Electrophysiologic substrate of torsade de pointes: dispersion of repolarization or early afterdepolarizations?

Recent experimental and clinical studies suggest that torsade de pointes may be precipitated by early afterdepolarizations in the Purkinje or ventricular muscle fibers. This hypothesis offers an alternative to the earlier one that attributes torsade to the underlying dispersion of repolarization. This review lists the clinical conditions associated with torsade de pointes and examines the experimental background of the two proposed electrophysiologic substrates of torsade, namely, the dispersion of repolarization and the early afterdepolarizations. The strengths and weaknesses of the two hypotheses are compared in relation to the following characteristics of torsade de pointes: facilitation by slow heart rate, suppression by pacing, R on T phenomenon, difficulty of induction by programmed stimulation, aggravation by hypokalemia, manifestation of an idiosyncratic reaction to class IA antiarrhythmic drugs, spontaneous termination, suppression by magnesium salts and isoproterenol and induction by such drugs as sotalol, bepridil and prenylamine. It appears that most clinical observations can be explained by either mechanism, but in some cases difficulties are encountered for the afterdepolarization hypothesis.

Factors affecting tolerance to digitalis.

A review of factors altering the safety margin between a therapeutic and a toxic dose of digitalis includes the consideration of: clinical conditions to which digitalis action may be undesirable, allergy and hypersensitivity to digitalis, physiologic factors modifying tolerance to digitalis, factors that change the amount of digitalis in the body, nervous and metabolic factors modifying tolerance to digitalis, modifications of digitalis tolerance produced by the status of the myocardium, and modifications of digitalis tolerance produced by diseases of other organs. The problems related to digitalis toxicity are more common than those of resistance to treatment. The most important factors contributing to decreased tolerance and risk of toxicity are: heart disease, poor renal function, hypokalemia and hypothyroidism. The roles of impaired liver function, chronic lung disease, acid-base disturbances, anesthesia, autonomic imbalance, calcium and magnesium are less important and less well established.

Ventricular fibrillation.

Ventricular fibrillation is the most common mechanism of sudden unexpected cardiac death in persons with asymptomatic or symptomatic coronary artery disease. The electrophysiologic mechanisms reviewed in this article include: automaticity of pacemaker fibers, transformation of nonpacemaker into pacemaker fibers, "injury" currents and reentry. Some of the conditions facilitating ventricular fibrillation include bradycardia, long QT syndrome, electrocution, electrolyte imbalance, drugs, sympathetic stimulation and myocardial ischemia. Electrophysiologic studies during acute myocardial ischemia suggest that the earliest activity at the onset of arrhythmia may originate at the sites of the surviving Purkinje fibers or at the epicardial rim. Reentrant arrhythmias arising in ischemic myocardium are attributed to nonhomogeneous distribution of local hyperkalemia and acidosis.

Prognosis of ventricular arrhythmias in relation to sudden cardiac death: therapeutic implications.

The hypothesis that ventricular arrhythmias represent an independent predictor of sudden cardiac death was examined by analyzing the published data. The frequency and complexity of ventricular arrhythmias increase progressively both with age and severity of heart disease, but no age- or disease-related norms have been established for clinical guidance. Simple and complex arrhythmias, including short runs of ventricular tachycardia, do not increase risk of sudden cardiac death in subjects without heart disease or with heart disease and normal myocardial function. Progression of nonsustained into sustained ventricular tachycardia in such individuals is rare. Simple and complex ventricular arrhythmias are not strong independent predictors of sudden death in survivors of myocardial infarction. In these, the overall incidence of sudden cardiac death averages 3.5 to 5% during the first year, but is about 15 to 20% per year in patients with severely impaired ventricular function. The results of this survey suggest that in patients with well preserved ventricular function, prophylactic use of antiarrhythmic drugs is not indicated, and that treatment of asymptomatic or mildly symptomatic ventricular arrhythmias is not likely to reduce the incidence of sudden cardiac death.

Electrocardiographic diagnosis of chamber enlargement.

The purpose of this article is to review the changing role of the electrocardiogram in the diagnosis of cardiac chamber enlargement. Electrocardiographic criteria for the diagnosis of ventricular hypertrophy and atrial enlargement are reviewed in relation to autopsy, angiographic, echocardiographic and imaging findings. The electrocardiographic theory underlying the recognition of hypertropphy or dilation incorporates a number of sound physical principles that may lead to meaningful correlations with the tissue mass, chamber diameter and intracardiac blood volume. However, there are limiting factors related to the variable orientation of the heart in the chest, variable extracardiac factors and nonspecificity of each depolarization and repolarization abnormality used in the diagnosis of hypertrophy or dilation. This explains the superiority of the new noninvasive methods, in particular echocardiography, in the diagnosis of hypertrophy. Echocardiography is superior to electrocardiography in the detection of mild hypertrophy, and is more useful in the serial follow-up of changes during progression or regression of chamber enlargement.

Pharmacologic treatment of cardiac arrhythmias: 25 years of progress.

This review of practical and theoretical advances in antiarrhythmic drug therapy consists of four parts. Part 1, on clinical applications, compares the approaches to treatment 25 years ago with those of today, examines the current status of antiarrhythmic drugs used 25 years ago, reports on drugs approved for clinical use during the past 25 years, reviews new experimental drugs and suggests an approach to classification of antiarrhythmic drugs. Part 2 summarizes the contributions of cellular electrophysiology to the understanding of drug action, with emphasis on the drug-induced block of the voltage- and time-dependent properties of the rapid sodium channel. The subsequent section contains a brief discussion of the impact made by the new knowledge and the new diagnostic technology on the contemporary practices. The main conclusions are 1) that the more rational approach to treatment has benefited proportionately more patients with supraventricular than with ventricular arrhythmias, and 2) that new advances have made it possible to design successful treatments for certain patients with problems that could not be resolved in the past.

Cardiac alternans: diverse mechanisms and clinical manifestations.

OBJECTIVES: The purpose of this review is to assemble the widely dispersed information about cardiac alternans and to categorize the types and mechanisms of alternans, their clinical manifestations and possible therapeutic implications. BACKGROUND: The phenomena of mechanical and electrical alternans have been of continuing interest to both physiologists and clinicians. Recent studies have enhanced this interest because of the reported association of alternans with experimental myocardial ischemia and cardiac arrhythmias. METHODS: The review formulates concepts based on extensive review of published studies and personal observations. RESULTS: Cardiac alternans has been subdivided into the following four categories: 1) mechanical, 2) electrical, 3) in association with myocardial ischemia, and 4) in association with cardiac motion. Mechanical alternans can be explained by hemodynamic or inotropic alterations, or both. Mechanical alternans in the ventricular muscle is accompanied by alternans of action potential shape. In the Purkinje fibers, action potential duration alternates without change in shape and is determined by the duration of the preceding diastolic interval. However, in ventricular muscle fiber, alternans can occur in the presence of constant diastolic intervals. T wave alternans reflects changes in action potential duration and is frequently associated with a long QT interval. Electrocardiographic manifestations of conduction alternans occur at many different sites within the conducting system and myocardium. During myocardial ischemia, additional mechanisms of repolarization alternans have been proposed. Alternans occurring in the presence of a large pericardial effusion is attributed to swinging motion of the heart maintaining two-beat periodicity. CONCLUSIONS: Since its origin as "pulsus alternans" described by Traube in 1872, the definition of alternans has evolved into a term encompassing multiple physiologic and pathologic phenomena that, although united by the term cardiac alternans, diverge widely with respect to etiology, mechanism and clinical significance.

Long QT: good, bad or indifferent?

A survey of current literature suggests an increasing interest in both the desirable and undesirable implications of a prolonged QT interval, the former perceived to be the beneficial effect of antiarrhythmic drugs that prolong the duration of ventricular action potential, and the latter considered to be a potential marker for sudden cardiac death in patients with ischemic heart disease. In addition, there has been an increasing interest in the congenital long QT syndrome associated with an apparent dysfunction of the autonomic nervous system and serious, potentially lethal ventricular arrhythmias. Circumstantial evidence suggests that these arrhythmias are due to increased dispersion of repolarization which may be aggravated by psychologic and emotional perturbations. In this review, the associations between the long QT interval, autonomic nervous system, dispersion of repolarization, antiarrhythmic drugs and ventricular arrhythmias are examined. Attention is directed to the difficulties of accurate QT measurement, problems related to the correction of the QT interval for heart rate and sex (QTc), the wide range of normal values and the modest QT alterations after various manipulations of the autonomic nervous system. Clinical conditions associated with marked, moderate and occasional QT lengthening are listed and discussed briefly in relation to the disturbances of nervous system, dispersion of ventricular repolarization and ventricular arrhythmias. It is proposed that the absence of relevant animal models of neurogenic or psychogenic QT prolongation hinders the investigation of the neurogenic factors associated with QT lengthening. QT prolongation is most often induced by antiarrhythmic drugs and ischemic heart disease. However, it is not known whether the occurrence of torsade de pointes type of ventricular tachycardia in patients treated with antiarrhythmic drugs is related to a critical drug dose or a critical degree of QTc prolongation. There is no conclusive evidence that QT lengthening has any predictive value either during the acute phase or during convalescence after myocardial infarction. Also, a serious deficiency in current knowledge is the lack of an established relation between the prolonged QT interval and the dispersion of ventricular repolarization. It is concluded that the number of unanswered questions discussed in this review still makes it difficult to judge when a prolonged QT interval is good, bad or indifferent.

QRS changes during percutaneous transluminal coronary angioplasty and their possible mechanisms.

OBJECTIVES: The purpose of the study was to describe the configuration, and investigate the mechanisms, of QRS changes occurring during percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: QRS changes during PTCA have been attributed to both a passive ST segment shift and conduction disturbances (peri-ischemic block). The direct relation between ST segment shift and QRS changes, however, has not been established, and the definition of conduction disturbances remains to be clarified. METHODS: Twelve-lead electrocardiograms (ECGs) were recorded before PTCA, at the end of 2 min of PTCA and after return to baseline values in 29 patients (left anterior descending coronary artery [LAD] in 13 patients, right coronary artery [RCA] in 14 and left circumflex coronary artery in 2). Electrocardiographic complexes before and during PTCA were superimposed to determine the amplitudes of initial, terminal and total QRS deflection; the relations of QRS changes to baseline (TP segment) and ST segment shift; and the duration of QRS and corrected QT intervals. RESULTS. 1) The direction of the initial QRS deflection was unchanged, but changes of its amplitude occurred. 2) Terminal QRS deflection changed in all patients with a ST segment shift > 17% of the R amplitude, and the correlation between the decrease in the S amplitude and ST segment shift was significant (r = 0.9, p < 0.01) in patients with LAD PTCA. Correlation between changes in total QRS amplitude and ST segment shift in patients with RCA PTCA was weaker (r = 0.54, p = 0.056). 3) Transient conduction disturbance manifested by QRS widening in selected leads occurred in 2 of 29 patients. CONCLUSIONS. 1) Changes in terminal QRS deflection during PTCA are proportional to the magnitude of the ST segment shift. 2) Conduction disturbances manifested by increased QRS duration occurred infrequently. We suggest that the term peri-ischemic block be applied only to changes in QRS configuration associated with QRS widening.

Role of potassium channels in cycle length dependent regulation of action potential duration in mammalian cardiac Purkinje and ventricular muscle fibres.

This review examines the putative role played by three repolarising potassium currents, namely the transient outward current (ito), the inward rectifying current (iK1), and the late outward rectifying current (iK), in the regulation of action potential duration in cardiac Purkinje and ventricular muscle fibres under normal physiological conditions. The role of other potassium currents, including the ATP activated current (iK,ATP) under these conditions is uncertain. Personal experiences and work of others are reviewed to summarise: (1) regulation of normal cycle length dependent action potential duration: (2) the characteristics of ito, iK1, and iK pertinent to repolarisation; and (3) the effects of potassium channel blockers and activators on cycle length dependent action potential duration. The presence of ito creates a notch after depolarisation and limits action potential duration at long cycles. Block of iK1 prolongs action potential duration predominantly by slowing phase 3 of the action potential. Block of iK prolongs the duration predominantly by lengthening phase 2 of the action potential, and the lengthening becomes more pronounced at longer cycles. Activation of iK,ATP shortens the duration, and the shortening becomes more pronounced at longer cycles. Each of the three major repolarising potassium currents appears to play a different role in modulating the action potential duration. Ito creates a notch which resets the early course of plateau, and also limits the duration at long cycles. IK1 contributes to maintenance of plateau and controls repolarisation course during phase 3 of the action potential. IK plays major role in controlling action potential duration within a wide range of cycle lengths in Purkinje fibres, and when present, also in ventricular muscle fibres.

Verapamil plasma levels and ventricular rate response in patients with atrial fibrillation and flutter.

The acute effect of verapamil on the ventricular rate in atrial fibrillation and flutter was studied in 15 patients, 13 of whom had heart rate inadequately controlled with digitalis. Plasma concentrations were measured 5 and 10 min after intravenous doses of 0.075 mg/kg and 0.15 mg/kg verapamil. In 9 patients who were clinically compensated, the 0.075-mg dose alone decreased the ventricular rate to under 100/min (responders); in the remaining 6, who had acute congestive heart failure manifested by orthopnea, rales, and pulmonary congestion, ventricular rates were above 100/min after the 0.075-mg dose (nonresponders). The 6 nonresponders received the 0.15-mg dose 30 min later. In all, the response was greater when plasma drug concentration rose after the high dose, although the rate decrease was smaller than in the 9 compensated patients who received the low dose. These results can be explained by assuming an antagonism of the verapamil effect by sympathetic stimulation in nonresponders.

Exercise testing for detection of myocardial ischemia in patients with abnormal electrocardiograms at rest.

This review consists of two parts: (1) discussion of the electrophysiologic mechanisms that are believed to produce ventricular repolarization changes during the electrocardiographic stress test, and (2) clinical assessment of the electrocardiographic changes with stress in patients with an abnormal electrocardiogram at rest. In the first part, the mechanisms of S-T segment elevation, S-T segment depression, T wave changes and linked S-T and T wave changes are reviewed. In the second part, all electrocardiographic abnormalities at rest are grouped into four categories: (1) changes that mask the manifestations of ischemia, (2) changes that stimulate or exaggerate the manifestations of ischemia, (3) changes that have no important effect on the manifestations of ischemia, and (4) changes that reproduce the patterns of acute myocardial infarction after an apparent healing. The reported studies of electrocardiographic stress testing in patients who have abnormal electrocardiogram at rest are summarized.

Coexistence of ventricular parasystole and ventricular couplets: mechanism and clinical significance.

In 78 consecutive patients with uniform ventricular ectopic complexes and without heart disease, ventricular couplets were present significantly more often when the coupling interval of ventricular ectopic complexes was variable than when it was fixed (P less than 0.04). In 69 consecutive patients with couplets, the prevalence of a variable coupling interval was significantly greater than that of (55 versus 14 cases; P less than 0.001). Among 55 patients with a variable coupling interval, ventricular parasystole was probable in 38 and possible in 17 patients. These results suggest that the association between ventricular couplets and parasystole is not coincidental. Of several possible mechanisms responsible for this association reentry within the parasystolic focus or its vicinity is the most probable. This may explain the observation that the couplets are seldom followed by consecutive ventricular ectopic complexes or ventricular tachycardia. If this hypothesis is correct, the clinical significance of ventricular couplets in the presence of ventricular parasystole may be similar to that of single reentrant ventricular ectopic complexes.

Ventricular monophasic action potential changes associated with neurogenic T wave abnormalities and isoproterenol administration in dogs.

Changes in the duration of monophasic action potentials on the anterior and posterior walls of the dog ventricle were correlated with changes in T wave polarity and duration of the Q-T interval after (1) left stellate ganglion transection, (2) right stellate ganglion stimulation, and (3) administration of isoproterenol before or after these procedures. Left stellate ganglion transection and right stellate ganglion stimulation produced similar changes in T wave polarity, but the former prolonged and the latter shortened the Q-T interval. All procedures changed the duration of the monophasic action potential and the Q-T interval in the same direction. The reversal of T wave polarity induced by left stellate ganglion transection, right stellate ganglion stimulation or administration of isoproterenol after left stellate ganglion transection was associated with an average change of 13 to 17 msec in the difference between the monophasic action potential durations on the anterior and posterior ventricular walls. Isoproterenol restored to normal the neurogenic T wave abnormalities produced by left stellate ganglion transection and right stellate ganglion stimulation. The drug shortened the previously prolonged monophasic action potential more than the normal monophasic action potential, and the normal monophasic action potential more than the previously shortened monophasic action potential. This study confirms that the T wave is a sensitive indicator of relatively small changes (less than 20 msec) in the sequence of ventricular repolarization and explains the mechanism by which isoproterenol "normalizes" the primary T wave abnormalities.

Effects of hyperkalemia on the electrocardiogram of patients receiving digitalis.

In a prospective and a retrospective study, the effects of hyperkalemia on the electrocardiogram (ECG) of patients treated with customary maintenance doses of digoxin were examined and the results were compared with the effects of hyperkalemia in patients not receiving digitalis. The prospective study included 11 patients treated and 11 not treated with digitalis, and the retrospective study 27 patients treated and 61 not treated with digitalis. In all patients serum potassium concentrations (Ks) were determined within 1 hour of the recorded electrocardiogram. Serum digoxin concentrations, measured in 11 patients in the prospective and in 4 in the retrospective study, ranged from 0.7 to 5.0 ng/ml, and exceeded 2.0 ng/ml in 10 of 15 patients. Since the results of the prospective and of the retrospective study were similar, they were combined. In patients treated with digitalis, Ks ranged from 5.5 to 6.6 mEq/liter in 21 patients, from 6.7 to 7.5 mEq/liter in 17 and from 7.6 to 8.5 mEq/liter in 6; the Ks was 9.1 mEq/liter in 1 patient. The ventricular rate in patients treated with digitalis ranged from 48 to 140 beats/min, and was not significantly different from that in untreated patients within each range of Ks. Atrioventricular (AV) junctional rhythm occurred more frequently in the electrocardiograms of digitalis-treated patients (15 of 45 vs 2 of 76, p less than 0.001). The average PR intervals were longer in patients treated with digitalis who had Ks greater than 6.6 mEq/liter, but no patient in the study had greater than first-degree AV block, and no patient required a pacemaker.(ABSTRACT TRUNCATED AT 250 WORDS)

Negative U wave: a highly specific but poorly understood sign of heart disease.

A negative U wave is highly specific for the presence of heart disease and is associated with other electrocardiographic abnormalities in more than 90 percent of patients. The three most common conditions associated with a negative U wave are systemic hypertension, aortic and mitral regurgitation and ischemic heart disease. The U wave vector is directed opposite to the QRS axis in the horizontal plane in patients with both left and right ventricular hypertrophy. In patients with ischemic heart disease, the U wave vector tends to be directed away from the site of the akinetic or dyskinetic region. The change from a negative to an upright U wave after a reduction in blood pressure, renal transplantation, insertion of a valve prosthesis or a coronary arterial bypass graft procedure is associated with a decrease in the QRS amplitude but with no consistent changes in T wave polarity. The timing of the U wave apex is dependent on the duration of ventricular repolarization but not on the duration of the QRS complex. This finding and other electrocardiographic observations are explained better by the ventricular relaxation than by the Purkinje fiber repolarization theory of U wave genesis.

The effects of amiodarone on repolarization and refractoriness of cardiac fibers.

The effects of superfusion (acute) and chronic amiodarone pretreatment on repolarization in dog Purkinje and guinea pig papillary muscle fibers were studied using standard microelectrode techniques. In dog Purkinje fibers superfusion with 5 and 50 micrograms/ml amiodarone shortened action potential duration, slowed restitution of premature action duration, and decreased the range of premature action potential durations. In Purkinje fibers from pretreated dogs action potential duration and range of premature action potential durations did not differ significantly from the corresponding control values but restitution was slowed. In guinea pig papillary muscle superfusion with 20 micrograms/ml amiodarone did not change action potential duration and restitution kinetics but in the muscle fibers from pretreated animals both the action potential duration and the range of premature action potential durations were increased. We concluded that the designation of 'class III action' applied to chronic amiodarone treatment in ventricular but not to chronic treatment in Purkinje fibers, and not to acute treatment in either fibers.

Use-dependent effects of amiodarone on Vmax in cardiac Purkinje and ventricular muscle fibers.

Superfusion with 5 micrograms/ml amiodarone for 3-4 h induced use-dependent Vmax block in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was exponential with tau of 289 +/- 30 ms in Purkinje (n = 7) and 282 +/- 47 ms in muscle (n = 6) fibers. The onset of frequency-dependent Vmax block was rapid, i.e. reached steady state after 4.2 +/- 0.5 beats (n = 5). The combination of rapid interaction with sodium channel and the reported action potential lengthening make amiodarone unique among Class I antiarrhythmic drugs.

What determines the choice of treatment in patients with supraventricular tachycardia?

I have outlined the approach to therapy of supraventricular tachyarrhythmias practiced by a cardiologist who is not performing special studies in the cardiac electrophysiology laboratory. This review includes the list of common and rare supraventricular arrhythmias, application of diagnostic noninvasive procedures, indications for referral for special electrophysiologic studies, and brief description of drugs and procedures used in the therapy of supraventricular tachyarrhythmias. In addition to general guidelines for treatment of these arrhythmias, I have outlined specific recommendations for patients with acute myocardial infarction, angina pectoris, ventricular dysfunction and congestive heart failure, obstructive cardiomyopathy, hyperthyroidism, AV accessory pathways, chronic obstructive lung disease, diabetes mellitus, hypertension, concomitant ventricular arrhythmias, tachycardia-bradycardia syndrome, and anxiety.

Noninvasive assessment of ventricular arrhythmias in clinical practice: prognostic implications.

Frequency and complexity of ventricular arrhythmias increases with age and increasing severity of heart disease. However, fatal ventricular fibrillation occurs frequently in the absence of symptomatic warning arrhythmias. Several classifications of ventricular arrhythmias are discussed. The morphology of ventricular premature complexes (VPC), their frequency and complexity at rest, during ordinary activity, or after exercise do not influence life expectancy of subjects without heart disease, nor in those with coronary artery disease with no history of myocardial infarction. In the survivors of myocardial infarction, the frequency and "complexity" of ventricular arrhythmias appears to be an independent risk factor for sudden and nonsudden cardiac death. However, the low specificity and predictive value of ventricular arrhythmias makes their assessment difficult for practical purposes. The prognosis of most patients with ventricular arrhythmias is determined predominantly by the condition of the heart. "Complex" arrhythmias at rest and during exercise do not appear to worsen prognosis and life expectancy in individuals without heart disease. Ambulatory electrocardiographic monitoring has serious limitations as a guide for clinical decision making. Ventricular tachycardias in patients with coronary artery disease are not strictly related to the frequency and "complexity" of ventricular premature complex, but correlate with the presence of ventricular aneurysms, poor ventricular function and late potentials in the signal-averaged high frequency electrocardiogram. Recording of such late potentials is a new and promising noninvasive technique for identification of patients with serious arrhythmias but the sensitivity and specificity of this method remains to be established.