Defining myocardial fiber bundle architecture in atrial digital twins.

A key component in developing atrial digital twins (ADT) - virtual representations of patients' atria - is the accurate prescription of myocardial fibers which are essential for the tissue characterization. Due to the difficulty of reconstructing atrial fibers from medical imaging, a widely used strategy for fiber generation in ADT relies on mathematical models. Existing methodologies utilze semi-automatic approaches, are tailored to specific morphologies, and lack rigorous validation against imaging fiber data. In this study, we introduce a novel atrial Laplace-Dirichlet-Rule-Based Method (LDRBM) for prescribing highly detailed myofiber orientations and providing robust regional annotation in bi-atrial morphologies of any complexity. The robustness of our approach is verified in eight extremely detailed bi-atrial geometries, derived from a sub-millimiter Diffusion-Tensor-Magnetic-Resonance Imaging (DTMRI) human atrial fiber dataset. We validate the LDRBM by quantitatively recreating each of the DTMRI fiber architectures: a comprehensive comparison with DTMRI ground truth data is conducted, investigating differences between electrophysiology (EP) simulations provided by either LDRBM and DTMRI fibers. Finally, we demonstrate that the novel LDRBM outperforms current state-of-the-art fiber models, confirming the exceptional accuracy of our methodology and the critical importance of incorporating detailed fiber orientations in EP simulations. Ultimately, this work represents a fundamental step toward the development of physics-based digital twins of the human atria, establishing a new standard for prescribing fibers in ADT.

Optimizing the Distribution of Ablation Lesions to Prevent Postablation Atrial Tachycardia: A Personalized Digital-Twin Study.

BACKGROUND: Although targeting atrial fibrillation (AF) drivers and substrates has been used as an effective adjunctive ablation strategy for patients with persistent AF (PsAF), it can result in iatrogenic scar-related atrial tachycardia (iAT) requiring additional ablation. Personalized atrial digital twins (DTs) have been used preprocedurally to devise ablation targeting that eliminate the fibrotic substrate arrhythmogenic propensity and could potentially be used to predict and prevent postablation iAT. OBJECTIVES: In this study, the authors sought to explore possible alternative configurations of ablation lesions that could prevent iAT occurrence with the use of biatrial DTs of prospectively enrolled PsAF patients. METHODS: Biatrial DTs were generated from late gadolinium enhancement-magnetic resonance images of 37 consecutive PsAF patients, and the fibrotic substrate locations in the DT capable of sustaining reentries were determined. These locations were ablated in DTs by representing a single compound region of ablation with normal power (SSA), and postablation iAT occurrence was determined. At locations of iAT, ablation at the same DT target was repeated, but applying multiple lesions of reduced-strength (MRA) instead of SSA. RESULTS: Eighty-three locations in the fibrotic substrates of 28 personalized biatrial DTs were capable of sustaining reentries and were thus targeted for SSA ablation. Of these ablations, 45 resulted in iAT. Repeating the ablation at these targets with MRA instead of SSA resulted in the prevention of iAT occurrence at 15 locations (18% reduction in the rate of iAT occurrence). CONCLUSIONS: Personalized atrial DTs enable preprocedure prediction of iAT occurrence after ablation in the fibrotic substrate. It also suggests MRA could be a potential strategy for preventing postablation AT.

Assessing the arrhythmogenic propensity of fibrotic substrate using digital twins to inform a mechanisms-based atrial fibrillation ablation strategy.

Atrial fibrillation (AF), the most common heart rhythm disorder, may cause stroke and heart failure. For patients with persistent AF with fibrosis proliferation, the standard AF treatment-pulmonary vein isolation-has poor outcomes, necessitating redo procedures, owing to insufficient understanding of what constitutes good targets in fibrotic substrates. Here we present a prospective clinical and personalized digital twin study that characterizes the arrhythmogenic properties of persistent AF substrates and uncovers locations possessing rotor-attracting capabilities. Among these, a portion needs to be ablated to render the substrate not inducible for rotors, but the rest (37%) lose rotor-attracting capabilities when another location is ablated. Leveraging digital twin mechanistic insights, we suggest ablation targets that eliminate arrhythmia propensity with minimum lesions while also minimizing the risk of iatrogenic tachycardia and AF recurrence. Our findings provide further evidence regarding the appropriate substrate ablation targets in persistent AF, opening the door for effective strategies to mitigate patients' AF burden.

Cardiac MRI Oversampling in Heart Digital Twins Improves Preprocedure Ventricular Tachycardia Identification in Postinfarction Patients.

BACKGROUND: Ventricular tachycardia (VT), which can lead to sudden cardiac death, occurs frequently in patients after myocardial infarction. Radiofrequency catheter ablation (RFA) is a modestly effective treatment of VT, but it has limitations and risks. Cardiac magnetic resonance (CMR)-based heart digital twins have emerged as a useful tool for identifying VT circuits for RFA treatment planning. However, the CMR resolution used to reconstruct these digital twins may impact VT circuit predictions, leading to incorrect RFA treatment planning. OBJECTIVES: This study sought to predict RFA targets in the arrhythmogenic substrate using heart digital twins reconstructed from both clinical and high-resolution 2-dimensional CMR datasets and compare the predictions. METHODS: High-resolution (1.35 × 1.35 × 3 mm), or oversampled resolution (Ov-Res), short-axis late gadolinium-enhanced CMR was acquired by combining 2 subsequent clinical resolution (Clin-Res) (1.35 × 1.35 × 6 mm) short-axis late gadolinium-enhanced CMR scans from 6 post-myocardial infarction patients undergoing VT ablation and used to reconstruct a total of 3 digital twins (1 Ov-Res, 2 Clin-Res) for each patient. Rapid pacing was used to assess VT circuits and identify the optimal ablation targets in each digital twin. VT circuits predicted by the digital twins were compared with intraprocedural electroanatomic mapping data and used to identify emergent VT. RESULTS: The Ov-Res digital twins reduced partial volume effects and better predicted unique VT circuits compared with the Clin-Res digital twins (66.6% vs 54.5%; P < 0.01). Only the Ov-Res digital twin successfully identified emergent VT after a failed initial ablation. CONCLUSIONS: Digital twin infarct geometry and VT circuit predictions depend on the magnetic resonance resolution. Ov-Res digital twins better predict VT circuits and emergent VT, which may improve RFA outcomes.

Elastic shape analysis for unsupervised clustering of left atrial appendage morphologies in atrial fibrillation patients.

Morphological variations in the left atrial appendage (LAA) are associated with different levels of ischemic stroke risk for patients with atrial fibrillation (AF). Studying LAA morphology can elucidate mechanisms behind this association and lead to the development of advanced stroke risk stratification tools. However, current categorical descriptions of LAA morphologies are qualitative and inconsistent across studies, which impedes advancements in our understanding of stroke pathogenesis in AF. To mitigate these issues, we introduce a quantitative pipeline that combines elastic shape analysis with unsupervised learning for the categorization of LAA morphology in AF patients. As part of our pipeline, we compute pairwise elastic distances between LAA meshes, and leverage these distances to cluster our shape data via hierarchical clustering. We demonstrate that our method accurately clusters LAA shapes and overcomes the limitations of the current qualitative LAA categorization systems.

A comprehensive stroke risk assessment by combining atrial computational fluid dynamics simulations and functional patient data.

Stroke, a major global health concern often rooted in cardiac dynamics, demands precise risk evaluation for targeted intervention. Current risk models, like the CHA 2 DS 2 -VASc score, often lack the granularity required for personalized predictions. In this study, we present a nuanced and thorough stroke risk assessment by integrating functional insights from cardiac magnetic resonance (CMR) with patient-specific computational fluid dynamics (CFD) simulations. Our cohort, evenly split between control and stroke groups, comprises eight patients. Utilizing CINE CMR, we compute kinematic features, revealing smaller left atrial volumes for stroke patients. The incorporation of patient-specific atrial displacement into our hemodynamic simulations unveils the influence of atrial compliance on the flow fields, emphasizing the importance of LA motion in CFD simulations and challenging the conventional rigid wall assumption in hemodynamics models. Standardizing hemodynamic features with functional metrics enhances the differentiation between stroke and control cases. While standalone assessments provide limited clarity, the synergistic fusion of CMR-derived functional data and patient-informed CFD simulations offers a personalized and mechanistic understanding, distinctly segregating stroke from control cases. Specifically, our investigation reveals a crucial clinical insight: normalizing hemodynamic features based on ejection fraction fails to differentiate between stroke and control patients. Differently, when normalized with stroke volume, a clear and clinically significant distinction emerges and this holds true for both the left atrium and its appendage, providing valuable implications for precise stroke risk assessment in clinical settings. This work introduces a novel framework for seamlessly integrating hemodynamic and functional metrics, laying the groundwork for improved predictive models, and highlighting the significance of motion-informed, personalized risk assessments.

Slow blood-flow in the left atrial appendage is associated with stroke in atrial fibrillation patients.

Background: Atrial fibrillation (AF) patients are at high risk of stroke with ∼90% clots originating from the left atrial appendage (LAA). Clinical understanding of blood-flow based parameters and their potential association with stroke for AF patients remains poorly understood. We hypothesize that slow blood-flow either in the LA or the LAA could lead to the formation of blood clots and is associated with stroke for AF patients. Methods: We retrospectively collected cardiac CT images of paroxysmal AF patients and dichotomized them based on clinical event of previous embolic event into stroke and non-stroke groups. After image segmentation to obtain 3D LA geometry, patient-specific blood-flow analysis was performed to model LA hemodynamics. In terms of geometry, we calculated area of the pulmonary veins (PVs), mitral valve, LA and LAA, orifice area of LAA and volumes of LA and LAA and classified LAA morphologies. For hemodynamic assessment, we quantified blood flow velocity, wall shear stress (WSS, blood-friction on LA wall), oscillatory shear index (OSI, directional change of WSS) and endothelial cell activation potential (ECAP, ratio of OSI and WSS quantifying slow and oscillatory flow) in the LA as well as the LAA. Statistical analysis was performed to compare the parameters between the groups. Results: Twenty-seven patients were included in the stroke and 28 in the non-stroke group. Examining geometrical parameters, area of left inferior PV was found to be significantly higher in the stroke group as compared to non-stroke group (p = 0.026). In terms of hemodynamics, stroke group had significantly lower blood velocity (p = 0.027), WSS (p = 0.018) and higher ECAP (p = 0.032) in the LAA as compared to non-stroke group. However, LAA morphologic type did not differ between the two groups. This suggests that stroke patients had significantly slow and oscillatory circulating blood-flow in the LAA, which might expose it to potential thrombogenesis. Conclusion: Slow flow in the LAA alone was associated with stroke in this paroxysmal AF cohort. Patient-specific blood-flow analysis can potentially identify such hemodynamic conditions, aiding in clinical stroke risk stratification of AF patients.

A comprehensive stroke risk assessment by combining atrial computational fluid dynamics simulations and functional patient data.

Stroke, a major global health concern often rooted in cardiac dynamics, demands precise risk evaluation for targeted intervention. Current risk models, like the CHA2DS2-VASc score, often lack the granularity required for personalized predictions. In this study, we present a nuanced and thorough stroke risk assessment by integrating functional insights from cardiac magnetic resonance (CMR) with patient-specific computational fluid dynamics (CFD) simulations. Our cohort, evenly split between control and stroke groups, comprises eight patients. Utilizing CINE CMR, we compute kinematic features, revealing smaller left atrial volumes for stroke patients. The incorporation of patient-specific atrial displacement into our hemodynamic simulations unveils the influence of atrial compliance on the flow fields, emphasizing the importance of LA motion in CFD simulations and challenging the conventional rigid wall assumption in hemodynamics models. Standardizing hemodynamic features with functional metrics enhances the differentiation between stroke and control cases. While standalone assessments provide limited clarity, the synergistic fusion of CMR-derived functional data and patient-informed CFD simulations offers a personalized and mechanistic understanding, distinctly segregating stroke from control cases. Specifically, our investigation reveals a crucial clinical insight: normalizing hemodynamic features based on ejection fraction fails to differentiate between stroke and control patients. Differently, when normalized with stroke volume, a clear and clinically significant distinction emerges and this holds true for both the left atrium and its appendage, providing valuable implications for precise stroke risk assessment in clinical settings. This work introduces a novel framework for seamlessly integrating hemodynamic and functional metrics, laying the groundwork for improved predictive models, and highlighting the significance of motion-informed, personalized risk assessments.

Up digital and personal: How heart digital twins can transform heart patient care.

Precision medicine is the vision of health care where therapy is tailored to each patient. As part of this vision, digital twinning technology promises to deliver a digital representation of organs or even patients by using tools capable of simulating personal health conditions and predicting patient or disease trajectories on the basis of relationships learned both from data and from biophysics knowledge. Such virtual replicas would update themselves with data from monitoring devices and medical tests and assessments, reflecting dynamically the changes in our health conditions and the responses to treatment. In precision cardiology, the concepts and initial applications of heart digital twins have slowly been gaining popularity and the trust of the clinical community. In this article, we review the advancement in heart digital twinning and its initial translation to the management of heart rhythm disorders.

Computational modeling of cardiac electrophysiology and arrhythmogenesis: toward clinical translation.

The complexity of cardiac electrophysiology, involving dynamic changes in numerous components across multiple spatial (from ion channel to organ) and temporal (from milliseconds to days) scales, makes an intuitive or empirical analysis of cardiac arrhythmogenesis challenging. Multiscale mechanistic computational models of cardiac electrophysiology provide precise control over individual parameters, and their reproducibility enables a thorough assessment of arrhythmia mechanisms. This review provides a comprehensive analysis of models of cardiac electrophysiology and arrhythmias, from the single cell to the organ level, and how they can be leveraged to better understand rhythm disorders in cardiac disease and to improve heart patient care. Key issues related to model development based on experimental data are discussed, and major families of human cardiomyocyte models and their applications are highlighted. An overview of organ-level computational modeling of cardiac electrophysiology and its clinical applications in personalized arrhythmia risk assessment and patient-specific therapy of atrial and ventricular arrhythmias is provided. The advancements presented here highlight how patient-specific computational models of the heart reconstructed from patient data have achieved success in predicting risk of sudden cardiac death and guiding optimal treatments of heart rhythm disorders. Finally, an outlook toward potential future advances, including the combination of mechanistic modeling and machine learning/artificial intelligence, is provided. As the field of cardiology is embarking on a journey toward precision medicine, personalized modeling of the heart is expected to become a key technology to guide pharmaceutical therapy, deployment of devices, and surgical interventions.

Predicting ventricular tachycardia circuits in patients with arrhythmogenic right ventricular cardiomyopathy using genotype-specific heart digital twins.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient's disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (PKP2, n = 8) and gene-elusive (GE, n = 8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy for PKP2 patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while in PKP2 patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC.

LASSNet: A Four Steps Deep Neural Network for Left Atrial Segmentation and Scar Quantification.

Accurate quantification of left atrium (LA) scar in patients with atrial fibrillation is essential to guide successful ablation strategies. Prior to LA scar quantification, a proper LA cavity segmentation is required to ensure exact location of scar. Both tasks can be extremely time-consuming and are subject to inter-observer disagreements when done manually. We developed and validated a deep neural network to automatically segment the LA cavity and the LA scar. The global architecture uses a multi-network sequential approach in two stages which segment the LA cavity and the LA Scar. Each stage has two steps: a region of interest Neural Network and a refined segmentation network. We analysed the performances of our network according to different parameters and applied data triaging. 200+ late gadolinium enhancement magnetic resonance images were provided by the LAScarQS 2022 Challenge. Finally, we compared our performances for scar quantification to the literature and demonstrated improved performances.

Evaluation of a deep learning-enabled automated computational heart modelling workflow for personalized assessment of ventricular arrhythmias.

Personalized, image-based computational heart modelling is a powerful technology that can be used to improve patient-specific arrhythmia risk stratification and ventricular tachycardia (VT) ablation targeting. However, most state-of-the-art methods still require manual interactions by expert users. The goal of this study is to evaluate the feasibility of an automated, deep learning-based workflow for reconstructing personalized computational electrophysiological heart models to guide patient-specific treatment of VT. Contrast-enhanced computed tomography (CE-CT) images with expert ventricular myocardium segmentations were acquired from 111 patients across five cohorts from three different institutions. A deep convolutional neural network (CNN) for segmenting left ventricular myocardium from CE-CT was developed, trained and evaluated. From both CNN-based and expert segmentations in a subset of patients, personalized electrophysiological heart models were reconstructed and rapid pacing was used to induce VTs. CNN-based and expert segmentations were more concordant in the middle myocardium than in the heart's base or apex. Wavefront propagation during pacing was similar between CNN-based and original heart models. Between most sets of heart models, VT inducibility was the same, the number of induced VTs was strongly correlated, and VT circuits co-localized. Our results demonstrate that personalized computational heart models reconstructed from deep learning-based segmentations even with a small training set size can predict similar VT inducibility and circuit locations as those from expertly-derived heart models. Hence, a user-independent, automated framework for simulating arrhythmias in personalized heart models could feasibly be used in clinical settings to aid VT risk stratification and guide VT ablation therapy. KEY POINTS: Personalized electrophysiological heart modelling can aid in patient-specific ventricular tachycardia (VT) risk stratification and VT ablation targeting. Current state-of-the-art, image-based heart models for VT prediction require expert-dependent, manual interactions that may not be accessible across clinical settings. In this study, we develop an automated, deep learning-based workflow for reconstructing personalized heart models capable of simulating arrhythmias and compare its predictions with that of expert-generated heart models. The number and location of VTs was similar between heart models generated from the deep learning-based workflow and expert-generated heart models. These results demonstrate the feasibility of using an automated computational heart modelling workflow to aid in VT therapeutics and has implications for generalizing personalized computational heart technology to a broad range of clinical centres.

Caveolin-3 and Caveolae regulate ventricular repolarization.

RATIONALE: Flask-shaped invaginations of the cardiomyocyte sarcolemma called caveolae require the structural protein caveolin-3 (Cav-3) and host a variety of ion channels, transporters, and signaling molecules. Reduced Cav-3 expression has been reported in models of heart failure, and variants in CAV3 have been associated with the inherited long-QT arrhythmia syndrome. Yet, it remains unclear whether alterations in Cav-3 levels alone are sufficient to drive aberrant repolarization and increased arrhythmia risk. OBJECTIVE: To determine the impact of cardiac-specific Cav-3 ablation on the electrophysiological properties of the adult mouse heart. METHODS AND RESULTS: Cardiac-specific, inducible Cav3 homozygous knockout (Cav-3KO) mice demonstrated a marked reduction in Cav-3 expression by Western blot and loss of caveolae by electron microscopy. However, there was no change in macroscopic cardiac structure or contractile function. The QTc interval was increased in Cav-3KO mice, and there was an increased propensity for ventricular arrhythmias. Ventricular myocytes isolated from Cav-3KO mice exhibited a prolonged action potential duration (APD) that was due to reductions in outward potassium currents (Ito, Iss) and changes in inward currents including slowed inactivation of ICa,L and increased INa,L. Mathematical modeling demonstrated that the changes in the studied ionic currents were adequate to explain the prolongation of the mouse ventricular action potential. Results from human iPSC-derived cardiomyocytes showed that shRNA knockdown of Cav-3 similarly prolonged APD. CONCLUSION: We demonstrate that Cav-3 and caveolae regulate cardiac repolarization and arrhythmia risk via the integrated modulation of multiple ionic currents.

Wavefront directionality and decremental stimuli synergistically improve identification of ventricular tachycardia substrate: insights from personalized computational heart models.

AIMS: Multiple wavefront pacing (MWP) and decremental pacing (DP) are two electroanatomic mapping (EAM) strategies that have emerged to better characterize the ventricular tachycardia (VT) substrate. The aim of this study was to assess how well MWP, DP, and their combination improve identification of electrophysiological abnormalities on EAM that reflect infarct remodelling and critical VT sites. METHODS AND RESULTS: Forty-eight personalized computational heart models were reconstructed using images from post-infarct patients undergoing VT ablation. Paced rhythms were simulated by delivering an initial (S1) and an extra-stimulus (S2) from one of 100 locations throughout each heart model. For each pacing, unipolar signals were computed along the myocardial surface to simulate substrate EAM. Six EAM features were extracted and compared with the infarct remodelling and critical VT sites. Concordance of S1 EAM features between different maps was lower in hearts with smaller amounts of remodelling. Incorporating S1 EAM features from multiple maps greatly improved the detection of remodelling, especially in hearts with less remodelling. Adding S2 EAM features from multiple maps decreased the number of maps required to achieve the same detection accuracy. S1 EAM features from multiple maps poorly identified critical VT sites. However, combining S1 and S2 EAM features from multiple maps paced near VT circuits greatly improved identification of critical VT sites. CONCLUSION: Electroanatomic mapping with MWP is more advantageous for characterization of substrate in hearts with less remodelling. During substrate EAM, MWP and DP should be combined and delivered from locations proximal to a suspected VT circuit to optimize identification of the critical VT site.

Advances in Cardiac Electrophysiology.

Despite the global COVID-19 pandemic, during the past 2 years, there have been numerous advances in our understanding of arrhythmia mechanisms and diagnosis and in new therapies. We increased our understanding of risk factors and mechanisms of atrial arrhythmias, the prediction of atrial arrhythmias, response to treatment, and outcomes using machine learning and artificial intelligence. There have been new technologies and techniques for atrial fibrillation ablation, including pulsed field ablation. There have been new randomized trials in atrial fibrillation ablation, giving insight about rhythm control, and long-term outcomes. There have been advances in our understanding of treatment of inherited disorders such as catecholaminergic polymorphic ventricular tachycardia. We have gained new insights into the recurrence of ventricular arrhythmias in the setting of various conditions such as myocarditis and inherited cardiomyopathic disorders. Novel computational approaches may help predict occurrence of ventricular arrhythmias and localize arrhythmias to guide ablation. There are further advances in our understanding of noninvasive radiotherapy. We have increased our understanding of the role of His bundle pacing and left bundle branch area pacing to maintain synchronous ventricular activation. There have also been significant advances in the defibrillators, cardiac resynchronization therapy, remote monitoring, and infection prevention. There have been advances in our understanding of the pathways and mechanisms involved in atrial and ventricular arrhythmogenesis.

Machine learning guided structure function predictions enable in silico nanoparticle screening for polymeric gene delivery.

Developing highly efficient non-viral gene delivery reagents is still difficult for many hard-to-transfect cell types and, to date, has mostly been conducted via brute force screening routines. High throughput in silico methods of evaluating biomaterials can enable accelerated optimization and development of devices or therapeutics by exploring large chemical design spaces quickly and at low cost. This work reports application of state-of-the-art machine learning algorithms to a dataset of synthetic biodegradable polymers, poly(beta-amino ester)s (PBAEs), which have shown exciting promise for therapeutic gene delivery in vitro and in vivo. The data set includes polymer properties as inputs as well as polymeric nanoparticle transfection performance and nanoparticle toxicity in a range of cells as outputs. This data was used to train and evaluate several state-of-the-art machine learning algorithms for their ability to predict transfection and understand structure-function relationships. By developing an encoding scheme for vectorizing the structure of a PBAE polymer in a machine-readable format, we demonstrate that a random forest model can satisfactorily predict DNA transfection in vitro based on the chemical structure of the constituent PBAE polymer in a cell line dependent manner. Based on the model, we synthesized PBAE polymers and used them to form polymeric gene delivery nanoparticles that were predicted in silico to be successful. We validated the computational predictions in two cell lines in vitro, RAW 264.7 macrophages and Hep3B liver cancer cells, and found that the Spearman's R correlation between predicted and experimental transfection was 0.57 and 0.66 respectively. Thus, a computational approach that encoded chemical descriptors of polymers was able to demonstrate that in silico computational screening of polymeric nanomedicine compositions had utility in predicting de novo biological experiments. STATEMENT OF SIGNIFICANCE: Developing highly efficient non-viral gene delivery reagents is difficult for many hard-to-transfect cell types and, to date, has mostly been explored via brute force screening routines. High throughput in silico methods of evaluating biomaterials can enable accelerated optimization and development for therapeutic or biomanufacturing purposes by exploring large chemical design spaces quickly and at low cost. This work reports application of state-of-the-art machine learning algorithms to a large compiled PBAE DNA gene delivery nanoparticle dataset across many cell types to develop predictive models for transfection and nanoparticle cytotoxicity. We develop a novel computational pipeline to encode PBAE nanoparticles with chemical descriptors and demonstrate utility in a de novo experimental context.

Arrhythmia in hypertrophic cardiomyopathy: Risk prediction using contrast enhanced MRI, T1 mapping, and personalized virtual heart technology.

BACKGROUND: Hypertrophic cardiomyopathy (HCM), a disease with myocardial fibrosis manifestation, is a common cause of sudden cardiac death (SCD) due to ventricular arrhythmias (VA). Current clinical risk stratification criteria are inadequate in identifying patients who are at risk for VA and in need of an implantable cardioverter defibrillator (ICD) for primary prevention. OBJECTIVE: We aimed to develop a risk prediction approach based on imaging biomarkers from the combination of late gadolinium contrast-enhanced (LGE) MRI and T1 mapping. We then aimed to compare the prediction to a virtual heart computational risk assessment approach based on LGE-T1 virtual heart models. METHODS: The methodology involved combining short-axis LGE-MRI with post-contrast T1 maps to define personalized thresholds for diffuse and dense fibrosis. The combined LGE-T1 maps were used to evaluate imaging biomarkers for VA risk prediction. The risk prediction capability of the biomarkers was compared with that of the LGE-T1 virtual heart arrhythmia inducibility simulation. VA risk prediction performance from both approaches was compared to clinical outcome (presence of clinical VA). RESULTS: Image-based biomarkers, including hypertrophy, signal intensity heterogeneity, and fibrotic border complexity, could not discriminate high vs low VA risk. LGE-T1 virtual heart technology outperformed all the image-based biomarker metrics and was statistically significant in predicting VA risk in HCM. CONCLUSIONS: We combined two MR imaging techniques to analyze imaging biomarkers in HCM. Raw and processed image-based biomarkers cannot discriminate patients with VA from those without VA. Hybrid LGE-T1 virtual heart models could correctly predict VA risk for this cohort and may improve SCD risk stratification to better identify HCM patients for primary preventative ICD implantation.