Cases Of Sudden Cardiac Death Research Articles

Anomalous origin of the right coronary artery evaluated with multidetector computed tomography and its clinical relevance

BackgroundAnomalous origin of the right coronary artery (AORCA) is a rare congenital anomaly that may cause myocardial ischemia and sudden death. MethodsWe reviewed the clinicopathological records of three cases of AORCA, and compared these with two cases of sudden cardiac death with AORCA revealed by autopsy. ResultsWe report three juvenile cases with an AORCA originating above the commissural junction between the left and right aortic sinuses, with interarterial and intramural compression. They presented with exertional symptoms and were diagnosed with an AORCA by multidetector computed tomography (MDCT), which successfully delineated the spatial resolution of the anomalous origin and course of the right coronary artery (RCA), in the operating room. All three underwent successful surgical unroofing of the RCA. Two cases of sudden cardiac death with AORCA revealed by autopsy showed a slit-like orifice, acute-angled take-off, and long intramural course of the RCA, resembling the RCAs of three juvenile cases. ConclusionsIt is crucial to be alert to the presentation of exertional symptoms, as sudden death may be the first manifestation of an anomalous coronary artery, such as those observed in these three cases. MDCT provided an excellent definition and spatial resolution of the unusual origin and intramural course of the RCA, facilitating the correct surgical remedy and resulting in a good outcome for the patients.

Forensic Pathological Study of 1656 Cases of Sudden Cardiac Death in Southern China.

Sudden cardiac death (SCD) is progressively threatening the lives of young people throughout the world. We conducted a retrospective study of SCD cases identified among sudden death cases based on comprehensive autopsies and pathological examinations in the Center for Medicolegal Expertise of Sun Yat-Sen University to investigate the exact etiological distribution and epidemiological features of SCD. One thousand six hundred fifty-six cases were identified, and SCD accounted for 43.0% of these sudden death cases. The mean age of the SCD cases—where the data of definite ages were accessible—was 38.2 years, and the highest incidence occurred among the 31- to 40-year-old cases (25.6%). The male-to-female ratio among SCD cases was 4.3:1, and this ratio peaked in the 41- to 50-year-old group (7.7:1). The places of death were confirmed in 1411 cases, and predominantly in hospitals (46.3%) and at home (33.8%). SCD occurred throughout the year with a marginally increase in April and May. The major causes of SCD were coronary atherosclerotic disease (CAD, 41.6%), unexplained sudden death (15.1%), and myocarditis (11.8%). Our data indicated that in the age group of younger affected persons (below 35 years old), sudden unexplained death and myocarditis were much more prevalent than CAD. According to anatomical examinations of the CAD-related SCD cases, the proportion of cases with coronary artery stenosis exceeding 75% (grade IV) was 67.2%. Moreover, the percentages of higher grades of coronary atherosclerosis increased with age. Among all branches of the coronary arteries, the left anterior descending branch was the most prone to atherosclerosis; atherosclerosis was present in this branch in 95.4% of the cases with atherosclerosis. Additionally, lesions of multiple branches of the coronary artery were associated with ageing. This is the first study to report the causes of death and basic epidemiological data related to SCD in Southern China.

The most common cause of sudden cardiac death in athletes

The positive impact of exercise on cardiovascular health is well known. Athletes, who are constantly physically active, are considered to be the healthiest members of our society. That is why their sudden death, during the training or competition, attracts the attention of the general public. Rarely, tragic events of sudden cardiac death (SCD) are the reason for questioning if by many positive there are also negative impact of physical exercise. The first case of SCD is recorded as far back as the year 490 BC, when the Greek soldier Pheidippides died after he conveyed news of the great victory of the Greeks over the Persians. Risk of SCD is recognized in the middle of the twentieth century. In our region, discussion about this issue began after the World Basketball Championship, which was held in Ljubljana in 1970, because of the sudden death of the national team member Trajko Rajkovic. One of the important goals of modern sports medicine is to reduce the risk of SCD in athletes to 'inevitable rarity'. Definition of SCD is considered to be any unexpected death due to sudden cardiac arrest. Pedo (Pedoe) has divided all causes of SCD in the sport into three categories: Commotio cordis (agitation of the heart), which results from blunt impact to the athletes chest with consequent fatal disorder of heart rhythm; SCD of athletes under the age of 35 because of structural, congenital and inflammatory heart disease, which includes hypertrophic cardiomyopathy as the most important cause of sudden cardiac death, congenital anomalies of the coronary arteries, arrhythmogenic right ventricular cardiomyopathy, myocarditis and other; SCD of athletes older than 35 years which is most common due coronary artery disease - atherosclerosis (the dominant risk in the marathon and half-marathon). .

Cardiomyopathies as a Cause of Sudden Cardiac Death (SCD) in Egypt: Recognition and Preventive Strategies Needed

This study aimed at evaluating the epidemiological characteristics and pathological features of different types of cardiomyopathies in Egypt, highlighting the role of the forensic pathologist in identifying cases of cardiomyopathies and initiating for their families a possible genetic study aiming at prevention of sudden death. All cases with sudden cardiac death (SCD) due to cardiomyopathies during the period from the beginning of January 2010 until the end of December 2014 (5 years) were included in this study. All hearts underwent detailed gross and histological examination. Circumstances of death, medical history, and post-mortem pathological findings were thoroughly  investigated. Out of 535 cases of sudden cardiac death, there were 22 cases (4.1%) diagnosed as having cardiomyopathies; sudden death was their first presentation. Eighteen cases (81.8%) were male, with the 4th decade (11 cases, 50%) being the most affected age; severe physical activity and exertion were evident in death circumstances of 14 cases (63.6%); pathological evaluation revealed that hypertrophic cardiomyopathy was the most frequent type, being diagnosed in 10 cases (45%). Cardiomyopathies are an infrequent cause of sudden cardiac death. Most deaths are in children and adults, so cases are of high social impact that demands multidisciplinary research and resources. In all cases of SCD, forensic autopsy should be done. Forensic study is the key to identifying an affected family and the starting point regarding assessing them.

Congenital long QT syndrome in children

Long QT syndrome (LQTS) is a cardiac repolarization disorder characterized by prolonged QT interval on the electrocardiogram (ECG) and increased propensity to ventricular tachyarrhythmias and cardiac events. LQTS might be acquired or congenital, which presents a group of channelopathies that occur due to mutation in one of 15 so far identified genes. The most frequent types of congenital LTQS are LQT1, LQT2 and LQT3. Prolonged or delayed repolarization leads to the increase of action potential duration which predisposes early afterdepolarization, as well as the amplification of transmural dispersion of repolarization, both contributing to the development of Torsades de Pointes ventricular tachycardia. Clinical manifestations of LQTS are palpitations, syncope, aborted cardiac arrest or sudden cardiac death, but it can also be asymptomatic. Trigger factors for symptoms are specific for certain genotype. LQTS examination includes thorough clinical and family history focused on distinctive data (repeated syncopes, cases of sudden cardiac death in the family, hereditary arrhythmias), resting ECG, exercise stress testing and genetic analysis, with additional methods (serial ECG records, 24h ECG Holter, epinephrine test). Clinical LQTS diagnosis is based on Schwartz's scoring system, while the criteria for final diagnosis of LQTS depend on Schwartz's score, QT interval duration, presence of pathogenic mutation and clinical symptoms. Treatment approach begins with lifestyle modifications and β-blockers therapy, while other options include implantable cardioverter- defibrillator, permanent pacemaker or surgical sympathectomy. Sudden cardiac death is the reason of 90% of sudden deaths in young athletes, while LQTS is one of its causes. Recommendations for physical activities in children with congenital LQTS arise from the ones for adults and they presume very strict limitations. Further researches are expected to advance the understanding of genotype-phenotype correlation of congenital LQTS and enable eventual genetically-guided personalized treatment, novel insight into rare LQTS types, as well as more precise recommendations for physical activity of LQTS children.

0491: Sudden cardiac death: clinical perspectives from the University of Maiduguri Teaching Hospital, Nigeria

Despite tremendous advances in the management of cardiovascular diseases and cardiac arrest, there is paucity of information regarding sudden cardiac death in sub-Saharan Africa. We present a two-year review of sudden cardiac death cases among patients managed at a Nigerian tertiary hospital. Patients admitted from January 2012 to December 2013 were prospectively followed-up and cases of sudden cardiac death identified. Diagnosis was based on records of events preceding death, direct interview of attending physician/nurses, and family members/eye witnesses for out-of-hospital sudden cardiac death. Causes of death were obtained from the death certificates for cases of in-hospital events. Three hundred and eighty eight (M:F=1:1.3) patients with a mean age of 42.22±19.30 years were admitted into the cardiac unit during the period, out of whom 56 (14.4%) died. Twenty three (41.1%) were classified as sudden cardiac death. The predominant etiology was ischemic cardiomyopathy (39.1%), followed by peripartum cardiomyopathy (21.7%) and dilated cardiomyopathy (17.4%). Rheumatic heart disease was diagnosed in 17.4%, while 4.3% had pulmonary hypertension. Nineteen (82.6%) of the subjects had congestive cardiac failure. Hypokalemia and hypocalcaemia were recorded in 2 (8.7%) patients who developed prolongation of the QT interval following commencement of diuretics. Chest-compression- only cardiopulmonary resuscitation was attempted in 12 (52.1%) with a success rate of 8.3%. Sudden cardiac death is common among our patients admitted with cardiovascular diseases. The most common etiology is ischemic cardiomyopathy, followed by peripartum cardiomyopathy. Most of the victims were young, and there were no optimum resuscitative measures.

Sudden Cardiac Death due to Subaortic Left Ventricular Aneurysm

Subaortic left ventricular aneurysm is a rare, mostly congenital condition, and occurs as a result of a defect in the alveolar fibrosa between the mitral and aortic annuli. Clinically, most subaortic left ventricular aneurysms are asymptomatic, but some of them cause arrhythmia, chest pain, and even sudden cardiac death. We report an autopsy case of sudden cardiac death due to subaortic left ventricular aneurysm in a 38-year-old male sailor.

Genetic analysis of Iranian family with hereditary cardiac arrhythmias by next generation sequencing.

Background:Cardiac arrhythmias are responsible for several cases of syncope and sudden cardiac death annually worldwide. Due to overlapping clinical symptoms in some cardiac arrhythmias genetic studies would help to confirm the primary clinical diagnosis made on the basis of solely clinical findings. In addition clinical management of the patient, family screening and provide appropriate counseling and risk assessment for the family members are other advantages of genetic study.Materials and Methods:Totally nine patients from a family included in this study. The primary diagnosis on the basis of clinical findings was second-degree atrioventricular (AV) block for this family. Mutation in SCN5A gene is frequently reported for second-degree AV block and hence the gene was analyzed using whole gene sequencing but no mutation was detected. Subsequently, the samples were subjected to customized Ampliseq 77 gene panel using next generation sequencing to detect the underlying molecular defects.Results:We found c. 5570T>A missense mutation in ANK2 gene for this family. Based on the Online Mendelian Inheritance in Man, ANK2 gene and the mutation detected correspond to long QT syndrome type 4.Conclusion:This mutation, although already known in other populations, but is reported for the first time in Iranian patients with cardiac arrhythmias. As the case with this family, genetic analysis of patients with cardiac arrhythmias would be helpful in reassessment of clinical diagnosis and therefore would help for patients’ management and in some cases re-evaluation of ongoing treatment may be needed.

A Large Retrospective Cohort of Patients Receiving Intravenous Olanzapine in the Emergency Department.

Olanzapine is an atypical antipsychotic with similar pharmacologic properties to droperidol. Due to the current droperidol shortage, the authors' clinical practice has been to substitute olanzapine for droperidol in many situations. At this time, olanzapine is U.S. Food and Drug Administration approved for oral and intramuscular (IM) use only, but due to its increased utility, intravenous (IV) olanzapine was recently approved for use in the study emergency department (ED). The authors sought to review the use and safety of IV olanzapine in the ED patient population. A retrospective review of consecutive patients receiving IV olanzapine between January 1, 2014, and July 1, 2014, was conducted. Data were collected via an electronic medical record review. The study was deemed exempt from informed consent by our institutional review board. A total of 713 patients received IV olanzapine during the study period. The median age was 38 years (range= 18 to 85 years), and 313 patients were male (43.9%). Primary indications for IV olanzapine administration included acute agitation (n=245, 34.4%), abdominal pain (n=165, 23.1%), headache (n=121, 17.0%), nausea and vomiting (n=107, 15.0%), pain (other; n=60, 8.4%), and unknown (n=15, 2.1%). IV dosing varied: 1.25 mg (n=20, 2.8%), 2.5 mg (n=185, 25.9%), 5 mg (n=507, 71.1%), and 10 mg (n=1, 0.1%). Forty-nine patients required a second dose of olanzapine (22 IV, 26 IM, one oral). The maximum total dose of olanzapine was 20 mg. Ninety-eight patients required a total of 146 doses of additional sedatives during their ED course. Other sedative medications included ketamine (n=17, 2.4%), haloperidol (n=48, 6.7%), and benzodiazepines (n=81, 11.4%). Hypoxia was noted in 74 patients (10.4%). Major respiratory complications, including airway stimulation or repositioning maneuvers and intubation, occurred in 15 patients (2.1%). After consensus review, one intubation was classified as "likely related" to olanzapine administration, and two were classified as "possibly related" to olanzapine. Akathisia likely occurred in four patients (0.6%), and no allergic reactions were identified. Electrocardiograms (ECGs) were performed in 322 patients. A total of 251 patients had an ECG performed before olanzapine administration (median QTc= 404 ms), and 88 patients had an ECG performed after olanzapine administration (median QTc= 415 ms). Acute alcohol and drug intoxication was common, 118 (16.5%) patients were positive for ethanol, and seven of 23 drug screens were positive for sympathomimetics. Thirty-four of 284 admissions (4.5%) were to intermediate or intensive care unit beds. No patients died while in the ED and no cases of sudden cardiac death were noted. In this large retrospective review, IV olanzapine appears to be a safe in the management of a variety of ED indications. Hypoxia was common, but serious airway compromise was rare.

A fast and cost-effective molecular diagnostic tool for genetic diseases involved in sudden cardiac death

BackgroundCardiomyopathies and arrhythmia syndromes are common genetic cardiac diseases that account for a significant number of sudden cardiac death (SCD) cases. MethodsNGS workflow based on a panel of 95 genes was developed on Illumina NextSeq500™ sequencer for sequencing prevalent SCD-causing genes. A cohort of 90 patients (56 genotype-positive, 27 genotype-negative and 7 new cases) was screened to evaluate this strategy in terms of sensitivity, specificity, practicability and cost. In silico analysis were performed using a pipeline based on NextGENe® software and a personalized Sophia Genetics pipeline. ResultsUsing our panel custom, 100% of targeted sequences were efficiently covered and all previously identified genetic variants were readily detected. Applied to 27 genotype-negative patients, this molecular strategy allowed the identification of pathogenic or likely pathogenic variants into 12 cases. It confirmed the involvement of HCN4 mutations in the combined bradycardia–myocardial non-compaction phenotype, and also suggested, for the first time, the involvement of PKP2, usually associated with arrhythmogenic right ventricular dysplasia, in ventricular non-compaction. ConclusionThis NGS approach is a fast, cheap, sensitive and high-throughput mutation detection method that is ready to be deployed in clinical laboratories and would provide new insights on physiopathology of SCD, more particularly of cardiomyopathies and arrhythmia syndromes.

Occupation and risk of sudden death in a United States community: a case–control analysis

ObjectiveWork environment is said to influence cardiovascular risk. We assessed whether nature of occupation affects risk of sudden cardiac death (SCD) in the general population.MethodsIn the ongoing, prospective Oregon Sudden...

T-wave reversal in the augmented unipolar right arm electrocardiographic lead is associated with increased risk of sudden death.

Repolarization abnormalities are associated with ventricular arrhythmias, and published studies report that a reversal of T wave polarity (positive or flat T wave) in lead aVR may be linked to increased cardiovascular mortality. We evaluated whether a positive or flat T wave in aVR is a risk marker for sudden cardiac death (SCD). SCD cases from the Oregon Sudden Unexpected Death Study (catchment population ~1 million) were compared to geographic controls with coronary artery disease and no history of SCD. Archived electrocardiograms performed prior and unrelated to the SCD event were evaluated. SCD cases (n = 691, 67.6 ± 14.9 years, 69% male) were more likely than controls (n = 663, 66.2 ± 11.6 years, 67% male) to have diabetes (40 vs 32%; p < 0.01), left ventricular ejection fraction (LVEF) ≤35% (27 vs 11 %; p < 0.01), prolonged QTc (≥450 ms; 54 vs 28%; p < 0.01) and positive (19 vs 13%; p < 0.01) or flat T wave (14 vs 7%; p < 0.01) in aVR. On multivariable analysis, a positive/flat T wave in aVR was independently associated with SCD (OR 1.9, 95% CI 1.3-2.8, p < 0.01). However, a positive T wave alone lost statistical significance in patients with LVEF ≤ 35% and QTc ≥ 450 ms. In a subgroup analysis among patients with normal LVEF, QTc, and no diabetes, a positive T wave in aVR (but not a flat T wave) remained associated with SCD (OR 2.8, 95% CI 1.2-6.1, p < 0.01). A positive or flat T wave in lead aVR was associated with SCD in subsets of patients. This simple ECG marker in this often-ignored lead may contribute to enhancement of SCD risk stratification, and warrants further evaluation.

Abstract 16587: Tpeak-to-tend Interval Corrected for Heart Rate: A More Precise Measure of Increased Sudden Death Risk?

Introduction: The Tpeak-to-Tend interval (Tpe) on the 12-lead electrocardiogram (ECG) predicts increased risk of sudden cardiac death (SCD). There has been some controversy on whether Tpe would be more useful if corrected for heart rate (Tpec). Hypothesis: We hypothesize that correcting the Tpe for heart rate will improve its predictive value for SCD. Methods: Cases of sudden cardiac death (SCD) (n=725; mean age 67.4 years; 95% CI 52.7 to 82.1 years; 67.7% males) from a large ongoing population based study of SCD in the Northwest US (population approx. one million) with an ECG available prior and unrelated to the SCD event were analyzed. Comparisons were made to control subjects with and without coronary artery disease (n=898; mean age 66.9 years; 95% CI 55.5 to 78.3 years; 63.7% males). The Tpe interval was corrected for heart rate using the Bazett (TpecBa) and Fridericia (TpecFd) formulae and the predictive value of Tpec for SCD was compared in logistic regression models. Results: The area-under-curve (AUC) for predicting SCD improved with both correction formulae, TpecBa at 0.628 and TpecFd at 0.606 compared to an uncorrected Tpe at 0.544 (see Figure). The optimal cut-off value for TpecBa and TpecFd was determined using the receiver-operating characteristics (ROC) curve. A TpecBa of more than 94ms and TpecFd of more than 88ms was predictive of SCD independent of age, gender, comorbidities (hypertension, diabetes mellitus, previous myocardial infarction), electrocardiographic left ventricular hypertrophy (LVH), severe left ventricular dysfunction (LVEF ≤35%), prolonged QTc (&gt;450ms) and prolonged QRS duration (&gt;120ms) with an odds ratio of 1.88 (95% CI, 1.36 to 2.60; p &lt;0.0001) and 1.90 (95% CI, 1.38 to 2.62; p &lt;0.0001) respectively. Conclusion: Correcting the Tpeak-to-Tend interval for heart rate, using either the Bazett and Fridericia formulae, improved the independent predictive value of this marker for assessment of SCD risk in the community.

Abstract 12142: Electrolyte Abnormalities and Risk of Sudden Death in the General Population

Introduction: Electrolyte abnormalities are a substrate for arrhythmogenesis and could be the trigger for sudden cardiac death (SCD). We sought to determine the potential role of electrolyte abnormalities, irrespective of kidney function, in the occurrence of sudden death in the community. Hypothesis: Electrolyte abnormalities increases the risk for SCD in the community regardless of kidney function. Methods: SCD cases and controls from a large population based study in Northwest US (approx 1 million population, 2002-2014) were included if age ≥18 yrs with creatinine clearance (CrCl) and serum electrolytes available for analysis. For cases, CrCl and electrolytes were required to be measured within 90 days of the SCD event. Demographics and lab results were analyzed using student t-tests and chi-square tests. Multiple logistic regression was used to estimate independent association of risk factors with SCD. Results: We evaluated 483 SCD cases (65.8% male) and 886 controls (66.4% male). Cases were more likely to be older (68.8±14.3 vs 67.2±11.3, p=0.03), of black race (9.8 vs 3.2%, p&lt;0.0001) and with worse CrCl (53.4±31.3 vs. 64.0±24.9 ml/min, p&lt;0.0001). Overall, cases had lower levels of mean Na (137.3±4.2 vs 138.3±3.4 mEq/L, p&lt;0.0001), Ca (9.0±0.7 vs 9.2±0.5 mg/dl, p&lt;0.0001) and Mg (2.0±0.5 vs 2.1±0.4 mg/dl, p=0.007); and higher mean K (4.2±0.6 vs 4.1 ±0.5mEq/L, p=0.0008). Prevalence of hyponatremia (&lt;136mEq/L), hyperkalemia (&gt;5.2mEq/L), hypocalcemia (&lt;8.5 mg/dl) and hypomagnesemia (&lt;1.7 mg/dl) were also higher in cases (27.0 vs 16.2%, p&lt;0.0001; 6.1 vs 1.4%, p&lt;0.0001; 19.7 vs 7.9%, p&lt;0.0001 and 20.4 vs 8.3%, p&lt;0.0001, respectively). Adjusting for age, race and kidney function only hyperkalemia [OR 4.65 (95% CI 1.37-15.81), p=0.01], hypocalcemia [2.94 (1.68-5.13), p=0.0001] and hypomagnesemia [2.52 (1.36-4.66), p=0.003] remained significant, conferring a more than two to five-fold increase in SCD risk. Conclusions: Electrolyte abnormalities remain independently associated with increased risk of SCD in the community, even after adjusting for renal function.

Abstract 16416: Wide QRS-T Angle on the 12-lead ECG as a Predictor of Sudden Death Beyond the LV Ejection Fraction

Introduction: If we are to improve risk stratification for sudden cardiac death (SCD) we should extend beyond the LV ejection fraction (LVEF). The frontal QRS-T angle has been shown to predict risk of SCD but its value independent of LVEF has not been investigated. Hypothesis: We hypothesize that a wide frontal QRS-T angle predicts SCD independent of LVEF. Methods: Cases of adult sudden cardiac arrest with an available electrocardiogram before the event were identified from a large ongoing population based study of SCD in the Northwest US (population approx. one million). Subjects with a computable frontal QRS-T angle were included. A total of 686 SCD cases (mean age 67.4 years; 95% CI, 52.5 to 82.3 years; 68.2% males; 83.5% whites) met criteria, and were compared to 871 controls with and without coronary artery disease (mean age 66.8 years, 55.3 to 78.3 years; 67.7% males; 90.6% whites) from the same geographical region. Results: The mean frontal QRS-T angle was higher in SCD cases (73.9 degrees; 95% CI, 17.5 to 130.3 degrees, p&lt;0.0001) compared to controls (51.1 degrees; 95% CI 5.0 to 97.2 degrees). Using a cut-off of more than 90 degrees, the frontal QRS-T angle was predictive of SCD, and remained predictive, after adjusting for age, sex, left ventricular ejection fraction (LVEF), prolonged QTc, prolonged QRS duration and baseline comorbidities (OR 1.80; 95% CI, 1.27 to 2.55, p=0.001). On the receiver operating characteristic (ROC) curve, the QRS-T angle demonstrated an area-under-curve (AUC) value of 0.614. Compared to the lowest quartile of QRS-T angle, the highest quartile had nearly a triple increase in the risk of SCD (OR 2.71; 95% CI; 2.03 to 3.60; p&lt;0.0001). Conclusion: A wide QRS-T angle greater than 90 degrees is associated with increased risk of sudden cardiac death independent of left ventricular ejection fraction.

Abstract 18006: Functional Effects of a Missense Common Variant in Neuregulin-1 Associated With Low Ejection Fraction and Sudden Cardiac Death

Objective: To investigate the functional effects and genotype-phenotype correlation of a coding variant within the Neuregulin-1 gene (NRG1), which we previously identified from a community-based study of sudden cardiac death (SCD). Methods: The Missense variant Met286Thr within NRG1 was characterized by transfecting NRG1 wild type and mutant in HEK293 cells with a tag placed on the extracellular domain for assessment of membrane expression. To study genotype-phenotype correlations, we performed a case-case analysis comparing SCD carrier cases of the risk allele (n=384) vs. non SCD carrier cases (n=888). A total of 1,272 SCD cases of European descent were included in the study. Regression models adjusted for age and sex were tested to evaluate the correlation of the risk allele and clinical variables obtained ECGs and Echocardiograms of SCD cases. Results: We found that, unlike wild type NRG1, the Met286Thr variant did not traffic to the cell membrane (Figure), indicating defects in antegrade protein transport. We also found that in the subset of SCD cases with echocardiograms available (n=253), carriers of the risk allele were more likely to present with low ejection fraction (LVEF ≤35%) compared with the non-carrier cases (P=0.02, OR= 2.26 [1.14-4.5]. Other investigated risk factors such as QT prolongation, QRS duration, heart rate, left ventricular hypertrophy and coronary artery disease were not significantly different (P&gt;0.05). Conclusions: We have identified a novel variant in the transmembrane domain of NRG1, which results in defective antegrade transport and is associated with SCD and low ejection fraction. These findings support a role for Met286Thr in trafficking pathways leading to both functional compromise and ventricular arrhythmogenesis.

Abstract 14767: Delayed R-Wave Peak Time on the 12-lead ECG is Associated With Increased Risk of Sudden Death

Background: Left ventricular hypertrophy (LVH) is associated with sudden cardiac death (SCD), and there is emerging evidence for unique electrical vs. ventricular myocardial mass related mechanisms. We investigated the correlation between delayed R-Wave Peak Time (DRWPT), or intrinsicoid deflection, in the lateral precordial leads and LV mass in patients who suffered SCD. Methods: In an ongoing prospective, population based study of SCD in a Northwestern US metro region (approx. 1 million population), SCD cases were compared to geographic controls with coronary artery disease (CAD) and no SCD. Archived ECGs (closest and unrelated to SCD event for cases) were evaluated for the presence of DRWPT defined as an intrinsicoid deflection of ≥ 0.05 seconds in V5 or V6. LV mass from echocardiograms and detailed clinical information was obtained for all subjects. Patients with wide QRS (&gt;100 ms) were excluded. Results: Cases (n=146, Age: 67.7 ± 14.6 yrs, Male: 55.5%) as compared to controls (n=227, Age: 66.3 ± 11.5 yrs, Male: 59.0%) were significantly more likely to have DRWPT on ECG (17.1% vs 9.2%, p=0.02). DRPWT correlated poorly with echo determined LVH (Kappa statistic 0.03) with no significant difference in mean adjusted LV Mass between those with DRWPT versus those without (104.3 ± 34.9 vs. 100.9 ± 33.5 g/m 2 , p =0.55). Multivariable analysis adjusting for diabetes, renal failure, LV dysfunction and angiotensin receptor blocker use demonstrated a significant association of DRWPT with SCD risk (OR: 2.2, 95% CI: 1.1-4.3, p=0.020). With the addition of echo LVH to the model, this risk was not significantly attenuated (OR: 2.6, 95% CI: 1.3-5.4, p=0.008). Conclusion: DRWPT was independently associated with SCD risk, and not correlated with increased LV mass. These findings suggest that abnormalities of myocardial conduction velocity should be explored as mechanisms of electrical risk in LVH and SCD.

Abstract 15959: N-6 Polyunsaturated Fatty Acids in RBC Membranes and Estimated Desaturase Activities and Risk of Sudden Cardiac Death

Introduction: Fatty acids in cell membranes modify the propensity for ventricular arrhythmias. In experimental studies, linoleic acid (LA;18:2n-6) has anti-arrhythmic effects, but its association with sudden cardiac death (SCD) risk has been inconsistent. Further, little is known about circulating levels of other n-6 polyunsaturated fatty acids(PUFA) and SCD risk. Methods: In a case-control analysis nested within 6 prospective cohort studies, we measured RBC levels of LA, γ-linolenic acid (GLA;18:3n-6), dihomo- γ-linoleic acid (DGLA;20:3n-6) and arachiodonic acid (AA; 20:4n-6) in 442 cases of SCD and 852 controls matched on age, sex, race, antecedent CVD, smoking status and fasting status using risk-set sampling. We estimated the activity of 2 key enzymes in n-6 PUFA metabolism, Δ-6desaurase (D6D), which converts LA to GLA, and Δ-5desaturase (D5D), which converts DGLA to AA, using their product to precursor ratios. The multivariable relative risks (RR) were estimated by conditional logistic regression adjusted for other CVD risk factors and n-3 PUFAs in each cohort separately and then combined with random effects meta-analyses. Results: DGLA was positivity linearly associated with risk of SCD while higher levels of AA were associated with lower risk of SCD. Additionally, higher D5D activity (DGLA/AA), representing greater metabolism of DGLA to AA, was inversely associated with risk (Table). Although LA demonstrated a U-shaped relation, with a nadir in SCD risk in quintile 3, the quadratic relation was not significant (p, quadratic trend = 0.95). Neither GLA nor D6D activity (GLA/LA) were associated with risk of SCD (Table). Conclusions: Higher RBC DGLA and lower RBC AA were associated with greater risk of SCD and greater estimated activity of the D5D was associated with lower risk. These n-6 PUFAs are not determined by n-6 PUFA intake and thus research on the regulation of DGLA and AA in cell membranes is warranted and may identify novel targets for SCD prevention.

Abstract 15888: N-3 Polyunsaturated Fatty Acids in Erythrocyte Membranes and Risk of Sudden Cardiac Death in Primary and Secondary Prevention

Introduction: Long-chain n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-arrhythmic effects in experimental studies and blood levels of EPA + DHA, an objective marker of intake, have been associated with lower risk of sudden cardiac death (SCD) in healthy populations. However, data from observational studies and clinical trials of n-3 PUFAs in secondary prevention have been mixed. Methods: We conducted a nested, case-control study among individuals from 6 prospective cohort studies. RBC levels of α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), and DHA were measured in 442 cases of SCD and 852 controls matched on age, sex, race, smoking status, fasting status and prevalent and incident CVD using risk-set sampling. The Omega-3 Index was estimated as EPA + DHA. Multivariable conditional logistic regression was used to estimate the relative risk (RR) separately in each cohort. The RRs were combined using random effect meta-analyses and stratified by presence of absence of known CVD prior to SCD. Results: In this population, the mean age was 64 years, 51% were women and 41% had prior CVD. Higher EPA and DHA levels, as summarized by the Omega-3 Index, were associated with lower risk of SCD in the entire population (Table). Compared to the lowest quintile, the RR in the highest quintile of the Omega-3 Index was 0.40 (95%CI, 0.21-0.77; P, trend= 0.04). When stratified by history of prior CVD, this association was restricted to individuals without prior CVD (Table, P, trend = 0.03). Neither DPA nor ALA was associated with risk of SCD in those with or without CVD. Conclusions: In this prospective nested, case-control study, the inverse association between long-chain n-3 PUFAs and SCD was limited to individuals without prior CVD. These data suggest that the utility of n-3 PUFAs as markers of SCD and/or as preventative dietary supplements may be greater in a primary prevention population.

Electrocardiographic Markers and Left Ventricular Ejection Fraction Have Cumulative Effects on Risk of Sudden Cardiac Death

ObjectivesThis study assessed potential improvement in predicting risk of sudden cardiac death (SCD) by adding selected risk markers from the 12-lead electrocardiogram (ECG) to the measurement of left ventricular ejection fraction (LVEF). BackgroundNovel strategies to improve risk stratification for SCD are needed. Given the modest odds associated with most individual risk markers, combining multiple markers may be a useful approach. MethodsFrom the ongoing Oregon Sudden Unexpected Death Study, SCD cases with pre-event LVEF data available were compared with those of matched control subjects with coronary artery disease. Resting heart rate, QRS duration (QRSD), and JTc intervals were measured from archived ECGs prior to and unrelated to the SCD event. Independent odds of SCD for individual and combined ECG markers were calculated. ResultsSCD cases (n = 317; 67.9 ± 12.9 years of age) were more likely than controls (n = 317; 67.9 ± 12.8 years of age) to have LVEF ≤35% (26% vs. 11%, respectively). Mean heart rate, QRSD, and JTc were significantly higher in cases (all p < 0.0001). In adjusted analyses, higher heart rate (odds ratio [OR]: 2.6 [95% confidence interval [CI]: 1.8 to 3.7]), QRSD (OR: 1.5 [95% CI: 1.0 to 2.5]), and JTc (OR: 2.3 [95% CI: 1.6 to 3.4]) were independently associated with SCD. When ECG markers were combined, SCD odds progressively increased with 1 (OR: 3.4 [95% CI: 2.1 to 5.4]) and ≥2 elevated markers (OR: 6.3 [95% CI: 3.3 to 12.1]). Addition of ECG markers to an adjusted model with LVEF improved discrimination (C statistic improved from 0.642 to 0.724) and net reclassification (by 22.7%; p < 0.0001). ConclusionsCombining selected 12-lead ECG markers with LVEF improves SCD risk prediction and warrants further investigation in prospective studies.