2Sir HN Medical Research Society, Sir HN Hospital and Research Centre, LT Road, Mumbai, 400002, India
Material and Methods: Twelve AMI patients with ABMSC therapy (ABMSC group) and seven AMI patients without this therapy (Controls) were followed up for 24 months. LV functions were analyzed by 2D Echocardiography (2D ECHO) while the long term effects of bone marrow infusion on any organ were assessed by clinical evaluation, pathological tests, ECG, Holter monitoring, chest X-ray and Sonography of abdomen and pelvic organs.
Results: Long term follow-up of 24 months of AMI patients with ABMSC therapy demonstrated no adverse clinical effects on cardiac or extra cardiac organs. 2D ECHO of ABMSC group demonstrated increase in LVEF from baseline at 6 month (3.8%) which was sustained at 24 month (1.63% increase) with improvement in LV functions. However, in the control group there was marginal increase in LVEF (1.5%) at sixth month which was decreased by 7.3% at 24 month as compared to baseline, with no change in LV functions.
Conclusion: This study demonstrated safety and feasibility of infusing ABMSCs in the culprit coronary artery. It also demonstrated better clinical course in stem cell therapy group as compared to patients without this therapy at 24 months follow-up.
Keywords: Autologous bone marrow stem cells; Acute myocardial infarction; Ventricular remodeling; Long-term effects; Left ventricular function; 2D-Echocardiography; Left ventricular ejection fraction; Left ventricular end diastolic volume; Left ventricular systolic volume
Stem cells are nothing but unspecialized and immature cells that have the ability to divide (self replicate) for indefinite periods-often throughout the life of the organism. Under the right conditions, or given the right signals, stem cells can differentiate into many different mature cell types such as heart cells, skins cells or nerve cells. It holds a great potential for regenerative medicine especially in replacing cells in tissues that hardly have intrinsic renewal capacity including the heart. Since early reports in animal models are more than 14 years ago [1-7], the stem cell field has made enormous advances in moving towards clinically applicable treatment options, and we are now at the dawn of a new era [8-9]. Over the past few years several promising results have been reported with the use of stem cells in various clinical trials [10-16] including ours [17] which demonstrates that intracoronary injection of autologous Bone Marrow Mononuclear Cells (BM-MNCs) improves LV function shortly after acute ST Elevation Myocardial Infarction (STEMI) analyzed at six months. However, more proof is needed on the long-term durability of this treatment effect. We present here our long term 24 month follow up of these patients who had received the Autologous Bone Marrow Stem Cell (ABMSC) therapy for AMI.
During 24 months follow-up, clinical evaluation showed that in ABMSC group one patient had complained of angina while in control group two. None had arrhythmias in both the groups. Repeated hospitalization for left ventricular failure was required for one patient (8.3%) in ABMSC group while three patients (42.8%) in control group. Repeated coronary intervention was required for four patients (33.3%) in ABMSC group while three in control group (42.8%). In both groups coronary re-intervention were required due to in-stent stenosis. Out of four patients of ABMSC group who had in-stent restenosis two had drug eluting stents and two had non-drug eluting stents. While out of the three patients who had in-stent restenosis in control group, two had drug eluting and one had non-drug eluting stent. None of the patient in either group had evidence of sub-acute or late thrombosis till 24 months follow-up. One patient in each group expired of pump failure. All the biochemical, heamatological and other tests of the remaining study subjects were normal at 24 months. There was no evidence of tumor formation or calcification. Thus, there were no adverse clinical effects on cardiac or extra cardiac organs at 24 month after ABMSC therapy.
Table 2 depicts LV functions of ABMSC and Control groups. 2D ECHO at 24 months demonstrated sustained improvement in LV functions as seen at 6 months in ABMSC group. In this group as compared to baseline (0 month) the LVEF was increased by 3.8%
|
ABMSC Group |
Controls |
Age (Years) |
49.7 + 8.3 |
49.7 + 8.2 |
Gender – Male |
10 |
5 |
Female |
2 |
2 |
BMI (Kg/m2) |
23.8 + 3.3 |
24.8 + 2.86 |
Risk Factors |
|
|
Hypertension |
5 |
4 |
Diabetes Mellitus |
4 |
4 |
Smoking |
6 |
3 |
Family history of Coronary artery disease |
1 |
2 |
Clinical History |
|
|
KILLIP CLASS I
|
10 |
4 |
II
|
2 |
3 |
Coronary Angiography |
|
|
Infarct related vessels LAD |
12 |
7 |
TIMI Grade Flow before PTCA I |
1 |
2 |
II |
5 |
2 |
III |
6 |
3 |
Lesion characteristics TYPE C |
12 |
4 |
TYPE B |
0 |
3 |
Re-analyzed Vessel |
2 |
2 |
PTCA |
10 |
05
|
Median time of onset of Chest pain to PCI (DAYS) |
3 |
5 |
Type of Stent |
|
|
Drug Eluting Stents
|
3 |
2 |
Non-drug eluting Stents |
7 |
3 |
Size & Length of Stent |
3.82 + 0.25 x 24.15 + 7.5 mm |
3.01 + 0.15 x 18.14 + 3.04 mm |
TIMI Grade Flow after PCI |
|
|
I |
0 |
0 |
II |
0 |
0 |
III |
10 |
5 |
Cell Therapy |
|
|
Time from stent to cell therapy (DAYS) |
6 |
|
No. of cells injected Nucleated Cell Count (millions) |
136.6 ± 67.1
|
|
% Viability |
93.28 ± 2.87
|
|
% of CD34+ / CD45+ |
0.84 ± 0.47
|
|
% of CD133+ / CD45+ |
0.21 ± 0.13
|
|
Similar to our findings, reports have been documented by Moccetti et al. [19] in a single-center, open-labeled study. They observed that at 4 months although there was no significant difference between the increase in LVEF in the BM-MNC group and the control group, the absolute increase at 5 years remained stable in the BM-MNC but not in the control group. The TOPCARE-AMI trial was the first randomized study investigating the effects of intracoronary infusion of Circulating Progenitor Cells (CPC) or Bone Marrow-derived progenitor Cells (BMC) in 59 patients with successfully reperfused AMI. Leistener et al. [20] in one of the TOPCARE interim reports assessed clinical course, NT-proBNP and MRI data as objective markers of
|
ABMSC Group (N = 12) |
Controls (N = 7) |
||||
|
0 months |
6 months |
24 months |
0 months |
6 months |
24 months |
LVEF (%) |
40.67 ± 6.76 |
44.5 ± 6.9 |
42.3 ± 9.1 |
39.4 ± 7.7 |
40.9 ± 8.7 |
33.6 ± 4.6 |
LVEDV (ml) |
98.7 ± 20.3 |
94.2 ± 18.9 |
91.6 ± 21.1 |
102 ± 18.4 |
107 ± 17.9 |
98.4 ± 21.4 |
LVESV (ml) |
59.1 ± 16.2 |
53.8 ± 13.9 |
53.0 ± 20.3 |
62.7 ± 15.2 |
64.3 ± 16.4 |
65.7 ± 15.8 |
ABMSC–Autologous Bone marrow Stem cells, LVEF-Left Ventricular Ejection Fraction, LVEDV-Left Ventricular End Diastolic Volume, LVESV-Left Ventricular Systolic Volume
LV function was assessed by two-dimensional speckle-tracking Echocardiography. Beitnes et al. [21] have reported that in this trial, from baseline to 3 years, LVEF changed from 45.7 to 47.5% in the mBMC group, and from 46.9 to 46.8% in the control group. There were no significant differences between groups in change of LV volumes, global systolic function, regional function, or diastolic function during 3 years follow-up. They concluded that no differences between groups, indicating beneficial effect of intracoronary mBMC injection, could be identified. Thus, both groups in ASTAMI experienced improvement of global, regional, and diastolic LV function after 3-6 months, with effects sustained at 3 years. The reason given for no improvement in patents due to stem cell therapy as compared to control was the method of cell separation they used from the other trials.
Heart muscle salvage after heart attack is the single important determinant factor for event free long term survival. Reversal of heart failure would require not only restoration of blood supply but also replacement of myocytes as and most importantly no adverse effects of these autologous cells supplied to other organs. In the present study and the major trials done with this aim, gives the evidence of sustained improvement on LV function and thus long term durability of the treatment.
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