Death In Young Adults Research Articles

The genetic basis of sudden death in young people - Cardiac and non-cardiac.

Sudden death is one of the major causes of death in young adults. Sudden death could be a result from both genetic and environmental or acquired factors. Understanding the genetic etiology is crucial to prevent preventable sudden death for those who are not aware of their genetic condition. In fact, the spectrum of causes of sudden death is complex and varied. In this study, we reviewed the genes that are associated with multiple causes of sudden death in terms of both sudden cardiac death and sudden noncardiac death. A summary of genetic risk factors of the major causes of genetic relevant sudden death is also provided. We believe this review could benefit the researchers who are interested in sudden death genetic studies or the young people who are concerning about their own risk on sudden death.

Anatomical Injury Clusters in Polytrauma Patients.

Polytrauma is a major cause of death in young adults. The trial was to identify clusters of interlinked anatomical regions to improve strategical operational planning in the acute situation. A total of 2219 polytrauma patients with an ISS (Injury Severity Score) ≥ 16 and an age ≥ 16 years was included into this retrospective cohort study. Pearson's correlation was performed amongst the AIS (Abbreviated Injury Scale) groups. The predictive quality was tested by ROC (Receiver Operating Curve) and their area under the curve. Independency was tested by the binary logistic regression, AIS ≥3 was taken as a significant injury. The analysis was conducted using IBM SPSS® 24.0. The highest predictive value was reached in the combination of thorax, abdomen, pelvis and spine injuries (ROC: abdomen for thorax 0.647, thorax for abdomen 0.621, pelvis for thorax 0.608, pelvis for abdomen 0.651, spine for thorax 0.617). The binary logistic regression revealed the anatomical regions thorax, abdomen pelvis and spine as per-mutative independent predictors for each other when a particular injury exceeded the AIS ≥3. The documented clusters of injuries in truncal trauma are crucial to define priorities in the polytrauma management.

Anomalía de Ebstein como causa de muerte súbita. Presentación del primer caso de autopsia forense en panamá

Sudden cardiac death in young adults is often the first manifestation of an underlying cardiac disease not diagnosed previously. We present the case of sudden death in a 33-year-old male which occurred immediately after significant physical exertion. The autopsy revealed the existence of Ebstein´s disease that had not been diagnosed during the patient´s lifetime. Ebstein´s anomaly is a very rare congenital malformation that affects the tricuspid valve and is characterized, among other findings, by a severe dilatation of the right atrium with displacement of the septal and posterior leaflets towards the apex of the right ventricle with atrialization of part of it. As far as we know, this is the first case diagnosed after forensic autopsy in Panama. Due to its low frequency, this anomaly presents diagnostic challenges so it is not usually identified in life. Therefore, it is necessary for pathologists and forensic specialists to be familiar with it and to bear in mind among the differential diagnoses in cases of sudden death, especially in adolescents and young adults. Finally, a historical journey through the interesting life and work of Dr. Wilhelm Ebstein is carried out.

Arterial fibromuscular dysplasia as a factor in sudden cardiac death in young adults

The objective of the study is to consider the problem of diagnostics of a rare vasculopathy, fibromuscular dysplasia of coronary arteries, by the case study of a 19-year-old serviceman, an athlete with sudden death occurred during slight physical exertion. After repeated histological examination as part of the forensic medical examination, the diagnosis was made: «multifocal fibromuscular dysplasia of the coronary arteries and ascending aortic arch, complicated by acute left ventricular failure.» This disease often manifests with the acute coronary syndrome in people of young age. Therefore, special attention was given to the macroscopic and histological features of fibromuscular dysplasia of arteries.

Parental Death and Mid-adulthood Depressive Symptoms: The Importance of Life Course Stage and Parent's Gender.

Traditional theories of grief suggest that individuals experience short-term increases in depressive symptoms following the death of a parent. However, growing evidence indicates that effects of parental bereavement may persist. Situating the short- and long-term effects of parental death within the life course perspective, we assess the combined influence of time since loss and life course stage at bereavement on mental health for maternal and paternal death. Using data from the National Longitudinal Study of Adolescent to Adult Health (N = 11,877) to examine biological parental death from childhood to mid-adulthood, we find that those who experience recent maternal or paternal death have heightened depressive symptoms. Furthermore, those who experience maternal death in childhood or paternal death in young adulthood exhibit long-term consequences for mental health. Our findings underscore the theoretical importance of early life course stages and parent's gender when determining whether depressive symptoms persist following parental bereavement.

CHARACTERISATION OF HYPERTROPHIC CARDIOMYOPATHY BY CARDIAC MAGNETIC RESONANCE IMAGING

Background: There are many causes of left ventricular hypertrophy which can result in arrhythmias and sudden cardiac death. Hypertrophic cardiomyopathy (HCM) is one of the commonly encountered cause of sudden cardiac death in young adults. Aim: Identifying the role of Cardiac MRI in characterising the diagnostic parameters of HCM. Materials and methods: 125 patients with clinical suspicion or genetic evidence of HCM referred for cardiac MRI between June 2013 to June 2021 were included under the study. Image interpretations were done by fellowship qualified cardiac imaging radiologist. Categorical variables were expressed using frequency and percentage. Numerical variables were presented using mean and standard deviation. Results: Out of the total population, 119 patients (95 %) had LV wall thickness > 13 mm, 48 patients (38.4%) had Left ventricle outflow tract obstruction (LVOTO) and 32 patients (25.6 %) had mid cavity obstruction, 39 patients (37.9 %) had myocardial scar > 15 % and asymmetric septal hypertrophy was the most frequently encountered left ventricle morphology Conclusion: Cardiac MRI detected HCM has a statistically significant association with the final diagnosis (histopathological and genetic correlation). CMRI hence serves as a reliable tool in identifying and characterising the various diagnostic and non- diagnostic parameters of HCM.

Abstract 13258: Transcriptomic Remodeling of Brugada Syndrome Arises During in vitro Cardiac Development

Introduction: Recent genetic data suggest that abnormal cardiac development participate to the pathogenesis of Brugada Syndrome (BrS), a rare inherited arrhythmia responsible for sudden cardiac death in young adults. In vitro cardiac differentiation of human induced pluripotent stem cells (hiPSCs) mimics cardiac development at the cellular level up to a prenatal stage. Objective: This study aims at defining whether BrS impairs cardiac differentiation of hiPSCs. Methods & Results: Transcriptomic kinetics (daily bulk 3’RNA-seq from day 0 to day 30 of in vitro cardiac differentiation) were generated in triplicate for 2 control hiPSC lines and 2 BrS-patient hiPSC lines. First, global analysis unveiled that BrS and control kinetics start to diverge as early as day 8, coinciding with the emergence of beating cells. The 500 most differentially expressed genes between BrS and control kinetics revealed 7 main distinct expression profiles. Interestingly, in one of the clusters (Cluster 2), enriched in genes involved in ventricular development ( e.g. IRX4 , NKX2-5 ), the expression levels were higher in BrS as compared to control, starting at day 8. Inversely, another cluster (Cluster 4), enriched in genes involved in atrial development ( e.g. TBX18 , PITX2 ), displayed an opposite expression profile. Cell-type annotation of single-cell RNA-seq data obtained at day 30 of cardiac differentiation for 1 control (n=2; 11,499 cells) and 1 BrS hiPSCs line (n=2; 12,142 cells) confirmed this ventricular-to-atrial imbalance with an average ventricular-to-atrial cell number ratio of 0.97 and 8.27 for control and BrS lines, respectively. Conclusion: This first transcriptomic kinetic study supports the hypothesis of an early developmental defect in BrS. Altogether, our data show that BrS hiPSCs are more prone to ventricular specification as compared to control cells. This suggests that an abnormal cell fate during cardiac differentiation may participate to BrS pathogeny.

A Simulation Study on Electrical Activity of Ventricular Endocardial Tissue due to SCN5A L812Q Mutation.

Brugada Syndrome is a rare arrhythmia, hereditary in nature. It is caused due to mutation in genes that encodes sodium ion channels and it results sudden cardiac death in young adults. This paper aims to model a two dimensional SCN5A L812Q mutated endocardial tissue by modifying the model equations for sodium ion channel in the Ten Tusscher model for human ventricular tissue. Results show that the propagation of electrical activity in the mutated cells is slower when compared to the normal cells of the endocardial tissue. From this it is concluded that there is a large reduction of sodium current in the mutated region of the endocardial tissue. This leads to reduction in the total ionic current as well and further reduces the membrane potential. It also leads to the slower propagation of action potential in the mutated region when compared to the normal endocardial tissue.Clinical Relevance- This establishes the propagation of electrical activity in endocardial tissue for SCN5A L812Q gene mutation that results in arrhythmia called Brugada Syndrome.

Lethal variants in humans: lessons learned from a large molecular autopsy cohort

BackgroundMolecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans.MethodsWe describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels.ResultsThe study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results.ConclusionsMolecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.

Specialized pro-resolving mediators prevents cardiac dysfunction by modulating Ca2+ handling and NRF2 axis

Abstract Background and purpose Myocarditis is a severe inflammatory heart disease and a leading cause of sudden death in young adults; but currently no specific treatment is available. Lipoxins and their derivatives promote the resolution of inflammation contributing to recover tissue homeostasis; but their role in cardiac inflammation is poorly understood. Methods and results BML-111, a stable lipoxin A4 receptor agonist, protects against cardiac dysfunction in a murine model of experimental autoimmune myocarditis (EAM) by preventing Ca2+ mishandling. Cardiac proteomic analysis revealed an enhanced cardiac oxidative profile in EAM-induced mice with reduced activation of NRF2, a master antioxidant transcription factor. In vitro analysis showed that 15-epi-lipoxin A4 increased systolic Ca2+ release and sarcoplasmic reticulum (SR)-Ca2+ load in cardiomyocytes isolated from wild-type mice and augmented the rate of SR-Ca2+ uptake by SERCA2a, but failed to induce any functional change in cells from Nrf2−/− mice. BML-111 increased SERCA2a cardiac expression in wild-type mice, and the transcriptional activity of Nrf2 determined SERCA2a expression in human ventricular cells. Human myocarditis-positive myocardium showed a reduced expression of both ATP2A2 (SERCA2a) and NF2L2 (NRF2). Conclusions Our results demonstrated new cardioprotective mechanisms of pro-resolving lipid mediators that may emerge as innovative treatments for myocarditis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ISCIII [PI17/01344]), Sociedad Española de Cardiología: Proyecto Traslacional 2019Fondo Europeo de Desarrollo Regional (FEDER), FSE, and CIBER-CV, a network funded by ISCIII

Role Of Laparoscopy In Blunt Abdominal Trauma: A Comparative Prospective Cohort Study Between Laparoscopy And Laparotomy In Patients With Blunt Abdominal Trauma

Abstract Background Trauma is considered to be the main leading cause of death in young adults under 35 years old. Blunt mechanisms accounts for about 95% of injuries. Generally, laparotomy is considered to be the standard procedure used in the trauma cases. Recently, laparoscopic techniques have been increasingly introduced as an alternative to open surgery in trauma cases. This study aims to assess the efficacy of Laparoscopy in management of patients with Blunt abdominal trauma in order to avoid unnecessary laparotomies. Objective To investigate the effectiveness and role of laparoscopy in the management of blunt abdominal trauma patients. Patients and Methods Observational prospective cohort study. Ain Shams University Surgery Hospital. All isolated blunt abdominal trauma patients at Ain Shams University Surgery hospital from 1/3/2019 to 1/9/2019. Eligibility and exclusion criteria applied as following: Eligibility criteria All patients with blunt abdominal trauma presented to ASUH. Patients with class I &class II according to ATLS guidelines for hemorrhagic shock in trauma patients. Patients aged 18 years old or above. Exclusion criteria: Patients with class III &class IV according to ATLS guidelines for hemorrhagic shock in trauma patients. Pregnant patients. Patients with old trauma presented after 24 hours. Patients discharged on demand. Results Laparoscopy decreased the operative time in comparison with laparotomy, the mean operative time for patients underwent laparoscopy is 123.28 minutes while in patients underwent laparotomy is 150.48. Also, time to pass gas post operative after laparoscopy is 1-3 days compared to 2-4 days after laparotomy which is in favor of laparoscopy which is associated with rapid recovery of patients. Laparoscopy is associated with decreased post operative ICU stay (1-3) days in comparison with Laparotomy (2-5) days and decreased total hospital stay. The rate of complications after laparoscopy is much less than after laparotomy, 2 patients with respiratory tract infections after laparoscopy and no mortality while six patients with respiratory tract infections, 6 patients with wound infection, one patient with deep venous thrombosis and 2 patients died after laparotomy. Conclusion Laparoscopy is found to be a good alternative to laparoscopy, as it is considered to be reliable and safe as a diagnostic and treatment method in hemodynamically stable patients with blunt abdominal trauma, it can be used to reduce the laparotomy rate, and it is associated with lower morbidity and mortality.

39-YEAR-OLD WITH LEGIONELLA MYOCARDITIS

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Myocarditis is an inflammatory condition of the myocardium. Legionella is a known rare infectious cause of myocarditis. Additionally, it has been implicated with pericarditis and prosthetic valve endocarditis. We present a case of a 39-year-old male with legionella pneumonia with myocarditis, acute renal failure, and rhabdomyolysis. CASE PRESENTATION: A 39-year-old male with no known past medical history presented to the emergency department with worsening dyspnea after a viral syndrome for 3 weeks. He was intubated in the emergency department for respiratory failure. Chest x-ray showed multifocal atypical infiltrates. Electrocardiogram significant for diffuse ST depressions. Echocardiogram revealed severe left ventricular systolic dysfunction with ejection fraction of 30% with no valvular abnormalities. Lab analysis revealed hyponatremia, elevated troponins and acute renal failure with rhabdomyolysis requiring hemodialysis. Atypical serology was positive for Legionella which was treated with levofloxacin and azithromycin. SARS-CoV-2 PCR was negative and urine drug screen was negative. He was diagnosed with myocarditis given the legionella culture, elevated troponins, significant for electrocardiogram and echocardiogram findings. DISCUSSION: The first case of Legionella myocarditis was reported in 1981 by Gross [1]. Symptoms of myocarditis can range from a mild flu-like illness to cardiogenic shock or sudden death. Myocarditis is the cause of 12% of sudden deaths in young adults [2]. Diagnosis is typically made clinically with non-diagnostic exams, as endomyocardial biopsy is only used for special circumstances when other testing are non-diagnostic. A literature review of Legionella myocarditis as of 2017 portrayed ten patients with positive Legionella urine antigens, with eight having reduced left ventricular ejection fraction on echocardiogram. Only two of those cases were based on cardiac biopsy [3]. CONCLUSIONS: Extrapulmonary manifestations of Legionella such as myocarditis have been reported even in the absence of overt pneumonia, and most often in immunocompromised patients. Clinicians should be aware of Legionella in the setting of unexplained myocarditis with findings as above. Treatment should be initiated for this reversible cause of myocarditis without delay, resulting in favorable prognosis. REFERENCE #1: Armengol, S., Domingo, C., Messales, E., (1992). Myocarditis: a rare complication during Legionella infection. DOI: 10.1016/0167-5273(92)90276-9 REFERENCE #2: Damasio, A.F, Rodriguez, L., Miranda, L/, Coelho, P., Banazol, N., Colaco, J., Fragata, J. (2014). Fulminant myocarditis caused by Legionella pneumophila: Case report. Revista Portuguesa de Cardiologia. Vol 33, Issue 3. https://doi.org/10.1016/j.repce.2013.09.015 REFERENCE #3: Erdogan, Haluk & Eldem, Halil. (2017). A Patient with Suspected Myocarditis Associated with Legionnaires' Disease: A Case Report and Review of the Literature. Mediterr J Infect Microb Antimicrob. 6. 10.4274/mjima.2017.2. DISCLOSURES: No relevant relationships by James McGee, source=Web Response No relevant relationships by Visala Natarajan, source=Web Response no disclosure on file for Ben Shamian

Inequities in adolescent and young adult deaths

On the heels of hard-won gains in infant and child survival in most parts of the world, we now have the largest generation of adolescents in human history. This shows the importance of realising the potential for young people to participate in shaping the future and contribute to communities they are part of. This potential, however, will not be fulfilled by merely being alive. We must consider the opportunities and threats that influence the wellbeing and agency of young people at this crucial stage of human development.

Molecular autopsy and subsequent functional analysis reveal de novo DSG2 mutation as cause of sudden death

Sudden cardiac death (SCD) is a common cause of death in young adults. In up to 80% of cases a genetic cause is suspected. Next-generation sequencing of candidate genes can reveal the cause of SCD, provide prognostic management, and facilitate pre-symptomatic testing and prevention in relatives. Here we present a proband who experienced SCD in his sleep for which molecular autopsy was performed.We performed a post-mortem genetic analysis of a 49-year-old male who died during sleep after competitive kayaking, using a Cardiomyopathy and Primary Arrhythmia next-generation sequencing panel, each containing 51 candidate genes. Autopsy was not performed.Genetic testing of the proband resulted in missense variants in KCNQ1 (c.1449C > A; p.(Asn483Lys)) and DSG2 (c.2979G > T; p.(Gln993His)), both absent from the gnomAD database. Familial segregation analysis showed de novo occurrence of the DSG2 variant and presence of the KCNQ1 variant in the proband's mother and daughter. KCNQ1 p.(Asn483Lys) was predicted to be pathogenic by MutationTaster. However, none of the KCNQ1 variant carrying family members showed long QTc on ECG or Holter. We further functionally analysed this variant using patch-clamp in a heterologous expression system (Chinese Hamster Ovary (CHO) cells) expressing the KCNQ1 mutant in combination with KCNE1 wild type protein and showed no significant changes in electrophysiological function of Kv7.1.Based on the above evidence, we concluded that the DSG2 p.(Gln993His) variant is the most likely cause of SCD in the presented case, and that there is insufficient evidence that the identified KCNQ1 p.(Asn483Lys) variant would confer risk for SCD in his mother and daughter. Fortunately, the DSG2 variant was not inherited by the proband's two children. This case report indicates the added value of molecular autopsy and the importance of subsequent functional study of variants to inform patients and family members about the risk of variants they might carry.

Inhibition of calpain reduces cell apoptosis by suppressing mitochondrial fission in acute viral myocarditis

Cardiomyocyte apoptosis is critical for the development of viral myocarditis (VMC), which is one of the leading causes of cardiac sudden death in young adults. Our previous studies have demonstrated that elevated calpain activity is involved in the pathogenesis of VMC. This study aimed to further explore the underlying mechanisms. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin were infected with coxsackievirus B3 (CVB3) to establish a VMC model. Apoptosis was detected with flow cytometry, TUNEL staining, and western blotting. Cardiac function was measured using echocardiography. Mitochondrial function was measured using ATP assays, JC-1, and MitoSOX. Mitochondrial morphology was observed using MitoTracker staining and transmission electron microscopy. Colocalization of dynamin-related protein 1 (Drp-1) in mitochondria was examined using immunofluorescence. Phosphorylation levels of Drp-1 at Ser637 site were determined using western blotting analysis. We found that CVB3 infection impaired mitochondrial function as evidenced by increased mitochondrial ROS production, decreased ATP production and mitochondrial membrane potential, induced myocardial apoptosis and damage, and decreased myocardial function. These effects of CVB3 infection were attenuated by inhibition of calpain both by PD150606 treatment and calpastatin overexpression. Furthermore, CVB3-induced mitochondrial dysfunction was associated with the accumulation of Drp-1 in the outer membrane of mitochondria and subsequent increase in mitochondrial fission. Mechanistically, calpain cleaved and activated calcineurin A, which dephosphorylated Drp-1 at Ser637 site and promoted its accumulation in the mitochondria, leading to mitochondrial fission and dysfunction. In summary, calpain inhibition attenuated CVB3-induced myocarditis by reducing mitochondrial fission, thereby inhibiting cardiomyocyte apoptosis.Graphical abstractCalpain is activated by CVB3 infection. Activated calpain cleaves calcineurin A and converts it to active form which could dephosphorylate Drp-1 at Ser637 site. Then, the active Drp-1 translocates from the cytoplasm to mitochondria and triggers excessive mitochondrial fission. Eventually, the balance of mitochondrial dynamics is broken, and apoptosis occurs.

Maladaptive Perfectionism, Impostor Phenomenon, and Suicidal Ideation Among Medical Students.

Suicide is a leading cause of death for young adults, and medical students experience elevated rates of suicide and suicidal ideation. The present study uses mediation analysis to explore relationships between suicidal ideation and two dysfunctional mindsets common among medical students: maladaptive perfectionism, high standards accompanied by excessive self-criticism, and impostor phenomenon, pervasive feelings of inadequacy despite evidence of competence and success. Two hundred and twenty-six medical students at a single institution completed an online survey which assessed maladaptive perfectionism, impostor phenomenon, and suicidal ideation. After calculating measures of association between all study variables, linear regression was conducted to establish the relationship between maladaptive perfectionism and suicidal ideation. To evaluate whether impostor phenomenon mediated the relationship between maladaptive perfectionism and suicidal ideation as hypothesized, a series of regression models were constructed and the regression coefficients were examined. The statistical significance of the indirect effect, representing the mediated relationship, was tested using bootstrapping. Significant positive associations between maladaptive perfectionism, impostor phenomenon, and suicidal ideation were observed. Impostor phenomenon score was found to mediate the relationship between maladaptive perfectionism and suicidal ideation. Medical students who exhibit maladaptive perfectionism are at increased risk for feelings of impostor phenomenon, which translates into increased risk for suicide. These results suggest that an intervention targeted at reducing feelings of impostor phenomenon among maladaptive perfectionists may be effective in reducing their higher risk for suicide. However, interventions promoting individual resilience are not sufficient; systemic change is needed to address medicine's "culture of perfection."

Inhibition of Calpain Alleviates Apoptosis in Coxsackievirus B3-induced Acute Virus Myocarditis Through Suppressing Endoplasmic Reticulum Stress.

Virus myocarditis (VMC) is a common cardiovascular disease and a major cause of sudden death in young adults. However, there is still a lack of effective treatments. Our previous studies found that calpain activation was involved in VMC pathogenesis. This study aims to explore the underlying mechanisms further. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin (Tg-CAST), the endogenous calpain inhibitor, were used to establish VMC model. Hematoxylin and eosin and Masson staining revealed inflammatory cell infiltration and fibrosis. An ELISA array detected myocardial injury. Cardiac function was measured using echocardiography. CVB3 replication was assessed by capsid protein VP1. Apoptosis was measured by TUNEL staining, flow cytometry, and western blot. The endoplasmic reticulum (ER) stress-related proteins were detected by western blot. Our data showed that CVB3 infection resulted in cardiac injury, as evidenced by increased inflammatory responses and fibrosis, which induced myocardial apoptosis. Inhibiting calpain, both by PD150606 and calpastatin overexpression, could attenuate these effects. Furthermore, ER stress was activated during CVB3 infection. However, calpain inhibition could downregulate some ER stress-associated protein levels such as GRP78, pancreatic ER kinase-like ER kinase (PERK), and inositol-requiring enzyme-1α (IRE-1α), and ER stress-related apoptotic factors, during CVB3 infection. In conclusion, calpain inhibition attenuated CVB3-induced myocarditis by suppressing ER stress, thereby inhibiting cardiomyocyte apoptosis.

Suicide in young Brazilian adults: 1997-2019 time series.

This study aimed to analyze the time series of suicide mortality in Brazilian young adults between 1997 and 2019. This is an ecological study on time series with individuals aged 20 to 29 years. The Prais-Winsten regression was used for trend analysis. The mean suicide coefficient in young Brazilians was 6.36/100 thousand inhabitants in the period, showing increasing overall, females, and male trends. Regarding marital status, there was a higher proportion of suicide among single people (79.02%). As for the Brazilian regions, the South presented the highest mean mortality coefficient (9.18/100 thousand inhabitants), and the Northeast, North, and Southeast regions showed an increasing trend. Most deaths occured at home (54.93%), and there was an increasing trend both at home, at health establishments, and other places. We conclude that the suicide trend in Brazilian young adults was increasing in the period, with more significant proportions among single people. Brazilian regions showed different trends, and households, health facilities, and other locations followed an increasing trend toward suicide deaths in young adults.

An Autopsy Study of Rheumatic Heart Disease: A Prevalent Iceberg Disease

Cardiovascular diseases are a chief cause of sudden death. Rheumatic Heart Disease (RHD) exists as a hidden burden in developing countries. It occurs as a sequelae to Rheumatic Fever caused by Group A β Hemolytic Streptococcus. Despite the existence of antibiotics and prophylaxis by Penicillin it is still prevalent. A 33 year old male was found unresponsive in his house and was later declared dead. He had a history of abdominal pain for the past 6 months for which he was on medication. There was no other relevant family and past history. He had no history of alcohol intake or smoking. Complete medico legal autopsy was done and confirmed to be RHD. RHD is an “iceberg” disease which is still prevalent in developing countries. A cross reaction between foreign antigen and cardiac proteins leads to formation of autoantibodies causing autoimmune reaction. Mitral valve is commonly involved. RHD diagnosis can be established using Jones criteria during clinical examination. RHD still exists despite use of advanced antibiotics and Penicillin prophylaxis and needs to be therefore considered as a diagnosis of sudden death of young adults.

Characterization and modelling of the abnormal electrophysiological response under beta-adrenergic stimulation in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Introduction Hypertrophic Cardiomyopathy (HCM) is the most common inheritable heart pathology and the main cause of sudden cardiac death in young adults. HCM patients often present an enhanced arrhythmogenicity that can lead to lethal arrhythmias, especially during exercise. Recent studies have shown an abnormal response of HCM myocytes to β-adrenergic stimulation (β-ARS), with prolongation of their action potential duration (APD). The mechanisms underlying this aberrant response to sympathetic stimulation remain unknown. Purpose To investigate the key ionic mechanisms underlying the HCM abnormal response to β-ARS using human-based experimental and computational methodologies. Methods Experimental ionic currents, action potential and calcium transient were recorded in human adult cardiomyocytes from control and HCM patients. Isoproterenol (10-7 mol/L) was used to elicit β-ARS. Whole-cell ruptured patch voltage clamp experiments were conducted to characterise L-type calcium and potassium currents, with recordings performed before and after 3 min of drug exposure. The latest models of human ventricular electrophysiology and beta-adrenergic receptor signalling were integrated and calibrated using the human measured data. Simulations under isoproterenol were performed to quantify the effects of β-ARS on the action potential and calcium transient. The role of the main ion currents affected by β-ARS and by HCM remodelling was evaluated. Results In vitro, isoproterenol shortened APD (-16 ± 3%) in control, while prolonging APD in HCM myocytes (+23 ± 8%). Analysis of the measured data indicated two possible mechanisms contributing to APD prolongation in HCM myocytes. Firstly, a protracted L-type calcium current, presenting slower inactivation kinetics in HCM compared to control. The relative increase of potassium currents under β-ARS was also lower in HCM myocytes. The developed in silico models of β-ARS replicated the behaviour observed in the experimental data, based on slower L-type calcium current inactivation kinetics and a smaller increase of potassium currents in HCM. In absence of β-ARS, simulated HCM cardiomyocytes exhibited prolonged APD compared to control (525 ± 88 vs 281 ± 56 ms, p < 0.001). Under β-ARS, APD in control was reduced (-16.46%), whereas APD was prolonged in HCM (+11.63%). Further analysis showed that the reduction of the potassium currents increment under β-ARS was the main cause of the APD prolongation in HCM myocytes, with L-type calcium inactivation minimally contributing to APD prolongation. Conclusions In this study we assessed the effects of β-ARS on ion currents and APD in control and HCM myocytes. Our modelling results suggest that the increase of potassium repolarising currents under β-ARS is greatly reduced in HCM cardiomyocytes, being the main mechanism underlying their APD prolongation. This APD prolongation may have severe consequences in HCM patients, increasing the risk of exercise-induced arrhythmias. Abstract Figure.