Christian Mewis

Ionic mechanisms of electrical remodeling in human atrial fibrillation

OBJECTIVES Atrial fibrillation (AF) is associated with a decrease in atrial ERP and ERP adaptation to rate as well as changes in atrial conduction velocity. The cellular changes in repolarization and the underlying ionic mechanisms in human AF are only poorly understood. METHODS Action potentials (AP) and ionic currents were studied with the patch clamp technique in single atrial myocytes from patients in chronic AF and compared to those from patients in stable sinus rhythm (SR). RESULTS The presence of AF was associated with a marked shortening of the AP duration and a decreased rate response of atrial repolarization. L-type calcium current (ICa,L) and the transient outward current (Ito) were both reduced about 70% in AF, whereas an increased steady-state outward current was detectable at test potentials between -30 and 0 mV. The inward rectifier potassium current (IKI) and the acetylcholine-activated potassium current (IKACh) were increased in AF at hyperpolarizing potentials. Voltage-dependent inactivation of the fast sodium current (INa) was shifted to more positive voltages in AF. CONCLUSIONS AF in humans leads to important changes in atrial potassium and calcium currents that likely contribute to the decrease in APD and APD rate adaptation. These changes contribute to electrical remodeling in AF and are therefore important factors for the perpetuation of the arrhythmia.

Clinical Experience with the New Detection Algorithms for Atrial Fibrillation of a Defibrillator with Dual Chamber Sensing and Pacing

ICD with DDD Pacemaker. Introduction: A major drawback of therapy with an implantable defibrillator is the nonspecificity of detection. Theoretically, adding atrial sensing information to a decision algorithm could improve specificity of detection.

Suppression of sustained ventricular tachyarrhythmias: a comparison of d,l-sotalol with no antiarrhythmic drug treatment

OBJECTIVES This study evaluates the clinical efficacy of d,l-sotalol in patients with sustained ventricular tachyarrhythmias. BACKGROUND D,l-sotalol is an important antiarrhythmic agent to prevent recurrences of sustained ventricular tachyarrhythmias (VT/VF). However, evidence is lacking that an antiarrhythmic agent like d,l-sotalol can reduce the incidence of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment. METHODS A prospective study was performed in 146 consecutive patients with inducible sustained ventricular tachycardia or ventricular fibrillation. In 53 patients, oral d,l-sotalol prevented induction of VT/VF during electrophysiological testing and patients were discharged on oral d,l-sotalol (sotalol group). In 93 patients, VT/VF remained inducible and a defibrillator (ICD) was implanted. After implantation of the device patients were randomly assigned to oral treatment with d,l-sotalol (ICD/sotalol group, n=46) or no antiarrhythmic medication (n=47, ICD-only group). RESULTS During follow-up, 25 patients (53.2%) in the ICD-only group had a VT/VF recurrence in comparison to 15 patients (28.3%) in the sotalol group and 15 patients (32.6%) in the ICD/sotalol group (p=0.0013). Therapy with d,l-sotalol, amiodarone or metoprolol was instituted in 12 patients (25.5%) of the ICD-only group due to frequent VT/VF recurrences or symptomatic supraventricular tachyarrhythmias. In nine patients, 17% of the sotalol group, an ICD was implanted after VT/VF recurrence, three patients (5.7%) received amiodarone. Total mortality was not different between the three groups. CONCLUSIONS D,l-sotalol significantly reduces the incidence of recurrences of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment.

Efficacy of Metoprolol and Sotalol in the Prevention of Recurrences of Sustained Ventricular Tachyarrhythmias in Patients with an Implantable Cardioverter Defibrillator

KETTERING, K., et al.: Efficacy of Metoprolol and Sotalol in the Prevention of Recurrences of Sustained Ventricular Tachyarrhythmias in Patients with an Implantable Cardioverter Defibrillator. ICDs provide protection against sudden cardiac death in patients with life‐threatening ventricular arrhythmias. Nevertheless, most ICD recipients receive adjunctive antiarrhythmic drug therapy to reduce the number of recurrent episodes and ICD discharges. The aim of the study was to compare the efficacy of metoprolol and d,l‐sotalol in preventing VT/VF recurrences in patients with an ICD in a prospective, randomized trial. One hundred patients (83 men, 17 women; mean age 59 years, SD ± 11 years) were randomized to receive metoprolol or sotalol after implantation of an ICD. There were no significant differences between the two groups with regard to age, sex, underlying cardiac disease, left ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The median follow‐up was 728 days (25th percentile: 530 days, 75th percentile: 943 days) in the metoprolol group and 727 days (25th percentile: 472 days, 75th percentile: 1,223 days) in the sotalol group (P = 0.52). Thirty‐three patients treated with metoprolol and 30 patients receiving sotalol had at least one episode during the follow‐up. Event‐free survival curves were generated for the two treatment arms using the Kaplan‐Meier method and showed no significant difference (P = 0.68). Eight patients treated with metoprolol and six patients treated with sotalol died during follow‐up. Total mortality was not significantly different between the two study groups (P = 0.43). Metoprolol is as efficacious as sotalol in preventing VT/VF recurrences in patients with an ICD.

β3-Adrenergic regulation of an ion channel in the heart—inhibition of the slow delayed rectifier potassium current IKs in guinea pig ventricular myocytes

Objectives: I Ks, the slow component of the delayed rectifier potassium current, underlies a strong β-adrenergic regulation in the heart. Catecholamines, like isoproterenol, induce a strong increase in I Ks. Recent work has pointed to an opposing biological effect of β1- and β3-adrenoceptors in the heart. However the role of these subtypes in the regulation of cardiac ion channel function is unknown. Methods: We investigated the effects of β1- and β3-adrenoceptor modulation on I Ks in guinea-pig ventricular myocytes, using patch-clamp techniques. Results: Superfusion with 100 nmol/l isoproterenol increased the step current amplitude by 81.3±8.0%. In contrast, after block of β1- (1 μmol/l atenolol) and β2-receptors (1 μmol/l ICI118,551), isoproterenol induced a reduction of the step current amplitude by 34.3±3.5%. The β3-selective agonist BRL37344 significantly reduced the I Ks step current at +70 mV in a concentration-dependent manner (IC50: 5.01 nmol/l). In the presence of bupranolol (β1-, β2- and β3-adrenoceptor antagonist), the effect of BRL37344 was markedly attenuated, from 27.3±5.6% (100 nmol/l BRL37344 alone) to 4.0±1.3% (100 nmol/l BRL37344+1 μmol/l bupranolol). BRL37344 (100 μmol/) did not alter current amplitudes of KvLQT1/minK expressed in CHO cells or in Xenopus oocytes, excluding a direct effect of BRL37344 on the channel. 1 μmol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD90:+7.8%) Conclusions: We have demonstrated a functional coupling between the β3-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for β3-adrenoceptors in cardiac electrophysiology and pathophysiology.

Long-term experience with subcutaneous ICD leads: a comparison among three different types of subcutaneous leads.

ICDs provide protection against sudden cardiac death in patients with life‐threatening arrhythmias. Nevertheless, efficacy of defibrillation remains an important issue to guarantee the future safety of patients who receive an ICD. There is a significant number of patients who need an additional subcutaneous lead to obtain a defibrillation safety margin of at least 10 J between the maximum output of the ICD and the energy needed for ventricular defibrillation. However, few data exists about the long‐term performance of different types of subcutaneous leads. Therefore, the aim of this study was to analyze the long‐term experience with three different types of subcutaneous leads. The study included 132 patients (109 men, 23 women; mean age 59.8 years [SD ± 10.7 years]). All of them received a subcutaneous lead in addition to a single chamber or dual chamber ICD between October 1990 and April 2002. Two patients received a second subcutaneous lead after the first lead had been removed so that a total of 134 subcutaneous leads were evaluated. Inclusion criteria for the implantation of an additional subcutaneous lead were (1) unsuccessful ventricular defibrillation at implant without a subcutaneous lead, (2) insufficient safety margin (< 10 J) between the maximum output of the ICD and the energy needed for ventricular defibrillation, or (3) clinical evaluation of a new subcutaneous lead (Medtronic 13014). There were no significant differences between the three study groups with regard to age, sex, underlying cardiac disease, left ventricular ejection fraction, NYHA class assessment and clinical arrhythmia. The results of the DFT testing during follow‐up (prehospital discharge test and 1 and 3 years) were compared to the baseline value obtained during the implantation procedure. All lead related complications were analyzed. Eighty‐two single element subcutaneous array electrodes (SQ‐A1), 31 subcutaneous three‐finger electrodes (SQ‐A3), and 21 subcutaneous patch electrodes (SQ‐P) were implanted during the study period. The median follow‐up was 1,499 days (25th percentile: 798 days, 75th percentile: 1,976 days) in the SQ‐A1 group, 2,209 days (25th percentile: 1,242 days, 75th percentile: 2,710 days) in the SQ‐A3 group, and 1,419 days (25th percentile: 787 days, 75th percentile: 2,838 days) in the SQ‐P group. None of the three groups had a significant change of the DFT during follow‐up compared to baseline. Major complications occurred in six (7.3%) patients in group SQ‐A1 and in two (9.5%) patients in group SQ‐P. There were no major complications in group SQ‐A3. Kaplan‐Meier curves analyzing freedom from subcutaneous lead related complications did not show a significant difference between the three study groups (P = 0.16). SQ‐A1, SQ‐A3, and SQ‐P leads provide stable DFTs during long‐term follow‐up. Major complications are rare. However, a careful follow‐up including chest radiographs at regular intervals is needed to detect potentially fatal complications like lead fractures.

Effect of amiodarone and sotalol on the defibrillation threshold in comparison to patients without antiarrhythmic drug treatment

AIM OF THE STUDY It is generally accepted that chronic therapy with antiarrhythmic drugs might increase the defibrillation threshold at implantation of an implantable cardioverter defibrillator. A recently published animal study showed a minor effect of the class 1 antiarrhythmic drug lidocaine on the defibrillation threshold if biphasic shocks were used. METHODS AND RESULTS We therefore performed a retrospective analysis in 89 patients who received an ICD capable of monophasic (n=18) or biphasic (n=71) shocks with a transvenous lead system. In all patients the defibrillation threshold was determined according to the same step down protocol. In the 18 patients with a monophasic device the effects of chronic therapy with amiodarone (n=7) on the defibrillation threshold were evaluated in comparison to a group without antiarrhythmic treatment (n=11). In those patients receiving a biphasic device the effects of chronic therapy with amiodarone (n=29), sotalol (n=20) or no antiarrhythmic medication (n=22) on the defibrillation threshold were evaluated. The groups receiving a monophasic device did not differ in respect to age, sex, underlying cardiac disease, clinical arrhythmia (VT/VF), clinical functional status, left ventricular ejection fraction and the number of patients with additional subcutaneous electrodes. These parameters as well as the type of implanted device were not different between patient groups receiving a biphasic device. Patients on chronic amiodarone therapy receiving a monophasic device had a significantly higher defibrillation threshold (29.1 +/- 8.8 J) than patients without antiarrhythmic treatment (19.1 +/- 5.1 J, P = 0.021). The groups did not differ significantly in respect to the impedance measured at the shocking lead (P = 0.13). In three patients on chronic amiodarone an epicardiac lead system had to be implanted due to an inadequate monophasic defibrillation threshold compared to no patient without antiarrhythmic drug treatment (P = 0.043). In the patients with a biphasic device the intraoperative defibrillation threshold was not significantly different between the three study groups (P = 0.44). No patient received an epicardiac lead system. The defibrillation threshold in the amiodarone group was 15.3 +/- 7.3 J, in the sotalol group 14.4 +/- 7.2 J and in the patients without antiarrhythmic drug treatment 17 +/- 6.1 J. As well, no significant difference was seen between the groups in respect of the impedance of the high voltage electrode (P = 0.2). CONCLUSION With the use of a biphasic device in combination with a transvenous lead system the intraoperative defibrillation threshold is not significantly different between patients on chronic amiodarone in comparison to patients without antiarrhythmic drug treatment or patients on chronic oral sotalol. This is in contrast to our findings with a monophasic device.

Enhanced detection criteria in implantable cardioverter defibrillators: sensitivity and specificity of the stability algorithm at different heart rates.

KETTERING, K., et al.: Enhanced Detection Criteria in Implantable Cardioverter Defibrillators: Sensitivity and Specificity of the Stability Algorithm at Different Heart Rates. Sensitivity and Specificity of the Stability Algorithm at Different Heart Rates. The lack of specificity in the detection of ventricular tachyarrhythmias remains a major clinical problem in the therapy with ICDs. The stability criterion has been shown to be useful in discriminating ventricular tachyarrhythmias characterized by a small variation in cycle lengths from AF with rapid ventricular response presenting a higher degree of variability of RR intervals. But RR variability decreases with increasing heart rate during AF. Therefore, the aim of the study was to determine if the sensitivity and specificity of the STABILITY algorithm for spontaneous tachyarrhythmias is related to ventricular rate. Forty‐two patients who had received an ICD (CPI Ventak Mini I, II, III or Ventak AV) were enrolled in the study. Two hundred ninety‐eight episodes of AF with rapid ventricular response and 817 episodes of ventricular tachyarrhythmias were analyzed. Sensitivity and specificity in the detection of ventricular tachyarrhythmias were calculated at different heart rates. When a stability value of 30 ms was programmed the result was a sensitivity of 82.7% and a specificity of 91.4% in the detection of slow ventricular tachyarrhythmias (heart rate < 150 beats/min). When faster ventricular tachyarrhythmias with rates between 150 and 169 beats/min (170–189 beats/min) were analyzed, a stability value of 30 ms provided a sensitivity of 94.5% (94.7%) and a specificity of 76.5% (54.0%). For arrhythmia episodes ≥ 190 beats/min, the same stability value resulted in a sensitivity of 78.2% and a specificity of 41.0%. Even when other stability values were taken into consideration, no acceptable sensitivity/specificity values could be obtained in this subgroup. RR variability decreases with increasing heart rate during AF while RR variability remains almost constant at different cycle lengths during ventricular tachyarrhythmias. Thus, acceptable performance of the STABILITY algorithm appears to be limited to ventricular rate zones < 170 beats/min.

Effect of a single element subcutaneous array electrode added to a transvenous electrode configuration on the defibrillation field and the defibrillation threshold.

Even with the use of biphasic shocks, up to 5% of patients need an additional subcutaneous lead to obtain a defibrillation safety margin of at least 10 J. The number of patients requiring additional subcutaneous leads may even increase, because recent generation devices have a < 34 J maximum output in order to decrease their size. In 20 consecutive patients, a single element subcutaneous array lead was implanted in addition to a transvenous lead system consisting of a right ventricular (RV) and a vena cava superior lead using a single infraclavicular incision. The RV lead acted as the cathode; the subcutaneous lead and the lead in the subclavian vein acted as the anode. The biphasic defibrillation threshold was determined using a binary search protocol. Patients were randomized as to whether to start them with the transvenous lead configuration or the combination of the transvenous lead and the subcutaneous lead. In addition, a simplified assessment of the defibrillation field was performed by determining the interelectrode area for the transvenous lead only and the transvenous lead in combination with the subcutaneous lead from a biplane chest X ray. The intraoperative defibrillation threshold was reconfirmed after 1 week, after 3 months, and after 12 months. The mean defibrillation threshold with the additional subcutaneous lead was significantly (P = 0.0001) lower (5.7 ± 2.9 J) than for the transvenous lead system (9.5 ± 4.6 J). With the subcutaneous lead, the impedance of the high voltage circuit decreased from 48.9 ± 7.4 Ω to 39.2 ± 5.0 Ω. In the frontal plane, the interelectrode area increased by 11.3%± 5.5% (P < 0.0001) and in the lateral plane by 29.5%± 12.4% (P < 0.0001). The defibrillation threshold did not increase during follow‐up. Complications with the subcutaneous electrode were not observed during a follow‐up of 15.8 ± 2 months. The single finger array lead is useful in order to lower the defibrillation threshold and can be used in order to lower the defibrillation threshold.

Atrial fibrillation in coronary artery disease.

To answer whether atrial ischemia plays an important role in the genesis of atrial fibrillation in patients with coronary artery disease, we analyzed the electrocardiograms obtained at the time of coronary angiography and left ventriculography in 3220 consecutive patients. Atrial fibrillation was found in 74 (2.3%). Among those with significant coronary artery disease were 49 (66.2%) patients with atrial fibrillation and 88.5% with sinus rhythm (P<0.02). Angiograms of patients with atrial fibrillation and significant (>50%) coronary stenosis were re-evaluated and results compared to the control group which consisted of 108 consecutive patients who were in sinus rhythm at the time of coronary angiography. There were no differences between groups with respect to either frequency of injury to the right coronary artery and circumflex branch of left coronary artery or localization of the injury to this region (before or after atrial branch take-off). But patients with atrial fibrillation significantly more often had heart failure (55.1% versus 18.5%, P<0.001) and three vessel disease (30.5% versus 20.4%, P=0.05) as well as mitral valve insufficiency (20.4% versus 10.2%, P<0.05). In conclusion, in patients with coronary disease, systolic heart failure may be more important than atrial ischemia in causing atrial fibrillation.