Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on NaV1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Reduction of fluoroscopy exposure and procedure duration during ablation of atrial fibrillation using a novel anatomical navigation system

Aims - Catheter ablation of atrial fibrillation (AF) is centred on pulmonary vein (PV) ablation with or without additional atrial substrate modification. These procedures may be prolonged with significant fluoroscopy exposure. This study evaluates a new non-fluoroscopic navigation system during ablation of AF. Methods and results - Seventy-two patients undergoing catheter ablation of symptomatic drug refractory AF were prospectively randomized to ablation with (n ¼ 35; study group) or without (n ¼ 37; control group) non-fluoroscopic navigation. PV isolation was performed in all patients. In patients with persistent or inducible sustained AF after PV isolation linear ablation was performed by joining the superior PVs. PV isolation was achieved in all patients; fluoroscopy (15.4+3.4 vs. 21.3+6.4 min; P , 0.001) and procedural (52+12 vs. 61+17 min; P ¼ 0.02) durations were significantly reduced in the study group. Linear block was achieved in 37 of the 39 patients; with a significant reduction in fluoroscopy (5.6+2.2 vs. 9.9+4.8 min; P ¼ 0.003) and procedural (14.7+5.5 vs. 26.6+16.9 min; P ¼ 0.007) durations in the study group. After a follow-up of 6.9+2.9 months (range 3–10), 26 (74%) patients in the non-fluoroscopic navigation group and 29 (78%) patients in the control group were arrhythmiafree after the first procedure. Conclusion - This prospectively randomized study demonstrates significant reduction of fluoroscopy exposure and procedural duration using supplementary non-fluoroscopic imaging system for AF ablation.Martin Rotter, Yoshihide Takahashi, Prashanthan Sanders, Michel Haïssaguerre, Pierre Jaïs, Li-Fern Hsu, Fréderic Sacher, Jean-Luc Pasquié, Jacques Clementy and Mélèze Hocin

Left atrial linear ablation to modify the substrate of atrial fibrillation using a new nonfluoroscopic imaging system

The definitive version is available at www.blackwell-synergy.comLinear left atrial ablation is performed in combination with pulmonary vein (PV) isolation to improve the clinical results of atrial fibrillation (AF) ablation. These procedures require long procedures and fluoroscopic exposure. The aim of the present study was to evaluate the performance of a new, nonfluoroscopic, real-time, three-dimensional navigation system for linear ablation at the left atrial roof and mitral isthmus. The study included 44 patients (54 +/- 10 years of age, 5 women) with drug-refractory AF, who underwent roof line or mitral isthmus linear ablation after 4-PV isolation. In 22 patients, ablation was performed with the navigation system (test group), and in the remainders linear ablation was performed with fluoroscopic guidance alone (control group). Conduction block was achieved in 20 patients (91%) in test group, and 21 patients (95%) in the control group (ns). Use of the navigation system was associated with a shorter fluoroscopic exposure for roof line (5.6 +/- 3.0 minutes vs 8.7 +/- 5.0 minutes, P < 0.05), and a trend for mitral isthmus ablation (7.8 +/- 7.8 minutes vs 12.1 +/- 5.9 minutes). It was also associated with a trend toward shorter procedure times for roof line (15.3 +/- 8.6 minutes vs 22.9 +/- 16.8 minutes) and mitral isthmus line (20.2 +/- 15.8 minutes vs 32.0 +/- 7.6 minutes) but no difference in duration of radiofrequency delivery. There was no procedural complication. The use of this new nonfluoroscopic imaging system was associated with a shorter fluoroscopic exposure as well as a trend toward shorter duration of linear ablation procedures for AF.Yoshihide Takahashi, Martin Rotter, Prashanthan Sanders, Pierre Jaïs, Mélèze Hocini, Li-Fern Hsu, Jean-Luc Pasquié, Frédéric Sacher, Stéphane Garrigue, Jacques Clémenty, Michel Haïssaguerr

Incidence and prevention of cardiac tamponade complicating ablation for atrial fibrillation

The definitive version is available at www.blackwell-synergy.comCardiac tamponade complicating catheter ablation of atrial fibrillation (AF) occurs in approximately 1% of pulmonary vein isolation (PVI), and up to 6% of linear ablation procedures. We reviewed 348 consecutive AF ablation (including repeat) procedures over 1 year, which all included PVI, with additional linear lesions at the mitral isthmus in 73%, and cavotricuspid isthmus (CTI) in 76%. An irrigated-tip ablation catheter was used, with power limited to 25-35 W for PVI and 45-60 W for linear lesions. Tamponade occurred in seven men and three women (2.9% of the population) during the creation of linear ablation lesions. Mechanical perforations occurred in two patients, and "popping" during radiofrequency (RF) energy delivery at the mitral isthmus in six, and at the CTI in two patients. Peak RF power was significantly higher in patients with than without tamponade (53 +/- 4 W vs 48 +/- 7 W; P = 0.02), and was greater than 48 W in all cases of "popping." In the following year, RF power for linear ablation was limited to </=42 W. Among 398 procedures, tamponade occurred in four patients (1.0%; P = 0.047 vs first year), three from "popping" and one from mechanical trauma. Procedural success rate remained the same despite reduction of power. Risk of tamponade was highest during linear ablation, mainly associated with high energy delivery and "popping." Reducing the energy limited, though did not eliminate this complication.Li-Fern Hsu, Pierre Jaîs, Mélèze Hocini, Prashanthan Sanders, Christophe Scavée, Fréderic Sacher, Yoshihide Takahashi, Martin Rotter, Jean-Luc Pasquie, Jacques Clémenty, Michel Haîssaguerr

Mapping and ablation of ventricular fibrillation

Sudden cardiac death frequently results from ventricular fibrillation (VF). While VF is frequently the eventual mode of death in patients with abnormal ventricular substrates, it has also been described in patients with structurally normally hearts. Until recently, the management of patients who have survived sudden cardiac death has focused on treating the consequences by implantation of a defibrillator. However, such therapy remains restricted in many countries, is associated with a prohibitive cost to the community, and may be a cause of significant morbidity in patients with frequent episodes or storms of arrhythmia. Evidence emerging from the study of fibrillation both in the atria and the ventricle suggests an important role for triggers arising from the Purkinje network or the right ventricular outflow tract in the initiation of VF. Initial experience in patients with idiopathic VF and even those with VF associated with abnormal repolarization syndromes (LQT or Brugada syndrome) or myocardial infarction suggests that long term suppression of recurrent VF may be feasible by the elimination of these triggers. With the development of new mapping and ablation technologies, and greater physician experience, catheter ablation of VF, with the ultimate aim of curing such patients at risks of sudden cardiac death, may not be an unrealistic goal in the future.Sanders P; Hsu LF; Hocini M; Jaïs P; Takahashi Y; Rotter M; Sacher F; Pasquié JL; Arentz T; Scavée C; Garrigue S; Clémenty J; Haïssaguerre

Changes in atrial fibrillation cycle length and inducibility during catheter ablation and their relation to outcome

© 2004 American Heart Association, Inc.BackgroundThe modification of atrial fibrillation cycle length (AFCL) during catheter ablation in humans has not been evaluated.Methods and resultsSeventy patients undergoing ablation of prolonged episodes of AF were randomized to pulmonary vein (PV) isolation or additional ablation of the mitral isthmus. Mean AFCL was determined at a distance from the ablated area (coronary sinus) at the following intervals: before ablation, after 2- and 4-PV isolations, and after linear ablation. Inducibility of sustained AF (> or =10 minutes) was determined before and after ablation. Spontaneous sustained AF (715+/-845 minutes) was present in 30 patients and induced in 26 (AFCL, 186+/-19 ms). PV isolation terminated AF in 75%, with the number of PVs requiring isolation before termination increasing with AF duration (P=0.018). PV isolation resulted in progressive or abrupt AFCL prolongation to various extents, depending on the PV: to 214+/-24 ms (PConclusionsAF ablation results in a decline in AF frequency, with a magnitude correlating with termination of AF and prevention of inducibility that is predictive of subsequent clinical outcome.Michel Haïssaguerre, Prashanthan Sanders, Mélèze Hocini, Li-Fern Hsu, Dipen C. Shah, Christophe Scavée, Yoshihide Takahashi, Martin Rotter, Jean-Luc Pasquié, Stéphane Garrigue, Jacques Clémenty, and Pierre Jaï

Electrophysiologic and clinical consequences of linear catheter ablation to transect the anterior left atrium in patients with atrial fibrillation

© 2004 Elsevier.Background While the Maze procedure is effective in maintaining sinus rhythm in patients with AF, it is associated with significant morbidity. This prospective clinical study evaluates the feasibility and consequences of limited LA linear ablation to transect the anterior LA in patients with AF. Methods Twenty-four patients (51.2 ± 7.3 years) with paroxysmal (n = 16) or chronic (n = 8) AF resistant to pulmonary vein (PV) isolation were studied. To transect the anterior LA, linear ablation was performed joining the superior PVs; this line was then connected to the anterior mitral annulus. Pulmonary vein isolation and cavotricuspid isthmus ablation were performed in all cases. Ablation was performed using an irrigated catheter with the endpoint of achieving complete linear block demonstrated by online double potentials, differential pacing techniques, and an activation detour. Results Of 20 patients in AF prior to linear ablation, arrhythmia terminated in 12 (60%), including half the patients with chronic AF, during ablation. Despite repeated ablation, complete linear block was achieved in only 14 of 24 patients (58%). Complete linear conduction block resulted in an activation detour around the mitral annulus and PVs with a delay of 158 ± 30 ms (P = .0001), significantly delayed activation of the lateral LA with prolongation of P-wave duration (P = .002), and characteristic change in P-wave morphology during sinus rhythm (P = .002). Of the 14 with anterior LA transection, 4 (29%) have had regular atrial tachycardias due to macroreentry through recovered gaps. Nine of these 14 (64%) have remained arrhythmia-free without antiarrhythmics compared to 3 of 10 (30%) with incomplete block at 28 ± 4 months following their last procedure (P = .2). Conclusions This study demonstrates the feasibility of catheter ablation to transect the anterior LA in humans. While being effective in the termination of AF, this configuration of linear lesions is technically challenging to complete, results in significant delayed LA activation, and is associated with modest long-term arrhythmia suppression.http://www.elsevier.com/wps/find/journaldescription.cws_home/702333/description#descriptio

Does mechanical morcellation of large glands compromise incidental prostate cancer detection on specimen analysis? A pathological comparison with open simple prostatectomy

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