Volker Kühlkamp

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.

Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: A randomized, double-blind, placebo-controlled study

OBJECTIVES The primary objective of the present study was to assess the efficacy of metoprolol CR/XL to reduce the risk of relapse after cardioversion of persistent atrial fibrillation to sinus rhythm. BACKGROUND Indirect data from studies with d,l sotalol provide evidence that the beta-blocking effects of the compound are important in maintaining sinus rhythm after cardioversion of atrial fibrillation. METHODS After successful conversion to sinus rhythm, 394 patients with a history of persistent atrial fibrillation were randomly assigned to treatment with metoprolol CR/XL or placebo. The two treatment groups were similar with respect to all pretreatment characteristics. Patients were seen on an outpatient basis for recording of resting electrocardiogram (ECG) after one week, one, three and six months of follow-up or whenever they felt that they had a relapse into atrial fibrillation or experienced an adverse event. RESULTS In the metoprolol CR/XL group, 96 patients (48.7%) had a relapse into atrial fibrillation compared with 118 patients (59.9%) in the placebo group (p = 0.005). Heart rate in patients after a relapse into atrial fibrillation was significantly lower in the metoprolol group (98 +/- 23 beats/min) than in the placebo group (107 +/- 27 beats/min). The rate of adverse events reported was similar in both groups when the difference in follow-up time was taken into account. CONCLUSIONS The results of this double-blind, placebo-controlled study in patients after cardioversion of persistent atrial fibrillation showed that metoprolol CR/XL was effective in preventing relapse into atrial fibrillation or flutter.

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.

Initial experience with an implantable cardioverter-defibrillator incorporating cardiac resynchronization therapy.

OBJECTIVES The purpose of this study was to evaluate an implantable cardioverter-defibrillator (ICD) incorporating biventricular pacing. BACKGROUND Biventricular pacing improves the symptoms of heart failure, a frequent problem in ICD recipients. METHODS This prospective multicenter study evaluated the safety and efficacy of an ICD with biventricular pacing. RESULTS A total of 84 patients with a standard ICD indication, symptomatic heart failure, left ventricular (LV) ejection fraction <35% and a QRS duration >130 ms were included in the trial. In 81 of 84 patients the LV lead was successfully implanted. Patients significantly improved in the 6-min hall-walk test (baseline 304 plus minus 131 m, three months 397 plus minus 142 m, p < 0.001), quality of life (baseline 38.9 plus minus 21.2, three months 26.5 plus minus 21.2, p < 0.001) and the New York Heart Association (NYHA) classification (baseline 2.8 plus minus 0.6, three months 2.2 plus minus 0.5). Left ventricular end-diastolic (from 79.6 plus minus 13.0 mm to 73.6 plus minus 12.9 mm, p = 0.002) and end-systolic (from 68.3 plus minus 13.5 mm to 63.9 plus minus 12.9 mm, p < 0.001) diameter decreased, and fractional shortening increased (from 16 plus minus 6% to 18 plus minus 6%, p = 0.018). Of the patients 26 experienced 472 episodes of spontaneous sustained ventricular tachyarrhythmias. All episodes were successfully terminated except for 16 episodes occurring in a patient with incessant ventricular tachycardia. Biventricular antitachycardia pacing was more effective than right ventricular antitachycardia pacing (p < 0.001). During follow-up (median 185 days, range 12 to 344 days) five patients died from progressive heart failure. CONCLUSIONS Incorporating biventricular pacing in an ICD is feasible and leads to an improvement of heart failure symptoms. Therefore, this therapy may become an option for patients who need ICD therapy in the presence of severe heart failure.

Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces ICa,Land Itoin rapid atrial pacing in rabbits ☆

OBJECTIVES The purpose of the study was to characterize the ionic and molecular mechanisms in the very early phases of electrical remodeling in a rabbit model of rapid atrial pacing (RAP). BACKGROUND Long-term atrial fibrillation reduces L-type Ca(2+) (I(Ca,L)) and transient outward K(+) (I(to)) currents by transcriptional downregulation of the underlying ionic channels. However, electrical remodeling starts early after the onset of rapid atrial rates. The time course of ion current and channel modulation in these early phases of remodeling is currently unknown. METHODS Rapid (600 beats/min) right atrial pacing was performed in rabbits. Animals were divided into five groups with pacing durations between 0 and 96 h. Ionic currents were measured by patch clamp techniques; messenger ribonucleic acid (mRNA) and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot, respectively. RESULTS L-type calcium current started to be reduced (by 47%) after 12 h of RAP and continued to decline as pacing continued. Current changes were preceded or paralleled by decreased mRNA expression of the Ca(2+) channel beta subunits CaB2a, CaB2b, and CaB3, whereas significant reductions in the alpha(1) subunit mRNA and protein expression began 24 h after pacing onset. Transient outward potassium current densities were not altered within the first 12 h, but after 24 h, currents were reduced by 48%. Longer pacing periods did not further decrease I(to). Current changes were paralleled by reduced Kv4.3 mRNA expression. Kv4.2, Kv1.4, and the auxiliary subunit KChIP2 were not affected. CONCLUSIONS L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.

Anxiety in patients with an automatic implantable cardioverter defibrillator: what differentiates them from panic patients?

OBJECTIVE Anxiety seems to be a frequent problem in patients with an automatic implantable cardioverter defibrillator (AICD). Distressing experiences before or after AICD implantation such as resuscitation, or AICD shocks are suspected as causes for enhanced anxiety levels. A closer examination of the level and structure of anxiety in AICD patients and a comparison with panic patients might help to examine additionally both conditioning and cognitive models of anxiety. METHODS There were 61 AICD patients examined with a specifically designed AICD questionnaire and standardized anxiety and depression questionnaires. Subgroups of AICD patients without, with some, and with definite anxiety related to AICD shocks were compared with panic patients and healthy control subjects. RESULTS Although fear of dying was greatly reduced by AICD implantation, approximately one third of the AICD patients, especially patients with definite anxiety related to AICD shocks, were characterized both by enhanced anxiety levels and avoidance behavior. These patients were comparable with panic patients in most questionnaire scores. Anxiety levels were not associated with objective AICD shock experiences or medical variables. CONCLUSIONS Anxiety in AICD patients seems to be unrelated to traumatic experiences, a finding that casts doubt on pure conditioning models of anxiety. Presumably, a life-threatening cardiac disorder increases the likelihood for catastrophic interpretations of bodily signs, especially in anxiety prone AICD patients. In accordance with cognitive models of panic disorder, this cognitive dysfunction could lead to anxiety and depression levels comparable with those of panic patients.

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.

Atrial L-type Ca2+-channel, β-adrenoreceptor, and 5-hydroxytryptamine type 4 receptor mRNAs in human atrial fibrillation

Abstract Molecular and electrical remodeling of ion channels determining action potential duration has been proposed as a major mechanism in chronic atrial fibrillation. We investigated the mRNA expression of the cardiac L-type Ca2+-channel subunits α1c, α2/δ1a, and β1b/c in atrial tissue of patients with chronic atrial fibrillation compared to patients in sinus rhythm. In addition, the mRNA expression of the 5-hydroxytryptamine type 4-, β1-, and β2-adrenergic receptors, which are known to stimulate the L-type Ca2+-current in human atrium, was analyzed and the effect of chronic β-blocker treatment on the mRNA expression of these receptors and of the L-type Ca2+-channel subunits was assessed. Total RNA was isolated from right atrial appendages of patients in sinus rhythm and of patients with chronic atrial fibrillation. Then, semiquantitative RT-PCR using 18 S RNA as the “housekeeping gene” was performed. In patients with chronic atrial fibrillation, there were only mild reductions in mRNA expression of the α1c-subunit (−15.5%, p = 0.13), and of the β1-subunit isoforms a and c (−13.3%, p = 0.14 and −16.6%, p = 0.18, respectively). However, mRNA expression of the α2/δ1-subunit (−31.5%, p < 0.01) and of the β1-subunit isoform b (−39.9%, p < 0.0005) was significantly reduced in patients with chronic AF. Taken together, the mRNA expression of the β1-subunit isoforms b and c, which are splice variants, was significantly down-regulated by 26.5% (p < 0.05) in these patients. The analysis of the β1c/β1b ratio resulted in a significant shift by 39.2% (p < 0.0001) in favor of β1c in patients with chronic atrial fibrillation. In the AF patients, the abundance of the 5-HT4-receptor transcript was significantly reduced by 36% (p < 0.05). The β-adrenoreceptor transcription was unchanged. In both SR and AF patients, chronic β-blocker treatment did neither significantly effect the mRNA expression of the L-type Ca2+channel subunits, the β-adrenoreceptor subtypes 1 and 2, nor that of the 5-HT4-receptor. Our data show that chronic AF is associated with a decrease in the atrial mRNA amount of auxiliary subunits of the L-type Ca2+-channel and of the 5-HT4-receptor. This supports the hypothesis that the observed alterations in mRNA transcription in AF patients may lead to a decrease in the availability of functional L-type Ca2+-channels and 5-HT4-receptors and/or reduce L-type Ca2+-current amplitude and density, thus, promoting and stabilizing the arrhythmia.

A randomized controlled trial of secondary prevention of anxiety and distress in a German sample of patients with an implantable cardioverter defibrillator.

Objective: To evaluate a minimal, easy, accessible intervention targeting anxiety and reduced quality of life in patients with an implantable cardioverter defibrillator (ICD). An estimated 24% to 87% of patients experience anxiety, and 10% to 15% have reduced quality of life. Methods: A total of 119 ICD patients were assigned randomly to usual medical aftercare (n = 63) or additional psychological treatment (n = 56) comprising of written information on medical and psychological consequences of an ICD plus 6 months of individual phone counseling. Treatment efficacy was evaluated by comparing T0 (immediately after implantation) and T1 (6 months later) assessments. Results: Although 75% of patients considered the program helpful, age moderated treatment efficacy. As indicated by triple interactions, only in the treatment group, anxiety (HADS-Anxiety, p < .01), psychological distress (SCL-K-9, p < .02), and somatic quality of life (SF-36-PCS, p < .01) improved in ICD patients aged <65 years but deteriorated in older patients (age, 65–75 years). Frequency of ICD discharges was associated with a symptom increase from T0 to T1 in all patients (HADS-Depression, CAQ-Avoidance, and ICD-Constraints; all p < .05). Conclusions: Our findings confirm that psychological treatments cannot be expected to have uniformly positive effects in ICD patients. Our minimal intervention may have adequately addressed ICD-related concerns in younger patients but may have fostered problems in older patients with fewer concerns. Therefore, our findings warrant custom treatment with particular attention to the elderly as well as patients with frequent ICD discharges. ANOVA = analysis of variance; ATP = antitachycardia pacing; BMI = body mass index; CAQ = Cardiac Anxiety Questionnaire; HADS = Hospital Anxiety and Depression Scale; ICD = implantable cardioverter defibrillator; MI = myocardial infarction; MANOVA = multivariate analysis of variance; QoL = quality of life; SCL-K-9 = Symptom Checklist, 9-item short form; SF-36-MCS = Medical Outcome Study Short Form-36 Health Survey: mental component summary; SF-36-PCS = Medical Outcome Study Short Form-36 Health Survey: physical component summary; T0 = assessment immediately after ICD implantation; T1 = assessment at the end of the intervention (i.e., 6 months later).

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.