Significant Cause Of Sudden Death Research Articles

Abstract We119: Treatment of Viral Myocarditis by Targeting the TRIM29-PERK Axis-Mediated ER Stress Immune Response

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo . Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo . Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

Trends and Outcomes of Catheter Ablation for Ventricular Tachycardia in a Community Cohort.

This study examined the trend in growth of catheter ablation for ventricular tachycardia (VT) performed in the United States with analysis of rates and predictors of major adverse events. Sustained VT is a significant cause of sudden death, heart failure (HF), and recurrent shocks in implantable cardioverter-defibrillator (ICD) recipients. Catheter ablation for VT reduces arrhythmia recurrence. Limited data are available regarding the use, safety, and long-term outcomes after VT ablation. Using the U.S. Medicare database linked to the Social Security Death Index, we examined the annual use of VT ablation in 21,073 patients over 12 years, with 30-day risk of mortality, nonfatal major adverse events (MAEs), 1-year risk of mortality, re-hospitalization, repeat ablation, and factors associated with adverse outcomes. Among 21,073 patients (age 70 ± 9 years; 77% men; 90% white), there were 1,581 (7.5%) non-fatal MAEs within 30 days. There were 963 (4.6%) vascular complications, 485 (2.3%) pericardial complications, and 201 (1%) strokes and/or transient ischemic attacks. Mechanical circulatory support use was infrequent (2.3%). The 30-day and 1-year mortality rates were 4.2% and 15.0%, respectively. The 1-year incidence of repeat ablation was 10.2 per 100 person-years and re-hospitalization for HF or VT was 15.4 per 100 person-years and 18 per 100 person-years, respectively. Patients with an ICD had increased 30-day (4.9% vs. 0.86%) and 1-year mortality (17.5% vs. 2.54% [22.9 per 100 person-years vs. 3.1 per 100 person-years]; hazard ratio [HR]: 2.93; 95% confidence interval [CI]: 2.21 to 3.88). Rates of hospitalization for HF (18 per 100 person-years vs. 1.8 per 100 person-years; HR: 4.00; 95% CI: 2.78 to 5.78) or VT recurrence (22.7 per 100 person-years vs. 2.1 per 100 person-years; HR: 5.70; 95% CI: 4.09 to 7.96) were also higher at 1year. Between 2000 and 2012, annual VT ablation volumes increased >4-fold. Catheter ablation for VT is frequently performed. Short-term MAEs and 1-year mortality is significant and is highest in patients with an ICD. These findings may provide greater insight of outcomes in an unselected real-world population undergoing VT ablation.

Arrhythmogenic right ventricular cardiomyopathy, Naxos island disease and Carvajal syndrome

The aim of this article is to present arrhythmogenic right ventricular cardiomyopathy (ARVC) and the associated cardiocutaneous syndromes, Naxos and Carvajal, with extension on the left ventricle and a new mutation of the desmoplakin gene. ARVC is an inherited cardiomyopathy characterized by myocyte necrosis, dominantly in the right ventricle. It is a significant cause of sudden death in children and adolescents. A thorough family history and modern diagnostic and treatment approach are prerequisites for prevention of sudden death syndrome. Diagnosis is more often established in adults than in children. Within ARVC there are two entity forms, referred to as the Naxos syndrome and the Carvajal syndrome. If ARVC also has palmoplantar keratoderma with distinctive hair features (woolly hair), it is described as Naxos syndrome, but if cardiomyopathy is spread over both ventricles, with even more severe changes on the left ventricle, the entity is referred to as Carvajal syndrome. Inheritance is autosomal recessive, and the mutation is in the desmoplakin gene. Genetic heterogeneity is less pronounced than in the Naxos syndrome. Typically, the disease mostly attacks the left ventricle. Conclusion – In order to prevent sudden cardiac death in children, it is important to recognize the special criteria for ARVC in children, published in 2010. These state the spectrum of phenotypic expressions with the primary changes to the right ventricle, but with the spread of cardiomyopathy to the left ventricle (Carvajal syndrome), and cardiocutaneous changes (Naxos syndrome).

Abstract 18117: Trends in the Utilization and Outcomes of Medicare Beneficiaries Undergoing Catheter Ablation for Ventricular Tachycardia

Background: Sustained ventricular tachycardia (VT) is a significant cause of sudden death, progressive ventricular dysfunction, and heart failure hospitalizations. Radiofrequency catheter ablation is used to control incessant VT and prevent or reduce the frequency of VT episodes. However, data regarding mortality and complication rates with VT ablation are limited. Objective: To measure the incidence of procedural complications, repeat ablations, hospitalization for heart failure and ventricular tachycardia, and short and long term mortality in patients undergoing VT ablation. Methods: We conducted a population-based, retrospective cohort study of all fee-for-service Medicare beneficiaries who underwent catheter ablation for VT between 2000 and 2012. The main outcome measures were major complications within 30 days and 1-year rates of death, repeat ablation and heart failure and VT hospitalization. Results: There were 21,073 patients that received a VT ablation during the study period (mean age 70 years; 77% were men; 90% were white). The ablation frequency increased from 647 in 2000 to 2,760 in 2012. The 30-day incidence of pericardial complications was 2.3%, vascular complications 6.8%, stroke or transient ischemic attack 1.5%, need for mechanical circulatory support 2.3%, and death 4.2%. The 1-year incidence per 1,000 person-years for repeat ablation was 81, death 176, and hospitalization for heart failure and VT 156 and 272, respectively (Figure). Conclusions: Utilization of catheter ablation for VT has increased over the past 12 years. Major complications after VT ablation are relatively infrequent, but not trivial. These findings should inform discussion of potential procedural complications and long term prognosis and may have considerable implications when discussing treatment options for patients with VT.

Familial arrhythmogenic right ventricular dysplasia in afrocaribbeans: treadmill stress test the key to early diagnosis

Arrhythmogenic right ventricular dysplasia is a rare entity and a significant cause of sudden death especially in the Italian population and athletes. The familial form is uncommon especially in the Afro-Caribbean population. This Index family represents an Autosomal Dominant form in a maternal parent who had sudden death at 39 years of age. The Index case was diagnosed at 18 years with increasing palpitations since 8 years of age, becoming symptomatic two decades younger than her mother. This was confirmed using the Treadmill Stress test. This is the 1st Case of Familial Arrhythmogenic right ventricular dysplasia documented in an Afro-Caribbean family. Learning objective Familial Arrhythmogenic right ventricular dysplasia is a rare entity and a significant cause of sudden death especially in the Italian population and athletes. This the first case of Autosomal Dominant type of ARVD with variable penetrance, documented in an Afro-Caribbean family where diagnosis was aided by Ventricular Tachycardia occurring during a Treadmill Stress Test.

Age and Mental Health Predict Early Device-Specific Quality of Life in Patients Receiving Prophylactic Implantable Defibrillators

BackgroundVentricular arrhythmia is a significant cause of sudden death. Implantable cardioverter-defibrillators (ICDs) offer at-risk patients a prophylactic treatment option. This prophylaxis is largely responsible for growth in utilization of ICDs. Identification of factors that may impact device-specific quality of life (QOL) is warranted. The influence of preimplant patient variables on postimplant device-specific QOL is unknown. The study aimed to determine whether preimplant psychosocial, generic health-related quality of life (HRQOL), personality disposition, or demographic factors predicted early postimplant device-specific QOL. MethodsA prospective cohort study design was employed in 70 adults receiving an ICD for primary prevention. Preimplant, we measured generic HRQOL, personality disposition, depressive symptoms, age, and sex. The primary outcome was 3-month ICD device-specific QOL as measured by the Florida Patient Acceptance Scale (FPAS). We applied hierarchical multivariate regression analysis. ResultsMean age was 64.8 ± 9.4 years; 12.9% were women. Most had ischemic heart disease (77%) and a heart failure history (54.3%). Preimplant prevalence of elevated depressive symptoms was 30%. Three months post implant, the mean adjusted FPAS score was 76.8 ± 12.98. Of the variance in FPAS scores, 37% was explained by the independent variables. Younger age and poor preimplant mental HRQOL contributed most to lower FPAS scores. ConclusionsPatient support and psychosocial interventions should target younger ICD candidates and those reporting poor preimplant mental HRQOL; these patients may be at risk for poor postimplant device-specific QOL.

Brugada Syndrome

The Brugada syndrome demonstrates characteristic electrocardiogram features and is a significant cause of sudden death in young adults with overtly normal cardiac structure and function. The genetic basis has not yet been fully elucidated but our understanding of the causative mutations and modifiers of arrhythmic events is advancing rapidly alongside sequencing technologies. We expect that the future will include risk stratification according to genotype and management tailored to the genetic diagnosis.

Altered Left Ventricular Tissue Velocities, Deformation and Twist in Children and Young Adults with Acute Myocarditis and Normal Ejection Fraction

Acute myocarditis is a significant cause of sudden death in young adults, and accurate screening for subclinical disease is needed. The aim of this study was to test the hypothesis that newer measures of tissue deformation and twist can detect ventricular dysfunction in patients with myocarditis and preserved left ventricular ejection fractions (LVEFs). Twenty-eight consecutive patients (median age, 26.5 years; interquartile range, 19.3-33.8 years) with normal LVEFs and cardiovascular magnetic resonance features of myocarditis were prospectively recruited. Left ventricular tissue velocities, deformation, and twist were measured and compared with values in 64 healthy controls (median age, 25.1 years; interquartile range, 13.5-31.7 years). Patients with myocarditis had reduced annular e' velocity and longitudinal and circumferential strain parameters (P < .01) but similar LVEFs. Reduced lateral e' velocity (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.34-2.34), longitudinal strain (OR, 1.81; 95% CI, 1.38-2.38), circumferential early diastolic strain rate (OR, 1.31; 95% CI, 1.08-1.71), increased twist rate (OR, 1.02; 95% CI, 1.01-1.04), and earlier time to peak twist (OR, 0.80; 95% CI, 0.72-0.88) were identified as independent predictors of myocarditis, with abnormalities in any two of five predictors having 93% sensitivity and 91% specificity. Longitudinal strain parameters and lateral e' velocity were improved at 1 year (P ≤ .03) but remained reduced compared with controls (P≤ .02). Patients with acute myocarditis and normal LVEFs had detectable left ventricular systolic and diastolic dysfunction on echocardiography. Tissue velocity, deformation, and twist parameters have the potential to improve the detection of patients with myocarditis and preserved LVEFs.

Sudden arrhythmic death and the cardiomyopathies: Molecular genetics and pathology

Cardiovascular disease is a significant cause of sudden death (SD) requiring autopsy investigation. Cardiomyopathies account for about one half of cases encountered, especially in young people <35 years of age. Among them, inherited cardiomyopathies at risk of SD include hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) as well as primary electrical disorders of the myocardium in the absence of structural abnormalities (channelopathies). The pathologist's task is to make the correct diagnosis and, when dealing with a genetic disease, to trigger widespread cardiological investigation of first-degree family members. This is especially important as SD can be the first and last clinical presentation of the underlying inherited cardiomyopathy and the only medical examination undertaken is that done by the pathologist. An accurate pathological diagnosis, which also includes access to molecular techniques (“molecular autopsy”), will provide vital information for the family in preventing a further tragedy. Therefore proper sampling to allow postmortem DNA analysis as well as accurate morphological evaluation, is mandatory, as recommended in the recently-published guidelines for autopsy investigation of SD from the Association for European Cardiovascular Pathology.

Can Novel Therapies for Arrhythmias Caused by Spontaneous Sarcoplasmic Reticulum Ca 2+ Release be Developed Using Mouse Models?

See related article, pages e77–e82 Ventricular arrhythmias are a significant cause of premature death in Western society and occur both in the absence and presence of heart disease. For example, in heart failure close to 50% of patients die of lethal forms of ventricular arrhythmias. In spite of a large amount of basic and clinical investigations, current pharmacotherapy for ventricular arrhythmias is inadequate, demonstrating the need for novel therapeutic approaches. Abnormal automaticity is responsible for induction and maintenance of different types of ventricular tachycardias. The form of abnormal automaticity that results from abnormal release of Ca2+ from a Ca2+ overloaded sarcoplasmic reticulum (SR), referred to as a “triggered arrhythmia”, is the topic of this editorial. In vitro studies have shown that increasing the SR Ca2+ load beyond a critical level causes spontaneous opening of the SR Ca2+ release channel (ryanodine receptor; RYR) and results in spontaneous SR Ca2+ release.1 The subsequent increase in cytosolic [Ca] activates an inward current through the sarcolemmal Na+/ Ca2+ exchanger which causes membrane depolarization.1,2 Spontaneous SR Ca2+ release during the diastolic interval causes depolarization (delayed after depolarizations; DADs) which has been shown to result in action potentials in single cells and in the intact heart when the aberrant release is adequately synchronized within and among cardiac myocytes.3,4 Factors that lead to DADs include increased heart rate and catecholamine stress, which both induce triggered arrhythmias by increasing SR Ca2+ loading.3 Whereas many molecules are involved in SR Ca2+ overload (DAD) related arrhythmias, abnormal opening …

Tumors Associated with Sudden Infant and Childhood Death

Tumors are rare causes of sudden death in infancy and early childhood. The goals of this study were to determine the types and frequency of the tumors associated with sudden death occurring in cases between birth and age 3 years. The San Diego Sudden Infant Death Syndrome/sudden unexplained death in childhood (SUDC) Research Project database and the literature were reviewed retrospectively. Sixty-eight cases, with the most (84%) affecting the heart and brain, were identified. Tumors are a rare but significant cause of sudden death in infancy and early childhood, and their diagnosis may have significant genetic implications for planning future pregnancies. The diagnosis of these lesions can be established only after thorough postmortem examination.

Treatment of congestive heart failure‐state of the art and future trends.

1. Cardiac failure is a clinical syndrome of symptoms and signs, which can be confirmed by imaging or invasive haemodynamic techniques. It may be caused by systolic or diastolic dysfunction, but systolic dysfunction rarely occurs alone. It is important to ascertain the degree to which each contributes, and the precise aetiology of the condition, particularly in relation to surgically correctable lesions. 2. Non-pharmacological approaches including weight loss, salt restriction and lifestyle changes may be beneficial in some patients, and diuretics, which reduce the load on the heart, are the traditional baseline therapy. 3. Digitalis has been used where problems with contractility predominate, but its beneficial effect has been disputed, and expectations of improvement in patients in sinus rhythm should not be too high. 4. Vasodilators have been considered as the next line of treatment. Arteriolar dilators tend to increase cardiac output, but have little effect on pulmonary artery wedge pressure, and venodilators tend to have the opposite effect. Probably both actions are necessary and angiotensin converting enzyme (ACE) inhibitors, which have both, have proved effective in terms of symptoms and survival. 5. Various other inotropic agents have been tried. Phosphodiesterase inhibitors improve exercise tolerance, but may increase the probability of serious arrhythmias, already a significant cause of sudden death. beta 1-partial adrenoceptor agonists such as xamoterol have shown some promise, and anti-arrhythmic therapy has also been considered. 6. Drugs which prevent progression of myocardial damage would prove a great advance, and beta-adrenoceptor antagonists and calcium channel blockers appear to have considerable potential in this area.

Sudden death and the competitive athlete: Perspectives on preparticipation screening studies

Sudden death in healthy athletes is uncommon but, when it occurs, the primary mechanism is cardiovascular. The major cause of sudden death in the young athlete is hypertrophic cardiomyopathy or related conditions characterized by left ventricular hypertrophy, aortic rupture due to cystic medial necrosis and congenital coronary artery abnormalities. In the middle-aged or older athlete, coronary artery disease is the most significant cause of sudden death. Noninvasive screening procedures are currently available that can detect most subjects at risk of sudden death. However, although some potentially lethal diseases can be excluded by a relatively simple screening program, other diseases require expensive procedures, such as echocardiography and exercise electrocardiographic stress testing. This means that the sensitivity of detecting diseases leading to sudden death increases in proportion to the financial resources that can be applied to the screening program. Thus, when a screening program designed to identify all cardiac diseases that have the potential to cause sudden death is planned by a community, school or nonprofessional athletic team, the costs will almost undoubtedly be considered prohibitive. The practicality of applying a community- or school-initiated screening program can be questioned because of the very low incidence of sudden unexpected death in young healthy individuals. It is therefore likely that comprehensive screening programs will be confined to individuals or organizations with adequate financial resources. Less expensive, limited screening can be undertaken by individuals or groups to identify some subjects at risk of sudden death during athletic competition.