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.     

经冠状动脉自体骨髓单个核细胞移植治疗缺血性心力衰竭

目的观察经冠状动脉自体骨髓单个核细胞(mononuclearbonemarrowcell,MBMC)移植治疗缺血性心力衰竭(IHF)的可行性、效果、安全性及不良反应。方法2002年12月至2004年3月,41例缺血性心力衰竭患者入选此前瞻性研究,分为两组。(1)细胞移植组:14例经梗死相关冠状动脉超选择性移植,于气囊充盈下高压注入2mLMBMC(2×106/mL),重复注入6～8次,平均共计(3.28±0.44)×107MBMC;13例经冠状动脉选择性移植,气囊未充盈下高压注入移植细胞,细胞数与上相同。(2)对照常规治疗组:共14例,除细胞移植外其他治疗均相同。结果27例细胞移植患者手术均安全,2例于细胞注入后15～30min感发冷,30min后好转;2例细胞注入时出现短暂自限性室性早搏,术后48h持续心电监测未出现新的心律失常;随访3个月时,细胞移植组心力衰竭症状明显好转,射血分数(EF)和心搏量(SV)增加,左心室收缩末期容积(LVESV)减少,正电子发射体层摄影(PET)心肌代谢显像示代谢活力心肌增加(23.94±7.28)%(P=0.015);术后第3天、第7天脑钠素(BNP)水平较术前明显下降,心钠素(ANP)水平在术后第7天明显上升;随访6个月1例心力衰竭加重再度住院,无一例死亡。对照组心功能恶化,再入院率71.4%,2例死亡。结论自体骨髓单个核细胞经冠状动脉移植修复心肌对改善心功能是安全有效的。     

Catheter-based transendocardial delivery of autologous bone-marrow-derived mononuclear cells in patients listed for heart transplantation

Growing evidence suggests that transplantation of autologous bone-marrow mononuclear cells (ABMMNCs) can improve the perfusion and contractile function of ischemic myocardium. This procedure could potentially benefit transplant candidates awaiting a donor heart. To study the safety and feasibility of ABMMNC injection, we performed a prospective, nonrandomized, open-label study in 5 heart transplant candidates with severe ischemic heart failure. Each patient underwent baseline single-photon emission computed tomography, a ramp treadmill protocol, 2-dimensional echocardiography, 24-hour Holter monitoring, and signal-averaged electrocardiography, which were repeated at 2 and 6 months. Transendocardial delivery of ABMMNCs was done with the aid of electromechanical mapping to identify viable myocardium. Each patient received 15 ABMMNC injections of 0.2 cc each. There were no deaths, significant arrhythmias, or other major complications. The ABMMNC injection reduced the amount of ischemic myocardium (not statistically significant). More important, exercise test results improved significantly. Myocardial volume oxygen consumption increased from 10.6 +/- 3 mL/kg/min (baseline) to 16.3 +/- 7 mL/kg/min (2 months) and 23 +/- 7 mL/kg/min (6 months) (P = 0.0091). In 4 of the 5 cases, this was such an improvement that the patients were no longer eligible for cardiac transplantation. In addition, metabolic equivalents improved from 3.03 +/- 0.66 (baseline) to 4.65 +/- 1.99 (2 months) and 6.5 +/- 2.0 (6 months) (P = 0.0092). In conclusion, ABMMNC injections were performed safely and resulted in improved exercise capacity. This technique may hold promise as an alternative to medical management in patients with severe ischemic heart failure who are ineligible for conventional revascularization.     

自体骨髓单个核细胞移植治疗冠心病心力衰竭的临床研究

目的:评价经冠状动脉内注射自体骨髓单个核细胞治疗冠心病心力衰竭患者的有效性。方法:82例冠心病心力衰竭患者随机入选本项前瞻性、对照试验(其中49例患者为细胞移植组,33例为常规治疗组)。2组患者均接受标准药物治疗,细胞移植组49例患者同时接受自体骨髓单个核细胞移植。1年后随访临床情况及超声心动图、单光子放射计算机断层显像术和血浆脑钠肽测定结果,比较2组治疗前后心功能指标和心肌灌注缺损区面积。结果:细胞移植组与常规治疗组比较,左室射血分数增加,心肌灌注缺损面积降低,血浆脑钠肽下降,差异均有统计学意义(P<0.05)。结论:经皮冠状动脉内移植骨髓单个核细胞治疗冠心病心力衰竭,能有效改善左室收缩功能和心肌灌注。     

经冠状动脉骨髓单个核细胞移植治疗重度心力衰竭

目的本研究对比观察一组治疗上除心脏移植外,不能或难于从其他任何治疗中获益的重度缺血性心力衰竭(end-stage ischemia heart failure,EIHF)患者,给予经冠状动脉自体骨髓单个核细胞(bone marrow mononuclear cells,BM-MNCs)移植,探索其治疗的可行性、安全性及不良反应。方法30例EIHF患者入选。分为:细胞移植组(n=16)和常规治疗组(n=14)。细胞移植组和常规治疗组治疗前、后随访观察临床表现、实验室检查、二维超声心动图、正电子断层心肌显像(PET)、Holter、血管活性肽等。梯度密度法分离自体BM-MNCs。细胞移植组:经冠状动脉选择性细胞移植,平均BM-MNCs(5．0±0．7)×107。常规治疗组:除细胞移植外其他治疗均同细胞移植组。结果16例细胞移植手术均安全。2例于细胞注入后15-30 min感全身发冷,30 min后好转。1例细胞注入时出现短暂自限性室性早搏。术后48 h持续心电监测未出现新的心律失常。细胞移植组:术后观察半年患者均未再发急性肺水肿,心力衰竭症状明显改善。3个月NYHA分级明显改善[(3．4±0．1)级→(2．4±0．2)级,P<0．001];左心室射血分数(LVEF)于术后7天、3个月分别较术前增加9．6％(P<0．05)、9．9％(P<0．001);:PET显示代谢活力心肌增加(10．3±3．4)％(P<0．01)。血浆脑型利钠肽(brain-type natriuretic peptide,BNP)显著降低,3天、7天分别较术前下降69．2％(P<0．05)、70．4％(P<0．05);心房利钠肽(atrial natriuretic peptide,ANP)增加,术后第7天为术前1．3倍(P< 0．05);6个月随访无一例死亡,仅1例心力衰竭加重住院。而对照组3个月心功能检测明显恶化; NYHA分级下降[(3．5±0．1)级→(3．9±0．1)级,P<0．05];LVEF较术前减低7．2％(P<0．001),与细胞移植组相比差异有显著统计学意义(P<0．001);6个月随访死亡2例;因心力衰竭恶化再住院率71．4％(10／14)。结论自体BM-MNCs经冠状动脉移植治疗EIHF患者是安全有效的,显著改善了近期预后。     

Clinical experience of the use of autologous mononuclear bone marrow cells in patients with ischemic heart disease and dilated cardiomyopathy

Between March 2003 and February 2005 cell therapy with mononuclear bone marrow cells (MBMC) was used in 38 and 4 patients with ischemic heart disease and dilated cardiomyopathy, respectively. Intracardiac administration of MBMC (87+/-12 millions) was carried out during coronary artery bypass surgery and/or left ventricular aneurysm resection (n=25) or in cardiac catheterization laboratory (n=17). For verification of cells fixation they were labeled with "Ceretec" 99mTc-HMPAO. Accumulation of labeled cells after 24 hours was 1.6+/-0.001%. After 6 months parameters of intracardiac hemodynamics and transitory myocardial perfusion defects improved significantly in all patients with ischemic heart disease.     

A dosing study of bone marrow mononuclear cells for transendocardial injection in a pig model of chronic ischemic heart disease

We studied the effect of the dose of bone marrow mononuclear cells, delivered via transendocardial injection, upon capillary density and fibrosis in pigs with chronic ischemic heart disease.Pigs (n = 16) that had undergone ameroid constrictor placement (left circumflex coronary artery) to induce chronic ischemia were divided equally into 4 groups on the basis of bone marrow mononuclear cell dose: control (saline injection) and 50, 100, or 200 × 10(6) bone marrow mononuclear cells. Thirty days after ameroid placement, each pig received 13 transendocardial NOGA-guided injections. An implantable loop recorder monitored possible arrhythmias caused by cell transplantation. Thirty days later, the pigs were killed, and their hearts were evaluated histopathologically for fibrosis and capillary density; the number of cells per segment was correlated with fibrosis and capillary density. No adverse events, arrhythmias, or cardiac inflammatory reactions were associated with cell therapy. Less fibrosis was seen in pigs that received 100 × 10(6) cells than in control pigs. A trend toward higher capillary density was seen with higher cell concentrations. Segments injected with more than 20 × 10(6) million cells had the highest capillary density and the least amount of fibrosis (P < 0.05 vs controls).In conclusion, transendocardial injections (up to 200 × 10(6) bone marrow mononuclear cells) were safe. Analyses of individual injected segments suggest potential benefit from higher cell concentrations per segment.     

自体骨髓单个核细胞移植治疗肝硬化的临床评价

目的探讨肝动脉插管自体骨髓单个核细胞（BM—MNCs）移植治疗肝硬化的安全性、可行性及疗效。方法201例肝硬化患者,其中131例进行自体骨髓单个核细胞移植,70例作为对照组。骨穿采集自体骨髓体外分离纯化骨髓单个核细胞。经肝动脉插管将其移植入肝脏。分别于移植后4、8、12、24周观察血清白蛋白（ALB）、胆碱酯酶（CHE）、凝血酶原活动度（PTA）及总胆红素（TBil）变化情况,观察患者并发症及预后。结果移植组患者移植前血清ALB、CHE及PTA分别为29．33g／L、2387．4U／L和46．4％。移植后4周分别升至32．37g／L、2875．9U／L和53．54％,12周分别为32．95g／L、3190．6U／L和57．24％,24周则分别为32．22g／L、3066．5U／L和56．02％。患者移植后24、周内血清ALB、CHE和PTA水平较治疗前均显著升高,而对照组则无明显升高,两组比较差异有统计学意义。而血清TBil在移植后24周内改善情况与对照组相比差异无统计学意义。两组患者24周内主要并发症发生率及预后情况差异无统计学意义。移植后无严重不良事件发生。结论自体骨髓单个核细胞移植能改善肝硬化患者肝脏合成能力,并有良好的安全性。     

自体骨髓单个核细胞移植治疗扩张型心肌病疗效观察

目的 观察扩张型心肌病患者经冠状动脉自体骨髓单个核细胞移植治疗的安全性及近中期疗效.方法 258例扩张型心肌病患者,传统治疗的基础上,根据是否行经冠状动脉自体骨髓单个核细胞移植分为移植组(n=71)和对照组(n=187).随访两组患者术前、术后1、3、6个月和1、2年超声心动图、动态心电图、6 min步行距离及心脏核素(SPECT)检查,记录年住院天数.结果 移植组6 min步行距离术后1个月明显优于对照组[(345±76)m比(286±104)m,P<0.05].术后各随访时间点比较,移植组均优于对照组(P<0.05).术后1个月,移植组左心窜射血分数(LVEF)明显高于对照组[(41.5±9.4)%比(37.3±6.6)%,P<0.05].术后2年时移植组LVEF略高于对照组,差异无统计学意义[(43.6±6.3)%比(43.2±6.0)%,P>0.05].术后3个月移植组缺血心肌节段数较术前减少,且较对照组少[分别为(2.0±1.0)个比(3.1±1.4)个和(2.0±1.0)个比(3.1±1.2)个,P均<0.05],而坏死心肌节段数移植前后无明显改变.两组患者牛存率比较,差异无统计学意义(95.4%比94.9%,P>0.05).但移植组患者年住院天数明显少于对照组[(23.6±13.4)d比(33.0±14.0)d,P<0.05].结论 经冠状动脉自体骨髓单个核细胞移植具有良好的安全性,能够提高扩张型心肌病患者的LVEF、增加6 min步行距离,减少年住院大数,且近期疗效显著,中期疗效与传统治疗相似.     

经冠状动脉注入自体骨髓单个核细胞的临床研究

目的评价经冠状动脉内注射自体骨髓单个核细胞治疗心肌梗死患者的有效性。方法共有35例前壁心肌梗死患者人选本项前瞻性、非随机、开放试验（其中20例患者为细胞移植组,15例为对照组）。两组患者均接受标准的介入治疗和药物治疗,细胞移植组的20例患者同时接受自体骨髓单个核细胞移植。两组患者均接受3个月的临床随访及6min步行试验、超声心动图、心肌双核素和心脏核磁等检查。结果3个月的检查结果提示,细胞移植组患者的左室射血分数与常规治疗组相比有显著统计学意义。同时细胞移植组患者的室间隔中段室壁运动位移和左室收缩末容积也有明显改变,细胞移植组显著增加代谢可恢复心肌区占左室的比例。结论经冠状动脉注入自体骨髓单个核细胞可以促进心肌梗死患者寿窜功能恢复和心肌灌沣改善．     

前壁心肌梗死患者自体骨髓单个核细胞移植治疗的可行性研究

目的　评价经冠状动脉内注射自体骨髓单个核细胞治疗心肌梗死患者的可行性。方法　本项前瞻性、非随机、对照研究入选2 2例陈旧性前壁心肌梗死患者(其中1 4例患者为细胞治疗组,8例患者为常规治疗组)。两组患者均接受标准的介入治疗和药物治疗,细胞移植组的1 4例患者采用Over the Wire(OTW )球囊导管将自体骨髓单个核细胞缓慢注入前降支。结果　细胞移植组中1例患者因支架内急性血栓形成而死亡。其余1 3例和常规治疗组的8例患者术中及术后无心肌缺血及心律失常的发生。两组患者均于术后3个月和6个月随访,并行6分钟步行试验、超声心动图、心肌双核素和心脏核磁等检查。3个月的检查结果提示,细胞移植组左室射血分数[( 4 0 .1 2±5 .52 ) %vs( 50 . 37±7. 31 ) % ,P =0 . 0 0 0 1 ],与常规治疗组差异有统计学意义[( 50 .37±7 .31 ) %vs ( 4 4. 0 9±3 .50 ) % ,P =0 . 0 35]。结论　前壁心肌梗死患者经冠状动脉内行自体骨髓单个核细胞移植具有良好的可行性,可以显著改善左室收缩功能。     

Pulmonary function and exercise capacity six months after hospital discharge of patients with severe COVID-19

IntroductionThe long-term consequences of COVID-19, especially pulmonary impairment, are frequent but not well understood. The knowledge about sequels or long COVID-19 are necessary, considering the high prevalence and need for specific public strategies.MethodThe study was conducted to evaluate symptoms (standardized questionnaire), pulmonary function (spirometry), and exercise capacity (6-minute-walk-test) at 30 (D30), 90 (D90), and 180 (D180) days after hospital discharge of patients surviving to severe COVID-19. We excluded in this follow up patients with comorbidities before COVID infection.Results44 patients were included and 31 (26 men) completed the 6-month follow-up (age mean 53.6 ± 9.6 years). At D180, 28% presented still at least one symptom. The most common was dyspnea (17.2%), followed by cough (13.8%), and myalgia (10.3%). All spirometric parameters showed progressive improvement from D30 to D180. However, 16% maintained a restrictive pattern on spirometry test, 44% presented desaturation on the 6-minute walk-test, and 25% walked < 75% of the predicted value.Conclusion6-months after hospital discharge, reduced pulmonary function and reduced exercise capacity was founded frequently and more than a quarter remained symptomatic. The persistent symptoms and functional impairment suggest that sequels and development of Long COVID-19 are very common. The identification of these patients to provide the necessary health care is a challenging task, considering the large number of patients infected and surviving to COVID-19 disease.     

Allogeneic bone marrow transplantation in patients with lymphoma relapsing after autologous marrow transplantation

Two patients who underwent autologous bone marrow transplantation for recurrent non-Hodgkin's lymphoma relapsed at 46 and 28 days after the transplant. Both patients had an HLA-identical sibling and were treated with high-dose chemotherapy and allogeneic marrow transplantation. One patient is now 24 months after the allogeneic transplant without evidence of disease. The second patient died on day 7 with interstitial pneumonia. We conclude that high-dose therapy and allogeneic bone marrow transplantation after failure of autologous transplantation for non-Hodgkin's lymphoma is feasible and should be considered in young patients with HLA-identical siblings.     

骨髓单个核细胞移植对缺血性心肌病患者血浆利钠肽水平的影响

目的:观察骨髓单个核细胞(mononuclear bone marrow cell,MBMC)移植对缺血性心肌病患者左心功能及血浆利钠肽的影响。方法:36例缺血性心肌病患者分为细胞移植组24例和常规治疗组12例。结果:治疗3d后移植组及对照组心房利钠肽(atrial natriuretic peptide,ANP)、脑利钠肽(brain natriuretic peptide,BNP)均无明显变化,治疗7d后,移植组BNP下降了67.76%,对照组下降了24.1%;移植组ANP上升36.65%,而对照组下降14%,超声心动图结果显示:移植组左心室射血分数(LVEF)由(34.8±1.27)%升至(44.45±2.08)%(P<0.001),对照组LVEF由(36.20±3.80)%升至(38.97±2.76)%(P<0.05)。结论:MBMC经冠状动脉移植后早期(1周内)可明显改善心力衰竭患者的心功能,其机制之一可能为外源ANP生成而发挥的利钠、利尿、扩血管作用。