Effect of lidocaine hydrochloride on membrane conductance in mammalian cardiac Purkinje fibers.

Lidocaine depresses automaticity in cardiac Purkinje fibers by decreasing the slope of slow diastolic depolarization, but the mechanisms of this effect are poorly understood. To test the proposal that the antiautomatic effect of lidocaine might be mediated by an increase in membrane potassium conductance, transmembrane voltage (V(m)) was measured in Purkinje fibers perfused with sodium-deficient Tyrode containing choline as the major cation. V(m) was varied by altering the external potassium concentration, [K](o), from 0.5 to 150 mM before and after lidocaine, 2.14 x 10(-5) M, a concentration considered equivalent to clinical plasma antiarrhythmic levels. In Purkinje fibers, resting V(m) varies linearly with [K](o) plotted on a logarithmic scale from 4 to 150 mM, approximately as predicted by the Nernst equation. At [K](o) of 0.5-2.7 mM, resting V(m) diverges from the predicted potassium equilibrium potential (V(K)) resulting in an increased driving force for the outward K(+) current (V(m) - V(K)). In choline Tyrode at [K](o) of 2.7 mM or less, lidocaine caused a significant increase in V(m), the change being a positive linear function of (V(m) - V(K)) with a P < 0.01. This effect was more striking in Purkinje fibers with a V(m) reduced by stretch. These findings imply that lidocaine increased membrane chord conductance for the potassium ion (gK).Current-voltage relationships using intracellular current pulses were performed in choline Tyrode at [K](o) of 0.5, 2.0, and 4.0 mM and, at each [K](o), lidocaine was found to increase membrane slope conductance (GK). The increase in GK was even more apparent when the current-voltage relationships in long Purkinje fibers was corrected for cable complications or when experiments were done in short Purkinje fibers. To minimize complications due to membrane rectifier properties, GK was measured using intracellular application of small hyperpolarizing current pulses as V(m) was decreased from -90 to -60 mv by increasing the [K](o) from 3 to 15 mM before and after lidocaine. Lidocaine increased the GK over this range of V(m). These results suggest that lidocaine increases membrane potassium conductance within the range of V(m) where the pacemaker potential is seen, an action which can account for its ability to suppress automaticity, and, in part, for its ability to prevent reentrant arrhythmias.

Effect of lidocaine on the electrophysiological properties of ventricular muscle and purkinje fibers.

Preparations of right ventricular papillary muscle and false tendon (Purkinje fiber) were obtained from dog hearts, placed in a bath perfused with Tyrode solution, and observed both under control conditions and during exposure to lidocaine in concentrations from 1 x 10(-7) to 5 x 10(-4) mole/liter. Transmembrane voltages were recorded from both ventricular muscle (VM) and Purkinje fibers (PF) of spontaneously beating and electrically driven preparations. Low concentrations (1 x 10(-6) and 1 x 10(-5) mole/liter) attenuated or abolished phase 4 (diastolic) depolarization and spontaneous firing in PF without decreasing their diastolic excitability. Concentrations of 1 x 10(-5) mole/liter produced maximal shortening of both action potential duration (APD) and effective refractory period (ERP) and made the ERP long relative to APD; the latter alteration was more prominent in VM. At concentrations /= 1 x 10(-4) mole/liter) did not cause further shortening of APD or ERP in either VM or PF but did produce a decrease in peak V(max) of phase 0 and membrane responsiveness. In most cases, these concentrations also caused a decrease in RP or DTMV(max) and action potential amplitude, with progression to bizarre action potential depolarization and inexcitability. These properties of lidocaine are strikingly different from those of quinidine or procaine amide. The mechanisms responsible for lidocaine's in vivo antiarrhythmic action are discussed.

The electrophysiologic effects of low and high digoxin concentrations on isolated mammalian cardiac tissue: reversal by digoxin-specific antibody.

The effects of digoxin on electrophysiologic properties were evaluated in isolated perfused cardiac tissue. In canine Purkinje fiber (PF)-ventricular muscle (VM) preparations, control measurements, using microelectrode technique, were made of: resting potential (RP), action potential (AP) amplitude, rate of rise, overshoot, duration (APD), membrane responsiveness, conduction velocity (CV), and refractory period. The preparation was then exposed to 1 x 10(-7) M digoxin and repeat measurements were carried out every 15 min. At slow (30/min) rates of stimulation APD initially prolonged then markedly shortened. With more rapid stimulation (75 and 120/min) no initial APD prolongation was observed. When stimulated at 75/min, RP and AP rate of rise, amplitude, and CV remained near control values for 60-75 min then rapidly decreased until electrical inexcitability (110+/-15 min). At that time fibers were perfused with serum containing digoxin-specific antibody (DSA) or one of a group of test solutions. In the preparations exposed to DSA, membrane characteristics improved by 15 min, and by 60 min approximated control values. No beneficial effect was seen with the various test solutions. DSA also reversed digoxin-induced enhanced phase 4 depolarization in PF. Effective (ERP) and Functional (FRP) refractory periods of rabbit atrioventricular (AV) node preparations were measured in the control state. The tissue was then exposed to 1 x 10(-7) M digoxin and refractory period measurements repeated. At a time when AV conduction prolonged by 20%, associated with marked prolongation of ERP and FRP, DSA or various test solutions were perfused. The prolongation in ERP, FRP, and AV conduction time rapidly returned to normal only in the DSA perfused tissue. It is concluded that DSA has the ability to reverse pronounced toxic electrophysiological effects of digoxin in in vitro cardiac tissue.

The mechanism of supraventricular tachycardia.

In six successive patients, none of whom had the Wolf-Parkinson-White syndrome, recurrent episodes of paroxysmal supraventricular tachycardia (SVT) were analyzed to determine the mechanism by which this arrhythmia is initiated and sustained. In each patient, simultaneous intracavitary atrial electrograms and surface electrocardiograms were recorded during the onset of numerous spontaneous episodes of SVT. Atrial premature depolarizations (APD) produced by programmed stimulation sequences were used to measure atrioventricular refractory periods and to produce atrial echoes and episodes of SVT. Stimulated APDs introduced during sustained episodes of SVT either altered its behavior or terminated it. The electrophysiologic behavior of SVT in these patients strongly suggests that the mechanism responsible for paroxysmal supraventricular tachycardia is atrial reentry utilizing the A-V conducting system.

Cost-effectiveness of catheter ablation in patients with ventricular tachycardia.

BACKGROUND: This study evaluated the cost-effectiveness of catheter ablation therapy versus amiodarone for treating ventricular tachycardia (VT) in patients with structural heart disease. The analysis used a societal perspective for a hypothetical cohort of VT patients with implantable cardioverter-defibrillators, who were experiencing frequent shocks. METHODS AND RESULTS: We calculated incremental cost-effectiveness of ablation relative to amiodarone over 5 years after treatment initiation. Event probabilities were from the Chilli randomized clinical trial (Chilli Cooled Ablation System, Cardiac Pathways Corporation, Sunnyvale, Calif), the literature, and a consensus panel. Costs were from 1998 national Medicare reimbursement schedules. Quality-of-life weights (utilities) were estimated using an established preference measurement technique. In a hypothetical cohort of 10 000 patients, 5-year costs were higher for patients undergoing ablation compared with amiodarone therapy ($21 795 versus $19 075). Ablation also produced a greater increase in quality of life (2.78 versus 2.65 quality-adjusted life-years [QALYs]). This yielded a cost-effectiveness ratio of $20 923 per QALY gained for ablation compared with amiodarone. Results were relatively insensitive to assumptions about ablation success and durability. In less severe patients with good ejection fractions who suffer their first VT episode, the incremental cost-effectiveness ratio was $6028 per QALY gained. These cost-effectiveness ratios are within the range generally thought to warrant technology adoption. CONCLUSIONS: This study demonstrates that, from a societal perspective, catheter ablation appears to be a cost-effective alternative to amiodarone for treating VT patients.

Patients with malignant or potentially malignant ventricular arrhythmias: opportunities and limitations of drug therapy in prevention of sudden death.

Almost 90% of patients resuscitated from out of hospital cardiac arrest have coronary heart disease and can be categorized in one of three groups: acute myocardial infarction, ischemic event or primary arrhythmic event. The patients who have acute myocardial infarction have the best prognosis, and those with primary arrhythmic events have the worst. Recent studies show that ventricular arrhythmias after myocardial infarction are associated with mortality independent of any association with left ventricular dysfunction. Ventricular arrhythmias that have caused cardiac arrest or hemodynamic collapse, that is, malignant arrhythmias, should be treated aggressively and evaluated carefully with one of two methods that have high predictive accuracy for outcome: 1) the Holter recording/exercise test approach, or 2) the electrophysiologic approach. It is not yet known whether treating potentially malignant ventricular arrhythmias after myocardial infarction with class I or III antiarrhythmic drugs will reduce mortality, but two clinical trials are under way in the United States to address this question. Beta-adrenergic blocking drugs do reduce mortality, probably as a result of both antiischemic and antiarrhythmic effects. Calcium channel blocking agents, various antiplatelet drugs and alpha-adrenergic blocking drugs are under investigation to determine their value in secondary prevention of ventricular fibrillation.

Diabetes and outcomes of coronary artery bypass graft surgery in patients with severe left ventricular dysfunction: results from The CABG Patch Trial database. The CABG Patch Trial Investigators and Coordinators.

OBJECTIVES: We examined the relationship between diabetes mellitus and outcomes after coronary artery bypass graft (CABG) surgery in patients with severe left ventricular (LV) dysfunction. BACKGROUND: Although diabetes is associated with poor outcomes after CABG surgery among unselected patients, the relationship between diabetes and mortality after CABG surgery among patients with LV dysfunction is less certain. METHODS: Using data from The CABG Patch Trial, a study of implantable cardiac defibrillator therapy, we analyzed 900 patients with ejection fraction <0.36 who underwent CABG surgery from 1990 to 1996. RESULTS: Diabetics comprised 38% of the patients, and 48% of diabetics were prescribed insulin. Diabetes was associated with hypertension, peripheral vascular disease, history of stroke, clinical heart failure and rales on physical exam. Diabetics were at higher risk for postoperative superficial sternal wound infection and renal failure. With an average follow-up time of 32 +/-16 months, actuarial all-cause mortality 48 months after CABG surgery was 26% in diabetics and 24% in nondiabetics (p = 0.66, log-rank test). Diabetes was not associated with long-term mortality in Cox multiple regression analyses. Actuarial re-hospitalization rates 48 months after CABG surgery were 85% in diabetics and 69% in nondiabetics (p = 0.0001, log-rank test). Diabetics had a 44% higher risk of re-hospitalization for any cause (p = 0.0001) and a 24% higher risk of re-admission for cardiac causes (p < 0.05). Unexpectedly, fewer arrhythmic events were found in diabetics. CONCLUSIONS: Diabetes was not a predictor of mortality after CABG surgery among patients with LV dysfunction despite associated comorbidities. However, diabetes was associated with increased postoperative complications and re-hospitalization.

Effect of long-term digoxin therapy on autonomic function in patients with chronic heart failure.

OBJECTIVES: This study was conducted to determine the effect of long-term digoxin therapy on autonomic function in patients with mild to moderate chronic heart failure. BACKGROUND: Chronic heart failure is characterized by increased sympathetic activity and decreased parasympathetic activity. Intravenous digitalis has been found to reduce sympathetic activity immediately in these patients, but whether short-term neurohormonal effects are sustained during long-term oral therapy has not been assessed. METHODS: We determined sympathetic activity in 26 patients with heart failure by measuring plasma norepinephrine levels and parasympathetic activity from variables of heart period variability derived from 24-h ambulatory electrocardiographic Holter recordings obtained before and after 4 to 8 weeks of digoxin therapy. RESULTS: After digoxin therapy, plasma norepinephrine decreased significantly from a mean +/- SEM of 552 +/- 80 to 390 +/- 37 ng/ml. In addition, the RR interval increased significantly from 719 +/- 19 to 771 +/- 20 ms. High frequency power increased from 84 +/- 24 to 212 +/- 72 ms2, and the root mean square of successive differences in RR interval increased from 20.3 +/- 1.8 to 27.0 +/- 3.4 ms, indicating a substantial increase in parasympathetic activity. Low frequency power, an index of baroreflex activity, was also significantly increased (239 +/- 80 to 483 +/- 144 ms2) by digoxin therapy. CONCLUSIONS: These results indicate 1) that long-term therapy with digoxin acts to ameliorate the autonomic dysfunction of patients with heart failure, and 2) that the short-term neurohormonal effects of digoxin are sustained during prolonged treatment with the drug.

Comparison of 24-hour parasympathetic activity in endurance-trained and untrained young men.

OBJECTIVES: This study compares 24-h parasympathetic activity in aerobically trained and untrained healthy young men. BACKGROUND: Higher values of parasympathetic nervous system activity are associated with a low mortality rate in patients after myocardial infarction, but it remains uncertain what therapeutic interventions can be used to increase parasympathetic activity. Although it is thought that exercise training can increase parasympathetic activity, studies have reported conflicting results, perhaps because this variable was measured for only brief intervals and usually inferred from changes in reflex responses induced by pharmacologic blockade. METHODS: Parasympathetic activity was assessed noninvasively from 24-h ECG recordings by calculating high frequency (0.15 to 0.40 Hz) beat to beat heart period variability in eight endurance-trained men (maximal oxygen consumption greater than or equal to 55 ml/kg per min) and eight age-matched (mean = 29 yr) untrained men (maximal oxygen consumption less than or equal to 40 ml/kg per min). The data were analyzed separately for sleeping hours when parasympathetic activity is dominant and also for waking hours. RESULTS: The geometric mean of high frequency power was greater in the trained than in the untrained men during the day (852 vs. 177 ms2, p less than 0.005), during the night (1,874 vs. 427 ms2, p less than 0.005) and over the entire 24 h (1,165 vs. 276 ms2, p less than 0.001). CONCLUSIONS: Parasympathetic activity is substantially greater in trained than in untrained men, and this effect is present during both waking and sleeping hours. These data suggest that exercise training may increase parasympathetic activity over the entire day and may therefore prove to be a useful adjunct or alternative to drug therapy in lessening the derangements of autonomic balance found in many cardiovascular diseases.

Frequency domain measures of heart period variability to assess risk late after myocardial infarction.

OBJECTIVES: To determine whether spectral measures of heart period (RR) variability predict death when measured late after infarction, we studied patients in the Cardiac Arrhythmia Pilot Study (CAPS) who survived for 1 year and had a 24-h electrocardiographic (ECG) recording made after the CAPS drug was washed out. BACKGROUND: Four components of the heart period power spectrum--ultra low frequency (< 0.0033 Hz), very low frequency (0.0033 to < 0.04 Hz), low frequency (0.04 to < 0.15 Hz) and high frequency power (0.15 to < 0.40 Hz)--plus total power (1.157 x 10(-5) to < 0.40 Hz) and the ratio of low to high frequency power predict mortality when measured < 30 days after myocardial infarction. However, these variables increase to steady state values by 3 months after infarction and the prognostic significance of recovery values is unknown. METHODS: The 24-h power spectral density was computed from ECG recordings made 1 year after infarction using fast Fourier transforms and the six measures listed were calculated. The values were dichotomized at cut points that maximized the association with mortality. RESULTS: Each measure of RR variability had a strong and significant univariate association with mortality; the relative risks for these variables ranged from 2.5 to 5.6. After adjustment for age, New York Heart Association functional class, rales in the coronary care unit, left ventricular ejection fraction and ventricular arrhythmias, some measures of heart period variability still had a strong and significant independent association with all-cause mortality. CONCLUSIONS: Spectral measures of heart period variability, measured late after infarction, predict death.

Predicting mortality after myocardial infarction from the response of RR variability to antiarrhythmic drug therapy.

OBJECTIVES: This study was designed to test the hypothesis that antiarrhythmic drugs that decrease RR variability will predict all-cause mortality during follow-up after myocardial infarction. BACKGROUND: RR variability, a noninvasive indicator of autonomic nervous system activity, predicts death after acute myocardial infarction independently of other risk predictors and changes substantially in response to some drugs. A previous study in patients with chronic heart disease and frequent ventricular premature complexes reported that flecainide decreased vagal modulation of RR intervals but amiodarone did not. The investigators of that study speculated that changes in RR variability during antiarrhythmic drug therapy predict an increased mortality rate during long-term drug treatment. To explore this hypothesis further, we compared the effects of encainide and flecainide, which increase long-term mortality substantially, on RR variability with the effects of placebo and moricizine, which have no significant effect on mortality during long-term treatment of unsustained ventricular arrhythmias after myocardial infarction. METHODS: The 24-h power spectral density was computed from the baseline electrocardiographic recordings and drug evaluation tapes, and six frequency domain measures of RR variability were calculated: ultra-low frequency (< 0.0033 Hz), very low frequency (0.0033 to < 0.04 Hz), low frequency (0.04 to < 0.15 Hz) and high frequency power (0.15 to < 0.40 Hz), plus total power (< 0.40 Hz) and the ratio of low to high frequency power. Changes in power spectral measures were related to drug treatment and to mortality. RESULTS: In the placebo group, values for RR interval and RR variability increased because of recovery from the effects of acute myocardial infarction. Contrasting placebo treatment with all three active antiarrhythmic drug treatments taken together showed that of all the measures of RR variability, only NN50, pNN50 and low frequency power changed significantly during drug treatment (Bonferroni adjusted p value < 0.025); these variables all decreased during drug therapy. Contrasting encainide and flecainide with moricizine, we found that the encainide and flecainide groups taken together showed a larger decrease in dLF than moricizine, but the difference was of borderline significance (Bonferroni adjusted p value < 0.08). Survival was significantly worse in the groups treated with encainide and flecainide than in the groups treated with placebo or moricizine (relative risk > 2.0, adjusted p < 0.05). The antiarrhythmic drug-induced change in measures of RR variability was not a significant predictor of all-cause mortality during a year of follow-up after myocardial infarction. CONCLUSIONS: Encainide, flecainide and moricizine all caused a decrease in RR variability in patients studied approximately 1 month after acute myocardial infarction. Encainide and flecainide caused a significant increase in mortality rates; placebo and moricizine did not. Baseline measurements of RR variability also predicted all-cause mortality after myocardial infarction. The decrease in RR variability produced by the three antiarrhythmic drugs did not predict mortality during follow-up.

Tissue digoxin concentrations and digoxin effect during the quinidine-digoxin interaction.

Quinidine elevates serum digoxin concentration in part by reducing the volume of distribution of digoxin, which implies that quinidine displaces digoxin from tissues. The purposes of this study were to: 1) measure the effect of quinidine on tissue digoxin concentrations, and 2) determine if quinidine alters the relation between myocardial digoxin concentration and digoxin effect on myocardial monovalent cation transport. Eighteen dogs were treated with tritiated digoxin until the steady-state serum digoxin concentration was between 1.0 and 1.5 ng/ml. All dogs continued receiving the same dose of digoxin while nine dogs were given quinidine as well. Quinidine was continued until the serum digoxin concentration had increased by at least 25%. At the end of treatment, the serum digoxin concentration in dogs treated with digoxin was 1.2 +/- 0.1 ng/ml compared with 2.1 +/- 0.5 ng/ml in dogs treated with digoxin and quinidine in combination (p less than 0.001). Digoxin concentration in myocardium, skeletal muscle, liver, kidney, stellate ganglion, vagus nerve, femoral nerve, brain and brainstem medulla was higher in dogs treated with a combination of digoxin and quinidine than in dogs treated with digoxin alone, but remained proportional to the serum digoxin concentration in all tissues except the brainstem medulla. Myocardial monovalent cation transport was measured using rubidium-86. The effect of digoxin on myocardial monovalent cation transport did not increase as the serum and myocardial digoxin concentrations increased after quinidine administration.

Time course of recovery of heart period variability after myocardial infarction.

Four components of the heart period power spectrum--ultra low frequency (less than 0.0033 Hz), very low frequency (0.0033 to less than 0.04 Hz), low frequency (0.04 to less than 0.15 Hz) and high frequency power (0.15 to 0.40 Hz)--plus total power (1.157 x 10(-5) to 0.4 Hz for a 24-h electrocardiographic [ECG] recording) all predict mortality after myocardial infarction. To determine the time course and magnitude of recovery for these measures of heart period variability, 68 patients in the Cardiac Arrhythmia Pilot Study (CAPS) placebo group who had 24-h ECG recordings at baseline, 3, 6 and 12 months after myocardial infarction were studied. The 24-h power spectral density was computed with use of fast Fourier transforms and divided into the four components listed previously. The values for the five frequency domain measures of heart period variability in the CAPS patients were similar to those found in 715 patients who participated in the Multicenter Post Infarction Program (MPIP), indicating that the CAPS sample is generally representative of postinfarction patients with respect to these measures. The values for the five measures were one third to one half of those found in 95 normal persons of similar age and gender. There was a substantial increase in all measures of heart period variability between the baseline 24-h ECG recording and the 3-month recording (p less than 0.001). Between 3 and 12 months, the values were quite stable for the group as a whole, as well as for individual patients (intraclass correlation coefficients greater than or equal to 0.66).(ABSTRACT TRUNCATED AT 250 WORDS)

The antiarrhythmic effect of nortriptyline in cardiac patients with ventricular premature depolarizations.

The effect of nortriptyline against ventricular arrhythmias was determined in 16 cardiac patients with 30 or more ventricular premature depolarizations per hour. Nortriptyline was administered orally, 0.5 mg/kg body weight per day, and increased by 0.5 mg/kg per day every third day until ventricular premature depolarizations were suppressed (greater than or equal to 80%), adverse effects occurred or a total daily dose of 3.5 mg/kg per day was given. Each patient had daily 24 hour continuous electrocardiograms, 12 lead standard electrocardiograms and physical examination; blood pressure was measured in the supine and standing position four times a day. Each patient also had radionuclide angiography at rest to measure ejection fraction before and at the effective or maximal dose. Thirteen patients (81%) had an antiarrhythmic response and 11 met the study criterion of at least 80% improvement. Doses ranged from 50 to 200 mg/day (mean 111 +/- 45), steady state plasma concentration ranged from 46 to 410 ng/ml (mean 153 +/- 96) and half-life of elimination of nortriptyline was 4 to 22 hours (mean 13 +/- 4). Administration of nortriptyline did not depress mean ejection fraction (before 42 +/- 12%, after 41 +/- 12%); it was associated with an orthostatic decrease in systolic blood pressure (mean -13 +/- 13 mm Hg). Nortriptyline is an effective antiarrhythmic agent which may be given twice a day even in patients with impaired ventricular function.

Relation between beta-adrenergic blocker use, various correlates of left ventricular function and the chance of developing congestive heart failure. The Multicenter Diltiazem Post-Infarction Research Group.

This study examined the relations among beta-adrenergic blocker use, various correlates of left ventricular function and the chance of developing congestive heart failure in patients after myocardial infarction. The study was performed with the placebo group of the Multicenter Diltiazem Post-Infarction Trial. Ejection fraction data were available in 1,084 patients; of these, 557 were receiving a beta-blocker and 527 were not. In addition to ejection fraction, other correlates of left ventricular function included the presence or absence of pulmonary rales, chest X-ray film evidence of pulmonary congestion and the presence of an S3 gallop. Beta-blocker use was less frequent in patients with an ejection fraction less than 30%, rales, an S3 gallop and pulmonary congestion on chest X-ray film. Twenty-one percent of patients with an ejection fraction less than 30%, 42% of patients with rales, 28% of patients with an S3 gallop and 28% of patients with pulmonary congestion were receiving beta-blocker therapy. For every correlate of left ventricular function, the chance of developing congestive heart failure was greater in patients with diminished left ventricular function than in those without. For each level of left ventricular function, the chance of developing congestive heart failure requiring treatment was greater in patients not taking a beta-blocker.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of atenolol and diltiazem on heart period variability in normal persons.

Several time and frequency domain measures of heart period variability are reduced 1 to 2 weeks after myocardial infarction, and a reduced standard deviation of normal RR intervals over a 24 h period (SDNN) is associated with increased mortality. The predictive accuracy of heart period variability may be reduced by drugs used to treat patients after myocardial infarction. Accordingly, a randomized, three period, placebo-controlled, crossover (Latin square) design was used to determine the effect of atenolol and diltiazem on time and frequency measures of heart period variability calculated from 24 h continuous electrocardiographic recordings during treatment with atenolol, diltiazem and placebo in 18 normal volunteers. During atenolol treatment, the 24 h average normal RR (NN) interval increased 24% (p less than 0.001). The three measures of tonic vagal activity were significantly increased (p less than 0.001) during atenolol treatment: percent of successive normal RR intervals greater than 50 ms = 69%, root mean square successive difference of normal RR intervals = 61% and high frequency power in the heart period power spectrum = 84%. Low frequency power also increased 45% (p less than 0.01), indicating that this variable also is an indicator of tonic vagal activity over 24 h. Diltiazem had no significant effect on the 24 h average NN interval or on any measure of heart period variability. The decreased mortality rate after myocardial infarction associated with beta-adrenergic blocker but not calcium channel blocker therapy may be attributed in part to an increase in vagal tone caused by beta-blockers.

Events in the Cardiac Arrhythmia Suppression Trial (CAST): mortality in the entire population enrolled.

To test the hypothesis that suppression of ventricular arrhythmias by antiarrhythmic drugs after myocardial infarction improves survival, the Cardiac Arrhythmia Suppression Trial (CAST) was initiated. Suppression was evaluated before randomization during an open label titration period. Patients whose arrhythmias were suppressed were randomized in the main study and those whose arrhythmias were partially suppressed were randomized in a substudy. Overall survival and survival free of arrhythmic death or cardiac arrest were lower [corrected] in patients treated with encainide or flecainide than in patients treated with placebo. However, the death rate in patients randomized to placebo therapy was lower than expected. This report describes the survival experience of all patients enrolled in CAST and compares it with mortality in other studies of patients with ventricular arrhythmias after myocardial infarction. As of April 18, 1989, 2,371 patients had enrolled in CAST and entered prerandomization, open label titration: 1,913 (81%) were randomized to double-blind, placebo-controlled therapy (1,775 patients whose arrhythmias were suppressed and 138 patients whose arrhythmias were partially suppressed during open label titration); and 458 patients (19%) were not randomized because they were still in titration, had died during titration or had withdrawn. Including all patients who enrolled in CAST, the actuarial (Kaplan-Meier) estimate of 1-year mortality was 10.3%. To estimate the "natural" mortality rate of patients enrolled in CAST, an analysis was done that adjusted for deaths that might be attributable to encainide or flecainide treatment either during prerandomization, open label drug titration or after randomization. Because the censoring procedure excluded patients treated with encainide or flecainide after randomization, the mortality estimate will be less than the unadjusted mortality estimate of 10.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic significance of ventricular premature depolarizations measured 1 year after myocardial infarction in patients with early postinfarction asymptomatic ventricular arrhythmia.

OBJECTIVES: The objective of this study was to examine the relation between death and the frequency of premature ventricular depolarizations measured approximately 1 year after myocardial infarction. BACKGROUND: The reported association between premature ventricular depolarizations and death in the weeks after myocardial infarction is in part the basis for the use of antiarrhythmic drugs. Such an association has not been reported on for observations obtained at a much greater interval after myocardial infarction. METHODS: We examined the association between mortality and premature ventricular depolarization rates measured 1 year after myocardial infarction in patients with asymptomatic ventricular arrhythmia early (between 6 and 90 days, median 28) after infarction, as measured by 24-h ambulatory electrocardiographic recording. The study group consisted of 502 patients enrolled in the Cardiac Arrhythmia Pilot Study during 1983 to 1985. They were followed up during the course of the study and subsequently by a National Death Index search (average follow-up interval 1,080 days). RESULTS: Death was recorded for 87 patients through 1987. Because patients were admitted to the Cardiac Arrhythmia Pilot Study only if they had greater than or equal to 10 ventricular premature depolarizations/h, the arrhythmia rate measured at baseline (that is, early after infarction) was not expected to, and did not, predict mortality. In 360 patients ventricular premature depolarization rates were measured approximately 1 year from their index myocardial infarction while they were not receiving antiarrhythmic therapy. In these patients, who had survived 1 year after the index infarction, the rate of ventricular premature depolarizations/h measured 1 year after infarction was highly predictive of subsequent death (p less than 0.001). Recent heart failure and a history of diabetes mellitus were also strongly predictive of death. CONCLUSION: The prognostic value of ventricular premature depolarizations observed 1 year after a myocardial infarction may be significant even in a sample selected for frequent ventricular premature depolarizations observed early after the event.

Comparison of baroreflex sensitivity and heart period variability after myocardial infarction.

In animals, baroreflex sensitivity is inversely related to the likelihood of ventricular fibrillation during myocardial ischemia. After myocardial infarction in human patients, reduced baroreflex sensitivity is associated with increased mortality. A reduced standard deviation of normal RR intervals over a 24 h period is also associated with reduced survival after myocardial infarction. Therefore, 32 normotensive men who had survived their first myocardial infarction were studied to define the relation between baroreflex sensitivity assessed with phenylephrine injection and three Holter electrocardiographic measures of tonic vagal activity: the percent of successive normal RR intervals greater than 50 ms, the root mean square successive difference of normal RR intervals and the power in the high frequency energy of the normal RR interval power spectrum. Correlations among the Holter measures of heart period variability were greater than or equal to 0.94, indicating that these measures are so strongly correlated that any one of them can be used to represent the others. Baroreflex sensitivity showed weaker correlations with the three Holter variables (0.57 to 0.63), indicating that the Holter measures did not accurately predict baroreflex sensitivity. Baroreflex sensitivity showed a stronger correlation with the three Holter variables during the night than during the day. Baroreflex sensitivity and tonic vagal activity reflected by Holter variables were reduced more in patients with inferior myocardial infarction than in those with anterior infarction. The relative utility of baroreflex sensitivity and Holter measures of tonic vagal activity in predicting sudden cardiac death after myocardial infarction needs to be evaluated in a large prospective study.

Cardiovascular effects of therapeutic doses of tricyclic antidepressants. A review.

Overdose of tricyclic antidepressants (TCAs) leave no doubt that TCA drugs at high concentrations have serious cardiac effects. It has been assumed that, to a lesser extent, these effects would occur at usual therapeutic concentration. Recent prospective, plasma-level-controlled studies have improved our understanding of these drugs and proved these assumptions to be inaccurate. The most common serious cardiovascular complication of most tricyclic drugs is orthostatic hypotension. Tricyclic antidepressants are essentially free of any other serious adverse effects in depressed patients without cardiovascular disease. In patients with preexisting bundle-branch disease, there is a risk of heart block. On the other hand, patients with ventricular arrhythmias are likely to have their arrhythmias improve with TCA therapy. Finally, therapeutic doses of TCA have little adverse effect on left ventricular performance. As a result, TCA drugs can often be used to benefit depressed patients with overt heart disease.