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Background: Intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC), after acute myocardial infarction (AMI), has been shown to improve myocardial function. However, therapeutic efficacy is limited, possibly because cell retention rates are low, suggesting that optimization of cell retention might increase therapeutic efficacy. Since retention of injected BMMNC is observed only within infarcted, but not remote, myocardium, we hypothesized that adhesion molecules on activated endothelium following reperfusion are essential. Consequently, we investigated the role of vascular cell adhesion molecule 1 (VCAM-1) in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion., Methods and Results: VCAM-1 expression in the infarct and remote region was quantified at 1, 3, 7, 14, and 35 days, post-reperfusion (n≥6 swine per group). Since expression levels were significantly higher at 3 days (2.41±0.62%) than at 7 days (0.98±0.28%; p<0.05), we compared the degree of cell retention at those time points in a follow-up study, in which an average of 43·106 autologous BMMNCs were infused intracoronary at 3, or 7 days, post-reperfusion (n = 6 swine per group) and retention was histologically quantified one hour after intracoronary infusion of autologous BMMNCs. Although VCAM-1 expression correlated with retention of BMMNC within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3±1.3% vs. 3.1±1.4%, p = 0.72). This was not due to the composition of infused bone marrow cell fractions (analyzed with flow cytometry; n = 5 per group), as cell composition of the infused BMMNC fractions was similar., Conclusion: These findings suggest that VCAM-1 expression influences to a small degree, but is not the principal determinant of, BMMNC retention.

Background: Angiotensin-(1-7) improves cardiac function and remodeling after myocardial infarction (MI). This may involve recruitment of hematopoietic progenitor cells that support angiogenesis. However, angiotensin-(1-7) is rapidly metabolized in plasma and tissue. The authors investigated in mice the effect of a metabolically stable angiotensin-(1-7) analogue, cyclic angiotensin-(1-7), on progenitor cell recruitment and on the heart post MI, when given in the angiogenesis phase of remodeling., Methods and Results: Angiogenic progenitor cell recruitment was measured by using flow cytometry 24 and 72 hours after a daily bolus injection of cyclic angiotensin-(1-7) in healthy C57BL/6 mice. Further, mice underwent MI or sham surgery and subsequently received saline or 2 different doses of cyclic angiotensin-(1-7) for 3 or 9 weeks. Cyclic angiotensin-(1-7) increased circulating hematopoietic progenitor cells at 24 hours but not 72 hours. Post MI, cyclic angiotensin-(1-7) diminished cardiomyocyte hypertrophy and reduced myogenic tone, without altering cardiovascular function or cardiac histology at 9 weeks. Importantly, cyclic angiotensin-(1-7)-treated mice had reduced cardiac capillary density at 3 weeks after MI but not after 9 weeks. Finally, cyclic angiotensin-(1-7) decreased tube formation by cultured human umbilical vein endothelial cells., Conclusions: Our results suggest that cyclic angiotensin-(1-7), when given early after MI, recruits progenitor cells but does not lead to improved angiogenesis, most likely because it simultaneously exerts antiangiogenic effect in adult endothelial cells. Apparently, optimal treatment with cyclic angiotensin-(1-7) depends on the time point of onset of application after MI., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Cell therapy is a field of growing interest in the prevention of post acute myocardial infarction (AMI) heart failure. Stem cell retention upon local delivery to the heart, however, is still unsatisfactory. CellBeads were recently developed as a potential solution to this problem. CellBeads are 170-μm alginate microspheres that contain mesenchymal stem cells (MSCs) genetically modified to express glucagon-like peptide-1 (GLP-1) supplementary to inherent paracrine factors. GLP-1 is an incretin hormone that has both antiapoptotic and cardioprotective effects. Transplanting CellBeads in the post-AMI heart might induce cardiomyocyte salvage and ultimately abrogate adverse cardiac remodeling. We aimed to investigate the feasibility of intracoronary infusion of CellBeads in a large animal model of AMI. Four pigs were used in a pilot study to assess the maximal safe dose of CellBeads. In the remaining 21 animals, an AMI was induced by balloon occlusion of the left circumflex coronary artery for 90 min. During reperfusion, 60,000 CellBeads (n = 11), control beads (n = 4), or lactated Ringers' (n = 6) were infused. Animals were sacrificed after 2 or 7 days, and the hearts were excised for histological analyses. Intracoronary infusion did not permanently affect coronary flow in any of the groups. Histological analysis revealed CellBeads containing viable MSCs up to 7 days. Viability and activity of the MSCs was confirmed by qPCR analysis that showed expression of recombinant GLP-1 and human genes after 2 and 7 days. CellBeads reduced inflammatory infiltration by 29% (p = 0.001). In addition, they decreased the extent of apoptosis by 25% (p = 0.001) after 2 days. We show that intracoronary infusion of 5 million encapsulated MSCs is safe and feasible. Also, several parameters indicate that the cells have paracrine effects, suggesting a potential therapeutic benefit of this new approach.

Exercise training attenuates left ventricular (LV) dysfunction after myocardial infarction (MI). It could be speculated that these effects of exercise are mediated by increased endothelial NO synthase (eNOS) activity. In the present study we tested the hypothesis that eNOS plays a critical role in the exercise-induced amelioration of LV dysfunction after MI. MI or sham was induced in eNOS(-/-), eNOS(+/-) and eNOS(+/+) mice. After 8 weeks of voluntary wheel running (approximately 7 km/day in all groups) or sedentary housing, global cardiac function was determined in vivo and (immuno)histochemistry was performed to assess cardiomyocyte size, fibrosis, capillary density and apoptosis in remote myocardium. At baseline eNOS(-/-) mice had higher mean aortic pressure compared to eNOS(+/-) and eNOS(+/+) mice, but had normal global cardiac function. MI resulted in marked LV remodeling, including cardiomyocyte hypertrophy and a reduction in capillary density, increased fibrosis and apoptosis, as well as LV systolic and diastolic dysfunction to the same extent in all genotypes. In eNOS(+/+) MI mice exercise abolished fibrosis and apoptosis in the remote myocardium, attenuated LV systolic dysfunction and ameliorated pulmonary congestion. These beneficial effects were lost in eNOS(+/-) and eNOS(-/-) mice, while LV systolic dysfunction and pulmonary congestion in eNOS(+/-) mice were exacerbated by exercise. In conclusion, the beneficial effects of exercise after MI on LV remodeling and dysfunction depend critically on endogenous eNOS. The observation that the lack of one eNOS allele is sufficient to negate all beneficial effects of exercise, strongly suggests that exercise depends on full eNOS expression., ((c) 2010 Elsevier Ltd. All rights reserved.)