Harpriya Chugh

Frequency and Determinants of Implantable Cardioverter Defibrillator Deployment Among Primary Prevention Candidates With Subsequent Sudden Cardiac Arrest in the Community

Background— The prevalence rates and influencing factors for deployment of primary prevention implantable cardioverter defibrillators (ICDs) among subjects who eventually experience sudden cardiac arrest in the general population have not been evaluated. Methods and Results— Cases of adult sudden cardiac arrest with echocardiographic evaluation before the event were identified from the ongoing Oregon Sudden Unexpected Death Study (population approximately 1 million). Eligibility for primary ICD implantation was determined from medical records based on established guidelines. The frequency of prior primary ICD implantation in eligible subjects was evaluated, and ICD nonrecipients were characterized. Of 2093 cases (2003–2012), 448 had appropriate pre– sudden cardiac arrest left ventricular ejection fraction information available. Of these, 92 (20.5%) were eligible for primary ICD implantation, 304 (67.9%) were ineligible because of left ventricular ejection fraction >35%, and the remainder (52, 11.6%) had left ventricular ejection fraction ⩽35% but were ineligible on the basis of clinical guideline criteria. Among eligible subjects, only 12 (13.0%; 95% confidence interval, 6.1%–19.9%) received a primary ICD. Compared with recipients, primary ICD nonrecipients were older (age at ejection fraction assessment, 67.1±13.6 versus 58.5±14.8 years, P=0.05), with 20% aged ≥80 years (versus 0% among recipients, P=0.11). Additionally, a subgroup (26%) had either a clinical history of dementia or were undergoing chronic dialysis. Conclusions— Only one fifth of the sudden cardiac arrest cases in the community were eligible for a primary prevention ICD before the event, but among these, a small proportion (13%) were actually implanted. Although older age and comorbidity may explain nondeployment in a subgroup of these cases, other determinants such as socioeconomic factors, health insurance, patient preference, and clinical practice patterns warrant further detailed investigation.

Frequency and Determinants of ICD Deployment among Primary Prevention Candidates with Subsequent Sudden Cardiac Arrest in the Community

Background— The prevalence rates and influencing factors for deployment of primary prevention implantable cardioverter defibrillators (ICDs) among subjects who eventually experience sudden cardiac arrest in the general population have not been evaluated. Methods and Results— Cases of adult sudden cardiac arrest with echocardiographic evaluation before the event were identified from the ongoing Oregon Sudden Unexpected Death Study (population approximately 1 million). Eligibility for primary ICD implantation was determined from medical records based on established guidelines. The frequency of prior primary ICD implantation in eligible subjects was evaluated, and ICD nonrecipients were characterized. Of 2093 cases (2003–2012), 448 had appropriate pre– sudden cardiac arrest left ventricular ejection fraction information available. Of these, 92 (20.5%) were eligible for primary ICD implantation, 304 (67.9%) were ineligible because of left ventricular ejection fraction >35%, and the remainder (52, 11.6%) had left ventricular ejection fraction ⩽35% but were ineligible on the basis of clinical guideline criteria. Among eligible subjects, only 12 (13.0%; 95% confidence interval, 6.1%–19.9%) received a primary ICD. Compared with recipients, primary ICD nonrecipients were older (age at ejection fraction assessment, 67.1±13.6 versus 58.5±14.8 years, P=0.05), with 20% aged ≥80 years (versus 0% among recipients, P=0.11). Additionally, a subgroup (26%) had either a clinical history of dementia or were undergoing chronic dialysis. Conclusions— Only one fifth of the sudden cardiac arrest cases in the community were eligible for a primary prevention ICD before the event, but among these, a small proportion (13%) were actually implanted. Although older age and comorbidity may explain nondeployment in a subgroup of these cases, other determinants such as socioeconomic factors, health insurance, patient preference, and clinical practice patterns warrant further detailed investigation.

The association between atrial fibrillation and sudden cardiac death: the relevance of heart failure.

OBJECTIVES The purpose of this study was to evaluate the role of congestive heart failure (CHF) in the association between atrial fibrillation (AF) and sudden cardiac death (SCD). BACKGROUND Recent studies have reported the possibility of an independent association between AF and SCD. We hypothesized that a history of CHF is a significant confounder of this association. METHODS In a prospective case-control analysis from the community (The Oregon-SUDS [Sudden Unexpected Death Study], 2002 to 2012), SCD cases (n = 652) with clinical records available (including electrocardiography and/or echocardiography) were compared with age- and sex-matched control patients with coronary artery disease. The association between AF and SCD was analyzed using multivariable logistic regression and propensity score matching. RESULTS Cases (age 67.3 ± 11.7 years, 65% male) were more likely than control patients (age 67.2 ± 11.4 years, 65% male) to have a history of AF (p = 0.0001), myocardial infarction (p = 0.007), CHF (p < 0.0001), stroke (p < 0.0001), and diabetes (p < 0.0001). In multivariate analysis without considering CHF, AF was a significant predictor of SCD (odds ratio [OR]: 1.6; 95% confidence interval [CI]: 1.2 to 2.0; p = 0.002). However, in a model that included CHF, the AF-SCD association was no longer significant (OR: 1.1; 95% CI: 0.8 to 1.5; p = 0.45), whereas CHF was a significant predictor of SCD (OR: 3.1; 95% CI: 2.4 to 4.1; p < 0.0001). Results on the basis of propensity score matching were consistent. CONCLUSIONS Our findings suggest that a history of CHF, including both systolic and diastolic symptomatic dysfunction, may partially explain the AF-SCD association.

Relationship Between Seizure Episode and Sudden Cardiac Arrest in Patients With Epilepsy A Community-Based Study

Background— Among patients with epilepsy, sudden cardiac arrest (SCA) is a major cause of death. It is commonly thought that SCA in epilepsy occurs after a seizure, though the strength of evidence supporting this is limited. We sought to evaluate the relationship between seizures and SCA in patients with epilepsy. Methods and Results— From the ongoing Oregon Sudden Unexpected Death Study, cases of SCA identified using prospective, multisource ascertainment (Portland metropolitan area, Oregon; population ≈1 million; February 1, 2002, to March 1, 2012) were evaluated for history of epilepsy. In the subset with witnessed SCA, clinical presentations were analyzed for evidence of seizure activity immediately before the event as well as lifetime clinical history, including nature of seizures before SCA. Only 34% of patients with history of epilepsy and a witnessed arrest had evidence of seizure activity before the arrest. Rates of survival to hospital discharge after attempted resuscitation were 2.7% in patients with history of epilepsy versus 11.9% for patients without epilepsy (P=0.014). Patients with epilepsy had a significantly lower rate of presentation with ventricular tachycardia/ventricular fibrillation as opposed to pulseless electrical activity/asystole (epilepsy, 26%; no epilepsy, 44%; P=0.002), despite nearly identical response times. Conclusions— In the majority (66%) of epilepsy patients, there was no relationship between seizure and SCA, implying that SCA in epilepsy patients often may not involve seizure as a trigger. The significantly worse rate of survival from SCA in epilepsy patients warrants urgent investigation.

Electrocardiographic versus echocardiographic left ventricular hypertrophy and sudden cardiac arrest in the community.

BACKGROUND Left ventricular hypertrophy (LVH) is associated with increased risk of sudden cardiac arrest (SCA). Whether LVH diagnosed by 12-lead ECG vs echocardiogram conveys identical or distinct risk information has not been previously evaluated. OBJECTIVE The purpose of this study was to compare the association between ECG vs echocardiographic LVH and SCA in the community. METHODS In a large, prospective population-based study (The Oregon Sudden Unexpected Death Study; population approximately 1 million), cases of SCA were compared to controls recruited from the same geographical area. The association between LVH and SCA was evaluated, specifically comparing LVH diagnosed by ECG vs echocardiogram. RESULTS Cases (n = 132, age 66.9 ± 13.5 years, 58.3% male) compared to controls (n = 211; age 66.2 ± 12 years, 59.2% male) were more likely to have both ECG LVH (12.1% vs 5.7%, P = .03) and echocardiographic LVH (35.0% vs 15.5%, P <.001). However, there was poor agreement between the tests (kappa statistic = 0.128). A large subgroup of patients with ECG LVH (57.1%) did not have echocardiographic LVH; conversely, 83.6% of patients with echocardiographic LVH did not have ECG LVH. In multivariate analysis, ECG LVH was significantly associated with SCA (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.1-6.0, P = .04). When echocardiographic LVH was added to the model, this association was only mildly attenuated (OR 2.4, 95% CI 1.0-6.0, P= .05), and echocardiographic LVH was also independently associated with SCA (OR 2.7, 95% CI 1.5-4.9, P = .001). CONCLUSION ECG and echocardiographic LVH may convey distinct risk information in patients with SCA, reflecting electrical vs anatomic remodeling. These findings have potential implications for SCA mechanisms and risk stratification.

A common missense variant in the neuregulin 1 gene is associated with both schizophrenia and sudden cardiac death

BACKGROUND Both schizophrenia and epilepsy have been linked to increased risk of sudden cardiac death (SCD). We hypothesized that DNA variants within genes previously associated with schizophrenia and epilepsy may contribute to an increased risk of SCD. OBJECTIVE To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy. METHODS From the ongoing Oregon Sudden Unexpected Death Study, comparisons were performed among 340 SCD cases presenting with ventricular fibrillation and 342 controls. We tested for the association between 17 single-nucleotide polymorphisms (SNPs) mapped to 14 loci previously implicated in schizophrenia and epilepsy by using logistic regression and assuming additive, dominant, and recessive genetic models. RESULTS The minor allele of the nonsynonymous SNP rs10503929 within the neuregulin 1 gene was associated with SCD under all 3 investigated models, with the strongest association for the recessive genetic model (recessive P = 4.01 × 10(-5), odds ratio [OR] 4.04; additive P = 2.84 × 10(-7), OR 1.9; and dominant P = 9.01 × 10(-6), OR 2.06). To validate our findings, we further explored the association of this variant in the Harvard Cohort SCD study. The SNP rs10503929 was associated with an increased risk of SCD under the recessive genetic model (P = .0005, OR 2.7). This missense variation causes a methionine to threonine change and functional effects are currently unknown. CONCLUSIONS The observed association between a schizophrenia-related neuregulin 1 gene variant and SCD may represent the first evidence of coexisting genetic susceptibility between 2 conditions that have an established clinical overlap. Further investigation is warranted to explore the molecular mechanisms of this variant in the pathogenesis of SCD.

Left Ventricular Diameter and Risk Stratification for Sudden Cardiac Death

Background Left ventricular (LV) diameter is routinely measured on the echocardiogram but has not been jointly evaluated with the ejection fraction (EF) for risk stratification of sudden cardiac death (SCD). Methods and Results From a large ongoing community‐based study of SCD (The Oregon Sudden Unexpected Death Study; population ≈1 million), SCD cases were compared with geographic controls. LVEF and LV diameter, measured using the LV internal dimension in diastole (categorized as normal, mild, moderate, or severe dilatation using American Society of Echocardiography definitions) were assessed from echocardiograms prior but unrelated to the SCD event. Cases (n=418; 69.5±13.8 years), compared with controls (n=329; 67.7±11.9 years), more commonly had severe LV dysfunction (EF ≤35%; 30.5% versus 18.8%; P<0.01) and larger LV diameter (52.2±10.5 mm versus 49.7±7.9 mm; P<0.01). Moderate or severe LV dilatation (16.3% versus 8.2%; P=0.001) and severe LV dilatation (8.1% versus 2.1%; P<0.001) were significantly more frequent in cases. In multivariable analysis, severe LV dilatation was an independent predictor of SCD (odds ratio 2.5 [95% CI 1.03 to 5.9]; P=0.04). In addition, subjects with both EF ≤35% and severe LV dilatation had higher odds for SCD compared with those with low EF only (odds ratio 3.8 [95% CI 1.5 to 10.2] for both versus 1.7 [95% CI 1.2 to 2.5] for low EF only), suggesting that severe LV dilatation additively increased SCD risk. Conclusion LV diameter may contribute to risk stratification for SCD independent of the LVEF. This readily available echocardiographic measure warrants further prospective evaluation.

Novel loci associated with increased risk of sudden cardiac death in the context of coronary artery disease.

Background Recent genome-wide association studies (GWAS) have identified novel loci associated with sudden cardiac death (SCD). Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD). Methods and Findings Using the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD) from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC). Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10−12, OR = 1.60) and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10−8, OR = 2.41). Conclusions Our findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.

Antipsychotic drugs are associated with pulseless electrical activity: The Oregon Sudden Unexpected Death Study

BACKGROUND There has been a paradigm shift in the manifestation of sudden cardiac arrest (SCA), with steadily decreasing rates of ventricular fibrillation/tachycardia (VF/VT) and a significant increase in the proportion of pulseless electrical activity (PEA) and asystole. OBJECTIVE Since PEA is marked by failure of myocardial contractility, we evaluated the potential role of drugs that affect cardiac contractility in the pathophysiology of human PEA. METHODS Subjects with out-of-hospital SCA (aged≥18 years) who underwent attempted resuscitation were evaluated in the ongoing Oregon Sudden Unexpected Death Study (2002-2009). Specific classes of medications with either negative or positive cardiac inotropic effects were evaluated for association with occurrence of PEA vs VF/VT by using Pearson χ(2) tests and logistic regression. RESULTS PEA cases (n = 309) were older than VF/VT cases (n = 509; 68±14 years vs 64±15 years; P<.0001) and were more likely to be women (39% vs 25%; P<.0001). In a logistic regression model adjusting for age, sex, comorbidities, disease burden, and resuscitation variables, antipsychotic drugs (odds ratio 2.40; 95% confidence interval 1.26-4.53) were significant predictors of PEA vs VF/VT. Conversely, use of digoxin was associated with the occurrence of VF/VT (P<.0001). CONCLUSIONS When drugs modifying myocardial contractility were evaluated in a comprehensive analysis of patients who suffered SCA, use of antipsychotic agents was a significant and independent predictor of manifestation with PEA.

Ischemic Heart Disease Diagnosed Before Sudden Cardiac Arrest Is Independently Associated With Improved Survival

Background Sudden cardiac arrest (SCA) is a significant public health problem, and rates of survival after resuscitation remain well below 10%. While several resuscitation‐related factors are consistently associated with survival from SCA, the impact of specific comorbid conditions has not been assessed. Methods and Results The Oregon Sudden Unexpected Study is an ongoing, multisource, community‐based study in Portland, Oregon. Patients with SCA who underwent attempted resuscitation between 2002 and 2012 were included in this analysis if there were both arrest and prearrest medical records available. Information from the emergency medical services system, medical examiner, public health division, hospitals, and clinics was used to adjudicate SCA, evaluate comorbidities, and identify medical treatments. Univariate and multivariate analyses were performed to investigate the influence of prearrest comorbidities on survival to hospital discharge. Among 1466 included patients, established resuscitation‐related predictors (Utstein factors) were associated with survival, consistent with prior reports. When a panel of prearrest comorbidities was evaluated along with Utstein factors, recognized coronary artery disease was significantly associated and predicted higher odds of survival (unadjusted odds ratio 1.5, P<0.001; adjusted odds ratio 1.5, P=0.02). In multivariable logistic models, prearrest coronary artery disease modified the survival effects of bystander cardiopulmonary resuscitation, but did not modify other Utstein factors. Conclusions An established diagnosis of coronary artery disease was associated with 50% higher odds of survival from resuscitated SCA after adjustment for all arrest‐related predictors. These findings raise novel potential mechanistic insights into survival after SCA, while highlighting the importance of early recognition and treatment of coronary artery disease.