Objectives: Ventricular tachycardias (VT) represent a frequent and potentially lethal complication in myocardial infarction. To improve electrophysiological properties of the myocardial scar, Connexin 43 (Cx43) overexpressing cardiac fibroblasts (cFB) were transplanted in a chronic murine infarction model, and short as well as long-term effects on VT occurrence were investigated.

Objective: Re-entry ventricular tachycardias (VT) caused by varying conduction velocities of native and lesioned myocardium represent a frequent and potentially lethal complication in myocardial infarction. To modulate this conduction inhomogeneity lentivirus based transduction of resident cells within the lesion with the gap junction protein Connexin 43 (Cx43) was performed.

Purpose: Inflammatory reaction has been experimentally associated with cardiac adaptation to pressure overload leading to myocardial fibrosis and heart failure. We have recently demonstrated that endogenous cannabinoids and the cannabinoid receptor 2 (CB2) are activated and accompanied by persistent inflammation in myocardium of patients with aortic valve stenosis. Therefore, we investigated the role of the CB2 in a pressure overload mouse model.

Objectives: The role of endocannabinoid system has been associated with cardioprotection, inflammation and fibrosis. Experimental studies showed a role for inflammation and active remodelling in myocardial hypertrophy. Therefore, we investigated the association of endocannabinoid system with myocardial hypertrophy in patients with aortic stenosis.

Objective: In the present study we performed electrophysiological investigation (EPI) after transplantation of embryonic cardiomyocytes (eCM) into infarcted myocardium using coronary artery ligation.

Objective: We performed cellular cardiomyoplasty employing embryonic cardiomyocytes (eCM) in a murine lesion model. To assess the therapeutic efficacy of transplanted cells we performed in vivo contrast enhanced cardiac MRI to assess left ventricular (LV) function.

Objective: Using a transgenic mouse model we investigated if improved cardiac performance, as shown after transplantation of embryonic cardiomyocytes (eCM), could also be achieved by injection of proteins and cytokines derived from lysed eCM.

Aufbauend auf ein murines Kryoinfarktmodell mit reproduzierbarer Infarktgröße, verlässlicher Einschränkung der linksventrikulären Myokardfunktion und niedriger primärer Sterblichkeit konnte der Einfluss der Transplantation verschiedenster Progenitor- und Stammzellen auf linksventrikuläre Kontraktilität, elektrische Vulnerabilität und postoperatives Überleben getestet werden. In die myokardiale Läsion implantierte, embryonale Kardiomyozyten intergrieren in den Gewebsverband, differenzieren in einen adulten Phänotyp und verbessern die Myokardfunktion. Diese Connexin 43 exprimierenden, kontraktilen Zellen koppeln elektrisch an das Wirtsmyokard, verbessern die elektrische Leitfähigkeit und schützen vor Post-Infarkt-Arrhythmien.

Transmural cryolesions of a defined size were generated on the free left ventricular wall M mice. Using this approach, reproducible myocardial infarctions with a predictable decrease in myocardial function were generated. The potency of cellular cardiomyoplasty, employing different stem and progenitor cells, to improve contractility and impair electrical vulnerability was investigated. In-tramyocardially injected fetal cardiomyocytes engrafted, showed further differentiation, increased left ventricular function and improved mid-term survival of the animals. Connexin 43 expressing cells coupled electrically to the host myocardium and reduced inducibility of ventricular arrhythmias.

Introduction Local ischemia in the heart during myocardial infarction will result in massive cell death of rhythmically contracting cardiomyocytes. Unfortunately, regeneration of cardiomyocytes is rare and during left ventricular (LV) remodeling affected tissue is replaced by non-contractile fibrotic tissue. Stem cell-based therapies can either provide the heart with new functional cardiomyocytes or exert paracrine effects, thereby positively affecting LV remodeling [1]. In this study, the global effects of skeletal myoblast (SM) and mesenchymal stem cell (MSC) transplantation on infarcted mouse hearts were determined noninvasively with in vivo contrast enhanced cardiac MRI. Both cell types were isolated from Swiss mice to enable a direct comparison. Methods Myocardial infarction was induced in male Swiss mice by either cryoinjury or permanent occlusion (ligation) of the left coronary artery, immediately followed by injection of PBS (sham) or 2·10 GFP-positive SM or MSC in the centre of the infarction [2]. Cells were isolated from 17.5d embryos and adult mice respectively. Non-operated Swiss mice served as controls. Each group consisted of 1-4 mice. After 14 days, longand short-axis ECG and respiratory triggered CINE FLASH images (TE/TR/α/NEX/FOV/matrix = 1.8ms/7ms/15/6/3x3cm/ 192x192) were acquired at 9.4T to determine LV global functional parameters. Infarct size was assessed on T1w short-axis multislice FLASH images (TR/α/slice thickness = 63ms/60/1mm) acquired before and up to 30min after the injection of 0.3mmol Gd-DTPA/kg. Data analysis was performed with CAAS-MRV FARM software (Pie Medical Imaging). Results Two weeks after the induction of myocardial infarction, infarct size was reduced by transplantation of either SM and MSC in both cryoinjured and permanently occluded hearts (figures 1&2). Ejection fractions (EF), end-diastolic and -systolic volumes (EDV and ESV, respectively) were improved in all treatment groups, except for mice with cryoinjury transplanted with SM. However, all functional parameters were still impaired compared to control mice. End-diastolic mass was decreased by ~17% in mice with permanent occlusion transplanted with SM or MSC, whereas only a minor decrease was found in mice with cryoinjury (not shown). Therapy was most effective in mice with permanent occlusion, where relative infarct size was decreased by 13.8% and 34.5% after transplantation of SM and MSC respectively. This was accompanied by an increase in EF of 24.8% and 63.6%, achieved by a reduction in EDV and ESV of 30-40%.

Several recent studies have suggested that bone marrow (BM) cells can contribute to non-hematopoietic cell lineages through cell fusion rather than transdiffentiation. As this phenomenon has been observed in multiple organs, including the brain and heart, without prior infliction of organ-specific insults, it has been proposed that BM cells might contribute to replacement of non-hematopoietic cell lineages during steady state, and that BM transplantation might be developed as a therapeutic modality in diseases of these organs. However, as all observations of BM-derived cell fusion in vivo have been made in lethally irradiated mice reconstituted with genetically marked BM cells, we addressed to what degree cell fusion occurs normally and/or in response to whole body irradiation. To be able to distinguish between these possibilities we used c-kit deficient (w 41 /w 41 ) mice, which unlike wild type mice do not require irradiation-induced myeloablation to facilitate reconstitution of transplanted BM cells. Noteworthy, no BM-derived cell fusion events were observed in the brain (purkinje neurons) or heart (cardiomyocytes) when unconditioned w 41 /w 41 mice were reconstituted with beta actin GFP transgenic BM cells. In striking contrast, following whole body irradiation (875 rad), BM-derived cell fusion was observed in recipient cardiomyocytes and purkinje neurons of all BM transplanted mice. Thus, spontaneous adult BM-derived cell fusion does not occur in steady state but is potently facilitated by irradiation-induced injuries to the organs in which cell fusion occurs.