European Heart Journal Advance Access published online on April 25, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn171
Four-year follow-up of treatment with intramyocardial skeletal myoblasts injection in patients with ischaemic cardiomyopathy
1 Department of Cardiology, Erasmus University Medical Centre, Thoraxcentre, Room Ba 587, Erasmus MC, Gravendijkwal 230, PO Box 2040, 3015 CE Rotterdam, The Netherlands
2 Interuniversity Cardiology Institute of the Netherlands, ICIN-KNAW, Utrecht, The Netherlands
Received 31 October 2007; revised 22 March 2008; accepted 4 April 2008.
* Corresponding author. Tel: +31 10 703 52 45, Fax: +31 10 703 43 20, Email: w.j.vandergiessen{at}erasmusmc.nl
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Abstract |
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Aims: Studies reporting improved left ventricular (LV) function of percutaneous skeletal myoblast (SkM) injection in patients with ischaemic cardiomyopathy had follow-up not exceeding 12 months, and did not include a control group. Our group has reported evidence for myoblast efficacy in the first five out of the 14 treated patients. The objective of the present evaluation was to assess if these effects were sustained at long-term follow-up. We compared function of patients treated with SkM 4 years earlier with a matched control group. Secondary endpoints included mortality, NYHA class, N-terminal pro-B-natriuretic peptide levels, incidence of arrhythmias, and quality of life.
Methods and results: Fourteen patients with ischaemic cardiomyopathy who underwent SkM injection were compared with 28 non-randomized control patients matched for age, sex, location, and extent of myocardial infarction. Contrast echocardiography and tissue Doppler imaging (TDI) was performed to compare global and regional LV function. At 4-year follow-up, three patients (21%) had died in the treated group and 11 patients (39%) in the control group (P = 0.8). In the survivors, LV ejection fraction (EF) was 35 ± 10% and 37 ± 9% in the SkM group and 36 ± 8% and 36 ± 6% in the controls at baseline and 4 years follow-up, respectively (P = 0.96 between groups at follow-up). TDI-derived systolic velocity in the injected sites was 5.4 ± 1.8 cm/s in the SkM group when compared with 5.1 ± 1.6 cm/s in corresponding sites in the control group (P = 0.47). None of the secondary endpoints showed a difference between the groups. However, in the patients fitted with an internal cardioverter defibrillator, more arrhythmias leading to interventions occurred in the treated group than in the control group, 87% and 13%, respectively (P = 0.015).
Conclusion: Percutaneous intramyocardial SkM injection in ischaemic cardiomyopathy has no sustained positive effect on resting global or regional LV function, respectively, at 4-year follow-up. Moreover, the procedure may induce a higher risk of developing serious arrhythmias, but larger patient series are required before more precise characterization of the safety and efficacy profile of the procedure is possible.
Key Words: Heart failure • Stem cells • Follow-up studies • Echocardiography • LV function
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Introduction |
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Adult myocardium is incapable of effective, spontaneous regeneration after ischaemic injury causing the injured area to develop into fibrous, non-contractile scar tissue. Therefore, heart failure (HF) following myocardial infarction (MI) can be viewed as a disease of cellular deficiency. The remaining healthy muscle must compensate for the loss in left ventricular (LV) function by means of compensatory hypertrophy and dilatation of the LV. The direct injection of autologous stem cells into the myocardial infarct area has been proposed to prevent deterioration of LV function and the post-infarct remodelling process. In pre-clinical studies, implantation of either skeletal myoblast cells (SkM) or bone marrow stem cells (BMC) suggested replacement of non-functioning myocardial scar with functioning muscle and improvement in myocardial performance.1–3 Preliminary data in human subjects receiving SkM as adjunct to coronary artery bypass grafting (CABG) indicate that cell implantation also improves LV function.4 Phase I trials showed that autologous SkM transplantation for the treatment of post-infarction HF was feasible.5,6 Our group has reported enhancement of LV systolic function in the first five patients receiving SkM as a stand-alone procedure by percutaneous approach after a follow-up of 3 months, which was sustained up to 6 months.7 In addition, by using the more sensitive technique of pressure–volume loops, we could demonstrate a significant increase in several indices of systolic function up to 12 months of follow-up.8 Both the surgical and the percutaneous study were, however, small phase two trials without a control group. The objective of the present evaluation was to assess if earlier effects of myoblast injections were sustained at long-term follow-up. In the present study, we compared the treated patients with a matched control group with respect to global and regional LV function as measured by contrast echocardiography including tissue Doppler imaging (TDI) after an average follow-up of 4 years. We also assessed the long-term safety of percutaneous injection of SkM by its effects on arrhythmias.
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Methods |
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Study population
Symptomatic patients with chronic ischaemic cardiomyopathy because of a previous MI involving the anterior, inferior, or lateral wall were included in the study. In total, 15 patients were treated with autologous SkMs in the period 2001–03. One patient refused informed consent leaving 14 patients for long-term follow-up (myoblast group). For each treated patient, we selected two controls matched using the following method: we performed a search for appropriate patients during the period 2001–03 in our patient database using the following search terms: MI and echocardiography. From the resulting 200 patients, we matched two per each treated patient, using the following matching criteria: age (range 5 years); sex, time since occurrence of the MI (range 5 years); LV ejection fraction (LVEF) (range 8%); location of the MI. Eligibility for inclusion for the treatment arm was based on: (i) age between 40 and 80 years old; (ii) LVEF between 20 and 45%; (iii) presence of a prior Q-wave MI and a large area of akinesia of the LV, confirmed by either LV angiography or echocardiography; (iv) New York Heart Association (NYHA) symptom class II or III. The main exclusion criteria were: (i) MI within 90 days before start of follow-up; (ii) HF secondary to valvular disease; (iii) severe non-cardiac illness that might affect survival or interfere with the interpretation of the study results. The median follow-up time was 48 [interquartile range (IQR) 37–58 months)] months in both groups. The study was approved by the Medical Ethics Committee of Erasmus MC. Patients gave written informed consent.
Cell therapy procedure
The SkMs were obtained via a biopsy of the patient quadriceps muscle under local anaesthesia. A median of 11 g (range 8.1–13.3 g) of muscle biopsy was excised through a 10 cm long surgical incision. The transport conditions were monitored using a programmable temperature monitor (Sensitech, Beverly, MA, USA). Upon receipt at the culturing facility, biopsies were processed according to Bioheart Inc, MyoCellTM protocols as described earlier.7 The cell re-injection procedure was performed in the cardiac catheterization laboratory after a culture period of approximately 17 days, which resulted in a mean of 325 million harvested cells. Transendocardial injections were made using a needle injection catheter as described before.7 The injections were made within the scar region with a known wall thickness of more than 5 mm as assessed by echocardiography. Treated patients received eight to 27 injections of 0.11–0.30 mL, containing three to 50 million cells per injection. A median of 206 (IQR 150–294) million total number of cells was injected in the anteroseptal wall in all patients. The cells had a mean desmin staining of 68 ± 23% and a viability of 95 ± 3%. Procedural complications did not occur.
Study endpoints
The primary endpoints were changes in global and regional LV function over time within both groups and the difference in LV function between the myoblast and the control group at 4 years. The assessment of LV function included LV end-diastolic diameter (LV-EDD), LV end-diastolic volume (LV-EDV), LVEF, myocardial performance index (Tei index), and TDI-derived regional peak systolic velocity.
Secondary endpoints were cardiac mortality, arrhythmias, change in NYHA class, the six-minute walking distance, hospitalization for either angina, arrhythmias, or HF, N-terminal pro-B-natriuretic peptide (NT-pro-BNP) levels, and finally health-related quality of life measured with the Short-Form Health Survey-36 (SF-36) questionnaire. The occurrence of arrhythmias was measured during the follow-up period by the internal cardioverter defibrillator (ICD) in all patients. We also measured the frequency and severity of arrhythmias determined by 24 h-Holter monitoring in all patients at the end of the follow-up period. The SF-36 questionnaire was divided into eight subscales: Physical Functioning, Role Physical Functioning, Mental Health, Vitality, Bodily Pain, and General Health.9 Scores on the subscales were linearly converted to a score between 0 and 100, with a higher score representing a better functioning.
The endpoints NYHA class, LV-EDD, LV-EDV, and LVEF were assessed at baseline as well as at follow-up in the treated and the control patients. The arrhythmias measured by ICD were assessed during the 4-year follow-up period. All other secondary endpoints were measured only at the end of follow-up.
Echocardiography
At baseline and at 4-year follow-up two-dimensional echocardiography was performed including contrast LV opacification, while at follow-up also TDI assessment was done. All patients were examined using an iE33 7500-ultrasound system (Philips, Best, The Netherlands) with a S3 transducer according to the recommendations of the American Society of Echocardiography.10,11 LV-EDD and LV end-systolic diameter (LV-ESD) were measured. LV-EDV, LV end-systolic volume (LV-ESV), and LVEF (by modified bi-plane Simpson rule) were calculated from the apical four-chamber and two-chamber views.12 To improve the reproducibility of two-dimensional echocardiographic assessment of LVEF, LV opacification using a commercially available contrast agent (SonoVue, Bracco, Geneva, Switzerland) was done. A bolus of 0.5 mL SonoVue was administered via iv route with additional boluses of 0.25 mL when needed.
Tissue Doppler imaging
TDI was applied by placing the sample volume at both sides of the mitral annulus in the apical four-, two-, and three-chamber views.13 Gain and filter settings were adjusted as needed to eliminate background noises and to allow for a clear tissue signal. Pulsed-wave TDI velocities were recorded end-expiratory at a sweep speed of 100 mm/s and measured using electronic callipers with the workstation EnConcert (Philips, Best, The Netherlands). From the six mitral annular velocity profiles, the systolic wave (Sm) and the early diastolic wave (E') were measured. The mitral annular E/E' ratio was calculated from the postero-septal and antero-lateral mitral annulus, as previously described.14–16 For each patient, the average of at least three measurements was calculated. The myocardial performance index, defined as isovolumic contraction time plus isovolumic relaxation time divided by ejection time was calculated from the postero-septal and antero-lateral mitral annulus TDI velocity profile, as previously described.16,17
Internal cardioverter defibrillator interrogation
During the 4-year follow-up, arrhythmias assessed by interrogation of the ICDs and defined as sustained ventricular fibrillation or polymorphic ventricular tachycardia (VT) and sustained monomorphic VT at a rate >120 b.p.m., were measured in the 17 patients fitted with an ICD (nine treated patients and eight control patients). The outcome measurement was intervention by the ICD. An intervention was defined as anti-tachycardia pacing or shocks for all causes. An intervention can either be appropriate or inappropriate. An appropriate therapy means intervention for ventricular arrhythmias by the ICD. An example of inappropriate intervention is a shock delivered by ICD because of atrial tachycardia. An independent expert electrophysiologist blinded to the treatment group reviewed all ICD data.
Statistical analyses
Kolmogorov–Smirnov test to evaluate normality was used for all variables in the analysis. Differences between patients and controls were analysed using the unpaired Student's t-test or Mann–Whitney U test as appropriate. Continuous variables are presented as mean ± SD or as median (IQR) when normal or skewed distribution, respectively. Categorical data presented as frequencies were compared using the 
2 test or Fisher's exact test depending on the distribution. Pre-selected baseline characteristics were: age, sex, time since prior MI, localization of the first MI, occurrence of multiple MI's, treatment with CABG of PCI, implantation of ICD, LV function, NYHA class, cardiovascular risk factors like multi-vessel disease, hypertension, hypercholesterolaemia, diabetes mellitus, smoking, family history and body mass index, and comorbidities like cerebrovascular accident and chronic obstructive pulmonary disease. All tests were two-sided and P < 0.05 was considered statistically significant. All statistics were performed using the SPSS 13.0 software package (SPSS Inc, Chicago, IL, USA).
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Results |
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A total of 42 patients were enrolled in the study: 14 patients treated with myoblasts and 28 matched controls. Baseline characteristics are summarized in Table 1. The median age was 62 (IQR 57–73) years. The median time after MI was 8 (IQR 3–12) years in the myoblast group and 8 (4–12) years in the control group. In all treated patients, the location of the infarct area was the LV anterior wall caused by their first MI or if they had multiple MI's in their second or third MI. There was no difference in cardiac history between the two groups in all pre-selected baseline characteristics, except for implantation of ICD (P = 0.065). ICD implantation was performed per protocol because of safety issues in the myoblast group after the fifth patient was treated with SkM during the trial. Both the myoblast-treated patients and the control patients were on stable medication regimen (aspirin, angiotension-converting enzyme inhibitors, β-blockers, diuretics, and statins) during the follow-up period. Procedural characteristics of the SkM group are summarized in Table 2.
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Primary endpoints
Left ventricular geometry and function
After 4-year follow-up, the myoblast group contained 11 patients and the control group had 17 patients. Twenty-eight patients underwent contrast echocardiography at follow-up. LV-EDD, LV-ESD, LV-EDVI, and LV-ESVI showed no difference between the two groups at baseline. Likewise, LVEF was similar between the SkM-treated patients and the controls, 32 ± 9% vs. 36 ± 8%, respectively, P = 0.29 (Table 3). Comparing baseline with follow-up data in only survivors of both groups also showed no difference. The LVEF as well as the LV-EDD, LV-ESD, LV-EDVI, and LV-ESVI were similar between the treated and control group (Table 4). Individual data show that both in the treated as well as in the control group, changes in LVEF over time varied between the individual patients within one group. When comparing the mean baseline LVEF with the mean LVEF within one group, there is no change in LVEF over time (Figure 1). The myocardial performance index and regional TDI-derived peak systolic velocities were not different between the SkMs treated patients and the control patients. Also the mean systolic mitral annular velocity of the injected wall (the antero-septal wall) was similar in treated patients (5.4 ± 1.8 cm/s) compared with control patients (5.1 ± 1.6 cm/s, P = 0.47). Also, early diastolic velocity was similar in the injected walls of the myoblast-treated and control groups (Table 5).
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Secondary endpoints
Cardiac mortality
At 4-years follow-up, 14 patients from the total study population (30%) had died, three patients (21%) in the myoblast group and 11 patients (39%) in the control group (P = 0.8). The first myoblast-treated patient died 9 days after procedure because of an arrhythmic event. This patient belonged to the early phase of the trial and did not have an ICD. A second myoblast-treated patient died of cardiogenic shock following an electrical storm 1 month after the procedure, despite the presence of an ICD. Because severe non-lethal arrhythmias also occurred in one other patient shortly after the procedure in the first cohort of patients (non-ICD cohort) the later treated patients were all fitted with an ICD before the cell injection procedure. Another treated patient died of HF after 43 months. In the control group, seven patients died because of HF (64% of total death in control group), one (9%) patient died because of ventricular fibrillation, and three (27%) patients died from non-cardiac causes.
Arrhythmias
We compared the nine treated with the eight control patients fitted with an ICD at follow-up. In the treated group, seven out of nine patients (87%) had received an intervention, compared with one out of eight patients (13%) in the control group (P = 0.015) (Table 6).
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At the end of the follow-up, Holter monitoring was performed in all survivors. The mean time of Holter monitoring was 21 h. Episodes of non-sustained VT's were recorded in five patients (46%) in the myoblast-treated group and nine (53%) in the control group (P = 0.7). The ventricular rate of the VT's in the patients of the myoblast group was slow (111–130 b.p.m.) with a mean length of nine ventricular complexes. In the control group, fast VT's (156–191 b.p.m.) with a mean length of four ventricular complexes were found in five patients. Episodes of sustained ventricular arrhythmias were not observed in either group (Table 7).
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Physical health status
No difference was found between the myoblast patients and the controls in hospitalization, including the reasons of re-admissions, NT-pro-BNP levels, and presence of angina during ordinary activity and performance during six-minute walk exercise test (Table 8). The NYHA class improved in the treated group (3.0 ± 0.5 to 2.6 ± 0.7). In this group, 36% of the patients improved in functional class. The other 64% of the patients remained in the same class. None of the patients worsened in functional class. In the control group, 18% of the patients improved in functional class, but 36% of the patients worsened in functional class. The remaining 46% stayed in the same NYHA functional class. There was no statistically significant difference between the groups (Figure 2).
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Quality-of-life questionnaire
In all eight subscales of the SF-36 questionnaire, the scores were similar between the groups (Figure 3).
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Discussion |
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In pre-clinical studies, implantation of SkM suggested replacement of non-functioning myocardial scar with functioning muscle and improvement in myocardial performance.1,3,18,19 Data in humans receiving SkM as adjunct to CABG indicate that cell implantation indeed may lead to improvement of LV function both on short-term,20 as well as after 4 years.6,21,22 It is obvious, however, that concomitant myocardial revascularization makes a separate appreciation of the role of cell transplantation in LV function improvement elusive. Short-term results from small studies using percutaneous SkM transplantation without adjunctive revascularization, however, also indicated positive effects on LV function,7,8 supporting enhancement of LV function by SkM. Unfortunately, all studies with or without revascularization lacked a control group without SkM injection. Therefore, in the present study we compared the long-term effects of SkM transplantation in our first cohort of percutaneously treated patients with a matched control group of ischaemic cardiomyopathy patients not receiving SkMs.
Primary endpoint
In this 4-year follow-up study, we sought to evaluate the long-term safety and efficacy of the percutaneous endocardial transplantation of autologous skeletal myoblasts in chronic ischaemic HF patients. The results of the present study indicate that transplantation of autologous SkMs in patients with depressed LV function because of a prior MI does not improve LV function compared with age-, sex-, and LV function matched controls at 4-year follow-up. LV internal diameters and volumes as well as LVEF did not change over time and were similar between the treated and control groups. In this context, it is of interest that most non-controlled, initial studies insinuated that untreated patients with ischaemic HF would show a decline in LV function. The present study indicates that the survivors in such a patient group remains remarkably stable over time, which is most likely because of improved medical therapy. These results are in agreement with results of the MAGIC trial where at 6-month follow-up both treated and placebo groups had comparable changes in global and regional LV function.23 They also emphasized a decrease in LV volume in the high-dose myoblast group, where in the present study only a trend towards a decrease in LV-EDVI was found. We support their conclusion that more study should be directed to the anti-remodelling potential of cell therapy. The use of contrast-enhanced echo like in the present study, which improves the reproducibility should be considered in such trials.24.
Secondary endpoints
The short-term frequency of severe VT's has been emphasized since the first clinical study with SkMs,4 but the long-term risk of arrhythmias after treatment with myoblasts was thus far unknown. In the present study, albeit small sample, we observed a difference in the patients fitted with an ICD, i.e. more interventions occurred in the SkM group than in the control group.
This indicates that the concerns around arrhythmias and myoblast therapy may still be valid. However, during 24 h-Holter monitoring at the end of follow-up, a significant amount of ventricular arrhythmias was found in both groups. Almost half of the patients in the treated group as well as in the control group experienced episodes of non-sustained VT's.
The higher frequency of arrhythmias in the treated group in the present study was seen also very early in treated group in the MAGIC trial. However, at 6-month follow-up, the frequency of arrhythmias was similar in the treated and placebo groups.23 Importantly, we have a 4-year follow-up period in the present study where most of the ICD events took place after 6 months.
Consistent with the primary endpoints, in this study a difference in exercise capacity, hospitalization, NT-pro-BNP levels, and health-related quality of life was not shown. There was a trend towards improvement of NYHA functional class over time in the treated group (P = 0.08), while the NYHA functional class remained the same over time in the control group. This suggests that the SkM-treated patients performed better and had a better clinical presentation than the patients in the control group. However, it is well recognized that in open studies evaluating invasive procedures, a substantial role for the placebo effect may be expected.25 In addition, results from the quality-of-life questionnaire did not point to the same direction.
Unresolved issues
Almost all small, phase I clinical trials showed improvement in LV function after SkM injection, but the results from larger, and more important randomized controlled trials treating patients with SkM injection are still pending. In the MAGIC trial (Myoblast Autologous Grafting in Ischemic Cardiomyopathy trial), patients were randomized into three groups (n = 97 total) receiving 400 x 106 or 800 x 106 SkMs, or medium only. The major adverse cardiac events did not show any difference between the groups at 30 days as well as at 6 months. Likewise, myoblast injection did not improve either global or regional LV function at 6-month follow-up in the treated patients over that in the placebo group. Of note, the incidence of ventricular arrhythmias was also similar between the groups.23 These results indicate that the number of cells injected might not be the most decisive factor for success, as the neutral results in the MAGIC trial were observed with four times the number of cells as in the present study. A more important variable may be the studied population, because in trials conducted in the acute phase of MI more, albeit modest, positive results were obtained.26–30 Alternatively, the phenotype of the injected cells might be essential to obtain better functional improvements, as cells allowed to differentiate into a preferred lineage in vitro before re-injection may provide better results as shown in a pre-clinical study.31
Study limitations
The efficacy assessment could be underpowered in this study by the small sample of myoblast-treated population. Lack of statistical significance is in this respect no conclusive evidence for lack of effect. However, our group has reported evidence for myoblast efficacy in five out of the 14 treated patients, which are described in this study, at 12 months follow-up.7 The objective of the present evaluation was to assess if these effects were sustained at long-term.
The trial was neither randomized nor blinded. However, the matching between the two groups was performed as fair as possible. The control group was matched for age, sex, and time since prior MI and localization of the infarction area, and LVEF. Because we did not match on ICD presence, we should be cautious in the interpretation of the difference in arrhythmia in both groups. The patients in the treated group were fitted with ICD per protocol, where the control patients were fitted with ICD for clinical indications. As expected, we observed considerable (average 30%) mortality in our study population over a period of 4 years, but the baseline LVEF data of those patients who died did not differ from the survivors. Still this does not exclude a selection bias introduced by loss of patients with a worse LVEF, because the patients who died might have been the patients with the most progressive decrease in clinical performance over time. This could have been resolved by, for instance, interim analysis every 6 months during the follow-up period. However, this was not included in the original study design.
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Conclusions |
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This study shows that intramyocardial SkM injection in chronic ischaemic HF patients has no sustained positive effect on resting global and regional LV function when compared with matched controls over a 4-year follow-up period. In addition, the ICD read-outs during the course of follow-up, but not the 24 h arrhythmia monitoring at 4 years, indicate a potential higher risk of developing ventricular arrhythmias.
Conflict of interest: none declared.
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