Submillimeter diffusion tensor imaging and late gadolinium enhancement cardiovascular magnetic resonance of chronic myocardial infarction.

BackgroundKnowledge of the three-dimensional (3D) infarct structure and fiber orientation remodeling is essential for complete understanding of infarct pathophysiology and post-infarction electromechanical functioning of the heart. Accurate imaging of infarct microstructure necessitates imaging techniques that produce high image spatial resolution and high signal-to-noise ratio (SNR). The aim of this study is to provide detailed reconstruction of 3D chronic infarcts in order to characterize the infarct microstructural remodeling in porcine and human hearts.MethodsWe employed a customized diffusion tensor imaging (DTI) technique in conjunction with late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) on a 3T clinical scanner to image, at submillimeter resolution, myofiber orientation and scar structure in eight chronically infarcted porcine hearts ex vivo. Systematic quantification of local microstructure was performed and the chronic infarct remodeling was characterized at different levels of wall thickness and scar transmurality. Further, a human heart with myocardial infarction was imaged using the same DTI sequence.ResultsThe SNR of non-diffusion-weighted images was >100 in the infarcted and control hearts. Mean diffusivity and fractional anisotropy (FA) demonstrated a 43% increase, and a 35% decrease respectively, inside the scar tissue. Despite this, the majority of the scar showed anisotropic structure with FA higher than an isotropic liquid. The analysis revealed that the primary eigenvector orientation at the infarcted wall on average followed the pattern of original fiber orientation (imbrication angle mean: 1.96 ± 11.03° vs. 0.84 ± 1.47°, p = 0.61, and inclination angle range: 111.0 ± 10.7° vs. 112.5 ± 6.8°, p = 0.61, infarcted/control wall), but at a higher transmural gradient of inclination angle that increased with scar transmurality (r = 0.36) and the inverse of wall thickness (r = 0.59). Further, the infarcted wall exhibited a significant increase in both the proportion of left-handed epicardial eigenvectors, and in the angle incoherency. The infarcted human heart demonstrated preservation of primary eigenvector orientation at the thinned region of infarct, consistent with the findings in the porcine hearts.ConclusionsThe application of high-resolution DTI and LGE-CMR revealed the detailed organization of anisotropic infarct structure at a chronic state. This information enhances our understanding of chronic post-infarction remodeling in large animal and human hearts

Elastic shape analysis computations for clustering left atrial appendage geometries of 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 from a cohort of 20 AF patients, and leverage these distances to cluster our shape data. We demonstrate that our method clusters LAA morphologies based on distinctive shape features, overcoming the innate inconsistencies of current LAA categorization systems, and paving the way for improved stroke risk metrics using objective LAA shape groups.Comment: Submitted as a conference paper to MICCAI 202

Nanoscale regulation of L-type calcium channels differentiates between ischemic and dilated cardiomyopathies.

Background Subcellular localization and function of L-type calcium channels (LTCCs) play an important role in regulating contraction of cardiomyocytes. Understanding how this is affected by the disruption of transverse tubules during heart failure could lead to new insights into the disease. Methods Cardiomyocytes were isolated from healthy donor hearts, as well as from patients with cardiomyopathies and with left ventricular assist devices. Scanning ion conductance and confocal microscopy was used to study membrane structures in the cells. Super-resolution scanning patch-clamp was used to examine LTCC function in different microdomains. Computational modeling predicted the impact of these changes to arrhythmogenesis at the whole-heart level. Findings We showed that loss of structural organization in failing myocytes leads to re-distribution of functional LTCCs from the T-tubules to the sarcolemma. In ischemic cardiomyopathy, the increased LTCC open probability in the T-tubules depends on the phosphorylation by protein kinase A, whereas in dilated cardiomyopathy, the increased LTCC opening probability in the sarcolemma results from enhanced phosphorylation by calcium-calmodulin kinase II. LVAD implantation corrected LTCCs pathophysiological activity, although it did not improve their distribution. Using computational modeling in a 3D anatomically-realistic human ventricular model, we showed how LTCC location and activity can trigger heart rhythm disorders of different severity. Interpretation Our findings demonstrate that LTCC redistribution and function differentiate between disease aetiologies. The subcellular changes observed in specific microdomains could be the consequence of the action of distinct protein kinases. Funding This work was supported by NIH grant (ROI-HL 126802 to NT-JG) and British Heart Foundation (grant RG/17/13/33173 to JG, project grant PG/16/17/32069 to RAC). Funders had no role in study design, data collection, data analysis, interpretation, writing of the repor

Mechanistic Inquiry into the Role of Tissue Remodeling in Fibrotic Lesions in Human Atrial Fibrillation

AbstractAtrial fibrillation (AF), the most common arrhythmia in humans, is initiated when triggered activity from the pulmonary veins propagates into atrial tissue and degrades into reentrant activity. Although experimental and clinical findings show a correlation between atrial fibrosis and AF, the causal relationship between the two remains elusive. This study used an array of 3D computational models with different representations of fibrosis based on a patient-specific atrial geometry with accurate fibrotic distribution to determine the mechanisms by which fibrosis underlies the degradation of a pulmonary vein ectopic beat into AF. Fibrotic lesions in models were represented with combinations of: gap junction remodeling; collagen deposition; and myofibroblast proliferation with electrotonic or paracrine effects on neighboring myocytes. The study found that the occurrence of gap junction remodeling and the subsequent conduction slowing in the fibrotic lesions was a necessary but not sufficient condition for AF development, whereas myofibroblast proliferation and the subsequent electrophysiological effect on neighboring myocytes within the fibrotic lesions was the sufficient condition necessary for reentry formation. Collagen did not alter the arrhythmogenic outcome resulting from the other fibrosis components. Reentrant circuits formed throughout the noncontiguous fibrotic lesions, without anchoring to a specific fibrotic lesion

Degradation of T-Tubular Microdomains and Altered cAMP Compartmentation Lead to Emergence of Arrhythmogenic Triggers in Heart Failure Myocytes: An in silico Study

Heart failure (HF) is one of the most common causes of morbidity and mortality worldwide. Although many patients suffering from HF die from sudden cardiac death caused by arrhythmias, the mechanism linking HF remodeling to an increased arrhythmogenic propensity remains incomplete. HF is typically characterized by a progressive loss of transverse tubule (T-tubule) domains, which leads to an altered distribution of L-type calcium channels (LTCCs). Microdomain degradation also causes the disruption of the β2 adrenergic receptor (β2AR) and phosphodiesterase (PDE) signaling localization, normally confined to the dyadic space. The goal of this study was to analyze how these subcellular changes affect the function of LTCCs and lead to the emergence of ventricular cell-level triggers of arrhythmias. To accomplish this, we developed a novel computational model of a human ventricular HF myocyte in which LTCCs were divided into six different populations, based on their location and signaling environment they experience. To do so, we included T-tubular microdomain remodeling which led to a subset of LTCCs to be redistributed from the T-tubular to the surface membrane and allowed for different levels of phosphorylation of LTCCs by PKA, based on the presence of β2ARs and PDEs. The model was used to study the behavior of the LTCC current (ICaL) under basal and sympathetic stimulation and its effect on cellular action potential. Our results showed that channels redistributed from the T-tubular membrane to the bulk of the sarcolemma displayed an altered function in their new, non-native signaling domain. Incomplete calcium dependent inactivation, which resulted in a longer-lasting and larger-in-magnitude LTCC current, was observed when we decoupled LTCCs from ryanodine receptors and removed them from the dyadic space. The magnitude of the LTCC current, especially in the surface sarcolemma, was also increased via phosphorylation by the redistributed β2ARs and PDEs. These changes in LTCC current led to the development of early afterdepolarizations. Thus, our study shows that altered LTCC function is a potential cause for the emergence of cell-level triggers of arrhythmia, and that β2ARs and PDEs present useful therapeutic targets for treatment of HF and prevention of sudden cardiac death

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

Dynamics of lattice spins as a model of arrhythmia

We consider evolution of initial disturbances in spatially extended systems with autonomous rhythmic activity, such as the heart. We consider the case when the activity is stable with respect to very smooth (changing little across the medium) disturbances and construct lattice models for description of not-so-smooth disturbances, in particular, topological defects; these models are modifications of the diffusive XY model. We find that when the activity on each lattice site is very rigid in maintaining its form, the topological defects - vortices or spirals - nucleate a transition to a disordered, turbulent state.Comment: 17 pages, revtex, 3 figure