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The aim of this study was to assess the safety and efficacy of a new subxiphoid hybrid epicardial-endocardial atrial fibrillation (AF) ablation and left atrial appendage (LAA) ligation approach for the treatment of persistent AF.

This study sought to prospectively study the development and then regression of premature ventricular contraction (PVC)-induced cardiomyopathy, with the hypothesis that structural left ventricular (LV) changes that are of potential clinical significance may endure beyond the period of exposure to PVCs.

ObjectiveBileaflet mitral valve prolapse (MVP) with either focal or diffuse myocardial fibrosis has been linked to ventricular arrhythmia and/or sudden cardiac arrest. Left ventricular (LV) mechanical dispersion by speckle-tracking echocardiography (STE) is a measure of heterogeneity of ventricular contraction previously associated with myocardial fibrosis. The aim of this study is to determine whether mechanical dispersion can identify MVP at higher arrhythmic risk.MethodsWe identified 32 consecutive arrhythmic MVPs (A-MVP) with a history of complex ventricular ectopy on Holter/event monitor (n=23) or defibrillator placement (n=9) along with 27 MVPs without arrhythmic complications (NA-MVP) and 39 controls. STE was performed to calculate global longitudinal strain (GLS) as the average peak longitudinal strain from an 18-segment LV model and mechanical dispersion as the SD of the time to peak strain of each segment.ResultsMVPs had significantly higher mechanical dispersion compared with controls (52 vs 42 ms, p=0.005) despite similar LV ejection fraction (62% vs 63%, p=0.42) and GLS (−19.7 vs −21, p=0.045). A-MVP and NA-MVP had similar demographics, LV ejection fraction and GLS (all p>0.05). A-MVP had more bileaflet prolapse (69% vs 44%, p=0.031) with a similar degree of mitral regurgitation (mostly trace or mild in both groups) (p>0.05). A-MVP exhibited greater mechanical dispersion when compared with NA-MVP (59 vs 43 ms, p=0.0002). Mechanical dispersion was the only significant predictor of arrhythmic risk on multivariate analysis (OR 1.1, 95% CI 1.02 to 1.11, p=0.006).ConclusionsSTE-derived mechanical dispersion may help identify MVP patients at higher arrhythmic risk.

This study investigated the outcome of wide-area left atrial appendage isolation (WLAAI) and subsequent LAA ligation in patients with recurrent atrial arrhythmias after pulmonary vein isolation (PVI).

Lipid profile changes in heart muscle have been previously linked to cardiac ischemia and myocardial infarction, but the spatial distribution of lipids and metabolites in ischemic heart remains to be fully investigated. We performed desorption electrospray ionization mass spectrometry imaging of hearts from in vivomyocardial infarction mouse models. In these mice, myocardial ischemia was induced by blood supply restriction via a permanent ligation of left anterior descending coronary artery. We showed that applying the machine learning algorithm of gradient boosting tree ensemble to the ambient mass spectrometry imaging data allows us to distinguish segments of infarcted myocardium from normally perfused hearts on a pixel by pixel basis. The machine learning algorithm selected 62 molecular ion peaks important for classification of each 200 μm-diameter pixel of the cardiac tissue map as normally perfused or ischemic. This approach achieved very high average accuracy (97.4%), recall (95.8%), and precision (96.8%) at a spatial resolution of ∼200 μm. In addition, we determined the chemical identity of 27 species, mostly small metabolites and lipids, selected by the algorithm as the most significant for cardiac pathology classification. This molecular signature of myocardial infarction may provide new mechanistic insights into cardiac ischemia, assist with infarct size assessment, and point toward novel therapeutic interventions.

This study sought to assess long-term clinical outcomes in adults with nonvalvular atrial fibrillation (AF) who are ineligible for oral anticoagulation therapy and underwent left atrial appendage (LAA) ligation with the Lariat device.

There is a great need for delivery strategies capable of efficiently localizing drugs to the damaged myocardium that do not require direct intramyocardial injection of therapeutic molecules. In the work discussed here, we exploited the myocardium-specific upregulation of matrix metalloproteinases (MMPs) that occurs during myocardium remodeling by designing a micellar vehicle containing an MMP-targeting peptide (MMP-TP). The binding of MMP-TP to MMP was evaluated with purified MMP-2 protein and U-937 cells induced to overexpress MMP. Inhibition of MMP-2 activity was not observed in the presence of unmodified micelles but was pronounced at a 5 mol % MMP-TP ligand density. In a FACS analysis, MMP-TP micelles containing 5 mol % of the MMP-targeting peptide showed ∼10-fold higher binding to activated U937 cells than plain micelles and micelles containing a control peptide with two amino acid replacements. MMP-TP-micelles and plain micelles were injected intravenously into C57BL/6 mice 1, 3, and 7 days after the induction of a myocardial infarction (MI). Immunohistochemistry performed on heart tissue sections revealed that MMP-TP-micelles colocalize with both MMP and infiltrating macrophages. MMP-TP micelles showed significantly enhanced accumulation to the necrotic area of the heart after MI on days 3 and 7 when compared to plain micelles and negative control peptide micelles. This is coincident with the measured temporal profile of MMP gene expression in the heart after MI. These results suggest that MMP-TP micelles are candidates for the development of targeted regenerative heart therapeutics because of their ability to target the infarcted myocardium in a MMP dependent manner.

We have developed a robust rat model of myocardial infarction (MI). Here we describe the step-by-step protocol for creating an ischemia-reperfusion rat model of MI. We also describe how to deliver therapeutic injections of mesenchymal stem cells (MSCs) together with fibrin, to show an application of this model. In addition, to confirm the presence of fibrin and cells in the infarct, visualization of MSCs and fibrin by histological techniques are also described. The ischemia-reperfusion MI model can be modified and generalized for use with various injectable polymers, cell types, drugs, DNA and combinations thereof. The model can be created in 7 days or less, depending on the timing of therapeutic intervention.

We have developed a robust rat model of myocardial infarction (MI). Here we describe the step-by-step protocol for creating an ischemia-reperfusion rat model of MI. We also describe how to deliver therapeutic injections of mesenchymal stem cells (MSCs) together with fibrin, to show an application of this model. In addition, to confirm the presence of fibrin and cells in the infarct, visualization of MSCs and fibrin by histological techniques are also described. The ischemia-reperfusion MI model can be modified and generalized for use with various injectable polymers, cell types, drugs, DNA and combinations thereof. The model can be created in 7 days or less, depending on the timing of therapeutic intervention.

Abstract: In this paper we consider the balancedness of dominating set games, introduced by Velzen 2003. We establish a new kind of 0-1 program formulation to model the domination problem on graphs, and give a strong connection between LP relaxation of this 0-1 program and the cost allocation problem concerning the core of a dominating set game. Duality theory on Lagrange dual is the main technique in our proof. In particular, we use this insight to give the equivalence of the balancedness for two different dominating set games.

Current efforts in cardiac tissue engineering center around the use of scaffolds that deliver cells to the epicardial surface. In this study, we examined the effects of fibrin glue as an injectable scaffold and wall support in ischemic myocardium. The left coronary artery of rats was occluded for 17 min, followed by reperfusion. Echocardiography was performed 8 days after infarction. One to 2 days later, either 0.5% bovine serum albumin (BSA) in phosphate-buffered saline, fibrin glue alone, skeletal myoblasts alone, or skeletal myoblasts in fibrin glue were injected into the ischemic left ventricle. Echocardiography was again performed 5 weeks after injection. The animals were then sacrificed and the hearts were fresh frozen and sectioned for histology and immunohistochemistry. Both the fractional shortening (FS) and infarct wall thickness of the BSA group decreased significantly after 5 weeks (p = 0.0005 and 0.02, respectively). In contrast, both measurements for the fibrin glue group, cells group, and cells in fibrin glue group did not change significantly (FS: p = 0.18, 0.89, and 0.19, respectively; wall thickness: p = 0.40, 0.44, 0.43, respectively). Fibrin glue is capable of preserving infarct wall thickness and cardiac function after a myocardial infarction in rats and may be useful as a biomaterial scaffold for myocardial cell transplantation.

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Many individual echocardiographic variables have been associated with heart failure (HF) in patients with stable coronary artery disease (CAD), but their combined utility for prediction has not been well studied.

Ischemic heart disease represents the leading cause of death worldwide. Heart failure following myocardial infarction (MI) is associated with severe fibrosis formation and cardiac remodeling. Recently, injectable hydrogels have emerged as a promising approach to repair the infarcted heart and improve heart function through minimally invasive administration. Here, a novel injectable human amniotic membrane (hAM) matrix is developed to enhance cardiac regeneration following MI. Human amniotic membrane is isolated from human placenta and engineered to be a thermoresponsive, injectable gel around body temperature. Ultrasound‐guided injection of hAM matrix into rat MI hearts significantly improves cardiac contractility, as measured by ejection fraction (EF), and decrease fibrosis. The results of this study demonstrate the feasibility of engineering as an injectable hAM matrix and its efficacy in attenuating degenerative changes in cardiac function following MI, which may have broad applications in tissue regeneration. Injectable hydrogels have emerged as a promising and attractive therapeutic strategy to halt progressive cardiac dysfunction following myocardial infarction (MI), through minimally invasive and localized administration. This study demonstrates that human placental tissue can be decellularized and engineered as the injectable thermoresponsive bioactive gel to significantly promote cardiac regeneration in a rat MI model.

Direct injection of marrow cells into injured myocardium improves cardiac function, however, repair may be limited by the number of stem cells that home and persist in the injured myocardium. Using nude rats that received a 17 min transient ligation of their left anterior descending artery, we tested whether anti-CD3 activated human T cells (ATC), G-CSF primed peripheral blood mononuclear cells (G-PBMC), or G-CSF primed purified CD34+ cells would target MI-specific injury antigens ICAM-1 or rat myosin light chain (MLC) when injected intra-jugularly 48 hrs after myocardial injury. ATC, G-PBMC, or CD34+ cells were armed (50 ng/106 cells) with anti-CD3 x anti-rat ICAM-1 or anti-CD45 x anti-MLC. Nude rats were euthanized at 24 hours or 5 weeks after treatment and hearts were frozen, sectioned, fixed, and stained accordingly. In a pilot experiment, ATC armed with OKT3 x anti-ICAM were detected at the MI sites by Cy3 staining but not in the adjacent normal myocardium 24 hrs after infusion; rats given unarmed ATC or ATC armed with anti-CD3 x anti-CD20 (irrelevant BiAb) did not stain. High numbers of cells in the MIs in rats given anti-human CD45 x anti-rat MLC-armed G-PBMC stained positive by tyramide-amplified IHC for the mouse IgG or human CD45 cells. Human cells stained for HLA-DR (>5000 cells/injured HPF) in MIs of rats treated with BiAb-armed cells compared to unarmed-treated rats (<500/injured HPF) by 24 hrs post-infusion. By 5 weeks, the persistent human marker was HLA-Class I in the MIs whereas only a few HLA-Class II cells remained; the number of Class I cells in the MIs of rats treated with BiAb-armed cells (45.3±4.9 Class I+ cells/HPF) was significantly greater compared to MIs of rats treated with unarmed cells (25.9±1.7 Class I+ cells/HPF). In order to determine whether Isolex column-purified CD34+ cells (99% CD34, 70% CD33, and negative for CD-4,-7,-10,-16,-19,-20, and -23) obtained from G-PBMC would lead to cells expressing Class I and troponin, actin, or VE-cadherin, the hearts from rats that received CD34+ cells alone (3 rats) or CD34+ cells armed with anti-CD45 x anti-MLC (6 rats) were harvested 5 weeks after the infusion, fresh frozen, and double stained for each antigen-pair. These double stains as well as confocal images on the same slides show evidence for myocytes staining for human Class I and the respective cardiac antigens. After 5 weeks, ECHOS showed that the fractional shortening of the armed group was significantly improved compared to the unarmed group (0.33 ± 0.06 vs 0.19 ± 0.03; P = 0.02). Additionally, average LV size of the armed group was significantly less dilated compared to the unarmed group (0.47 ± 0.12 vs 0.67 ± 0.04; p = 0.04). Our studies show that arming CD34+ cells with BiAbs can target SC to MIs. The targeted SC express surface markers for human Class I and the muscle proteins troponin, actin, and cadherin; ECHO data suggest improved cardiac function. Studies are underway to maximize BiAb-armed CD34+ cell delivery to provide optimal recovery of cardiac function and to further characterize the cells that develop from the CD34+ cells.

Direct injection of marrow cells into injured myocardium improves cardiac function, however, repair may be limited by the number of stem cells that home and persist in the injured myocardium. Using nude rats that received a 17 min transient ligation of their left anterior descending artery, we tested whether anti-CD3 activated human T cells (ATC), G-CSF primed peripheral blood mononuclear cells (G-PBMC), or G-CSF primed purified CD34+ cells would target MI-specific injury antigens ICAM-1 or rat myosin light chain (MLC) when injected intra-jugularly 48 hrs after myocardial injury. ATC, G-PBMC, or CD34+ cells were armed (50 ng/106cells) with anti-CD3 x anti-rat ICAM-1 or anti-CD45 x anti-MLC. Nude rats were euthanized at 24 hours or 5 weeks after treatment and hearts were frozen, sectioned, fixed, and stained accordingly. In a pilot experiment, ATC armed with OKT3 x anti-ICAM were detected at the MI sites by Cy3 staining but not in the adjacent normal myocardium 24 hrs after infusion; rats given unarmed ATC or ATC armed with anti-CD3 x anti-CD20 (irrelevant BiAb) did not stain. High numbers of cells in the MIs in rats given anti-human CD45 x anti-rat MLC-armed G-PBMC stained positive by tyramide-amplified IHC for the mouse IgG or human CD45 cells. Human cells stained for HLA-DR (>5000 cells/injured HPF) in MIs of rats treated with BiAb-armed cells compared to unarmed-treated rats (<500/injured HPF) by 24 hrs post-infusion. By 5 weeks, the persistent human marker was HLA-Class I in the MIs whereas only a few HLA-Class II cells remained; the number of Class I cells in the MIs of rats treated with BiAb-armed cells (45.3±4.9 Class I+ cells/HPF) was significantly greater compared to MIs of rats treated with unarmed cells (25.9±1.7 Class I+ cells/HPF). In order to determine whether Isolex column-purified CD34+ cells (99% CD34, 70% CD33, and negative for CD-4,-7,-10,-16,-19,-20, and -23) obtained from G-PBMC would lead to cells expressing Class I and troponin, actin, or VE-cadherin, the hearts from rats that received CD34+ cells alone (3 rats) or CD34+ cells armed with anti-CD45 x anti-MLC (6 rats) were harvested 5 weeks after the infusion, fresh frozen, and double stained for each antigen-pair. These double stains as well as confocal images on the same slides show evidence for myocytes staining for human Class I and the respective cardiac antigens. After 5 weeks, ECHOS showed that the fractional shortening of the armed group was significantly improved compared to the unarmed group (0.33 ± 0.06 vs 0.19 ± 0.03; P= 0.02). Additionally, average LV size of the armed group was significantly less dilated compared to the unarmed group (0.47 ± 0.12 vs 0.67 ± 0.04; p = 0.04). Our studies show that arming CD34+ cells with BiAbs can target SC to MIs. The targeted SC express surface markers for human Class I and the muscle proteins troponin, actin, and cadherin; ECHO data suggest improved cardiac function. Studies are underway to maximize BiAb-armed CD34+ cell delivery to provide optimal recovery of cardiac function and to further characterize the cells that develop from the CD34+ cells.