Numerous studies have shown a beneficial effect of cardiosphere-derived cell (CDC) therapy on regeneration of injured myocardium. Paracrine signaling by CDC secreted exosomes may contribute to improved cardiac function. However, it has not yet been demonstrated by a genetic approach that exosome release contributes to the therapeutic effect of transplanted CDCs. By employing a lentiviral knockdown (KD) strategy against neutral spingomyelinase 2 (nSMase2), a crucial gene in exosome secretion, we have defined the role of physiologically secreted human CDC-derived exosomes on cardiac fibroblast, endothelial cell and primary cardiomyocyte proliferation, cell death, migration and angiogenesis using a series of in vitro coculture assays. We found that secretion of hCDC-derived exosomes was effectively inhibited by nSMase2 lentiviral KD and shRNAi expression was stable and constitutive. hCDC exosome release contributed to the angiogenic and pro-migratory effects of hCDCs on HUVECs, decreased proliferation of fibroblasts, and decreased apoptosis of cardiomyocytes. These in vitro reactions support a role for exosome secretion as a paracrine mechanism of stem cell-mediated cardiac repair in vivo. Importantly, we have established a novel tool to test constitutive inhibition of exosome secretion in stem cell populations in animal models of cardiac disease.

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Renal insufficiency (RI) is a prognostic marker in patients with cardiovascular disease. In this study, the latest standard of glomerular filtration rate (GFR) calculation, that is the modification of diet in renal disease (MDRD) study equation, is used to measure the difference in the outcome of coronary artery bypass graft (CABG) surgery in various GFR groups. Between 2000 and 2005, 1,055 patients underwent CABG surgery and were categorized into 5 groups according to the National Kidney Foundation guidelines: stage 1 = normal renal function; stage 2 = mild RI; stage 3 = moderate RI; stage 4 = severe RI; stage 5 = end-stage renal failure (excluded). Precautions were taken in RI patients to avoid perioperative hypotension, fluid overload and limited cardioplegia; cardiopulmonary bypass time was kept at a minimum by performing an essential number of grafts only. Thirty-day mortality occurred in 5 of 1,052 patients (0.48%) with no statistical difference in stages 1–4. There was increase in bleed requiring reoperation and total complications from stages 1 to 4, but it was not statistically significant. Preoperative renal dysfunction in CABG surgery patients is an important predictor of outcome. Patients undergoing CABG surgery can have acceptable results without significant increase in complications and mortality provided that risk factors are minimized perioperatively.

Purpose Currently, only a small fraction of patients are able to receive reperfusion therapy for myocardial infarctions. We hypothesize that myometrial cell patch transplantation could be an alternative approach for the treatment of myocardial infarction. Design We performed a preliminary study to determine the feasibility of this novel therapeutic approach in a rabbit model. Procedures Six adult female New Zealand rabbits were used. Myocardial infarction was induced by left anterior descending artery ligation. A segment of uterus was removed via a laparotomy incision, and this uterine segment was transplanted as an autologous graft over the infarcted myocardium, which was then reinforced by greater omentum. Statistical methods and outcome measures Hemodynamic measurements and histological studies. Main findings: All uterine myometrial patches survived in the test animals. Fluoroscopic hemodynamic measurements were made for ejection fractions at 8 weeks after the application of the uterine patch. Histological study demonstrated well-healed myometrial-myocardium junctions with minimum scar tissue. Angiogenesis occurred in the transplanted myometrium. Connexin 43 expression was demonstrated in the transplanted patches. Conclusion Our noncontrolled preliminary rabbit experiments indicate that patches of uterine myometrium reinforced by greater omentum can be used as autologous transplant therapy for infracted myocardium. This is an innovative technique that could lead to future treatment for individuals who may suffer from an infarcted myocardium and may not be eligible for traditional reperfusion therapy.