Human Mesenchymal Stromal Cells Improve Cardiac Perfusion in an Ovine Immunocompetent Animal Model.

BACKGROUND: Mesenchymal stromal cells (MSCs) hold considerable promise in the treatment of ischemic heart disease. Most preclinical studies of MSCs for acute myocardial infarction (AMI) have been performed either in syngeneic animal models or with human cells in xenogeneic immunodeficient animals. A preferable pre-clinical model, however, would involve human MSCs in an immunocompetent animal. METHODS: AMI was generated in adult sheep by inducing ischemia reperfusion of the second diagonal branch. Sheep (n = 10) were randomized to receive an intravenous injection of human MSCs (1 × 10(6) cells/kg) or phosphate buffered saline. Cardiac function and remodeling were evaluated with echocardiography. Perfusion scintigraphy was used to identify sustained myocardial ischemia. Interaction between human MSCs and ovine lymphocytes was assessed by a mixed lymphocyte response (MLR). RESULTS: Sheep receiving human MSCs showed significant improvement in myocardial perfusion at 1 month compared with baseline measurements. There was no change in ventricular dimensions in either group after 1 month of AMI. No adverse events or symptoms were observed in the sheep receiving human MSCs. The MLR was negative. CONCLUSION: The immunocompetent ovine AMI model demonstrates the clinical safety and efficacy of human MSCs. The human cells do not appear to be immunogenic, further suggesting that immunocompetent sheep may serve as a suitable pre-clinical large animal model for testing human MSCs.

Ischemia-induced model of diastolic dysfunction in sheep.

BACKGROUND: Ischemic heart failure with normal ejection fraction (HFNEF) is an increasingly recognized entity that carries similar morbidity and mortality than low ejection fraction heart failure. Animal models of diastolic dysfunction mimicking this condition are lacking and are essential for the development of therapeutic strategies. METHODS AND RESULTS: Eight Corriedale sheep, 18 ± 5 months old, were included in the study. Basal echocardiography and myocardial perfusion evaluation (SPECT) was performed. Acute myocardial infarction (AMI) was made by occlusion (90 min) and reperfusion of the second diagonal branch of the anterior descending coronary artery. Two months after AMI, echocardiography and SPECT evaluation were performed prior to sacrifice. Basal and 2 months echocardiography showed similar fractional shortening and ventricular dimensions in each animal except for an increase in left atrial diameter. No mitral regurgitation was evidenced. SPECT imaging and pathology confirmed infarction in the apical, apico-anterior, and apico-septal segments. CONCLUSION: A novel model of ischemia-induced diastolic dysfunction with preserved ventricular thickness and ejection fraction is described. This model opens the possibility of testing therapeutic options for patients with this condition.