Unexplained Sudden Cardiac Death Research Articles

Açıklanamayan Ani Kardiyak Ölümlerinde Moleküler Patolojinin Önemi: Kardiyomiyopatilerin Epigenetiği

Açıklanamayan Ani Kardiyak Ölümlerinde Moleküler Patolojinin Önemi: Kardiyomiyopatilerin Epigenetiği

Abstract 12229: Bundle Branch Reentrant Ventricular Tachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia

Introduction: Bundle branch reentrant ventricular tachycardia (BBRVT) is a life-threatening ventricular arrhythmia occurring secondary to macroreentry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease. Hypothesis: Idiopathic BBRVT may be secondary to genetic mutations associated with conduction system disease. Methods & Results: We identified 6 cases of BBRVT associated with normal biventricular size and function from 6 centers across North America. Study participants were screened for mutations within pre-specified genes linked to cardiac conduction system disease. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Na v 1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage-dependence of activation consistent with a loss-of-function. The SCN5A c.4719C>T splice-site mutation has previously been reported as disease causing in 3 cases of Brugada syndrome, while the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was non-inducible in all cases and no clinical recurrences were observed during follow-up. Conclusions: Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening ventricular arrhythmia. This provides further insight into its underlying pathophysiology and emphasizes that conduction system disease, in the absence of ventricular dilation, serves as a sufficient substrate for BBRVT. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation.

A Prospective Study of Sudden Cardiac Death among Children and Young Adults

BackgroundSudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults.MethodsWe prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation.ResultsA total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred.ConclusionsThe addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.)

BILEAFLET MITRAL VALVE PROLAPSE AND THE RISK OF VENTRICULAR DYSRHYTHMIAS AND DEATH

Bileaflet mitral valve prolapse (BiMVP) is common among survivors of otherwise unexplained sudden cardiac death, but prognostic implications of BiMVP are unknown. This study evaluated whether patients with BiMVP are at higher risk for ventricular dysrhythmias, implantable cardioverter-defibrillator

Bileaflet Mitral Valve Prolapse and Risk of Ventricular Dysrhythmias and Death.

Bileaflet mitral valve prolapse (BiMVP) is common among survivors of otherwise unexplained sudden cardiac death, but prognostic implications of BiMVP are unknown. This study evaluated whether patients with BiMVP are at higher risk for ventricular dysrhythmias, ICD placement, or death compared to controls with either single-leaflet mitral valve prolapse (SiMVP) or no mitral valve prolapse (MVP). This retrospective, matched cohort study included 18,786 patients who underwent echocardiography at Mayo Clinic between June 1990 and September 2014. The study included three cohorts: BiMVP, SiMVP, and controls without MVP. We assessed rates of ventricular dysrhythmias, ICD placement, and all-cause mortality between groups. BiMVP was associated with higher rates of ventricular tachycardia compared to SiMVP and controls (adjusted HR 1.48 [1.14-1.92], P = 0.003 and 1.40 [1.04-1.88], P = 0.026, respectively); however, there were no statistically significant differences in rates of ventricular fibrillation/cardiac arrest or ICD placement between groups. BiMVP was associated with a lower rate of all-cause mortality compared to SiMVP and controls (adjusted HR 0.86 [0.79-0.94], P = 0.0008, and 0.55 [0.50-0.60], P < 0.0001, respectively). Although BiMVP is associated with ventricular tachycardia, it is not associated with an increased risk of cardiac arrest/ventricular fibrillation or ICD implantation and is, paradoxically, associated with a better survival compared to SiMVP or matched controls. The findings suggest that, despite its association with ventricular tachycardia, BiMVP in the absence of other risk factors does not seem to portend a poor prognosis at the population level.

Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes

BackgroundLong QT syndromes (LQTS) are characterized by prolonged QTc interval on electrocardiogram (ECG) and manifest with syncope, seizures or sudden cardiac death. Long QT 1–3 constitute about 75% of all inherited LQTS. We classified a cohort of Indian patients for the common LQTS based on T wave morphology and triggering factors to prioritize the gene to be tested. We sought to identify the causative mutations and mutation spectrum, perform genotype-phenotype correlation and screen family members. MethodsThirty patients who fulfilled the criteria were enrolled. The most probable candidate gene among KCNQ1, KCNH2 and SCN5A were sequenced. ResultsOf the 30 patients, 22 were classified at LQT1, two as LQT2 and six as LQT3. Mutations in KCNQ1 were identified in 17 (77%) of 22 LQT1 patients, KCNH2 mutation in one of two LQT2 and SCN5A mutations in two of six LQT3 patients. We correlated the presence of the specific ECG morphology in all mutation positive cases. Eight mutations in KCNQ1 and one in SCN5A were novel and predicted to be pathogenic by in-silico analysis. Of all parents with heterozygous mutations, 24 (92%) of 26 were asymptomatic. Ten available siblings of nine probands were screened and three were homozygous and symptomatic, five heterozygous and asymptomatic. ConclusionsThis study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members.

Abstract 13720: Mitral Valve Prolapse And Sudden Death: A Systematic Review

Introduction: Mitral valve prolapse (MVP) is commonly observed as a benign finding in the general population. There is a suggestion from the literature that MVP is associated with unexplained sudden cardiac death (SCD) in patients with otherwise “structurally normal hearts”. Aim: We performed a systematic review 1) to determine the prevalence of MVP in unexplained SCD cohorts, 2) to determine the presence of MVP in the general population and 3) to evaluate the incidence of SCD in patients with MVP. Methods: An electronic search of the English medical literature (Pubmed, Medline, Cochrane and EMBase) was conducted on 1st July 2014. 667 references were imported into Endnote and reviewed. Reference lists of relevant studies and review articles were screened to retrieve non-indexed articles. All patients with known precipitants for death or cardiac arrest were excluded. 20 studies were identified with 13 examining MVP in unexplained SCD and 7 examining SCD in patients with MVP. A random effects model was utilized and meta-analysis was performed using STATA version 13.0. Results: The cause for SCD was not identified in 28.3% of autopsy studies. The prevalence of MVP in cohorts with unexplained SCD was 13.3% (95% CI 6.8, 21.3). The community prevalence of MVP was 1.6% (95% CI 1, 2.8) and the incidence of unexplained SCD in the MVP population was 0.2% (0.1, 0.3) per year. Based on current census data, we project that MVP presently affects approximately 5.1 million people in the United States and is estimated to climb to 6.3 million by 2050. Accordingly, the number of SCD victims with MVP will climb from 10, 200 to 12, 600. Bileaflet prolapse, moderate to severe mitral regurgitation, ventricular fibrosis and ventricular ectopy were observed more commonly in patients with unexplained SCD and MVP. Conclusion: The prevalence of MVP in victims of unexplained SCD is high. Although the incidence of life threatening arrhythmic events in the general MVP population remains low, the absolute number of people exposed to the risk of SCD will be large given the high prevalence of MVP. Further work is required to delineate potential risk factors for sudden death in patients with MVP.

17The brugada syndrome and cardiomyopathy: altered collagen and gap junction expression

Background: Brugada syndrome (BrS) is considered an inherited arrhythmia syndrome, though it may represent a concealed cardiomyopathy confined to the right ventricular outflow tract (RVOT). We aimed to ascertain fibrosis and gap junction expression in ventricular myocardium following sudden cardiac death (SCD) due to BrS. Methods: The BrS cohort consisted of 6 cases of unexplained SCD referred for specialist whole heart autopsy whose family were diagnosed with BrS. Comparisons were made to matched homograft control hearts (n=6) and cases of arrhythmogenic right ventricular cardiomyopathy (ARVC, n=5). Morphometric evaluation of collagen and fat content of left (LV) and right (RV) ventricles and RVOT by picrosirius red-staining was undertaken. Gap junction expression was assessed by Connexin43 (Cx43) immunostaining in the RVOT. Results: Collagen in controls was predominantly perivascular in long fine fibres and diffuse reticular interstitial networks. Interstitial long collagen strands were thickened in BrS, with evidence of epicardial patchy replacement fibrosis. ARVC was characterised by both interstitial and dense patchy replacement fibrosis. Maximal collagen content, indicative of fibrosis, was present in the RVOT (p=0.003) and epicardium (p=0.001) in all three disease groups, with RV more fibrosed than LV (p=0.020). ARVC cases exhibited the most fibrosis (p=0.001), while BrS cases were significantly more fibrosed than controls (OR 1.42; p=0.024). No significant difference in fat content was observed between BrS and controls (p=0.133). BrS cases showed a reduced Cx43 signal in comparison to controls (OR 0.59; p=0.001), which remained significant after adjusting for collagen content (Figure). However, lateralisation and dispersion of Cx43 over the cellular surface was seen in both control and BrS sections. In ARVC, Cx43 signal was severely reduced in comparison to BrS (OR 0.61; p=0.002). Discussion: BrS associates with generalised ventricular myocardial fibrosis and reduced RVOT gap junction expression in comparison with controls, with ARVC demonstrating similar but more severe abnormalities. Thus, BrS may represent a disease of myocardial architecture, with baseline properties of the RVOT predisposing it to more severe fibrosis. We speculate that myocyte electrical uncoupling indicated by gap junction abnormalities and changes in conduction related to fibrosis confer arrhythmic risk. ![Graphic][1] Figure Scatterplot of Cx43:collagen ratio in RVOT by myocardial zone (filled data points=mean) demonstrating significant differences between ARVC, BrS and Control cohorts, but no difference from epi- to endo-cardium. [1]: /embed/inline-graphic-1.gif

Feasibility and outcomes of ajmaline provocation testing for Brugada syndrome in children in a specialist paediatric inherited cardiovascular diseases centre

ObjectivesBrugada syndrome (BrS) is an inherited arrhythmia syndrome that causes sudden cardiac death in the young. The class Ia antiarrhythmic ajmaline can be used to provoke the diagnostic ECG pattern....

077 AJMALINE PROVOCATION TESTING FOR BRUGADA SYNDROME IN CHILDREN: THE GREAT ORMOND STREET EXPERIENCE

Background Brugada syndrome (BS) is a genetic disorder characterised by J point elevation in the right ventricular leads, ventricular arrhythmia and sudden cardiac death (SCD). The diagnostic ECG changes can be provoked by sodium channel blocking agents including ajmaline. Although ajmaline testing is well established in adults, there are few data on its safety and outcomes in paediatric cohorts3. Here we describe a single centre experience of ajmaline testing for BS in a large cohort of children. Methods and results 100 consecutive patients aged 18 years or younger who underwent an ajmaline challenge between September 2004 and May 2012 were included. Mean age at the time of ajmaline challenge was 12.6 years (range 2.0–18.4 years), and 54 were male. The indication for ajmaline challenge was a family history of BS in 49 patients, family history of unexplained sudden cardiac death (without a confirmed family history of BS) in 40, symptoms in 9 (syncope/collapse, n=5; chest pain, n=1; palpitations, n=3), family history of long QT syndrome in 1 patient, and development of bradycardia with abnormal ECG during general anaesthesia in 1 patient. There were no serious adverse events associated with the ajmaline tests. A diagnostic type I response was seen in 19 individuals, of which 13 had a family history of BS, 5 had a family history of SCD without confirmed BS, and 1 patient had syncope as an indication for the challenge. Although a positive result was more common in those patients with a family history of BS, this association did not reach statistical significance. 5 individuals with a positive ajmaline test underwent electrophysiological studies; ventricular arrhythmias were not inducible in any. All patients are alive with no documented ventricular arrhythmias after a median follow-up time of 3.6 years. Conclusions Ajmaline provocation testing in children is feasible and safe when performed in an appropriate setting by an experienced team. A type I response is more common in patients with a family history of BS, but the test may be helpful in identifying a diagnosis in families with unexplained SCD. Overall, BS appears to be associated with a very low risk of ventricular arrhythmia in the paediatric population.

Interictal Electrocardiographic and Echocardiographic Changes in Patients With Generalized Tonic-Clonic Seizures

Partial and generalized seizures often affect autonomic functions during seizures, and interictal and postictal periods. We investigated possible interictal electrocardiographic abnormalities in patients with generalized tonic-clonic seizures (GTCS), together with evaluating any structural heart changes by echocardiography in these patients in comparison with healthy controls. We studied 120 definite GTCS patients (76 males and 44 females) who are neither diabetic nor under any medical treatment, and 60 healthy controls with a mean age of 25.2 ± 9.3 and 27.3 ± 7.5 years; respectively. Resting systolic and diastolic arterial blood pressures were measured, and standard 12-lead electrocardiograms and a 2-dimensional echocardiographic examination were performed. In univariate analysis, GTCS patients (compared to controls) had significantly lower means of PR interval (147.2 ± 18.6 versus 153.8 ± 22.6 msec; P = 0.037), QT interval (362.8 ± 22.9 versus 379.9 ± 29.3 msec; P < 0.001), and QTc interval (425.5 ± 20.7 versus 441.6 ± 19.9 msec; P < 0.001) but significantly higher mean left atrial diameter (3.49 ± 0.64 versus 3.09 ± 0.45 cm; P < 0.001). After adjusting for age, gender, and body mass index in a multivariate adjusted logistic regression model, left atrial diameter (OR = 3.941 [1.739 - 8.932]) and QTc (OR = 0.924 [0.895 - 0.954]) were significantly and independently associated with GTCS. In conclusion, patients with epilepsy may be predisposed to disturbances of autonomic functions with subsequent cardiac arrhythmias due to the effects of recurrent seizures on cardiac microstructure. Further work is needed to stratify the risk of sudden unexplained cardiac death (SUDEP) on the basis of interictal autonomic parameters to improve prognosis.

Epinephrine test for sudden cardiac death—is it too early?

Unexplained sudden cardiac death (SCD) is a major health problem, and prediction and identification of high-risk populations remain a challenge. Epinephrine stress testing could help to identify individuals at risk of SCD, but more research is required before this test could be recommended for routine use.

Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.

The placental origins of sudden cardiac death

Most sudden cardiac deaths are due to cardiac arrhythmias, and abnormalities in the autonomic nervous system could underlie them. There is growing evidence that coronary heart disease is associated with alterations of fetal development as a result of variations in the processes of placentation that control fetal nutrition. We hypothesized that placental size would be associated with sudden cardiac death. We examined sudden cardiac death within the Helsinki Birth Cohort of 13 345 men and women. One hundred eighty-seven (2.7%) men and 47 (0.7%) women had sudden unexplained cardiac death outside hospital. Sudden death was associated with a thin placenta, the hazard ratio being 1.47 [95% confidence interval (CI) 1.11-1.93, P = 0.006] for each g/cm(2) decrease in thickness. Sudden death was independently associated with poor educational attainment (P < 0.0001). Both of these associations were independent of socio-economic status in later life. Sudden death may be initiated by impaired development of the autonomic nervous system in utero as a result of shallow invasion of the spiral arteries in the maternal endometrium and consequent fetal malnutrition.

Cardiac ventricular repolarization reserve: a principle for understanding drug-related proarrhythmic risk.

Cardiac repolarization abnormalities can be caused by a wide range of cardiac and non-cardiac compounds and may lead to the development of life-threatening Torsades de Pointes (TdP) ventricular arrhythmias. Drug-induced torsades de pointes is associated with unexpected and unexplained sudden cardiac deaths resulting in the withdrawal of several compounds in the past. To better understand the mechanism of such unexpected sudden cardiac deaths, the concept of repolarization reserve has recently emerged. According to this concept, pharmacological, congenital or acquired impairment of one type of transmembrane ion channel does not necessarily result in excessive repolarization changes because other repolarizing currents can take over and compensate. In this review, the major factors contributing to repolarization reserve are discussed in the context of their clinical significance in physiological and pathophysiological conditions including drug administration, genetic defects, heart failure, diabetes mellitus, gender, renal failure, hypokalaemia, hypothyroidism and athletes' sudden deaths. In addition, pharmacological support of repolarization reserve as a possible therapeutic option is discussed. Some methods for the quantitative estimation of repolarization reserve are also recommended. It is concluded that repolarization reserve should be considered by safety pharmacologists to better understand, predict and prevent previously unexplained drug-induced sudden cardiac deaths.

Data Question Association of Antipsychotics, Cardiac Deaths

Data Question Association of Antipsychotics, Cardiac Deaths

50 Diagnostic role of exercise tolerance testing in familial premature sudden cardiac death

<h3>Background</h3> Investigation of blood relatives for evidence of an inherited cardiac condition is advocated following an unexplained sudden cardiac death (SCD). <h3>Aim</h3> We determined the diagnostic yield of exercise tolerance testing (ETT) in investigation of inherited cardiac conditions following familial premature SCD. <h3>Methods</h3> Between 2006 and 2010, we evaluated 308 blood relatives of 148 SCD victims, who completed at least 3 min of the Bruce protocol. ETTs were analysed for: QT prolongation; Brugada type 1 pattern; ST depression: blood pressure (BP) response; multiple ventricular ectopics or arrhythmia. Individual pathological phenotypes were determined by a combination of 12-lead ECG, echocardiogram, 24-h holter monitor, with additional MRI, CT coronary angiography and genetic mutation analysis, as appropriate. <h3>Results</h3> Thirty (9.8%) patients had an abnormality during ETT, details of which are summarised in Abstract 50 figure 1. All ETTs with abnormal QT prolongation and dynamic Brugada pattern were associated with diagnoses of long QT syndrome and Brugada syndrome respectively. An example of dynamic Brugada phenotype is given in Abstract 50 figure 2. Ventricular ectopy was seen in 15 patients, of whom 5 demonstrated phenotypic cardiomyopathy or channelopathy on further investigations. No patients with significant ST depression had evidence of coronary abnormalities on imaging. No hypotensive BP response was seen, but exertional hypertension was associated with systemic hypertension. <h3>Conclusion</h3> The ETT is a useful diagnostic adjunct when evaluating relatives of victims of premature SCD. Reliable diagnostic indicators include inappropriate QT prolongation and dynamic Brugada pattern. Ventricular ectopy is non-specific, but is associated with both cardiomyopathic and channelopathic processes in a significant minority. ST segment depression, however, is unhelpful and should be viewed in the context of the patient9s cardiovascular risk profile.

Founder mutations in the Netherlands: familial idiopathic ventricular fibrillation and DPP6

In this part of a series on founder mutations in the Netherlands, we review familial idiopathic ventricular fibrillation linked to the DPP6 gene. Familial idiopathic ventricular fibrillation determines an intriguing subset of the inheritable arrhythmia syndromes as there is no recognisable phenotype during cardiological investigation other than ventricular arrhythmias highly associated with sudden cardiac death. Until recently, it was impossible to identify presymptomatic family members at risk for fatal events. We uncovered several genealogically linked families affected by numerous sudden cardiac deaths over the past centuries, attributed to familial idiopathic ventricular fibrillation. Notably, ventricular fibrillation in these families was provoked by very short coupled monomorphic extrasystoles. We were able to associate their phenotype of lethal arrhythmic events with a haplotype harbouring the DPP6 gene. While this gene has not earlier been related to cardiac arrhythmias, we are now able, for the first time, to identify and to offer timely treatment to presymptomatic family members at risk for future fatal events solely by genetic analysis. Therefore, when there is a familial history of unexplained sudden cardiac deaths, a link to the DPP6 gene may be explored as it may enable risk evaluation of the remaining family members. In addition, when closely coupled extrasystoles initiate ventricular fibrillation in the absence of other identifiable causes, a link to the DPP6 gene should be suspected.

Genetic Risk in Early Repolarization Syndrome

Early Repolarization (ER) has been associated to idiopathic ventricular fibrillation and sudden cardiac death (SCD) in the general population. Recent population-based studies clearly demonstrate that ER is heritable (H2=0.49). The identification of mutations in the KCNJ8 and CACNAB2b suggests a genetic substrate however the genetic transmission of ER is still poorly documented. We have screened relatives in 3 families affected by ER. In the first family the proband died during an electrical storm and presented an ER pattern. Eleven unexplained SCD occurred and familial screening identified 12 relatives with an ER aspect out of 30 relatives (prevalence 57%). In the second family the proband experienced electrical storms at 45 years old associated with an ER pattern. We identified 3 others unexplained SCD and 25 ER among 82 available ECGs (prevalence 34%). In the third family four patients experienced SCD, one of them presented an ER pattern. Sixteen other patients presented an ER pattern (17/29, prevalence 62%). Valsalva maneuver was performed for 80 relatives. It increased J wave amplitude in 17/20 affected patients and revealed an ER in 17 relatives. In conclusion our study suggests that ERS is transmitted as an autosomal dominant disease.

Sudden cardiac death and sport in Luxembourg: Incitement for a public health strategy

Sudden cardiac death and sport in Luxembourg: Incitement for a public health strategy