A prospective randomized trial of tocainide in patients following myocardial infarction

One hundred forty-six patients with recent acute myocardial infarction were grouped at random into those treated with tocainide, an oral analogue of lignocaine, or placebo and followed up for 6 months. In addition to standard investigations, a 24-hour ambulatory taped ECG recording was obtained prior to randomization and thereafter at 2, 8, 16, and 24 hours after discharge. The ECGs were analyzed by means of an automated, computerized reporting system. Forty-two patients had significant ventricular arrhythmias, 10 of whom had effective plasma levels of tocainide compared with 27 patients on placebo (P < 0.005). In the placebo patients with increasing mobilization there was a consistent rise in the number of ventricular ectopic beats per day. There was no such increase in the tocainide patients (p < 0.01). Side effects were few and the incidence of central nervous system side effects was similar in both the tocainide and placebo groups. There was no conclusive evidence of myocardial depression, heart rate and blood pressure being unchanged over the 6-month period. Although ventricular arrhythmias were suppressed, the number of patients in the study was too small to draw conclusions regarding the mortality rate.     

Metabolism of apolipoprotein A-I in healthy young adults.

The metabolism of 125I-labeled apolipoprotein A-I bound to high-density lipoproteins by an in vitro transfer procedure was studied in 10 healthy young adults (5 males and 5 females). Both sexes handled the labeled apolipoprotein similarly, and no statistically significant differences were found in the derived kinetic data. The mean (+/- 1 SD) plasma apolipoprotein A-I concentrations (males, 105 +/- 19 mg/dl; females, 111 +/- 13.8 mg/dl) and half-lives (males, 4.46 +/- 0.45 days; females, 4.64 +/- 0.70 days) were similar, as were the fractional rates of catabolism (FCR) of the apoprotein derived from the above data (FCR in males, 27% of intravascular pool/day; FCR in females, 25% of intravascular pool/day). The absolute catabolic rate of the apoprotein, equivalent under steady-state conditions to the synthetic rate, was 12.1 +/- 1.6 mg/kg/day in males and 11.9 +/- 2.4 mg/kg/day in females.     

An analysis of electrocardiographic,radiographic, and vectorcardiographic findings in patients with implanted cardiac pacemakers

In patients with implanted cardiac pacemakers, the radiological appearances, and the configuration of the 12-lead ECG have been conventionally used both to locate the site of the electrode implantation and to diagnose electrode placement errors. These techniques have limitations, and in the present study vectorcardiographic data derived from the pacemaker stimulus and the spread to ventricular depolarization has been added to improve accuracy. Three hundred patients with implanted cardiac pacemakers were studied. Unusual QRS complexes as determined from the 12-lead ECG were found in 37 (12%) and the position of the pacemaker electrodes determined from the lateral chest x-ray was outside normal (R.V. apex) in 61 patients (20.3%). A combined interpretation of the ECG, chest x-ray, and the vectorcardiogram agreed on positioning (correct or incorrect) in all but 17 patients (5.6%). Three patients had a perforated right ventricle, while further study of the other 14 suggested malpositioning of the catheter electrode in the right ventricle or in the coronary venous system. An analysis of the ECG patterns, x-ray appearances, and vectorcardiograms is presented with respect to the diagnosis of pacemaker electrode placement errors and a logical tree for establishing the position of the pacemaker is introduced.     

A study of the antiarrhythmic action of certain beta-blocking agents

The effects of the beta-blocking agents, MJ-1999 (sotalol) and practolol, against ouabain and digoxin-induced ventricular rhythm disturbances were studied to evaluate the nature of the action which is involved in the antiarrhythmic action of these beta-blocking agents. Sotalol and practolol, in doses that have been reported to have little effect on cardiac excitability, protected against digoxin-induced arrhythmias. Practolol, but not the low dose of sotalol, protected against ouabain-induced cardiotoxicity. The dose of sotalol necessary to protect against ouabain-induced arrhythmias was five times greater than that necessary to protect against digoxin-induced arrhythmia and has been reported to directly depress cardiac excitability. The maximum rate of ventricular tachycardia produced by ouabain or digoxin was slower in the animals pretreated with practolol but not in those pretreated with sotalol. The slowing in heart rate produced by beta-blocking agents could not be correlated with the protection afforded against either digoxin or ouabain-induced arrhythmia. The data suggest that the capacity of beta-receptor blocking agents to reduce cardiac excitability may not be the only mechanism responsible for their antiarrhythmic action. Both practolol and sotalol protected against digoxin-induced arrhythmias and the only action common to both agents is beta blockade. Therefore, it is suggested that the beta blocking action is responsible for the antiarrhythmic action against digoxin-induced arrhythmias. However, since only practolol protected against ouabain-induced rhythm disturbances in doses which do not depress cardiac excitability and since it differs from sotalol in that it has the capacity to depress adrenergic nervous activity in these doses, it is suggested that the neural depressant action of practolol is responsible, at least in part, for its antiarrhythmic action against ouabain-induced cardiotoxicity.     

Mechanism of antiarrhythmic action of beta-blocking agents

We investigated the antiarrhythmic effect of beta-blocking agents. Using 35 anesthetized dogs, the chest was opened and the left anterior descending coronary artery (LAD) was ligated for 30 min and the ventricular multiple response threshold (VMRT) was observed in the time course. The dogs were divided into five groups premedicated intravenously ten min before LAD ligation with either isotonic saline (the control group), D,L-propranolol (0.5 mg/kg), D-propranolol (0.5 mg/kg), D,L-pindolol (0.1 mg/kg), or D,L-acebutolol (2.5 mg/kg). Thirty min after ligation, myocardial mitochondria were prepared from the ischemic and the non-ischemic areas, and then the content of mitochondrial long-chain acyl-CoA and Ca++-binding activity were measured. The value of VMRT 1.59 +/- 0.21 mA before ligation decreased to 0.99 +/- 0.13 mA 30 min after ligation. Content of acyl-CoA in mitochondria from the ischemic area increased significantly compared to those from the non-ischemic area. Mitochondrial Ca++-binding activity in the ischemic area decreased significantly compared to that in the non-ischemic area. Each administration of three beta-blocking agents prevented the decreases in VMRT and Ca++-binding activity and excessive accumulation of acyl-CoA; D-propranolol had no effect. These results suggest that the antiarrhythmic action of beta-blocking agents is based, at least in part, on the protection from decrease in Ca++-binding activity due to mitochondrial dysfunction induced by the excessive accumulation of long-chain acyl-CoA in mitochondria.     

The effect of noradrenaline on blood flow and oxygen consumption in normal and ischemic areas of myocardium

The effects of infusions of noradrenaline (1.0 μg/Kg./min.) were studied in dogs 2 to 3 hr. after acute ligation of the anterior descending branch of the left coronary artery. The model allowed blood flow to be simultaneously measured in the ischemic (infarcting) region and in the normal myocardium. Sampling blood from a local vein (draining the ischemic region) and from the coronary sinus (draining the normal myocardium) allowed comparisons to be made of oxygen consumption by the two regions.Coronary artery ligation resulted in a marked decrease in cardiac output and external cardiac work and an increase in left ventricular end-diastolic pressure with an unchanged LV $\text{dP}\text{dt}$. This is indicative of reduced myocardial contractility. Blood flow in the area supplied by the ligated vessel fell to a mean of 17.6 ± 2.7 ml./100 Gm./min., which is about 20 per cent of the normal flow in this region.Infusing noradrenaline 2 to 3 hr. after ligation increased systemic arterial pressure, LV $\text{dP}\text{dt}$ max, external cardiac work, and blood flow and oxygen consumption in normal areas of the myocardium. There was some evidence that pulmonary shunting was increased by the drug.Noradrenaline also markedly increased peripheral coronary pressure and blood flow in the ischemic region, as assessed by ¹³³Xenon clearance and by retrograde flow from the ligated vessel. Oxygen consumption in the ischemic region was also increased by noradrenaline. It is suggested that part of the increase in flow occurs in the endocardial region since the effective subendocardial perfusion pressure is increased by noradrenaline. This increase in flow would account for the reduction in infarct size which has been observed by other workers when the systemic arterial pressure is raised.     

Prediction of response to class I antiarrhythmic drugs during electrophysiologic study of ventricular tachycardia

We have retrospectively examined data from 41 patients studied in our laboratory for symptomatic ventricular arrhythmia in order to test whether any clinical or electrophysiologic variables could be identified which would predict the patient's response to class I antiarrhythmic drugs. All patients had (1) clinically documented paroxysmal sustained ventricular tachycardia (VT) or ventricular fibrillation remote from acute myocardial infarction, (2) inducible sustained VT during control electrophysiologic study (EPS), and (3) EPS after one or more of the following class I antiarrhythmic drugs: intravenous procainamide (36 patients), oral quinidine (30 patients), and oral disopyramide (36 patients). Initially, patients were divided into those who had noninducible or only nonsustained VT after any of the tested drugs (responders), and those who continued to have inducible sustained VT after all tested drugs (nonresponders). A logistic regression technique demonstrated no independent contribution to drug response by any of the following variables: sex, arteriosclerotic heart disease, cardiomegaly, age, time since the initial episode of VT, and cycle length of VT during control study. The number of antiarrhythmic drugs the patient had received prior to study was found to be a significant independent contributor (p < 0.03), with responders having received an average of 2.5 drugs compared with 4.2 for nonresponders. In addition to the logistic regression, 12 other clinical and electrophysiologic variables were not predictors of drug response. The question was also asked, “Does response or nonresponse to one class I drug predict response or nonresponse to the others?” Significant concordance of response and nonresponse was demonstrated for procainamide and quinidine, but not for either of these drugs and disopyramide. Drug therapy for inducible sustained VT therefore remains empiric.     

Stress electrocardiography in the evaluation of aortocoronary bypass surgery

Forty-five patients having saphenous vein aortocoronary bypass surgery were studied prospectively by pre- and post-operative hypoxemia and graded exercise electrocardiography. The stress electrocardiographic results were correlated with the degree of symptomatic relief and the angiographic evidence of graft patency and the distribution and evolution of coronary occlusive disease.Forty-one of the total group of 45 patients (91 per cent) and 32 of 34 (94 per cent) with one or more documented open grafts had excellent or good symptomatic improvement. Incongruously, five of seven patients with closed grafts also had significant clinical improvement.Functional improvement was documented in 53 per cent of patients after aortocoronary bypass surgery, in terms of postoperative reversal of the preoperatively positive stress ECG or persistance of a negative stress ECG, together with the achievement of significantly greater mean maximum exercise and heart rate. All of these patients had one or more patent saphenous vein bypass grafts. Forty-seven per cent of the patients failed to display objective evidence of improvement: post-operatively the stress ECG either remained positive, or became so, and, collectively, the group was unable to significantly increase the mean maximum exercise level or heart rate, in comparison to that achieved before surgery. Only 65 per cent of these subjects had one or more patent bypass grafts.Stress electrocardiography and quantitation of the maximum work and heart rate achieved by exercise provide accurate assessments of the relief of myocardial ischemia produced by myocardial revascularization. In this study, when the post-operative stress ECG was negative and the patient was able to achieve significantly greater exercise and heart rate, the probability of patency of one or more bypass grafts was virtually certain. On the other hand, when the postoperative stress ECG was positive and little or no increase in exercise and heart rate was possible, there was high probability of graft occlusion or significant residual coronary disease.     

Comparison of ventricular parasystole with other dysrhythmias after acute myocardial infarction

Three hundred and sixty-nine patients suffering from a recent myocardial infarction were studied over a period of 16 months in a coronary-care unit. Particular attention was paid to ventricular arrhythmias and especially ventricular parasystole. Ventricular parasystole was found in 4 per cent of the patients, identification being helped by the recording of long strips of ECG at slow speed when ventricular ectopic activity was noted.The study has shown that ventricular parasystolic rhythms after acute myocardial infarction are probably benign in contrast to most other ventricular arrhythmias which are associated with an increased mortality.     

Hemodynamic effects of newer antiarrhythmic drugs

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodynamic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodynamic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verapamil are administered either acutely by the intravenous route or chronically by the oral route.     

High density and low density lipoprotein subfractions in survivors of myocardial infarction and in control subjects

The major lipoprotein classes (very low, low and high density lipoproteins, VLDL, LDL and HDL) and three lipoprotein subfractions (HDL₂, HDL₃ and LDL₂) of 31 male survivors of myocardial infarction (MI) have been compared with those of 24 ostensibly normal subjects. The two groups had similar ages, relative weights, smoking and dietary habits, and physical activities. The MI survivors had significantly higher concentrations of total and VLDL-triglyceride and total and LDL-cholesterol than the control subjects. The differences in HDL-cholesterol, and total apolipoproteins A-1 and B were of borderline significance. HDL₂ was significantly lower and LDL₂ was higher in the MI survivors. There was no difference in HDL₃. The differences in lipoprotein subfractions could be ascribed to differences in cholesterol, phospholipid and proteins, but not in triglyceride. The data suggest that the minor HDL₂ subfraction shows a closer association with established coronary heart disease than does total HDL-cholesterol. The increased LDL-cholesterol concentration in the MI survivors can be ascribed at least partly to an increase in the major subfraction, LDL₂.     

Progress in pacemaker technology

Extensive experience has been obtained with Medtronic pacemakers in Glasgow, where over 400 patients have received their primary implant. In this seven and a half years' review the technical reliability of both asynchronous and demand generators is determined in terms of failed implant lifetimes and incomplete implant lifetimes. Results are expressed in terms of frequency distribution bar charts and percentage failure curves which provide factual evidence from the field that progress has indeed been made in making generators more reliable. These results provide firm bases against which more recent and future implants will be judged.     

Suppression of high-grade ventricular ectopic activity by antiarrhythmic drug treatment as a marker for survival in patients with chronic coronary artery disease

In order to investigate the relationship between the ease of suppression of complex (frequent multiform, repetitive, and early) ventricular premature beats (VPBs) and subsequent survival, 50 consecutive patients with chronic coronary artery disease (CAD) were followed retrospectively during a mean observation period of 16 months. A total of 124 drug trials were performed using single or combined class I, II, and III antiarrhythmic drugs. Thirty-nine patients were considered "responders" (elimination of Lown classes greater than or equal to IVa and reduction of greater than 30 multiform VPBs to occasional unifocal VPBs during Holter monitoring), whereas in 11 patients VPBs could not be adequately suppressed ("nonresponders"). There were no significant differences in age and congestive heart failure in the two groups. There were three deaths (one sudden) in the 39 "responders" but five deaths (three sudden) in the 11 "nonresponders" (p less than 0.01 for all deaths, p less than 0.05 for sudden deaths). Cumulative probability of survival at 12 months was 0.93 for "responders" and 0.64 for "nonresponders" (p less than 0.005). Significant side effects necessitated drug withdrawal in four patients. Our data suggest that survival in patients with CAD is better when complex VPBs can be suppressed.     

Digoxin uptake into peripheral autonomic cardiac nerves: Possible mechanism of digitalis-induced antiarrhythmic and toxic electrophysiologic actions

It is generally accepted that certain cardiac rhythm disturbances are due to imbalances between the sympathetic and parasympathetic nervous systems. We have provided evidence that digoxin is concentrated in the peripheral nervous system of the heart as well as in the central nervous system. Previous findings have indicated that cardiac glycosides may directly or indirectly affect autonomic neurotransmitters. Therefore the uptake of digoxin into the peripheral cardiac nervous system may play an important role in both the antiarrhythmic and toxic electrophysiologic actions of digoxin.     

Study of the normal and failing isolated human heart: decreased response of failing heart to isoproterenol

We evaluated the effects of isoproterenol in right ventricular papillary muscles derived from normal and failing isolated human hearts. Basal values for the peak force developed, rate of force development (dF/dt), and time to peak tension (TPT) were similar in both groups. Isoproterenol produced a significantly smaller (p less than 0.05) increase in peak force developed and dF/dt in failing papillary muscles. The half equivalent dose (ED50) of isoproterenol was fivefold higher in failing muscle as compared to normal muscle. We conclude that failing cardiac muscle demonstrates decreased responsiveness to beta-receptor mediated stimulation.