Association of electrocardiographic spatial heterogeneity of repolarization and spatial heterogeneity of atrial depolarization with left ventricular fibrosis.

AIMS: To evaluate the relationship between spatial heterogeneity of electrocardiographic repolarization and spatial heterogeneity of atrial depolarization with arrhythmic substrate represented by left ventricular fibrosis. METHODS AND RESULTS: We assessed the associations of T- and P-wave morphology parameters analysed from the standard 12-lead electrocardiograms with left ventricular fibrosis in 378 victims of unexpected sudden cardiac death (SCD) who underwent medico-legal autopsy. Based on autopsy findings, the SCD victims were categorized into four different groups according to different stages of severity of left ventricular fibrosis (substantial fibrosis, moderate patchy fibrosis, scattered mild fibrosis, no fibrosis). T-wave and P-wave area dispersion (TWAd: 0.0841 ± 0.496, 0.170 ± 0.492, 0.302 ± 404, 0.296 ± 0.476, P = 0.008; PWAd: 0.574 ± 0.384, 0.561 ± 0.367, 0.654 ± 0.281, 0.717 ± 0.257, P = 0.011, respectively; low values abnormal), non-dipolar components of T-wave and P-wave morphology (T_NonDipolarABS: 0.0496 ± 0.0377, 0.0571 ± 0.0487, 0.0432 ± 0.0476, 0.0380 ± 0.0377, P = 0.027; P_NonDipolarABS: 0.0132 ± 0.0164, 0.0130 ± 0.0135, 0.0092 ± 0.0117, 0.0069 ± 0.00472, P = 0.005, respectively, high values abnormal), T-wave morphology dispersion (TMD: 45.9 ± 28.3, 40.5 ± 25.8, 35.5 ± 24.9, 33.0 ± 24.6, P = 0.030, respectively, high values abnormal), and P-wave heterogeneity (PWH: 20.0 ± 9.44, 19.7 ± 8.87, 17.9 ± 9.78, 15.4 ± 4.60, P = 0.019, respectively, high values abnormal) differed significantly between the groups with different stages of left ventricular fibrosis. After adjustment with heart weight, T_NonDipolarABS [standardized ß (sß) = 0.131, P = 0.014], PWAd (sß = -0.161, P = 0.003), P_NonDipolarABS (sß = 0.174, P = 0.001), and PWH (sß = 0.128, P = 0.015) retained independent association, and TWAd (sß = -0.091, P = 0.074) and TMD (sß = 0.097, P = 0.063) tended to retain their association with the degree of myocardial fibrosis. CONCLUSION: Our findings suggest that abnormal values of T- and P-wave morphology are associated with arrhythmic substrate represented by ventricular fibrosis partly explaining the mechanism behind their prognostic significance.

Use of Psychotropic Medication in Victims of Sudden Cardiac Death with Nonischemic Heart Disease.

BACKGROUND: Nonischemic heart disease (NIHD) is the underlying pathology in about 20% of sudden cardiac deaths (SCDs). Psychotropic medication has been reported as a risk factor for SCD among patients with coronary artery disease, but similar information concerning NIHD is scarce. OBJECTIVES: We evaluated the use of psychotropic medication in victims of SCD due to NIHD and compared it to the general medication use in Finland. METHOD: Study population was derived from the Finnish Genetic Study of Arrhythmic Events (Fingesture) (n = 5,869, mean age: 65 ± 12, 79% males; 1,404 victims of SCD due to NIHD, mean age: 57 ± 13, 77% males). All deaths occurred in Northern Finland during 1998-2017. All victims underwent a medicolegal autopsy. Data on use of medication were defined using postmortem toxicology results and patient records. Subjects with neither toxicological analysis nor information of medication use available were excluded. Information on general medication use was derived from Finnish Statistics on Medicines 2018 and presented as defined daily dose/1,000 inhabitants/day. RESULTS: Psychotropic medication was used by 579 (41%) subjects with NIHD, whereas in the general population, only 12% were estimated to use psychotropics. The results were similar in subgroups of psychotropic medication: 27% versus 2.3% for benzodiazepines, 19% versus 7.5% for antidepressants, and 18% versus 2.2% for antipsychotics. CONCLUSIONS: Use of psychotropic medication is common in victims of SCD due to NIHD compared to the general population.

Plaque histology and myocardial disease in sudden coronary death: the Fingesture study.

AIMS: At least 50% of deaths due to coronary artery disease (CAD) are sudden cardiac deaths (SCDs), but the role of acute plaque complications on the incidence of sudden death in CAD is somewhat unclear. The present study aimed to investigate plaque histology and concomitant myocardial disease in sudden coronary death. METHODS AND RESULTS: The study population is derived from the Fingesture study, which has collected data from 5869 consecutive autopsy-verified SCD victims in Northern Finland (population ≈600 000) between 1998 and 2017. In this substudy, histological examination of culprit lesions was performed in 600 SCD victims whose death was due to CAD. Determination of the cause of death was based on the combination of medical records, police reports, and autopsy data. Plaque histology was classified as either (i) plaque rupture or erosion, (ii) intraplaque haemorrhage, or (iii) stable plaque. The mean age of the study subjects was 64.9 ± 11.2 years, and 82% were male. Twenty-four per cent had plaque rupture or plaque erosion, 24% had an intraplaque haemorrhage, and 52% had a stable plaque. Myocardial hypertrophy was present in 78% and myocardial fibrosis in 93% of victims. The presence of myocardial hypertrophy or fibrosis was not associated with specific plaque histology. CONCLUSION: Less than half of sudden deaths due to CAD had evidence of acute plaque complication, an observation which is contrary to historical perceptions. The prevalence of concomitant myocardial disease was high and independent of associated plaque morphology.

MiR-185-5p regulates the development of myocardial fibrosis.

BACKGROUND: Cardiac fibrosis stiffens the ventricular wall, predisposes to cardiac arrhythmias and contributes to the development of heart failure. In the present study, our aim was to identify novel miRNAs that regulate the development of cardiac fibrosis and could serve as potential therapeutic targets for myocardial fibrosis. METHODS AND RESULTS: Analysis for cardiac samples from sudden cardiac death victims with extensive myocardial fibrosis as the primary cause of death identified dysregulation of miR-185-5p. Analysis of resident cardiac cells from mice subjected to experimental cardiac fibrosis model showed induction of miR-185-5p expression specifically in cardiac fibroblasts. In vitro, augmenting miR-185-5p induced collagen production and profibrotic activation in cardiac fibroblasts, whereas inhibition of miR-185-5p attenuated collagen production. In vivo, targeting miR-185-5p in mice abolished pressure overload induced cardiac interstitial fibrosis. Mechanistically, miR-185-5p targets apelin receptor and inhibits the anti-fibrotic effects of apelin. Finally, analysis of left ventricular tissue from patients with severe cardiomyopathy showed an increase in miR-185-5p expression together with pro-fibrotic TGF-ß1 and collagen I. CONCLUSIONS: Our data show that miR-185-5p targets apelin receptor and promotes myocardial fibrosis.

Temporal Trends in the Incidence and Characteristics of Sudden Cardiac Death among Subjects under 40 Years of Age in Northern Finland during 1998-2017.

BACKGROUND: Although the mean age of sudden cardiac death (SCD) victims has increased during recent decades, overall incidence has remained relatively stable. Small but very important proportion of SCDs occur in subjects under 40 years of age and temporal trends in the incidence and characteristics of SCD in this age-group are not well known. METHODS: The Fingesture study has prospectively gathered data from 5,869 consecutive autopsy verified SCD victims in Northern Finland during 1998-2017. On the basis of Finnish law, all who die unexpectedly undergo autopsy. RESULTS: Out of total 5,869 SCDs, 160 occurred in subjects under 40 years of age (3%) indicating a total incidence of 2.9/100,000/year. Incidence decreased during the study period: 4.0/100,000/year (n = 50) in 1998-2002, 3.7/100,000/year (n = 45) in 2003-2007, 2.5/100,000/year (n = 36) in 2008-2012, and 1.5/100,000/year (n = 29) in 2013-2017. Coronary artery disease (CAD) was the cause of death in 46 SCD victims (29%). Among nonischemic causes, most common were obesity-related hypertrophic myocardial disease (24%), primary myocardial fibrosis (19%), and hypertensive myocardial disease (6%). The incidence of SCD caused by CAD decreased as follows: 1.5/100,000/year in 1998-2002, 1.2/100,000/year in 2003-2007, 0.6/100,000/year in 2008-2012, and 0.2/100,000/year in 2013-2017. Proportion of male gender (81%) and obesity as a comorbidity (body mass index >30 kg/m2, 40%) remained relatively stable during the period (p = 0.58 and p = 0.79, respectively). CONCLUSIONS: The incidence of SCD in subjects under 40 years of age has decreased in Northern Finland during 1998-2017. According to autopsy data, most of the deaths are due to nonischemic myocardial diseases and relative proportion of CAD has decreased.

Sudden Cardiac Death in Women.

BACKGROUND: Despite recent progress in profiling of risk for sudden cardiac death (SCD) and prevention and intervention of cardiac diseases, SCD remains a major cause of death. Among women, the incidence of SCD is significant, but lower than in men, particularly in the premenopausal and early postmenopausal years. Possibly, as a consequence of the difference in population burden, the mechanisms and risk markers of SCD are not as well defined for women. The aim of this study was to determine the autopsy findings and causes of death among women in a large SCD population. Additionally, we sought to classify prior ECG characteristics in male and female subjects with SCD. METHODS: The Fingesture study has systematically collected clinical and autopsy data from subjects with SCD in Northern Finland between 1998 and 2017. The cohort consists of 5869 subjects with SCD. Previously recorded ECGs were available and analyzed in 1101 subjects (18.8% of total population; and in 25.3% of women). RESULTS: Female subjects with SCD were significantly older than men: 70.1±13.1 years versus 63.5±11.8 years (mean ± standard deviation, P<0.001). The most frequently identified cause of death was ischemic heart disease in both sexes: 71.7% among women versus 75.7% among men, P=0.005. In contrast, women were more likely to have nonischemic cause of SCD than men (28.3% versus 24.3%, P=0.005). The prevalence of primary myocardial fibrosis was higher among women (5.2%, n=64) than in men (2.6%, n=120; P<0.001). Female subjects with SCD were more likely to have normal prior ECG tracings (22.2% versus 15.3% in men, P<0.001). A normal ECG was even more common among nonischemic female subjects with SCD (27.8% versus 16.2% in men, P=0.009). However, ECG markers of left ventricular hypertrophy, with or without repolarization abnormalities, were more common among women (8.2%; 17.9%) than in men (4.9%; 10.6%, P=0.036; P<0.001, respectively). CONCLUSIONS: Women were considerably older at the time of SCD and more commonly had nonischemic causes. Women were also more likely to have a prior normal ECG than men, but an increased marker for SCD risk based on ECG criteria for left ventricular hypertrophy with repolarization abnormalities was more commonly observed in women.

RNU6B, a frequent reference in miRNA expression studies, differentiates between deaths caused by hypothermia and chronic cardiac ischemia.

Here, we tested the usefulness of small non-coding RNAs as references in quantitative RT-PCR expression analyses in hypothermia and chronic cardiac ischemia as the primary causes of death. Cq values of RNU6B, SCARNA17, SNORD25, and SNORA73A were determined from human cadaver samples of hypothermia and cardiac deaths. Average Cq values of RNU6B were higher in hypothermic and average SCARNA17 Cq values in chronic ischemic samples, but no difference in SNORD25 and SNORA73A Cq values could be seen between the groups. RNU6B expression levels were calculated using SNORD25, SNORA73A, and their combination as the reference in normalization. Expression of RNU6B, a widely used reference, was found to be significantly lower in hypothermia than in chronic cardiac ischemia. In these conditions, RNU6B is a useful marker differentiating hypothermia deaths from chronic ischemic heart disease deaths, but not a valid reference for normalization in expression studies.

Presumed adverse events in health care are a frequent indication for medico-legal autopsy in Finland.

The medico-legal autopsy is an essential tool in investigating deaths caused by an adverse event in health care, for both clinical risk management and for professional liability issues. However, there are no statistics available regarding the frequency of autopsies performed due to suspected adverse events. This study aimed to determine the number of medico-legal autopsies done because of presumed adverse events, whether these events were unintentional, medical errors or cases in which malpractice was suspected. Furthermore, differences in treatment types, causes and manner of death were analyzed. The data was obtained from all medico-legal autopsies performed in Northern Finland and Lapland during 2014-2015 (n = 2027). Adverse events were suspected in 181 (8.9%) cases. The suspicions of an adverse event occurring were most often related to medication, gastrointestinal surgery and orthopedic surgery. The manner of death was classified as medical (or surgical) treatment or investigative procedure in 22 (12.2%) cases. The causes of death were completely unrelated to the suspected adverse event in 41 (22.7%) cases. In conclusion, the frequency of presumed adverse events was quite high in this data set, but in the majority of the cases, the suspicion of an adverse event causing death was disproved by an autopsy. Nonetheless, proper investigation of these cases is essential to ensure legal protection of the deceased, next of kin and health care personnel, as well as to support clinical risk management.

Primary Myocardial Fibrosis as an Alternative Phenotype Pathway of Inherited Cardiac Structural Disorders.

BACKGROUND: Myocardial fibrosis is a common postmortem finding among young individuals with sudden cardiac death. Because there is no known single cause, we tested the hypothesis that some cases of myocardial fibrosis in the absence of identifiable causes (primary myocardial fibrosis [PMF]) are associated with genetic variants. METHODS: Tissue was obtained at autopsy from 4031 consecutive individuals with sudden cardiac death in Northern Finland, among whom PMF was the only structural finding in 145 subjects with sudden cardiac death. We performed targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function when autopsies did not identify a secondary basis for myocardial fibrosis. All variants with an effect on protein and with a minor allele frequency <0.01 were classified as pathogenic or variants of uncertain significance on the basis of American College of Medical Genetics consensus guidelines. RESULTS: Among the 96 specimens with DNA passing quality control (66%), postmortem genetic tests identified 24 variants of known or uncertain significance in 26 subjects (27%). Ten were pathogenic/likely pathogenic variants in 10 subjects (10%), and 14 were variants of uncertain significance in 11 genes among 16 subjects (17%). Five variants were in genes associated with arrhythmogenic right ventricular cardiomyopathy, 6 in hypertrophic cardiomyopathy-associated genes, and 11 in dilated cardiomyopathy-associated genes; 2 were not associated with these disorders. Four unique variants of uncertain significance cosegregated among multiple unrelated subjects with PMF. No pathogenic/likely pathogenic variants were detected in ion channel-encoding genes. CONCLUSIONS: A large proportion of subjects with PMF at autopsy had variants in genes associated with arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy without autopsy findings of those diseases, suggesting that PMF can be an alternative phenotypic expression of structural disease-associated genetic variants or that risk-associated fibrosis was expressing before the primary disease. These findings have clinical implications for postmortem genetic testing and family risk profiling.

Fragmented QRS complex as a predictor of exercise-related sudden cardiac death.

INTRODUCTION: Little is known about the association between electrocardiographic abnormalities and exercise-related sudden cardiac death. Therefore, our aim was to identify possible electrocardiographic findings related to exercise-induced sudden cardiac death. METHODS AND RESULTS: The FinGesture study includes 3,989 consecutive sudden cardiac deaths in northern Finland between 1998 and 2012, out of whom a total of 647 subjects had a previously recorded electrocardiography acquired from the archives of Oulu University Hospital. In 276 of these cases the death was witnessed, and the activity at the time of death was either rest or physical exercise (PE); in 40 (14%) cases sudden cardiac death was exercise-related and in 236 (86%) cases death took place at rest. Fragmented QRS complex in at least two consecutive leads within anterior leads (V1-V3) was more common in the exercise-group compared to rest-group (17 of 40, 43% vs. 51 of 236, 22%, P  =  0.005). Pathologic Q wave in anterior leads was more common in the PE group (9 of 40, 23% vs. 26 of 236, 11%; P  =  0.044). Median QRS duration was prolonged in the exercise-group compared to the rest-group (100 milliseconds vs. 94 milliseconds, P = 0.047). QTc interval, the prevalence of inverted T-waves, or other electrocardiographic abnormalities did not differ significantly between the two groups. CONCLUSIONS: As a conclusion, fragmented QRS complex in the anterior leads is associated with an increased risk of sudden cardiac death during PE.

Sudden Unexpected Death From Unusually Large Primary Cardiac B-cell Lymphoma.

Primary cardiac lymphomas represent approximately 1% to 2% of primary cardiac neoplasms and 5% of malignant cardiac neoplasms. Here we present a case of sudden unexpected death of a middle-aged male resulting from an unusually large cardiac B-cell lymphoma. The neoplasm infiltrated the myocardium of the right atrium and ventricle and, to a lesser extent, the wall of the left atrium and pulmonary trunk. Extensive infiltration of the heart by the primary cardiac lymphoma, combined with the complete lack of symptoms, makes this case unusual.

Victims of lethal hypothermia have decreased levels of thrombomodulin in myocardium and urine.

Severe cold stress has been shown to cause changes in the expression and secretion of thrombomodulin (TM), an endothelial protein regulating haemostasis and inflammation. To further evaluate TM as a cold stress indicator, relative TM mRNA and TM protein levels in the myocardium and the concentrations of TM in serum and urine were analysed in different causes of death (hypothermia main cause, n = 80; hypothermia contributory cause, n = 26; cardiovascular disease (CVD) main cause, n = 94; trauma main cause, n = 45; other main cause, n = 25). Urinary catecholamine concentrations and myocardial heat shock factor 1 (HSF1) transcript levels were also studied. The TM mRNA and the TM protein levels in myocardium and urine were significantly lower in hypothermia deaths than those in the controls. Post-mortem interval did not correlate with urinary TM concentration. The sensitivity and specificity of urinary TM assay to detect hypothermia deaths were 70.8 and 70.3 %, respectively. Catecholamine concentrations in urine correlated significantly with TM concentration in urine and TM mRNA levels in all groups excluding CVD deaths. There were no differences in the HSF1 transcript levels and no correlation to TM levels. These findings provide further evidence that cold stress and hypothermia affect TM expression and secretion and that they are possibly linked to catecholamine action. Thus, measuring post-mortem TM levels may provide additional support to diagnosing hypothermia in medico-legal examination. The results may also provide additional knowledge for the treatment of hypothermic patients and the use of hypothermia for medical purposes.

Changes in cardiac thrombomodulin and heat shock transcription factor 1 expression and peripheral thrombomodulin and catecholamines during hypothermia in rats.

Effects of hypothermia and rewarming on thrombomodulin, catecholamines and heat shock transcription factor 1 (HSF1) were studied in rats. The aims of this study were to clarify whether cold stress, under anesthesia, is sufficient to change levels of thrombomodulin in healthy endothelium and in the circulation and whether adrenaline, noradrenaline and HSF1 could act as regulators in the process. Rats were divided into control, mild hypothermia (2 and 4.5 hours at + 21 °C; MH1, MH2), severe hypothermia (2 and 4.5 h at + 10 °C; SH1, SH2) and two rewarming groups (2 h at + 10 °C followed by 2 h at + 21 °C or 3 h at + 28 °C; SHW1, SHW2) (n = 15/group, except n = 6 in MH1). Fentanyl-fluanisone-midazolam was used as anesthetic. Low levels of thrombomodulin in plasma and myocardial arterioles/venules measured by ELISA and immunohistochemistry were associated with significant increase of thrombomodulin transcript level in SH1 rats analyzed by quantitative PCR. Plasma adrenaline correlated negatively with the relative amount of myocardial thrombomodulin transcripts and positively with plasma thrombomodulin in SH. Transcript levels of thrombomodulin and HSF1 correlated strongly (r = 0.83; p < 0.001) in SH. Plasma/urine ratio of thrombomodulin and plasma adrenaline (r = 0.87; p = 0.005) or noradrenaline (r = 0.78; p = 0.023) were strongly correlated in SHW1 rats. Hence, cellular and soluble levels of thrombomodulin are modified by cold stress in healthy rats, possibly via catecholamines and HSF1.

Day-of-the-week variation of sudden unexpected cardiac death.

Background: There has been some controversy about the day-of-the-week (septadian) variation of unexpected sudden cardiac death (SCD). Methods: We evaluated the incidence of unexpected SCD on different days of the week in a consecutive series of 5869 SCD victims from Northern Finland [the FINGESTURE study (Finnish Genetic Study of Arrhythmic Events)]. As it is mandatory in Finland, a medico-legal autopsy was performed on all unexpected sudden death victims. The autopsies were performed between the years 1998-2017. Results: The mean incidence of unexpected SCD was higher at weekends (during the days from Friday to Sunday, peaking on Saturday) than during the days from Monday to Thursday (8.54 ± 0.72 vs. 7.22 ± 0.19 SCDs per day of the week per 100,000 inhabitants per year, p < 0.001). Regardless of sex or ischemic versus non-ischemic etiology of SCD, the distribution of the occurrence of SCD among the days of the week was similar compared with the whole SCD cohort. Conclusion: The incidence of unexpected SCD was highest at weekends (during the days from Friday to Sunday, peaking on Saturday).

The burden of sudden cardiac arrest in the setting of acute coronary syndrome.

BACKGROUND: The incidence of sudden cardiac arrest (SCA) during acute coronary syndrome is somewhat unclear, since often subjects dying before the first healthcare contact are not included in the estimates. We aimed to investigate the complete incidence of SCA during ACS. METHODS: The study population consists of two cohorts. The first cohort includes 472 ACS patients from Northern Ostrobothnia, Finland from year 2016 and the second cohort 162 autopsy-verified SCD subjects (extrapolated) from the same region and year, whose death was attributable to coronary artery disease (CAD) and ACS. An extrapolation of SCA incidence during ACS was done by utilizing autopsy data and data from prior autopsy study on this sample. RESULTS: The overall incidence of SCA in the setting of ACS was 17.5%. The incidence of SCA was 20.6% in all ACS subjects without prior CAD diagnosis, and 25.4% in STEMI subjects without prior CAD diagnosis. In subjects with previously diagnosed CAD, the incidence of SCA was 10.9% in all ACS subjects and 16.1% in STEMI subjects. There was a statistically significant difference in the incidence of SCA between subjects with and without prior CAD diagnoses (p=0.0052). CONCLUSION: The inclusion of ACS-SCA subjects dying before the first emergency medical service (EMS) contact results in a higher and likely more accurate estimation of SCA during ACS. The incidence of SCA was higher among subjects without prior CAD diagnosis. The high mortality rate highlights the importance of early ACS detection to reduce the burden of CAD-related premature deaths.

Novel Genetic Variants Associated with Primary Myocardial Fibrosis in Sudden Cardiac Death Victims.

Myocardial fibrosis is a common finding in victims of sudden cardiac death (SCD). Whole exome sequencing was performed in 127 victims of SCD with primary myocardial fibrosis as the only pathological finding. These cases are derived from the Fingesture study which has collected data from autopsy-verified SCD victims in Northern Finland. A computational approach was used to identify protein interactions in cardiomyocytes. Associations of the identified variants with cardiac disease endpoints were investigated in the Finnish national genetic study (FinnGen) dataset. We identified 21 missense and one nonsense variant. Four variants were estimated to affect protein function, significantly associated with SCD/primary myocardial fibrosis (Fingesture) and associated with cardiac diseases in Finnish population (FinnGen). These variants locate in cartilage acidic protein 1 (CRATC1), calpain 1 (CAPN1), unc-45 myosin chaperone A (UNC45A) and unc-45 myosin chaperone B (UNC45B). The variants identified contribute to function of extracellular matrix and cardiomyocytes.

Causes and characteristics of unexpected sudden cardiac death in octogenarians/nonagenarians.

INTRODUCTION: The risk for sudden cardiac death (SCD) increases with ageing. METHODS: We evaluated causes and characteristics of unexpected SCD in SCD victims aged ≥ 80 years in a consecutive series of 5,869 SCD victims in Northern Finland. All the victims underwent medico-legal autopsy as medico-legal autopsy is mandatory in cases of unexpected sudden death in Finland. All the non-cardiac deaths such as pulmonary embolism and cerebral hemorrhage were excluded from the study, as were unnatural deaths such as intoxications. RESULTS: Among SCD victims ≥ 80 years, 91.0% of SCDs were due to ischemic heart disease (IHD) determined in autopsy and 9.0% due to non-ischemic heart disease (NIHD), whereas among those < 80 years, only 72.6% of SCDs were due to IHD and 27.4% due to NIHD (P < .001). Severe fibrosis in myocardium was more common whereas heart weight and liver weight, body mass index and abdominal fat thickness, were lower among SCD victims aged ≥ 80 years than among victims aged < 80 years. In those with IHD as etiology of SCD, at least 75% stenosis in one or more major coronary vessels was more common in SCD victims aged ≥ 80 years than among victims aged < 80 years (P = .001). SCD victims 80 years or older were less likely to die during physical activity than those under 80 years old (5.6% vs. 15.9%, P < .001). Dying in sauna was more common among those ≥ 80 years than among those < 80 years (5.5% vs. 2.6%, P < .001). CONCLUSION: In victims of unexpected SCD aged ≥ 80 years, the autopsy-based etiology of SCD was more commonly IHD than in those aged < 80 years. In SCD victims aged ≥ 80 years, severe fibrosis in myocardium, representing arrhythmic substrate, was more common than in the younger ones.

Primary myocardial fibrosis - a distinct entity characterized by heterogeneous histology.

Primary myocardial fibrosis (PMF), defined as myocardial fibrosis in the absence of identifiable causes, may represent a common alternative phenotype in various cardiomyopathies and contribute to sudden cardiac death (SCD). No previous definitions of histopathological characteristics exist for PMF. We aimed to evaluate whether common features of fibrosis could be identified. PMF cases (n = 28) were selected from the FinGesture cohort consisting of 5,869 SCD victims that underwent a medicolegal autopsy. Twelve trauma controls and 10 ischemic heart disease cases were selected as reference groups. Further 3 PMF cases and 5 ischemic heart disease cases from autopsies performed in the University of Copenhagen, Denmark, were selected for a validation substudy. Relative area of fibrosis, amount of diffuse and perivascular fibrosis, and location of fibrosis were assessed from left ventricle myocardial samples stained with Masson trichrome. Further evaluations were performed with alpha-smooth muscle actin (α-SMA), vimentin, and CD68 stainings. Mean relative area of fibrosis was 5.8 ± 10.7%, 1.0 ± 0.7%, and 7.0 ± 7.4% in PMF, trauma controls, and ischemic cases, respectively. Fibrosis in the PMF group was mostly located in other sites than the endocardium. Most cases with fibrosis had vimentin-positive but α-SMA-negative stromal cells within fibrotic areas. Histopathologically, PMF represents a heterogeneous entity with variable fibrotic lesions affecting the whole myocardium and a suggested significant role of fibroblasts. These findings may bring validation to PMF being a common manifestation of cardiomyopathies. Evidently, PMF stands out as a particular entity demanding special attention as a cause of SCD.

Bioprotective role of platelet-derived microvesicles in hypothermia: Insight into the differential characteristics of peripheral and splenic platelets.

BACKGROUND: Most platelets are present in peripheral blood, but some are stored in the spleen. Because the tissue environments of peripheral blood vessels and the spleen are quite distinct, the properties of platelets present in each may also differ. However, no studies have addressed this difference. We previously reported that hypothermia activates splenic platelets, but not peripheral blood platelets, whose biological significance remains unknown. In this study, we focused on platelet-derived microvesicles (PDMVs) and analyzed their biological significance connected to intrasplenic platelet activation during hypothermia. METHODS: C57Bl/6 mice were placed in an environment of -20 °C, and their rectal temperature was decreased to 15 °C to model hypothermia. Platelets and skeletal muscle tissue were collected and analyzed for their interactions. RESULTS: Transcriptomic changes between splenic and peripheral platelets were greater in hypothermic mice than in normal mice. Electron microscopy and real-time RT-PCR analysis revealed that platelets activated in the spleen by hypothermia internalized transcripts, encoding tissue repairing proteins, into PDMVs and released them into the plasma. Plasma microvesicles from hypothermic mice promoted wound healing in the mouse myoblast cell line C2C12. Skeletal muscles in hypothermic mice were damaged but recovered within 24 h after rewarming. However, splenectomy delayed recovery from skeletal muscle injury after the mice were rewarmed. CONCLUSIONS: These results indicate that PDMVs released from activated platelets in the spleen play an important role in the repair of skeletal muscle damaged by hypothermia.

The incidence of iatrogenic deaths in the Finnish cause-of-death statistics; a retrospective study.

PURPOSE: An adverse event in health care leading to death is a significant event when assessing patient safety. This study was designed in order to assess, how many iatrogenic deaths are registered in Finland annually, and what type of treatment they are mostly related to. METHODS: Material was collected using cause of death-statistics that includes "manner of death"-classification in Finland in 2014-2015. RESULTS: There were 350 cases that met the criteria of the study. In a majority of the cases (264, 75%), a medico-legal autopsy was performed. This represents only 1.4% of all medicolegal autopsies during the study period in Finland. The cases were most often related to medication (30%) or known high-risk procedures such as gastrointestinal surgery (23%) and cardiothoracic surgery (11%). Only 12% of the cases had no prior significant medical history. Patient characteristics were somewhat different among the surgical disciplines, probably reflecting treatment practices. CONCLUSION: Deaths that are classified as iatrogenic are mostly related to known high-risk surgery or medication. Further studies are needed to assess the true incidence of malpractice among this material.