Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators.

BACKGROUND: Evidence suggests that physiologic pacing (dual-chamber or atrial) may be superior to single-chamber (ventricular) pacing because it is associated with lower risks of atrial fibrillation, stroke, and death. These benefits have not been evaluated in a large, randomized, controlled trial. METHODS: At 32 Canadian centers, patients without chronic atrial fibrillation who were scheduled for a first implantation of a pacemaker to treat symptomatic bradycardia were eligible for enrollment. We randomly assigned patients to receive either a ventricular pacemaker or a physiologic pacemaker and followed them for an average of three years. The primary outcome was stroke or death due to cardiovascular causes. Secondary outcomes were death from any cause, atrial fibrillation, and hospitalization for heart failure. RESULTS: A total of 1474 patients were randomly assigned to receive a ventricular pacemaker and 1094 to receive a physiologic pacemaker. The annual rate of stroke or death due to cardiovascular causes was 5.5 percent with ventricular pacing, as compared with 4.9 percent with physiologic pacing (reduction in relative risk, 9.4 percent; 95 percent confidence interval, -10.5 to 25.7 percent [the negative value indicates an increase in risk]; P=0.33). The annual rate of atrial fibrillation was significantly lower among the patients in the physiologic-pacing group (5.3 percent) than among those in the ventricular-pacing group (6.6 percent), for a reduction in relative risk of 18.0 percent (95 percent confidence interval, 0.3 to 32.6 percent; P=0.05). The effect on the rate of atrial fibrillation was not apparent until two years after implantation. The observed annual rates of death from all causes and of hospitalization for heart failure were lower among the patients with a physiologic pacemaker than among those with a ventricular pacemaker, but not significantly so (annual rates of death, 6.6 percent with ventricular pacing and 6.3 percent with physiologic pacing; annual rates of hospitalization for heart failure, 3.5 percent and 3.1 percent, respectively). There were significantly more perioperative complications with physiologic pacing than with ventricular pacing (9.0 percent vs. 3.8 percent, P<0.001). CONCLUSIONS: Physiologic pacing provides little benefit over ventricular pacing for the prevention of stroke or death due to cardiovascular causes.

Distinctive properties of perindopril among converting enzyme inhibitors in congestive heart failure.

Converting enzyme inhibitors constitute a major advance in the management of patients with congestive heart failure (CHF). Not only do they improve the hemodynamics of these patients, but they also prolong the survival. Certain patients with CHF, however, may not tolerate conventional converting enzyme inhibitors because of hypotension, renal dysfunction or other side effects. Perindopril is a third generation converting enzyme inhibitor that produces profound and prolonged angiotensin-converting enzyme (ACE) inhibition (24 h after a single dose). Despite a more sustained ACE inhibition than captopril and enalapril, perindopril is devoid of the first dose hypotensive effects noted with these other drugs. Furthermore, several studies of perindopril in CHF showed serum creatinine and urea to remain stable, reflecting favourable renal tolerance. This is in contrast to the modest decrease in renal function observed with most other converting enzyme inhibitors.

Holter monitor recording for the detection of myocardial ischemia: validation of a new recorder and chest lead positions.

OBJECTIVE: To validate the Reynolds Tracker II Holter system using newly described lead positions during both upright treadmill exercise and in the recumbent position following exercise. The specific lead positions HL1 and HL2 were chosen to detect anterior and postero-inferior myocardial ischemia, respectively, without interfering with the surgical field in the hypothetical situation of open-heart surgery. Similar lead positions have previously been used to monitor myocardial ischemia during induction of anesthesia, but have never been validated by comparison with 12-lead modified electrocardiogram (ECG) recording. METHODS: To validate the authors' 'chosen' Holter lead positions (HL1 and HL2), both at the fifth intercostal space just lateral to the midclavicular line and on the back, 1.5 cm to the left of the vertebral column, respectively) 49 candidates for routine treadmill exercise testing underwent a simultaneous Holter monitor recording using the described lead positions. DATA ANALYSIS: The Holter ECG recordings were separately analyzed by two physicians unaware of patients' identity. RESULTS: Using the modified 12-lead ECG as the 'gold standard', the sensitivity of Holter for detecting ischemia (defined as 0.1 mV or ST depression lasting at least 60 s) was 77 and 83%, and its specificity was 100 and 92%, respectively, for observers 1 and 2. Most episodes of myocardial ischemia were detected by the modified lead V5 for the 12-lead ECG and by HL1 for the Holter recording. Using the Holter Tracker II system and the chosen lead positions, it was possible to detect successfully most episodes of exercise-induced myocardial ischemia. CONCLUSION: Holter monitoring might be useful in detecting perioperative myocardial ischemia.

Sudden death in congestive heart failure.

Despite significant advances in recent years in the diagnosis and treatment of congestive heart failure, sudden unexpected cardiac death is still considered a major epidemiologic problem among those patients. This article lists some of the predisposing factors to the development of cardiac arrhythmias and sudden death in patients with congestive heart failure. These include electrolyte or autonomic nervous system inbalance, the use of certain anti-arrhythmic drugs, or intermittent myocardial ischemia. This paper shows that an advanced degree of left ventricular dysfunction and the preference frequent or complex ventricular arrhythmias appear to be major predictors of total and sudden mortality among patients with congestive heart failure. A screening of 24 hours ambulatory Holter monitor recording appears to be useful in identifying patients at risk of sudden cardiac death.

[Ventricular arrhythmia in patients with hypertension and left ventricular hypertrophy]. / Arythmies ventriculaires chez l'hypertendu affecté d'hypertrophie ventriculaire gauche.

Left ventricular hypertrophy is a problem in itself in patients with hypertension. Hypertensives with left ventricular hypertrophy have a higher incidence of ventricular arrhythmias and sudden death. This article reviews the epidemiological evidence in favour of this association. Although the mechanism of ventricular arrhythmias in patients with left ventricular hypertrophy in unclear, several hypotheses have been suggested including cellular electrophysiological changes, alterations of the myocardial tissue and silent myocardial ischemia. The management of ventricular arrhythmias in hypertensive patients implies an effort to prevent left ventricular hypertrophy by early and aggressive treatment and a judicious choice of antihypertensive agents capable of reducing left ventricular hypertrophy. It is also important to avoid hypokalemia and other electrolytic disorders. Antiarrhythmic drugs should be reserved for symptomatic patients who do not respond to other preventive measures.

The incidence of myocardial ischemia during anesthesia for coronary artery bypass surgery in patients receiving pancuronium or vecuronium.

This study was performed to compare the incidence of prebypass myocardial ischemia in patients receiving fentanyl and enflurane for anesthesia along with either pancuronium or vecuronium. Ninety-eight patients with normal left ventricular function were randomly allocated to receive either pancuronium 0.15 mg.kg-1 or vecuronium 0.15 mg.kg-1 in a double-blind manner after fentanyl 40 micrograms.kg-1 for induction of anesthesia for elective coronary artery bypass grafting (CABG). Premedication included diazepam 0.15 mg.kg-1 po, morphine 0.10 mg.kg-1, and scopolamine 0.005 mg.kg-1 im. Two lead Holter monitor recordings (leads V6 and V9) from the time of arrival in the operating suite to institution of cardiopulmonary bypass were analyzed for ischemia by a cardiologist blinded to the choice of muscle relaxant. Intraoperatively, heart rates greater than 90 beats.min-1 and systolic blood pressure +/- 20% of ward values were treated with propranolol, enflurane, or phenylephrine. Nitroglycerin was infused for ECG signs of ischemia or pulmonary hypertension. After induction of anesthesia the heart rate and cardiac index were consistently decreased in patients receiving vecuronium and also lower in these patients compared with those receiving pancuronium. Thirty-two per cent of patients receiving pancuronium received propranolol for heart rates greater than 90 beats.min-1 versus 7% of those who received vecuronium (P approximately 0.01). Eight patients developed 13 episodes of ischemia after administration of the muscle relaxant: four who received pancuronium (n = 44; 9%) and four receiving vecuronium (n = 54; 7%). Four episodes occurred at induction or tracheal intubation, two in each group. There were four perioperative myocardial infarctions as determined by ECG and CPK-MB levels, two in each group.(ABSTRACT TRUNCATED AT 250 WORDS)

The incidence of prebypass dysrhythmias in patients undergoing coronary artery surgery.

The incidence of dysrhythmias during the prebypass period of coronary artery surgery has not been accurately reported. Using Holter monitoring of the electrocardiogram, this study was undertaken to determine the incidence of dysrhythmias and ischemia and their relationship to specific events during the prebypass period. The role of preoperative calcium entry blockers (CEB), beta-adrenergic blockers (BB), or both on the incidence of dysrhythmias and ischemia was also studied. One hundred thirty-eight patients were premedicated with morphine, scopolamine, and diazepam. Anesthesia was induced with fentanyl or sufentanil followed by either pancuronium or vecuronium and maintained with sufentanil or enflurane. All 138 patients experienced a dysrhythmia during the prebypass period. Seventy-five percent of the patients had at least one episode of a supraventricular dysrhythmia (SVD), 39% had a sinus bradycardia, and 20% had a conduction abnormality. Ninety-two percent of the patients had premature ventricular contractions (PVC) and, surprisingly, 76% had non-sustained ventricular tachycardia. One patient developed ventricular fibrillation and one had ventricular tachycardia. The peak incidence of dysrhythmias occurred at insertion of the pulmonary artery (PA) catheter and at aortic dissection. The incidence of prebypass ischemia was 18%, but these patients did not have a higher incidence of ventricular dysrhythmias. Preoperative CEBs and BBs did not influence the incidence of ischemia or dysrhythmias with the exception of SVD; there was a significantly lower incidence at PA catheterization in patients taking CEBs preoperatively (P < .05). It can be concluded that dysrhythmias are very common during the prebypass period. The low rate of progression to life-threatening dysrhythmias may be related to the fact that the majority occurred during mechanical stimulation and that patients were chronically taking CEBs and/or BBs preoperatively.

Combination of theophylline and salbutamol for arrhythmias in severe COPD.

We conducted a single-bind placebo controlled study using 24-hour continuous ambulatory electrocardiographic recordings. The arrhythmogenic potential of the combination of salbutamol and theophylline was investigated in 25 ambulatory subjects with severe chronic airflow obstruction (mean age 65 +/- 8 SD, mean FEV1 31 percent +/- 13 SD predicted). Asymptomatic arrhythmias were very prevalent in the study population: 76 percent of the patients had runs of supraventricular tachycardia while 24 percent had runs of ventricular tachycardia. Individual arrhythmia frequency showed greater between-test variability than previously described in non-COPD subjects. The mode of administration of salbutamol may have affected arrhythmia frequency in that subjects using aerosol nebulizers had more ventricular extrasystoles than those using metered dose inhalers. Although the addition of theophylline to salbutamol significantly increased heart rate and supraventricular extrasystoles, there was no statistically significant increase in ventricular arrhythmias.

Hemodynamic variables and the incidence of prebypass ischemia during sufentanil/O2/pancuronium anesthesia in patients undergoing coronary artery surgery.

It has been suggested that sufentanil is a superior anesthetic to fentanyl for patients undergoing myocardial revascularization. This study was performed to determine the incidence of prebypass myocardial ischemia using sufentanil, 20 micrograms/kg for patients undergoing coronary artery bypass grafting (CABG). Twenty-seven patients with normal left ventricular function, scheduled for elective CABG, were studied. Anesthesia was induced with sufentanil, 10 micrograms/kg; and pancuronium, 0.1 mg/kg, was given for muscle relaxation. Further increments of sufentanil, 5 micrograms/kg, were given before skin incision and sternotomy. All patients had ECG leads V6 and V9 recorded continuously with a Holter monitor from arrival in the operating room until the start of bypass. Hemodynamic profiles were recorded at specific intervals in the prebypass period. Seven patients (25.9%) developed prebypass myocardial ischemia, three at intubation, and three at aortic dissection. Fourteen patients developed hypertension and 14 had hypotension, defined as increases or decreases greater than 20% from baseline values, respectively. Only five patients had neither hypotension nor hypertension. Three patients (11.1%) had perioperative myocardial infarctions, two of whom had prebypass myocardial ischemia. It is concluded that the incidence of prebypass ischemia with sufentanil anesthesia approximates 26%, which is similar to other studies using sensitive ECG monitoring techniques for the detection of ST segment changes. Hemodynamic instability, in the form of bradycardia, hypertension and hypotension, but not tachycardia, may have contributed to the incidence of prebypass ischemia.

Acute intravenous and long-term oral hemodynamic effects of encainide.

The short- and long-term hemodynamic effects of encainide, a new class IC antiarrhythmic agent, were studied in 25 patients (mean age 61 +/- 11) with complex symptomatic ventricular arrhythmia and left ventricular dysfunction. Ninety-two percent had previous myocardial infarction and 8% had dilated cardiomyopathy. Seventy-five percent had congestive heart failure, class III or IV, according to the New York Heart Association. All patients underwent a nuclear ventriculogram performed at least 3 days after discontinuing previous antiarrhythmic drugs. Nuclear ventriculograms were repeated 1 to 6 weeks later while the patients were receiving therapeutic doses of encainide ranging from 75 to 300 [corrected] mg/day. Nuclear ventriculograms were also repeated after 6 months or 1 year of encainide therapy in 16 of these patients. Encainide did not have significant effects on heart rate, blood pressure, left ventricular ejection fraction, systolic or end-diastolic volumes. None of the patients showed a worsening of congestive heart failure during encainide therapy. These results compare favorably with those of other class I antiarrhythmic agents. A review of published reports on the hemodynamic effects of intravenous encainide shows it to have a mild but statistically significant dose-related depressant effect on cardiac function. This effect, however, appears to be no different from that of other newer class I agents.

Drug interaction studies and encainide use in renal and hepatic impairment.

The effect of encainide administration on steady-state plasma digoxin levels was evaluated in 17 patients receiving stable doses of digoxin. A paired t test, comparing plasma digoxin levels (mean +/- standard error) before encainide therapy (1.05 +/- 0.14 ng/ml) and after 2 weeks of encainide, 100 mg/day (1.03 +/- 0.11 ng/ml) or 200 mg/day (1.2 +/- 0.2 ng/ml), indicates no significant (p greater than 0.05) change in digoxin levels. These results were confirmed in a second study of 10 patients with severe congestive heart failure. Also, no difference in efficacy of either drug was observed and changes in dosing of digoxin were not required. Plasma concentrations of encainide and its 2 major metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide, significantly increased by 31.6%, 43.1% and 35.6% after concomitant cimetidine administration in 13 healthy adult men receiving 75 mg/day of encainide. However, a retrospective evaluation of 33 patients receiving both drugs did not reveal any clinically significant interactions. Retrospective evaluation of patients enrolled in clinical studies who received concomitant digoxin (268), antiarrhythmics (118), anticoagulants (78), antidiabetics (40), antipsychotics (23), beta blockers (88), calcium-channel blockers (24) or diuretics (229) did not reveal any clinically significant interactions with encainide. Similarly, in vitro protein binding studies did not reveal any clinically significant interactions with encainide or its major metabolites. Six patients with moderate to severe renal impairment (creatinine clearance 10 to 38 ml/min) received 25 mg of encainide, 3 times/day, for 7 doses. Plasma encainide, ODE and 3-methoxy-O-demethyl concentrations were similar to those observed in normal subjects who had received twice the dose of encainide, and steady-state apparent oral clearance of encainide was reduced by 66% with renal impairment. Based on these data it is recommended that in patients with moderate to severe renal impairment encainide be initiated at one-third the normal dose, or 25 mg once a day. Doses may be elevated in small increments at 1-week intervals if needed for efficacy. The effect of hepatic impairment on the pharmacokinetics of encainide was studied in 7 patients with clinically documented cirrhosis. Compared with normal subjects studied using a similar protocol, the plasma concentrations of encainide were elevated significantly due to a 6-fold decrease in oral clearance. However, since plasma concentrations of the active metabolite ODE were correspondingly lower, specific encainide dosing instructions for patients with hepatic impairment are not indicated.

Usefulness and safety of cimetidine in patients receiving mexiletine for ventricular arrhythmia.

Cimetidine, a commonly used H2 receptor antagonist, was found to adversely interact with many drugs metabolized by the liver, including class I antiarrhythmic agents, lidocaine and quinidine. Mexiletine is a new class I antiarrhythmic agent similar to lidocaine which when used orally may have significant gastric side effects. Since some patients with peptic ulcer disease or gastric hyperacidity on mexiletine may benefit from the addition of cimetidine, it was important to rule out any significant adverse interaction between the two drugs in such patients. Eleven patients currently receiving long-term oral mexiletine for the treatment of complex ventricular arrhythmia underwent a double-blind crossover trial where they were maintained on their usual dose of mexiletine, and cimetidine, 300 mg orally every 6 hours, or placebo were added for a 1-week period each. Peak and trough mexiletine blood levels were not significantly altered by cimetidine. Similarly, there was no significant change in the frequency and severity of ventricular arrhythmia when cimetidine was added to mexiletine. Cimetidine reduced gastric side effects of mexiletine in 50% of patients who had complained of such symptoms on mexiletine alone or on mexiletine and placebo. We conclude that cimetidine can effectively reduce gastric side effects of mexiletine in many patients without adversely affecting the plasma concentration or the efficacy of the drug.

Hemodynamic effects of encainide in patients with ventricular arrhythmia and poor ventricular function.

Gated cardiac scanning was used to evaluate the hemodynamic effects of encainide in 19 patients (1 woman) with complex ventricular arrhythmia and depressed left ventricular (LV) function (ejection fraction less than 45%). Patients were 36 to 80 years old (average 61). All were candidates for long-term encainide therapy after having failed with currently available antiarrhythmics. Sixty-three percent had congestive heart failure before they received encainide. All were evaluated in the hospital before encainide therapy by a gated cardiac scan performed at least 3 days after discontinuing all antiarrhythmic drugs. Patients received oral encainide in doses of 75 to 200 mg. Gated cardiac scans were repeated 1 to 2 weeks later when an 80% reduction in frequency of premature ventricular complexes was observed on a 24-hour Holter recording. No patient had worsening of congestive heart failure during encainide therapy. Encainide did not significantly affect ejection fraction, which averaged 22 +/- 10% before and 25 +/- 14% (SD) after encainide (difference not significant [NS]). Other hemodynamic variables, including heart rate, blood pressure, stroke volume and end-diastolic volume, remained unchanged during encainide therapy. Digoxin blood levels in 10 patients averaged 1.04 +/- 0.43 before and 1.22 +/- 0.47 mg/ml (NS) during encainide therapy. Thus, encainide given orally in clinically effective doses does not appear to have significant hemodynamic effects in patients with ventricular arrhythmia and depressed LV function.