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Danna A Spears, Michael H Gollob Division of Cardiology – Electrophysiology, University Health Network, Toronto General Hospital, Toronto, ON, Canada Abstract: A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening. Keywords: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, short QT syndrome, genetics

The article presents information on a case study related to the brugada syndrome. A 42 year old man with a history of depression, asthma, and obstructive sleep apnoea presented with ventricular fibrillation at home. On admission to hospital, his medications were desipramine 400 mg at night time, omeprazole 20 mg daily, and bromocriptine 2.5 mg at night time. One month before admission, his desipramine dose had been increased from 300 mg. He denied suicidal ideation or drug overdose, street drug use, or other non-prescription drug use. Two years before his presentation an ECG was normal. His medications at that time were: fluoxetine 100 mg daily, omeprazole 20 mg daily, and moclobemide 300 mg three times daily. His presenting ECG was significantly different from his previous ECG.

Background: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings., Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering., Results: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches., Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: The diagnosis of Brugada syndrome by 12-lead electrocardiography (ECG) is challenging because the diagnostic type 1 pattern is often transient., Objectives: This study sought to improve Brugada syndrome diagnosis by using deep learning (DL) to continuously monitor for Brugada type 1 in 24-hour ambulatory 12-lead ECGs (Holters)., Methods: A convolutional neural network was trained to classify Brugada type 1. The training cohort consisted of 10-second standard/high precordial leads from 12-lead ECGs (n = 1,190) and 12-lead Holters (n = 380) of patients with definite and suspected Brugada syndrome. The performance of the trained model was evaluated in 2 testing cohorts of 10-second standard/high precordial leads from 12-lead ECGs (n = 474) and 12-lead Holters (n = 716)., Results: DL achieved a receiver-operating characteristic area under the curve of 0.976 (95% CI: 0.973-0.979) in classifying Brugada type 1 from 12-lead ECGs and 0.975 (95% CI: 0.966-0.983) from 12-lead Holters. Compared with cardiologist reclassification of Brugada type 1, DL had similar performance and produced robust results in experiments evaluating scalability and explainability. When DL was applied to consecutive 10-second, clean ECGs from 24-hour 12-lead Holters, spontaneous Brugada type 1 was detected in 48% of patients with procainamide-induced Brugada syndrome and in 33% with suspected Brugada syndrome. DL detected no Brugada type 1 in healthy control patients., Conclusions: This novel DL model achieved cardiologist-level accuracy in classifying Brugada type 1. Applying DL to 24-hour 12-lead Holters significantly improved the detection of Brugada type 1 in patients with procainamide-induced and suspected Brugada syndrome. DL analysis of 12-lead Holters may provide a robust, automated screening tool before procainamide challenge to aid in the diagnosis of Brugada syndrome., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Irisin, encoded by the FNDC5 (fibronectin type III domain containing 5) gene, is a novel myokine that has been implicated as an essential mediator of exercise benefits. Effects of irisin on heart physiology is still ambiguous. This study aimed to evaluate the impact of exogenous administration of irisin on heart physiology and the pharmacokinetic profile of pump-administered irisin. To do so, Sprague Dawley rats were implanted with an irisin-loaded osmotic pump (5 μg/kg/day) for 42 days, and other animals were administered with single bolus subcutaneous injections of irisin (5 µg/kg). Body weights and blood samples were collected weekly for 42 days for serum irisin quantification and histopathology. Clinical biochemistry analyses were performed. Heart mRNA expression was assessed in 26 selected genes. Chronic interventional exogenous irisin significantly reduced body weight without affecting the heart myocyte size and significantly reduced creatine kinase enzyme level. Blood CBC, serum biochemistry, and heart morphology were normal. Gene expression of FNCD5, Raf1, CPT1, IGF-1, and CALCIN, encoding for heart physiology, increased while PGC1, Nox4, and Mfn1 significantly decreased. Nevertheless, irisin increased the expression of cardioprotective genes and inhibited some genes that harm heart physiology. Administration of irisin promotes myocardial functions and could be translated into clinical settings after preclinical profiling.

Background: The SCN5A mutation, P1332L, is linked to a malignant form of congenital long QT syndrome, type 3 (LQT3), and affected patients are highly responsive to the Na+ channel blocking drug, mexiletine. In contrast, A647D is an atypical SCN5A mutation causing Brugada syndrome. An asymptomatic male with both P1332L and A647D presented with varying P wave/QRS aberrancy and mild QTc prolongation which did not shorten measurably with mexiletine., Objective: We characterized the biophysical properties of P1332L, A647D and wild-type (WT) Na+ channels as well as their combinations in order to understand our proband's phenotype and to guide mexilitine therapy., Methods: Na+ channel biophysics and mexilitine-binding kinetics were assessed using heterologous expression studies in CHO-K1 cells and human ventricular myocyte modeling., Results: Compared to WT, P1332L channels displayed a hyperpolarizing shift in inactivation, slower inactivation and prominent late Na+ currents (INa). While A647D had no effect on the biophysical properties of INa, it reduced peak and late INa density when co-expressed with either WT or P1332L. Additionally, while P1332L channels had greater sensitivity to block by mexiletine compared to WT, this was reduced in the presence of A647D. Modelling studies revealed that mixing P1332L with A647D channels, action potential durations were shortened compared to P1332L, while peak INa was reduced compared to either A647D coexpressing with WT or WT alone., Conclusions: While A647D mitigates the lethal LQT3 phenotype seen with P1332L, it also reduces mexilitine sensitivity and decreases INa density. These results explain our proband's mild repolarization abnormality and prominent conduction defect in the atria and ventricles, but also suggest that expression of P1332L with A647D yields a novel disease phenotype for which mexiletine pharmacotherapy is no longer suitable., Competing Interests: The authors have declared that no competing interests exist.

Background: Nonsustained ventricular tachycardia (NSVT) detected by ambulatory Holter (Holter NSVT) is a major risk factor for sudden cardiac death in hypertrophic cardiomyopathy (HCM). We hypothesized that the prognostic utility of Holter NSVT in HCM would improve with prolonged monitoring and a higher heart rate cut-off for detection., Methods: We enrolled 60 patients (44 ± 14 years) with HCM, who had a prophylactic implantable cardioverter defibrillator (ICD). Positive Holter NSVT (prior to implant) was defined as ≥3 beats at ≥120 beats per minute (bpm). We assessed the prevalence of rapid NSVT (RNSVT) detected by their ICD within 12 months of its implant, defined as 4-16 beats at ≥150-200 bpm. The primary outcome was appropriate ICD therapy (antitachycardia pacing and shocks) for sustained ventricular arrhythmia (VA)., Results: Holter NSVT was detected in 34 patients. RNSVT occurred in 21 (35%) patients of whom five did not have Holter NSVT. Over a median follow-up of 61 (interquartile range 29, 129) months after ICD implant, nine patients had VA. RNSVT, but not Holter NSVT, was significantly associated with VA (hazard ratio 6.2, 95% confidence interval [1.3-30], P = 0.01) by multivariable Cox regression analysis that included conventional risk factors. Receiver operating characteristic analysis for RNSVT (area under curve 0.80, P = 0.005) showed that the occurrence of ≥2 episodes of RNSVT discriminated patients for VA optimally (sensitivity 78%, specificity 84%, positive predictive value 47%, negative predictive value 96%)., Conclusions: In this pilot study, RNSVT detected by continuous monitoring independently predicted VA in HCM and offered superior discrimination of VA risk compared to conventional risk factors, including Holter NSVT. Future studies are needed to validate these findings in a larger, unselected HCM cohort., (©2016 Wiley Periodicals, Inc.)

Expression of the G protein subunit Goα has been shown to be prominent in the atria of the rat heart and to be significantly associated with atrial natriuretic factor (ANF)-containing atrial-specific secretory granules by immunocytochemistry. In addition, differential expression profile analysis using oligonucleotide arrays has shown that the Goα isoform 1 (Goα1) is 2.3-fold more abundant in the atria than it is in the ventricles. In the present report, we show protein-protein interaction between Goα and ANF by yeast two-hybrid and by immunoprecipitation. A cardiac conditional Goα knockout model developed for the present study showed a 90% decrease in Goα expression and decreased atrial expression and ANF and brain natriuretic peptides (BNP) content. Expression of chromogranin A, a specific atrial granule core constituent, was not affected. Morphometric assessment of atrial tissue showed a very significant decrease in atrial-specific granule density as well as granule core electron density. Atrial electrical activity was not affected. The results obtained are compatible with the suggestion that Goα plays a role in ANF sorting during intracellular vectorial transport and with the presence of a mechanism that preserves the molar relationship between cellular ANF and BNP stores in the face of the decreased production of these hormones., (© 2015 Society for Endocrinology.)

Background: There is a substantial mortality rate in patients admitted alive after out-of-hospital cardiac arrest. The primary objective of our study was to examine trends in in-hospital survival in out-of-hospital cardiac arrest survivors in Canada between 1994 and 2004. The secondary objective was to examine predictors of in-hospital survival in these patients., Methods: Data on hospital admissions from April 1, 1994, to March 31, 2004, were obtained from the Health Person-oriented Information Database, maintained by Statistics Canada. We included all patients with a primary diagnosis of cardiac arrest who survived to hospital admission. We assessed survival to hospital discharge in all patients admitted alive., Results: In Canada, 13,263 patients survived community arrest between 1994 and 2004. The annual incidence of hospital admission after out-of-hospital cardiac arrest decreased by 33%, from 5.37 per 100,000 in 1994 to 3.63 per 100,000 in 2004 (P < .0001 for trend). Subsequently, 5,045 patients (38.03%) survived to hospital discharge. The survival rate did not change during the duration of the study. Invasive coronary artery disease management was associated with a greatly increased chance of survival (odds ratio 21.98, 95% CI 17.62-27.42). Also male gender, heart failure, and acute myocardial ischemia were independent positive predictors of survival to hospital discharge; greater age and comorbidities were negative predictors of survival. Finally, there were significant interprovincial variations in survival rates., Conclusions: Our study, the largest of its kind, has 4 main findings. Firstly, between 1993 and 2004, there was a significant and steady decline in admission rates after community cardiac arrest. Second, there was no change in the in-hospital survival rates. Thirdly, invasive management of coronary artery disease was associated with a greatly improved chance of survival, and finally, there were important regional variations in survival rates., (Copyright 2010 Mosby, Inc. All rights reserved.)

Clinical trials provide evidence that an empiric approach of implantable cardioverter-defibrillator (ICD) implantation in heart failure patients (ejection fraction =/< 35%) with mild to moderate symptoms reduces mortality rate as compared to the best available medical therapy. However, ejection fraction alone is unable to predict death by progressive pump failure or sudden arrhythmic death, and consequently over half of all patients will not require device therapy over long-term follow-up. Thus, the approach of empiric ICD implantation results in excessive cost in the absence of more specific risk stratification for sudden death. This review summarizes the current noninvasive risk stratifying strategies available in predicting susceptibility to sudden arrhythmic death in heart failure populations.

Background: The three-dimensional contributions to human atrial activation in sinus rhythm have not been specifically characterized. We evaluated the sequence of endocardial and epicardial activation and voltage of the atria during normal sinus rhythm., Methods and Results: The study group includes 35 patients with history of symptomatic atrial fibrillation. Prior to catheter ablation of atrial fibrillation, we performed multielectrode electroanatomic mapping during sinus rhythm, endocardially of the RA, LA, and coronary sinus (CS) and, in 10 patients, epicardially of the transverse sinus and oblique sinus. Following activation of the atrial region of the sinus node, the epicardial transverse sinus was activated 11 +/- 18 msec later, while the earliest endocardial LA activation occurred in the region of Bachmann's bundle at 31 +/- 13 msec, significantly earlier than the earliest epicardial LA activation of the oblique sinus at 54 +/- 10 msec (P < 0.002). The posterior LA revealed complex types of activation in 66% of patients analyzed, due to the convergence of wavefront propagation from the CS, oblique sinus, and endocardial LA. Bipolar voltage measurements revealed significantly higher values for the epicardium (mean 3.05 +/- 1.31 mv) than for the endocardium (mean 1.65 +/- 0.75 mv), P < 0.0001 between both groups., Conclusions: In sinus rhythm, we have characterized endocardial and epicardial atrial activation and voltage, and provide an analysis and understanding of the genesis of the P wave complex in humans.

The terminology and technology of molecular genetics and recombinant DNA have become an essential part of academic cardiology and will soon be applied at the bedside. The treatise includes a brief summary of the essentials of the DNA molecule, the more common techniques, and their application to genetics and molecular cardiology. It is written to be understood by physicians, scientists, and paramedical personnel who would not necessarily have a background in molecular biology. Inherent in the DNA molecule are three properties fundamental to all of the diagnostic and therapeutic applications, namely, the ability of DNA to separate into single strands, recombine (annealment or hybridization), and the presence of the negative charge enables DNA fragments to be separated easily by electrophoresis. Genetic linkage analysis of a family with an inherited disease enables one to identify the gene without knowing its protein product. Over 50 diseases in cardiology due to single-gene disorders have been identified and multiple mutations have been detected. The new therapeutic frontier will be stem cells and nuclear transfer. Identification of genes responsible for coronary artery disease made possible by genome-wide single nucleotide polymorphism (SNP) mapping techniques paves the way for personalized medicine.

Surveys of pacing practice have shown a steady increase in pacemaker implantation rates in the past 15 years, despite no major changes in United States guidelines for permanent pacing. There are no data to explain why this is occurring. In this study, records were extracted from the National Hospital Discharge Survey to investigate this. There were 3 major findings. First, age-adjusted implantation rates increased progressively over the study period from 370 per million in 1990 to 612 per million in 2002. Second, it was found that the escalating implantation rate is attributable to increasing implantation for isolated sinus node dysfunction (SND). Implantation for SND increased significantly over the study period (by 102%), whereas implantation for all other indications did not. The increasing implantation for SND is due primarily to the increasing prevalence of SND, with a lesser increase in implantation rate relative to prevalence rate. The third major finding of this study is that there has been a progressive relative and absolute increase in the dual-chamber implantation rate. In 2002, 82.8% of all initial pacemaker implantations were dual-chamber devices. Furthermore, the National Hospital Discharge Survey data indicate that the major randomized pacing trials seem to have had no impact on pacing practice in the United States. In conclusion, age-adjusted implantation rates increased progressively over the study period. This escalating implantation rate is primarily attributable to increasing implantation for SND.

Background: Numerous reports have demonstrated an association between autonomic tone and atrial fibrillation (AF). Pulmonary vein (PV) denervation during catheter ablation of AF has been shown to significantly reduce recurrence of AF., Objectives: The purpose of this study was to assess the safety and efficacy of high-frequency stimulation at mapping cardiac ganglionated plexuses in patients undergoing catheter ablation of AF., Methods: Fourteen patients with a history of symptomatic AF underwent a single transseptal approach and electroanatomic mapping of the left atrium, right atrium, and coronary sinus. Using high-frequency stimulation with patients under general anesthesia (20-50 Hz, 5-15 V, pulse width 10 ms), mapping of ganglionated plexuses was performed. Radiofrequency (RF) ablation was performed during AF guided by complex fractionated atrial electrograms. Lesions were mostly delivered circumferentially in the antral area of the PVs, predominantly over and adjacent to regions of ganglionated plexuses., Results: There was a mean of 4 +/- 1 (range 2-6) ganglionated plexuses per patient, and a mean total of 3 +/- 1 RF applications were delivered over positive vagal sites. Although a vagal response occurred infrequently during ablation (0.9%), postablation high-frequency stimulation failed to provoke a vagal response in 30 (88%) of 34 previously positive vagal sites that underwent ablation., Conclusion: Ganglionated plexuses can be precisely mapped using high-frequency stimulation and are located predominantly in the path of lesions delivered during ablation of AF. Objective documentation of modification of autonomic tone can be documented in the majority of patients. Future studies are required to determine the specific role of mapping and targeting of ganglionated plexuses in patients undergoing catheter ablation of AF.

Background: Cardiac arrest with preserved left ventricular function may be caused by uncommon genetic conditions. Although these may be evident on the ECG, long-term monitoring or provocative testing is often necessary to unmask latent primary electrical disease., Methods and Results: Patients with unexplained cardiac arrest and no evident cardiac disease (normal left ventricular function, coronary arteries, and resting corrected QT) underwent pharmacological challenge with adrenaline and procainamide infusions to unmask subclinical primary electrical disease. Family members underwent noninvasive screening and directed provocative testing on the basis of findings in the proband. Eighteen patients (mean+/-SD age, 41+/-17 years; 11 female) with unexplained cardiac arrest were assessed. The final diagnosis was catecholaminergic ventricular tachycardia (CPVT) in 10 patients (56%), Brugada syndrome in 2 patients (11%), and unexplained (idiopathic ventricular fibrillation) in 6 patients (33%). Of 55 family members (mean+/-SD age, 27+/-17 years; 33 female), 9 additional affected family members were detected from 2 families, with a single Brugada syndrome patient and 8 CPVT patients., Conclusions: Provocative testing with adrenaline and procainamide infusions is useful in unmasking the etiology of apparent unexplained cardiac arrest. This approach helps to diagnose primary electrical disease, such as CPVT and Brugada syndrome, and provides the opportunity for therapeutic intervention in identified, asymptomatic family members who harbor the same disease.