TY  - JOUR
AB  - Background:Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF.Methods:Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation.Results:Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13).Conclusions:Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.
AU  - Shoemaker, M.B.*
AU  - Husser, D.*
AU  - Roselli, C.*
AU  - Al Jazairi, M.*
AU  - Chrispin, J.*
AU  - Kühne, M.*
AU  - Neumann, B.*
AU  - Knight, S.*
AU  - Sun, H.*
AU  - Mohanty, S.*
AU  - Shaffer, C.*
AU  - Thériault, S.*
AU  - Rinke, L.L.*
AU  - Siland, J.E.*
AU  - Crawford, D.M.*
AU  - Ueberham, L.*
AU  - Zardkoohi, O.*
AU  - Büttner, P.*
AU  - Geelhoed, B.*
AU  - Blum, S.*
AU  - Aeschbacher, S.*
AU  - Smith, J.D.*
AU  - van Wagoner, D.R.*
AU  - Freudling, R.
AU  - Müller-Nurasyid, M.
AU  - Montgomery, J.*
AU  - Yoneda, Z.*
AU  - Wells, Q.*
AU  - Issa, T.*
AU  - Weeke, P.*
AU  - Jacobs, V.*
AU  - van Gelder, I.C.*
AU  - Hindricks, G.*
AU  - Barnard, J.*
AU  - Calkins, H.*
AU  - Darbar, D.*
AU  - Michaud, G.*
AU  - Kääb, S.*
AU  - Ellinor, P.*
AU  - Chung, M.*
AU  - Nazarian, S.*
AU  - Cutler, M.J.*
AU  - Sinner, M.F.*
AU  - Conen, D.*
AU  - Rienstra, M.*
AU  - Bollmann, A.*
AU  - Roden, D.M.*
AU  - Lubitz, S.*
C1  - 58720
C2  - 48506
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
TI  - Genetic susceptibility for atrial fibrillation in patients undergoing atrial fibrillation ablation.
JO  - Circ.-Arrhythmia Electrophysiol.
VL  - 13
IS  - 3
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 1941-3149
ER  - 

TY  - JOUR
AB  - Background: We developed a novel electrocardiographic marker, T-wave area dispersion (TW-Ad), which measures repolarization heterogeneity by assessing interlead T-wave areas during a single cardiac cycle and tested whether it can identify patients at risk for sudden cardiac death (SCD) in the general population. Methods and Results: TW-Ad was measured from standard digital 12-lead ECG in 5618 adults (46% men; age, 50.9±12.5 years) participating in the Health 2000 Study - an epidemiological survey representative of the Finnish adult population. Independent replication was performed in 3831 participants of the KORA S4 Study (Cooperative Health Research in the Region of Augsburg; 49% men; age, 48.7±13.7 years; mean follow-up, 8.8±1.1 years). During follow-up (7.7±1.4 years), 72 SCDs occurred in the Health 2000 Survey. Lower TW-Ad was univariately associated with SCD (0.32±0.36 versus 0.60±0.19; P<0.001); it had an area under the receiver operating characteristic curve of 0.809. TW-Ad (≤0.46) conferred a hazard ratio of 10.8 (95% confidence interval, 6.8-17.4; P<0.001) for SCD; it remained independently predictive of SCD after multivariable adjustment for clinical risk markers (hazard ratio, 4.6; 95% confidence interval, 2.7-7.4; P<0.001). Replication analyses performed in the KORA S4 Study confirmed an increased risk for cardiac death (unadjusted hazard ratio, 5.5; 95% confidence interval, 3.2-9.5; P<0.001; multivariable adjusted hazard ratio, 1.9; 95% confidence interval, 1.1-3.5; P<0.05). Conclusion: Low TW-Ad, reflecting increased heterogeneity of repolarization, in standard 12-lead resting ECGs is a powerful and independent predictor of SCD in the adult general population.
AU  - Kenttä, T.V.*
AU  - Sinner, M.F.*
AU  - Nearing, B.D.*
AU  - Freudling, R.
AU  - Porthan, K.*
AU  - Tikkanen, J.T.*
AU  - Müller-Nurasyid, M.
AU  - Schramm, K.
AU  - Viitasalo, M.*
AU  - Jula, A.*
AU  - Nieminen, M.S.*
AU  - Peters, A.
AU  - Salomaa, V.*
AU  - Oikarinen, L.*
AU  - Verrier, R.L.*
AU  - Kääb, S.*
AU  - Junttila, M.J.*
AU  - Huikuri, H.V.*
C1  - 52976
C2  - 44390
CY  - Philadelphia
TI  - Repolarization heterogeneity measured with T-wave area dispersion in standard 12-lead ECG predicts sudden cardiac death in general population.
JO  - Circ.-Arrhythmia Electrophysiol.
VL  - 11
IS  - 2
PB  - Lippincott Williams & Wilkins
PY  - 2018
SN  - 1941-3149
ER  - 

TY  - JOUR
AB  - Background-Mutations in genes including SCN5A encoding the a-subunit of the cardiac sodium channel (hNav1.5) cause Brugada syndrome via altered function of cardiac ion channels, but more than two-thirds of Brugada syndrome remains pathogenetically elusive. T-tubules and sarcoplasmic reticulum are essential in excitation of cardiomyocytes, and sarcolemmal membrane-associated protein (SLMAP) is a protein of unknown function localizing at T-tubules and sarcoplasmic reticulum. Methods and Results-We analyzed 190 unrelated Brugada syndrome patients for mutations in SLMAP. Two missense mutations, Val269Ile and Glu710Ala, were found in heterozygous state in 2 patients but were not found in healthy individuals. Membrane surface expression of hNav1.5 in the transfected cells was affected by the mutations, and silencing of mutant SLMAP by small interfering RNA rescued the surface expression of hNav1.5. Whole-cell patch-clamp recordings of hNav1.5-expressing cells transfected with mutant SLMAP confirmed the reduced hNav1.5 current. Conclusions-The mutations in SLMAP may cause Brugada syndrome via modulating the intracellular trafficking of hNav1.5 channel. (Circ Arrhythm Electrophysiol. 2012;5:1098-1107.)
AU  - Ishikawa, T.*
AU  - Sato, A.*
AU  - Marcou, C.A.*
AU  - Tester, D.J.*
AU  - Ackerman, M.J.*
AU  - Crotti, L.
AU  - Schwartz, P.J.*
AU  - On, Y.K.*
AU  - Park, J.E.*
AU  - Nakamura, K.*
AU  - Hiraoka, M.*
AU  - Nakazawa, K.*
AU  - Sakurada, H.*
AU  - Arimura, T.*
AU  - Makita, N.*
AU  - Kimura, A.*
C1  - 22669
C2  - 30925
SP  - 1098-1107
TI  - A novel disease gene for Brugada syndrome: Sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5.
JO  - Circ.-Arrhythmia Electrophysiol.
VL  - 5
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 1941-3149
ER  - 

TY  - JOUR
AU  - Schwartz, P.J.*
AU  - Crotti, L.
AU  - Insolia, R.*
C1  - 22673
C2  - 30924
SP  - 868-877
TI  - Long-QT syndrome: From genetics to management.
JO  - Circ.-Arrhythmia Electrophysiol.
VL  - 5
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 1941-3149
ER  -