The inspection paradox: an important consideration in the evaluation of rotor lifetimes in cardiac fibrillation

Background and Objective: Renewal theory is a statistical approach to model the formation and destruction of phase singularities (PS), which occur at the pivots of spiral waves. A common issue arising during observation of renewal processes is an inspection paradox, due to oversampling of longer events. The objective of this study was to characterise the effect of a potential inspection paradox on the perception of PS lifetimes in cardiac fibrillation. Methods: A multisystem, multi-modality study was performed, examining computational simulations (Aliev-Panfilov (APV) model, Courtmanche-Nattel model), experimentally acquired optical mapping Atrial and Ventricular Fibrillation (AF/VF) data, and clinically acquired human AF and VF. Distributions of all PS lifetimes across full epochs of AF, VF, or computational simulations, were compared with distributions formed from lifetimes of PS existing at 10,000 simulated commencement timepoints. Results: In all systems, an inspection paradox led towards oversampling of PS with longer lifetimes. In APV computational simulations there was a mean PS lifetime shift of +84.9% (95% CI, ± 0.3%) (p < 0.001 for observed vs overall), in Courtmanche-Nattel simulations of AF +692.9% (95% CI, ±57.7%) (p < 0.001), in optically mapped rat AF +374.6% (95% CI, ± 88.5%) (p = 0.052), in human AF mapped with basket catheters +129.2% (95% CI, ±4.1%) (p < 0.05), human AF-HD grid catheters 150.8% (95% CI, ± 9.0%) (p < 0.001), in optically mapped rat VF +171.3% (95% CI, ±15.6%) (p < 0.001), in human epicardial VF 153.5% (95% CI, ±15.7%) (p < 0.001). Conclusion: Visual inspection of phase movies has the potential to systematically oversample longer lasting PS, due to an inspection paradox. An inspection paradox is minimised by consideration of the overall distribution of PS lifetimes

PO-616-05 THE INSPECTION PARADOX: AN IMPORTANT CONSIDERATION IN THE EVALUATION OF ROTOR LIFETIMES IN CARDIAC FIBRILLATION

Background and Objective: Renewal theory is a statistical approach to model the formation and destruction of phase singularities (PS), which occur at the pivots of spiral waves. A common issue arising during observation of renewal processes is an inspection paradox, due to oversampling of longer events. The objective of this study was to characterise the effect of a potential inspection paradox on the perception of PS lifetimes in cardiac fibrillation. Methods: A multisystem, multi-modality study was performed, examining computational simulations (Aliev-Panfilov (APV) model, Courtmanche-Nattel model), experimentally acquired optical mapping Atrial and Ventricular Fibrillation (AF/VF) data, and clinically acquired human AF and VF. Distributions of all PS lifetimes across full epochs of AF, VF, or computational simulations, were compared with distributions formed from lifetimes of PS existing at 10,000 simulated commencement timepoints. Results: In all systems, an inspection paradox led towards oversampling of PS with longer lifetimes. In APV computational simulations there was a mean PS lifetime shift of +84.9% (95% CI, ± 0.3%) (p < 0.001 for observed vs overall), in Courtmanche-Nattel simulations of AF +692.9% (95% CI, ±57.7%) (p < 0.001), in optically mapped rat AF +374.6% (95% CI, ± 88.5%) (p = 0.052), in human AF mapped with basket catheters +129.2% (95% CI, ±4.1%) (p < 0.05), human AF-HD grid catheters 150.8% (95% CI, ± 9.0%) (p < 0.001), in optically mapped rat VF +171.3% (95% CI, ±15.6%) (p < 0.001), in human epicardial VF 153.5% (95% CI, ±15.7%) (p < 0.001). Conclusion: Visual inspection of phase movies has the potential to systematically oversample longer lasting PS, due to an inspection paradox. An inspection paradox is minimised by consideration of the overall distribution of PS lifetimes

Renewal theory as a universal quantitative framework to characterize phase singularity regeneration in mammalian cardiac fibrillation

BACKGROUND: Despite a century of research, no clear quantitative framework exists to model the fundamental processes responsible for the continuous formation and destruction of phase singularities (PS) in cardiac fibrillation. We hypothesized PS formation/destruction in fibrillation could be modeled as self-regenerating Poisson renewal processes, producing exponential distributions of interevent times governed by constant rate parameters defined by the prevailing properties of each system. METHODS: PS formation/destruction were studied in 5 systems: (1) human persistent atrial fibrillation (n=20), (2) tachypaced sheep atrial fibrillation (n=5), (3) rat atrial fibrillation (n=4), (5) rat ventricular fibrillation (n=11), and (5) computer-simulated fibrillation. PS time-to-event data were fitted by exponential probability distribution functions computed using maximum entropy theory, and rates of PS formation and destruction (λf/λd) determined. A systematic review was conducted to cross-validate with source data from literature. RESULTS: In all systems, PS lifetime and interformation times were consistent with underlying Poisson renewal processes (human: λf, 4.2%/ms±1.1 [95% CI, 4.0-5.0], λd, 4.6%/ms±1.5 [95% CI, 4.3-4.9]; sheep: λf, 4.4%/ms [95% CI, 4.1-4.7], λd, 4.6%/ms±1.4 [95% CI, 4.3-4.8]; rat atrial fibrillation: λf, 33%/ms±8.8 [95% CI, 11-55], λd, 38%/ms [95% CI, 22-55]; rat ventricular fibrillation: λf, 38%/ms±24 [95% CI, 22-55], λf, 46%/ms±21 [95% CI, 31-60]; simulated fibrillation λd, 6.6-8.97%/ms [95% CI, 4.1-6.7]; R2 ≥0.90 in all cases). All PS distributions identified through systematic review were also consistent with an underlying Poisson renewal process. CONCLUSIONS: Poisson renewal theory provides an evolutionarily preserved universal framework to quantify formation and destruction of rotational events in cardiac fibrillation.Dhani Dharmaprani, Madeline Schopp, Pawel Kuklik, Darius Chapman, Anandaroop Lahiri ... Lewis Mitchell ... et al

Impaired right ventricular calcium cycling is an early risk factor in r14del-phospholamban arrhythmias

The inherited mutation (R14del) in the calcium regulatory protein phospholamban (PLN) is linked to malignant ventricular arrhythmia with poor prognosis starting at adolescence. However, the underlying early mechanisms that may serve as prognostic factors remain elusive. This study generated humanized mice in which the endogenous gene was replaced with either human wild type or R14del-PLN and addressed the early molecular and cellular pathogenic mechanisms. R14del-PLN mice exhibited stress-induced impairment of atrioventricular conduction, and prolongation of both ventricular activation and repolarization times in association with ventricular tachyarrhythmia, originating from the right ventricle (RV). Most of these distinct electrocardiographic features were remarkably similar to those in R14del-PLN patients. Studies in isolated cardiomyocytes revealed RV-specific calcium defects, including prolonged action potential duration, depressed calcium kinetics and contractile parameters, and elevated diastolic Ca-levels. Ca-sparks were also higher although SR Ca-load was reduced. Accordingly, stress conditions induced after contractions, and inclusion of the CaMKII inhibitor KN93 reversed this proarrhythmic parameter. Compensatory responses included altered expression of key genes associated with Ca-cycling. These data suggest that R14del-PLN cardiomyopathy originates with RV-specific impairment of Ca-cycling and point to the urgent need to improve risk stratification in asymptomatic carriers to prevent fatal arrhythmias and delay cardiomyopathy onset. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

The Virtual Ventricular Wall: A Tool for Exploring Cardiac Propagation and Arrhythmogenesis

Methods for the experimental and clinical investigation of cardiac arrhythmias are limited to inferring propagation within the myocardium, from surface measurements, or from electrodes at a few sites within the cardiac wall. Biophysically and anatomically detailed computational models of cardiac tissues offer a powerful way for studying the electrical propagation processes and arrhythmias within the virtual heart. We use virtual tissues to study and visualise the effects of patho- and physiological conditions, and pharmacological interventions on transmural propagation in the virtual ventricular walls. Class III drug actions are quantitatively explained by changes induced in the transmural dispersion of action potential duration. We illustrate the automated construction of a virtual anisotropic ventricle from Diffusion Tensor MRI for individual hearts, and use it to explore mechanisms leading to ventricular fibrillation. The virtual ventricular wall provides an effective tool for exploring, evaluating and visualising processes during the initiation and maintenance of ventricular arrhythmias

The BaBar detector: Upgrades, operation and performance

Contains fulltext : 121729.pdf (preprint version ) (Open Access