Postmortem genetic testing of the ryanodine receptor 2 (RYR2) gene in a cohort of sudden unexplained death cases.

The aim of this investigation was to identify pathogenic variants of the ryanodine receptor 2 (RYR2) gene in a cohort of persons aged 0-40 years who died of sudden unexpected death syndrome (SUD), including a cohort of infants who died of sudden infant death syndrome (SIDS). We genetically screened 29 of the 105 exons of the RYR2 gene associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 74 cases of SUD without reported structural abnormalities of the heart. Cases were selected from the case database at the Institute of Forensic Medicine, and subsequent mutational screening by DNA sequencing was performed to detect variants in DNA samples extracted from blood samples of deceased persons. A total of 7 of the examined 74 cases were heterozygous for a rare sequence variant in the RYR2 gene. We identified five novel missense variants (p.Q486H, p.D1872N, p.G2367R, p.E4213D, and p.H4579Y), one synonymous variant (p.L4767L), and one previously reported missense variant (p.G4315E). Follow-up studies were possible in family members of three probands (p.Q486H, p.D1872N, and p.H4579Y), and clinical examinations were conducted in family members of two of these probands (p.Q486H and p.H4579Y). In conclusion, we identified a higher prevalence of variants in the CPVT-associated gene RYR2 than in a previously reported cohort of SIDS (9.4% vs. 1-2%). Segregation studies show that one variant (p.H4579Y) co-segregates with CPVT and is presumed to be pathogenic.

Molecular autopsy in young sudden cardiac death victims with suspected cardiomyopathy.

The aim of this investigation was to identify and characterise pathogenic mutations in a sudden cardiac death (SCD) cohort suspected of cardiomyopathy in persons aged 0-40 years. The study material for the genetic screening of cardiomyopathies consisted of 41 cases and was selected from the case database at the Institute of Forensic Medicine. Mutational screening by DNA sequencing was performed to detect mutations in DNA samples from deceased persons suspected of suffering from hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricle cardiomyopathy (ARVC). A total of 9 of the examined 41 cases had a rare sequence variant in the MYBPC3, MYH7, LMNA, PKP2 or TMEM43 genes, of which 4 cases (9.8%) were presumed to be pathogenic mutations. The presumed pathogenic mutations were distributed with one case of suspected HCM and DCM (MYH7; p.R442H), one case of suspected DCM (LMNA; p.R471H), and two cases of suspected ARVC (PKP2; p.R79X and LMNA; p.R644C). The presented data adds important information on the genetic elements of SCD in the young, and calls for expert pathological evaluation and molecular autopsy in the post-mortem examination of SCD victims with structural anomalies of the heart.

Spontaneous coronary artery dissection: a Western Denmark Heart Registry study.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS) that associates with a high acute-phase mortality rate, whereas long-term outcome is less well described. OBJECTIVE: To describe the incidence, predictors, and prognosis of SCAD. DESIGN: Retrospective case-identification study from the Western Denmark Heart Registry and the database of the Forensic Institute at Aarhus University from 1999 through 2007. RESULTS: SCAD was documented in 22 of 32,869 (0.7 per thousand) angiograms in the angiographic registry. The SCAD incidence among cases of ACS was 22 of 11,175 (2.0 per thousand). None was seen in the forensic database. The mean age was 48.7 +/- 8.9 years (range: 37-71 years). Females constituted 17 of 22 (77%) patients and all had undergone one or more pregnancies; two cases occurred in the postpartum period. The left descending artery (LAD) was the predominant site of entry. The age distribution, prevalence of the cardiovascular risk factors, presence of coronary atherosclerosis, and entry of the dissection were comparable among genders. Treatment was percutaneous coronary intervention in 13 of 22 (59%), coronary artery bypass operation in 2 of 22 (9%), and medical treatment in 7 of 22 (32%) patients. The mean follow-up period was 3.6 +/- 2.9 years. One patient suffered from recurrent SCAD; another patient died suddenly. The MACE- (cardiac death, nonfatal myocardial infarction, and new revascularization) free survival was 81% after 24 months. CONCLUSION: SCAD is a rare disease that mainly affects younger women. Compared with earlier reports, the prognosis seems to be improved by early diagnosis and interventional treatment.

Effects of temperature and histopathologic preparation on the size and morphology of atherosclerotic carotid arteries as imaged by MRI.

Using magnetic resonance imaging the effects of temperature, formalin fixation, and decalcification on the size and morphology of atherosclerotic arteries were evaluated. Ten ex vivo carotid arteries were scanned fresh at body and room temperature and formalin-fixed and decalcified at room temperature. Different spin-echo pulse sequences were used and absolute T2 values calculated. During processing for histopathology, the contrast between the arterial layers increased. From body to room temperature there were significant increases in size (4%-7%), T2 of media (60--> 68 msec), and fibrous plaque component (95--> 110 msec). Formalin fixation caused significant increases in size (2%-3%) and media T2 (68--> 74 msec). Decalcification caused significant shrinkage (2%-5%) and decrease in T2 of media (74--> 53 msec) and fibrous plaque component (118--> 76 msec). Thus temperature and preparation have profound effects on contrast, size, and T2 of atherosclerotic arteries. Ex vivo experiments should be performed on fresh specimens at body temperature. J. Magn. Reson. Imaging 1999;10:876-885.

Distribution of early atherosclerotic lesions in the human abdominal aorta correlates with wall shear stresses measured in vivo.

OBJECTIVES: to study the relationship between wall shear stresses measured in vivo and early atherosclerotic lesions in the abdominal aorta. MATERIALS: eight young volunteers for in vivo wall shear-stress measurements. Abdominal aortas from 10 young adults without signs or history of atherosclerotic disease were obtained by autopsy for histomorphometric measurements. METHODS: wall shear stresses were measured in the abdominal aorta above and below the renal arteries using a magnetic resonance technique with high resolution for imaging and blood velocity mapping. At identical abdominal aortic locations, intimal thickness was measured blindly using histomorphometric techniques and correlated to wall shear-stress variables using linear-regression analysis. RESULTS: intimal thickness showed a linear decrease with mean wall shear stress (r=-0.90, p<0.01) and with maximum wall shear stress (r=-0.86, p<0.01). CONCLUSIONS: intimal thickness in the normal abdominal aorta is associated with mean, maximum and oscillating wall shear stresses. These in vivo data corroborate previous in vitro studies suggesting that low and oscillating wall shear stresses are localising factors for intimal thickening and hence the early development of atherosclerosis.

A histomorphometric method for evaluating topographic differences in degree of early atherosclerosis within the human aorta.

The aim of the study was to develop an unbiased topographically oriented method of evaluating early atherosclerotic lesions in the aorta and to apply this to a series of human aortas from young adults. A systematic sampling procedure and histomorphometric analysis of intimal thickening is described. Results from a group of 15 young adults (aged 18-40 years) showed a characteristic pattern with increasing intimal thickening when moving distally from the thoracic to the upper and finally to the lower abdominal aorta, but also a shift in the localization of the most pronounced intimal thickening from the posterior to the anterior and back to the posterior aspect. This pattern was found in aortas both with minimal and with more pronounced atherosclerosis, and supports the view that the early intimal thickening precedes the atherosclerotic lesions and marks the sites of predilection for the more advanced disease processes. An increase in intimal thickness with age could be demonstrated in the aortas without overt atherosclerosis. The simple sampling procedure, well-defined sampling sites, and ability to demonstrate and quantitate differences in intimal thickening and plaque morphology make this method well suited for relating morphometric data to other parameters of interest when studying the etiology and dynamics of atherosclerotic disease.

Prevalence of cannabinoids in urine samples from forensic autopsies.

Urine samples from 393 forensic autopsies were tested for the presence of cannabinoids by means of the radio-immunoassay test kit from DPC, Los Angeles. Fifteen per cent were found positive, mainly men and young adults. Use of cannabis was found to be closely related to drug addiction, and thus in cannabis-positive drug addicts, non-natural manners and causes of death dominate. In non-addicts the prevalence of cannabis use was 7.5%, and in non-addicted cannabis users, manners and causes of death were not very different from those found in cannabis-negatives.

Wall shear stress and early atherosclerotic lesions in the abdominal aorta in young adults.

OBJECTIVES: To study the correlation between wall shear stress and early atherosclerotic lesions in the abdominal aorta. DESIGN: Blinded histomorphometric studies. Comparison with in vitro data. MATERIALS: Abdominal aortic haemodynamics were simulated in a realistic pulsatile flow model. Abdominal aortas from 10 young adults with no signs of atherosclerotic disease were obtained during autopsy. METHODS: Quantitative wall shear stresses were measured at rest and exercise in one suprarenal and two infrarenal positions using laser Doppler anemometry. Intimal thickening indices were measured blindly at the corresponding locations using histomorphometric methods, and compared to wall shear stress variables using linear regression analysis. RESULTS: Intimal thickness index increased significantly with age. Intimal thickness index was significantly lower in the suprarenal than the infrarenal aorta, and higher at the distal posterior vessel wall compared to the anterior wall. Intimal thickness index correlated significantly with mean, minimum and oscillating wall shear stresses measured at rest. CONCLUSION: Intimal thickness in the undiseased abdominal aorta correlated significantly with mean, minimum and oscillating wall shear stresses at rest measured in a pulsatile flow model. No correlations were found with maximum shear stress parameters. Exercise changed the local wall shear stresses away from the characteristics associated with intimal thickness index.

Atherosclerosis in the human brachial artery.

OBJECTIVES: We sought to assess the prevalence of atherosclerotic lesions in the human brachial artery. BACKGROUND: Many investigators have recently studied endothelial and vascular function in the brachial circulation in humans to further their understanding of coronary artery disease and early atherogenesis. However, the prevalence of brachial atherosclerosis and its relation to coronary disease have never been documented. METHODS: Arterial segments from the brachial, common carotid and left anterior descending coronary arteries were obtained during autopsy in 52 consecutively examined subjects (35 men, 17 women; 21 to 79 years old, mean [+/-SD] age 51 +/- 16) and studied by light microscopy using standard histologic techniques. Severity of the atherosclerotic lesions was categorized as fatty streaks (grade 1), fibrous plaques (grade 2) and advanced lesions (grade 3). RESULTS: Atherosclerotic lesions of any grade were found in the brachial artery in 39 (75%) subjects, common carotid artery in 51 (98%) and left anterior descending coronary artery in 52 (100%), and the prevalence and severity of disease increased with age in all three arteries. The grade of lesion severity in the brachial and coronary arteries was significantly correlated (r = 0.41, p = 0.003), as was severity in the brachial and carotid arteries (r = 0.53, p = 0.0001) and the carotid and coronary arteries (r = 0.69, p = 0.0001). The correlation between the brachial artery and the left anterior descending coronary artery was highly significant in subjects < or = 50 years old (r = 0.54, p = 0.002), but not in those > or = 50 years old (r = 0.37, p = NS). CONCLUSIONS: Atherosclerosis is common in the human brachial artery and is significantly correlated with both coronary and carotid disease. These results suggest that the brachial circulation may serve as a reasonable "surrogate" for studying atherosclerosis, particularly in younger adults.

Arrhythmogenic right ventricular dysplasia as a cause of sudden death.

Arrhythmogenic right ventricular dysplasia (ARVD) is a poorly understood and often underdiagnosed disorder of the right ventricle, characterized by replacement of myocardium by fibroadipose tissue, arrhythmic manifestations, and sudden death. The disease occurs in families and is inherited as an autosomal dominant trait. This report describes five cases of ARVD identified by autopsy. In three of the cases, sudden death occurred in the young (16-28 years old) during or shortly after exercise. In another case, a 46-year-old man with no relevant medical history was found dead in his bathroom. In the last case, a 57-year-old woman died from pulmonary thromboembolism. In none of the subjects had the disease been diagnosed or suspected before death. Only one (a 21-year-old man) had previous typical symptoms of the disease. Autopsy examination showed right ventricle dilation and, in four cases, cardiomegaly. The right ventricular myocardium of all hearts was almost replaced by adipose tissue and to a variable degree by fibrous tissue, while the left ventricle myocardium demonstrated no, or only scattered, fibro-fatty infiltration. Postmortem diagnosis of ARVD can be important in identifying possible affected family members in order to initiate treatment.

Alcohol and drugs (medical and illicit) in fatal road accidents in a city of 300,000 inhabitants.

During a 1-year period all fatal road accidents in the police district of Aarhus, Denmark, were investigated regarding the presence of alcohol, medical drugs or narcotic substances, and the nature of the accident. Out of a total of 30 accidents 24 were investigated. Two thirds had been caused by the victim him- or herself. In one third of the accidents alcohol was present and considered an important contributory factor. Medical drugs and narcotic substances played a lesser role.

[Suicide among the elderly in the county of Arhus. A 10-year retrospective study of suicide among persons aged 65 and over]. / Selvmord hos aeldre i Arhus Amt. En 10-års retrospektiv underøgelse af selvmord hos personer over 65 år.

During a ten year period (1983 to 1992) 337 suicides (188 men and 149 women) were registered among people over 65 years of age in the county of Aarhus. The suicide rate (number of deaths per 100,000 living people) decreased during the period from 1983 to 1990. For men the rate was highest over the age of 80, whereas for women the rate was highest before the age of 70. The analyses showed, that the majority of the suicides were committed with violent methods. Previous attempts were registered in 25%. The decision to commit suicide was not associated with health conditions. The percentage of suicide victims living in nursing-homes was slightly higher than that of the background population. In 25% of the 116 suicides a farewell letter was found, despondency was slated as the main cause - not painful or incurable diseases. Prevention of suicide among elderly people is not clarified in this study.

[Alcohol, drugs and narcotics in suicides in the Aarhus police district]. / Alkohol, medicin og narkotika ved suicidier i Aarhus Politikreds.

For a period of one year all suicides in Aarhus police district were investigated with a view to identifying the presence of alcohol or drugs in the body of the deceased. Fifty-one suicides occurred, 46 of which were examined. One third of the suicides were due to poisoning and one fourth to hanging. Alcohol was detected in 20% and drugs or narcotics were found in approximately 60%. The most frequent findings were benzodiazepines, analgetics, antidepressants and carbon monoxide. Approximately 40% of the deceased had received psychiatric treatment.

[Methanol poisoning in alcohol abusers]. / Traespritforgiftning hos alkoholmisbrugere.

Methanol (wood alcohol) is sold in Denmark only to factories and laboratories with a certified knowledge of the substance or to individuals holding a special licence. Methanol is nowadays used as a solvent or for syntheses only. During a six-year period three cases of methanol poisoning were found in a selected forensic material. A screening for alcohols is routinely performed in connection with all medicolegal autopsies when the presence of alcohols cannot be ruled out in advance. All three cases concerned men accustomed to a substantial intake of alcohol. Two of the cases were accidental deaths due to methanol poisoning. The third case was suicide committed by the ingestion of a herbicide containing methanol. Methanol poisonings are rare, but do still occur. It is, therefore, important for physicians to be aware of the symptoms and know the treatment.

Sudden death caused by thrombosed coronary artery aneurysm. Two unusual cases of Kawasaki disease.

Kawasaki disease primarily affects children below 5 years of age, and fatal coronary complications usually occur within 6-12 months following the acute illness. We report 2 unusual fatal cases of thrombosed coronary artery aneurysms. The first case was an 11-year-old boy, who died suddenly 2 months after the acute illness. He had a classical clinical picture, but was misdiagnosed. The second case was a 29-year-old man without history of recent febrile episodes or cardiac symptoms. Both subjects fulfilled the stage 4 criteria of Kawasaki disease (healing stage) with extensive old myocardial damage. The cases illustrate the great variation in the clinical picture of Kawasaki disease. Teenagers can also be affected, and extensive myocardial damage may be asymptomatic for many years.

[Blood pressure check-up--routine blood pressure measurements in a patient with arteriovenous shunt and under dialysis]. / Blodtrykskontrol--konventionel BT-måling hos dialysepatient med arteriovenøs shunt.

A case of untreated hypertension in a patient, where blood pressure could be measured in the right arm only is presented. At autopsy, the brachio-cephalic artery was found to be occluded explaining why blood pressure values were low. Significant left ventricular hypertrophy indicating high central blood pressure was found. Sudden death followed a spontaneous intracerebral bleeding. The value of conventional blood pressure measurement in patients with arteriovenous shunt because of chronic dialysis is discussed.