Differential profile and biochemical effects of antiautonomic membrane receptor antibodies in ventricular arrhythmias and sinus node dysfunction.

BACKGROUND: The relationship between anti-beta-adrenergic (anti-betaR) and anti-M(2)-cholinergic (anti-M2R) receptor antibodies (Abs) and cardiac arrhythmias and their biochemical effects have not been systematically investigated. METHODS AND RESULTS: We studied 41 patients, 28 with ventricular arrhythmias (primary or due to Chagas' heart disease or idiopathic dilated cardiomyopathy; group I), 13 with sinus node dysfunction (primary or caused by Chagas' heart disease; group II), and 10 healthy controls (group III). The chronotropic effects of the IgG and immunopurified anti-beta(1)RAbs or anti-M2RAbs were assessed on cultured cardiomyocytes before and after exposure to atropine and propranolol. The biochemical effects of the IgG from 9 patients from group I, 6 from group II, and 6 controls were evaluated on COS7 cells transfected with genes encoding for beta(1),beta(2)-adrenergic receptors (cAMP increment) or M(2)-cholinergic receptors (phosphatidylinositol increment). The IgG from group I patients exerted a positive chronotropic action, with a high prevalence of anti-betaRAbs (75%) and low prevalence of anti-M2RAbs (10.7%) and induced a clear-cut and long-lasting increment in cAMP. The IgG from group II patients depressed chronotropism, with a high prevalence of anti-M2RAbs (76.9%) and low prevalence of anti-betaRAbs (15.4%) and evoked a marked augmentation of phosphatidylinositol. CONCLUSIONS: Our results demonstrate a strong correlation between anti-betaRAbs and ventricular arrhythmias and anti-M2RAbs and sinus node dysfunction. Anti-betaRAbs increase and anti-M2RAbs inhibit cAMP production. These findings offer new insight into the etiology and pathophysiology of cardiac arrhythmias, with therapeutic implications.

Efficacy of amiodarone for the termination of chronic atrial fibrillation and maintenance of normal sinus rhythm: a prospective, multicenter, randomized, controlled, double blind trial.

OBJECTIVE: We sought to assess the efficacy and safety of amiodarone for restoration and maintenance of sinus rhythm in patients with chronic atrial fibrillation in a prospective, randomized, double blind trial. BACKGROUND: Restoration and preservation of sinus rhythm is difficult in patients with chronic atrial fibrillation. The efficacy of oral amiodarone has not been conclusively established. METHODS: Ninety-five patients with chronic atrial fibrillation, lasting an average of 35.6 months, were randomized to either amiodarone (600 mg/d) (47 patients) or placebo (48 patients) during four weeks. Nonresponders underwent electric cardioversion, and those who reverted continued with amiodarone (200 mg/d) or placebo. End-points were successful cardioversion and sinus rhythm maintenance. RESULTS: Sixteen patients (34.04%) in the amiodarone group reverted within 27.28 +/- 8.85 days in comparison with 0% in the placebo group (P < 0.000009). The conversion rate rose to 51.72% in patients with chronic atrial fibrillation lasting less than 12 months. Twenty-eight patients in the amiodarone group and 39 in the placebo group underwent electric cardioversion, which was successful in 19 patients (67.8%) of the amiodarone group and in 15 (38.46%) of the placebo group (P = 0.017). Altogether, conversion was obtained in 79.54% of the amiodarone group patients and in 38.46% of the placebo group patients (P < 0.0001). During follow-up, atrial fibrillation relapsed in 13 (37.14%) of 35 patients of the amiodarone group within 8.84 +/- 8.57 months and in 12 (80%; P = 0.009) of 15 patients of the placebo group within 2.74 +/- 3.41 months. CONCLUSIONS: Oral amiodarone restored sinus rhythm in one third of patients with chronic atrial fibrillation, increased the success rate of electric cardioversion, decreased the number of relapses and delayed their occurrence.

Lidocaine-sensitive atrial tachycardia: lidocaine-sensitive, rate-related, repetitive atrial tachycardia: a new arrhythmogenic syndrome.

OBJECTIVES: The goal of this study was to report a variety of atrial tachycardia that might be caused by an unusual electrophysiologic substrate. BACKGROUND: The mechanism of atrial tachycardias is attributed to re-entry, abnormal automaticity or triggered activity, based on their electropharmacological responses. A rate-related and lidocaine-sensitive atrial tachycardia has not been reported. METHODS: Eight patients (3 women and 5 men, aged 14 to 60 years) with repetitive, uniform atrial tachycardias were studied. In six patients the arrhythmia had been refractory to at least three antiarrhythmic agents (class 1A and C sodium channel blockers, amiodarone, beta-adrenergic blocking agents, verapamil, digoxin). Conventional electrocardiograms, Holter recordings and B mode echocardiograms were performed in each patient. Intravenous lidocaine and verapamil were tested in the eight patients. Six patients underwent an electrophysiologic study. RESULTS: The baseline electrocardiogram showed nearly incessant runs of atrial tachycardia in all patients. The mean atrial ectopic cycle length ranged from 376 to 502 ms. In seven patients a progressive prolongation of the cycle length from the beginning to the end of the salvos was documented. The arrhythmia was suppressed by increments of sinus node rate and by atrial pacing at cycle lengths longer than that of the atrial tachycardia. In all patients the arrhythmia was abolished by intravenous lidocaine, whereas intravenous verapamil was ineffective. Four symptomatic patients were successfully treated with radiofrequency ablation of the ectopic focus, and two patients were treated with oral mexiletine. CONCLUSIONS: The peculiar electropharmacological responses of this arrhythmia suggest an uncommon underlying mechanism that remains to be elucidated.

High prevalence of antibodies against beta 1- and beta 2-adrenoceptors in patients with primary electrical cardiac abnormalities.

OBJECTIVES: This study sought to determine the prevalence of autoantibodies directed against the beta-adrenoceptors in patients with primary electrical cardiac abnormalities, including atrial arrhythmias, ventricular arrhythmias and conduction disturbances, in the absence of any other cardiac abnormality. BACKGROUND: Using synthetic peptides corresponding to the predicted sequences for the second extracellular loop of the human beta 1- and beta 2-adrenoceptors as antigenic targets, autoantibodies directed against the beta-adrenoceptors were recently shown to occur in patients with idiopathic dilated cardiomyopathy and Chagas' heart disease. METHODS: Eighty-six patients (57 with primary electrical abnormalities, 29 with idiopathic dilated cardiomyopathy) and 101 healthy and cardiopathic control subjects were studied. Antibodies against the beta 1- and beta 2-peptides were detected with an enzyme immunoassay performed in blinded manner. In nine selected (seropositive) cases, the immunoglobulin G (IgG) fraction was tested for functional effects on the rate of beating of cultured neonatal rat cardiomyocytes. RESULTS: Antibodies recognizing the beta 1- and beta 2-peptides were found in 11 (52.3%) of 21 patients with ventricular arrhythmias (p < 0.01), 5 (35.7%) of 14 patients with conduction disturbances (p < 0.05), 3 (13.6%) of 22 patients with atrial arrhythmias (p > 0.05) and 11 (37.9%) of 29 patients with dilated cardiomyopathy (p < 0.05) compared with 15 (14.8%) of 101 control subjects. A rapid increase in the rate of beating of the cultured cardiomyocytes was induced by IgG from a selected group of patients, suggesting an agonist-like interaction with a functional epitope. This response was mediated by stimulation of both the beta 1- and beta 2-adrenoceptors in the patients with primary ventricular arrhythmias but only the beta 1-adrenoceptors in the patients with idiopathic dilated cardiomyopathy. CONCLUSIONS: Primary ventricular arrhythmias and conduction disturbances, like idiopathic cardiomyopathy, show a high prevalence of antibodies interacting with functional epitopes of the beta-adrenoceptors, suggesting a common or similar abnormal immunoregulatory process.

Antibodies to beta-adrenergic receptors disclosing agonist-like properties in idiopathic dilated cardiomyopathy and Chagas' heart disease.

Recent studies confirm the existence of antibodies (Abs) to beta-adrenoceptors in patients with idiopathic dilated cardiomyopathy and Chagas' heart disease. These Abs can be shown to exert both stimulatory and inhibitory effects, which may play a role in the development of the cardiac abnormalities known to occur in these diseases, including advanced heart failure. The hypothesis is advanced that Chagas' heart disease and some forms of idiopathic dilated cardiomyopathy may represent, at least partially, a form of "adrenergic cardiomyopathy."

Overdrive prolongation of refractoriness and fatigue in the early stages of human bundle branch disease.

OBJECTIVES: The aim of this study was to assess the response of refractoriness in normal and diseased human bundle branches to changes in cycle length, as well as during a long period of continuous overdrive pacing. BACKGROUND: The anterograde refractory period of the bundle branches in patients with functional bundle branch block shortens as the rate is increased. The rate-dependent response of refractoriness in diseased bundle branches is quite different. However, this difference has not been precisely delineated, and its physiologic meaning is uncertain. METHODS: Refractoriness of the bundle branches was measured by the extrastimulus technique in 16 patients with tachycardia-dependent bundle branch block and 10 patients with functional bundle branch block, both after basic trains of 8 atrial-paced impulses at different cycle lengths and during a 10-min period of continuous overdrive pacing. RESULTS: The baseline refractory period in the bundle branches of patients with functional bundle branch block measured 430 +/- 32 ms (mean +/- SD) and shortened to 368 +/- 30 ms at the shortest cycle length. The maximal effect was reached within the 1st min of overdrive pacing. The baseline refractory period of the bundle branches was significantly longer in patients with tachycardia-dependent bundle branch block (611 +/- 184 ms) and demonstrated a cumulative overdrive prolongation in 15 (83%) of 18 studies with typical manifestations of fatigue. In two other studies, this occurred only after ajmaline administration. CONCLUSIONS: A rate- and time-dependent prolongation of refractoriness frequently occurs in diseased human bundle branches. When absent, this response may be induced under the effects of sodium channel blockers. This would suggest that an abnormality in the recovery from inactivation of the sodium channel might underlie the early stages of bundle branch disease.

Cardiac arrhythmias in Chagas' heart disease.

Chagas' disease is a chronic parasitosis affecting most Latin American countries. Its most important clinical manifestation is a late developing chronic myocarditis and, much less frequently, an early acute myocarditis. Chagasic myocardial damage is microfocal and disseminated throughout the heart. In most cases, the coexistence of areas of myocytic degeneration, inflammatory infiltration, and fibrosis suggests a permanent evolving process. Commonly, chronic chagasic myocarditis resembles a dilated cardiomyopathy, with characteristic ECG abnormalities (atrial and ventricular extrasystoles, intraventricular and/or AV conduction disturbances, and primary ST-T wave changes). Since myocardial damage is scattered throughout the heart, the ECG abnormalities (arrhythmias, conduction disturbances, and repolarization changes) are also representative of the widespread cardiac involvement. Thus, sick sinus syndrome, atrial extrasystoles, intraatrial conduction disturbances, and atrial fibrillation or flutter are common findings in different stages of the disease. At the ventricular level, both conduction disturbances and arrhythmias are conspicuous expressions of the myocardial damage. Right bundle branch block alone or in combination with left anterior hemiblock are the most common conduction defects. Further compromise of the conduction system can lead to different degrees of AV block. Chagas' disease is the main cause of bundle branch block and AV block in endemic areas. In advanced cases of Chagas' heart disease, ventricular premature contractions are extremely frequent, multiform, and repetitive (couplets and runs of ventricular tachycardia), and show R on T phenomenon. These arrhythmias are usually aggravated by increased sympathetic tone, implying an enhanced risk of cardiac sudden death among chagasic patients, which is sometimes the first manifestation of the illness. Chronic chagasic myocarditis is the leading cause of cardiovascular death, mostly as a consequence of heart failure and sudden death, in areas where the disease is endemic.

Contrasting effects of verapamil and procainamide on rate-dependent bundle branch block: pharmacologic evidence for the role of depressed sodium channel responses.

The mechanisms responsible for intermittent bundle branch block are still under debate. The role of the time-dependent behavior of the slow calcium channel has recently been emphasized. To test this hypothesis and ascertain the possible involvement of the fast sodium channel, the effects of the slow calcium channel blocker verapamil and the fast sodium channel blocker procainamide were compared in 10 patients with intermittent bundle branch block. All 10 patients showed bundle branch block during spontaneous sinus rhythm. Maneuvers to slow cardiac rate (that is, carotid sinus massage, Valsalva maneuver) were performed to identify normal conduction as well as phase 4 bundle branch block. Thus, the ranges of diastolic intervals (RR) resulting in phase 3 (tachycardia-dependent) bundle branch block, phase 4 (bradycardia-dependent) bundle branch block and normal conduction were measured in two control studies performed before intravenous administration of verapamil (control 1) and procainamide (control 2) and at the peak effect of both drugs. In the control studies, all 10 patients showed phase 3 bundle branch block, whereas phase 4 bundle branch block occurred in only 4 patients. The ranges of phase 3 bundle branch block, phase 4 bundle branch block and normal conduction were very similar in control studies 1 and 2. The phase 3 bundle branch block range was slightly shortened by verapamil (983 +/- 83.5 ms in control 1; 930 +/- 69.4 ms at the peak effect of verapamil), whereas phase 4 bundle branch block remained unchanged. In contrast, conduction was systematically worsened by procainamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Identification of major Trypanosoma cruzi antigenic determinants in chronic Chagas' heart disease.

To identify Trypanosoma cruzi target antigens in overt Chagas' heart disease, a parasite lambda gt11 cDNA library was screened with the serum of a patient with a severe chagasic heart involvement (JL). Using a phage dot array immunoassay, 5 highly antigenic clones, JL1, JL5, JL7, JL8, and JL9, were probed with sera from clinically characterized T. cruzi infected subjects. The correlation of cloned T. cruzi antigen recognition with the clinical status of the subjects led to the identification of a recombinant antigen, JL5, that reacted predominantly with sera from patients with Chagas' heart disease. The antigenic determinant of the JL5 recombinant was a small 35 amino acid peptide. The nucleotide and the deduced amino acid sequence, together with other experimental data, allowed identification as the C-terminal portion of a T. cruzi P ribosomal protein. The C-terminal undecapeptide in JL5, EDDDMGFGLFD, was highly homologous to the same region of the human P protein SD(D/E)DMGFGLFD. The latter sequence has been identified as the P protein epitope in systemic lupus erythematosus (SLE). Positive SLE sera reacted with the JL5 recombinant phage, suggesting that the T. cruzi P protein might induce antibodies with a similar specificity to that of P antibodies in SLE.

Chronic idiopathic idioventricular tachycardia caused by slow response automaticity.

A 22-year-old female, asymptomatic and without any evidence of cardiac disease, was found to have a persistent idioventricular tachycardia (IVT). Sinus rhythm and IVT rates were similar and showed parallel changes in successive resting electrocardiograms. Both IVT and sinus rhythm were transiently slowed or suppressed by vagal stimulation and accelerated by sympathetic stimulation. Long periods of atrial overdrive pacing, at a rate 62% faster than the spontaneous rate of IVT, depressed both ectopic and sinus activity. Fast channel blocking agents (lidocaine, disopyramide), and digoxin and amiodarone failed to modify IVT significantly. Verapamil, a calcium channel blocking drug, allowed total control of the arrhythmia. These electrophysiologic and pharmacologic responses suggest that the IVT may relate to the automatic activity of a ventricular focus of the "slow response" type, functionally resembling an "additional" sinus node with preserved innervation. During an 88-month follow-up, the patient continued to be asymptomatic, warning arrhythmias were never found and the features of IVT remained unmodified.

Estudio clínico multicéntrico comparativo de la flecainida y la amiodarona en el tratamiento de las arritmias ventriculares asociadas a la cardiopatia chagasica cronica / Flecainide and amiodarone in the treatment of ventricular arrhythmias associated with chagas heart disease

En 81 pacientes con miocarditis crónica chagásica (MCC) y arritmias ventriculares (AV) pertenecientes a 4 centros cardiológicos se evaluó comparativamente la eficacia y seguridad de flecainida (F) y amiodarona (A) utilizando un protocolo abierto, randomizado y paralelo. Fueron incluídos pacientes con un número de extrasístoles ventriculares (EV) no inferior a 1200/24 hs y/o formas repetitivas. Los pacientes fueron tratados durante 60 días con una de las drogas (F: 200 a 400 mg/día; A: 800 a 400 mg/día; dosis ajustada según respuesta) y evaluados clínicamente con exámenes de laboratorio, ECG en reposo y ECG ambulatorios continuos de 24 hs (H) días - 7; - 1; 8/9; 15/16; y 59/60). Los porcentajes de reducción de EV obtenidos a los 9, 16 y 60 días con F fueron 73.1%; 82.9% y 92.4% y con A77.6%; 90.1% y 90.7%. Después de 60 días de tratamiento, la Fredujo las duplas en 92.5% y los episodios de taquicardia ventricular en 96.5% y la A, 95.2% y 92.6%, respectivamente. El tratamiento debió ser interrumpido en 6 pacientes; 3 con F (2 por bradicardia sinusal extrema y 1 por TV iterativa), y 3 con A (1 por TV sostenida y 2 por fotodermatosis severa). Aunque existieron algunas diferencias llamativas en los resultados de los distintos centros, El análisis estadísticos en conjunto sugiere una similar eficacia de F y A en el tratamiento de las AV de la MCC

[Comparative multicenter clinical study of flecainide and amiodarone in the treatment of ventricular arrhythmias associated with chronic Chagas cardiopathy]. / Estudio clínico multicéntrico comparativeo de la flecainida y la amiodarona en el tratamiento de las arritmias ventriculares asociadas a la cardiopatía chagásica cronica.

Eighty one patients with ventricular arrhythmias associated with chronic Chagas disease participated in this multi-clinic study. Treatment with Amiodarone and Flecainide were compared using an open, parallel, randomized experimental design. Inclusion criteria required the selected patients to have 1,200 premature ventricular contractions per 24 hours and/or repetitive ventricular arrhythmias. Patients received 60 days of treatment with either Flecainide at 200 to 400 mg per day or Amiodarone 800 to 400 mg per day. This dosage was adjusted to the therapeutic response. Clinical and laboratory evaluations, electrocardiogram and 24 hour Holters were performed at study days: -7, -1, 8/9, 15/16 and 59/60. The percentage reduction of premature ventricular contractions at days 9, 16 and 60 were: 73.1%, 82.9% and 92.4% with Flecainide and 77.6%, 90.1% and 90.7% with Amiodarone. At the end of the study, Flecainide had induced a 92.5% reduction in couplets and 96.5% reduction in ventricular tachycardia. For the same parameters the percentages following Amiodarone were 95.2% and 92.6% respectively. Treatment was discontinued in three patients in the Flecainide group (two because of prolonged sinus node bradycardia and one because of sustained ventricular tachycardia). In the Amiodarone group, treatment was discontinued also in three patients (one because of sustained ventricular tachycardia and two because of severe photosensitive dermatosis). Although there were some differences in the results form center to center, the conclusions from the overall data indicate a similar, therapeutic effect with both drugs.

Supernormal conduction in the accessory pathway of patients with overt or concealed ventricular pre-excitation.

It was recently shown that supernormal conduction in the diseased His-Purkinje system is more common than previously thought, and is always associated with prolongation of refractoriness. To assess whether supernormal conduction could also occur in the accessory pathway of patients with ventricular pre-excitation, 21 patients with manifestly prolonged refractoriness in the accessory pathway were studied. Under these conditions, programmed atrial stimulation revealed a phase of supernormal conduction in 16 (76%) of the 21. Therefore, what was believed to be a nonexistent or exceptional physiologic event was shown to be a rather common finding, at least under certain circumstances. Supernormal conduction occurred in all 7 patients with an anterograde refractory period of 480 to 980 ms, and in 5 of 10 patients with a refractory period greater than 1.0 second or with no anterograde conduction. Supernormal conduction could not be demonstrated in four patients with a refractory period less than or equal to 440 ms, but appeared in all four patients after the refractory period was prolonged by a rapid rate of stimulation or administration of ajmaline. The electrophysiologic changes underlying the occurrence of supernormal conduction in the accessory pathway are similar to those previously reported for the bundle branch system. The demonstration of supernormal conduction in the accessory pathway may uncover the presence of concealed ventricular pre-excitation. Supernormal conduction over the accessory pathway may facilitate a rapid ventricular response during atrial fibrillation, even if the refractory period is prolonged.

Comparative antiarrhythmic efficacy of verapamil, 17-monochloracetylajmaline, mexiletine and amiodarone in patients with severe chagasic myocarditis: relation with the underlying arrhythmogenic mechanisms.

The antiarrhythmic effects of verapamil, 17-monochloracetylajmaline, mexiletine and amiodarone were compared in 14 patients with chagasic myocarditis. Drugs and placebo were administered orally in the following order: placebo and verapamil, placebo and 17-monochloracetylajmaline, placebo and mexiletine (1 week each) and placebo and amiodarone (4 weeks each). A 24 hour ambulatory electrocardiographic recording was obtained after administration of each placebo and drug. Verapamil had no effect on the number of ventricular premature complexes, ventricular couplets and runs of ventricular tachycardia. 17-Monochloracetylajmaline did not reduce the number of ventricular premature complexes and ventricular couplets but caused a moderate reduction in runs of ventricular tachycardia. Mexiletine failed to significantly reduce ventricular premature complexes but caused a moderate decrease in both ventricular couplets and runs of ventricular tachycardia. Amiodarone was the only one of the four drugs that caused a substantial reduction of ventricular premature complexes (logarithmic mean 97.8%; p less than 0.001), total suppression of runs of ventricular tachycardia in 11 of 11 patients and suppression of ventricular couplets in 8 of 14 patients and a significant reduction in the remaining 6 patients. The much greater efficacy of amiodarone as compared with the two sodium channel modifiers (17-monochloracetylajmaline and mexiletine) and one calcium channel blocker (verapamil) suggests that its potent antiarrhythmic activity is probably related to other peculiar and still undefined electrophysiologic and pharmacologic properties.

Efficacy of amiodarone during long-term treatment of malignant ventricular arrhythmias in patients with chronic chagasic myocarditis.

Oral amiodarone was administered to 24 patients with chronic chagasic myocarditis (CCM) and malignant ventricular arrhythmias. Control 24-hour Holter recordings revealed frequent ventricular premature beats (VPBs) (157 to 2572/hr; mean 714 +/- 125), multiform VPBs, and countless numbers of ventricular couplets in all patients, R-on-T phenomenon in 17 patients, and ventricular tachycardia in 21 patients. Amiodarone caused total and persistent suppression of ventricular couplets and tachycardia and greater than 93% reduction of VPB number in 22 patients, during a follow-up of 26.6 months (range 2 to 55 months). In 1 patient, ventricular couplets and tachycardia persisted despite the fact that a 98.2% reduction of VPB number was achieved. This latter patient was the only one in the whole group who experienced sudden death. The maximal antiarrhythmic effect was attained gradually after 3 to 26 weeks (mean 7.4). In four patients in whom treatment was discontinued after 3 to 12 months, the antiarrhythmic protection lasted 4 to 9 weeks. In nine patients the dose of amiodarone was 600 to 800 mg/day. In 15 patients the dose had to be increased to 800 to 1000 mg/day. Despite the presence of congestive heart failure in seven patients and intraventricular block in 17 patients, no limiting side effects were observed. Amiodarone proved to be extremely effective and safe against the most malignant ventricular arrhythmias of CCM.