Marja-Leena Kortelainen

Family History and the Risk of Sudden Cardiac Death as a Manifestation of an Acute Coronary Event

Background— Observational studies have suggested that a parental history of sudden death increases one’s risk of dying suddenly. This study tested the hypothesis that a family history of sudden cardiac death (SCD) is a risk factor for SCD caused by an acute coronary event. Methods and Results— A retrospective case-control study included (1) consecutive victims of SCD (n=138) whose deaths were verified to be due to an acute coronary event without a history of prior myocardial infarction at medicolegal autopsy, (2) consecutive patients surviving an acute myocardial infarction (AMI; n=254), and (3) healthy control subjects (n=470). Family history of AMI and SCD among the first-degree relatives was ascertained in each study group. The incidence of SCD in the 1223 first-degree relatives of SCD victims was higher (5.2%) than that in the 2326 relatives of AMI survivors (3.3%; odds ration [OR] 1.6, 95% confidence interval [CI] 1.2 to 2.2, P<0.01) or the 3748 relatives of controls (OR 2.2; 95% CI 1.6 to 3.0, P<0.001). The history of SCD in 2 or more first-degree relatives was also higher (10.9%) among SCD victims than among AMI survivors (3.5%; OR 3.3, 95% CI 1.4 to 7.8, P<0.01) or controls (1.1%; OR 11.3, 95% CI 4.0 to 31.8, P<0.001). The family history of AMI did not differ between the SCD and AMI groups. Male gender and current smoking were the only coronary risk factors that were more prevalent among SCD victims than among AMI survivors (P<0.001 for both). Conclusions— Subjects with a family history of SCD have an increased risk of dying suddenly during an acute coronary event.

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Association of Early Repolarization and Sudden Cardiac Death During an Acute Coronary Event

Background— Electrocardiographic early repolarization (ER) pattern has been previously associated with arrhythmic mortality and with an increased risk of ventricular fibrillation. We hypothesized that there is an association between ER and sudden cardiac death (SCD) during an acute coronary event. Methods and Results— The present study included 432 consecutive victims of SCD because of acute coronary event and 532 survivors of such an event, in whom 12-lead ECGs recorded before and unrelated to the event could be evaluated. SCDs were verified by medicolegal autopsy to be because of acute coronary event. ER was defined as an elevation of the QRS-ST junction in at least 2 inferior or lateral leads, manifested as QRS notching or slurring. The prevalence of ER pattern ≥0.1 mV was more common in cases (62/432; 14.4%) than controls (42/532; 7.9%) (P=0.001). The victims of SCD were younger, were more commonly men and smokers, had lower body mass index, had elevated heart rate, had prolonged QRS complex, and had lower prevalence of history of prior cardiovascular disease than controls. After adjustments for baseline differences, the odds ratio for J waves without ST-segment elevation in the SCD group was 2.15 (95% CI, 1.20–3.85; P=0.01). Conclusions— Higher prevalence of ER in a standard 12-lead ECG in victims of SCD than in survivors of an acute coronary event suggests that the presence of ER increases the vulnerability to fatal arrhythmia during acute myocardial ischemia and provides a plausible mechanistic link between this ECG pattern and higher arrhythmic mortality of middle-aged/elderly subjects.

Cardiac abnormalities in patients with mitochondrial DNA mutation 3243A>G

BackgroundTissues that depend on aerobic energy metabolism suffer most in diseases caused by mutations in mitochondrial DNA (mtDNA). Cardiac abnormalities have been described in many cases, but their frequency and clinical spectrum among patients with mtDNA mutations is unknown.MethodsThirty-nine patients with the 3243A>G mtDNA mutation were examined, methods used included clinical evaluation, electrocardiogram, Holter recording and echocardiography. Autopsy reports on 17 deceased subjects were also reviewed. The degree of 3243A>G mutation heteroplasmy was determined using an Apa I restriction fragment analysis. Better hearing level (BEHL0.5–4 kHz) was used as a measure of the clinical severity of disease.ResultsLeft ventricular hypertrophy (LVH) was diagnosed in 19 patients (56%) by echocardiography and in six controls (15%) giving an odds ratio of 7.5 (95% confidence interval; 1.74–67). The dimensions of the left ventricle suggested a concentric hypertrophy. Left ventricular systolic or diastolic dysfunction was observed in 11 patients. Holter recording revealed frequent ventricular extrasystoles (>10/h) in five patients. Patients with LVH differed significantly from those without LVH in BEHL0.5–4 kHz, whereas the contribution of age or the degree of the mutant heteroplasmy in skeletal muscle to the risk of LVH was less remarkable.ConclusionsStructural and functional abnormalities of the heart were common in patients with 3243A>G. The risk of LVH was related to the clinical severity of the phenotype, and to a lesser degree to age, suggesting that patients presenting with any symptoms from the mutation should also be evaluated for cardiac abnormalities.

Psychotropic medications and the risk of sudden cardiac death during an acute coronary event

AIMS Psychotropic medication increases cardiac mortality, but the reasons for this association are not clear. We studied the role of psychotropic drugs as a triggering factor of sudden cardiac death (SCD) during an acute coronary event. METHODS AND RESULTS The use of medication was compared between victims of SCD and survivors of an acute coronary event in a case-control study including a consecutive series of victims of SCD (n= 1814, mean age 65 ± 11 years) verified to be due to an acute coronary event at medico-legal autopsy and consecutive series of patients surviving an acute myocardial infarction (AMI; n= 1171, mean age 66 ± 12 years). The medication history was obtained from autopsy/hospital records and interviews with relatives of SCD victims and AMI patients. The use of antipsychotics [9.7 vs. 2.4%, odds ratio (OR) 4.4, 95% confidence interval (CI) 2.9-6.6; P< 0.001] and antidepressants (8.6 vs. 5.5%, OR: 1.6, 95% CI: 1.2-2.2; P= 0.003) was more common in the SCD than AMI group, but the use of benzodiazepines did not differ between the groups (11.7 vs. 13.2%; P= 0.270). The use of antipsychotics remained as a significant risk factor for SCD after adjustment for confounding variables (OR: 3.4, 95% CI: 1.8-6.5; P< 0.001). Combined use of phenothiazines and any antidepressant was associated with a very high risk of SCD (OR: 18.3, 95% CI: 2.5-135.3; P< 0.001). CONCLUSION The use of psychotropic drugs, especially combined use of antipsychotic and antidepressant drugs, is strongly associated with an increased risk of SCD at the time of an acute coronary event.

Long-term alcohol consumption and brown adipose tissue in man.

SummaryThe purpose of the present work was to study whether long-term alcohol consumption in man affects the develeopment of brown adipose tissue. The adipose tissue around the thoracic aorta and common carotid arteries was collected at medicolegal autopsies on adults with a positive record of heavy alcohol consumption. Adults without any evident history of alcohol consumption served as controls. Histochemical reactions of the oxidative mitochondrial enzymes, cytochrome oxidase and succinate dehydrogenase were studied in samples of this adipose tissue and the activities of the enzymes were measured biochemically.There was histological evidence of some multilocular adipose tissue around the thoracic aorta and common carotid arteries of the alcohol consumers, whereas the adipose tissue from the non-drinkers was mostly unilocular resembling white adipose tissue. Histochemical evidence of brown adipose tissue was found in all alcohol consumers, but also in some of the controls. Biochemical cytochrome oxidase (CYO) and succinate dehydrogenase measurements in isolated mitochondria showed activity in 70% of the cases of drinkers and in one of the eight controls. Activity of CYO was measurable in the mitochondria from two other controls. The protein content of the samples from the alcoholics was twice that of the controls. The results suggest that chronic alcohol intake may induce a change in the white adipose tissue around the thoracic aorta and common carotid arteries of human adults into brown fat.

Increased adrenaline to noradrenaline ratio is a superior indicator of antemortem hypothermia compared with separate catecholamine concentrations.

Abstract:  The significance of urinary catecholamines and small gastric mucosal bleedings, Wischnewsky’s spots, in postmortem diagnosis of hypothermia deaths was evaluated. Autopsy cases (n = 358) were divided into hypothermia, suspected hypothermia, and control groups. The catecholamine levels did not correlate with the length of the postmortem period. The adrenaline to noradrenaline ratio was most effective in detecting hypothermia (68.9% sensitivity, 78.1% specificity). The median adrenaline concentrations were significantly higher in hypothermia than in control groups. The control group containing mostly sudden cardiac deaths with no cold exposure had a noradrenaline level comparable to the hypothermia groups. The sensitivity and specificity of determining Wischnewsky’s spots in hypothermia deaths were 63.9% and 88.3%, respectively. The adrenaline to noradrenaline ratio is more suitable in proving antemortem cold stress than either of these independently, and its diagnostic value is comparable to that of Wischnewsky’s spots.

Extent and Composition of Coronary Lesions and Degree of Cardiac Hypertrophy in Relation to Abdominal Fatness in Men Under 40 Years of Age

The relationship of the extent and composition of coronary lesions and the degree of cardiac hypertrophy to anthropometric indicators of abdominal fatness and the amount of intra-abdominal fat was investigated in a group of 32 forensic autopsy cases that consisted of sudden deaths from violent causes of previously healthy men under 40 years of age. Body height and weight, waist and hip circumferences, and the thickness of the subscapular and abdominal subcutaneous fat were measured; the body mass index (BMI) and waist-to-hip ratio (WHR) were calculated; and omental, mesenteric, and perirenal fat deposits and the heart were weighed. The degree of coronary narrowing was determined visually, and the extent of coronary lesions was measured by planimetry. The thickness of the intima and intima-media was measured by computerized image analysis. Intimal macrophage foam cells and smooth muscle cells were detected by immunohistochemistry. Significant positive correlations were found between WHR and the overall degree of coronary narrowing and the intima-media thicknesses of the left anterior descending artery and right coronary artery when adjusted for age. Intima-media thickness was also related to tertiles of WHR. Heart weight indexed to height showed a significant positive correlation with BMI, waist circumference, WHR, and the size of intra-abdominal fat deposits, of which WHR was the best predictor of mild cardiac hypertrophy. The results indicate that the severity of clinically silent lesions in the atherosclerosis-prone regions of the coronary arteries is associated with WHR in young male individuals who also have mild myocardial hypertrophy associated with abdominal fatness and an accumulation of intra-abdominal fat. These associations between fat distribution and early cardiovascular changes point to a powerful need for preventive action with respect to weight gain in young men to alleviate progression of the lesions.

Extreme obesity and associated cardiovascular disease verified at autopsy: time trends over 3 decades.

Abstract Extreme obesity is a strong predictor of premature death, but the prevalence of cardiovascular disease in morbidly obese populations is largely unknown. The aim of the present study was to find out whether there has been an increase in extreme obesity with body mass index 40.0 kg/m2 or greater in medicolegal autopsy material in a known geographical area in Finland during a period of 3 decades and to examine the prevalence and time trends of associated cardiovascular disease in this obesity category. Autopsy reports of 235 cases examined in 1975 to 2006 were analyzed. The number of extremely obese individuals increased from 0.6% of the yearly amount of autopsies in the 1970s and 1980s to 2.8% and 2.5% in 2005 and 2006, respectively. The most frequent cause of death was cardiomyopathy or cardiomegaly (28.9%), followed by coronary heart disease (24.3%). Either coronary arteries were lesion-free, or only fatty streaks had been observed in 46.8% of the women and in 43.1% of the men. No significant changes in the average body mass index or severity of coronary atherosclerosis were observed. Younger individuals younger than 40 years began to appear more often after 1995. An increased trend of extreme obesity in a region where autopsy frequency is high may refer to a general increase of this obesity category. A large number of extremely obese people are resistant to coronary atherosclerosis, but cardiac hypertrophy may be accompanied by several mechanisms leading to sudden death even among the youngest extremely obese individuals.

Fatal complications of intramuscular and intra-articular injections

SummaryFour fatalities related to intramuscular and intra-articular injections are reported. In two of these cases a Staphylococcus aureus sepsis developed, as a consequence of injections into the left hip joint in one and in the lateral upper quadrant of the gluteal region in the other. The intra-articular injection of triamcinolone produced severe pain, but no marked signs of purulent arthritis were seen at autopsy, probably because of the anti-inflammatory effect of the corticosteroid. A cutaneous infection was seen in the gluteal region of the other patient, but no apparent abscess formation. In another case of intra-articular injection, purulent knee joint arthritis developed after an injection of glucosaminoglycan. The patient died of renal insufficiency, which was probably connected with the treatment of the arthritis with tobramycin and cefuroxim. The fourth case was that of a mentally ill patient who suffered sudden cardiac arrest after an intramuscular injection of chlorpromazine, but with no apparent signs of an anaphylactic reaction. It is suggested that vasodilatation and drop in blood pressure caused by the chlorpromazine could have had some effect, while cardiotoxicity of other psychotropic drugs with which he had been treated cannot be ruled out.ZusammenfassungEs wird über vier Fälle berichtet, in denen intramuskuläre und intra-artikuläre Injektionen Komplikationen mit tödlichem Ausgang zur Folge hatten. In zwei von diesen Fällen erwies sich eine intramuskuläre bzw. intra-artikuläre Injektion als Ausgangspunkt einer Staphylokokkensepsis. Auf die intra-artikuläre Injektion ins Hüftgelenk folgten große Schmerzen, die Autopsie zeigte aber keine augenfälligen Anzeichen einer pyogenen Arthritis. Dieses Phänomen steht wahrscheinlich in Zusammenhang mit der anti-inflammatorischen Wirkung der Kortikosteroide. Im anderen Fall bestand eine lokale Hautinfektion (kein glutealer Abszess!). Trotzdem wurde Staphylococcus aureus im Blut nachgewiesen und andere lokale Infektionen konnten nicht diagnostiziert werden. Weiterhin wird eine Komplikation nach intra-artikulärer Injektion eines Glykosaminoglykanpräparats beschrieben, die eine schwere Infektion eines Kniegelenks verursachte. Dieser Patient starb an einer Niereninsuffizienz, die wahrscheinlich in Verbindung mit einer Antibiotikabehandlung mit Tobramycin und Cefuroxim stand. In diesem Material wird außerdem der Fall eines psychotischen Patienten beschrieben, der nach intramuskulärer Chlorpromazininjektion einen plötzlichen Herzstillstand erlitt, bei dem aber keine deutlichen Anzeichen einer anaphylaktischen Reaktion auftraten. Es wird vermutet, daß Vasodilatation und Blutdrucksenkung, verursacht durch Chlorpromazin, dem Tod des Patienten verursacht haben könnten. Die Kardiotoxizität anderer Psychopharmaka, mit denen der Mann behandelt war, kann auch nicht ausgeschlossen werden.