Jonnalagedda S.M. Sarma

Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise : A crossover open-label study of five drug regimens

OBJECTIVES We compared the effects of five pharmacologic regimens on the circadian rhythm and exercise-induced changes of ventricular rate (VR) in patients with chronic atrial fibrillation (CAF). BACKGROUND Systematic comparison of standardized drug regimens on 24 h VR control in CAF have not been reported. METHODS In 12 patients (11 male, 69+/-6 yr) with CAF, the effects on VR by 5 standardized daily regimens: 1) 0.25 mg digoxin, 2) 240 mg diltiazem-CD, 3) 50 mg atenolol, 4) 0.25 mg digoxin + 240 mg diltiazem-CD, and 5) 0.25 mg digoxin + 50 mg atenolol; were studied after 2 week treatment assigned in random order. The VR data were analyzed by ANOVA with repeated measures. The circadian phase differences were evaluated by cosinor analysis. RESULTS The 24-h mean (+/-SD) values of VR (bpm) were - digoxin: 78.9 +/- 16.3, diltiazem: 80.0+/-15.5, atenolol: 75.9+/-11.7, digoxin + diltiazem: 67.3+/-14.1 and digoxin + atenolol: 65.0+/-9.4. Circadian patterns were significant in each treatment group (p < 0.001). The VR on digoxin + atenolol was significantly lower than that on digoxin (p < 0.0001), diltiazem (p < 0.0002) and atenolol (p < 0.001). The time of peak VR on Holter was significantly delayed with regimens 3 and 5 which included atenolol (p < 0.03). During exercise, digoxin and digoxin + atenolol treatments resulted in the highest and lowest mean VR respectively. The exercise Time-VR plots of all groups were nearly parallel (p = ns). The exercise duration was similar in all treatment groups (p = ns). CONCLUSIONS This study indicates that digoxin and diltiazem, as single agents at the doses tested, are least effective for controlling ventricular rate in atrial fibrillation during daily activity. Digoxin + atenolol produced the most effective rate control reflecting a synergistic effect on the AV node. The data provides a basis for testing the effects of chronic suppression of diurnal fluctuations of VR on left atrial and ventricular function in CAF.

Electrophysiological Effects of Dronedarone (SR33589), a Noniodinated Benzofuran Derivative, in the Rabbit Heart Comparison With Amiodarone

BACKGROUND To overcome the side effects of amiodarone (AM), its noniodinated analogue, dronedarone (SR), was synthesized. In this study, its electrophysiological effects were compared with those of AM in rabbit hearts. METHODS AND RESULTS Five animal groups (n=7 each) for 3 weeks received daily oral treatment of 1 of these regimens: (1) control, vehicle only; (2) AM 50 mg/kg (AM50); (3) AM 100 mg/kg (AM100); (4) SR 50 mg/kg (SR50); and (5) SR 100 mg/kg (SR100). ECGs were recorded before drug and at 3 weeks of drug before euthanasia. Action potentials were recorded from isolated papillary muscle and sinoatrial node by microelectrode techniques. The short-term effects were studied in controls (n=5) at various concentrations of SR (0 to 10 micromol/L) in tissue bath. Action potential duration at 50% (APD(50)) and 90% (APD(90)) repolarization and upstroke dV/dt (V(max)) at various cycle lengths were compared by ANOVA with repeated measures. Compared with control, AM and SR increased RR, QT, and QTc intervals (P<0.0001 for all). Ventricular APD(50) and APD(90) were lengthened by 20% to 49% as a function of dose (P<0.005 to <0.0001) and cycle length (P<0.001). SR100 effects were greater than those of AM100 (P<0.002). V(max) was decreased by both AM100 (P<0.0001) and SR100 (P<0.01). Sinoatrial node automaticity was slowed in treated groups compared with that of the control group (P<0.0001 for all). CONCLUSIONS The electrophysiological effects of dronedarone are similar to those of AM but more potent, despite deletion of iodine from its molecular structure, a finding of importance for the development of future class III antiarrhythmic compounds.

Circadian and power spectral changes of RR and QT intervals during treatment of patients with angina pectoris with nadolol providing evidence for differential autonomic modulation of heart rate and ventricular repolarization

This study evaluates the effects of autonomic manipulation by chronic beta blockade with nadolol on the circadian and power spectral changes of heart rate and QT interval. It was hypothesized that differential innervation of the atria and ventricles by sympathetic and parasympathetic fibers may produce differential effects on heart rate and QT interval variabilities. Holter recordings of 12 male patients (age 63 +/- 7 years) with stable angina were analyzed before and after 3 weeks of nadolol therapy. The QT intervals were individually normalized by an exponential formula to study the circadian variation of QTc. Power spectra of RR and uncorrected QT intervals were obtained by fast-Fourier analysis from 256 consecutive sinus beats during the day at maximal heart rate and during the night at minimal heart rate. Frequency-specific variability was determined from areas under the spectral plots. Both heart rate and QTc exhibited significant circadian patterns (p < 0.01) in opposite phase with each other. Mean heart rate was significantly reduced with nadolol (81 +/- 12 vs 67 +/- 12 beats/min, p < 0.001), with greater reduction during daytime. The mean QTc was unexpectedly reduced after nadolol treatment, with borderline significance (p = 0.06). The RR variability in the frequency range of 0.05 to 0.25 Hz was significantly increased with nadolol at 3:00 A.M. (p < 0.01) but not at 1:00 P.M. The QT variability in the same frequency range of was not significantly increased with nadolol. The power spectra of RR and QT intervals were dissimilar except at the lower frequencies around 0.05 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian rhythmicity of rate-normalized QT interval in hypothyroidism and its significance for development of class III antiarrhythmic agents

Lengthening of repolarization and refractoriness occurs in hypothyroidism; it is associated with a reduced probability of arrhythmias, with the converse occurring in hyperthyroidism. Because the QT interval and its circadian rhythmicity relative to heart rate is poorly defined in man, we used our new computer-assisted technique to measure QT interval in our analysis of 24-hour Holter tapes before and after (8 to 12 weeks) thyroxine (T4) replacement in 10 patients with hypothyroidism; the findings were compared to those in 6 normal control subjects. QTc interval was prolonged (p less than 0.02) and heart rate decreased (p less than 0.005) during the hypothyroid state. Data were analyzed for circadian rhythmicity by repeated-measures analysis. Circadian variation in QTc and heart rate was statistically significant during hypothyroid and euthyroid states (p less than 0.001) as well as in control subjects, but the circadian rhythmicity of QTc interval and heart rate were out of phase; the maximum prolongation of QTc occurred between midnight and 6 A.M., at a time when heart was at its lowest. QTc interval remained significantly prolonged after 8 to 12 weeks of T4 replacement, when biochemical indexes of hypothyroidism had returned to normal values. The computer-assisted QTc interval determination technique that we used, and our data on the circadian rhythmicity of QTc and heart rate, have significant implications for the development of new class III antiarrhythmic agents.

Antiarrhythmic Agents for Atrial Fibrillation: Focus on Prolonging Atrial Repolarization

Atrial fibrillation (AF) has been the subject of considerable attention and intensive clinical research in recent years. Current opinion among physicians on the management of AF favors the restoration and maintenance of normal sinus rhythm. This has several potential benefits, including the alleviation of arrhythmia-associated symptoms, hemodynamic improvements, and possibly a reduced risk of thromboembolic events. After normal sinus rhythm has been restored, antiarrhythmic therapy is necessary to reduce the frequency of AF recurrence. In the selection of an antiarrhythmic agent, both efficacy and safety should be taken into consideration. Many antiarrhythmic agents have the capacity to provoke proarrhythmia, which may result in an increase in mortality. This is of particular concern with sodium-channel blockers in the context of patients with structural heart disease. Flecainide and propafenone are well tolerated and effective in maintaining sinus rhythm in patients without significant cardiac disease but with AF. Recent interest has focused on the use of class III antiarrhythmic agents, such as amiodarone, sotalol, dofetilide (recently approved), ibutilide (approved for chemical conversion of AF and atrial flutter), and azimilide (still to be approved) in patients with AF and structural heart disease. To date, amiodarone and sotalol still hold the greatest interest, and although controlled clinical trials with these agents have been few, a number are in progress and some have been recently completed. These agents are effective in maintaining normal sinus rhythm in patients with paroxysmal and persistent AF and are associated with a low incidence of proarrhythmia when used appropriately. Because of the relative paucity of placebo-controlled trials of antiarrhythmic agents in patients with AF, experience until recently has tended to dictate treatment decisions. Increasingly, selection of drug therapy is being based on a careful and individualized benefit-risk evaluation by means of controlled clinical trials, an approach that is likely to dominate the overall approach to the control of atrial fibrillation in the largest numbers of cases of the arrhythmia. Pharmacologic therapy is likely to be dominated by compounds that exert their predominant effect by prolonging atrial repolarization.

Effects of amiodarone on the circadian rhythm and power spectral changes of heart rate and QT interval: Significance for the control of sudden cardiac death☆

Effects of chronic amiodarone therapy on the circadian rhythmicity and power spectral changes of heart rate and QT intervals from Holter recordings were evaluated in three groups of patients: group 1 baseline (n = 10); group 2, treated for 3 to 6 months (n = 11); and group 3, treated for > 1 year (n = 13). Amiodarone reduced heart rate, which reached steady state at 3 to 6 months; bradycardia was evident during the entire 24 hours. The corrected QT (QTc) interval increased as a function of treatment duration. It was 457 +/- 39, 530 +/- 28 (p < 0.001), and 581 +/- 36 (p < 0.0002) msec for groups 1, 2, and 3, after 6 months, respectively. The circadian rhythmicity of QTc was abolished in group 3. Power spectral analysis showed a tendency for amiodarone to reduce both R-R and QT interval variabilities, suggesting inhibition of autonomic control on the heart by the drug. The effectiveness of amiodarone against ventricular arrhythmias may result in part from the sustained bradycardia in concert with continuous uniform prolongation of myocardial repolarization.

Mechanisms of action of antiarrhythmic drugs relative to the origin and perpetuation of cardiac arrhythmias.

Most cardiologists and electrophysiologists will undoubtedly agree that there are two main aspects to the rational approaches for controlling cardiac arrhythmias. Clearly, the first is a clear understanding of the precise mechanisms of the arrhythmia requiring treatment and prevention. The second is the precision with which the treatment modality, especially antiarrhythmic drugs, can be matched with the substrate in which the arrhythmia arises. The success in terminating and preventing such arrhythmias, ventricular or supraventricular, depends critically on the appropriateness of the match between the arrhythmogenic substrate and the pharmacodynamic properties of the antiarrhythmic agent in use. The converse might also occur. For example, it is well known that potent sodium-channel blockers given to patients with severely reduced ventricular function may increase mortality by inducing potentially fatal reactions. In contrast, the match between beta-blockade and arrhythmogenic substrate as for example in the post-infarct patient may result in mortality reduction by reducing sudden cardiac death. The more immediate and definable objective may include the control of arrhythmia symptoms and prolongation of survival, anticipation of side effects, and proarrhythmic reactions. The longer-term objective is to study structure-activity relationships, which may permit the development of newer compounds as the ideal antiarrhythmic drug remains elusive. Many decades ago, such an approach led to the identification of the single dominant action of drugs on certain elec-

Dose-Dependent Effects of Oral Dronedarone on the Circadian Variation of RR and QT Intervals in Healthy Subjects: Implications for Antiarrhythmic Actions

Dronedarone, a non-iodinated benzofuran derivative, was developed as a potentially less toxic alternative to amiodarone. This study describes Holter data of dronedarone in humans. Five groups of healthy subjects were given 1 of 5 oral doses of dronedarone in a twice-daily regimen or placebo. Holter recordings of circadian rhythmicity of RR and QT intervals were evaluated. Dronedarone prolonged RR and QT intervals as a function of dose, without effect on circadian patterns. The relative prolongation of QT, QTc, and RR by dronedarone was significant. The QTc interval did not exhibit a clearly recognizable circadian pattern, suggesting that the circadian pattern of the QT interval was mostly a reflection of circadian changes in the RR interval in the study population. Dronedarone resembled amiodarone in class III and sympatholytic effects, indicating its potential as a unique antiarrhythmic compound seemingly devoid of the side effects mediated by iodine in amiodarone.

Antiarrhythmic and Arrhythmogenic Actions of Varying Levels of Extracellular Magnesium: Possible Cellular Basis for the Differences in the Efficacy of magnesium and Lidocaine in Torsade de Pointes.

Background: In recent years, there has been an increasing use of antiarrhythmic drugs that act predominantly by prolonging myocardial repolarization. An inevitable electrophysiologic con sequence of these drugs is the development of torsade de pointes as a proarrhythmic reaction. Both intravenous lidocaine and magnesium sulphate have been used in the acute control of such a proarrhythmia. Their electrophysiologic mechanisms in this setting are not well defined. Methods and Results: Using the standard microelectrode techniques, the effects of magne sium (Mg) and lidocaine on action potential duration (APD), and on barium-induced sponta neous action potentials, were studied in canine Purkinje fiber preparations. The objective was to clarify the direct and indirect effects of magnesium on triggered activities due to early afterdepolarizations. Superfusion in media with 0.1 mM Mg and 2.5 mM K produced more pronounced increases in APD measured at -20mV repolarization time [APD20] than those in a solution with 5 mM K. This effect was further enhanced at lower stimulation frequencies. The striking prolongation of APD20 by solutions with low potassium concentrations dimin ished as the Mg concentration was increased. In solutions with 2.5 mM K, Mg produced con centration-dependent decreases in APD20. This effect was greater at lower stimulation fre quencies. Lidocaine at 4.0 × 10-5 M produced a marked shortening of the APD in the entire voltage range. On barium-induced automaticity, Mg markedly suppressed the spontaneous firing frequency of the abnormal automaticity in a concentration-dependent manner. With 10 mM Mg, such action potentials appeared only sporadically. Magnesium also decreased the amplitude and the maximum upstroke velocity of these action potentials. In contrast, lido caine at 4.0 × 10-5 M exhibited no significant effects on action potentials due to barium- induced abnormal automaticity, or on additional depolarizations developing from the repolar ization phase of these action potentials. Conclusions: The data indicate that (i) hypomagnesemia may be arrhythmogenic when com bined with hypokalemia and bradycardia leading to a prolongation of the plateau phase of the action potential, (ii) magnesium administration may suppress triggered activities mainly by a direct inhibition of the development of triggered potentials, and (iii) lidocaine may suppress triggered potentials only indirectly by preventing the development of early afterdepolariza tions due to the shortening effect on the APD. These findings are consistent with the clinical observation of a high incidence of torsade de pointes in the setting of hypokalemia and hypo magnesemia induced by a chronic diuretic therapy. They are also consistent with the marked effectiveness of intravenous Mg relative to the inconsistent clinical effects of lidocaine in controlling torsade de pointes.

Effects of Sotalol on the Circadian Rhythmicity of Heart Rate and QT Intervals With a Noninvasive Index of Reverse-Use Dependency.

Background: The effects of sotalol on the 24-hour profile of the QT interval relative to that of the heart rate (HR) may be helpful in determining the time course of the drugs action in controlling cardiac arrhythmias. This has not been previously determined. Thus, the objec tive of the current study was to evaluate the influence of the drug on the circadian rhyth micity of HR and QT intervals from Holter recordings in ambulatory patients. Reverse-use dependency (RUD) of sotalol was also studied noninvasively from Holter recordings. Methods and Results: Holter recordings of 18 patients with ventricular arrhythmias were analyzed before and after 3-7 days of treatment with sotalol. We developed and used a sig nal processing system. A new noninvasive index to evaluate RUD was defined and applied to sotalol as a test agent. Sotalol significantly reduced HR from 76.9 ± 3.2 to 60.0 ± 1.1 (P < .001). The mean QT interval increased from 393 ± 11 ms to 489 ± 9 ms, whereas the mean normalized QT (QTc) interval increased from 415 ± 5 ms to 487 ± 5 ms (P < .001) during the drug treatment. Circadian rhythmicity of RR interval was abolished, but the circadian rhythms of the QT and QTc intervals were maintained during continuous treatment with sotalol. This finding is in contrast to amiodarone, which abolished the circadian rhythmicity of QTc interval while maintaining that of RR interval. RUD index was increased from 0.13 ± 0.08 to 0.24 ± 0.10 (P < .001) after sotalol, consistent with increased RUD with sotalol. Conclusions: The effects of sotalol on the circadian rhythmicity of HR and QTc interval are dissociated. They are in direct contrast to those reported for amiodarone, a difference that may be of clinical significance. The RUD index introduced here provides a noninvasive parameter for comparing short-term as well as long-term effects of class III antiarrhythmic drugs on RUD.