Heart Rate Variability, Deceleration Capacity of Heart Rate, and Death: A Veteran Twins Study.

BACKGROUND: Autonomic function can be measured noninvasively using heart rate variability (HRV), which indexes overall sympathovagal balance. Deceleration capacity (DC) of heart rate is a more specific metric of vagal modulation. Higher values of these measures have been associated with reduced mortality risk primarily in patients with cardiovascular disease, but their significance in community samples is less clear. METHODS AND RESULTS: This prospective twin study followed 501 members from the VET (Vietnam Era Twin) registry. At baseline, frequency domain HRV and DC were measured from 24-hour Holter ECGs. During an average 12-year follow-up, all-cause death was assessed via the National Death Index. Multivariable Cox frailty models with random effect for twin pair were used to examine the hazard ratios of death per 1-SD increase in log-transformed autonomic metrics. Both in the overall sample and comparing twins within pairs, higher values of low-frequency HRV and DC were significantly associated with lower hazards of all-cause death. In within-pair analysis, after adjusting for baseline factors, there was a 22% and 27% lower hazard of death per 1-SD increment in low-frequency HRV and DC, respectively. Higher low-frequency HRV and DC, measured during both daytime and nighttime, were associated with decreased hazard of death, but daytime measures showed numerically stronger associations. Results did not substantially vary by zygosity. CONCLUSIONS: Autonomic inflexibility, and especially vagal withdrawal, are important mechanistic pathways of general mortality risk, independent of familial and genetic factors.

Heart murmur detection from phonocardiogram recordings: The George B. Moody PhysioNet Challenge 2022.

Cardiac auscultation is an accessible diagnostic screening tool that can help to identify patients with heart murmurs, who may need follow-up diagnostic screening and treatment for abnormal cardiac function. However, experts are needed to interpret the heart sounds, limiting the accessibility of cardiac auscultation in resource-constrained environments. Therefore, the George B. Moody PhysioNet Challenge 2022 invited teams to develop algorithmic approaches for detecting heart murmurs and abnormal cardiac function from phonocardiogram (PCG) recordings of heart sounds. For the Challenge, we sourced 5272 PCG recordings from 1452 primarily pediatric patients in rural Brazil, and we invited teams to implement diagnostic screening algorithms for detecting heart murmurs and abnormal cardiac function from the recordings. We required the participants to submit the complete training and inference code for their algorithms, improving the transparency, reproducibility, and utility of their work. We also devised an evaluation metric that considered the costs of screening, diagnosis, misdiagnosis, and treatment, allowing us to investigate the benefits of algorithmic diagnostic screening and facilitate the development of more clinically relevant algorithms. We received 779 algorithms from 87 teams during the Challenge, resulting in 53 working codebases for detecting heart murmurs and abnormal cardiac function from PCG recordings. These algorithms represent a diversity of approaches from both academia and industry, including methods that use more traditional machine learning techniques with engineered clinical and statistical features as well as methods that rely primarily on deep learning models to discover informative features. The use of heart sound recordings for identifying heart murmurs and abnormal cardiac function allowed us to explore the potential of algorithmic approaches for providing more accessible diagnostic screening in resource-constrained environments. The submission of working, open-source algorithms and the use of novel evaluation metrics supported the reproducibility, generalizability, and clinical relevance of the research from the Challenge.

Association between PTSD and Impedance Cardiogram-based contractility metrics during trauma recall: A controlled twin study.

Post-traumatic stress disorder (PTSD) is an independent risk factor for incident heart failure, but the underlying cardiac mechanisms remained elusive. Impedance cardiography (ICG), especially when measured during stress, can help understand the underlying psychophysiological pathways linking PTSD with heart failure. We investigated the association between PTSD and ICG-based contractility metrics (pre-ejection period (PEP) and Heather index (HI)) using a controlled twin study design with a laboratory-based traumatic reminder stressor. PTSD status was assessed using structured clinical interviews. We acquired synchronized electrocardiograms and ICG data while playing personalized-trauma scripts. Using linear mixed-effects models, we examined twins as individuals and within PTSD-discordant pairs. We studied 137 male veterans (48 pairs, 41 unpaired singles) from Vietnam War Era with a mean (standard deviation) age of 68.5(2.5) years. HI during trauma stress was lower in the PTSD vs. non-PTSD individuals (7.2 vs. 9.3 [ohm/s2 ], p = .003). PEP reactivity (trauma minus neutral) was also more negative in PTSD vs. non-PTSD individuals (-7.4 vs. -2.0 [ms], p = .009). The HI and PEP associations with PTSD persisted for adjusted models during trauma and reactivity, respectively. For within-pair analysis of eight PTSD-discordant twin pairs (out of 48 pairs), PTSD was associated with lower HI in neutral, trauma, and reactivity, whereas no association was found between PTSD and PEP. PTSD was associated with reduced HI and PEP, especially with trauma recall stress. This combination of increased sympathetic activation and decreased cardiac contractility combined may be concerning for increased heart failure risk after recurrent trauma re-experiencing in PTSD.

Association of Autonomic Activation with traumatic reminder challenges in posttraumatic stress disorder: A co-twin control study.

Post-traumatic stress disorder (PTSD) has been associated with cardiovascular disease (CVD), but the mechanisms remain unclear. Autonomic dysfunction, associated with higher CVD risk, may be triggered by acute PTSD symptoms. We hypothesized that a laboratory-based trauma reminder challenge, which induces acute PTSD symptoms, provokes autonomic dysfunction in a cohort of veteran twins. We investigated PTSD-associated real-time physiologic changes with a simulation of traumatic experiences in which the twins listened to audio recordings of a one-minute neutral script followed by a one-minute trauma script. We examined two heart rate variability metrics: deceleration capacity (DC) and logarithmic low frequency (log-LF) power from beat-to-beat intervals extracted from ambulatory electrocardiograms. We assessed longitudinal PTSD status with a structured clinical interview and the severity with the PTSD Symptoms Scale. We used linear mixed-effects models to examine twin dyads and account for cardiovascular and behavioral risk factors. We examined 238 male Veteran twins (age 68 ± 3 years old, 4% black). PTSD status and acute PTSD symptom severity were not associated with DC or log-LF measured during the neutral session, but were significantly associated with lower DC and log-LF during the traumatic script listening session. Long-standing PTSD was associated with a 0.38 (95% confidence interval, -0.83,-0.08) and 0.79 (-1.30,-0.29) standardized unit lower DC and log-LF, respectively, compared to no history of PTSD. Traumatic reminders in patients with PTSD lead to real-time autonomic dysregulation and suggest a potential causal mechanism for increased CVD risk, based on the well-known relationships between autonomic dysfunction and CVD mortality.

Passively Captured Interpersonal Social Interactions and Motion From Smartphones for Predicting Decompensation in Heart Failure: Observational Cohort Study.

BACKGROUND: Heart failure (HF) is a major cause of frequent hospitalization and death. Early detection of HF symptoms using smartphone-based monitoring may reduce adverse events in a low-cost, scalable way. OBJECTIVE: We examined the relationship of HF decompensation events with smartphone-based features derived from passively and actively acquired data. METHODS: This was a prospective cohort study in which we monitored HF participants' social and movement activities using a smartphone app and followed them for clinical events via phone and chart review and classified the encounters as compensated or decompensated by reviewing the provider notes in detail. We extracted motion, location, and social interaction passive features and self-reported quality of life weekly (active) with the short Kansas City Cardiomyopathy Questionnaire (KCCQ-12) survey. We developed and validated an algorithm for classifying decompensated versus compensated clinical encounters (hospitalizations or clinic visits). We evaluated models based on single modality as well as early and late fusion approaches combining patient-reported outcomes and passive smartphone data. We used Shapley additive explanation values to quantify the contribution and impact of each feature to the model. RESULTS: We evaluated 28 participants with a mean age of 67 years (SD 8), among whom 11% (3/28) were female and 46% (13/28) were Black. We identified 62 compensated and 48 decompensated clinical events from 24 and 22 participants, respectively. The highest area under the precision-recall curve (AUCPr) for classifying decompensation was with a late fusion approach combining KCCQ-12, motion, and social contact features using leave-one-subject-out cross-validation for a 2-day prediction window. It had an AUCPr of 0.80, with an area under the receiver operator curve (AUC) of 0.83, a positive predictive value (PPV) of 0.73, a sensitivity of 0.77, and a specificity of 0.88 for a 2-day prediction window. Similarly, the 4-day window model had an AUC of 0.82, an AUCPr of 0.69, a PPV of 0.62, a sensitivity of 0.68, and a specificity of 0.87. Passive social data provided some of the most informative features, with fewer calls of longer duration associating with a higher probability of future HF decompensation. CONCLUSIONS: Smartphone-based data that includes both passive monitoring and actively collected surveys may provide important behavioral and functional health information on HF status in advance of clinical visits. This proof-of-concept study, although small, offers important insight into the social and behavioral determinants of health and the feasibility of using smartphone-based monitoring in this population. Our strong results are comparable to those of more active and expensive monitoring approaches, and underscore the need for larger studies to understand the clinical significance of this monitoring method.

Issues in the automated classification of multilead ecgs using heterogeneous labels and populations.

Objective.The standard twelve-lead electrocardiogram (ECG) is a widely used tool for monitoring cardiac function and diagnosing cardiac disorders. The development of smaller, lower-cost, and easier-to-use ECG devices may improve access to cardiac care in lower-resource environments, but the diagnostic potential of these devices is unclear. This work explores these issues through a public competition: the 2021 PhysioNet Challenge. In addition, we explore the potential for performance boosting through a meta-learning approach.Approach.We sourced 131,149 twelve-lead ECG recordings from ten international sources. We posted 88,253 annotated recordings as public training data and withheld the remaining recordings as hidden validation and test data. We challenged teams to submit containerized, open-source algorithms for diagnosing cardiac abnormalities using various ECG lead combinations, including the code for training their algorithms. We designed and scored the algorithms using an evaluation metric that captures the risks of different misdiagnoses for 30 conditions. After the Challenge, we implemented a semi-consensus voting model on all working algorithms.Main results.A total of 68 teams submitted 1,056 algorithms during the Challenge, providing a variety of automated approaches from both academia and industry. The performance differences across the different lead combinations were smaller than the performance differences across the different test databases, showing that generalizability posed a larger challenge to the algorithms than the choice of ECG leads. A voting model improved performance by 3.5%.Significance.The use of different ECG lead combinations allowed us to assess the diagnostic potential of reduced-lead ECG recordings, and the use of different data sources allowed us to assess the generalizability of the algorithms to diverse institutions and populations. The submission of working, open-source code for both training and testing and the use of a novel evaluation metric improved the reproducibility, generalizability, and applicability of the research conducted during the Challenge.

Age, sex and race bias in automated arrhythmia detectors.

Despite the recent explosion of machine learning applied to medical data, very few studies have examined algorithmic bias in any meaningful manner, comparing across algorithms, databases, and assessment metrics. In this study, we compared the biases in sex, age, and race of 56 algorithms on over 130,000 electrocardiograms (ECGs) using several metrics and propose a machine learning model design to reduce bias. Participants of the 2021 PhysioNet Challenge designed and implemented working, open-source algorithms to identify clinical diagnosis from 2- lead ECG recordings. We grouped the data from the training, validation, and test datasets by sex (male vs female), age (binned by decade), and race (Asian, Black, White, and Other) whenever possible. We computed recording-wise accuracy, area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), F-measure, and the Challenge Score for each of the 56 algorithms. The Mann-Whitney U and the Kruskal-Wallis tests assessed the performance differences of algorithms across these demographic groups. Group trends revealed similar values for the AUROC, AUPRC, and F-measure for both male and female groups across the training, validation, and test sets. However, recording-wise accuracies were 20% higher (p < 0.01) and the Challenge Score 12% lower (p = 0.02) for female subjects on the test set. AUPRC, F-measure, and the Challenge Score increased with age, while recording-wise accuracy and AUROC decreased with age. The results were similar for the training and test sets, but only recording-wise accuracy (12% decrease per decade, p < 0.01), Challenge Score (1% increase per decade, p < 0.01), and AUROC (1% decrease per decade, p < 0.01) were statistically different on the test set. We observed similar AUROC, AUPRC, Challenge Score, and F-measure values across the different race categories. But, recording-wise accuracies were significantly lower for Black subjects and higher for Asian subjects on the training (31% difference, p < 0.01) and test (39% difference, p < 0.01) sets. A top performing model was then retrained using an additional constraint which simultaneously minimized differences in performance across sex, race and age. This resulted in a modest reduction in performance, with a significant reduction in bias. This work provides a demonstration that biases manifest as a function of model architecture, population, cost function and optimization metric, all of which should be closely examined in any model.

The temporal relationships between sleep disturbance and autonomic dysregulation: A co-twin control study.

INTRODUCTION: Sleep disturbance is associated with autonomic dysregulation, but the temporal directionality of this relationship remains uncertain. The objective of this study was to evaluate the temporal relationships between objectively measured sleep disturbance and daytime or nighttime autonomic dysregulation in a co-twin control study. METHODS: A total of 68 members (34 pairs) of the Vietnam Era Twin Registry were studied. Twins underwent 7-day in-home actigraphy to derive objective measures of sleep disturbance. Autonomic function indexed by heart rate variability (HRV) was obtained using 7-day ECG monitoring with a wearable patch. Multivariable vector autoregressive models with Granger causality tests were used to examine the temporal directionality of the association between daytime and nighttime HRV and sleep metrics, within twin pairs, using 7-day collected ECG data. RESULTS: Twins were all male, mostly white (96%), with mean (SD) age of 69 (2) years. Higher daytime HRV across multiple domains was bidirectionally associated with longer total sleep time and lower wake after sleep onset; these temporal dynamics were extended to a window of 48 h. In contrast, there was no association between nighttime HRV and sleep measures in subsequent nights, or between sleep measures from previous nights and subsequent nighttime HRV. CONCLUSIONS: Daytime, but not nighttime, autonomic function indexed by HRV has bidirectional associations with several sleep dimensions. Dysfunctions in autonomic regulation during wakefulness can lead to subsequent shorter sleep duration and worse sleep continuity, and vice versa, and their influence on each other may extend beyond 24 h.

Breathing rate and heart rate as confounding factors in measuring T wave alternans and morphological variability in ECG.

OBJECTIVE: High morphological variability magnitude (MVM) and microvolt T wave alternans (TWA) within an electrocardiogram (ECG) signifies increased electrical instability and risk of sudden cardiac death. However, the influence of breathing rate (BR), heart rate (HR), and signal-to-noise ratio (SNR) is unknown and may inflate measured values. APPROACH: We synthesize ECGs with morphologies derived from the Physikalisch-Technische Bundesanstalt Database. We calculate MVM and TWA at varying BRs, HRs and SNRs. We compare the MVM and TWA of signal with versus without breathing at varying HRs and SNRs. We then quantify the percentage of MVM and TWA estimates affected by BR and HR in a healthy population and assess the effect of removing these affected estimates on a method for classifying individuals with and without post-traumatic stress disorder (PTSD). MAIN RESULTS: For signals with high SNR (>15 dB), MVM is significantly increased when BRs are > 9 respirations/minute (rpm) and HRs are < 100 beats/minute (bpm). Increased TWAs are detected for HR/BR pairs of 60/15, 60/30 and 120/30 bpm/rpm. For 18 healthy participants, 8.33% of TWA windows and 66.76% of MVM windows are affected by BR and HR. On average, the number of windows with TWA elevations > 47 µV decreases by 23% after excluding regions with significant BR and HR effect. Adding HR and BR to a morphological variability feature increases the classification performance by 6% for individuals with and without PTSD. SIGNIFICANCE: Physiological BR and HR significantly increase MVM and TWA , indicating that BR and HR should be considered separately as confounders. The code for this work has been released as part of an open-source toolbox.

Classification of 12-lead ECGs: the PhysioNet/Computing in Cardiology Challenge 2020.

OBJECTIVE: Vast 12-lead ECGs repositories provide opportunities to develop new machine learning approaches for creating accurate and automatic diagnostic systems for cardiac abnormalities. However, most 12-lead ECG classification studies are trained, tested, or developed in single, small, or relatively homogeneous datasets. In addition, most algorithms focus on identifying small numbers of cardiac arrhythmias that do not represent the complexity and difficulty of ECG interpretation. This work addresses these issues by providing a standard, multi-institutional database and a novel scoring metric through a public competition: the PhysioNet/Computing in Cardiology Challenge 2020. APPROACH: A total of 66 361 12-lead ECG recordings were sourced from six hospital systems from four countries across three continents; 43 101 recordings were posted publicly with a focus on 27 diagnoses. For the first time in a public competition, we required teams to publish open-source code for both training and testing their algorithms, ensuring full scientific reproducibility. MAIN RESULTS: A total of 217 teams submitted 1395 algorithms during the Challenge, representing a diversity of approaches for identifying cardiac abnormalities from both academia and industry. As with previous Challenges, high-performing algorithms exhibited significant drops ([Formula: see text]10%) in performance on the hidden test data. SIGNIFICANCE: Data from diverse institutions allowed us to assess algorithmic generalizability. A novel evaluation metric considered different misclassification errors for different cardiac abnormalities, capturing the outcomes and risks of different diagnoses. Requiring both trained models and code for training models improved the generalizability of submissions, setting a new bar in reproducibility for public data science competitions.

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

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) [n = 10; age 61 ± 9 years; left ventricular ejection fraction (LVEF) 60 ± 9%], and three comparison groups: healthy individuals (n = 10; age 28 ± 6 years; LVEF > 70%), ICM patients with LV hypertrophy (LVH) and known VT (n = 10; age 64 ± 9 years; LVEF 31 ± 15%), and ICM patients with LVH and no known VT (n = 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); P = 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); P = 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); P = 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.

Does Sex Modify an Association of Electrophysiological Substrate with Sudden Cardiac Death? The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND­: Sex is a well-recognized risk factor for sudden cardiac death (SCD). We hypothesized that sex modifies the association of electrophysiological (EP) substrate with SCD. METHODS­: Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n=14,725; age, 54.2±5.8 yrs; 55% female, 74% white) were included. EP substrate was characterized by heart rate, QRS, QTc, Cornell voltage, spatial ventricular gradient (SVG), and sum absolute QRST integral (SAI QRST) ECG metrics. Two competing outcomes were adjudicated SCD and nonSCD. Interaction of ECG metrics with sex was studied in Cox proportional hazards and Fine-Gray competing risk models. Model 1 was adjusted for prevalent cardiovascular disease (CVD) and risk factors. Time-updated model 2 was additionally adjusted for incident non-fatal CVD. Relative hazard ratio (RHR) and relative sub-hazard ratio (RSHR) with a 95% confidence interval for SCD and nonSCD risk for women relative to men was calculated. Model 1 was adjusted for prevalent CVD and risk factors. Time-updated model 2 was additionally adjusted for incident non-fatal CVD. RESULTS­: Over a median follow-up of 24.4 years, there were 530 SCDs (incidence 1.72 (1.58-1.88)/1000 person-years). Women as compared to men experienced a greater risk of SCD associated with Cornell voltage (RHR 1.18(1.06-1.32); P=0.003), SAI QRST (RHR 1.16(1.04-1.30); P=0.007), and SVG magnitude (RHR 1.24(1.05-1.45); P=0.009), independently from incident CVD. CONCLUSION­: In women, the global EP substrate is associated with up to 24% greater risk of SCD than in men, suggesting differences in underlying mechanisms and the need for sex-specific SCD risk stratification.

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

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.

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

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%, P=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; P<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; P<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; P<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.

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

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 Nav1.5 (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.

A Multi-Scale Investigation of Global Electrical Heterogeneity: Effects of Body Habitus, Respiration, and Tissue Conductivity.

Extracardiac factors such as respiration, fluid overload and body habitus have important effects on the ECG voltage. Vectorcardiographic (VCG) Global Electrical Heterogeneity (GEH) is associated with sudden cardiac death (SCD). Risk of SCD is especially high in end-stage renal disease patients (ESRD) on dialysis. However, extracardiac factors challenge ECG interpretation in ESRD patients. The effects of extracardiac factors on GEH have not been fully studied. To1 assess effects of extracardiac factors on ECG, we conducted a multi-scale study. An experimental data of ESRD patients and a previously developed biophysically detailed heart-torso model were used to investigate the effects of respiration, fluid overload and body habitus on the VCG and GEH.

The Reproducibility of Global Electrical Heterogeneity ECG Measurements.

BACKGROUND: Global electrical heterogeneity (GEH) is a useful predictor of adverse clinical outcomes. However, reproducibility of GEH measurements on 10-second routine clinical ECG is unknown. METHODS: Data of the prospective cohort study of incident hemodialysis patients (n=253; mean age 54.6±13.5y; 56% male; 79% African American) were analysed. Two random 10-second segments of 5-minute ECG recording in sinus rhythm were compared. GEH was measured as spatial QRS-T angle, spatial ventricular gradient (SVG) magnitude and direction (azimuth and elevation), and a scalar value of SVG measured by (1) sum absolute QRST integral (SAI QRST), and (2) QT integral on vector magnitude signal (iVMQT). Bland-Altman analysis was used to calculate agreement. RESULTS: For all studied vectorcardiographic metrics, agreement was substantial (Lin's concordance coefficient >0.98), and precision was perfect (>99.99%). 95% limits of agreement were ±14° for spatial QRS-T angle, ±13° for SVG azimuth, ±4° for SVG elevation, ±14 mV*ms for SVG magnitude, and ±17 mV*ms for SAI QRST. SAI QRST and iVMQT were in substantial agreement with each other. CONCLUSION: Reproducibility of a 10-second automated GEH ECG measurements was substantial, and precision was perfect.

Torso geometry reconstruction and body surface electrode localization using three-dimensional photography.

We conducted a prospective clinical study (n=14; 29% female) to assess the accuracy of a three-dimensional (3D) photography-based method of torso geometry reconstruction and body surface electrodes localization. The position of 74 body surface electrocardiographic (ECG) electrodes (diameter 5mm) was defined by two methods: 3D photography, and CT (marker diameter 2mm) or MRI (marker size 10×20mm) imaging. Bland-Altman analysis showed good agreement in X (bias -2.5 [95% limits of agreement (LoA) -19.5 to 14.3] mm), Y (bias -0.1 [95% LoA -14.1 to 13.9] mm), and Z coordinates (bias -0.8 [95% LoA -15.6 to 14.2] mm), as defined by the CT/MRI imaging, and 3D photography. The average Hausdorff distance between the two torso geometry reconstructions was 11.17±3.05mm. Thus, accurate torso geometry reconstruction using 3D photography is feasible. Body surface ECG electrodes coordinates as defined by the CT/MRI imaging, and 3D photography, are in good agreement.

Trigger vs. Substrate: Multi-Dimensional Modulation of QT-Prolongation Associated Arrhythmic Dynamics by a hERG Channel Activator.

Background: Prolongation of the QT interval of the electrocardiogram (ECG), underlain by prolongation of the action potential duration (APD) at the cellular level, is linked to increased vulnerability to cardiac arrhythmia. Pharmacological management of arrhythmia associated with QT prolongation is typically achieved through attempting to restore APD to control ranges, reversing the enhanced vulnerability to Ca2+-dependent afterdepolarisations (arrhythmia triggers) and increased transmural dispersion of repolarisation (arrhythmia substrate) associated with APD prolongation. However, such pharmacological modulation has been demonstrated to have limited effectiveness. Understanding the integrative functional impact of pharmacological modulation requires simultaneous investigation of both the trigger and substrate. Methods: We implemented a multi-scale (cell and tissue) in silico approach using a model of the human ventricular action potential, integrated with a model of stochastic 3D spatiotemporal Ca2+ dynamics, and parameter modification to mimic prolonged QT conditions. We used these models to examine the efficacy of the hERG activator MC-II-157c in restoring APD to control ranges, examined its effects on arrhythmia triggers and substrates, and the interaction of these arrhythmia triggers and substrates. Results: QT prolongation conditions promoted the development of spontaneous release events underlying afterdepolarisations during rapid pacing. MC-II-157c applied to prolonged QT conditions shortened the APD, inhibited the development of afterdepolarisations and reduced the probability of afterdepolarisations manifesting as triggered activity in single cells. In tissue, QT prolongation resulted in an increased transmural dispersion of repolarisation, which manifested as an increased vulnerable window for uni-directional conduction block. In some cases, MC-II-157c further increased the vulnerable window through its effects on INa. The combination of stochastic release event modulation and transmural dispersion of repolarisation modulation by MC-II-157c resulted in an integrative behavior wherein the arrhythmia trigger is reduced but the arrhythmia substrate is increased, leading to variable and non-linear overall vulnerability to arrhythmia. Conclusion: The relative balance of reduced trigger and increased substrate underlies a multi-dimensional role of MC-II-157c in modulation of cardiac arrhythmia vulnerability associated with prolonged QT interval.