Rare Coding Variants Associated with Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-ancestry Analysis

Background - Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between ECG intervals and rare genetic variation at a population level are poorly understood. Methods - Using a discovery sample of 29,000 individuals with whole-genome sequencing from TOPMed and replication in nearly 100,000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured ECG traits (RR, P-wave, PR, and QRS intervals and corrected QT interval [QTc]). Results - We found that rare variants associated with population-based ECG intervals identify established monogenic SCD genes ( KCNQ1 , KCNH2 , SCN5A ), a controversial monogenic SCD gene ( KCNE1 ), and novel genes ( PAM , MFGE8 ) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of first-degree atrioventricular block ( P =8.4x10 -5 ). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked QTc prolongation ( P =4x10 -25 ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal ECG intervals. Conclusions - Our findings indicate that large-scale high-depth sequence data and ECG analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked ECG interval prolongation.

The role of resistance to inhibitors of cholinesterase 8b in the control of heart rate

We have assessed the role of ric-b8 in the control of heart rate after the gene was implicated in a recent genome-wide association study of resting heart rate. We developed a novel murine model in which it was possible to conditionally delete ric-8b in the sinoatrial (SA) node after the addition of tamoxifen. Despite this, we were unable to obtain homozygotes and thus studied heterozygotes. Haploinsufficiency of ric-8b in the sinoatrial node induced by the addition of tamoxifen in adult animals leads to mice with a reduced heart rate. However, other electrocardiographic intervals (e.g., PR and QRS) were normal, and there was no apparent arrhythmia such as heart block. The positive chronotropic response to isoprenaline was abrogated, whereas the response to carbachol was unchanged. The pacemaker current If(funny current) has an important role in regulating heart rate, and its function is modulated by both isoprenaline and carbachol. Using a heterologous system expressing HCN4, we show that ric-8b can modulate the HCN4 current. Overexpression of ric-8b led to larger HCN4 currents, whereas silencing ric-8b led to smaller currents. Ric-8b modulates heart rate responses in vivo likely via its actions on the stimulatory G-protein.

Validation of a portable ECG monitor for the diagnosis of arrhythmias in horses compared to a standard electrocardiograph

Electrocardiography (ECG) is a main diagnostic tool for diagnostics of rhythm disturbances. Since most pathological arrhythmias are only visible during movement and exercises the registration of exercising ECG becomes a mandatory diagnostic tool for monitoring of high-performance horses. Portable ECG monitor, developed together with specialists of National Technical University of Ukraine “Igor Sikorsky Kyiv Polytechnic Institute” is an electrocardiograph with telemetric data transmission system and four electrodes providing six-lead real-time ECG recordings at rest and during exercise. The objective of current study was validation of portable ECG monitor for diagnostics of arrhythmias in horses compared to a standard electrocardiograph. With this aim the ECG was performed by both devices simultaneously on animals with normal rhythm and rhythm disturbances. The ECG traces were therefore analyzed and compared. 14 horses of Ukrainian riding, Friesian, and Arabian breeds were divided in two groups: experimental one with arrhythmias, and control one with normal rhythm. ECG was performed by both devices simultaneously during rest, exercise, and post-exercise period. Electrocardiographic parameters were measured manually using on-screen calipers. Obtained data was analyzed using GraphPad Prism software by linear regression method for continuous parameters (HR, duration of QRS complex, PR, and QT intervals, and amplitude of P and S waves). For nominal parameters (rhythm, excitability, and conduction disorders) the analysis of sensitivity and specificity was performed. A total of 196 ECG records were analysed. Electrocardiographic intervals had high correlation: for HR and PR interval the correlation coefficient amounted to 0.98, for QRS complex and QT interval – to 0.97, for P and S waves – to 0.96. Among detected rhythm disturbances were physiological (second degree AV block first Mobitz type and SA block) and pathological arrhythmias (SVT and SVPCs). The sensitivity and specificity for rhythm, excitability, and conduction disorders of the portable ECG monitor compared to a standard electrocardiograph was 100 %. The portable ECG monitor allows to easily perform ECG registration during rest and exercises and to detect arrhythmias and other ECG abnormalities with accuracy, compared to a standard electrocardiograph.

Retention of Baseline Electrocardiographic Knowledge After a Blended-Learning Course

Background Among nurses, skill retention after an electrocardiography blended-learning course is unknown. Objectives To compare 3- and 8-week electrocardiography test scores, compare scores by nurse and work characteristics and self-assessed electrocardiographic competence, and compare 1-year work retention with 3- and 8-week scores and change in scores from week 3 to week 8. Methods Data were collected on demographics, comfort with electrocardiography expectations, electrocardiography competence levels, and 1-year work retention. Correlational and comparative statistics were used in analyses. Results Of 69 nurses, 58% were somewhat comfortable with interventions for abnormal rhythms. Test scores were higher at 3 weeks than at 8 weeks: mean difference, 26%; P < .001. Scores at 8 weeks reflected intermediate skill retention and were not associated with nurse characteristics, electrocardiography background, comfort with rhythms and measurements, or 1-year work retention. Nurses with greater comfort for intervening when rhythm abnormalities occurred had higher median 8-week scores (P = .01) than did nurses with less comfort, and perceptions of electrocardiographic competence were associated with 8-week scores (r = 0.28; P = .02). Reduction in scores at 8 weeks was less severe in nurses with greater comfort at 3 weeks in measuring electrocardiographic intervals (P = .008) and applying therapeutic interventions (P = .009). Conclusions Skill retention and competence in electrocardiographic interpretation were intermediate and correlated with baseline self-assessment. Electrocardiographic interpretation, measurement, and interventions should be reinforced at the bedside.