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.

Familial clustering of unexplained heart failure - A Danish nationwide cohort study.

AIMS: To determine whether a family history of unexplained heart failure (HF) in first-degree relatives (children or sibling) increases the rate of unexplained HF. METHODS AND RESULTS: Using Danish nationwide registry data (1978-2017), we identified patients (probands) diagnosed with first unexplained HF (HF without any known comorbidities) in Denmark, and their first-degree relatives. All first-degree relatives were followed from the HF date of the proband and until an event of unexplained HF, exclusion diagnosis, death, emigration, or study end, whichever occurred first. Using the general population as a reference, we calculated adjusted standardized incidence ratios (SIR) of unexplained HF in the three groups of relatives using Poisson regression models. We identified 55,110 first-degree relatives to individuals previously diagnosed with unexplained HF. Having a family history was associated with a significantly increased unexplained HF rate of 2.59 (95%CI 2.29-2.93). The estimate was higher among siblings (SIR 6.67 [95%CI 4.69-9.48]). Noteworthy, the rate of HF increased for all first-degree relatives when the proband was diagnosed with HF in a young age (≤50 years, SIR of 7.23 [95%CI 5.40-9.68]) and having >1 proband (SIR of 5.28 [95%CI 2.75-10.14]). The highest estimate of HF was observed if the proband was ≤40 years at diagnosis (13.17 [95%CI 8.90-19.49]. CONCLUSION: A family history of unexplained HF was associated with a two-fold increased rate of unexplained HF among first-degree relatives. The relative rate was increased when the proband was diagnosed at a young age. These data suggest that screening families of unexplained HF with onset below 50 years is indicated.

Discovery of plasma proteins associated with ventricular fibrillation during first ST-elevation myocardial infarction via proteomics.

AIMS: The underlying biological mechanisms of ventricular fibrillation (VF) during acute myocardial infarction are largely unknown. To our knowledge, this is the first proteomic study for this trait, with the aim to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n = 110) and without VF (control, n = 120) before guided catheter insertion for primary percutaneous coronary intervention. The plasma proteome was investigated using mass spectrometry-based proteomics on plasma samples collected within 24 h of symptom onset, and one patient was excluded in quality control. In 229 STEMI patients {72% men, median age 62 years [interquartile range (IQR): 54-70]}, a median of 257 proteins (IQR: 244-281) were quantified per patient. A total of 26 proteins were associated with VF; these proteins were involved in several biological processes including blood coagulation, haemostasis, and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 [ACTBL2, fold change (FC) 2.25, P < 0.001, q = 0.023], and coagulation factor XIII-A (F13A1, FC 1.48, P < 0.001, q = 0.023). None of the proteins were correlated with anterior infarct location. CONCLUSION: Ventricular fibrillation due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1), suggesting that they may represent novel underlying molecular VF mechanisms. Further research is needed to determine whether these proteins are predictive biomarkers or acute phase response proteins to VF during acute ischaemia.

Myocardial scarring and recurrence of ventricular arrhythmia in patients surviving an out-of-hospital cardiac arrest.

INTRODUCTION: Prediction of recurrent ventricular arrhythmia (VA) in survivors of an out-of-hospital cardiac arrest (OHCA) is important, but currently difficult. Risk of recurrence may be related to presence of myocardial scarring assessed with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Our study aims to characterize myocardial scarring as defined by LGE-CMR in survivors of a VA-OHCA and investigate its potential role in the risk of new VA events. METHODS: Between 2015 and 2022, a total of 230 VA-OHCA patients without ST-segment elevation myocardial infarction had CMR before implantable cardioverter-defibrillator implantation for secondary prevention at Copenhagen University Hospital, Rigshospitalet, and Hospital Clínic, University of Barcelona, of which n = 170 patients had a conventional (no LGE protocol) CMR and n = 60 patients had LGE-CMR (including LGE protocol). Scar tissue including core, border zone (BZ) and BZ channels were automatically detected by specialized investigational software in patients with LGE-CMR. The primary endpoint was recurrent VA. RESULTS: After exclusion, n = 52 VA-OHCA patients with LGE-CMR and a mean left ventricular ejection fraction of 49 ± 16% were included, of which 18 (32%) patients reached the primary endpoint of VA. Patients with recurrent VA in exhibited greater scar mass, core mass, BZ mass, and presence of BZ channels compared with patients without recurrent VA. The presence of BZ channels identified patients with recurrent VA with 67% sensitivity and 85% specificity (area under the ROC curve (AUC) 0.76; 95% CI: 0.63-0.89; p < .001) and was the strongest predictor of the primary endpoint. CONCLUSIONS: The presence of BZ channels was the strongest predictor of recurrent VA in patients with an out of-hospital cardiac arrest and LGE-CMR.

Differences among young unwitnessed sudden cardiac death, according to time from last seen alive: Insights from a 15-year nationwide study.

BACKGROUND: More than half of all sudden cardiac deaths (SCDs) are unwitnessed, but the composition of the unwitnessed SCD population is poorly described. OBJECTIVE: The purpose of this study was to compare clinical and autopsy characteristics of young unwitnessed SCD subjects, based on the time from last contact to being found dead. METHODS: All unwitnessed SCD subjects aged 1-35 years in Denmark from 2000-2014 identified through a multisource approach were included. Time from last seen alive to being found dead was dichotomized to <1 hour or 1-24 hours. Clinical characteristics and autopsy results were compared, and predictors of autopsy were assessed by logistic regression. RESULTS: Of 440 unwitnessed SCD subjects, 366 (83%) had not been seen alive within 1 hour of being found dead. Comorbidities differed between the groups, with more epilepsy (17% vs 5%) and psychiatric diseases (13% vs 7%) in the 24-hour group. Patients in the 24-hour group died more frequently during sleep (64% vs 23%), the autopsy rate was higher (75% vs 61%), and deaths were more often unexplained after autopsy (69% vs 53%). Having been seen within 1 hour of death independently decreased the chance of being autopsied (odds ratio 0.51; 95% confidence interval 0.27-1.00; P = .0497). CONCLUSION: The majority of unwitnessed SCD subjects had not been seen alive within 1 hour of being found dead. Clinical- and autopsy-related characteristics differed between the 2 groups. Differences were mainly attributable to death-related circumstances and comorbidities. Excluding SCD cases not seen alive within 1 hour of being found dead would severely underestimate the burden of SCD.

Bundle branch block in cardiac arrest survivors without ischemic heart disease.

Aims: Cardiac arrest (CA) survivors with left/right bundle branch block (LBBB/RBBB) and no ischemic heart disease (IHD) have not been previously characterized. The aim of this study was to describe heart failure, implantable cardioverter defibrillator (ICD) therapy and mortality in this population. Methods: Between 2009 and 2019 we consecutively identified all CA survivors with a consistent bundle branch block (BBB) defined as a QRS ≥ 120 ms, who had a secondary prophylactic ICD implanted. Patients with congenital and ischemic heart disease (IHD) were excluded. Results: Among 701 CA-survivors who survived to discharge and received an ICD, a total of 58 (8%) were free from IHD and had BBB; 46 (79%) had LBBB, 10 (17%) had RBBB and 2 (3%) had non-specific BBB (NSBBB). The prevalence of LBBB was 7%. Pre-arrest ECG were available in 34 (59%) patients; 20 patients (59%) had LBBB, 6 (18%) had RBBB, 2 (6%) had NSBBB, 1 had (3%) incomplete LBBB, and 4 (12%) without BBB. At discharge, patients with LBBB had a significantly lower left ventricular ejection fraction (LVEF) than patients with other types of BBB, p < 0.001. During follow-up, 7 (12%) died after a median of 3.6 years (IQR: 2.6-5.1) with no difference between BBB subtypes. Conclusion: We identified 58 CA-survivors with BBB and no IHD. The prevalence of LBBB among all CA-survivors was high, 7%. During CA hospitalization LBBB patients presented with a significantly lower LVEF than patients with other types of BBB (P < 0.001). ICD treatment and mortality did not differ between BBB subtypes during follow-up.

Risk of Sudden Infant Death Syndrome Among Siblings of Children Who Died of Sudden Infant Death Syndrome in Denmark.

Importance: Sudden infant death syndrome (SIDS) remains a leading cause of death during the first year of life. The etiology of SIDS is complex and remains largely unknown. Objective: To evaluate whether siblings of children who died of SIDS have a higher risk of SIDS compared with the general pediatric population. Design, Setting, and Participants: This register-based cohort study used Danish nationwide registers. Participants were all infants (<1 year) in Denmark between January 1, 1978, and December 31, 2016, including siblings of children who died of SIDS. Siblings were followed up from the index cases' date of SIDS, date of birth, or immigration, whichever came first, and until age 1 year, emigration, developing SIDS, death, or study end. The median (IQR) follow-up was 1 (1-1) year. Data analysis was conducted from January 2017 to October 2022. Main Outcomes and Measures: Standardized incidence ratios (SIRs) of SIDS were calculated with Poisson regression models relative to the general population. Results: In a population of 2 666 834 consecutive births (1 395 199 [52%] male), 1540 infants died of SIDS (median [IQR] age at SIDS, 3 [2-4] months) during a 39-year study period. A total of 2384 younger siblings (cases) to index cases (first sibling with SIDS) were identified. A higher rate of SIDS was observed among siblings compared with the general population, with SIRs of 4.27 (95% CI, 2.13-8.53) after adjustment for sex, age, and calendar year and of 3.50 (95% CI, 1.75-7.01) after further adjustment for mother's age (<29 years vs ≥29 years) and education (high school vs after high school). Conclusions and Relevance: In this nationwide study, having a sibling who died of SIDS was associated with a 4-fold higher risk of SIDS compared with the general population. Shared genetic and/or environmental factors may contribute to the observed clustering of SIDS. The family history of SIDS should be considered when assessing SIDS risk in clinical settings. A multidisciplinary genetic evaluation of families with SIDS could provide additional evidence.

Long-term risk of new-onset arrhythmia in ST-segment elevation myocardial infarction according to revascularization status.

AIMS: Emerging data show that complete revascularization (CR) reduces cardiovascular death and recurrent myocardial infarction in ST-segment elevation myocardial infarction (STEMI). However, the influence of revascularization status on development of arrhythmia in the long-term post-STEMI phase is poorly described. We hypothesized that incomplete revascularization (ICR) compared with CR in STEMI is associated with an increased long-term risk of new-onset arrhythmia. METHODS AND RESULTS: Patients with STEMI treated with primary percutaneous coronary intervention (PPCI) at Copenhagen University Hospital, Rigshospitalet, Denmark, with CR or ICR were identified via the Eastern Danish Heart registry from 2009 to 2016. Using unique Danish administrative registries, the outcomes were assessed. The primary outcome was new-onset arrhythmia defined as a composite of atrial fibrillation/flutter (AF), sinoatrial block, advanced second- or third-degree atrioventricular block, ventricular tachycardia/fibrillation (VT), or cardiac arrest (CA), with presentation >7 days post-PPCI. Secondary outcomes were the components of the primary outcome and all-cause mortality. A total of 5103 patients (median age: 62.0 years; 76% men) were included, of whom 4009 (79%) and 1094 (21%) patients underwent CR and ICR, respectively. Compared with CR, ICR was associated with a higher risk of new-onset arrhythmia [hazard ratio (HR), 1.33; 95% confidence interval (CI), 1.07-1.66; P = 0.01], AF (HR, 1.29; 95% CI, 1.00-1.66; P = 0.05), a combined outcome of VT and CA (HR, 1.77; 95% CI, 1.10-2.84; P = 0.02) and all-cause mortality (HR, 1.27; 95% CI, 1.05-1.53; P = 0.01). All HRs adjusted. CONCLUSION: Among patients with STEMI, ICR was associated with an increased long-term risk of new-onset arrhythmia and all-cause mortality compared with CR.

Exercise Testing Using Sprint Protocol vs Bruce Protocol in Catecholaminergic Polymorphic Ventricular Tachycardia.

We present the case of a relative of a patient with catecholaminergic polymorphic ventricular tachycardia. This relative underwent a standard (Bruce) exercise stress test (EST), which had normal results. He then underwent our modified "sprint" EST, with positive results. This report underlines how the sprint EST may provoke arrhythmias better than the standard Bruce EST. (Level of Difficulty: Advanced.).

Nationwide study of mortality and sudden cardiac death in young persons diagnosed with chronic kidney disease.

AIMS: The aim of this study was to compare short- and long-term risk of sudden cardiac death (SCD) among persons aged 18-49 years with and without chronic kidney disease (CKD). METHODS AND RESULTS: Using Danish nationwide health registries, all persons aged 18-49 years diagnosed with earlier stages of CKD or chronic kidney failure from 1 July 1995 through 2009 were identified. Non-exposed subjects matched on sex and birth-year were identified. All SCD in the Danish population aged 18-49 years in 2000-2009 have previously been identified using information from the Danish nationwide health registries, death certificates, and autopsy reports. In total, 9308 incident cases of earlier stage CKD and 1233 incident cases of chronic kidney failure were included. Among patients with earlier stage CKD, the absolute risk of SCD 1, 5, and 10 years after diagnosis was 0.14%, 0.37%, and 0.68%, respectively. Compared with age- and sex-matched subjects the corresponding relative risk (RR) was 20.3 [95% confidence interval (CI) 8.4-48.8], 7.1 (95% CI 4.2-12.0), and 6.1 (95% CI 3.8-9.7), respectively. Among patients with chronic kidney failure, the absolute 1-, 5-, and 10-year risk of SCD was 0.17%, 0.56%, and 2.07%, respectively. The corresponding RR was 12.5 (95% CI 1.4-111.6), 7.9 (95% CI 2.3-27.0), and 10.1 (95% CI 4.5-22.6). CONCLUSION: Persons with earlier stage CKD and chronic kidney failure had increased risk of SCD compared with the background population with a 6- to 20-fold increased risk of SCD. These findings underline the importance of early cardiovascular risk monitoring and assessment in persons with CKD.

[Cardiac arrest in a patient with long QT syndrome receiving androgen deprivation therapy].

This is a case report of a 72-year-old male with a newly diagnosed prostate cancer, who was treated with androgen deprivation therapy and anti-androgen. The patient was diagnosed with congenital long QT syndrome (LQTS), and a markedly worsening of the QT-prolongation was observed, after the hormonal therapy was initiated. He ultimately suffered an initially resuscitated cardiac arrest but did not survive to discharge. Pharmaceutical treatments in patients with LQTS should always be handled with caution, and if a treatment with a known or probable QT-prolonging drug is initiated, a cardiologist should be consulted.

Nationwide burden of sudden cardiac death: A study of 54,028 deaths in Denmark.

BACKGROUND: A large proportion of all deaths are sudden cardiac deaths (SCDs). Reliable estimates of nationwide incidence of SCD, however, are missing. OBJECTIVES: The goals of this study were to estimate SCD burden across all age groups in Denmark and to compare it with the estimates of other common causes of death. METHODS: All deaths in Denmark (population of 5.5 million) in 2010 were manually reviewed case by case. Autopsy reports, death certificates, and information from nationwide health registries were systematically examined to identify all SCD cases in 2010. According to the level of detail of the available information, all deaths were categorized as either non-SCD, definite SCD, probable SCD, or possible SCD. RESULTS: There were 54,028 deaths in Denmark in 2010, of which 6867 (13%) were categorized as SCD (591 (9%) definite SCD, 1568 (23%) probable SCD, and 4708 (68%) possible SCD). The incidence rate of definite SCD was 11 (95% confidence interval 10-12) per 100,000 person-years. Including definite, probable, and possible SCD cases, the highest possible overall SCD incidence rate was 124 (95% confidence interval 121-127) per 100,000 person-years. Estimated SCD burden was similar to or greater than the estimates of all other common causes of death. Of all SCD cases, 49% were not diagnosed with cardiovascular disease before death. CONCLUSION: SCD accounted for up to 13% of all deaths. Almost half of all SCD cases occurred in persons without a history of cardiovascular disease. Consequently, the optimization of risk stratification and prevention of SCD in the general population should be given high priority.

Correction: Seasonality of ventricular fibrillation at first myocardial infarction and association with viral exposure.

[This corrects the article DOI: 10.1371/journal.pone.0226936.].

Febrile seizures prior to sudden cardiac death: a Danish nationwide study.

Aims: Febrile seizure (FS) is a common disorder affecting 2-5% of children up to 5 years of age. The aim of this study was to determine whether FS in early childhood are over-represented in young adults dying from sudden cardiac death (SCD). Methods and results: We included all deaths (n = 4595) nationwide and through review of all death certificates, we identified 245 SCD in Danes aged 1-30 years in 2000-09. Through the usage of nationwide registries, we identified all persons admitted with first FS among SCD cases (14/245; 5.7%) and in the corresponding living Danish population (71 027/2 369 785; 3.0%) and also in victims of transport accidents (26/917; 2.8%). The frequency of FS among SCD cases was significantly increased by an odds ratio of 1.96 [95% confidence interval (CI) 1.14-3.36; P = 0.021] compared with the living Danish population and with an odds ratio of 2.08 (95% CI 1.07-4.04; P = 0.046) compared with transport accident victims. SCD cases did not differ statistically in birth year (P = 0.272), age at SCD (P = 0.667) or prior medical conditions, except for epilepsy (P < 0.001), when comparing SCD with and without prior FS. The most common cause of death in autopsied SCD cases with FS was sudden arrhythmic death syndrome (5/8; 62.5%). Conclusion: In conclusion, this study demonstrates a significantly two-fold increase in the frequency of FS prior to death in young SCD cases compared with the two control groups, suggesting that FS could potentially contribute in a risk stratification model for SCD and warrant further studies.