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1.
The Optimal Timing of Primary Prevention Implantable Cardioverter-Defibrillator Referral in the Rapidly Changing Medical Landscape.
Wong, JA, Roberts, JD, Healey, JS
The Canadian journal of cardiology. 2021;(4):644-654
Abstract
The use of implantable cardioverter-defibrillators (ICDs) significantly reduces the risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Current guidelines, which are based on seminal clinical trials published nearly 2 decades ago, recommend that patients be on optimal medical therapy for HF for a minimum of 3 months before referral for prophylactic ICD. This waiting period allows for left ventricular reverse remodelling and improvement in HF symptoms, which may render primary prevention ICD implantation unnecessary. However, medical therapy for HFrEF has significantly evolved since the publication of these landmark trials. Given the plethora of medical therapy options now available for HFrEF, it is appropriate to reassess the duration of this waiting period. In the present review, we examine the landmark randomised trials in primary prevention of sudden cardiac death in patients with HFrEF, summarise the novel medical therapies (sacubitril-valsartan, sodium-glucose cotransporter 2 inhibitors, ivabradine, vericiguat, and omecamtiv mecarbil) that have emerged since the publication of those trials, discuss the optimal timing of ICD referral, and review subtypes of nonischemic cardiomyopathy where timing of ICD insertion is guided by alternative criteria. With the steps now needed to optimise medical therapy for HFrEF, in terms of both classes of drugs and doses of each agent, it can easily take up to 6 months to achieve optimisation. Following that, waiting periods of 3 months for ischemic cardiomyopathy and 6 months for nonischemic cardiomyopathy may be required to allow adequate reverse remodelling before reevaluating for ICD implantation.
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2.
Cardiorespiratory optimal point during exercise testing and sudden cardiac death: A prospective cohort study.
Laukkanen, JA, Savonen, K, Hupin, D, Araújo, CGS, Kunutsor, SK
Progress in cardiovascular diseases. 2021;:12-18
Abstract
BACKGROUND Cardiorespiratory optimal point (COP) during exercise, a potentially useful submaximal cardiopulmonary exercise testing (CPET) variable, may be an independent risk factor for cardiovascular disease outcomes. However, the relationship of COP with risk of sudden cardiac death (SCD) has not been previously investigated. We sought to evaluate the association between COP during exercise and SCD risk and determine whether COP improves SCD risk prediction. METHODS COP, the minimum value of the ventilatory equivalent for oxygen (VE/VO2) in a given minute of a CPET, was ascertained in 2190 men who underwent clinical exercise testing. Hazard ratios (HRs) (95% confidence intervals [CIs]) and measures of risk discrimination for SCD were calculated. RESULTS A total of 240 SCDs death occurred during a median follow-up of 28.8 years. COP was linearly associated with SCD in a dose-response manner. In a multivariable model comprising several established and emerging CVD risk factors, the HR (95% CI) for SCD was 2.51 (1.36-4.62) per standard deviation increase in COP. This was minimally attenuated to 2.36 (1.27-4.37) on further adjustment for high sensitivity C-reactive protein. The association did not vary importantly in several relevant clinical subgroups. Addition of COP to a SCD risk score was associated with a C-index change of 0.0086 (0.0005 to 0.0167; p = .038) and difference in -2 log likelihood (p = .017). CONCLUSIONS COP during exercise is strongly, inversely and independently associated with SCD in a graded fashion. COP during exercise may potentially be used for the prediction of the long-term risk for SCD beyond established CVD risk factors.
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3.
Familial Dilated Cardiomyopathy and Sudden Cardiac Arrest: New Association with a SCN5A Mutation.
Rico, Y, Ramis, MF, Massot, M, Torres-Juan, L, Pons, J, Fortuny, E, Ripoll-Vera, T, González, R, Peral, V, Rossello, X, et al
Genes. 2021;(12)
Abstract
Dilated cardiomyopathy (DCM) has significant morbidity and mortality. Familial transmission is reported in 20-35% of cases, highlighting the role of genetics in this disorder. We present an interesting family in which the index case is a 64-year-old woman who survived a sudden cardiac arrest. She presented left ventricular dilatation and dysfunction, which indicated the presence of DCM, as well as a history of DCM and sudden arrest in her family (mother and sister). Genetic testing identified a heterozygous mutation c.74A > G missense change that causes an amino acid, p.Glu25Gly, change in the N-terminal domain of the SCN5A protein. After performing an exhaustive family medical history, we found that this previously not described mutation segregated within the family. All relatives with the DCM phenotype were carriers, whereas none of the noncarriers showed signs of heart disease, so this mutation is the most likely cause of the disease. This is the first time that a variant in the N-terminal domain of SCN5A has been associated with DCM.
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4.
Cardiac involvement in Wilson disease: Review of the literature and description of three cases of sudden death.
Chevalier, K, Benyounes, N, Obadia, MA, Van Der Vynckt, C, Morvan, E, Tibi, T, Poujois, A
Journal of inherited metabolic disease. 2021;(5):1099-1112
Abstract
Wilson disease (WD) is a rare genetic condition that results from a build-up of copper in the body. It requires life-long treatment and is mainly characterized by hepatic and neurological features. Copper accumulation has been reported to be related to the occurrence of heart disease, although little is known regarding this association. We have conducted a systematic review of the literature to document the association between WD and cardiac involvement. Thirty-two articles were retained. We also described three cases of sudden death. Cardiac manifestations in WD include cardiomyopathy (mainly left ventricular (LV) remodeling, hypertrophy, and LV diastolic dysfunction, and less frequently LV systolic dysfunction), increased levels of troponin, and/or brain natriuretic peptide, electrocardiogram (ECG) abnormalities, and rhythm or conduction abnormalities, which can be life-threatening. Dysautonomia has also been reported. The mechanism of cardiac damage in WD has not been elucidated. It may be the result of copper accumulation in the heart, and/or it could be due to a toxic effect of copper, resulting in the release of free oxygen radicals. Patients with signs and/or symptoms of cardiac involvement or who have cardiovascular risk factors should be examined by a cardiologist in addition to being assessed by their interdisciplinary treating team. Furthermore, ECG, cardiac biomarkers, echocardiography, and 24-hours or more of Holter monitoring at the diagnosis and/or during the follow-up of patients with WD need to be evaluated. Cardiac magnetic resonance imaging, although not always available, could also be a useful diagnostic tool, allowing assessment of the risk of ventricular arrhythmias and further guidance of the cardiac workup.
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5.
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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6.
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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7.
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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8.
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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9.
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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10.
Ketogenesis in arrhythmogenic cardiomyopathy.
Huynh, K
Nature reviews. Cardiology. 2020;(5):266