenia/terapia , Neutrófilos/patología , Citometría de Flujo , Fluorescencia , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Luz , Potenciales de la Membrana , Neutropenia/congénito , Neutropenia/fisiopatología , Neutrófilos/metabolismo , Dispersión de Radiación , Transducción de SeñalRESUMEN
We have previously reported an altered surface marker expression and chemotaxis of G-CSF-induced neutrophils from patients with severe congenital neutropenia. However, effects of G-CSF and influence of the underlying disease on neutrophils could not be discerned. In this study we have evaluated the effects of G-CSF on neutrophil phenotype and function in patients under chemotherapy and in healthy test subjects. We found a significantly enhanced expression of Fc gamma RI, CD14 and CD54 and a decrease in the level of Fc gamma RIII during G-CSF treatment. In addition, motility of G-CSF-induced neutrophils was significantly decreased. The effects were seen in patients under cytotoxic chemotherapy and in healthy test subjects. Surface marker alterations and neutrophil motility were affected by G-CSF administration in a dose-dependent manner. Kinetic studies on neutrophils from healthy test subjects demonstrated that all effects could be seen after a single administration of 300 micrograms G-CSF and began to appear within 4 h. Release of partially immature neutrophils from the bone marrow and indirect activation of these cells by G-CSF are discussed as possible reasons for the findings presented. They demonstrate that G-CSF has profound effects on neutrophil phenotype and function in vivo which might have clinical implications.
Asunto(s)
Antígenos de Superficie/sangre , Antineoplásicos/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Neutrófilos/inmunología , Quimiotaxis de Leucocito , Relación Dosis-Respuesta Inmunológica , Humanos , Cinética , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Receptores de IgG/análisis , Proteínas Recombinantes/farmacologíaRESUMEN
Recently, a superoxide-generating NADPH-oxidase system in human fibroblasts has been described. Therefore, we reassessed the possible use of this cell type for prenatal diagnosis of CGD patients comparing normal and CGD peripheral blood neutrophils (PMN) and skin fibroblasts in their reactive oxygen intermediate (ROI)-producing capacity. While PMN of the CGD patient showed a clearly reduced respiratory burst activity, which correlated well with the measured content of cytochrome b558, fibroblasts of the same individual showed no impaired production of superoxide anion or H2O2 upon stimulation by cytokines (TNF and IL-1) or other agents (Ca2+ ionophores and PAF, unpublished results). Furthermore, fibroblasts of the CGD patient or of normal donors could be inhibited in ROI production by diphenylene iodonium (DPI) and 2-iodobiphenyl. In contrast to PMN, no inhibition of the fibroblast NADPH-oxidase system was observed using staurosporin, an inhibitor of proteinkinase C. These data demonstrate, in contrast to previous studies, that fibroblasts are able to produce ROI. Nevertheless, since fibroblasts obtained from a CGD patient exhibited no difference in ROI production compared with fibroblasts obtained from healthy donors, they are not suitable for prenatal diagnosis of CGD.
Asunto(s)
Enfermedad Granulomatosa Crónica/metabolismo , NADPH Oxidasas , Neutrófilos/metabolismo , Piel/metabolismo , Superóxidos/metabolismo , Cromosoma X , Calcimicina/farmacología , Células Cultivadas , Niño , Grupo Citocromo b/biosíntesis , Grupo Citocromo b/metabolismo , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Enfermedad Granulomatosa Crónica/sangre , Enfermedad Granulomatosa Crónica/genética , Humanos , Interleucina-1/farmacología , Cinética , Masculino , Neutrófilos/efectos de los fármacos , Factor de Activación Plaquetaria/farmacología , Valores de Referencia , Superóxidos/sangre , Factor de Necrosis Tumoral alfa/farmacologíaAsunto(s)
Complejos Cardíacos Prematuros/fisiopatología , Ritmo Circadiano/fisiología , Sistema de Conducción Cardíaco/fisiopatología , Síndrome de QT Prolongado/fisiopatología , Sotalol/uso terapéutico , Taquicardia Ventricular/fisiopatología , Complejos Cardíacos Prematuros/tratamiento farmacológico , Electrocardiografía Ambulatoria , Femenino , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Síndrome de QT Prolongado/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Taquicardia Ventricular/tratamiento farmacológicoAsunto(s)
Muerte Súbita Cardíaca , Electrocardiografía , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Left ventricular remodeling after an acute myocardial infarction may result in progressive left ventricular dilation that may be associated with increased mortality. We studied the effects of the phosphodiesterase inhibitor milrinone on left ventricular remodeling after acute myocardial infarction. METHODS AND RESULTS: Rats (n = 90) were randomized to undergo either left coronary artery ligation or sham operation. Three weeks after surgery, rats received either no treatment or milrinone, which was continued until 2 days before the rats were killed. Ninety days after the initial surgery, hemodynamic measurements were made before and after volume loading. The rats were killed, the hearts were removed, and passive pressure-volume curves were obtained. The hearts were fixed at a constant pressure and analyzed morphometrically. Compared with untreated infarcted rats, milrinone-treated infarcted rats had a lower left ventricular end-diastolic pressure (1.7 +/- 0.4 versus 4.3 +/- 1.4 mm Hg, p less than 0.05), a lower left ventricular volume (1.25 +/- 0.20 versus 2.37 +/- 0.30 ml/kg, p less than 0.001) and a lower left ventricular wall stress index (1.3 +/- 0.2 versus 1.7 +/- 0.1, p less than 0.05). Left ventricular chamber stiffness was higher in milrinone-treated infarcted rats than in untreated infarcted rats. Milrinone had no cardiac effect on uninfarcted animals. CONCLUSION: Chronic milrinone therapy after acute myocardial infarction improves cardiac hemodynamic indexes and attenuates progressive left ventricular dilation.
Asunto(s)
Corazón/efectos de los fármacos , Infarto del Miocardio/fisiopatología , Piridonas/farmacología , Animales , Femenino , Corazón/fisiopatología , Ventrículos Cardíacos , Hemodinámica/efectos de los fármacos , Milrinona , Miocardio/patología , Inhibidores de Fosfodiesterasa/farmacología , Ratas , Ratas Endogámicas , Estrés MecánicoRESUMEN
Statistical criteria for suppression and aggravation of ventricular arrhythmia were defined by means of 50 short-term drug tests performed in 24 patients. Each patient's spontaneous variability (SV) was evaluated by linear regression analysis of hour-to-hour changes in ectopy during 24- to 48-hour Holter monitoring. The response to a single oral dose of disopyramide, 300 mg, flecainide, 200 mg, and propafenone, 450 mg, was measured during a trial lasting 4 hours. Lidocaine was administered intravenously in incremental doses of up to 4 mg/min and was evaluated over 3 hours. Threshold values of ventricular arrhythmia corresponding to 95% confidence limits were calculated from baseline recordings and were used to ascertain the likelihood of a true drug effect. The minimum decrease in hourly ectopy indicating arrhythmia suppression averaged 90.9%, while an increase of at least 947% was required for a proarrhythmic effect. When these efficacy criteria were applied, 16 of 50 short-term tests revealed no drug effect. In contrast, when a 70% threshold derived from studies of daily variability was employed, only 7 of 50 trials were negative. Thus individual determination of hourly arrhythmia variability yields more stringent criteria than extrapolation from day-to-day spontaneous variation.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antiarrítmicos/sangre , Arritmias Cardíacas/sangre , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/epidemiología , Enfermedad Crónica , Evaluación de Medicamentos/métodos , Electrocardiografía Ambulatoria , Femenino , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Estudios Retrospectivos , Factores de TiempoRESUMEN
Day to day variability of ventricular ectopic activity was analyzed in 45 patients with a history of malignant ventricular tachyarrhythmias who underwent two successive 24 h periods of ambulatory electrocardiographic (ECG) monitoring in the absence of antiarrhythmic drugs; 26 were male and 19 female, with a mean age of 56 years (range 15 to 76). The total number of single ventricular premature beats, couplets and ventricular tachycardia beats and runs on days 1 and 2 demonstrated a consistent overall correlation (r = 0.76 to 0.84). Individual variability was evaluated by regression analysis with determination of 95% confidence limits. The minimal decrease in arrhythmia density necessary to distinguish true drug effect from spontaneous variability was 64% for single ventricular premature beats, 83% for couplets, 90% for ventricular tachycardia runs and 93% for ventricular tachycardia beats. To meet the criteria for arrhythmia aggravation, the arrhythmia density had to increase by 400, 877, 1,500 and 2,400%, respectively. Multivariate analysis disclosed an inverse relation between day to day arrhythmia variability and baseline arrhythmia density and age. Variability was more pronounced in patients with coronary artery disease but was not influenced by the type of presenting arrhythmia or left ventricular function. The diurnal distribution of arrhythmias and heart rate followed a distinct circadian pattern. These data indicate that, despite good group reproducibility, spontaneous arrhythmia variability in individuals is substantial, necessitating standards to define both drug effect and arrhythmia aggravation.
Asunto(s)
Ritmo Circadiano , Electrocardiografía , Taquicardia/fisiopatología , Adolescente , Adulto , Anciano , Femenino , Frecuencia Cardíaca , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Monitoreo FisiológicoRESUMEN
The efficacy of intracoronary administration of lidocaine was studied in three groups of dogs with experimental myocardial infarction induced by occlusion of the left anterior descending coronary artery (LAD). Group 1 included 14 anesthetized and group 2, 7 conscious animals to which lidocaine 1.4 micrograms/kg/minute was administered as an intracoronary infusion. Group 3 consisted of 17 anesthetized dogs that received an intracoronary bolus of lidocaine 40 micrograms/kg over 30 seconds. In group 1, lidocaine reduced ventricular arrhythmia by 59 +/- 30% (p less than 0.001), whereas systemic lidocaine achieved a reduction by 61 +/- 37% (p 0.06). In seven dogs, lidocaine blood levels were measured in the great cardiac and femoral veins. At the end of the infusion the drug concentration was 3.4 +/- 2.2 micrograms/ml in the great cardiac and 1.3 +/- 1.1 micrograms/ml in the femoral vein (p less than 0.05). The reduction in ventricular arrhythmia correlated with the great cardiac vein lidocaine concentration (r = 0.70; p less than 0.05), but not with the drug level in the femoral vein (r = 0.06; NS). In group 2, lidocaine was ineffective by both routes of administration. This may have been related to higher sympathetic activity, as suggested by an elevated heart rate in conscious compared to anesthetized animals (186 +/- 6 vs 164 +/- 21 bpm; p 0.0054). In group 3, bolus injections of lidocaine into the LAD reduced ventricular arrhythmia by 66% (p 0.001). We conclude that by perfusing the infarcted zone with lidocaine, a significant antiarrhythmic effect can be achieved with 2% of the systemic dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Arritmias Cardíacas/prevención & control , Lidocaína/administración & dosificación , Infarto del Miocardio/tratamiento farmacológico , Animales , Arritmias Cardíacas/complicaciones , Vasos Coronarios , Perros , Relación Dosis-Respuesta a Droga , Femenino , Ventrículos Cardíacos , Inyecciones Intraarteriales , Lidocaína/efectos adversos , Masculino , Infarto del Miocardio/complicacionesRESUMEN
Brain serotoninergic neurons are known to participate in cardiovascular regulation. Administration of the serotonin precursor 5-l-hydroxytryptophan in conjunction with the monamine oxidase inhibitor phenelzine and the selective peripheral l-amino acid decarboxylase inhibitor carbidopa has been shown to raise the repetitive extrasystole threshold in the canine heart. The present investigation demonstrates that this drug regimen increases the cerebrospinal fluid concentration of serotonin and its major metabolite, 5-hydroxyindoleacetic acid, by 330 and 830%, respectively. By contrast, cerebrospinal fluid concentrations of norepinephrine and its major brain metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate, and of dopamine's metabolite, 3, 4-dihydroxyphenylacetic acid, were not significantly altered. Concomitantly, the ventricular fibrillation threshold was elevated by 42% and the effective refractory period prolonged by 7%. Efferent sympathetic neural activity was suppressed in the normal heart (from 7.9 +/- 1.3 to 3.9 +/- 1.1 impulses/s). The surge in sympathetic activity associated with acute myocardial ischemia was markedly attenuated. These results indicate that enhancement of central serotoninergic neurotransmission can reduce the susceptibility to ventricular fibrillation mediated through a decline in sympathetic neural traffic to the heart.
Asunto(s)
5-Hidroxitriptófano/farmacología , Carbidopa/farmacología , Corazón/efectos de los fármacos , Fenelzina/farmacología , Serotonina/líquido cefalorraquídeo , Fibrilación Ventricular/fisiopatología , Ácido 3,4-Dihidroxifenilacético/líquido cefalorraquídeo , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Enfermedad Coronaria/fisiopatología , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Ácido Hidroxiindolacético/metabolismo , Masculino , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Norepinefrina/líquido cefalorraquídeo , Serotonina/metabolismoRESUMEN
The relationship between arrhythmia density observed during ambulatory monitoring, left ventricular ejection fraction (EF), and response to antiarrhythmic drug therapy was evaluated in 94 patients presenting with ventricular fibrillation (VF) (n = 20) or ventricular tachycardia (VT) (n = 74). Following baseline studies, an average of 4.9 antiarrhythmic drugs were tested singly in each patient. Univariate and multivariate analyses revealed that the density of VT on baseline ambulatory monitoring and initial left ventricular EF were independent predictors of drug efficacy. The 45 patients with an EF less than or equal to 35% responded to 34 +/- 29% of drugs tested, whereas the 49 with an EF greater than 35% had arrhythmia suppression with 46 +/- 28% of agents (p less than 0.038). Patients exhibiting VT during greater than or equal to 50% of monitoring hours responded to 32 +/- 26% of drugs, whereas those with VT during less than 50% of hours showed arrhythmia suppression with 48 +/- 29% of antiarrhythmic agents tested (p = 0.009). During a mean follow-up period of 12.9 months, the annual sudden death mortality for all patients was 9.3%. However, 8 of the 55 patients responding to less than 50% of drugs tested died suddenly and 17 had recurrent VT. By contrast, only 1 of the 39 patients responding to greater than or equal to 50% of the antiarrhythmic drugs tested died suddenly and two experienced recurrent VT (p = 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antiarrítmicos/uso terapéutico , Taquicardia/fisiopatología , Fibrilación Ventricular/fisiopatología , Atención Ambulatoria , Electrofisiología , Femenino , Estudios de Seguimiento , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico , Contracción Miocárdica/efectos de los fármacos , Volumen Sistólico/efectos de los fármacos , Taquicardia/tratamiento farmacológico , Fibrilación Ventricular/tratamiento farmacológicoRESUMEN
The antiarrhythmic effect of encainide was evaluated in 140 patients with documented symptomatic ventricular tachycardia or ventricular fibrillation refractory to conventional agents. In 102 patients with reproducible spontaneous arrhythmia, noninvasive methods, including ambulatory monitoring and exercise testing, were used to evaluate drug efficacy, while in the remaining 38 patients electrophysiologic testing was performed. Side effects necessitated drug discontinuation in 10 patients before noninvasive evaluation. Of the remaining 92 patients 44 (48%) responded to encainide. Of the 38 patients who underwent electrophysiologic study, 1 discontinued encainide because of side effects and in 4 patients the spontaneous occurrence of sustained ventricular tachycardia precluded repeat study. Of the remaining 33 patients, 10 (30%) were rendered noninducible with encainide. The drug was more effective in those with a left ventricular ejection fraction greater than 35% (p less than 0.03) and in those presenting with nonsustained ventricular tachycardia. Side effects were reported in 53 of 140 patients (38%) and were primarily nausea, vomiting, headaches and tremors. Aggravation of arrhythmia occurred in 4% of patients with a history of nonsustained arrhythmia and in 25% of those with a history of sustained ventricular tachycardia or ventricular fibrillation. Worsening of arrhythmia was not related to mean dose of drug, mean blood level or electrocardiographic changes; it was more likely to occur in patients with a markedly reduced left ventricular ejection fraction (average 32%) and in those with a history of sustained ventricular tachyarrhythmia (p less than 0.05). Long-term encainide therapy was continued in 48 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Arritmias Cardíacas/tratamiento farmacológico , Adulto , Anciano , Anilidas/efectos adversos , Ensayos Clínicos como Asunto , Electrofisiología , Encainida , Femenino , Cefalea/inducido químicamente , Ventrículos Cardíacos , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Volumen Sistólico/efectos de los fármacos , Taquicardia/tratamiento farmacológico , Factores de Tiempo , Fibrilación Ventricular/tratamiento farmacológico , Vómitos/inducido químicamenteRESUMEN
To examine the impact of hypokalemia on cardiac electrical stability, the thresholds for repetitive extrasystole and ventricular fibrillation were determined before and after potassium depletion in 15 chloralose-anesthetized dogs. A reduction in serum potassium concentration from 3.6 to 2.1 mEq/L induced by hemodialysis decreased the repetitive extrasystole threshold by 30% and the ventricular fibrillation threshold by 25% (p less than 0.01). The increase in ventricular vulnerability following acute coronary occlusion was markedly augmented by concomitant potassium depletion. Thus, hypokalemia enhances the propensity for ventricular fibrillation in the normal as well as in the ischemic canine heart. These findings shed light on clinical observations of enhanced susceptibility to life-threatening arrhythmias during acute myocardial ischemia in hypokalemic patients.