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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 26-30

The Effect of Intracoronary Infusion of Bone Marrow-derived Mononuclear Cells on Clinical Outcome and Cardiac Function in Chronic Heart Failure Patients: An Uncontrolled Study


1 Rajaie Cardiovascular, Medical and Research Center, Tehran, Iran
2 Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Tehran, Iran

Date of Web Publication26-Feb-2018

Correspondence Address:
Dr. Ahmad Amin
Rajaie Cardiovascular, Medical and Research Center, Valiasr Avenue, Nyayesh Cross, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/rcm.rcm_38_17

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  Abstract 


Objective: To evaluate the effect of bone marrow-derived mononuclear cells (BM-MNCs) on clinical outcome and cardiac function in chronic heart failure (HF). Methods: An uncontrolled, open-label trial was performed on symptomatic patients (New York Heart Association [NYHA] Functional Classification II–IV) receiving maximal medical therapy for at least 2 months, with a left ventricular (LV) ejection fraction <25%. Patients were divided into ischemic and nonischemic subgroups. All patients underwent BM aspiration, isolation of BM-MNCs using a standardized system, and intracoronary infusion of BM-MNCs. Primary endpoints assessed in 36 months were changes in (1) LV systolic function and LV end-diastolic diameter by echocardiography and (2) clinical improvement. Secondary measures included other echocardiography measures and major adverse cardiac events and HF hospitalization. Phenotypic and functional analyses of the cell product were performed by the Royan Institute for stem Cell Biology and Technology laboratory. Results: We enrolled 58 patients in our study. There was a significant improvement to exercise and functional capacity (evaluated by NYHA classification and 6-min walking distance) with both groups (for all P < 0.001). A significant decline in serum N-terminal Prohormone of Brain Natriuretic Peptide(NT- ProBNP) was observed in ischemic group (P = 0.01), but it was not statistically significant in nonischemic group. No significant changes were found in LV systolic and diastolic function, right ventricular size and function, severity of Mitral and Tricuspid regurgitation and pulmonary arterial pressure. There was minimal decrease in LV end-diastolic diameter which was statistically significant in ischemic and nonischemic group (P = 0.008 and P = 0.01 accordingly). Our study revealed a remarkably safe profile for BM-MNC infusion. Conclusion: It seems that intracoronary infusion of bone marrow-derived mononuclear stem cells is a safe treatment for patients with advanced HF and further studies need to address the best type of cell, route of administration, and criteria for patient selection.

Keywords: Heart failure, intracoronary infusion, stem cell


How to cite this article:
Amin A, Firouzi A, Mohamadifar A, Naderi N, Ghadrdoost B, Madani H, Aghdami N. The Effect of Intracoronary Infusion of Bone Marrow-derived Mononuclear Cells on Clinical Outcome and Cardiac Function in Chronic Heart Failure Patients: An Uncontrolled Study. Res Cardiovasc Med 2018;7:26-30

How to cite this URL:
Amin A, Firouzi A, Mohamadifar A, Naderi N, Ghadrdoost B, Madani H, Aghdami N. The Effect of Intracoronary Infusion of Bone Marrow-derived Mononuclear Cells on Clinical Outcome and Cardiac Function in Chronic Heart Failure Patients: An Uncontrolled Study. Res Cardiovasc Med [serial online] 2018 [cited 2019 May 20];7:26-30. Available from: http://www.rcvmonline.com/text.asp?2018/7/1/26/226167




  Introduction Top


Heart failure (HF) is a progressive disease with significant morbidity and mortality. Our current therapeutic approach to HF relies on treating patient's symptoms with diuretics and digitalis along with the use of neurohormonal blockers such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists, to counteract the detrimental effects of compensatory mechanisms on cardiovascular system. Biventricular pacemakers and intracardiac defibrillators are helpful in selected HF patients. However, despite all these measures, HF remains a devastating disease with significant burden. Cardiac transplantation – still the only cure for end-stage HF – needs an integrated teamwork service before and after the procedure and there are also the issues with the limited numbers of donors and eligibility of the recipients. Therefore, there is always a need for new and improved therapies to help HF patients.

Replacement of dead or dysfunctional cardiac myocytes through cell-based therapies sounds like a logical and novel option for the treatment of HF. Cell-based therapies may achieve true cardiac regeneration by renewing the pool of functionally active cardiac myocytes or may lead to cardiac repair by supporting neovascularization, supplementing or augmenting the cytoprotective mechanism. These mechanisms may occur naturally or by favorably influencing the remodeling processes.[1],[2],[3],[4],[5] Among all types of stem cells, bone marrow-derived ones are the best in terms of safety and availability.[2],[6]

The clinical trials published to date were only performed on patients with acute myocardial infarction and chronic ischemic HF; hence, there is limited data about the effect of cell therapy in patients with chronic nonischemic HF.[7],[8],[9]


  Methods Top


Study design

This is an uncontrolled, open-label trial designed to evaluate the safety and efficacy of bone marrow-derived mononuclear cells (BM-MNCs) in patients with advanced chronic-ischemic and nonischemic-HF with left ventricular ejection fraction (LVEF) of <25% and NYHA Functional Classification II–IV. The primary objective was to determine if intracoronary injection of BM-MNC improves LV performance and clinical outcome during the 36 months of follow-up compared to baseline levels. Patients were enrolled only if they had been on guideline-recommended medical treatment for at least 2 months. Patients were excluded from the study if persistent azotemia (Cr >2 in 2 readings at least 2 weeks apart), hyperbilirubinemia (total bilirubin >3) and active infection were present.

Study procedure

The study was conducted at Rajaie Cardiovascular, Medical and Research Center and Royan Institute for Stem Cell Biology and Technology. The protocol was reviewed and approved by the ethics committee of Rajaie Cardiovascular Medical and Research Center. Written informed consent was obtained from all patients according to the ethical standards given in the Declaration of Helsinki. All selected patients underwent baseline testing and BM harvest and cell processing.

Baseline assessments were both clinical and paraclinical, including: (1) NYHA classification of HF-related symptoms, (2) 6-min walking distance (6MWD), (3) serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level, and (4) echocardiography.

Demographic and clinical variables were determined by interviews and documents from patient's medical records.

Patients were all followed up monthly for the first 3 months and then every 3 months for a total of 3 years. Major and cardiovascular events were recorded including mortalities, all hospitalization, cardiovascular hospitalization, and HF hospitalization.

Cell separation

Under sedation and local anesthesia, approximately 150 ml of BM was aspirated from the posterior iliac crest of patients on the same day of injection at the hospital.[1] This sample was transferred to Royan Institute for preparation, and then the autologous BM-MNCs were isolated under good manufacturing practice conditions.

At first, the MNCs were counted by a Nucleo Counter (ChemoMetec A/S, Denmark) and isolated by the Ficoll-Paque open system (Lymphodex, inno-TRAIN, REF: 002041600). In summary, the samples were placed on phosphate-buffered saline (PBS) (Milteny Biotech GmbH, REF: 700-25) and centrifuged for 30 min at 400 g through Ficoll-Paque (Lymphodex, inno-TRAIN, REF: 002041600) without brake. In the next step, MNC layer was isolated and washed in PBS. After the determination of cell counts and viability using trypan blue staining and NucleoCounter, cell pellet was suspended in 10 ml normal saline with 2% human serum albumin. Two 5 ml vials including cell suspension were retransported to the hospital for intracoronary transplantation in <5 h of obtaining the sample.

Flow cytometry assay

Flow cytometric analysis could determine the expression of specific cell markers within the heterogeneous MNC population. We used a characterization panel including CD133/2 (293C3)-PE (Milteny Biotech GmbH, Cat No. 130-090-853), anti-hVEGFR2/KDR-PE (R and D systems, #FAB357P), CD31-FITC conjugated mouse IgG1 (BD PharmingenTM, #555445), CD45-FITC/34-PE (BD Biosciences, #341071), mouse IgG2b-PE (BD Biosciences, BD Pharmingen, #556656), mouse IgG1-RPE (Dako, #X0928), and mouse IgG1FITC/mouse IgG1RPE (Dako, #X0932). The BD FACSCalibur flow cytometry system (BD Biosciences, San Jose, CA, USA) with 488 nm blue laser and BD CellQuest pro software (Becton Dickinson, USA) was used for cellular analysis.

Cell injection procedure

Patients were sent to catheterization lab and selective coronary angiography was performed on them. MNC solution was injected through a microcatheter (BALT) into the proximal third of all three coronary artery vessels, before the major branches, to have the least possible wash-out and a more reliable way to the microcirculation.

All patients remained in hospital overnight and discharged with guideline-recommended therapy.

Echocardiography

Echocardiographic measurements were performed according to the American society of echocardiography guidelines, using a General Electric Vivid 7 (GE Medical Systems, Vingmed Ultrasound AS, Horten, Norway) and included LV size and function, right ventricular (RV) size and function, severity of mitral and tricuspid regurgitation, and estimation of pulmonary arterial pressure. Diastolic function was also measured.

Clinical assessment

Clinical improvement was measured by NYHA class and 6MWD. Serum NT-proBNP level was measured for all patients and changes were assessed at all follow-up visits. Major and cardiovascular events were recorded, including mortalities, all hospitalization, cardiovascular hospitalization, and HF hospitalization.

Statistical analysis

Statistical analysis was performed with SPSS 15 for Windows (SPSS Inc., Chicago, IL, USA). Data were expressed as mean values ± standard deviation for interval and count (%) for categorical variables. All variables were tested for normal distribution with Kolmogorov–Smirnov test. Repeated-measures ANOVA followed by Bonferroni posttest was used to assess parametric distributions. For nonparametric distributions, Friedman's test was applied and P < 0.05 was considered statistically significant.


  Results Top


Baseline characteristics

Fifty-eight patients, including 52 (89.6%) men and 6 (10.3%) women, were enrolled in the study with the mean age of 38 ± 5. Etiology of HF was ischemia in 30 (51.7%) patients and idiopathic in 28 (48.2%) patients. Most patients (56.8%) were NYHA class III at baseline. Baseline LVEF was 17.50 ± 5.04% in ischemic group and 13.04 ± 3.68% in the nonischemic group. [Table 1] depicts general characteristics of the patients and [Table 2] demonstrates echocardiographic characterization of the study population.
Table 1: Baseline characteristics of the patients

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Table 2: Echocardiographic findings of study population

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Clinical improvement (New York Heart Association Classification, 6-min walking distance, and N-terminal prohormone of brain natriuretic peptide)

There was a significant improvement in clinical symptoms assessed by NYHA classification in both groups (ischemic and nonischemic) of patients (P< 0.001). Around 56.8% of patients were NYHA class III at baseline. The decrease in the number of patients who were NYHA Class III was statistically significant over time. Although there was a constant clinical improvement over 32 months following the injection, it was more prominent in the first 3 months of injection.

The 6MWD measured 362.75 ± 10 m in ischemic group and 270.55 ± 12 m in the nonischemic group at baseline and increased to 465.33 ± 10 m and 396.50 ± 13 m, respectively (P< 0.001) [Table 3].
Table 3: Clinical and paraclinical changes after cell delivery

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Serum NT-proBNP level in ischemic and nonischemic groups was measured 3023.38 ± 49 pg/ml and 5768.39 ± 85 pg/ml, respectively, at baseline. Consistent decline in NT-proBNP level was observed during study in both groups. This level reached to 1299.50 ± 18 pg/ml in ischemic group (P = 0.01) and 1788.75 ± 17 pg/ml (P = 0.12) in nonischemic group. It was statistically significant only in ischemic group [Table 3].

Echocardiography

Baseline LVEF was measured 17.50 ± 5.04% for ischemic group and 13.04 ± 3.68% for nonischemic group. After 32 months of follow-up, LVEF changed to 17.44 ± 4.54% (P = 0.44) in ischemic group and 13.79 ± 3.23% (P = 0.29) in nonischemic group, which is not statistically significant.

Baseline LV end-diastolic diameter was 6.65 ± 0.80 cm in ischemic group and 6.90 ± 0.61 cm in nonischemic group. After 32 months of follow-up, it decreased to 6.43 ± 0.66 cm (P = 0.008) and 6.69 ± 0.62 cm (P = 0.01), respectively. The difference was statistically significant. Measurements of RV end-diastolic diameter, grading of diastolic dysfunction, pulmonary arterial pressure, and severity of mitral and tricuspid regurgitation showed no significant difference after 32 months of follow-up [Table 4] and [Figure 1] and [Figure 2].
Table 4: Echocardiographic changes after cell delivery

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Figure 1: There was no remarkable change in PAP after cell delivery. PAP: Pulmonary arterial pressure

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Figure 2: Diastolic function showed no significant change after cell delivery. DDG: Diastolic dysfunction grade

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Safety outcomes

During the trial, there were no in-hospital events related to the delivery of cells. Furthermore, no arrhythmia, tumor, or ectopic tissue formation were observed.

Ten patients died during follow-up: 5 due to pump failure, 3 by sudden cardiac death, and 2 by noncardiac causes. All seemed unlikely to be associated with cell therapy. Six patients were admitted with acute HF – at least once – over the 32 months following cell therapy. One patient in nonischemic group underwent heart transplantation.


  Discussion Top


With the aging of the population and shortage of donor organs, HF is becoming a major global challenge. The past decade witnessed translation of stem cell-based technology into formulated clinical trial experiences.

The treatment of nonischemic heart disease is not yet addressed in clinical trials, but initial pilot studies have been performed with moderate improvement on contractile function.

Human BM stem cells are a desirable source for organ repair due to the accessibility of harvest, propensity to propagate in culture, favorable biological profile, and extensive clinical experience.[2],[6] The totality of evidence from the trials using various BM cells for patients with acute MI or ischemic HF has revealed a remarkable safety profile.[10] In our limited experience with 58 patients, there were no side effects attributable to these cells. Moreover, we had a favorable response in clinical status along with improvement in paraclinical markers showing severity of HF. NT-proBNP is a well-known marker of a failing heart and the higher the level is in a HF setting, the poorer the prognosis will be. This improvement in clinical and paraclinical parameters shows a new horizon in applying stem cell therapy on this group of patients. However, there are certain issues remaining unanswered in this regard.

Despite marked improvements in clinical and paraclinical state, echocardiography did not show dramatic improvement, and when it did, the improvements were far behind expectations. This finding, along with the fact that clinical improvement is most prominent in the first 3 months after injection, increases the possibility of a “placebo effect.” However, echocardiography, which has been relied on as the only tool to measure the improvement in myocardial state, is certainly not capable of showing all subtle changes. Even an inconspicuous change (which may not be achievable by well-known therapies) can mean a lot to a failing heart. Theoretically, this might be attributed to a diastolic boost (resulting from stem cells recruiting fibroblasts to build a stronger scaffold around the weak myocardium), better myocardial perfusion (angiogenesis), or a better synchrony in contraction and relaxation. Anyway, our patients did not show a marked improvement in echocardiographic-derived indexes of myocardial function, but they improved clinically and remained stable during their follow-up.

There are certain factors affecting the result of stem cell therapy, including the type and number of stem cells, route of administration, and patient's general medical status (azotemia, inflammation, oxidative stress, and so on). Further investigations need to be done looking at these factors. Moreover, baseline severity of the failing myocardium is also very important as less severe HFs might get more benefit from stem cell therapy. This should also be addressed in further studies.


  Conclusion Top


It seems that intracoronary injection of BM-derived mononuclear stem cells is a safe treatment in patients with advanced HF. Although there have been promising results, stem cell therapy should still be considered an investigational field in the treatment of HF, and further studies need to address best type of cell, route of administration, and criteria for patient selection. It is noteworthy to say that stem cell therapy should never replace guideline-recommended standard therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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