Rare variants in HCN4 identified in the general population are associated with complete atrioventricular (AV) block, 1. degree AV block and bundle branch block, results from 50.000 exomes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J Jensen ◽  
O.B Vad ◽  
C Paludan-Muller ◽  
P.R Lundegaard ◽  
J.H Svendsen ◽  
...  
Keyword(s):  
General Population ◽  
Rare Variants ◽  
Cardiac Conduction ◽  
European Ancestry ◽  
Funding Source ◽  
Av Block ◽  
Bundle Branch Block ◽  
Genome Wide ◽  
Logistic Mixed Effects Model ◽  
Complete Av Block

Abstract Background/Introduction Cardiac conduction disorders cover disorders such as atrioventricular (AV) block and bundle branch block. Genome-wide association studies have identified more than 100 genetic loci for atrial fibrillation, including HCN4 loci associated with duration of the PR interval, a proxy for AV dysfunction. Recent candidate studies suggest an association between HCN4 variants and AV-block. Purpose We seek to determine the contribution of rare genetic variants in HCN4 to complete AV-block, 1. degree AV-block and bundle branch block (BBB) in the general population. Methods The UK Biobank is a population-based study of 500 000 individuals including a subset with genome-wide genotyping and exome sequencing (n=45,596). In this case-control study, we included persons of genetically determined white-European ancestry and analyzed their exome data. Analyses were performed using a logistic mixed-effects model. A gene-based burden analysis and single variant test were performed to examine the relationship between HCN4 variants and complete AV-block, 1. degree AV-block and BBB in the general population. Results The study included 43,371 persons. In an analysis of the HCN4 genes a significant association between rare variants (MAF<0.01) in HCN4 gene was found (complete AV-block, P=2.5x10–5, 1. degree AV-block, P=1.3x10–3 and BBB, P=0.01) (Figure 1A). The association to complete AV block was mostly driven by the variants Ser835Phe (P=2.7e-3), Glu153Gly (P=3.5e-3) and Arg378Cys (P=6.3e-3) (Figure 1B). Conclusions Rare HCN4 variants contribute to the risk of complete AV-block, 1. degree AV-block and BBB in the general population. These HCN4 variants seem to confer a substantial penetrance. Clinical screening for some of these variants seems appropriate. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Hallas Møller - Novo nordisk

scholarly journals CARDIAC CONDUCTION DISTURBANCES FOLLOWING TRANSAPICAL «MEDLAB-KT» AORTIC VALVE IMPLANTATION: FIRST RESULTS

2019 ◽  
Vol 26 (2(96)) ◽  
pp. 14-18
Author(s):  
O. V. Popylkova ◽  
S. S. Durmanov ◽  
V. V. Bazylev ◽  
A. B. Voevodin
Keyword(s):  
Aortic Valve ◽  
De Novo ◽  
Early Postoperative Period ◽  
Cardiac Conduction ◽  
Block Type ◽  
Av Block ◽  
Bundle Branch Block ◽  
Conduction Disturbances ◽  
Conduction Abnormalities ◽  
Complete Av Block

Aim: to assess cardiac conduction disturbances after transcatheter aortic valve replacement (TAVR) with the “MedLab-KT” device in early postoperative period.Methods. The study comprised 80 patients (mean age 72,4±5,1 years; 42,5% males) undergoing successful TAVR with the “MedLab-KT”. Before operation, all patients were evaluated with 12-lead ECG and 24-hour Holter monitoring, transthoracic and transesophageal echocardiography, computed tomography, coronarography. In 29 (36,3%) patients cardiac conduction abnormalities were detected before operation: 1st degree atrioventricular (AV) block was found in 17 patients, including concomitant left anterior hemiblock (LAH) in 7 patients, and right bundle branch block (RBBB) in 3 (LAH+RBBB). Second degree AV-block type 1 was found in 1 patient. LAH – in 2, RBBB – in 5, and left bundle branch block (LBBB) – in 4. Post-operative follow-up was limited to hospital stay (13,4±7,4 days).Results. De-novo conduction abnormalities (reversible and irreversible) were detected in 41 patients (51,3%). Post-TAVR complete AV-block was found in 6 (7,5%) patients, and required temporal pacing. In 4 of those patients AV-block was transient and resolved within 1 day. In 2 (2,5%) patients permanent pacing was required due to irreversible distal AV-block. In one case AV-block developed 2 days after TAVR in a patient with pre-existent 1st degree AV-block in combination with LAH+RBBB. Another patient developed complete AV-block at 3d day after TAVR; in this case there was pre-existent 1st degree AV-block plus LAH. Persistent interventricular block was found in 35 patients: complete LBBB - in 17 patients and complete RBBB – in 1 patient. There were no statistically significant predictors of conduction disturbance development following TAVR.

GENECHOC study: genetic markers of arrhythmic risk in heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Anys ◽  
S Rigade ◽  
S Rigade ◽  
E Baron ◽  
E Baron ◽  
...  
Keyword(s):  
Heart Failure ◽  
Genetic Markers ◽  
Left Ventricular ◽  
European Ancestry ◽  
Left Ventricular Ejection ◽  
P Value ◽  
Funding Source ◽  
Ventricular Ejection Fraction ◽  
Cardioverter Defibrillator ◽  
Genome Wide

Abstract Background Ventricular arrhythmic events are responsible for 50% of death in heart failure but no reliable predictive marker is known to discriminate patients at risk of fatal arrhythmia. Interestingly, familial predisposition has been reported suggesting a role of genetic factors. Purpose Identify genetic markers increasing the arrhythmic risk in heart failure population. Method We prospectively included heart failure patients with left ventricular ejection fraction (LVEF) under 35% and a cardioverter defibrillator in primary prevention in 22 French centres between 2009 and 2017. Patients were followed for 72 months and divided into two groups: cases with an arrhythmic event during follow-up and controls. A Genome Wide Association Study (GWAS) was done. Single Nucleotide Polymorphisms (SNPs) genotyping was performed on Affymetrix Axiom Precision Medicine Research Array plates. To complement the directly genotyped SNPs we performed large-scale imputation based on the Haplotype Reference Consortium European ancestry panel leading to a dataset of 7,5 million of SNPs. Results 332 cases and 567 controls were included (86% men, mean age at implantation 52±11 years). 78% of patients had ischaemic cardiopathy, 20% had dilated cardiomyopathy. Mean LVEF was 27±5%. No statistical difference was found between cases and controls on clinical parameters, biological results, electrocardiographic measures. No locus shows genome-wide significant association (p<5.10–8) on the GWAS analysis. However, 16 signals with a p-value between 5.10–8 and 5.10–5 were investigated. eQTL and chromatin conformation point to 35 genes with cardiac expression previously associated with heart failure, cardiomyopathies, cardiogenesis, arrhythmias and inflammation. Variants identified point to regulatory regions of the genome and may then propose a molecular mechanism predisposing patients to arrhythmias. Conclusion No locus raises genome-wide significance, but several signals with a nominal p-value point to relevant genes and pathways. Replication of the GWAS is ongoing on a cohort of 156 new patients with a less severe cardiopathy implanted with a cardioverter defibrillator in secondary prevention. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Nantes University Hospital

scholarly journals Complete heart block associated with Remdesivir in COVID-19: a case report

2021 ◽  
Vol 5 (7) ◽  
Author(s):  
Vijairam Selvaraj ◽  
Chirag Bavishi ◽  
Simaben Patel ◽  
Kwame Dapaah-Afriyie
Keyword(s):  
Atrial Fibrillation ◽  
Pacemaker Implantation ◽  
Av Block ◽  
Bundle Branch Block ◽  
Chronotropic Response ◽  
Case Summary ◽  
History Of ◽  
Electrocardiogram Ecg ◽  
Complete Atrioventricular ◽  
Complete Av Block

Abstract Background Since the pandemic began in 2020, Remdesivir has been widely used for the treatment of coronavirus disease-2019 (COVID-19). Here, we describe a case of a patient with COVID-19 who developed transient complete atrioventricular (AV) block and bradycardia after initiating treatment with Remdesivir. Case summary A 72-year-old male with a history of atrial fibrillation and lung cancer was hospitalized for COVID-19. Electrocardiogram (ECG) on admission demonstrated atrial fibrillation and right bundle branch block. He was started on a course of Dexamethasone and Remdesivir. Within 24 h of starting Remdesivir, he was noted to be in atrial fibrillation with ventricular rates between 30 and 40 b.p.m. On Day 5 of Remdesivir therapy, ECG demonstrated complete AV block. Having completed the Remdesivir regimen, during the next 48 h, he was closely monitored, and the AV block resolved spontaneously. As he remained asymptomatic and had an adequate chronotropic response with activity, pacemaker implantation was not recommended. Discussion Despite the widespread use of Remdesivir, there is little known information about its cardiac toxicity. Daily ECGs and close cardiac surveillance of patients who develop severe bradycardia or AV block are essential. Discontinuation of the medication usually results in the resolution of these cardiac disturbances.

Abstract 048: Association Analyses of up to ∼263,000 Individuals Provide New Insights into the Biology and Genetic Architecture of the Extremes of Anthropometric Traits

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Erik Ingelsson ◽  
Reedik Mägi ◽  
Stefan Gustafsson ◽  
Andrea Ganna ◽  
Eleanor Wheeler ◽  
...  
Keyword(s):  
General Population ◽  
Genetic Architecture ◽  
Class Ii ◽  
Overweight And Obesity ◽  
European Ancestry ◽  
Continuous Measure ◽  
Phenotypic Variance ◽  
Obesity Class ◽  
Genome Wide ◽  
Meta Analyses

Anthropometric traits have a strong genetic component with heritability estimates between 40–70% for body mass index (BMI) and ∼80% for height; however, established loci only account for a small fraction (1–10%) of the phenotypic variance of these complex traits. It has been hypothesized that the extremes of the distributions of these traits are enriched for genetic loci and may have a distinct genetic architecture compared to the general population. To explore the genetic contribution of the extremes (defined as the upper and lower 5th percentile) of BMI, height, and waist-hip ratio [WHR] adjusted for BMI and clinical classes of obesity (including overweight and obesity classes I, II, and III), we conducted meta-analyses of ∼2.8 million SNPs from 49 genome-wide association studies of European ancestry totaling from 4,774 cases and 5,481 controls (extreme WHR) to 93,015 cases and 65,840 controls (overweight) for these traits. The most promising loci from each meta-analysis (P<5 x 10 −6 ) were taken forward for replication into up to 65,332 cases and 39,294 controls. In meta-analyses of the combined stages, we observed genome-wide significant associations (P<5 x 10 −8 ) for 191 loci (extreme BMI, height and WHR: 10, 96 and 2 loci, respectively; overweight and obesity classes I, II, and III: 25, 33, 24 and 1 loci, respectively). Out of these 191 loci, we identified 9 novel loci that have not been previously associated with anthropometric traits when studying the whole distributions (P<5 x 10 −8 ), including three loci for extreme height ( ZNF36, H6PD , RSRC1 ), three for obesity class II ( OLFM4 , HS6ST3 , AK5/ZZZ3 ), two for obesity class I ( GNAI3/MIR197/GNAT2, HNF4G ), and two for overweight ( RPTOR, HNF4G ). Several loci for obesity were located near genes expressed primarily in the brain (e.g. CACNA1D, AK5 ), suggesting a neuronal influence, whereas the loci for overweight were near genes involved in other processes, such as mTOR signaling (e.g. RPTOR ). All of the novel loci discovered for the extremes and obesity classes were nominally associated with the trait as a continuous measure in the general population (N = 123,865) but at a lesser significance level (P range: 0.003 – 1.4x10 −5 ). A polygenetic risk score including all independent SNPs associated with BMI (at different P-value thresholds) revealed that significantly more of the variance was explained for the extremes of BMI and obesity class II, than for BMI as a continuous measure in the population (variance explained, 20%, 10% and 5%, respectively), suggesting a greater genetic influence on the extremes. Investigations are underway to evaluate haplotypes and additional signals at known BMI and height loci in the extreme samples to explore allelic heterogeneity. In conclusion, this study identifies additional loci and provides novel insights into the genetic architecture of the extremes of anthropometric traits.

Non-selective para-hisian stimulation used for QRS normalization guided by non-invasive electrical synchrony method in patients with electrical conduction disorders

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Logarzo ◽  
D Ortega ◽  
L Barja ◽  
A Paolucci ◽  
G Revollo ◽  
...  
Keyword(s):  
Electrical Conduction ◽  
Conduction System ◽  
Funding Source ◽  
Av Block ◽  
Bundle Branch Block ◽  
Novel Device ◽  
Non Invasive ◽  
Conduction Disorders ◽  
Implant Technique

Abstract Introduction Para-hisian stimulation produces a physiological cardiac activation through normal conduction system. Frequently it is used in patients with no electrical conduction disorders. We developed an implant technique guided by non-invasive electrical synchrony using conventional screw-in leads. Non-selective para-hisian stimulation can normalize electrical conduction disorders. Synchromax is a novel device used to evaluate non-invasive cardiac electrical synchrony. It is easy to understand, fast to obtain, non-invasive and reproducible. Synchromax was analyzed in previous studies and correlated with other methods. Objective Evaluate usefulness and safety of non-selective para-hisian stimulation guided by non-invasive cardiac electrical synchrony method using conventional screw-in leads to normalize electrical conduction disorders. Materials and methods 421 patients with para-hisian stimulation were analyzed retrospectively. 139 patients had different intraventricular and auriculo-ventricular electrical disorders. Non-selective para-hisian stimulation guided by no-invasive electrical synchrony method (Synchromax) was performed in all cases. Synchrony index and curves were analyzed according curves chart. Type 2 curve and index between 0,1 and 0,4 were considered synchronous. Type 8 curve and index more than 0.7 were considered dyssynchronous. Results Mean age 71 years (±7 years). 65,4% males. 30,9% had 2° and 3° grade AV block associated. Patients were divided in 5 groups: 1-Right bundle branch block (RBBB): 43 patients 2-Left bundle branch block (LBBB): 33 patients 3-Brugada Syndrome: 8 patients 4-Left anterior hemi-block (LAHB) 30 patients. 5-RBBB associated with LAHB: 25 patients. QRS normalization was achieved in 87% of the cases using non-selective para-hisian stimulation guided by Synchromax with conventional screw in leads. A ventricular approach was performed during implantation. Electrical synchrony was not solved in 13% of patients mostly in LBBB and RBBB associated with LAHB. Two dislodgments were evidenced. Conclusions Non-selective para-hisian stimulation guided by Synchromax method using conventional screw in leads solved most of intraventricular electrical disorders. It is also safe to use in patients with auriculo-ventricular electrical disorder. Funding Acknowledgement Type of funding source: None

scholarly journals Analysis of PTRHD1 common and rare variants in European patients with Parkinson’s disease

2020 ◽  
Author(s):  
Yuri L. Sosero ◽  
Sara Bandres-Ciga ◽  
Ziv Gan-Or ◽  
Lynne Krohn
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Age At Onset ◽  
European Population ◽  
European Ancestry ◽  
Genome Wide ◽  
Meta Analyses

AbstractThree family studies identified three different variants in the peptidyl-tRNA hydrolase domain containing 1 gene (PTRHD1) in patients affected by syndromic parkinsonism. In the current study, our objective was to investigate whether PTRHD1 variants are associated with Parkinson’s disease (PD) risk and age at onset (AAO). To evaluate the association between PTRHD1 and PD risk, we analyzed whole genome sequencing (WGS) data of 1,647 PD cases and 1,050 healthy controls, as well as genome-wide imputed genotyping data on 14,671 PD cases and 17,667 controls, all of European ancestry. Furthermore, we examined the association of PTRHD1 with PD risk and AAO using summary statistics data from the most recent PD genome-wide association study (GWAS) meta-analyses. Our results show no association between PTRHD1 and PD risk or AAO. We conclude that PTRHD1 does not play a major role in PD in the European population. Further large-scale studies including subjects with different ancestry and family trios might further clarify the relationship of this gene with PD and atypical parkinsonism.

Prevalence of abnormalities in electrocardiogram conduction in dialysis patients: a comparative study

2020 ◽  
Author(s):  
Firas Ajam ◽  
Arda Akoluk ◽  
Anas Alrefaee ◽  
Natasha Campbell ◽  
Avais Masud ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Cardiac Conduction ◽  
Future Research ◽  
Dialysis Patients ◽  
Bundle Branch Block ◽  
Conduction Abnormality ◽  
Ckd Stage ◽  
Stage 1 ◽  
Electrocardiogram Ecg ◽  
Ecg Abnormalities

ABSTRACT Background: The electrocardiogram (ECG) can aid in identification of chronic kidney disease (CKD) patients at high risk for cardiovascular diseases. Cohort studies describe ECG abnormalities in patients on hemodialysis (HD), but we did not find data comparing ECG abnormalities among patients with normal kidney function or peritoneal dialysis (PD) to those on hemodialysis. We hypothesized that ECG conduction abnormalities would be more common, and cardiac conduction interval times longer, among patients on hemodialysis vs. those on peritoneal dialysis and CKD 1 or 2. Methods: Retrospective review of adult inpatients’ charts, comparing those with billing codes for “Hemodialysis” vs. inpatients without those charges, and an outpatient peritoneal dialysis cohort. Patients with CKD 3 or 4 were excluded. Results: One hundred and sixty-seven charts were reviewed. ECG conduction intervals were consistently and statistically longer among hemodialysis patients (n=88) vs. peritoneal dialysis (n=22) and CKD stage 1 and 2 (n=57): PR (175±35 vs 160±44 vs 157±22 msec) (p=0.009), QRS (115±32 vs. 111±31 vs 91±18 msec) (p=0.001), QT (411±71 vs. 403±46 vs 374±55 msec) (p=0.006), QTc (487±49 vs. 464±38 vs 452±52 msec) (p=0.0001). The only significantly different conduction abnormality was prevalence of left bundle branch block: 13.6% among HD patients, 5% in PD, and 2% in CKD 1 and 2 (p=0.03). Conclusion: To our knowledge, this is the first study to report that ECG conduction intervals are significantly longer as one progresses from CKD Stage 1 and 2, to PD, to HD. These and other data support the need for future research to utilize ECG conduction times to identify dialysis patients who could potentially benefit from proactive cardiac evaluations and risk reduction.

scholarly journals Shedding Light on the African Enigma: In Vitro Testing of Homo sapiens-Helicobacter pylori Coevolution

2021 ◽  
Vol 9 (2) ◽  
pp. 240
Author(s):  
Bruno Cavadas ◽  
Marina Leite ◽  
Nicole Pedro ◽  
Ana C. Magalhães ◽  
Joana Melo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Helicobacter Pylori ◽  
Host Response ◽  
Homo Sapiens ◽  
European Ancestry ◽  
Genome Wide ◽  
Expression Host ◽  
H Pylori ◽  
Human Ancestry

The continuous characterization of genome-wide diversity in population and case–cohort samples, allied to the development of new algorithms, are shedding light on host ancestry impact and selection events on various infectious diseases. Especially interesting are the long-standing associations between humans and certain bacteria, such as the case of Helicobacter pylori, which could have been strong drivers of adaptation leading to coevolution. Some evidence on admixed gastric cancer cohorts have been suggested as supporting Homo-Helicobacter coevolution, but reliable experimental data that control both the bacterium and the host ancestries are lacking. Here, we conducted the first in vitro coinfection assays with dual human- and bacterium-matched and -mismatched ancestries, in African and European backgrounds, to evaluate the genome wide gene expression host response to H. pylori. Our results showed that: (1) the host response to H. pylori infection was greatly shaped by the human ancestry, with variability on innate immune system and metabolism; (2) African human ancestry showed signs of coevolution with H. pylori while European ancestry appeared to be maladapted; and (3) mismatched ancestry did not seem to be an important differentiator of gene expression at the initial stages of infection as assayed here.

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