Patient With Presyncope and Variable PR Interval and QRS Morphology.
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SUBMITTER: Bittner A
PROVIDER: S-EPMC8414434 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeRisk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase.Experimental approachFour compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model.Key resultsMeaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav 1.5 block (3-7%) and Cav 1.2 binding (13-21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3-4.6% and PR 2.3-10%), suggesting that worst-case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data.Conclusion and implicationsSmall changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non-arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies.
| S-EPMC5595766 | biostudies-literature
Project description:Alternating bundle branch block pattern on electrocardiogram (ECG) is a concerning finding with important prognostic implications. This ECG challenge explores the electrophysiological mechanism of a case of alternating bundle branch block with alternating PR intervals. (Level of Difficulty: Beginner.).
| S-EPMC8312116 | biostudies-literature
Project description:The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.
| S-EPMC2850197 | biostudies-literature
Project description: Not available
| S-EPMC10653491 | biostudies-literature
Project description:BACKGROUND:One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability. METHODS AND RESULTS:We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; P=0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P=0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; P=0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]). CONCLUSIONS:The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
| S-EPMC5434456 | biostudies-literature
Project description:The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n?=?6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5 x 10??) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta ?=?5.1 msec per minor allele, 95% CI ?=?4.1-6.1, p?=?3 x 10?²³). This SNP was also associated with PR interval (beta?=?2.4 msec per minor allele, 95% CI?=?1.8-3.0, p?=?3 x 10?¹?) in individuals of European ancestry (n?=?14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p?=?0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.
| S-EPMC3037415 | biostudies-literature
Project description:BackgroundElectrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.MethodsWe performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.ResultsWe identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10-6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10-11) and SCN5A (P=1.1×10-7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus.ConclusionsWe identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.
| S-EPMC5951629 | biostudies-literature
Project description:ObjectiveThe authors hypothesized that genetic association between atrial fibrillation (AF)-associated and PR-associated genetic loci was biologically mediated through slower conduction velocities for some or all of these loci.DesignProspectively collected cohort study.SettingSingle tertiary care university hospital.ParticipantsA total of 1227 Caucasian patients who underwent coronary artery bypass grafting (CABG).InterventionsA total of 677 single nucleotide polymorphisms previously associated with ambulatory AF or PR interval were tested for association with postoperative atrial fibrillation (poAF) and preoperative PR interval, maximum PR interval, maximum change in PR interval, and maximum change in PR interval from preoperative PR interval.Measurements and main resultsThe incidence of new-onset poAF was 31%. All of the PR interval variables were longer in the poAF cohort. Two variants on 1q21 and 12 on 4q25 were associated with poAF after adjustment for false discovery rate (FDR), but no variants were associated with PR interval variables after adjustment for FDR. Several variants were associated with both poAF and PR interval variables at p<0.05, but none of them remained significant after adjusting for FDR.ConclusionIt was found that patients with poAF have significantly longer PR interval. Genetic variants in both the 1q21 and 4q25 regions associate with poAF after CABG surgery, but the authors were unable to find association between these variants and PR interval after adjusting for FDR.
| S-EPMC5103707 | biostudies-literature
Project description:SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF.Patients prospectively enrolled in the Vanderbilt AF registry with electrocardiograms in normal sinus rhythm and/or AF within 1 year of enrollment were genotyped for two common SCN10A variants rs6795970 and rs12632942. Both variants were associated with the PR interval duration in a gene-dose effect on unadjusted analysis; after adjustment for the covariates age, gender, body mass index, hypertension, congestive heart failure, and medication usage, the association remained for rs6795970 only (P = 0.012, partial R(2) = 0.0139). On unadjusted analysis, heart rate response during AF was associated with rs6795970 (P = 0.035, partial R(2) = 0.015), but not with rs12632942 (P = 0.89), and neither association was significant after adjustment for covariates.The common variant rs6795970 in SCN10A is associated with the PR interval duration among healthy patients and those with AF. In addition, this single nucleotide polymorphism trended towards an association with heart rate response during AF indicating the importance of this common SCN10A polymorphism as a marker of atrioventricular conduction.
| S-EPMC3977588 | biostudies-literature
Project description:BACKGROUND:Myriad manifestations of cardiovascular involvement have been described in patients with coronavirus disease 2019 (COVID-19), but there have been no reports of COVID-19 affecting the cardiac conduction system. The PR interval on the electrocardiogram (ECG) normally shortens with increasing heart rate (HR). The case of a patient with COVID-19 manifesting Mobitz type 1 atrioventricular (AV) block that normalized as the patient's condition improved prompted us to investigate PR interval behavior in patients with COVID-19. OBJECTIVE:The purpose of this study was to characterize PR interval behavior in hospitalized patients with COVID-19 and to correlate that behavior with clinical outcomes. METHODS:This study was a cross-sectional cohort analysis of confirmed COVID-19 cases (March 26, 2020, to April 25, 2020). We reviewed pre-COVID-19 and COVID-19 ECGs to characterize AV conduction by calculating the PR interval to HR (PR:HR) slope. Clinical endpoints were death or need for endotracheal intubation. RESULTS:ECGs from 75 patients (246 pre-COVID-19 ECGs and 246 COVID-19 ECGs) were analyzed for PR:HR slope. Of these patients, 38 (50.7%) showed the expected PR interval shortening with increasing HR (negative PR:HR slope), whereas 37 (49.3%) showed either no change (8 with PR:HR slope = 0) or paradoxical PR interval prolongation (29 with positive PR:HR slope) with increasing HR. Patients without PR interval shortening were more likely to die (11/37 [29.7%] vs 3/38 [7.9%]; P = .019) or require endotracheal intubation (16/37 [43.2%] vs 8/38 [21.1%]; P = .05) compared to patients with PR interval shortening. CONCLUSION:Half of patients with COVID-19 showed abnormal PR interval behavior (paradoxical prolongation or lack of shortening) with increasing HR. This finding was associated with increased risk of death and need for endotracheal intubation.
| S-EPMC7289083 | biostudies-literature