Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Automated Quantification of QT-Intervals by an Algorithm: A Validation Study in Patients with Chronic Obstructive Pulmonary Disease

Dario Kohlbrenner,1,2 Maya Bisang,1 Sayaka S Aeschbacher,1 Emanuel Heusser,1 Silvia Ulrich,1,2 Konrad E Bloch,1,2 Michael Furian1,3 1Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland; 2Faculty of Medicine, University of Zurich, Zurich, Switzerland; 3Swiss University of Traditional Chinese Medicine, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland, Email [email protected] Objectives: To assess the diagnostic accuracy of a purpose-designed QTc-scoring algorithm versus the established hand-scoring in patients with chronic obstructive pulmonary disease (COPD) undergoing sleep studies.Methods: We collected 62 overnight electrocardiogram (ECG) recordings in 28 COPD patients. QT-intervals corrected for heart rate (QTc, Bazett) were averaged over 1-min periods and quantified, both by the algorithm and by cursor-assisted hand-scoring. Hand-scoring was done blinded to the algorithm-derived results. Bland-Altman statistics and confusion matrixes for three thresholds (460, 480, and 500ms) were calculated.Results: A total of 32944 1-min periods and corresponding mean QTc-intervals were analysed manually and by computer. Mean difference between manual and algorithm-based QTc-intervals was − 1ms, with limits of agreement of − 18 to 16ms. Overall, 2587 (8%), 357 (1%), and 0 QTc-intervals exceeding the threshold 460, 480, and 500ms, respectively, were identified by hand-scoring. Of these, 2516, 357, and 0 were consistently identified by the algorithm. This resulted in a diagnostic classification accuracy of 0.98 (95% CI 0.98/0.98), 1.00 (1.00/1.00), and 1.00 (1.00/1.00) for 460, 480, and 500ms, respectively. Sensitivity was 0.97, 1.00, and NA for 460, 480, and 500ms, respectively. Specificity was 0.98, 1.00, and 1.00 for 460, 480, and 500ms, respectively.Conclusion: Overall, 8% of nocturnal 1-min periods showed clinically relevant QTc prolongations in patients with stable COPD. The automated QTc-algorithm accurately identified clinically relevant QTc-prolongations with a very high sensitivity and specificity. Using this tool, hospital sleep laboratories may identify asymptomatic patients with QTc-prolongations at risk for malignant arrhythmia, allowing them to consult a cardiologist before an eventual cardiac event.Keywords: QTc, long-QT syndrome, COPD, algorithm, validity, EC

Exercise Performance of Lowlanders with Chronic Obstructive Pulmonary Disease Acutely Exposed to 2048 m: A Randomized Cross-Over Trial

Konstantinos Bitos,1 Tobias Kuehne,1 Tsogyal D Latshang,1 Sayaka S Aeschbacher,1 Fabienne Huber,1 Deborah Flueck,1 Elisabeth D Hasler,1 Philipp M Scheiwiller,1 Mona Lichtblau,1 Silvia Ulrich,1 Konrad E Bloch,1 Michael Furian1,2 1University Hospital Zurich, Department of Respiratory Medicine, Zurich, Switzerland; 2Swiss University of Traditional Chinese Medicine, Research Department, Bad Zurzach, SwitzerlandCorrespondence: Michael Furian, University Hospital Zurich, Department of Pulmonology, Raemistrasse 100, Zurich, 8092, Switzerland, Email [email protected]: Amongst the millions of travelers to high altitude worldwide are many with chronic obstructive pulmonary disease (COPD), but data regarding the effects of acute exposure to altitude on exercise performance are limited. The current study investigated how acute exposure to moderate altitude influences exercise performance in COPD patients, providing novel insights to the underlying physiological mechanisms.Methods: Twenty-nine COPD patients, GOLD grade 2– 3, median (quartile) forced expiratory volume in 1 second (FEV1) of 60% predicted (46; 69) performed cycling incremental ramp exercise test (IET) at 490 m and after acute exposure of 2– 6 hours to 2048 m or vice versa, according to a randomized cross-over design. Exercise performance and breath-by-breath analyses of the last 30 seconds of each IET were compared between locations.Results: At 2048 m compared to 490 m, the maximum power output (Wmax) was 77 watts (62;104) vs 88 watts (75;112), median reduction 5 watts (95% CI, 2 to 8, P< 0.05), corresponding to a median reduction of 6% (95% CI, 2 to 11, P< 0.05) compared to 490 m. The peak oxygen uptake (V’O2peak) was 70% predicted (56;86) at 2048 m vs 79% predicted (63;90) at 490 m, median reduction of 6% (95% CI, 3 to 9, P< 0.05). The oxygen saturation by pulse oximetry (SpO2) at 2048 m was reduced by 8% (95% CI, 4 to 9, P< 0.05) compared to 490 m. The minute ventilation (V’E) increased by 2.8L/min (95% CI, 0.9 to 4.2, P< 0.05) at 2048 m. The maximum heart rate and the subjective sense of dyspnea and leg fatigue did not change.Conclusion: Lowlanders with moderate-to-severe COPD acutely exposed to 2048 m reveal small but significant reduction in cycling IET along with a reduced V’O2peak. As dyspnea perception and maximal heart rate were unchanged, the lower blood oxygenation and exaggerated ventilatory response were culprit factors for the reduced performance.Keywords: COPD, exercise, high altitude, hypoxia, hypoxemia, cardiopulmonary exercise testin