Proarrhythmic drugs, drug levels, and polypharmacy in victims of sudden arrhythmic death syndrome: An autopsy-based study from Denmark.

BACKGROUND: Sudden arrhythmic death syndrome (SADS), characterized by an unknown or inconclusive cause of death at autopsy, together with a negative or non-lethal toxicology screening, is the most common cause of sudden cardiac death (SCD) in victims under the age of 35. The complete causality of SADS remains unclear, with drugs being a potential risk factor. OBJECTIVE: To describe the toxicological profiles of SADS victims, focusing on proarrhythmic drugs, drug levels, and polypharmacy. METHODS: All deaths in Denmark from 2000-2019 aged 1-35 years and 2007-2019 aged 36-49 years were examined through death certificates, national registries, and autopsy reports with toxicology screenings. We investigated all sudden unexpected death victims with an autopsy performed, and where cause of death was unknown or inconclusive, including negative or non-lethal drug findings (SADS). RESULTS: We identified 477 SADS victims; 313 (66%) had a positive toxicology screening (adjudicated non-lethal), with an average of 2.8 drugs/case. More than half of the SADS victims with a positive toxicology screening had QT-prolonging or brugadogenic drugs present. Polypharmacy was present in 66%, psychotropic polypharmacy in 37%, and QT-prolonging polypharmacy in 22%, with the most frequent overall and QT-prolonging drug combination being an antipsychotic and a psychoanaleptic drug. QT-prolonging drugs were more often present at suprapharmacological levels than non-QT-prolonging drugs. CONCLUSION: A majority of the SADS population had a positive toxicology, with a notably large proportion having proarrhythmic drugs and polypharmacy. This highlights the need for future focus on drugs as a risk factor for SADS.

Sex- and Lifestyle-Related Factors are Associated with Altered Hepatic CYP Protein Levels in People Diagnosed with Mental Disorders.

In this study, we used human postmortem tissue to investigate hepatic protein expression levels of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 by LC-MS/MS in a population of people suffering from mental disorders (n = 171). We report hepatic protein levels of these six CYP isoforms in 171 individuals in total, and define a focused population dataset of 116 individuals after excluding 55 samples due to low microsomal protein per gram of liver (MPPGL) yield. Postmortem decay was most likely the reason for the low MPPGL yield in the 55 samples. In the focused population, we found women to have significantly higher protein levels of CYP3A4 than men in addition to decreased CYP3A4 protein levels among obese individuals. Furthermore, MPPGL was negatively correlated with body mass index (BMI). An increase in CYP1A2 protein levels was observed among smokers, and increased CYP2E1 protein levels were observed among individuals with a history of alcohol abuse. Finally, individuals who received phenobarbital (CYP3A4 inducer) had significantly higher CYP3A4 levels. In conclusion, lifestyle-related factors prevalent among people suffering from mental disorders are associated with altered CYP protein levels, which may alter drug metabolism and affect the efficacy of commonly prescribed drugs. Furthermore, this investigation demonstrates that postmortem hepatic tissue can be used to study how lifestyle and effectors affect hepatic CYP-levels in a large cohort of patients. SIGNIFICANCE STATEMENT: Using a large number of postmortem hepatic tissue specimens (n=116) originating from the autopsy of individuals diagnosed with mental disorders, we were able to show that hepatic CYP-levels were affected by alcohol, smoking, BMI, and sex and that MPPGL was affected by BMI. These lifestyle-related changes may alter drug metabolism and affect the efficacy of commonly prescribed drugs. It is a novel approach to use a large postmortem cohort to investigate how lifestyle and effectors affect hepatic CYP-levels.

The impact of modifiable risk factors in the association between socioeconomic status and sudden cardiac death in a prospective cohort study: equal access to healthcare, unequal outcome.

AIMS: Low socioeconomic status is associated with all-cause mortality and cardiac risk factors. Furthermore, sudden cardiac death (SCD) is among the leading causes of death in the general population, and an identification of high-risk subgroups is needed. The aim of this study was to investigate the association between income and education level and incidence of SCD and to calculate the impact of modifiable mediating risk factors. METHODS AND RESULTS: Participants in the Copenhagen City Heart Study were followed up from 1993 to 2016. Sudden cardiac death was identified using high-quality death certificates, autopsy reports, discharge summaries, and national registry data. Hazard ratios were calculated using Cox proportional hazards regression, and adjusted cumulative incidences were predicted using cause-specific Cox models. Mediation analyses were performed using a marginal structural model approach. During 24 years of follow-up, 10 006 people participated, whereof 5514 died during the study period with 822 SCDs. Compared with long education, persons with elementary school level education had an SCD incidence rate ratio (IRR) of 2.48 [95% confidence interval (CI) 1.86-3.31], and low income was likewise associated with an SCD IRR of 2.34 (95% CI 1.85-2.96) compared with high income. In the association between education and SCD, the combined mediating effect of smoking, physical activity, and body mass index accounted for ∼20% of the risk differences. CONCLUSION: We observed an inverse association between both income and education and the risk of SCD, which was only in part explained by common cardiac risk factors, implying that further research into the competing causes of SCD is needed and stressing the importance of targeted preventive measures.

Low socioeconomic status (e.g. education and income) has previously been found associated with an increased risk of death and with different heart diseases. Sudden cardiac death (SCD) is among the leading causes of death in the general population, and predicting who is at high risk is difficult. Finding people or groups at high risk is important to improve prevention. That is why we decided to investigate whether socioeconomic status is also associated with the risk of SCD and to calculate the impact of modifiable lifestyle factors on this risk. We followed ∼10 000 people from a general population cohort for 24 years and observed 822 sudden cardiac deaths. The lowest income and education groups had more than twice the risk of SCD compared with the high groups. Differences in smoking, physical activity, and body mass index explained ∼20% of this increase.

Sudden unexpected death in epilepsy in persons younger than 50 years: A retrospective nationwide cohort study in Denmark.

OBJECTIVE: Persons with epilepsy have an increased mortality including a high risk of sudden unexplained death (SUD), also referred to as sudden unexpected death in epilepsy (SUDEP). We aimed to evaluate the risk of SUDEP in comparison to other causes of death and the risk of SUD in persons with and without epilepsy. METHODS: We undertook a retrospective population-based cohort study of all Danish citizens with and without epilepsy aged 1-49 years during 2007-2009. All deaths in the population were evaluated, and all cases of SUD identified. Primary causes of death in persons with epilepsy were evaluated independently by three neurologists and one neuropediatrician, using the unified SUDEP criteria. RESULTS: The three most frequent causes of death in persons with epilepsy were cancer (2.38 per 1000 person-years), SUDEP (1.65 per 1000 person-years), and pneumonia (1.09 per 1000 person-years) compared with cancer (.17 per 1000 person-years), accident-related deaths (.14 per 1000 person-years), and cardiovascular disease (.09 per 1000 person-years) in persons without epilepsy. Considering definite, definite plus, and probable cases, the SUDEP incidence was .27 per 1000 person-years (95% confidence interval [CI] = .11-.64) in children aged 1-17 years and 1.21 per 1000 person-years (95% CI = .96-1.51) in adults aged 18-49 years. Adjusted for age and sex, persons with epilepsy younger than 50 years had a 10.8-fold (95% CI = 9.97-11.64, p < .0001) increased all-cause mortality and a 34.4-fold (95% CI = 23.57-50.28, p < .0001) increased risk of SUD compared with persons without epilepsy. SUDEP accounted for 23.3% of all SUD. SIGNIFICANCE: This nationwide study of all deaths in persons with epilepsy younger than 50 years found a lower SUDEP risk in children compared with adults, and that epilepsy was a major risk factor for SUD in the background population. This underlines the importance of addressing risk factors for SUDEP to prevent premature death.

Undiagnosed acromegaly as an underlying cause of sudden death.

We report a case of sudden death in a 31-year-old male diagnosed at autopsy with clinical undiagnosed acromegaly. The purpose of this report is to underline the importance of health professionals reacting to phenotypic acromegaly, such as acral enlargement and/or unexplained hypertension, including a range of severe comorbidities, to avoid a fatal outcome. Recent studies have shown that the increased mortality seen in acromegaly patients can be reversed with modern treatment aimed at normalizing GH and IGF-I levels. One year before death, the presented case was diagnosed with hypertension, but was otherwise described as healthy. The forensic autopsy, including post-mortem CT, showed phenotypic facial and body characteristics for acromegaly, general visceromegaly, and a pituitary tumor. The cause of death was heart failure due to end-stage acromegalic cardiopathy. Because the disease is slowly progressive, the individual himself, and the people close to him, might not have considered the acromegaly-related facial changes as abnormal.

Cardiovascular disease in patients with severe mental illness.

Individuals diagnosed with schizophrenia or bipolar disorder have a life expectancy 15-20 years shorter than that in the general population. The rate of unnatural deaths, such as suicide and accidents, is high for these patients. Despite this increased proportion of unnatural deaths, physical conditions account for approximately 70% of deaths in patients with either schizophrenia or bipolar disorder, with cardiovascular disease contributing 17.4% and 22.0% to the reduction in overall life expectancy in men and women, respectively. Risk factors for cardiovascular disease, such as smoking, unhealthy diet and lack of exercise, are common in these patients, and lifestyle interventions have been shown to have small effects. Pharmacological interventions to reduce risk factors for cardiovascular disease have been proven to be effective. Treatment with antipsychotic drugs is associated with reduced mortality but also with an increased risk of weight gain, dyslipidaemia and diabetes mellitus. These patients have higher risks of both myocardial infarction and stroke but a lower risk of undergoing interventional procedures compared with the general population. Data indicate a negative attitude from clinicians working outside the mental health fields towards patients with severe mental illness. Education might be a possible method to decrease the negative attitudes towards these patients, thereby improving their rates of diagnosis and treatment.

Increased risk of fatal intoxication and polypharmacy among psychiatric patients at death.

Patients suffering from psychiatric disorders have an excess mortality and a shorter life span expectancy compared to the general population. Furthermore, they are treated with multiple drugs and are known to have an increased risk of drug abuse. In this study, we aimed at investigating the pharmaceutical drug and drug of abuse profiles of the deceased included in the Danish prospective autopsy-based forensic study on psychiatric patients, SURVIVE. Using the postmortem systematic toxicological analysis results, we identified 129 different consumed compounds in our population (n = 443). Polypharmacy (≥5 compounds) was detected in 39.5% of the deceased. Deceased with a psychiatric diagnosis or who died from a fatal intoxication had significantly more compounds at the time of their death compared to having either no psychiatric diagnosis or another cause of death, respectively. Evidence of drug abuse was present, as 29.8% of our total population had consumed either methadone or illicit drugs of abuse, excluding tetrahydrocannabinol. Of those deceased with a psychiatric diagnosis, 33.6% had either consumed methadone or illicit drugs of abuse, a greater number than those without a psychiatric diagnosis. Fatal intoxication was the most frequent cause of death (40.6%) with methadone as the major intoxicant. Here, we found that those without a psychiatric diagnosis had fewer fatal pharmaceutical drug intoxications compared to the psychiatric diagnosis groups. Our findings add further context to understanding the excess mortality of psychiatric patents, since there is an increased occurrence of fatal intoxication, polypharmacy, and drug abuse in this population.

Concentrations of aripiprazole and dehydroaripiprazole in hair segments from deceased individuals with mental disorders.

Segmental hair analysis provides information regarding previous long-term drug exposure, which is useful in the evaluation of cause of death for individuals with mental disorders. The aim was to analyze postmortem concentrations of the antipsychotic drug aripiprazole and its active metabolite dehydroaripiprazole in hair segments from individuals with known aripiprazole intake. Hair samples were collected during autopsy. Each sample was segmented into one to six 1cm segments, depending on the length of the hair shaft. Pulverized hair was extracted and analyzed using a previously published ultra-high-performance liquid chromatography-tandem mass spectrometric method. The 10th-90th percentile of aripiprazole concentrations in all hair segments (n=78) from 17 individuals were 0.024ng/mg-11ng/mg with a median of 2.3ng/mg, and the 10th-90th percentile concentrations of dehydroaripiprazole were 0.020ng/mg-11ng/mg, with a median of 2.6ng/mg, in all hair segments (n=71). The metabolite-to-parent drug ratios ranged from 0.21 to 1.5, with a median of 0.72. The administered doses were calculated for each individual based on aripiprazole prescription data and pharmacy pickups, giving dose estimates of 1mg-32mg daily. A positive significant correlation was observed between concentrations in hair and blood, whereas no trends were observed between the concentrations in hair and the estimated doses. Besides aripiprazole, other antipsychotic drugs were found in several hair segments, indicating a high degree of polypharmacy among all subjects. The present study establishes concentrations of aripiprazole and dehydroaripiprazole in hair segments from 17 deceased individuals with long-term aripiprazole use. In addition, hair analysis demonstrates the possibility of evaluating polypharmacy.

Comparison of hippocampal volume measurement by autopsy and post-mortem magnetic resonance imaging.

We present an autopsy-validated, non-invasive, magnetic resonance imaging (MRI) based segmentation algorithm, for determining hippocampal volume. A segmentation algorithm was developed to assess the volume of the hippocampus. Deceased individuals with severe mental illness were used to evaluate the use of MRI imaging to determine hippocampal volume as this group has previously been associated with altered hippocampal volume diagnosed on MRI. The accuracy of the MR- scanning protocol for volume measurement was tested on a water filled phantom control with a known volume of 500 ml, and a difference of 0.08% was found. Thus the scanning protocol was deemed to have produced acceptable results when comparing volume measures of a pair of segmented hippocampi obtained at the 1 T MR scanner and a 3 T MR scanner using the software program Mimics®. The segmentation algorithm was tested by a volume comparison obtained using anterior and posterior landmarks (in situ) and the exact volume of the dissected hippocampus (ex situ). The in situ and ex situ hippocampal volumes were highly correlated; R2 was 96%, with a mean difference of 4-5%. Cases were also examined for intra- and inter-observer agreement. This study presents a validated segmentation algorithm that can be used to determine the hippocampal volume using post-mortem MR and anatomical landmarks.

"Nutrition or no nutrition?": Chylothorax or leakage of total parenteral nutrition?

Total parenteral nutrition (TPN) using a central line is an invasive and widely used procedure associated with several complications. Pleural effusion secondary to the leakage of alimentation into the pleural cavity is a rare but encountered complication of central-line TPN administration. This case study focuses on a postmortem examination of an 84-year-old woman, hospitalized due to malnutrition and dysphagia. The left internal jugular vein was cannulated, with no post-procedural x-ray check-up of the catheter tip position. An autopsy revealed 800 ml of milky-white fluid in the left pleural cavity, raising the issue of whether the pleural effusion was of chylous or TPN origin. The aim of this case study was to describe the postmortem diagnostic approach of the fluid analysis. Suspecting chylothorax, we first analyzed the triglyceride (TG) levels in the fluid, which, according to the literature, is the best parameter to detect chyle when lipoprotein electrophoresis (chylomicron %) is unavailable. Biochemistry showed increased levels of TG, which can be found in both chylous and TPN fluid. We then added glucose and potassium to the biochemical analysis, again showing increased levels at 46 mmol/L and 22 mmol/L, respectively. We had no information about the given TPN, and thus, comparing the final chemical results with the TPN composition was impossible. The presence of increased levels of triglycerides, glucose, and potassium in the white fluid more strongly resembled a standard TPN than chyle. Hence, by using these three measurements, we concluded that the milky-white fluid was a leakage of TPN.

Can acute stress be fatal? A systematic cross-disciplinary review.

In this review it is discussed if acute stress can be fatal. The review is based on literature searches on PubMed, PsycINFO as well as Web of Science. Literature concerning the conditions excited delirium syndrome (ExDS), malignant catatonia, takotsubo cardiomyopathy (TCM), and capture myopathy (CM) is reviewed and compared. The aim of the article is to identify and discuss a possible fatalness as well as a common pathophysiology behind these conditions. This includes a deregulated autonomic nervous system, neurocardiac reasons for myocardial damage, and rhabdomyolysis. We conclude that these conditions could be different manifestations of the same pathophysiological phenomenon. In addition, we suggest that it is possible to die from acute stress, but that it requires a prior sensitization, as seen in cocaine abusers and certain psychiatric patients, to render individuals disposed to an extreme autonomic nerve reaction. Lay summary This article compares different conditions in humans and in other animals, where it appears as if the human or animal dies with no other reason than being submitted to an extreme condition of mental stress. The conditions examined via a literature search are excited delirium syndrome, malignant catatonia and takotsubo cardiomyopathy in humans, and a capture myopathy in different mammals. The article theoretically suggests that one can die solely from acute stress, but that different forms sensitization probably goes ahead of such a fatal stress reaction. E.g. in cocaine addicts, some psychiatric patients, and in wild animals formerly subjected to stress an extreme sympathetic stress response might be immediately fatal. The article also theorizes that excited delirium syndrome, malignant catatonia, and capture myopathy could be more severe and acute variants of the temporary condition seen in takotsubo patients, also known as patients with broken heart syndrome.

Post-mortem toxicology in young sudden cardiac death victims: a nationwide cohort study.

Aims: Several drugs increase the risk of ventricular fibrillation and sudden cardiac death (SCD). We aimed to investigate in detail the toxicological findings of all young SCD throughout Denmark. Methods and results: Deaths in persons aged 1-49 years were included over a 10-year period. Death certificates and autopsy reports were retrieved and read to identify cases of sudden death and establish cause of death. All medico-legal autopsied SCD were included and toxicological reports collected. Positive toxicology was defined as the presence of any substance (licit and/or illicit). All toxicological findings had previously been evaluated not to have caused the death (i.e. lethal concentrations were excluded). We identified 620 medico-legal autopsied cases of SCD, of which 77% (n = 477) were toxicologically investigated post-mortem, and 57% (n = 270) had a positive toxicology profile. Sudden cardiac death with positive toxicology had higher rates of sudden arrhythmic death syndrome (SADS), compared with SCD with negative toxicology (56% vs. 42%, P < 0.01). In total, 752 agents were detected, and polypharmacy (defined as the presence of more than one drug) was present in 61% (n = 164), all substances combined. Psychotropic drugs were the most frequent (62%, n = 467), and 82% (n = 385) were in pharmacological or subpharmacological levels. Conclusion: We found that more than half of all toxicologically investigated SCD victims have positive post-mortem toxicological findings, and polypharmacy is displayed in a considerable proportion. SCD with positive toxicology had higher rate of SADS, suggesting that the compounds may play a proarrhythmic role in these cases.

Epicardial adipose tissue volume estimation by postmortem computed tomography of eviscerated hearts.

Epicardial adipose tissue (EAT) may play a role in the development of coronary artery disease. The purpose of this study was to evaluate a method based on postmortem computed tomography (PMCT) for the estimation of EAT volume. We PMCT-scanned the eviscerated hearts of 144 deceased individuals, who underwent a medicolegal autopsy. Using Mimics® we performed segmentation of the images and obtained the volumes of EAT and myocardium. Total heart volume was calculated by adding the volumes of EAT and myocardium. Total heart weight, including EAT, myocardium and attached vessels, was measured during autopsy. Inter-observer analysis was performed on 30 randomly chosen subjects. We included 132 individuals in the results (age range: 22-94 years; 56% men). Twelve individuals were excluded due to inadequate PMCT scanning. Median EAT volume was 73.0 mL (Interquartile range; IQR: 45.6-113.7 mL) in men and 64.8 mL (IQR: 44.0-98.0 mL) in women, which accounted for 20.4 ± 10.2% and 21.9 ± 9.5% of total heart volume, respectively. This corresponded with former autopsy studies. Total heart volume measured by PMCT was highly correlated with heart weight (R2 = 90%). Mean inter-observer difference of EAT volume was -1.7 mL (95% limits of agreement: -37.0-33.6 mL), with an Intra Class Correlation of 0.91. It was possible to estimate EAT volume using PMCT on eviscerated human hearts. Our method was fast and accurate with good inter-observer agreement. This is a useful method to determine EAT at autopsy, and we will apply this method in future research.

The presence of enterovirus, adenovirus, and parvovirus B19 in myocardial tissue samples from autopsies: an evaluation of their frequencies in deceased individuals with myocarditis and in non-inflamed control hearts.

PURPOSE: Multiple viruses have been detected in cardiac tissue, but their role in causing myocarditis remains controversial. Viral diagnostics are increasingly used in forensic medicine, but the interpretation of the results can sometimes be challenging. In this study, we examined the prevalence of adenovirus, enterovirus, and parvovirus B19 (PVB) in myocardial autopsy samples from myocarditis related deaths and in non-inflamed control hearts in an effort to clarify their significance as the causes of myocarditis in a forensic material. METHODS: We collected all autopsy cases diagnosed with myocarditis from 1992 to 2010. Eighty-four suicidal deaths with morphologically normal hearts served as controls. Polymerase chain reaction was used for the detection of the viral genomes (adenovirus, enterovirus, and PVB) in myocardial tissue specimens. The distinction between acute and persistent PVB infection was made by the serological determination of PVB-specific immunoglobulins M and G. RESULTS: PVB was detected in 33 of 112 (29 %) myocarditis cases and 37 of 84 (44 %) control cases. All of the samples were negative for the presence of adenovirus and enterovirus. Serological evidence of an acute PVB infection, determined by the presence of immunoglobulin M, was only present in one case. In the remaining cases, PVB was considered to be a bystander with no or limited association to myocardial inflammation. CONCLUSION: In this study, adenovirus, enterovirus, and PVB were found to be rare causes of myocarditis. The detection of PVB in myocardial autopsy samples most likely represents a persistent infection with no or limited association with myocardial inflammation. The forensic investigation of myocardial inflammation demands a thorough examination, including special attention to non-viral causes and requires a multidisciplinary approach.

Fatal lawn mower related projectile injury.

Fatal lawn mower related injuries are a relatively rare occurrence. In a forensic setting, the primary aim is to reconstruct the injury mechanism and establish the cause of death. A relatively rare, but characteristic type of injury is a so-called projectile or missile injury. This occurs when the operator or a bystander is impacted by an object mobilized from the grass by the rotating mower blades. This type of injury often leaves only modest external trauma, which increases the risk of overlooking an entry wound. In this paper we present a case of a fatal lawn mower related projectile injury which was initially overlooked, later interpreted as a possible gunshot homicide, and finally identified as a lawn mower related projectile injury when autopsy revealed a piece of metal thread in the main bronchus to the right middle lobe, hemopericardium, and right-sided hemothorax. To our knowledge, this injury mechanism has not previously been reported as a cause of death. This case illustrates the importance of postmortem radiological imaging and interdisciplinary cooperation when establishing manner and cause of death in unusual cases.

Quantitative diagnosis of lymphocytic myocarditis in forensic medicine.

The aim of this study was to establish quantitative diagnostic criteria for lymphocytic myocarditis on autopsy samples by using a stereological cell profile counting method. We quantified and compared the presence of lymphocytes and macrophages in myocardial autopsy specimens from 112 deceased individuals who had been diagnosed with myocarditis according to the Dallas criteria and 86 control subjects with morphologically normal hearts. We found the mean number to be 52.7 lymphocyte profiles/mm(2) (range 3.7-946; standard deviation 131) in the myocarditis group and 9.7 (range 2.1-25.9; standard deviation 4.6) in the control group. The cut-off value for the diagnosis of myocarditis was determined by calculating sensitivity plus specificity, which reached the highest combination at 13 lymphocyte profiles/mm(2) (sensitivity 68%; specificity 83%). A considerable proportion of subjects in both the myocarditis and control groups had lymphocyte profile counts below 30/mm(2), representing a diagnostic challenge due to the increased risk of creating false negative or false positive results. We found it practically impossible to obtain a reliable macrophage count. The present data add new important information on lymphocyte counts in inflamed and non-inflamed myocardium. We suggest a cut-off value in the range of 11-16 lymphocyte profiles/mm(2) for a reliable diagnosis of lymphocytic myocarditis from autopsy samples. To evaluate small inflammatory changes at low lymphocyte counts, a multidisciplinary approach should be implemented, in which diagnostic tools are used ancillary to histological examination. We advise against semi-quantification of macrophages based on cell profile counting.

Autopsy practice in forensic pathology - evidence-based or experience-based? a review of autopsies performed on victims of traumatic asphyxia in a mass disaster.

Current autopsy practice in forensic pathology is to a large extent based on experience and individual customary practices as opposed to evidence and consensus based practices. As a result there is the potential for substantial variation in how knowledge is applied in each case. In the present case series, we describe the variation observed in autopsy reports by five different pathologists of eight victims who died simultaneously from traumatic asphyxia due to compression during a human stampede. We observed that there was no mention of the availability of medical charts in five of the reports, of potentially confounding resuscitation efforts in three reports, of cardinal signs in seven reports and of associated injuries to a various degree in all reports. Further, there was mention of supplemental histological examination in two reports and of pre-autopsy radiograph in six reports. We inferred that reliance on experience and individual customary practices led to disparities between the autopsy reports as well as omissions of important information such as cardinal signs, and conclude that such reliance increases the potential for error in autopsy practice. We suggest that pre-autopsy data-gathering and the use of check lists specific to certain injury causes are likely to result in less deviation from evidence-based practices in forensic pathology. Pre-autopsy data-gathering and check lists will help ensure a higher degree of standardization in autopsy reports thus enhancing the quality and accuracy of the report as a legal document as well as rendering it more useful for data-gathering efforts.

Characteristics of human infant primary fibroblast cultures from Achilles tendons removed post-mortem.

Primary cell cultures were investigated as a tool for molecular diagnostics in a forensic setting. Fibroblast cultures had been established from human Achilles tendon resected at autopsies, from cases of sudden infant death syndrome and control infants who died in traumatic events (n=41). After isolation of primary cultures cells were stored at -135°C, and re-established up to 15 years later for experimental intervention. Growth characteristics in cultures were evaluated in relation to the age of the donor, the post mortem interval before sampling, and the storage interval of cells before entry into the study. High interpersonal variation in growth rates and cell doubling time was seen, but no statistically significant differences were found with increasing age of the donor (mean 19 weeks), length of post-mortem interval prior to sampling (6-100 h), or increase in years of storage. Fibroblast cultures established from post-mortem tissue are renewable sources of biological material; they can be the foundation for genetic, metabolic and other functional studies and thus constitute a valuable tool for molecular and pathophysiological investigations in biomedical and forensic sciences.

The prevalence of mutations in KCNQ1, KCNH2, and SCN5A in an unselected national cohort of young sudden unexplained death cases.

INTRODUCTION: Sudden unexplained death account for one-third of all sudden natural deaths in the young (1-35 years). Hitherto, the prevalence of genopositive cases has primarily been based on deceased persons referred for postmortem genetic testing. These deaths potentially may represent the worst of cases, thus possibly overestimating the prevalence of potentially disease causing mutations in the 3 major long-QT syndrome (LQTS) genes in the general population. We therefore wanted to investigate the prevalence of mutations in an unselected population of sudden unexplained deaths in a nationwide setting. METHODS: DNA for genetic testing was available for 44 cases of sudden unexplained death in Denmark in the period 2000-2006 (equaling 33% of all cases of sudden unexplained death in the age group). KCNQ1, KCNH2, and SCN5A were sequenced and in vitro electrophysiological studies were performed on novel mutations. RESULTS: In total, 5 of 44 cases (11%) carried a mutation in 1 of the 3 genes corresponding to 11% of all investigated cases (R190W KCNQ1, F29L KCNH2 (2 cases), P297S KCNH2 and P1177L SCN5A). P1177L SCN5A has not been reported before. In vitro electrophysiological studies of P1177L SCN5A revealed an increased sustained current suggesting a LQTS phenotype. CONCLUSION: In a nationwide setting, the genetic investigation of an unselected population of sudden unexplained death cases aged 1-35 years finds a lower than expected number of mutations compared to referred populations previously reported. We therefore conclude that the prevalence of mutations in the 3 major LQTS associated genes may not be as abundant as previously estimated.

Sudden cardiac death in young adults: environmental risk factors and genetic aspects of premature atherosclerosis.

Familial hypercholesterolemia (FH) is a genetic disorder that may lead to premature coronary heart disease (CHD) and sudden cardiac death (SCD). Mutations in the LDLR or APOB genes cause FH. We have screened the LDLR and the ligand-binding region of APOB genes in 52 cases of SCD. Deceased patients were younger than 40 years of age and were suspected of having FH. The LDLR and APOB genes were examined via PCR, high-resolution melting, and DNA sequencing. Therein, it was observed that 7.7% of the screened patients exhibited a rare sequence variant in the LDLR gene, with 5.7% suspected of being pathogenic mutations. Lipid profiles and genetic testing for FH could be considered when autopsy reveals significant atherosclerosis of the coronary arteries in young adults. First-degree family members are advised to seek medical advice and testing to determine their own risks of atherosclerosis to prevent premature CHD and SCD.