Bradycardia-dependent long QT syndrome, sudden death and late potentials.
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Arrhythmias, Cardiac↗
Biomedical subjects
B Surawicz
Publications and source records attributed to B Surawicz.
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.
Animals↗
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.
Action Potentials↗
Familial congenital sinus rhythm anomalies: clinical and pathological correlations.
We describe pathological abnormalities in a 72-year-old male member of a family with a congenital absence of sinus rhythm and a tendency to develop atrial fibrillation at an early age, and in a 54-year-old female member of a family with cardiomyopathy and progressive conduction system disease manifested by first-degree atrioventricular (AV) block, left bundle branch block, and atrial arrhythmias. Both patients died suddenly. The absence of sinus rhythm in case 1 could be explained by marked atrophy, degeneration, and isolation of the sinoatrial (SA) node. The SA node was also diseased in the member of the other family with atrial arrhythmias. Additional common features in both cases included: fatty metamorphosis and degenerative changes of the approaches to the SA node, the atrial preferential fibers, and the approaches to the AV node, a small AV node, degenerative changes of the bundle branches, and floppy AV valves. These findings show that the pathological substrate of familial supraventricular arrhythmias consists of a diffuse involvement of the entire conduction system, bearing resemblance to pathological findings in elderly subjects with acquired sick sinus syndrome.
Aged↗
Effects of propranolol on premature action potentials in canine Purkinje and ventricular muscle.
We compared the effects of a low (0.09 microgram/ml) concentration of propranolol expected to produce only beta-adrenoceptor blockade and a high concentration (0.9 microgram/ml) expected to produce additional direct local anesthetic-like electrophysiological effects on basic and premature action potentials. Both isolated dog cardiac Purkinje and ventricular muscle fibers were examined using conventional microelectrode techniques. The low concentration of propranolol produced no significant electrophysiological change in either fiber type. The high concentration of propranolol shortened the action potential duration and refractoriness while decreasing the maximal upstroke velocity (Vmax) in both Purkinje and ventricular muscle fibers at a constant basic cycle length. In Purkinje fibers, the high concentration also slowed the kinetics of restitution of the action potential duration (tau c from 124.6 +/- 6.5 to 201.4 +/- 16.0 ms, p less than 0.01, n = 7), slowed the recovery kinetics of Vmax, and shifted the early portion of the normalized restitution curve toward longer action potential duration values in both fiber types. The range of premature action potential durations, defined as the difference between action potential durations during the first 100 ms of restitution, was decreased by the high concentration of propranolol in both Purkinje and ventricular muscle fibers by 39.5% and 33.9%, respectively. These findings indicate that (a) low concentrations of propranolol produced no direct electrophysiological effect, and (b) high concentrations of propranolol produced several potential antiarrhythmic effects in addition to the previously reported effects on Vmax and the action potential duration.
Action Potentials↗
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.
Adrenergic beta-Antagonists↗
Ventricular arrhythmias: why is it so difficult to find a pharmacologic cure?
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Adolescent↗
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.
Animals↗
Is hypomagnesemia or magnesium deficiency arrhythmogenic?
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Animals↗
Effect of altered repolarization course induced by antiarrhythmic drugs and constant current pulses on duration of premature action potentials in canine cardiac Purkinje fibers.
The purpose of this study was to elucidate the mechanism of the upward shift of the electrical restitution curve, i.e., the lengthening of premature action potential duration (APDt) expressed as percentage of basic APD, induced by class I antiarrhythmic drugs in dog Purkinje fibers. In this study, six class I antiarrhythmic drugs lengthened APDt at a diastolic interval of 20 ms by 2.5-14.1%. The drugs also decreased the ratio of APD at 50% to APD at 90% of repolarization from 70.8 +/- 1.8% (n = 60) to 47.4-60.8%. The relation between the decrease in the ratio of APD50 to APD90 of the basic AP and lengthening of the normalized APDt was linear (r = 0.92; p less than 0.01). We attributed the lengthening of normalized APDt to the decreased ratio of APD50 to APD90, and applied repolarizing current pulses in short (less than or equal to 2 mm) fibers to simulate the drug-induced decrease in the ratio of APD50 to APD90. The altered repolarization course of basic AP by the current pulse during late plateau and early phase 3 caused APDt lengthening. The relation between the current-induced decrease in the ratio of APD50 to APD90 of the basic AP and the lengthening of normalized APDt was linear (r = 0.91; p less than 0.01). The slope of regression line describing this relation was similar to that in the presence of drugs. These results suggest that lengthening of the normalized APDt by class I antiarrhythmic drugs results from a more rapid repolarization during phase 2 of the preceding basic AP, possibly due to lesser influence of the delayed outward rectifying current. The lengthening of APDt by class I drugs may contribute to their antiarrhythmic action.
Action Potentials↗
Action potential duration alternans in dog Purkinje and ventricular muscle fibers. Further evidence in support of two different mechanisms.
An abrupt shortening of cycle length causes action potential duration (APD) alternation in both canine Purkinje (P) and ventricular (V) muscle fibers. Our recent study suggested that APD alternans is determined by the process controlling APD during electrical restitution in P but not in V fibers. In the latter, alternans was attributed to changes in the availability of intracellular calcium [Ca2+]i. We examined this hypothesis further with the following pharmacologic probes known to alter restitution or action of [Ca2+]i: tetradotoxin (0.5-3.0 microM), lidocaine HCl (2.0-12.0 micrograms/ml), sotalol (10 microM), nicorandil (10-20 microM), 4-amino-pyridine (0.5 microM), ryanodine (10 microM), caffeine (2 mM), and ARL 115 BS (100 microM). Alternans in P fibers persisted under all studied conditions but varied in magnitude depending on the time constant and amplitude of restitution. In V fibers, the magnitude of alternans did not correlate with APD changes during restitution, and APD alternans was associated with the alternans of action potential shape and alternans of developed tension. Alternans in V was suppressed by caffeine at 2.0 mM [Ca2+]o when tension was increased and by ryanodine at 1.0 mM [Ca2+]o when tension was decreased. Alternans in V was not altered by changes in [Ca2+]o within the range of 1.0-4.0 mM; by ARL 115 BS, a compound that increases myofibrillar sensitivity to calcium; or by any other pharmacologic probes. We concluded that in P fibers, APD alternans was determined by the factors controlling APD in the absence of alternans; V fibers posses an independent mechanism of alternans linked to alternans of tension and controlled by [Ca2+]i; in V fibers, alternans could be suppressed by both positive and negative inotropic interventions; and calcium released from sarcoplasmic reticulum plays an important role in the V alternans.
Action Potentials↗
Frequency-dependent and independent effects of tetrodotoxin on Vmax in cardiac fibers.
Superfusion with 3 microM tetrodotoxin (TTX) induced both a use-dependent and a frequency-independent depression of the rate rise of the action potential (Vmax) in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was fast and exponential with a time constant of 225.4 +/- 7.1 ms in dog Purkinje fibers (n = 6). The onset kinetics of the frequency-dependent Vmax block was rapid, i.e. reached steady state after 3.0 +/- 0.3 beats in guinea pig ventricular muscle (n = 6). The rapid use-dependent interactions with sodium channel make TTX similar to antiarrhythmic drugs with fast kinetics i.e. lidocaine, mexiletine, and tocainide, but unlike antiarrhythmic drugs, TTX-induces a large frequency-independent Vmax block at the same concentrations.
Action Potentials↗
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.
Action Potentials↗
Follow-up of the family with congenital absence of sinus rhythm.
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Adult↗
Alternans of action potential duration after abrupt shortening of cycle length: differences between dog Purkinje and ventricular muscle fibers.
The purpose of this study was to determine whether the alternans of action potential duration (APD) occurring in Purkinje and ventricular muscle fibers after an abrupt shortening of cycle length can be explained by the two factors controlling the cycle length-dependent APD changes (i.e., restitution and memory effect). Action potentials were recorded simultaneously from dog Purkinje fibers and ventricular muscle fibers using conventional microelectrode techniques. APD change during alternans was dependent on the preceding diastolic interval in the same manner as during restitution in Purkinje fibers but not in ventricular muscle fibers. The course of memory change was not affected by the presence of alternans in either fiber type. In Purkinje fibers, APD alternans was attenuated by a Ca2+ channel blocker, nisoldipine (2 X 10(-6) M), and augmented by a Ca2+ channel agonist, Bay K 8644 (3 X 10(-8) M). These effects were attributed to the changes in the kinetics and the amplitude of restitution. In ventricular muscle fibers, APD alternans was always preceded and accompanied by alternans of action potential shape. Alternans of both action potential shape and APD was suppressed by nisoldipine (2 X 10(-6) M) and attenuated by Bay K 8644 (3 X 10(-8) M). These results show that in Purkinje fibers, APD during alternans can be explained by restitution and memory effect. However, in ventricular muscle fibers, the mechanism of APD alternans is linked to factors controlling action potential shape. These findings are compatible with the hypothesis that APD alternans in Purkinje fibers depends on the differences in the recovery of membrane currents generated by the preceding action potential and in ventricular muscle fibers on the differences in the concentration and/or handling of intracellular calcium.
Action Potentials↗
Contributions of cellular electrophysiology to the understanding of the electrocardiogram.
The understanding of cardiac action potential and membrane currents has broadened the theoretical foundation and enhanced the clinical usefulness of the electrocardiogram. An improved understanding of the morphology of the electrocardiographic waveform has resulted from: correlations between Vmax of depolarization and QRS complex, plateau of the ventricular action potential and S-T segment, terminal repolarization and T-wave, from definitions of action potential differences responsible for the T-wave, and recordings of action potential alternans. Cellular electrophysiology has contributed to the understanding of certain mechanisms of cardiac standstill. Many disturbances of conduction and refractoriness associated with ventricular arrhythmias can be attributed to the following derangements at the cellular level: slowing of terminal repolarization, development of diastolic depolarization in fibers with stable resting membrane potential, after-depolarizations, currents of injury resulting from non-uniform polarization, increased dispersion of action potential durations, and co-existence of slow conduction and short premature action potentials.
Action Potentials↗
Effect of mexiletine, amiodarone and disopyramide on the excitability and refractoriness of canine cardiac fibers: possible relation to antiarrhythmic drug action and classification.
We tested the hypothesis of Campbell that the effect of the sodium channel-blocking antiarrhythmic drugs on postrepolarization refractoriness i.e., relation between action potential duration (APD) and effective refractory period (ERP) is determined by the drug's effect on the recovery from Vmax block. We studied the effects of two antiarrhythmic drugs with fast (mexiletine, amiodarone), and one with slow (disopyramide) kinetics of recovery from Vmax block, at two different basic cycle lengths (BCL), on ERP/APD ratio in cardiac dog Purkinje and ventricular muscle fibers. ERP was measured using stimuli of 2 ms duration and 1.0 to 5.0 times diastolic threshold strength. The three drugs altered the kinetics of recovery from Vmax block in the manner previously reported by us and other investigators. In both fiber types, mexiletine increased and the other two drugs did not change the ERP/APD ratio. We concluded that the magnitude of postrepolarization refractoriness could not be predicted from the kinetics of the Vmax block. Also, the effect of the drug on the ERP/APD ratio could be altered by changes in the stimulus strength and the BCL.
Amiodarone↗
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.
Anti-Arrhythmia Agents↗