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1.
Sudden Cardiac Death in Brugada Syndrome.
Kabra, N, Gupta, R, Aronow, WS, Frishman, WH
Cardiology in review. 2020;(4):203-207
Abstract
The Brugada syndrome is an inherited channelopathy that alters the main transmembrane ion currents that constitute the cardiac action potential. These changes not only modify the resting electrocardiogram but also predispose patients to develop malignant ventricular tachyarrhythmias that can lead to syncope, cardiac arrest, and sudden cardiac death. This syndrome is responsible for nearly 20% of all sudden cardiac deaths in patients with structurally normal hearts and up to 12% of all sudden cardiac deaths. Brugada syndrome is diagnosed by its characteristic electrocardiogram consisting of a coved-type ST-segment elevation of at least 2 mm followed by a negative T wave in either one of the right precordial leads. These changes can be observed spontaneously or after administration of a sodium channel blocker. While our understanding of this disease has increased tremendously since its first description in 1992, the primary therapeutic option remains implantation of an implantable cardioverter-defibrillator to avoid sudden cardiac death. Therefore, tremendous effort is being made to effectively risk stratify patients to determine who would benefit from implantable cardioverter-defibrillator implantation.
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2.
Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community.
Tester, DJ, Bombei, HM, Fitzgerald, KK, Giudicessi, JR, Pitel, BA, Thorland, EC, Russell, BG, Hamrick, SK, Kim, CSJ, Haglund-Turnquist, CM, et al
JAMA cardiology. 2020;(3):13-18
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Abstract
IMPORTANCE The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death. OBJECTIVE To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families. DESIGN, SETTING, AND PARTICIPANTS Two large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019. MAIN OUTCOMES AND MEASURES The identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families. RESULTS A homozygous duplication, involving approximately 26 000 base pairs of intergenic sequence, RYR2's 5'UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests. CONCLUSIONS AND RELEVANCE In this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning.
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3.
Role of Oxidative Stress in the Genesis of Ventricular Arrhythmias.
Adameova, A, Shah, AK, Dhalla, NS
International journal of molecular sciences. 2020;(12)
Abstract
Ventricular arrhythmias, mainly lethal arrhythmias, such as ventricular tachycardia and fibrillation, may lead to sudden cardiac death. These are triggered as a result of cardiac injury due to chronic ischemia, acute myocardial infarction and various stressful conditions associated with increased levels of circulating catecholamines and angiotensin II. Several mechanisms have been proposed to underlie electrical instability of the heart promoting ventricular arrhythmias; however, oxidative stress which adversely affects ion homeostasis due to changes in the ion channel structure and function, seems to play a critical role in eliciting different types of ventricular arrhythmias. Prevention or mitigation of the severity of ventricular arrhythmias due to antioxidants has been indicated as the fundamental contribution in the field of preventive cardiology; however, novel interventions have to be developed for greater effectiveness and specificity in attenuating the adverse effects of oxidative stress. In this review, we have attempted to discuss proarrhythmic effects of oxidative stress differing in time and concentration dependence and highlight a molecular and cellular concept how it alters cardiac cell automaticity and conduction velocity sensitizing the probability of ventricular arrhythmias with resultant sudden cardiac death due to ischemic heart disease and other stressful situations. It is concluded that pharmacological approaches targeting multiple mechanisms besides oxidative stress might be more effective in the treatment of ventricular arrhythmias than current antiarrhythmic therapy.
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Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia-Related Genes.
Chahal, CAA, Salloum, MN, Alahdab, F, Gottwald, JA, Tester, DJ, Anwer, LA, So, EL, Murad, MH, St Louis, EK, Ackerman, MJ, et al
Journal of the American Heart Association. 2020;(1):e012264
Abstract
Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na+ and K+ ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.
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Impact of Different Doses of Omega-3 Fatty Acids on Cardiovascular Outcomes: a Pairwise and Network Meta-analysis.
Lombardi, M, Chiabrando, JG, Vescovo, GM, Bressi, E, Del Buono, MG, Carbone, S, Koenig, RA, Van Tassell, BW, Abbate, A, Biondi-Zoccai, G, et al
Current atherosclerosis reports. 2020;(9):45
Abstract
PURPOSE OF REVIEW Omega-3 fatty acid (O3FA) supplementation has shown conflicting evidence regarding its benefit in cardiovascular events. We performed a pairwise and network meta-analysis to elucidate the benefit of different doses of O3FA supplementation in cardiovascular prevention. RECENT FINDINGS Fourteen studies were identified providing data on 125,763 patients. A prespecified cut-off value of < 1 g per day was set for low-dose (LD) O3FA and > 1 g per day for high-dose (HD) O3FA. The efficacy outcomes of interest were total death, cardiac death, sudden cardiac death, myocardial infarction, stroke, coronary revascularization, unstable angina, and major vascular events. Safety outcomes of interest were bleeding, gastrointestinal disturbances, and atrial fibrillation events. HD treatment was associated with a lower risk of cardiac death (IRR 0.79, 95% CI [0.65-0.96], p = 0.03 versus control), myocardial infarction (0.71 [0.62-0.82], p < 0.0001 versus control and 0.79 [0.67-0.92], p = 0.003 versus LD), coronary revascularization (0.74 [0.66-0.83], p < 0.0001 versus control and 0.74 [0.66-0.84], p < 0.0001 versus LD), unstable angina (0.73 [0.62-0.86], p = 0.0001 versus control and 0.74 [0.62-0.89], p = 0.002 versus LD), and major vascular events (0.78 [0.71-0.85], p < 0.0001 versus control and 0.79 [0.72-0.88], p < 0.0001 versus LD). HD treatment was associated with increased risk for bleeding events (1.49 [1.2-1.84], p = 0.0002 versus control and 1.63 [1.16-2.3], p = 0.005 versus LD) and increased atrial fibrillation events compared to control (1.35 [1.1-1.66], p = 0.004). HD O3FA treatment was associated with lower cardiovascular events compared to LD and to control, but increased risk for bleeding and atrial fibrillation events.
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Ketogenesis in arrhythmogenic cardiomyopathy.
Huynh, K
Nature reviews. Cardiology. 2020;(5):266
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Channelopathies That Lead to Sudden Cardiac Death: Clinical and Genetic Aspects.
Skinner, JR, Winbo, A, Abrams, D, Vohra, J, Wilde, AA
Heart, lung & circulation. 2019;(1):22-30
Abstract
Forty per cent (40%) of sudden unexpected natural deaths in people under 35 years of age are associated with a negative autopsy, and the cardiac ion channelopathies are the prime suspects in such cases. Long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are the most commonly identified with genetic testing. The cellular action potential driving the heart cycle is shaped by a specific series of depolarising and repolarising ion currents mediated by ion channels. Alterations in any of these currents, and in the availability of intracellular free calcium, leaves the myocardium vulnerable to polymorphic ventricular tachycardia or ventricular fibrillation. Each channelopathy has its own electrocardiogram (ECG) signature, typical mode of presentation, and most commonly related gene. Long QT type 1 (gene, KCNQ1) and CPVT (gene, RyR2) typically present with cardiac events (ie syncope or cardiac arrest) during or immediately after exercise in young males; long QT type 2 (gene, KCNH2) after startle or during the night in adult females-particularly early post-partum, and long QT type 3 and Brugada syndrome (gene, SCN5A) during the night in young adult males. They are commonly misdiagnosed as seizure disorders. Fever-triggered cardiac events should also raise the suspicion of BrS. This review summarises genetics, cellular mechanisms, risk stratification and treatments. Beta blockers are the mainstay of treatment for long QT syndrome and CPVT, and flecainide is remarkably effective in CPVT. Brugada syndrome is genetically a more complex disease than the others, and risk stratification and management is more difficult.
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8.
Diagnostic evaluation and arrhythmia mechanisms in survivors of unexplained cardiac arrest.
Deif, B, Roberts, JD
Pacing and clinical electrophysiology : PACE. 2019;(10):1320-1330
Abstract
Identifying the cause of unexplained cardiac arrest is critical for appropriate management of both survivors and their family members. Aborted cardiac arrests whose cause remains unknown following investigation with a surface ECG, echocardiogram, and coronary angiogram are deemed unexplained. Many of these unexplained arrests are felt to be secondary to concealed forms of cardiac channelopathies and latent or subtle cardiomyopathies. This recognition has led to evaluating a diagnostic role for a series of additional investigations, including advanced imaging, genetic testing, and provocative forms of testing, including sodium channel blockade and treadmill testing. Despite evidence of an improved diagnostic yield through their systematic usage, clinical guidelines have yet to endorse a formal algorithm delineating investigations that must be performed before assigning a label of idiopathic ventricular fibrillation, which has resulted in markedly variables thresholds for concluding this diagnosis. Debate remains regarding the need for an invasive electrophysiology study among these patients, though identification of arrhythmic culprits requiring intracardiac electrograms for diagnostic confirmation have suggested a potential role when an initial comprehensive evaluation is unrevealing. Although progress is being made, the sizeable portion of arrests that remain unexplained despite completion of a comprehensive evaluation highlights an ongoing need for further research and additional tools to help unravel the ongoing mysteries of these near fatal events.
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Predictors of cardiac arrhythmic events in non coronary artery disease patients.
Balla, C, Vitali, F, Brieda, A, Gualandi, F, Ferlini, A, Bertini, M, Ferrari, R
BMC cardiovascular disorders. 2019;(1):104
Abstract
Arrhythmic sudden cardiac death (SCD) represents a major worldwide public health problem accounting for 15-20% of deaths. Risk stratification to identify patients at risk of SCD is crucial in order to implement preventive measures in the general population. Several biomarkers have been tested exploring different pathophysiological mechanisms of cardiac conditions. Conflicting results have been described limiting so far their use in clinical practice. The use of new biomarkers such as microRNAs and sex hormones and the emerging role of genetic on risk prediction of SCD is a current research topic showing promising results.This review outlines the role of plasma biomarkers to predict ventricular arrhythmias and SCD in non coronary artery disease with a special focus on their relationship with the genetic biomarkers.
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Effectiveness of single- vs dual-coil implantable defibrillator leads: An observational analysis from the SIMPLE study.
Neuzner, J, Hohnloser, SH, Kutyifa, V, Glikson, M, Dietze, T, Mabo, P, Vinolas, X, Kautzner, J, O'Hara, G, Lawo, T, et al
Journal of cardiovascular electrophysiology. 2019;(7):1078-1085
Abstract
INTRODUCTION Dual-coil leads (DC-leads) were the standard of choice since the first nonthoracotomy implantable cardioverter/defibrillator (ICD). We used contemporary data to determine if DC-leads offer any advantage over single-coil leads (SC-leads), in terms of defibrillation efficacy, safety, clinical outcome, and complication rates. METHODS AND RESULTS In the Shockless IMPLant Evaluation study, 2500 patients received a first implanted ICD and were randomized to implantation with or without defibrillation testing. Two thousand and four hundred seventy-five patients received SC-coil or DC-coil leads (SC-leads in 1025/2475 patients; 41.4%). In patients who underwent defibrillation testing (n = 1204), patients with both lead types were equally likely to achieve an adequate defibrillation safety margin (88.8% vs 91.2%; P = 0.16). There was no overall effect of lead type on the primary study endpoint of "failed appropriate shock or arrhythmic death" (adjusted HR 1.18; 95% CI, 0.86-1.62; P = 0.300), and on all-cause mortality (SC-leads: 5.34%/year; DC-leads: 5.48%/year; adjusted HR 1.16; 95% CI, 0.94-1.43; P = 0.168). However, among patients without prior heart failure (HF), and SC-leads had a significantly higher risk of failed appropriate shock or arrhythmic death (adjusted HR 7.02; 95% CI, 2.41-20.5). There were no differences in complication rates. CONCLUSION In this nonrandomized evaluation, there was no overall difference in defibrillation efficacy, safety, outcome, and complication rates between SC-leads and DC-leads. However, DC-leads were associated with a reduction in the composite of failed appropriate shock or arrhythmic death in the subgroup of non-HF patients. Considering riskier future lead extraction with DC-leads, SC-leads appears to be preferable in the majority of patients.