Rare SCN10A variants associated with cardiac conduction system diseases

Abstract Background The genetic bases of cardiac conduction-system disease (CCSD) range from ion channelopathies to mutations in many other genes. Genome-wide association studies have shown common variants in SCN10A influence cardiac conduction. However, it has not yet to be determined whether vulnerability to CCSD is associated with rare coding sequence variation in the SCN10A gene. Purpose We sought to determine the clinical impact of rare variants in SCN10A in patients with CCSD and classified the variants according to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Methods We performed screening for rare variants (minor allele frequency ≤0.001) in SCN10A in CCSD patients with an onset at a young age under 65 or those who had a family history of pacemaker implantation (PMI) (n=40; 18 female; mean age, 41±18 years). We transiently expressed engineered variants in ND 7/23 cells, and conducted whole-cell voltage clamp experiments to clarify the functional properties of the Nav1.8 current. Results We identified nine rare variants in SCN10A in 7 patients. Two patients were carriers of two rare variants in SCN10A and 5 were carriers of one rare variant in SCN10A. Four patients were affected with sinus node dysfunction, 1 were atrioventricular block, and 2 were both dysfunctions. We performed electrophysiological study for 8 of 9 rare variants. It demonstrated that 2 rare variants showed gain-of-function, and 3 rare variants showed loss-of-function. We finally determined 5 likely pathogenic variants in SCN10A in 5 patients (12.5%) according to the ACMG standards and guidelines. All 5 patients underwent a pacemaker implantation at an average age of 43±16. Conclusions These results demonstrate that SCN10A variants play a pivotal role in enhanced susceptibility of CCSD. We suggest the importance for screening SCN10A variants in clinical settings. Funding Acknowledgement Type of funding source: None

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Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Cardiovascular Research ◽

10.1093/cvr/cvaa010 ◽

2020 ◽

Vol 116 (13) ◽

pp. 2116-2130 ◽

Cited By ~ 1

Author(s):

Kenshi Hayashi ◽

Ryota Teramoto ◽

Akihiro Nomura ◽

Yoshihiro Asano ◽

Manu Beerens ◽

...

Keyword(s):

Rare Variants ◽

Electrophysiological Study ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Functional Studies ◽

Pathogenic Variants ◽

Uncertain Significance ◽

Standards And Guidelines

Abstract Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as ‘pathogenic’ by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from ‘Uncertain significance’ to ‘Likely pathogenic’ in six probands. Conclusion Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.

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The cardiac conduction system in Hurler syndrome: pathological features and clinical implications

Cardiology in the Young ◽

10.1017/s1047951100000858 ◽

1992 ◽

Vol 2 (2) ◽

pp. 196-199

Author(s):

Louis Tsun-cheung Chow ◽

Wing-Hing Chow

Keyword(s):

Sinus Node ◽

Fibrous Tissue ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Clinical Implications ◽

Hurler Syndrome ◽

Pathological Features ◽

Hydropic Degeneration ◽

Dense Fibrous Tissue

SummaryWe studied the cardiac conduction system in a case of Hurler syndrome. There was dense fibrosis of the supporting matrix of the sinus node and accumulation of mucopolysaccharide in the nodal cells. The bundle branches showed prominent hydropic degeneration, being encased and punctuated by dense fibrous tissue. These changes in the conduction system may predispose to the development of arrhythmias, accounting for the sudden deaths in Hurler syndrome.

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Incidence of carditis and predictors of pacemaker implantation in patients hospitalized with Lyme disease

PLoS ONE ◽

10.1371/journal.pone.0259123 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0259123

Author(s):

Uwajachukwumma A. Uzomah ◽

Guy Rozen ◽

Seyed Mohammadreza Hosseini ◽

Ayman Shaqdan ◽

Pablo A. Ledesma ◽

...

Keyword(s):

Lyme Disease ◽

Pacemaker Implantation ◽

Permanent Pacemaker ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Permanent Pacemaker Implantation ◽

System Disease ◽

Lyme Carditis ◽

Conduction System Disease

Background Lyme carditis, defined as direct infection of cardiac tissue by Borrelia bacteria, affects up to 10% of patients with Lyme disease. The most frequently reported clinical manifestation of Lyme carditis is cardiac conduction system disease. The goal of this study was to identify the incidence and predictors of permanent pacemaker implantation in patients hospitalized with Lyme disease. Methods A retrospective cohort analysis of the Nationwide Inpatient sample was performed to identify patients hospitalized with Lyme disease in the US between 2003 and 2014. Patients with Lyme carditis were defined as those hospitalized with Lyme disease who also had cardiac conduction disease, acute myocarditis, or acute pericarditis. Patients who already had pacemaker implants at the time of hospitalization (N = 310) were excluded from the Lyme carditis subgroup. The primary study outcome was permanent pacemaker implantation. Secondary outcomes included temporary cardiac pacing, permanent pacemaker implant, and in-hospital mortality. Results Of the 96,140 patients hospitalized with Lyme disease during the study period, 10,465 (11%) presented with Lyme carditis. Cardiac conduction system disease was present in 9,729 (93%) of patients with Lyme carditis. Permanent pacemaker implantation was performed in 1,033 patients (1% of all Lyme hospitalizations and 11% of patients with Lyme carditis-associated conduction system disease). Predictors of permanent pacemaker implantation included older age (OR: 1.06 per 1 year; 95% CI:1.05–1.07; P<0.001), complete heart block (OR: 21.5; 95% CI: 12.9–35.7; P<0.001), and sinoatrial node dysfunction (OR: 16.8; 95% CI: 8.7–32.6; P<0.001). In-hospital mortality rate was higher in patients with Lyme carditis (1.5%) than in patients without Lyme carditis (0.5%). Conclusions Approximately 11% of patients hospitalized with Lyme disease present with carditis, primarily in the form of cardiac conduction system disease. In this 12-year study, 1% of all hospitalized patients and 11% of those with Lyme-associated cardiac conduction system disease underwent permanent pacemaker implantation.

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P3826Gene therapy for cardiac conduction system dysfunction in heart failure

European Heart Journal ◽

10.1093/eurheartj/ehz745.0668 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

L Stuart ◽

I Y Oh ◽

Y Wang ◽

S Nakao ◽

T Starborg ◽

...

Keyword(s):

Heart Failure ◽

Ion Channel ◽

Transgene Expression ◽

Ex Vivo ◽

Sinus Node ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Gfp Expression ◽

Free Running

Abstract Background and purpose Heart failure (HF) is characterised by generalised dysfunction of the cardiac conduction system (CCS). Ion channel and structural remodelling in the CCS have been widely demonstrated in animal models of cardiovascular disease. As Purkinje fibres (PFs) are minute strands of tissue, little is known about their ultrastructure and remodelling in disease. Furthermore, given the role for microRNAs (miRs) in CCS molecular remodelling, we aimed to develop a tissue specific method for delivering therapeutic transgenes, such as miR sponges. Methods New Zealand rabbits were used for PF ultrastructural studies. HF was induced via pressure and volume overload. Free running PFs were processed for serial block face scanning electron microscopy (SBF-SEM). Manual contrast-based segmentation techniques were used on IMOD software to determine the 3D cellular ultrastructure. To target transgene expression to the CCS, adenoviral plasmids were cloned expressing a GFP reporter gene. GFP transcription was placed under control of the KCNE1 promoter, a K+ channel subunit expressed throughout the CCS, or the HCN4 promoter, a key pacemaker ion channel, to target the sinus node. The strong ubiquitous cytomegalovirus (CMV) promoter was used as a positive control. Adenovirus was produced using via transfection into the 293A cell line for viral packaging and amplification. Results Purkinje cells (PCs) formed a central core within PFs, encapsulated by an extensive collagen matrix. PCs were uninucleated and spindle shaped with an irregular membrane. Gap junctions were abundant and distributed along the lateral surface of cells, and there was a trend towards decreased expression in HF (p=0.0526, n=3 cells analysed per group). Hypertrophy and nuclear membrane breakdown were evident in HF PCs, the latter facilitating mitochondrial entry. Using the CMV-GFP adenoviral construct, abundant GFP expression was conferred in ex vivo sinus node tissue, isolated sinus node myocytes, and neonatal ventricular rat cardiomyocytes (NRCMs). The KCNE1 promoter conferred relatively high GFP expression in NRCMs, greater than that from the HCN4 promoter. In isolated sinus node myocytes, the HCN4 promoter conferred greater transgene expression than in NRCMs. In ex vivo sinus node tissue, only the CMV construct was capable of driving significant GFP expression. Notably, expression was largely confined to the sinus node, with only sparse expression detected in the surrounding atrial muscle. Conclusions SBF-SEM revealed ultrastructure of free running PFs in situ, and uncovered novel structural changes in HF that are likely to be pro-arrhythmic. Preliminary data suggest that 1.2 kb and 0.8 kb fragments of the HCN4 promoter are capable of driving sinus node specific transgene expression. Further tests are warranted to confirm the utility of these promoters to express therapeutic transgenes, such as miR sponges to competitively inhibit miR activity in vitro and in vivo. Acknowledgement/Funding The British Heart Foundation

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Dynamical behavior of cardiac conduction system under external disturbances: simulation based on microcontroller technology

Physica Scripta ◽

10.1088/1402-4896/ac47ba ◽

2022 ◽

Author(s):

Rodrigue Fonkou ◽

Patrick Louodop ◽

Pierre Kisito Talla

Keyword(s):

Blood Pressure ◽

Electric Current ◽

Sinus Node ◽

Dynamical Behavior ◽

Heart Rhythm ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Very High Frequency ◽

Purkinje Fibers

Abstract The heart rhythm is one of the most interesting aspects of the dynamic behavior of biological systems. Understanding heart rhythms is essential in the dynamic analysis of the heart. Each type of dynamic behaviour can describe normal or pathological physiology. The heart is made up of nodes ranging from SA node (natural pacemaker) to Purkinje fibers. The electric current originates in the sinus node and travels through the heart until it reaches the Purkinje fibers, causing after its passage through each of the nodes a heartbeat thus constituting the electrocardiogram (ECG). Since the origin of the electric current is the sinus node, in this article we study numerically and experimentally by microcontroller the influence of the sinus node on the propagation of electric current through the heart. A study of the sinus node in its autonomous state shows us that in their coupled state, the nodes of the heart qualitatively reproduce the time series of the action potential of this latter, which leads to the recording of the ECG. A study when the sinus node is subjected to periodic pulsed excitation E 1(t) = kP(t), assumed to come from blood pressure, with P(t) the blood pressure, shows that for some selected frequencies, it is found that the nodes of the heart and the ECG exhibit responses having the same shape and the same frequencies as those of the pulsatile blood pressure. This suggests the possibility of using such a conversion and excitation mechanism to replicate the functioning of cardiac conduction system. The chaotic analysis of the sinus node subjected to a sinusoidal type disturbance (E 0sin(ωt)) is also presented, it shows that in its chaotic state, the nodes of the heart, as well as the ECG, provide very high frequency signals. This requires the control of the sinus node (natural pacemaker) in such a situation

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SEM, TEM, and IHC Analysis of the Sinus Node and Its Implications for the Cardiac Conduction System

Anatomy Research International ◽

10.1155/2013/961459 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6

Author(s):

D. Mandrioli ◽

F. Ceci ◽

T. Balbi ◽

C. Ghimenton ◽

G. Pierini

Keyword(s):

Electron Microscopy ◽

Sinus Node ◽

Atrioventricular Node ◽

Definite Description ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Ordered Structure ◽

Healthy Individuals ◽

Optical And Electron Microscopy

More than 100 years after the discovery of the sinus node (SN) by Keith and Flack, the function and structure of the SN have not been completely established yet. The anatomic architecture of the SN has often been described as devoid of an organized structure; the origin of the sinus impulse is still a matter of debate, and a definite description of the long postulated internodal specialized tract conducting the impulse from the SN to the atrioventricular node (AVN) is still missing. In our previously published study, we proposed a morphologically ordered structure for the SN. As a confirmation of what was presented then, we have added the results of additional observations regarding the structural particularities of the SN. We investigated the morphology of the sinus node in the human hearts of healthy individuals using histochemical, immunohistochemical, optical, and electron microscopy (SEM, TEM). Our results confirmed that the SN presents a previously unseen highly organized architecture.

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Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.119.002874 ◽

2020 ◽

Vol 13 (5) ◽

pp. 387-395

Author(s):

Lu-Chen Weng ◽

Amelia Weber Hall ◽

Seung Hoan Choi ◽

Sean J. Jurgens ◽

Jeffrey Haessler ◽

...

Keyword(s):

Atrial Fibrillation ◽

Rare Variants ◽

Association Studies ◽

Low Frequency ◽

P Wave ◽

Cardiac Conduction ◽

Genome Wide Association Studies ◽

Genetic Loci ◽

Wave Duration ◽

P Wave Duration

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci ( TTN , CAND2 , SCN10A , PITX2 , CAV1 , SYNPO2L , SOX5 , TBX5, MYH6, RPL3L ). The top variants at known sarcomere genes ( TTN, MYH6 ) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A ) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

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Effect of xylazine, medetomidine and dexmedetomidine on cardiac conduction in pigs

Medycyna Weterynaryjna ◽

10.21521/mw.6057 ◽

2018 ◽

Vol 74 (1) ◽

pp. 6057-2018

Author(s):

ALICJA CEPIEL ◽

AGNIESZKA NOSZCZYK-NOWAK ◽

ADRIAN JANISZEWSKI ◽

ROBERT PASŁAWSKI ◽

URSZULA PASŁAWSKA

Keyword(s):

Electrophysiological Study ◽

Companion Animals ◽

Conduction System ◽

Cardiac Conduction ◽

Cardiac Conduction System ◽

Electrophysiological Activity ◽

Study Results ◽

Electrophysiological Studies ◽

Animal Preparation ◽

Heart Arrhythmias

The majority of anaesthetics used in studies regarding heart arrhythmias may affect the cardiac conduction system, thus influencing the results. In veterinary medicine, xylazine, medetomidine and dexmedetomidine are commonly used for premedication in laboratory and companion animals. To date, there have been no studies assessing the effect of these substances on the cardiac conduction system. The aim of this study was to assess the effect of xylazine, medetomidine and dexmedetomidine on the parameters of the cardiac conduction system in pigs. The study was carried out on 18 Great White Polish male pigs weighing from 21 to 40 kg. The animals were divided into three equal groups. The animals from the first group received xylazine at a dose of 2 mg/kg i.v.; those from the second group received medetomidine at 40 mcg/kg i.v.; and those from the third group received dexmedetomidine at 10 mcg/kg i.v. The electrophysiological activity of the heart was analysed using an invasive electrophysiological study (EPS). During the EPS, a decrease in the heart rate after substance administration was observed in all animals, but there were no statistically significant differences in the cardiac conduction parameters. A pro-arrhythmic effect of xylazine was observed, but no statistically significant changes in the EPS parameters were noted. Our results indicate that medetomidine and dexmedetomidine may be used as standard premedication drugs in electrophysiological studies in pigs. Their use may facilitate animal preparation procedures without affecting study results..

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First in situ 3D visualization of the human cardiac conduction system and its transformation associated with heart contour and inclination

Scientific Reports ◽

10.1038/s41598-021-88109-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tomokazu Kawashima ◽

Fumi Sato

Keyword(s):

3D Visualization ◽

Sinus Node ◽

Conduction System ◽

Cardiac Conduction ◽

Imaging Modalities ◽

Cardiac Conduction System ◽

Living Body ◽

Rotation Axes ◽

Internal Arrangement

AbstractCurrent advanced imaging modalities with applied tracing and processing techniques provide excellent visualization of almost all human internal structures in situ; however, the actual 3D internal arrangement of the human cardiac conduction system (CCS) is still unknown. This study is the first to document the successful 3D visualization of the CCS from the sinus node to the bundle branches within the human body, based on our specialized physical micro-dissection and its CT imaging. The 3D CCS transformation by cardiac inclination changes from the standing to the lying position is also provided. Both actual dissection and its CT image-based simulation identified that when the cardiac inclination changed from standing to lying, the sinus node shifted from the dorso-superior to the right outer position and the atrioventricular conduction axis changed from a vertical to a leftward horizontal position. In situ localization of the human CCS provides accurate anatomical localization with morphometric data, and it indicates the useful correlation between heart inclination and CCS rotation axes for predicting the variable and invisible human CCS in the living body. Advances in future imaging modalities and methodology are essential for further accurate in situ 3D CCS visualization.

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