2014 Cardiovascular Risks SRP Evidence Review Final Report

The 2014 Cardiovascular Risks Standing Review Panel (from here on referred to as the SRP) met for a site visit in Houston, TX on December 17-18, 2014. The SRP reviewed the updated evidence report for The Risk of Orthostatic Intolerance During re-Exposure to Gravity (OI Risk). The SRP found the 2014 OI Evidence Report to be a well written, comprehensive overview of the OI risk; that clearly documents the key scientific evidence relevant for both mechanistic understanding and countermeasure development. The 2014 OI Evidence Report could be further strengthened by addressing the points discussed below

Effects of Electrical and Structural Remodeling on Atrial Fibrillation Maintenance: A Simulation Study

Atrial fibrillation, a common cardiac arrhythmia, often progresses unfavourably: in patients with long-term atrial fibrillation, fibrillatory episodes are typically of increased duration and frequency of occurrence relative to healthy controls. This is due to electrical, structural, and contractile remodeling processes. We investigated mechanisms of how electrical and structural remodeling contribute to perpetuation of simulated atrial fibrillation, using a mathematical model of the human atrial action potential incorporated into an anatomically realistic three-dimensional structural model of the human atria. Electrical and structural remodeling both shortened the atrial wavelength - electrical remodeling primarily through a decrease in action potential duration, while structural remodeling primarily slowed conduction. The decrease in wavelength correlates with an increase in the average duration of atrial fibrillation/flutter episodes. The dependence of reentry duration on wavelength was the same for electrical vs. structural remodeling. However, the dynamics during atrial reentry varied between electrical, structural, and combined electrical and structural remodeling in several ways, including: (i) with structural remodeling there were more occurrences of fragmented wavefronts and hence more filaments than during electrical remodeling; (ii) dominant waves anchored around different anatomical obstacles in electrical vs. structural remodeling; (iii) dominant waves were often not anchored in combined electrical and structural remodeling. We conclude that, in simulated atrial fibrillation, the wavelength dependence of reentry duration is similar for electrical and structural remodeling, despite major differences in overall dynamics, including maximal number of filaments, wave fragmentation, restitution properties, and whether dominant waves are anchored to anatomical obstacles or spiralling freely

Comparison of Bayesian Models for Uncertainty Quantification in Aerodynamic Databases of Reusable Launch Vehicles

The German Aerospace Center (DLR) is currently involved in the CALLISTO project, aiming to develop a demonstrator for a reusable launch vehicle. For assessing the aerodynamic flying qualities of such a vehicle, an aerodynamic database model is crucial, with a key element being the estimation of uncertainties. Traditionally, experts have been consulted in a time-consuming and tedious process to characterize these uncertainties. In contrast, this thesis further establishes an automated, data-driven approach utilizing Bayesian inference and compares the suitability of different models to do so. In the course of this study, Spline, Fourier Series, and Gaussian Process models were evaluated in terms of predictive accuracy and data coverage. Accuracy was measured using maximum residual error, root mean squared error, and median absolute deviation, while uncertainty estimation was assessed using a coverage probability metric. Three methods were employed: in-sample validation, stratified k-fold cross-validation, and hold-out validation. Gaussian Processes proved most accurate in in-sample prediction while providing a high data coverage. Some generalized linear models, which include Spline and Fourier models, tended to overfit, but others showed even slightly better accuracy than Gaussian process models when generalizing on new data. However, this advantage was offset by reduced data coverage, which presumably stems from an increased bias. Increasing the data coverage of the most accurate generalized linear model artificially with white noise made it challenging to identify a clear winner. This thesis contributes significantly to the establishment of Bayesian methods in aerodynamic database model generation. It implements a framework that eases the integration of additional models and offers a streamlined method for predictions on new data through Bayesian inference. In this way, the limitations of the conventional approach are overcome. Through the out-of-sample evaluation of predictive accuracy, especially generalized linear models have been found to hold potential for future modeling. Simply adding white noise for uncertainty quantification led to inaccuracies, suggesting the need for more precise methods in the future. Having effectively compared models for the relationship between the Angle of Attack and the aerodynamic force coefficient Cz , this methodology can be adapted for other variables, thus broadening its applicability in aerospace research

Evaluating fluctuations in human atrial fibrillatory cycle length using monophasic action potentials

Objective: To study fluctuations in intracardiac atrial fibrillation (AF) cycle length (CL). Background: Sites of short AF CL may be good ablation targets, and cycle lengthening predicts ablation success. However, the optimum method for measuring AF CL, and its stability, are unclear. We hypothesized that autocorrelation better estimates AF CL than spectral dominant frequency (DF), which is susceptible to double counting, using monophasic action potentials (MAPs) to separate atrial activation from artifact. Methods: In 28 patients with paroxysmal or persistent AF, we analyzed 49 AF epochs using MAPs at the high (HRA) and low (LRA) right atrium. We estimated AF CL over 2 seconds, 10 seconds, and 2 minutes using spectral DF and autocorrelation in MAPs and filtered bipoles. Results: In the HRA, manually measured CL was 167 ± 25 ms. Spectral DF poorly estimated AF CL in bipolar signals (R = 0.31; P = NS), due to double counting, but accurately estimated MAP CL (R = 0.73, P \u3c 0.001). Autocorrelation estimated MAP (R = 0.92; P \u3c 0.001) and bipolar (R = 0.83; P \u3c 0.001) CL, with lower errors than spectral DF (P \u3c 0.0001). Over time, changes in DF consistently preceded reciprocal changes in organization (P \u3c 0.001). Finally, excluding inaccurate spectra, DF and AF organization differed between HRA and LRA over 2 seconds, but correlated over 10 seconds and 2 minutes (P \u3c 0.05). Conclusions: AF CL is better estimated by autocorrelation than spectral DF, particularly for bipoles, and stable when measured for \u3e10 seconds. Notably, changes in AF CL preceded reciprocal changes in organization, yet changes in organization did not precede changes in AF CL. These results may help to interpret AF CL fluctuations. © 2006, The Authors

Computational Mapping Identifies Localized Mechanisms for Ablation of Atrial Fibrillation

<div><p>Atrial fibrillation (AF) is the most common heart rhythm disorder in the Western world and a common cause of hospitalization and death. Pharmacologic and non-pharmacologic therapies have met with limited success, in part due to an incomplete understanding of the underlying mechanisms for AF. AF is traditionally characterized by spatiotemporally disorganized electrical activation and, although initiating triggers for AF are described, it is unclear whether AF is sustained by spatially meandering continuous excitation (re-entrant waves), localized electrical sources within the atria, or some other mechanism. This has limited therapeutic options for this condition. Here we show that human AF is predominantly caused by a small number (1.8±0.9) of localized re-entrant waves or repetitive focal beats, that remain stable with limited spatial migration over prolonged periods of time. Radiofrequency ablation that selectively targeted the sites of these sources was able to immediately terminate fibrillation and eliminate the arrhythmia with high success. Our results show that human AF, despite apparent spatiotemporal disorganization, is often perpetuated by a few spatially-constrained and temporally conserved sources whose targeted ablation can eliminate this complex rhythm disorder.</p> </div

AF Termination by ablation of a Stable RA Rotor.

<p><b>A</b>. Isochrones show a RA rotor and concurrent LA focal beat during persistent AF. <b>B</b>. Spatially constrained rotational center locus. <b>C</b>. Ablation lesions at lateral RA rotor on patient specific geometry (performed 2 hours after initial recording of rotor). A total of 11 lesions were applied (shown), with AF termination to sinus rhythm at 5.5 minutes. The red lesion indicates where ablation terminated AF. <b>D</b>. Electrograms AF terminating to sinus rhythm with localized ablation at rotor (total duration 5.5 minutes) (ECG lead I, intracardiac electrodes in RA, LA and CS). <b>E</b>. Isochrones of sinus rhythm. After ablation, the patient remains AF-free at 12 months on implanted cardiac monitor. Scale bar 1 cm.</p