Transplantation of stem cells may improve regional perfusion and post-infarct ventricular function, but the optimal dose and efficacy of cell delivery via the intravenous route has not been determined. This study tested the hypothesis that intravenous infusion of bone marrow-derived mesenchymal stem cells (MSCs) enhances regional perfusion and improves ventricular function after myocardial infarction. In a closed-chest pig model, the LAD coronary artery was occluded for 75 min by angioplasty balloon inflation followed by 12 weeks of reperfusion. After 15 min of reperfusion, pigs randomly received 1 of 4 treatments: (1) Vehicle (Control, n = 10); (2) 1 x 10(6) MSCs/kg (1 mill, n = 7); (3) 3 x 10(6) MSCs/kg (3 mill, n = 8) and (4) 10 x 10(6) MSCs/kg (10 mill, n = 8). Angiogenesis was demonstrated by immunohistochemical staining, myocardial blood flow (steady state and vasodilator reserve) was measured using 15 microm neutron-activated microspheres, and cardiac function was determined by contrast left ventriculography (ejection fraction) and pressure-volume relationships. After 12 week of reperfusion, von Willebrand Factor-positive vessels and tissue vascular endothelial growth factor (VEGF) expression in the scar zone was significantly greater in all MSCs-treated animals relative to Control. Steady state myocardial blood flow in the scar tissue was comparable among groups. However, adenosine recruited vasodilator reserve in the scar zone induced by intracoronary adenosine was significantly higher in the MSC-treated animals compared to Control. Furthermore, preload-recruitable stroke work and systolic performance were significantly greater compared to Control. In conclusion, these data demonstrate that intravenous delivery of MSCs during early reperfusion augments vasculogenesis, enhances regional perfusion, and improves post-infarct ventricular function. The results suggest that intravenous infusion of MSCs is an effective modality for the treatment of ischemia/reperfusion induced myocardial injury.
Multiple echocardiographic criteria have been proposed to diagnose mechanical dyssynchrony in patients with heart failure without being validated against a model of cardiac dyssynchrony with heart failure. This study examines which of these methods can detect dyssynchrony in a canine model. Adult mongrel dogs underwent His-bundle ablation and right-ventricular pacing for 4 wk at either 110 bpm to induce dyssynchrony without heart failure (D group, n = 12) or 170 bpm to induce dyssynchrony with heart failure (DHF group, n = 9). To induce heart failure with narrow QRS, atria were paced at 190 bpm for 4 wk (HF group, n = 8). Tissue Doppler imaging (TDI) and two-dimensional echocardiography were performed at baseline and at end of study. Standard deviation of time to peak systolic velocity (color-coded TDI), time to peak S wave on pulse-wave TDI, time to peak radial and circumferential strain by speckle-tracking analysis (E(rr) and E(cc), respectively), and septal-to-posterior wall motion delay on M mode were obtained. In D group, only E(rr) and E(cc) were increased by dyssynchrony. In contrast, all the echocardiographic parameters of dyssynchrony appeared significantly augmented in the DHF group. Receiver-operator curve analysis showed good sensitivity of E(rr) (90%) and E(cc) (100%) to detected dyssynchrony without heart failure and excellent sensitivity and specificity of E(rr) and E(cc) to detect dyssynchrony with heart failure. Radial strain by speckle tracking is more accurate than TDI velocity to detect cardiac dyssynchrony in a canine model of dyssynchrony with or without heart failure.
In this acute canine model of AV block, QRS duration shortened and LV performance improved with epicardial biventricular pacing compared to standard single-site ventricular pacing.
Background-NO has been advocated as an adjunct to cardioplegia solutions. However, NO undergoes a rapid biradical reaction with superoxide anions to produce peroxynitrite (ONOO Ϫ ). ONOO Ϫ in crystalloid cardioplegia solution induces injury to coronary endothelium and to systolic function after cardioplegia and reperfusion. However, ONOO Ϫ may be degraded to less lethal or cardioprotective intermediates with glutathione (GSH) in reactions separate from its well known antioxidant effects. We hypothesized that GSH detoxifies ONOO Ϫ and reverses defects in endothelial function and systolic function when present in crystalloid cardioplegia. Methods and Results-In anesthetized dogs on cardiopulmonary bypass, a 45-minute period of global normothermic ischemia was followed by 60 minutes of intermittent cold crystalloid cardioplegia (Plegisol) and 2 hours of reperfusion. The cardioplegia solution contained 5 mol/L authentic ONOO Ϫ ; catalase was included to attenuate the potential antioxidant effects of GSH and to unmask the effects on ONOO Ϫ . In 1 group (CPϩGSH, nϭ5), the cardioplegia contained 500 mol/L GSH, whereas 1 group received crystalloid cardioplegia without GSH (CCP, nϭ6). There were no group differences in postcardioplegia left ventricular systolic function (end-systolic pressure-volume relation, impedance catheter: CCP 10.0Ϯ2.4 versus CPϩGSH 10.6Ϯ1.3 mm Hg/mL) or diastolic chamber stiffness (coefficient: CCP 0.35Ϯ0.2 versus CPϩGSH 0.31Ϯ0.18). Myocardial neutrophil accumulation (myeloperoxidase activity) was attenuated in CPϩGSH versus CCP (2.2Ϯ0.7 versus 5.4Ϯ1.2, PϽ0.05). In postexperimental coronary arteries, maximal endothelium-dependent relaxation was greater in CPϩGSH than in CCP (118Ϯ6% versus 92Ϯ5%, PϽ0.05), with a smaller EC 50 value (Ϫ7.10Ϯ0.05 versus Ϫ6.98Ϯ0.03, respectively, PϽ0.05). Smooth muscle relaxation was complete in both groups. The adherence of neutrophils to postexperimental coronary arteries as a measure of endothelial function was less in CPϩGSH than in CCP (98Ϯ18 versus 234Ϯ36 neutrophils/mm 2 , PϽ0.05). Nitrosoglutathione, a byproduct of the reaction between ONOO Ϫ and GSH, was greater in CPϩGSH than in CCP (4.1Ϯ2.3 versus 0.4Ϯ0.2 g/mL, PϽ0.05). Conclusions-GSH in crystalloid cardioplegia detoxifies ONOO Ϫ and forms cardioprotective nitrosoglutathione, resulting in attenuated neutrophil adherence and selective endothelial protection through the inhibition of neutrophil-mediated damage. (Circulation. 2000;102[suppl III]:III-332-III-338.)
Tomographic myocardial imaging with Tc-99m sestamibi during moderately severe partial coronary occlusion underestimated the area of the defect relative to Tl-201 or to the pathologic reference standard in dogs. Defect contrast was sharper with tomographic myocardial Tl-201 than with tomographic myocardial Tc-99m sestamibi during moderately severe partial coronary occlusion.
Adenosine may mediate coronary vasodilation during work-related hyperemia and during ischemia. We tested whether adenosine blockade with 8-p-sulfophenyltheophylline (PSPT) prevented dobutamine-induced hyperemia or magnified the reductions in flow due to vasopressin. Control (n = 8) and test (n = 7) dogs received paired infusions of dobutamine (70 micrograms/min iv for 5 min). Test dogs received PSPT (10 mg/kg iv) between doses. In both groups, paired infusions elicited comparable increases in oxygen consumption. However, in test dogs, the hyperemia was reduced significantly. Thus adenosine mediates the hyperemia of dobutamine. Separately, control dogs (n = 9) received vasopressin (0.6 microgram ic over 5 min); test dogs (n = 7) received PSPT before vasopressin. Vasopressin maximally increased coronary resistance by 3 min; effects were gone by 10 min. With PSPT, coronary resistance was increased further and remained high beyond 10 min. Thus adenosine-mediated vasodilation moderates the severity and duration of ischemia. These results indicate the importance of adenosine in mediating coronary flow during increased demand and reduced supply.
Efficiency of intracoronary (IC) adenoviral vector transfection is impaired by the vascular endothelium. Ischemia and substances that increase vascular permeability (sodium nitroprusside, nitroglycerin) may augment adenoviral vector transfection efficiency (TE). We tested whether TE of adenoviral vector following IC infusion is improved by nitrates or by ischemia. Fluoroscopically guided angioplasty balloon catheters occluded the coronary artery in Yorkshire pigs and delivered adenoviral type 5 vector encoding the luciferase gene (Ad5Luc, 10 11 viral particles). TE (luciferase activity) was minimal and was not augmented by IC co-administration of 50 lg/ min sodium nitroprusside to nonischemic myocardium. Two (but not one) 3-min episodes of occlusion tended to increase luciferase activity ( p = 0.06), and luciferase activity was further increased by IC co-administration of nitroglycerin ( p < 0.001). After 75 min of coronary artery occlusion, luciferase activity was greater than with shorter periods of ischemia, and was significantly greater in the ischemia-reperfused zone compared to the border zone 3 and 14 days after infusion; there was no transfection in nonischemic myocardium. IC delivery of Ad5Luc into post-ischemic myocardium caused no local inflammation or hemodynamic instability. We conclude that the uptake of IC Ad5 to ischemic reperfused myocardium validates use of IC Ad5 delivery protocols in future human gene therapy trials in patients following myocardial ischemia.
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