RESUMEN
BACKGROUND: Vagal stimulation shortens the atrial effective refractory period (AERP) and maintains atrial fibrillation (AF). This study investigated whether the parasympathetic pathways that innervate the atria can be identified and ablated by use of transvenous catheter stimulation and radiofrequency current catheter ablation (RFCA) techniques. METHODS AND RESULTS: In 11 dogs, AERPs were determined at 7 atrial sites during bilateral cervical vagal nerve stimulation (VNS) and electrical stimulation of the third fat pad (20 Hz) in the right pulmonary artery (RPA). VNS shortened the AERP at all sites (from 123+/-4 to 39+/-4 ms, P<0.001) and increased the covariance of AERP (COV-AERP) (from 9+/-3% to 27+/-13%, P<0.001). RPA stimulation shortened the AERP at all sites from 123+/-4 to 66+/-13 ms (P<0.001) and increased the COV-AERP from 9+/-3% to 30+/-12% (P<0.001). In 7 dogs, transvascular RFCA of the parasympathetic pathways along the RPA was performed, and in 3 dogs, additional RFCA of parasympathetic fibers along the inferior (n=2) or superior (n=1) vena cava was performed. RFCA blunted the AERP shortening at all sites during VNS (114+/-4 ms after RFCA), abolished the increase of COV-AERP during VNS (12+/-7% after RFCA), and led to an increase of the baseline AERP (123+/-4 ms before versus 127+/-3 ms after RFCA, P=0.002). Before RFCA, AF could be induced and maintained as long as VNS was continued, whereas after RFCA, AF was no longer inducible during VNS. CONCLUSIONS: -Transvascular atrial parasympathetic nerve system modification by RFCA abolishes vagally mediated AF. This antifibrillatory procedure may provide a foundation for investigating the usefulness of neural ablation in chronic animal models of AF and eventually in patients with AF and high vagal tone.
Asunto(s)
Fibrilación Atrial/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Ablación por Catéter , Corazón/inervación , Nervio Vago/fisiopatología , Animales , Fibrilación Atrial/cirugía , Nodo Atrioventricular/fisiopatología , Perros , Estimulación Eléctrica , Corazón/fisiopatología , Atrios Cardíacos/patología , Atrios Cardíacos/fisiopatología , Sistema de Conducción Cardíaco/fisiopatología , Sistema Nervioso Parasimpático/fisiopatología , Nodo Sinoatrial/fisiopatologíaRESUMEN
BACKGROUND: The purpose of this study was to determine how often accessory atrioventricular (AV) pathways (AP) cross the AV groove obliquely. With an oblique course, the local ventriculoatrial (VA) interval at the site of earliest atrial activation (local-VA) and the local-AV interval at the site of earliest ventricular activation (local-AV) should vary by reversing the direction of the paced ventricular and atrial wavefronts, respectively. METHODS AND RESULTS: One hundred fourteen patients with a single AP were studied. Two ventricular and two atrial pacing sites on opposite sides of the AP were selected to reverse the direction of the ventricular and atrial wavefronts along the annulus. Reversing the ventricular wavefront increased local-VA by >/=15 ms in 91 of 106 (91%) patients. With the shorter local-VA, the ventricular potential overlapped the atrial potential along a 17.2+/-8.5-mm length of the annulus. No overlap occurred with the opposite wavefront. Reversing the atrial wavefront increased local-AV by >/=15 ms in 32 of 44 (73%) patients. With the shorter local-AV, the atrial potential overlapped the ventricular potential along an 11.9+/-8.9-mm length of the annulus. No overlap occurred with the opposite wavefront. Mapping during longer local-VA or local-AV identified an AP potential in 102 of 114 (89%) patients. Catheter ablation eliminated AP conduction in all 111 patients attempted (median, 1 radiofrequency application in 99 patients with an AP potential versus 4.5 applications without an AP potential). CONCLUSIONS: Reversing the direction of the paced ventricular or atrial wavefront reveals an oblique course in most APs and facilitates localization of the AP potential for catheter ablation.
Asunto(s)
Nodo Atrioventricular/fisiopatología , Estimulación Cardíaca Artificial , Sistema de Conducción Cardíaco/fisiopatología , Adolescente , Adulto , Anciano , Ablación por Catéter , Niño , Preescolar , Femenino , Atrios Cardíacos/fisiopatología , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: The purpose of this study was to characterize the circuit of macroreentrant right atrial tachycardia (MacroAT) in patients after surgical repair of congenital heart disease (SR-CHD). METHODS AND RESULTS: Sixteen patients with atrial tachycardia (AT) after SR-CHD were studied (atrial septal defect in 6, tetralogy of Fallot in 4, and Fontan procedure in 6). Electroanatomic right atrial maps were obtained during 15 MacroATs in 13 patients, focal AT in 1 patient, and atrial pacing in 2 patients without stable AT. A large area of low bipolar voltage (=0.5 mV) involved most of the free wall in all patients and contained 2 to 7 dense scars or lines of double potentials, forming 29 narrow channels (width =2.7 cm) between scars in all but 1 patient, who had a single scar and only focal AT. All 15 MacroATs were propagated through narrow channels. Ablation within the channel eliminated all 15 MacroATs with 1 to 3 (median 1) radiofrequency applications. Ablation was performed in 9 other channels identified during MacroAT (5 patients) and in 5 channels identified during atrial pacing (2 patients). Conduction block was obtained across 28 of 29 channels. After ablation, reproducible sustained right AT was not induced in any patient. During follow-up (median 13.5 months), new MacroATs, atrial fibrillation, or palpitations occurred in 3 of 16 patients. CONCLUSIONS: MacroAT after SR-CHD requires a large area of low voltage containing >/=2 scars forming narrow channels. Ablation within the channels eliminates MacroAT.
Asunto(s)
Defectos del Tabique Interatrial/cirugía , Taquicardia/etiología , Adulto , Aleteo Atrial , Función del Atrio Derecho , Ablación por Catéter , Electrofisiología , Femenino , Estudios de Seguimiento , Procedimiento de Fontan , Defectos del Tabique Interatrial/complicaciones , Defectos del Tabique Interatrial/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Taquicardia/fisiopatología , Taquicardia/cirugíaRESUMEN
A young woman with palpitation and syncope was found to have ventricular tachyarrhythmia and a congenital long QT interval. The QT interval was shortened and the arrhythmia suppressed by propranolol. Electrograms recorded at various sites in both ventricles revealed a distinct diastolic slow wave that followed the T wave and measured 1.1 mV. Epinephrine infusion and emotion augumented this diastolic wave and induced ventricular ectopic complexes arising from this potential. Similar endocardial recordings in eight patients without a long QT interval showed diastolic slow waves that never exceeded 0.28 mV. In normal canine myocardium, afterdepolarizations can be induced by norepinephrine and blocked by propranolol. These findings suggest that the long QT syndrome is associated with abnormally large afterdepolarizations in ventricular myocardial cells, which are enhanced by beta-adrenergic stimulation to attain threshold and produce firing.
Asunto(s)
Electrocardiografía , Taquicardia/congénito , Adulto , Muerte Súbita/etiología , Epinefrina/farmacología , Femenino , Humanos , Propranolol/uso terapéutico , Estrés Psicológico/complicaciones , Síncope/etiología , Taquicardia/complicaciones , Taquicardia/fisiopatologíaRESUMEN
Electrocardiographic monitoring and provocative ventricular pacing were used to evaluate control and nadolol treatment groups 6 to 24 hours after left anterior descending coronary artery ligation in the dog. During the 6 to 24 hour period, the control group (n = 20) developed ventricular triplets at rates exceeding 270/min. Seven dogs spontaneously developed sustained monomorphic ventricular tachycardia (421 +/- 12 beats/min) at 13 +/- 2 hours. Sustained monomorphic ventricular tachycardia was present for 38 +/- 8 seconds before ventricular fibrillation developed. One dog developed recurrent monomorphic ventricular tachycardia, with six episodes lasting from 8 to 72 seconds (375 to 425 beats/min). At 24 hours, ventricular pacing produced sustained monomorphic ventricular tachycardia (378 +/- 12 beats/min) in 9 of 13 surviving animals. Nadolol administration 6 hours after coronary artery ligation (n = 19) lowered both the rate (241 +/- 8 versus 328 +/- 8 beats/min; p = 0.001) and the incidence (8 +/- 6 versus 198 +/- 61 per hour; p = 0.004) of rapid ventricular triplets and prevented sudden arrhythmic death (0%; p = 0.005). Nadolol failed to prevent sustained monomorphic ventricular tachycardia (88%; 365 +/- 12 beats/min) produced by ventricular pacing. The data suggest that nadolol prevents spontaneous sustained monomorphic ventricular tachycardia by selectively suppressing the arrhythmia trigger (rapid ventricular triplets) without altering the underlying arrhythmia substrate.
Asunto(s)
Arritmias Cardíacas/prevención & control , Muerte Súbita/etiología , Infarto del Miocardio/tratamiento farmacológico , Nadolol/uso terapéutico , Animales , Arritmias Cardíacas/fisiopatología , Fenómenos Biomecánicos , Perros , Electrocardiografía , Electrofisiología , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatologíaRESUMEN
OBJECTIVES: To identify intravascular sites for continuous, stable parasympathetic stimulation (PS) in order to control the ventricular rate during atrial fibrillation (AF). BACKGROUND: Ventricular rate control during AF in patients with congestive heart failure is a significant clinical problem because many drugs that slow the ventricular rate may depress ventricular function and cause hypotension. Parasympathetic stimulation can exert negative dromotropic effects without significantly affecting the ventricles. METHODS: In 22 dogs, PS was performed using rectangular stimuli (0.05 ms duration, 20 Hz) delivered through a catheter with an expandable electrode-basket at its end. The catheter was positioned either in the superior vena cava (SVC, n = 6), coronary sinus (CS, n = 10) or right pulmonary artery (RPA, n = 6). The basket was then expanded to obtain long-term catheter stability. Atrial fibrillation was induced and maintained by rapid atrial pacing. RESULTS: Nonfluoroscopic (SVC) and fluoroscopic (CS/RPA) identification of effective intravascular PS sites was achieved within 3 to 10 min. The ventricular rate slowing effect during AF started and ceased immediately after on-offset of PS, respectively, and could be maintained over 20 h. In the SVC, at least a 50% increase of ventricular rate (R-R) intervals occurred at 22 +/- 11 V (331 +/- 139 ms to 653 +/- 286 ms, p < 0.001), in the CS at 16 +/- 10 V (312 +/- 102 ms vs. 561 +/- 172 ms, p < 0.001) and in the RPA at 18 +/- 7 V (307 +/- 62 ms to 681 +/- 151 ms, p < 0.001). Parasympathetic stimulation did not change ventricular refractory periods. CONCLUSIONS: Intravascular PS results in a significant ventricular rate slowing during AF in dogs. This may be beneficial in patients with AF and rapid ventricular response since many drugs that decrease atrioventricular conduction have negative inotropic effects which could worsen concomitant congestive heart failure.
Asunto(s)
Fibrilación Atrial/fisiopatología , Ganglios Parasimpáticos/fisiopatología , Frecuencia Cardíaca/fisiología , Ventrículos Cardíacos/fisiopatología , Animales , Fibrilación Atrial/diagnóstico , Atropina , Cateterismo Venoso Central , Cateterismo Periférico , Plexo Cervical/efectos de los fármacos , Plexo Cervical/cirugía , Perros , Estimulación Eléctrica , Electrocardiografía , Ventrículos Cardíacos/inervación , Parasimpatectomía , Parasimpatolíticos , Pericardio/inervación , Arteria Pulmonar , Vena Cava SuperiorRESUMEN
OBJECTIVES: The aim of the present study was to test, in vivo and in vitro, the influence of adrenergic activation on action potential prolongation induced by the potassium channel blocking agent d-sotalol. BACKGROUND: d-Sotalol is not effective against myocardial ischemia-dependent ventricular fibrillation in the presence of elevated sympathetic activity. Most potassium channel blockers, such as d-sotalol, affect only one of the two components of Ik (Ikr) but not the other (Iks). Iks is activated by isoproterenol. An unopposed activation of Iks might account for the loss of anti-fibrillatory effect by d-sotalol in conditions of high sympathetic activity. METHODS: In nine anesthetized dogs we tested at constant heart rate (160 to 220 beats/min) the influences of left stellate ganglion stimulation on the monophasic action potential prolongation induced by d-sotalol. In two groups of isolated guinea pig ventricular myocytes we tested the effect of isoproterenol (10(-9) mol/liter) on the action potential duration at five pacing rates (from 0.5 to 2.5 Hz) in the absence (n = 6) and in the presence (n = 8) of d-sotalol. RESULTS: In control conditions, both in vivo and in vitro, adrenergic stimulation did not significantly change action potential duration. d-Sotalol prolonged both monophasic action potential duration in dogs and action potential duration of guinea pig ventricular myocytes by 19% to 24%. Adrenergic activation, either left stellate ganglion stimulation in vivo or isoproterenol in vitro, reduced by 40% to 60% the prolongation of action potential duration produced by d-sotalol. CONCLUSIONS: Sympathetic activation counteracts the effects of potassium channel blockers on the duration of repolarization and may impair their primary antifibrillatory mechanism. An intriguing clinical implication is that potassium channel blockers may not offer effective protection from malignant ischemic arrhythmias that occur in a setting of elevated sympathetic activity.
Asunto(s)
Sistema de Conducción Cardíaco/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Sotalol/farmacología , Sistema Nervioso Simpático/fisiología , Fibrilación Ventricular/prevención & control , Potenciales de Acción/efectos de los fármacos , Animales , Estimulación Cardíaca Artificial , Células Cultivadas , Perros , Estimulación Eléctrica , Cobayas , Sistema de Conducción Cardíaco/fisiopatología , Técnicas In Vitro , Isoproterenol/farmacología , Miocardio/citología , Canales de Potasio/fisiología , Ganglio Estrellado/fisiología , Fibrilación Ventricular/fisiopatologíaRESUMEN
The goal of radiofrequency catheter ablation and the criterion for efficacy is the elimination of arrhythmogenic myocardium. The application of radiofrequency current in the heart clearly results in lower morbidity and mortality rates than thoracic and cardiac surgical procedures in general, and comparisons of therapy with radiofrequency catheter ablation and therapy with thoracic and cardiac surgical procedures in randomized clinical trials is unwarranted. Trials of radiofrequency catheter ablation versus medical or implantable cardioverter-defibrillator therapy may be indicated in certain conditions, such as ventricular tachycardia associated with coronary artery disease. Randomized trials are recommended for new and radical departures in technology that aim to accomplish the same goals as radiofrequency catheter ablation. Surveillance using registries and/or databases is necessary in the assessment of long-term safety and efficacy.
Asunto(s)
Arritmias Cardíacas/prevención & control , Ablación por Catéter/instrumentación , Desfibriladores Implantables , Marcapaso Artificial , American Heart Association , Estimulación Cardíaca Artificial , Ensayos Clínicos como Asunto , Aprobación de Recursos , Europa (Continente) , Humanos , Selección de Paciente , Vigilancia de Productos Comercializados , Proyectos de Investigación , Sociedades Médicas , Estados UnidosRESUMEN
High-resolution electrocardiography utilizes computer processing to record low-levels signals not normally observed on standard electrocardiographs. Cardiac late potentials occur at the end of or after the QRS complex and require these methods to be quantified. A brief overview of the methods used to record late potentials is presented. These include lead placement, computer-implemented signal averaging, high-pass filtering, and feature extraction for characterizing the late potential. The major application of late- potential analysis has been in patients after myocardial infarction. Several of these studies are reviewed that demonstrate the usefulness of this new approach in identifying those patients at greatest risk for developing ventricular tachycardia. The most impressive studies have been those that compare late potentials with measures of ventricular performance and ventricular ectopy.
Asunto(s)
Electrocardiografía , Procesamiento de Imagen Asistido por Computador , Potenciales de Acción , Arritmias Cardíacas/fisiopatología , Corazón/fisiopatología , HumanosRESUMEN
His bundle pacing was achieved in 10 anaesthetized open chest dogs by stimulation from bipolar electrode catheters positioned in the aortic root and right heart. Recordings were taken directly through plunge wires from the right atrium, high ventricular septum, and epicardial sites on the right and left ventricles. Six types of response were seen during A-V junctional stimulation: (1) low atrial pacing; (2) combined atrial and His bundle pacing; (3) His bundle pacing; (4) combined atrial, ventricular septal, and His bundle pacing; (5) combined septal and His bundle pacing; and (6) ventricular pacing. Pacing of the His bundle in combination with the atrium and/or ventricular septum is designated as non-selective, whereas stimulation of the His bundle alone is considered selective pacing. Non-selective His bundle pacing can be recognized from the surface leads by changes in onset and amplitude of the QRS with appreciable T-wave alterations. Although electrode position was an important determinant of the type of pacing achieved, a variety of patterns of stimulation resulted from variation in the modalities of the pacing stimulus, ie, polarity, intensity, and duration. Unless these factors are considered, selective His bundle pacing may not be achieved.
Asunto(s)
Fascículo Atrioventricular/fisiología , Sistema de Conducción Cardíaco/fisiología , Animales , Función Atrial , Perros , Estimulación Eléctrica/instrumentación , Electrodos , Tabiques Cardíacos/fisiología , Función VentricularRESUMEN
OBJECTIVES: This study aims at clarifying the role of cellular Ca2+ overload and spontaneous sarcoplasmic reticulum (SR) Ca2+ release in the generation of early afterdepolarizations (EAD) by isoproterenol. The involvement of a Ca(2+)-activated membrane current in isoproterenol-induced EAD is investigated. METHODS: Membrane potential and contraction (an indicator of SR Ca2+ release) were recorded in canine left ventricular myocytes at pacing cycle lengths (CL) of 300-4000 ms. Threshold concentration for EAD was 20-50 mmol/l isoproterenol. Ni2+ (2.0-5.0 mmol/l) was used at normal and high (5.4 mmol/l) [Ca2+]o to examine the role of Ca2+ current and/or Na(+)-Ca2+ exchange (1Na-Ca) in EAD. RESULTS: In all cells delayed afterdepolarizations (DAD) appeared during isoproterenol. In most (approximately equal to 70%) cells EAD were also generated, which were fast-pacing dependent, occurring only at CL of 400-1000 ms. EAD were always initiated by a delay in repolarization. Early aftercontractions preceded the EAD upstrokes, often occurring without them. They coincided with the initial delays in repolarization. During treatment with isoproterenol, Ni2+ and high [Ca2+]o, EAD and DAD were suppressed despite the continued presence of early and delayed aftercontractions. CONCLUSIONS: Our data indicate that beta-adrenergic EAD share a common ionic mechanism with DAD in terms of cellular Ca2+ overload and spontaneous SR Ca2+ release. beta-Adrenergic EAD consist of two phases: (1) a conditional phase coinciding with the onset of an early aftercontraction, often followed by (2) an EAD upstroke. A Ca2(+)-activated membrane current, probably I Na-Ca, is necessary at least for the initiation of these EAD.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Corazón/efectos de los fármacos , Isoproterenol/farmacología , Contracción Miocárdica/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Antiarrítmicos/farmacología , Calcio/metabolismo , Cationes , Células Cultivadas , Perros , Corazón/fisiología , Potenciales de la Membrana/efectos de los fármacos , Níquel/farmacología , Propanolaminas/farmacología , Retículo Sarcoplasmático/efectos de los fármacos , Retículo Sarcoplasmático/metabolismo , Factores de TiempoRESUMEN
The antiarrhythmic efficacy, safety, and tolerance of atenolol was evaluated in 32 patients with an average of at least 60 ventricular ectopic depolarizations/hr. Patients received, single-blind, the following treatments for 2 weeks each: placebo and atenolol, 50, 100, and 200 mg daily. A 24-hour ambulatory ECG recording was obtained each week. Reduction in ventricular ectopic frequency by at least 75% occurred in six of 32 patients receiving 50 mg daily, five of 30 patients receiving 100 mg daily, and three of 21 patients receiving 200 mg daily (P = not significant for any paired dose comparison). No patient who failed to respond to a lower dose responded to 200 mg daily. The frequency of ventricular tachycardia was reduced by at least 75% in eight of 17 patients receiving 50 mg daily, seven of 16 patients receiving 100 mg daily, and eight of 11 receiving 200 mg daily (P = not significant for any paired dose comparison). Atenolol was discontinued because of adverse effects in 12 patients. The results indicate that atenolol is more effective in suppressing ventricular tachycardia than in suppressing overall ventricular ectopy.
Asunto(s)
Arritmias Cardíacas/tratamiento farmacológico , Atenolol/uso terapéutico , Adulto , Anciano , Atención Ambulatoria , Atenolol/efectos adversos , Ritmo Circadiano , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Taquicardia/tratamiento farmacológicoRESUMEN
Coronary artery aneurysms were found in 16 men between 37 and 62 years of age, mean 51 years. Aneurysms were of two types: saccular and fusiform. They involved the right coronary artery in 13 (87 per cent), the circumflex artery in eight (50 per cent) and the left anterior descending artery in five (31 per cent). In some patients, more than one vessel was involved. Twelve patients presented with angina pectoris, three with congestive heart failure and one with both. Five were in functional class II, eight were in class III and three were in class IV at the beginning of the study. The electrocardiogram showed evidence of previous myocardial infarction in four patients; four patients had left ventricular hypertrophy, one had left axis deviation, one had left bundle branch block, one had right bundle branch block, two had first degree atrioventricular block and seven had abnormalities in the S-T segment and T wave. Obstructive coronary disease was present in all; the obstruction score was from 1 to 4 in three patients, from 5 to 9 in four patients and from 10 to 14 in the remaining nine. Similar aneurysms were found in the pulmonary artery of one patient and in the abdominal aorta of three patients; in seven of 14 patients with adequate venous angiograms, varicosities of the coronary venous tree were observed. Left ventricular dysfunction and angina pectoris were noted in patients with significant obstructive coronary disease (greater than 70 per cent) and also in patients without obstruction but with coronary aneurysms. Ten patients were treated surgically; nine underwent aortocoronary bypass and one mitral valve replacement. Criteria for bypass was the presence of obstructive disease and medically unresponsive angina pectoris. All but one surgically treated patient showed improvement. The functional class in medically treated patients was unchanged. Fourteen patients were still alive at the completion of the study. The findings of this study suggest that angina pectoris and left ventricular dysfunction can occur with coronary artery aneurysm without coronary artery obstructions. Coronary aneurysms may be a subset of atherosclerosis, and this process may involve other vascular territories. The prognosis in those patients appears to be no worse than in patients with obstructive coronary disease and no aneurysms.
Asunto(s)
Aneurisma/diagnóstico , Enfermedad Coronaria/diagnóstico , Contracción Miocárdica , Adulto , Aneurisma/etiología , Aneurisma/cirugía , Angina de Pecho/diagnóstico , Angiografía Coronaria , Puente de Arteria Coronaria , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/etiología , Electrocardiografía , Insuficiencia Cardíaca/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
The conditions associated with prolapse of the posterior leaflet of the mitral valve are multiple. The mechanisms of mitral valve prolapse as well as the pathogenesis of pain and ectopic impulse formation are reviewed. Propranolol appears to be the drug of choice for the symptomatic treatment of patients with this syndrome since it decreases myocardial oxygen demand and wall tension thus reducing or abolishing the discrepancy between myocardial oxygen demand and supply within the mitral apparatus. It has also been reported to modify the auscultatory findings associated with this condition. The frequency of this mitral valve abnormality in patients with obstructive coronary artery disease is reviewed. It appears that prolapse of the posterior leaflet scallops in patients with significant obstructive coronary artery disease represents an intermediate stage before mitral insufficiency occurs. This group of patients with papillary muscle dysfunction includes those with prolapsed leaflets without mitral insufficiency, those with systolic murmurs and compensated heart failure and others with progressive cardiac decompensation and severe mitral regurgitation.
Asunto(s)
Auscultación Cardíaca , Soplos Cardíacos , Enfermedades de las Válvulas Cardíacas/fisiopatología , Válvula Mitral , Animales , Arritmias Cardíacas/complicaciones , Arritmias Cardíacas/fisiopatología , Presión Sanguínea , Cardiomiopatías/complicaciones , Circulación Coronaria , Enfermedad Coronaria/complicaciones , Perros , Endocarditis Bacteriana/complicaciones , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/patología , Humanos , Válvula Mitral/patología , Válvula Mitral/fisiopatología , Contracción Miocárdica , Dolor/etiología , Músculos Papilares/fisiopatología , Propranolol/uso terapéutico , Infecciones Estreptocócicas/complicacionesRESUMEN
The synthesis of the title ketone has been completed via a type of Mannich reaction starting from 4- thianone . An X-ray diffraction analysis has revealed that the solid system is a chair-boat conformer with the sulfur atom in the boat portion of the bicyclic ring compound. Wolff- Kishner reduction of the ketone group gave 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane, which was isolated as the hydroperchlorate . However, X-ray diffraction analysis of the salt showed this solid to be a chair-chair conformer. Addition of phenylmagnesium bromide to the ketone gave a tertiary alcohol with the C-C6H5 bond being equatorial with respect to the thiane ring and axial with respect to the piperidine ring. The reaction of the Grignard reagent with the ketone to give this alcohol seems to be very stereospecific. An X-ray analysis of the hydroperchlorate of the alcohol confirmed the system to be a chair-chair form in the solid. The title compounds were screened for antiarrhythmic activity in anesthetized mongrel dogs in which myocardial infarctions had been created when the left anterior descending coronary artery was ligated. Vagal-induced slowing of the sinus mode firing rate was used to determine the underlying ventricular automaticity in the dogs, which averaged 164 +/- 27 beats/min. Ventricular pacing was initiated to rates between 240 and 390/min. This technique resulted in the induction of rapid and sustained ventricular tachycardia. At doses of 3 and 6 mg/kg of body weight, 7-benzyl-3-thia-7-azabicyclo [3.3.1]nonane hydroperchlorate in alcohol (the solution was administered intravenously) was able to suppress markedly the induced ventricular tachycardia in five of six dogs. The compound also caused a 10-15% increase in blood pressure within a few minutes. The antiarrhythmic properties of this compound and others of related structure are discussed, and some comparison is made with the action of lidocaine in similar dog preparations.
Asunto(s)
Antiarrítmicos/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes , Compuestos Bicíclicos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/síntesis química , Animales , Compuestos Bicíclicos con Puentes/farmacología , Cristalización , Perros , Frecuencia Cardíaca/efectos de los fármacos , Lidocaína/farmacología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estereoisomerismo , Difracción de Rayos XRESUMEN
Several 3,7-diheterabicyclo[3.3.1]nonanes (DHBCNs) were prepared and screened in the Harris dog model for their ability to abolish pace-induced and sustained ventricular tachycardia (SVT) or prevent induction of ventricular tachycardia. In addition, an electrophysiological examination was made in the infarcted hearts of each animal to determine if more than one class activity was present. The examples exhibited predominately class III antiarrhythmic activity via a prolongation of the ventricular effective refractory period (VERP) in the models, although there may well be an underlying class Ib action present as exemplified by the ability of several of the agents to slow conduction in the myocardial infarcted dog hearts. 3-[4-(1H-Imidazol-1-yl)benzoyl]-7-isopropyl-3,7-diazabicyclo[3.3.1]nonan e dihydroperchlorate displayed powerful class III activity in the model systems while several other DHBCNs exhibited various degrees of class III action. An X-ray diffraction analysis revealed that this compound has a 3,7-diazabicyclo[3.3.1]nonane bicyclic unit in a chair-chair conformation.
Asunto(s)
Antiarrítmicos/química , Antiarrítmicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Imidazoles/química , Imidazoles/farmacología , Taquicardia Ventricular/tratamiento farmacológico , Animales , Antiarrítmicos/síntesis química , Presión Sanguínea/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Cristalografía por Rayos X , Perros , Electrofisiología , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/síntesis química , Lidocaína/farmacología , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Infarto del Miocardio/complicaciones , Taquicardia Ventricular/prevención & controlRESUMEN
The standard method for measuring myocardial blood flow (MBF) with radioactive microspheres requires processing of selected tissue samples usually from the excised heart, and consequent loss of exact relation to myocardial morphology. A computer-based image processing method was developed by using [99mTc]microspheres (mean particle size 20 microns) for quantitative analysis of MBF in 25 dogs. A computer-controlled gamma camera was used to obtain the images of radioactive microsphere distribution in transaxial slices of the ex vivo heart. Any portion of these slice images could be quantitated by using a computer program based on modification of the formula for determining MBF by the standard microsphere method. Regional myocardial perfusion calculated by this technique correlated well with values obtained with reference microspheres (r = 0.96) over a broad range of MBF. The results show that our new method, accurately and with high resolution, delineated zones of differing MBF and confirmed the increase of MBF in surviving myocardium with healing.
Asunto(s)
Circulación Coronaria , Corazón/diagnóstico por imagen , Animales , Perros , Técnicas In Vitro , Métodos , Microesferas , Infarto del Miocardio/diagnóstico por imagen , Cintigrafía , TecnecioRESUMEN
In recent years, the results of large randomized and controlled trials of antiarrhythmic agents for primary and secondary prevention of ventricular tachycardia and ventricular fibrillation have changed perceptions of the actions of antiarrhythmic agents regarding both efficacy and risk. The premature termination of the CAST trials of primary prevention in postinfarct patients highlighted the proarrhythmic risk and inefficacy of the sodium channel blockers (class I action), encainide, flecainide, and moricizine, in patients at relatively low risk for death in the long term. The excess mortality with therapy was attributed to proarrhythmia due to facilitation of reentry, especially during acute ischemia. About the same time, European trials with amiodarone, a complex agent with antiadrenergic action and powerful action to prolong refractoriness (class III action), indicated enhanced survival after infarction with amiodarone but not with agents with class I action. Recent verbal reports of larger and placebo-controlled trials (EMIAT and CAM-IAT) confirm a significant reduction in arrhythmia mortality, possibly with a favorable trend in total mortality. While an older trial with dl-sotalol (class III and beta-blocking actions) showed a trend toward improved survival after infarction, a recent trial with d-sotalol in patients with recent infarction or remote infarction and heart failure was prematurely terminated because of excess mortality attributed to proarrhythmia (torsades de pointes), indicating the importance of beta-blocking properties of a class III agent. A secondary prevention trial (ESVEM) in patients surviving an episode of VT or VF showed significant superiority of dl-sotalol compared to an array of agents that block sodium channels with respect to both efficacy and tolerance. Occurrence rates of arrhythmias treated with drugs tested for efficacy either by suppression of inducible arrhythmias or by suppression of spontaneous ectopy were higher and equivalent for both testing methods. A secondary prevention trial of amiodarone and multiple agents that block sodium channels in survivors of cardiac arrest (CASCADE) showed a significant increased efficacy of amiodarone but poorer long-term tolerance compared with the other agents. Comparative analysis of the results of the various trials suggests that class III action coupled with antiadrenergic action is more efficacious in both primary and secondary prevention of life-threatening ventricular arrhythmias and that lethal proarrhythmias may be the predominant effect in attempts at primary prevention in low-risk populations due to class I or so-called pure class III action.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Antagonistas Adrenérgicos beta/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Amiodarona/uso terapéutico , Arritmias Cardíacas/fisiopatología , Sistema de Conducción Cardíaco/efectos de los fármacos , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Infarto del Miocardio/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Sotalol/efectos adversos , Sotalol/uso terapéutico , Taquicardia Ventricular/prevención & control , Fibrilación Ventricular/prevención & controlRESUMEN
Substantial gains have been made toward clarifying the mechanisms of arrhythmia in ischemia in animal models. After coronary occlusion in the dog, ischemic myocardial cells have reduced resting potential and slowed and diminished upstrokes of action potentials due to depression of fast channels. As a result, conduction is slow and irregular, especially at shorter cycle lengths, because refractoriness is altered by a delay in recovery of the fast channels beyond the completion of repolarization. These abnormalities occur during the acute phase of arrhythmia in the first half hour after occlusion and persist in surviving the subepicardial layers of myocardial cells for days to weeks. Reentry has been mapped in these surviving layers. Reentrant circuits form around regions of functional block formed by interfaces between responding and refractory myocardium. Standard antiarrhythmic agents generally are fast-channel blockers that further depress conduction and prolong refractoriness in ischemic tissue, causing block in slow conducting segments of the reentry circuits. However, antiarrhythmic agents may cause or accentuate reentrant arrhythmias by virtue of the same depressant actions. The greater likelihood of antiarrhythmic agents suppressing rather than producing reentrant arrhythmias may be due to enhanced depressant effects of antiarrhythmic agents on very slowly conducting tissues that are involved in reentry circuits. After the acute phase, arrhythmias occurring 1 to 4 days after coronary occlusion are probably largely automatic, although the potential for reentry remains if the cycle length is shortened. Abnormally enhanced automaticity and triggered activity are demonstrable in the surviving Purkinje network in regions of infarction, but the role of these phenomena in vivo has not been clarified.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Arritmias Cardíacas/fisiopatología , Enfermedad Coronaria/fisiopatología , Electrocardiografía , Potenciales de Acción , Animales , Antiarrítmicos/farmacología , Vasos Coronarios/fisiopatología , Modelos Animales de Enfermedad , Perros , Electrofisiología , Sistema de Conducción Cardíaco/fisiopatología , Miocardio/patologíaRESUMEN
In recent years an enhanced interest among researchers combined with the availability of new technologies has increased our knowledge of the mechanisms that generate arrhythmias in patients with ischemic heart disease. Convincing evidence has been obtained to support the occurrence of reentry in ischemic myocardium. This has been especially apparent in canine studies in the surviving layers overlying infarctions several days after coronary occlusion. In this planar model, the reentry circuit forms a figure-8 configuration around an arc of functional block due to refractoriness; the center of the arc is the site of unidirectional block and reentry. The reentry circuit is sustained by wavefronts of activation encircling segments in which the tissue on either side is alternately receptive and refractory, a variant of the leading circle model of reentry. The relatively prolonged refractoriness in ischemic tissue is due to time-dependent refractoriness, i.e., postrepolarization refractoriness, which is most prominent in more severely depolarized cells. Slow conduction is related in part to primary depression of the fast channels. There is a great variation in refractory periods in ischemic tissue because of variation in action potential duration and in the duration of time-dependent refractoriness. The depolarized resting potentials of cells in acute ischemia are due in part to extracellular accumulation of potassium and intracellular accumulation of calcium. In the latter stages of ischemia it is likely that abnormalities of ion distribution across the sarcolemma play a role. It has also been demonstrated that ischemic Purkinje fibers show abnormal automaticity, i.e., enhanced phase 4 depolarization at depolarized diastolic potentials, and afterdepolarizations with triggered firing.(ABSTRACT TRUNCATED AT 250 WORDS)