Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up

OBJECTIVES: We report on the procedural and six-month results of the first percutaneous and stand-alone study on myocardial repair with autologous skeletal myoblasts. BACKGROUND: Preclinical studies have shown that skeletal myoblast transplantation to injured myocardium can partially restore left ventricular (LV) function. METHODS: In a pilot safety and feasibility study of five patients with symptomatic heart failure (HF) after an anterior wall infarction, autologous skeletal myoblasts were obtained from the quadriceps muscle and cultured in vitro for cell expansion. After a culturing process, 296 +/- 199 million cells were harvested (positive desmin staining 55 +/- 30%). With a NOGA-guided catheter system (Biosense-Webster, Waterloo, Belgium), 196 +/- 105 million cells were transendocardially injected into the infarcted area. Electrocardiographic and LV function assessment was done by Holter monitoring, LV angiography, nuclear radiography, dobutamine stress echocardiography, and magnetic resonance imaging (MRI). RESULTS: All cell transplantation procedures were uneventful, and no serious adverse events occurred during follow-up. One patient received an implantable cardioverter-defibrillator after transplantation because of asymptomatic runs of nonsustained ventricular tachycardia. Compared with baseline, the LV ejection fraction increased from 36 +/- 11% to 41 +/- 9% (3 months, p = 0.009) and 45 +/- 8% (6 months, p = 0.23). Regional wall analysis by MRI showed significantly increased wall thickening at the target areas and less wall thickening in remote areas (wall thickening at target areas vs. 3 months follow-up: 0.9 +/- 2.3 mm vs. 1.8 +/- 2.4 mm, p = 0.008). CONCLUSIONS: This pilot study is the first to demonstrate the potential and feasibility of percutaneous skeletal myoblast delivery as a stand-alone procedure for myocardial repair in patients with post-infarction HF. More data are needed to confirm its safety.     

Autologous myoblast transplantation for chronic ischemic mitral regurgitation.

OBJECTIVES: This study was designed to assess whether post-myocardial infarction (MI) in-scar transplantation of skeletal myoblasts (SM) could reduce chronic ischemic mitral regurgitation (MR) by decreasing left ventricular (LV) remodeling. BACKGROUND: Extensive work has confirmed the relationship between ischemic MR and post-myocardial infarction (MI) remodeling of the LV. METHODS: An infero-posterior MI was created in 13 sheep, thereby resulting in increasing MR. Two months post-MI, the animals were randomized and in-scar injected with expanded autologous SM (n = 6, mean: 251 x 10(6) cells) or culture medium only (n = 7). Three-dimensional echocardiography was performed at baseline, before transplantation, and for two months thereafter (sacrifice), with measurements of LV end-diastolic and end-systolic volumes (ESV), ejection fraction (EF), MR stroke volume, and leaflet tethering distance; wall motion score index (WMSi) was assessed by two-dimensional echo. RESULTS: Measurements were similar between groups at baseline and before transplantation. At sacrifice, transplantation was found to have reduced MR progression (regurgitant volume change: -1.83 +/- 0.32 ml vs. 5.9 +/- 0.7 ml in control group, p < 0.0001) and tethering distance (-0.41 +/- 0.09 cm vs. 0.44 +/- 0.12 cm in control group, p < 0.001), with significant improvement of EF (2.01 +/- 0.94% vs. -4.86 +/- 2.23%, p = 0.02), WMSi (-0.25 +/- 0.11 vs. 0.13 +/- 0.03 in controls, p < 0.01) and a trend to a lesser increase in ESV (23.3 +/- 3.5 ml vs. 35.4 +/- 4.2 ml in control group, p = 0.055). CONCLUSIONS: Autologous skeletal myoblast transplantation attenuates mild-to-moderate chronic ischemic MR, which otherwise is progressive, by decreasing tethering distance and improving EF and wall motion score, thereby enhancing valve coaptation. These data shed additional light on the mechanism by which skeletal myoblast transplantation may be cardioprotective.     

Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction

OBJECTIVES: This phase I trial was designed to assess the feasibility and safety of autologous skeletal myoblast transplantation in patients with severe ischemic cardiomyopathy. BACKGROUND: Experimentally, myoblast grafting into postinfarction myocardial scars improves left ventricular function. METHODS: Ten patients were included on the basis of the following criteria: 1) severe left ventricular dysfunction (ejection fraction < or = 35%); 2) the presence of a postinfarction akinetic and nonviable scar, as assessed by dobutamine echocardiography and 18-fluorodeoxyglucose positron emission tomography; and 3) an indication of coronary bypass in remote areas. Skeletal myoblasts were grown from a biopsy taken at the thigh. RESULTS: An average of 871 x 10(6) cells (86% of myoblasts) were obtained after a mean period of 16 days and implanted uneventfully across the scar at the time of bypass. Except for one patient whose early death was unrelated to the cell transplantation, all patients had an uncomplicated postoperative course. Four patients showed delayed episodes of sustained ventricular tachycardia and were implanted with an internal defibrillator. At an average follow-up of 10.9 months, the mean New York Heart Association functional class improved from 2.7 +/- 0.2 preoperatively to 1.6 +/- 0.1 postoperatively (p < 0.0001), and the ejection fraction increased from 24 +/- 1% to 32 +/- 1% (p < 0.02). A blinded echocardiographic analysis showed that 63% of the cell-implanted scars (14 of 22) demonstrated improved systolic thickening. One noncardiac death occurred 17.5 months after transplantation. CONCLUSIONS: These preliminary data suggest the feasibility and safety of autologous skeletal myoblast transplantation in severe ischemic cardiomyopathy, with the caveat of an arrhythmogenic potential. New-onset contraction of akinetic and nonviable segments suggests a functional efficacy that requires confirmation by randomized studies.     

Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction.

AIM: Experimental animal studies suggest that the use of skeletal myoblast in patients with myocardial infarction may result in improved cardiac function. The aim of the study was to assess the feasibility and safety of this therapy in patients with myocardial infarction. METHODS AND RESULTS: Twelve patients with old myocardial infarction and ischaemic coronary artery disease underwent treatment with coronary artery bypass surgery and intramyocardial injection of autologous skeletal myoblasts obtained from a muscle biopsy of vastus lateralis and cultured with autologous serum for 3 weeks. Global and regional cardiac function was assessed by 2D and ABD echocardiogram. 18F-FDG and 13N-ammonia PET studies were used to determine perfusion and viability. Left ventricular ejection fraction (LVEF) improved from 35.5+/-2.3% before surgery to 53.5+/-4.98% at 3 months (P=0.002). Echocardiography revealed a marked improvement in regional contractility in those cardiac segments treated with skeletal myoblast (wall motion score index 2.64+/-0.13 at baseline vs 1.64+/-0.16 at 3 months P=0.0001). Quantitative 18F-FDG PET studies showed a significant (P=0.012) increased in cardiac viability in the infarct zone 3 months after surgery. No statistically significant differences were found in 13N-ammonia PET studies. Skeletal myoblast implant was not associated with an increase in adverse events. No cardiac arrhythmias were detected during early follow-up. CONCLUSIONS: In patients with old myocardial infarction, treatment with skeletal myoblast in conjunction with coronary artery bypass is safe and feasible and is associated with an increased global and regional left ventricular function,improvement in the viability of cardiac tissue in the infarct area and no induction of arrhythmias.     

Stress and tissue Doppler echocardiographic evidence of effectiveness of myoblast transplantation in patients with ischaemic heart failure

BACKGROUND: There is experimental evidence that transplanting skeletal myoblasts (SM) into the post-infarction myocardial scar improves regional and global left ventricular (LV) function. AIMS: To evaluate short- and long-term regional and global LV functional effects of percutaneously transplanted SM in patients with ischaemic heart failure. METHODS AND RESULTS: Ten patients (mean age 60+/-10 years, 8 males) with dilated ischaemic cardiomyopathy underwent percutaneous injection of autologous myoblasts. Regional and global LV function was evaluated by 2-dimensional echocardiography and tissue Doppler imaging (TDI) at rest and during low-dose dobutamine infusion to assess contractile reserve. After a baseline examination, sequential follow-ups were performed at 1, 3, and 6 months and 1 year. NYHA functional class decreased from 2.7+/-0.5 to 1.9+/-0.5 (p<0.01) at one year. LV function and volumes at rest remained unchanged while contractile reserve significantly improved during follow-up. At low-dose dobutamine infusion, the peak systolic velocity in the regions of myoblasts injection significantly increased at TDI examination (from 7.7+/-2.1 to 8.6+/-1.8 cm/s, p=0.02); LV ejection fraction improved (from 40+/-9% to 46+/-8%, p<0.0001) and end-systolic volumes decreased (from 56+/-28 to 50+/-25 ml/m(2), p=0.001) at 1 year. CONCLUSION: In patients with ischaemic heart failure, percutaneous injection of autologous myoblasts may improve regional and global LV systolic function during dobutamine infusion, at 1-year follow-up.     

Leptin: a parameter for metabolic changes in heart failure

OBJECTIVE: Advanced chronic heart failure is a hypercatabolic state with an imbalance between anabolic and catabolic metabolism and finally progressive loss of both muscle mass and adipose tissue. Leptin, the product of the obesity gene, is a hormone secreted by adipocytes. Therefore, we tested the hypothesis that plasma leptin concentrations are reduced in advanced chronic heart failure. METHODS: In 20 patients with chronic congestive heart failure (LVEF 23 +/- 6%) and 20 healthy controls (LVEF 65 +/- 8%) matched for gender, age, and body mass index, fasting plasma leptin (ELISA) and TNF alpha (ELISA) were measured. Follow-up examination was performed after 1 year. RESULTS: The fasting plasma leptin concentrations of patients with NYHA grade III (8.4 +/- 3.8 ng/ml*) and NYHA grade IV (4.6 +/- 2.4 ng/ml dagger) were significantly lower as compared with the controls (11.2 +/- 3.1 ng/ml; *p < 0.05, dagger p < 0.01). In patients with NYHA grade II plasma leptin levels were significantly elevated as compared with the healthy controls (14.9 +/- 4.2 ng/ml). TNF alpha was higher in heart failure patients than in healthy controls (8.6 +/- 3.6 pg/ml; 5.9 +/- 2.1 pg/ml; respectively; p < 0.05), but did not correlate with the NYHA functional class. Mortality of the controls was 0%, whereas 15% (n = 3) in the congestive heart failure group; one patient (5%) needs an urgent heart transplantation. All of those patients had leptin concentrations below 5 ng/ml. CONCLUSIONS: Plasma leptin concentrations correlate with the NYHA functional class suggesting anabolic metabolism in NYHA class II and catabolic metabolism in advanced heart failure which might be of prognostic relevance.     

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。     

Repeated implantation is a more effective cell delivery method in skeletal myoblast transplantation for rat myocardial infarction.

BACKGROUND: Several clinical trials are underway to determine whether autologous skeletal myoblast transplantation is an effective and safe therapeutic strategy for severe heart failure due to myocardial infarction (MI). It remains unclear whether repeated skeletal myoblast implantation is a feasible and effective cell delivery method for the infarcted myocardium. METHODS AND RESULTS: Four weeks after a coronary ligation, male syngeneic Lewis rats were assigned to 3 treatment groups: 3 episodes of skeletal myoblasts (6x10(6)) transplantation (group I), a bolus transplantation of myoblasts (18x10(6)) (group II), or culture medium injection (group III). Eight weeks after the first treatment, echocardiography, cardiac catheterization and histological examination were performed to compare the therapeutic effects on left ventricular (LV) systolic and diastolic functions, and the engrafted myoblast volume. Repeated myoblast implantation significantly improved LV function and resulted in significantly larger engrafted volume and LV contractility compared with a bolus transplantation with the same number of myoblasts. CONCLUSIONS: Repeated skeletal myoblast transplantation is a safe and effective therapeutic strategy for the infarcted myocardium.     

Functional assessment of myoblast transplantation for cardiac repair with magnetic resonance imaging

BACKGROUND: Contraction of transplanted myoblasts and their effects on function and remodeling after myocardial infarction remain controversial. AIM: We used magnetic resonance imaging (MRI) to study wall thickening and left ventricular (LV) function and geometry after myoblast transplantation. METHODS AND RESULTS: Three weeks after cryo-infarction rabbits were randomized to receive an injection of approximately 2 x 10(8) myoblasts (n=8) or medium (n=9) into the scar. Cine MRI and contrast enhanced (ce) MRI images were acquired before injection (baseline) and 4 weeks later (endpoint). Regional wall thickening was measured at the site of transmural hyperenhancement. In the control group, regional wall thickening decreased to -15.3+/-8.6% at baseline, which further decreased to -18.3+/-5.7% at endpoint. Further, end-diastolic volume increased from 3.96+/-0.27 to 5.00+/-0.46 ml and end-systolic volume from 2.23+/-0.19 to 2.96+/-0.30 ml (both P<0.05 vs. baseline), which was accompanied by increased LV wall volumes (P<0.05 vs. baseline). In contrast, myoblast transplantation increased regional wall thickening from -11.9+/-15.9% at baseline to 26.9+/-17.0% (P<0.05 vs. control), which resulted in significantly improved two-dimensional ejection fractions at the infarct level and prevented the increase in end-diastolic and end-systolic volumes and wall volume. CONCLUSION: Intracardiac myoblast transplantation after myocardial infarction improves regional wall thickening and prevents progressive left ventricular remodeling.     

Prognostic value of cardiopulmonary exercise testing in children with heart failure secondary to idiopathic dilated cardiomyopathy in a non-beta-blocker therapy setting

BACKGROUND: Peak oxygen consumption and resting left ventricular ejection fraction (LVEF) are independent predictors of survival in adult heart failure (HF) patients. Aim: To evaluate these factors in children. METHODS: We prospectively studied 31 children with NYHA class I to III HF (mean LVEF 26+/-10%; mean age 8.6+/-1.9 years). All had dilated cardiomyopathy and were awaiting heart transplantation. A cardiopulmonary treadmill exercise test was performed and LVEF determined by radionuclide ventriculography. RESULTS: During a median follow-up of 1282 days, 20 children reached at least one end-point (death or heart transplantation). Clinical data from the 11 children without events and the 20 children with events are as follows: NYHA class 1+/-0 vs. 2+/-0.9 (p<0.01); SBP 118+/-17 vs. 102+/-16 (p=0.01); DBP 70+/-10 vs. 61+/-10 (p=0.02); heart rate 165+/-22 vs. 148+/-22 (NS); double-product 19+/-4 vs. 15+/-4 (p=0.01); end-tidal carbon dioxide tension (PetCO2) 35+/-5 vs. 30+/-6 (NS); oxygen consumption (VO2) 22+/-5.4 vs. 18.3+/-5.7 (NS); exercise time 19+/-4 vs. 13+/-6 (p<0.003), and LVEF 31+/-8 vs. 22+/-10 (p=0.02). These variables all correlated with prognosis on univariate analysis. In multivariate analysis, only decreasing exercise time and LVEF were predictive of events during follow-up (p<0.001 and 0.04). CONCLUSION: These findings suggest that reduction in LVEF and exercise tolerance in children with heart failure is predictive of functional status.     

Improvement of left ventricular ejection fraction, heart failure symptoms and prognosis after revascularization in patients with chronic coronary artery disease and viable myocardium detected by dobutamine stress echocardiography.

OBJECTIVES: This study was designed to address, in patients with severe ischemic left ventricular dysfunction, whether dobutamine stress echocardiography (DSE) can predict improvement of left ventricular ejection fraction (LVEF), functional status and long-term prognosis after revascularization. BACKGROUND: Dobutamine stress echocardiography can predict improvement of wall motion after revascularization. The relation between viability, improvement of function, improvement of heart failure symptoms and long-term prognosis has not been studied. METHODS: We studied 68 patients with DSE before revascularization; 62 patients underwent resting echocardiography/radionuclide ventriculography before and three months after revascularization. Long-term follow-up data (New York Heart Association [NYHA] functional class, Canadian Cardiovascular Society [CCS] classification and events) were acquired up to two years. RESULTS: Patients with > or =4 viable segments on DSE (group A, n = 22) improved in LVEF at three months (from 27+/-6% to 33+/-7%, p < 0.01), in NYHA functional class (from 3.2+/-0.7 to 1.6+/-0.5, p < 0.01) and in CCS classification (from 2.9+/-0.3 to 1.2+/-0.4, p < 0.01); in patients with <4 viable segments (group B, n = 40) LVEF and NYHA functional class did not improve, whereas CCS classification improved significantly (from 3.0+/-0.8 to 1.3+/-0.5, p < 0.01). A higher event rate was observed at long-term follow-up in group B versus group A (47% vs. 17%, p < 0.05). CONCLUSIONS: Patients with substantial viability on DSE demonstrated improvement in LVEF and NYHA functional class after revascularization; viability was also associated with a favorable prognosis after revascularization.     

Influence of patient-prosthesis mismatch on long-term results after aortic valve replacement with a stented bioprosthesis

BACKGROUND AND AIMS OF THE STUDY: The study aim was to compare long-term results of bioprostheses implanted in the aortic position, with and without patient-prosthesis mismatch (defined as effective orifice area (EOA)/body surface area (BSA) < or =0.85 cm2/m2). METHODS: Between 1986 and 1990, 90 consecutive patients (mean age 72.6 years; mean BSA 1.77+/-0.2 m2) each received an aortic Medtronic Intact valve (19 mm, n = 35; 21 mm, n = 29; >23 mm, n = 26). Of these patients, 64 had a patient-prosthesis mismatch, and 26 had no mismatch. Median follow up was 7.3 years. RESULTS: At 10 years postoperatively, there was no significant inter-group difference in actuarial freedom from thromboembolism (90.7% in mismatch group, 79.6% in no-mismatch group; p = 0.16), hemorrhage (86% versus 83.3%; p = 0.59), endocarditis (98.2% versus 86.7%; p = 0.1), structural valve deterioration (97% versus 100%; p = 0.57) and reoperation (96.4% versus 94.8%; p = 0.2). At the same time, overall actuarial survival was 42.1+/-6.5% in the mismatch group and 22.6+/-8.6% in the no-mismatch group (p = 0.08). By multivariate analysis, the main risk factor for late death was a preoperative left ventricular ejection fraction (LVEF) <50% (p = 0.001). Freedom from cardiac death was 70+/-6% and 35.7+/-11% in the mismatch and no-mismatch groups respectively (p = 0.005), but this was not significantly different when LVEFs were paired (LVEF >50% p = 0.33, LVEF <50% p = 0.28). The NYHA functional status of survivors showed 94.4% of the mismatch group and 100% of the no-mismatch group to be in NYHA classes I and II (p = 1). CONCLUSION: Within this patient population it was not possible to demonstrate any negative effects of patient-prosthesis mismatch at 10 years after Intact aortic valve replacement; the LVEF was the only predictor for late death.     

Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with refractory, advanced chronic heart failure

BACKGROUND: In advanced chronic heart failure (CHF) 20% of patients do not tolerate beta-blockers and 50% do not reach target doses. AIM: To test whether levosimendan or prostaglandin E1 (PGE1) can facilitate uptitration of beta-blockers in advanced CHF. METHODS AND RESULTS: Seventy-five advanced CHF patients (LVEF<35%, NYHA class IIIb or IV) intolerant to beta-blocker uptitration to target doses (10 mg bisoprolol/day) were randomised to a monthly 24 h infusion with levosimendan (n=39) or a chronic infusion with PGE1 (n=36) for 3 months. Bisoprolol was uptitrated following predefined criteria. At 12 weeks, bisoprolol dose increased from 4 mg to 10 mg in both groups. Heart failure worsening occurred in 29 levosimendan patients (74%) versus 16 PGE1 patients (44%, p=0.008). Uptitration was impossible in 9 levosimendan patients (23%) versus 2 PGE1 patients (6%, p=0.03). The combined endpoint of death or urgent heart transplantation or implantation of a ventricular assist device was reached by 12 levosimendan patients (31%) versus 4 PGE1 patients (11%, p=0.04). After 1 year, LVEF increased from 23+/-7% to 28+/-11% (p=0.0004), and BNP decreased from 994+/-806 to 659+/-564 pg/ml (p=0.03). CONCLUSION: Levosimendan and PGE1 facilitate uptitration of beta-blockers in previously intolerant CHF patients. PGE1 treatment allowed uptitration in more patients and resulted in a better clinical outcome compared to levosimendan. This approach increased LVEF and decreased BNP after 1 year.     

Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial).

AIMS: Experimental studies have demonstrated that bone marrow (BM) cells can induce angiogenesis in ischaemic myocardium. Recently, several non-randomized pilot studies have also suggested that direct BM cells implantation appears to be feasible and safe in patients with severe coronary artery diseases (CAD). METHODS AND RESULTS: We performed a randomized, blinded, and placebo-controlled trial in 28 CAD patients. After BM harvesting, we assigned patients to receive low dose (1 x 10(6) cells/0.1 mL, n = 9), high dose (2 x 10(6) cells/0.1 mL, n = 10) autologous BM cells or control (0.1 mL autologous plasma/injection, n = 9) catheter-based direct endomyocardial injection as guided by electromechanical mapping. Our primary endpoint was the increase in exercise treadmill time and our secondary endpoints were changes in Canadian Cardiovascular Society (CCS) and New York Heart Association (NYHA) class, and myocardial perfusion and left ventricular ejection fraction (LVEF) assessed by single-photon emission computed tomography and magnetic resonance imaging, respectively. A total 422 injections (mean 14.6 +/- 0.7 per patient) were successfully performed at 41 targeted ischaemic regions without any acute complication. Baseline exercise treadmill time was 439 +/- 182 s in controls and 393 +/- 136 s in BM-treated patients, and changed after 6 months to 383 +/- 223s and 464 +/- 196 s [BM treatment effect +0.43 log seconds (+53%), 95% CI 0.11-0.74, P = 0.014]. Compared with placebo injection, BM implantation was associated with a significant increase in LVEF (BM treatment effect +5.4%, 95% CI 0.4-10.3, P = 0.044) and a lower NYHA class (odds ratio for treatment effect 0.12, 95% CI 0.02-0.73, P = 0.021) after 6 months, but CCS reduced similarly in both groups. We observed no acute or long-term complications, including ventricular arrhythmia, myocardial damage, or development of intramyocardial tumour or calcification associated with BM implantation. CONCLUSION: Direct endomyocardial implantation of autologous BM cells significantly improved exercise time, LVEF, and NYHA functional class in patients with severe CAD who failed conventional therapy.     

Skeletal myoblast transplantation through a catheter-based coronary sinus approach: an effective means of improving function of infarcted myocardium.

AIMS: This study was designed to assess the functional effects of a transvenous coronary sinus technique of skeletal myoblast delivery in infarcted myocardium. METHODS AND RESULTS: An anterior myocardial infarction was created percutaneously in 14 sheep. Simultaneously, a muscle biopsy was harvested and expanded. Two weeks later, sheep were instrumented percutaneously with a dedicated catheter incorporating an extendable needle for puncture of the venous wall and, under endovascular ultrasound guidance, a microcatheter was advanced through the needle into the target scar for cell delivery. Following the baseline echocardiographic assessment of left ventricular (LV) function, sheep were randomly allocated to receive four-staged in-scar injections of either autologous cells (n=7) or culture medium (n=7). Two months later, LV function was reassessed blindly and hearts were explanted for subsequent histological and immunohistochemical analysis. There were no acute procedural complications. Baseline LV ejection fraction (EF) was significantly lower in transplanted sheep than in controls [38% (35-48) vs. 51% (38-55), respectively, P=0.03; median (range)]. Two months later, LVEF was significantly higher in the transplanted group than in controls [50% (47-56) vs. 39% (36-47), respectively, P=0.002]. Clusters of myoblasts were identified by histology and immunohistochemistry in three of the seven transplanted sheep. CONCLUSION: These data suggest the functional efficacy of the transvenous coronary sinus technique as a less invasive means of cell delivery to infarcted myocardium.     

Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation

OBJECTIVES: We report histological analysis of hearts from patients with end-stage heart disease who were transplanted with autologous skeletal myoblasts concurrent with left ventricular assist device (LVAD) implantation. BACKGROUND: Autologous skeletal myoblast transplantation is under investigation as a means to repair infarcted myocardium. To date, there is only indirect evidence to suggest survival of skeletal muscle in humans. METHODS: Five patients (all male; median age 60 years) with ischemic cardiomyopathy, refractory heart failure, and listed for heart transplantation underwent muscle biopsy from the quadriceps muscle. The muscle specimen was shipped to a cell isolation facility where myoblasts were isolated and grown. Patients received a transplant of 300 million cells concomitant with LVAD implantation. Four patients underwent LVAD explant after 68, 91, 141, and 191 days of LVAD support (three transplant, one LVAD death), respectively. One patient remains alive on LVAD support awaiting heart transplantation. RESULTS: Skeletal muscle cell survival and differentiation into mature myofibers were directly demonstrated in scarred myocardium from three of the four explanted hearts using an antibody against skeletal muscle-specific myosin heavy chain. An increase in small vessel formation was observed in one of three patients at the site of surviving myotubes, but not in adjacent tissue devoid of engrafted cells. CONCLUSIONS: These findings represent demonstration of autologous myoblast cell survival in human heart. The implanted skeletal myoblasts formed viable grafts in heavily scarred human myocardial tissue. These results establish the feasibility of myoblast transplants for myocardial repair in humans.     

双核素单光子断层显像评价骨髓单个核细胞移植后急性心肌梗死患者存活心肌变化

目的 利用双核素[^201 铊（Tl）及^18 F-脱氧葡萄糖（FDG）]单光子断层显像（SPECT）方法评价经冠状动脉自体骨髓单个核细胞（BM-MNC）移植对急性心肌梗死患者心功能和存活心肌的影响。方法 40例首次ST段抬高急性心肌梗死患者,成功完成PCI术后,随机分为细胞移植组（n=20）和对照组（n=20）,急诊冠状动脉造影术同时,经微导管于梗死相关动脉内支架远端注入自体BM-MNC悬液或等量的肝素生理盐水。研究终点为PCI术后6个月时双核素（^201 Tl及^18F-FDG）SPECT测定存活心肌的变化。结果 随访6个月时,两组患者左心室射血分数均有显著提高,但移植组患者左室射血分数改善幅度更显著[（7．6±2．8）％比（3．0±2．8）％,P〈0．001]。^201 Tl-SPECT显示移植组患者左心室心肌灌注明显改善,心肌灌注缺损面积减少（6．7±3．0）％,同时^18 F—FDG-SPECT结果显示梗死边缘区心肌灌注-代谢不匹配面积明显增加,提示存活心肌明显增加。结论 自体BM-MNC可以改善急性心肌梗死后梗死边缘区心肌灌注,增加局部存活心肌,提高左心室功能。     

Autologous myoblast transplantation after myocardial infarction increases the inducibility of ventricular arrhythmias

BACKGROUND: Small scale clinical trials suggested the feasibility and the efficacy of autologous myoblast transplantation to improve ventricular function after myocardial infarction. However, these trials were hampered by unexpected episodes of life-threatening ventricular tachyarrhythmias (VT). We investigated cardiac electrical stability after myoblast transplantation to the myocardium. METHODS AND RESULTS: Seven days after coronary ligation, Wistar rats were randomized into 3 groups: a control group receiving no further treatment, a vehicle group injected with culture medium into the infarcted myocardium, and a myoblast group injected with autologous myoblasts. Holter monitoring did not discriminate the myoblast from the vehicle groups. Programmed Electrical Stimulation (PES) was performed to evaluate further a cardiac substrate for arrhythmia susceptibility. The occurrence of sustained VT during PES was similar in control and vehicle groups (5/17 and 4/19 rats, respectively; p=0.50). In contrast, 13/20 rats (65%) from the myoblast group showed at least one episode of sustained VT during PES (p<0.05 and p<0.005 versus control and vehicle groups). As a further control group, rats injected with autologous bone marrow mononuclear cells into the infarcted myocardium did not show increased susceptibility to PES. CONCLUSIONS: In an infarcted rat model, myoblast transplantation but not bone marrow mononuclear cells or myocardial injection per se induces electrical ventricular instability. Because ventricular arrhythmias are life-threatening disorders, we suggest that such preclinical evaluation should be conducted for any new source of cells to be injected into the myocardium.     

Efficacy of nasal bi-level positive airway pressure in congestive heart failure patients with cheyne-stokes respiration and central sleep apnea.

BACKGROUND: Cheyne - Stokes respiration with central sleep apnea (CSR-CSA) contributes to the poor prognosis in patients with congestive heart failure (CHF). Bi-level positive airway pressure (bi-level PAP) may be an effective alternative for treating CSR-CSA and CHF. METHODS AND RESULTS: Fourteen patients with CSR-CSA were divided into 2 groups, a control group that included 7 patients who decided to receive only conventional medications and a group of 7 patients that received bi-level PAP. Left ventricular ejection fraction (LVEF), mitral regurgitation (MR) area, plasma brain natriuretic peptide (BNP) concentration and the New York Heart Association (NYHA) functional class were evaluated initially (baseline) and 3 months later. In the control group, there were no significant changes in cardiac function during the study period. In contrast, in the group that received bi-level PAP, there were significant improvements in LVEF (from 36.3+/-2.9% to 46.0+/-4.0%, p = 0.02), MR area (from 30.4+/-7.6% to 20.0+/-5.1%, p = 0.02), BNP (from 993.6+/-332.0 pg/ml to 474.0+/-257.6 pg/ml, p = 0.02) and NYHA functional class (from 3.1+/-0.1 to 2.1+/-0.1, p = 0.03). CONCLUSION: Treatment with bi-level PAP improved cardiac functions in CHF patients with CSR-CSA.     

Dobutamine as bridge to angiotensin-converting enzyme inhibitor-nitrate therapy in endstage heart failure

BACKGROUND: Intravenous inotropic intervention in congestive heart failure is generally associated with a poor prognosis and is largely used as a "bridge" to mechanical support or heart transplantation. HYPOTHESIS: We hypothesized that the inotropic support afforded by dobutamine may serve as a bridge to the introduction and intensification of angiotensin-converting enzyme (ACE) inhibitor-nitrate therapy. METHODS: We studied the efficacy of transitioning inotrope-dependent patients in endstage heart failure from intravenous dobutamine to high-dose ACE inhibitor-nitrates, with 1-year follow-up. Forty-nine sequential dobutamine-dependent patients with left ventricular ejection fraction (LVEF) 17+/-17% were treated with increasing lisinopril (1.9+/-1.5 to 46+/-28 mg/day) and isosorbide dinitrate (7+/-6 to 229+/-161 mg/day). Outpatient dobutamine was continued or repeat infusions pursued, as indicated, and dobutamine was tapered when feasible. RESULTS: During the following year, 14 of 49 patients required repeat dobutamine, with home treatment with dobutamine for 6.3+/-3.7 months (n = 5). At 1 year, New York Heart Association (NYHA) classification improved from 3.6+/-0.5 to 1.9+/-1.0, p < 0.0001; yearly hospitalizations fell from 2.7+/-2.3 to 1.2+/-3.0, p = 0.02; and LVEF rose from 17+/-7% to 24+/-11%, p < 0.0001. At 1 year, 14 patients who remained dobutamine dependent had significantly more severe symptoms than dobutamine-independent patients (n = 35). Transplant or death occurred in 7 of 14 patients with follow-up dobutamine, and in 5 of 35 patients free of subsequent dobutamine, p = 0.03. Patients with poor outcome (transplant n = 10, death n = 12) continued to be more limited (NYHA 2.7+/-0.9 vs. 1.7+/-0.9, p = 0.0002), with more follow-up hospitalizations (3.6+/-5.4 vs. 0.6+/-0.8, p = 0.0004), and no improvement in LVEF (17+/-8vs. 28+/-11%, p = 0.003). CONCLUSIONS: Of the patients on dobutamine inotropic support, 70% were successfully transitioned to ACE inhibitor-nitrate therapy, with improved symptoms and LVEF, and with reduced hospitalizations and follow-up dobutamine or transplant. Thirty percent of patients with continued need for dobutamine had a significantly poorer 1-year clinical outcome.