Toxicological profile using mass spectrometry in sudden cardiac arrest survivors admitted to a tertiary centre.

BACKGROUND: There has been no previous thorough toxicological examination of a cohort of patients with resuscitated sudden cardiac arrest. We aimed to determine the qualitative and quantitative drug composition in a resuscitated sudden cardiac arrest population, using forensic toxicology, with focus on prescribed, non-prescribed, and commonly abused drugs. METHODS: Individuals aged 18-90 years with resuscitated sudden cardiac arrest of presumed cardiac causes were prospectively included from a single tertiary center. Data from the sudden cardiac arrest hospitalization was collected from medical reports. Drugs used during resuscitation or before the blood sampling were identified and excluded in each patient. Mass spectrometry-based toxicology was performed to determine the absence or presence of most drugs and to quantify the findings. RESULTS: Among 186 consecutively enrolled resuscitated sudden cardiac arrest patients (median age 62 years, 83% male), 90% had a shockable rhythm, and were primarily caused by ischemic heart disease (66%). In total, 90 different drugs (excluding metabolites) were identified, and 82% of patients had at least one drug detected (median of 2 detected drugs (IQR:1-4)) (polypharmacy). Commonly abused drugs were present in 16%, and QT-prolonging drugs were present in 12%. Polypharmacy (≥5drugs) were found in 19% of patients. Importantly, none had potentially lethal concentrations of any drugs. CONCLUSION: In resuscitated sudden cardiac arrest patients with cardiac arrest of presumed cardiac cause, routine toxicological screening provides limited extra information. However, the role of polypharmacy in sudden cardiac arrest requires further investigation. No occult overdose-related cardiac arrests were identified.

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.

Physical activity and risk of instant and 28-day case-fatality in myocardial infarction.

BACKGROUND: While physical activity reduces risk of developing myocardial infarction (MI), it is unknown whether a history of physical activity is also protective of fatal arrhythmia and case-fatality in patients who have suffered an acute MI. METHODS: 104,801 individuals included in 2003-2014 in the Copenhagen General Population Study (CGPS), a prospective population-based study with self-reported leisure time physical activity (LTPA) in three categories measured at baseline, were followed until 2014 through national registries. The 1,517 individuals who suffered a first time MI during follow-up constituted the study population. Outcomes were fatal MI, defined as date of death same as date of MI (including out-of-hospital deaths) and 28-day fatality. Through multivariable analyses the association between baseline LTPA and outcomes were assessed adjusted for CVD risk factors. RESULTS: Of 1,517 MI events, 117 (7.7%) were fatal and another 79 (5.6%) lead to death within 28 days. Median time from baseline to MI was 3.6 years (IQR 1.7-5.8). LTPA was associated with lower risk of fatal MI with odds ratios of 0.40 (95% CI: 0.22-0.73) for light and 0.41 (0.22-0.76) for moderate/high LTPA after multivariable adjustment with sedentary LTPA as reference. Age, alcohol-intake, education and smoking were identified as other predictors for fatal MI. We found no association between LTPA and 28-day case fatality. CONCLUSIONS: Among individuals with MI, those that have engaged in any light or moderate physical activity were more likely to survive their MI. Results are consistent with effect of exercise preconditioning on risk of fatal arrhythmia.

How to prevent SCD in the young?

Sudden cardiac death in the young (SCDY) is always a devastating event. The death is sudden and unexpected and often in a person who was thought to be healthy. In recent years our understanding of these tragic events have drastically improved; 10-20years ago we did not know how often SCD occurred in the young, and we had sparse knowledge on the role of inheritance. We have found that SCD corresponds to 7% of all deaths with an overall (highest possible) incidence rate of 2.8 per 100,000 person-years (autopsy rate of sudden death cases of 75%). This incidence rate is higher than in the Veneto region (1.0), in the Netherlands (1.6), and in the UK (1.8), but can be explained by differences in definition and methodological factors. Cause of death in SCDY also differs to some extent between countries. Recent data suggest that there are identifiable risk factors for SCDY such as symptoms, comorbidities and polypharmacy. SCDY is to some extent preventable and this can be achieved through several initiatives: 1. better OCHA treatment including readily available AEDs, 2. family screening on the families left behind, and 3. better diagnostics and treatment for patients at risk for SCDY.

Spontaneous corynebacterium spondylodiskitis in an immunocompetent patient: A case report and literature review.

BACKGROUND: Spontaneous Corynebacterium spondylodiskitis is an unusual diagnosis of spondylodiskitis, especially in healthy patients without any significant past medical history. MATERIALS AND METHODS: We describe the case of a 78-year-old man with progressive low back pain for 3 months, irradiating down the lower limbs through L5 and S1 root pathways, associated with distal muscle weakness in both lower limbs. He had no history of trauma or medical problems. Laboratory investigation revealed elevated serum C-reactive protein (CRP) and erythrocyte sedimentation rate, without leukocytosis. The magnetic resonance findings demonstrated an extensive L5-S1 spondylodiskitis and L4-L5 anterolisthesis. Prior to spinopelvic fixation and posterolateral fusion, a substantial debridement was performed. The obtained tissue samples were submitted to pathological and microbiological studies, which identified Corynebacterium infection. RESULTS: One month after surgery, the pain diminished dramatically and the CRP titer diminished significantly. CONCLUSION: Although cases are very rare, spontaneous Corynebacterium spondylodiskitis, with substantial invasion of the spine, may develop in patients lacking any history of medical or surgical problems.

Giant Leaking Colloid Cyst Presenting with Aseptic Meningitis: Review of the Literature and Report of a Case.

BACKGROUND: Colloid cysts are benign third ventricle lesions that need to be diagnosed correctly because of their association with sudden death. Chemical or aseptic meningitis is a rare presentation of a colloid cyst. METHODS: We present a case of a 69-year-old man with fever, alteration of mental status, and meningismus. Microbiological examination of the cerebrospinal fluid revealed aseptic meningitis. Brain imaging revealed a third ventricular colloid cyst with hydrocephalus. RESULTS: The tumor was resected via endoscopic intervention. There were no persistent operative complications related to the endoscopic procedure. CONCLUSIONS: Chemical or aseptic meningitis is an unusual clinical manifestation of a colloid cyst, complicating the differential diagnosis, especially in the elderly.

Primary Meningeal Melanocytoma in the Left Temporal Lobe Associated with Nevus Ota: a Case Report and Review of the Literature.

BACKGROUND: Primary melanocytic neoplasms of the central nervous system are rare lesions arising from melanocytes of the leptomeninge that are found at highest density underneath the brain stem and along the upper cervical spinal cord. Thus most reported cases of meningeal melanocytomas are located in the posterior fossa and the spinal cord, and presentation of a supratentorial tumor is rare. METHODS: A 19-year-old man presented with a headache and seizure at our department. Neurological examinations were otherwise normal. On physical examination he had asymptomatic, bluish, speckled, and well-demarcated hyperpigmented macules on the left midface extraorally. A left temporal space-occupying lesion was seen on magnetic resonance imaging. The mass was hyperintense on T1-weighted images and isointense on T2-weighted images. Enhancement was shown on contrast-enhanced magnetic resonance imaging (MRI). The preoperative diagnosis was meningioma. RESULT: Gross complete resection was performed. Pathological studies led to the diagnosis of meningeal melanocytoma World Health Organization (WHO) grade I. The patient received oncologic consultation. Because total resection of the tumor was achieved and its histopathologic grade was benign (WHO grade I), radiotherapy was not advised for the patient and he followed up every 6 months. No tumor was seen on follow-up MRI one year after surgery. CONCLUSION: Presentation of meningeal melanocytoma in the supratentorial compartment is rare, and its combination with nevus Ota has been reported in very few cases. Although this lesion is benign, it might behave aggressively. Complete surgical resection of the lesion is the preferred therapeutic option.

Incidence and risk factors of ventricular fibrillation before primary angioplasty in patients with first ST-elevation myocardial infarction: a nationwide study in Denmark.

BACKGROUND: We aimed to investigate the incidence and risk factors for ventricular fibrillation (VF) before primary percutaneous coronary intervention (PPCI) among patients with ST-segment elevation myocardial infarction (STEMI) in a prospective nationwide setting. METHODS AND RESULTS: In this case-control study, patients presenting within the first 12 hours of first STEMI who survived to undergo angiography and subsequent PPCI were enrolled. Over 2 years, 219 cases presenting with VF before PPCI and 441 controls without preceding VF were enrolled. Of the 219 case patients, 182 (83%) had STEMI with out-of-hospital cardiac arrest due to VF, and 37 (17%) had cardiac arrest upon arrival to the emergency room. Medical history was collected by standardized interviews and by linkage to national electronic health records. The incidence of VF before PPCI among STEMI patients was 11.6%. Multivariable logistic regression analysis identified novel associations between atrial fibrillation and alcohol consumption with VF. Patients with a history of atrial fibrillation had a 2.80-fold odds of experiencing VF before PPCI (95% CI 1.10 to 7.30). Compared with nondrinkers, patients who consumed 1 to 7 units, 8 to 14 units, or >15 units of alcohol per week had an odds ratio (OR) of 1.30 (95% CI, 0.80 to 2.20), 2.30 (95% CI, 1.20 to 4.20), or 3.30 (95% CI, 1.80 to 5.90), respectively, for VF. Previously reported associations for preinfarction angina (OR 0.46; 95% CI 0.32 to 0.67), age of <60 years (OR 1.75; 95% CI 1.20 to 2.60), anterior infarction (OR 2.10; 95% CI 1.40 to 3.00), preprocedural thrombolysis in myocardial infarction flow grade 0 (OR 1.65; 95% CI 1.14 to 2.40), and family history of sudden death (OR 1.60; 95% CI 1.10 to 2.40) were all associated with VF. CONCLUSION: Several easily assessed risk factors were associated with VF occurring out-of-hospital or on arrival at the emergency room before PPCI in STEMI patients, thus providing potential avenues for investigation regarding improved identification and prevention of life-threatening ventricular arrhythmias.

New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is a rare autosomal dominantly inherited connective tissue disorder with an estimated prevalence of 1:5,000. More than 1000 variants have been previously reported to be associated with MFS. However, the disease-causing effect of these variants may be questionable as many of the original studies used low number of controls. To study whether there are possible false-positive variants associated with MFS, four in silico prediction tools (SIFT, Polyphen-2, Grantham score, and conservation across species) were used to predict the pathogenicity of these variant. RESULTS: Twenty-three out of 891 previously MFS-associated variants were identified in the ESP. These variants were distributed on 100 heterozygote carriers in 6494 screened individuals. This corresponds to a genotype prevalence of 1:65 for MFS. Using a more conservative approach (cutoff value of >2 carriers in the EPS), 10 variants affected a total of 82 individuals. This gives a genotype prevalence of 1:79 (82:6494) in the ESP. A significantly higher frequency of MFS-associated variants not present in the ESP were predicted to be pathogenic with the agreement of ≥3 prediction tools, compared to the variants present in the ESP (p = 3.5 × 10-15). CONCLUSIONS: This study showed a higher genotype prevalence of MFS than expected from the phenotype prevalence in the general population. The high genotype prevalence suggests that these variants are not the monogenic cause of MFS. Therefore, caution should be taken with regard to disease stratification based on these previously reported MFS-associated variants.

Sports-related sudden cardiac death in a competitive and a noncompetitive athlete population aged 12 to 49 years: data from an unselected nationwide study in Denmark.

BACKGROUND: Preparticipation screening programs have been suggested to reduce the numbers of sports-related sudden cardiac deaths (SrSCD). OBJECTIVE: The purpose of this study was to identify and characterize all SrSCD aged 12-49 years and to address the difference in incidence rates between competitive and noncompetitive athletes. METHODS: All deaths among persons aged 12-49 years from 2007-2009 were included. Death certificates were reviewed. History of previous admissions to hospital was assessed, and discharge summaries and autopsy reports were read. Sudden cardiac deaths (SCDs) and SrSCD cases were identified. RESULTS: In the 3-year period, there were 881 SCDs, of which we identified 44 SrSCD. In noncompetitive athletes aged 12-35 years, the incidence rate of SrSCD was 0.43 (95% confidence interval [CI] 0.16-0.94) per 100,000 athlete person-years vs 2.95 (95% CI 1.95-4.30) in noncompetitive athletes aged 36-49 years. In competitive athletes, the incidence rate of SrSCD was 0.47 (95% CI 0.10-1.14) and 6.64 (95% CI 2.86-13.1) per 100,000 athlete person-years in those aged 12-35 years and 36-49 years, respectively. The incidence rate of SCD in the general population was 10.7 (95% CI 10.0-11.5) per 100.000 person-years. CONCLUSION: The incidence rates of SrSCD in noncompetitive and competitive athletes are not different. The study showed an increase in the incidence rate of SrSCD in persons aged 36-49 years in both noncompetitive and competitive athletes compared to those aged 12-35 years. Importantly, SCD in the general population is much more prevalent than is SrSCD in all age groups.

Nationwide (Denmark) study of symptoms preceding sudden death due to arrhythmogenic right ventricular cardiomyopathy.

In this study, we investigated medical history and symptoms before death in all subjects aged 1 to 35 years who died a sudden cardiac death (SCD) from arrhythmogenic right ventricular cardiomyopathy (ARVC) in Denmark in the years 2000 to 2006. All deaths (n=6,629) in subjects aged 1 to 35 years in Denmark in the period 2000 to 2006 were included. A total of 16 cases of SCD due to ARVC were identified based on histopathologic examination. Information on medical history was retrieved from The National Patient Registry, general practitioners, and hospitals. Symptoms before death were compared with 2 control groups in the same age group and time interval: one consisting of subjects who died in traffic accidents (n=74) and the other consisting of patients who died a SCD due to coronary artery disease (CAD; n=34). In the case group, 8 of the 16 patients with ARVC experienced antecedent cardiac symptoms and 7 of them sought medical attention. None were diagnosed with ARVC before death. Only 1 patient in the healthy control group and 31 of the 39 patients with CAD experienced cardiac symptoms before death. A total of 6 patients of the 16 with ARVC died during strenuous physical activity and 4 of the deaths were sports-related SCDs. In conclusion, antecedent cardiac symptoms before SCD in the young were seen in 1/2 of the patients who died because of ARVC, and this is significantly higher than in the healthy control group. When considering the ARVC and CAD groups collectively, antecedent cardiac symptoms are seen in the majority.

Transplantation of adult monkey neural stem cells into a contusion spinal cord injury model in rhesus macaque monkeys.

OBJECTIVE: Currently, cellular transplantation for spinal cord injuries (SCI) is the subject of numerous preclinical studies. Among the many cell types in the adult brain, there is a unique subpopulation of neural stem cells (NSC) that can self-renew and differentiate into neurons. The study aims, therefore, to explore the efficacy of adult monkey NSC (mNSC) in a primate SCI model. MATERIALS AND METHODS: In this experimental study, isolated mNSCs were analyzed by flow cytometry, immunocytochemistry, and RT-PCR. Next, BrdU-labeled cells were transplanted into a SCI model. The SCI animal model was confirmed by magnetic resonance imaging (MRI) and histological analysis. Animals were clinically observed for 6 months. RESULTS: Analysis confirmed homing of mNSCs into the injury site. Transplanted cells expressed neuronal markers (TubIII). Hind limb performance improved in trans- planted animals based on Tarlov's scale and our established behavioral tests for monkeys. CONCLUSION: Our findings have indicated that mNSCs can facilitate recovery in contusion SCI models in rhesus macaque monkeys. Additional studies are necessary to determine the im- provement mechanisms after cell transplantation.

[Sudden unexpected cardiac death in an 18-year-old female with familial hypercholesterolaemia]. / Pludselig uventet hjertedød hos en 18-årig kvinde med familiær hyperkolesterolæmi.

Familial hypercholesterolaemia (FH) is a well-defined but underdiagnosed dyslipidaemia occurring in 1:500 persons. We report a case where an 18-year-old woman with an untreated FH dies a sudden cardiac death due to acute myocardial infarction. In patients with FH atherosclerotic manifestations are common at a young age and FH should always be suspected in patients with P-low-density lipoprotein cholesterol level above 5 mmol/l (4 mmol/l for persons < 16 years of age). Patients with FH should be referred to specialized units so that family members with FH systematically are identified.