Genetic factors may influence outcome from cardiac arrest. In Seattle, WA, paramedics collected blood specimens from patients who had suffered cardiac arrest outside of a medical institution (out of hospital cardiac arrest). We examined associations between apolipoprotein E (APOE) genotype and outcome in 134 who died “in the field”, 131 who died in the hospital, 198 patients who were discharged from hospital alive, and 64 control subjects. APOE genotype was not significantly related to outcome, including being alive at and being independent by 3 months after the arrest. Specifically, having one or two alleles of APOE ε4 or having APOE ε3/ε3 was not related to outcome, even after controlling for age, sex, race, and initial rhythm. We failed to confirm previous studies and found no significant associations between APOE genotype and outcome from out of hospital cardiac arrest.
- apolipoprotein E
- heart arrest
- APOE, apolipoprotein E
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Whether genetic factors influence outcome after cardiac arrest is uncertain. Three alleles of the apolipoprotein E gene (APOE ε2, ε3, and ε4) encode three isoforms of the protein (E2, E3, and E4), which exert differential effects on response of nervous tissue to injury.1 In a study of transgenic mice, APOE ε4 was associated with greater hippocampal damage after global cerebral ischaemia,2 contrary to results in 58 humans who died after surviving a mean of 5.7 days after cardiac arrest.3 In another study of 80 patients admitted after cardiac arrest, having the APOE ε3/ε3 genotype was associated with a better survival and neurological outcome.4 If genetic factors affect outcome after cardiac arrest, they could provide clues about pathophysiology and could suggest novel treatments. We explored associations of outcome with APOE genotype using blood specimens collected by paramedics from patients they treated for out of hospital cardiac arrest.
As part of another study,5 paramedics in Seattle have collected blood specimens from patients with out of hospital cardiac arrest since 1988. Regardless of the outcome of resuscitation, paramedics collect the specimens as soon as possible after return of spontaneous circulation or immediately upon cessation of resuscitative efforts. Blood was collected into tubes containing EDTA, and transported to the Clinical Nutrition Research Laboratory at Harborview Medical Center, where the white blood cells were separated and stored at −70°C.
APOE genotyping was attempted on all specimens collected from 1989 to 1995 from patients who had survived to hospital discharge. DNA was prepared from buffy coat preparations by a modification of a salting out procedure.6 The APOE genotypes were determined using previously described PCR conditions7 and HhaI restriction digest methods.8 For comparison, genotyping was also attempted on randomly selected specimens collected in the same time interval from an approximately equal number of patients who died in hospital; about one third this number of patients who died “in the field”; and about one third this number of community control subjects from the study described above.5 Genotyping was performed without knowledge of any clinical information, and was successful in 90.5% of patients: 80.8% for those who died in the field; 93.0% for those who died in hospital; 92.0% for those who survived to hospital discharge; and 87.7% for control subjects. We subsequently reclassified patients based on the most current and accurate information collected by personnel with the pre-hospital emergency medical system in Seattle (Medic One), as part of continuing efforts to improve the quality of care of these patients. We included those who died in the emergency department with those who died in the field. With this redistribution, APOE genotype was available on: 134 who died in the field, 131 who died in hospital, 198 patients who survived to be discharged from hospital, and 64 control subjects.
We also used this database to obtain information on patients’ age, sex, race (white v other), and initial rhythm (ventricular fibrillation v other). For patients discharged from the hospital, personnel used medical records and telephone follow up to decide survival status at 3 months and recovery of independence at any time by 3 months after the cardiac arrest. Personnel collected all of the information without knowledge of the results of the genotyping.
Outcomes used in this study included: death in the field, death in hospital, survival to discharge from hospital, survival at 3 months, and independence by 3 months. To evaluate associations between these outcomes and genotype, we used logistic regression, with the outcome as the dependent variable and the genotype as the independent variable. In addition to unadjusted models, we also evaluated models adjusted for age, sex, race and initial rhythm. An association was considered significant if the p value for the genotype coefficient in the logistic regression model was <0.05. Race was unknown in three patients. Survival status at 3 months was unknown for 19 patients. In these patients, the independence status at the last contact was used for the status by 3 months. No other variables had missing values, and the maximum number of missing values for any model was 20 patients, occurring in models where the dependent variable was survival at 3 months. Analyses were performed using SPSS statistical software (version 10.0 for Macintosh; SPSS Inc., Chicago, IL, USA). The Human Subjects Review Committee at the University of Washington approved the study.
Characteristics of the study groups are shown in table 1, and the results of the APOE genotyping in the four study groups are shown in table 2. In the unadjusted and adjusted models, having one or two alleles of APOE ε4 was not significantly related to the outcomes examined: having a cardiac arrest v being a control (24.2% v 25.0% respectively, having one or two alleles of APOE ε4); for all cardiac arrest patients, being resuscitated and admitted v not (24.3% v 23.9%); and for patients admitted, surviving to discharge v not (22.2% v 27.5%); surviving to 3 months v not (21.6% v 27.0%); or being independent by 3 months v not (22.6% v 26.1%). Similarly, in the unadjusted and adjusted models, having the APOE ε3/ε3 genotype was not significantly related to the outcomes examined: having a cardiac arrest v being a control (66.7% v 64.1% respectively, having APOE ε3/ε3 genotype); for all cardiac arrest patients, being resuscitated and admitted v not (67.5% v 64.9%); and for patients admitted, surviving to discharge v not (69.7% v 64.1%); surviving to 3 months v not (70.4% v 65.5%); or being independent by 3 months v not (69.0% v 65.8%). Associations with genotypes for survival at and independence by 3 months remained insignificant when only those discharged from the hospital were considered.
How apolipoprotein E genotypes affect outcomes from brain injury is uncertain but seemingly dependent upon the mechanism of injury.1 Detrimental effects of having one or two alleles of APOE ε4 have been demonstrated for traumatic brain injury9 and haemorrhagic stroke10–12 but not for ischaemic stroke.11,13 As expected, based on previous studies of hippocampal damage and neurological outcome in patients with cardiac arrest,3,4 we found that having one or two alleles of APOE ε4 was not associated with outcome. In this regard, global and focal brain ischaemia are similar. Unlike a previous study,4 we found that APOE ε3/ε3 genotype was also not significantly associated with any of the outcomes examined. Why the results from the two studies differ is unclear. We examined a larger number and a less select group of patients than in the previous study. Perhaps the results would have differed if we had succeeded in genotyping all the specimens, but the genotyping was performed without any clinical information, making such a bias unlikely. Perhaps more detailed determination of neurological outcome is needed to identify such associations. Even if an association with APOE genotype is lacking, it is likely that other genetic factors that affect the response to global brain ischaemia accompanying cardiac arrest exist. Understanding such genetic factors may hold the key to understanding brain protection and resuscitation.
The study was possible only because of the outstanding efforts of the firefighters and paramedics of the Seattle Fire Department. We also appreciate the dedicated work of staff of the Medic One Program in determining demographics and outcomes.
This study was supported by grants from the National Heart, Lung, and Blood Institute (HL41993 DSS), the National Institute of Aging (P50 AG05136, GDS), and the Medic One Foundation.
Competing interest: none declared