Comparison of the Effects of Adenosine, Inosine, and Their Combination as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction

Adenosine and inosine are both key intracellular energy substrates for nucleotide synthesis by salvage pathways, especially during ischemic stress conditions. Additionally they both possess cell protective and cell repair properties. The objective of this study is to detect potential advantages of the combination of adenosine and inosine versus each drug alone, in terms of ventricular function, infarct size reduction and angiogenesis. Myocardial ischemia was created in rodents and treated with adenosine, inosine or their combination. Results of experiments showed that the combination of both drugs significantly reduced infarct size and improved myocardial angiogenesis and ventricular function. The two compounds, while chemically similar, use different intracellular pathways, allowing for complementary biological activities without overlapping. The drug combination at specific 1 : 5 adenosine : inosine dose ratio demonstrated positive cardiologic effects, deserving further evaluation as an adjunct to reperfusion techniques during and after acute coronary syndrome. The association of adenosine and inosine may contribute to reduce myocardial infarction morbidity and mortality rates

Cell based approaches for myocardial regeneration and artificial myocardium

Ischemic myocardial disease, the main cause of heart failure, is a major public health and economic problem. Given the aging population, heart failure is becoming an increasing clinical issue and a substantial financial burden. Thus, research in heart failure is of relevant interest and importance, involving specialties such as cellular and molecular biology, tissue engineering, genetics, biophysics and electrophysiology. Stem cell-based regenerative therapy is undergoing experimental and clinical trials in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction or in patients presenting non-ischemic dilated cardiomyopathies. This biological approach is particularly attractive due to the potential for myocardial regeneration with a variety of myogenic and angiogenic cell types. The development of a bio-artificial myocardium using biological or synthetic matrix is a new challenge. © 2007 Bentham Science Publishers Ltd

Association of electrostimulation with cell transplantation in ischemic heart disease

BackgroundUntil now, cell therapy has constituted a passive therapeutic approach; the only effects seem to be related to the reduction of the myocardial fibrosis and the limitation of the adverse ventricular remodeling. Cardiac resynchronization therapy is indicated in patients with heart failure to correct conduction disorders associated with chronic systolic and diastolic dysfunction. The association of electrostimulation with cellular cardiomyoplasty could be a way to transform passive cell therapy into “dynamic cellular support.” Electrostimulation of ventricles following skeletal myoblast implantation should induce the contraction of the transplanted cells and a higher expression of slow myosin, which is better adapted for chronic ventricular assistance. The purpose of this study is to evaluate myogenic cell transplantation in an ischemic heart model associated with cardiac resynchronization therapy.MethodsTwenty two sheep were included. All animals underwent myocardial infarction by ligation of 2 coronary artery branches (distal left anterior descending artery and D2). After 4 weeks, autologous cultured myoblasts were injected in the infarcted areas with or without pacemaker implantation. Atrial synchronized biventricular pacing was performed using epicardial electrodes. Echocardiography was performed at 4 weeks (baseline) and 12 weeks after infarction.ResultsEchocardiography showed a significant improvement in ejection fraction and limitation of left ventricular dilatation in cell therapy with cardiac resynchronization therapy as compared with the other groups. Viable cells were identified in the infarcted areas. Differentiation of myoblasts into myotubes and enhanced expression of slow myosin heavy chain was observed in the electrostimulated group. Transplantation of cells with cardiac resynchronization therapy caused an increase in diastolic wall thickening in the infarcted zone relative to cells-only group and cardiac resynchronization therapy–only group.ConclusionsBiventricular pacing seems to induce synchronous contraction of transplanted myoblasts and the host myocardium, thus improving ventricular function. Electrostimulation was related with enhanced expression of slow myosin and the organization of myoblasts in myotubes, which are better adapted at performing cardiac work. Patients with heart failure presenting myocardial infarct scars and indication for cardiac resynchronization therapy might benefit from simultaneous cardiac pacing and cell therapy

Increased entropy production in diaphragm muscle of PPAR alpha knockout mice: PPAR alpha knockout mouse diaphragm and entropy production

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Association between a cell-seeded collagen matrix and cellular Cardiomyoplasty for myocardial support and regeneration

The objective of cellular cardiomyoplasty is to regenerate the myocardium using implantation of living cells. Because the extracellular myocardial matrix is deeply altered in ischemic cardiomyopathies, it could be important to create a procedure aiming at regenerating both myocardial cells and the extracellular matrix. We evaluated the potential of a collagen matrix seeded with cells and grafted onto infarcted ventricles. A myocardial infarction was created in 45 mice using coronary artery ligation. Animals were randomly assigned to 4 local myocardial treatment groups. Group I underwent sham treatment (injection of cell culture medium). Group II underwent injection of human umbilical cord blood mononuclear cells (HUCBCs). Group III underwent injection of HUCBCs and fixation onto the epicardium of a collagen matrix seeded with HUCBCs. Group IV underwent fixation of collagen matrix (without cells) onto the infarct. Echocardiography was performed on postoperative days 7 and 45, followed by histological studies. Echocardiography showed that the association between the cell-loaded matrix and the intrainfarct cell implants was the most efficient approach to limiting postischemic ventricular dilation and remodeling. Ejection fraction improved in both cell-treated groups. The collagen matrix alone did not improve left ventricular (LV) function and remodeling. Histology in Group III showed fragments of the collagen matrix thickening and protecting the infarct scars. Segments of the matrix were consistently aligned along the LV wall, and cells were assembled within the collagen fibers in large populations. Intramyocardial injection of HUCBCs preserves LV function following infarction. The use of a cell-seeded matrix combined with cell injections prevents ventricular wall thinning and limits postischemic remodeling. This tissue engineering approach seems to improve the efficiency of cellular cardiomyoplasty and could emerge as a new therapeutic tool for the prevention of adverse remodeling and progressive heart failure

Autologous Myoblast Transplantation for Chronic Ischemic Mitral Regurgitation

International audienceObjectives: This study was designed to assess whether post-myocardial infarction (MI) in-scar transplantation of skeletal myoblasts (SM) could reduce chronic ischemic mitral regurgitation (MR) by decreasing left ventricular (LV) remodeling.Background: Extensive work has confirmed the relationship between ischemic MR and post-myocardial infarction (MI) remodeling of the LV.Methods: An infero-posterior MI was created in 13 sheep, thereby resulting in increasing MR. Two months post-MI, the animals were randomized and in-scar injected with expanded autologous SM (n = 6, mean: 251 x 10(6) cells) or culture medium only (n = 7). Three-dimensional echocardiography was performed at baseline, before transplantation, and for two months thereafter (sacrifice), with measurements of LV end-diastolic and end-systolic volumes (ESV), ejection fraction (EF), MR stroke volume, and leaflet tethering distance; wall motion score index (WMSi) was assessed by two-dimensional echo.Results: Measurements were similar between groups at baseline and before transplantation. At sacrifice, transplantation was found to have reduced MR progression (regurgitant volume change: -1.83 +/- 0.32 ml vs. 5.9 +/- 0.7 ml in control group, p < 0.0001) and tethering distance (-0.41 +/- 0.09 cm vs. 0.44 +/- 0.12 cm in control group, p < 0.001), with significant improvement of EF (2.01 +/- 0.94% vs. -4.86 +/- 2.23%, p = 0.02), WMSi (-0.25 +/- 0.11 vs. 0.13 +/- 0.03 in controls, p < 0.01) and a trend to a lesser increase in ESV (23.3 +/- 3.5 ml vs. 35.4 +/- 4.2 ml in control group, p = 0.055).Conclusions: Autologous skeletal myoblast transplantation attenuates mild-to-moderate chronic ischemic MR, which otherwise is progressive, by decreasing tethering distance and improving EF and wall motion score, thereby enhancing valve coaptation. These data shed additional light on the mechanism by which skeletal myoblast transplantation may be cardioprotective