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Depression is commonly present in patients with coronary heart disease (CHD) and is independently associated with increased cardiovascular morbidity and mortality. Screening tests for depressive symptoms should be applied to identify patients who may require further assessment and treatment. This multispecialty consensus document reviews the evidence linking depression with CHD and provides recommendations for healthcare providers for the assessment, referral, and treatment of depression.

OBJECTIVESWe examined the relationship between diabetes mellitus and outcomes after coronary artery bypass graft (CABG) surgery in patients with severe left ventricular (LV) dysfunction.BACKGROUNDAlthough 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.METHODSUsing data from The CABG Patch Trial, a study of implantable cardiac defibrillator therapy, we analyzed 900 patients with ejection fraction

Background Patients with coronary heart disease, left ventricular dysfunction, and abnormalities on signal-averaged electrocardiograms have an increased risk of sudden death. We evaluated the effect on survival of the prophylactic implantation of cardioverter–defibrillators in such patients at the time of coronary-artery bypass surgery. Methods Over the course of five years, 37 clinical centers screened all patients who were scheduled for elective coronary bypass surgery. Patients were eligible for the trial if they were less than 80 years old, had a left ventricular ejection fraction of less than 0.36, and had abnormalities on signal-averaged electrocardiograms. We identified 1422 eligible patients, enrolled 1055, and randomly assigned 900 to therapy with an implantable cardioverter–defibrillator (446 patients) or to the control group (454 patients). The primary end point of the study was overall mortality, and the two groups were compared in an intention-to-treat analysis. Results The base-line characte...

OBJECTIVE To determine the clinical significance of silent and symptomatic myocardial ischemia detected by noninvasive testing in stable postcoronary patients. DESIGN Cohort study with a mean 23-month follow-up. SETTING Ambulatory outpatients after recent hospitalization for an acute coronary event. PATIENTS Nine hundred thirty-six patients (76% male; mean age, 58 years) who were clinically stable 1 to 6 months after hospitalization for acute myocardial infarction or unstable angina. INTERVENTIONS Noninvasive testing involved rest, ambulatory, and exercise electrocardiograms and stress thallium-201 scintigraphy. MAIN OUTCOME MEASURES Cox regression analysis was used to evaluate the risk (hazard ratio) of first recurrent primary events (cardiac death, nonfatal infarction, or unstable angina) or restricted events (cardiac death or nonfatal infarction) associated with ischemic noninvasive test results. RESULTS ST segment depression on the rest electrocardiogram was the only noninvasive test variable that identified a significantly increased risk (P = .05) for first recurrent primary events (hazard ratio; 95% confidence limits): rest electrocardiogram ST depression (1.5; 1.00, 2.25); ambulatory electrocardiogram ST depression (0.86; 0.49, 1.51); exercise electrocardiogram ST depression (1.13; 0.82, 1.56); and stress thallium-201 reversible defects (1.3; 0.96, 1.74). Test results were similar for first recurrent restricted events, and in patients with and without angina. Significantly increased risk (P < .05) was noted when exercise-induced ST depression occurred in patients who also had reduced exercise duration (hazard ratio, 3.4) or when reversible thallium-201 defects occurred in patients who also had increased lung uptake (hazard ratio, 2.8). Each high-risk subset made up less than 3% of the population and contained less than 6% of patients with first primary events. CONCLUSION Detection of silent or symptomatic myocardial ischemia by non-invasive testing in stable patients 1 to 6 months after an acute coronary event is not useful in identifying patients at increased risk for subsequent coronary events.

Experience with combined transvenous pacemaker and implantable cardioverter-defibrillator insertion in 21 patients is described. Special techniques are needed to avoid potentially lethal pacemaker-implantable cardioverter-defibrillator interaction. Separation between leads for the two devices should be maximized. The electrophysiologic criteria for successful device function can be met, even when some leads for both devices must be placed by a transvenous approach.

The controlled clinical trial, i.e., a prospective study that compares the effect of one or more interventions against a control in human subjects, is the most definitive method to determine the benefit/risk ratio for a treatment. Some of the elements are a clear statement of the primary and secondary hypothesis, carefully defined end points, randomization, double blinding, and concomitant controls for the experimental treatment using either placebo or standard treatment. Randomization tends to produce study groups that are comparable with respect to both known and unknown factors that influence the outcome, and also removes bias in the assignment of subjects to treatments to ensure that statistical hypothesis testing will have valid significance levels. An adequate sample size is critically important for a successful trial. The Cardiac Arrhythmia Suppression Trial (CAST) is a randomized, placebo-controlled, double-blind, international, multicenter clinical trial to determine whether suppression of ventricular arrhythmias after myocardial infarction with long-term antiarrhythmic drug treatment will reduce arrhythmic death. Survivors of myocardial infarction who are less than 80 years of age and have greater than or equal to six ventricular premature depolarizations (VPD) per hour on a 24-hour continuous ECG recording obtained between 6 days and 2 years after myocardial infarction are eligible for CAST.(ABSTRACT TRUNCATED AT 250 WORDS)

In this issue of the Journal, Siscovick et al. report a case-control study that evaluated the risk of cardiac arrest associated with diuretic treatment of hypertension1. The authors are aware of th...

IN 1977, we first reported the antiarrhythmic effect of imipramine hydrochloride. 1 Prior to that time, physicians generally believed that the tricyclic antidepressants (TCAs) caused arrhythmia. That belief stemmed from the propensity of overdoses of these drugs to provoke arrhythmias. 2 However, it subsequently became apparent, both from our studies 3-6 and the work of others, 7 that at plasma concentrations therapeutic for depression, 8 TCAs suppress arrhythmias, and their cardiac effects closely resemble those of class I antiarrhythmic drugs. 9,10 Until recently, it was our belief that depressed patients with preexisting arrhythmias would benefit from the antiarrhythmic effect of TCAs. 11,12 Unfortunately, recent studies indicate that this opinion may need to be revised. Ventricular premature depolarizations (VPDs) are a well-documented risk factor for sudden death after myocardial infarction (MI) 13,14 and the assumption had been that drugs that suppress VPDs would reduce this associated mortality. However, in 1983, Furberg

We enrolled 250 patients with acute myocardial infarction after they had been discharged from the cardiac intensive care unit. Among 236 patients who performed a low-level exercise test just before hospital discharge, 52 (22%) had exercise-induced ST depression of at least 0.1 mV in ECG lead V5, 102 (43%) had ventricular arrhythmias, and 121 (51%) had an exercise capacity of shorter than 6 minutes. We used multiple logistic regression analysis to investigate the association of exercise variables with 1-year cardiac mortality. Exercise duration and ventricular premature depolarizations (VPDs) were significantly associated with 1-year mortality after acute myocardial infarction, both with and without control of the influence of other exercise variables statistically; the association of exercise-induced ST depression with 1-year cardiac mortality was not statistically significant. Standardized regression coefficients showed that the variables ranked in the following order in terms of predictive value: exercise duration, VPD frequency and ST depression. Jackknife techniques showed that multiple logistic regression using the three exercise variables was highly accurate in predicting 1-year mortality.

To improve methods for evaluating human sinus node function (SNF), we developed a transvenous electrode catheter technique for direct recording of sinus node electrograms in adults. Sinus node electrograms (SNE) characterized by low-frequency, anatomically localized pre-P-wave potentials were obtained in 19 of 23 patients. The SNE configuration was similar to that previously found for endocardial SNE recordings in in vitro atrial preparations, in open-chest dogs and during human open heart surgery. In 16 patients with normal SNF, directly recorded sinoatrial conduction times (SACTs) were 46-116 msec. In three patients with sick sinus syndrome, SACT was 110-126 msec. In 15 of the 19 patients, SACT was estimated by the atrial premature stimulus technique and was compared with the directly measured SACT. When atrial premature depolarizations produced no sinus node depression, the mean differences between the direct and estimated SACT was 1.8 +/- 5.6 msec.

Stimulated whole saliva was collected from 73 patients, 18 with the diagnosis of digitalis toxicity; 22 were nontoxic receiving digitalis and a diuretic, 17 nontoxic receiving digitalis alone, and 16 were normal subjects. Salivary potassium and calcium concentrations were significantly higher in the group with digitalis toxicity than in the nontoxic groups. Whole-saliva potassium concentrations alone identified most of the toxic patients studied. In most cases in which the salivary potassium concentration alone failed to identify digitalis toxicity, the product of potassium and calcium did. The diagnostic usefulness of the salivary electrolyte determination is not dependent on the type of digitalis preparation used. This experience with whole-saliva potassium and calcium concentrations, coupled with earlier animal work, suggests that salivary potassium and calcium analysis is a reliable, rapid and simple method of identifying patients with digitalis toxicity.

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(-5) mole/liter, lidocaine either caused a slight increase or no change in peak maximum rate of phase 0 depolarization (V(max)) and membrane responsiveness, the relationship between transmembrane activation voltage (MAV) and V(max) of the resultant action potential; these concentrations had no significant effect on resting potential (RP) in VM, maximal diastolic transmembrane voltage (DTMV(max)) in PF, or action potential amplitude in either fiber type. High (toxic) 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.

Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this important possible interaction between digoxin and quinidine, charts from 863 cardiology patients were reviewed. Ninety two patients received both drugs after having been on digoxin alone; 38 were ineligible for the study because of insufficient data and 27 were excluded because of changing renal function and/or concomitant antiarrhythmic drug therapy, leaving 27. Serum digoxin increased in 25 of the 27 study patients (93%) during quinidine therapy; mean serum digoxin rose from 1.4 ng/ml before quinidine to 3.2 ng/ml during quinidine. Anorexia, nausea and/or vomiting developed in 16 patients (59%) during quinidine therapy, but disappeared in all 10 patients in whom digoxin alone was reduced in dose, suggesting that digoxin had a causative role in the appearance of these symptoms although they developed only after quinidine had begun. Three of thirteen patients with only atrial arrhythmias on digoxin prior to quinidine developed new ventricular premature depolarizations (VPD) after starting quinidine; two of these three as well as four patients with prior VPDs developed new ventricular tachycardia, ventricular fibrillation, asystole, or sudden death. When starting quinidine in patients who are taking digoxin, the clinical course, ECG and serum digoxin should be followed closely.

We examined the effects of digitalis therapy on postinfarction mortality throughout a 24-month to 48-month follow-up in 867 patients who survived an acute myocardial infarction. During follow-up, 145 patients died (16.7% mortality). At the time of hospital discharge, 31% of the patients were taking digitalis. The digitalis-treated patients were older, had more medical-cardiac risk factors, and had a higher mortality rate throughout the follow-up than the nondigitalis-treated patients. Statistical techniques were used to adjust for clinical imbalances between the digitalis-treated patients and nondigitalis-treated patients. The survival analysis (n = 728 patients) utilized the Cox regression model, and the digitalis-associated mortality risk was identified only after all significant covariates were allowed, so that mortality could be predicted as accurately as possible. Digitalis therapy was associated with a significantly increased postinfarction mortality risk after adjustment for the predictor covariates (relative risk 2.3, 95% confidence interval 1.4-3.7, p less than 0.001). The findings from this large multicenter study suggest that it would be prudent to exercise caution in the use of digitalis in postinfarction patients.

We compared the effects of quinidine and three alternate antiarrhythmic drugs on serum digoxin concentration in 63 patients before and during administration of quinidine, procainamide, disopyramide, or mexiletine. Quinidine increased digoxin concentration by at least 0.5 nmol/L in 21 of 22 patients: Mean serum digoxin rose from 1.2 nmol/L to 2.4 nmol/L (P less than 0.001). Procainamide, disopyramide, or mexiletine increased serum digoxin by 0.5 nmol/L in one of 41 patients. Anorexia, nausea, and vomiting develop soon after starting quinidine therapy in 10 of the 22 patients who received quinidine but in only five of the 41 patients who received procainamide, disopyramide, or mexiletine (P less than 0.01). Quinidine prolonged the PR intervals from 160 +/- 14 ms to 183 +/- 26 ms, but procainamide, disopyramide, and mexiletine did not change the PR interval (P less than 0.005). In digitalized patients, quinidine increases serum digoxin concentration, increases digoxin's effect on atrioventricular conduction, and produces more adverse gastrointestinal effects than procainamide, disopyramide, or mexiletine.

To the Editor.— The detection of digitalis toxicity remains an important problem in medicine. Recently, two techniques have been identified that may prove useful. The first was the ability to quantitate plasma glycoside levels by radioimmunoassay, and the second, the demonstration of an effect on the salivary glands of cardiac glycosides, which results in elevated potassium and calcium concentrations in the salivary secretion. There now exists a large literature, including several reviews that discuss the potential and limitations of the plasma glycoside radioimmunoassays in defining digitalis toxic states. Since the salivary phenomenon has been more recently described, the clinical potential and limitations are not yet as fully defined. Doherty of the University of Arkansas has challenged, in editorials ( Ann Intern Med 79:229, 1973), letters (226:1228, 1973), and reviews, both the existence of an effect of glycosides on salivary electrolytes and any possible clinical use in patients receiving digitalis. The existence of alteration

Excerpt Several large, double-blind, randomized, placebo-controlled clinical trials have shown that beta-adrenergic blocking drugs reduce the mortality rate and incidence of nonfatal myocardial inf...

The serum digoxin concentration increased in 25 of 27 study patients (93%), and the mean serum digoxin concentration rose from 1.4 ng/ml to 3.2 ng/ml during quinidine therapy. Anorexia, nausea, or vomiting developed in 16 patients (59%) but disappeared in all ten patients for whom the digoxin dose alone was reduced, suggesting that digoxin excess caused these symptoms. Ventricular premature depolarizations developed in three patients after starting quinidine therapy; ventricular tachycardia developed in one patient, and another died suddenly. When starting quinidine therapy in patients who are taking digoxin, the clinical course, ECG, and serum digoxin level should be followed closely. (JAMA240:533-534, 1978)

• Overdoses 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 bundlebranch 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.

Bretylium tosylate (Bretylol) has recently been approved for parenteral use against resistant ventricular arrhythmias. The pharmacologic action of bretylium is complex, and its antiarrhythmic action differs significantly from other drugs. Bretylium is an adrenergic neuronal blocking agent taken up selectively at peripheral adrenergic nerve terminals, where it initially releases norepinephrine (sympathomimetic effect) and then produces adrenergic neuronal blockade. It has direct cardiac membrane effect to prolong action potential duration and effective refractory period but, unlike other membrane active antiarrhythmic agents, does not depress conduction velocity or automaticity. Bretylium increases ventricular fibrillation threshold and prevents the decrease in ventricular fibrillation threshold associated with myocardial ischemia. It does not depress myocardial contractility. Clinical studies have shown parenteral bretylium to be effective in suppressing ventricular arrhythmias, particularly recurrent, drug resistant ventricular tachycardia or ventricular fibrillation.

Previous studies of the effect of tricyclic antidepressants on left ventricular function in depressed patients with moderate to severe ventricular impairment have focused primarily on imipramine hydrochloride. In a prior study, we found that although imipramine had no effect on ejection fraction as measured by first-pass radionuclide angiography, the treatment could not be tolerated by 50% of the patients because of intolerable drug-induced orthostatic hypotension. Nortriptyline hydrochloride is an effective antidepressant that, in depressed patients without heart disease, causes significantly less orthostatic hypotension than imipramine. To see if this advantage could be safely extended to patients with congestive failure, we measured the effect of nortriptyline on ejection fraction and blood pressure in 21 depressed patients with left ventricular impairment. Ejection fraction was unchanged by nortriptyline treatment, and orthostatic hypotension developed in only one (5%) of 21 patients. Nortriptyline emerges as a relatively safe treatment for depression in patients with left ventricular impairment. ( JAMA 1986;256:3253-3257)