scholarly journals The first results of gene panel sequencing in sudden cardiac death in young men

Author(s):  
В.Н. Максимов ◽  
Д.Е. Иванощук ◽  
П.С. Орлов ◽  
А.А. Иванова ◽  
С.К. Малютина ◽  
...  

Цель исследования: поиск причинных мутаций в генах-кандидатах внезапной сердечной смерти (ВСС) у мужчин, умерших в возрасте до 45 лет. Группа ВСС (30 образцов) была сформирована c использованием критериев ВСС ВОЗ и Европейского общества кардиологов. Средний возраст 31,3±5,3 года. Геномную ДНК выделяли из ткани миокарда методом фенол-хлороформной экстракции. Выполнили секвенирование клинического экзома. На первом этапе проанализировали результаты секевнирования 16 генов, мутации в которых приводят к ССЗ, ассоциированным с повышенным риском ВСС: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1, SCN10A. Из 30 образцов с ВСС при анализе результатов секвенирования 16 генов было обнаружено 6 вероятно патогенных миссенс-мутаций в 7 образцах (23,3 %). В гене SCN10A обнаружено 2 мутации, в KCNH2, KCNE1, AKAP9, SNTA1 - по одной мутации. Подводя первые итоги пилотного исследования ВСС можно сделать следующие предварительные выводы: необходимо продолжение исследований в области молекулярной аутопсии в России, для повышения результативности поиска причинных мутаций, желательны снижение возраста случаев ВСС включаемых в исследование, а также работа с семьями умерших ВСС. Objective: Search for causal mutations in candidate genes for sudden cardiac death (SCD) in men who die before the age of 45. Materials and methods. The SCD group (30 samples) was formed using the criteria for sudden cardiac death of the WHO and the European Society of Cardiology. The average age is 31,3±5,3 years. Genomic DNA was isolated from myocardial tissue using phenol-chloroform extraction. Clinical exome sequencing was performed. At the first stage, the results of sequencing of 16 genes were analyzed, mutations in which result in CVD associated with an increased risk of SCD: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNJ5, KCNJ5, SNTA1, SCN10A. Results. Of 30 samples with SCD, when analyzing the results of sequencing 16 genes, 6 probably pathogenic missense mutations were found in 7 samples (23.3%). 2 mutations were found in the SCN10A gene, one mutation in KCNH2, KCNE1, AKAP9, SNTA1. Findings. Summing up the first results of a pilot SCD study, the following preliminary conclusions can be drawn: it is necessary to continue research in the field of molecular autopsy in Russia, in order to increase the effectiveness of the search for causative mutations, it is desirable to reduce the age of SCD cases included in the study, as well as work with families of deceased SCD.

2020 ◽  
Vol 25 (10) ◽  
pp. 3880
Author(s):  
V. N. Maksimov ◽  
D. E. Ivanoshchuk ◽  
P. S. Orlov ◽  
A. A. Ivanova ◽  
S. K. Malyutina ◽  
...  

Aim. To search for causal mutations in candidate genes responsible for the development of sudden cardiac death (SCD) in men who died under the age of 45.Material and methods. The SCD group (n=37) was formed using the criteria the World Health Organization and the European Society of Cardiology. Autopsy material was collected from men who died suddenly outside medical institutions and underwent forensic medical examination according to the standard protocol. Autopsy revealed no morphological changes that could explain sudden death. The mean age was 32,4±6,4 years. Genomic DNA was isolated from myocardial tissue using phenol-chloroform extraction. Clinical exome sequencing was performed. At first, we analyzed the results of sequencing of 24 genes, mutations in which lead to cardiovascular diseases associated with an increased risk of SCD: KCNQ1, KCNH2, SCN5A, AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KNCJNE2, KCNE2, SCN4B, SNTA1, MYH2, APOB, KCNA5, TGFB3, NEB, PDX1, FLNC, PLEC, KCND3.Results. Of 37 samples, we revealed 13 probable pathogenic missense mutations in 9 samples (24,3%). Of 13 probable pathogenic variants, 5 were new.Conclusion. This pilot study provides following conclusions: it is necessary to continue molecular autopsy research in Russia; to increase the effectiveness of detecting causal mutations, it is necessary to reduce the age of patients with SCD included in the study; studying the families of deceased; cooperation of experienced specialists — forensic pathologist, laboratory geneticist, cardiologist.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Soroush ◽  
A Aarnoudse ◽  
F Shokri ◽  
M Van Den Berg ◽  
F Ahmadizar ◽  
...  

Abstract Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None


Heart ◽  
2020 ◽  
pp. heartjnl-2020-317701
Author(s):  
Guixin Wu ◽  
Jie Liu ◽  
Shuiyun Wang ◽  
Shiqin Yu ◽  
Ce Zhang ◽  
...  

ObjectiveElevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with heart failure-related death in hypertrophic cardiomyopathy (HCM), but the relationship between NT-proBNP level and sudden cardiac death (SCD) in HCM remains undefined.MethodsThe study prospectively enrolled 977 unrelated patients with HCM with available NT-proBNP results who were prospectively enrolled and followed for 3.0±2.1 years. The Harrell’s C-statistic under the receiver operating characteristic curve was calculated to evaluate discrimination performance. A combination model was constructed by adding NT-proBNP tertiles to the HCM Risk-SCD model. The correlation between log NT-proBNP level and cardiac fibrosis as measured by late gadolinium enhancement (LGE) or Masson’s staining was analysed.ResultsDuring follow-up, 29 patients had SCD. Increased log NT-proBNP levels were associated with an increased risk of SCD events (adjusted HR 22.27, 95% CI 10.93 to 65.63, p<0.001). The C-statistic of NT-proBNP in predicting SCD events was 0.80 (p<0.001). The combined model significantly improved the predictive efficiency of the HCM Risk-SCD model from 0.72 to 0.81 (p<0.05), with a relative integrated discrimination improvement of 0.002 (p<0.001) and net reclassification improvement of 0.67 (p<0.001). Furthermore, log NT-proBNP levels were significantly correlated with cardiac fibrosis as detected either by LGE (r=0.257, p<0.001) or by Masson’s trichrome staining in the myocardium (r=0.198, p<0.05).ConclusionNT-proBNP is an independent predictor of SCD in patients with HCM and may help with risk stratification of this disease.


2016 ◽  
Vol 91 (1) ◽  
pp. 22-29 ◽  
Author(s):  
F. Cann ◽  
M. Corbett ◽  
D. O'Sullivan ◽  
S. Tennant ◽  
H. Hailey ◽  
...  

Heart ◽  
2017 ◽  
Vol 104 (5) ◽  
pp. 423-429 ◽  
Author(s):  
Brittany M Bogle ◽  
Nona Sotoodehnia ◽  
Anna M Kucharska-Newton ◽  
Wayne D Rosamond

ObjectiveVital exhaustion (VE), a construct defined as lack of energy, increased fatigue and irritability, and feelings of demoralisation, has been associated with cardiovascular events. We sought to examine the relation between VE and sudden cardiac death (SCD) in the Atherosclerosis Risk in Communities (ARIC) Study.MethodsThe ARIC Study is a predominately biracial cohort of men and women, aged 45–64 at baseline, initiated in 1987 through random sampling in four US communities. VE was measured using the Maastricht questionnaire between 1990 and 1992 among 13 923 individuals. Cox proportional hazards models were used to examine the hazard of out-of-hospital SCD across tertiles of VE scores.ResultsThrough 2012, 457 SCD cases, defined as a sudden pulseless condition presumed due to a ventricular tachyarrhythmia in a previously stable individual, were identified in ARIC by physician record review. Adjusting for age, sex and race/centre, participants in the highest VE tertile had an increased risk of SCD (HR 1.48, 95% CI 1.17 to 1.87), but these findings did not remain significant after adjustment for established cardiovascular disease risk factors (HR 0.94, 95% CI 0.73 to 1.20).ConclusionsAmong participants of the ARIC study, VE was not associated with an increased risk for SCD after adjustment for cardiovascular risk factors.


Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mengjun Wang ◽  
Valerio Zaca ◽  
Alice Jiang ◽  
Itamar Ilsar ◽  
Matthew Ebinger ◽  
...  

Heart failure (HF) is associated with a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Patients with HF in whom these lethal arrhythmias can be induced by electrophysiological (EP) testing carry a high risk of sudden cardiac death. We showed that chronic electrical carotid baroreflex activation therapy (BAT) with the Rheos® System (CVRx, Inc.) improves LV function, attenuates LV remodeling and restores autonomic sympathetic-parasympathetic balance in dogs with HF. This study examined the effects of long-term therapy with BAT on the induction of VT or VF in dogs with coronary microembolization-induced HF (LV ejection fraction ~20%). Eleven dogs with HF underwent EP testing at baseline prior to therapy and after 3 and 6 months of therapy with BAT and again 6 weeks after withdrawal of BAT therapy (n = 7) or no therapy at all (Control, n = 4). Programmed ventricular stimulation was performed from the right ventricular apex and included delivery of up to 4 extrastimuli at progressively shorter coupling intervals (in steps of 10 msec). The extrastimuli were delivered following 8 ventricular paced beats with a drive cycle length between 600 and 200 msec. If a sustained monomorphic VT or VF could not be induced, isoproterenol infusion was initiated to increase the sinus rate by ~30% and the EP stimulation protocol was repeated. At baseline, a sustained VT or VF was induced in all 11 dogs (100%). After 3 and 6 months of follow-up, all Control dogs (100%) were induced into sustained VT or VF. After 3 months of BAT, only 3 of 7 dogs (43%) were induced into sustained VT or VF. After 6 months of BAT, only 2 of 7 dogs (29%) were induced into sustained VT or VF. Finally after withdrawal of BAT therapy, all dogs (100%) were again induced into systained VT or VF. In addition to improving LV function and attenuating LV remodeling, long-term monotherapy with BAT markedly increases the threshold for lethal ventricular arrhythmias in dogs with chronic HF. This is a marked improvement over inducibility of lethal arrhythmias seen in historical untreated controls. This benefit of BAT supports the continued exploration of this device as a therapeutic modality for treating patients with chronic HF and increased risk of sudden cardiac death.


Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-215632
Author(s):  
Yun-Jiu Cheng ◽  
Zhen-Guang Chen ◽  
Feng-Juan Yao ◽  
Li-Juan Liu ◽  
Ming Zhang ◽  
...  

BackgroundGrowing evidence suggests that compromised lung health may be linked to cardiovascular disease. However, little is known about its association with sudden cardiac death (SCD).ObjectivesWe aimed to assess the link between impaired lung function, airflow obstruction and risk of SCD by race and gender in four US communities.MethodsA total of 14 708 Atherosclerosis Risk in Communities (ARIC) study participants who underwent spirometry and were asked about lung health (1987–1989) were followed. The main outcome was physician-adjudicated SCD. Fine-Gray proportional subdistribution hazard models with Firth’s penalised partial likelihood correction were used to estimate the HRs.ResultsOver a median follow-up of 25.4 years, 706 (4.8%) subjects experienced SCD. The incidence of SCD was inversely associated with FEV1 in each of the four race and gender groups and across all smoking status categories. After adjusting for multiple measured confounders, HRs of SCD comparing the lowest with the highest quintile of FEV1 were 2.62 (95% CI 1.62 to 4.26) for white males, 1.80 (95% CI 1.03 to 3.15) for white females, 2.07 (95% CI 1.05 to 4.11) for black males and 2.62 (95% CI 1.21 to 5.65) for black females. The above associations were consistently observed among the never smokers. Moderate to very severe airflow obstruction was associated with increased risk of SCD. Addition of FEV1 significantly improved the predictive power for SCD.ConclusionsImpaired lung function and airflow obstruction were associated with increased risk of SCD in general population. Additional research to elucidate the underlying mechanisms is warranted.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Lars Grosse-Wortmann ◽  
Laurine van der Wal ◽  
Aswathy Vaikom House ◽  
Lee Benson ◽  
Raymond Chan

Introduction: Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) has been shown to be an independent predictor of sudden cardiac death (SCD) in adults with hypertrophic cardiomyopathy (HCM). The clinical significance of LGE in pediatric HCM patients is unknown. Hypothesis: LGE improves the SCD risk prediction in children with HCM. Methods: We retrospectively analyzed the CMR images and reviewed the outcomes pediatric HCM patients. Results: Amongst the 720 patients from 30 centers, 73% were male, with a mean age of 14.2±4.8 years. During a mean follow up of 2.6±2.7 years (range 0-14.8 years), 34 experienced an episode of SCD or equivalent. LGE (Figure 1A) was present in 34%, with a mean burden of 14±21g, or 2.5±8.2g/m2 (6.2±7.7% of LV myocardium). The presence of ≥1 adult traditional risk factor (family history of SCD, syncope, LV thickness >30mm, non-sustained ventricular tachycardia on Holter) was associated with an increased risk of SCD (HR=4.6, p<0.0001). The HCM Risk-Kids score predicted SCD (p=0.002). The presence of LGE was strongly associated with an increased risk (HR=3.8, p=0.0003), even after adjusting for traditional risk factors (HR adj =3.2, p=0.003) or the HCM Risk-Kids score (HR adj =3.5, p=0.003). Furthermore, the burden of LGE was associated with increased risk (HR=2.1/10% LGE, p<0.0001). LGE burden remained independently associated with an increased risk for SCD after adjusting for traditional risk factors (HRadj=1.5/10% LGE, p=0.04) or HCM Risk-Kids (HRadj=1.9/10% LGE, p=0.0018, Figure 1B). The addition of LGE burden improved the predictive model using traditional risk markers (C statistic 0.67 vs 0.77, p=0.003) and HCM Risk-Kids (C statistic 0.68 vs 0.74, p=0.045). Conclusions: Quantitative LGE is an independent risk factor for SCD in pediatric patients with HCM and improves the performance of traditional risk markers and the HCM Risk-Kids Score for SCD risk stratification in this population.


2017 ◽  
Vol 26 ◽  
pp. S186 ◽  
Author(s):  
T. Agbaedeng ◽  
R. Mahajan ◽  
D. Munawar ◽  
A. Elliott ◽  
D. Twomey ◽  
...  

2021 ◽  
Vol 19 ◽  
Author(s):  
Jean-Jacques Monsuez ◽  
Marilucy Lopez-Sublet

: Persons living with HIV infection (PLWH) have been recognized to have an increased risk of sudden cardiac death (SCD). Prevention of this risk should theoretically be included in their long-term management. However, only a few approaches have been proposed to optimize such interventions. Targeting detection of the commonly associated conditions such as coronary artery disease, left ventricular dysfunction, heart failure, QT interval prolongation and ventricular arrhythmias is the first step of this prevention. However, although detection of the risk of SCD is a suitable challenge in PLWH, it remains uncertain whether optimized treatment of the identified risks would unequivocally translate into a decrease in SCD rates.


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