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Introduction: The 30-50% non-response rate to cardiac resynchronization therapy (CRT) calls for improved patient selection and optimized pacing lead placement. The study aimed to develop a novel technique using patient-specific cardiac models and machine learning (ML) to predict an optimal left ventricular (LV) pacing site (ML-PS) that maximizes the likelihood of LV ejection fraction (LVEF) improvement in a given CRT candidate. To validate the approach, we evaluated whether the distance DPS between the clinical LV pacing site (ref-PS) and ML-PS is associated with improved response rate and magnitude. Materials and methods: We reviewed retrospective data for 57 CRT recipients. A positive response was defined as a more than 10% LVEF improvement. Personalized models of ventricular activation and ECG were created from MRI and CT images. The characteristics of ventricular activation during intrinsic rhythm and biventricular (BiV) pacing with ref-PS were derived from the models and used in combination with clinical data to train supervised ML classifiers. The best logistic regression model classified CRT responders with a high accuracy of 0.77 (ROC AUC = 0.84). The LR classifier, model simulations and Bayesian optimization with Gaussian process regression were combined to identify an optimal ML-PS that maximizes the ML-score of CRT response over the LV surface in each patient. Results: The optimal ML-PS improved the ML-score by 17 ± 14% over the ref-PS. Twenty percent of the non-responders were reclassified as positive at ML-PS. Selection of positive patients with a max ML-score >0.5 demonstrated an improved clinical response rate. The distance DPS was shorter in the responders. The max ML-score and DPS were found to be strong predictors of CRT response (ROC AUC = 0.85). In the group with max ML-score > 0.5 and DPS< 30 mm, the response rate was 83% compared to 14% in the rest of the cohort. LVEF improvement in this group was higher than in the other patients (16 ± 8% vs. 7 ± 8%). Conclusion: A new technique combining clinical data, personalized heart modelling and supervised ML demonstrates the potential for use in clinical practice to assist in optimizing patient selection and predicting optimal LV pacing lead position in HF candidates for CRT.

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Biophysical models are increasingly used to gain mechanistic insights by fitting and reproducing experimental and clinical data. The inherent variability in the recorded datasets, however, presents a key challenge. In this study, we present a novel approach, which integrates mechanistic modeling and machine learning to analyze in vitro cardiac mechanics data and solve the inverse problem of model parameter inference. We designed a novel generative adversarial network (GAN) and employed it to construct virtual populations of cardiac ventricular myocyte models in order to study the action of Omecamtiv Mecarbil (OM), a positive cardiac inotrope. Populations of models were calibrated from mechanically unloaded myocyte shortening recordings obtained in experiments on rat myocytes in the presence and absence of OM. The GAN was able to infer model parameters while incorporating prior information about which model parameters OM targets. The generated populations of models reproduced variations in myocyte contraction recorded during in vitro experiments and provided improved understanding of OM's mechanism of action. Inverse mapping of the experimental data using our approach suggests a novel action of OM, whereby it modifies interactions between myosin and tropomyosin proteins. To validate our approach, the inferred model parameters were used to replicate other in vitro experimental protocols, such as skinned preparations demonstrating an increase in calcium sensitivity and a decrease in the Hill coefficient of the force-calcium (F-Ca) curve under OM action. Our approach thereby facilitated the identification of the mechanistic underpinnings of experimental observations and the exploration of different hypotheses regarding variability in this complex biological system.

Asunto(s)

Contracción Miocárdica , Urea , Animales , Miocitos Cardíacos , Miosinas/metabolismo , Ratas , Urea/análogos & derivados , Urea/farmacología

RESUMEN

Background: Up to 30-50% of chronic heart failure patients who underwent cardiac resynchronization therapy (CRT) do not respond to the treatment. Therefore, patient stratification for CRT and optimization of CRT device settings remain a challenge. Objective: The main goal of our study is to develop a predictive model of CRT outcome using a combination of clinical data recorded in patients before CRT and simulations of the response to biventricular (BiV) pacing in personalized computational models of the cardiac electrophysiology. Materials and Methods: Retrospective data from 57 patients who underwent CRT device implantation was utilized. Positive response to CRT was defined by a 10% increase in the left ventricular ejection fraction in a year after implantation. For each patient, an anatomical model of the heart and torso was reconstructed from MRI and CT images and tailored to ECG recorded in the participant. The models were used to compute ventricular activation time, ECG duration and electrical dyssynchrony indices during intrinsic rhythm and BiV pacing from the sites of implanted leads. For building a predictive model of CRT response, we used clinical data recorded before CRT device implantation together with model-derived biomarkers of ventricular excitation in the left bundle branch block mode of activation and under BiV stimulation. Several Machine Learning (ML) classifiers and feature selection algorithms were tested on the hybrid dataset, and the quality of predictors was assessed using the area under receiver operating curve (ROC AUC). The classifiers on the hybrid data were compared with ML models built on clinical data only. Results: The best ML classifier utilizing a hybrid set of clinical and model-driven data demonstrated ROC AUC of 0.82, an accuracy of 0.82, sensitivity of 0.85, and specificity of 0.78, improving quality over that of ML predictors built on clinical data from much larger datasets by more than 0.1. Distance from the LV pacing site to the post-infarction zone and ventricular activation characteristics under BiV pacing were shown as the most relevant model-driven features for CRT response classification. Conclusion: Our results suggest that combination of clinical and model-driven data increases the accuracy of classification models for CRT outcomes.

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Computational models of the cardiovascular system and specifically heart function are currently being investigated as analytic tools to assist medical practice and clinical trials. To achieve clinical utility, models should be able to assimilate the diagnostic multi-modality data available for each patient and generate consistent representations of the underlying cardiovascular physiology. While finite element models of the heart can naturally account for patient-specific anatomies reconstructed from medical images, optimizing the many other parameters driving simulated cardiac functions is challenging due to computational complexity. With the goal of streamlining parameter adaptation, in this paper we present a novel, multifidelity strategy for model order reduction of 3-D finite element models of ventricular mechanics. Our approach is centered around well established findings on the similarity between contraction of an isolated muscle and the whole ventricle. Specifically, we demonstrate that simple linear transformations between sarcomere strain (tension) and ventricular volume (pressure) are sufficient to reproduce global pressure-volume outputs of 3-D finite element models even by a reduced model with just a single myocyte unit. We further develop a procedure for congruency training of a surrogate low-order model from multi-scale finite elements, and we construct an example of parameter optimization based on medical images. We discuss how the presented approach might be employed to process large datasets of medical images as well as databases of echocardiographic reports, paving the way towards application of heart mechanics models in the clinical practice.

Asunto(s)

Insuficiencia Cardíaca/diagnóstico por imagen , Ventrículos Cardíacos/diagnóstico por imagen , Modelos Cardiovasculares , Contracción Miocárdica/fisiología , Función Ventricular Izquierda/fisiología , Anciano , Fenómenos Biomecánicos , Simulación por Computador , Ecocardiografía , Femenino , Análisis de Elementos Finitos , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Sarcómeros/fisiología

RESUMEN

Patient specific models of ventricular mechanics require the optimization of their many parameters under the uncertainties associated with imaging of cardiac function. We present a strategy to reduce the complexity of parametric searches for 3-D FE models of left ventricular contraction. The study employs automatic image segmentation and analysis of an image database to gain geometric features for several classes of patients. Statistical distributions of geometric parameters are then used to design parametric studies investigating the effects of: (1) passive material properties during ventricular filling, and (2) infarct geometry on ventricular contraction in patients after a heart attack. Gaussian Process regression is used in both cases to build statistical models trained on the results of biophysical FEM simulations. The first statistical model estimates unloaded configurations based on either the intraventricular pressure or the end-diastolic fiber strain. The technique provides an alternative to the standard fixed-point iteration algorithm, which is more computationally expensive when used to unload more than 10 ventricles. The second statistical model captures the effects of varying infarct geometries on cardiac output. For training, we designed high resolution models of non-transmural infarcts including refinements of the border zone around the lesion. This study is a first effort in developing a platform combining HPC models and machine learning to investigate cardiac function in heart failure patients with the goal of assisting clinical diagnostics.