Mechanism Of Sudden Cardiac Death Research Articles

Ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2 -/- Mice.

Intracellular Ca2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (ent-verticilide B1; "ent-B1") in RyR2 single channel and [3H]ryanodine binding assays, and in Casq2 -/- cardiomyocytes and mice, a gene-targeted model of SCD. ent-B1 inhibited RyR2 single channels and RyR2-mediated spontaneous Ca2+ release in Casq2 -/- cardiomyocytes with sub-micromolar potency. ent-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. ent-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 minutes and half-life of 45 minutes after intraperitoneal administration of 3 mg/kg in mice. In vivo, ent-B1 significantly reduced catecholamine-induced ventricular arrhythmias in Casq2 -/- mice in a dose-dependent manner. Hence, we have identified a novel chemical entity - ent-B1 - that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics. SIGNIFICANCE STATEMENT: The cardiac ryanodine receptor (RyR2) is an untapped target in the stagnant field of antiarrhythmic drug development. We have confirmed RyR2 as an antiarrhythmic target in a mouse model of sudden cardiac death and shown the therapeutic efficacy of a second enantiomeric natural product.

Sudden Cardiac Death from Acute Myocardial Infarction Caused by Unruptured Ascending Aortic Aneurysm Involving the Sinus of Valsalva: An Autopsy Case

Ascending aortic aneurysm of the thorax is a condition characterized by an increase in the diameter of the ascending aorta between the aortic valve and the brachiocephalic artery. Most patients with ascending aortic aneurysm are asymptomatic and do not require treatment; the rates of dissection, rupture, and mortality are also low. In this report, we describe the autopsy findings in a case of sudden death due to acute myocardial infarction secondary to the previously asymptomatic, unruptured, and undissected aortic aneurysm of the thoracic ascending aorta extending to the sinus of Valsalva. The findings in this case emphasize the importance of preventive management of asymptomatic ascending aortic aneurysms, and possible mechanisms of sudden cardiac death in patients with uncomplicated ascending aortic aneurysm is also discussed.

Understanding the mechanisms of sudden cardiac death in bipolar disorder: Functional asymmetry in brain-heart interactions as a potential culprit

The risk of sudden cardiac death is remarkably high in patients with bipolar disorder. The risk is especially elevated, 32 times greater than in the general population, in patients younger than 30 years old. Early atherosclerosis and general lifestyle risk factors might play a role but are insufficient to account for this greatly inflated risk of sudden cardiac death. A recent mechanistic model of the pathophysiology of bipolar disorder highlights dysfunctional changes in functional hemispheric lateralization that are proposed to arise as a consequence of aberrant midbrain signaling at the level of the paraventricular nucleus of the hypothalamus. The paraventricular nucleus is also a key region involved in regulating bodily physiology, including the balanced autonomic control of cardiac function. Further, the sympathetic innervation of the heart is configured anatomically such that exaggerated imbalanced right-left stimulation of the heart can predispose to fatal arrhythmia. Correspondingly, lateralization of cortical activity related to emotional arousal and acute stress, if not otherwise corrected, may drive asymmetric sympathetic effects on the heart. In cardiac patients, asymmetric midbrain lateralization is associated with increased proarrhythmic changes during mental and physical stress challenges, predisposing vulnerable patients to lethal arrhythmias. Here, we propose that similar mechanisms involving lateralized brain–heart interactions account for the increased risk of sudden cardiac death in patients with bipolar disorder. We explore the evidence for, and implications of, this model.

Mitral Valve Prolapse and Mitral Annular Disjunction Arrhythmic Syndromes: Diagnosis, Risk Stratification and Management.

Although mitral valve prolapse (MVP) is usually considered a benign clinical condition, it has been linked with ventricular arrhythmias and sudden cardiac death in patients with a certain "arrhythmic" phenotype, raising awareness and mandating a specific risk stratification protocol. Mitral annular disjunction (MAD) is considered a "red flag" in malignant MVP syndrome along with bileaflet myxomatous prolapse, female gender, negative or biphasic T waves in the inferior leads, fibrosis in the papillary muscles or inferobasal wall detected by cardiac magnetic resonance imaging and complex arrhythmias of right bundle branch morphology. MAD seems to play a critical role in the chain of morphofunctional abnormalities which lead to increased mechanical stretch and subsequent fibrosis mainly in the papillary muscles, forming the vulnerable anatomic substrate prone to arrhythmogenesis, and associated with long-term severe ventricular arrhythmias. Arrhythmogenesis in MVP/MAD patients is not fully understood but a combination between a substrate and a trigger has been established with premature ventricular contraction triggered ventricular fibrillation being the main mechanism of sudden cardiac death (SCD). Certain characteristics mostly recognized by non-invasive imaging modalities serve as risk factors and can be used to diagnose and identify high risk patients with MAD, while treatment options include catheter ablation, device therapy and surgical intervention. This review focuses on the clinical presentation, the arrhythmogenic substrate, and the incidence of ventricular arrhythmias and SCD in MAD population. The current risk stratification tools in MAD arrhythmogenic entity are discussed.

Effects of Adaptive Servo-Ventilation on Nocturnal Ventricular Arrhythmia in Heart Failure Patients With Reduced Ejection Fraction and Central Sleep Apnea-An Analysis From the SERVE-HF Major Substudy.

BackgroundThe SERVE-HF trial investigated the effect of treating central sleep apnoea (CSA) with adaptive servo-ventilation (ASV) in patients with heart failure with reduced ejection fraction (HFrEF).ObjectiveThe aim of the present ancillary analysis of the SERVE-HF major substudy (NCT01164592) was to assess the effects of ASV on the burden of nocturnal ventricular arrhythmias as one possible mechanism for sudden cardiac death in ASV-treated patients with HFrEF and CSA.MethodsThree hundred twelve patients were randomized in the SERVE-HF major substudy [no treatment of CSA (control) vs. ASV]. Polysomnography including nocturnal ECG fulfilling technical requirements was performed at baseline, and at 3 and 12 months. Premature ventricular complexes (events/h of total recording time) and non-sustained ventricular tachycardia were assessed. Linear mixed models and generalized linear mixed models were used to analyse differences between the control and ASV groups, and changes over time.ResultsFrom baseline to 3- and 12-month follow-up, respectively, the number of premature ventricular complexes (control: median 19.7, 19.0 and 19.0; ASV: 29.1, 29.0 and 26.0 events/h; p = 0.800) and the occurrence of ≥1 non-sustained ventricular tachycardia/night (control: 18, 25, and 18% of patients; ASV: 24, 16, and 24% of patients; p = 0.095) were similar in the control and ASV groups.ConclusionAddition of ASV to guideline-based medical management had no significant effect on nocturnal ventricular ectopy or tachyarrhythmia over a period of 12 months in alive patients with HFrEF and CSA. Findings do not further support the hypothesis that ASV may lead to sudden cardiac death by triggering ventricular tachyarrhythmia.

Effect of hyperglycaemia in combination with moxifloxacin on cardiac repolarization in male and female patients with type I diabetes

BackgroundPatients with Type 1 diabetes mellitus have been shown to be at a two to ten-fold higher risk of sudden cardiac death (SCD) (Svane et al., Curr Cardiol 2020; 22:112) than the general population, but the underlying mechanism is unclear. Hyperglycaemia is a recognised cause of QTc prolongation; a state patients with type 1 diabetes are more prone to, potentially increasing their risk of ventricular arrhythmia. Understanding the QTc prolongation effect of both hyperglycaemia and the concomitant additive risk of commonly prescribed QTc-prolonging drugs such as Moxifloxacin may help to elucidate the mechanism of sudden cardiac death in this cohort. This single-blinded, placebo-controlled study investigated the extent to which hyperglycaemia prolongs the QTc in controlled conditions, and the potential additive risk of QTc-prolonging medications.Methods21 patients with type 1 diabetes mellitus were enrolled to a placebo-controlled crossover study at a single clinical trials unit. Patients underwent thorough QTc assessment throughout the study. A ‘hyperglycaemic clamp’ of oral and intravenous glucose was administered with a target blood glucose of > 25 mM and maintained for 2 h on day 1 and day 3, alongside placebo on day 1 and moxifloxacin on day 3. Day 2 served as a control day between the two active treatment days.Thorough QTc assessment was conducted at matched time points over 3 days, and regular blood sampling was undertaken at matched time intervals for glucose levels and moxifloxacin exposure.ResultsConcentration-effect modelling showed that acute hyperglycaemia prolonged the QTc interval in female and male volunteers with type 1 diabetes by a peak mean increase of 13 ms at 2 h. Peak mean QTc intervals after the administration of intravenous Moxifloxacin during the hyperglycaemic state were increased by a further 9 ms at 2 h, to 22 ms across the entire study population. Regression analysis suggested this additional increase was additive, not exponential.Hyperglycaemia was associated with a significantly greater mean QTc-prolonging effect in females, but the mean peak increase with the addition of moxifloxacin was the same for males and females. This apparent sex difference was likely due to the exclusive use of basal insulin in the male patients, which provided a low level of exogenous insulin during the study assessments thereby mitigating the effects of hyperglycaemia on QTc. This effect was partially overcome by Moxifloxacin administration, suggesting both hyperglycaemia and moxifloxacin prolong QTc by different mechanisms, based on subinterval analysis.ConclusionsHyperglycaemia was found to be a significant cause of QTc prolongation and the additional effect of a QTc-prolonging positive control (moxifloxacin) was found to be additive. Given the high risk of sudden cardiac death in type 1 diabetes mellitus, extra caution should be exercised when prescribing any medication in this cohort for QTc effects, and further research needs to be undertaken to elucidate the exact mechanism underlying this finding and explore the potential prescribing risk in diabetes.Trial RegistrationNCT number: NCT01984827.Graphical abstract

Sudden cardiac death in a case of Crohn's disease with COVID-19

Rationale: The mechanism of sudden cardiac death in COVID-19 can be multifactorial. Cardiac hypersensitivity to 5-ASA therapy leading to myocarditis has been reported in some cases. Cytokine storm syndrome and idiosyncratic reaction with mesalazine use may lead to sudden cardiac death in COVID-19. Use of immunosuppressants in hospitalized COVID-19 patients should be continued with caution, especially in patients with inflammatory bowel disease. Patient's concern: A 75-year-old man who was tested positive for SARS-CoV-2 was admitted with a history of shortness of breath for the last two days. He was a known case of Crohn's disease treated with mesalazine. Diagnosis: COVID-19 pneumonia with underlying Crohn's disease leading to sudden cardiac death. Intervention: Remdesivir, antibiotics, steroids, low molecular weight heparin, tablet zinc, tab vitamin C, and other supportive treatment were started. Because of increased inflammatory markers, itolizumab was given to the patient on the 2nd day. Outcome: On the 5th day of the intensive care unit, the patient complained of sudden chest pain with respiratory distress leading to bradycardia and asystole and could not be resuscitated. Lessons: Causes for sudden cardiac death in COVID-19 pneumonia patients with Crohn's disease is multifactorial. Although mesalazine may be a safe and effective drug in the management of inflammatory bowel disease, it can induce sytokine strom syndrome and idiosyncratic reactions that could be one of the reasons of sudden cardic death. Therefore, we should be aware of its serious and potentially life-threatening complications, especially in COVID-19 infected patients.

Sudden cardiac deaths have higher proportion of left stellate ganglionitis.

One of the hypothesized mechanisms of sudden cardiac death in humans is an arrhythmia precipitated by increased sympathetic outflow to a compromised heart. The stellate ganglia provide the main sympathetic innervation to the heart, where the left stellate ganglion appears to play a role in arrhythmogenesis. Case reports of sudden cardiac death have described left stellate ganglion inflammation but no larger studies have been performed. Thus, we have specifically assessed whether the left stellate ganglion was inflamed in those dying from sudden cardiac death versus other causes of death. Thirty-one left stellate ganglia were resected from cadavers diagnosed with sudden cardiac deaths and compared with 18 ganglia from cadavers diagnosed with non-sudden cardiac deaths. Ganglia were stained with hematoxylin and eosin and lymphocytic aggregates compared. The proportion of left stellate ganglion inflammation (77%) was significantly higher in deaths from sudden cardiac deaths than non-sudden cardiac deaths (33%). This study provides information on a previously recognized, but understudied, structure that may help understand sudden cardiac death. We found high prevalence of stellate ganglion inflammation and propose that this may trigger sympathetic storms.

To the Editor - Are we close to a major impact on prevention of sudden cardiac death among coronary artery disease patients?

We read with great interest the article from Hooks and colleagues1 showing that ventricular tachycardia (VT) or ventricular fibrillation (VF) was the initial rhythm in ∼50% of the in-hospital cardiac arrests among patients with heart failure and preserved ejection fraction—indeed, confirming that VT/VF is a significant mechanism of sudden cardiac death (SCD) leading to a major proportion of cardiac mortality in patients with heart failure and preserved ejection fraction.2 In a recent autopsy study of 5869 SCD victims in the Fingesture registry in Finland,3 the majority of patients had evidence of myocardial scaring on autopsy, although they had no known clinical history of coronary artery disease (CAD) prior to the cardiac arrest.

Stellate ganglionitis and sudden cardiac death

Introduction: One of the hypothesised mechanisms of sudden cardiac death is an arrhythmia precipitated by increased sympathetic outflow to a compromised heart. The stellate ganglia provide sympathetic innervation to the heart and play a role in arrhythmogenesis.

Correction to: Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 2: Population and Clinical Considerations.

Correction to: Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 2: Population and Clinical Considerations.

Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 1: Basic and Translational Aspects.

Sudden cardiac death (SCD), the unexpected death due to acquired or genetic cardiovascular disease, follows distinct 24-hour patterns in occurrence. These 24-hour patterns likely reflect daily changes in arrhythmogenic triggers and the myocardial substrate caused by day/night rhythms in behavior, the environment, and endogenous circadian mechanisms. To better address fundamental questions regarding the circadian mechanisms, the National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death. We present a 2-part report of findings from this workshop. Part 1 summarizes the workshop and serves to identify research gaps and opportunities in the areas of basic and translational research. Among the gaps was the lack of standardization in animal studies for reporting environmental conditions (eg, timing of experiments relative to the light dark cycle or animal housing temperatures) that can impair rigor and reproducibility. Workshop participants also pointed to uncertainty regarding the importance of maintaining normal circadian rhythmic synchrony and the potential pathological impact of desynchrony on SCD risk. One related question raised was whether circadian mechanisms can be targeted to reduce SCD risk. Finally, the experts underscored the need for studies aimed at determining the physiological importance of circadian clocks in the many different cell types important to normal heart function and SCD. Addressing these gaps could lead to new therapeutic approaches/molecular targets that can mitigate the risk of SCD not only at certain times but over the entire 24-hour period.

Understanding Circadian Mechanisms of Sudden Cardiac Death: A Report From the National Heart, Lung, and Blood Institute Workshop, Part 2: Population and Clinical Considerations.

Sudden cardiac death (SCD) is the sudden, unexpected death due to abrupt loss of heart function secondary to cardiovascular disease. In certain populations living with cardiovascular disease, SCD follows a distinct 24-hour pattern in occurrence, suggesting day/night rhythms in behavior, the environment, and endogenous circadian rhythms result in daily spans of increased vulnerability. The National Heart, Lung, and Blood Institute convened a workshop, Understanding Circadian Mechanisms of Sudden Cardiac Death to identify fundamental questions regarding the role of the circadian rhythms in SCD. Part 2 summarizes research gaps and opportunities in the areas of population and clinical research identified in the workshop. Established research supports a complex interaction between circadian rhythms and physiological responses that increase the risk for SCD. Moreover, these physiological responses themselves are influenced by several biological variables, including the type of cardiovascular disease, sex, age, and genetics, as well as environmental factors. The emergence of new noninvasive biotechnological tools that continuously measure key cardiovascular variables, as well as the identification of biomarkers to assess circadian rhythms, hold promise for generating large-scale human data sets that will delineate which subsets of individuals are most vulnerable to SCD. Additionally, these data will improve our understanding of how people who suffer from circadian disruptions develop cardiovascular diseases that increase the risk for SCD. Emerging strategies to identify new biomarkers that can quantify circadian health (eg, environmental, behavioral, and internal misalignment) may lead to new interventions and therapeutic targets to prevent the progression of cardiovascular diseases that cause SCD.

Research Progress on Molecular Markers Related to Unexplained Sudden Cardiac Death and Its Forensic Application.

Routine pathological examination of unexplained sudden cardiac death (USCD) lacks significant morphological characteristics. In the field of forensic medicine, molecular biology methods have been used to find the cause of death by detecting genes and research related to the mechanism of sudden cardiac death has been carried out. From the molecular pathology point of view, the application of multiple levels of biomarkers to resolve the causes of USCD has already shown potential and provides an important path for forensic identification of USCD. This article reviews the latest research progress on USCD-related genes, RNA, proteins and USCD, and summarizes forensic application.

Purkinje triggers of ventricular fibrillation in patients with hypertrophic cardiomyopathy.

Ventricular fibrillation (VF) is the main mechanism of sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). The origin of VF and the success of catheter ablation to eliminate recurrent episodes in this population are poorly understood. From 2010 to 2014, five patients with HCM (age 21 ± 9 years, three female) underwent invasive electrophysiological studies and ablation at our center after resuscitation from recurrent (9 ± 7) episodes of VF. Ventricular premature beats (VPBs), seen to initiate VF in certain cases, were recorded noninvasively before the ablation procedure. Postprocedural computed tomography (CT) was performed to correlate ablation sites with myocardial hypertrophy in three patients. Outcomes were assessed by clinical follow-up and implantable cardioverter-defibrillator interrogations. VPB triggers were localized invasively to the distal left Purkinje conduction system (left posterior fascicle [2], left anterior fascicle [1], and both fascicles [2]). All targeted VF triggers were successfully eliminated by radiofrequency ablation in the left ventricle. Among patients with postablation CT imaging, 93 ± 12% of ablation sites corresponded to hypertrophied segments. Over 50 ± 38 months, four of five patients were free from primary VF without antiarrhythmic drug therapy. One patient who had 13 episodes of VF before ablation had a single recurrence. In our study of patients with HCM and recurrent VF, VF was not initiated from the myocardium but rather from Purkinje arborization. These sources colocalized with the hypertrophic substrate, suggesting electromechanical interaction. Focal ablation at these sites was associated with a marked reduction in VF burden.

Causes and mechanisms of sudden cardiac death in children

The paper presents basic morphological criteria of the diagnosis of sudden cardiac death related to different diseases in young people. Attention is drawn to cardiomyopathies, channelopathies, connective tissue dysplasias, Marfan syndrome with cystic medial necrosis, sudden arrhythmic death. Initiating events in sudden cardiac death are discussed. Besides morphological manifestations, the paper dwells upon major genetic events and clinical presentation of the diseases. It is based on both existing publications and own data.

Zebrafish Heart as a Model to Elucidate the Mechanisms of Sudden Cardiac Death

The heart of zebrafish has been used as a simple, low-cost model to study development, structure and function of the heart from early to late stages of life. Also, it has been established as a model to study different cardiac pathologies generated through different methods. Cardiac pathologies include from functional disorders such as arrhythmia, to structural disorders such as hypertrophic heart disease; in many of them, genetic and molecular aspects have been associated. Noteworthy, some of these genetic and molecular factors have been invoked as causes of sudden cardiac death in humans. This adverse outcome is common in many cardiovascular pathologies and can occur at any age. Unfortunately, etiology and physiopathology of sudden cardiac death are unclear, so extensive research in this area is required. This mini-review highlight three related points: First, the relevance of sudden cardiac death in humans. Second, advances in knowledge of the development, function and pathologies in the zebrafish heart model. Finally, the possibility of using the zebrafish model for the study of sudden cardiac. For this review, a literature search was performed using the PubMed database and the search engine Google Scholar: the words sudden cardiac death, zebrafish, arrhythmias, cardiomyopathies were combined for this search.

Association of arterial hypertension gene polymorphisms with the risk of sudden cardiac death in young people

Abstract. The frequency of occurrence of arterial hypertension genes in individuals at risk of sudden cardiac death was studied. The relationship between risk factors for sudden cardiac death and the presence of polymorphisms of arterial hypertension genes was revealed. There was a high incidence of homozygous risk variants AGTR2 AA and CYP11B2 TT-polymorphisms responsible for the development of left ventricular hypertrophy, including in young individuals. A correlation was found between deaths in close relatives under 50 years of age and the presence of polymorphisms in the CYP11B2 344 CT gene in young people at risk of sudden cardiac death. We have obtained data indicating the feasibility of conducting a study of the polymorphism of the CYP11B2 gene in the presence of a risk of sudden cardiac death. A direct correlation was found between the presence of fatal outcomes in relatives under 50 years of age by the mechanism of sudden cardiac death and the number of homozygous variants of arterial hypertension genes. Mathematical models for predicting the presence of polymorphisms in genes responsible for the possibility of arterial hypertension are constructed. Among the constructed mathematical models, the most informative were models for detecting carriers of mutations in the genes ADD1 1378 GT, CYP11B2 344 CT and NOS3 894 GT. The expediency of the analysis to search for mutations of arterial hypertension genes, especially in the CYP11B2 344 CT gene, for the possibility of earlier and more intensive preventive measures in young people is shown. The data obtained indicate that there are relationships between the risk of sudden cardiac death, some known predictors of its occurrence, and the genes for arterial hypertension.

A Perspective on Personalized Therapies in Hypertrophic Cardiomyopathy.

A dominant mechanism of sudden cardiac death in the young is the progression of maladaptive responses to genes encoding proteins linked to hypertrophic cardiomyopathy. Most are mutant sarcomere proteins that trigger the progression by imposing a biophysical defect on the dynamics and levels of myofilament tension generation. We discuss approaches for personalized treatments that are indicated by recent advanced understanding of the progression.

Nonsustained ventricular tachycardia in heart failure with preserved ejection fraction

Ventricular tachycardia (VT) is a common arrhythmia in heart failure with reduced ejection fraction but its incidence, predictors, and significance have not been determined in heart failure with preserved ejection fraction (HFpEF). We performed a retrospective review of arrhythmias in two cohorts of patients with an HFpEF diagnosis. Patients in cohort 1 (n=40) underwent routine arrhythmia surveillance with a 14-day ambulatory electrocardiogram (ECG) monitor. Patients in cohort 2 (n=85) had cardiac pacemakers and underwent routine device interrogations. In cohort 1, 13 patients (32.5%) had one or more episodes of nonsustained VT (NSVT) on ambulatory ECG. In cohort 2, 38 patients (44.7%) had NSVT on cardiac pacemaker interrogations. During a median (interquartile range) follow-up of 3.0 (1.6 to 5.1) years, 15 (12%) patients died (20% of patients with NSVT versus 6.8% of those without NSVT; P=.03). In logistic regression analysis, NSVT was associated with a 3.4-fold higher odds of death (95% confidence interval 1.08 to 10.53; P=.04) in HFpEF. In conclusion, patients with HFpEF have a relatively high, and possibly underappreciated, burden of NSVT, which confers a higher risk of mortality. The frequent episodes of NSVT in these patients may provide insight into the mechanism of sudden cardiac death in HFpEF.