The emergency medical service has a crucial role to unravel the genetics of sudden cardiac arrest in young, out of hospital resuscitated patients: Interim data from the MAP-IT study.

BACKGROUND: Genetics of sudden cardiac deaths (SCD) remains frequently undetected. Genetic analysis is recommended in undefined selected cases in the 2021 ERC-guideline. The emergency medical service and physicians (EMS) may play a pivotal role for unraveling SCD by saving biomaterial for later molecular autopsy. Since for high-throughput DNA-sequencing (NGS) high quality genomic DNA is needed. We investigated in a prospective proof-of-concept study the role of the EMS for the identification of genetic forms of SCDs in the young. METHODS: We included patients aged 1-50 years with need for cardiopulmonary resuscitation attempts (CPR). Cases with non-natural deaths were excluded. In two German counties with 562,904 residents 39,506 services were analysed. Paired end panel-sequencing was performed, and variants were classified according to guidelines of the American College of Medical Genetics (ACMG). RESULTS: 769 CPR-attempts were recorded (1.95% of all EMS-services; CPR-incidence 68/100,000). In 103 cases CPR were performed in patients < 50y. 58% died on scene, 26% were discharged from hospital. 24 subjects were included for genotyping. Of these 33% died on scene, 37.5% were discharged from hospital. 25% of the genotyped patients were carriers of (likely) pathogenic (ACMG-4/-5) variants. 67% carried variants with unknown significance (ACMG-3). 2 of them had familial history for arrhythmogenic cardiomyopathy or had to be re-classified as ACMG-4 carriers due to whole exome sequencing. CONCLUSION: The EMS contributes especially in fatal OHCA-cases to increase the yield of identified genetic conditions by collecting a blood sample on scene. Thus, the EMS can contribute significantly to primary and secondary prophylaxis in affected families.

Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation in a 5-Year-Old Pediatric Patient.

Out-of-hospital cardiac arrest in pediatric population is rare and predominantly has respiratory aetiology. Authors present the relatively unique case of out-of hospital cardiac arrest in 5-years old pediatric patient due to ventricular fibrillation (VF) as the initial rhythm during the advanced life support. The patient was resuscitated by his parents and the initial rhythm was VF. After defibrillation the patient was admitted to the pediatric intensive care were another two episodes of VF was detected and treated. After standard postresuscitation care, patient was weaned from sedation and extubated with good neurologic outcome. Genetic screening of the 7 genes associated with cardiac channelopathies (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, RYR2, CASQ2) found mutation in gene KCHN2 and gene SCN5A, that were according to actual data considered benign. This case highlights the need for automated external defibrillator implementation in basic life support also in pediatric population and possible role of genetic predisposition in emergence of fibrillation.

Early blood transcriptomic signature predicts patients' outcome after out-of-hospital cardiac arrest.

BACKGROUND: Early prognostication is a major challenge after out-of-hospital cardiac arrest (OHCA). AIMS: We hypothesized that a genome-wide analysis of blood gene expression could offer new prognostic tools and lines of research. METHODS: Sixty-nine patients were enrolled from an ancillary study of the clinical trial NCT00999583 that tested the effect of erythropoietin (EPO) after OHCA. Blood samples were collected in comatose survivors of OHCA at hospital admission and 1 and 3 days after resuscitation. Gene expression profiles were analyzed (Illumina HumanHT-12 V4 BeadChip; >34,000 genes). Patients were classified into two categories representing neurological favorable outcome (cerebral performance category [CPC] = 1-2) vs unfavorable outcome (CPC > 2) at Day 60 after OHCA. Differential and functional enrichment analyses were performed to compare transcriptomic profiles between these two categories. RESULTS: Among the 69 enrolled patients, 33 and 36 patients were treated or not by EPO, respectively. Among them, 42% had a favorable neurological outcome in both groups. EPO did not affect the transcriptomic response at Day-0 and 1 after OHCA. In contrast, 76 transcripts differed at Day-0 between patients with unfavorable vs favorable neurological outcome. This signature persisted at Day-1 after OHCA. Functional enrichment analysis revealed a down-regulation of adaptive immunity with concomitant up-regulation of innate immunity and inflammation in patients with unfavorable vs favorable neurological outcome. The transcription of many genes of the HLA family was decreased in patients with unfavorable vs favorable neurological outcome. Concomitantly, neutrophil activation and inflammation were observed. Up-stream regulators analysis showed the implication of numerous factors involved in cell cycle and damages. A logistic regression including a set of genes allowed a reliable prediction of the clinical outcomes (specificity = 88%; Hit Rate = 83%). CONCLUSIONS: A transcriptomic signature involving a counterbalance between adaptive and innate immune responses is able to predict neurological outcome very early after hospital admission after OHCA. This deserves confirmation in a larger population.

Catecholaminergic Polymorphic Ventricular Tachycardia: The Cardiac Arrest Where Epinephrine Is Contraindicated.

OBJECTIVES: To raise awareness among pediatric intensive care specialists of catecholaminergic polymorphic ventricular tachycardia; an uncommon cause of polymorphic ventricular tachycardia and ventricular fibrillation arrest in children and young adults where epinephrine (adrenaline), even when given according to international protocols, can be counter-productive and life-threatening. We review three cases of cardiac arrest in children, later proven to be catecholaminergic polymorphic ventricular tachycardia related, where delay in recognition of this condition resulted in significantly longer resuscitation efforts, more interventions, and a longer time to return of spontaneous circulation. DESIGN: Retrospective case series. SETTING: Tertiary children's hospital. PATIENTS AND RESULTS: Three previously well children 4, 5, and 10 years old presented with cardiac arrest triggered by light activity, partial water immersion, and running, respectively. Initial resuscitation was bystander cardiopulmonary resuscitation and community defibrillation in all three cases. Electrocardiograms revealed multifocal ventricular ectopy, and in two (4 and 10 yr old), this correlated with repeated administration of epinephrine during repeated ventricular tachycardia and ventricular fibrillation cardiac arrest resuscitation cycles. This ultimately resolved immediately (at 78 and 140 min, respectively) with IV opiates once catecholaminergic polymorphic ventricular tachycardia was suspected. During recovery, on extracorporeal membrane oxygenation, epinephrine challenge in two children induced polymorphic ventricular tachycardia, bidirectional ventricular tachycardia, and ventricular fibrillation, which was cardioverted with flecainide in the 4-year-old. The third case was recognized early as catecholaminergic polymorphic ventricular tachycardia and was managed by avoiding epinephrine and using opiates and general anesthesia after the initial (single) cardioversion, and had a much better clinical course, without recourse to extracorporeal membrane oxygenation. All three carried de novo RyR2 (cardiac ryanodine) mutations. CONCLUSIONS: Those involved in resuscitation of young people should be aware of catecholaminergic polymorphic ventricular tachycardia and be suspicious of persistent ventricular ectopy, polymorphic, or bidirectional ventricular tachycardia during resuscitation. Appropriate management is avoidance of epinephrine, administration of general anesthesia, IV opiates, and consideration of flecainide.

Double de novo mutations in dilated cardiomyopathy with cardiac arrest.

Here we report the identification of two novel mutations in a previously asymptomatic young man who suffered an out-of-hospital sudden cardiac arrest. During following evaluation, diagnosis of early stage dilated cardiomyopathy was established, while electrocardiogram monitoring showed frequent complex ventricular arrhythmias, incomplete right bundle branch block and prolonged QT duration. No reversible causes explaining the clinical presentation were established and an automatic implantable cardioverter defibrillator was therefore implanted. Heterozygous mutations in human protein coding genes NKX2-5 and RBM20 are associated with a wide array of pathological phenotypes some of which are sudden cardiac death, unexplained syncope and either combined or isolated congenital heart diseases such as dilated cardiomyopathy.

Induced hypothermia is associated with reduced circulating subunits of mitochondrial DNA in cardiac arrest patients.

Induced hypothermia may protect from ischemia reperfusion injury. The mechanism of protection is not fully understood and may include an effect on mitochondria. Here we describe the effect of hypothermia on circulating mitochondrial (mt) DNA in a substudy of a multicenter randomized trial (the Target Temperature Management trial). Circulating levels of mtDNA were elevated in patients with cardiac arrest at all-time points compared to healthy controls. After 24 h of temperature management, patients kept at 33 °C had significantly lower levels of COX3, NADH1 and NADH2 compared to baseline, in contrast to those kept at 36 °C. After regain of temperature, cytochrome - B was significantly reduced in patients kept at 33 °C with cardiac arrest. Cardiac arrest results in circulating mtDNA levels, which reduced during a temperature management protocol in patients with a target temperature of 33 °C.

Acute Kidney Injury Predicts Mortality after Charcoal Burning Suicide.

A paucity of literature exists on risk factors for mortality in charcoal burning suicide. In this observational study, we analyzed the data of 126 patients with charcoal burning suicide that seen between 2002 and 2013. Patients were grouped according to status of renal damage as acute kidney injury (N = 49) or non-acute kidney injury (N = 77). It was found that patients with acute kidney injury suffered severer complications such as respiratory failure (P = 0.002), myocardial injury (P = 0.049), hepatic injury (P < 0.001), rhabdomyolysis (P = 0.045) and out-of-hospital cardiac arrest (P = 0.028) than patients without acute kidney injury. Moreover, patients with acute kidney injury suffered longer hospitalization duration (16.9 ± 18.3 versus 10.7 ± 10.9, P = 0.002) and had higher mortality rate (8.2% versus 0%, P = 0.011) than patients without injury. In a multivariate Cox regression model, it was demonstrated that serum creatinine level (P = 0.019) and heart rate (P = 0.022) were significant risk factors for mortality. Finally, Kaplan-Meier analysis revealed that patients with acute kidney injury suffered lower cumulative survival than without injury (P = 0.016). In summary, the overall mortality rate of charcoal burning suicide population was 3.2%, and acute kidney injury was a powerful predictor of mortality. Further studies are warranted.

Circulating microRNAs and sudden cardiac arrest outcomes.

AIM: MicroRNAs (miRNAs) have regulatory functions in organs critical in resuscitation from sudden cardiac arrest due to ventricular fibrillation (VF-SCA); therefore, circulating miRNAs may be markers of VF-SCA outcome. METHODS: We measured candidate miRNAs (N=45) in plasma using qRT-PCR among participants of a population-based VF-SCA study. Participants were randomly selected cases who died in the field (DF, n=15), died in hospital (DH, n=15), or survived to discharge (DC, n=15), and, age-, sex-, and race-matched controls (n=15). MiRNA levels were compared using ANOVA, t-tests, and fold-changes. RESULTS: Mean age of groups ranged from 66.9 to 69.7. Most participants were male (53-67%) and white (67%). Comparing cases to controls, plasma levels of 17 miRNAs expressed in heart, brain, liver, and other tissues (including miR-29c, -34a, -122, -145, -200a, -210, -499-5p, and -663b) were higher and three non-specific miRNAs lower (miR-221, -330-3p, and -9-5p). Among DH or DC compared with DF cases, levels of two miRNAs (liver-specific miR-122 and non-specific miR-205) were higher and two heart-specific miRNAs (miR-208b and -499-5p) lower. Among DC vs. DF cases, levels of three miRNAs (miR-122, and non-specific miR-200a and -205) were higher and four heart-specific miRNAs (miR-133a, -133b, -208b, and -499-5p) lower. Among DC vs. DH cases, levels of two non-specific miRNAs (miR-135a and -9-3p) were lower. CONCLUSIONS: Circulating miRNAs expressed in heart, brain, and other tissues differ between VF-SCA cases and controls and are related to resuscitation outcomes. Measurement of miRNAs may clarify mechanisms underlying resuscitation, improve prognostication, and guide development of therapies. Results require replication.

In the Wrong Place with the Wrong SNP: The Association Between Stressful Neighborhoods and Cardiac Arrest Within Beta-2-adrenergic Receptor Variants.

BACKGROUND: Sudden cardiac arrest has been linked independently both to stressful neighborhood conditions and to polymorphisms in the ADRB2 gene. The ADRB2 gene mediates sympathetic activation in response to stress. Therefore, if neighborhood conditions cause cardiac arrest through the stress pathway, the ADRB2 variant may modify the association between neighborhood conditions, such as socioeconomic deprivation and incidence of cardiac arrest. METHODS: The Cardiac Arrest Blood Study Repository is a population-based repository of specimens and other data from adult cardiac arrest patients residing in King County, Washington. Cases (n = 1,539) were 25- to 100-year-old individuals of European descent who experienced out-of-hospital cardiac arrest from 1988 to 2004. Interactions between neighborhood conditions and the ADRB2 genotype on cardiac arrest risk were assessed in a case-only study design. Gene-environment independence was assessed in blood samples obtained from King County residents initially contacted by random-digit dialing. RESULTS: Fewer than 4% of study subjects resided in socioeconomically deprived neighborhoods. Nonetheless, the case-only analysis indicated the presence of supramultiplicative interaction of socioeconomic deprivation and the homozygous Gln27Glu variant (case-only odds ratio: 1.8 [95% confidence interval: 1.0, 2.9]). Interactions between population density and the homozygous Gln27Glu variant were weaker (case-only odds ratio: 1.2 [95% confidence interval: 0.97, 1.5]). CONCLUSIONS: Findings support a supramultiplicative interaction between the Gln27Glu ADRB2 variant and socioeconomic deprivation among individuals of European descent. This result is consistent with the hypothesis that the elevation in cardiac arrest risk associated with socioeconomic deprivation operates through the stress pathway.

Circulating cell-free DNA levels correlate with postresuscitation survival rates in out-of-hospital cardiac arrest patients.

Early prediction of prognosis is helpful in cardiac arrest patients. Plasma cell-free DNA, which increases rapidly after cell death, is a novel biomarker for the prognosis of critical ill patients. Changes in the plasma cell-free DNA level and its role for the early prognosis of cardiac arrest patients remain unclear. We prospectively enrolled adult out-of-hospital cardiac arrest (OHCA) patients with sustained return of spontaneous circulation. The resuscitation variables were recorded following the Utstein recommendation. The plasma cell-free DNA concentration was determined by quantitative real-time polymerase chain reaction assay of ß-globin gene. A total of 42 patients were enrolled for the study. The plasma cell-free DNA level within 2h after cardiac arrest was higher in the non-survival group than the survival-to-discharge group (median level 1659.9 g.e./mL vs. 1121.6g.e./mL, p=0.003 by non-parametric test). The plasma cell-free DNA level at 72 h became no difference between these two groups. The optimal cutoff value of plasma cell-free DNA for predicting survival-to-discharge was 1,170 g.e./mL by ROC curve analysis (area under curve 0.752, p=0.010). A plasma cell-free DNA level higher than 1,170 g.e./mL and was an independent predictor for in-hospital mortality by multiple logistic regression analysis (adjusted odds ratio of 12.35, p=0.023) and was also associated with higher 90 day mortality (p=0.021 by log-rank test). In conclusion, the plasma cell-free DNA level increases during the early post-cardiac arrest phase and can be an early prognostic factor for OHCA patients.

Cardiac genetic investigation of young sudden unexplained death and resuscitated out of hospital cardiac arrest.

Nearly 30% of young sudden deaths have negative autopsies and these sudden unexplained deaths (SUDs) are presumed to be due to heritable cardiac arrhythmias attributed to cardiac ion channel disorders. Comprehensive cardiac and genetic testing of families of SUD is helpful in the detection of inherited cardiac genetic conditions. It frequently provides a clue to the cause of death in SUD victims and allows early diagnosis and opportunities to prevent SUD in other family members. Out of Hospital Cardiac Arrest (OHCA) victims and their families also require similar assessment, although the role of genetic testing in this group should be reserved to patients where a clinical diagnosis is established. A team approach with multidisciplinary specialised clinics and increased access to genetic analysis is very helpful in achieving these goals.