Arrhythmias and ion channelopathies causing sudden cardiac death in Hispanic/Latino and Indigenous populations.

The limited literature and increasing interest in studies on cardiac electrophysiology, explicitly focusing on cardiac ion channelopathies and sudden cardiac death in diverse populations, has prompted a comprehensive examination of existing research. Our review specifically targets Hispanic/Latino and Indigenous populations, which are often underrepresented in healthcare studies. This review encompasses investigations into genetic variants, epidemiology, etiologies, and clinical risk factors associated with arrhythmias in these demographic groups. The review explores the Hispanic paradox, a phenomenon linking healthcare outcomes to socioeconomic factors within Hispanic communities in the United States. Furthermore, it discusses studies exemplifying this observation in the context of arrhythmias and ion channelopathies in Hispanic populations. Current research also sheds light on disparities in overall healthcare quality in Indigenous populations. The available yet limited literature underscores the pressing need for more extensive and comprehensive research on cardiac ion channelopathies in Hispanic/Latino and Indigenous populations. Specifically, additional studies are essential to fully characterize pathogenic genetic variants, identify population-specific risk factors, and address health disparities to enhance the detection, prevention, and management of arrhythmias and sudden cardiac death in these demographic groups.

New-onset atrial arrhythmias associated with mortality in black and white patients hospitalized with COVID-19.

BACKGROUND: Specific details about cardiovascular complications, especially arrhythmias, related to the coronavirus disease of 2019 (COVID-19) are not well described. OBJECTIVE: We sought to evaluate the incidence and predictive factors of cardiovascular complications and new-onset arrhythmias in Black and White hospitalized COVID-19 patients and determine the impact of new-onset arrhythmia on outcomes. METHODS: We collected and analyzed baseline demographic and clinical data from COVID-19 patients hospitalized at the Tulane Medical Center in New Orleans, Louisiana, between March 1 and May 1, 2020. RESULTS: Among 310 hospitalized COVID-19 patients, the mean age was 61.4 ± 16.5 years, with 58,7% females, and 67% Black patients. Black patients were more likely to be younger, have diabetes and obesity. The incidence of cardiac complications was 20%, with 9% of patients having new-onset arrhythmia. There was no significant difference in cardiovascular outcomes between Black and White patients. A multivariate analysis determined age ≥60 years to be a predictor of new-onset arrhythmia (OR = 7.36, 95% CI [1.95;27.76], p = .003). D-dimer levels positively correlated with cardiac and new-onset arrhythmic event. New onset atrial arrhythmias predicted in-hospital mortality (OR = 2.99 95% CI [1.35;6.63], p = .007), a longer intensive care unit length of stay (mean of 6.14 days, 95% CI [2.51;9.77], p = .001) and mechanical ventilation duration(mean of 9.08 days, 95% CI [3.75;14.40], p = .001). CONCLUSION: Our results indicate that new onset atrial arrhythmias are commonly encountered in COVID-19 patients and can predict in-hospital mortality. Early elevation in D-dimer in COVID-19 patients is a significant predictor of new onset arrhythmias. Our finding suggest continuous rhythm monitoring should be adopted in this patient population during hospitalization to better risk stratify hospitalized patients and prompt earlier intervention.

Clinical and cardiac characteristics of COVID-19 mortalities in a diverse New York City Cohort.

INTRODUCTION: Electrocardiographic characteristics in COVID-19-related mortality have not yet been reported, particularly in racial/ethnic minorities. METHODS AND RESULTS: We reviewed demographics, laboratory and cardiac tests, medications, and cardiac rhythm proximate to death or initiation of comfort care for patients hospitalized with a positive SARS-CoV-2 reverse-transcriptase polymerase chain reaction in three New York City hospitals between March 1 and April 3, 2020 who died. We described clinical characteristics and compared factors contributing toward arrhythmic versus nonarrhythmic death. Of 1258 patients screened, 133 died and were enrolled. Of these, 55.6% (74/133) were male, 69.9% (93/133) were racial/ethnic minorities, and 88.0% (117/133) had cardiovascular disease. The last cardiac rhythm recorded was VT or fibrillation in 5.3% (7/133), pulseless electrical activity in 7.5% (10/133), unspecified bradycardia in 0.8% (1/133), and asystole in 26.3% (35/133). Most 74.4% (99/133) died receiving comfort measures only. The most common abnormalities on admission electrocardiogram included abnormal QRS axis (25.8%), atrial fibrillation/flutter (14.3%), atrial ectopy (12.0%), and right bundle branch block (11.9%). During hospitalization, an additional 17.6% developed atrial ectopy, 14.7% ventricular ectopy, 10.1% atrial fibrillation/flutter, and 7.8% a right ventricular abnormality. Arrhythmic death was confirmed or suspected in 8.3% (11/133) associated with age, coronary artery disease, asthma, vasopressor use, longer admission corrected QT interval, and left bundle branch block (LBBB). CONCLUSIONS: Conduction, rhythm, and electrocardiographic abnormalities were common during COVID-19-related hospitalization. Arrhythmic death was associated with age, coronary artery disease, asthma, longer admission corrected QT interval, LBBB, ventricular ectopy, and usage of vasopressors. Most died receiving comfort measures.

Nationwide Trends in Prevalent Cardiovascular Risk Factors and Diseases in Young Adults: Differences by Sex and Race and In-Hospital Outcomes.

OBJECTIVES: Prevalence and trends in all cardiovascular disease (CVD) risk factors among young adults (18-39 years) have not been evaluated on a large scale stratified by sex and race. The aim of this study was to establish the prevalence and temporal trend of CVD risk factors in US inpatients younger than 40 years of age from 2007 through 2014 with racial and sex-based distinctions. In addition, the impact of these risk factors on inpatient outcomes and healthcare resource utilization was explored. METHODS: A cross-sectional nationwide analysis of all hospitalizations, comorbidities, and complications among young adults from 2007 to 2014 was performed. The primary outcomes were frequency, trends, and race- and sex-based differences in coexisting CVD risk factors. Coprimary outcomes were trends in all-cause mortality, acute myocardial infarction, arrhythmia, stroke, and venous thromboembolism in young adults with CVD risk factors. Secondary outcomes were demographics and resource utilization in young adults with versus without CVD risk factors. RESULTS: Of 63 million hospitalizations (mean 30.5 [standard deviation 5.9] years), 27% had at least one coexisting CVD risk factor. From 2007 to 2014, admission frequency with CVD risk factors increased from 42.8% to 55.1% in males and from 16.2% to 24.6% in females. Admissions with CVD risk were higher in male (41.4% vs 15.9%) and white (58.4% vs 53.8%) or African American (22.6% vs 15.9%) patients compared with those without CVD risk. Young adults in the Midwest (23.9% vs 21.1%) and South (40.8% vs 37.9%) documented comparatively higher hospitalizations rates with CVD risk. Young adults with CVD risk had higher all-cause in-hospital mortality (0.4% vs. 0.3%) with a higher average length of stay (4.3 vs 3.2 days) and charges per admission ($30,074 vs $20,124). CONCLUSIONS: Despite modern advances in screening, management, and interventional measures for CVD, rising trends in CVD risk factors across all sex and race/ethnic groups call for attention by preventive cardiologists.

Decreased Vagal Activity and Deviation in Sympathetic Activity Precedes Development of Diabetes.

OBJECTIVE: The objective of this study was to examine whether altered heart rate variability (HRV) could predict the risk of diabetes in Asians. RESEARCH DESIGN AND METHODS: A cohort study was conducted in 54,075 adults without diabetes who underwent 3-min HRV measurement during health checkups between 2011 and 2014 at Kangbuk Samsung Hospital. We analyzed the time domain (SD of the normal-to-normal interval [SDNN] and root mean square differences of successive normal-to-normal intervals [RMSSD]) and the frequency domain (total power, normalized low-frequency power [LF], and normalized high-frequency power [HF] and LF/HF ratio). We compared the risk of diabetes until 2017 according to tertiles of heart rate and HRV variables, with tertile 1 serving as the reference group. RESULTS: During 243,758.2 person-years, 1,369 subjects were diagnosed with diabetes. Both time and frequency domain variables were lower in the group with diabetes, with the exception of those with normalized LF and LF/HF ratio. In Cox analysis, as SDNN, RMSSD, and normalized HF tertiles increased, the risk of diabetes decreased (hazard ratios [95% CIs] of tertile 3: 0.81 [0.70-0.95], 0.76 [0.65-0.90], and 0.78 [0.67-0.91], respectively), whereas the risk of diabetes increased in the case of heart rate, normalized LF, and LF/HF ratio (hazard ratios [95% CIs] of tertile 3: 1.41 [1.21-1.65], 1.32 [1.13-1.53], and 1.31 [1.13-1.53), respectively) after adjusting for age, sex, BMI, smoking, drinking, systolic blood pressure, lipid level, CRP, and HOMA of insulin resistance. CONCLUSIONS: Abnormal HRV, especially decreased vagal activity and deviation in sympathovagal imbalance to sympathetic activity, might precede incident diabetes.

Bringing Critical Race Praxis Into the Study of Electrophysiological Substrate of Sudden Cardiac Death: The ARIC Study.

Background Race is an established risk factor for sudden cardiac death (SCD). We sought to determine whether the association of electrophysiological substrate with SCD varies between black and white individuals. Methods and Results Participants from the ARIC (Atherosclerosis Risk in Communities) study with analyzable ECGs (n=14 408; age, 54±6 years; 74% white) were included. Electrophysiological substrate was characterized by ECG metrics. Two competing outcomes were adjudicated: SCD and non-SCD. Interaction of ECG metrics with race was studied in Cox proportional hazards and Fine-Gray competing risk models, adjusted for prevalent cardiovascular disease, risk factors, and incident nonfatal cardiovascular disease. At the baseline visit, adjusted for age, sex, and study center, blacks had larger spatial ventricular gradient magnitude (0.30 mV; 95% CI, 0.25-0.34 mV), sum absolute QRST integral (18.4 mV*ms; 95% CI, 13.7-23.0 mV*ms), and Cornell voltage (0.30 mV; 95% CI, 0.25-0.35 mV) than whites. Over a median follow-up of 24.4 years, SCD incidence was higher in blacks (2.86 per 1000 person-years; 95% CI, 2.50-3.28 per 1000 person-years) than whites (1.37 per 1000 person-years; 95% CI, 1.22-1.53 per 1000 person-years). Blacks with hypertension had the highest rate of SCD: 4.26 (95% CI, 3.66-4.96) per 1000 person-years. Race did not modify an association of ECG variables with SCD, except QRS-T angle. Spatial QRS-T angle was associated with SCD in whites (hazard ratio, 1.38; 95% CI, 1.25-1.53) and hypertension-free blacks (hazard ratio, 1.52; 95% CI, 1.09-2.12), but not in blacks with hypertension (hazard ratio, 1.15; 95% CI, 0.99-1.32) (P-interaction=0.004). Conclusions Race did not modify associations of electrophysiological substrate with SCD and non-SCD. Electrophysiological substrate does not explain racial disparities in SCD rate.

Early repolarization pattern in an ethnically diverse population: Increased risk in Hispanics.

BACKGROUND: Early repolarization (ER) pattern on ECG is associated with an increased mortality in Caucasians. This study analyzed the association between ER pattern and all-cause mortality in a population of multiple ethnicities. METHODS: A total of 20 000 individuals were randomly selected and their ECGs were analyzed for ER pattern using the 2015 consensus: end-QRS notching or slurring with a J-point (Jp) ≥0.1 mV in contiguous inferior or lateral leads. Exclusion criteria were age <18, QRS duration of ≥120 ms, and acute myocardial infarction. Kaplan-Meier survival curves were used to assess crude survival, and multivariable logistic regression models were used to determine predictors of all-cause mortality. RESULTS: A total of 17 901 patients with a mean age of 53 met inclusion criteria. Individuals were 62% female, 14% White, 37% Black, 40% Hispanic, and 9% other. Median follow-up time was 6.4 years. ER pattern was noted in 995 (5.6%) patients. Jp ≥2 mm was noted in 282 (1.6%) patients. In those with ER pattern and Jp ≥1 mm, there was no difference in mortality when compared to individuals without Jp elevation (odds ratio [OR]: 0.962, 95% confidence of interval [CI]: 0.819-1.131). Patients with Jp ≥2 mm had a significantly increased all-cause mortality (OR: 1.333, 95% CI: 1.009-1.742). This increased mortality was also significant in Hispanic patients with Jp ≥2 mm (OR: 1.584, 95% CI: 1.003-2.502). CONCLUSION: ER pattern with Jp ≥2 mm is associated with increased mortality in a multiethnic population, apparently driven by an increased risk in Hispanics.

Impact of Ethnicity on the Prevalence of Early Repolarization Pattern in Children: Comparison Between Caucasian and African Populations.

The patterns and prevalence of early repolarization pattern (ER) in pediatric populations from ethnic backgrounds other than Caucasian have not been determined. Black African children (ages 4-12) from north-west Madagascar were prospectively recruited and their ECGs compared with those of age- and sex-matched Caucasian ethnicity individuals. ER was defined by ≥ 0.1 mV J-point elevation in at least two contiguous inferior and/or lateral ECG leads. A total of 616 children were included. There was a trend toward a higher frequency of ER in the Africans compared to the Caucasians (23.3% vs. 17.1%, respectively, p = 0.053). The subtype (slurred vs. notched) and location of ER (lateral, inferior, or inferior-lateral) were significantly different in the two groups (p < 0.001 and p = 0.020, respectively). There was no significant difference in the number of high-risk ECG features of ERP (i.e., horizontal/descendent pattern, inferior or inferior-lateral location or J-waves ≥ 2 mm) between African and Caucasian children. On the multivariate analysis, African ethnicity was an independent predictive factor of ER (OR 3.57, 95% CI 2.04-6.25, p < 0.001). African children have an increased risk of ER compared to Caucasian counterparts. Future studies should clarify the clinical and prognostic significance of ER in the pediatric population, and whether ethnicity has an impact on the outcomes.

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome.

BACKGROUND: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs). OBJECTIVE: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs. METHODS: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group. RESULTS: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility. CONCLUSION: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.

Racial Disparities and Outcomes After Left Ventricular Assist Device Implantation as Bridge to Transplantation or Destination Therapy.

OBJECTIVE: We sought to investigate outcomes after left ventricular assist device (LVAD) implantation in advanced heart failure patients stratified by race. METHODS: Patients who had LVADs inserted at a single center as a bridge to transplant (BTT) or destination therapy (DT) were divided into 3 groups based on race: Caucasian, African American (AA), and Hispanic. Postoperative outcomes including complications, discharge disposition, and survival at defined time points were compared. Cox proportional hazards were used to identify factors associated with 1-year all-cause survival. RESULTS: A total of 158 patients who had LVADs as BTT (n = 63) and DT (n = 95) were studied. Of these, 56% (n = 89) were Caucasians, 35% (n = 55) were AA, and 9% (n = 14) were Hispanics. AA patients had higher BMI and lower socioeconomic status and educational level, and were more likely to be single or divorced. Operative outcomes were similar among all 3 groups. Unadjusted 30-day, 6-month, 1-year, and 2-year survival rates for Caucasians versus AA versus Hispanics were 82% versus 89% versus 93%, P = 0.339; 74% versus 80% versus 71%, P = 0.596; 67% versus 76% versus 71%, P = 0.511; and 56% versus 62% versus 68%, P = 0.797. On multivariate analysis, device-related infection, malfunction, and abnormal rhythm were factors associated with overall all-cause mortality. CONCLUSION: AA patients who undergo LVAD implantation as BTT or DT have lower socioeconomic status and educational level compared to their Caucasian or Hispanic counterparts. These differences, however, do not translate into postimplant survival outcomes.

A Population-wide study of electrocardiographic (ECG) norms and the effect of demographic and anthropometric factors on selected ECG characteristics in young, Southeast Asian males-results from the Singapore Armed Forces ECG (SAFE) study.

BACKGROUND: Routine use of pre-participation electrocardiograms (ECGs) has been used by the Singapore Armed Forces, targeting early detection of significant cardiac diseases. We aim to describe the impact of demographic and anthropometric factors on ECG variables and establish a set of electrocardiographic reference ranges specific to a young male multiethnic Southeast Asian cohort. METHODS AND RESULTS: Between November 1, 2009, and December 31, 2014, 144,346 young male conscripts underwent pre-participation screening that included a 12-lead ECG, demographic and anthropometric measurements. The Chinese population had the longest PR interval (146.7 ± 19.7 vs. 145.21 ± 19.2 in Malays vs. 141.2 ± 18.8 ms in Indians), QRS duration (94.5 ± 9.8 vs. 92.6 ± 9.7 in Malays vs. 92.5 ± 9.4 ms in Indians) and QTcB interval (408.3 ± 21.3 vs. 403.5 ± 21.6 in Malays vs. 401.2 ± 21.4 ms in Indians) (all p < 0.001). Body mass index (BMI) >25 kg/m2 and body fat >25% were independently associated with lower prevalence of increased QRS voltage on ECG. Systolic blood pressure of >140 mmHg or diastolic blood pressure of >90 mmHg independently increased the prevalence of increased QRS voltage on ECG. CONCLUSIONS: Electrocardiographic parameters vary across different ethnicities and in comparison with international norms. In our population, diagnosis of increased QRS voltage by ECG is less prevalent with obesity and increased body fat. Further analysis of gold standard measurements for the diagnosis of LVH in our population is ongoing, to improve the accuracy of the ECG screening process.

Prevalence and significance of T-wave inversion in Arab and Black paediatric athletes: Should anterior T-wave inversion interpretation be governed by biological or chronological age?

BACKGROUND: International electrocardiographic (ECG) recommendations regard anterior T-wave inversion (ATWI) in athletes under 16 years to be normal. DESIGN: The aim of this study was to identify the prevalence, distribution and determinants of TWI by ethnicity, chronological and biological age within paediatric athletes. A second aim was to establish the diagnostic accuracy of international ECG recommendations against refinement within athletes who present with ECG variants isolated to ATWI (V1-V4) using receiver operator curve analysis. Clinical context was calculated using Bayesian analysis. METHODS: Four hundred and eighteen Arab and 314 black male athletes (11-18 years) were evaluated by ECG, echocardiogram and biological age (by radiological X-ray) assessment. RESULTS: A total of 116 (15.8%) athletes presented with ATWI (V1-V4), of which 96 (82.8%) were observed in the absence of other ECG findings considered to be abnormal as per international recommendations for ECG interpretation in athletes; 91 (12.4%) athletes presented with ATWI confined to V1-V3, with prevalence predicted by black ethnicity (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.3-3.5) and biological age under 16 years (OR 2.0, 95% CI 1.2-3.3). Of the 96 with ATWI (V1-V4) observed in the absence of other ECG findings considered to be abnormal, as per international recommendations for ECG interpretation in athletes, diagnostic accuracy was 'fail' (OR 0.47, 95% CI 0.00-1.00) for international recommendations and 'excellent' (OR 0.97, 95% CI 0.92-1.00) when governed by biological age under 16 years, providing a positive and negative likelihood ratio of 15.8 (95% CI 1.8-28.1) and 0.0 (95% CI 0.0-0.8), respectively. CONCLUSION: Interpretation of ECG variants isolated with ATWI (V1-V4) using international recommendations (chronological age <16 years) warrants caution, but governance by biological age yielded an 'excellent' diagnostic accuracy. In the clinical context, the 'chance' of detecting cardiac pathology within a paediatric male athlete presenting with ATWI in the absence of other ECG findings considered to be abnormal, as per international recommendations for ECG interpretation in athletes (positive likelihood ratio 15.8), was 14.4%, whereas a negative ECG (negative likelihood ratio 0.0) was 0%.

Differences in Risk of Sudden Cardiac Death Between Blacks and Whites.

BACKGROUND: Prior studies have consistently demonstrated that blacks have an approximate 2-fold higher incidence of sudden cardiac death (SCD) than whites; however, these analyses have lacked individual-level sociodemographic, medical comorbidity, and behavioral health data. OBJECTIVES: The purpose of this study was to evaluate whether racial differences in SCD incidence are attributable to differences in the prevalence of risk factors or rather to underlying susceptibility to fatal arrhythmias. METHODS: The Reasons for Geographic and Racial Differences in Stroke study is a prospective, population-based cohort of adults from across the United States. Associations between race and SCD defined per National Heart, Lung, and Blood Institute criteria were assessed. RESULTS: Among 22,507 participants (9,416 blacks and 13,091 whites) without a history of clinical cardiovascular disease, there were 174 SCD events (67 whites and 107 blacks) over a median follow-up of 6.1 years (interquartile range: 4.6 to 7.3 years). The age-adjusted SCD incidence rate (per 1,000 person-years) was higher in blacks (1.8; 95% confidence interval [CI]: 1.4 to 2.2) compared with whites (0.7; 95% CI: 0.6 to 0.9), with an unadjusted hazard ratio of 2.35; 95% CI: 1.74 to 3.20. The association of black race with SCD risk remained significant after adjustment for sociodemographics, comorbidities, behavioral measures of health, intervening cardiovascular events, and competing risks of non-SCD mortality (hazard ratio: 1.97; 95% CI: 1.39 to 2.77). CONCLUSIONS: In a large biracial population of adults without a history of cardiovascular disease, SCD rates were significantly higher in blacks as compared with whites. These racial differences were not fully explained by demographics, adverse socioeconomic measures, cardiovascular risk factors, and behavioral measures of health.

An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation.

Calcium regulation plays a central role in cardiac function. Several variants in the calcium channel Cav1.2 have been implicated in arrhythmic syndromes. We screened patients with Brugada syndrome, short QT syndrome, early repolarisation syndrome, and idiopathic ventricular fibrillation to determine the frequency and pathogenicity of Cav1.2 variants. Cav1.2 related genes, CACNA1C, CACNB2 and CACNA2D1, were screened in 65 probands. Missense variants were introduced in the Cav1.2 alpha subunit plasmid by mutagenesis to assess their pathogenicity using patch clamp approaches. Six missense variants were identified in CACNA1C in five individuals. Five of them, A1648T, A1689T, G1795R, R1973Q, C1992F, showed no major alterations of the channel function. The sixth C-terminal variant, Cavα1c-T1787M, present mostly in the African population, was identified in two patients with resuscitated cardiac arrest. The first patient originated from Cameroon and the second was an inhabitant of La Reunion Island with idiopathic ventricular fibrillation originating from Purkinje tissues. Patch-clamp analysis revealed that Cavα1c-T1787M reduces the calcium and barium currents by increasing the auto-inhibition mediated by the C-terminal part and increases the voltage-dependent inhibition. We identified a loss-of-function variant, Cavα1c-T1787M, present in 0.8% of the African population, as a new risk factor for ventricular arrhythmia.

Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion.

BACKGROUND: T-wave inversion (TWI) is common in patients with cardiomyopathy. However, up to 25% of athletes of African/Afro-Caribbean descent (black athletes) and 5% of white athletes also have TWI of unclear clinical significance despite comprehensive clinical evaluation and long-term follow-up. The aim of this study was to determine the diagnostic yield from genetic testing, beyond clinical evaluation, when investigating athletes with TWI. METHODS: We investigated 50 consecutive asymptomatic black and 50 white athletes 14 to 35 years of age with TWI and a normal echocardiogram who were referred to a UK tertiary center for cardiomyopathy and sports cardiology. Subjects underwent exercise testing, 24-hour ambulatory ECG, signal-averaged ECG, cardiac magnetic resonance imaging, and a blood-based analysis of a comprehensive 311-gene panel for cardiomyopathies and ion channel disorders associated with TWI, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, long-QT syndrome, and Brugada syndrome. RESULTS: In total, 21 athletes (21%) were diagnosed with cardiac disease on the basis of comprehensive clinical investigations. Of these, 8 (38.1%) were gene positive (myosin binding protein C[ MYBPC3], myosin heavy chain 7 [ MYH7], galactosidase alpha [ GLA], and actin alpha, cardiac muscle 1 [ ACTC1] genes) and 13 (61.9%) were gene negative. Of the remaining 79 athletes (79%), 2 (2.5%) were gene positive (transthyretin [ TTR] and sodium voltage-gated channel alpha subunit 5 [ SCN5A] genes) in the absence of a clinical phenotype. The prevalence of newly diagnosed cardiomyopathy was higher in white athletes compared with black athletes (30.0% versus 12%; P=0.027). Hypertrophic cardiomyopathy accounted for 90.5% of all clinical diagnoses. All black athletes and 93.3% of white athletes with a clinical diagnosis of cardiomyopathy or a genetic mutation capable of causing cardiomyopathy exhibited lateral TWI as opposed to isolated anterior or inferior TWI; the genetic yield of diagnoses from lateral TWI was 12.3%. CONCLUSIONS: Up to 10% of athletes with TWI revealed mutations capable of causing cardiac disease. Despite the substantial cost, the positive diagnostic yield from genetic testing was one half that from clinical evaluation (10% versus 21%) and contributed to additional diagnoses in only 2.5% of athletes with TWI in the absence of a clear clinical phenotype, making it of negligible use in routine clinical practice.

Genome-wide association study of heart rate and its variability in Hispanic/Latino cohorts.

BACKGROUND: Although time-domain measures of heart rate variability (HRV) are used to estimate cardiac autonomic tone and disease risk in multiethnic populations, the genetic epidemiology of HRV in Hispanics/Latinos has not been characterized. OBJECTIVE: The purpose of this study was to conduct a genome-wide association study of heart rate (HR) and its variability in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Women's Health Initiative Hispanic SNP-Health Association Resource project (n = 13,767). METHODS: We estimated HR (bpm), standard deviation of normal-to-normal interbeat intervals (SDNN, ms), and root mean squared difference in successive, normal-to-normal interbeat intervals (RMSSD, ms) from resting, standard 12-lead ECGs. We estimated associations between each phenotype and 17 million genotyped or imputed single nucleotide polymorphisms (SNPs), accounting for relatedness and adjusting for age, sex, study site, and ancestry. Cohort-specific estimates were combined using fixed-effects, inverse-variance meta-analysis. We investigated replication for select SNPs exceeding genome-wide (P <5 × 10-8) or suggestive (P <10-6) significance thresholds. RESULTS: Two genome-wide significant SNPs replicated in a European ancestry cohort, 1 one for RMSSD (rs4963772; chromosome 12) and another for SDNN (rs12982903; chromosome 19). A suggestive SNP for HR (rs236352; chromosome 6) replicated in an African-American cohort. Functional annotation of replicated SNPs in cardiac and neuronal tissues identified potentially causal variants and mechanisms. CONCLUSION: This first genome-wide association study of HRV and HR in Hispanics/Latinos underscores the potential for even modestly sized samples of non-European ancestry to inform the genetic epidemiology of complex traits.

Electrocardiographic Predictors of Heart Failure With Reduced Versus Preserved Ejection Fraction: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Several markers detected on the routine 12-lead ECG are associated with future heart failure events. We examined whether these markers are able to separate the risk of heart failure with reduced ejection fraction (HFrEF) from heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed data of 6664 participants (53% female; mean age 62±10 years) from MESA (Multi-Ethnic Study of Atherosclerosis) who were free of cardiovascular disease at baseline (2000-2002). A competing risks analysis was used to compare the association of several baseline ECG predictors with HFrEF and HFpEF detected during a median follow-up of 12.1 years. A total of 127 HFrEF and 117 HFpEF events were detected during follow-up. In a multivariable adjusted model, prolonged QRS duration, delayed intrinsicoid deflection, left-axis deviation, right-axis deviation, prolonged QT interval, abnormal QRS-T axis, left ventricular hypertrophy, ST/T-wave abnormalities, and left bundle-branch block were associated with HFrEF. In contrast, higher resting heart rate, abnormal P-wave axis, and abnormal QRS-T axis were associated with HFpEF. The risk of HFrEF versus HFpEF was significantly differently for delayed intrinsicoid deflection (hazard ratio: 4.90 [95% confidence interval (CI), 2.77-8.68] versus 0.94 [95% CI, 0.29-2.97]; comparison P=0.013), prolonged QT interval (hazard ratio: 2.39 [95% CI, 1.55-3.68] versus 0.52 [95% CI, 0.23-1.19]; comparison P<0.001), and ST/T-wave abnormalities (hazard ratio: 2.47 [95% CI, 1.69-3.62] versus 1.13 [95% CI, 0.72-1.77]; comparison P=0.0093). CONCLUSIONS: Markers of ventricular repolarization and delayed ventricular activation are able to distinguish between the future risk of HFrEF and HFpEF. These findings suggest a role for ECG markers in the personalized risk assessment of heart failure subtypes.

iPSCORE: A Resource of 222 iPSC Lines Enabling Functional Characterization of Genetic Variation across a Variety of Cell Types.

Large-scale collections of induced pluripotent stem cells (iPSCs) could serve as powerful model systems for examining how genetic variation affects biology and disease. Here we describe the iPSCORE resource: a collection of systematically derived and characterized iPSC lines from 222 ethnically diverse individuals that allows for both familial and association-based genetic studies. iPSCORE lines are pluripotent with high genomic integrity (no or low numbers of somatic copy-number variants) as determined using high-throughput RNA-sequencing and genotyping arrays, respectively. Using iPSCs from a family of individuals, we show that iPSC-derived cardiomyocytes demonstrate gene expression patterns that cluster by genetic background, and can be used to examine variants associated with physiological and disease phenotypes. The iPSCORE collection contains representative individuals for risk and non-risk alleles for 95% of SNPs associated with human phenotypes through genome-wide association studies. Our study demonstrates the utility of iPSCORE for examining how genetic variants influence molecular and physiological traits in iPSCs and derived cell lines.

Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.

BACKGROUND: Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation. METHODS AND RESULTS: Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant. CONCLUSIONS: We identify the first disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.

Electrocardiographic early repolarization characteristics and clinical presentations in the young: a benign finding or worrisome marker for arrhythmias.

BACKGROUND: The early ECG repolarization QRS pattern (ERp), with J-point elevation of 0.1 mV in two contiguous inferior and/or lateral leads, can be associated with ventricular arrhythmias among adults. The significance of an ERp in the young is unknown. OBJECTIVE: The purpose of this study was to assess the prevalence of ERp among young patients (pts), describe and correlate the characteristics with clinical presentations and any arrhythmias. METHODS: This was a 1 y retrospective review of ECGs obtained from patients referred specifically for documented arrhythmias, possible arrhythmia-related symptoms or sports clearance. ECGs were analyzed for ERp (J-point, ascending/horizontal patterns, location) and correlated with presenting complaints. RESULTS: Of 301 patient ECGs, an ERp was found in 177 (59%), (pts age 11.7 ± 4.3 y); 54% male; 23% Caucasian. Of these, 6 pts had a family history of sudden cardiac death. Arrhythmias (72% atrial) occurred in 22 pts. Only 3 pts had ventricular arrhythmias (1 successfully ablated). The ascending ST segment and elevated J-point occurred in 77% and 51% of pts with and without arrhythmias respectively. In 73% of all pts, the ERp location was in inferior/lateral leads. Neither gender, ethnicity, large J-point, lead location, nor the combination of a horizontal ST segment with large J-point correlated with any arrhythmias. CONCLUSIONS: ERp, especially the diffuse ascending pattern, is common among the young, in those of European ethnicity, found equally in both genders, and with no apparent correlation with atrial nor ventricular arrhythmias.