Nonalcoholic Fatty Liver Disease: An Emerging Driver of Cardiac Arrhythmia.

Cardiac arrhythmias and the resulting sudden cardiac death are significant cardiovascular complications that continue to impose a heavy burden on patients and society. An emerging body of evidence indicates that nonalcoholic fatty liver disease (NAFLD) is closely associated with the risk of cardiac arrhythmias, independent of other conventional cardiometabolic comorbidities. Although most studies focus on the relationship between NAFLD and atrial fibrillation, associations with ventricular arrhythmias and cardiac conduction defects have also been reported. Mechanistic investigations suggest that a number of NAFLD-related pathophysiological alterations may potentially elicit structural, electrical, and autonomic remodeling in the heart, contributing to arrhythmogenic substrates in the heart. NAFLD is now the most common liver and metabolic disease in the world. However, the upsurge in the prevalence of NAFLD as an emerging risk factor for cardiac arrhythmias has received little attention. In this review, we summarize the clinical evidence and putative pathophysiological mechanisms for the emerging roles of NAFLD in cardiac arrhythmias, with the purpose of highlighting the notion that NAFLD may serve as an independent risk factor and a potential driving force in the development and progression of cardiac arrhythmias.

Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction.

BACKGROUND: Genetic variants in SCN10A, encoding the neuronal voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, encoding the major essential cardiac sodium channel NaV1.5. METHODS: The expression of SCN10A was investigated in mouse and human hearts. With the use of CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by genome-wide association studies single-nucleotide polymorphism mapping and expression quantitative trait loci analysis. RESULTS: We found that cardiomyocytes of the atria, sinoatrial node, and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (Scn10a-short). Transcription occurs from an intronic enhancer-promoter complex, whereas full-length Scn10a transcript was undetectable in the human and mouse heart. Expression quantitative trait loci analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, whereas the expression of Scn5a, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that noncoding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts NaV1.5-mediated sodium current and heart rhythm. CONCLUSIONS: Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that noncoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.

Anatomy of the cardiac conduction system.

The specialized cardiomyocytes that constitute the conduction system in the human heart, initiate the electric impulse and result in rhythmic and synchronized contraction of the atria and ventricles. Although the atrioventricular (AV) conduction axis was described more than a century ago by Sunao Tawara, the anatomic pathway for propagation of impulse from atria to the ventricles has been a topic of debate for years. Over the past 2 decades, there has been a resurgence of conduction system pacing (CSP) by implanting pacing leads in the His bundle region in lieu of chronic right ventricular pacing that is associated with worse clinical outcomes. The inherent limitations of implanting the leads in the His bundle region has led to the emergence of left bundle branch area pacing in the past 3 years as an alternative strategy for CSP. The clinical experience from performing CSP has helped electrophysiologists gain deeper insight into the anatomy and physiology of cardiac conduction system. This review details the anatomy of the cardiac conduction system, and highlights some of the recently published articles that aid in better understanding of the AV conduction axis and its variations, the knowledge of which is critical for CSP. The remarkable evolution in technology has led to visualization of the cardiac conduction system using noninvasive, nondestructive high-resolution contrast-enhanced micro-computed tomography imaging that may aid in future CSP. We also discuss from anatomical perspective, the differences seen clinically with His bundle pacing and left bundle branch area pacing.

His bundle pacing: Tips and tricks.

His bundle (HB) pacing is an established modality for achieving physiological pacing with a low risk of long-term lead-related complications. The development of specially designed lead and delivery tools has improved the feasibility and safety of HB pacing (HBP). Knowledge of the anatomy of HB region and the variations is essential for successful implantation. Newer delivery systems have further improved procedural outcomes. Challenging implant cases can be successfully performed by reshaping the current sheaths, using "sheath in sheath" technique or "two-lead implantation technique." Special attention to the lead parameters at implant, programming, and follow-up is necessary for successful long-term outcomes with HBP. Widespread use of HBP by electrophysiologists and further advances in dedicated delivery systems and leads are essential to further improve the effectiveness of the implantation.

Clinical outcomes of His-Purkinje conduction system pacing.

His-Purkinje conduction system pacing (HPCSP) in the form of His bundle pacing (HBP) and left bundle branch pacing (LBBP) allows normal left ventricular activation, thereby preventing the adverse consequences of right ventricular pacing. HBP has been established for several years with centers from China, Europe, and North America reporting their experience. There is international guidance as to how to implant such systems with the differing patterns of His bundle capture clearly described. LBBP is a more recent innovation with potential advantages including improved pacing parameters. HPCSP has been extensively studied in a variety of indications including cardiac resynchronization therapy, atrioventricular node ablation, and bradycardia pacing. This review will focus on the clinical outcomes of HPCSP including mortality and morbidity of heart failure hospitalization and symptoms.

Predictors of high-degree conduction disturbances and pacemaker implantation after transcatheter aortic valve replacement: Prognostic role of the electrophysiological study.

BACKGROUND: Predictors of high-degree atrioventricular block (HAVB) after transcatheter aortic valve replacement (TAVR) are recognized, but the electrophysiological study's (EPS) role is still a subject to debate. The objective of our study was to determine factors associated with PPM implantation including the potential role of EPS before and/or after TAVR. METHODS AND RESULTS: Seventy four consecutive patients (pts) were included and 21 pts (28.4%) received a PPM during the immediate postoperative follow-ups (until Day 5): HAVB in 15 pts (71.4%), prophylactic implantation due to a documented increased HV interval ≥ 95-100 ms plus LBBB in 2 pts (9.5%), a high-degree HV block evidenced at the EPS plus LBBB in 3 pts (14.3%) and one additional patient was implanted for AV-block in presence of AFib (4.8%). In the multivariate model 1 including parameters before TAVR, both prosthesis diameter and PR lengthening remained significantly associated with PPM as well RBBB. In the multivariate model 2 including parameters after TAVR, only HV remained significantly associated with the risk of PPM (OR = 1.15 (1.05-1.26), p = .004). When all the significant variables in models 1 and 2 were analyzed together in model 3, only HV after TAVR remained significantly associated with an increased risk of PPM. CONCLUSIONS: In this prospective observational study, it was revealed that a Day 4-5 EPS is likely to more precisely stratify the risk of PPM implantation regarding its ability to discover asymptomatic severe infra-hisian conduction disturbances particularly in presence of LBBB. Multivariate analysis confirmed the prognostic value of HV alteration.

Long-term outcome of intraventricular conduction delays in the general population.

BACKGROUND: Previous population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD). METHODS: We studied long-term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12-lead ECG. For left bundle branch block (LBBB) and non-specific IVCD (NSIVCD), two different definitions were used. RESULTS: During 16.5 years' follow-up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04-2.31, p = .032) and 1.27 (95% confidence interval 0.80-2.02, p = .308) for the Strauss' definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R-R' pattern was not associated with any adverse outcome. CONCLUSIONS: In a population study with long-term follow-up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder.

Reduced Na+ current in Purkinje fibers explains cardiac conduction defects and arrhythmias in Duchenne muscular dystrophy.

Cardiac arrhythmias significantly contribute to mortality in Duchenne muscular dystrophy (DMD), a degenerative muscle disease triggered by mutations in the gene encoding for the intracellular protein dystrophin. A major source for the arrhythmias in patients with DMD is impaired ventricular impulse conduction, which predisposes for ventricular asynchrony, decreased cardiac output, and the development of reentrant mechanisms. The reason for ventricular conduction impairments and the associated arrhythmias in the dystrophic heart has remained unidentified. In the present study, we explored the hypothesis that dystrophin-deficient cardiac Purkinje fibers have reduced Na+ currents (INa), which would represent a potential mechanism underlying slowed ventricular conduction in the dystrophic heart. Therefore, by using a Langendorff perfusion system, we isolated Purkinje fibers from the hearts of adult wild-type control and dystrophin-deficient mdx mice. Enhanced green fluorescent protein (eGFP) expression under control of the connexin 40 gene allowed us to discriminate Purkinje fibers from eGFP-negative ventricular working cardiomyocytes after cell isolation. Finally, we recorded INa from wild-type and dystrophic mdx Purkinje fibers for comparison by means of the whole cell patch clamp technique. We found substantially reduced INa densities in mdx compared with wild-type Purkinje fibers, suggesting that dystrophin deficiency diminishes INa. Because Na+ channels in the Purkinje fiber membrane represent key determinants of ventricular conduction velocity, we propose that reduced INa in Purkinje fibers at least partly explains impaired ventricular conduction and the associated arrhythmias in the dystrophic heart.NEW & NOTEWORTHY Dystrophic cardiac Purkinje fibers have abnormally reduced Na+ current densities. This explains impaired ventricular conduction in the dystrophic heart.

The long-term therapeutic effects of His-Purkinje system pacing on bradycardia and cardiac conduction dysfunction compared with right ventricular pacing: A systematic review and meta-analysis.

AIMS: His-Purkinje system pacing has been demonstrated as a synchronized ventricular pacing strategy via pacing His-Purkinje system directly, which can decrease the incidence of adverse cardiac structure alteration compared with right ventricular pacing (RVP). The purpose of this meta-analysis was to compare the effects of His-Purkinje system pacing and RVP in patients with bradycardia and cardiac conduction dysfunction. METHODS: PubMed, Embase, Cochrane Library, and Web of Science were systematically searched from the establishment of databases up to 15 December 2019. Studies on long-term clinical outcomes of His-Purkinje system pacing and RVP were included. Chronic paced QRS duration, chronic pacing threshold, left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), all-cause mortality, and heart failure hospitalization were collected for meta-analysis. RESULTS: A total of 13 studies comprising 2348 patients were included in this meta-analysis. Compared with RVP group, patients receiving His-Purkinje system pacing showed improvement of LVEF (mean difference [MD], 5.65; 95% confidence interval [CI], 4.38-6.92), shorter chronic paced QRS duration (MD, - 39.29; 95% CI, - 41.90 to - 36.68), higher pacing threshold (MD, 0.8; 95% CI, 0.71-0.89) and lower risk of heart failure hospitalization (odds ratio [OR], 0.65; 95% CI, 0.44-0.96) during the follow-up. However, no statistical difference existed in LVEDV, LVESV and all-cause mortality between the two groups. CONCLUSION: Our meta-analysis suggests that His-bundle pacing is more suitable for the treatment of patients with bradycardia and cardiac conduction dysfunction.

The AMP-activated protein kinase modulates hypothermia-induced J wave.

BACKGROUND: The mechanism underlying the occurrence of the J wave in low temperature remains unclear. However, low temperature is associated with metabolic disorder and 5' AMP-activated protein kinase (AMPK), which modulates ionic currents and cardiac metabolism. This study investigated whether AMPK regulation can modulate the occurrence of the J wave at low temperature. METHODS: Unipolar and bipolar leads were used to record monophasic action potential (the endocardium and epicardium) and pseudo-electrocardiograms (inferior leads) to study the cardiac electrical activity. Measurements were taken in isolated Langendorff rabbit hearts at both 30℃ and 37℃ before and after administration of 4-aminopyridine (an ultrarapid delayed rectifier potassium current inhibitor, IKur , 50 µmol L-1 ), PF06409577 (an AMPK activator, 1 µmol L-1 ), compound C (an AMPK inhibitor, 10 µmol L-1 ) and glibenclamide (an ATP-sensitive inward rectifier potassium channel inhibitor, IKATP , 20 µmol L-1 ). RESULTS: The amplitude of the J wave (2.46 ± 0.34 mV vs. 1.11 ± 0.23 mV, P < .01) at 30℃ (n = 15) was larger than that at 37℃ (n = 15). PF06409577 (1 µmol L-1 ) increased the J waves at both 30℃ and 37℃. In contrast, compound C (10 µmol L-1 ) reduced J wave at both 37℃ and 30℃. Low-temperature-induced J waves were individually suppressed by 4-AP (50 µmol L-1 ) and glibenclamide (20 µmol L-1 ). CONCLUSIONS: AMPK inhibition reduces low-temperature-induced J waves and possible ventricular arrhythmogenesis by modulating IKATP and IKur channels.

Variants of accessory pathways.

Variant accessory pathways include atriofascicular, nodofascicular, nodoventricular, atrio-Hisian, and fasciculoventricular pathways. Atriofascicular pathways are the most common with others occurring rarely. The anatomical descriptions, electrocardiographic findings, electrophysiologic findings, and clincial manifestations are discussed.

Experimental analysis of the onset mechanism of TdP reported in an LQT3 patient during pharmacological treatment with serotonin-dopamine antagonists against insomnia and nocturnal delirium.

Torsade de pointes (TdP) occurred in a long QT syndrome type 3 (LQT3) patient after switching perospirone to blonanserin. We studied how their electropharmacological effects had induced TdP in the LQT3 patient. Perospirone hydrochloride (n = 4) or blonanserin (n = 4) of 0.01, 0.1, and 1 mg/kg, i.v. was cumulatively administered to the halothane-anesthetized dogs over 10 min. The low dose of perospirone decreased total peripheral vascular resistance, but increased heart rate and cardiac output, facilitated atrioventricular conduction, and prolonged J-Tpeakc. The middle dose decreased mean blood pressure and prolonged repolarization period, in addition to those observed after the low dose. The high dose further decreased mean blood pressure with the reduction of total peripheral vascular resistance; however, it did not increase heart rate or cardiac output. It tended to delay atrioventricular conduction and further delayed repolarization with the prolongation of Tpeak-Tend, whereas J-Tpeakc returned to its baseline level. Meanwhile, each dose of blonanserin decreased total peripheral vascular resistance, but increased heart rate, cardiac output and cardiac contractility in a dose-related manner. J-Tpeakc was prolonged by each dose, but Tpeak-Tend was shortened by the middle and high doses. These results indicate that perospirone and blonanserin may cause the hypotension-induced, reflex-mediated increase of sympathetic tone, leading to the increase of inward Ca2+ current in the heart except that the high dose of perospirone reversed them. Thus, blonanserin may have more potential to produce intracellular Ca2+ overload triggering early afterdepolarization than perospirone, which might explain the onset of TdP in the LQT3 patient.

Dynamic QT response to cold-water face immersion in long-QT syndrome type 3.

BACKGROUND: Abnormal dynamics of QT intervals in response to sympathetic nervous system stimulation are used to diagnose long-QT syndrome (LQTS). We hypothesized that parasympathetic stimulation with cold-water face immersion following exercise would influence QT dynamics in patients with LQTS type 3 (LQT3). METHODS: Study participants (n = 42; mean age = 11.2 years) comprised 20 genotyped LQTS children and 22 healthy children. The LQTS group was divided into LQT3 (n = 12) and non-LQT3 (n = 8) subgroups. Provocative testing for assessing QT dynamics comprised a treadmill exercise followed by cold-water face immersion. The QT intervals were automatically measured at rest and during exercise, recovery, and cold-water face immersion. The QT/heart rate (HR) relationship was visualized by plotting beat-to-beat confluence of the data. RESULTS: The QT/HR slopes, determined by linear regression analysis, were steeper in the LQTS group than in the control group during exercise and immersion tests: -2.16 ± 0.63 versus -1.21 ± 0.28, P < 0.0001, and -2.02 ± 0.76 vs -0.75 ± 0.24, P < 0.0001, respectively. The LQT3 patients had steeper slopes in the immersion test than did non-LQT3 and control individuals: -2.42 ± 0.52 vs -1.40 ± 0.65, P < 0.0001, and vs -0.75 ± 0.24, P < 0.0001. CONCLUSIONS: The QT dynamics of LQT3 patients differ from those of other LQTS subtypes during the post-exercise cold-water face immersion test in this study. Abnormal QT dynamics during the parasympathetic provocative test are concordant with the fact that cardiac events occur when HRs are lower or during sleep in LQT3 patients.

Alternative sites of ventricular pacing: His bundle pacing.

Since its introduction right ventricular apical (RVA) pacing has been the mainstay in cardiac pacing. However, in recent years there has been an upsurge of interest in permanent His bundle pacing (HBP), given the scientific evidence of the harmful role of dyssynchronous ventricular activation, induced by RVA pacing, in promoting the onset of heart failure and atrial fibrillation. After an intermediate period in which attention was focused on algorithms aimed at minimizing ventricular pacing, with partially inadequate and harmful results, scientific attention shifted to HBP, which proved to ensure a physiological electro-mechanical activation of the ventricles. The encouraging results obtained have allowed the introduction of HBP in recent guidelines for cardiac pacing in patients with bradicardia and cardiac conduction delay. Recent studies have also demonstrated the potential of HBP in patients with left bundle branch block and heart failure. HBP is promising as an attractive way to achieve physiological stimulation in patients with an indication for cardiac resynchronization therapy (CRT). Comparative studies of HB-CRT and biventricular pacing have shown similar results in numerically modest cohorts, although HB-CRT has been shown to promote better ventricular electrical resynchronization as demonstrated by a greater QRS narrowing. A widespread use of this pacing tecnique also depends on improvements in technology, as well as further validation of effectiveness in large randomised clinical trials.

A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources.

KEY POINTS: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) capture patient-specific genotype-phenotype relationships, as well as cell-to-cell variability of cardiac electrical activity Computational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimes We have developed a whole-cell model of iPSC-CMs, composed of single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM outputs We have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC-CMs This framework links molecular mechanisms to cellular-level outputs by revealing unique subsets of model parameters linked to known iPSC-CM phenotypes ABSTRACT: There is a profound need to develop a strategy for predicting patient-to-patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient-specific proclivity to cardiac disease utilizes induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). A major strength of this approach is that iPSC-CMs contain donor genetic information and therefore capture patient-specific genotype-phenotype relationships. A cited detriment of iPSC-CMs is the cell-to-cell variability observed in electrical activity. We postulated, however, that cell-to-cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole-cell model of iPSC-CMs composed of simple model components comprising ion channel models with single exponential voltage-dependent gating variable rate constants, parameterized to fit experimental iPSC-CM data for all major ionic currents. By optimizing ionic current model parameters to multiple experimental datasets, we incorporate experimentally-observed variability in the ionic currents. The resulting population of cellular models predicts robust inter-subject variability in iPSC-CMs. This approach links molecular mechanisms to known cellular-level iPSC-CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyse the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacological interventions for studying the mechanisms of rare events, such as arrhythmia triggers.

Clinical and genetic characteristics of childhood-onset myotonic dystrophy.

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is caused by a CTG (cytosine-thymine-guanine) trinucleotide repeat expansion. Congenital DM (CDM) presents in the first month of life, whereas individuals with infantile and juvenile DM1 have later onset of symptoms. METHODS: We performed a retrospective chart review of patients with childhood-onset DM1 seen at one of three locations in Dallas, Texas between 1990 and 2018. Symptoms, disease course, cognitive features, and family history were reviewed. RESULTS: Seventy-four patients were included; CDM was diagnosed in 52 patients. There was maternal inheritance in 74% of patients. CTG repeat number ranged from 143 to 2300. Neuropsychiatric and cognitive deficits were common. Over half of the patients had GI disturbances, and orthopedic complications were common. DISCUSSION: Myotonic dystrophy type 1 in children requires a multidisciplinary approach to management. Presenting symptoms vary, and repeat expansion size does not necessarily directly relate to severity of symptoms. A consensus for outcome measures is required.

Evaluation of a real-time magnetic resonance imaging-guided electrophysiology system for structural and electrophysiological ventricular tachycardia substrate assessment.

AIMS: Potential advantages of real-time magnetic resonance imaging (MRI)-guided electrophysiology (MR-EP) include contemporaneous three-dimensional substrate assessment at the time of intervention, improved procedural guidance, and ablation lesion assessment. We evaluated a novel real-time MR-EP system to perform endocardial voltage mapping and assessment of delayed conduction in a porcine ischaemia-reperfusion model. METHODS AND RESULTS: Sites of low voltage and slow conduction identified using the system were registered and compared to regions of late gadolinium enhancement (LGE) on MRI. The Sorensen-Dice similarity coefficient (DSC) between LGE scar maps and voltage maps was computed on a nodal basis. A total of 445 electrograms were recorded in sinus rhythm (range: 30-186) using the MR-EP system including 138 electrograms from LGE regions. Pacing captured at 103 sites; 47 (45.6%) sites had a stimulus-to-QRS (S-QRS) delay of ≥40 ms. Using conventional (0.5-1.5 mV) bipolar voltage thresholds, the sensitivity and specificity of voltage mapping using the MR-EP system to identify MR-derived LGE was 57% and 96%, respectively. Voltage mapping had a better predictive ability in detecting LGE compared to S-QRS measurements using this system (area under curve: 0.907 vs. 0.840). Using an electrical threshold of 1.5 mV to define abnormal myocardium, the total DSC, scar DSC, and normal myocardium DSC between voltage maps and LGE scar maps was 79.0 ± 6.0%, 35.0 ± 10.1%, and 90.4 ± 8.6%, respectively. CONCLUSION: Low-voltage zones and regions of delayed conduction determined using a real-time MR-EP system are moderately associated with LGE areas identified on MRI.

Molecular and genetic insights into progressive cardiac conduction disease.

Progressive cardiac conduction disease (PCCD) is often a primarily genetic disorder, with clinical and genetic overlaps with other inherited cardiac and metabolic diseases. A number of genes have been implicated in PCCD pathogenesis with or without structural heart disease or systemic manifestations. Precise genetic diagnosis contributes to risk stratification, better selection of specific therapy and allows familiar cascade screening. Cardiologists should be aware of the different phenotypes emerging from different gene-mutations and the potential risk of sudden cardiac death. Genetic forms of PCCD often overlap or coexist with other inherited heart diseases or manifest in the context of multisystem syndromes. Despite the significant advances in the knowledge of the genetic architecture of PCCD and overlapping diseases, in a measurable fraction of PCCD cases, including in familial clustering of disease, investigations of known cardiac disease-associated genes fail to reveal the underlying substrate, suggesting that new causal genes are yet to be discovered. Here, we provide insight into genetics and molecular mechanisms of PCCD and related diseases. We also highlight the phenotypic overlaps of PCCD with other inherited cardiac and metabolic diseases, present unmet challenges in clinical practice, and summarize the available therapeutic options for affected patients.

Case reports of a c.475G>T, p.E159* lamin A/C mutation with a family history of conduction disorder, dilated cardiomyopathy and sudden cardiac death.

BACKGROUND: Patients with some mutations in the lamin A/C (LMNA) gene are characterized by the presence of dilated cardiomyopathy (DCM), conduction abnormalities, ventricular tachyarrhythmias (VT), and sudden cardiac death (SCD). Various clinical features have been observed among patients who have the same LMNA mutation. Here, we show a family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, and a family history of conduction disorder, DCM, VT, and SCD. CASE PRESENTATION: A proband (female) with atrial fibrillation and bradycardia was implanted with a pacemaker in her fifties. Twenty years later, she experienced a loss of consciousness due to polymorphic VT. She had a serious family history; her mother and elder sister died suddenly in their fifties and sixties, respectively, and her nephew and son were diagnosed as having DCM. Genetic screening of the proband, her son, and nephew identified a nonsense mutation (c.475G > T, p.E159*) in the LMNA gene. Although the proband's left ventricular ejection fraction remained relatively preserved, her son and nephew's left ventricular ejection fraction were reduced, resulting in cardiac resynchronization therapy by implantation of a defibrillator. CONCLUSIONS: In this family with cardiac laminopathy with a c.475G > T, p.E159* LMNA mutation, DCM, SCD, and malignant VT occurred. Clinical manifestation of various atrial and ventricular arrhythmias and heart failure with reduced ejection fraction occurred in an age-dependent manner in all family members who had the nonsense mutation. It appears highly likely that the E159* LMNA mutation is related to various cardiac problems in the family of the current report.

Old teaching tools should not be forgotten: The value of the Lewis ladder diagram in understanding bigeminal rhythms.

As medical education evolves, some traditional teaching methods often get forgotten. For generations, the Lewis ladder diagram (LLD) has helped students understand the mechanisms of cardiac arrhythmias and conduction disorders. Similarly, clinicians have used LLDs to communicate their proposed mechanisms to their colleagues and trainees. In this article, we revisit this technique of constructing the LLD and demonstrate this process by describing the mechanisms of various bigeminal rhythms.