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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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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.
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The Risk for Sudden Cardiac Death Among Patients Living With Heart Failure and Human Immunodeficiency Virus.
Alvi, RM, Neilan, AM, Tariq, N, Hassan, MO, Awadalla, M, Zhang, L, Afshar, M, Rokicki, A, Mulligan, CP, Triant, VA, et al
JACC. Heart failure. 2019;(9):759-767
Abstract
OBJECTIVES The aim of this study was to determine the incidence of sudden cardiac death (SCD) among persons living with human immunodeficiency virus infection (PHIV) with heart failure (HF), who were hospitalized for HF, and the risk factors associated with it. BACKGROUND HF is associated with an increased risk for SCD. PHIV are at heightened risk for HF. METHODS This was a retrospective study of 2,578 patients hospitalized with HF from a single academic center, of whom 344 were PHIV. The outcome of interest was SCD. Subgroup analyses were performed by strata of viral load (VL) and left ventricular ejection fraction (LVEF) <35%, 35% to 49%, and ≥50%. RESULTS Of 2,578 patients with HF, 2,149 (86%) did not have implantable cardioverter-defibrillators; of these, there were 344 PHIV and 1,805 uninfected control subjects. Among PHIV with HF, 313 (91%) were prescribed antiretroviral therapy and 64% were virally suppressed. There were 191 SCDs over a median follow-up period of 19 months. Compared with control subjects, PHIV had a 3-fold increase in SCD (21.0% vs. 6.4%; adjusted odds ratio: 3.0; 95% confidence interval: 1.78 to 4.24). Among PHIV, cocaine use, lower LVEF, absence of beta-blocker prescription, and VL were predictors of SCD. The SCD rate among PHIV with undetectable VL was similar to the rate among uninfected subjects. Similar findings were observed by LVEF strata. Among PHIV with HF without conventional indications for an implantable cardioverter-defibrillator, the rate of SCD was 10% per year. CONCLUSIONS PHIV hospitalized with HF are at a markedly increased risk for SCD. SCD risk was increased in patients with lower LVEFs, lower CD4 counts, and higher VL.
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BASIC AND CLINICAL INSIGHTS IN CATECHOLAMINERGIC (FAMILIAL) POLYMORPHIC VENTRICULAR TACHYCARDIA.
Márquez, MF, Totomoch-Serra, A, Rueda, A, Avelino-Cruz, JE, Gallegos-Cortez, A
Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion. 2019;(4):226-236
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal disease, whose characteristic ventricular tachycardias are adrenergic-dependent. Although rare, CPVT should be considered in the differential diagnosis of young individuals with exercise-induced syncope. Mutations in five different genes (RYR2, CASQ2, CALM1, TRDN, and TECRL) are associated with the CPVT phenotype, although RYR2 missense mutations are implicated in up to 60 % of all CPVT cases. Genetic testing has an essential role in the diagnosis, management, pre-symptomatic diagnosis, counseling, and treatment of the proband; furthermore, genetic information can be useful for offspring and relatives. By expert consensus, CPVT gene testing is a Class I recommendation for patients with suspected CPVT. Beta-adrenergic and calcium-channel blockers are the cornerstones of treatment due to the catecholaminergic dependence of the arrhythmias. Unresponsive patients are treated with an implantable cardioverter-defibrillator to reduce the risk of sudden cardiac death. In the present article, a brief review of the genetic and molecular mechanisms of this intriguing disease is provided.
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Usefulness of Single Nucleotide Polymorphisms as Predictors of Sudden Cardiac Death.
Tamariz, L, Balda, J, Pareja, D, Palacio, A, Myerburg, RJ, Conway, D, Davis, L, Goldberger, JJ
The American journal of cardiology. 2019;(12):1900-1905
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Abstract
The pathophysiology of sudden cardiac death (SCD) remains incompletely understood. Genetic mutations can create a favorable substrate for SCD. Our aim is to evaluate the evidence of single nucleotide polymorphisms (SNPs) as predictors of SCD. We searched the Medline database (2000 to 2017) and selected all case-control or cohort studies that reported associations between SNPs and SCD. Our search terms included "polymorphisms" and "sudden death." We collected the study design, population ethnic background, gene testing strategy, the association between the SNP and SCD, and the cardiovascular comorbidities of the population. Our search yielded 723 studies, of which we included 24 based upon our inclusion criteria. The studies had a total population of 78,165 participants, with a median age of 62.5 years (IQR 56 to 66) and 35% (IQR 13 to 32) were female. Almost all studies were conducted in white patients of European descent and the most commonly used genetic strategy was candidate gene panels. Fifteen of the studies had a case-control design that included SCD patients without known heart disease as the comparison group and the other 9 studies included patients with heart failure and coronary artery disease. The studies evaluated 53 SNPs and the most common genetic loci were SCN5A, RyR2, CASQ2, NOSA1P, and AGTR. SNPs with the 3 strongest statistically significant ORs >1 were: rs6684209 of CASQ2 (odds ratio [OR] 19), rs3814843 of CALM1 (OR 5.5), and rs35594137 of GJA5 (OR 3.6). In Conclusion, many SNPs are associated with SCD, with the strongest associations seen in SNPs of genes related to intracellular calcium handling. These findings were generated primarily using a candidate gene strategy in white patients with European descent.
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Relative peak exercise oxygen pulse is related to sudden cardiac death, cardiovascular and all-cause mortality in middle-aged men.
Laukkanen, JA, Araújo, CGS, Kurl, S, Khan, H, Jae, SY, Guazzi, M, Kunutsor, SK
European journal of preventive cardiology. 2018;(7):772-782
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Abstract
Background Preliminary evidence suggests that peak exercise oxygen pulse - peak oxygen uptake/heart rate-, a variable obtained during maximal cardiopulmonary exercise testing and a surrogate of stroke volume, is a predictor of mortality. We aimed to assess the associations of peak exercise oxygen pulse with sudden cardiac death, fatal coronary heart disease and cardiovascular disease and all-cause mortality. Design A prospective study. Methods Peak exercise oxygen pulse was assessed in a maximal cycling test at baseline in 2227 middle-aged men of the Kuopio Ischaemic Heart Disease cohort study using expired gas variables and electrocardiograms. Relative peak exercise oxygen pulse was obtained by dividing the absolute value by body weight. Results During a median follow-up of 26.1 years 1097 subjects died; there were 220 sudden cardiac deaths, 336 fatal coronary heart diseases and 505 fatal cardiovascular diseases. Relative peak exercise oxygen pulse (mean 19.5 (4.1) mL per beat/kg/102) was approximately linearly associated with each outcome. Comparing extreme quartiles of relative peak exercise oxygen pulse, hazard ratios (95% confidence intervals) for sudden cardiac death, fatal coronary heart disease and cardiovascular disease, and all-cause mortality on adjustment for cardiovascular risk factors were 0.55 (0.36-0.83), 0.58 (0.42-0.81), 0.60 (0.46-0.79) and 0.59 (0.49-0.70), respectively ( P < 0.001 for all). The hazard ratios were unchanged on further adjustment for C-reactive protein and the use of beta-blockers. The addition of relative peak exercise oxygen pulse to a cardiovascular disease mortality risk prediction model significantly improved risk discrimination (C-index change 0.0112; P = 0.030). Conclusion Relative peak exercise oxygen pulse measured during maximal exercise was linearly and inversely associated with fatal cardiovascular and all-cause mortality events in middle-aged men. In addition, relative peak exercise oxygen pulse provided significant improvement in cardiovascular disease mortality risk assessment beyond conventional risk factors.
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Cardiac imaging to detect coronary artery disease in athletes aged 35 years and older. A scoping review.
Braber, TL, Reitsma, JB, Mosterd, A, Willemink, MJ, Prakken, NHJ, Halle, M, Sharma, S, Velthuis, BK
Scandinavian journal of medicine & science in sports. 2018;(3):1036-1047
Abstract
Sudden cardiac death (SCD) is a devastating event in athletes. Screening efforts that were first directed at athletes younger than 35 years are now focusing on the rapidly growing group of older sportspersons. Athletes aged ≥35 years have a 10-fold increased risk of exercise-related cardiac arrest, mostly due to coronary artery disease (CAD). Although cardiac imaging is pivotal in identifying CAD, the role of imaging modalities in screening asymptomatic older sportspersons remains unclear. We performed a scoping review to identify the role of cardiac imaging to detect CAD in older sportspersons and to identify gaps in the existing literature. We searched MEDLINE, EMBASE and the Cochrane library for studies reporting data on cardiac imaging of CAD in sportspersons ≥35 years. The systematic search yielded 1737 articles, and 14 were included in this scoping review. Imaging modalities included two echocardiography, one unenhanced computed tomography (CT) for coronary artery calcium scoring (CACS), three CACS and contrast-enhanced CT angiography (CCTA), two CACS and cardiac magnetic resonance (CMR), one CCTA with CMR and echocardiography, two CCTA, two CMR, and one myocardial perfusion imaging article. The low number of relevant articles and the selection bias introduced by studying specific groups, like veteran marathon runners, indicate the need for future research. Cardiac CT (CACS and CCTA) probably has the highest potential for pre-participation screening, with high diagnostic value to detect CAD and low radiation dose. However, currently there is insufficient evidence for incorporating routine cardiac imaging in the pre-participation screening of asymptomatic sportspersons over 35 years.
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Ion Channel Disorders and Sudden Cardiac Death.
Garcia-Elias, A, Benito, B
International journal of molecular sciences. 2018;(3)
Abstract
Long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are inherited primary electrical disorders that predispose to sudden cardiac death in the absence of structural heart disease. Also known as cardiac channelopathies, primary electrical disorders respond to mutations in genes encoding cardiac ion channels and/or their regulatory proteins, which result in modifications in the cardiac action potential or in the intracellular calcium handling that lead to electrical instability and life-threatening ventricular arrhythmias. These disorders may have low penetrance and expressivity, making clinical diagnosis often challenging. However, because sudden cardiac death might be the first presenting symptom of the disease, early diagnosis becomes essential. Genetic testing might be helpful in this regard, providing a definite diagnosis in some patients. Yet important limitations still exist, with a significant proportion of patients remaining with no causative mutation identifiable after genetic testing. This review aims to provide the latest knowledge on the genetic basis of cardiac channelopathies and discuss the role of the affected proteins in the pathophysiology of each one of these diseases.