Intramyocardial bone marrow cell transplantation and the progression of coronary atherosclerosis in patients with chronic myocardial ischemia

BACKGROUND: Cell therapy has been proposed as a novel treatment strategy for patients with ischemic heart disease. However, two recent studies suggested that cardiac cell transplantation might aggravate coronary atherosclerosis. The aim of the current study was to assess whether intramyocardial bone marrow cell transplantation in patients with chronic myocardial ischemia is associated with progression of coronary atherosclerosis. METHODS: In 30 patients with chronic ischemia, bone marrow was aspirated from the iliac crest. During mononuclear cell isolation, coronary angiography was performed. Thereafter, 94+/-18 x 10(6) cells were injected intramyocardially (NOGA system) in regions with ischemia on technetium-99m tetrofosmin SPECT. RESULTS: During the 12-month follow-up period, there was no clinical evidence of progression of atherosclerosis. CCS class improved from 3.4+/-0.5 to 2.4+/-0.8 at 3 months, 2.4+/-0.9 at 6 months and 2.5+/-0.9 at 12 months (P<0.01). MRI-determined left ventricular ejection fraction increased from 51+/-12% to 54+/-12% at 3 months (P<0.01) and the number of ischemic segments per patient on SPECT decreased from 5.2+/-2.6 to 2.1+/-2.2 at 3 months (P<0.01). Repeat coronary angiography at 4 months revealed that bone marrow cell transplantation did not decrease minimal luminal diameter (1.81+/-0.80 mm versus 1.79+/-0.82 mm, P = NS) or mean luminal diameter (2.48+/-0.85 mm versus 2.46+/-0.86 mm, P = NS). Similarly, the percentage diameter stenosis (32+/-19% versus 32+/-20%, P = NS) and the atheromatosis severity score (4.78+/-2.40 versus 4.80+/-2.40, P = NS) remained unchanged. CONCLUSION: Intramyocardial bone marrow cell transplantation in patients with chronic myocardial ischemia was not associated with significant progression of atherosclerosis.     

Intramyocardial injection of autologous bone marrow mononuclear cells in patients with chronic myocardial infarction and severe left ventricular dysfunction

The present study investigated the safety, feasibility, and potential efficacy of autologous bone marrow cell injection in patients with chronic myocardial infarction and severe left ventricular (LV) dysfunction. In 15 patients (63 +/- 9 years; 14 men) bone marrow was aspirated from the iliac crest. Using the NOGA system (Biosense-Webster, Waterloo, Belgium), 94 +/- 14 x 10(6) bone marrow-derived mononuclear cells were injected into the infarction border zone. Bone marrow cell injection was performed without periprocedural complications in all patients. At 2.5 months, 1 patient died from worsening heart failure. New York Heart Association class improved from 3.5 +/- 0.5 at baseline to 2.7 +/- 0.8 at 3 months (p <0.01) and 2.9 +/- 0.8 at 6 months (p <0.01 vs baseline). LV ejection fraction (technetium-99m tetrofosmin single-photon emission computed tomography) increased from 23 +/- 8% to 27 +/- 9% at 3 months (p = 0.02) and regional wall thickening improved from 12.8 +/- 5.9% to 15.3 +/- 7.2% at 3 months (p = 0.02). Injected myocardial segments displayed a significant improvement in regional wall thickening (6.6 +/- 6.3% vs 11.7 +/- 7.0% at 3 months, p <0.01) and perfusion score (3.5 +/- 0.7 vs 3.0 +/- 0.9 at 3 months, p = 0.02) and a trend toward an improved fluorine-18 fluorodeoxyglucose score (2.9 +/- 0.9 vs 2.6 +/- 1.0 at 3 months, p = 0.06). Regional wall thickening (16.5 +/- 8.9% vs 19.1 +/- 9.1% at 3 months, p = NS), perfusion score (1.8 +/- 0.4 vs 1.7 +/- 0.5 at 3 months, p = NS), and fluorodeoxyglucose score (1.7 +/- 0.4 vs 1.6 +/- 0.4 at 3 months, p = NS) did not improve in noninjected myocardial segments. In conclusion, bone marrow cell injection in patients with chronic myocardial infarction and severe LV dysfunction is safe and feasible and appears to be associated with a decrease in heart failure symptoms and an improved LV function.     

Intramyocardial bone marrow cell transplantation and the progression of coronary atherosclerosis in patients with chronic myocardial ischemia

Background: Cell therapy has been proposed as a novel treatment strategy for patients with ischemic heart disease. However, two recent studies suggested that cardiac cell transplantation might aggravate coronary atherosclerosis. The aim of the current study was to assess whether intramyocardial bone marrow cell transplantation in patients with chronic myocardial ischemia is associated with progression of coronary atherosclerosis. Methods: In 30 patients with chronic ischemia, bone marrow was aspirated from the iliac crest. During mononuclear cell isolation, coronary angiography was performed. Thereafter, 94±18x10⁶ cells were injected intramyocardially (NOGA system) in regions with ischemia on technetium‐99m tetrofosmin SPECT. Results: During the 12‐month follow‐up period, there was no clinical evidence of progression of atherosclerosis. CCS class improved from 3.4±0.5 to 2.4±0.8 at 3 months, 2.4±0.9 at 6 months and 2.5±0.9 at 12 months (P<0.01). MRI‐determined left ventricular ejection fraction increased from 51±12% to 54±12% at 3 months (P<0.01) and the number of ischemic segments per patient on SPECT decreased from 5.2±2.6 to 2.1±2.2 at 3 months (P<0.01). Repeat coronary angiography at 4 months revealed that bone marrow cell transplantation did not decrease minimal luminal diameter (1.81±0.80?mm versus 1.79±0.82?mm, P = NS) or mean luminal diameter (2.48±0.85?mm versus 2.46±0.86?mm, P = NS). Similarly, the percentage diameter stenosis (32±19% versus 32±20%, P = NS) and the atheromatosis severity score (4.78±2.40 versus 4.80±2.40, P = NS) remained unchanged. Conclusion: Intramyocardial bone marrow cell transplantation in patients with chronic myocardial ischemia was not associated with significant progression of atherosclerosis.     

Electromechanical mapping versus positron emission tomography and single photon emission computed tomography for the detection of myocardial viability in patients with ischemic cardiomyopathy

OBJECTIVES: We compared catheter-based electromechanical mapping (NOGA system, Biosense-Webster, Haifa, Israel) with positron emission tomography (PET) and single photon emission computed tomography (SPECT) for prediction of reversibly dysfunctional myocardium (RDM) and irreversibly dysfunctional myocardium (IDM) in patients with severe left ventricular dysfunction. Furthermore, we established the optimal discriminatory value of NOGA measurements for distinction between RDM and IDM. BACKGROUND: The NOGA system can detect viable myocardium but has not been used for prediction of post-revascularization contractile function in patients with ischemic cardiomyopathy. METHODS: Twenty patients (19 males, age [mean +/- SD] 60 +/- 16 years, ejection fraction [EF] 29 +/- 6%) underwent viability testing with NOGA and PET or SPECT before revascularization. Left ventricular function was studied at baseline and six months after revascularization. RESULTS: The EF increased to 34 +/- 13% at six months (p < 0.05 vs. baseline). The 58 RDM and 57 IDM regions differed with regard to unipolar voltage amplitude (UVA) (9.2 +/- 3.9 mV vs. 7.6 +/- 4.0 mV, p < 0.05), normalized UVA (106 +/- 54% vs. 75 +/- 39%, p < 0.05), and tracer uptake (76 +/- 17% vs. 60 +/- 20%, p < 0.05). The NOGA local shortening did not distinguish between RDM and IDM (6.4 +/- 5.8% vs. 5.4 +/- 6.6%). By receiver operating characteristic curve analysis, myocardial tracer uptake had better diagnostic performance than UVA (area under curve [AUC] +/- SE: 0.82 +/- 0.04 vs. 0.63 +/- 0.05, p < 0.05) and normalized UVA (AUC +/- SE: 0.70 +/- 0.05, p < 0.05). Optimal threshold was defined as the value yielding sensitivity = specificity for prediction of RDM. Sensitivity and specificity were 59% at a UVA of 8.4 mV, 65% at a normalized UVA of 83%, and 78% at a tracer uptake of 69%. CONCLUSIONS: The NOGA system may discriminate RDM from IDM with optimal discriminatory values for UVA and normalized UVA of 8.4 mV and 83%, respectively. However, the diagnostic performance does not reach the level obtained by PET and SPECT in patients with severe heart failure.     

Effects of lidocaine and procainamide on normal and abnormal intraventricular electrograms during sinus rhythm

The effect of lidocaine (n = 6) and procainamide (n = 12) on electrogram characteristics from electrically normal right ventricular and electrically abnormal left ventricular endocardial sites was determined in 18 patients with prior myocardial infarction. Bipolar electrograms were recorded during sinus rhythm with No. 6F catheters positioned at a left ventricular abnormal site (electrograms fulfilling two of the following criteria: amplitude less than 3 mV, duration greater than 70 msec, or an amplitude to duration ratio less than .046) and normal sites at the right ventricular apex (RVA) and right ventricular outflow tract (RVOT). All electrograms were recorded from the same location before and after intravenous lidocaine or procainamide administered to obtain mean serum concentrations of 4.2 +/- 0.6 and 9.42 +/- 2 micrograms/ml respectively. Lidocaine and procainamide had no significant effect on sinus cycle length or electrogram amplitude. After lidocaine, no significant change in QRS width (112 +/- 23 vs 114 +/- 24 msec), left ventricular electrogram duration (76 +/- 21 vs 78 +/- 15 msec), or right ventricular electrogram duration (RVA 33 +/- 9 vs 33 +/- 10 msec, RVOT 31 +/- 9 vs 33 +/- 11 msec) was noted during sinus rhythm. At a paced cycle length of 600 msec, there was also no change in the paced QRS duration (197 vs 198 msec), the RVA electrogram duration (30 vs 32 msec), the RVOT electrogram duration (49 vs 52 msec), or the left ventricular electrogram duration (102 vs 108 msec).(ABSTRACT TRUNCATED AT 250 WORDS)     

Deterioration of left ventricular function following atrio-ventricular node ablation and right ventricular apical pacing in patients with permanent atrial fibrillation.

AIMS: Transcatheter radiofrequency ablation of the atrio-ventricular (AV) node followed by ventricular pacing has been shown to improve symptoms and quality of life of patients with atrial fibrillation (AF). It is assumed that function improves, but this has been less well demonstrated. The aim of this study was to assess the long-term effect of AV node ablation and ventricular pacing on left ventricular ejection fraction (LVEF) in patients with permanent AF. METHODS AND RESULTS: All 12 patients studied had permanent AF for at least 12 months (mean age 70 years, range 41 to 78). LVEF was determined 6 days and 3 months after AV node ablation by radionuclide ventriculography, at a paced rate of 80 beats . min (-1). Cardiac dimensions were measured by means of transthoracic echocardiography. No major changes in pharmacological therapy were made during 3 months follow-up period. LVEF showed a significant deterioration after 3 months follow-up period for the group (47.5 +/- 14.4%; 6 days after ablation vs 43.2 +/- 13.7%; 3 months after ablation, P < 0.05). There were no significant differences in left ventricular cavity dimensions directly after AV node ablation and 3 months later (LVEDD 51.2 +/- 10.7 mm vs 52.6 +/- 8.6 mm, P = NS: LVESD: 36.1 +/- 14.2 mm vs 36.6 +/- 9.7 mm, P = NS). Left atrial size did not show reduction 3 months after AV node ablation (50.8 +/- 13.6 mm vs 51.0 +/- 14.1 mm, P = NS). CONCLUSION: The restoration of a regular ventricular rhythm following AV node ablation for patients in permanent AF does not result in improvement in left ventricular function.     

Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study

OBJECTIVES: We conducted a pilot study to evaluate the feasibility of transendocardial delivery of autologous bone marrow (ABM) strategy in patients with severe symptomatic chronic myocardial ischemia not amenable to conventional revascularization. BACKGROUND: Transendocardial injection of ABM cells appears to enhance perfusion of ischemic porcine myocardium. METHODS: Ten patients underwent transendocardial injection of freshly aspirated and filtered unfractionated ABM using left ventricular electromechanical guidance. Twelve injections of 0.2 ml each were successfully delivered into ischemic noninfarcted myocardium pre-identified by single-photon emission computed tomography perfusion imaging. RESULTS: Autologous bone marrow injection was successful in all patients and was associated with no serious adverse effects; in particular, there was no arrhythmia, evidence of infection, myocardial inflammation, or increased scar formation. Two patients were readmitted for recurrent chest pain. At three months, Canadian Cardiovascular Society angina score significantly improved (3.1 +/- 0.3 vs. 2.0 +/- 0.94, p = 0.001), as well as stress-induced ischemia occurring within the injected territories (2.1 +/- 0.8 vs. 1.6 +/- 0.8, p < 0.001). Treadmill exercise duration, available in nine patients, increased, but the change was not significant (391 +/- 155 vs. 485 +/- 198, p = 0.11). CONCLUSIONS: This study provides preliminary clinical data indicating feasibility of catheter-based transendocardial delivery of ABM to ischemic myocardium.     

Safety of catheter-based intramyocardial autologous bone marrow cells implantation for therapeutic angiogenesis

The long-term safety and efficacy of autologous bone marrow cell implantation into the myocardium remains undefined. We studied the long-term clinical outcome of 12 patients with severe coronary artery disease who underwent electromechanical mapping-guided catheter-based autologous bone marrow cell implantation. Magnetic resonance imaging at 3 and 6 months showed no evidence of intramyocardial tumor formation, myocardial damage, or worsening of left ventricular ejection fraction. No sustained arrhythmia was detected on 24-hour Holter monitoring. After 44 +/- 10 months of follow-up, 1 patient had died of stroke at 8 months and another patient had died of myocardial infarction at 20 months. Computed tomography at 36 months or postmortem examination showed no tumor formation or intramyocardial calcification at the treated sites, and no sustained ventricular arrhythmia or sudden death was observed. Autologous bone marrow cell implantation into the ischemic human myocardium was not associated with long-term major adverse events regarding tumor, scar, or calcification formation, and the arrhythmogenic risk was low.     

Influence of CD34(+) marrow cell dose on outcome of HLA-identical sibling allogeneic bone marrow transplants in patients with chronic myeloid leukaemia

In order to study the influence of bone marrow CD34(+) cell dose on the outcome of allogeneic bone marrow transplantation (BMT), we analysed the results of BMT from HLA-identical siblings donors in 50 patients with chronic myeloid leukaemia (CML). The median numbers of nucleated cells (NC) and CD34(+) cells infused were 2.18 x 10(8)/kg (0.05-4.14 x 10(8)/kg) and 3.12 x 10(6)/kg (0.35-8.52 x 10(6)/kg), respectively. All patients engrafted. In univariate analysis, there was no correlation between the number of CD34(+) cells infused and the time to neutrophil recovery (P = 0.17). The Kaplan-Meier estimate of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 53 +/- 14% and 2-year survival was 46 +/- 15%. A number of CD34(+) cells infused greater than the median was the main factor increasing survival (P = 0.0006) and decreasing 100 day transplant-related mortality (P = 0.009). Patient-, disease- and transplant-related characteristics were not statistically different among patients receiving more or less than the median number of CD34(+) cells. The rate of infectious deaths was significantly higher in patients receiving less than 3.12 x 10(6) CD34/kg (48% vs 16%, P = 0.01). In a multivariable analysis, two factors associated with increased risk of death were advanced disease status at transplant (HR: 2.5 (95% CI: 1.09-5.75), P = 0.03) and a lower number of marrow CD34(+) cells infused/kg (HR: 4.55 (95% CI: 1.87-10.90), P = 0.0008).     

骨髓基质细胞结合血管内皮生长因子基因治疗猪慢性心肌缺血的疗效

目的：探讨骨髓基质细胞（BMSCs）结合血管内皮生长因子（VEGF）基因心内膜注射治疗猪慢性心肌缺血模型的疗效。方法：建立猪心肌梗塞模型．胸骨穿刺抽取骨髓,分离培养BMSCs,将VEGF165基因转染到BMSCs中．4周后进行左室心内膜电机械标测并行心内膜注射等操作,按照注射成分不同分为3组．联合组（n=8）注射转染VEGF。基因的BMSCs,细胞组（n=8）注射BMSCs,对照组（n=6）注射生理盐水。于细胞移植后4周分别进行左室心内膜电机械标测、选择性冠脉造影及超声心动图检查。结果：术后4周时联合组较细胞组及对照组的心梗面积明显缩小．侧支循环、心脏泵血功能以及心肌收缩力改善更加明显（P〈0．05～〈0．01）。结论：自体BMSCs结合VEGF165基因治疗心肌梗塞效果显著。     

自体移植骨髓来源的内皮细胞促进兔颈动脉内皮损伤修复

目的将骨髓来源的内皮细胞自体移植于兔颈动脉球囊损伤模型,观察内皮修复及管壁组织结构的变化,以探讨骨髓来源的内皮细胞对内皮损伤的作用。方法分离骨髓单个核细胞,体外培养并诱导分化为内皮细胞,以溴脱氧尿嘧啶核苷标记细胞建立兔颈动脉球囊损伤模型,实验组移植2ml密度为10^6／ml的骨髓来源的内皮细胞,对照组输注2ml磷酸盐缓冲溶液。Evan’s蓝染色检测各组内皮覆盖率;免疫荧光染色检测移植细胞在内膜的分布,HE染色检测血管组织学变化。结果实验组内皮覆盖率显著高于对照组（P〈0．05）,移植第7天为（54．1％±8．2％）和（30．0％±5．5％）,移植后第14天为（81．8％±6．0％）和（63．6％±8．4％）。移植的细胞参与内膜修复,术后第7天荧光面积比值为（2．3％±0．5％）,第14天为（4．2％±1．7％）,实验组内膜及中膜增生程度较对照组明显减轻。结论骨髓来源的内皮细胞移植是促进内皮损伤的有效方法。     

Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease

The present report contains the final results of a Phase I study that evaluated the feasibility, safety, and potential efficacy of intramyocardial injection of autologous bone marrow (BM) in "no-option" patients with refractory angina and myocardial ischemia. Twenty-seven patients underwent electromechanic mapping-guided transendomyocardial injections (n = 12, 0.2 ml each) of unfractionated autologous BM cells directed to ischemic, noninfarcted myocardial territory. Patients were injected with 28 +/- 27 x 10(6)/ml nucleated cells containing 2.2 +/- 1.4% CD34+ cells. The autologous BM injection procedure was successful in all patients and was associated with no adverse events. At 3 months, the Canadian Cardiovascular Society angina score (3.2 +/- 0.5 vs 2.0 +/- 0.91, p = 0.001) and treadmill exercise duration (418 +/- 136 vs 489 +/- 142 seconds, p = 0.017) had improved significantly. The stress-induced ischemia score within the injected territories (118 segments) had also improved (2.2 +/- 0.8 vs 1.7 +/- 1.1, p < 0.001). At 1 year, the clinical improvement was sustained, although 5 patients had undergone revascularization procedures. The number of total injected nucleated cells (CD45+), progenitor cells (CD34+), and the magnitude of secreted vascular endothelial growth factor and macrophage chemoattractant protein-1 by cultured BM cells failed to predict the clinical response. In conclusion, the 3- and 12-month study results have indicated the safety of catheter-based transendocardial delivery of autologous BM cells in patients with advanced symptomatic ischemic heart disease and may suggest sustained potential efficacy. The cellular and humeral characteristics of autologous BM cells did not predict the clinical response, underscoring the advisability of additional mechanistic exploration.     

Cell therapy in patients with left ventricular dysfunction due to myocardial infarction

Objectives: The purpose of this study was to determine the impact of autologous transplantation of mononuclear bone marrow cells on myocardial function in patients with left ventricular (LV) dysfunction due to an acute myocardial infarction. Methods: The randomized study included 82 patients with a first acute myocardial infarction treated with a stent implantation. This presentation is a subanalysis of 47 patients with left ventricular dysfunction–EF (ejection fraction) ≤ 40%. Group H patients (n = 17) received higher number (100,000,000) of cells; Group L patients (n = 13) received lower number (10,000,000) of cells. The patients of control Group C (n = 17) were not treated with cells. The Doppler tissue imaging and single photon emission computed tomography were performed before cell transplantation and 3 months later. Results: At 3 months of follow‐up, the baseline EF of 35%, 36%, 35% in Groups H, L, and C increased by 6% (P < 0.01 vs. baseline), 5% (P < 0.01 vs. baseline), and 4% (P = NS vs. baseline), respectively, as assessed by single photon emission computed tomography (P = NS between groups). The baseline number of akinetic segments of 6.9, 7.0, and 6.2 in H, L, and C groups decreased by 1.7 (P < 0.01 vs. baseline), 1.5 (P < 0.01 vs. baseline), and 0.7 (P = NS vs. baseline, P = NS between groups), respectively, as demonstrated by echocardiography. Conclusion: In our study, the statistically important effect of transplantation of mononuclear bone marrow cells on myocardial function was not found. Only an insignificant trend toward the improvement of global LV EF fraction was found at 3‐month follow‐up.     

Increased peripheral platelet destruction and caspase-3-independent programmed cell death of bone marrow megakaryocytes in myelodysplastic patients

To investigate underlying mechanisms of thrombocytopenia in myelodysplastic syndrome (MDS), radiolabeled platelet studies were performed in 30 MDS patients with platelet counts less than 100 x 10(9)/L. Furthermore, plasma thrombopoietin and glycocalicin index (a parameter of platelet or megakaryocyte destruction) were determined. Mean platelet life (MPL), corrected for the degree of thrombocytopenia, was reduced in 15 of 30 patients (4.3 +/- 0.9 days [mean +/- SD] vs 6.0 +/- 1.3, P = .0003). Platelet production rate (PPR) was reduced in 25 of 30 patients (68 +/- 34 x 10(9)/d vs 220 +/- 65, P < .0001). Thrombopoietin levels were not significantly correlated with the PPR. However, the glycocalicin index was significantly higher compared with controls (15 +/- 16 vs 0.7 +/- 0.2, P = .001) and significantly correlated with the PPR (P = .02, r = -0.5), but not with the MPL (P = 1.8). Ultrastructural studies demonstrated necrosis-like programmed cell death (PCD) in mature and immature megakaryocytes (n = 9). Immunohistochemistry of the bone marrow biopsies demonstrated no positive staining of MDS megakaryocytes for activated caspase-3 (n = 24) or cathepsin D (n = 21), while activated caspase-8 was demonstrated in a subgroup of patients (5/21) in less than 10% of megakaryocytes. These results indicate that the main cause of thrombocytopenia in MDS is caspase-3-independent necrosis-like PCD resulting in a decreased PPR in conjunction with an increased glycocalicin index.     

Comparison of the left ventricular electromechanical map before percutaneous coronary stent revascularization and at one-month follow-up in patients with a recent ST elevation infarction.

The study aimed to evaluate the safety and potential of percutaneous transluminal electromechanical mapping (NOGA) in patients with regional myocardial wall dysfunction after a recent ST elevation myocardial infarction (STEMI). Regional myocardial wall dysfunction is a major cause of morbidity in survivors of ST elevation myocardial infarction. Fifteen males who recently had suffered a STEMI were studied prospectively with coronary angiography, ventriculography, and NOGA before and 1 month after percutaneous coronary intervention (PCI). The left ventricular angiographic ejection fraction increased from 50% +/- 11% before PCI to 56% +/- 10% at follow-up (P = 0.006). Qualitative analysis of the NOGA color map identified and outlined an area of regional wall dysfunction in all patients. Quantitative analysis of the NOGA maps showed improvements at follow-up after PCI in regional wall parameters of the infarct area (bipolar voltage: 1.7 +/- 1.4 mV before intervention, 2.2 +/- 1.6 mV at follow-up, P = 0.05; local shortening, a NOGA parameter on wall motion: 3.5% +/- 6.2% before, 7.4% +/- 5.8% at follow-up, P = 0.01), whereas there were no changes in the noninfarcted area (bipolar voltage: 2.7 +/- 2.5 mV before intervention, 2.8 +/- 2.6 mV at follow-up, P = 0.99; local shortening: 7.8% +/- 7.8% before, 8.2% +/- 7.8% at follow-up, P = 0.99). There were no complications to the NOGA procedures. In patients treated with PCI for a recent STEMI, NOGA might be considered used in the quantification of myocardial recovery and in the outlining of myocardial areas of incomplete or no recovery.     

匹他伐他汀促进小鼠血管新生作用及其机制的研究

目的探讨匹他伐他汀对小鼠血管新生的促进作用及其可能的作用机制。方法建立野生型C3H／He小鼠下肢缺血模型并分为2组,缺血对照组,匹他伐他汀组。使用激光多普勒血流测定仪测定实验小鼠投药前、下肢缺血手术后双下肢血流。免疫荧光组化sP法计数缺血肢毛细血管数。免疫酶组化直接法计数缺血肢磷酸化蛋白激酶Akt（p-Akt）阳性细胞数。蛋白印迹杂交方法检测缺血肢血管内皮生长因子蛋白表达。镉还原Griess法测定实验结束后血清一氧化氮代谢产物含量。结果匹他伐他汀使实验小鼠术后缺血肢血流恢复明显,缺血肢与非缺血肢血流面积比明显增加;缺血肢毛细血管密度明显增加、p-Akt活性增加（p-Akt阳性细胞数明显增加）;血中一氧化氮代谢产物含量明显增高;缺血肢血管内皮生长因子蛋白表达增强。结论匹他伐他汀有促进小鼠血管新生的作用。     

粒细胞集落刺激因子动员自体外周血干细胞移植治疗急性心肌梗死的临床研究

目的观察经皮经腔冠状动脉内移植自体外周血干细胞(PBSC)治疗急性心肌梗死(AMI)的疗效。方法自2003年11月至2005年1月共入选AMI患者70例,随机分为干细胞移植组和对照组,两组均为35例。干细胞治疗组在常规AMI治疗(药物与介入治疗)基础上应用粒细胞集落刺激因子(GCSF)皮下注射动员自体骨髄干细胞,连用5天,第6天分离外周血干细胞悬液,将采集后的干细胞悬液经OVERTHEWIRE球囊导管中心腔注入梗死相关动脉(IRA),进行外周血干细胞移植;对照组经AMI常规方法(药物与介入)治疗。在外周血干细胞动员、采集及经冠状动脉回输过程中观察其不良反应。两组患者在移植前及移植后6个月应用超声心动图评价左室形态及心功能变化,室壁节段性运动积分;比较两组患者生存率及心脏事件发生率。结果6个月时干细胞移植组心脏收缩末容积(ESV)明显减小[(63.8±23.9)ML比(52.6±20.3)ML,P=0.01],舒张末容积(EDV)无显著性变化[(134.2±36.7)ML比(119.2±30.3)ML,P=0.07];左室射血分数(LVEF)显著增高[(50.0±8.2)%比(57.1±7.8)%,P<0.001];左室壁节段性运动积分指数(WMSI)明显减低[(1.219±0.190)比(1.101±0.118),P<0.001]。对照组介入术前及术后6个月随访ESV、EDV、LVEF及WMSI均无统计学差异(P=0.490、0.259、0.117、0.395)。两组术后6个月生存率及心脏事件发生率无统计学差异。不良反应:在PBSC动员、分离、采集及回输中总的不良反应共25例次,其中动员时不良反应占37.1%(13/35),分离和采集中的不良反应占14.3%(5/35),经冠状动脉回输过程中出现的不良反应占20.0%(7/35)。结论经皮经腔冠状动脉内移植自体PBSC治疗AMI可以在近期有效地减少心肌梗死缺血面积,减轻左室重构,改善心功能。     

Silent versus symptomatic dipyridamole-induced ischemia after myocardial infarction: clinical and prognostic significance.

The prevalence and prognostic significance of silent myocardial ischemia were prospectively assessed in 217 patients (mean age 57 +/- 9 years, 83% male) recovering from a first uncomplicated acute myocardial infarction and undergoing a dipyridamole echocardiography test before hospital discharge. Clinical, angiographic, exercise electrocardiographic (ECG) and dipyridamole echocardiographic variables were also examined. Of the 217 patients, 89 had no echocardiographically proved dyssynergy after dipyridamole, whereas 128 had dipyridamole-induced wall motion abnormalities that were silent in 94 (Group I) and symptomatic in 34 (Group II). There was no intergroup difference with respect to dipyridamole time (i.e., the time from onset of the test to frank dyssynergy: 7 +/- 3 vs. 8 +/- 3 min; p = NS); prevalence of inferior myocardial infarction (69% vs. 71%; p = NS); ischemic ECG changes during the test (83% vs. 71%; p = NS); diabetes (8.5% vs. 6%; p = NS); ongoing medical therapy; multivessel disease (57% vs. 56%; p = NS); and baseline left ventricular ejection fraction (57 +/- 13% vs. 57 +/- 10%; p = NS). There was also no significant difference between Group I and Group II with respect to wall motion score index at peak dipyridamole effect (1.77 +/- 0.39 vs. 1.78 +/- 0.36; p = NS). Patients were followed up for 24 +/- 4 and 25 +/- 5 months, respectively (p = NS). Life table analysis revealed no difference in unstable angina, reinfarction and death between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantification of fatty tissue mass by magnetic resonance imaging in arrhythmogenic right ventricular dysplasia

INTRODUCTION: Arrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder in which the pathological substrate is a fatty or fibro-fatty replacement of the right ventricular (RV) myocardium. METHODS AND RESULTS: Magnetic resonance imaging (MRI) studies were performed in 10 patients with arrhythmogenic right ventricular dysplasia and in 24 matched controls in order to assess right ventricular epicardial/intramyocardial fatty tissue mass, RV myocardial mass, and RV functional parameters. Functional abnormalities were found in all ARVD cases. Patients with ARVD showed increased fatty tissue compared to controls (8.2 +/- 4 g vs. 2.0 +/- 1.0 g; P = 0.001), whereas no significant differences were found in RV myocardial mass (29.5 +/- 9.2 g vs. 23.2 +/- 6.7 g; P = NS). A correlation coefficient between 0.87 and 0.97 was found for repeated measurements. CONCLUSION: Quantification of fatty tissue with MRI is feasible and constitutes an objective method for differentiating normal from pathological conditions. This approach may lead to a complete diagnostic assessment of ARVD with the potential application for monitoring the evolution of the disease.     

Cardiotrophin-1 protects the human myocardium from ischemic injury. Comparison with the first and second window of protection by ischemic preconditioning

BACKGROUND: There are reports suggesting that cardiotrophin 1 (CT-1) is cytoprotective. We investigated the cardioprotective effects of CT-1 on the human myocardium and compared this benefit with the early and delayed protection afforded by ischemic preconditioning (PC). METHODS: Right atrium specimens were prepared and incubated in buffer solution at 37 degrees C for 30 min stabilisation, before entering one of the three following studies. In study 1, muscles (n=6/group) were allocated to one of four groups: (i) aerobic control - incubated in oxygenated media for 210 min, (ii) ischemia alone - 90 min ischemia followed by 120 min reoxygenation, (iii) PC by 5 min ischemia-5 min reoxygenation before 90 min ischemia-120 min reoxygenation and (iv) CT-1 (1 nM) - 90 min ischemia-120 min reoxygenation with exposure to CT-1 throughout the protocol. In study 2, muscles (n=6/group) were allocated to one of four protocols as in study 1with the exception that were incubated for 24 h followed by 30 or 90 min ischemia-120 min reoxygenation on day 2. In study 3, the same groups were employed as in study 2 with the exception that only a 30-min period of ischemia was used and that CT-1 antibody (5 microg/ml) was added to all groups throughout the experimental protocol. Creatine kinase (CK, U/g wet wt.) leakage into the medium and MTT reduction (OD/mg wet wt.), an index of cell viability, were assessed at the end of the experiment. RESULTS: In study 1, a first window of cardioprotection was observed with PC (CK=4.39+/-0.34; MTT=0.58+/-0.03 vs. CK=7.11+/-0.4;MTT=0.32+/-0.02 in the ischemic alone group; P<0.001) but not with CT-1(CK=6.65+/-0. 67; MTT=0.31+/-0.03, P=NS vs. ischemia alone). In study 2, PC applied on day 1 was protective against 30-min ischemia (CK=3.28+/-0. 43; MTT=0.68+/-0.046, P<0.001 vs. ischemia alone) but not against 90-min ischemia (CK=7.13+/-0.66; MTT=0.24+/-0.03, P=NS vs. ischemia alone) induced on day 2 (second window). However, when the tissue was exposed to CT-1 for 24 h, protection was similar to that of PC when subjected to 30 min of ischemia (CK=2.95+/-0.71; MTT=0.77+/-0. 05, P=NS vs. PC) and greater than PC when subjected to 90 min of ischemia (CK=4.56+/-0.51; MTT=0.39+/-0.03, P=0.002 vs. PC). In study 3, the CT-1 antibody did not affect the protection induced by PC (CK=3.36+/-0.6; MTT=0.69+/-0.06) but it abolished the protection obtained with CT-1(CK=5.15+/-0.81; MTT=0.42+/-0.06, P=NS vs. ischemia alone group). CONCLUSIONS: CT-1 exhibits a significant protection of the human myocardium against ischemic injury when tissue is exposed to this factor for a long period (e.g. 24 h) but not when exposed for a short period (e.g. 2 h). In addition, the protection afforded by long exposure to CT-1 is as potent or even greater than the one obtained by the second window of PC. The protection induced by CT-1 but not that induced by PC can be abolished by CT-1 antibody suggesting that their beneficial action is attained by different mechanisms.