Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation

Preclinical and clinical studies have demonstrated that stem cell transplantation can improve the left ventricular (LV) contractile performance, yet the underlying mechanisms remain unknown. We examined whether mesenchymal stem cell (MSC) transplantation-induced beneficial effects are secondary to paracrine-associated improvements in LV contractile performance, wall stress, and myocardial bioenergetics in hearts with postinfarction LV remodeling. Myocardial contractile function and bioenergetics were compared 4 wk after acute myocardial infarction in normal pigs (n = 6), untreated pigs with myocardial infarction (MI group; n = 6), and pigs receiving autologous MSC transplantation (MI + MSC group; n = 5). A distal occlusion of the left anterior descending coronary artery instigated significant myocardial hypertrophy. Ejection fraction decreased from 55.3 +/- 3.1% (normal) to 30.4 +/- 2.3% (MI group; P < 0.01) and to 45.4 +/- 3.1% (MI + MSC group; P < 0.01 vs. MI). Hearts in the MI group developed severe contractile dyskinesis in the infarct zone and border zone (BZ). MSC transplantation significantly improved contractile performance from dyskinesis to active contraction (P < 0.01 vs. MI). BZ systolic wall stress was severely increased in MI hearts but significantly improved after MSC transplantation (P < 0.01 vs. MI). The BZ demonstrated profound bioenergetic abnormalities in MI pigs; this was significantly improved after MSC transplantation (P < 0.01 vs. MI). Patchy spared myocytes were found in the infarct zone of hearts receiving MSC transplantation but not in control hearts. These data demonstrate that MSC transplantation into the BZ causes significant improvements in myocardial contractile performance and reduction in wall stress, which ultimately results in significant bioenergetic improvements. Low cell engraftment indicates that MSCs did not provide a structural contribution to the damaged heart and that the observed beneficial effects likely resulted from paracrine repair mechanisms.     

二维斑点追踪技术评价犬心梗后自体骨髓CD34＋干细胞移植对心肌功能的影响

目的应用二维斑点追踪成像超声心动图（2D-STE）,评价犬心梗后自体骨髓CD34＋干细胞移植对心肌功能的影响。方法 12只杂种犬行冠脉左前降支结扎术,导致前壁心肌梗死,随机分为两组,A组为对照组,结扎术后两周二次开胸手术,经心肌注射磷酸盐缓冲液（PBS）1 mL;B组为治疗组,结扎术后两周二次开胸手术,经心肌注射含自体骨髓CD34＋干细胞的磷酸盐缓冲液1 mL。应用STE对12只犬结扎术前、术后左室短轴基底段及心尖段心室节段径向应变（RS）、圆周方向应变（CS）以及局部心肌旋转（Rot）进行分析,并对对照组和治疗组治疗后的RS、CS及Rot变化进行比较。结果心肌梗死后梗死节段的RS、CS以及Rot均下降,治疗后治疗组梗死段RS及Rot较对照组好转。结论 STE能够评价左室短轴局部心肌的收缩功能,心肌梗死后梗死段短轴各方向应变减低,自体骨髓CD34＋干细胞移植能够提高局部心肌的收缩功能。     

Early improvement in cardiac tissue perfusion due to mesenchymal stem cells

The underlying mechanism(s) of improved left ventricular function (LV) due to mesenchymal stem cell (MSC) administration after myocardial infarction (MI) remains highly controversial. Myocardial regeneration and neovascularization, which leads to increased tissue perfusion, are proposed mechanisms. Here we demonstrate that delivery of MSCs 3 days after MI increased tissue perfusion in a manner that preceded improved LV function in a porcine model. MI was induced in pigs by 60-min occlusion of the left anterior descending coronary artery, followed by reperfusion. Pigs were assigned to receive intramyocardial injection of allogeneic MSCs (200 million, approximately 15 injections) (n = 10), placebo (n = 6), or no intervention (n = 8). Resting myocardial blood flow (MBF) was serially assessed by first-pass perfusion magnetic resonance imaging (MRI) over an 8-wk period. Over the first week, resting MBF in the infarct area of MSC-treated pigs increased compared with placebo-injected and untreated animals [0.17 +/- 0.03, 0.09 +/- 0.01, and 0.08 +/- 0.01, respectively, signal intensity ratio of MI to left ventricular blood pool (LVBP); P < 0.01 vs. placebo, P < 0.01 vs. nontreated]. In contrast, the signal intensity ratios of the three groups were indistinguishable at weeks 4 and 8. However, MSC-treated animals showed larger, more mature vessels and less apoptosis in the infarct zones and improved regional and global LV function at week 8. Together these findings suggest that an early increase in tissue perfusion precedes improvements in LV function and a reduction in apoptosis in MSC-treated hearts. Cardiac MRI-based measures of blood flow may be a useful tool to predict a successful myocardial regenerative process after MSC treatment.     

The similar effect of transplantation of marrow-derived mesenchymal stem cells with or without prior differentiation induction in experimental myocardial infarction

Marrow-derived mesenchymal stem cells (MSCs) have been heralded as a source of great promise for the regeneration of the infarcted heart. There is no clear data indicating whether or not in vitro differentiation of MSCs into major myocardial cells can increase the beneficial effects of MSCs. The aim of this study is to address this issue. To induce MSCs to transdifferentiate into cardiomyocyte-like and endothelial-like cells, 5-azacytidine and vascular endothelial growth factor (VEGF) were used, respectively. Myocardial infarction in rabbits was generated by ligating the left anterior descending coronary artery. Animals were divided into three experimental groups: I, control group; II, undifferentiated mesenchymal stem cell transplantation group; III, differentiated mesenchymal stem cell transplantation group; which respectively received peri-infarct injections of culture media, autologous undifferentiated MSCs and autologous differentiated MSCs. General pathology, immunohistochemistry, electron microscopy and echocardiography were performed in order to search for myocardial regeneration and improvement of cardiac function. In Groups II and III, implanted cells transdifferentiate into myocardial cells within 28 days post injection in a similar manner, and well-developed ultra structures formed within transplanted cells. Improvements in left ventricular function and reductions in infarcted area were observed in both cell-transplanted groups to the same degree. Vascular density was similar in Groups II and III and significantly higher in these groups compared with the control group. There is no need for prior differentiation induction of marrow-derived MSCs before transplantation and peri-infarct implantation of MSCs can efficiently regenerate the infarcted myocardium and improve cardiac function.     

Primary percutaneous coronary intervention in the left main stem of a monocoronary artery

In a 71-year-old female with evolving anterior wall myocardial infarction, coronary angiography revealed a monocoronary artery which arose from the right sinus of Valsalva. Originating from a short common trunk, the left main stem showed a thrombotic lesion that occluded the left anterior descending coronary artery while the circumflex artery was obstructed. Intracoronary administration of abciximab, followed by stenting of the transition between the left anterior descending coronary artery and the main stem, and final kissing balloon inflation of the bifurcation resulted in an excellent angiographic result and favourable clinical outcome. (Neth Heart J 2009;17:274–6.)     

Exercise training preserves coronary flow and reduces infarct size after ischemia-reperfusion in rat heart.

The effect of endurance training on the resistance of the heart to left ventricular (LV) functional deficit and infarction after a transient regional ischemia and subsequent reperfusion was examined. Female Sprague-Dawley rats were randomly assigned to an endurance exercise training (Tr) group or a sedentary (Sed) control group. After 20 wk of training, hearts were excised, perfused, and instrumented for assessment of LV mechanical function, and the left anterior descending coronary artery was occluded to induce a transient regional ischemia (1 h) that was followed by 2 h of reperfusion. Throughout much of the regional ischemia-reperfusion protocol, coronary flow rates, diastolic function, and LV developed pressure were better preserved in hearts from Tr animals. During the regional ischemia, coronary flow to myocardium outside the ischemic zone at risk (ZAR) was maintained in Tr hearts, whereas it progressively fell in Sed hearts. On release of the coronary artery ligature, flow to the ZAR was greater in Tr than in Sed hearts. Infarct size, expressed as a percentage of the ischemic ZAR, was significantly smaller in hearts from Tr rats (24 +/- 3 vs. 32 +/- 2% of ZAR, P < 0.05). Mn- and CuZn-SOD protein expression were higher in the LV myocardium of Tr animals (P < 0.05 for both isoforms). Our data indicate that long-term exercise training leads to infarct sparing and better maintenance of coronary flow and mechanical function after ischemia-reperfusion.     

Dietary coenzyme Q(10) supplement renders swine hearts resistant to ischemia-reperfusion injury

To examine whether nutritional supplementation of coenzyme Q(10) (CoQ(10)) can reduce myocardial ischemia-reperfusion injury, a group of swine was fed a regular diet supplemented with CoQ(10) (5 mg x kg(-1) x day(-1)) for 30 days. Another group of pigs that were fed a regular diet supplemented with placebo served as a control. After 30 days, isolated in situ pig hearts were prepared and hearts were perfused with a cardiopulmonary pump system. Each heart was subjected to 15 min of regional ischemia by snaring of the left anterior descending coronary artery, followed by 60 min of hypothermic cardioplegic global ischemia and 120 min of reperfusion. After the experiments were completed, myocardial infarct size was measured by triphenyltrazolium chloride staining methods. Postischemic left ventricular contractile function was better recovered in the CoQ(10) group than in the control group of pigs. CoQ(10)-fed pigs revealed less myocardial infarction and less creatine kinase release from the coronary effluent compared with control pigs. The experimental group also demonstrated a smaller amount of malonaldehyde in the coronary effluent and a higher content of the endogenous antioxidants ascorbate and thiol. Significant induction of the expression of ubiquitin mRNA was also found in the hearts of the CoQ(10)-fed group. The results of this study demonstrate that nutritional supplementation of CoQ(10) renders the hearts resistant to ischemia-reperfusion injury, probably by reducing the oxidative stress.     

培养于生物降解支架膜内的胚胎干细胞可修复小鼠的梗塞心肌

我们以往的研究表明,直接在心肌梗塞（myocardial infarction,MI）动物的心脏缺血区注射胚胎干细胞（embryonic stemceils,ESCs）可以提高其心肌功能,干细胞组织工程学可以使组织再生、修复。本研究旨在观察将ESCs接种到生物降解膜内并移植到梗塞部位的效果。通过结扎小鼠左冠状动脉制作MI模型,将培养3d的带有小鼠ESCs的聚羟基乙酸膜（polyglycolicacid,PGA）移植到心肌缺血及边缘区表面。实验小鼠分成4组：假手术组、MI组、MI＋PGA组、MI＋ESC组,移植操作8周后检测血流动力学和心肌功能。MI组的血压和左心室功能显著降低。与MI组和MI＋PGA组相比,MI＋ESC组的血压和心室功能显著改善,存活率也显著增高,在梗塞区检测到GFP阳性组织,表明ESCs存活,并可能有心肌再生。以上结果表明,移植生物降解膜内的ESCs可修复小鼠梗塞区心肌细胞并提高心脏功能。将ESCs和生物降解材料联合运用可能为修复受损心脏提供一个新的治疗方法。     

Restored perfusion and reduced inflammation in the infarcted heart after grafting stem cells with a hyaluronan‐based scaffold

The aim of this study is to investigate the blood perfusion and the inflammatory response of the myocardial infarct area after transplanting a hyaluronan‐based scaffold (HYAFF^®11) with bone marrow mesenchymal stem cells (MSCs). Nine‐week‐old female pigs were subjected to a permanent left anterior descending coronary artery ligation for 4 weeks. According to the kind of the graft, the swine subjected to myocardial infarction were divided into the HYAFF^®11, MSCs, HYAFF^®11/MSCs and untreated groups. The animals were killed 8 weeks after coronary ligation. Scar perfusion, evaluated by Contrast Enhanced Ultrasound echography, was doubled in the HYAFF^®11/MSCs group and was comparable with the perfusion of the healthy, non‐infarcted hearts. The inflammation score of the MSCs and HYAFF^®11/MSCs groups was near null, revealing the role of the grafted MSCs in attenuating the cell infiltration, but not the foreign reaction strictly localized around the fibres of the scaffold. Apart from the inflammatory response, the native tissue positively interacted with the HYAFF^®11/MSCs construct modifying the extracellular matrix with a reduced presence of collagene and increased amount of proteoglycans. The border‐zone cardiomyocytes also reacted favourably to the graft as a lower degree of cellular damage was found. This study demonstrates that the transplantation in the myocardial infarct area of autologous MSCs supported by a hyaluronan‐based scaffold restores blood perfusion and almost completely abolishes the inflammatory process following an infarction. These beneficial effects are superior to those obtained after grafting only the scaffold or MSCs, suggesting that a synergic action was achieved using the cell‐integrated polymer construct.     

Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning

Remote ischemic preconditioning reduces myocardial infarction (MI) in animal models. We tested the hypothesis that the systemic protection thus induced is effective when ischemic preconditioning is administered during ischemia (PerC) and before reperfusion and examined the role of the K(+)-dependent ATP (K(ATP)) channel. Twenty 20-kg pigs were randomized (10 in each group) to 40 min of left anterior descending coronary artery occlusion with 120 min of reperfusion. PerC consisted of four 5-min cycles of lower limb ischemia by tourniquet during left anterior descending coronary artery occlusion. Left ventricular (LV) function was assessed by a conductance catheter and extent of infarction by tetrazolium staining. The extent of MI was significantly reduced by PerC (60.4 +/- 14.3 vs. 38.3 +/- 15.4%, P = 0.004) and associated with improved functional indexes. The increase in the time constant of diastolic relaxation was significantly attenuated by PerC compared with control in ischemia and reperfusion (P = 0.01 and 0.04, respectively). At 120 min of reperfusion, preload-recruitable stroke work declined 38 +/- 6% and 3 +/- 5% in control and PerC, respectively (P = 0.001). The force-frequency relation was significantly depressed at 120 min of reperfusion in both groups, but optimal heart rate was significantly lower in the control group (P = 0.04). There were fewer malignant arrhythmias with PerC during reperfusion (P = 0.02). These protective effects of PerC were abolished by glibenclamide. Intermittent limb ischemia during myocardial ischemia reduces MI, preserves global systolic and diastolic function, and protects against arrhythmia during the reperfusion phase through a K(ATP) channel-dependent mechanism. Understanding this process may have important therapeutic implications for a range of ischemia-reperfusion syndromes.     

Long-term evaluation of a selective retrograde coronary venous perfusion model in pigs (Sus scrofa domestica)

The lack of suitable target vessels remains a challenge for aortocoronary bypass grafting in end-stage coronary heart disease. This study aimed to investigate the arterialization of cardiac veins as an alternative myocardial revascularization strategy in an experimental long-term model in pigs. Selective retrograde perfusion of a coronary vein (aorta to coronary vein bypass, retrobypass) before ligation of the ramus interventricularis paraconalis (equivalent to the left anterior descending artery in humans) was performed in 20 German Landrace pigs (Sus scrofa domestica). Retroperfusion of the left anterior descending vein was performed in 10 pigs (RP+) but not in the other 10 (RP-), and the vena cordis magna was ligated (L+) in 5 pigs in each of these groups but left open (L-) in the remaining animals. Hemodynamic performance (for example, cardiac output) was significantly better in the group that underwent selective retroperfusion with proximal ligation of vena cordis magna (RP+L+; 4.1 L/min) compared with the other groups (RP+L-, 2.5 L/min; RP-L+, 2.2 L/min; RP-L-, 1.9 L/min). Long-term survival was significantly better in RP+L+ pigs (112±16 d) than in all other groups. Histologic follow-up studies showed significantly less necrosis in the RP+L+ group compared with all other groups. Venous retroperfusion is an effective technique to achieve long-term survival after acute occlusion of the left anterior descending artery in a pig model. In this model, proximal ligation of vena cordis magna is essential.     

Left ventricular strain, rotation, and torsion as markers of acute myocardial ischemia

This study investigates how tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) describe regional myocardial deformation during controlled reductions of left anterior descending (LAD) coronary artery perfusion pressure. In eight anesthetized pigs, a shunt with constrictor was installed from the brachiocephalic artery to the LAD. Data were obtained with open shunt, followed by four degrees of stenosis (S1-S4) of increasing severity: S1, ～15%; S2, ～35%; S3, ～50%; and S4, ～60% reductions of LAD perfusion pressure. At each situation, microspheres for perfusion measurements were injected and left ventricular (LV) short- and long-axis cineloops were recorded. In the anterior wall, radial, circumferential, and longitudinal one-layer STE strain, one-layer radial TDI strain, and three-layer radial TDI and STE strain were measured. LV peak mean rotation was measured at six equidistant levels from apex to base (in 7 pigs). LV torsion was calculated from end-systolic mean rotation. With open shunt, three-layer TDI analysis showed a transmural strain gradient with no perfusion gradient. Perfusion, one-layer TDI strain, and strain in the mid- and subendocardium from three-layer TDI were reduced at S2 (P < 0.05). STE strain was not affected until S3 (P < 0.05). Peak mean rotation, increasing toward the apex, decreased at the three apical levels at S4 (P < 0.05). LV torsion did not decrease (P = 0.26). In conclusion, TDI strain detected dysfunction already with minor changes in global hemodynamics, whereas STE strain was first reduced with moderate changes. LV peak mean rotation was not reduced until severe reduction of LAD perfusion pressure, but remained increasingly counterclockwise toward the apex. LV torsion remained unaffected by ischemia.     

Myocardial Connective Tissue Growth Factor (CCN2/CTGF) Attenuates Left Ventricular Remodeling after Myocardial Infarction

Aims

Myocardial CCN2/CTGF is induced in heart failure of various etiologies. However, its role in the pathophysiology of left ventricular (LV) remodeling after myocardial infarction (MI) remains unresolved. The current study explores the role of CTGF in infarct healing and LV remodeling in an animal model and in patients admitted for acute ST-elevation MI.

Methods and Results

Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate controls (NLC) were subjected to permanent ligation of the left anterior descending coronary artery. Despite similar infarct size (area of infarction relative to area at risk) 24 hours after ligation of the coronary artery in Tg-CTGF and NLC mice, Tg-CTGF mice disclosed smaller area of scar tissue, smaller increase of cardiac hypertrophy, and less LV dilatation and deterioration of LV function 4 weeks after MI. Tg-CTGF mice also revealed substantially reduced mortality after MI. Remote/peri-infarct tissue of Tg-CTGF mice contained reduced numbers of leucocytes, macrophages, and cells undergoing apoptosis as compared with NLC mice. In a cohort of patients with acute ST-elevation MI (n = 42) admitted to hospital for percutaneous coronary intervention (PCI) serum-CTGF levels (s-CTGF) were monitored and related to infarct size and LV function assessed by cardiac MRI. Increase in s-CTGF levels after MI was associated with reduced infarct size and improved LV ejection fraction one year after MI, as well as attenuated levels of CRP and GDF-15.

Conclusion

Increased myocardial CTGF activities after MI are associated with attenuation of LV remodeling and improved LV function mediated by attenuation of inflammatory responses and inhibition of apoptosis.     

Evaluating the role of autologous mesenchymal stem cell seeded on decellularized pericardium in the treatment of myocardial infarction: an animal study

Inappropriate left ventricular remodeling following myocardial infarction (MI) can result in subsequent severe dysfunction. In this study, we tested the hypothesis that decellularized pericardium (DP) or seeded pericardial patch with autologous adipose-derived mesenchymal stem cells (ADMSCs) could be safely used in a MI scar and could improve heart function. Twelve rabbits were randomly divided into three equal groups. Four weeks after MI induction by ligation of the left anterior descending artery in 12 rabbits, animals of G1 (n = 4) received DP patch with labeled ADMSCs. DP patch was implanted in animals of G2 (n = 4). Rabbits of G3 (n = 4) remained without any intervention after MI induction (control group). Serial examinations including echocardiography, electrocardiography (ECG), scanning electron microscopy, histology and immunohistochemistry (IHC) were performed to evaluate the efficacy of the implanted scaffolds on recovery of the infracted myocardium. The results demonstrated that left ventricular contractile function and myocardial pathological changes were significantly improved in rabbits implanted with either DP or ADMSC-seeded pericardium. However, the seeded pericardium was more effective in scar repairing 2 months after the operation, IHC staining with Desmin and CD34 and positive immunofluorescence staining verified the differentiation of ADMSCs to functional cardiomyocytes. This approach may involve the application of autologous ADMSCs seeded on pericardial patch in an attempt to regenerate a contractible myocardium in an animal model of MI.     

Interaction between left ventricular wall motion and intraventricular flow propagation in acute and chronic ischemia

Myocardial ischemia has been associated with left ventricular (LV) postsystolic shortening. The combination of tissue Doppler imaging and high frame-rate acquisition of two-dimensional color flow makes it possible to study the interaction between LV wall motion and intraventricular flow propagation. The aim of this study was to examine in a clinical model the impact that acute myocardial ischemia and prior myocardial infarct might have on LV flow patterns and to explain the underlying mechanisms from the tissue Doppler data. LV flow propagation and tissue velocities during early diastole were studied in 18 healthy individuals, 17 patients with prior anterior myocardial infarct, and 16 patients before and during percutaneous coronary intervention (PCI) of the left anterior descending artery. Normal individuals had intraventricular flow propagation toward the apex during isovolumic relaxation. During this early diastolic time phase, myocardial velocities measured at mid- and apical septal segment were directed away from the apex. Before PCI, patients without myocardial infarction had similar findings as in normal individuals. In contrast, each patient with either prior myocardial infarction or PCI-induced acute ischemia had flow propagation opposite to normal individuals, and tissue velocities reversed toward the apex during early diastole. Reversal of early diastolic LV flow propagation in acute and chronic anterior myocardial ischemia reflects postsystolic shortening in the dyskinetic apical and septal myocardial segments.     

小型猪急性心肌梗死模型的建立及其评价

目的探索结扎小型猪冠状动脉左前降支（LAD）建立急性心肌梗死模型及进行血流评价的方法。方法小型猪20头全麻下开胸暴露心脏,预阻断LAD（第二对角支）15min,后予结扎,术中心电图动态监测,术后进行冠状动脉造影,心肌酶学监测以确定模型建立情况,冠状动脉造影以及^13N-NH3 PET心肌血流测定评价手术后血流改变。结果20头小型猪中有16头存活4周,成活率80％,开胸手术中1头因麻醉意外死亡,3头死于术后呼吸不畅。结扎后心电图呈动态变化,24h后血清心肌酶谱（CK,CK—MB,cTnI）较术前明显增高,差异有统计学意义（P〈0．05）,冠状动脉造影显示LAD血流中断,TIMI分级为0级,^13N—NH3 PET检查显示手术后缺损面积百分比（27．0±5．0）较手术前（4．0±3．2）有显著性差异,证实心梗模型建立成功。结论本实验中开胸手术成功率高,术后血流评价方法可用于手术前后冠脉血流和心肌血流的比较以及对心肌梗死后治疗效果进行评价。     

Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats.

Massive loss of cardiac myocytes after myocardial infarction (MI) is a common cause of heart failure. The present study was designed to investigate the improvement of cardiac function in MI rats after embryonic stem (ES) cell transplantation. MI in rats was induced by ligation of the left anterior descending coronary artery. Cultured ES cells used for cell transplantation were transfected with the marker green fluorescent protein (GFP). Animals in the treated group received intramyocardial injection of ES cells in injured myocardium. Compared with the MI control group injected with an equivalent volume of the cell-free medium, cardiac function in ES cell-implanted MI animals was significantly improved 6 wk after cell transplantation. The characteristic phenotype of engrafted ES cells was identified in implanted myocardium by strong positive staining to sarcomeric alpha-actin, cardiac alpha-myosin heavy chain, and troponin I. GFP-positive cells in myocardium sectioned from MI hearts confirmed the survival and differentiation of engrafted cells. In addition, single cells isolated from cell-transplanted MI hearts showed rod-shaped GFP-positive myocytes with typical striations. The present data demonstrate that ES cell transplantation is a feasible and novel approach to improve ventricular function in infarcted failing hearts.     

Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium

Neovascularization induced by vascular endothelial growth factor (VEGF) represents an appealing approach for treating ischemic heart disease. However, VEGF therapy has been associated with transient therapeutic effects and potential risk for hemangioma growth. Adult mesenchymal stem cells (MSCs) derived from bone marrow are a promising source for tissue regeneration and repair. In order to achieve a safe and persistent angiogenic effect, we have explored the potential of autologous MSCs transplantation to enhance angiogenesis and cardiac function of ischemic hearts. One week after myocardial infarction induced by occlusion of left anterior descending artery, autologous MSCs expanded in vitro was administrated intramyocardially into the infarct area of the same donor rats. By 2 months, MSCs implantation significantly elevated VEGF expression levels, accompanied by increased vascular density and regional blood flow in the infarct zone. The neovascularization resulted in a decreased apoptosis of hypertrophied myocytes and markedly improved the left ventricular contractility (ejection fraction: 79.9+/-7.6% vs. 37.2+/-6.9% in control animals). Therefore, mechanisms underlying MSCs improvement of cardiac functions may involve neovascularization induced by differentiation of MSCs to endothelial cells and para-secretion of growth factors, in addition to the apoptosis reduction and previously reported cardiomyocytes regeneration. Two months after cell transplantation, there are significant improvement of left ventricular function. Hence, autologous MSCs transplantation may represent a promising therapeutic strategy free of ethical concerns and immune rejection, for neovascularization in ischemic heart diseases.     

Angiographic evidence of coronary occlusion and resolution

A case of myocardial infarction with angiographically demonstrated occlusion of the left anterior descending coronary artery is presented. Repeat angiography 18 months later revealed patent coronary arteries despite persistent electrocardiographic infarction pattern. Coronary artery occlusion resulting in infarction may not, therefore, be permanent.     

Bioenergetic and functional consequences of stem cell-based VEGF delivery in pressure-overloaded swine hearts

In an established swine model of severe left ventricular (LV) hypertrophy (LVH), the bioenergetic and functional consequences of transplanting autologous mesenchymal stem cells (MSCs) overexpressing vascular endothelial growth factor (VEGF-MSCs) into the LV were evaluated; transplantation was accomplished by infusion of VEGF-MSCs into the interventricular cardiac vein. Specifically, the hypertrophic response to aortic banding was compared in seven pigs treated with 30 million VEGF-MSCs, eight pigs treated with 30 million MSCs without VEGF modification, and 19 untreated LVH pigs. Eight pigs without banding or cell transplantation (normal) were also studied. Four weeks postbanding, LV wall thickening (MRI), myocardial blood flow (MBF), high-energy phosphate levels ((31)P magnetic resonance spectroscopy), and hemodynamic measurements were obtained under basal conditions and during a catecholamine-induced high cardiac workstate (HCW). Although 9 of 19 untreated banded pigs developed clinical evidence of biventricular failure, no MSCs-treated animal developed heart failure. MSCs engraftment was present in both cell transplant groups, and both baseline and HCW MBF values were significantly increased in hearts receiving VEGF-MSCs compared with other groups (P < 0.05). During HCW, cardiac inotropic reserve (defined as the percent increase of rate pressure product at HCW relative to baseline) was normal in the VEGF-MSCs group and significantly decreased in all other banded groups. Additionally, during HCW, the myocardial energetic state [reflected by the phosphocreatine-to-ATP ratio (PCr/ATP)] of VEGF-MSCs-treated hearts remained stable, whereas in all other groups, PCr/ATP decreased significantly from baseline values (P < 0.05, each group). Myocardial von Willebrand factor and VEGF mRNA expressions and myocardial capillary density were significantly increased in VEGF-MSCs-treated hearts (P < 0.05). Hence, in the pressure-overloaded LV, transplantation of VEGF-MSCs prevents LV decompensation, induces neovascularization, attenuates hypertrophy, and improves MBF, myocardial bioenergetic characteristics, and contractile performance.