Background-The present study examined whether transplantation of adherent bone marrow-derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion. Methods and Results-Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55Ϯ5.6% to 30Ϯ5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP ( 31 P magnetic resonance spectroscopy; 1.06Ϯ0.30 in infarcted hearts [nϭ9] versus 1.90Ϯ0.15 in normal hearts [nϭ8; PϽ0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34Ϯ0.29; nϭ7; PϽ0.05). The BZ protein expression of creatine kinase-mt and creatine kinase-m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7Ϯ9.8%, PϽ0.01), whereas the left ventricular ejection fraction improved to 42.0Ϯ6.5% (PϽ0.05 versus myocardial infarction). Only 0.35Ϯ0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, nϭ6; no cyclosporine A, nϭ7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and Ϸ2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (PϽ0.05). Conclusions-Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.

Current therapies for heart failure due to transmural left ventricular (LV) infarction are limited. We have developed a novel patch method for delivering autologous bone marrow stem cells to sites of myocardial infarction for the purpose of improving LV function and preventing LV aneurysm formation. The patch consisted of a fibrin matrix seeded with autologous porcine mesenchymal stem cells labeled with lacZ. We applied this patch to a swine model of postinfarction LV remodeling. Myocardial infarction was produced by using a 60-min occlusion of the left anterior descending coronary artery distal to the first diagonal branch followed by reperfusion. Results were compared between eight pigs with stem cell patch transplantation, six pigs with the patch but no stem cells (P), and six pigs with left anterior descending coronary artery ligation alone (L). Magnetic resonance imaging data collected 19 +/- 1 days after the myocardial infarction indicated a significant increase of LV systolic wall thickening fraction in the infarct zone of transplanted hearts compared with P or L hearts. Blue X-gal staining was observed in the infarcted area of transplanted hearts. PCR amplification of specimens from the X-gal-positive area revealed the Ad5 RSV-lacZ vector fragment DNA sequence. Light microscopy demonstrated that transplanted cells had differentiated into cells with myocyte-like characteristics and a robust increase of neovascularization as evidenced by von Willebrand factor-positive angioblasts and capillaries in transplanted hearts. Thus this patch-based autologous stem cell procedure may serve as a therapeutic modality for myocardial repair.

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Regions of myocardial infarct (MI) are surrounded by a border zone (BZ) of normally perfused but dysfunctional myocardium. Although systolic dysfunction has been attributed to elevated wall stress in this region, there is evidence that intrinsic abnormalities of contractile performance exist in BZ myocardium. This study examined whether decreases of high-energy phosphates (HEP) and mitochondrial F 1F0-ATPase (mtATPase) subunits typical of failing myocardium exist in BZ myocardium of compensated postinfarct remodeled hearts. Eight pigs were studied 6 wk after MI was produced by ligation of the left anterior descending coronary artery (LAD) distal to the second diagonal. Animals developed compensated LV remodeling with a decrease of ejection fraction from 54.6 Ϯ 5.4% to 31 Ϯ 2.1% (MRI) 5 wk after LAD occlusion. The remote zone (RZ) myocardium demonstrated modest decreases of ATP and mtATPase components. In contrast, BZ myocardium demonstrated profound abnormalities with ATP levels decreased to 42% of normal, and phosphocreatine-to-ATP ratio ( 31 Pmagnetic resonance spectroscopy) decreased from 2.06 Ϯ 0.19 in normal hearts to 1.07 Ϯ 0.10, with decreases in ␣-, ␤-, OSCP, and IF 1 subunits of mtATPase, especially in the subendocardium. The reduction of myocardial creatine kinase isoform protein expression was also more severe in the BZ relative to the RZ myocardium. These abnormalities were independent of a change in mitochondrial content because the mitochondrial citrate synthase protein level was not different between the BZ and RZ. This regional heterogeneity of ATP content and expression of key enzymes in ATP production suggests that energetic insufficiency in the peri-infarct region may contribute to the transition from compensated LV remodeling to congestive heart failure. heart failure; metabolism; adenosine 5Ј-triphosphate; hypertrophy; border zone AFTER MYOCARDIAL INFARCTION, a period of compensated left ventricular (LV) remodeling with hemodynamic stability may be followed by the development of congestive heart failure (CHF). The mechanisms that contribute to the transition from compensated remodeling to CHF remain unclear but may be related to progressive contractile dysfunction of the region of viable myocardium that surrounds the infarct (border zone) (13). Tethering to the infarct causes an increase in the radius of curvature of the surrounding viable myocardium, thereby increasing wall stress, and likely energy demands, in this border zone (2,9,35). Using a porcine model of postinfarction LV remodeling, we previously observed modest reductions of ATP and the phosphocreatine (PCr)-to-ATP ratio in the remote noninfarcted myocardium of animals with compensated remodeling but marked abnormalities in animals that developed overt CHF (41). The levels of mitochondrial F 1 F 0 -ATP synthase (mtATPase; the final reaction in the pathway that links carbon substrate utilization to oxidative ATP synthesis) in myocardium remote from the infarct were also decreased in animals that developed overt CHF but not in animal...

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BackgroundAutonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). We hypothesized that chronic vagus nerve stimulation (VNS) could prevent left ventricular (LV) remodeling and dysfunction in a canine HF model induced by chronic mitral regurgitation (MR).Methods and resultsAfter the MR inducing procedure, 12 survived canines were randomly divided into the control (n = 6) and the VNS (n = 6) groups. At month 2, a VNS stimulator system was implanted in all canines. From month 3 to month 6, VNS therapy was applied in the VNS group but not in the control group. At month 6, compared with the control group, the canines in VNS group had significantly higher cardiac output (2.3 ± 0.3 versus 2.9 ± 0.4 L/min, P < 0.05, LV forward stroke volume (20.1 ± 3.7 versus 24.8 ± 3.9 ml, P < 0.05), and end-systolic stiffness constant (2.2 ± 0.3 versus 2.7 ± 0.3, P < 0.05). NT-proBNP and C-reactive protein were decreased significantly in the VNS group. However, no statistical difference was found in LV ejection fraction, LV end-diastolic dimension, LV end-diastolic volume, myocyte cross-sectional area, or collagen volume fraction between two groups.ConclusionsChronic VNS therapy may ameliorate MR-induced LV contractile dysfunction and improve the expression of biomarkers, but has less effect in improving LV chamber remodeling.