Arrhythmogenic right ventricular dysplasia/cardiomyopathy: need for an international registry. Study Group on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation.

Arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) is a heart muscle disease characterized by peculiar RV involvement and electrical instability that precipitates ventricular arrhythmias and sudden death. The purpose of the present consensus report of the Study Group on ARVD/C of the Working Groups on Myocardial and Pericardial Disease and Arrhythmias of the European Society of Cardiology and of the Scientific Council on Cardiomyopathies of the World Heart Federation is to review the considerable progress in our understanding of the etiopathogenesis, morbid anatomy, and clinical presentation of ARVD/C since it first was described in 1977. The present article focuses on important but still unanswered issues, mostly regarding risk stratification, clinical outcome, and management of affected patients. Because ARVD/C is relatively uncommon and any one center may have experience with only a few patients, an international registry is being established to accumulate information and enhance the numbers of patients that can be analyzed and thus answer pending questions. The registry also will facilitate pathological, molecular, and genetics research on the causes and pathogenesis of the ARVD/C. Furthermore, availability of an international database will enhance awareness of this largely unrecognized condition among the medical community. Physicians are encouraged to enroll patients in the International Registry of ARVD/C.

Pharmacokinetic interactions between digoxin and other drugs.

Drug interactions with digoxin are important because of this agent's narrow therapeutic index. Among the drugs that can decrease digoxin bioavailability are cholestyramine, antacid gels, kaolin-pectate, certain antimicrobial drugs and cancer chemotherapeutic agents. In selected patients, antibiotics may enhance digoxin bioavailability by eliminating intestinal flora that metabolize digoxin. Antiarrhythmic drugs, such as quinidine and amiodarone, can markedly increase steady state serum digoxin levels. Certain calcium channel blocking drugs, particularly verapamil, have a similar effect. Potassium-sparing diuretic drugs, such as spironolactone, can alter digoxin pharmacokinetics. Indomethacin may decrease renal excretion of digoxin in preterm infants. Finally, rifampin, an antibiotic used in the treatment of tuberculosis, may lower steady state serum digoxin levels in patients with severe renal disease. Physicians must maintain constant vigilance whenever medications are added to or withdrawn from a therapeutic regimen that includes digoxin.

Radiofrequency catheter ablation of common atrial flutter in 80 patients.

OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of radiofrequency catheter ablation of common atrial flutter and to determine the optimal target sites in a large series of patients. BACKGROUND: Recent studies report the efficacy of radiofrequency current application in the low right atrial region to interrupt and prevent recurrences of common atrial flutter. However, larger groups of patients are required to confirm the efficacy of this technique and to specify the target sites. METHODS: Two different approaches were used to target the ablation site in 80 consecutive patients. In the first 50 patients, target sites were localized using both anatomic landmarks and electrophysiologic variables. Three anatomic landmarks were used: area 1 = between the tricuspid valve and inferior vena cava orifice; area 2 = between the tricuspid valve and coronary sinus ostium; area 3 = between the inferior vena cava and coronary sinus. The electrophysiologic criterion was to ablate when there was a stable atrial electrogram during the plateau phase. In the next 30 patients we assessed the effect of application of radiofrequency energy in a single line in area 1, 2 or 3 in groups of 10 patients. RESULTS: Overall atrial flutter was interrupted and rendered noninducible after a single session in 72 patients (90%) and could not be interrupted in 8 (10%). The mean (+/- SD) number of radiofrequency applications was 12 +/- 8. After a mean (+/- SD) follow-up of 20 +/- 8 months, recurrences occurred in 14 patients (17%). The location of the final successful site in the first group of 50 patients was in area 1 in 39%, area 2 in 36% and area 3 in 25%. In the next 30 patients, when lines of radiofrequency lesions were placed at several sites, they produced success rates of 70%, 40% and 10% at areas 1, 2 and 3, respectively. CONCLUSIONS: Radiofrequency catheter ablation of atrial flutter can be performed with a high success rate and is safe. The highest success rate is achieved with radiofrequency energy applied in the isthmus between the inferior vena cava orifice and tricuspid valve.

Closed chest catheter desiccation of the atrioventricular junction using radiofrequency energy--a new method of catheter ablation.

Closed chest catheter ablation of the atrioventricular (AV) junction has been performed with direct current or laser energy. The effect of 750 kHz radiofrequency energy on ablation of the AV junction was evaluated in 13 dogs. The radiofrequency energy was generated from an electrosurgical generator in the bipolar mode. The radiofrequency output was delivered between two distal electrodes (bipolar ablation) in eight dogs, and between the distal electrode and an external patch electrode (unipolar ablation) in another five dogs at varying power (watts) but with a constant pulse duration of 10 seconds. Complete AV block was achieved in 11 dogs and second degree AV block in 2. During the 4 to 7 day follow-up period, complete AV block persisted in 9 of the 11 dogs with initial complete heart block. The other two had return of AV conduction; one had persistent 2:1 AV block and the other had persistent first degree AV block. Of the two dogs with initial second degree AV block, one developed complete AV block, the other had resumption of 1:1 AV conduction with a normal PR interval. Energy was delivered in 1 to 13 applications per dog. One hundred to 700 J per application was delivered with bipolar ablation and 10 to 100 J with unipolar ablation. There was no damage to the catheter unless the catheter was repeatedly used in excess of 1,500 J of total energy. Ventricular arrhythmias were not observed. Pathologic examination showed well delineated coagulation necrosis at the AV junction without surrounding hemorrhage or mural thrombus. Microscopic findings consisted of necrosis with cell infiltration in the periphery of necrosis. Most injuries involved the AV node, the approaches to the AV node and the penetrating bundle. In conclusion, catheter ablation of the AV junction with radiofrequency energy is safe. It can effectively induce discrete areas of necrosis and produce various degrees of AV block. In addition, ablation by radiofrequency energy has distinct advantages as compared with catheter ablation with direct current or laser energy.

Physician utilization of laboratory procedures to monitor outpatients with congestive heart failure.

Little is known about how different types of physicians use laboratory procedures in the management of outpatients with congestive heart failure. We therefore analyzed data from a national survey of randomly selected general practitioners, internists, and cardiologists to assess their management of outpatients with New York Heart Association class II congestive heart failure. Most of the 2704 respondents (90%) scheduled office visits between two and four months apart. Body weight, serum electrolytes, and chest roentgenograms were followed regularly by 98% or more of respondents, at median intervals of one to two months, three to five months, and 12 to 17 months, respectively. Serum digoxin levels in patients taking digoxin were followed by 90% of respondents at a median interval of 12 months. Echocardiography, radionuclide ventriculography, and exercise testing were used by fewer respondents (81%, 61%, and 61%, respectively), each at a median interval of 18 months or longer. Cardiologists were significantly more likely to follow patients using either echocardiography, radionuclide ventriculography, or exercise testing. The estimated yearly cost of following a class II congestive heart failure outpatient varied nearly fourfold from the lowest quartile of physicians ($303) to the highest ($1167). Cardiologists were disproportionately represented among the high-cost users. In addition, physicians who were younger or who practiced in an urban setting were significantly more likely to be high-cost users. Thus, simple laboratory tests were used most frequently to follow patients with heart failure, but differences in use of more expensive tests led to large differences in cost. Test use for similar patients is affected by characteristics of both the physician and practice setting.

Kinetic evaluation of the propranolol-quinidine combination.

The kinetics of quinidine and propranolol, administered singly and in combination, were evaluated in 5 healthy subjects. The orally administered doses resulted in plasma concentrations within the therapeutic range. For each drug the average steady-state plasma concentration, maximal plasma concentration, and time of maximum plasma concentration were not altered by the presence of the other drugs. This study shows no kinetic interaction between quinidine and propranolol in normal subjects.

Digoxin bioavailability: formulations and rates of infusions.

The bioavailability of digoxin (lanoxin) tablets, oral aqueous solution of digoxin, and capsules containing a solution of digoxin was compared with digoxin given intravenously over 1 and 3 hr. The mean peak serum concentration of digoxin after the 1-hr intravenous infusion was 5 ng/ml, after the 3-hr infusion, 3.5 ng/ml, and after the oral solution, 2.0 ng/ml. There was an equivalent bioavailability of the oral solution and reference tablets of digoxin. The digoxin in capsules tended to be better absorbed than the reference tablets. There was 21% more digoxin excreted over 6 days after the 3 hr iv infusion than after the 1 hr iv infusion. This indicates that the calculated bioavailability of an orally administered dose of digoxin may vary with the rapidity of injection of the intravenous standard. It is estimated that an oral tablet of digoxin of 0.5 mg has about the same bioavailability as 0.35 of digoxin given by slow intravenous infusion (or 0.4 mg if calculated against a rapid intravenous injection).

Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers.

To determine the mechanism of the amiodarone-phenytoin interaction, seven healthy male subjects were given intravenous phenytoin, 5 mg/kg, before (phase I) and after (phase II) 3 weeks of oral amiodarone, 200 mg/day. Serum AUC increased from 245 +/- 37.6 to 342 +/- 87.3 mg.hr/L (p = 0.007); area under the first moment curve increased from 5666 +/- 1003 to 11,632 +/- 4198 mg.hr2/L (p = 0.008); the time-averaged total body clearance decreased from 1.57 +/- 0.3 to 1.17 +/- 0.33 L/hr (p = 0.0004); and the apparent elimination half-life increased from 16.1 +/- 1.32 to 22.6 +/- 3.8 hours (p = 0.001) for phenytoin during phase II. The volume of distribution at steady state and the unbound fraction for phenytoin remained unchanged. However, the formation of p-hydroxyphenytoin as a function of serum phenytoin concentration decreased during phase II. These findings suggest that amiodarone inhibits phenytoin metabolism. These observations also suggest that phenytoin doses will need to be reduced when coadministered with amiodarone. The magnitude of this reduction is difficult to predict because of the saturable pharmacokinetics of phenytoin, and therapeutic monitoring is recommended if amiodarone is added to the phenytoin regimen.

Effect of intravenous metoprolol on reversible obstructive airways disease.

We gave increasing doses of metoprolol intravenously to seven subjects with stable chronic obstructive pulmonary disease (COPD) who were also receiving their usual bronchodilators. Six of the seven tolerated up to 0.2mg/kg metoprolol without adverse effects, although there were declines in forced expiratory volume in 1 sec (FEV1). At 0.15 mg/kg mean FEV1 fell 12% (p less than 0.025), and at 0.2 mg/kg mean decline in FEV1 was 15% (p less than 0.01). These findings suggest that 0.2 mg/kg metoprolol may be given intravenously to most patients with COPD in addition to previously administered bronchodilators without precipitating clinically significant adverse effects. Any side effects that develop can be reversed by beta agonists.

Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in normal subjects.

The kinetics of digitoxin and two of its metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six normal subjects. Mean t 1/2s and total body clearances were 134.4, 15.4, and 0.59 hr and 2.66, 27.3, and 1071 ml/min. Mean renal clearance of the monodigitoxoside was more rapid (7.24 ml/min) than those of digitoxin (0.81 ml/min) or the bisdigitoxoside (0.94 ml/min). The volumes of distribution were of the same order, 0.45 l/kg for digitoxin, 0.57 l/kg for the bisdigitoxoside, and 0.83 l/kg for the monodigitoxoside. The short t 1/2 of monodigitoxoside would make it unsuitable for clinical use, but the bisdigitoxoside of digitoxigenin has a t 1/2 of an intermediate length and may have significant therapeutic advantages.

Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in renal insufficiency.

The kinetics of digitoxin and two of its major metabolites, the bis- and monodigitoxosides of digitoxigenin, were determined in six subjects with renal insufficiency and compared to those in six age- and sex-matched normal control subjects. No significant differences between the two groups were found in elimination t 1/2, total body clearance, or volume of distribution. Average renal clearances of all three drugs were reduced in subjects with renal failure, but the differences were significant only in the case of digitoxin. The bis-digitoxoside of digitoxigenin has kinetic properties that offer clinical advantages.

Atenolol for ventricular ectopy: a dose-response study.

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.

Digitalis pharmacokinetics and metabolism.

The pharmacokinetics of the cardiac glycofides have been elucidated as a result of the development of assays of sufficient sensitivity to measure the concentration of digitalis compounds in biological fluids. Digoxin can accumulate in the body without the administration of a loading dose, and a steady state blood concentration will be reached in 5 to 7 days. Digitoxin requires 35 days to accumulate to a plateau. If a loading dose of digoxin is used, it should be approximately three times the estimated daily maintenance dose. Factors that determine the selection of the appropriate maintenance dose of digoxin include renal function and lean body mass. Digitoxin is less dependent on renal function for its elimination than is digoxin. Knowledge of the pharmacokinetics of digitalis preparations is useful in determining how to change from one cardiac glycoside to another, each with different half-lives. One should wait 3 days before starting digoxin therapy when changing from maintenance digitoxin to digoxin (assuming normal renal function). The pharmacokinetics of changing from ouabain to digoxin without loss of digitalis effect are described. The metabolism of the commonly used digitalis preparations are summarized.

Clinical characteristics and results of noninvasive tests in 60 diabetic patients after acute myocardial infarction.

Diabetic patients who survive myocardial infarction have more similarities than differences when compared with nondiabetic patients. Silent myocardial infarctions were not more common in the diabetic population. The higher percentage of women among diabetic patients with infarction has been well recognized. Of the primary risk factors, hypertension was more common in diabetic patients. Clearly, a history of ischemic heart disease was more common in diabetic patients. The course in the coronary care unit was similar for both the diabetic and nondiabetic patient groups. Likewise, there were no striking differences in left ventricular ejection fractions or results of 24-hour Holter monitoring between the groups. The fact that a higher percentage of diabetic patients were excluded from taking the limited activity treadmill test, primarily because of angina after infarction, may account for the observation that the percent of patients with an ischemic response to exercise and the percent with exercise-induced ventricular ectopy did not differ between diabetic and nondiabetic groups.

Clinical correlations in patients with acute myocardial infarction and left ventricular thrombus detected by two-dimensional echocardiography.

Eleven of forty-nine patients with acute myocardial infarction had left ventricular thrombus identified by two-dimensional echocardiography. The patients with thrombi had a greater incidence of transmural infarction, high-grade ventricular ectopy on ambulatory monitoring and lower radionuclide ejection fractions than the patients without thrombi. Most of the patients were receiving full-dose heparin and/or warfarin anticoagulation from the time of admission to the hospital. Thus the thrombi either developed prior to hospital admission or developed during anticoagulation therapy. Two patients with thrombi had peripheral emboli complicating their infarction. One of these patients was undergoing anticoagulation at the time of his embolus.

Prognosis of patients with diabetes mellitus after acute myocardial infarction.

Sixty patients with diabetes mellitus who survived the coronary care unit phase of acute myocardial infarction (AMI) were followed an average of 19 months and the prognosis of diabetic patients was compared with that of 719 nondiabetic patients. The mortality rate was 25% in diabetic patients and 8% in nondiabetic patients. These patients had been entered in a Multicenter Postinfarction Program, where analysis of the total data base showed 4 significant prognostic factors: cardiac symptoms before AMI, pulmonary rales when the patient was in the coronary care unit, more than 10 ventricular premature complexes per hour recorded on Holter monitor just before discharge, and a radionuclide ejection fraction of less than 40%. Of these 4 factors, only cardiac symptoms before AMI was significantly more common in diabetic patients (57% in diabetic vs 36% in nondiabetic patients). When each of these 4 factors was stratified for severity, the mortality rate was always higher in diabetic patients. The data were examined to determine other factors in diabetic patients who died. Pulmonary rales was significantly more common in diabetic patients who died (6% in survivors vs 42% in patients who died). In a multivariate analysis of both diabetic and nondiabetic patients, 5 factors were significant determinants of prognosis. They are, in order of entry into the model, rales (p less than 0.001), ejection fraction less than 40% (p less than 0.001), diabetes (p less than 0.001), symptoms before AMI (p = 0.009), and more than 10 ventricular premature complexes per hour (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Superiority of a vertical sternal lead for detection of arrhythmias during ambulatory electrocardiographic monitoring.

In a preliminary study comparing 7 sets of bipolar leads with standard modified V1 and V5 leads, a vertical sternal lead system with the negative lead just below the suprasternal notch, and the positive lead over the xiphoid had the greatest P-wave area. In the current study, the vertical sternal and modified V1 leads were obtained simultaneously using 2-channel ambulatory electrocardiographic recorders in 50 consecutive patients undergoing diagnostic ambulatory electrocardiography for suspected arrhythmias. The vertical sternal lead provided tracings with a larger P-wave area compared with that of the modified V1 (0.58 +/- 0.44 vs 1.23 +/- 0.69 mm2; p less than 0.0001), and a greater QRS complex (9.23 +/- 4.16 vs 11.78 +/- 4.90 mm; p = 0.006). During premature atrial contractions and supraventricular tachycardia, P-wave visibility was significantly better in the sternal lead than in V1 (p less than 0.001). Furthermore, sternal lead tracings were superior with regard to overall quality and noise level. It is suggested that the vertical sternal lead replace the currently used modified V1 during ambulatory electrocardiographic monitoring. This lead system in conjunction with the standard modified V5 lead should be useful in the differential diagnosis of atrial arrhythmias.

Efficacy, plasma concentrations and adverse effects of a new sustained release procainamide preparation.

To assess the efficacy, plasma drug concentrations and adverse effects of a new sustained release preparation of procainamide, 33 patients with heart disease were studied in an acute dose-ranging protocol and a chronic treatment protocol. Patients initially received a daily dose of 3 g of sustained release procainamide; this dose was increased by 1.5 g daily until ventricular premature depolarizations were suppressed by 75 percent or more, adverse drug effects occurred or a total daily dose of 7.5 g of sustained-release procainamide was reached. Twenty-five patients (76 percent) had at least a 75 percent reduction (range 75 to 100percent [mean +/- standard deviation 91 +/- 8.2]) in ventricular permature depolarization frequency at a dosage of 4.8 +/- 1.46 g/day (range 3.0 to 7.5). Despite the 8 hour dosing interval, the variation between maximal and minimal plasma procainamide and N-acetylprocainamide concentrations under steady state conditions was very small. Mean maximal procainamide and N-acetylprocainamide plasma concentrations were 10.4 +/- 6.02 and 12.0 +/- 7.40 micrograms/ml, respectively. The respective mean minimal concentrations were 6.8 +/- 4.50 and 8.7 +/- 5.99 micrograms/ml. In nine patients (27 percent) treatment with sustained release procainamide resulted in conversion of the antinuclear antibody test from negative to positive. Adverse drug effects occurred in 17 (52 percent) of the subjects. In general, adverse effects were minor and abated within 24 hours after administration of the drug was stopped. One patient had the procainamide-induced systemic lupus erythematosus-like syndrome.

Steady-state interaction between amiodarone and phenytoin in normal subjects.

Amiodarone has been reported to increase phenytoin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction at steady-state. Pharmacokinetic parameters for phenytoin were determined after 14 days of oral phenytoin, 2 to 4 mg/kg/day, before and after oral amiodarone, 200 mg daily for 6 weeks in 7 healthy male subjects. During amiodarone therapy, area under the serum concentration time curve for phenytoin was increased from 208 +/- 82.8 (mean +/- standard deviation) to 292 +/- 108 mg.hr/liter (p = 0.015). Both the maximum and 24-hour phenytoin concentrations were increased from 10.75 +/- 3.75 and 6.67 +/- 3.51 micrograms/ml to 14.26 +/- 3.97 (p = 0.016) and 10.27 +/- 4.67 micrograms/ml (p = 0.012), respectively, during concomitant amiodarone treatment. Amiodarone caused a decrease in the oral clearance of phenytoin from 1.29 +/- 0.30 to 0.93 +/- 0.25 liters/hr (p = 0.002). These results were due to a reduction in phenytoin metabolism by amiodarone as evidenced by a decrease in the urinary excretion of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, 149 +/- 39.7 to 99.3 +/- 40.0 mg (p = 0.041) and no change in the unbound fraction of the total phenytoin concentration expressed as a percentage, 10.3 +/- 2.7 versus 10.7 +/- 2.1% (p = 0.28) during coadministration of amiodarone. The alterations in phenytoin pharmacokinetics suggest that steady-state doses of phenytoin of 2 to 4 mg/kg/day should be reduced at least 25% when amiodarone is concurrently administered. All dosage reductions should be guided by clinical and therapeutic drug monitoring.

Effects of non-right-handedness on risk for sudden death associated with coronary artery disease.

The hypothesis that non-right-handedness is associated with sudden cardiac death was tested based on evidence that sympathetic imbalance may contribute to ventricular arrhythmogenesis and evidence that left-handers may have a shorter lifespan than right-handers. The study included 26 patients with coronary artery disease (CAD), a history of ventricular tachycardia-ventricular fibrillation (VT-VF), and implanted defibrillators, and 26 patients with CAD and no history of serious arrhythmias who were matched for age, sex, and New York Heart Association functional class. Patients with any history of neurologic disorders were excluded. Left-handers either wrote with the left hand or were converted from left- to right-handedness in childhood. Non-right-handers used the left hand for writing, drawing, or throwing. Handedness rates in patients with VT-VF and case-control subjects were compared with published norms in the general population to take expected rates into account. The rates of left-handedness (6 of 26 or 23.1%) and non-right-handedness (9 of 26 or 34.6%) in patients with VT-VF were significantly higher (p < 0.003 and p < 0.0001, 2-tailed, respectively) than those of similarly aged adults in the general population (left-handedness, 5%; non-right-handedness, 10.2%). The rates of left-handedness (2 of 26 or 7.7%) and non-right-handedness (4 of 26 or 15.4%) observed in the case-control group correspond closely to the expected values for that group (left-handedness, 1.3 of 26 or 5%; non-right-handedness, 2.65 of 26 or 10.2%) derived from the general population rates and were not significantly different from them.(ABSTRACT TRUNCATED AT 250 WORDS)