Myofiber Stress Research Articles

Personalized evaluation of the passive myocardium in ischemic cardiomyopathy via computational modeling using Bayesian optimization.

Biomechanics-based patient-specific modeling is a promising approach that has proved invaluable for its clinical potential to assess the adversities caused by ischemic heart disease (IHD). In the present study, we propose a framework to find the passive material properties of the myocardium and the unloaded shape of cardiac ventricles simultaneously in patients diagnosed with ischemic cardiomyopathy (ICM). This was achieved by minimizing the difference between the simulated andthe target end-diastolic pressure-volume relationships (EDPVRs) using black-box Bayesian optimization, based on the finite element analysis (FEA). End-diastolic (ED) biventricular geometry and the location of the ischemia were determined from cardiac magnetic resonance (CMR) imaging. We employed our pipeline to model the cardiac ventricles of three patients aged between 57 and 66years, with and without the inclusion of valves. An excellent agreement between the simulated and thetarget EDPVRs has been reached. Our results revealed that the incorporation of valvular springs typically leads to lower hyperelastic parameters for both healthy and ischemic myocardium, as well as a higher fiber Green strain in the viable regions compared to models without valvular stiffness. Furthermore, the addition of valve-related effects did not result in significant changes in myofiber stress after optimization. We concluded that more accurate results could be obtained when cardiac valves were considered in modeling ventricles. The present novel and practical methodology paves the way for developing digital twins of ischemic cardiac ventricles, providing a non-invasive assessment for designing optimal personalized therapies in precision medicine.

The Stiffness of the Ascending Aorta Has a Direct Impact on Left Ventricular Function: An In Silico Model.

During systole, longitudinal shortening of the left ventricle (LV) displaces the aortic root toward the apex of the heart and stretches the ascending aorta (AA). An in silico study (Living Left Heart Human Model, Dassault Systèmes Simulia Corporation) demonstrated that stiffening of the AA affects myocardial stress and LV strain patterns. With AA stiffening, myofiber stress increased overall in the LV, with particularly high-stress areas at the septum. The most pronounced reduction in strain was noted along the septal longitudinal region. The pressure-volume loops showed that AA stiffening caused a deterioration in LV function, with increased end-systolic volume, reduced systolic LV pressure, decreased stroke volume and effective stroke work, but elevated end-diastolic pressure. An increase in myofiber contractility indicated that stroke volume and effective stroke work could be recovered, with an increase in LV end-systolic pressure and a decrease in end-diastolic pressure. Longitudinal and radial strains remained reduced, but circumferential strains increased over baseline, compensating for lost longitudinal LV function. Myofiber stress increased overall, with the most dramatic increase in the septal region and the LV apex. We demonstrate a direct mechanical pathophysiologic link between stiff AA and reduced longitudinal left ventricular strain which are common in patients with HFpEF.

Myocardial biomechanical effects of fetal aortic valvuloplasty

Fetal critical aortic stenosis with evolving hypoplastic left heart syndrome (CAS-eHLHS) can progress to a univentricular (UV) birth malformation. Catheter-based fetal aortic valvuloplasty (FAV) can resolve stenosis and reduce the likelihood of malformation progression. However, we have limited understanding of the biomechanical impact of FAV and subsequent LV responses. Therefore, we performed image-based finite element (FE) modeling of 4 CAS-eHLHS fetal hearts, by performing iterative simulations to match image-based characteristics and then back-computing physiological parameters. We used pre-FAV simulations to conduct virtual FAV (vFAV) and compared pre-FAV and post-FAV simulations. vFAV simulations generally enabled partial restoration of several physiological features toward healthy levels, including increased stroke volume and myocardial strains, reduced aortic valve (AV) and mitral valve regurgitation (MVr) velocities, reduced LV and LA pressures, and reduced peak myofiber stress. FAV often leads to aortic valve regurgitation (AVr). Our simulations showed that AVr could compromise LV and LA depressurization but it could also significantly increase stroke volume and myocardial deformational stimuli. Post-FAV scans and simulations showed FAV enabled only partial reduction of the AV dissipative coefficient. Furthermore, LV contractility and peripheral vascular resistance could change in response to FAV, preventing decreases in AV velocity and LV pressure, compared with what would be anticipated from stenosis relief. This suggested that case-specific post-FAV modeling is required to fully capture cardiac functionality. Overall, image-based FE modeling could provide mechanistic details of the effects of FAV, but computational prediction of acute outcomes was difficult due to a patient-dependent physiological response to FAV.

The dependency of fetal left ventricular biomechanics function on myocardium helix angle configuration

The helix angle configuration of the myocardium is understood to contribute to the heart function, as finite element (FE) modeling of postnatal hearts showed that altered configurations affected cardiac function and biomechanics. However, similar investigations have not been done on the fetal heart. To address this, we performed image-based FE simulations of fetal left ventricles (LV) over a range of helix angle configurations, assuming a linear variation of helix angles from epicardium to endocardium. Results showed that helix angles have substantial influence on peak myofiber stress, cardiac stroke work, myocardial deformational burden, and spatial variability of myocardial strain. A good match between LV myocardial strains from FE simulations to those measured from 4D fetal echo images could only be obtained if the transmural variation of helix angle was generally between 110 and 130°, suggesting that this was the physiological range. Experimentally discovered helix angle configurations from the literature were found to produce high peak myofiber stress, high cardiac stroke work, and a low myocardial deformational burden, but did not coincide with configurations that would optimize these characteristics. This may suggest that the fetal development of myocyte orientations depends concurrently on several factors rather than a single factor. We further found that the shape, rather than the size of the LV, determined the manner at which helix angles influenced these characteristics, as this influence changed significantly when the LV shape was varied, but not when a heart was scaled from fetal to adult size while retaining the same shape. This may suggest that biomechanical optimality would be affected during diseases that altered the geometric shape of the LV.

CCN2 participates in overload-induced skeletal muscle hypertrophy

The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix (ECM) remodeling and increases in muscle cross-sectional area. Indeed, matricellular proteins serve a key role as communication vehicles that facilitate the propagation of signaling stimuli required for muscle adaptation to environmental challenges. We found that the matricellular protein cellular communication network factor 2 (CCN2), also known as connective tissue growth factor (CTGF), is induced during a time course of overload-driven skeletal muscle hypertrophy in mice. To elucidate the role of CCN2 in mediating the hypertrophic response, we utilized genetically engineered mouse models for myofiber-specific CCN2 gain- and loss-of-function and then examined their response to mechanical stimuli through muscle overload. Interestingly, myofiber-specific deletion of CCN2 blunted muscle's hypertrophic response to overload without interfering with ECM deposition. On the other hand, when in excess through transgenic CCN2 overexpression, CCN2 was efficient in promoting overload-induced aberrant ECM accumulation without affecting myofiber growth. Altogether, our genetic approaches highlighted independent ECM and myofiber stress adaptation responses, and positioned CCN2 as a central mediator of both. Mechanistically, CCN2 acts by regulating focal adhesion kinase (FAK) mediated transduction of overload-induced extracellular signals, including interleukin 6 (IL6), and their regulatory impact on global protein synthesis in skeletal muscle. Overall, our study highlights the contribution of muscle-derived extracellular matrix factor CCN2 for proper hypertrophic muscle growth.

Ventricular wall stress and wall shear stress homeostasis predicts cardiac remodeling during pregnancy: A modeling study.

Pregnancy is a unique and dynamic process characterized by significant changes in the maternal cardiovascular system that are required to satisfy the increased maternal and fetal metabolic demands. Profound structural and hemodynamic adaptations occur during healthy pregnancy that allows the mother to maintain healthy hemodynamics and provide an adequate uteroplacental blood circulation to ensure physiological fetal development. Investigating these adaptations is crucial for understanding the physiology of pregnancy and may provide important insights for the management of high‐risk pregnancies. However, no previous modeling studies have investigated the maternal cardiac structural changes that occur during gestation. This study, therefore, had two aims. The first was to develop a lumped parameter model of the whole maternal circulation that is suitable for studying global hemodynamics and cardiac function at different stages of gestation. The second was to test the hypothesis that myofiber stress and wall shear stress homeostasis principles can be used to predict cardiac remodeling that occurs during normal pregnancy. Hemodynamics and cardiac variables predicted from simulations with and without controlled cardiac remodeling algorithms were compared and evaluated with reference clinical data. While both models reproduced the hemodynamic variations that arise in pregnancy, importantly, we show that the structural changes that occur with pregnancy could be predicted by assuming invariant homeostatic “target” values of myocardial wall stress and chamber wall shear stress.

Numerical Simulation Study on the Mechanism of Formation of Apical Aneurysm in Hypertrophic Cardiomyopathy With Midventricular Obstruction.

Apical aneurysm was observed to be associated with midventricular obstruction (MVO) in hypertrophic cardiomyopathy (HCM). To investigate the genesis of the apical aneurysm, the idealized numerical left ventricular models (finite-element left ventricle models) of the healthy left ventricle, subaortic obstruction, and midventricular obstruction in HCM of left ventricle were created. The mechanical effects in the formation of apical aneurysm were determined by comparing the myofiber stress on the apical wall between these three models (healthy, subaortic obstruction, and midventricular obstruction models). In comparing the subaortic obstruction model and MVO model with HCM, it was found that, at the time of maximum pressure, the maximum value of myofiber stress in MVO model was 75.0% higher than that in the subaortic obstruction model (654.5 kPa vs. 373.9 kPa). The maximum stress on the apex of LV increased 79.9, 69.3, 117.8% than that on the myocardium around the apex in healthy model, subaortic obstruction model, and MVO model, respectively. Our results indicated that high myofiber stress on the apical wall might initiate the formation process of the apical aneurysm.

Abstract 12568: Impact of Aortic Stenosis on Myofiber Stress: Translational Application of Left Ventricle-Aortic Coupling Simulations

Introduction: Grading aortic stenosis (AS) has traditionally relied on measuring hemodynamic parameters of transvalvular pressure gradient, ejection jet velocity, or estimating valve orifice area. Recent research has highlighted limitations of these criteria at effectively grading AS in presence of left ventricle (LV) dysfunction. We hypothesize that simulations coupling the aorta and LV will provide meaningful insight into myocardial biomechanical derangements that accompany AS. Reference data from the normal ventricle should first be obtained. Methods: A multi-domain cardiac model with representative anatomy and material properties was used to create AS simulations. Finite element analysis was performed with ABAQUS FEA®. An anisotropic hyperelastic model was assigned to the aorta and LV passive properties, while time-varying elastance function governed LV active response. Mild and severe AS were created by restricting the aortic valve orifice area. Results: Global LV myofiber end systolic (ES) stress (mean±SD) was 9.31±10.33 kPa at baseline (no AS), 13.13±10.29 kPa for mild AS, and 16.18±10.59 kPa with severe AS. Mean LV myofiber ES strains were -22.4±8.7%, -22.2±8.9%, and -21.9±9.2%, respectively. Mild and severe AS had significant stress elevation compared to baseline (mild AS vs base; p<0.01, severe AS vs base; p<0.001) and when compared to each other (p<0.01). See Figure 1 . Ventricular regions that experienced greatest magnitude ES stress were (severe AS vs baseline) basal inferior (39.87±14.73 vs 30.02±12.08 kPa; p<0.01), mid-anteroseptal (32.29±11.56 vs 24.79±12.00 kPa; p<0.001), and apex (27.99±8.44 vs 23.52±10.19 kPa; p<0.001). Conclusions: Isolated AS in a normal heart was simulated, and significantly elevated LV myofiber stress was quantified. This data serves as a comparison to future studies that will incorporate patient-specific ventricular geometries and material parameters, aiming to correlate LV biomechanics to AS severity.

Effect of infarct stiffness on non-infarcted left and right ventricular tissue remodeling: a computational study based on myocardial mechano-transduction

Abstract Background/Introduction The mechanical properties of infarcted myocardium are important determinants of cardiac pump function and risk of developing heart failure following myocardial infarction (MI). Purpose To better understand the effects of infarct stiffness on compensatory hypertrophy and dilation of non-infarcted tissue in the left (LV) and right ventricle (RV), by using a computational model. Methods The CircAdapt computational model of the human heart and circulation was applied to simulate an acute MI involving 20% of LV wall mass. The simulation was validated using previously published experimental data. Subsequently, two degrees of increased infarct stiffness were simulated. In all three simulations, a model of structural myocardial adaptation of the non-infarcted tissue was applied, based on sensing of mechanical loading of myocytes and extracellular matrix (ECM). Results Mild and severe stiffening of the infarct reduced the increase of LV end-diastolic volume (EDV) from +23 mL to +17 mL and +16 mL, respectively, and the increase of LV non-infarcted tissue mass from +31% to +21% and +18%. RV EDV decreased after adaptation, and mild and severe infarct stiffening reduced the decrease of RV EDV from −21 mL to −12 mL and −10 mL, respectively. Increase of RV tissue mass was reduced from +13% to +8% and +7% with mild and severe infarct stiffening. In the LV, reduced dilation and hypertrophy were driven mainly by a reduction of maximum stress in the ECM and a higher stress between the myocytes and ECM following infarct stiffening. The decreased RV hypertrophy, but not EDV reduction, was caused by a reduction of maximum RV ECM stress and maximum RV active myofiber stress. Conclusions Model simulations predicted that a stiffened LV infarct reduces both LV and RV non-infarcted tissue hypertrophy as well as LV dilation. In LV remodeling, maximum ECM stress and stress between myocyte and ECM played a more prominent role than in RV remodeling, while maximum active stress was more important in the RV. Overview of all model simulations Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the Netherlands Organisation for Scientific Research and the Dutch Heart Foundation.

Mechanical difference of left ventricle between rabbits of myocardial infarction and hypertrophy

The analysis of cardiac wall stress is of importance to understand the development of heart failure (HF). The aim of the study is to carry out the cardiac mechanics analysis to show the changes of left ventricular (LV) wall stresses after LV hypertrophy (LVH) and myocardial infarction (MI). Here, LVH and MI were generated in rabbit hearts through the transverse aortic constriction (TAC) and the distal left circumflex (LCx) artery ligation operations, respectively. Physiological and CT measurements were carried out at postoperative 2 and 4 weeks, based on which a finite element (FE) model was developed to perform the mechanics computation. We found a gradual increase of end-diastolic myofiber stress in free wall and interventricular septum of LVH and MI (higher stress in the free wall than the septum). In the interventricular septum, the 4-weeks LVH group has the highest ED myofiber stresses (11.378 ± 3.022 kPa), while the 4-weeks MI group has the highest ED myofiber stresses (13.494 ± 2.835 kPa) in the free wall. LVH increased myocardial volume (3.49 ± 0.07 and 4.52 ± 0.26 ml at postoperative 2 and 4 weeks) while MI increased LV volume (from 2.75 ± 0.29 to 4.19 ± 0.27 ml). LVH and MI had different distributions of local myofiber stress.

Cardiac wall mechanics analysis in hypertension-induced heart failure rats with preserved ejection fraction

Although cardiac wall mechanics is of importance for understanding heart failure with preserved ejection fraction (HFpEF), there is a lack of relevant mechanics studies. The aim of this study was to analyze the changes in stress and strain in the left ventricle (LV) in hypertension-induced HFpEF rats. Based on experimental measurements in DSS rats fed with high-salt (HS) and low-salt (LS) diets, LV stress and strain were computed throughout the cardiac cycle using Continuity software. HS-feeding increased myofiber stress and strain along both the transmural and longitudinal directions at the end-diastolic state but resulted in a lower absolute value of strain and relatively unchanged stress at the end-systolic state. Moreover, the end-diastolic stress and strain decreased with increasing radial position from the endocardial towards the epicardial walls despite negligible changes along the longitudinal direction. The changes in LV wall mechanics characterized the elevated diastolic LV stiffness and slow LV relaxation in HS-fed rats of HFpEF. These findings denote that a vicious cycle of increased stress and strain and diastolic dysfunction can prompt the development of HFpEF.

Prediction of Left Ventricular Mechanics Using Machine Learning.

The goal of this paper was to provide a real-time left ventricular (LV) mechanics simulator using machine learning (ML). Finite element (FE) simulations were conducted for the LV with different material properties to obtain a training set. A hyperelastic fiber-reinforced material model was used to describe the passive behavior of the myocardium during diastole. The active behavior of the heart resulting from myofiber contractions was added to the passive tissue during systole. The active and passive properties govern the LV constitutive equation. These mechanical properties were altered using optimal Latin hypercube design of experiments to obtain training FE models with varied active properties (volume and pressure predictions) and varied passive properties (stress predictions). For prediction of LV pressures, we used eXtreme Gradient Boosting (XGboost) and Cubist, and XGBoost was used for predictions of LV pressures, volumes as well as LV stresses. The LV pressure and volume results obtained from ML were similar to FE computations. The ML results could capture the shape of LV pressure as well as LV pressure-volume loops. The results predicted by Cubist were smoother than those from XGBoost. The mean absolute errors were as follows: XGBoost volume: 1.734 ± 0.584 ml, XGBoost pressure: 1.544 ± 0.298 mmHg, Cubist volume: 1.495 ± 0.260 ml, Cubist pressure: 1.623 ± 0.191 mmHg, myofiber stress: 0.334 ± 0.228 kPa, cross myofiber stress: 0.075 ± 0.024 kPa, and shear stress: 0.050 ± 0.032 kPa. The simulation results show ML can predict LV mechanics much faster than the FE method. The ML model can be used as a tool to predict LV behavior. Training of our ML model based on a large group of subjects can improve its predictability for real world applications.

Foreword

Progressive thinning and dilation of the LV due to ischemic heart failure (IHF) increases wall stress and myocardial oxygen consumption. Injectable biopolymers implanted in the myocardial wall have been used to increase wall thickness to reduce chamber volume, decrease wall stress, and improve cardiac function. We sought to evaluate the efficacy of a biopolymer (Algisyl-LVR) to prevent left ventricular (LV) remodeling in a swine model of IHF.IHF was induced in 11 swine by occluding the marginal obtuse branches of the left circumflex artery. Eight weeks later, Algisyl-LVR was injected into the LV myocardial free wall in five of the 11 animals. Echocardiographic examinations were done every 2 weeks for 16 weeks.Within eight weeks of treatment, the ejection fraction increased from 30.5% ± 7.7% to 42.4% ± 3.5% (treated group) vs. 37.3% ± 3.8% to 34.3% ± 2.9% (control), p < 0.01. Stroke volume increased from 18.5 ± 9.3 mL to 41.3 ± 13.3 mL (treated group) vs. 25.4 ± 2.3 mL to 31.4 ± 5.3 mL (control), p < 0.05. Wall thickness in end-diastole of the infarcted region changed from 0.69 ± 0.06 cm to 0.81 ± 0.13 cm (treated group) vs. 0.73 ± 0.09 cm to 0.68 ± 0.11 cm (control), p < 0.05. Sphericity index remained almost unchanged after treatment, although differences were found at the end of the study between both groups (p < 0.001). Average myofiber stress changed from 16.3 ± 5.8 kPa to 10.2 ± 4.0 kPa (treated group) vs. 15.2 ± 4.8 kPa to 17.9 ± 5.6 kPa (control), p < 0.05.Algisyl-LVR is an effective strategy that serves as a micro-LV assist device to reduce stress and hence prevent or reverse maladaptive cardiac remodeling caused by IHF in swine.

Investigating the Role of Interventricular Interdependence in Development of Right Heart Dysfunction During LVAD Support: A Patient-Specific Methods-Based Approach.

Predictive computation models offer the potential to uncover the mechanisms of treatments whose actions cannot be easily determined by experimental or imaging techniques. This is particularly relevant for investigating left ventricular mechanical assistance, a therapy for end-stage heart failure, which is increasingly used as more than just a bridge-to-transplant therapy. The high incidence of right ventricular failure following left ventricular assistance reflects an undesired consequence of treatment, which has been hypothesized to be related to the mechanical interdependence between the two ventricles. To investigate the implication of this interdependence specifically in the setting of left ventricular assistance device (LVAD) support, we introduce a patient-specific finite-element model of dilated chronic heart failure. The model geometry and material parameters were calibrated using patient-specific clinical data, producing a mechanical surrogate of the failing in vivo heart that models its dynamic strain and stress throughout the cardiac cycle. The model of the heart was coupled to lumped-parameter circulatory systems to simulate realistic ventricular loading conditions. Finally, the impact of ventricular assistance was investigated by incorporating a pump with pressure-flow characteristics of an LVAD (HeartMate II™ operating between 8 and 12 k RPM) in parallel to the left ventricle. This allowed us to investigate the mechanical impact of acute left ventricular assistance at multiple operating-speeds on right ventricular mechanics and septal wall motion. Our findings show that left ventricular assistance reduces myofiber stress in the left ventricle and, to a lesser extent, right ventricle free wall, while increasing leftward septal-shift with increased operating-speeds. These effects were achieved with secondary, potentially negative effects on the interventricular septum which showed that support from LVADs, introduces unnatural bending of the septum and with it, increased localized stress regions. Left ventricular assistance unloads the left ventricle significantly and shifts the right ventricular pressure-volume-loop toward larger volumes and higher pressures; a consequence of left-to-right ventricular interactions and a leftward septal shift. The methods and results described in the present study are a meaningful advancement of computational efforts to investigate heart-failure therapies in silico and illustrate the potential of computational models to aid understanding of complex mechanical and hemodynamic effects of new therapies.

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. By applying the framework using data obtained from 3 healthy human biventricles, we extracted clinically important quantities as well as explored the role of fiber angles on heart function. Our results show that steep fiber angles at the endocardium and epicardium are required to produce simulated motion compatible with measured strain and volume data. We also find that the contraction and subsequent systolic stresses in the right ventricle are significantly lower than that in the left ventricle. Variability of the estimated quantities with respect to both patient data and modeling choices are also found to be low. Because of its high efficiency, this framework may be applicable to modeling of patient specific cardiac mechanics for diagnostic purposes.

A Research about Single‐Point Ligated Ischemic Heart Failure Rabbits in Physiology and Biomechanics

ObjectiveAnimal models are important to study basic mechanism and biomechanics of ischemic heart failure (HF). Among a four heart chambers, the left ventricular (LV) plays the most significant mechanical part of pumping blood to the entire body. Biomechanical and morphological analyses can reflect the function of LV. The single‐point ligated HF model is a typical rabbit heart failure model, which can reveal the mechanism of heart failure. Left ventricular myofiber stress and strain analyzing is an effective biomechanical method in HF study. We aim at studying the physiological and biomechanical behave of the ischemic heart failure model.MethodBy single‐point ligation method, we establish the ischemic heart failure model. We ligate the left circumflex coronary arteries of 6 New Zealand white rabbits. The rabbits are scanned by Computed Tomography (CT), with short‐axis slice separated by 1.25 mm, after 2‐weeks and 4‐weeks. To determine regional stress and strain distributions in rabbit ventricular myocardium, an anatomically detailed nonlinear finite element model was used, which can solve the equations of stress equilibrium during passive filling of the left ventricle. At same time, the paraffin sections have be surveyed in pathology.ResultThe volume can be calculated by 3‐D reconstructed model, which range from 1528.33 mm3 (SD 286.23) at 2‐weeks to 1990.72 mm3 (SD 178.71) at 4‐weeks. The strain and stress get bigger from 2‐weeks to 4‐weeks. The huge change can be found at the pathology sections.ConclusionsThis research find the changing regulation of the strain and stress. Based on biomechanics and physiology, a new method for evaluating the function of the left ventricular is presented.Support or Funding InformationThis research is supported in part by the National Natural Science Foundation of China Grant 11372010(Y Huo); Shenzhen Science and Technology Innovation Institution (China) Grant JCYJ20160427170536358 (Y Huo).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Efficacy of intramyocardial injection of Algisyl-LVR for the treatment of ischemic heart failure in swine

BackgroundProgressive thinning and dilation of the LV due to ischemic heart failure (IHF) increases wall stress and myocardial oxygen consumption. Injectable biopolymers implanted in the myocardial wall have been used to increase wall thickness to reduce chamber volume, decrease wall stress, and improve cardiac function. We sought to evaluate the efficacy of a biopolymer (Algisyl-LVR) to prevent left ventricular (LV) remodeling in a swine model of IHF. MethodsIHF was induced in 11 swine by occluding the marginal obtuse branches of the left circumflex artery. Eight weeks later, Algisyl-LVR was injected into the LV myocardial free wall in five of the 11 animals. Echocardiographic examinations were done every 2weeks for 16weeks. ResultsWithin eight weeks of treatment, the ejection fraction increased from 30.5%±7.7% to 42.4%±3.5% (treated group) vs. 37.3%±3.8% to 34.3%±2.9% (control), p<0.01. Stroke volume increased from 18.5±9.3mL to 41.3±13.3mL (treated group) vs. 25.4±2.3mL to 31.4±5.3mL (control), p<0.05. Wall thickness in end-diastole of the infarcted region changed from 0.69±0.06cm to 0.81±0.13cm (treated group) vs. 0.73±0.09cm to 0.68±0.11cm (control), p<0.05. Sphericity index remained almost unchanged after treatment, although differences were found at the end of the study between both groups (p<0.001). Average myofiber stress changed from 16.3±5.8kPa to 10.2±4.0kPa (treated group) vs. 15.2±4.8kPa to 17.9±5.6kPa (control), p<0.05. ConclusionsAlgisyl-LVR is an effective strategy that serves as a micro-LV assist device to reduce stress and hence prevent or reverse maladaptive cardiac remodeling caused by IHF in swine.

Computational sensitivity investigation of hydrogel injection characteristics for myocardial support.

Biomaterial injection is a potential new therapy for augmenting ventricular mechanics after myocardial infarction (MI). Recent in vivo studies have demonstrated that hydrogel injections can mitigate the adverse remodeling due to MI. More importantly, the material properties of these injections influence the efficacy of the therapy. The goal of the current study is to explore the interrelated effects of injection stiffness and injection volume on diastolic ventricular wall stress and thickness. To achieve this, finite element models were constructed with different hydrogel injection volumes (150µL and 300 µL), where the modulus was assessed over a range of 0.1kPa to 100kPa (based on experimental measurements). The results indicate that a larger injection volume and higher stiffness reduce diastolic myofiber stress the most, by maintaining the wall thickness during loading. Interestingly, the efficacy begins to taper after the hydrogel injection stiffness reaches a value of 50kPa. This computational approach could be used in the future to evaluate the optimal properties of the hydrogel.

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. Results show that the peak right ventricle (RV) pressure was substantially higher in the PAH patient (65 mmHg versus 20 mmHg), who also has a significantly reduced ejection fraction (EF) in both ventricles (left ventricle (LV): 39% versus 66% and RV: 18% versus 64%). Peak systolic circumferential strain was comparatively lower in both the left ventricle (LV) and RV free wall (RVFW) of the PAH patient (LV: -6.8% versus -13.2% and RVFW: -2.1% versus -9.4%). Passive stiffness, contractility, and myofiber stress in the PAH patient were all found to be substantially increased in both ventricles, whereas septum wall in the PAH patient possessed a smaller curvature than that in the LV free wall. Simulations using the PAH model revealed an approximately linear relationship between the septum curvature and the transseptal pressure gradient at both early-diastole and end-systole. These findings suggest that PAH can induce LV remodeling, and septum curvature measurements may be useful in quantifying transseptal pressure gradient in PAH patients.

Injectable Shear-Thinning Hydrogels for Minimally Invasive Delivery to Infarcted Myocardium to Limit Left Ventricular Remodeling.

Injectable, acellular biomaterials hold promise to limit left ventricular remodeling and heart failure precipitated by infarction through bulking or stiffening the infarct region. A material with tunable properties (eg, mechanics, degradation) that can be delivered percutaneously has not yet been demonstrated. Catheter-deliverable soft hydrogels with in vivo stiffening to enhance therapeutic efficacy achieve these requirements. We developed a hyaluronic acid hydrogel that uses a tandem crosslinking approach, where the first crosslinking (guest-host) enabled injection and localized retention of a soft (<1 kPa) hydrogel. A second crosslinking reaction (dual-crosslinking) stiffened the hydrogel (41.4±4.3 kPa) after injection. Posterolateral infarcts were investigated in an ovine model (n≥6 per group), with injection of saline (myocardial infarction control), guest-host hydrogels, or dual-crosslinking hydrogels. Computational (day 1), histological (1 day, 8 weeks), morphological, and functional (0, 2, and 8 weeks) outcomes were evaluated. Finite-element modeling projected myofiber stress reduction (>50%; P<0.001) with dual-crosslinking but not guest-host injection. Remodeling, assessed by infarct thickness and left ventricular volume, was mitigated by hydrogel treatment. Ejection fraction was improved, relative to myocardial infarction at 8 weeks, with dual-crosslinking (37% improvement; P=0.014) and guest-host (15% improvement; P=0.058) treatments. Percutaneous delivery via endocardial injection was investigated with fluoroscopic and echocardiographic guidance, with delivery visualized by magnetic resonance imaging. A percutaneous delivered hydrogel system was developed, and hydrogels with increased stiffness were found to be most effective in ameliorating left ventricular remodeling and preserving function. Ultimately, engineered systems such as these have the potential to provide effective clinical options to limit remodeling in patients after infarction.