Death In Young Adults Research Articles

6 Prevalence and CMR characteristics of apical HCM: Abstract 6 Table 1

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young adults. The 3 main phenotypes are asymmetric (most common), concentric and apical. Literature suggests apical HCM is rare and more benign, but data is scarce. We sought to describe prevalence and characteristics of apical HCM in a large CMR service. Methods We reviewed 3,100 scans (Jan 2014–Mar 2015). Protocol included cines, early and late gadolinium enhancement imaging. 114 consecutive HCM patients were identified. Asymmetric HCM defined as septal/ free wall thickness ratio > 1.3; apical HCM as apical wall thickness > 15mm or apical/basal wall thicknesses ≥ 1.3–1.5. Concentric HCM defined as symmetrical hypertrophy of ventricular wall without regional preferences. Non-apical HCM (asymmetric and concentric phenotypes) were compared with apical HCM. Fisher’s exact t-test and unpaired t-test were performed for statistical significance (P-value Results 10 patients were excluded, leaving 104 patients, median age 60years; 70% male. 70% had non-apical HCM (5 patients concentric HCM, the rest asymmetric HCM) and 30% apical HCM. Mean maximum LV wall thickness, indexed LV mass, stroke volume, prevalence of LVOTO and SAM were greater in non-apical group. Presence of LGE was high in both groups (>85%) and wasn’t statistically different. Univariate predictors of apical HCM included maximum LV wall thickness, indexed stroke volume, LVOT obstruction (Table 1). In the multivariate model, maximum wall thickness remained the only significant predictor. Conclusions Our study suggests that prevalence of apical HCM is almost 1/3rd of all observed cases. It also demonstrates that prevalence of LGE was high in apical HCM, suggesting that better prognosis of apical HCM based on the absence of myocardial fibrosis, should be reconsidered. Further large trials are needed to better understand the pathophysiology.

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice.

The prevention of organ damage and early death in young adults is a major clinical concern in sickle cell disease (SCD). However, mechanisms that control adult progression of SCD during the transition from adolescence are poorly defined with no cognate prophylaxis. Here, we demonstrate in a longitudinal cohort of homozygous SCD (SS) mice a link between intravascular hemolysis, vascular inflammation, lung injury, and early death. Prophylactic Nrf2 activation in young SS mice stabilized intravascular hemolysis, reversed vascular inflammation, and attenuated lung edema in adulthood. Enhanced Nrf2 activation in endothelial cells in vitro concurred with the dramatic effect on vascular inflammation in the mice. BM chimeric SS mice lacking Nrf2 expression in nonhematopoietic tissues were created to dissect the role of nonerythroid Nrf2 in SCD progression. The SS chimeras developed severe intravascular hemolysis despite having erythroid Nrf2. In addition, they developed premature vascular inflammation and pulmonary edema and died younger than donor littermates with intact nonhematopoietic Nrf2. Our results reveal a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD. Furthermore, we show that prophylactic augmentation of Nrf2-coordinated cytoprotection effectively impedes onset of the severe adult phenotype of SCD in mice.

Increased miR-155-5p and reduced miR-148a-3p contribute to the suppression of osteosarcoma cell death.

Osteosarcoma (OS) is the most common cancer of bone and the 5th leading cause of cancer-related death in young adults. Currently, 5-year survival rates have plateaued at ~70% for patients with localized disease. Those with disseminated disease have an ~20% 5-year survival. An improved understanding of the molecular genetics of OS may yield new approaches to improve outcomes for OS patients. To this end, we applied murine models that replicate human OS to identify and understand dysregulated microRNAs (miRNAs) in OS. miRNA expression patterns were profiled in murine primary osteoblasts, osteoblast cultures and primary OS cell cultures (from primary and paired metastatic locations) isolated from two genetically engineered murine models of OS. The differentially expressed miRNA were further assessed by a cross-species comparison with human osteoblasts and OS cultures. We identified miR-155-5p and miR-148a-3p as deregulated in OS. miR-155-5p suppression or miR-148a-3p overexpression potently reduced proliferation and induced apoptosis in OS cells, yet strikingly, did not impact normal osteoblasts. To define how these miRNAs regulated OS cell fate, we used an integrated computational approach to identify putative candidate targets and then correlated these with the cell biological impact. Although we could not resolve the mechanism through which miR-148a-3p impacts OS, we identified that miR-155-5p overexpression suppressed its target Ripk1 (receptor (TNFRSF)-interacting serine-threonine kinase 1) expression, and miR-155-5p inhibition elevated Ripk1 levels. Ripk1 is directly involved in apoptosis/necroptosis. In OS cells, small interfering RNA against Ripk1 prevented cell death induced by the sequestration of miR-155-5p. Collectively, we show that miR-148a-3p and miR-155-5p are species-conserved deregulated miRNA in OS. Modulation of these miRNAs was specifically toxic to tumor cells but not normal osteoblasts, raising the possibility that these may be tractable targets for miRNA-based therapies for OS.

Childhood Household Dysfunction, Social Inequality and Alcohol Related Illness in Young Adulthood. A Swedish National Cohort Study.

The aim of this paper is to estimate the cumulative effect of childhood household dysfunction (CHD) on alcohol related illness and death later in life and to test the interaction between CHD and socioeconomic background. The study utilised Swedish national registers including data of a Swedish national cohort born 1973–82 (n = 872 912), which was followed from age 18 to 29–40 years. Cox regression analyses were used to calculate hazard ratios (HR) for alcohol related illness or death in young adulthood. The CHD measure consisted of seven indicators: parental alcohol/drug misuse, mental health problems, criminality, death, divorce, social assistance, and child welfare interventions. Childhood socioeconomic position (SEP) was indicated by parental occupational status. Outcomes were alcohol related inpatient hospital care, specialised outpatient care or deaths. Using the highest socioeconomic group without CHD experience as a reference, those in the same socioeconomic group with one indicator of CHD had HRs of 2.1 [95% CI: 1.7–2.5], two CHD indicators 5.6 [4.4–7.1], three or more indicators 9.4 [7.1–12.4] for retrieving inpatient care. Socioeconomic disadvantage further increased the risks–those with low socioeconomic background and three CHD indicators or more had a HR of 12.5 [10.9–14.3]. Testing for interaction suggests that the combined HRs deviates from additivity [Synergy index: 1.6, 95% CI: 1.4–1.9]. The results for outpatient care were similar, but not as pronounced. In conclusion, this Swedish national cohort study shows that childhood household dysfunction is strongly and cumulatively associated to alcohol related illness later in life and that it interacts with socioeconomic disadvantage.

Commentary on Imtiaz et al. (2016): The burden of disease attributable to cannabis-implications for policy.

The contribution that current patterns of cannabis use make to the burden of disease is very useful information, but it cannot decide policy. Sameer Imtiaz and colleagues have used the methods developed as part of the 2010 Global Burden of Disease Comparative Risk Assessment to estimate the contribution that cannabis use made to the burden of disease (BoD) in 2012 in Canada, a developed country where the prevalence of cannabis use is among the highest in the world 1. They included among the cannabis-related causes of disease burden: cannabis use disorders (CUD), road traffic injuries and deaths, schizophrenia and lung cancer. CUD are a consequence of cannabis use by definition; recent meta-analyses suggest that cannabis use modestly increases the risk of road traffic injuries and deaths, and there is reasonable evidence that regular cannabis is a contributory cause of the onset of psychoses 2, although some argue that we cannot exclude the possibility of residual confounding 3. The inclusion of lung cancer is more contentious, given that a recent meta-analysis concluded that there was not sufficient evidence to assess whether cannabis smoking increased the risk of lung cancer 4. The authors included uncertainty bounds around their estimates to reflect the fact that many of these estimated risks are based on a small number of epidemiological studies which have weakly quantified cannabis use. Their comparison of the BoD attributable to alcohol, tobacco and cannabis shows that cannabis contributes a very small fraction of the contribution of alcohol and tobacco. This reflects the combined effects of the very large difference in the prevalence of the regular use of these three drugs and the fact that there is a much larger research literature linking alcohol and tobacco to many more causes of death and disability than cannabis. A comparison of BoD attributed to cannabis and opioids shows that cannabis use is much more prevalent than opioid use, but the opioid drugs make a much larger contribution to BoD because they cause many more deaths in young adults by overdose, suicide, accidents and blood-borne virus (BBV) infections. Only 20 years ago, statements about the comparative harms of cannabis, alcohol, tobacco and opioids were highly controversial. Some authors (e.g. 5) insisted that such comparisons could not and should not be made. A paper that Robin Room, Susan Bondy and I prepared for a 1997 World Health Organization (WHO) report on the health effects of cannabis 6 caused enormous public controversy and was disowned by WHO (see 7). The successful development of the comparative risk assessment approach used in the GBD estimates has thankfully put paid to these objections to comparative assessments of contributions that different types of drugs make to BoD. Imtiaz et al. acknowledge an important qualification that applies to all such comparisons; namely, that they reflect the BoD attributable to current patterns of cannabis use. Those who defend current cannabis policies can argue reasonably that these policies can claim some credit for this fact. Many adults in developed countries have used cannabis at some time in their lives, but only a very small proportion of these (approximately 10%) have used regularly, and a still smaller proportion have used daily over decades. The latter is a miniscule proportion by comparison with the proportions of tobacco smokers who smoke daily and alcohol consumers who drink in a risky manner. It is clear that CUD can affect a substantial number of young people in developed societies. This fact demands the policy response suggested by the authors; namely, screening and early intervention in medical settings where problem cannabis users are likely to be seen. Is the contribution that cannabis use makes to BoD enough to justify a change from current prohibitionist policies to more liberal policies that may include legalization for recreational use, as has occurred in four US states? This is properly a matter for democratic deliberation that considers the social and economic costs and benefits of adopting different policies towards cannabis. Data on the effects of cannabis on BoD, as used currently, will play a useful role in such deliberations, but it cannot be decisive 8. None. I thank Sarah Yeates for her assistance in preparing this commentary.

Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientific rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02291237.

Distinct structural changes in wild-type and amyloidogenic chicken cystatin caused by disruption of C95–C115 disulfide bond

Human cystatin C (HCC) amyloid angiopathy (HCCAA) is characterized by tissue deposition of amyloid fibrils in blood vessels, which can lead to recurrent hemorrhagic stroke. Wild-type HCC forms part of the amyloid deposits in brain arteries of elderly people with amyloid angiopathy. A point mutation causing a glutamine to a leucine substitution at residue 68 in the HCC polypeptide chain greatly increases the amyloidogenic propensity of HCC and causes a more severe cerebral hemorrhage and premature death in young adults. In this study, we used molecular dynamics simulations to assess the importance of disulfide bridge formation upon the stability of chicken cystatin and how this may influence the propensity for amyloid formation. We found that disulfide bridge formation between Cys95 and Cys115 in human cystatin played a critical role in overall protein stability. Importantly, Cys95–Cys115 influenced cystatin structure in regions of the protein that play key roles in the protein-folding transitions that occur, which enable amyloid fibril formation. We hypothesized that correct disulfide bridge formation is a critical step in stabilizing cystatin toward its native conformation. Disrupting Cys95–Cys115 disulfide bridge formation within cystatin appears to significantly enhance the amyloidogenic properties of this protein. In addition, by combining in silico studies with our previous experimental results on Eps1, a molecular chaperone of the PDI family, we proposed that age-related HCCAA, may possess a different pathogenic mechanism compared with its amyloidogenic counterpart, the early onset amyloidogenic cystatin-related CAA.

Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation.

Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a nonpsychoactive constituent of marijuana that exerts antiinflammatory effects independent of classical cannabinoid receptors. Recently, 80 clinical trials have investigated the effects of CBD in various diseases from inflammatory bowel disease to graft versus host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received U.S. Food and Drug Administration approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T-cell infiltration, profound inflammatory response and fibrosis (measured by quantitative real-time polymerase chain reaction, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with a pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ T cell-mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation.

Statin Induced Regression of Cardiomyopathy Trial: A Randomized, Placebo-controlled Double-blind Trial.

Background:Hypertrophic cardiomyopathy (HCM), characterized by a thickened, fibrotic myocardium, remains the most common cause of sudden cardiac death in young adults. Based on animal and clinical data, we hypothesized that atorvastatin would induce left ventricular (LV) mass regression.Methods:Statin Induced Regression of Cardiomyopathy Trial (SIRCAT) was a randomized, placebo-controlled study. The primary endpoint was change in LV mass measured by cardiac magnetic resonance imaging 12 months after treatment with once-daily atorvastatin 80 mg or placebo. A key secondary endpoint was diastolic dysfunction measured echocardiographically by transmitral flow velocities. SIRCAT is registered with www.clinicaltrials.gov (NCT00317967).Results:Of 222 screened patients, 22 were randomized evenly to atorvastatin and placebo. The mean age was 47 ± 10 years, and 15 (68%) were male. All subjects completed the protocol. At baseline, LV masses were 197 ± 76 g and 205 ± 82 g in the placebo and atorvastatin groups, respectively. After 12 months treatment, the LV masses in the placebo and atorvastatin groups were 196 ± 80 versus 206 ± 92 g (P = 0.80), respectively. Echocardiographic indices were not different in the two groups at baseline. After 12 months, diastolic dysfunction as assessed using transmitral flow velocities E/E', A/A', and peak systolic mitral velocity showed no benefit from atorvastatin.Conclusions:In patients with HCM, atorvastatin did not cause LV mass regression or improvements in LV diastolic function.

Traumatic Brain Injury Models in Animals.

Traumatic brain injury (TBI) is the leading cause of death in young adults in industrialized nations and in the developing world the WHO considers TBI a silent epidemic caused by an increasing number of traffic accidents. Despite the major improvement of TBI outcome in the acute setting in the past 20 years, the assessment, therapeutic interventions, and prevention of long-term complications remain a challenge. In order to get a deeper insight into the pathology of TBI and advancement of medical understanding and clinical progress experimental animal models are an essential requirement. This chapter provides an overview of most commonly used experimental animal TBI models and the pathobiological findings based on current data. In addition, limitations and advantages of each TBI model are mentioned. This will hopefully give an insight into the possibilities of each model and be of value in choosing one when designing a study.

Sudden unexpected deaths of young adults in a tertiary care hospital for a period of four years

Introduction Sudden unexpected natural death of a young adult is rare, but has a disproportionate impact on the community. This always requires a systematic forensic autopsy. At the completion of the autopsy it is expected to have the answers for all unanswered questions. However it is a challenge to the forensic pathologist since there are many sudden deaths without significant morphological anomalies. Objective : The aim of the study was to identify the causes and characteristics of sudden death among the young adults (less than 40 years of age) Study Design : Retrospective descriptive study was done based on the reports of post mortems performed on young adults who had died suddenly and unexpectedly due to natural reasons during past 4 years. The information was gathered on a pro-forma to fulfill the objectives. The data was analyzed using SPSS statistical package version 18. Results : Out of 54 autopsies analyzed, 78 % were males. 39% of the victims were of the age group of 36 to 40 years. 33% of the victims were brought to hospital before death. In 76% of the cases, a cause of death could be identified after macroscopic autopsy examination and the percentage increased to 89% after microscopy. Microscopy revealed or confirmed the cause of death in 52% of the cases. 44% were victims of sudden cardiac death. Cause of death was unascertained at the end of all the investigations in 11% of the cases. Conclusions Cause of death has a cardiac origin in majority of sudden unexpected deaths in young adults in the sample examined. Macroscopic autopsy examination could identify a cause of death in majority while abnormalities identified at microscopic examination accounted for death in nearly half of the sudden unnatural deaths in young adults. Medico-Legal Journal of Sri Lanka 2014; 2(1) : 15-21

Abstract 12532: Cellular and Cardiac Microtissue Assays of iPSC-derived Myocytes With the Hypertrophic Cardiomyopathy Mutation in MYH7-Val606Met

Introduction: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease affecting 1 in 500 people and is the leading cause of sudden cardiac death in young adults. Mutations in β-myosin heavy chain ( MYH7 ) account for one-third of cases, but the underlying pathogenesis remains unclear. In this study, we investigated myocytes derived from CRISPR-Cas9-engineered isogenic induced pluripotent stem cell cardiomyocytes (iPSC-CMs) with a missense mutation Val606Met by single-cell and microtissue functional assays. Hypothesis: We hypothesize that iPSC-CMs with Val606Met will recapitulate features of HCM in single cell and microtissue assays, such as changes in contractile function and hypertrophic signaling. Methods & Results: Val606Met mutations in MYH7 (VM/+, VM/VM) were introduced by targeting an iPSC line using CRISPR-Cas9. Transfected iPSCs were isolated by FACS to detect green fluorescent protein, clones were expanded, and mutational events were confirmed by Sanger sequencing. Mutant iPSCs, like isogenic wildtype control iPSCs, were differentiated into cardiomyocytes with >90% efficiency. Microtissue studies of mutant iPSC-CMs exhibited increases in contractility (WT=2.96±0.23μN, VM/+ = 3.51±0.34μN, VM/VM = 4.63±0.51; R 2 = 0.963). Mutant iPSC-CMs also showed evidence of altered signaling by increases in spontaneous beating rate (WT < VM/+ < VM/VM; R 2 =0.946), cell size (compared to WT, ~20% increases in both VM/+, p=0.04 and VM/VM, p=0.038), and sarcomere content (compared to WT, ~20% increases in both VM/+, p=4e-06 and VM/VM, p=0.11). These changes are supported by activated expression in myocytes of hypertrophic genes such as NPPA , NPPB , and ACTA2 as well as transcriptional up-regulation of TGF-β. Conclusions: Isogenic iPSC-CMs with MYH7 variant Val606Met created by CRISPR-Cas9 recapitulate features of HCM in vitro . Our data confirms Val606Met as a pathogenic mutation that causes increased contractility in cardiac microtissues and myocyte hypertrophy. We speculate that increased myocyte-derived TGF-β signaling may contribute to the HCM phenotype. This approach could also be used for better understanding of genotype-phenotype correlations in HCM.

Sudden cardiac death in young adults with previous hospital-based psychiatric inpatient and outpatient treatment: a nationwide cohort study from Denmark.

Psychiatric patients have premature mortality compared to the general population. The incidence of sudden cardiac death (SCD) in psychiatric patients is unknown in a nationwide setting. The aim of this study was to compare nationwide SCD incidence rates in young individuals with and without previous psychiatric disease. Nationwide, retrospective cohort study including all deaths in people aged 18-35 years in 2000-2006 in Denmark. The unique Danish death certificates and autopsy reports were used to identify SCD cases. Psychiatric disease was defined as a previous psychiatric hospital contact and was identified using The Danish Psychiatric Central Research Register. All diagnoses in Danish registries are coded according to ICD-8 or ICD-10. All hospital records were retrieved manually. Among 5,178 deaths, 395 were due to SCD and autopsies were performed on 262 (66%). In 77 SCD cases, a previous psychiatric hospital contact was identified. The SCD incidence rate in psychiatric patients was 14.8 (95% CI, 11.7-18.5) per 100,000 person-years versus 3.8 (95% CI, 3.4-4.3) per 100,000 person-years in individuals without psychiatric hospital contact (incidence rate ratio = 3.9; 95% CI, 3.0-5.0; P < .01). Incidence rates per 100,000 persons-years were the highest in patients with schizophrenia-spectrum disorders (38.9; 95% CI, 26.4-55.2) and substance-related disorders (31.6; 95% CI, 19.3-48.8). SCDs in psychiatric patients compared to nonpsychiatric patients were more often unexplained (65% vs 40%, P = .02), and cardiac symptoms were reported prior to death in 46% of psychiatric patients. Patients with prior psychiatric hospital contact have a 4-fold increased risk of SCD. Since almost 50% had possible cardiac symptoms prior to death, cardiovascular risk monitoring and management in the mentally ill are essential.

Stolen lives and missed opportunities: The deaths of young adults and children in prison

Stolen lives and missed opportunities: The deaths of young adults and children in prison

New cause of death in young adults: Association between illicit drug abuse and amyotrophic lateral sclerosis

Background: Neurodegenerative effects of illicit drugs have been proposed in many investigations. Amyotrophic lateral sclerosis is a fatal motor neuron disease characterized by degeneration of motor neurons, but the risk of amyotrophic lateral sclerosis among drug abusers is unknown. Methods: A nested case–control study was conducted in a teaching hospital to examine the association between drug abuse and amyotrophic lateral sclerosis. The study population included persons 18 to 40 years of age who were admitted in an electrodiagnostic medicine clinic for more than two year during the study period (January 2013 through April 2015) For each subject with ALS, 2 smoking-matched controls without ALS were randomly selected from the same population. Self-reported history of drug abuse was acceptable in both groups. Results: A total of 17 persons with ALS and 34 controls were identified, of whom 10 (58.8 percent) and 8 (23.5), respectively, had history of drug abuse. Persons with history of drug abuse had an increased risk of ALS (adjusted odds ratio, 2.6; 95 percent confidence interval, 1.2 to 5.7) as compared with controls. Conclusion: Drug abuse is an important risk factor for ALS, at least among young adults. The risk among drug abusers was at least or about double that among control group. The burden of mortality due to background ALS in drug abusers needs to be determined in future investigations.

Sudden Cardiac Death in Three Generations of the Same Family: A case report

Every one of us has heard about tragic and sudden death of a healthy young person and which is often stated as ‘inexplicable’. The current case report focuses on a 20 year old young man with hypertrophic cardiomyopathy facing premature death with history of similar sudden premature death of his grandmother, father and brother. Hypertrophic cardiomyopathy is the commonest cause of sudden cardiac death in young adults and is also an important substrate for heart failure disability at any age.Cardiovasc. j. 2015; 8(1): 73-77

Massive parallel sequencing applied to the molecular autopsy in sudden cardiac death in the young

Sudden cardiac death in the young is a very traumatic event that occurs often in apparently healthy individuals without an explainable cause of death after a comprehensive medico-legal investigation. Knowledge about the pathologies with a risk of sudden death is increasingly showing a greater underlying genetic heterogeneity, which provides one of the main handicaps for molecular autopsy. On the other hand the enormous technological advances in sequencing technologies, allow us to analyse as many genes as we want at a cost increasingly reduced. The sum of these two factors (increased knowledge of genetics and available technologies) allow us to make an individualized study of the causes of sudden cardiac death in young adults, through massive sequencing of all potential genes involved in the process. We define this approach as massive genomic autopsy, and with this review we will try to explain the possible scenarios and methods available for its implementation.

Application of next-generation semiconductor sequencing technologies in genetic diagnosis of inherited cardiomyopathies

Inherited cardiomyopathy is the most common hereditary cardiac disease. It also causes a significant proportion of sudden cardiac deaths in young adults and athletes. So far, approximately one hundred genes have been reported to be involved in cardiomyopathies through different mechanisms. Therefore, the identification of the genetic basis and disease mechanisms of cardiomyopathies are important for establishing a clinical diagnosis and genetic testing. Next-generation semiconductor sequencing (NGSS) technology platform is a high-throughput sequencer capable of analyzing clinically derived genomes with high productivity, sensitivity and specificity. It was launched in 2010 by Life Technologies of USA, and it is based on a high density semiconductor chip, which was covered with tens of thousands of wells. NGSS has been successfully used in candidate gene mutation screening to identify hereditary disease. In this review, we summarize these genetic variations, challenge and application of NGSS in inherited cardiomyopathy, and its value in disease diagnosis, prevention and treatment.

Analysis of Statistical Biases in Studies Used to Formulate Guidelines: The Case of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) The Case of ARVC

To analyze the statistical biases in the studies used to derive cardiac magnetic resonance-based major and minor criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC is a rare disorder of the heart that can lead to sudden death in young adults. Cardiac magnetic resonance imaging (CMR) plays a role in the diagnosis by contributing to the criteria set by experts. The original criteria emphasized qualitative analysis of CMR. The criteria were modified in 2010 to provide quantitative cutoffs. We apply the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool for systematic review of diagnostic accuracy to the studies cited in the guidelines written in 1994 and revised in 2010. We use the signaling questions in QUADAS-2 to identify different types of statistical bias. The studies have understandable biases that affect the sensitivity and specificity of CMR in the diagnosis of ARVC, as well as the truth of the disease state. There is potential to overdiagnose ARVC particularly in low prevalence populations.

Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects

Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome first described as a new clinical entity in 1992. Electrocardiographically characterized by distinct coved type ST segment elevation in the right-precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young adults, and less frequently in infants and children. The electrocardiographic manifestations of BrS are often concealed and may be unmasked or aggravated by sodium channel blockers, a febrile state, vagotonic agents, as well as by tricyclic and tetracyclic antidepressants. An implantable cardioverter defibrillator is the most widely accepted approach to therapy. Pharmacologic therapy is designed to produce an inward shift in the balance of currents active during the early phases of the right ventricular action potential (AP) and can be used to abort electrical storms or as an adjunct or alternative to device therapy when use of an implantable cardioverter defibrillator is not possible. Isoproterenol, cilostazol, and milrinone boost calcium channel current and drugs like quinidine, bepridil, and the Chinese herb extract Wenxin Keli inhibit the transient outward current, acting to diminish the AP notch and thus to suppress the substrate and trigger for ventricular tachycardia or fibrillation. Radiofrequency ablation of the right ventricular outflow tract epicardium of patients with BrS has recently been shown to reduce arrhythmia vulnerability and the electrocardiographic manifestation of the disease, presumably by destroying the cells with more prominent AP notch. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of BrS as well as the approach to therapy.