Natalia A. Trayanova - US grants

DESCRIPTION (adapted from the applicant's description): The objective of this proposal is to study the relationship between cardiac tissue structure and the electrical events in the process of defibrillation. Defibrillation current traverses the myocardium along convoluted intracellular and extracellular pathways channeled by the tissue structure. It distributes across cell membranes, thus, inducing change in transmembrane potential throughout the myocardium. It is postulated that in the process of defibrillation, the dominant shock-induced transmembrane potential change in the tissue arises from its macroscopic fibrous organization. In particular, changes in the fiber orientation in space, as well as non-uniformity of the extracellular electric field along fibers, are responsible for large-scale transmembrane potential change in the tissue bulk. These spatially distributed regions of induced membrane depolarization and hyperpolarization affect pre-existing reentrant activations in the fibrillating myocardium . More specifically, graded responses and new activations arise in regions of depolarization at the make of the shock. They combine with excitations emanating from regions of hyperpolarization at the break of the shock to ultimately result in either prevention of further wavefront propagation or, for weak shocks, reinitiation of fibrillation. To test these hypotheses, computer simulations will be carried out in (1) anatomically based rabbit ventricular geometry and fiber architecture, (2) accurate description of myocardial ionic current dynamics under strong electric fields, (3) representation of membrane electroporation, and (4) adequate protocols for the generation of reentrant activation patterns. The specific aims are to: (i) analyze rigorously the relationship between myocardial fibrous organization and shock-induced transmembrane potential changes, and (ii) characterize the interaction between shock-induced potential change and inherent refractoriness of the fibrillating myocardium. Experimental measurements are proposed to validate the defibrillation model expected to guide experimental design and interpretation of experimental findings related to electrical defibrillation of the heart.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cardiac fibrillation is disorganized electrical behavior of the heart, and its consequence is the loss of coordinated muscle contraction. Electrical defibrillation by timely application of a strong electric shock to the heart has long been used as an effective therapy for this otherwise lethal disturbance of cardiac rhythm. In recent years defibrillation therapy has dramatically expanded due to its improved accessibility and functionality. Despite the critical role that the technique plays in saving human life, the fundamental mechanisms by which electrical shocks halt life-threatening disturbances in cardiac rhythm are not completely understood. Mechanical contraction follows the electrical activation of the heart. However, it has long been known that there is a cross-talk between the electrical and mechanical processes which could play a role in anti-arrhythmia therapy. Owing to the complexities in cardiac structure and behavior, mechanical contributions have never before been considered in the investigation of cardiac defibrillation mechanisms. The objective of this research is to determine the contribution of mechanoelectrical feedback in the process of cardiac defibrillation, and thus, to increase our knowledge of the mechanisms by which the exposure of the heart to strong electric shocks terminates fibrillation. This application seeks to establish collaboration between the Computational Cardiac Electrophysiology Group at Tulane University and the National Biomedical Computation Resource and thus, to take full advantage of the combination of state-of-the-art approaches in modeling cardiac defibrillation and mechanical contraction, respectively, developed by the two groups. Upon completion, the project is expected to bring a new level of understanding to how the complex electro-mechanical events in the heart can be used to benefit anti-arrhythmia therapy. As a collaborative project of the NBCR this research will promote extensions to the development of Continuity and its anatomic, electrical and mechanical models and algorithms that will permit greater integration with bidomain models of the heart and torso, opening in up to the large array of applications in cardiac pacing, shock and electrocardiography.

[unreadable] DESCRIPTION (provided by applicant): The highly heterogeneous structural substrate in the infarcted heart can have a major contribution to the mechanisms of defibrillation. However, the role of infarct structure and surviving cell electrophysiology on post-shock behavior and the outcome of the defibrillation shock have never been quantified. The overall objective of this research is to provide a new level of understanding of the mechanisms for ventricular defibrillation under the conditions of myocardial infarction. We hypothesize that increases in the upper limit of vulnerability and defibrillation threshold in the infarcted ventricles result from 1) dramatically altered virtual electrode polarization in the infarcted region, stemming from the different responses of myocytes and myofibroblasts to the shock, and 2) the convoluted pattern of post-shock propagation in the region of infarction, involving propagation pathways through depressed border zone regions and conduction through the fibroblast-rich scar. To test the hypotheses, we propose to develop, from magnetic resonance imaging, immunohistochemical, and electrophysiological data, detailed high-resolution 3D anatomically-accurate bidomain models of 1) isolated rabbit ventricular wedge-like preparations with healed infarction, and 2) intact rabbit ventricles with healed infarction (Specific Aim 1). Using the new anatomical-accurate model of the isolated preparation, and in combination with microelectrode and optical recordings from the region of infarct, we propose to characterize virtual electrode polarization and post-shock propagation patterns in the isolated rabbit ventricular preparation with healed infarction (Specific Aim 2). Once the detailed post-shock behavior of the infarct zone is investigated, we propose to use the realistic model of the infarcted ventricles in combination with panoramic optical mapping experiments, to determine the changes in the upper limit of vulnerability and defibrillation threshold and to elucidate the mechanisms responsible for these changes (Specific Aim 3). The combined tightly-coupled simulation/experimental approach to defibrillation, as proposed in this application, overcomes the inability of current experimental techniques to resolve electrical behavior confined to the depth of the ventricular wall during and after the shock. The new insights into the success and failure of defibrillation to be obtained by this project are expected to ultimately lead to rational rather than trial-and-error advancements in defibrillation procedure in patients with myocardial infarction. The proposed combined experimental/simulation research will elucidate the mechanisms for ventricular defibrillation in hearts with myocardial infarction, and will thus address a problem central to the clinical aspect of defibrillation. Knowledge of these mechanisms could suggest new routes to optimizing defibrillation procedure or could lead to the development of novel interventions that lower defibrillation threshold. [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite the importance of defibrillation therapy, understanding of mechanisms by which electric shocks halt life-threatening arrhythmias remains incomplete. While recent experimental advances have provided new characterizations of tissue responses to shocks, mechanistic inquiry into the success and failure of defibrillation is hampered by the inability of current experimental techniques to resolve, with sufficient accuracy, electrical behavior confined to the depth of the ventricles. The overall objective of this study is, by employing realistic 3D computer simulations, to bring a new level of understanding of the post-shock events in the heart that lead to the failure of the shock. Current models do not incorporate anatomical microheterogeneities, which could play an important role. Specifically, in this project we examine, in bidomain models of cardiac micro-structure, mechanisms underlying the ``isoelectric window", the quiescent period often preceding the first postshock activation following failed shocks.

DESCRIPTION (provided by applicant): Partial support is requested for the 2009 Gordon Research Conference (GRC) on Cardiac Arrhythmia Mechanisms, to be held February 15-20, 2008 at Il Ciocco, Braga, Italy. This is the fourth Gordon Research Conference on Cardiac Arrhythmia Mechanisms. The meeting convenes biannually, with past meeting held in 2003, 2005, and 2007. These meetings provide a venue for international scientific discourse on the mechanisms that underlie disturbances in cardiac rhythm and lethal arrhythmias, and the novel approaches to therapy and prevention. The GRC meetings have profoundly affected our scientific community by rendering it unusually collaborative and interactive. They draw participation from every aspect of our community, from graduate students and postdoctoral fellows through to senior faculty, with participation both national and international, and from academia and industry, to successfully address major issues in the fight against sudden cardiac death. The overall score of the previous conference held in 2007 was 1.2 on a scale of 1 (best) to 5 (worst). We are extremely pleased with the outstanding ratings by the participants of the 2007 GRC on Cardiac Arrhythmia Mechanisms, and we will work hard to maintain and even surpass the quality of the preceding meeting. The proposed 2009 Gordon Research Conference on Cardiac Arrhythmia Mechanisms will focus on both basic science and clinically relevant key scientific topics. The meeting will allow unique opportunities to bring together groups of outstanding investigators, experts in various relevant fields, including molecular biology, molecular genetics, cellular electrophysiology, biophysics, imaging, biomedical engineering, mathematics, and clinical cardiology to interact and share ideas about the underlying mechanisms of complex life-threatening cardiac arrhythmias. The participants of the 2007 conference expressed their desire to steer the 2009 conference towards the clinical translation of cardiac arrhythmia mechanisms research. Accordingly, the Theme of our 2009 GRC is Translational Aspects of Cardiac Arrhythmias Research. The selection of proposed topics as well as speakers and discussion leaders reflects this emphasis. The organization of each session ensures that the sequence of speakers will lead the audience through what is known about a given subject at the level of the gene, the protein, the cell, the organ, and the organism in a systematic and didactic way, culminating with a presentation by a clinician/scientist that integrates and translates the presented topics into clinical research and practice. The presentations will define and analyze the latest and most important information on arrhythmia mechanisms and how these could result in novel antiarrhythmia therapies and prevention. We intend to invite the top experts and young promising investigators in their respective fields to this forum, where they will present and together discuss the most exciting new contributions to the understanding of the mechanisms of cardiac rhythm disturbances. Specific attention will be paid to increasing the participation of young investigators and well as women and minority researchers. This proposal outlines novel approaches to increasing the informal interaction between established and young investigators. The proposed preliminary program will also target both established and young female investigators.

0933029
Trayanova


The overall objective of this research is to investigate the genesis of stretch-induced ventricular ectopy and the mechanisms by which it degrades into reentrant arrhythmias in the ischemic heart. The overarching hypothesis is that the origin of ectopic activations in acute regional ischemia arises from mechanical stretch of the ischemic region during systole. Specifically, it is hypothesized that: 1) Depolarization of the ischemic region caused by end-systolic stretch and subsequent opening of mechano-sensitive channels leads to ventricular premature beats originating at the ischemic border, and 2) The incidence of ventricular premature beats increases as ischemia progresses due to the higher level of strain developed as a result of increased end-diastolic pressure and tissue compliance. The hypothesis regarding the mechanism of degeneration of ventricular premature beats into reentrant arrhythmias posits that this degeneration stems from reduced excitability and dispersion in refractoriness and conduction velocity resulting from combined electrophysiological and mechanical changes in the ischemic region.

To test these hypotheses, the project will develop a three-dimensional anatomically-accurate bidomain electromechanical model of the rabbit ventricles with acute regional ischemia. The model will be able to represent the mechanical and electrophysiological characteristics and behavior of ischemic tissue, including mechano-electric feedback mechanisms. This novel powerful model will be used to provide new mechanistic insight into the origins of ectopic activity and an understanding of how stretch-induced electrophysiological changes can exacerbate the existing pro-arrhythmic ischemic substrate and thus facilitate the degradation of ventricular ectopy into reentrant arrhythmias. The new insights into the role of mechano-electric feedback in arrhythmogenesis could ultimately lead to rational rather than empirical advancements in anti-arrhythmia therapies in patients with ischemic cardiac disease.

In addition to the benefits to human health as outlined above, broader impacts resulting from the proposed activity include 1) advancement in the integration of research and education, 2) broadening the participation of underrepresented groups, and 3) fostering the development and dissemination of the next-generation engineering methods and technologies. The proposed research will provide an integrated array of simulation tools for electromechanical modeling of cardiac arrhythmogenesis in the diseased heart that will be made available to the broader community. Undergraduate and graduate students participating in the project will be trained in interdisciplinary approaches to clinically-relevant problems in biomedical engineering. Particular emphasis will be placed on the involvement of women and under-represented minority students in the project, consistent with the PI's long-term research activities.

DESCRIPTION (provided by applicant): An estimated 5.7 million people in the U.S. have heart failure and more than 292,000 die from heart failure-related complications each year. While much is known about the mechanisms of cardiac hypertrophic growth and subsequent decompensation leading to failure, few therapeutic strategies are available, and these are aimed primarily at relieving symptoms, preventing hospitalization, and improving the quality of life of patients, with little overall effect on mortality. Recent research has provided new insights into the molecular signaling pathways involved in the progression of the disease; however, heart failure remains a complex multifactorial problem. A comprehensive mechanistic understanding of heart failure requires not just elucidation of targets/pathways modified during the progression of the disease, but an integrative understanding of how alterations at the level of genes and proteins affect the sophisticated interplay between the electrophysiological, Ca2+ handling, and energetic subsystems of the cardiac cell. This proposal brings together leaders in the areas of excitation-contraction coupling, mitochondrial biology, redox modulation, proteomics, and computational biology to investigate how the remodeling of ion transport pathways and mitochondrial proteins contribute to maladaptive responses in a pressure-overload model of hypertrophy, which progresses to heart failure over several weeks. The central hypothesis to be explored is that alterations in Ca2+m dynamics not only contribute to impaired energy supply and demand matching following pressure-overload, but also significantly compromise the pathways responsible for handling reactive oxygen (ROS) and nitrogen (RNS) species in the mitochondria and the cell. This imbalance results in ROS/RNS-dependent modifications of key proteins involved in EC coupling and mitochondrial oxidative phosphorylation, with concomitant effects on function that contribute to cellular injury or death. A vicious circle of these complex deleterious interactions could thus mediate decompensation of the failing heart. (End of Abstract)

DESCRIPTION (provided by applicant): Heart failure is a disease that is continually increasing in prevalence worldwide. In the United States, nearly 6 million people suffer from heart failure and it is the most common inpatient diagnosis in the elderly. The economic impact for 2009 has been estimated at $37.2 billion. Treatment of this disease with 2-blockers and/or inhibitors of renin-angiotensin signaling has decreased mortality and morbidity over the years, but mortality still approaches 60% within 5 years of diagnosis. Fatal arrhythmias, known as Sudden Cardiac Death (SCD), account for about half of the early deaths in HF, with progressive cardiac decompensation accounting for the remainder. Many factors contribute to the pathology of HF, including changes in the neurohumoral environment, alterations in ion channel and transporter activity, modulation of cell death pathways, and remodeling of the inherent structure of the tissue. Recent evidence indicates that alterations in the reduction- oxidation (redox) potential of the cytoplasm, sarcoplasmic reticulum, and the mitochondria of the heart may be a key factor involved in the progression of cardiac hypertrophy and failure. In heart failure (HF), there is evidence that oxidative stress may contribute to impaired function, and this may arise as a consequence of altered ion homeostasis, energetic deficiencies, and post-translational modification of protein targets. Moreover, a large number of ion channels, transporters, and signaling pathways have been shown to be modulated either directly by reactive oxygen species (ROS), or by changes in the thiol status or redox carrier concentration. Some, or many, of these targets, could contribute to an enhanced susceptibility of the failing heart to arrhythmogenesis and SCD. A comprehensive view of how shifts in metabolism and redox balance influence the electrophysiological substrate requires a systems biology approach to the problem, involving deconstruction of how individual ion channels, transporters and signaling pathways are affected by redox modulators, and how the performance of the integrated system is changed. Specifically, in this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts (pressure-overload model). An iterative, experimental/computational systems biology approach combining both horizontal and vertical integration will be taken. These approaches will be used to build biophysically-detailed cellular and whole-heart models of redox/antioxidant pathways and their downstream effects on ion channels and transporters, with the goal of defining how metabolic and oxidative stress leads to arrhythmias, pump failure, and SCD. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Narrative Heart failure is a disease that is continually increasing in prevalence worldwide. In this proposal, our objective is to examine how enhanced oxidative stress alters the electrophysiology, Ca2+ regulatory processes, and arrhythmia susceptibility of myocytes from failing hearts. An overriding goal will be to define the specific alterations that have the greatest influence on whole heart function, so as to narrow down the number of targets to pursue for therapeutic intervention to treat heart failure.

DESCRIPTION (provided by applicant): This proposal is in response to PAR-08-023 "Predictive Models of the Heart in Health and Disease". Heart failure is a major cause of morbidity and mortality, contributing significantly to global health expenditure. Heart failure patients often exhibit contractile dyssynchrony, which diminishes cardiac systolic function. Cardiac resynchronization therapy (CRT) employs bi-ventricular pacing to re-coordinate the contraction of the heart. CRT has been shown to improve heart failure symptoms and reduce hospitalization, yet approximately 30% of patients fail to respond to the therapy. The poor predictive ability of current approaches to identify potential responders to CRT reflects the incomplete understanding of the complex pathophysiologic and electromechanical factors that underlie mechanical dyssynchrony. Specifically, given that a large portion of CRT non-responders are heart failure patients with chronic myocardial infarction (MI), it is of paramount importance to the improvement in CRT effectiveness that the contribution of chronic MI to dyssynchronous heart failure (DHF) is identified, and the mechanisms by which it limits CRT benefit thoroughly explored. The present application addresses this need. The overall objective of this research is to elucidate the role of chronic MI in heart failure dyssyn- chrony and its effect on CRT effectiveness. To achieve the objective of the proposed research, we will de- flop, from magnetic resonance imaging (MRI) and diffusion tensor MRI scans, individualized 3D image-based multiscale computational models of ventricular electromechanics in canine hearts that incorporate the deleterious- ous structural, mechanical, and electrophysiological remodeling associated with DHF and chronic MI, from the level of the molecule to that of the intact heart. This powerful predictive modeling approach will then be used 1) to provide mechanistic insight into the contribution of the infarct location and of the degree of transmural scar extent to left ventricular heart failure contractile dyssynchrony, and 2) to determine the optimal CRT strategy. The development of a validated predictive model of ventricular electromechanics in the setting of DHF and chronic MI (DHF+MI heart model), as proposed in this application, overcomes the inability of current experimental techniques to simultaneously record the 3D electrical and mechanical activity of the heart with high spatiotemporal resolution, and thus to provide an understanding of the contribution of chronic MI to heart failure dyssynchrony and CRT effectiveness. The new basic-science insights into the electromechanical behavior in the DHF+MI heart to be acquired under this study are expected to ultimately lead to rational optimization of CRT delivery in patients with ischemic cardiomyopathy and to improvements in the selection criteria for viable CRT candidates. PUBLIC HEALTH RELEVANCE: Cardiac resynchronization therapy (CRT) employs bi-ventricular pacing to re-coordinate the contraction of the heart, yet approximately 30% of patients fail to respond to the therapy. In the current environment which emphasizes reducing health care costs and optimizing therapy, robust diagnostic approaches to identify patients that would benefit from CRT and distinguish those who could not, would have a dramatic personal, medical and economic impact. The proposed project offers mechanistic insight into heart failure dissynchrony and CRT that can contribute to the development of such approaches.

The conceptual premise of the proposed research is that integrating new modeling and computational approaches into the analysis of heart function will enable the development of transformative simulation-guided analytical tools for characterizing heart function in the not-too-distant future. The goal of the project is to develop multi-physics models of ventricles in normal and abnormal hearts that run efficiently on large-scale, heterogeneous computer systems. The research will focus on applying these computational tools to healthy hearts and also to those with arrhythmia or other disorders. One novel aspect of the work incorporates the direct computation of heart sounds which should significantly advance non-invasive diagnosis of diastolic dysfunction. Beyond cardiac function and heart disease, the impact of the research extends to the areas of computational biophysics, biomechanics, computer engineering and fluid mechanics, as well as to other organ systems. The research will produce an integrated array of simulation tools for electromechanical/hemodynamical modeling in normal and diseased hearts that will be made available to the broader community though effective data management. Research training of students and postdocs will contribute to a new generation of scientists and engineers who can apply computational thinking across disciplinary boundaries. Educational impact within the PIs? universities will be enhanced by translating the research into new and existing courses; impact outside the PIs institutions will be achieved via planned high-school and minority-focused outreach activities.

DESCRIPTION (provided by applicant): I propose to develop a highly innovative patient-specific MRI-based heart modeling environment that represents cardiac functions from molecular processes to electrophysiological and electromechanical interactions at the organ level. I term this environment virtual electrophysiology lab, and propose to translate it into th clinic and apply it to the non-invasive diagnosis and treatment of heart rhythm and contractile disorders in patients with structural heart disease. This pioneering effort offers to integrate, fo the first time, computational modeling of the heart, traditionally a basic-science discipline, withn the milieu of contemporary patient care. The robust and inexpensive non-invasive approaches for individualized arrhythmia risk stratification and guidance of electrophysiological therapies proposed here will lead to optimized therapy delivery and reduction in health care costs, and will have a dramatic personal, medical and economic impact on society. This project seeks to shift the paradigm of cardiac patient care by utilizing the virtual electrophysiology laboratory environment in three applications pertinent to patients with myocardial infarction: 1. Noninvasive prediction of the optimal ablation targets for infarct-related ventricular tachycardia. The vital electrophysiology lab will be used to accurately identify the optimal targets of ablation in each patient heart non-invasively prior to the clinical procedure. Delivery of ablation will then be swit and precise, eradicating all infarct-related ventricular tachycardias with minimum lesion sizes. This will result in a dramatic improvement in the efficacy of and tolerance for the therapy, as wel as in reduction of post-procedure complications. 2. Arrhythmia risk assessment to determine the need for implantable defibrillator deployment. Personalized simulations of arrhythmia inducibility will be used as a noninvasive, inexpensive, and risk-free surrogate for a clinical elect

? DESCRIPTION (provided by applicant): Heart failure (HF) is a major cause of morbidity and mortality, contributing signi?cantly to global health expenditure. Sudden death due to arrhythmia is responsible for over 50% of deaths among HF patients; however, the mechanisms linking HF-induced molecular remodeling to increased sudden death risk remain poorly understood. This has resulted in ineffective pharmacologic therapy for preventing sudden arrhythmic death and in inadequate approaches to arrhythmia risk strati?cation of HF patients. The overall objective of the proposed research is to explore a novel set of mechanisms by which HF remodeling, from the sub-cellular microdomain to the whole heart, leads to increased risk of lethal arrhythmias in human HF. Speci?cally, we propose to investigate how the impact of the degradation of myocyte microdomains on L-type Ca channel and cellular function is ampli?ed regionally by the heterogeneities in electrophysiological remodeling and adrenergic innervation as well as by the disease-induced remodeling in ventricular structure to produce i) arrhythmia triggers and ii) their degeneration into ventricular ?brillation (VF). The project presents an integrated experimental/computational approach to arrhythmogenesis in human HF. Super-resolution scanning patch clamp will provide novel insight into how disruption of sub-cellular compartments affects L-type Ca channel functioning in the HF cell. This data will be used as input into an integrative human HF myocyte model, which following validation, will be implemented in organ-level HF models. Protein and microstructure distribution data informing the organ-level models will be gathered in experiments with explanted HF human hearts. Model components will be combined with MRI scans of HF human heart geometry/structure to develop multiscale HF ventricular models which will then be used to determine the mechanisms responsible for the formation of 1) hot spots, from which triggered activity emanates, and 2) arrthythmogenic substrates at heart rates near rest, causing the degradation of triggered activity into VF. Simulation results regarding the arrhythmogenic substrate and VF likelihood at these heart rates will be validated in a clinical study of HF patients. Completion of the studies proposed here will result in a greater understanding of the mechanisms leading to arrhythmias and sudden death in human HF. Such mechanistic understanding is expected to reduce the impact of HF on its victims and on the health-care system 1) by suggesting targeted and effective new molecular therapies, and 2) by leading to new and improved approaches to arrhythmia risk strati?cation of HF patients.

Life-threatening ventricular tachycardia (VT) remains a major complication of myocardial infarction. Catheter ablation aims to destroy the VT substrate, diseased myocardium that slows local conduction sufficiently to perpetuate circuit reentry. The current understanding of the VT substrate revolves around the interaction of surviving strands of viable myocardium primarily at the periphery of infarct scar. Our preliminary data, however, suggests that critical VT circuit sites are viable myocardial strands that reside in the scar core, and are often surrounded by intra-myocardial fat deposition. Intra-myocardial fat is not a simple bystander; it is metabolically active and vascular, an effective insulator of conductive fibers, and modulates local conduction properties. This proposal will investigate the mechanistic consequence of intra-myocardial fat deposition upon impulse conduction and the propensity to sustain VT in adults with prior myocardial infarction. We propose to use MRI and CT images of patients with post-infarct VT to 1) to define the prevalence and distribution of myocardial fat deposition in patients with prior infarction and VT, 2) to characterize the conduction and repolarization properties of viable channels within scar based upon proximity to myocardial fat, 3) to examine the association of VT circuit sites with proximity to myocardial fat, and 4) to dissect the contribution of myocardial fat to VT events using patient-specific models, and to evaluate the diagnostic performance of model-predicted optimal ablation sites with and without inclusion of myocardial fat. Our group has extensive experience with MRI safety and image optimization in defibrillator recipients. Additionally, we have assembled a team of experts in image acquisition and analysis, epidemiology, biostatistics, simulations, and VT management. The findings of this study will have wide applicability to our mechanistic understanding and management of post-infarct VT.

PROJECT SUMMARY This application is in response to PAR-15-085: Predictive Multiscale Models for Biomedical, Biological, Behavioral, Environmental and Clinical Research (Interagency U01), with Cutting Edge Challenge: Predictive multiscale models to improve clinical workflow, standard operating procedures, patient-specific modeling for diagnosis and therapy planning. Atrial ?brillation (AF) is the most prevalent sustained cardiac arrhythmia, leading to morbidity and mortality in 1-2% of the population and contributing signi?cantly to global health care costs. For patients in whom AF can- not be treated by drugs, the recommended therapy is catheter-based ablation to isolate arrhythmia triggers and eliminate the substrate for arrhythmia perpetuation. However, outcomes of the procedure are poor ( 50% suc- cess rate) in patients with persistent AF (PsAF) due to the presence of extensive atrial ?brosis, which confounds ablation strategies. There is an urgent need for new approaches that can result in swift and accurate iden- ti?cation of optimal ablation targets for PsAF and thereby improve the ef?cacy of and increase the tolerance for the therapy, as well as reduce post-procedure complications and repeated ablations. The overall objective of this application is to develop and validate a novel personalized multiscale modeling strategy for determining the optimal targets for catheter ablation of the fibrotic substrate in patients with PsAF. We propose to develop and validate atrial models reconstructed from MRI images of pa- tients with PsAF and fibrotic remodeling. The models will integrate mechanistically functions from the molecular level to the electrophysiological interactions in the intact organ. We will parametrize and validate the simula- tion approach with experimental measurements in explanted human atria and animal models. We will use the validated personalized modeling strategy to determine, in retrospective patient studies, what constitutes a set of optimal ablation lesions that terminate AF with the least likelihood of recurrence. The project will culminate with a pilot prospective patient study, where AF ablation will be executed directly at the simulation-predicted targets. Successful execution of the proposed studies will pave the way for a major paradigm shift in the clinical procedure of AF ablation in patients with fibrotic remodeling, resulting in a dramatic improvement in the efficacy of the therapy. Importantly, completion of this project will result in a major leap forward in the integration of computational modeling in the diagnosis and treatment of cardiac disease.

PROJECT SUMMARY Ventricular tachycardia (VT), a life-threatening fast heart rhythm, occurs frequently in patients with myocardial infarction, leading to sudden cardiac death. Catheter-based ablation offers the possibility of permanent cure by interrupting the VT reentrant circuit. Unfortunately, eliminating infarct-related VT with ablation has achieved only modest success, 50-88%. This stems from limitations associated with the current VT electrical mapping and the use of the clinical VT maps to identify the target locations for ablation. Employing new strategies that provide comprehensive understanding of the complex phenomena in the zone of infarct, and how they correlate to clinical measures is a quest of paramount clinical signi?cance, as will lead to a signi?cant improvement in the identi?cation of optimal ablation targets for infarct-related VT. The overall objective of this project is to apply novel imaging and modeling methodologies to provide a comprehensive understanding of the complex micro-structural and electrophysiological (EP) factors that establish speci?c VT pathways in the zone of the healed infarct and to determine how these factors are re?ected in clinical imaging and EP measurements. Our ability to achieve this objective stems from new developments by our team, such as the invention of a new MRI pulse sequence that allows us to acquire non- destructively images of entire human and large animal hearts ex-vivo at previously unattainable (sub-millimeter) resolution. We will use our new sub-millimeter imaging capability to acquire contrast-enhanced and diffusion- tensor MRI of swine and human hearts ex-vivo and develop individualized models from these images. These high resolution ex-vivo models will be used to test a number of novel mechanistic hypotheses elucidating how the complex spatially-distributed structural and EP characteristics of the healed infarct establish preferential VT pathways through it. We will then conduct simulation and experimental research to establish the relationship between the infarct structural and EP characteristics at the sub-millimeter scale that give rise to speci?c VT pathways, and the image features and electrical signatures in corresponding clinical-resolution measurements. Successful execution of the proposed studies will provide a new understanding of the signatures of the com- plex infarct-related micro-structural and EP remodeling as they are manifested in clinical measurements. The new insight will enable improved determination of the optimal ablation option for a given VT, leading to a signi?cant advancement in the ef?cacy of the therapy.

Recent reports demonstrate the critical influence of COVID-19 on the cardiovascular system, with up to 20% of COVID-19 patients suffering acute cardiac injury. Approaches to identify COVID-19 patients at risk for cardiac dysfunction have not yet been developed, and no alerting clinical parameters are available to address the impending decline of cardiac function and mortality. The goal of this project is to develop a machine learning approach to identify COVID-19 patients at risk for cardiac dysfunction and sudden cardiac death. Utilizing such an approach will provide early warning and enable the delivery of early goal-directed therapy, reducing mortality and optimizing allocation of resources. The machine learning classifier is to be distributed to any interested healthcare institution, to augment their ability to successfully treat patients. This project also provides fundamental new scientific knowledge: how COVID-19-related cardiac injury could result in cardiac dysfunction and sudden cardiac death. Such knowledge is of paramount importance in the fight against COVID-19 and the post-disease adverse effects on human health.

Features that will serve as input into the machine learning classifier will be extracted from both time series (ECG, cardiac-specific laboratory values, continuously-obtained vital signs) and imaging data (CT, echocardiography). Data will be collected from patients admitted to Johns Hopkins Hospital and Johns Hopkins Health System; other hospitals in the Chesapeake area; and potetially hospitals in NYC, with a confirmed diagnosis of COVID-19 based on nucleic acid or polymerase chain reaction testing. We will develop a time-varying risk score that will determine the posterior probability of hemodynamically-significant cardiac disease outcome within 24 hours of certain time points. For new patients, the model will be used to perform a baseline prediction which will be updated in a Bayesian fashion each time new data becomes available.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.