History Of Sudden Cardiac Death Research Articles

Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next Generation Sequencing

Introduction: Multiple likely pathogenic/pathogenic (LP/P) variants in hypertrophic cardiomyopathy (HCM) were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in the setting of comprehensive and targeted panels. Methods: Of 758 HCM probands, we included 382 seen in a specialised centre with ≥45 cardiomyopathy genes screened. There were 224 (59%) probands with ≥1 rare variant (allele frequency ≤0.02%). Variants were analysed using varying sized panels to represent comprehensive or targeted testing. Results: Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance (VUS) and 66 (17%) probands had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) VUS and 14 (4%) probands had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n = 412) cluster-adjusted analyses identified a phenotype effect, with younger age (OR 0.95, 95%CI 0.92-0.98, p = 0.004) and family history of sudden cardiac death (OR 3.5, 95%CI 1.3-9.9, p = 0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel, but not larger panels. Further, those with multiple variants had worse event-free survival from all cause death, cardiac transplantation and cardiac arrest (log-rank p = 0.008). Conclusion: No proband had multiple LP/P variants, in contrast to previous reports quoting a 5% yield. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in HCM.

Cardiac Arrest with Clozapine and Olanzapine: Revealing Long QT Syndrome.

The authors describe a rare case of "concealed" congenital Long QT Syndrome (LQTS) Type 3 in a patient with treatment resistant schizophrenia and no known personal or family history of cardiac disease. The patient in this Case Report had a hidden genetic condition revealed only following the essential administration of antipsychotics. As a result, this patient experienced an aborted cardiac arrest and a total of five episodes of ventricular tachycardia (VT) requiring cardioversion. Successful control of the VT occurred with an Automatic Internal Defibrillator (AID), judicious use of antipsychotic medications, and anti-arrhythmic medications. Risk factors for this rare anomaly include history of syncopy, unexplained ventricular arrhythmias, history of sudden cardiac death in a young family member, unusual reaction to initial dosages of medication known to prolong QTc which includes antipsychotics (particularly in combination). The work-up for those with risk factors would be a thorough family history of sudden cardiac death, baseline ECG, electrolytes, cardiology and electrophysiological consultation, and when indicated a genetic analysis for the Long QT Syndrome (LQTS). Monitoring includes ongoing patient assessment for symptoms, ECGs and electrolytes when indicated such as when medication and dosages are adjusted, AID interviewing, and cardiac and electrophysiological follow-up.

Systematic ajmaline challenge in patients with long QT 3 syndrome caused by the most common mutation: a multicentre study.

Overlap syndromes of long QT 3 syndrome (LQT3) and the Brugada syndrome (BrS) have been reported. Identification of patients with an overlapping phenotype is crucial before initiation of Class I antiarrhythmic drugs for LQT3. Aim of the present study was to elucidate the yield of ajmaline challenge in unmasking the Brugada phenotype in patients with LQT3 caused by the most common mutation, SCN5A-E1784K. Consecutive families in tertiary referral centres diagnosed with LQT3 caused by SCN5A-E1784K were included in the study. Besides routine clinical work-up, ajmaline challenge was performed after informed consent. A total of 23 subjects (11 female, mean age 27 ± 14 years) from 4 unrelated families with a family history of sudden cardiac death and familial diagnosis of the SCN5A-E1784K mutation underwent ajmaline challenge and genetic testing. Sixteen subjects (9 female) were found to be heterozygous carriers of SCN5A-E1784K. Ajmaline challenge was positive in 12 out of the 16 (75%) mutation carriers, but negative in all non-carriers. Following ajmaline, a significant shortening of the rate-corrected JT (JTc) interval was observed in mutation carriers. The baseline JTc interval was significantly longer in mutation carriers with a positive ajmaline challenge compared with those with a negative one. Overlap of LQT3 and BrS in patients carrying the most common mutation is high. Therefore, ajmaline challenge represents an important step to rule out potential BrS overlap in these patients before starting sodium channel blockers for the beneficial effect of QT shortening in LQT3.

New Insights Into the Genetic Basis of Inherited Arrhythmia Syndromes.

Inherited arrhythmia syndromes encompass several different diseases, including long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), and progressive cardiac conduction system disease (PCCD).1 The heart is typically structurally normal with no evidence of disease macroscopically. They are an important cause for sudden cardiac death in the young, and an autopsy is typically negative.2,3 Ventricular arrhythmias are caused by mutations of ion channels and their interacting proteins, predominantly involving potassium, sodium, and calcium handling.4 Genetic studies have identified the specific genetic abnormalities that underpin these diseases, even permitting diagnosis in the deceased using postmortem genetic testing (the molecular autopsy).3 Most arrhythmia syndromes are inherited in an autosomal dominant manner, such that first-degree family members have a 50% chance of inheriting the disease. Identification of the mutation allows for predictive genetic testing in other living family members.4 Variable penetrance is common in all arrhythmia syndromes, the same mutation in the same family causing wide variation in phenotype.4 This suggests that other factors such as genetic modifiers and environmental factors may influence the phenotype. This review will highlight the latest developments in understanding the genetic basis of inherited arrhythmia syndromes and discusses the new opportunities and challenges faced with evolving genetic technologies including determining pathogenicity and the utility of large genetic databases. Finally, we will discuss newly described entities that continue the evolving theme of genetic syndromes with phenotypic overlap. Early views that a single genotype associates with a particular phenotype continue to be challenged by our greater understanding of the genotype–phenotype relationship. ### Long QT Syndrome Congenital LQTS is diagnosed in the presence of a prolonged corrected QT (QTc) interval after secondary causes (eg, QT-prolonging medications or electrolyte abnormalities) are excluded.1 The 2013 Heart Rhythm …

Cardiology News / Recent Literature Review / Third Quarter 2016

HCS Panhellenic Congress : Athens, 20-22/10/2016 TCT Conference: Washington, DC, 29/10-2/11/2016 AHA Scientific Sessions: New Orleans, 12-16/11/2016 AF Symposium : Orlando, 12-14/1/2017 ACC.17 : Washington, DC, 17-19/3/2017 HRS Scientific sessions: Chicago, 10-13/5/2017 EHRA Europace-Cardiostim : Vienna, 18-21/6/2017 ESC Congress: Barcelona, 26-30/8/2017 PO ST 2 Study: Patients with Vasovagal Syncope Improved Modestly with Fludrocortisone 0.2 mg daily with Insignificant 31% Reduction in the Hazard of Fainting in the Intent-to-Treat Analysis Among 210 patients (71% female, median age 30 years) with recurrent vasovagal syncope randomized to fludrocortisone or placebo at highest tolerated doses from 0.05 mg to 0.2 mg daily, there was a marginally nonsignificant reduction in syncope in the fludrocortisone group (hazard ratio - HR: 0.69; p = 0.069). In a multivariable model, fludrocortisone significantly reduced the likelihood of syncope (HR: 0.63; p = 0.024). When the analysis was restricted to outcomes after 2 weeks of dose stabilization, there was a significant benefit due to fludrocortisone (HR: 0.51; p = 0.019) (Sheldon R et al, J Am Coll Cardiol 2016;68:1-9). Patients With Variant Angina Presenting With Aborted Sudden Arrhythmic Death (SCD) Face a Worse Prognosis Than Those Without SCD, While Therapy With Vasodilator Drugs is not Sufficiently Protective/ Additional ICD Implantation Might be Necessary as a Secondary Prevention Treatment Among 188 patients with variant angina with atherosclerosis (ASCD) and 1,844 patients with variant angina without ASCD (predictors of ASCD: age, hypertension, hyperlipidemia, family history of sudden cardiac death, multivessel spasm, and left anterior descending artery spasm), over a median of 7.5 years, the incidence of cardiac death was higher in ASCD patients (24.1 vs 2.7 per 1,000 patient-years; hazard ratio - HR: 7.26; p< 0.001). Death from any cause also occurred more frequently in ASCD patients (27.5 vs 9.6 per 1,000 patient-years; HR: 3; p< 0.001). The incidence rate of recurrent ventricular tachyarrhythmia in ASCD patients was 32.4 per 1,000 patient-years, and the composite of cardiac death and ventricular tachyarrhythmia was 44.9 per 1,000 patient-years. A total of 24 ASCD patients received ICDs (Ahn JM et al, J Am Coll Cardiol 2016; 68:137-145.)... (excerpt)

Brugada syndrome in the young: an assessment of risk factors predicting future events.

To investigate the clinical characteristics, prognoses, and presence of risk factors in young patients with Brugada syndrome (BS). A consecutive cohort of 128 young BS patients (≤25 years old at diagnosis) was analysed. Eighty-eight patients (69%) were asymptomatic, whereas 40 (31%) presented with clinical manifestations of BS. Markers of prognosis and risk were identified upon comparison of these two groups. A history of malignant syncope was strong predictors of ventricular arrhythmic events. Family history of sudden cardiac death (SCD) and mutations in the SCN5A gene did not associate with increased risk. Symptomatic patients presented with significantly abnormal baseline electrical characteristics when compared with the asymptomatic cohort, including spontaneous type I electrocardiograph (ECG) patterns, sinus node dysfunction (SND), first-degree atrioventricular (AV) block, and intra-ventricular conduction delay. The symptomatic group more frequently exhibited atrial arrhythmias. Electrophysiological studies resulted positive more frequently in symptomatic patients, but no risk association for future events could be determined. During the follow-up period (mean: 65 months), 10 arrhythmic events occurred in nine symptomatic patients (event rate: 4.5% per year). No events occurred in the asymptomatic group. Variables significantly associated with arrhythmic events during follow-up were presence of symptoms at diagnosis and spontaneous type I ECG. The presence of atrial arrhythmias and conduction abnormalities was also associated with the risk of arrhythmic events during follow-up. Symptomatic BS in the young age is a rare but malignant condition that can manifest with a spectrum of electrical abnormalities (i.e. SND, atrial tachycardias, AV block, and infra-nodal conduction delay) and result in the extreme cases in lethal arrhythmic events and SCD.

Electrocardiographic early repolarization characteristics and clinical presentations in the young: a benign finding or worrisome marker for arrhythmias.

The early ECG repolarization QRS pattern (ERp), with J-point elevation of 0.1mV in two contiguous inferior and/or lateral leads, can be associated with ventricular arrhythmias among adults. The significance of an ERp in the young is unknown. The purpose of this study was to assess the prevalence of ERp among young patients (pts), describe and correlate the characteristics with clinical presentations and any arrhythmias. This was a 1y retrospective review of ECGs obtained from patients referred specifically for documented arrhythmias, possible arrhythmia-related symptoms or sports clearance. ECGs were analyzed for ERp (J-point, ascending/horizontal patterns, location) and correlated with presenting complaints. Of 301 patient ECGs, an ERp was found in 177 (59%), (pts age 11.7±4.3y); 54% male; 23% Caucasian. Of these, 6 pts had a family history of sudden cardiac death. Arrhythmias (72% atrial) occurred in 22 pts. Only 3 pts had ventricular arrhythmias (1 successfully ablated). The ascending ST segment and elevated J-point occurred in 77% and 51% of pts with and without arrhythmias respectively. In 73% of all pts, the ERp location was in inferior/lateral leads. Neither gender, ethnicity, large J-point, lead location, nor the combination of a horizontal ST segment with large J-point correlated with any arrhythmias. ERp, especially the diffuse ascending pattern, is common among the young, in those of European ethnicity, found equally in both genders, and with no apparent correlation with atrial nor ventricular arrhythmias.

Amiodarone use in patients listed for heart transplant is associated with increased 1-year post-transplant mortality

Pre-transplant amiodarone use has been postulated as a risk factor for morbidity and mortality after orthotopic heart transplantation (OHT). We assessed pre-OHT amiodarone use and tested the hypothesis that it is associated with impaired post-OHT outcomes. We performed a retrospective cohort analysis of adult OHT recipients from the registry of the International Society for Heart and Lung Transplantation (ISHLT). All patients had been transplanted between 2005 and 2013 and were stratified by pre-OHT amiodarone use. We derived propensity scores using logistic regression with amiodarone use as the dependent variable, and assessed the associations between amiodarone use and outcomes with Kaplan-Meier analysis after matching patients 1:1 based on propensity score, and with Cox regression with adjustment for propensity score. Of the 14,944 OHT patients in the study cohort, 32% (N = 4,752) received pre-OHT amiodarone. Amiodarone use was higher in recent years (29% in 2005 to 2007, 32% in 2008 to 2010, 35% in 2011 to 2013). Amiodarone-treated patients were older and more frequently had a history of sudden cardiac death (27% vs 13%) and pre-OHT mechanical circulatory support. Key donor characteristics and allograft ischemia times were similar between groups. In propensity-matched analyses, amiodarone-treated patients had higher rates of cardiac reoperation (15% vs 13%) and permanent pacemaker (5% vs 3%) after OHT and before discharge. Amiodarone-treated patients also had higher 1-year mortality (hazard ratio 1.15, 95% confidence interval 1.02 to 1.30), but the risks of early graft failure, retransplantation and rehospitalization were similar between groups. Amiodarone use before OHT was independently associated with increased 1-year mortality. The need for amiodarone therapy should be carefully and continuously assessed in patients awaiting OHT.

Risk factors for cardiac events in patients with Brugada syndrome: A PRISMA-compliant meta-analysis and systematic review.

Introduction:Inconsistent results have been reported about the risk stratification of patients with Brugada syndrome. We have summarized the evidence regarding the strength of association between 6 risk factors (family history of sudden cardiac death [SCD] or syncope, inducible ventricular arrhythmias on electrophysiology study [EPS], spontaneous type 1 Brugada electrocardiogram [ECG], male sex, family history of SCD, and sodium voltage-gated channel alpha subunit 5 [SCN5A] gene mutation) and subsequent cardiac events in Brugada syndrome patients.Methods:Pubmed, Ovid, Embase, and the Cochrane Library were searched for studies published between January 1992 and March 2016. Only prospective studies (27 studies, 4494 patients) that reported estimates with 95% confidence intervals (CIs) of cardiac events for the 6 risk factors were included.Results:Family history of SCD or syncope (risk ratio [RR] 4.97, 95% CI 3.96–6.23, P < 0.001), inducible ventricular arrhythmia on EPS (RR 3.56, 95% CI 1.30–9.74, P = 0.01), and spontaneous type 1 Brugada ECG (RR 4.07, 95% CI 2.23–7.41, P < 0.001) were associated with an increased risk of future cardiac events. Spontaneous type 1 Brugada ECG was associated with an elevated risk of future cardiac events in patients without a family history of SCD.Conclusions:Inducible ventricular arrhythmias on EPS, spontaneous type 1 Brugada ECG, and family history of SCD or syncope indicate a high risk of future cardiac events in patients with Brugada syndrome. Spontaneous type 1 Brugada ECG significantly increased the risk of future cardiac events in patients without family history of SCD.

168-02: Myocardial contraction duration of the left ventricle segments as risk markers for early detection cardiac events in patients with LQTS

Purpose: The aim of this study was to investigate whether prolonged myocardial contraction duration in walls of the left ventricle assessed by tissue Doppler imaging (TDI) may serve as risk markers for early detection cardiac events in patients with LQTS. Methods: This was a prospective study being performed in Namazi and Shahid Faghihi Hospitals of Shiraz University of Medical Sciences. Thirty two participants who had a typical electrocardiogram (ECG) with prolong QT pattern were divided into low and high risk groups. High risk group was 21 patients with implantable cardioverter defibrillator (ICD) who had experienced syncope or a QTc longer than 500 milliseconds or a family history of sudden cardiac death or complex ventricular arrhythmias. Low risk group was 11 asymptomatic patients treated with beta blockers who had not experienced syncope, a QTc longer than 500 milliseconds, a family history of sudden cardiac death, and complex ventricular arrhythmias. Myocardial contraction duration in 12 LV segments was obtained using tissue Doppler imaging (TDI) and then was compared between two study groups. Results: The most significant difference regarding the mean of contraction duration between two groups was in base and middle of inferior segment (P = 0.0001). Contraction duration ≥460 ms showed a sensitivity of 71% and a specificity of 82% in the inferior segments of left ventricle. Area under curve was 0.89 in base of inferior segment and, 0.88 in middle of inferior segment. Conclusion: This study showed that myocardial contraction duration can be of important value for early detection cardiac events in patients with LQTS. Prolonged contraction duration in inferior segment was better related to cardiac events compared with other cardiac segment. Finally, we concluded that TD measurements could become part of the routine clinical evaluation and screening for differentiating high risk patients than low risk patients as a new phenotypic marker. Keywords: Long-QT syndrome, Tissue Doppler imaging, Contraction duration

New approaches to predicting the risk of sudden death

In this review article, we will explore some of the contemporary methods for predicting sudden cardiac death (SCD). These include experimental methods yet to be adopted in the clinical setting, and methods that have been extrapolated from observational data in those with a history of SCD. We will discuss how these relate to the different aetiologies and disease processes. We will also explore how these may be used in the clinical setting to decide on management.

Stratification du risque de la mort subite dans la cardiomyopathie hypertrophique en 2016

Patients with hypertrophic cardiomyopathy (HCM) are at an increased risk of death from many causes and sudden cardiac death is one of them. The study of the sudden cardiac death of patients with HCM has allowed the identification of risk factors and among them major risk factor are: family history of sudden cardiac death, the occurrence of syncope/dizziness, the existence of non-sustained ventricular tachycardia an abnormal blood pressure response during stress test, presence of severe left ventricular hypertrophy≥30mm. Risk stratification for sudden cardiac death is essential, for symptomatic or asymptomatic HCM patients. Two approaches are possible: the classical approach or risk stratification methods with major risk factors and the new approach using the risk-calculator recommended by the ESC. Both methods are not in opposition but complementary. The risk stratification in hypertrophic cardiomyopathy should be still improved to be sure that only the most high-risk patients receive an implantable cardiac defibrillator.

Prognostic significance of fever-induced Brugada syndrome

In Brugada syndrome (BrS), spontaneous type 1 electrocardiogram (ECG) is an established risk marker for fatal arrhythmias whereas drug-induced type 1 ECG shows a relatively benign prognosis. No study has analyzed the prognosis of fever-induced type 1 ECG (F-type1) in a large BrS cohort. The objectives of this study were to assess the prognosis of F-type1 in asymptomatic BrS and to compare the effects of fever and drugs on ECG parameters. One hundred twelve patients with BrS who developed F-type1 were retrospectively enrolled. Prognosis was evaluated in 88 asymptomatic patients. In a subgroup (n = 52), ECG parameters of multiple ECGs (at baseline, during fever, and after drug challenge) were analyzed. Eighty-eight asymptomatic patients had a mean age of 45.8 ± 18.7 years, and 71.6% (67 of 88) were men. Twenty-one percent (18 of 88) had a family history of sudden cardiac death, and 26.4% (14 of 53) carried a pathogenic SCN5A mutation. Drug challenge was positive in 29 of 36 patients tested (80.6%). The risk of ventricular fibrillation in asymptomatic patients was 0.9%/y (3 of 88; 43.6 ± 37.4 months). ST-segment elevation in lead V2 during fever and after drug challenge was not significantly different (0.41 ± 0.21 ms during fever and 0.40 ± 0.30 ms after drug challenge; P > .05). Fever shortened the PR interval compared to baseline, whereas drug challenge resulted in prolonged PR interval and QRS duration (PR interval: 169 ± 29 ms at baseline, 148 ± 45 ms during fever, and 202 ± 35 ms after drug challenge; QRS duration: 97 ± 18 ms at baseline, 92 ± 28 ms during fever, and 117 ± 21 ms after drug challenge). Patients with BrS who develop F-type1 are at risk of arrhythmic events. F-type1 appears to develop through a more complex mechanism as compared with drug-induced type 1 ECG.

Flecainide challenge test: Predictors of unmasking of type 1 Brugada ECG pattern among those with non-type 1 Brugada ECG pattern

BackgroundMany subjects in community have non-type 1 Brugada pattern ECG with atypical symptoms, relevance of which is not clear. Provocative tests to unmask type 1 Brugada pattern in these patients would help in diagnosing Brugada Syndrome. However sensitivity and specificity of provocating drugs are variable. MethodsWe studied 29 patients referred to our institute with clinical presentation suggestive but not diagnostic of Brugada or with non-Type 1 Brugada pattern ECG. Flecainide Challenge Test (FCT) was done in these patients (IV Flecainide test in 4 patients and Oral Flecainide in 25 patients). Resting 12-lead ECG with standard precordial leads and ECG with precordial leads placed 1 Intercostal space above were performed after flecainide administration every 5 min for first 30 min and every 30 min thereafter until ECG became normal or upto 6 h. The positivity was defined as inducible Type 1 Brugada pattern in atleast 2 right sided leads. ResultMedian age was 35(range = 5–65) years. In 16 (55%) patients the Type 1 Brugada pattern was unmasked. There were no episodes of major AV block, atrial or ventricular tachyarrhythmia. Three groups were considered for analysis: Group 1(n = 9) – FCT Positive among patients with non-type 1 Brugada ECG pattern, Group 2(n = 4) – FCT Negative among the patients with non-type 1 Brugada ECG pattern, and Group 3(n = 7) – FCT Positive among patients with no spontaneous Brugada ECG pattern. Binary logistic regression analysis found that family h/o SCD was predictive of FCT positivity in Group 1 (Odd’s ratio 21, 95% Confidence interval 1.04 to 698.83, p = 0.004). ConclusionOral flecainide is useful and safe for unmasking of Type I Brugada pattern. In our study, among the many variables studied, family history of sudden cardiac death was the only predictor of flecainide test positivity among those with non-Type 1 Brugada pattern.

P8 Sudden cardiac death in childhood

Introduction and objectives Sudden cardiac death (SCD) in the paediatric population is an uncommon event. No clear information is available regarding the prevalence of the various causes in the entire population and studies usually reflect the accumulation of autopsy cases in a single centre. We performed a retrospective study from the SCD database in our Institution based on national referrals for SCD in order to characterise the potential underlying cause of SCD in the paediatric population. Methods We evaluated all patients under the age of 18 with who were referred to our Institution for post mortem examination from 1991 to 2013. Results We identified 398 patients (266 female). The median age at death was 14 (minimum 0, maximum 17). 39% of death occurred whilst the child was at rest; 22% on or immediately after exercise (Figure 1). In 21 patients (5%) there was known congenital heart disease. In 31% of patients there was a family history of SCD, in 14% of CM, and in 5% of arrhythmia. In 18% of patients syncope had been previously reported prior to death but many had no symptoms (Figure 2). The main cause of death was sudden arrhythmic death (SAD) 54% followed by cardiomyopathy (CM) 15%, miscellaneous 11%, congenital heart disease 8%, myocarditis 6% and coronary anomalies 5% (Figure 3). Conclusions Sudden death in the paediatric population is caused by presumed primary arrhythmia syndrome in just over half of all cases. In our series we found CM as the second leading cause of death. Knowledge of these causes and their relative prevalences is of great clinical utility, and particularly awareness of their exact morphology can help plan preventative strategies to reduce their future occurrence.

Spectrum of MYBPC3 Gene Mutations in Patients with Hypertrophic Cardiomyopathy, Reporting Two Novel Mutations from North-West of Iran

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death (SCD) in children and young adults and is the most frequent genetically determined cardiovascular disease following autosomal dominant pattern of inheritance. A number of genes have been shown to be responsible for HCM including MYBPC3. Cmybc, the protein encoded by MYBPC3 is a sarcomeric thick filament protein that interacts with titin, myosin, and actin to control sarcomeric gathering. Mutations in the MYBPC3 gene have been found to be associated with a history of sudden cardiac death in HCM patients. The main objective of the present study was to investigate the type and frequency of mutations in the MYBPC3 gene in HCM patients from the North-West of Iran. All the exons and exon-intron flanking regions of the MYBPC3 gene were assessed by PCR-SSCP, and the PCR products with divergent pattern of bands on polyacrylamide gel were sent for bi-directional sequencing. Mutational screening of a cohort of 42 HCM cases led to the identification of 14 MYBPC3 variations. Three cases out of those variations were frameshift, 1 case was splice site, 3 cases were missense, 2 cases were synonymous, and 5 cases were intronic variants. MYBPC3 mutations (28.5%) represent the most prevalent cause of inherited HCM. The age of onset was 39.3 in MYBPC3 carrier patients. Multiple gene mutations were recognized in 1 case (2.3%). The results obtained from the present study indicate a significant role of MYBPC3 gene mutations in HCM disease and can be used for pre-symptomatic diagnosis of at risk family members of affected individuals.

The Prognostic Value of Family History for the Estimation of Cardiovascular Mortality Risk in Men: Results from a Long-Term Cohort Study in Lithuania.

AimTo evaluate the additional prognostic value of family history for the estimation of cardiovascular (CVD) mortality risk in middle-aged urban Lithuanian men.MethodsThe association between family history of CVD and the risk of CVD mortality was examined in a population-based cohort of 6,098 men enrolled during 1972–1974 and 1976–1980 in Kaunas, Lithuania. After up to 40 years of follow-up, 2,272 deaths from CVD and 1,482 deaths from coronary heart disease (CHD) were identified. Multivariate Cox proportional hazards models were used to estimate hazard ratios (HR) for CVD and CHD mortality.ResultsAfter adjustment for traditional CVD risk factors, the HR for CVD mortality was 1.24 (95% CI 1.09–1.42) and for CHD mortality 1.20 (1.02–1.42) in men with first-degree relatives having a history of myocardial infarction (MI), compared to men without positive family history. A significant effect on the risk of CVD and CHD mortality was also observed for the family history of sudden cardiac death and any CVD. Addition of family history of MI, sudden death, and any CVD to traditional CVD risk factors demonstrated modest improvement in the performance of Cox models for CVD and CHD mortality.ConclusionsFamily history of CVD is associated with a risk of CVD and CHD mortality significantly and independently of other risk factors in a middle-aged male population. Addition of family history to traditional CVD risk factors improves the prediction of CVD mortality and could be used for identification of high-risk individuals.

T-wave reversal in the augmented unipolar right arm electrocardiographic lead is associated with increased risk of sudden death.

Repolarization abnormalities are associated with ventricular arrhythmias, and published studies report that a reversal of T wave polarity (positive or flat T wave) in lead aVR may be linked to increased cardiovascular mortality. We evaluated whether a positive or flat T wave in aVR is a risk marker for sudden cardiac death (SCD). SCD cases from the Oregon Sudden Unexpected Death Study (catchment population ~1 million) were compared to geographic controls with coronary artery disease and no history of SCD. Archived electrocardiograms performed prior and unrelated to the SCD event were evaluated. SCD cases (n = 691, 67.6 ± 14.9 years, 69% male) were more likely than controls (n = 663, 66.2 ± 11.6 years, 67% male) to have diabetes (40 vs 32%; p < 0.01), left ventricular ejection fraction (LVEF) ≤35% (27 vs 11 %; p < 0.01), prolonged QTc (≥450 ms; 54 vs 28%; p < 0.01) and positive (19 vs 13%; p < 0.01) or flat T wave (14 vs 7%; p < 0.01) in aVR. On multivariable analysis, a positive/flat T wave in aVR was independently associated with SCD (OR 1.9, 95% CI 1.3-2.8, p < 0.01). However, a positive T wave alone lost statistical significance in patients with LVEF ≤ 35% and QTc ≥ 450 ms. In a subgroup analysis among patients with normal LVEF, QTc, and no diabetes, a positive T wave in aVR (but not a flat T wave) remained associated with SCD (OR 2.8, 95% CI 1.2-6.1, p < 0.01). A positive or flat T wave in lead aVR was associated with SCD in subsets of patients. This simple ECG marker in this often-ignored lead may contribute to enhancement of SCD risk stratification, and warrants further evaluation.

Abstract 14706: Cardiac Phenotype in Children Undergoing Screening for Familial Hypertrophic Cardiomyopathy: Is it Time to Change Screening Guidelines?

Introduction: Current hypertrophic cardiomyopathy (HCM) screening guidelines recommend that clinical and/or genetic screening of children with family history of HCM be initiated from age 10 years (European Society of Cardiology 2014) or 12 years (American Heart Association 2011) onward and earlier only in the presence of malignant family history, presence of symptoms and/or participation in competitive sports. We assessed the proportion of asymptomatic children undergoing HCM screening that developed HCM phenotype or major adverse cardiac events (MACE) prior to age 12 years. Methods: This was a single centre retrospective study of HCM kindreds referred for screening to our cardiomyopathy clinic. Index cases with HCM, and cases with secondary cardiomyopathy (metabolic, neuromuscular, syndromic) were excluded. Genotype and phenotype status at initial screening and last follow-up were analyzed. MACE was defined as occurrence of death, transplant, resuscitated cardiac arrest, implantation of ICD or myectomy. Results: From 2005-2014, 427 children were referred for cardiac screening secondary to a family history of HCM. Of these, 379 (88.8%) had first-degree relatives with HCM and 146 (34.1%) had a family history of sudden cardiac death. The median age at first screening was 7.4 years (range 1 day-17 years), and median follow-up duration was 3 years. 45% (13/29 tested) phenotype-positive children, and 53% (32/60 tested) phenotype-negative children has positive genetic testing. 27/427 (6.3%) were phenotype-positive (maximal LV wall thickness Z-score &gt;2.0) at initial screening and an additional 13 (3%) became phenotype-positive during follow-up. The median age at positive phenotypic diagnosis of HCM was 8 years (range 5 days-17 years) with 24 children being &lt;12 years old (5.6%). 11/427 (2.6%) suffered a MACE during follow-up. Median age at MACE occurrence was 10.9 years (range 6-15 years) with 6 children being &lt;12 years old at occurrence of MACE (1.4%). Conclusion: Overall, more than 5% children being screened for HCM were phenotype-positive and 1.4% suffered a MACE before 12 years of age. These data suggest the importance of revising existing guidelines to recommend clinical and/or genetic screening of HCM of all family members independent of age.

Family History of Sudden Cardiac Death of the Young: Prevalence and Associated Factors.

Sudden cardiac death of the young (SCDY) is a devastating event for families and communities. Family history is a significant risk factor for this potentially preventable cause of death, however a complete and detailed family history is not commonly obtained during routine health maintenance visits. To estimate the proportion of adults with a family history of SCDY, the Michigan Department of Health and Human Services (MDHHS) Genomics Program included two questions within the 2007 Michigan Behavioral Risk Factor Survey (MiBRFS). Prevalence estimates and 95% confidence intervals were calculated. Among adults in Michigan, 6.3% reported a family history of SCDY, with a greater prevalence among blacks, those with lower household income, and those with less education. Among those reporting a family history of SCDY, 42.3% had at least one first-degree relative and 26.2% had multiple affected family members. This is the first study to demonstrate the prevalence of family history of SCDY while also highlighting key sociodemographic characteristics associated with increased prevalence. These findings should guide evidence-based interventions to reach those at greatest risk.