Electrocardiographic deep learning for predicting post-procedural mortality: a model development and validation study.

BACKGROUND: Preoperative risk assessments used in clinical practice are insufficient in their ability to identify risk for postoperative mortality. Deep-learning analysis of electrocardiography can identify hidden risk markers that can help to prognosticate postoperative mortality. We aimed to develop a prognostic model that accurately predicts postoperative mortality in patients undergoing medical procedures and who had received preoperative electrocardiographic diagnostic testing. METHODS: In a derivation cohort of preoperative patients with available electrocardiograms (ECGs) from Cedars-Sinai Medical Center (Los Angeles, CA, USA) between Jan 1, 2015 and Dec 31, 2019, a deep-learning algorithm was developed to leverage waveform signals to discriminate postoperative mortality. We randomly split patients (8:1:1) into subsets for training, internal validation, and final algorithm test analyses. Model performance was assessed using area under the receiver operating characteristic curve (AUC) values in the hold-out test dataset and in two external hospital cohorts and compared with the established Revised Cardiac Risk Index (RCRI) score. The primary outcome was post-procedural mortality across three health-care systems. FINDINGS: 45 969 patients had a complete ECG waveform image available for at least one 12-lead ECG performed within the 30 days before the procedure date (59 975 inpatient procedures and 112 794 ECGs): 36 839 patients in the training dataset, 4549 in the internal validation dataset, and 4581 in the internal test dataset. In the held-out internal test cohort, the algorithm discriminates mortality with an AUC value of 0·83 (95% CI 0·79-0·87), surpassing the discrimination of the RCRI score with an AUC of 0·67 (0·61-0·72). The algorithm similarly discriminated risk for mortality in two independent US health-care systems, with AUCs of 0·79 (0·75-0·83) and 0·75 (0·74-0·76), respectively. Patients determined to be high risk by the deep-learning model had an unadjusted odds ratio (OR) of 8·83 (5·57-13·20) for postoperative mortality compared with an unadjusted OR of 2·08 (0·77-3·50) for postoperative mortality for RCRI scores of more than 2. The deep-learning algorithm performed similarly for patients undergoing cardiac surgery (AUC 0·85 [0·77-0·92]), non-cardiac surgery (AUC 0·83 [0·79-0·88]), and catheterisation or endoscopy suite procedures (AUC 0·76 [0·72-0·81]). INTERPRETATION: A deep-learning algorithm interpreting preoperative ECGs can improve discrimination of postoperative mortality. The deep-learning algorithm worked equally well for risk stratification of cardiac surgeries, non-cardiac surgeries, and catheterisation laboratory procedures, and was validated in three independent health-care systems. This algorithm can provide additional information to clinicians making the decision to perform medical procedures and stratify the risk of future complications. FUNDING: National Heart, Lung, and Blood Institute.

Artificial Intelligence in Ventricular Arrhythmias and Sudden Death.

Sudden cardiac arrest due to lethal ventricular arrhythmias is a major cause of mortality worldwide and results in more years of potential life lost than any individual cancer. Most of these sudden cardiac arrest events occur unexpectedly in individuals who have not been identified as high-risk due to the inadequacy of current risk stratification tools. Artificial intelligence tools are increasingly being used to solve complex problems and are poised to help with this major unmet need in the field of clinical electrophysiology. By leveraging large and detailed datasets, artificial intelligence-based prediction models have the potential to enhance the risk stratification of lethal ventricular arrhythmias. This review presents a synthesis of the published literature and a discussion of future directions in this field.

Racial and Ethnic Considerations in Patients With Atrial Fibrillation: JACC Focus Seminar 5/9.

Atrial fibrillation (AF) affects at least 60 million individuals globally and is associated with substantial impacts on morbidity, mortality, and health care expenditures. This review focuses on how race and ethnicity influence AF epidemiology, risk prediction, treatment, and outcomes; knowledge gaps in these areas are identified. Most AF studies have predominantly included White populations, with an underrepresentation of racial and ethnic groups, including but not limited to Black, Hispanic, and Indigenous individuals. Enhancement and implementation of AF risk prediction, prevention, and management call for studies that will gather accurate race-based epidemiologic data and evaluate social determinants and genetic factors in the context of multiple races and ethnicities. Available studies highlight inequities in access to treatment as well as outcomes between White individuals and persons of other races/ethnicities. These inequities will need to be addressed by a renewed emphasis on structural and social determinants of health that contribute to AF.

The influence of cryoballoon manipulation on luminal esophageal temperature during ablation for atrial fibrillation.

BACKGROUND: Esophageal injury is related to a reduction in luminal esophageal temperature (LET) in second-generation cryoballoon (CB) ablation; however, methods to prevent these reductions in temperature have not been well characterized. METHODS: Esophageal temperature was continuously monitored using a LET probe in patients undergoing pulmonary vein (PV) isolation using the second-generation CB. A rotational maneuver of the CB was performed if the initial ablation resulted in a decrease of more than 4℃ in LET. The refrigerant injector near the distal CB pole was used as a fluoroscopic marker to measure the nearest distance between the CB and the LET probe. RESULTS: A total of 52 consecutive patients were enrolled in this study. The rotation was applied in 19 patients and 20 PVs (seven left superior pulmonary veins [LSPVs], seven left inferior PVs [LIPVs], and six right inferior PVs [RIPVs]) with a reduction in LET of more than 4℃ during freezing. The nadir temperature of CB applications was similar before and after CB rotation in all PVs. There was significant difference in the minimum LET before and after rotation during freezing in LSPVs (28.4 ± 3.7 vs 32.4 ± 2.3℃, P = .02), LIPVs (28.4 ± 1.4 vs 32.6 ± 2.7, P = .01) and RIPVs (26.1 ± 4.3 vs 34.0 ± 1.3℃, P = .002). The differences in mean balloon to LET distance were measured for all veins before and after rotation; LSPV (right anterior oblique [RAO], 11.0 ± 1.7 vs 13.8 ± 4.5 mm, P = .05); LIPV (RAO, 10.7 ± 4.3 vs 14.6 ± 6.1 mm, P = .03); RIPV (LAO, 11.8 ± 5.5 vs 14.2 ± 5.7 mm, P = .01). CONCLUSIONS: CB rotational maneuvers during ablation can prevent significant reduction in LET and may prevent esophageal injury during the procedure.

Risk Factors of Sudden Cardiac Death in the Young: Multiple-Year Community-Wide Assessment.

BACKGROUND: Prevention of sudden cardiac arrest (SCA) in the young remains a largely unsolved public health problem, and sports activity is an established trigger. Although the presence of standard cardiovascular risk factors in the young can link to future morbidity and mortality in adulthood, the potential contribution of these risk factors to SCA in the young has not been evaluated. METHODS: We prospectively ascertained subjects who experienced SCA between the ages of 5 and 34 years in the Portland, Oregon, metropolitan area (2002-2015, catchment population ≈1 million). We assessed the circumstances, resuscitation outcomes, and clinical profile of subjects who had SCA by a detailed evaluation of emergency response records, lifetime clinical records, and autopsy examinations. We specifically evaluated the association of standard cardiovascular risk factors and SCA, and sports as a trigger for SCA in the young. RESULTS: Of 3775 SCAs in all age groups, 186 (5%) occurred in the young (mean age 25.9±6.8, 67% male). In SCA in the young, overall prevalence of warning signs before SCA was low (29%), and 26 (14%) were associated with sports as a trigger. The remainder (n=160) occurred in other settings categorized as nonsports. Sports-related SCAs accounted for 39% of SCAs in patients aged ≤18, 13% of SCAs in patients aged 19 to 25, and 7% of SCAs in patients aged 25 to 34. Sports-related SCA cases were more likely to present with shockable rhythms, and survival from cardiac arrest was 2.5-fold higher in sports-related versus nonsports SCA (28% versus 11%; P=0.05). Overall, the most common SCA-related conditions were sudden arrhythmic death syndrome (31%), coronary artery disease (22%), and hypertrophic cardiomyopathy (14%). There was an unexpectedly high overall prevalence of established cardiovascular risk factors (obesity, diabetes mellitus, hypertension, hyperlipidemia, smoking) with ≥1 risk factors in 58% of SCA cases. CONCLUSIONS: Sports was a trigger of SCA in a minority of cases, and, in most patients, SCA occurred without warning symptoms. Standard cardiovascular risk factors were found in over half of patients, suggesting the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages.

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

OBJECTIVE: Work environment is said to influence cardiovascular risk. We assessed whether nature of occupation affects risk of sudden cardiac death (SCD) in the general population. METHODS: In the ongoing, prospective Oregon Sudden Unexpected Death Study (catchment population 1 million), working-age SCD cases (18-65 years) were compared with controls who died from any cause. Usual occupation obtained from death certificates was classified using the US Census Bureau standard occupational classification descriptions and categorised as white collar, blue collar or homemaker. Odds ratio (OR) for SCD by occupation category was obtained and clinical profile of SCD cases was compared by occupation type. RESULTS: Among SCD cases (n=646; 74% male) compared to controls (n=622; 73.6% male), the proportion of white collar workers was higher among male SCD cases (52.7% vs 43.7%; p=0.01); the difference in females was smaller (59.5% vs 55%; p=0.62). Adjusting for race and smoking status, male white collar workers had a higher risk of SCD compared to blue collar workers (OR=1.67, (1.26 to 2.23), p<0.001). A similar, non-significant trend was observed among females (OR 1.49 (0.81 to 2.75); p=0.20). White collar SCD cases were less likely to be current smokers (34.7% vs 45.3%, p=0.008), drug misusers (13.1% vs 18.5%) or have diabetes (21.4% vs 28.2%, both p=0.07) compared to blue collar workers. Other cardiac risk factors were similar. CONCLUSIONS: A white collar occupation was associated with increased risk of SCD, when compared to blue collar occupations. Since differences in conventional risk factors did not explain this elevated risk, work-related behavioural and psychosocial stressors warrant a closer evaluation.

Iron-Sensitive Cardiac Magnetic Resonance Imaging for Prediction of Ventricular Arrhythmia Risk in Patients With Chronic Myocardial Infarction: Early Evidence.

BACKGROUND: Recent canines studies have shown that iron deposition within chronic myocardial infarction (CMI) influences the electric behavior of the heart. To date, the link between the iron deposition and malignant ventricular arrhythmias in humans with CMI is unknown. METHODS AND RESULTS: Patients with CMI (n=94) who underwent late-gadolinium-enhanced cardiac magnetic resonance imaging before implantable cardioverter-defibrillator implantation for primary and secondary preventions were retrospectively analyzed. The predictive values of hypointense cores (HIC) in balanced steady-state free precession images and conventional cardiac magnetic resonance imaging and ECG malignant ventricular arrhythmia parameters for the prediction of primary combined outcome (appropriate implantable cardioverter-defibrillator therapy, survived cardiac arrest, or sudden cardiac death) were studied. The use of HIC within CMI on balanced steady-state free precession as a marker of iron deposition was validated in a canine MI model (n=18). Nineteen patients met the study criteria with events occurring at a median of 249 (interquartile range of 540) days after implantable cardioverter-defibrillator placement. Of the 19 patients meeting the primary end point, 18 were classified as HIC+, whereas only 1 was HIC-. Among the cohort in whom the primary end point was not met, there were 28 HIC+ and 47 HIC- patients. Receiver operating characteristic curve analysis demonstrated an additive predictive value of HIC for malignant ventricular arrhythmias with an increased area under the curve of 0.87 when added to left ventricular ejection fraction (left ventricular ejection fraction alone, 0.68). Both cardiac magnetic resonance imaging and histological validation studies performed in canines demonstrated that HIC regions in balanced steady-state free precession images within CMI likely result from iron depositions. CONCLUSIONS: Hypointense cores within CMI on balanced steady-state free precession cardiac magnetic resonance imaging can be used as a marker of iron deposition and yields incremental information toward improved prediction of malignant ventricular arrhythmias.

Sex hormone levels in patients with sudden cardiac arrest.

BACKGROUND: Sex hormones are known to have significant effects on the pathophysiology of cardiovascular disease. OBJECTIVE: The purpose of this study was to study the association between sex hormone levels and sudden cardiac arrest (SCA). METHODS: In the ongoing Oregon Sudden Unexpected Death Study (catchment population approximately 1 million), cases of SCA were compared with matched controls. Testosterone and estradiol levels were measured from blood samples drawn at the time of the SCA event in cases and during a routine visit in controls. RESULTS: Among cases (n = 149, age 64.1 ± 11.7 years, 73.2% male), compared to controls (n = 149, 64.2 ± 11.6 years, 72.5% male), median testosterone levels were significantly lower in males (4.4 vs 5.4 ng/mL, P = .01). Median estradiol levels were higher in male (68 vs 52 pg/mL, P <.001) and female cases (54 vs 36 pg/mL, P <.001). In multivariate analysis, higher testosterone levels were associated with lower SCA odds only in males (odds ratio [OR] 0.75, 95% confidence interval [CI] 0.58-0.96, P = .02). Higher estradiol levels were associated with higher SCA odds in both males (OR 2.0, 95% CI 1.5-2.6, P <.001) and females (OR 3.5, 95% CI 1.9-6.4, P <.001). A higher testosterone/estrogen ratio was associated with lower SCA odds in males only (OR 0.5, 95% CI 0.4-0.7, P <.001). In a canine model of SCA, plasma testosterone levels were not significantly altered by the cardiac arrest event. CONCLUSION: We observed significant differences in sex hormone levels in patients who suffered SCA, with potential mechanistic implications. The role of sex hormones in the genesis of fatal ventricular arrhythmias warrants further exploration.

Public health burden of sudden cardiac death in the United States.

BACKGROUND: Sudden cardiac death (SCD) is a leading cause of death in the United States, but the relative public health burden is unknown. We estimated the burden of premature death from SCD and compared it with other diseases. METHODS AND RESULTS: Analyses were based on the following data sources (using most recent sources that provided appropriately stratified data): (1) leading causes of death among men and women from 2009 US death certificate reporting; (2) individual cancer mortality rates from 2008 death certificate reporting from the Centers for Disease Control and Prevention's National Program of Cancer Registries; (3) county, state, and national population data for 2009 from the US Census Bureau; and (4) SCD rates from the Oregon Sudden Unexpected Death Study (SUDS) population-based surveillance study of SCD between 2002 and 2004. Cases were identified from multiple sources in a prospectively designed surveillance program. Incidence, counts, and years of potential life lost for SCD and other major diseases were compared. The age-adjusted national incidence of SCD was 60 per 100 000 population (95% confidence interval, 54-66 per 100,000). The burden of premature death for men (2.04 million years of potential life lost; 95% uncertainty interval, 1.86-2.23 million) and women (1.29 million years of potential life lost; 95% uncertainty interval, 1.13-1.45 million) was greater for SCD than for all individual cancers and most other leading causes of death. CONCLUSIONS: The societal burden of SCD is high relative to other major causes of death. Accordingly, improved national surveillance with the goal of optimizing and monitoring SCD prevention and treatment should be a high priority.

Elevated plasma free fatty acids are associated with sudden death: a prospective community-based evaluation at the time of cardiac arrest.

BACKGROUND: In cohort studies, elevated levels of plasma nonesterified free fatty acids (NEFAs) have been associated with increased risk of sudden cardiac death (SCD) in men, but blood samples were drawn several years before SCD. OBJECTIVE: To confirm this relationship by evaluating levels of plasma NEFAs at the time of the SCD event in a group of both men and women. METHODS: From the ongoing Oregon Sudden Unexpected Death Study, we compared levels of plasma NEFAs in 149 SCD cases presenting with ventricular fibrillation (mean age 64 ± 12 years; 73% men) and 149 age- and sex-matched controls with coronary artery disease. Plasma was processed from blood drawn at the time of arrest (cases) and at a routine visit (controls). The levels of plasma NEFAs were compared after categorizing into quartiles on the basis of control values. Conditional logistic regression was used to predict adjusted odds ratio for SCD associated with plasma NEFA levels per increased quartile. RESULTS: The plasma NEFA levels were significantly higher in SCD cases than in controls (median 0.39 mmol/L [interquartile range 0.28-0.60 mmol/L] vs 0.32 mmol/L [interquartile range 0.20-0.49 mmol/L]; P = .002). There were no significant differences in body mass index, smoking, and diabetes. The odds ratio for SCD was 1.42 (95% confidence interval 1.14-1.78) per quartile increase in the plasma NEFA level (P = .002). Individuals with plasma NEFA levels above the prespecified cutoff point of 0.32 mmol/L were at increased risk of SCD (odds ratio 2.00; 95% confidence interval 1.20-3.34; P = .008). CONCLUSION: These findings strengthen the role of plasma NEFA as a potential biomarker for the assessment of SCD risk.

Iron deposition following chronic myocardial infarction as a substrate for cardiac electrical anomalies: initial findings in a canine model.

PURPOSE: Iron deposition has been shown to occur following myocardial infarction (MI). We investigated whether such focal iron deposition within chronic MI lead to electrical anomalies. METHODS: Two groups of dogs (ex-vivo (n = 12) and in-vivo (n = 10)) were studied at 16 weeks post MI. Hearts of animals from ex-vivo group were explanted and sectioned into infarcted and non-infarcted segments. Impedance spectroscopy was used to derive electrical permittivity ([Formula: see text]) and conductivity ([Formula: see text]). Mass spectrometry was used to classify and characterize tissue sections with (IRON+) and without (IRON-) iron. Animals from in-vivo group underwent cardiac magnetic resonance imaging (CMR) for estimation of scar volume (late-gadolinium enhancement, LGE) and iron deposition (T2*) relative to left-ventricular volume. 24-hour electrocardiogram recordings were obtained and used to examine Heart Rate (HR), QT interval (QT), QT corrected for HR (QTc) and QTc dispersion (QTcd). In a fraction of these animals (n = 5), ultra-high resolution electroanatomical mapping (EAM) was performed, co-registered with LGE and T2* CMR and were used to characterize the spatial locations of isolated late potentials (ILPs). RESULTS: Compared to IRON- sections, IRON+ sections had higher[Formula: see text], but no difference in[Formula: see text]. A linear relationship was found between iron content and [Formula: see text] (p<0.001), but not [Formula: see text] (p = 0.34). Among two groups of animals (Iron (<1.5%) and Iron (>1.5%)) with similar scar volumes (7.28% ± 1.02% (Iron (<1.5%)) vs 8.35% ± 2.98% (Iron (>1.5%)), p = 0.51) but markedly different iron volumes (1.12% ± 0.64% (Iron (<1.5%)) vs 2.47% ± 0.64% (Iron (>1.5%)), p = 0.02), QT and QTc were elevated and QTcd was decreased in the group with the higher iron volume during the day, night and 24-hour period (p<0.05). EAMs co-registered with CMR images showed a greater tendency for ILPs to emerge from scar regions with iron versus without iron. CONCLUSION: The electrical behavior of infarcted hearts with iron appears to be different from those without iron. Iron within infarcted zones may evolve as an arrhythmogenic substrate in the post MI period.

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.

BACKGROUND: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. METHODS: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. FINDINGS: In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. INTERPRETATION: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. FUNDING: Bill & Melinda Gates Foundation.

Biological pacemaker created by percutaneous gene delivery via venous catheters in a porcine model of complete heart block.

BACKGROUND: Pacemaker-dependent patients with device infection require temporary pacing while the infection is treated. External transthoracic pacing is painful and variably effective, while temporary pacing leads are susceptible to superinfection. OBJECTIVE: To create a biological pacemaker delivered via venous catheters in a porcine model of complete heart block, providing a temporary alternative/adjunct to external pacing devices without additional indwelling hardware. METHODS: Complete atrioventricular (AV) nodal block was induced in pigs by radiofrequency ablation after the implantation of a single-chamber electronic pacemaker to maintain a ventricular backup rate of 50 beats/min. An adenoviral vector cocktail (K(AAA) + H2), expressing dominant-negative inward rectifier potassium channel (Kir2.1AAA) and hyperpolarization-activated cation channel (HCN2) genes, was injected into the AV junctional region via a NOGA Myostar catheter advanced through the femoral vein. RESULTS: Animals injected with K(AAA) + H2 maintained a physiologically relevant ventricular rate of 93.5 ± 7 beats/min (n = 4) compared with control animals (average rate, 59.4 ± 4 beats/min; n = 6 at day 7 postinjection; P <.05). Backup electronic pacemaker utilization decreased by almost 4-fold in the K(AAA) + H2 group compared with the control (P <.05), an effect maintained for the entire 14-day window. In contrast to the efficacy of gene delivery into the AV junctional region, open-chest, direct injection of K(AAA) + H2 (or its individual vectors) into the ventricular myocardium failed to elicit significant pacemaker activity. CONCLUSIONS: The right-sided delivery of K(AAA) + H2 to the AV junctional region provided physiologically relevant biological pacing over a 14-day period. Our approach may provide temporary, bridge-to-device pacing for the effective clearance of infection prior to the reimplantation of a definitive electronic pacemaker.

Contribution of sudden cardiac death to total mortality in India - a population based study.

INTRODUCTION: Epidemiology of sudden cardiac death (SCD) in India is understudied. METHODS: We assessed proportion of SCD among total mortality in a population in Southern India using a staged, questionnaire-based kindred-wide approach. Detailed questionnaires (DQs) were completed by medical trainees from 8 medical colleges. Preliminary questionnaires evaluated total deaths in the kindred of a respondent. Deaths due to obvious non-cardiac causes were excluded. DQs were completed for the remaining deaths and categorized using a three-member adjudication system. RESULTS: A total population of 22,724 was evaluated by 478 respondents, (278 M and 200 F). Out of a total of 2185 deaths, 1691 (77.4%) were recallable. A total of 173 (10.3%; 128 M and 45 F; mean age - 60.8 ± 14 years) deaths were adjudicated as SCD. Of these, 82 (47.3%) were ≤ 60 years of age. Prior MI, LV dysfunction and prior aborted SCD were found in 33.5%, 22.5% and 5.7% respectively. Coronary artery disease (CAD) was observed in 66 (38%) and acute myocardial infarction documented in 30 (17%). At least 1 of 3 CAD risk factors - hypertension, diabetes, or smoking was observed in 80.6%. Proportion of subjects with at least one risk factor for CAD were similar in the age groups above and below 50 years (67.6% vs. 81.7%, p=0.065). CONCLUSIONS: SCD contributed to 10.3% of overall mortality in this population from Southern India. On an average, SCD cases were 5-8 years younger compared to populations reported in the western hemisphere, with a high prevalence of major risk factors for CAD.

Fish oil supplementation and risk of ventricular tachycardia and ventricular fibrillation in patients with implantable defibrillators: a randomized controlled trial.

CONTEXT: Clinical studies of omega-3 polyunsaturated fatty acids (PUFAs) have shown a reduction in sudden cardiac death, suggesting that omega-3 PUFAs may have antiarrhythmic effects. OBJECTIVE: To determine whether omega-3 PUFAs have beneficial antiarrhythmic effects in patients with a history of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial performed at 6 US medical centers with enrollment from February 1999 until January 2003. PATIENTS: Two hundred patients with an implantable cardioverter defibrillator (ICD) and a recent episode of sustained VT or VF. INTERVENTION: Patients were randomly assigned to receive fish oil, 1.8 g/d, 72% omega-3 PUFAs, or placebo and were followed up for a median of 718 days (range, 20-828 days). MAIN OUTCOME MEASURES: Time to first episode of ICD treatment for VT/VF, changes in red blood cell concentrations of omega-3 PUFAs, frequency of recurrent VT/VF events, and predetermined subgroup analyses. RESULTS: Patients randomized to receive fish oil had an increase in the mean percentage of omega-3 PUFAs in red blood cell membranes from 4.7% to 8.3% (P<.001), with no change observed in patients receiving placebo. At 6, 12, and 24 months, 46% (SE, 5%), 51% (5%), and 65% (5%) of patients randomized to receive fish oil had ICD therapy for VT/VF compared with 36% (5%), 41% (5%), and 59% (5%) for patients randomized to receive placebo (P = .19). In the subset of 133 patients whose qualifying arrhythmia was VT, 61% (SE, 6%), 66% (6%), and 79% (6%) of patients in the fish oil group had VT/VF at 6, 12, and 24 months compared with 37% (6%), 43% (6%), and 65% (6%) of patients in the control group (P = .007). Recurrent VT/VF events were more common in patients randomized to receive fish oil (P<.001). CONCLUSION: Among patients with a recent episode of sustained ventricular arrhythmia and an ICD, fish oil supplementation does not reduce the risk of VT/VF and may be proarrhythmic in some patients.

Postmortem molecular screening in unexplained sudden death.

OBJECTIVES: We examined the prevalence of defects in arrhythmia-related candidate genes among patients with unexplained sudden cardiac death (SCD). BACKGROUND: Patients with unexplained sudden death may constitute up to 5% of overall SCD cases. For such patients, systematic postmortem genetic analysis of archived tissue, using a candidate gene approach, may identify etiologies of SCD. METHODS: We performed analysis of KCNQ1 (KVLQT1), KCNH2 (HERG), SCN5A, KCNE1, and KCNE2 defects in a subgroup of 12 adult subjects with unexplained sudden death, derived from a 13-year, 270-patient autopsy series of SCD. Archived, paraffin-embedded myocardial tissue blocks obtained at the original postmortem examination were the source of deoxyribonucleic acid for genetic analysis. RESULTS: Two patients were found to have the same HERG defect, a missense mutation in exon 7 (nucleotide change G1681A, coding effect A561T). The mutation was heterozygous in Patient 1, but Patient 2 appeared to be homozygous for the defect. Patch-clamp recordings showed that the A561T mutant channel expressed in human embryonic kidney cells failed to generate HERG current. Western blot analysis implicated a trafficking defect in the protein, resulting in loss of post-translational processing from the immature to the mature form of HERG. No mutations were detected among the remaining four candidate genes. CONCLUSIONS: In this autopsy series, only 2 of 12 patients with unexplained sudden death were observed to have a defect in HERG among five candidate genes tested. It is likely that elucidation of SCD mechanisms in such patients will await the discovery of multiple, novel arrhythmia-causing gene defects.

Genomics in sudden cardiac death.

Sudden cardiac death (SCD) remains a public health problem of major magnitude. Contrary to earlier expectations, and despite decreased overall cardiac mortality, SCD rates appear to be rising in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. With the exception of the implantable defibrillator, there are few effective approaches to SCD prevention and even fewer clues concerning patient phenotypes predisposed to life-threatening arrhythmias. Clinical variables such as ejection fraction predict mortality but are not sensitive enough to identify many high SCD risk patients. The predictive power of autonomic dysregulation and markers such as lipid levels, hypertension, diabetes, and smoking is quite low in subclinical heart disease, the population in which the majority of SCDs occur. This review addresses advances in genomic science applicable to the SCD public health problem in both rare and common forms of heart disease. These include novel bioinformatic approaches to both identify candidate genes/pathways and identify previously unknown functional genetic elements, as well as methods to comprehensively screen these elements. We also discuss the possibility of applying high-density genome-wide SNP analyses to examine genetic contributions to arrhythmia susceptibility in community-based, case-control studies of common forms of SCD. The development of novel strategies to identify contributors to susceptibility in common cardiac phenotypes is most likely to lead to new and relevant therapeutic targets for SCD.

Nonautomatic focal atrial tachycardia: characterization and ablation of a poorly understood arrhythmia in 38 patients.

Nonautomatic focal atrial tachycardia (NAFAT) is a rare and poorly understood arrhythmia either due to microreentry or triggered mechanism. NAFAT was defined as a focal atrial tachycardia which was inducible with pacing maneuvers in the electrophysiology lab. We reviewed the charts and EP study reports of all 38 patients with NAFAT, who underwent an EP study at our center between April 1994 and September 2000. Patients' were predominantly female (n = 31, 82%), aged 11-78 years (median 46). The mean age at presentation was 31 years (range 7-71 years). None of the patients had structural heart disease or had undergone prior heart surgery. Electroanatomic mapping (EAM) was performed in 22 patients and showed no scars in the atrium. A total of 45 foci were identified (range 1-3 foci/patient). Anatomically NAFAT foci were predominantly right atrial (n = 35) rather than left (n = 10). The NAFAT cycle length ranged from 270 to 490 (mean +/- SD; 380 +/- 69 ms) and was significantly lower in patients younger than 24 years of age. Ablation, attempted for 42 foci was successful in 33 (79%). The success rate in the EAM group was 20/25 foci (80%) compared to 13/18 (72%) in the non-EAM group. In conclusion, NAFAT is a rare arrhythmia which predominantly affects women with no other associated cardiac disease. It mainly occurs in the right atrium, affects all ages and is amenable to catheter ablation.