Left Ventricular Model Research Articles

Endocardial Fibrotic Lesions Have a Greater Effect on Peak Longitudinal Strain than Epicardial Fibrotic Lesions in Hypertrophic Cardiomyopathy Patients.

Peak longitudinal strain (PLS) of the left ventricular (LV) myocardium by transthoracic echocardiogram (TTE) is useful to detect LV myocardial damage. We hypothesized that myocardial fibrosis (MF) in the LV myocardium may influence PLS. Eighteen hypertrophic cardiomyopathy (HCM) patients (14 males; 58 ± 17 years old) underwent 1.5 Tesla cardiac magnetic resonance (CMR) and TTE. Patients with previous myocardial infarction were excluded. We used TTE to assess whole-layer PLS in an American Heart Association-defined 17-segment LV model. Whole-layer PLS was calculated using Echo PAC, version 113 (GE Healthcare). MF was assessed by T1-weighted CMR of the LV endocardial layer, the LV epicardial layer, or both the LV endocardial and epicardial layers for each lesion. Of the 306 segments, MF was detected in the LV endocardial layer only (13 segments), in the LV epicardial layer only (9 segments), or in both LV endocardial and epicardial layers (59 segments). PLS values were significantly lower in segments with MF affecting only the LV endocardial layer (7% ± 4%) (P < 0.05) and where MF was observed in both the LV endocardial and epicardial layers (9% ± 5%) (P = 0.001) compared with segments without MF (13% ± 7%). No significant difference in PLS values was detected between the MF segments for the LV epicardial layer only (10% ± 6%) and those without MF (13% ± 7%) (P > 0.05). In HCM patients, fibrotic lesions in the LV endocardium have a greater adverse effect on PLS than those in the LV epicardium. Our results are significant for HCM patients with fibrotic lesions within the LV endocardium.

Electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure.

To investigate the electrophysiological changes of autonomic cells in left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with chronic heart failure. Guinea pigs model of iron deficiency anemia complicated with chronic heart failure in 10 guinea pigs of the experimental group was made by feeding a low iron diet, pure water and subcutaneous injection of isoproterenol. The control group consisting of 11 guinea pigs was given normal food, normal water and injected with normal saline. The left ventricular outflow tract model specimen was also prepared. The standard microelectrode technique was used to observe electrophysiological changes of autonomic cells in the outflow tract of left ventricular heart failure complicated with iron deficiency anemia in guinea pig model. The indicators of observation were maximal diastolic potential, action potential amplitude, 0 phase maximal depolarization velocity, 4 phase automatic depolarization velocity, repolarization 50% and 90%, and spontaneous discharge frequency. Compared with the control group, 4 phase automatic depolarization velocity, spontaneous discharge frequency and 0 phase maximal depolarization velocity decreased significantly (P<0.01) and action potential amplitude reduced (P<0.01) in model group. Moreover, repolarization 50% and 90% increased (P<0.01). There are electrophysiological abnormalities of the left ventricular outflow tract in guinea pigs with iron deficiency anemia complicated with heart failure.

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. We show that our model is able to reproduce a linear end‐systolic pressure volume relationship, a curvilinear end‐diastolic pressure volume relationship and a linear relationship between myocardial oxygen consumption and pressure–volume area. We also show that the validated model can predict realistic LV strain‐time profiles in the longitudinal, circumferential, and radial directions. The predicted strain‐time profiles display key features that are consistent with those measured in humans, such as having similar peak strains, time‐to‐peak‐strain, and a rapid change in strain during atrial contraction at late‐diastole. Our model shows that the myocardial strains are sensitive to not only LV contractility, but also to the LV loading conditions, especially to a change in afterload. This result suggests that caution must be exercised when associating changes in myocardial strain with changes in LV contractility. The methodically validated multiscale model will be used in future studies to understand human heart diseases.

Apelin‑13 promotes cell proliferation in the H9c2 cardiomyoblast cell line by triggering extracellular signal‑regulated kinase 1/2 and protein kinase B phosphorylation.

Apelin‑13 (APL‑13), a peptide hormone that serves as a ligand for G‑protein coupled receptors, has been demonstrated to be highly expressed in left ventricular hypertrophy rat models. It has been implicated in cardio‑protection under pathological states. The present study aimed to assess the physiological proliferation effect of APL‑13 in cultured H9c2 cardiomyoblast cells, and to elucidate the underlying mechanisms. Cell proliferation was determined by MTT assay. The extracellular signal‑regulated kinase (ERK) 1/2 and protein kinase B (Akt) signaling pathway was identified, and protein expression levels were detected using western blot analysis. The results demonstrated that APL‑13 markedly increased cell proliferation. Western blotting results suggested that APL‑13 significantly enhanced the expression of phosphoinositide ERK1/2 and Akt activation in a dose‑dependent manner. U0126 (10µM; ERK1/2 inhibitor) and/or 10µM LY294002 (Akt inhibitor) were used to help to determine the APL‑signaling mechanism. As a result, LY294002 and U0126 partially blocked the APL‑13 induced H9c2 proliferation. In conclusion, these data suggested that APL‑13 has a proliferative effect on myocardium cells via the Akt and ERK1/2 signaling pathways, and provide potential novel pharmaceutical targets for cardiovascular disease.

Computational Analysis of the Mode of Action of Disopyramide and Quinidine on hERG-Linked Short QT Syndrome in Human Ventricles.

The short QT syndrome (SQTS) is a rare cardiac disorder associated with arrhythmias and sudden death. Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, IKr, underlie SQTS variant 1 (SQT1), in which treatment with Na+ and K+ channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy. This study used computational modeling to gain mechanistic insights into the actions of two such drugs, disopyramide and quinidine, in the setting of SQT1. The O'Hara-Rudy (ORd) human ventricle model was modified to incorporate a Markov chain formulation of IKr describing wild type (WT) and SQT1 mutant conditions. Effects of multi-channel block by disopyramide and quinidine, including binding kinetics and altered potency of IKr/hERG channel block in SQT1 and state-dependent block of sodium channels, were simulated on action potential and multicellular tissue models. A one-dimensional (1D) transmural ventricular strand model was used to assess prolongation of the QT interval, effective refractory period (ERP), and re-entry wavelength (WL) by both drugs. Dynamics of re-entrant excitation waves were investigated using a 3D human left ventricular wedge model. In the setting of SQT1, disopyramide, and quinidine both produced a dose-dependent prolongation in (i) the QT interval, which was primarily due to IKr block, and (ii) the ERP, which was mediated by a synergistic combination of IKr and INa block. Over the same range of concentrations quinidine was more effective in restoring the QT interval, due to more potent block of IKr. Both drugs demonstrated an anti-arrhythmic increase in the WL of re-entrant circuits. In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias. This computational modeling study provides novel insights into the clinical efficacy of disopyramide and quinidine in the setting of SQT1; it also dissects ionic mechanisms underlying QT and ERP prolongation. Our findings show that both drugs demonstrate efficacy in reversing the SQT1 phenotype, and indicate that disopyramide warrants further investigation as an alternative to quinidine in the treatment of SQT1.

YIA-BS5 - Brown Adipose Tissue Function Plays a Critical Role in the Development of Heart Failure during Pressure Overload

Heart failure (HF) is one of the main causes of mortality worldwide. It has been reported that low body temperature is linked to cardiac systolic dysfunction as well as to poor clinical outcome in patients with HF; however the underlying mechanisms and pathological implications are largely unknown. Brown adipose tissue (BAT) was initially characterized as an organ involved in thermogenic response, and studies suggest that BAT has crucial roles for the maintenance of systemic metabolism in obesity. Here we show that BAT dysfunction develops with heart failure and promotes cardiac remodeling by inducing systemic metabolic dysfunction. We generated a left ventricular (LV) pressure-overload model in mice with a thoracic aortic constriction (TAC). Cardiac systolic dysfunction developed in four weeks after operation, together with a reduction of the thermogenic response to acute cold exposure and an increase of TUNEL-positive cells in BAT. In-vitro studies with differentiated brown adipocytes suggested that the chronic activation of adrenergic signaling reduced mitochondrial membrane potential and increased apoptotic cells. The transplantation of healthy BAT into mice undergoing TAC improved thermogenic response and ameliorated cardiac dysfunction. Studies with metabolome analyses indicated that BAT dysfunction has a causal role for accumulation of one metabolite which contributes to the progression of cardiac metabolic remodeling and dysfunction. Maintenance of BAT homeostasis would become a novel therapeutic target for heart failure.

PP.24.22] HIGHER PULSE WAVE VELOCITY IS ASSOCIATED WITH NON-RECOVERY OF LEFT VENTRICULAR SYSTOLIC FUNCTION IN PATIENTS AFTER MYOCARDIAL INFARCTION

Objective: Functional recovery or irreversible negative remodeling of injured myocardial segments has different prognostic implication in patients with myocardial infarction (MI) undergoing coronary percutaneous intervention (PCI). Increased pulse wave velocity (PWV),is one of the important risk factors of cardiovascular events in different clinical conditions. The aim of the study was to assess the relationship between PWV and changes of left ventricular (LV) systolic function in patients with acute MI. Design and method: In 112 patients with acute MI and PCI (68% male,age 61.1 ± 9.5 years (M ± SD),57.2% with ST-elevation MI (STEMI),smokers 35%,arterial hypertension 83%,diabetes 7%,blood pressure (BP) 128 ± 8/82 ± 87mmHg, LV ejection fraction (LVEF) 48.2 ± 4.6%). Arterial stiffness was assessed using applanation tonometry. Global longitudinal peak strain (GLPS) by speckle tracking echocardiography (STE) was calculated in a 16-segment LV model as the average segmental value on the basis of three apical imaging planes. Cardiac adverse remodeling was defined by ratio [follow up - initial LV end diastolic volume (LVEDV)] / initial LVEDV) more than 20%. Mann-Whitney and Spearman tests were considered significant if p < 0.05. Results: Baseline GLPS >20% was not detected in any patient. GLPS increased from 14.4 ± 2.4 to 17.4 ± 3.5% in 4 weeks (p < 0.05) and to 18.1 ± 2.7 in 6 months after PCI (p < 0.05). GLPS normalized (>20%) in 31 (28%) patients after 4 weeks and 6 months. After 6 months adverse cardiac remodeling was found in 81 (72%) patients (53% STEMI). Achieved GLPS differed significantly in patients with vs without adverse cardiac remodeling (16.7 ± 1.9 vs 21.4 ± 1.2%, p < 0.001). Mean carotid-femoral PWV decreased from 11.1 ± 2.1 to 8.7 ± 1.8 m/s,p < 0.05. Patients without vs with GLPS normalization in 6 months after PCI were older (62.5 ± 8.5 vs 60.6 ± 9.9 years, p < 0.05), more frequent male (71vs 66.2%, χ2 = 11.1;p < 0.05),smokers (36.2vs 31.2%, χ2 = 3.4;p < 0.04),STEMI (58.7vs 53%, χ2 = 7.7; p < 0.05),had higher systolic BP (134 ± 10vs 130 ± 6 mmHg, p < 0.03),baseline PWV (11.4 ± 1.9vs 10.4 ± 2.6 m/s, p < 0.03),lower baseline EF (47.6 ± 4.9 vs 49.6 ± 3.5%, p < 0.05). A significant correlation was found between decreased δspeckle tracking and higher PWV (r = −0.31,p < 0.05) and speckle tracking and LVEDV after 6 months (r = −0.75,p < 0.05). Conclusions: 65% of patients with MI treated with PCI failed to normalize GLPS after 6 months. Adverse cardiac remodeling was revealed in 72% of patients and they more often had non-recovery of left ventricular longitudinal function. Higher baseline PWV is associated with less effective recovery of LV function.

Geometry as a Confounder When Assessing Ventricular Systolic Function: Comparison Between Ejection Fraction and Strain

BackgroundPreserved left ventricular (LV) ejection fraction (EF) and reduced myocardial strain are reported in patients with hypertrophic cardiomyopathy, ischemic heart disease, diabetes mellitus, and more. ObjectivesThe authors performed a combined mathematical and echocardiographic study to understand the inconsistencies between EF and strains. MethodsAn analytical equation showing the relationship between EF and the 4 parameters, global longitudinal strain (GLS), global circumferential strain (GCS), wall thickness, and short-axis diameter, was derived from an elliptical LV model. The equation was validated by measuring the 4 parameters by echocardiography in 100 subjects with EF ranging from 16% to 72% and comparing model-predicted EF with measured EF. The effect of the different parameters on EF was explored in the model and compared with findings in the patients. ResultsCalculated EF had very good agreement with measured EF (r = 0.95). The model showed that GCS contributes more than twice as much to EF than GLS. A significant reduction of GLS could be compensated by a small increase of GCS or wall thickness or reduced diameter. The model further demonstrated how EF can be maintained in ventricles with increased wall thickness or reduced diameter, despite reductions in both longitudinal and circumferential shortening. This was consistent with similar EF in 20 control subjects and 20 hypertrophic cardiomyopathy patients with increased wall thickness and reductions in both circumferential and longitudinal shortening (all p < 0.01). ConclusionsReduced deformation despite preserved EF can be explained through geometric factors. Due to geometric confounders, strain better reflects systolic function in patients with preserved EF.

Modeling Left Ventricular Blood Flow Using Smoothed Particle Hydrodynamics.

This study aims to investigate the capability of smoothed particle hydrodynamics (SPH), a fully Lagrangian mesh-free method, to simulate the bulk blood flow dynamics in two realistic left ventricular (LV) models. Three dimensional geometries and motion of the LV, proximal left atrium and aortic root are extracted from cardiac magnetic resonance imaging and multi-slice computed tomography imaging data. SPH simulation results are analyzed and compared with those obtained using a traditional finite volume-based numerical method, and to in vivo phase contrast magnetic resonance imaging and echocardiography data, in terms of the large-scale blood flow phenomena usually clinically measured. A quantitative comparison of the velocity fields and global flow parameters between the in silico models and the in vivo data shows a reasonable agreement, given the inherent uncertainties and limitations in the modeling and imaging techniques. The results indicate the capability of SPH as a promising tool for predicting clinically relevant large-scale LV flow information.

Modeling young and adult patients with cirrhosis through a three element windkessel (WK3e).

Measurement of hemodynamic parameters constitutes an important tool in the management of patients with cirrhosis. In recent years, non-invasive measurements have gain attention, due to the potential complications associated to invasive procedures. To characterize the hemodynamic alterations of cirrhosis in young and adult subjects, through a three element windkessel (WK3e). Individuals were divided in three age groups: Young Healthy group (control, CG), Young Cirrhotic Group (YCG) and Adult Cirrhotic Group (ACG). A Finapres® Nova device was used to obtain cardiac output (CO), heart rate and arterial blood pressure. Systemic arterial compliance (C), peripheral resistance (R) and characteristic impedance (Zc) were also provided. Effective arterial elastance (Ea), left ventricular work (LVW), input impedance, efficiency and model cutoff frequency (WKCF) were assessed based on the provided data. CO resulted to be higher in ACG than in CG and YGC. LVW, C and WKcf showed an increase, while R and Ea showed a decrease. However, this behavior was not observed in YCG. Cirrhosis was properly modeled in young and adult subjects in terms of non-invasive measurements and a WK3e.

Computational Analysis of Intra-Ventricular Flow Pattern Under Partial and Full Support of BJUT-II VAD.

BackgroundPartial support, as a novel support mode, has been widely applied in clinical practice and widely studied. However, the precise mechanism of partial support of LVAD in the intra-ventricular flow pattern is unclear.Material/MethodsIn this study, a patient-specific left ventricular geometric model was reconstructed based on CT data. The intra-ventricular flow pattern under 3 simulated conditions – “heart failure”, “partial support”, and “full support” – were simulated by using fluid-structure interaction (FSI). The blood flow pattern, wall shear stress (WSS), time-average wall shear stress (TAWSS), oscillatory shear index (OSI), and relative residence time (RRT) were calculated to evaluate the hemodynamic effects.ResultsThe results demonstrate that the intra-ventricular flow pattern is significantly changed by the support level of BJUT-II VAD. The intra-ventricular vortex was enhanced under partial support and was eliminated under full support, and the high OSI and RRT regions changed from the septum wall to the cardiac apex.ConclusionsIn brief, the support level of the BJUT-II VAD has significant effects on the intra-ventricular flow pattern. The partial support mode of BJUT-II VAD can enhance the intra-ventricular vortex, while the distribution of high OSI and RRT moved from the septum wall to the cardiac apex. Hence, the partial support mode of BJUT-II VAD can provide more benefit for intra-ventricular flow pattern.

Orthogonal decomposition of left ventricular remodeling in myocardial infarction

Left ventricular size and shape are important for quantifying cardiac remodeling in response to cardiovascular disease. Geometric remodeling indices have been shown to have prognostic value in predicting adverse events in the clinical literature, but these often describe interrelated shape changes. We developed a novel method for deriving orthogonal remodeling components directly from any (moderately independent) set of clinical remodeling indices. Results: Six clinical remodeling indices (end-diastolic volume index, sphericity, relative wall thickness, ejection fraction, apical conicity, and longitudinal shortening) were evaluated using cardiac magnetic resonance images of 300 patients with myocardial infarction, and 1991 asymptomatic subjects, obtained from the Cardiac Atlas Project. Partial least squares (PLS) regression of left ventricular shape models resulted in remodeling components that were optimally associated with each remodeling index. A Gram–Schmidt orthogonalization process, by which remodeling components were successively removed from the shape space in the order of shape variance explained, resulted in a set of orthonormal remodeling components. Remodeling scores could then be calculated that quantify the amount of each remodeling component present in each case. A one-factor PLS regression led to more decoupling between scores from the different remodeling components across the entire cohort, and zero correlation between clinical indices and subsequent scores. Conclusions: The PLS orthogonal remodeling components had similar power to describe differences between myocardial infarction patients and asymptomatic subjects as principal component analysis, but were better associated with well-understood clinical indices of cardiac remodeling. The data and analyses are available from www.cardiacatlas.org.

Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase.

Pulmonary hypertension (PH) is a devastating disorder, for which no therapy is curative. It has been reported that pulmonary vascular remodeling, associated with increasing mean pulmonary arterial pressure and upregulated expression of endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), RhoA/RhoH-kinase results in the development of PH. Oxidative stress and the RhoA/Rho-kinase pathway are also thought to be involved in the pathophysiology of PH. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors) with pleiotropic effects and are potential agents for the treatment of PH. In this study, we investigated the beneficial effects of simvastatin on the development of PH secondary to left ventricular dysfunction. A PH secondary to left ventricular dysfunction model was established in 6-week-old aortic-banded rats. The pulmonary expression of Rho kinase, ET-1, eNOS, p-eNOS, nitrite/nitrate (NOx), cGMP, p47Phox , and p67Phox were investigated in the early-treatment group, to which was administered simvastatin (30 mg/kg/day) from days 1 to 42 or the late-treatment group, to which was administered simvastatin (30 mg/kg/day) from days 29 to 42. Simvastatin attenuated the mean pulmonary artery pressure, pulmonary arteriolar remodeling, plasma brain natriuretic peptide, ET-1, reactive oxygen species, and the NADPH oxidase 2 regulatory subunits, p47Phox and p67Phox , and upregulated pulmonary p-eNOS, NOx, and cGMP in both the early- and late-treated groups. Inhibiting HMG-CoA reductase may have therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction through the Rho-kinase pathway and NADPH oxidase. A translational study in humans is needed to substantiate these findings. Pediatr Pulmonol. 2017;52:443-457. © 2016 Wiley Periodicals, Inc.

Ambulatory systolic blood pressure and obesity are independently associated with left ventricular hypertrophic remodeling in children

BackgroundChildren with obesity have hypertrophic cardiac remodeling. Hypertension is common in pediatric obesity, and may independently contribute to hypertrophy. We hypothesized that both the degree of obesity and ambulatory blood pressure (ABP) would independently associate with measures of hypertrophic cardiac remodeling in children.MethodsChildren, aged 8–17 years, prospectively underwent cardiovascular magnetic resonance (CMR) and ABP monitoring. Left ventricular (LV) mass indexed to height2.7 (LVMI), myocardial thickness and end-diastolic volume were quantified from a 3D LV model reconstructed from cine balanced steady state free precession images. Categories of remodeling were determined based on cutoff values for LVMI and mass/volume. Principal component analysis was used to define a “hypertrophy score” to study the continuous relationship between concentric hypertrophy and ABP.ResultsSeventy-two children were recruited, and 68 of those (37 healthy weight and 31 obese/overweight) completed both CMR and ABP monitoring. Obese/overweight children had increased LVMI (27 ± 4 vs 22 ± 3 g/m2.7, p < 0.001), myocardial thickness (5.6 ± 0.9 vs 4.9 ± 0.7 mm, p < 0.001), mass/volume (0.69 ± 0.1 vs 0.61 ± 0.06, p < 0.001), and hypertrophy score (1.1 ± 2.2 vs −0.96 ± 1.1, p < 0.001). Thirty-five percent of obese/overweight children had concentric hypertrophy. Ambulatory hypertension was observed in 26% of the obese/overweight children and none of the controls while masked hypertension was observed in 32% of the obese/overweight children and 16% of the controls. Univariate linear regression showed that BMI z-score, systolic BP (24 h, day and night), and systolic load correlated with LVMI, thickness, mass/volume and hypertrophy score, while 24 h and nighttime diastolic BP and load also correlated with thickness and mass/volume. Multivariate analysis showed body mass index z-score and systolic blood pressure were both independently associated with left ventricular mass index (β=0.54 [p < 0.001] and 0.22 [p = 0.03]), thickness (β=0.34 [p < 0.001] and 0.26 [p = 0.001]) and hypertrophy score (β=0.47 and 0.36, both p < 0.001).ConclusionsIn children, both the degree of obesity and ambulatory blood pressures are independently associated with measures of cardiac hypertrophic remodeling, however the correlations were generally stronger for the degree of obesity. This suggests that interventions targeted at weight loss or obesity-associated co-morbidities including hypertension may be effective in reversing or preventing cardiac remodeling in obese children.

Investigating Shear Wave Physics in a Generic Pediatric Left Ventricular Model via In Vitro Experiments and Finite Element Simulations.

Shear wave elastography (SWE) is a potentially valuable tool to noninvasively assess ventricular function in children with cardiac disorders, which could help in the early detection of abnormalities in muscle characteristics. Initial experiments demonstrated the potential of this technique in measuring ventricular stiffness; however, its performance remains to be validated as complicated shear wave (SW) propagation characteristics are expected to arise due to the complex non-homogenous structure of the myocardium. In this work, we investigated the (i) accuracy of different shear modulus estimation techniques (time-of-flight (TOF) method and phase velocity analysis) across myocardial thickness and (ii) effect of the ventricular geometry, surroundings, acoustic loading, and material viscoelasticity on SW physics. A generic pediatric (10-15-year old) left ventricular model was studied numerically and experimentally. For the SWE experiments, a polyvinylalcohol replicate of the cardiac geometry was fabricated and SW acquisitions were performed on different ventricular areas using varying probe orientations. Additionally, the phantom's stiffness was obtained via mechanical tests. The results of the SWE experiments revealed the following trends for stiffness estimation across the phantom's thickness: a slight stiffness overestimation for phase speed analysis and a clear stiffness underestimation for the TOF method for all acquisitions. The computational model provided valuable 3-D insights in the physical factors influencing SW patterns, especially the surroundings (water), interface force, and viscoelasticity. In conclusion, this paper presents a validation study of two commonly used shear modulus estimators for different ventricular locations and the essential role of SW modeling in understanding SW physics in the pediatric myocardium.

Effect of Transmural Extent of the Simulated Infarction in a Left Ventricular Model on Displacement and Strain Distribution Estimated from Synthetic Ultrasonic Data

The identification of a sub-endocardial infarction is of major interest in cardiology. This study evaluates the sensitivity of selected measures to the thickness of such an infarction. Synthetic ultrasonic data (long-axis view) of left ventricular models with inclusions were generated using Field II and meshes obtained from finite-element simulations, which also provided the reference for the estimates obtained from ultrasonic data. The displacements, the first and second component of the principal strain (ε1 and ε2), and several measures derived from these quantities were estimated. All estimates, except for the poorly estimated ε2, exhibited sensitivity to the presence and transmurality of the inclusion. The most sensitive was the gradient of the averaged transmural profiles of ε1, and ε1 averaged over the area corresponding to the transmural inclusion. The inflection point of the ε1 profile shifted toward the outer wall with increasing thickness of the non-transmural inclusion.

A viscoactive constitutive modeling framework with variational updates for the myocardium

We present a constitutive modeling framework for contractile cardiac mechanics by formulating a single variational principle from which incremental stress–strain relations and kinetic rate equations for active contraction and relaxation can all be derived. The variational framework seamlessly incorporates the hyperelastic behavior of the relaxed and contracted tissue along with the rate–and length–dependent generation of contractile force. We describe a three-element, Hill-type model that unifies the active tension and active deformation approaches. As in the latter approach, we multiplicatively decompose the total deformation gradient into active and elastic parts, with the active deformation parametrizing the contractile Hill element. We adopt as internal variables the fiber, cross-fiber, and sheet normal stretch ratios. The kinetics of these internal variables are modeled via definition of a kinetic potential function derived from experimental force–velocity relations. Additionally, we account for dissipation during tissue deformation by adding a Newtonian viscous potential. To model the force activation, the kinetic equations are coupled with the calcium transient obtained from a cardiomyocyte electrophysiology model. We first analyze our model at the material point level using stress and strain versus time curves for different viscosity values. Subsequently, we couple our constitutive framework with the finite element method (FEM) and study the deformation of three-dimensional tissue slabs with varying cardiac myocyte orientation. Finally, we simulate the contraction and relaxation of an ellipsoidal left ventricular model and record common kinematic measures, such as ejection fraction, and myocardial tissue volume changes.

Application of the Kalman Filter for Faster Strong Coupling of Cardiovascular Simulations.

In this paper, we propose a method for reducing the computational cost of strong coupling for multiscale cardiovascular simulation models. In such a model, individual model modules of myocardial cell, left ventricular structural dynamics, and circulatory hemodynamics are coupled. The strong coupling method enables stable and accurate calculation, but requires iterative calculations which are computationally expensive. The iterative calculations can be reduced, if accurate initial approximations are made available by predictors. The proposed method uses the Kalman filter to estimate accurate predictions by filtering out noise included in past values. The performance of the proposed method was assessed with an application to a previously published multiscale cardiovascular model. The proposed method reduced the number of iterations by 90% and 62% compared with no prediction and Lagrange extrapolation, respectively. Even when the parameters were varied and number of elements of the left ventricular finite-element model increased, the number of iterations required by the proposed method was significantly lower than that without prediction. These results indicate the robustness, scalability, and validity of the proposed method.

Heart failure with preserved ejection fraction in hypertension.

Hypertension is the most prevalent risk factor in heart failure with preserved ejection fraction (HFpEF) and plays a key role in the disease. The continued lack of effective therapies to improve outcomes in HFpEF underscores the knowledge gaps regarding the pathophysiology of HFpEF. This review builds on fundamental concepts in pressure overload-induced left ventricular modeling, and summarizes recent knowledge gained regarding the mechanisms underlying the transition from hypertensive heart disease to HFpEF. The pathophysiology of hypertensive HFpEF extends beyond the development of left ventricular hypertrophy and diastolic dysfunction to myocardial contractile dysfunction, beyond left atrial structural dilatation to left atrial functional decline, beyond macrovascular stiffening to microvascular dysfunction, beyond central cardiac triggers to systemic endothelial inflammation, beyond fibrosis to titin changes, and beyond collagen deposition to qualitative changes in collagen. The central paradigm involves a systemic proinflammatory state triggering a downstream cascade of cardiac microvascular endothelial activation, oxidative stress, and abnormal myocardial cyclic guanosine monophosphate signaling, leading to microvascular rarefaction, chronic ischemia, fibrosis and progression to HFpEF. Recent advances have provided insights into the pathophysiology of HFpEF in hypertension. Such knowledge provides novel opportunities for therapeutic strategies in the treatment of hypertensive HFpEF.

Assessment of drug-induced proarrhythmia: The importance of study design in the rabbit left ventricular wedge model

In the present study, we investigated an impact of the stimulation rate on the detection of the proarrhythmic potential of 10 reference compounds with effects on different cardiac ion channels in the isolated arterially-perfused rabbit left ventricular wedge preparation. The compounds were tested in the wedge model using two distinct protocols; including baseline stimulation at 1-Hz followed by a brief period at 0.5-Hz, either without an additional brief period of 2-Hz stimulation (i.e. Protocol 1) or with 2-Hz stimulation (i.e. Protocol 2). As expected, QT-prolonging drugs (ibutilide and quinidine) prolonged the QT interval, similarly increased the Torsades de Pointes (TdP) score, and elicited early afterdepolarizations (EADs) in both protocols. HMR1556 and JNJ-303 (IKs blockers) also prolonged the QT interval up to 1μM similarly in both protocols. Nifedipine (Ca2+ antagonist) shortened the QT interval, and reduced force of contraction similarly in both protocols. However, Na+ channel blockers (Ia, Ib, Ic) widened the QRS duration more in Protocol 2 than in Protocol 1. Furthermore, it was only possible to detect non-TdP-like ventricular tachycardia/fibrillation (VT/VF) induced by Na+ blockers and by QT-shortening drugs (levcromakalim and mallotoxin) using the 2-Hz stimulation (Protocol 2).Our data suggest that the inclusion of a brief period of fast stimulation at 2Hz is critical for detecting drug-induced slowing of conduction (QRS widening), QT shortening and associated (non-TdP-like) VT/VF, which are distinct from the QT prolongation/TdP proarrhythmia in isolated, arterially-perfused rabbit left ventricular wedges.