The Benefit of Enhanced Contractility in the Infarct Borderzone: A Virtual Experiment

Objectives: Contractile function in the normally perfused infarct borderzone (BZ) is depressed. However, the impact of reduced BZ contractility on left ventricular (LV) pump function is unknown. As a consequence, there have been no therapies specifically designed to improve BZ contractility. We tested the hypothesis that an improvement in borderzone contractility will improve LV pump function. Methods: From a previously reported study, magnetic resonance imaging (MRI) images with non-invasive tags were used to calculate 3D myocardial strain in five sheep 16 weeks after anteroapical myocardial infarction. Animal-specific finite element (FE) models were created using MRI data and LV pressure obtained at early diastolic filling. Analysis of borderzone function using those FE models has been previously reported. Chamber stiffness, pump function (Starling’s law) and stress in the fiber, cross fiber, and circumferential directions were calculated. Animal-specific FE models were performed for three cases: (a) impaired BZ contractility (INJURED); (b) BZ-contractility fully restored (100% BZ IMPROVEMENT); or (c) BZ-contractility partially restored (50% BZ IMPROVEMENT). Results: 100% BZ IMPROVEMENT and 50% BZ IMPROVEMENT both caused an upward shift in the Starling relationship, resulting in a large (36 and 26%) increase in stroke volume at LVPED = 20 mmHg (8.0 ml, p < 0.001). Moreover, there were a leftward shift in the end-systolic pressure volume relationship, resulting in a 7 and 5% increase in LVPES at 110 mmHg (7.7 ml, p < 0.005). It showed that even 50% BZ IMPROVEMENT was sufficient to drive much of the calculated increase in function. Conclusion: Improved borderzone contractility has a beneficial effect on LV pump function. Partial improvement of borderzone contractility was sufficient to drive much of the calculated increase in function. Therapies specifically designed to improve borderzone contractility should be developed

Relationship of Transmural Variations in Myofiber Contractility to Left Ventricular Ejection Fraction: Implications for Modeling Heart Failure Phenotype With Preserved Ejection Fraction

The pathophysiological mechanisms underlying preserved left ventricular (LV) ejection fraction (EF) in patients with heart failure and preserved ejection fraction (HFpEF) remain incompletely understood. We hypothesized that transmural variations in myofiber contractility with existence of subendocardial dysfunction and compensatory increased subepicardial contractility may underlie preservation of LVEF in patients with HFpEF. We quantified alterations in myocardial function in a mathematical model of the human LV that is based on the finite element method. The fiber-reinforced material formulation of the myocardium included passive and active properties. The passive material properties were determined such that the diastolic pressure-volume behavior of the LV was similar to that shown in published clinical studies of pressure-volume curves. To examine changes in active properties, we considered six scenarios: (1) normal properties throughout the LV wall; (2) decreased myocardial contractility in the subendocardium; (3) increased myocardial contractility in the subepicardium; (4) myocardial contractility decreased equally in all layers, (5) myocardial contractility decreased in the midmyocardium and subepicardium, (6) myocardial contractility decreased in the subepicardium. Our results indicate that decreased subendocardial contractility reduced LVEF from 53.2 to 40.5%. Increased contractility in the subepicardium recovered LVEF from 40.5 to 53.2%. Decreased contractility transmurally reduced LVEF and could not be recovered if subepicardial and midmyocardial contractility remained depressed. The computational results simulating the effects of transmural alterations in the ventricular tissue replicate the phenotypic patterns of LV dysfunction observed in clinical practice. In particular, data for LVEF, strain and displacement are consistent with previous clinical observations in patients with HFpEF, and substantiate the hypothesis that increased subepicardial contractility may compensate for subendocardial dysfunction and play a vital role in maintaining LVEF

Single-Cell Profiling of Epigenetic Modifiers Identifies PRDM14 as an Inducer of Cell Fate in the Mammalian Embryo

SummaryCell plasticity or potency is necessary for the formation of multiple cell types. The mechanisms underlying this plasticity are largely unknown. Preimplantation mouse embryos undergo drastic changes in cellular potency, starting with the totipotent zygote through to the formation of the pluripotent inner cell mass (ICM) and differentiated trophectoderm in the blastocyst. Here, we set out to identify and functionally characterize chromatin modifiers that define the transitions of potency and cell fate in the mouse embryo. Using a quantitative microfluidics approach in single cells, we show that developmental transitions are marked by distinctive combinatorial profiles of epigenetic modifiers. Pluripotent cells of the ICM are distinct from their differentiated trophectoderm counterparts. We show that PRDM14 is heterogeneously expressed in 4-cell-stage embryos. Forced expression of PRDM14 at the 2-cell stage leads to increased H3R26me2 and can induce a pluripotent ICM fate. Our results shed light on the epigenetic networks that govern cellular potency and identity in vivo.Video Abstrac

Relationship of Transmural Variations in Myofiber Contractility to Left Ventricular Ejection Fraction: Implications for Modeling Heart Failure Phenotype With Preserved Ejection Fraction

The pathophysiological mechanisms underlying preserved left ventricular (LV) ejection fraction (EF) in patients with heart failure and preserved ejection fraction (HFpEF) remain incompletely understood. We hypothesized that transmural variations in myofiber contractility with existence of subendocardial dysfunction and compensatory increased subepicardial contractility may underlie preservation of LVEF in patients with HFpEF. We quantified alterations in myocardial function in a mathematical model of the human LV that is based on the finite element method. The fiber-reinforced material formulation of the myocardium included passive and active properties. The passive material properties were determined such that the diastolic pressure-volume behavior of the LV was similar to that shown in published clinical studies of pressure-volume curves. To examine changes in active properties, we considered six scenarios: (1) normal properties throughout the LV wall; (2) decreased myocardial contractility in the subendocardium; (3) increased myocardial contractility in the subepicardium; (4) myocardial contractility decreased equally in all layers, (5) myocardial contractility decreased in the midmyocardium and subepicardium, (6) myocardial contractility decreased in the subepicardium. Our results indicate that decreased subendocardial contractility reduced LVEF from 53.2 to 40.5%. Increased contractility in the subepicardium recovered LVEF from 40.5 to 53.2%. Decreased contractility transmurally reduced LVEF and could not be recovered if subepicardial and midmyocardial contractility remained depressed. The computational results simulating the effects of transmural alterations in the ventricular tissue replicate the phenotypic patterns of LV dysfunction observed in clinical practice. In particular, data for LVEF, strain and displacement are consistent with previous clinical observations in patients with HFpEF, and substantiate the hypothesis that increased subepicardial contractility may compensate for subendocardial dysfunction and play a vital role in maintaining LVEF

Looking towards the future: patient-specific computational modeling to optimize outcomes for transcatheter mitral valve repair

Severe mitral valve regurgitation (MR) is a heart valve disease that progresses to end-stage congestive heart failure and death if left untreated. Surgical repair or replacement of the mitral valve (MV) remains the gold standard for treatment of severe MR, with repair techniques aiming to restore the native geometry of the MV. However, patients with extensive co-morbidities may be ineligible for surgical intervention. With the emergence of transcatheter MV repair (TMVR) treatment paradigms for MR will evolve. The longer-term outcomes of TMVR and its effectiveness compared to surgical repair remain unknown given the differing patient eligibility for either treatment at this time. Advances in computational modeling will elucidate answers to these questions, employing techniques such as finite element method and fluid structure interactions. Use of clinical imaging will permit patient-specific MV models to be created with high accuracy and replicate MV pathophysiology. It is anticipated that TMVR technology will gradually expand to treat lower-risk patient groups, thus pre-procedural computational modeling will play a crucial role guiding clinicians towards the optimal intervention. Additionally, concerted efforts to create MV models will establish atlases of pathologies and biomechanics profiles which could delineate which patient populations would best benefit from specific surgical vs. TMVR options. In this review, we describe recent literature on MV computational modeling, its relevance to MV repair techniques, and future directions for translational application of computational modeling for treatment of MR

Endoventricular patch plasty for dyskinetic anteroapical left ventricular aneurysm increases systolic circumferential shortening in sheep

ObjectiveEndoventricular patch plasty (Dor procedure) has gained favor as a surgical treatment for heart failure associated with large anteroapical myocardial infarction. We tested the hypotheses that the Dor procedure increases systolic circumferential shortening and longitudinal shortening in noninfarcted left ventricular regions in sheep.MethodsIn 6 male Dorsett sheep, the left anterior descending coronary artery and its second diagonal branch were ligated 40% of the distance from the apex to the base. Sixteen weeks after myocardial infarction, a Dor procedure was performed with a Dacron patch that was 50% of the infarct neck dimension. Two weeks before and 2 and 6 weeks after the Dor procedure, animals underwent magnetic resonance imaging with tissue tagging in multiple short-axis and long-axis slices. Fully three-dimensional strain analyses were performed. All 6 end-systolic strain components were compared in regions 1 cm, 2 cm, 3 cm, and 4 cm below the valves, as well as in the anterior, posterior, and lateral left ventricular walls and the interventricular septum.ResultsCircumferential shortening increased from before the Dor procedure to 6 weeks after repair in nearly every left ventricular region (13/16). The greatest regional change in circumferential shortening was found in the equatorial region or 2 cm below the base and in the posterior wall (from 9.0% to 18.4%; P < .0001). Longitudinal shortening increased 2 weeks after the Dor procedure but then returned near baseline by 6 weeks after the Dor procedure.ConclusionThe Dor procedure significantly increases systolic circumferential shortening in nearly all noninfarcted left ventricular regions in sheep