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Symposium Clinical 1
Treatment of Severe Cardiac Arrhythmias
Chikaya Omichi, M.D.
Cedars-Sinai Medical Center, Los Angeles, California

Tsuyoshi Shiga, M.D.
Tokyo Women's Medical University, Tokyo, Japan

Hideo Mitamura, M.D.
Keio University, Tokyo, Japan

Kenzo Hirao, M.D.
Tokyo Medical and Dental University Tokyo, Japan

Ichiro Watanabe, M.D.
Nihon University, Japan

Koichiro Kumagai, M.D.
Fukuoka University, Fukuoka, Japan
 
  • Amiodarone Infusion, Wavefront Dynamics and Ventricular Fibrillation
  • Therapeutic approaches to VF
  • Electrical remodeling and selection of antiarrhythmic drugs
  • Relationship between Ic-Atrial Flutter and Therapeutic Drug Monitoring
  • Low-Energy Internal Cardioversion of Chronic AF
  • Pulmonary Venous Foci-Initiated AF


  • Research from six Japanese centers was presented in this session, after a review of the prevention of sudden cardiac death in high-risk patients and the use of internal cardioverter defibrillators for primary and secondary prevention for sudden cardiac death.

    Hypertrophic cardiomyopathy (HCM), long QT syndrome, idiopathic ventricular fibrillation, Brugada syndrome, and arrhythmogenic right ventricular dysplasia are associated with a high risk for sudden cardiac death (SCD) prevention. Clinical predictors associated with increased risk of SCD include young men with a history of syncope and a positive family history of SCD, markers such as non-sustained ventricular tachycardia, inducible ventricular arrhythmias during electrophysiologic testing, ischemia during exercise testing, and severe HCM. Hypertrophy exceeding 30 mm of thickness is reported to have a 15% positive predictive value. The relative risk of SCD increases as the number of predictors increase.

    ICD implantation is a class II indication for high-risk patients according to the current guidelines, and the value of anti-arrhythmic therapy and electrophysiologic study is limited. The ICD has been shown to be most effective in the primary prevention trials and its benefit is most marked in patients with ejection fractions at least less than 40% and probably less than 30%. For secondary prevention, ICD implantation is a class I indication, and drugs or ablation for frequent discharges can be implemented, especially in patients with recurrent monomorphic ventricular tachycardia. For patients with severe heart failure associated with these disease syndromes, medical therapy or heart transplantation can be considered. Adjunctive therapy of beta blockers, aspirin, statins and ACE inhibitors should be used routinely.





    Amiodarone Infusion, Wavefront Dynamics and Ventricular Fibrillation


    Intravenous amiodarone has gained popularity for the emergent management of life-threatening ventricular arrhythmias, and it has been recently reported that treatment with amiodarone results in a higher rate of survival to hospital admission in patients with cardiac arrest due to refractory ventricular arrhythmia. However, the mechanisms of the antifibrillatory action of amiodarone are not fully understood.

    Amiodarone was shown to progressively increase the cycle length of ventricular fibrillation (VF) in a swine model by Omichi and colleagues at Cedars-Sinai Medical Center, Los Angeles, California. A reduction of the low amplitude and fast activation in VF, leading to the transition to ventricular tachycardia (VT) or a slower cycle length of VF was demonstrated. Amiodarone reduced the density of wavelets and suppressed spontaneous wavebreaks, and progressively increased the cycle length of the reentrant wavefront and the central core area. This study demonstrated that amiodarone flattens the action potential duration (APD) restitution curve and reduced the incidence of spontaneous wavebreaks

    Figure 1. Amiodarone effect on transmembrane action potential.
    Click to enlarge

    Figure 2. APD restitution curves with a slope less than 1 during VF and pacing were flattened with amiodarone.
    Click to enlarge
    Amiodarone reduced the low amplitude of fast activation seen at baseline and also increased the cycle length of VF from 71 ms to 103 ms. Amiodarone slowed the rate of VF in 4 of 6 cases, terminated VF in 1 case, and converted VF to VT in 1 case. The effect of amiodarone on the transmembrane action potential is shown in Figure 1. Amiodarone significantly increased the mean cycle length (CL) of VF from 80 to 110 ms (p<0.05 versus baseline). APD90 was significantly increased from 70 ms to 90 ms after amiodarone. The diastolic interval increased progressively from 12 ms to 20 ms after amiodarone infusion.

    Amiodarone reduced the density of the wavelets from 0.65 ± 0.08/cm2 at baseline to 0.41 ± 0.10/cm2 (p<0.05), and significantly reduced the number of wavelengths from 35/second to 11/second (p<0.05). The cycle length of the reentrant wavefront increased significantly from 78.2 ± 19.0 ms at baseline to 108.9 ± 13.3 ms after amiodarone infusion in each case (p<0.05), and the central core area increased from 0.9 ± 0.3 mm2 to 4.1 ± 3.8 mm2 after amiodarone (p<0.01). Amiodarone flattened the AP90 restitution curves with a slope less than 1 during VF and pacing (Figure 2). The slope maximum of the AP90 restitution curves in each case was significantly decreased from 2.2 to 1.2 after amiodarone (p<0.05).

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    Therapeutic approaches to VF


    A retrospective study of VF in patients with or without structural heart disease (SHD) was undertaken due to the lack of therapeutic guidelines in Japan for the long-term management of survivors of VF and SCD. Combination therapy of ICD and drug therapy may prevent SCD, heart failure death, and total cardiac death in patients with underlying SHD, concluded Tsuyoshi Shiga, MD, Tokyo Women's Medical University. ICD therapy alone can prevent SCD and total cardiac death in patients without SHD and idiopathic VF. Beta blockers as an adjunctive therapy with ICD can reduce the excessive number of ICD discharges.

    Despite compelling uncontrolled data, controlled data from clinical trials are needed to support the observed effects of beta blockers in this retrospective study, stated Shiga. Amiodarone seems to have antifibrillatory effects in VF and powerfully suppresses premature ventricular contractions. It also has a non-competitive anti-adrenergic action, thus beta blocker-type side effect can be avoided. Amiodarone increases the wavelength.

    In the 33 cases of idiopathic VF without SHD (23 Brugada syndrome, mean age 43 years, 28 male) no deaths were observed after ICD implantation. At 1 and 5 years, 30% and 50% of patients had an ICD discharge, respectively. The ICD discharge rate was higher in the patients with Brugada syndrome compared to patients without, although the number of Brugada patients was small. In the Brugada patients with inducible VF, 3 of the 5 had ICD discharge, while those without inducible VF had no ICD discharge.

    In the 33 cases with SHD, the ICD discharge rate was the same as in the patients without SHD. No SCD occurred in patients with an ICD, but the total cardiac mortality was 7% at 1 year and 37% at 6 years. Thus, ICD seems to prevent SCD, but not total cardiac death. Ten of the patients had CAD, with a higher percentage being non-ischemic (hypertrophic or idiopathic dilated cardiomyopathy), which may be unique to the Japanese population, and the mean age was 50 years and 23 were male.

    Of the 20 patients treated with an ICD, 3 patients died from heart failure death, but not SCD. In 12 patients treated with amiodarone alone, 4 patients died from SCD; no heart failure deaths. In the patients treated with an ICD, 3 of the 9 patients died, while none of the 12 patients treated with an ICD and drug therapy died. The left ventricular ejection fraction was less than 30% in the 3 patients who died.

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    Electrical remodeling and selection of antiarrhythmic drugs


    Pharmacologic conversion of (AF) can be difficult, particularly when the AF has been sustained for weeks. It has been reported that prolonged atrial tachyarrhythmia causes intracellular calcium overload, leading to electrical remodeling characterized by changes in structure and function of ion channels. Thus, it is reasonable to consider that the antiarrhythmic efficacy of drugs affecting these channels or receptors may also change.

    The serial changes of electrophysiologic (EP) effects of three different drugs that block the Ina (pilsicainide), Ikr (E4031), and IKs (azimilide) channels, respectively, were studied in a canine model of rapid atrial tachycardia. The study conducted by Mitamura and colleagues at Keio University in Tokyo then evaluated whether a calcium channel blocker can prevent the development of atrial electrical remodeling in the same model.

    Figure 3. The effective refractory period is increased with the IKr blocker E4031.
    Click to enlarge
    The effective refractory period (ERP) became progressively shorter over the 14-day period of rapid atrial pacing, indicating electrical remodeling. In the pilsicainide group (0.6mg/kg loading + 0.04 mg/kg/min maintenance), the ERP was prolonged, the conduction velocity (CV) decreased, and the wavelength (WL) increased significantly at baseline, but these effects dissipated after 2 days of rapid pacing. In the E4031 group (30 mcg/kg/3 min + 0.1 mcg/kg/min) the ERP was increased, particularly when the pacing cycle length was 400 compared to 200 (Figure 3). This drug prolonged ERP in a reverse use-dependent fashion. The effect of prolonging ERP was unaffected by the duration of rapid atrial pacing. No effect on CV was seen with this drug, as expected.

    The WL is a product of ERP and CV, and the difference between pilsicainide and E4031 was easily apparent. With pilsicainide, the WV was only prolonged at p0, before the initiation of rapid atrial pacing, but rapid atrial pacing did not prolong the WL. In contrast, E4031 increased the WL throughout the study period, which was more marked when the cycle length was 400.

    Figure 4. The IKs blocker azimilide prolonged the effective refractory period.
    Click to enlarge
    Pilsicainide failed to suppress the induction of AF in all dogs in the group, whereas E4031 suppressed the induction of AF in 1 of 3 inducible dogs. Azimilide, a combined IKr and IKs blocker, prevented the induction of AF. Azimilide does not have a reverse use-dependent pattern, like E4031, as shown by its ability to prolong ERP at both 200 and 400 cycle length (Figure 4).

    The EP effects of sodium channel blockers waned as rapid atrial pacing persisted, while the EF effects of potassium channel blockers were well preserved. Since a pure Ikr blocker showed a reverse use-dependent effect, only a combined Ikr plus Iks blocker was effective in preventing AF inducibility in the electrically-remodeled canine atrium.

    Treatment with a calcium blocker prevented the development of pacing-induced atrial electrical remodeling in the canine atrium. Verapamil (oral 8 mg/kg/day) was begun 1 week prior to rapid atrial pacing in 8 dogs. In the 12 control dogs, the ERP decreased over the 14 days of rapid atrial pacing, whereas in the verapamil-treated dogs the ERP was longer than in the control dogs and did not change over the 14 days. CV was not decreased in the verapamil-treated dogs. AF was induced after 7 days of rapid atrial pacing in the control dogs, whereas the duration of induced AF was shortened in the verapamil-treated dogs.
    This study showed that drugs blocking ion channels with downregulation, such as sodium channel blockers, may lose their efficacy, stated Mitamura. The efficacy of other drugs, such as IKr and IKs blockers, may be preserved. Prevention of calcium overload by calcium blockers can prevent atrial electrical remodeling. Understanding these concepts will help to select appropriate drugs for the management of persistent atrial tachyarrhythmias.

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    Relationship between Ic-Atrial Flutter and Therapeutic Drug Monitoring


    Atrial flutter (AFL) can be documented after the initiation of treatment with several antiarrhythmic drugs in patients with atrial fibrillation (AF). In class 1c-AFL patients, combination therapy with catheter ablation of the right atrial isthmus and continued drug therapy (hybrid therapy) is reported to be a promising means to achieve and maintain sinus rhythm (SR). A prospective study conducted by Hirao and colleagues at Tokyo Medical and Dental University showed that AF could be converted into AFL with the class 1c drug, pilsicainide, especially with a high dose. Catheter ablation of class 1c-AFL and persistent pilsicainide was effective in reducing AF. Further and larger trials with this therapy including the intravenous administration of a class 1c drug is needed to elucidate the real benefit of hybrid therapy for AF, stated Hirao.

    In Group 1 (83 patients with AF, 70 paroxysmal or persistent), pilsicainide caused paroxysmal or persistent AFL in 12 patients. Catheter ablation was performed in 10 of the 12 class 1c-AFL patients; 2 patients refused. In Group 2 (10 patients with AF and AFL), 7 patients had catheter ablation after pilsicainide treatment.

    Catheter ablation for isthmus-dependent AFL was successful in 12 patients. In 11 patients who continued to receive pilsicainide after successful catheter ablation, SR persisted in 6 patients. In the 5 patients with recurrent AF, pilsicainide was changed to another class I drug, which maintained SR. In 1 patient who preferred not to have any antiarrhythmic agent, SR rhythm has been maintained.

    Figure 5. The dose and plasma concentration of pilsicainide in patients with and without class Ic-atrial flutter.
    Click to enlarge
    The dose of pilsicainide associated with conversion of AF to 1c-AFL was significantly higher than the dose not associated with this conversion (181.3 ± 38.6 mg/day vs 144.9 ± 32.5 mg/d, respectively; p<0.05) (Figure 5). The plasma concentration was also significantly higher in the patients converted to 1c-AFL than those who did not (0.86 mcg/mL ± 0.45 vs 0.55 mcg/mL ± 0.32 mcg/mL; p<0.05). The duration of AF was 28 months in the patients with inducible Class 1c AFL, 49 months in the AF patients, and 19 months in the patients with suppressed AF and maintenance of SR (p<0.05).

    The incidence of 1c-AFL was 6.1% in the patients who maintained the initial dose of pilsicainide and 47.1% in the patients in whom the dose was increased. The overall incidence of 1c-AFL was 14.5%. Permanent AF or AF with a long history tended to convert to 1c-AFL less frequently. Successful catheter ablation of 1c-AFL with continued pilsicainide was effective in 4 patients and partially effective in 4 patients. Limitations to this study noted by Hirao include the fact that short-lasting paroxysmal or non-symptomatic episodes of 1c-AFL may not be recorded, and drug complications, especially the risk for 1c-AFL with 1:1 AV conduction.

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    Low-Energy Internal Cardioversion of Chronic AF


    Early recurrence of AF is common after cardioversion of chronic AF. The currently used clinical parameters of the duration of the antecedent episode and the size of the left atrium on echocardiogram are weak predictors of outcome. Frequency analysis of the ECG and signal-averaging ECG of the P-wave duration (P-SAE) after cardioversion was prospectively applied to predict the recurrence of AF after internal atrial cardioversion (IACV) in 22 patients with chronic, non-valvular AF (mean age 63 years, 15 males, mean AF duration 21 months).

    IACV was successful in all 22 patients, with a mean energy of 8.6 J. Nine of the 22 patients who completed the 3-month follow-up had documented recurrence of AF, stated Ichiro Watanabe, MD, Nihon University. Neither clinical nor echocardiographic variables predicted the recurrence. The peak frequency of AF is higher and the filtered P wave duration (FPD) derived from the P-SAE was longer in patients who went on to early recurrence after IACV than in the patients who remained in SR. The peak frequency of AF and the FPD derived from P-SAE better predict outcome than clinical or echocardiographic variables and may be useful for the management of patients with AF, stated Watanabe.

    The average peak frequency of AF was 7.36 ± 0.44 Hz in recurrent cases, compared to 6.65 ± 0.33 Hz non-recurrent cases (p<0.001), establishing a cut-off of 7 Hz. For a peak frequency greater than 7 Hz, there were 7 recurrent cases and 2 non-recurrent cases. For a peak frequency less than 7 Hz, there were 2 recurrent cases and 10 non-recurrent cases (p<0.001).

    The average filtered P wave duration (FPD) was 161.5 ± 10.6 ms for recurrent cases and 151.2 ± 19.6 ms for non-recurrent cases (p<0.05). For an FPD greater than 145 ms, there were 8 recurrent cases and 6 non-recurrent cases, and for an FPD less than 145 ms there were no recurrent cases and 7 non-recurrent cases (p<0.02). No statistical difference was found for the clinical and echocardiographic parameters of age, AF duration, left ventricular ejection fraction and left atrium diameter.

    IACV was successful in all 22 patients, with a mean energy of 8.6 J. Nine of the 22 patients who completed the 3-month follow-up had documented recurrence of AF. Neither clinical nor echocardiographic variables predicted the recurrence. The peak frequency of AF is higher and the FPD derived from the P-SAE was longer in patients who go on to early recurrence after IACV than in the patients who remained in SR. The peak frequency of AF and the FPD derived from P-SAE better predict outcome than clinical or echocardiographic variables and may be useful for the management of patients with AF.

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    Pulmonary Venous Foci-Initiated AF


    Figure 6. Focal ablation with a basket catheter.
    Click to enlarge
    Kumagai and colleagues showed in a prospective study that the focal sources initiating AF usually are located in the pulmonary vein (PV), and careful mapping and elimination of these foci and atrio-PV conduction can cure AF. Therefore, combination therapy of focal ablation and PV isolation is more effective that either strategy alone, stated Kumagai. .

    Mapping was performed in 60 patients (age 60 years, 45 males) during spontaneous atrial premature beats (APB) or AF initiation with isoproterenol infusion or APB after cardioversion. A PV confirmed by the earliest atrial activation was targeted for ablation. The elimination of AF was the defined endpoint. If patients had no APB or AF initiations, all APB displaying distinct and late PV potential during sinus rhythm were targeted for PV isolation. The endpoint was determined by abolition of PV potentials and/or creating atrial PV conduction blocks. After identification of the PV site, the basket catheter was positioned within the PV (Figure 6).

    Of the 104 foci identified, 90% originated from the PV and 10% originated from the atrial tissue; 47% of the patients had one focus, 31% two foci, and 22% had 3-4 foci. The first ablation was successful in 28 patients. In the 17 patients who underwent a second ablation, the recurrence was from the same source in 7 patients, from a different part of the same PV in 3, from a different PV in 2, and the PV potentials and A-PV conduction in 5 patients. Pericardial effusion occurred in 2 patients after successful ablation but no PV stenosis was observed. The success rate for ablation was 81% for one focus, 56% for two foci, and 44% for 3-4 foci. The success rate for paroxysmal AF was 73%, 46% persistent AF, and 40% permanent AF. The success rate for focal ablation only and for PV isolation ablation only was 60%, and 75% for combined focal ablation and PV isolation.

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