Automatic motion estimation with applications to hiPSC-CMs.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are an effective tool for studying cardiac function and disease, and hold promise for screening drug effects on human tissue. Understanding alterations in motion patterns within these cells is crucial for comprehending how the administration of a drug or the onset of a disease can impact the rhythm of the human heart. However, quantifying motion accurately and efficiently from optical measurements using microscopy is currently time consuming.

Do calcium channel blockers applied to cardiomyocytes cause increased channel expression resulting in reduced efficacy?

In the initial hours following the application of the calcium channel blocker (CCB) nifedipine to microtissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug's efficacy. Here, we investigate the possibility that these temporal changes in CCB effects are associated with adaptations in the expression of calcium ion channels in cardiomyocyte membranes. To explore this, we employ a recently developed mathematical model that delineates the regulation of calcium ion channel expression by intracellular calcium concentrations.

A cell-based framework for modeling cardiac mechanics.

Cardiomyocytes are the functional building blocks of the heart-yet most models developed to simulate cardiac mechanics do not represent the individual cells and their surrounding matrix. Instead, they work on a homogenized tissue level, assuming that cellular and subcellular structures and processes scale uniformly. Here we present a mathematical and numerical framework for exploring tissue-level cardiac mechanics on a microscale given an explicit three-dimensional geometrical representation of cells embedded in a matrix.

Computational models of ventricular mechanics and adaptation in response to right-ventricular pressure overload.

Pulmonary arterial hypertension (PAH) is associated with substantial remodeling of the right ventricle (RV), which may at first be compensatory but at a later stage becomes detrimental to RV function and patient survival. Unlike the left ventricle (LV), the RV remains understudied, and with its thin-walled crescent shape, it is often modeled simply as an appendage of the LV. Furthermore, PAH diagnosis is challenging because it often leaves the LV and systemic circulation largely unaffected.

Validating the Arrhythmogenic Potential of High-, Intermediate-, and Low-Risk Drugs in a Human-Induced Pluripotent Stem Cell-Derived Cardiac Microphysiological System.

Evaluation of arrhythmogenic drugs is required by regulatory agencies before any new compound can obtain market approval. Despite rigorous review, cardiac disorders remain the second most common cause for safety-related market withdrawal. On the other hand, false-positive preclinical findings prohibit potentially beneficial candidates from moving forward in the development pipeline.

Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips.

The immature physiology of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) limits their utility for drug screening and disease modelling. Here we show that suitable combinations of mechanical stimuli and metabolic cues can enhance the maturation of hiPSC-derived cardiomyocytes, and that the maturation-inducing cues have phenotype-dependent effects on the cells' action-potential morphology and calcium handling. By using microfluidic chips that enhanced the alignment and extracellular-matrix production of cardiac microtissues derived from genetically distinct sources of hiPSC-derived cardiomyocytes, we identified fatty-acid-enriched maturation media that improved the cells' mitochondrial structure and calcium handling, and observed divergent cell-source-dependent effects on action-potential duration (APD).

Computational Modeling Studies of the Roles of Left Ventricular Geometry, Afterload, and Muscle Contractility on Myocardial Strains in Heart Failure with Preserved Ejection Fraction.

Global longitudinal strain and circumferential strain are found to be reduced in HFpEF, which some have interpreted that the global left ventricular (LV) contractility is impaired. This finding is, however, contradicted by a preserved ejection fraction (EF) and confounded by changes in LV geometry and afterload resistance that may also affect the global strains. To reconcile these issues, we used a validated computational framework consisting of a finite element LV model to isolate the effects of HFpEF features in affecting systolic function metrics.

Identifying Drug Response by Combining Measurements of the Membrane Potential, the Cytosolic Calcium Concentration, and the Extracellular Potential in Microphysiological Systems.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) offer a new means to study and understand the human cardiac action potential, and can give key insight into how compounds may interact with important molecular pathways to destabilize the electrical function of the heart. Important features of the action potential can be readily measured using standard experimental techniques, such as the use of voltage sensitive dyes and fluorescent genetic reporters to estimate transmembrane potentials and cytosolic calcium concentrations. Using previously introduced computational procedures, such measurements can be used to estimate the current density of major ion channels present in hiPSC-CMs, and how compounds may alter their behavior.

Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes.

Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient's electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome.

Computational translation of drug effects from animal experiments to human ventricular myocytes.

Using animal cells and tissues as precise measuring devices for developing new drugs presents a long-standing challenge for the pharmaceutical industry. Despite the very significant resources that continue to be dedicated to animal testing of new compounds, only qualitative results can be obtained. This often results in both false positives and false negatives.

Improved Computational Identification of Drug Response Using Optical Measurements of Human Stem Cell Derived Cardiomyocytes in Microphysiological Systems.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) hold great potential for drug screening applications. However, their usefulness is limited by the relative immaturity of the cells' electrophysiological properties as compared to native cardiomyocytes in the adult human heart. In this work, we extend and improve on methodology to address this limitation, building on previously introduced computational procedures which predict drug effects for adult cells based on changes in optical measurements of action potentials and Ca transients made in stem cell derived cardiac microtissues.

Multisite pacing and myocardial scars: a computational study.

Cardiac resynchronization therapy (CRT) is a frequently effective treatment modality for dyssynchronous heart failure, however, 30% of patients do not respond, usually due to suboptimal activation of the left ventricle (LV). Multisite pacing (MSP) may increase the response rate, but its effect in the presence of myocardial scars is not fully understood. We use a computational model to study the outcome of MSP in an LV with scars in two different locations and of two different sizes.

Arrhythmogenic Current Generation by Myofilament-Triggered Ca Release and Sarcomere Heterogeneity.

Heterogeneous mechanical dyskinesis has been implicated in many arrhythmogenic phenotypes. Strain-dependent perturbations to cardiomyocyte electrophysiology may contribute to this arrhythmogenesis through processes referred to as mechanoelectric feedback. Although the role of stretch-activated ion currents has been investigated using computational models, experimental studies suggest that mechanical strain may also promote arrhythmia by facilitating calcium wave propagation.

Computational quantification of patient-specific changes in ventricular dynamics associated with pulmonary hypertension.

Pulmonary arterial hypertension (PAH) causes an increase in the mechanical loading imposed on the right ventricle (RV) that results in progressive changes to its mechanics and function. Here, we quantify the mechanical changes associated with PAH by assimilating clinical data consisting of reconstructed three-dimensional geometry, pressure, and volume waveforms, as well as regional strains measured in patients with PAH ( = 12) and controls ( = 6) within a computational modeling framework of the ventricles. Modeling parameters reflecting regional passive stiffness and load-independent contractility as indexed by the tissue active tension were optimized so that simulation results matched the measurements.

Detecting undetectables: Can conductances of action potential models be changed without appreciable change in the transmembrane potential?

Mathematical models describing the dynamics of the cardiac action potential are of great value for understanding how changes to the system can disrupt the normal electrical activity of cells and tissue in the heart. However, to represent specific data, these models must be parameterized, and adjustment of the maximum conductances of the individual contributing ionic currents is a commonly used method. Here, we present a method for investigating the uniqueness of such resulting parameterizations.

Inversion and computational maturation of drug response using human stem cell derived cardiomyocytes in microphysiological systems.

While cardiomyocytes differentiated from human induced pluripotent stems cells (hiPSCs) hold great promise for drug screening, the electrophysiological properties of these cells can be variable and immature, producing results that are significantly different from their human adult counterparts. Here, we describe a computational framework to address this limitation, and show how in silico methods, applied to measurements on immature cardiomyocytes, can be used to both identify drug action and to predict its effect in mature cells. Our synthetic and experimental results indicate that optically obtained waveforms of voltage and calcium from microphysiological systems can be inverted into information on drug ion channel blockage, and then, through assuming functional invariance of proteins during maturation, this data can be used to predict drug induced changes in mature ventricular cells.

Electromechanical Model to Predict Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy (CRT) can substantially improve dyssynchronous heart failure and reduce mortality. However, one-third of the CRT patients derive no measurable benefit from CRT, due to suboptimal placement of the left ventricular (LV) lead. We introduce a pipeline for improved CRT-therapy by creating an electromechanical model using patient-specific geometric parameters allowing individualization of therapy.

In vivo estimation of elastic heterogeneity in an infarcted human heart.

In myocardial infarction, muscle tissue of the heart is damaged as a result of ceased or severely impaired blood flow. Survivors have an increased risk of further complications, possibly leading to heart failure. Material properties play an important role in determining post-infarction outcome.

Efficient estimation of personalized biventricular mechanical function employing gradient-based optimization.

Individually personalized computational models of heart mechanics can be used to estimate important physiological and clinically-relevant quantities that are difficult, if not impossible, to directly measure in the beating heart. Here, we present a novel and efficient framework for creating patient-specific biventricular models using a gradient-based data assimilation method for evaluating regional myocardial contractility and estimating myofiber stress. These simulations can be performed on a regular laptop in less than 2 h and produce excellent fit between measured and simulated volume and strain data through the entire cardiac cycle.

Organ-level validation of a cross-bridge cycling descriptor in a left ventricular finite element model: effects of ventricular loading on myocardial strains.

Although detailed cell-based descriptors of cross-bridge cycling have been applied in finite element (FE) heart models to describe ventricular mechanics, these multiscale models have never been tested rigorously to determine if these descriptors, when scaled up to the organ-level, are able to reproduce well-established organ-level physiological behaviors. To address this void, we here validate a left ventricular (LV) FE model that is driven by a cell-based cross-bridge cycling descriptor against key organ-level heart physiology. The LV FE model was coupled to a closed-loop lumped parameter circulatory model to simulate different ventricular loading conditions (preload and afterload) and contractilities.

An integrative appraisal of mechano-electric feedback mechanisms in the heart.

Mechanically-induced alterations in cardiac electrophysiology are referred to as mechano-electric feedback (MEF), and play an important role in electrical regulation of cardiac performance. The influence of mechanical stress and strain on electrophysiology has been investigated at all levels, however the role of MEF in arrhythmia remains poorly understood. During the normal contraction of the heart, mechano-sensitive processes are an implicit component of cardiac activity.

High-resolution data assimilation of cardiac mechanics applied to a dyssynchronous ventricle.

Computational models of cardiac mechanics, personalized to a patient, offer access to mechanical information above and beyond direct medical imaging. Additionally, such models can be used to optimize and plan therapies in-silico, thereby reducing risks and improving patient outcome. Model personalization has traditionally been achieved by data assimilation, which is the tuning or optimization of model parameters to match patient observations.

Patient-Specific Computational Analysis of Ventricular Mechanics in Pulmonary Arterial Hypertension.

Patient-specific biventricular computational models associated with a normal subject and a pulmonary arterial hypertension (PAH) patient were developed to investigate the disease effects on ventricular mechanics. These models were developed using geometry reconstructed from magnetic resonance (MR) images, and constitutive descriptors of passive and active mechanics in cardiac tissues. Model parameter values associated with ventricular mechanical properties and myofiber architecture were obtained by fitting the models with measured pressure-volume loops and circumferential strain calculated from MR images using a hyperelastic warping method.

Ventricular structure in ARVC: going beyond volumes as a measure of risk.

Background: Altered right ventricular structure is an important feature of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), but is challenging to quantify objectively. The aim of this study was to go beyond ventricular volumes and diameters and to explore if the shape of the right and left ventricles could be assessed and related to clinical measures. We used quantifiable computational methods to automatically identify and analyse malformations in ARVC patients from Cardiovascular Magnetic Resonance (CMR) images.