Publications by authors named "Larisa G Tereshchenko"

110 Publications

Functional outcomes of sleep predict cardiovascular intermediary outcomes and all-cause mortality in incident hemodialysis patients.

J Clin Sleep Med 2021 Mar 29. Epub 2021 Mar 29.

Department of Medicine, The Miriam Hospital, Warren Alpert Medical School of Brown University, Providence, RI.

Study Objectives: Patients with end-stage kidney disease (ESKD) commonly experience sleep disturbances. Sleep disturbance has been inconsistently associated with mortality risk in hemodialysis patients, but the burden of symptoms from sleep disturbances has emerged as a marker that may shed light on these discrepancies and guide treatment decisions. This study examines whether functional outcomes of sleep are associated with increased risk of intermediary CV outcomes or mortality among adults initiating hemodialysis.

Methods: In 228 participants enrolled in the Predictors of Arrhythmic and Cardiovascular risk in ESRD (PACE) study, the Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), which assesses functional outcomes of daytime sleepiness, was administered within 6 months of enrollment. Intermediary CV outcomes included QTc [ms], heart rate variance [ms²], left ventricular mass index [g/m², LVMI], and left ventricular hypertrophy [LVH]. The association of FOSQ-10 score with all-cause mortality was examined using proportional hazards regression. Results: Mean age was 55 years, median BMI was 28 kg/m² (IQR 24,33), with 70% African Americans. Median FOSQ-10 score was 19.7 (IQR: 17.1,20.0). A 10% lower FOSQ-10 score was associated with increased mortality risk (HR 1.09, 95%CI 1.01-1.18). Lower FOSQ-10 scores were associated with longer QTc duration and lower heart rate variance, but not LVMI or LVH.

Conclusions: In adults initiating dialysis, sleep-related functional impairment is common and is associated with intermediary cardiovascular disease measures and increased mortality risk. Future studies should assess the impact of screening for sleep disturbances in ESKD patients to identify individuals at increased risk for cardiovascular complications and death.
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http://dx.doi.org/10.5664/jcsm.9304DOI Listing
March 2021

Competing risks in patients with primary prevention implantable cardioverter-defibrillators: Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study.

Heart Rhythm 2021 Mar 6. Epub 2021 Mar 6.

Oregon Health & Science University, Portland, Oregon. Electronic address:

Background: Global electrical heterogeneity (GEH) is associated with sudden cardiac death in the general population. Its utility in patients with systolic heart failure who are candidates for primary prevention (PP) implantable cardioverter-defibrillators (ICDs) is unclear.

Objective: This purpose of this study was to investigate whether GEH is associated with sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies in patients with heart failure and PP ICDs.

Methods: We conducted a multicenter retrospective cohort study. GEH was measured by spatial ventricular gradient (SVG) direction (azimuth and elevation) and magnitude, QRS-T angle, and sum absolute QRST integral on preimplant 12-lead electrocardiograms. Survival analysis using cause-specific hazard functions compared the strength of associations with 2 competing outcomes: sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies and all-cause death without appropriate ICD therapies.

Results: We analyzed 2668 patients (mean age 63 ± 12 years; 23% female; 78% white; 43% nonischemic cardiomyopathy; left ventricular ejection fraction 28% ± 11% from 6 academic medical centers). After adjustment for demographic, clinical, device, and traditional electrocardiographic characteristics, SVG elevation (hazard ratio [HR] per 1SD 1.14; 95% confidence interval [CI] 1.04-1.25; P = .004), SVG azimuth (HR per 1SD 1.12; 95% CI 1.01-1.24; P = .039), SVG magnitude (HR per 1SD 0.75; 95% CI 0.66-0.85; P < .0001), and QRS-T angle (HR per 1SD 1.21; 95% CI 1.08-1.36; P = .001) were associated with appropriate ICD therapies. Sum absolute QRST integral had different associations in infarct-related cardiomyopathy (HR 1.29; 95% CI 1.04-1.60) and nonischemic cardiomyopathy (HR 0.78; 95% CI 0.62-0.96) (P = .022).

Conclusion: In patients with PP ICDs, GEH is independently associated with appropriate ICD therapies. The SVG vector points in distinctly different directions in patients with 2 competing outcomes.
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http://dx.doi.org/10.1016/j.hrthm.2021.03.006DOI Listing
March 2021

Characteristics of Cardiac Memory in Patients with Implanted Cardioverter-defibrillators: The Cardiac Memory with Implantable Cardioverter-defibrillator (CAMI) Study.

J Innov Card Rhythm Manag 2021 Feb 15;12(2):4395-4408. Epub 2021 Feb 15.

Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA.

This study sought to determine factors associated with cardiac memory (CM) in patients with implantable cardioverter-defibrillators (ICDs). Patients with structural heart disease [n = 20; mean age: 72.6 ± 11.6 years; 80% male; mean left ventricular ejection fraction (LVEF): 31.7 ± 7.6%; history of myocardial infarction in 75% and nonsustained ventricular tachycardia (NSVT) in 85%] and preserved atrioventricular conduction received dual-chamber ICDs for primary (80%) or secondary (20%) prevention. Standard 12-lead electrocardiograms were recorded in AAI and DDD modes before and after seven days of right ventricular (RV) pacing in DDD mode with a short atrioventricular delay. The direction (azimuth and elevation) and magnitude of spatial QRS, T, and spatial ventricular gradient vectors were measured before and after seven days of RV pacing. CM was quantified as the degree of alignment between QRS and T vectors (QRS -T angle). Circular statistics and mixed models with a random slope and intercept were adjusted for changes in cardiac activation, LVEF, known risk factors, and the use of medications known to affect CM occurring on days 1 through 7. The QRS-T angle strongly correlated (circular r = -0.972; p < 0.0001) with a T-T angle. In the mixed models, CM-T azimuth changes [+132° (95% confidence interval (CI): 80°-184°); p < 0.0001] were counteracted by the history of MI [-180° (95% CI: -320° to -40°); p = 0.011] and female sex [-162° (95% CI: -268° to -55°); p = 0.003]. A CM-T area increase [+15 (95% CI: 6-24) mV*ms; p < 0.0001] was amplified by NSVT history [+27 (95% CI: 4-46) mV*ms; p = 0.007]. These findings suggest that preexistent electrical remodeling affects CM in response to RV pacing, that CM exhibits saturation behavior, and that women reach CM saturation more easily than men.
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http://dx.doi.org/10.19102/icrm.2021.120204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909362PMC
February 2021

Sex differences in vectorcardiogram of African-Americans with and without cardiovascular disease: a cross-sectional study in the Jackson Heart Study cohort.

BMJ Open 2021 01 31;11(1):e042899. Epub 2021 Jan 31.

Department of Medicine, Cardiovascular Division, Oregon Health & Science University School of Medicine, Portland, Oregon, USA

Objectives: We hypothesised that (1) the prevalent cardiovascular disease (CVD) is associated with global electrical heterogeneity (GEH) after adjustment for demographic, anthropometric, socioeconomic and traditional cardiovascular risk factors, (2) there are sex differences in GEH and (3) sex modifies an association of prevalent CVD with GEH.

Design: Cross-sectional, cohort study.

Setting: Prospective African-American The Jackson Heart Study (JHS) with a nested family cohort in 2000-2004 enrolled residents of the Jackson, Mississippi metropolitan area.

Participants: Participants from the JHS with analysable ECGs recorded in 2009-2013 (n=3679; 62±12 y; 36% men; 863 family units). QRS, T and spatial ventricular gradient (SVG) vectors' magnitude and direction, spatial QRS-T angle and sum absolute QRST integral (SAI QRST) were measured.

Outcome: Prevalent CVD was defined as the history of (1) coronary heart disease defined as diagnosed/silent myocardial infarction, or (2) revascularisation procedure defined as prior coronary/peripheral arterial revascularisation, or (3) carotid angioplasty/carotid endarterectomy, or (4) stroke.

Results: In adjusted mixed linear models, women had a smaller spatial QRS-T angle (-12.2 (95% CI -19.4 to -5.1)°; p=0.001) and SAI QRST (-29.8 (-39.3 to -20.3) mV*ms; p<0.0001) than men, but larger SVG azimuth (+16.2(10.5-21.9)°; p<0.0001), with a significant random effect between families (+20.8 (8.2-33.5)°; p=0.001). SAI QRST was larger in women with CVD as compared with CVD-free women or men (+15.1 (3.8-26.4) mV*ms; p=0.009). Men with CVD had a smaller T area (by 5.1 (95% CI 1.2 to 9.0) mV*ms) and T peak magnitude (by 44 (95%CI 16 to 71) µV) than CVD-free men. T vectors pointed more posteriorly in women as compared with men (peak T azimuth + 17.2(8.9-25.6)°; p<0.0001), with larger sex differences in T azimuth in some families by +26.3(7.4-45.3)°; p=0.006.

Conclusions: There are sex differences in the electrical signature of CVD in African-American men and women. There is a significant effect of unmeasured genetic and environmental factors on cardiac repolarisation.
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http://dx.doi.org/10.1136/bmjopen-2020-042899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852937PMC
January 2021

Worsening Kidney Function Is the Major Mechanism of Heart Failure in Hypertension: The ALLHAT Study.

JACC Heart Fail 2021 Feb 11;9(2):100-111. Epub 2020 Nov 11.

Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon, USA. Electronic address:

Objectives: The authors aimed to quantify the extent to which the effect of antihypertensive drugs on incident heart failure (HF) is mediated by their effect on kidney function.

Background: The authors hypothesized that the dynamic change in kidney function is the mechanism behind differences in the rate of incident HF in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) participants randomized to lisinopril and chlorthalidone, in comparison with those randomized to amlodipine and doxazosin.

Methods: Causal mediation analysis of ALLHAT data (1994 to 2002) included participants with available baseline and 24- to 48-month estimated glomerular filtration rate (eGFR) (N = 27,918; mean age 66 ± 7.4 years; 32.4% Black, 56.3% men). Change in eGFR was the mediator. Incident symptomatic HF was the primary outcome. Hospitalized/fatal HF was the secondary outcome. Linear regression (for mediator) and logistic regression (for outcome) analyses were adjusted for demographics, cardiovascular disease, and risk factors.

Results: There were 1,769 incident HF events, including 1,359 hospitalized/fatal HF events. In fully adjusted causal mediation analysis, the relative change in eGFR mediated 18% of the effect of chlorthalidone, and 33% of lisinopril on incident symptomatic HF, and 25% of the effect of chlorthalidone, and 41% of lisinopril on hospitalized/fatal HF. In participants with diabetes, the relative change in eGFR mediated nearly 50% of the effect of lisinopril on incident symptomatic HF, whereas in diabetes-free participants, only 17%.

Conclusions: On the risk difference scale, change in eGFR accounts for up to 50% of the mechanism by which antihypertensive medications affect HF. (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; NCT00000542).
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http://dx.doi.org/10.1016/j.jchf.2020.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855256PMC
February 2021

Applying Artificial Intelligence to ECG Analysis: Promise of a Better Future.

Circ Arrhythm Electrophysiol 2020 08 4;13(8):e009111. Epub 2020 Aug 4.

Knight Cardiovascular Institute, Department of Medicine, Oregon Health & Science University, School of Medicine, Portland.

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http://dx.doi.org/10.1161/CIRCEP.120.009111DOI Listing
August 2020

Global electrical heterogeneity associated with drug-induced torsades de pointes.

Heart Rhythm 2021 Jan 8;18(1):57-62. Epub 2020 Aug 8.

Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Drugs belonging to diverse therapeutic classes can prolong myocardial refractoriness or slow conduction. These drugs may be effective and well-tolerated, but the risk of sudden cardiac death from torsades de pointes (TdP) remains a major concern. The corrected QT interval has significant limitations when used for risk stratification. Measurement of global electrical heterogeneity (GEH) could help identify the substrate vulnerable to drug-induced ventricular arrhythmias.

Objective: The purpose of this study was to improve risk stratification for drug-induced TdP by measuring GEH on the electrocardiogram (ECG).

Methods: We analyzed ECG data from a case-control study of patients with a history of drug-induced TdP as well as age- and sex-matched controls. Vectorcardiograms were constructed from ECGs. GEH was measured via the spatial ventricular gradient (SVG) vector (magnitude, azimuth, and elevation). Log odds coefficients for TdP were estimated using multivariable logistic regression.

Results: Among 17 cases (47% male; age 58.9 ± 12.5 years) and 17 controls (29% male; age 61.0 ± 12.2 years), 34 ECGs were analyzed. SVG azimuth was significantly different between cases and controls (3.4 vs 22.0 degrees, respectively; P = 0.02). After adjusting for sex and QTc interval, odds of TdP increased by a factor of 3.2 for each 1 SD change in SVG azimuth from the control group mean (95% confidence interval 1.07-9.14; P = .04). QTc was not significant in the multivariable analysis (P = .20).

Conclusion: SVG azimuth is correlated with a history of drug-induced TdP independent of QTc. GEH measurement may help identify patients at high risk for drug-induced arrhythmias.
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http://dx.doi.org/10.1016/j.hrthm.2020.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796973PMC
January 2021

The Association Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and the Number of Covid-19 Confirmed Cases and Deaths in the United States: Geospatial Study.

medRxiv 2020 Jun 1. Epub 2020 Jun 1.

Background: The novel coronavirus SARS-Cov2 uses the angiotensin-converting enzyme 2 (ACE2) receptor as an entry point to the cell. Cardiovascular disease (CVD) is a risk factor for the novel coronavirus disease (Covid-19) with poor outcomes. We hypothesized that the rate of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) use is associated with the rate of Covid-19 confirmed cases and deaths.

Methods: We conducted a geospatial study using publicly available county-level data. The Medicare ACEIs and ARBs prescription rate was exposure. The Covid-19 confirmed case and death rates were outcomes. Spatial autoregression models were adjusted for the percentage of Black residents, children, residents with at least some college degree, median household income, air quality index, CVD hospitalization rate in Medicare beneficiaries, and CVD death rate in a total county population.

Results: The ACEI use had no effect on Covid-19 confirmed case rate. An average ACEIs use (compared to no-use) was associated with a higher Covid-19 death rate by 1.1 (95%CI 0.4-1.8)%. If the use of ACEIs increases by 0.5% for all counties, the Covid-19 death rate will drop by 0.4% to 0.7(95%CI 0.3-1.1)%; P<0.0001. An average ARBs use (compared to no-use) was associated with a higher Covid-19 confirmed case rate (by 4.2; 95%CI 4.1-4.3 %) and death rate (by 1.1; 95%CI 0.7-1.5 %). Each percent increase in ARBs use was associated with an increase in confirmed case rate by 0.2(0.03-0.4)% and death rate by 0.14(0.08-0.21)%.

Conclusions: ARBs, but not ACEIs use rate, is associated with Covid-19 confirmed case rate.
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http://dx.doi.org/10.1101/2020.05.31.20118802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302286PMC
June 2020

Mechanisms of Arrhythmogenicity in Hypertrophic Cardiomyopathy: Insight From Non-invasive Electrocardiographic Imaging.

Front Physiol 2020 24;11:344. Epub 2020 Apr 24.

Department of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, United States.

Background: Mechanisms of arrhythmogenicity in hypertrophic cardiomyopathy (HCM) are not well understood.

Objective: To characterize an electrophysiological substrate of HCM in comparison to ischemic cardiomyopathy (ICM), or healthy individuals.

Methods: We conducted a prospective case-control study. The study enrolled HCM patients at high risk for ventricular tachyarrhythmia (VT) [ = 10; age 61 ± 9 years; left ventricular ejection fraction (LVEF) 60 ± 9%], and three comparison groups: healthy individuals ( = 10; age 28 ± 6 years; LVEF > 70%), ICM patients with LV hypertrophy (LVH) and known VT ( = 10; age 64 ± 9 years; LVEF 31 ± 15%), and ICM patients with LVH and no known VT ( = 10; age 70 ± 7 years; LVEF 46 ± 16%). All participants underwent 12-lead ECG, cardiac CT or MRI, and 128-electrode body surface mapping (BioSemi ActiveTwo, Netherlands). Non-invasive voltage and activation maps were reconstructed using the open-source SCIRun (University of Utah) inverse problem-solving environment.

Results: In the epicardial basal anterior segment, HCM patients had the greatest ventricular activation dispersion [16.4 ± 5.5 vs. 13.1 ± 2.7 (ICM with VT) vs. 13.8 ± 4.3 (ICM no VT) vs. 8.1 ± 2.4 ms (Healthy); = 0.0007], the largest unipolar voltage [1094 ± 211 vs. 934 ± 189 (ICM with VT) vs. 898 ± 358 (ICM no VT) vs. 842 ± 90 μV (Healthy); = 0.023], and the greatest voltage dispersion [median (interquartile range) 215 (161-281) vs. 189 (143-208) (ICM with VT) vs. 158 (109-236) (ICM no VT) vs. 110 (106-168) μV (Healthy); = 0.041]. Differences were also observed in other endo-and epicardial basal and apical segments.

Conclusion: HCM is characterized by a greater activation dispersion in basal segments, a larger voltage, and a larger voltage dispersion through LV.

Clinical Trial Registration: www.clinicaltrials.gov Unique identifier: NCT02806479.
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http://dx.doi.org/10.3389/fphys.2020.00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194131PMC
April 2020

Eligibility for subcutaneous implantable cardioverter-defibrillator in congenital heart disease.

Heart Rhythm 2020 05;17(5 Pt B):860-869

Oregon Health & Science University, Knight Cardiovascular Institute, Portland, Oregon. Electronic address:

Background: Adult congenital heart disease (ACHD) patients can benefit from a subcutaneous implantable cardioverter-defibrillator (S-ICD).

Objective: The purpose of this study was to assess left- and right-sided S-ICD eligibility in ACHD patients, use machine learning to predict S-ICD eligibility in ACHD patients, and transform 12-lead electrocardiogram (ECG) to S-ICD 3-lead ECG, and vice versa.

Methods: ACHD outpatients (n = 101; age 42 ± 14 years; 52% female; 85% white; left ventricular ejection fraction [LVEF] 56% ± 9%) were enrolled in a prospective study. Supine and standing 12-lead ECG were recorded simultaneously with a right- and left-sided S-ICD 3-lead ECG. Peak-to-peak QRS and T amplitudes; RR, PR, QT, QTc, and QRS intervals; Tmax, and R/Tmax (31 predictor variables) were tested. Model selection, training, and testing were performed using supine ECG datasets. Validation was performed using standing ECG datasets and an out-of-sample non-ACHD population (n = 68; age 54 ± 16 years; 54% female; 94% white; LVEF 61% ± 8%).

Results: Forty percent of participants were ineligible for S-ICD. Tetralogy of Fallot patients passed right-sided screening (57%) more often than left-sided screening (21%; McNemar χP = .025). Female participants had greater odds of eligibility (adjusted odds ratio [OR] 5.9; 95% confidence interval [CI] 1.6-21.7; P = .008). Validation of the ridge models was satisfactory for standing left-sided (receiver operating characteristic area under the curve [ROC AUC] 0.687; 95% CI 0.582-0.791) and right-sided (ROC AUC 0.655; 95% CI 0.549-0.762) S-ICD eligibility prediction. Validation of transformation matrices showed satisfactory agreement (<0.1 mV difference).

Conclusion: Nearly half of the contemporary ACHD population is ineligible for S-ICD. The odds of S-ICD eligibility are greater for female than for male ACHD patients. Machine learning prediction of S-ICD eligibility can be used for screening of S-ICD candidates.
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http://dx.doi.org/10.1016/j.hrthm.2020.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197388PMC
May 2020

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

J Am Heart Assoc 2020 02 30;9(3):e015012. Epub 2020 Jan 30.

Knight Cardiovascular Institute Oregon Health and Science University Portland OR.

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) (-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.
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http://dx.doi.org/10.1161/JAHA.119.015012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033892PMC
February 2020

Dynamic predictive accuracy of electrocardiographic biomarkers of sudden cardiac death within a survival framework: the Atherosclerosis Risk in Communities (ARIC) study.

BMC Cardiovasc Disord 2019 11 14;19(1):255. Epub 2019 Nov 14.

Knight Cardiovascular Institute, Department of Medicine, Oregon Health & Science University School of Medicine, 3181 SW Sam Jackson Park Rd; UHN62, Portland, OR, 97239, USA.

Background: The risk of sudden cardiac death (SCD) is known to be dynamic. However, the accuracy of a dynamic SCD prediction is unknown. We aimed to measure the dynamic predictive accuracy of ECG biomarkers of SCD and competing non-sudden cardiac death (non-SCD).

Methods: Atherosclerosis Risk In Community study participants with analyzable ECGs in sinus rhythm were included (n = 15,716; 55% female, 73% white, age 54.2 ± 5.8 y). ECGs of 5 follow-up visits were analyzed. Global electrical heterogeneity and traditional ECG metrics (heart rate, QRS, QTc) were measured. Adjudicated SCD was the primary outcome; non-SCD was the competing outcome. Time-dependent area under the receiver operating characteristic curve (ROC(t) AUC) analysis was performed to assess the prediction accuracy of a continuous biomarker in a period of 3,6,9 months, and 1,2,3,5,10, and 15 years using a survival analysis framework. Reclassification improvement as compared to clinical risk factors (age, sex, race, diabetes, hypertension, coronary heart disease, stroke) was measured.

Results: Over a median 24.4 y follow-up, there were 577 SCDs (incidence 1.76 (95%CI 1.63-1.91)/1000 person-years), and 829 non-SCDs [2.55 (95%CI 2.37-2.71)]. No ECG biomarkers predicted SCD within 3 months after ECG recording. Within 6 months, spatial ventricular gradient (SVG) elevation predicted SCD (AUC 0.706; 95%CI 0.526-0.886), but not a non-SCD (AUC 0.527; 95%CI 0.303-0.75). SVG elevation more accurately predicted SCD if the ECG was recorded 6 months before SCD (AUC 0.706; 95%CI 0.526-0.886) than 2 years before SCD (AUC 0.608; 95%CI 0.515-0.701). Within the first 3 months after ECG recording, only SVG azimuth improved reclassification of the risk beyond clinical risk factors: 18% of SCD events were reclassified from low or intermediate risk to a high-risk category. QRS-T angle was the strongest long-term predictor of SCD (AUC 0.710; 95%CI 0.668-0.753 for ECG recorded within 10 years before SCD).

Conclusion: Short-term and long-term predictive accuracy of ECG biomarkers of SCD differed, reflecting differences in transient vs. persistent SCD substrates. The dynamic predictive accuracy of ECG biomarkers should be considered for competing SCD risk scores. The distinction between markers predicting short-term and long-term events may represent the difference between markers heralding SCD (triggers or transient substrates) versus markers identifying persistent substrate.
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http://dx.doi.org/10.1186/s12872-019-1234-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854807PMC
November 2019

Hemodialysis Procedure-Associated Autonomic Imbalance and Cardiac Arrhythmias: Insights From Continuous 14-Day ECG Monitoring.

J Am Heart Assoc 2019 10 28;8(19):e013748. Epub 2019 Sep 28.

Oregon Health & Science University Portland OR.

Background In patients with end-stage kidney disease, sudden cardiac death is more frequent after a long interdialytic interval, within 6 hours after the end of a hemodialysis session. We hypothesized that the occurrence of paroxysmal arrhythmias is associated with changes in heart rate and heart rate variability in different phases of hemodialysis. Methods and Results We conducted a prospective ancillary study of the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease cohort. Continuous ECG monitoring was performed using an ECG patch, and short-term heart rate variability was measured for 3 minutes every hour (by root mean square of the successive normal-to-normal intervals, spectral analysis, Poincaré plot, and entropy), up to 300 hours. Out of enrolled participants (n=28; age 54±13 years; 57% men; 96% black; 33% with a history of cardiovascular disease; left ventricular ejection fraction 70±9%), arrhythmias were detected in 13 (46%). Nonsustained ventricular tachycardia occurred more frequently during/posthemodialysis than pre-/between hemodialysis (63% versus 37%, =0.015). In adjusted for cardiovascular disease time-series analysis, nonsustained ventricular tachycardia was preceded by a sudden heart rate increase (by 11.2 [95% CI 10.1-12.3] beats per minute; <0.0001). During every-other-day dialysis, root mean square of the successive normal-to-normal intervals had a significant circadian pattern (Mesor 10.6 [ 95% CI 0.9-11.2] ms; amplitude 1.5 [95% CI 1.0-3.1] ms; peak at 02:01 [95% CI 20:22-03:16] am; <0.0001), which was replaced by a steady worsening on the second day without dialysis (root mean square of the successive normal-to-normal intervals -1.41 [95% CI -1.67 to -1.15] ms/24 h; <0.0001). Conclusions Sudden increase in heart rate during/posthemodialysis is associated with nonsustained ventricular tachycardia. Every-other-day hemodialysis preserves circadian rhythm, but a second day without dialysis is characterized by parasympathetic withdrawal.
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http://dx.doi.org/10.1161/JAHA.119.013748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806026PMC
October 2019

Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil.

Heart Rhythm 2020 03 17;17(3):460-467. Epub 2019 Sep 17.

Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Electrocardiographic (ECG) markers of antiarrhythmic drug (AAD) activity could be used to optimize efficacy and minimize toxicity. Vectorcardiographic global electrical heterogeneity (GEH) is associated with ventricular arrhythmias and sudden death, but it is unclear how GEH measurements change in response to AADs.

Objective: The purpose of this study was to characterize acute effects of AADs on GEH measurements.

Methods: We analyzed double-blind placebo-controlled trial data from healthy volunteers given 1 dose of placebo, dofetilide, quinidine, ranolazine, or verapamil on subsequent visits. Serial ECGs and plasma drug concentrations were collected. Vectorcardiographic GEH parameters (spatial ventricular gradient [SVG], spatial QRST angle, sum absolute QRST integral, and SVG-QRS peak angle) were measured. Placebo-corrected change from baseline was regressed on drug concentration stratified by sex using linear mixed effects models.

Results: Among 22 persons (11 (50%) male median age 27 ± 5 years), 5232 ECGs were analyzed. Dofetilide and quinidine were associated with significant changes in more GEH parameters (5) compared with verapamil (2) and ranolazine (1). The most notable change occurred in SVG azimuth, with largest changes (degrees per unit normalized drug concentration) in dofetilide (6.1; 95% confidence interval [CI] 4.2-8.0) and quinidine (9.4; 95% CI 6.7-12.0), and smaller effects in verapamil (4.4; 95% CI 2.9-5.9) and ranolazine (5.4; 95% CI 3.5-7.3). AAD-induced GEH changes significantly differed in men and women.

Conclusion: AADs change GEH measurements. These changes, which differ by sex, are likely driven by alterations in ion channel function and dispersion of depolarization or repolarization. GEH measurement may allow early assessment of favorable or adverse AAD effects.
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http://dx.doi.org/10.1016/j.hrthm.2019.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056537PMC
March 2020

Plasticizer Interaction With the Heart: Chemicals Used in Plastic Medical Devices Can Interfere With Cardiac Electrophysiology.

Circ Arrhythm Electrophysiol 2019 07 28;12(7):e007294. Epub 2019 Jun 28.

Sheikh Zayed Institute for Pediatric Surgical Innovation (R.J., D. McCullough, L.S., D. McInerney, J.H., N.G.P.), Children's National Health System, Washington DC.

Background: Phthalates are used as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients.

Methods: Optical mapping of transmembrane voltage and pacing studies were performed on isolated, Langendorff-perfused rat hearts to assess cardiac electrophysiology after MEHP exposure compared with controls. MEHP dose was chosen based on reported blood concentrations after an exchange transfusion procedure.

Results: Thirty-minute exposure to MEHP increased the atrioventricular node (147 versus 107 ms) and ventricular (117 versus 77.5 ms) effective refractory periods, compared with controls. Optical mapping revealed prolonged action potential duration at slower pacing cycle lengths, akin to reverse use dependence. The plateau phase of the action potential duration restitution curve steepened and became monophasic in MEHP-exposed hearts (0.18 versus 0.06 slope). Action potential duration lengthening occurred during late-phase repolarization resulting in triangulation (70.3 versus 56.6 ms). MEHP exposure also slowed epicardial conduction velocity (35 versus 60 cm/s), which may be partly explained by inhibition of Na1.5 (874 and 231 µmol/L half-maximal inhibitory concentration, fast and late sodium current).

Conclusions: This study highlights the impact of acute MEHP exposure, using a clinically relevant dose, on cardiac electrophysiology in the intact heart. Heightened clinical exposure to plasticized medical products may have cardiac safety implications-given that action potential triangulation and electrical restitution modifications are a risk factor for early after depolarizations and cardiac arrhythmias.
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http://dx.doi.org/10.1161/CIRCEP.119.007294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693678PMC
July 2019

Associations of serum and dialysate electrolytes with QT interval and prolongation in incident hemodialysis: the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) study.

BMC Nephrol 2019 04 18;20(1):133. Epub 2019 Apr 18.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Prolonged QT interval in hemodialysis patients may be associated with sudden cardiac death, however, few studies examined the longitudinal associations of modifiable factors such as serum and dialysate concentrations of calcium, potassium, and magnesium with corrected QT (QTc) prolongation in incident hemodialysis patients.

Methods: In 330 in-center hemodialysis participants from the PACE study who were followed up for one year, we examined the associations of predialysis serum electrolytes (total calcium [Ca], corrected Ca [cCa], ionized Ca [iCa], potassium [K], magnesium [Mg]), dialysate (dCa and dK), and serum-to-dialysate gradient measures with QTc interval and prolongation (≥460 ms in women and ≥ 450 ms in men).

Results: At the first study visit, 47% had QTc prolongation. Lower iCa and K were associated with longer QTc interval independent of potential confounders (QTc difference = 8.55[95% CI: 2.13, 14.97] ms for iCa; QTc difference = 9.89[1.58, 18.20] ms for K). Lower iCa was also associated with a higher risk of QTc prolongation. At 1 year of follow-up, 31% had persistent QTc prolongation. In longitudinal analyses, the associations of iCa and K with QTc interval remained significant, and lower K was associated with a higher risk of QTc prolongation while the association of iCa with QTc prolongation was borderline statistically significant. Serum Mg, dCa or dK, and respective gradients were not associated with QTc interval or prolongation.

Conclusion: Prolonged QTc is very common in incident hemodialysis participants and persists over follow-up. Ionized Ca and K are consistently inversely associated with QTc prolongation, which suggests closer monitoring for a low calcium or potassium level to mitigate risk.
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http://dx.doi.org/10.1186/s12882-019-1282-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474045PMC
April 2019

Prevention of Heart Failure in Hypertension-Disentangling the Role of Evolving Left Ventricular Hypertrophy and Blood Pressure Lowering: The ALLHAT Study.

J Am Heart Assoc 2019 04;8(8):e011961

1 The Knight Cardiovascular Institute Oregon Health & Science University Portland OR.

Background Hypertension is a known risk factor for heart failure ( HF ), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy ( LVH ). We studied the extent to which blood pressure ( BP ) change and evolving LVH contribute to the effect that lisinopril, doxazosin, and amlodipine have on HF compared with chlorthalidone. Methods and Results We conducted causal mediation analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) data (1994-2002; in-trial follow-up). ALLHAT participants with available serial ECG s and BP measurements were included (n=29 892; mean age 67±4 years; 32% black; 56% men): 11 008 were randomized to chlorthalidone, 5967 to doxazosin, 6593 to amlodipine, and 6324 to lisinopril. Evolving ECG LVH and BP lowering served as mediators. Incident symptomatic HF was the primary outcome. Linear regression (for mediator) and logistic regression (for outcome) models were adjusted for mediator-outcome confounders (demographic and clinical characteristics known to be associated both with both LVH /hypertension and HF ). A large majority of participants (96%) had ECG LVH status unchanged, but 4% developed evolving ECG LVH . On average, BP decreased by 11/7 mm Hg. In adjusted Cox regression analyses, progressing ECG LVH (hazard ratio [ HR ] 1.78 [95% CI 1.43-2.22]), resolving ECG LVH ( HR 1.33 [95% CI 1.03-1.70]), and baseline ECG LVH (1.17 [95% CI 1.04-1.31]) carried risk of incident HF . After full adjustment, evolving ECG LVH mediated 4% of the effect of doxazosin on HF . Systolic BP lowering mediated 12% of the effect of doxazosin, and diastolic BP lowering mediated 10% of the effect of doxazosin, 7% of the effect of amlodipine, and borderline 9% of the effect of lisinopril on HF . Conclusions Evolving ECG LVH and BP change account for 4% to 13% of the mechanism by which antihypertensive medications prevent HF . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00000542.
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http://dx.doi.org/10.1161/JAHA.119.011961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507192PMC
April 2019

Early Heart Rate Variability and Electroencephalographic Abnormalities in Acutely Brain-Injured Children Who Progress to Brain Death.

Pediatr Crit Care Med 2019 01;20(1):38-46

Center for Policy and Research in Emergency Medicine, Department of Emergency Medicine, Oregon Health and Science University, Portland, OR.

Objectives: Heart rate variability is controlled by the autonomic nervous system. After brain death, this autonomic control stops, and heart rate variability is significantly decreased. However, it is unknown if early changes in heart rate variability are predictive of progression to brain death. We hypothesized that in brain-injured children, lower heart rate variability is an early indicator of autonomic system failure, and it predicts progression to brain death. We additionally explored the association between heart rate variability and markers of brain dysfunction such as electroencephalogram and neurologic examination between brain-injured children who progressed to brain death and those who survived.

Design: Retrospective case-control study.

Setting: PICU, single institution.

Patients: Children up to 18 years with a Glasgow Coma Scale score of less than 8 admitted between August of 2016 and December of 2017, who had electrocardiographic data available for heart rate variability analysis, were included.

Exclusion Criteria: patients who died of causes other than brain death. Twenty-three patients met inclusion criteria: six progressed to brain death (cases), and 17 survived (controls). Five-minute electrocardiogram segments were used to estimate heart rate variability in the time domain (SD of normal-normal intervals, root mean square successive differences), frequency domain (low frequency, high frequency, low frequency/high frequency ratio), Poincaré plots, and approximate entropy.

Interventions: None.

Measurements And Main Results: Patients who progressed to brain death exhibited significantly lower heart rate variability in the time domain, frequency domain, and Poincaré plots (p < 0.01). The odds of death increased with decreasing low frequency (odds ratio, 4.0; 95% CI, 1.2-13.6) and high frequency (odds ratio, 2.5; 95% CI, 1.2-5.4) heart rate variability power (p < 0.03). Heart rate variability was significantly lower in those with discontinuous or attenuated/featureless electroencephalogram versus those with slow/disorganized background (p < 0.03).

Conclusions: These results support the concept of autonomic system failure as an early indicator of impending brain death in brain-injured children. Furthermore, decreased heart rate variability is associated with markers of CNS dysfunction such as electroencephalogram abnormalities.
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http://dx.doi.org/10.1097/PCC.0000000000001759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660831PMC
January 2019

Importance of the heart vector origin point definition for an ECG analysis: The Atherosclerosis Risk in Communities (ARIC) study.

Comput Biol Med 2019 01 17;104:127-138. Epub 2018 Nov 17.

Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address:

Aim: Our goal was to investigate the effect of a global XYZ median beat construction and the heart vector origin point definition on predictive accuracy of ECG biomarkers of sudden cardiac death (SCD).

Methods: Atherosclerosis Risk In Community study participants with analyzable digital ECGs were included (n = 15,768; 55% female, 73% white, mean age 54.2 ± 5.8 y). We developed an algorithm to automatically detect the heart vector origin point on a median beat. Three different approaches to construct a global XYZ beat and two methods to locate origin point were compared. Global electrical heterogeneity was measured by sum absolute QRST integral (SAI QRST), spatial QRS-T angle, and spatial ventricular gradient (SVG) magnitude, azimuth, and elevation. Adjudicated SCD served as the primary outcome.

Results: There was high intra-observer (kappa 0.972) and inter-observer (kappa 0.984) agreement in a heart vector origin definition between an automated algorithm and a human. QRS was wider in a median beat that was constructed using R-peak alignment than in time-coherent beat (88.1 ± 16.7 vs. 83.7 ± 15.9 ms; P < 0.0001), and on a median beat constructed using QRS-onset as a zeroed baseline, vs. isoelectric origin point (86.7 ± 15.9 vs. 83.7 ± 15.9 ms; P < 0.0001). ROC AUC was significantly larger for QRS, QT, peak QRS-T angle, SVG elevation, and SAI QRST if measured on a time-coherent median beat, and for SAI QRST and SVG magnitude if measured on a median beat using isoelectric origin point.

Conclusion: Time-coherent global XYZ median beat with physiologically meaningful definition of the heart vector's origin point improved predictive accuracy of SCD biomarkers.
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http://dx.doi.org/10.1016/j.compbiomed.2018.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400224PMC
January 2019

Association of Abdominal Adiposity with Cardiovascular Mortality in Incident Hemodialysis.

Am J Nephrol 2018 14;48(6):406-414. Epub 2018 Nov 14.

Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada,

Background: The risk of cardiovascular mortality is high among adults with end-stage renal disease (ESRD) undergoing hemodialysis. Waist-to-hip ratio (WHR), a metric of abdominal adiposity, is a predictor of cardiovascular disease (CVD) and mortality in the general population; however, no studies have examined the association with CVD mortality, particularly sudden cardiac death (SCD), in incident hemodialysis.

Methods: Among 379 participants incident (< 6 months) to hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD study, we evaluated associations between WHR and risk of CVD mortality, SCD, and non-CVD mortality in Cox proportional hazards regression models.

Results: At study enrollment, mean age was 55 years with 41% females, 73% African Americans, and 57% diabetics. Mean body mass index was 29.3 kg/m2, and mean WHR was 0.95. During a median follow-up time of 2.5 years, there were 35 CVD deaths, 15 SCDs, and 48 non-CVD deaths. Every 0.1 increase in WHR was associated with higher risk (hazard ratio [95% CI]) of CVD mortality (1.75 [1.06-2.86]) and SCD (2.45 [1.20-5.02]), but not non-CVD mortality (0.93 [0.59-1.45]), independently of demographics, body mass index, comorbidities, inflammation, and traditional CVD risk factors.

Conclusions: WHR is significantly associated with CVD mortality including SCD, independently of other CVD risk factors in incident hemodialysis. This simple, easily obtained bedside metric may be useful in dialysis patients for CVD risk stratification.
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http://dx.doi.org/10.1159/000494281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510390PMC
November 2019

Vectorcardiogram in athletes: The Sun Valley Ski Study.

Ann Noninvasive Electrocardiol 2019 05 7;24(3):e12614. Epub 2018 Nov 7.

Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon.

Background: Global electrical heterogeneity (GEH) is associated with sudden cardiac death (SCD) in adults of 45 years and above. However, GEH has not been previously measured in young athletes. The goal of this study was to establish a reference for vectorcardiograpic (VCG) metrics in male and female athletes.

Methods: Skiers (n = 140; mean age 19.2 ± 3.5 years; 66% male, 94% white; 53% professional athletes) were enrolled in a prospective cohort. Resting 12-lead ECGs were interpreted per the International ECG criteria. Associations of age, sex, and athletic performance with GEH were studied.

Results: In age and training level-adjusted analyses, male sex was associated with a larger T vector [T peak magnitude +186 (95% CI 106-266) µV] and a wider spatial QRS-T angle [+28.2 (17.3-39.2)°] as compared to women. Spatial QRS-T angle in the ECG left ventricular hypertrophy (LVH) voltage group (n = 21; 15%) and normal ECG group did not differ (67.7 ± 25.0 vs. 66.8 ± 28.2; p = 0.914), suggesting that ECG LVH voltage in athletes reflects physiological remodeling. In contrast, skiers with right ventricular hypertrophy (RVH) voltage (n = 26, 18.6%) had wider QRS-T angle (92.7 ± 29.6 vs. 66.8 ± 28.2°; p = 0.001), larger SAI QRST (194.9 ± 30.2 vs. 157.8 ± 42.6 mV × ms; p < 0.0001), but similar peak SVG vector magnitude (1976 ± 548 vs. 1939 ± 395 µV; p = 0.775) as compared to the normal ECG group. Better athletic performance was associated with the narrower QRS-T angle. Each 10% worsening in an athlete's Federation Internationale de' Ski downhill ranking percentile was associated with an increase in spatial QRS-T angle by 2.1 (95% CI 0.3-3.9) degrees (p = 0.013).

Conclusion: Vectorcardiograpic adds nuances to ECG phenomena in athletes.
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http://dx.doi.org/10.1111/anec.12614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476648PMC
May 2019

Global Electrical Heterogeneity: Mechanisms and Clinical Significance.

Comput Cardiol (2010) 2018 Sep 24;45. Epub 2019 Jun 24.

Oregon Health & Science University, Portland, Oregon, USA.

This review summarizes recent findings and discusses a clinical significance of a vectorcardiographic (VCG) Global electrical heterogeneity (GEH). GEH concept is based on the concept of the spatial ventricular gradient (SVG), which is a global measure of the dispersion of total recovery time. We quantify GEH by measuring five features of the SVG vector (SVG magnitude, direction (azimuth and elevation), a scalar value, and spatial QRS-T angle) on orthogonal XYZ ECG. In analysis of more than 20,000 adults we showed that GEH is independently associated with sudden cardiac death (SCD) after adjustment for demographics, cardiovascular disease (time-updated incident non-fatal cardiovascular events [coronary heart disease, heart failure, stroke, atrial fibrillation, use of beta-blockers], and known risk factors [cholesterol, triglycerides, physical activity index, smoking, diabetes, obesity, hypertension, anti-hypertensive medications, creatinine, alcohol intake, left ventricular ejection fraction, and time-updated ECG metrics (heart rate, QTc, QRS duration, ECG-left ventricular hypertrophy, bundle branch block or interventricular conduction delay)]. This finding suggests that GEH represents an independent electrophysiological substrate of SCD.
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http://dx.doi.org/10.22489/cinc.2018.165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158901PMC
September 2018

Does plastic chemical exposure contribute to sudden death of patients on dialysis?

Heart Rhythm 2019 02 23;16(2):312-317. Epub 2018 Aug 23.

Children's National Health System, Sheikh Zayed Institute, Heart Institute, Washington, District of Columbia.

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http://dx.doi.org/10.1016/j.hrthm.2018.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361677PMC
February 2019

Left anterior fascicular block: The need for a re-appraisal.

Int J Cardiol 2018 10 20;269:31-32. Epub 2018 Jul 20.

Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2018.07.079DOI Listing
October 2018

The utility of routine clinical 12-lead ECG in assessing eligibility for subcutaneous implantable cardioverter defibrillator.

Comput Biol Med 2018 11 8;102:242-250. Epub 2018 May 8.

Oregon Health & Science University, Knight Cardiovascular Institute, Portland, OR, USA. Electronic address:

Introduction: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a life-saving device. Recording of a specialized 3-lead electrocardiogram (ECG) is required for S-ICD eligibility assessment. The goals of this study were: (1) evaluate the effect of ECG filtering on S-ICD eligibility, and (2) simplify S-ICD eligibility assessment by development of an S-ICD ineligibility prediction tool, which utilizes the widely available routine 12-lead ECG.

Methods And Results: Prospective cross-sectional study participants [n = 68; 54% male; 94% white, with wide ranges of age (18-81 y), body mass index (19-53), QRS duration (66-150 ms), and left ventricular ejection fraction (37-77%)] underwent 12-lead supine, 3-lead supine and standing ECG recording. All 3-lead ECG recordings were assessed using the standard S-ICD pre-implantation ECG morphology screening. Backward, stepwise, logistic regression was used to build a model for 12-lead prediction of S-ICD eligibility. Select electrocardiogram waves and complexes: QRS, R-, S, and T-amplitudes on all 12 leads, averaged QT interval, QRS duration, and R/T ratio in the lead with the largest T wave (R/T) were included as predictors. The effect of ECG filtering on ECG morphology was evaluated. A total of 9 participants (13%) failed S-ICD screening prior to filtering. Filtering at 3-40 Hz, similar to the S-ICD default, reduced S-ICD ineligibility to 4%. A regression model that included R, S, T, and R/T perfectly predicted S-ICD eligibility, with an Area Under the Receiver Operating Characteristic Curve of 1.0.

Conclusion: Routine clinical 12-lead ECG can be used to predict S-ICD eligibility. ECG filtering may improve S-ICD eligibility.
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http://dx.doi.org/10.1016/j.compbiomed.2018.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218287PMC
November 2018

Understanding Mechanisms of Cardiac Resynchronization Therapy Response to Improve Patient Selection and Outcomes.

Circ Arrhythm Electrophysiol 2018 04;11(4):e006290

Division of Cardiovascular Medicine, Harvard-Thorndike Electrophysiology Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (J.W.W.). Knight Cardiovascular Institute, Oregon Health and Science University, Portland (E.A.P.-A., L.G.T.).

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http://dx.doi.org/10.1161/CIRCEP.118.006290DOI Listing
April 2018

Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study).

J Am Heart Assoc 2018 04 5;7(8). Epub 2018 Apr 5.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

Background: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH.

Methods And Results: We tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near ) was associated with QRS-T angle (white standardized β+0.16 [95% CI 0.13-0.19]; =1.5×10), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; =2.1×10), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; =5.9×10). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near ), 5 (), 11 (11p11.2 region cluster), and 7 (near ) are novel ECG phenotype-associated loci. Several loci significantly associated with gene expression in the left ventricle ( locus-with ; locus-with ), and atria ( locus-with expression of a long non-coding RNA and ).

Conclusions: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH-loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.
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http://dx.doi.org/10.1161/JAHA.117.008160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015433PMC
April 2018

Improving sudden cardiac death risk stratification by evaluating electrocardiographic measures of global electrical heterogeneity and clinical outcomes among patients with implantable cardioverter-defibrillators: rationale and design for a retrospective, multicenter, cohort study.

J Interv Card Electrophysiol 2018 Jun 14;52(1):77-89. Epub 2018 Mar 14.

Beth Israel Deaconess Medical Center, Boston, MA, USA.

Purpose: Implantable cardioverter-defibrillators (ICDs) improve survival of systolic heart failure (HF) patients who are at risk of sudden cardiac death (SCD). We recently showed that electrocardiographic (ECG) global electrical heterogeneity (GEH) is independently associated with SCD in the community-dwelling cohort and developed GEH SCD risk score. The Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study is a retrospective multicenter cohort designed with two goals: (1) validate an independent association of ECG GEH with sustained ventricular tachyarrhythmias and appropriate ICD therapies and (2) validate GEH ECG risk score for prediction of sustained ventricular tachyarrhythmias and appropriate ICD therapies in systolic HF patients with primary prevention ICD.

Methods: All records of primary prevention ICD recipients with available data for analysis are eligible for inclusion. Records of ICD implantation in patients with inherited channelopathies and cardiomyopathies are excluded. Raw digital 12-lead pre-implant ECGs will be used to measure GEH (spatial QRST angle, spatial ventricular gradient magnitude, azimuth, and elevation, and sum absolute QRST integral). The primary endpoint is defined as a sustained ventricular tachyarrhythmia event with appropriate ICD therapy. All-cause death without preceding sustained ventricular tachyarrhythmia with appropriate ICD therapy will serve as a primary competing outcome. The study will draw data from the academic medical centers.

Results: We describe the study protocol of the first multicenter retrospective cohort of primary prevention ICD patients with recorded at baseline digital 12-lead ECG.

Conclusion: Findings from this study will inform future trials to identify patients who are most likely to benefit from primary prevention ICD.

Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT03210883.
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http://dx.doi.org/10.1007/s10840-018-0342-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556174PMC
June 2018

Global ECG Measures and Cardiac Structure and Function: The ARIC Study (Atherosclerosis Risk in Communities).

Circ Arrhythm Electrophysiol 2018 03;11(3):e005961

From the Brigham and Women's Hospital (T.B.-S., A.M.S., S.D.S.) and Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center (J.W.W., A.E.B.), Harvard Medical School, Boston, MA; Knight Cardiovascular Institute, Oregon Health & Science University, Portland (M.K., J.T., L.G.T.); Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (W.S.P., L.G.T.); and Epidemiological Cardiology Research Center, Cardiology Section, Department of Medicine, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC (E.Z.S.).

Background: Electric excitation initiates myocardial mechanical contraction and coordinates myocardial pumping. We hypothesized that ECG global electric heterogeneity (GEH) and its longitudinal changes are associated with cardiac structure and function.

Methods And Results: Participants from the ARIC study (Atherosclerosis Risk in Communities) (N=5114; 58% female; 22% blacks) with resting 12-lead ECGs (visits 1-5) and echocardiographic assessment of left ventricular (LV) ejection fraction, LV global longitudinal strain, LV mass index, LV end-diastolic volume index, and LV end-systolic volume index at visit 5 were included. Longitudinal analysis included ARIC participants (N=14 609) with measured GEH at visits 1 to 4. GEH was quantified by spatial ventricular gradient, QRS-T angle, and sum absolute QRS-T integral. Cross-sectional and longitudinal regressions were adjusted for manifest and subclinical cardiovascular disease. Having 4 abnormal GEH parameters was associated with a 6.4% (95% confidence interval, 5.5-7.3) LV ejection fraction decline, a 24.2 g/m (95% confidence interval, 21.5-26.9) increase in LV mass index, a 10.3 mL/m (95% confidence interval, 8.9-11.7) increase in LV end-diastolic volume index, and a 7.8 mL/m (95% confidence interval, 6.9-8.6) increase in LV end-systolic volume index. Altogether, clinical and ECG parameters accounted for approximately one third of LV volume and 20% of systolic function variability. The associations were significantly stronger in cardiovascular disease. Sum absolute QRS-T integral increased by 20 mV*ms for each 3-year period in participants who demonstrated LV dilatation at visit 5. Sudden cardiac death victims demonstrated rapid GEH worsening, whereas those with LV dysfunction demonstrated slow GEH worsening. Healthy aging was associated with a distinct pattern of spatial ventricular gradient azimuth decrement.

Conclusions: GEH is a marker of subclinical abnormalities in cardiac structure and function.
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http://dx.doi.org/10.1161/CIRCEP.117.005961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836803PMC
March 2018

Proposed In-Training Electrocardiogram Interpretation Competencies for Undergraduate and Postgraduate Trainees.

J Hosp Med 2018 03 8;13(3):185-193. Epub 2017 Nov 8.

Department of Medicine, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada.

Despite its importance in everyday clinical practice, the ability of physicians to interpret electrocardiograms (ECGs) is highly variable. ECG patterns are often misdiagnosed, and electrocardiographic emergencies are frequently missed, leading to adverse patient outcomes. Currently, many medical education programs lack an organized curriculum and competency assessment to ensure trainees master this essential skill. ECG patterns that were previously mentioned in literature were organized into groups from A to D based on their clinical importance and distributed among levels of training. Incremental versions of this organization were circulated among members of the International Society of Electrocardiology and the International Society of Holter and Noninvasive Electrocardiology until complete consensus was reached. We present reasonably attainable ECG interpretation competencies for undergraduate and postgraduate trainees. Previous literature suggests that methods of teaching ECG interpretation are less important and can be selected based on the available resources of each education program and student preference. The evidence clearly favors summative trainee evaluation methods, which would facilitate learning and ensure that appropriate competencies are acquired. Resources should be allocated to ensure that every trainee reaches their training milestones and should ensure that no electrocardiographic emergency (class A condition) is ever missed. We hope that these guidelines will inform medical education programs and encourage them to allocate sufficient resources and develop organized curricula. Assessments must be in place to ensure trainees acquire the level-appropriate ECG interpretation skills that are required for safe clinical practice.
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http://dx.doi.org/10.12788/jhm.2876DOI Listing
March 2018