Rüdiger Becker

EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy

The purpose of this Consensus Statement is to focus on implantable cardioverter-defibrillator (ICD) deactivation in patients with irreversible or terminal illness. This statement summarizes the opinions of the Task Force members, convened by the European Heart Rhythm Association (EHRA) and the Heart Rhythm Society (HRS), based on ethical and legal principles, as well as their own clinical, scientific, and technical experience. It is directed to all healthcare professionals who treat patients with implanted ICDs, nearing end of life, in order to improve the patient dying process. This statement is not intended to recommend or promote device deactivation. Rather, the ultimate judgement regarding this procedure must be made by the patient (or in special conditions by his/her legal representative) after careful communication about the deactivations consequences, respecting his/her autonomy and clarifying that he/she has a legal and ethical right to refuse it. Obviously, the physician asked to deactivate the ICD and the industry representative asked to assist can conscientiously object to and refuse to perform device deactivation.

Continuous Stroke Unit Electrocardiographic Monitoring Versus 24-Hour Holter Electrocardiography for Detection of Paroxysmal Atrial Fibrillation After Stroke

Background and Purpose— Cardioembolism in paroxysmal atrial fibrillation (pxAF) is a frequent cause of ischemic stroke. Sensitive detection of pxAF after stroke is crucial for adequate secondary stroke prevention; the optimal diagnostic modality to detect pxAF on stroke units is unknown. We compared 24-hour Holter electrocardiography (ECG) with continuous stroke unit ECG monitoring (CEM) for pxAF detection. Methods— Patients with acute ischemic stroke or transient ischemic attack were prospectively enrolled. After a 12-channel ECG on admission, all patients received 24-hour Holter ECG and CEM. Additionally, ECG monitoring data underwent automated analysis using dedicated software to identify pxAF. Patients with a history of atrial fibrillation or with atrial fibrillation on the admission ECG were excluded. Results— Four hundred ninety-six patients (median age, 69 years; 61.5% male) fulfilled all inclusion criteria (ischemic stroke: 80.4%; transient ischemic attack: 19.6%). Median stroke unit stay lasted 88.8 hours (interquartile range, 65.0–122.0). ECG data for automated CEM analysis were available for a median time of 64.0 hours (43.0–89.8). Paroxysmal AF was documented in 41 of 496 patients (8.3%). Of these, Holter detected pxAF in 34.1%; CEM in 65.9%; and automated CEM in 92.7%. CEM and automated CEM detected significantly more patients with pxAF than Holter (P<0.001), and automated CEM detected more patients than CEM (P<0.001). Conclusions— Automated analysis of CEM improves pxAF detection in patients with stroke on stroke units compared with 24-hour Holter ECG. The comparative usefulness of prolonged or repetitive Holter ECG recordings requires further evaluation.

Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death

BACKGROUND Cardiac light-chain amyloidosis carries a high risk for death predominantly from progressive cardiomyopathy or sudden death (SCD). Independent risk factors for SCD are syncope and complex nonsustained ventricular arrhythmias. OBJECTIVE The purpose of this study was to test whether prophylactic placement of an implantable cardioverter-defibrillator (ICD) reduces SCD in patients with cardiac amyloidosis. METHODS Nineteen patients with histologically proven cardiac amyloidosis and a history of syncope and/or ventricular extra beats (Lown grade IVa or higher) received an ICD. RESULTS During a mean follow-up of 811 +/- 151 days, two patients with sustained ventricular tachyarrhythmias were successfully treated by the ICD. Two patients underwent heart transplantation, and seven patients died due to electromechanical dissociation (n = 6) or glioblastoma (n = 1). Nonsurvivors more often showed progression of left ventricular wall thickness, low-voltage pattern, ventricular arrhythmias (Lown grade IVa or higher), and higher N-terminal pro-brain natriuretic peptide levels than did survivors. Bradycardias requiring ventricular pacing (VVI 40/min <1%, DDD 60/min 6% +/- 1%) occurred only rarely. CONCLUSION Patients with cardiac amyloidosis predominantly die as a result of electromechanical dissociation and other diagnoses not amenable to ICD therapy. Selected patients with cardiac amyloidosis may benefit from ICD placement. Better predictors of arrhythmia-associated SCD and randomized trials are required to elucidate the impact of ICD placement in high-risk patients with cardiac amyloidosis.

Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model

AIMS Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and effective treatment of AF still remains an unmet medical need. AF is associated with atrial conduction disturbances caused by electrical and/or structural remodelling. We hypothesized that AF suppresses expression of the gap junction protein connexin (Cx) 43 and that Cx43 gene transfer to both atria would prevent persistent AF. The first aim of this study was to assess whether AF is associated with connexin remodelling in a porcine model. A strategy to suppress persistent AF by gene therapy was then developed and evaluated in vivo. METHODS AND RESULTS AF was induced in domestic pigs via atrial burst pacing, causing a 62.4% reduction in atrial Cx43 protein. Adenoviruses encoding for Cx43 (AdCx43) or green fluorescent protein (AdGFP) were injected into both atria, followed by epicardial electroporation to enhance transgene expression. Combining direct injection of adenoviruses with electroporation achieved GFP reporter gene expression in ∼50% of atrial cells in vivo. AdCx43-treated animals exhibited a 2.5-fold increase in atrial Cx43 protein content and did not develop persistent AF during the observation period of 14 days. In contrast, control animals developed persistent AF within 7.4 ± 0.5 days. Rapid ventricular heart rates during AF led to deterioration of cardiac function in control pigs but not in pigs treated with AdCx43. CONCLUSION Our results highlight the contribution of Cx43 to the pathophysiology of AF and demonstrate the viability of gene therapy for prevention of atrial arrhythmias.

Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study

AIMS Atrial fibrillation (AF) is linked to cardiomyocyte apoptosis, leading to atrial remodelling and reduction in electrical conduction velocity. We hypothesized that genetic suppression of an apoptotic key enzyme, caspase 3, would prevent the development of persistent AF by reducing apoptosis which may serve as an arrhythmogenic substrate. METHODS AND RESULTS Atrial fibrillation was induced in domestic pigs by atrial burst pacing via an implanted cardiac pacemaker. Study animals were then assigned to receive either Ad-siRNA-Cas3 gene therapy to inactivate caspase 3 or green fluorescent protein (Ad-GFP) as a control. Adenoviruses were applied using a hybrid technique employing right and left atrial virus injection followed by epicardial electroporation to increase expression of plasmid DNA. In pigs treated with Ad-siRNA-Cas3, the onset of AF was suppressed or significantly delayed compared with controls (10.3 ± 1.2 days vs. 6.0 ± 1.6 days; P= 0.04). Electrical mapping revealed prolonged atrial conduction in the control group that was prevented by Ad-siRNA-Cas3 gene therapy. On the molecular level, Ad-siRNA-Cas3 application resulted in down-regulation of caspase 3 expression and suppression of apoptotic activity. CONCLUSION Knockdown of caspase 3 by atrial Ad-siRNA-Cas3 gene transfer suppresses or delays the onset of persistent AF by reduction in apoptosis and prevention of intra-atrial conduction delay in a porcine model. These results highlight the significance of apoptosis in the pathophysiology of AF and demonstrate short-term efficacy of gene therapy for suppression of AF.

Regulation of two-pore-domain (K2P) potassium leak channels by the tyrosine kinase inhibitor genistein

Two‐pore‐domain potassium (K2P) channels mediate potassium background (or ‘leak’) currents, controlling excitability by stabilizing membrane potential below firing threshold and expediting repolarization. Inhibition of K2P currents permits membrane potential depolarization and excitation. As expected for key regulators of excitability, leak channels are under tight control from a plethora of stimuli. Recently, signalling via protein tyrosine kinases (TKs) has been implicated in ion channel modulation. The objective of this study was to investigate TK regulation of K2P channels.

Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go–related gene mutant

BACKGROUND Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Gene therapy-dependent modulation of atrial electrophysiology may provide a more specific alternative to pharmacological and ablative treatment strategies. OBJECTIVE We hypothesized that genetic inactivation of atrial repolarizing ether-a-go-go-related gene (ERG) K(+) currents using a dominant-negative mutant would provide rhythm control in AF. METHODS Ten domestic swine underwent pacemaker implantation and were subjected to atrial burst pacing to induce persistent AF. Animals were then randomized to receive either AdCERG-G627S to suppress ERG/I(Kr) currents or green fluorescent protein (AdGFP) as control. Adenoviruses were applied using a novel hybrid technique combining atrial virus injection and epicardial electroporation to increase transgene expression. RESULTS In pigs treated with AdCERG-G627S, the onset of persistent AF was prevented (n = 2) or significantly delayed compared with AdGFP controls (12 ± 2.1 vs. 6.2 ± 1.3 days; P < .001) during 14-day follow-up. Effective refractory periods were prolonged in the AdCERG-G627S group compared with AdGFP animals (221.5 ± 4.7 ms vs. 197.0 ± 4.7 ms; P < .006). Impairment of left ventricular ejection fraction (LVEF) during AF was prevented by AdCERG-G627S application (LVEF(CERG-G627S) = 62.1% ± 4.0% vs. LVEF(GFP) = 30.3% ± 9.1%; P < .001). CONCLUSION Inhibition of ERG function using atrial AdCERG-G627S gene transfer suppresses or delays the onset of persistent AF by prolongation of atrial refractoriness in a porcine model. Targeted gene therapy represents an alternative to pharmacological or ablative treatment of AF.

cAMP Sensitivity of HCN Pacemaker Channels Determines Basal Heart Rate But Is Not Critical for Autonomic Rate Control

Background—HCN channels activate the pacemaker current If, which is thought to contribute significantly to generation and regulation of heart rhythm. HCN4 represents the dominant isotype in the sinoatrial node and binding of cAMP was suggested to be necessary for autonomic heart rate regulation. Methods and Results—In a candidate gene approach, a heterozygous insertion of 13 nucleotides in exon 6 of the HCN4 gene leading to a truncated cyclic nucleotide-binding domain was identified in a 45-year-old woman with sinus bradycardia. Biophysical properties determined by whole-cell patch-clamp recording of HEK293 cells demonstrated that mutant subunits (HCN4-695X) were insensitive to cAMP. Heteromeric channels composed of wild-type and mutant subunits failed to respond to cAMP-like homomeric mutant channels, indicating a dominant-negative suppression of cAMP-induced channel activation by mutant subunits. Pedigree analysis identified 7 additional living carriers showing similar clinical phenotypes, that is, sinus node dysfunction with mean resting heart rate of 45.9±4.6 bpm (n=8) compared with 66.5±9.1 bpm of unaffected relatives (n=6; P<0.01). Clinical evaluation revealed no ischemic or structural heart disease in any family member. Importantly, mutant carriers exhibited normal heart rate variance and full ability to accelerate heart rate under physical activity or pharmacological stimulation. Moreover, mutant carriers displayed distinctive sinus arrhythmias and premature beats linked to adrenergic stress. Conclusions—In humans, cAMP responsiveness of If determines basal heart rate but is not critical for maximum heart rate, heart rate variability, or chronotropic competence. Furthermore, cAMP-activated If may stabilize heart rhythm during chronotropic response.

Successful acute and long-term management of electrical storm in Brugada syndrome using orciprenaline and quinine/quinidine

Brugada syndrome (BrS) is an inherited electrical disorder characterized by ST segment elevation in the right precordial ECG leads and a widened QRS complex [1–5]. BrS accounts for approximately 20% of sudden cardiac deaths in the absence of obvious structural heart disease [1]. Typical ECG manifestations are often concealed but may be unmasked by sodium channel blockers during intravenous drug challenge [6]. Mutations in the gene encoding for the cardiac sodium channel a-subunit, SCN5A, were identified in 18–30% of Brugada syndrome cases [2]. Ventricular fibrillation (VF) and sudden death occur usually at rest and at night. While incessant ventricular tachycardia may be observed in patients with coronary artery disease, congestive heart failure, myocarditis, or drug-induced long QT syndrome [7–10], electrical storm (ES; defined as C3 VF episodes in 24 h) associated with BrS is a seldom reported, potentially lethal event [11–13]. Radiofrequency catheter ablation of VF-triggering premature ventricular complexes, extracorporeal membrane oxygenation, or even heart transplantation as last resort may be required in order to provide circulatory and respiratory support and to prevent a fatal outcome in these rare cases [14–17]. Clinical management of ES in Brugada syndrome primarily relies on reported cases owing to its low prevalence and to the lack of randomized clinical studies. Case report

TASK1 (K2P3.1) K+ channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation

BACKGROUND AND PURPOSE TASK1 (K2P3.1) two‐pore‐domain K+ channels contribute substantially to the resting membrane potential in human pulmonary artery smooth muscle cells (hPASMC), modulating vascular tone and diameter. The endothelin‐1 (ET‐1) pathway mediates vasoconstriction and is an established target of pulmonary arterial hypertension (PAH) therapy. ET‐1‐mediated inhibition of TASK1 currents in hPASMC is implicated in the pathophysiology of PAH. This study was designed to elucidate molecular mechanisms underlying inhibition of TASK1 channels by ET‐1.