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ORIGINAL CLINICAL SCIENCE
Intramyocardial bone marrow mononuclear cell transplantation in ischemic heart failure: Long-term follow-up Miia Lehtinen, MD,a Tommi Pätilä, MD, PhD,a Esko Kankuri, MD, PhD,b Kirsi Lauerma, MD, PhD,c Juha Sinisalo, MD, PhD,d Mika Laine, MD, PhD,d Markku Kupari, MD, PhD,d Antti Vento, MD, PhD,a and Ari Harjula, MD, PhDa,b,1 for the Helsinki BMMC Collaboration From the aDepartment of Cardiothoracic Surgery, Heart and Lung Center, Helsinki University Central Hospital; b Institute of Biomedicine, Pharmacology, University of Helsinki; cDivision of Roentgenology, HUS Medical Imaging Center; and the dDepartment of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
KEYWORDS: myocardial infarction; heart failure; bypass surgery; bone marrow mononuclear cells
BACKGROUND: Long-term results regarding treatment of chronic ischemic heart failure with bone marrow mononuclear cells (BMMCs) have been few. We received encouraging results at the 1-year follow-up of patients treated with combined coronary artery bypass grafting (CABG) and BMMCs, so we decided to extend the follow-up. METHODS: The study patients had received injections of BMMCs or vehicle into the myocardial infarction border area during CABG in a randomized and double-blind manner. We could contact 36 of the 39 patients recruited for the original study. Pre-operatively and after an extended follow-up period, we performed magnetic resonance imaging, measured pro-B-type amino-terminal natriuretic peptide, reviewed patient records from the follow-up period, and determined current quality of life with the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey. RESULTS: The median follow-up time was 60.7 months (interquartile range [IQR], 45.1–72.6 months). No statistically significant difference was detected in change of pro-B-type amino-terminal natriuretic peptide values or in quality of life between groups. The median change in left ventricular ejection fraction was 4.9% (IQR, –2.1% to 12.3%) for controls and 3.9% (IQR, –5.2% to 10.2%) for the BMMC group (p ¼ 0.647). Wall thickening in injected segments increased by a median of 17% (IQR, –5% to 30%) for controls and 15% (IQR, –12% to 19%) for BMMC patients (p ¼ 0.434). Scar size in injected segments increased by a median of 2% (IQR, –7% to 19%) for controls but diminished for BMMC patients, with a median change of –17% (IQR, –30% to –6%; p ¼ 0.011). CONCLUSIONS: In the treatment of chronic ischemic heart failure, combining intramyocardial BMMC therapy with CABG fails to affect cardiac function but can sustainably reduce scar size, even in the longterm. J Heart Lung Transplant ]]]];]:]]]–]]] r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
1 The Collaborators in the Helsinki BMMC Collaboration group are listed in the Appendix. Reprint requests: Miia Lehtinen, MD, Surgery, Biomedicum Helsinki 1, Haartmaninkatu 8, 00290 Helsinki, Finland. Telephone: þ358-9-19125000. Fax: þ358-9-471-75858. E-mail address: miia.1.1ehtinen@helsinki.fi
During the past decade, multiple trials have investigated effects of bone marrow mononuclear cells (BMMCs) in the treatment of chronic ischemic heart disease and acute myocardial infarction. Despite promising findings in animal trials,1,2 clinical trials have failed to show unequivocal
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results. Furthermore, follow-up times have been almost invariably quite limited, ranging from 4 to 18 months. Between 2006 and 2011, we conducted a randomized, double-blinded clinical trial (ClinicalTrials.gov Identifier: NCT00418418) investigating the safety and efficacy of BMMC transplantation as an adjunct to coronary artery bypass graft (CABG) surgery.3 Initially, follow-up was 1 year post-operatively. According to our results, BMMCs seemed to have no effect on global or local left ventricular (LV) function, but the scar size was significantly diminished in the BMMC-treated areas compared with placebo. Encouraged by this result, we decided to continue the study and invited our patients for a late follow-up visit. As in the pre-operative assessment, LV function and scar size were analyzed by cardiac magnetic resonance imaging (MRI). In addition, we measured the circulating pro-B-type amino-terminal natriuretic peptide (proBNP) concentration, determined the current New York Heart Association (NYHA) Functional Classification, and used the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey to assess the post-operative health-related quality of life (HRQoL). In this report we document the long-term results of intramyocardial BMMC injections combined with CABG using randomized double-blinded techniques.
Methods This study was approved by the Institutional Ethics Committee (Dnro HUS 456/E6/05).
Patients The original study protocol and the 1-year follow-up results of our trial have been published previously.3 Patients were included in the original trial if they met the following inclusion criteria: age between 18 and 75 years, provided informed consent, LV ejection fraction (LVEF) between r45% and Z15%, and NYHA class II to IV heart failure symptoms. Criteria for exclusion were:
A. heart failure due to LV outflow track obstruction; B. history of life-threatening ventricular arrhythmias or resuscita-
Helsinki University Meilahti Hospital Cell Processing Laboratory.3 The cell suspension was divided into six 1-ml syringes for the treatment group; control patients received only vehicle medium by syringes. The patients were assigned randomly, and the syringe contents were masked to ensure double-blinded technique. After the bone marrow aspiration, a standard CABG operation was performed. After the bypass anastomoses were finished and the heart remained in cardiac arrest, the BMMCs were injected into pre-defined sites in the infarction border area. The infarction and its border area were localized pre-operatively by imaging data, and this information was used to target the injections to the border area during surgery. The injection procedure was carefully photographed during the procedure, and the areas injected were specified in patient documents for analysis.
Follow-up After the original 1-year follow-up, patients were monitored in the outpatient clinic of Helsinki University Central Hospital or in a regional health center according to local routines. In Spring 2013, the patients were invited for a late follow-up research visit at our institution. For end point measures in this long-term follow-up, we determined (1) changes in the LV measurements and scar size between the pre-operative and late post-operative MRI studies, (2) concomitant changes in NYHA class and plasma proBNP concentration; (3) hospitalizations due to cardiac failure, and (4) the patients’ current HRQoL by the SF-36 questionnaire. The SF-36 is a standardized questionnaire with specified mean and standard deviation (SD) values for 8 different dimensions of the instrument per different cohorts that reflect (1) physical functioning; (2) role-physical, measuring role limitations because of physical health problems; (3) role-psychological, assessing role limitations as a result of emotional impairment; (4) vitality, assessing the feeling of energy or fatigue; (5) mental health; (6) social functioning, measuring ability to perform normal social activities; (7) bodily pain; and (8) subjective general health perceptions. The investigator transformed the scores for each dimension to a 0- to 100-point scale for comparisons between groups. A lower score means greater limitations to activities or more distress with social and emotional problems. As a reference, we used values for a Finnish cohort with any chronic disease and compared their SF-36 mean scores with the scores of our study patients.
tion, or insertion of implantable cardioverter-defibrillator (ICD);
C. stroke or other disabling condition within 3 months before D. E. F. G.
screening; severe valve disease; other serious disease limiting life expectancy; contraindications for coronary angiogram or MRI; or participation in another clinical trial.
Eligible patients received optimal pre-operative medication for heart failure and coronary disease for a minimum of 4 weeks, after which the screening echocardiogram was repeated. If the LVEF was still r45%, the patient was included in the study after informed consent, and a CABG operation was scheduled, with preoperative studies performed during the waiting period.
Procedure Bone marrow aliquots (100 ml) were harvested from all patients from the posterior iliac crests under anesthesia before surgery. The mononuclear cell fraction was obtained by standard methods of
Cardiac MRI Cardiac MRI was performed with a 1.5-T Sonata scanner and phase-array cardiac coil (Siemens AG, Erlangen, Germany). Images were obtained with electrocardiography gating and during breath holding. Transaxial haste sequence covered the entire heart to study morphology and to obtain further orientation data. LV structure and function were imaged by standardized MRI protocol.4 True fast imaging with steady-state precession cine series were obtained at the vertical and horizontal long axis for scout to line up short-axis images. The stack of short-axis images was obtained from the mitral valve plane through the apex. Slice thickness was 8 mm with a 2-mm gap, and temporal resolution was 28 to 40 msec. To detect the myocardial scar, late gadolinium enhancement (LGE) was imaged with a 2 dimensional segmented inversion recovery gradient echo sequence 12 to 20 minutes after an injection of Dotarem (279.3 mg/ml; dose 0.2 mmol/kg). LGE images were obtained at the same views and slice/gap thickness as cine imaging.
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Inversion time was determined from a T1 scout sequence and ranged between 240 and 300 msec. For LV volumetry, all short-axis cine images were evaluated by Qmass software (Medis Medical Imaging Systems, Leiden, the Netherlands). Endocardial and epicardial borders were planimetered at end diastole and end systole. The papillary muscles were included in the ventricular blood pool. The planimetry resulted in LV end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF. According to the American Heart Association guidelines, the LV was divided into 16 segments (the 17th segment of apex was excluded from analyses due to its susceptibility to artifacts),5 and wall thickening (WT) was assessed for each segment with the Siemens Leonardo workstation and Argus software (Siemens AG). For scar-volume assessment, the same 16 LV segments were assessed for LGE with Qmass software. The threshold value for scar tissue was set to 5 SD above normal myocardium, and the threshold value for transmural scar was set to 50%. For each patient, the pre-operative and post-operative values for analyses of WT, scar volume, and transmural scar were the averages over all injected segments, over all non-injected segments, and over the 16 segments in total. One investigator blinded to treatment analyzed all MRI imaging data.
Statistical methods The Mann-Whitney U test was used for non-normally distributed continuous variables, with results reported as medians and interquartile range (IQR). For normally distributed parameters,
3 we used Student’s t-test and reported results as means (SD). Categoric variables were analyzed with Fisher’s exact test. To test for the effect of the differences in length of the follow-up periods, we used it as a covariate in the analysis of covariance model. All p-value testing was 2-sided, with statistical significance at p o 0.05. Computation was achieved with PASW Statistics 18 software (IBM Inc, Armonk, NY).
Results We were able to contact 36 of the 39 patients (92%) recruited for the original study. One control patient and 2 BMMC group patients had died after the 1-year follow-up, and 6 patients refused to participate in the long-term study (Figure 1). We were able to reanalyze data of 17 control (89%) and 13 BMMC (65%) patients. The median follow-up time was 60.7 months (IQR, 45.1– 72.6 months; Table 1). Decompensated cardiac failure caused 1 hospitalization in the control group and 2 hospitalizations in the BMMC group; 1 BMMC patient was hospitalized twice and diagnosed with aortic stenosis, which was later treated surgically. Two patients in both groups had sustained cerebral infarction during the long-term follow-up. One patient in both groups was diagnosed with cancer, a control patient with prostatic carcinoma and a BMMC patient with sigmoid adenocarcinoma.
Figure 1 Study flow-diagram. BMMC, bone marrow mononuclear cell; CABG, coronary artery bypass grafting; ICD, implantable cardioverter-defibrillator; MRI, magnetic resonance imaging; PM, pacemaker.
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Follow-Up Time and Events During the Long-Term Follow-Up
Variables
Placebo
BMMC
Patients participating in the original study, No. Death after the 1-year follow-up, No.a Patients participating in long-term follow-up, No. Age at 2013, median (IQR) yearsb Follow-up, median (IQR) monthsb Heart failure hospitalization, No.b,c Myocardial infarction, No.b ICD or pacemaker, No.b Percutaneous coronary intervention, No.b Coronary artery bypass grafting, No.b Stroke, No.b Cancer, No.b
19 1 17 67 (63–77) 61.2 (48.3–72.8) 1 0 1 0 0 2 1
20 2 13 70 (63–75) 51.9 (44.9–72.4) 2 0 2 0 0 2 1
p-value 1.000 0.851 0.902 0.934 1.000 0.565 1.000 1.000 1.000 1.000
BMMC, bone marrow mononuclear cell; ICD, implantable cardioverter-defibrillator; IQR, interquartile range. a Calculated for the patients participating in the original study (n ¼ 39). b Calculated for the patients participating in the long-term follow-up (n ¼ 30). c Heart failure hospitalizations shown as the number of hospital stays per group during the long-term follow-up.
For the control patients, the median plasma proBNP value was 684 ng/liter (IQR, 320–2,071 ng/liter) pre-operatively and 358 ng/liter (IQR, 214–680 ng/liter) after the long-term followup, and respective values for BMMC patients were 1,236 ng/liter (IQR, 449–2,615 ng/liter) and 819 ng/liter (IQR 383–2,083 ng/ liter). The between-group difference in the change was not statistically significant (p ¼ 0.357). NYHA class had improved from the pre-operative median of class IV in both groups to class III in control patients and class II in BMMC patients (p ¼ 0.473). The scores for each of the 8 dimensions measured with the SF-36 HRQoL questionnaire at the end of the follow-up were similar in both groups. Compared with the reference group (Finns with a chronic disease), no statistically significant differences were found in any dimensions of QoL; neither were any statistically significant differences detectable when scores between the 2 study groups were compared (p 4 0.05; Figure 2).
MRI analysis was successful in 25 (14 controls and 11 BMMC patients) pre-operatively and after long-term follow-up. One control and 2 BMMC patients had received an ICD or a pacemaker, contraindicating MRI. Three control patients and 5 BMMC patients refused MRI. For those patients participating in the long-term MRI follow-up, the median LVEF change was 4.9% (IQR, –2.1% to 12.3%) for controls and 3.9% (IQR, –5.2% to 10.2%) for BMMC patients (p ¼ 0.647). LVEDV changed a median of –63 ml (IQR, –95 to –19 ml) in the control group and –37 ml (IQR, –87 to –8 ml) in the BMMC group (p ¼ 0.767), and the concomitant changes in LVESV were –38 ml (IQR –85 to –2 ml) and –21 ml (IQR, –70 to –3 ml; p ¼ 0.647), respectively (Figure 3). Depending on the size and location of the myocardial scar, the infarction border area that received cell or placebo injections comprised 1 to 4 myocardial American Heart
Figure 2 Means and standard deviations (whiskers) of scores for different dimensions of the Medical Outcomes Study Short-Form 36 (SF-36) health-related quality of life questionnaire for placebo-treated control patients, patients treated with bone marrow mononuclear cells (BMMCs), and a reference cohort.
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Figure 4 Scar size preoperatively (Pre) and after long-term follow up in 2013 (Post) in injected (placebo or bone marrow mononuclear cells [BMMC]), non-injected, and all segments in total in both study groups. The horizontal line in the middle of each box indicates the median, the box boarders indicate the 75th and 25th quartiles, and the whiskers indicate the range.
Discussion
Figure 3 (A) Left ventricular ejection fraction and (B) left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) are shown pre-operatively (Pre) and after long-term followup in 2013 (Post) in both groups. The horizontal line in the middle of each box indicates the median, the box boarders indicate the 75th and 25th quartiles, and the whiskers indicate the range. BMMC, bone marrow mononuclear cells.
Association segments. WT in injected segments increased a median of 17% (IQR, –5% to 30%) in placebo-treated controls and 15% (IQR, –12% to 19%) in BMMC-treated patients (p ¼ 0.434) during the long-term follow-up. Scar size increased a median 2% (IQR, –7% to 19%) in placebo-treated segments but diminished in BMMC-treated segments a median of 17% (IQR –30% to –6%; p ¼ 0.011). The proportion of transmural scar showed a similar trend: it remained unchanged (IQR –8% to 25%) in placebo-injected segments and diminished a median of 23% (IQR, –36% to –3%) in BMMC-injected segments (p ¼ 0.093; Figure 4). The different lengths of the long-term follow-up periods did not affect these results. During the period after the first post-operative follow-up visit at 1 year, WT in injected segment increased a median of 9% (IQR, 2%–24%) for controls and 7% (IQR, –16% to 19%) for BMMC patients (p ¼ 0.352). During this same period, scar size in the injected segments had increased a median of 1% (IQR, –14% to 6%) in the control group and diminished a median of 5% (IQR, –16% to 8%) in the BMMC group (p ¼ 0.886; Figure 5); changes of the proportion of transmural scar in the injected segments were 0% (IQR, –25% to 5%) and –1% (IQR, –16% to 8%), respectively (p ¼ 0.931).
The results of our study suggest that treatment of ischemic heart failure with intramyocardial BMMC therapy and CABG may sustainably reduce scar size, even in the long-term. Because the myocardial scar retained its diminished size after the first follow-up visit at 1 year, the cells seem to execute their beneficial effects during the first months after injections. The results are in line with our previous findings. After 1 year of follow-up, we noticed that the scar size in injected segments rose by a median 5.1% for controls but fell by 13.1% for BMMC patients3; after the current long-term follow-up, the measured change in scar size from preoperative measurements remained practically the same in both groups. The therapy apparently fails to influence LVEF, volume, or local WT assessed by MRI, because we detected no differences in changes of these parameters during the 1-year or long-term follow-up. No difference was detected in QoL between the groups after the long-term follow-up. To the best of our knowledge, this trial with randomized double-blinded techniques provides the longest follow-up results on ischemic heart failure patients treated with intramyocardial BMMC therapy and CABG. Few studies have investigated the long-term effects of BMMC therapy compared with a control group with followup periods of 3 years or longer. Beitnes et al6 studied intracoronary BMMC treatment for 100 patients with acute myocardial infarction and reported their results for a followup of 36 months. They detected a small improvement in exercise time with BMMC treatment but no difference in change in LVEF or scar.6 The Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) trial studied the intracoronary treatment in acute myocardial infarction. Despite optimistic results from short-term followup, there was no sustained change in LVEF after 5 years of follow-up; change in scar size was not reported.7 However, in their study of the effects of intracoronary BMMC for chronic heart failure, Strauer et al8 reported that the therapy improved cardiac function, QoL, and survival during a 5-year follow-up.
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Figure 5 The trend of change in mean (A) left ventricular end-diastolic volume (LVEDV), (B) left ventricular end-systolic volume (LVESV), (C) left ventricular ejection fraction (LVEF), and (D) scar size in the injected segments pre-operatively (Pre) and at post-operative assessments after 1-year of follow-up (1 y) and after long-term follow-up in 2013. *p o 0.05 (statistically significant difference between the groups). BMMC, bone marrow mononuclear cells.
Unlike most other BMMC trials, we chose our trial patients with chronic ischemic heart failure. When treating acute myocardial infarction, injury in the heart may still be reversible if the treatment has a chance to act on the insult right after its onset.9 Unfortunately, many patients suffer from “silent” myocardial infarctions that are only detected when symptoms of heart failure develop, sometimes many years after the infarction, and the heart is extensively remodeled.10 A recent meta-analysis11 used the pooled data of 50 published BMMC trials to evaluate possible long-term benefits of the treatment. The authors concluded from their analyses that bone marrow cells could improve LV function, infarct size, and remodeling in patients with acute or chronic ischemic heart disease and that the effects were evident even after longterm follow-up. The cell treatment also reduced the incidence of death and recurrent myocardial infarction. These results are in line with our findings to some extent. We also detected a reduction in scar size with BMMC injections, but in our study no superiority in cardiac function was observed for BMMC treatment over placebo. However, most of the trials analyzed in the meta-analysis studied treatment for acute myocardial infarction, after which the detrimental effects might still be preventable, leading to more pronounced functional effects. Secondly, in our study, the CABG might have been a confounding factor influencing the BMMC effect. CABG
could have imposed such a positive effect on LV function that it concealed the minor influence of the BMMC treatment. In other trials, percutaneous coronary intervention or inconsistency between patients’ concurrent pharmacotherapy might have similar confounding effects.12 To minimize this confounding effect of pharmacotherapy, we executed a pre-operative pharmacotherapy optimization period before final patient selection, which putatively assured more homogeneity among our study patients during the long-term follow-up as well. Future trials should pay careful attention to these possibly confounding factors.13 To date, no consensus has been made about the exact mechanism of how bone marrow-derived cells affect cardiac histology and remodeling: can they generate vascular structures,1,14 cause positive paracrine effects,15 or, in fact, differentiate or transdifferentiate into cardiomyocytes?2 Experimental studies report results in favor of and against these properties, and clinical trials mirror this variability by reporting both improvement in cardiac function and no improvement at all. Because we observed a sustained reduction in scar size, a biologic effect is likely to occur in the treated area. Compared with the literature, the median 17% reduction detected in our study in scar size of the BMMC-treated segments was quite remarkable: for example, in the recent meta-analysis, the mean reduction in scar size was 4.03% with BMMC therapy.11 Thus, with our techniques, the BMMC effect on scar size seems more positive and comparable
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to, for example, the results of the Cardiosphere-Derived Autologous Stem Cells to Reverse Ventricular Dysfunction (CADUCEUS) trial.16 In that trial, an intracoronary infusion of cardiosphere-derived cells reduced the scar size also statistically significantly, with a mean 12.3% during 1-year follow-up. As the reduction in scar size detected in LGE-MRI reflects a reduction in the amount of extracellular matrix, one explanation for the benefits of BMMCs might be that these cells have beneficial effects on reverse remodeling via their positive paracrine effects on extracellular matrix, which is important in cardiac remodeling. As we pointed out previously,3 a change in scar size is not a negligible issue. An extensive scar may function as an arrhythmogenic center and affects prognosis,17,18 although the possible advantage of scar reduction was not reflected in the numbers of deaths or inserted pacemakers or ICDs, even in this long-term study. Our original trial was designed to answer the question of efficacy of intramyocardial BMMC treatment during 1-year of follow-up. However, due to exciting results, we were determined to continue and contacted our study patients again. Unfortunately, during the years, many patients had been lost to follow-up, and 65% of the BMMC patients could finally participate in the long-term study. This is a limitation in our study and demands relative caution when interpreting current results. Any new treatment modalities are utterly welcome for the treatment of ischemic heart failure, including BMMC therapies.19 According to our long-term results, with follow-up up to 7 years, it appears that intramyocardial BMMC therapy fails to achieve any beneficial effects on cardiac function. The sustained reduction in scar size by the cell therapy is intriguing. Revealing its clinical relevance and effects on, for example, survival will warrant large-scale clinical studies.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. The project was supported by the Heart Research Foundation, the Academy of Finland (Decision 138494) and by Government Subsidy for Medical Research Block Grants (TYH2010103).
Appendix Collaborators in the Helsinki BMMC Collaboration group: Pekka Hämmäinen, Department of Cardiothoracic Surgery, Heart and Lung Center, Helsinki University Central Hospital; Miia Holmström, Division of Roentgenology, HUS Medical Imaging Center, Helsinki University Central Hospital; Jukka Schildt, Aapo Ahonen, and Päivi Nikkinen, Division of Nuclear Medicine, HUS Medical Imaging Center, Helsinki University Central Hospital; Anne Nihtinen, Department of Hematology, Helsinki University Central Hospital; Riitta Alitalo, Stem Cell Laboratory, Department of Clinical Chemistry and Hematology, HUSLAB, Helsinki University Central Hospital; and Reino Pöyhiä, Department of Anesthesiology and Intensive Care, Helsinki University Central Hospital, Helsinki, Finland.
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References 1. Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001;104: 1046-52. 2. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701-5. 3. Patila T, Lehtinen M, Vento A, et al. Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass. J Heart Lung Transplant 2014;33: 567-74. 4. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E. Society for Cardiovascular Magnetic Resonance Board of Trustees Task Force on Standardized Protocols. Standardized cardiovascular magnetic resonance imaging (CMR) protocols, Society for Cardiovascular magnetic resonance: board of trustees task force on standardized protocols. J Cardiovasc Magn Reson 2008;10:35. 5. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-42. 6. Beitnes JO, Hopp E, Lunde K, et al. Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study. Heart 2009;95:1983-9. 7. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur Heart J 2009;30:2978-84. 8. Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail 2010;12: 721-9. 9. Hellawell JL, Margulies KB. Myocardial reverse remodeling. Cardiovasc Ther 2012;30:172-81. 10. Mann DL. Mechanisms and models in heart failure: a combinatorial approach. Circulation 1999;100:999-1008. 11. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 2012;126:551-68. 12. Wollert KC, Drexler H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol 2010;7:204-15. 13. Joseph J. Needling the heart to rejuvenate: the promise of intramyocardial injection of bone marrow stem cells. J Heart Lung Transplant 2014;33:565-629. 14. Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430-6. 15. Burchfield JS, Iwasaki M, Koyanagi M, et al. Interleukin-10 from transplanted bone marrow mononuclear cells contributes to cardiac protection after myocardial infarction. Circ Res 2008;103:203-11. 16. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiospherederived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379: 895-904. 17. Kwon DH, Halley CM, Carrigan TP, et al. Extent of left ventricular scar predicts outcomes in ischemic cardiomyopathy patients with significantly reduced systolic function: a delayed hyperenhancement cardiac magnetic resonance study. JACC Cardiovasc Imaging 2009;2: 34-44. 18. Boyé P, Abdel-Aty H, Zacharzowsky U, et al. Prediction of lifethreatening arrhythmic events in patients with chronic myocardial infarction by contrast-enhanced CMR. JACC Cardiovasc Imaging 2011;4:871-9. 19. Braunwald E. Heart Failure. JACC Heart Fail 2013;1:1-20.
ORIGINAL CLINICAL SCIENCE
Intramyocardial bone marrow mononuclear cell transplantation in ischemic heart failure: Long-term follow-up Miia Lehtinen, MD,a Tommi Pätilä, MD, PhD,a Esko Kankuri, MD, PhD,b Kirsi Lauerma, MD, PhD,c Juha Sinisalo, MD, PhD,d Mika Laine, MD, PhD,d Markku Kupari, MD, PhD,d Antti Vento, MD, PhD,a and Ari Harjula, MD, PhDa,b,1 for the Helsinki BMMC Collaboration From the aDepartment of Cardiothoracic Surgery, Heart and Lung Center, Helsinki University Central Hospital; b Institute of Biomedicine, Pharmacology, University of Helsinki; cDivision of Roentgenology, HUS Medical Imaging Center; and the dDepartment of Cardiology, Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland.
KEYWORDS: myocardial infarction; heart failure; bypass surgery; bone marrow mononuclear cells
BACKGROUND: Long-term results regarding treatment of chronic ischemic heart failure with bone marrow mononuclear cells (BMMCs) have been few. We received encouraging results at the 1-year follow-up of patients treated with combined coronary artery bypass grafting (CABG) and BMMCs, so we decided to extend the follow-up. METHODS: The study patients had received injections of BMMCs or vehicle into the myocardial infarction border area during CABG in a randomized and double-blind manner. We could contact 36 of the 39 patients recruited for the original study. Pre-operatively and after an extended follow-up period, we performed magnetic resonance imaging, measured pro-B-type amino-terminal natriuretic peptide, reviewed patient records from the follow-up period, and determined current quality of life with the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey. RESULTS: The median follow-up time was 60.7 months (interquartile range [IQR], 45.1–72.6 months). No statistically significant difference was detected in change of pro-B-type amino-terminal natriuretic peptide values or in quality of life between groups. The median change in left ventricular ejection fraction was 4.9% (IQR, –2.1% to 12.3%) for controls and 3.9% (IQR, –5.2% to 10.2%) for the BMMC group (p ¼ 0.647). Wall thickening in injected segments increased by a median of 17% (IQR, –5% to 30%) for controls and 15% (IQR, –12% to 19%) for BMMC patients (p ¼ 0.434). Scar size in injected segments increased by a median of 2% (IQR, –7% to 19%) for controls but diminished for BMMC patients, with a median change of –17% (IQR, –30% to –6%; p ¼ 0.011). CONCLUSIONS: In the treatment of chronic ischemic heart failure, combining intramyocardial BMMC therapy with CABG fails to affect cardiac function but can sustainably reduce scar size, even in the longterm. J Heart Lung Transplant ]]]];]:]]]–]]] r 2015 International Society for Heart and Lung Transplantation. All rights reserved.
1 The Collaborators in the Helsinki BMMC Collaboration group are listed in the Appendix. Reprint requests: Miia Lehtinen, MD, Surgery, Biomedicum Helsinki 1, Haartmaninkatu 8, 00290 Helsinki, Finland. Telephone: þ358-9-19125000. Fax: þ358-9-471-75858. E-mail address: miia.1.1ehtinen@helsinki.fi
During the past decade, multiple trials have investigated effects of bone marrow mononuclear cells (BMMCs) in the treatment of chronic ischemic heart disease and acute myocardial infarction. Despite promising findings in animal trials,1,2 clinical trials have failed to show unequivocal
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2015.01.989
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results. Furthermore, follow-up times have been almost invariably quite limited, ranging from 4 to 18 months. Between 2006 and 2011, we conducted a randomized, double-blinded clinical trial (ClinicalTrials.gov Identifier: NCT00418418) investigating the safety and efficacy of BMMC transplantation as an adjunct to coronary artery bypass graft (CABG) surgery.3 Initially, follow-up was 1 year post-operatively. According to our results, BMMCs seemed to have no effect on global or local left ventricular (LV) function, but the scar size was significantly diminished in the BMMC-treated areas compared with placebo. Encouraged by this result, we decided to continue the study and invited our patients for a late follow-up visit. As in the pre-operative assessment, LV function and scar size were analyzed by cardiac magnetic resonance imaging (MRI). In addition, we measured the circulating pro-B-type amino-terminal natriuretic peptide (proBNP) concentration, determined the current New York Heart Association (NYHA) Functional Classification, and used the Medical Outcomes Study Short-Form 36 (SF-36) Health Survey to assess the post-operative health-related quality of life (HRQoL). In this report we document the long-term results of intramyocardial BMMC injections combined with CABG using randomized double-blinded techniques.
Methods This study was approved by the Institutional Ethics Committee (Dnro HUS 456/E6/05).
Patients The original study protocol and the 1-year follow-up results of our trial have been published previously.3 Patients were included in the original trial if they met the following inclusion criteria: age between 18 and 75 years, provided informed consent, LV ejection fraction (LVEF) between r45% and Z15%, and NYHA class II to IV heart failure symptoms. Criteria for exclusion were:
A. heart failure due to LV outflow track obstruction; B. history of life-threatening ventricular arrhythmias or resuscita-
Helsinki University Meilahti Hospital Cell Processing Laboratory.3 The cell suspension was divided into six 1-ml syringes for the treatment group; control patients received only vehicle medium by syringes. The patients were assigned randomly, and the syringe contents were masked to ensure double-blinded technique. After the bone marrow aspiration, a standard CABG operation was performed. After the bypass anastomoses were finished and the heart remained in cardiac arrest, the BMMCs were injected into pre-defined sites in the infarction border area. The infarction and its border area were localized pre-operatively by imaging data, and this information was used to target the injections to the border area during surgery. The injection procedure was carefully photographed during the procedure, and the areas injected were specified in patient documents for analysis.
Follow-up After the original 1-year follow-up, patients were monitored in the outpatient clinic of Helsinki University Central Hospital or in a regional health center according to local routines. In Spring 2013, the patients were invited for a late follow-up research visit at our institution. For end point measures in this long-term follow-up, we determined (1) changes in the LV measurements and scar size between the pre-operative and late post-operative MRI studies, (2) concomitant changes in NYHA class and plasma proBNP concentration; (3) hospitalizations due to cardiac failure, and (4) the patients’ current HRQoL by the SF-36 questionnaire. The SF-36 is a standardized questionnaire with specified mean and standard deviation (SD) values for 8 different dimensions of the instrument per different cohorts that reflect (1) physical functioning; (2) role-physical, measuring role limitations because of physical health problems; (3) role-psychological, assessing role limitations as a result of emotional impairment; (4) vitality, assessing the feeling of energy or fatigue; (5) mental health; (6) social functioning, measuring ability to perform normal social activities; (7) bodily pain; and (8) subjective general health perceptions. The investigator transformed the scores for each dimension to a 0- to 100-point scale for comparisons between groups. A lower score means greater limitations to activities or more distress with social and emotional problems. As a reference, we used values for a Finnish cohort with any chronic disease and compared their SF-36 mean scores with the scores of our study patients.
tion, or insertion of implantable cardioverter-defibrillator (ICD);
C. stroke or other disabling condition within 3 months before D. E. F. G.
screening; severe valve disease; other serious disease limiting life expectancy; contraindications for coronary angiogram or MRI; or participation in another clinical trial.
Eligible patients received optimal pre-operative medication for heart failure and coronary disease for a minimum of 4 weeks, after which the screening echocardiogram was repeated. If the LVEF was still r45%, the patient was included in the study after informed consent, and a CABG operation was scheduled, with preoperative studies performed during the waiting period.
Procedure Bone marrow aliquots (100 ml) were harvested from all patients from the posterior iliac crests under anesthesia before surgery. The mononuclear cell fraction was obtained by standard methods of
Cardiac MRI Cardiac MRI was performed with a 1.5-T Sonata scanner and phase-array cardiac coil (Siemens AG, Erlangen, Germany). Images were obtained with electrocardiography gating and during breath holding. Transaxial haste sequence covered the entire heart to study morphology and to obtain further orientation data. LV structure and function were imaged by standardized MRI protocol.4 True fast imaging with steady-state precession cine series were obtained at the vertical and horizontal long axis for scout to line up short-axis images. The stack of short-axis images was obtained from the mitral valve plane through the apex. Slice thickness was 8 mm with a 2-mm gap, and temporal resolution was 28 to 40 msec. To detect the myocardial scar, late gadolinium enhancement (LGE) was imaged with a 2 dimensional segmented inversion recovery gradient echo sequence 12 to 20 minutes after an injection of Dotarem (279.3 mg/ml; dose 0.2 mmol/kg). LGE images were obtained at the same views and slice/gap thickness as cine imaging.
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Inversion time was determined from a T1 scout sequence and ranged between 240 and 300 msec. For LV volumetry, all short-axis cine images were evaluated by Qmass software (Medis Medical Imaging Systems, Leiden, the Netherlands). Endocardial and epicardial borders were planimetered at end diastole and end systole. The papillary muscles were included in the ventricular blood pool. The planimetry resulted in LV end-diastolic volume (EDV), end-systolic volume (ESV), and LVEF. According to the American Heart Association guidelines, the LV was divided into 16 segments (the 17th segment of apex was excluded from analyses due to its susceptibility to artifacts),5 and wall thickening (WT) was assessed for each segment with the Siemens Leonardo workstation and Argus software (Siemens AG). For scar-volume assessment, the same 16 LV segments were assessed for LGE with Qmass software. The threshold value for scar tissue was set to 5 SD above normal myocardium, and the threshold value for transmural scar was set to 50%. For each patient, the pre-operative and post-operative values for analyses of WT, scar volume, and transmural scar were the averages over all injected segments, over all non-injected segments, and over the 16 segments in total. One investigator blinded to treatment analyzed all MRI imaging data.
Statistical methods The Mann-Whitney U test was used for non-normally distributed continuous variables, with results reported as medians and interquartile range (IQR). For normally distributed parameters,
3 we used Student’s t-test and reported results as means (SD). Categoric variables were analyzed with Fisher’s exact test. To test for the effect of the differences in length of the follow-up periods, we used it as a covariate in the analysis of covariance model. All p-value testing was 2-sided, with statistical significance at p o 0.05. Computation was achieved with PASW Statistics 18 software (IBM Inc, Armonk, NY).
Results We were able to contact 36 of the 39 patients (92%) recruited for the original study. One control patient and 2 BMMC group patients had died after the 1-year follow-up, and 6 patients refused to participate in the long-term study (Figure 1). We were able to reanalyze data of 17 control (89%) and 13 BMMC (65%) patients. The median follow-up time was 60.7 months (IQR, 45.1– 72.6 months; Table 1). Decompensated cardiac failure caused 1 hospitalization in the control group and 2 hospitalizations in the BMMC group; 1 BMMC patient was hospitalized twice and diagnosed with aortic stenosis, which was later treated surgically. Two patients in both groups had sustained cerebral infarction during the long-term follow-up. One patient in both groups was diagnosed with cancer, a control patient with prostatic carcinoma and a BMMC patient with sigmoid adenocarcinoma.
Figure 1 Study flow-diagram. BMMC, bone marrow mononuclear cell; CABG, coronary artery bypass grafting; ICD, implantable cardioverter-defibrillator; MRI, magnetic resonance imaging; PM, pacemaker.
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Follow-Up Time and Events During the Long-Term Follow-Up
Variables
Placebo
BMMC
Patients participating in the original study, No. Death after the 1-year follow-up, No.a Patients participating in long-term follow-up, No. Age at 2013, median (IQR) yearsb Follow-up, median (IQR) monthsb Heart failure hospitalization, No.b,c Myocardial infarction, No.b ICD or pacemaker, No.b Percutaneous coronary intervention, No.b Coronary artery bypass grafting, No.b Stroke, No.b Cancer, No.b
19 1 17 67 (63–77) 61.2 (48.3–72.8) 1 0 1 0 0 2 1
20 2 13 70 (63–75) 51.9 (44.9–72.4) 2 0 2 0 0 2 1
p-value 1.000 0.851 0.902 0.934 1.000 0.565 1.000 1.000 1.000 1.000
BMMC, bone marrow mononuclear cell; ICD, implantable cardioverter-defibrillator; IQR, interquartile range. a Calculated for the patients participating in the original study (n ¼ 39). b Calculated for the patients participating in the long-term follow-up (n ¼ 30). c Heart failure hospitalizations shown as the number of hospital stays per group during the long-term follow-up.
For the control patients, the median plasma proBNP value was 684 ng/liter (IQR, 320–2,071 ng/liter) pre-operatively and 358 ng/liter (IQR, 214–680 ng/liter) after the long-term followup, and respective values for BMMC patients were 1,236 ng/liter (IQR, 449–2,615 ng/liter) and 819 ng/liter (IQR 383–2,083 ng/ liter). The between-group difference in the change was not statistically significant (p ¼ 0.357). NYHA class had improved from the pre-operative median of class IV in both groups to class III in control patients and class II in BMMC patients (p ¼ 0.473). The scores for each of the 8 dimensions measured with the SF-36 HRQoL questionnaire at the end of the follow-up were similar in both groups. Compared with the reference group (Finns with a chronic disease), no statistically significant differences were found in any dimensions of QoL; neither were any statistically significant differences detectable when scores between the 2 study groups were compared (p 4 0.05; Figure 2).
MRI analysis was successful in 25 (14 controls and 11 BMMC patients) pre-operatively and after long-term follow-up. One control and 2 BMMC patients had received an ICD or a pacemaker, contraindicating MRI. Three control patients and 5 BMMC patients refused MRI. For those patients participating in the long-term MRI follow-up, the median LVEF change was 4.9% (IQR, –2.1% to 12.3%) for controls and 3.9% (IQR, –5.2% to 10.2%) for BMMC patients (p ¼ 0.647). LVEDV changed a median of –63 ml (IQR, –95 to –19 ml) in the control group and –37 ml (IQR, –87 to –8 ml) in the BMMC group (p ¼ 0.767), and the concomitant changes in LVESV were –38 ml (IQR –85 to –2 ml) and –21 ml (IQR, –70 to –3 ml; p ¼ 0.647), respectively (Figure 3). Depending on the size and location of the myocardial scar, the infarction border area that received cell or placebo injections comprised 1 to 4 myocardial American Heart
Figure 2 Means and standard deviations (whiskers) of scores for different dimensions of the Medical Outcomes Study Short-Form 36 (SF-36) health-related quality of life questionnaire for placebo-treated control patients, patients treated with bone marrow mononuclear cells (BMMCs), and a reference cohort.
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Figure 4 Scar size preoperatively (Pre) and after long-term follow up in 2013 (Post) in injected (placebo or bone marrow mononuclear cells [BMMC]), non-injected, and all segments in total in both study groups. The horizontal line in the middle of each box indicates the median, the box boarders indicate the 75th and 25th quartiles, and the whiskers indicate the range.
Discussion
Figure 3 (A) Left ventricular ejection fraction and (B) left ventricular end-diastolic volume (EDV) and end-systolic volume (ESV) are shown pre-operatively (Pre) and after long-term followup in 2013 (Post) in both groups. The horizontal line in the middle of each box indicates the median, the box boarders indicate the 75th and 25th quartiles, and the whiskers indicate the range. BMMC, bone marrow mononuclear cells.
Association segments. WT in injected segments increased a median of 17% (IQR, –5% to 30%) in placebo-treated controls and 15% (IQR, –12% to 19%) in BMMC-treated patients (p ¼ 0.434) during the long-term follow-up. Scar size increased a median 2% (IQR, –7% to 19%) in placebo-treated segments but diminished in BMMC-treated segments a median of 17% (IQR –30% to –6%; p ¼ 0.011). The proportion of transmural scar showed a similar trend: it remained unchanged (IQR –8% to 25%) in placebo-injected segments and diminished a median of 23% (IQR, –36% to –3%) in BMMC-injected segments (p ¼ 0.093; Figure 4). The different lengths of the long-term follow-up periods did not affect these results. During the period after the first post-operative follow-up visit at 1 year, WT in injected segment increased a median of 9% (IQR, 2%–24%) for controls and 7% (IQR, –16% to 19%) for BMMC patients (p ¼ 0.352). During this same period, scar size in the injected segments had increased a median of 1% (IQR, –14% to 6%) in the control group and diminished a median of 5% (IQR, –16% to 8%) in the BMMC group (p ¼ 0.886; Figure 5); changes of the proportion of transmural scar in the injected segments were 0% (IQR, –25% to 5%) and –1% (IQR, –16% to 8%), respectively (p ¼ 0.931).
The results of our study suggest that treatment of ischemic heart failure with intramyocardial BMMC therapy and CABG may sustainably reduce scar size, even in the long-term. Because the myocardial scar retained its diminished size after the first follow-up visit at 1 year, the cells seem to execute their beneficial effects during the first months after injections. The results are in line with our previous findings. After 1 year of follow-up, we noticed that the scar size in injected segments rose by a median 5.1% for controls but fell by 13.1% for BMMC patients3; after the current long-term follow-up, the measured change in scar size from preoperative measurements remained practically the same in both groups. The therapy apparently fails to influence LVEF, volume, or local WT assessed by MRI, because we detected no differences in changes of these parameters during the 1-year or long-term follow-up. No difference was detected in QoL between the groups after the long-term follow-up. To the best of our knowledge, this trial with randomized double-blinded techniques provides the longest follow-up results on ischemic heart failure patients treated with intramyocardial BMMC therapy and CABG. Few studies have investigated the long-term effects of BMMC therapy compared with a control group with followup periods of 3 years or longer. Beitnes et al6 studied intracoronary BMMC treatment for 100 patients with acute myocardial infarction and reported their results for a followup of 36 months. They detected a small improvement in exercise time with BMMC treatment but no difference in change in LVEF or scar.6 The Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) trial studied the intracoronary treatment in acute myocardial infarction. Despite optimistic results from short-term followup, there was no sustained change in LVEF after 5 years of follow-up; change in scar size was not reported.7 However, in their study of the effects of intracoronary BMMC for chronic heart failure, Strauer et al8 reported that the therapy improved cardiac function, QoL, and survival during a 5-year follow-up.
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Figure 5 The trend of change in mean (A) left ventricular end-diastolic volume (LVEDV), (B) left ventricular end-systolic volume (LVESV), (C) left ventricular ejection fraction (LVEF), and (D) scar size in the injected segments pre-operatively (Pre) and at post-operative assessments after 1-year of follow-up (1 y) and after long-term follow-up in 2013. *p o 0.05 (statistically significant difference between the groups). BMMC, bone marrow mononuclear cells.
Unlike most other BMMC trials, we chose our trial patients with chronic ischemic heart failure. When treating acute myocardial infarction, injury in the heart may still be reversible if the treatment has a chance to act on the insult right after its onset.9 Unfortunately, many patients suffer from “silent” myocardial infarctions that are only detected when symptoms of heart failure develop, sometimes many years after the infarction, and the heart is extensively remodeled.10 A recent meta-analysis11 used the pooled data of 50 published BMMC trials to evaluate possible long-term benefits of the treatment. The authors concluded from their analyses that bone marrow cells could improve LV function, infarct size, and remodeling in patients with acute or chronic ischemic heart disease and that the effects were evident even after longterm follow-up. The cell treatment also reduced the incidence of death and recurrent myocardial infarction. These results are in line with our findings to some extent. We also detected a reduction in scar size with BMMC injections, but in our study no superiority in cardiac function was observed for BMMC treatment over placebo. However, most of the trials analyzed in the meta-analysis studied treatment for acute myocardial infarction, after which the detrimental effects might still be preventable, leading to more pronounced functional effects. Secondly, in our study, the CABG might have been a confounding factor influencing the BMMC effect. CABG
could have imposed such a positive effect on LV function that it concealed the minor influence of the BMMC treatment. In other trials, percutaneous coronary intervention or inconsistency between patients’ concurrent pharmacotherapy might have similar confounding effects.12 To minimize this confounding effect of pharmacotherapy, we executed a pre-operative pharmacotherapy optimization period before final patient selection, which putatively assured more homogeneity among our study patients during the long-term follow-up as well. Future trials should pay careful attention to these possibly confounding factors.13 To date, no consensus has been made about the exact mechanism of how bone marrow-derived cells affect cardiac histology and remodeling: can they generate vascular structures,1,14 cause positive paracrine effects,15 or, in fact, differentiate or transdifferentiate into cardiomyocytes?2 Experimental studies report results in favor of and against these properties, and clinical trials mirror this variability by reporting both improvement in cardiac function and no improvement at all. Because we observed a sustained reduction in scar size, a biologic effect is likely to occur in the treated area. Compared with the literature, the median 17% reduction detected in our study in scar size of the BMMC-treated segments was quite remarkable: for example, in the recent meta-analysis, the mean reduction in scar size was 4.03% with BMMC therapy.11 Thus, with our techniques, the BMMC effect on scar size seems more positive and comparable
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to, for example, the results of the Cardiosphere-Derived Autologous Stem Cells to Reverse Ventricular Dysfunction (CADUCEUS) trial.16 In that trial, an intracoronary infusion of cardiosphere-derived cells reduced the scar size also statistically significantly, with a mean 12.3% during 1-year follow-up. As the reduction in scar size detected in LGE-MRI reflects a reduction in the amount of extracellular matrix, one explanation for the benefits of BMMCs might be that these cells have beneficial effects on reverse remodeling via their positive paracrine effects on extracellular matrix, which is important in cardiac remodeling. As we pointed out previously,3 a change in scar size is not a negligible issue. An extensive scar may function as an arrhythmogenic center and affects prognosis,17,18 although the possible advantage of scar reduction was not reflected in the numbers of deaths or inserted pacemakers or ICDs, even in this long-term study. Our original trial was designed to answer the question of efficacy of intramyocardial BMMC treatment during 1-year of follow-up. However, due to exciting results, we were determined to continue and contacted our study patients again. Unfortunately, during the years, many patients had been lost to follow-up, and 65% of the BMMC patients could finally participate in the long-term study. This is a limitation in our study and demands relative caution when interpreting current results. Any new treatment modalities are utterly welcome for the treatment of ischemic heart failure, including BMMC therapies.19 According to our long-term results, with follow-up up to 7 years, it appears that intramyocardial BMMC therapy fails to achieve any beneficial effects on cardiac function. The sustained reduction in scar size by the cell therapy is intriguing. Revealing its clinical relevance and effects on, for example, survival will warrant large-scale clinical studies.
Disclosure statement None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose. The project was supported by the Heart Research Foundation, the Academy of Finland (Decision 138494) and by Government Subsidy for Medical Research Block Grants (TYH2010103).
Appendix Collaborators in the Helsinki BMMC Collaboration group: Pekka Hämmäinen, Department of Cardiothoracic Surgery, Heart and Lung Center, Helsinki University Central Hospital; Miia Holmström, Division of Roentgenology, HUS Medical Imaging Center, Helsinki University Central Hospital; Jukka Schildt, Aapo Ahonen, and Päivi Nikkinen, Division of Nuclear Medicine, HUS Medical Imaging Center, Helsinki University Central Hospital; Anne Nihtinen, Department of Hematology, Helsinki University Central Hospital; Riitta Alitalo, Stem Cell Laboratory, Department of Clinical Chemistry and Hematology, HUSLAB, Helsinki University Central Hospital; and Reino Pöyhiä, Department of Anesthesiology and Intensive Care, Helsinki University Central Hospital, Helsinki, Finland.
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References 1. Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001;104: 1046-52. 2. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701-5. 3. Patila T, Lehtinen M, Vento A, et al. Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: a prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass. J Heart Lung Transplant 2014;33: 567-74. 4. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E. Society for Cardiovascular Magnetic Resonance Board of Trustees Task Force on Standardized Protocols. Standardized cardiovascular magnetic resonance imaging (CMR) protocols, Society for Cardiovascular magnetic resonance: board of trustees task force on standardized protocols. J Cardiovasc Magn Reson 2008;10:35. 5. Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 2002;105:539-42. 6. Beitnes JO, Hopp E, Lunde K, et al. Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study. Heart 2009;95:1983-9. 7. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur Heart J 2009;30:2978-84. 8. Strauer BE, Yousef M, Schannwell CM. The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study. Eur J Heart Fail 2010;12: 721-9. 9. Hellawell JL, Margulies KB. Myocardial reverse remodeling. Cardiovasc Ther 2012;30:172-81. 10. Mann DL. Mechanisms and models in heart failure: a combinatorial approach. Circulation 1999;100:999-1008. 11. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 2012;126:551-68. 12. Wollert KC, Drexler H. Cell therapy for the treatment of coronary heart disease: a critical appraisal. Nat Rev Cardiol 2010;7:204-15. 13. Joseph J. Needling the heart to rejuvenate: the promise of intramyocardial injection of bone marrow stem cells. J Heart Lung Transplant 2014;33:565-629. 14. Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430-6. 15. Burchfield JS, Iwasaki M, Koyanagi M, et al. Interleukin-10 from transplanted bone marrow mononuclear cells contributes to cardiac protection after myocardial infarction. Circ Res 2008;103:203-11. 16. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiospherederived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379: 895-904. 17. Kwon DH, Halley CM, Carrigan TP, et al. Extent of left ventricular scar predicts outcomes in ischemic cardiomyopathy patients with significantly reduced systolic function: a delayed hyperenhancement cardiac magnetic resonance study. JACC Cardiovasc Imaging 2009;2: 34-44. 18. Boyé P, Abdel-Aty H, Zacharzowsky U, et al. Prediction of lifethreatening arrhythmic events in patients with chronic myocardial infarction by contrast-enhanced CMR. JACC Cardiovasc Imaging 2011;4:871-9. 19. Braunwald E. Heart Failure. JACC Heart Fail 2013;1:1-20.
