Sequence variants with large effects on cardiac electrophysiology and disease.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadFeatures of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease

Changes in blood volume shunting in patients with atrial septal defects : Assessment of heart function with cardiovascular magnetic resonance during dobutamine stress

Background: The purpose of this study was to determine the effect of stress on left-to-right shunting in patients with atrial septal defect (ASD) and to investigate if the degree of shunting, cardiac output (CO), and right ventricular (RV) volumes are related to exercise capacity. Methods: Twenty-six patients with a secundum ASD and 16 healthy volunteers were studied with rest/stress cardiac magnetic resonance using 20 μg/kg/min dobutamine and 0.25-0.75 mg atropine to quantify CO, pulmonary to systemic flow ratio (QP/QS), and left ventricular (LV) and RV volumes. Peak oxygen uptake (VO2 peak) was determined on ergospirometry. Results: In patients with ASD the QP/QS decreased from 2.0 ± 0.2 at rest to 1.5 ± 0.1 (P < 0.001) during dobutamine stress (n = 20) and shunt volume per heartbeat decreased from 70 ± 9 to 38 ± 9 mL (P < 0.001). However, absolute shunt volume per minute was unchanged (5.1 ± 0.8 vs. 4.5 ± 1.0 L/min, P = 0.32) explained by a higher increase in systemic CO during stress (90 ± 11%) compared with pulmonary CO (43 ± 7%, P < 0.001). In ASD patients, VO2 peak correlated with aortic CO during stress (r = 0.77) and QP/QS at rest (r = -0.48) but not during stress (P = 0.09). VO2 peak did not correlate with RV volumes in patients. Conclusion: Pulmonary to systemic flow ratio and shunt volume per heartbeat decrease during stress in ASD patients. This may be explained by an enhanced LV diastolic function during stress and may have implications to detect disturbances in LV compliance in ASD patients. A high systemic CO during stress is a strong predictor of exercise capacity

Transcatheter closure of atrial septal defect in adults : time-course of atrial and ventricular remodeling and effects on exercise capacity

Investigate ventricular and atrial remodeling following atrial septal defect (ASD) closure and examine if pulmonary-to-systemic flow ratio (QP/QS) and right ventricular (RV) volume predict improvement, determined as percentage of predicted oxygen uptake (VO2%). Long-term cardiovascular magnetic resonance (CMR) data on atrial and ventricular remodeling after ASD-closure is limited and treatment effect on exercise capacity is debated. Sixteen patients undergoing transcatheter ASD closure and 16 age and sexmatched controls were studied. CMR was performed before treatment, the day after and 3 and 12 months later. Exercise test with gas analysis was performed before and 12 months after treatment. QP/QS decreased from 2.1 ± 0.5 to 1.4 ± 0.3 at day 1 and 1.1 ± 0.1 at 3 and 12 months. Left ventricular (LV) volumes increased and normalized on day 1 whereas left atrial volumes were unchanged. RV and right atrial volumes decreased the first 3 months. LV and RV volumes had not equalized at 12 months (RV/LV ratio 1.2 ± 0.1, P < 0.01) and RV ejection fraction remained decreased compared to controls. Improvement of VO2% after ASD closure (P < 0.01) was inversely related to QP/QS at rest (r = − 0.56, P < 0.05) but unrelated to RV end-diastolic volume (P = 0.16). Following transcatheter ASD closure, LV adaptation is rapid and RV adaptation is prolonged, with decreased systolic RV function. Patients with smaller shunts had larger improvement in VO2% suggesting patients with defects of borderline hemodynamic significance might benefit from closure. This may be due to impaired LV diastolic function influencing shunt size and exercise capacity following ASD closure

Sequence variants with large effects on cardiac electrophysiology and disease

Features of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease

Variants in NKX2-5 and FLNC Cause Dilated Cardiomyopathy and Sudden Cardiac Death.

To access publisher's full text version of this article click on the hyperlink belowDilated cardiomyopathy (DCM) is an important cause of heart failure. Variants in >50 genes have been reported to cause DCM, but causative variants have been found in less than half of familial cases. Variants causing DCM in Iceland have not been reported before. We performed a genome-wide association study on DCM based on whole genome sequencing. We tested the association of 32.5 million sequence variants in 424 cases and 337 689 population controls in Iceland. We identified 2 DCM variants in established cardiomyopathy genes, a missense variant p.Phe145Leu in NKX2-5 carried by 1 in 7100 Icelanders ( P=7.0×10 Two rare variants in NKX2-5 and FLNC, carried by 1 in 2400 Icelanders, cause familial DCM in Iceland. These genes have recently been associated with DCM. Given the serious consequences of these variants, we suggest screening for them in individuals with DCM and their family members, with subsequent monitoring of carriers, offering early intervention

Agreement of left ventricular mass in steady state free precession and delayed enhancement MR images: implications for quantification of fibrosis in congenital and ischemic heart disease

<p>Abstract</p> <p>Background</p> <p>Left ventricular mass (LVM) is used when expressing infarct or fibrosis as a percentage of the left ventricle (LV). Quantification of LVM is interchangeably carried out in cine steady state free precession (SSFP) and delayed enhancement (DE) magnetic resonance imaging (MRI). However, these techniques may yield different LVM. Therefore, the aim of the study was to compare LVM determined by SSFP and DE MRI in patients and determine the agreement with these sequences with ex vivo data in an experimental animal model.</p> <p>Methods</p> <p>Ethics committees approved human and animal studies. Informed written consent was obtained from all patients. SSFP and DE images were acquired in 60 patients (20 with infarction, 20 without infarction and 20 pediatric patients). Ex vivo MRI was used as reference method for LVM in 19 pigs and compared to in vivo SSFP and DE.</p> <p>Results</p> <p>LVM was greater in SSFP than in DE (p < 0.001) with a bias of 5.0 ± 6.7% in humans (r²= 0.98), and a bias of 7.3 ± 6.7% (p < 0.001) in pigs (r²= 0.83). Bias for SSFP and DE images compared to ex vivo LVM was -0.2 ± 9.0% and -7.7 ± 8.5% respectively.</p> <p>Conclusions</p> <p>LVM was higher when measured with SSFP compared to DE. Thus, the percentage infarction of the LV will differ if SSFP or DE is used to determine LVM. There was no significant difference between SSFP and ex vivo LVM suggesting that SSFP is more accurate for LVM quantification. To avoid intrinsic error due to the differences between the sequences, we suggest using DE when expressing infarct as a percentage of LVM.</p