An In Silico Cardiomyocyte Reveals the Impact of Changes in CaMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism, and crossbridge cycling in HCM at the single-cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism, and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by (a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways and (b) increased Ca2+ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine-to-ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half-sarcomere model, we also compared the fraction of detached, weakly bound, and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force-producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply and demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.

[An increasing prevalence of epilepsy and stagnating or decreasing health care resources makes nationwide implementation challenging]. / Följsamhet till ordination en av utmaningarna i epilepsivården.

The Swedish national guidelines for epilepsy stipulate regular health care contacts in the years following diagnosis, referral for epilepsy surgery in cases of pharmacoresistant epilepsy, multidisciplinary teams, and adequate patient information particularly for women of childbearing age. The last years have seen advances in many research areas of relevance for the basic epilepsy care, and Sweden has contributed regarding pharmacotherapy, seizure-related risks, sudden unexpected death in epilepsy (SUDEP), and digital tools. An increasing prevalence of epilepsy and stagnating or decreasing health care resources makes nationwide implementation of this knowledge challenging and increases the risk of unequal access to care. Innovation and focus on prioritized groups, such as newly diagnosed and persons with pharmacoresistant epilepsy or comorbidities, will be needed.

Genetic Testing Yield and Clinical Characteristics of Hypertrophic Cardiomyopathy in Understudied Ethnic Groups: Insights From a New Zealand National Registry.

BACKGROUND: Aotearoa/New Zealand has a multiethnic population. Patients with hypertrophic cardiomyopathy (HCM) are enrolled in the national Cardiac Inherited Diseases Registry New Zealand. Here, we report the characteristics of Cardiac Inherited Diseases Registry New Zealand HCM probands with and without pathogenic or likely pathogenic (P/LP) genetic variants for HCM, and assess genetic testing yield and variant spectrum by self-identified ethnicity. METHODS: Probands with HCM and enrolled in Cardiac Inherited Diseases Registry New Zealand who have undergone clinical genetic testing over a 17-year period were included. Clinical data, family history, and genetic test results were analyzed. RESULTS: Of 336 probands, 121 (36%) were women, 220 (66%) were European ethnicity, 41 (12%) were Maori, 26 (8%) were Pacific people, and 49 (15%) were other ethnicities. Thirteen probands (4%) presented with sudden death and 19 (6%) with cardiac arrest. A total of 134 (40%) had a P/LP variant identified; most commonly in the MYBPC3 gene (60%) followed by the MYH7 gene (24%). A P/LP variant was identified in 27% of Maori or Pacific probands versus 43% European or other ethnicity probands (P=0.022); 16% of Maori or Pacific probands had a variant of uncertain significance identified, compared with 9% of European or other ethnicity probands (P=0.092). Women more often had a P/LP variant identified than men (48% versus 35%; P=0.032), and variant-positive probands were younger at clinical diagnosis than variant of uncertain significance/variant-negative probands (39±17 versus 50±17 years; P<0.001) and more likely to have experienced cardiac arrest or sudden death events over their lifetime (P=0.002). CONCLUSIONS: Carriage of a P/LP variant in HCM probands is associated with presentation at younger age, and cardiac arrest or sudden death events. Maori or Pacific probands were less likely to have a P/LP variant identified than European or other ethnicity probands.

Hallazgos histopatológicos en la disección y rotura de la aorta torácica. Estudio de 54 casos de autopsia / Histopathological findings in dissection and rupture of the thoracic aorta. Study of 54 autopsy cases

Introducción la disección/rotura de la aorta torácica tiene una alta mortalidad, constituyendo de 3,9 a 5,4% de las muertes súbitas en series forenses. Los hallazgos histopatológicos de la media asociados a estas entidades han recibido múltiples términos y definiciones. En 2016, la Asociación Europea de Patología Cardiovascular junto con la Sociedad de Patología Cardiovascular publicaron un documento de consenso, aplicado a muestras quirúrgicas, para unificar criterios. El objetivo de este trabajo es valorar su aplicación en las autopsias forenses. Un objetivo secundario es estudiar cambios inflamatorios útiles para la datación. Material y métodos se revisaron las preparaciones histológicas de aorta de 54 casos de muertes súbitas por rotura/disección aórtica estudiados entre 2019 y 2022. Resultados se observó degeneración de la media en 49 casos (90,8%) (severa en 42,9%). Por lesiones, el orden de frecuencia fue: fragmentación y/o pérdida de las fibras elásticas (74,1%); acúmulo de matriz mucoide extracelular (61,1%); pérdida de núcleos de células musculares lisas (48,1%) y colapso de la media (44,4%). Algunas lesiones del documento no pudieron ser valoradas. No se encontraron diferencias significativas por edad; presencia o no de colagenopatías; o válvulas aórticas bi/tricúspides. Se observó tejido de granulación o infiltrado neutrofílico en los fallecidos con dolor de varios días o <24 h antes de la muerte, respectivamente. Conclusión con la aplicación del documento se encuentran lesiones en la media en >90% de los casos y pueden estudiarse las lesiones fundamentales. La respuesta inflamatoria frente a la rotura/disección parece correlacionarse con el momento de la disección/rotura. (AU)

Introduction Thoracic aortic dissection/rupture has a high mortality, constituting 3.9-5.4% of sudden deaths in forensic series. Medial histopathological findings associated with these entities have received multiple terms and definitions. In 2016, the European Association for Cardiovascular Pathology and the Society for Cardiovascular Pathology published a consensus document, applied to surgical specimens, to unify criteria. The aim of this work is to assess its application in forensic autopsies. A secondary objective is to study inflammatory changes useful for dating. Material and methods Aortic histological preparations of the 54 cases of sudden deaths due to aortic rupture/dissection studied between 2019 and 2022 were reviewed. Results Medial degeneration was observed in 49 cases (90.8%) (severe in 42.9%). By lesions, the order of frequency was: fragmentation and/or loss of elastic fibers (74.1%); accumulation of extracellular mucoid matrix (61.1%); loss of smooth muscle cell nuclei (48.1%) and collapse of the media (44.4%). Some lesions of the consensus paper could not be assessed. No significant differences were found by age; presence or not of collagenopathies; or bi/tricuspid aortic valves. Granulation tissue or neutrophilic infiltrate was observed in those deceased with pain several days or <24 h before death, respectively. Conclusion With the application of the document, lesions in the media are found in >90% of cases and fundamental lesions can be studied. The inflammatory response to rupture/dissection appears to correlate with the timing of dissection/rupture. (AU)

The real incidence of sudden death: Fair estimations or futile speculations?

BACKGROUND: The true incidence of sudden death remains undetermined, with controversial results from various publications over time and countries. AIM: To investigate if different estimations would reach the values usually reported for France. METHODS: Three different kinds of estimations were used. First, the number of resuscitated sudden deaths and necropsies for sudden death in the Haute-Garonne French administrative department (i.e. county) over the last 10years was expanded to the national level. Second, sudden death coding of death certificates was collected at the national level. Third, the total number of out-of-hospital cardiac arrests leading to any emergency call (with/without intervention) in Haute-Garonne over the last 10years was expanded to the national level. RESULTS: There was a mean of 26 resuscitated sudden deaths and 145 necropsies for sudden death each year in Haute-Garonne, i.e. 12 to 14 sudden deaths for 100,000 inhabitants, and 7700 to 9400 sudden deaths yearly when related to the whole French population, according to the year of inclusion. Based on death certificates, a mean of 6584 sudden deaths was registered each year in France. Finally, there were about 600 yearly calls/interventions for out-of-hospital cardiac arrests in Haute-Garonne, i.e. 40 to 50 sudden deaths for 100,000 inhabitants, and 16,000 to 27,000 sudden deaths yearly for the whole French territory, according to the year of inclusion. CONCLUSIONS: The incidence of sudden death ranges from 6500 to 27,000 in France according to the calculation methods. This huge difference raises the question of the true current incidence of sudden death, which may have been overestimated previously or may be underestimated in France. More straight prospective surveys are needed to solve this question, because of relevant implications for priorities that should be given to sudden death.

Sudden Death in a Child With Ocular Lesions.

This case report describes a patient treated for ocular lesions who died suddenly at age 8 years and was diagnosed postmortem with Carney complex.

Secondary Analysis of the Salt Substitute and Stroke Study (SSaSS): Effects of Potassium-Enriched Salt on Cardiac Outcomes.

BACKGROUND: The SSaSS (Salt Substitute and Stroke Study) has shown that use of a potassium-enriched salt lowers the risk of stroke, total cardiovascular events, and premature death. The effects on cause-specific cardiac outcomes are reported here. METHODS: SSaSS was an unblinded, cluster-randomised trial assessing the effects of potassium-enriched salt compared with regular salt among 20 995 Chinese adults with established stroke and older age and uncontrolled hypertension. Post hoc efficacy analyses were performed using an intention-to-treat method and a hierarchical Poisson regression model adjusting for clustering to obtain rate ratios and 95% CIs. We assessed acute coronary syndrome, heart failure, arrhythmia, and sudden death. RESULTS: Over a mean 4.74 years follow-up, there were 695 acute coronary syndrome events, 454 heart failure events, 230 arrhythmia events, and 1133 sudden deaths recorded. The rates of events were lower in potassium-enriched salt group for all outcomes but CIs were wide for most: acute coronary syndrome (6.32 versus 7.65 events per 1000 person-years; rate ratio, 0.80 [95% CI, 0.65-0.99]); heart failure (9.14 versus 11.32 events per 1000 person-years; rate ratio, 0.88 [95% CI, 0.60-1.28]); arrhythmia (4.43 versus 6.20 events per 1000 person-years; rate ratio, 0.59 [95% CI, 0.35-0.98]); and sudden death (11.01 versus 11.76 events per 1000 person-years; rate ratio, 0.94 [95% CI, 0.82-1.07]; all P>0.05 with adjustment for multiple comparisons). CONCLUSIONS: These results suggest that use of potassium-enriched salt is more likely to prevent than cause cardiac disease but the post hoc nature of these analyses precludes definitive conclusions. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02092090.

Asymmetrical cortical surface area decrease in epilepsy patients with postictal generalized electroencephalography suppression.

Postictal generalized electroencephalographic suppression is a possible electroencephalographic marker for sudden unexpected death in epilepsy. We aimed to investigate the cortical surface area abnormalities in epilepsy patients with postictal generalized electroencephalographic suppression. We retrospectively included 30 epilepsy patients with postictal generalized electroencephalographic suppression (PGES+), 21 epilepsy patients without postictal generalized electroencephalographic suppression (PGES-), and 30 healthy controls. Surface-based analysis on high-resolution T1-weighted images was conducted and cortical surface areas were compared among the three groups, alongside correlation analyses with seizure-related clinical variables. Compared with PGES- group, we identified reduced surface area in the bilateral insula with more extensive distribution in the right hemisphere in PGES+ group. The reduced right insular surface area was associated with younger seizure-onset age. When compared with healthy controls, PGES- group presented reduced surface area in the left caudal middle frontal gyrus; PGES+ group presented more widespread surface area reductions in the right posterior cingulate gyrus, left postcentral gyrus, middle frontal gyrus, and middle temporal gyrus. Our results suggested cortical microstructural impairment in patients with postictal generalized electroencephalographic suppression. The significant surface area reductions in the insular cortex supported the autonomic network involvement in the pathology of postictal generalized electroencephalographic suppression, and its right-sided predominance suggested the potential shared abnormal brain network for postictal generalized electroencephalographic suppression and sudden unexpected death in epilepsy.

Pathological causes of sudden death in autopsied children with reference to peculiar findings: An Egyptian perspective.

Childhood is a long period extending up to the age of 18 years. Childhood encompasses different developmental stages; each stage has specific characteristics. This 5-year study included 244 autopsied children who died unexpectedly due to natural causes. This study was conducted in the forensic pathology unit of the Egyptian Forensic Medicine Authority (EFMA). Pathological causes of death were diagnosed in 181 cases, representing nearly three-quarters (74.2 %) of cases. Males represented 60.8 % of these cases. More than half (51.4 %) of deaths due to natural disease occurred within the first month of life. The diagnosis was established for the first-time during autopsy in 58 % of cases. Prematurity complications and infections were the cause of death in 35.9 % and 30.4 % of deaths attributed to natural pathologies, respectively. Prematurity complications are the most common cause of death in perinatal (63.6) and neonatal (71.4 %) periods. Whereas infection is the most common cause of death during infancy (55 %), childhood (52.8 %), and adolescence (43.8 %). Pneumonia was the most common infection (61.8 %). This study highlighted cases with peculiar pathologies that include cardiomyopathies (idiopathic dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and Arrhythmogenic right ventricular cardiomyopathy (ARVD)), Waterhouse-Friderichsen syndrome (WFS), ruptured cerebral cavernous hemangioma, and cerebellar medulloblastoma.

Sex differences in coronary atherosclerosis during the pre- and postmenopausal period: The Tampere Sudden Death Study.

BACKGROUND AND AIMS: Women are believed to be protected from coronary heart disease (CHD) by the effects of estrogen but detailed studies on the vessel wall level are missing. We aimed to measure sex differences in atherosclerosis during the premenopausal and postmenopausal periods directly at the coronary arteries. METHODS: We analyzed statistics for sex differences in CHD mortality in Finland in 2020. Coronary atherosclerosis was measured using computer-assisted morphometry in 10-year age groups of 185 white Caucasian women and 515 men from the Tampere Sudden Death Study. RESULTS: CHD mortality was rare in both women and men before 50 years of age. After 50 years of age, male mortality increased rapidly, with women reaching equal levels in the oldest age groups. In the autopsy series, there were no differences in fatty streak, fibrotic or calcified plaque areas, nor in the plaque area or stenosis percentage in coronary arteries between premenopausal women and men in the same age group. The plaque area remained 25 % smaller in both coronaries in postmenopausal women aged 51-70 years compared to men. In the oldest postmenopausal group (≥70 years), plaque area reached the level of men. In the postmenopausal period, coronary stenosis in the left anterior descending (LAD) artery remained lower among women. CONCLUSION: We did not detect any major sex-difference in coronary atherosclerosis in the premenopausal period when women are considered to be protected from CHD. However, in line with CHD mortality statistics, postmenopausal women showed a slower speed of coronary atherosclerosis development compared to men.

Epilepsy's effect on cardiac rhythm and the autonomic nervous system.

OBJECTIVE: Sudden unexpected death in epilepsy is the most common cause of death in young patients with epilepsy. The aim of this study was to evaluate changes in interictal electrocardiogram parameters and sympathetic skin responses as markers of autonomic dysfunction in patients with epilepsy and to determine their effects on the type and duration of epilepsy, frequency of seizures, and responses to treatment. METHODS: A total of 97 patients with epilepsy and 94 healthy controls were recruited. We recorded their clinical and demographic characteristics and analyzed sympathetic skin response latency and amplitude, electrocardiogram recordings, and seven cardiac rhythm parameters: P-wave duration, PR segment, QRS duration, QT interval, QT interval distribution, Tpe duration, and Tpe/QT interval ratio. RESULTS: P-wave durations, T-wave durations, QT and QT interval durations, and Tpe and sympathetic skin response latency were significantly longer among patients with epilepsy than the controls, and their heart rate was significantly lower. However, sympathetic skin response latency and heart rate were negatively correlated, and T-wave duration, QT duration, QT interval duration, and Tpe were positively correlated. CONCLUSION: Our results from interictal electrocardiograms indicate clinically significant arrhythmias among patients with epilepsy and the correlation of such arrhythmias with sympathetic skin responses. Thus, noninvasive tests that evaluate the autonomic system should be used to predict the risk of sudden unexpected death in epilepsy among patients with epilepsy.

Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.

Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes. A curated set of 30 benign and 30 pathogenic missense variants were used to establish the range of normal and abnormal function. The extent to which variants reduced protein function was quantified using Z scores, the number of standard deviations from the mean of the normalized current density of the set of benign variant controls. A Z score of -2 defined the threshold for abnormal loss of function, which corresponds to 55% wild-type function. More extreme Z scores were observed for variants with a greater loss-of-function effect. We propose that the Z score for each variant can be used to inform the application and weighting of abnormal and normal functional evidence criteria (PS3 and BS3) within the American College of Medical Genetics and Genomics variant classification framework. The validity of this approach was demonstrated using a series of 18 KCNH2 missense variants detected in a childhood onset LQTS cohort, where the level of function assessed using our assay correlated to the Schwartz score (a scoring system used to quantify the probability of a clinical diagnosis of LQTS) and the length of the corrected QT (QTc) interval.

Video Analyses of Sudden Unexplained Deaths in Toddlers.

BACKGROUND AND OBJECTIVES: More than 2,900 US children aged younger than 4 years die from unknown causes each year, accounting for more than 219,000 life years lost annually. They are mostly sleep-related and unwitnessed with unremarkable autopsies, limiting our understanding of death mechanisms. We sought to understand potential mechanisms of death by evaluating videos of sudden deaths in toddlers. METHODS: In our registry of 301 sudden unexplained child deaths, a series of 7 consecutively enrolled cases with home video recordings of the child's last sleep period were independently assessed by 8 physicians for video quality, movement, and sound. RESULTS: Four boys and 3 girls (13-27 months at death) with terminal videos shared similar demographic features to the 293 other registry cases without video recordings. Five video recordings were continuous and 2 were triggered by sound or motion. Two lacked audio. All continuous recordings included a terminal convulsive event lasting 8-50 seconds; 4 children survived for >2.5 minutes postconvulsion. Among discontinuous videos, time lapses limited review; 1 suggested a convulsive event. Six were prone with face down, and 1 had autopsy evidence of airway obstruction. Primary cardiac arrhythmias were not supported; all 7 children had normal cardiac pathology and whole-exome sequencing identified no known cardiac disease variants. DISCUSSION: Audio-visual recordings in 7 toddlers with unexplained sudden deaths strongly implicate that deaths were related to convulsive seizures, suggesting that many unexplained sleep-related deaths may result from seizures.

DNA methylation profiling reveals potential biomarkers of ß-lactams induced fatal anaphylactic shock.

Anaphylaxis is a serious reaction of systemic hypersensitivity with that rapid onset and sudden death. Drug hypersensitivity, particularly induced by ß-lactams, is one of the most frequent causes of anaphylaxis in adults. But identification of anaphylactic shock, in forensic sciences recently, is difficult, because it mainly depends on nonspecific characteristic morphological changes, as well as exclusion and circumstantial evidence. Here, we detected DNA methylation signatures of ß-lactams-induced fatal anaphylactic shock with the Illumina Infinium Human Methylation EPIC BeadChip, to screen potential forensic biomarkers and reveal the molecular mechanisms of drug-induced anaphylaxis with fatal shock and sudden death. Our results indicated that DNA methylation was associated with ß-lactams-induced fatal anaphylactic shock, in which the hypomethylation played a vital role. We found that 1459 differentially methylated positions (DMPs) were mainly involved in ß-lactams-induced fatal anaphylactic shock by regulating MAPK and other signaling pathways. 18 DNA methylation signatures that could separate ß-lactams-induced anaphylactic shock from healthy individuals were identified. The altered methylation of DMPs can affect the transcription of corresponding genes and promote ß-lactams-induced fatal anaphylactic shock. The results suggest that DNA methylation can detect forensic identification markers of drug-induced anaphylaxis with fatal shock and sudden death, and it is an effective method for the forensic diagnosis.

Sudden Unexpected Death in Epilepsy During Ambulatory Video-EEG Monitoring at Home.

BACKGROUND AND OBJECTIVES: We report the recording of sudden unexpected death in epilepsy (SUDEP) in a 68-year-old man with recent onset cryptogenic epilepsy, captured by video-EEG monitoring, at home in the company of his wife while sitting in a chair. This was only the third seizure of his life, the first 2 occurring 19 days previously. This rare event is a novel case of SUDEP recorded with ambulatory video EEG at home. The video is included by permission. METHODS: Electroclinical seizure and cardiorespiratory analysis was ascertained using a combination of video, EEG (Natus, standard 10-20 electrode), ECG, and sound. Respiratory rate was ascertained based on chest, abdominal, and facial respiratory movements, together with video and audio. RESULTS: The unique video-EEG recording illustrates the time course of apnea and bradycardia leading to terminal apnea in conjunction with prolonged postictal generalized EEG suppression. DISCUSSION: This case is illustrative of a wide spectrum of SUDEP cases, ranging from the highly intractable to the patient with newly diagnosed epilepsy with very few seizures. It illustrates that patients can succumb to SUDEP while awake and in the sitting position (1) very early in their epilepsy course, (2) without recognized risk factors other than generalized convulsive seizures, (3) even when accompanied.