Efficacy and safety of hybrid epicardial and endocardial ablation versus endocardial ablation in patients with persistent and longstanding persistent atrial fibrillation: a randomised, controlled trial.

Background: Endocardial catheter ablation (CA) has limited long-term benefit for persistent and longstanding persistent atrial fibrillation (PersAF/LSPAF). We hypothesized hybrid epicardial-endocardial ablation (HA) would have superior effectiveness compared to CA, including repeat (rCA), in PersAF/LSPAF. Methods: CEASE-AF (NCT02695277) is a prospective, multi-center, randomized controlled trial. Nine hospitals in Poland, Czech Republic, Germany, United Kingdom, and the Netherlands enrolled eligible participants with symptomatic, drug refractory PersAF and left atrial diameter (LAD) > 4.0 cm or LSPAF. Randomization was 2:1 to HA or CA by an independent statistician and stratified by site. Treatment assignments were masked to the core rhythm monitoring laboratory. For HA, pulmonary veins (PV) and left posterior atrial wall were isolated with thoracoscopic epicardial ablation including left atrial appendage exclusion. Endocardial touch-up ablation was performed 91-180 days post-index procedure. For CA, endocardial PV isolation and optional substrate ablation were performed. rCA was permitted between days 91-180. Primary effectiveness was freedom from AF/atrial flutter/atrial tachycardia >30-s through 12-months absent class I/III anti-arrhythmic drugs except those not exceeding previously failed doses. It was assessed in the modified intention-to-treat (mITT) population who had the index procedure and follow-up data. Major complications were assessed in the ITT population who had the index procedure. Thirty-six month follow-up continues. Findings: Enrollment began November 20, 2015 and ended May 22, 2020. In 154 ITT patients (102 HA; 52 CA), 75% were male, mean age was 60.7 ± 7.9 years, mean LAD was 4.7 ± 0.4 cm, and 81% had PersAF. Primary effectiveness was 71.6% (68/95) in HA versus 39.2% (20/51) in CA (absolute benefit increase: 32.4% [95% CI 14.3%-48.0%], p < 0.001). Major complications through 30-days after index procedures plus 30-days after second stage/rCA were similar (HA: 7.8% [8/102] versus CA: 5.8% [3/52], p = 0.75). Interpretation: HA had superior effectiveness compared to CA/rCA in PersAF/LSPAF without significant procedural risk increase. Funding: AtriCure, Inc.

[17-year-old patient with polymorphic premature ventricular contractions]. / 17-jähriger Patient mit polymorpher ventrikulärer Extrasystolie.

A 17-year-old patient with premature ventricular contractions and normal left ventricular function was referred for reablation after an unsuccessful catheter ablation attempt. Holter monitoring demonstrated a high burden of premature ventricular contractions, present throughout the whole recording. The patient reported occasional paralytic attacks; his face had a dysmorphic appearance with a wide distance between the eyes, a caudal insertion of the ears, and a high forehead. These three features resulted in a clinical diagnosis that was confirmed by molecular biology and completely changed the therapeutic strategy.

[Ventricular arrhythmias in ion channel diseases]. / Ventrikuläre Arrhythmien bei Ionenkanalerkrankungen.

In patients with ion channel disease the predominant arrhythmias are polymorphic ventricular tachycardias (VT), torsade de pointes tachycardia and ventricular fibrillation (VF). In only extremely rare cases is very rapid monomorphic ventricular tachycardia observed. This is why implantable cardioverter-defibrillators (ICDs) should always be programmed for treatment of VF only with high detection rates to avoid inappropriate discharges. In idiopathic VF and catecholaminergic polymorphic ventricular tachycardia (CPVT), no baseline electrocardiographic abnormalities can be detected, whereas in Brugada syndrome, long QT syndrome, early repolarisation syndrome and Anderson-Tawil syndrome alterations of the baseline ECG are very important to identify patients at risk.

[Ion channel diseases in children]. / Ionenkanalerkrankungen bei Kindern.

Ion channel diseases are responsible for the occurrence of supraventricular bradycardia and tachycardia, ventricular tachycardia, syncope and sudden death. In the present paper the specific considerations for diagnostic pathways and therapeutic decision making will be focused on for the largest clinical entities, such as the long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia and Andersen-Tawil syndrome. All diseases are characterized by a specific pathognomic electrocardiographic (ECG) alteration. For most of the diseases a variety of mutations have been identified that code for different ion channel proteins. All have a high potential of arrhythmogenicity in common. It is important to know that the ECG alterations are often only transient, which makes repetitive recordings and sometimes provocation maneuvers necessary. The time of onset of disease varies so that the initiation of diagnostics starts at different ages. Therapy often remains an individual choice and is influenced by a number of factors, such as a family history of sudden death.

[Brugada syndrome]. / Brugada-Syndrom.

Brugada syndrome is an ion channel disease which is associated with an increased risk of sudden cardiac death. Most probably the pathogenesis of ventricular fibrillation in these patients is a combination of both genetically determined repolarisation abnormalities and conduction delay in the right ventricular epicardium. The highest risk of sudden cardiac death is present in patients who have experienced syncope before, who reveal the pathognomic electrocardiographic changes already at rest and who have inducible ventricular fibrillation. Asymptomatic patients who have the J point elevations only after administration of a sodium channel blocker seem to be at lower risk. Most recently the latest joint consensus recommendations of the largest societies for diagnostic criteria, indications for genetic testing and therapy have been published.

Addition of a defibrillation electrode in the low right atrium to a right ventricular lead does not reduce ventricular defibrillation thresholds.

Transvenous unipolar active can defibrillation systems have proven to be effective in treating ventricular tachyarrhythmias. However, a further reduction of ventricular defibrillation thresholds (V-DFT) would increase the longevity, reduce the size of pulse generators, and help to avoid additional leads in patients with inacceptable high V-DFTs. In a finite difference computer model, the extension of the right ventricular (RV) defibrillation coil into the low right atrium led to a 40% reduction of unipolar V-DFT. To evaluate this finding, we conducted a prospective, randomized study in 11 patients receiving an ICD. Extension of the RV electrode was simulated by adding a second coil placed in the low right atrium with the same polarity. Using a binary search protocol, V-DFT was determined with and without the additional electrode in each patient. Total shock impedance was significantly lower in the two coil (low RA) configuration, compared to the single coil (RV) configuration. Corresponding values were 49.9 +/- 6.7 Ohm and 61.1 +/- 9.3 Ohm, respectively (P < 0.01, paired t-test). However, there was no reduction, but even a nonsignificant increase in V-DFTs. Mean V-DFT in the RV configuration was 12.0 +/- 5.6 J and 16.3 +/- 7.8 J in the low RA configuration (P = 0.09, paired t-test). Despite a reduction in total impedance, the addition of a defibrillation coil in the low right atrium does not reduce ventricular defibrillation thresholds.

Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I(Ca,L) and I(to) in 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.

beta3-Adrenergic regulation of an ion channel in the heart-inhibition of the slow delayed rectifier potassium current I(Ks) in guinea pig ventricular myocytes.

OBJECTIVES: I(Ks), the slow component of the delayed rectifier potassium current, underlies a strong beta-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 beta(1)- and beta(3)-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 beta(1)- and beta(3)-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 beta(1)- (1 micromol/l atenolol) and beta(2)-receptors (1 micromol/l ICI118,551), isoproterenol induced a reduction of the step current amplitude by 34.3+/-3.5%. The beta(3)-selective agonist BRL37344 significantly reduced the I(Ks) step current at +70 mV in a concentration-dependent manner (IC(50): 5.01 nmol/l). In the presence of bupranolol (beta(1)-, beta(2)- and beta(3)-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 micromol/l bupranolol). BRL37344 (100 micromol/) 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 micromol/l BRL37344 mildly prolonged action potentials in guinea pig ventricle (APD(90):+7.8%) CONCLUSIONS: We have demonstrated a functional coupling between the beta(3)-adrenoceptor and ion channel function in the mammalian heart. Our findings point to a potential role for beta(3)-adrenoceptors in cardiac electrophysiology and pathophysiology.

Changes in renal and systemic hemodynamics after NO-synthase inhibition in males with family history of hypertension.

BACKGROUND: Nitric oxide (NO) plays an important role in the regulation of blood pressure and renal hemodynamics. METHODS: To further investigate the role of NO in human hypertension, we studied the effect of systemic injection of N(G)-monomethyl-L-arginine (L-NMMA) on renal hemodynamics, urinary sodium excretion (FE(Na)), systemic hemodynamics and several vasoactive hormones in 5 healthy male subjects with (group H) and without (group N) family history of hypertension. An intravenous infusion of L-NMMA (3 mg/kg over 10 min) or placebo was given in a randomized, double-blinded manner. GFR and ERPF were measured by inulin- and PAH-clearances. Norepinephrine infusion (0.1 microg/kg/min over 60 min) served as vasoconstrictive control infusion. RESULTS: L-NMMA induced a significant decrease in ERPF (-135 +/- 49 vs. 7 +/- 31 ml/min/1.73 m(2) with placebo, p < 0.05), a decrease in FE(Na) (-1.2 +/- 0.6% with L-NMMA vs. 0.0 +/- 0.1% with placebo), and a significant increase in diastolic blood pressure (+7 +/- 1 vs. -2 +/- 1 mm Hg with placebo) in group N, only. A sustained drop in plasma renin activity (-0.1 +/- 0.1 vs. 0.3 +/- 0.1 ng/ml/h with placebo) could also be seen in this group, only. Subjects with family history of hypertension showed minor or even no response (changes in diastolic blood pressure: L-NMMA: 5 +/- 3 mm Hg, placebo: 0 +/- 2 mm Hg; changes in ERPF: L-NMMA: -89 +/- 57 ml/min/1.73 m(2), placebo: -34 +/- 28 ml/min/1.73 m(2); changes in plasma renin activity: L-NMMA: -0.0 +/- 0.3 ng/ml/h, placebo: -0.1 +/- 0.2 ng/ml/h). The vasoconstrictive effect of norepinephrine infusion did not differ between both groups. CONCLUSION: Our data indicate that systemic NO synthetase inhibition by L-NMMA results in a blunted effect on systemic blood pressure and the renal hemodynamic system in subjects with family history of hypertension.