Propafenone during acute myocardial ischemia in patients: a double-blind, randomized, placebo-controlled study.

OBJECTIVES: The proarrhythmic risk of class I antiarrhythmic agents in combination with myocardial ischemia is mainly the result of their effects on ventricular repolarization. This study was designed to evaluate the effect of class Ic antiarrhythmic agents on QT dispersion during myocardial ischemia. BACKGROUND: QT interval dispersion on the 12-lead electrocardiogram (ECG) has been suggested as a noninvasive marker of inhomogeneous ventricular repolarization and susceptibility to ventricular arrhythmias. METHODS: In a randomized, double-blind study, 98 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) were pretreated with propafenone or placebo. QT dispersion was defined as a maximal minus minimal QT interval on the 12-lead ECG before and after PTCA. The power of the study to detect clinically meaningful differences in QT dispersion was 0.75, and a twofold increase in QT dispersion in the propafenone group compared with the placebo group was considered clinically relevant. RESULTS: The QT and corrected QT (QTc) intervals increased significantly during occlusion of the left anterior descending coronary artery (LAD) (9% and 11%, respectively, p < 0.05), whereas occlusion of the circumflex and right coronary arteries had no effect. QTc dispersion increased significantly in the propafenone group during ischemia (+52%, p = 0.002, vs. +23%, p = 0.15). The most considerable effect on QT dispersion was observed during LAD occlusion and ischemia of the anterior wall (+74%, p = 0.025). Corrected JT dispersion (+57%, p = 0.017, vs. +24%, p = 0.23) and the QT dispersion ratio (+1.6%, p = 0.031, vs. 0.9%, p = 0.34) showed similar effects. Plasma levels of propafenone (522 +/- 165 micrograms/liter) did not influence the results. CONCLUSIONS: During myocardial ischemia, particularly during LAD occlusion, propafenone results in a significant increase in QT dispersion. The results indicate that QT interval prolongation and enhanced QT dispersion reflect inhomogeneous ventricular repolarization generated by the ischemic anterior wall of the myocardium. These observations may demonstrate a clinically important interaction between myocardial ischemia, repolarization variables and propafenone.

Usefulness of carvedilol in unstable angina pectoris.

The safety and efficacy of adding oral carvedilol (25 mg twice daily) to standardized treatment of unstable angina was assessed in a multicenter, randomized, double-blind, placebo- controlled trial on 116 patients with acute unstable angina. Patients were monitored in an intensive care unit and underwent 48-hour Holter monitoring to assess transient ischemia. Carvedilol as adjunctive therapy resulted in a significant reduction of median heart rate (65 vs 75 beats/min, p <0.05), mean systolic blood pressure (133 vs 130 mm Hg, p <0.05), and mean rate-pressure product (8,337 vs 10,042, p <0.05). Carvedilol reduced the ischemic burden during 48 hours of treatment by 75% (49 vs 204 minutes), including a 36% reduction of patients with ischemic episodes (p <0.05), a 66% reduction of the mean number of ischemic episodes (8 vs 24, p <0.05), and a 76% reduction in the mean duration of ischemic episodes (50 vs 205 minutes, p <0.05). Side effects occurred in 8 of 59 patients (13.6%) in the carvedilol group and in 5 of 54 patients (8.8%) given placebo. Although not significant, the early onset of maximal blood pressure reduction and the delayed effect on heart rate were closely correlated to drug-induced hypotension and bradycardia in the carvedilol group. Thus, carvedilol as an adjunctive to standardized treatment effectively reduces heart rate and blood pressure, and thus the ischemic burden in patients with unstable angina pectoris, but requires close monitoring of patients at risk for bradycardia or hypotension.

Drug-induced torsade de pointes. Incidence, management and prevention.

Torsade de pointes is a particular form of polymorphic ventricular tachycardia causing few haemodynamic symptoms, but carries a poor prognosis because of recurrence and sudden death in up to 31% of patients. A wide range of agents have been shown to aggravate and even to cause torsade de pointes by prolonging the QT interval or increasing QT dispersion. For the majority of substances the incidence of torsade de pointes remains unclear, but is of the order of 3 to 15% for a wide range of agents. Elicitation of proarrhythmia by drug-induced QT prolongation is mainly based on increased cellular excitability and/or abnormal dispersion of ventricular repolarisation. Torsade de pointes has been shown to be related to bradycardia-dependent early after-depolarisations and/or increased dispersion of repolarisation. Clinically, patients with predisposing factors prior to medication should be considered at risk of drug-mediated proarrhythmia. Typically, torsade de pointes occurs during the first days of antiarrhythmic therapy. During this phase, QT interval measurement and assessment of the QTc time should be performed frequently. Phases of bradycardia or occurrence of ventricular extra beats with a long coupling interval may be of help to identify patients at high risk of proarrhythmic events. As a first attempt in managing this arrhythmia, magnesium sulphate has been shown to be effective in many patients. In case of recurrence of torsade de pointes, the use of a temporary pacemaker with pacing at about 100 to 120 beats/min is the therapy of choice until the causative agent has been completely eliminated.

Comparison of knee joint cartilage thickness in triathletes and physically inactive volunteers based on magnetic resonance imaging and three-dimensional analysis.

The objective of this study was to employ quantitative magnetic resonance imaging for the analysis of knee joint cartilage thickness in triathletes and physically inactive volunteers. The right knee joints of nine male triathletes (10 hours training per week for at least 3 years) and nine inactive male volunteers (<1 hour of physical activity per week throughout life) were imaged with a previously validated fat-suppressed gradient echo sequence. The cartilage plates were reconstructed three-dimensionally, and the cartilage thickness was computed independently of the original section orientation with a three-dimensional Euclidian distance transformation. There was a high interindividual variability of the mean and the maximal cartilage thickness values in all surfaces, both in the triathletes and in the inactive volunteers. In the patella, the femoral trochlea, and the lateral femoral condyle, the mean and maximal cartilage thickness values were slightly higher in the triathletes, but they were somewhat lower in the medial femoral condyle, and in the medial and lateral tibial plateau. However, the differences did not attain statistical significance. These results are unexpected in view of the functional adaptation observed in other musculoskeletal tissues, such as muscle and bone, in which a more obvious relationship with the magnitude of the applied mechanical stress has been observed.

Clusters of life-threatening ventricular arrhythmias in patients with implanted cardioverter-defibrillators: prevalence, characteristics, and risk stratification.

BACKGROUND: Series of discharges from an implanted defibrillator (ICD) to terminate life-threatening ventricular tachyarrhythmias are one particular aspect of energy use and success of ICD therapy. Little is known about prevalence. characteristics, and risk stratification of so-called "cluster arrhythmias." HYPOTHESIS: The objective of this study was to examine the frequency of cluster arrhythmias, to characterize the temporal relationship precisely, and to assess the accompanying circumstances of their occurrence, whereby risk stratification was to be made if appropriate. METHODS: In all, 63 consecutive patients were followed prospectively over 727 +/- 684 days to determine the presence and characteristics of cluster arrhythmias (45,801 patient days). In 30 patients, 374 ICD episodes of ventricular tachyarrhythmias were analyzed for their temporal relationship. After a first successfully terminated ventricular tachyarrhythmia, further ICD discharges within 3 h were observed during 145 of 374 (39%) episodes; mean time interval between these arrhythmias was 25 +/- 32 min. RESULTS: Arrhythmia clusters occurred in 19 of 30 (63%) patients. In multivariate analysis, only underlying heart disease was predictive for accumulation of ventricular tachyarrhythmias. Cluster arrhythmias were more frequent among patients with ischemic heart disease than among those with nonischemic heart disease (40.0 vs. 29.2%, p < 0.05). Ejection fraction, age, gender, and other parameters were not predictive for occurrence of arrhythmia clusters. In 4 of 19 patients, accumulation of ICD discharges was predictive for new onset of myocardial ischemia elicited by exercise test. CONCLUSIONS: Cluster arrhythmias are most common in patients with ICDs with coronary heart disease and may indicate disease progression and increasing instability, for example, due to new onset of myocardial ischemia.

Torsade de pointes complicating drug treatment of low-malignant forms of arrhythmia: four cases reports.

In patients with malignant ventricular arrhythmias, antiarrhythmic therapy is known to carry a substantial risk of proarrhythmia. This risk is usually considered to be low when supraventricular arrhythmias or benign ventricular arrhythmias are considered. We were able to collect data on four patients without a history of life-threatening arrhythmias, in whom antiarrhythmic therapy was used and resulted in documented ventricular fibrillation or torsade de pointes. In Cases No. 1 and 2, atrial fibrillation was treated with either quinidine or quinidine and sotalol in combination. In both patients Holter monitoring, 4-12 h after conversion to sinus rhythm, documented the spontaneous occurrence of torsade de pointes degenerating into ventricular fibrillation and requiring DC shock for termination. In Case No. 3, atrial fibrillation was treated with sotalol and amiodarone for 2 months when incessant episodes of torsade de pointes were documented. In Case No. 4, frequent but unsustained ventricular arrhythmias were treated with amiodarone in a patient suffering dilative cardiomyopathy. After 6 days of treatment at a heart rate of 54 beats/min, a marked QT increase was associated with the occurrence of repetitive episodes of polymorphic ventricular tachycardia degenerating into ventricular fibrillation. None of the patients presented significant electrolyte abnormalities in the laboratory. A pathologic increase of the QTc-time was documented in Cases No. 1, 3, and 4. In all patients antiarrhythmic therapy was withdrawn after the proarrhythmic event and the patient became free of malignant tachyarrhythmias. Antiarrhythmic therapy also carries a considerable risk of proarrhythmia when "benign" cardiac arrhythmias are treated. The risk seems to be lower than in patients with malignant arrhythmias, however it includes the occurrence of lethal tachyarrhythmias. Special attention should be paid to the selection of antiarrhythmic agents when used in combination.

[Antiarrhythmic therapy in patients with heart failure]. / Therapie kardialer Arrhythmien bei Herzinsuffizienz.

In patients with severe chronic heart failure, many deaths are sudden due to life-threatening ventricular arrhythmias. Supraventricular arrhythmias such as paroxysmal or chronic atrial fibrillation may also cause serious complications in those patients due to acute loss of atrial contraction, pump failure during rapid ventricular response and embolic events. Two therapeutic strategies are currently available for therapy and prevention of malignant ventricular arrhythmias and subsequent sudden arrhythmic death: antiarrhythmic drug therapy and implantable defibrillators. However, selection of the most beneficial strategy for the individual patient to reduce the risk of sudden death remains a major challenge in cardiology. Betablockers exert a favorable antiarrhythmic action without increasing proarrhythmia, thus betablockers may serve as a basic medication in patients at risk for sudden death. However, the general use of antiarrhythmic drug therapy for symptomatic ventricular arrhythmias is not recommended, as these drugs have been shown to increase mortality in patients with severe congestive heart failure due to proarrhythmic or negative inotropic effects (e.g. class Ia antiarrhythmics). Even class III antiarrhythmic drugs such as amiodarone, which has been studied sufficiently in patients with left ventricular dysfunction, is not effective enough for significant reduction of cardiac mortality in patients with symptomatic ventricular arrhythmias and depressed ventricular function (e.g. EMIAT, CAMIAT). But as a positive result of available studies, amiodarone does not increase mortality in those patients. Dofetilide has also not been shown to prolong life significantly by suppressing malignant ventricular arrhythmias (DIAMOND-Study). In patients with symptomatic ventricular arrhythmias or aborted sudden death, ICD therapy has been proven to be superior to antiarrhythmic drug therapy in cardiac mortality reduction as a secondary prevention strategy (e.g. AVID, CASH, CIDS). For primary prevention of sudden arrhythmic death in high risk patients, 2 studies (MADIT, MUSST) have already demonstrated favorable results, decreasing mortality by ICD therapy in selected patient populations with partly-reduced ventricular function and unsustained but inducible ventricular tachycardias. This topic is, however, undergoing further evaluation by ongoing trials (e.g. MADIT II, SCD-HeFT). From available data, antiarrhythmic drug therapy in high risk patients is not justified on a routine basis, whereas ICD therapy as a secondary and perhaps primary prevention strategy will significantly reduce cardiac mortality in patients with severe heart failure. Sotalol, a class III antiarrhythmic agent, has recently been shown to reduce ICD-shock delivery which indicates that concomitant drug therapy in patients with an ICD device already implanted may be beneficial in terms of reducing ICD discharges due to ventricular and supraventricular tachycardias. In patients with paroxysmal atrial fibrillation and congestive heart failure, restitution of sinus rhythm is the primary therapeutic goal which can be safely achieved by amiodarone and dofetilide (DIAMOND). In the latter, continuous monitoring of the patient is mandatory because of increased risk of torsade de pointes arrhythmias during the first days of drug administration. In patients with chronic atrial fibrillation rate control and anticoagulation with warfarin is the primary therapeutic option, which can be achieved with either drug treatment (Digoxin, betablockers, amiodarone) or by His bundle ablation with subsequent pacemaker insertion.

The differentiation of propafenone from other class Ic agents, focusing on the effect on ventricular response rate attributable to its beta-blocking action.

Propafenone, encainide and flecainide have been categorized as class Ic antiarrhythmic drugs, since they produce similar clinical electrophysiological effects. However, propafenone has also modes of action that differ substantially from pure class Ic activity. The most distinctive electrophysiological difference from other class Ic antiarrhythmic drugs stems from its structural similarity with other beta-adrenoceptor antagonists. The potency of the beta-adrenoceptor blocking property of propafenone has been estimated to range from 1/20 to 1/50 that of propranolol on a molar basis. Because the plasma concentrations of propafenone during long-term treatment may be up to 50 or more times that of propranolol, the beta-adrenoceptor blocking effect may be clinically relevant. However, although the beta-adrenoceptor blocking effects are readily demonstrable in vitro, clinical data are more inconsistent, because the beta-adrenoceptor blocking action has been reported as being undetectable to significant. During atrial fibrillation, with or without accessory pathways, propafenone exerts effective and prompt control of the ventricular rate in patients who fail to convert to sinus rhythm. However, compared with other class Ic antiarrhythmic drugs, propafenone has not been proved generally better in controlling the ventricular rate.

Automatic learning of rules. A practical example of using artificial intelligence to improve computer-based detection of myocardial infarction and left ventricular hypertrophy in the 12-lead ECG.

The authors developed a computer program that detects myocardial infarction (MI) and left ventricular hypertrophy (LVH) in two steps: (1) by extracting parameter values from a 10-second, 12-lead electrocardiogram, and (2) by classifying the extracted parameter values with rule sets. Every disease has its dedicated set of rules. Hence, there are separate rule sets for anterior MI, inferior MI, and LVH. If at least one rule is satisfied, the disease is said to be detected. The computer program automatically develops these rule sets. A database (learning set) of healthy subjects and patients with MI, LVH, and mixed MI+LVH was used. After defining the rule type, initial limits, and expected quality of the rules (positive predictive value, minimum number of patients), the program creates a set of rules by varying the limits. The general rule type is defined as: disease = lim1l < p1 < or = lim1u and lim2l < p2 < or = lim2u and ... limnl < pn < or = limnu. When defining the rule types, only the parameters (p1 ... pn) that are known as clinical electrocardiographic criteria (amplitudes [mV] of Q, R, and T waves and ST-segment; duration [ms] of Q wave; frontal angle [degrees]) were used. This allowed for submitting the learned rule sets to an independent investigator for medical verification. It also allowed the creation of explanatory texts with the rules. These advantages are not offered by the neurons of a neural network. The learned rules were checked against a test set and the following results were obtained: MI: sensitivity 76.2%, positive predictive value 98.6%; LVH: sensitivity 72.3%, positive predictive value 90.9%. The specificity ratings for MI are better than 98%; for LVH, better than 90%.

Stepwise strategy of using short- and long-term heart rate variability for risk stratification after myocardial infarction.

Independent of other established risk factors, depressed heart rate variability (HRV) has been shown to be a powerful predictor of cardiac events after MI. Unfortunately, the need of 24-hour ECG recording and subsequent laborious editing of Holter data limits the clinical use of long-term HRV. In order to perform post-MI risk stratification more efficiently, we evaluated the value of short-term HRV estimates for preselection of patients who might benefit from long-term HRV assessment. Two measures were assessed from 24-hour ambulatory ECGs recorded in 729 survivors of acute MI prior to hospital discharge. In addition to a complete 24-hour HRV index, a standard deviation of normal-to-normal RR intervals (SDNN) was obtained from the first stationary and ectopic free 5-minute segment of the Holter recording. Predictive power (relation between positive predictive accuracy and sensitivity) of a complete 24-hour HRV index in identifying patients who suffered from cardiac mortality or arrhythmic events during a 2-year follow-up was compared to the predictive power of assessing the 24-hour HRV index limited to 50%, 40%, or 20% of patients with the lowest values of 5-minute SDNN. The HRV index was significantly lower in patients who died (19 +/- 11 units) or had an arrhythmic event (AE) (18 +/- 11 units) compared to those who survived without an event (28 +/- 10 resp. 27 +/- 11 units; P < 0.001). Similarly, 5-minute SDNN was significantly lower in patients who died (25 +/- 12 ms) or suffered an AE (26 +/- 13 ms) compared to survivors (40 +/- 19 ms resp. 39 +/- 19 ms; P < 0.001). When limited to patients with depressed 5-minute SDNN, assessment of the HRV index performed better than 5-minute SDNN alone in positive prediction of cardiac events. Preselected assessment of the lowest HRV index in 50% to 20% of the total population yielded a 2-year cardiac event prediction rate as high as analysis of the HRV index in all patients. Long-term HRV assessment for risk stratification after MI in patients preselected by depressed short-term SDNN is safe and efficient, and allows a practical identification of patients with the highest likelihood of cardiac events during long-term follow-up.

Impact of electrocardiogram recording format on QT interval measurement and QT dispersion assessment.

The aim of this study was to determine the effect of recording conditions on the operator dependent measures of QT dispersion in patients with known and/or suspected repolarization abnormalities. Among several methods for risk stratification, QT dispersion has been suggested as a simple estimate of repolarization abnormalities. In a cohort of high and low risk patients, different components of the repolarization process were assessed in the 12-lead ECG using three different paper speeds and amplifier gains. To assess measurement error and reproducibility, a straight line was repeatedly measured. The operator error was 0.675 +/- 0.02 mm and the repeatability of the measurement error was 31 +/- 6%. The QT interval was most frequently measurable in V2-V5. Depending on the lead selected for analysis, the incidence of visible U waves was greatest in the precordial leads with high amplifier gain and low paper speed, strongly affecting QT interval measurement. The timing of the onset of the QRS complex (QRS onset dispersion) or offset of the T wave was strongly dependent on the paper speed. Paper speed, but not amplifier gain, had a significant shortening effect on the measurement of the maximum QT interval. As QT interval measurement in each ECG lead incorporates QRS onset and T wave offset (depending on the number of visible U waves), the dispersion of each of these parameters significantly affected QT dispersion. Thus, QT dispersion appears to reflect merely the presence of more complex repolarization patterns in patients at risk of arrhythmias.