[Show abstract][Hide abstract] ABSTRACT: A decade ago, stem or progenitor cells held the promise of tissue regeneration in human myocardium, with the expectation that these therapies could rescue ischemic myocyte damage, enhance vascular density and rebuild injured myocardium. The accumulated evidence in 2014 indicates, however, that the therapeutic success of these cells is modest and the tissue regeneration involves much more complex processes than cell-related biologics. As the quest for the ideal cell or combination of cells continues, alternative cell types, such as resident cardiac cells, adipose-derived or phenotypic modified stem or progenitor cells have also been applied, with the objective of increasing both the number and the retention of the reparative cells in the myocardium. Two main delivery routes (intracoronary and percutaneous intramyocardial) of stem cells are currently used preferably for patients with recent acute myocardial infarction or ischemic cardiomyopathy. Other delivery modes, such as surgical or intravenous via peripheral veins or coronary sinus have also been utilized with less success. Due to the difficult recruitment of patients within conceivable timeframe into cardiac regenerative trials, meta-analyses of human cardiac cell-based studies have tried to gather sufficient number of subjects to present a statistical compelling statement, reporting modest success with a mean increase of 0.9-6.1% in left ventricular global ejection fraction. Additionally, nearly half of the long-term studies reported the disappearance of the initial benefit of this treatment. Beside further extensive efforts to increase the efficacy of currently available methods, pre-clinical experiments using new techniques such as tissue engineering or exploiting paracrine effect hold promise to regenerate injured human cardiac tissue.
Journal of Molecular and Cellular Cardiology 07/2014; 75. DOI:10.1016/j.yjmcc.2014.06.016 · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to investigate the changes in absolute myocardial blood flow (AMF) after intracoronary injections of mesenchymal SC (MSC) and compared to controls in closed-chest reperfused acute myocardial infarction (AMI) in pigs. Male MSCs, transiently transfected with Luciferase (Luc-MSC) were delivered (9.7 ± 1.2 x 10(6)) intracoronary in the open infarct-related artery one-week post-AMI in female pigs (group MSC), while saline was injected with the same injection rate in controls (group C). The AMF was measured immediately after, and 3, 12 and 24 h post-intracoronary Luc-MSC or saline injections. In vitro bioluminescence images and quantitative real-time TaqMan PCR measurements were performed to quantify the sex-mismatched MSCs. No difference between the groups was observed regarding the weight, heart rate, blood pressure and global ejection fraction 1-week post-AMI. The baseline AMF were similar in the groups (61.3 ± 15. vs 61.1 ± 12.0 ml/min). AMF was decreased significantly immediately after intracoronary MSC delivery (42.0 ± 12.4 vs 57.7 ± 15.7 ml/min p = 0.013), and remained low at 3 h (40.9 ± 13.4 vs 55.8 ± 4.9 ml/min, p = 0.004), 12 h (43.0 ± 3.7 vs 57.8 ± 5.4 ml/min, p = 0.001) with incomplete recovery at 24 h (47.2 ± 5.5 vs 62.1 ± 14.1 ml/min, p = 0.038) as compared to controls, respectively. In vitro bioluminescence displayed transfected Luc-MSCs along the proximal and mid part of the LAD, with limited number (295 ± 101 sry copied/million cardiac cells) of Y-chromosome-MSCs in the infarcted area. Intracoronary injection of SCs results in immediate decrease of AMF, with delayed recovery. The delivery of the SC into the injured myocardium might be hindered by the altered coronary pressure and flow conditions.
[Show abstract][Hide abstract] ABSTRACT: We have investigated the effect of stem cell delivery on the release of hypoxia-inducible factor 1 alpha (HIF-1alpha) in peripheral circulation and myocardium in experimental myocardial ischemia. Closed-chest, reperfused myocardial infarction (MI) was created in domestic pigs. Porcine mesenchymal stem cells (MSCs) were cultured and delivered (9.8 +/- 1.2 x 10(6)) either percutaneously NOGA-guided transendocardially (Group IM) or intracoronary (Group IC) 22 +/- 4 days post-MI. Pigs without MSC delivery served as sham control (Group S). Plasma HIF-1alpha was measured at baseline, immediately post- and at follow-up (FUP; 2 h or 24 h) post-MSC delivery by ELISA kit. Myocardial HIF-1alpha expression of infarcted, normal myocardium, or border zone was determined by Western blot. Plasma level of HIF-1alpha increased immediately post-MI (from 278 +/- 127 to 631 +/- 375 pg/ml, p < 0.05). Cardiac delivery of MSCs elevated the plasma levels of HIF-1alpha significantly (p < 0.05) in groups IC and IM immediately post-MSC delivery, and returned to baseline level at FUP, without difference between the groups IC and IM. The myocardial tissue HIF-1alpha expression in the infarcted area was higher in Group IM than in Group IC or S (1,963 +/- 586 vs. 1,307 +/- 392 vs. 271 +/- 110 activity per square millimeter, respectively, p < 0.05), while the border zone contained similarly lower level of HIF-1alpha, but still significantly higher as compared with Group S. Trend towards increase in myocardial expression of HIF-1alpha was measured in Group IM at 24 h, in contrast to Group IC. In conclusion, both stem cell delivery modes increase the systemic and myocardial level of HIF-1alpha. Intramyocardial delivery of MSC seems to trigger the release of angiogenic HIF-1alpha more effectively than does intracoronary delivery.
Journal of Cardiovascular Translational Research 04/2010; 3(2):114-21. DOI:10.1007/s12265-009-9154-1 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the sub-study of the MYSTAR randomised trial was to analyse the changes in myocardial perfusion in NOGA-defined regions of interest (ROI) with intramyocardial injections of autologous bone marrow mononuclear cells (BM-MNC) using an elaborated transformation algorithm. Patients with recent first acute myocardial infarction (AMI) and left ventricular (LV) ejection fraction (EF) between 30-45% received BM-MNC by intramyocardial followed by intracoronary injection 68 +/- 34 days post-AMI (pooled data of MYSTAR). NOGA-guided endocardial mapping and 99m-Sestamibi-SPECT (single photon emission computer tomography) were performed at baseline and at three months follow-up (FUP). ROI was delineated as a best polygon by connecting of injection points of NOGA polar maps. ROIs were projected onto baseline and FUP polar maps of SPECT calculating the perfusion severity of ROI. Infarct size was decreased (from 27.2 +/- 10.7% to 24.1 +/- 11.5%, p<0.001), and global EF increased (from 38 +/- 6.1% to 41.5 +/- 8.4%, p<0.001) three months after BM-MNC delivery. Analysis of ROI resulted in a significant increase in unipolar voltage (index of myocardial viability) (from 7.9 +/- 3.0 mV to 9.9 +/- 2.7 mV at FUP, p<0.001) and local linear shortening (index of local wall motion disturbances) (from 11.0 +/- 3.9% to 12.7 +/- 3.4%, p=0.01). NOGA-guided analysis of the intramyocardially treated area revealed a significantly increased tracer uptake both at rest (from 56.7 +/- 16.1% to 62.9 +/- 14.2%, p=0.003) and at stress (from 59.3 +/- 14.2% to 62.3 +/- 14.9%, p=0.01). Patients exhibiting >or=5% improvement in perfusion defect severity received a significantly higher number of intramyocardial BM-MNC. In conclusion, combined cardiac BM-MNC delivery induces significant improvement in myocardial viability and perfusion in the intramyocardially injected area.
Thrombosis and Haemostasis 03/2010; 103(3):564-71. DOI:10.1160/TH09-08-0520 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cell-based therapy is a promising, novel therapeutic strategy for cardiovascular disease. The rapid transition of this approach from the benchside to clinical trials has left a gap in the understanding of the mechanisms of cell therapy. Monitoring of cell homing and the fate of cardially delivered stem cells is fundamental for clarification of the myocardial regenerative process. Noninvasive imaging techniques allow an in vivo evaluation of the survival, migration and differentiation of implanted stem cells over time, and by this means, can help to answer unresolved questions. The most promising in vivo tracking methods involve the direct, nonspecific labeling of cells including MRI, radionuclide imaging and the use of reporter-gene imaging. This review summarizes the most important results of animal and human studies in which the fate and biodistribution of cardially delivered stem cells are assessed through different in vivo tracking methods.
Regenerative Medicine 06/2009; 4(3):407-22. DOI:10.2217/rme.09.14 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Combined intracoronary and intramyocardial administration might improve outcomes for bone-marrow-derived stem cell therapy for acute myocardial infarction (AMI). We compared the safety and feasibility of early and late delivery of stem cells with combined therapy approaches.
Patients with left ventricular ejection fraction less than 45% after AMI were randomly assigned stem cell delivery via intramyocardial injection and intracoronary infusion 3-6 weeks or 3-4 months after AMI. Primary end points were changes in infarct size and left ventricular ejection fraction 3 months after therapy.
A total of 60 patients were treated. The mean changes in infarct size at 3 months were -3.5 +/- 5.1% (95% CI -5.5% to -1.5%, P = 0.001) in the early group and -3.9 +/- 5.6% (95% CI -6.1% to -1.6%, P = 0.002) in the late group, and changes in ejection fraction were 3.5 +/- 5.6% (95% CI 1.3-5.6%, P = 0.003) and 3.4 +/- 7.0% (95% CI 0.7-6.1%, P = 0.017), respectively. At 9-12 months after AMI, ejection fraction remained significantly higher than at baseline in both groups. In the early and late groups, a mean of 200.3 +/- 68.7 x 10(6) and 194.8 +/- 60.4 x 10(6) stem cells, respectively, were delivered to the myocardium, and 1.30 +/- 0.68 x 10(9) and 1.29 +/- 0.41 x 10(9) cells, respectively, were delivered into the artery. A high number of cells was required for significant improvements in the primary end points.
Combined cardiac stem cell delivery induces a moderate but significant improvement in myocardial infarct size and left ventricular function.
Nature Clinical Practice Cardiovascular Medicine 12/2008; 6(1):70-81. DOI:10.1038/ncpcardio1388 · 7.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To review the milestones in stem cell therapy for ischemic heart disease from early basic science to large clinical studies and new therapeutic approaches.
Basic research and clinical trials (systematic review) were used. The heart has the ability to regenerate through activation of resident cardiac stem cells or through recruitment of a stem cell population from other tissues, such as bone marrow. Although the underlying mechanism is yet to be made clear, numerous studies in animals have documented that transplantation of bone marrow-derived stem cells or circulating progenitor cells following acute myocardial infarction and ischemic cardiomyopathy is associated with a reduction in infarct scar size and improvements in left ventricular function and myocardial perfusion.
Cell-based cardiac therapy has expanded considerably in recent years and is on its way to becoming an established cardiovascular therapy for patients with ischemic heart disease. There have been recent insights into the understanding of mechanisms involved in the mobilization and homing of the imported cells, as well as into the paracrine effect, growth factors, and bioactive molecules. Additional information has been obtained regarding new stem cell sources, cell-based gene therapy, cell-enhancement strategies, and tissue engineering, all of which should enhance the efficacy of human cardiac stem cell therapy.
The recently published trials using bone marrow-origin stem cells in cardiac repair reported a modest but significant benefit from this therapy. Further clinical research should aim to optimize the cell types utilized and their delivery mode, and pinpoint optimal time of cell transplantation.
[Show abstract][Hide abstract] ABSTRACT: Previous data suggest that bone marrow-derived stem cells (BM-SCs) decrease the infarct size and beneficially affect the postinfarction remodeling.
The Myocardial Stem Cell Administration After Acute Myocardial Infarction Study is a multicenter, prospective, randomized, single-blind clinical trial designed to compare the early and late intracoronary or combined (percutaneous intramyocardial and intracoronary) administration of BM-SCs to patients after acute myocardial infarction (AMI) with reopened infarct-related artery. The primary end points are the changes in resting myocardial perfusion defect size and left ventricular ejection fraction (gated single photon emission computed tomography [SPECT] scintigraphy) 3 months after BM-SCs therapy. The secondary end points relate to evaluation of (1) the safety and feasibility of the application modes, (2) the changes in left ventricular wall motion score index (transthoracic echocardiography), (3) myocardial voltage and segmental wall motion (NOGA mapping), (4) left ventricular end-diastolic and end-systolic volumes (contrast ventriculography), and (5) the clinical symptoms (Canadian Cardiovascular Society [CCS] anina score and New York Heart Association [NYHA] functional class) at follow-up. Three hundred sixty patients are randomly assigned into 1 of 4 groups: group A, early treatment (21-42 days after AMI) with intracoronary injection; group B, early treatment with combined application; group C, late treatment (3 months after AMI) with intracoronary delivery; and group D, late treatment with combined administration of BM-SCs. Besides the BM-SCs therapy, the standardized treatment of AMI is applied in all patients.
The Myocardial Stem Cell Administration After Acute Myocardial Infarction Trial is the first randomized trial to investigate the effects of the combined (intramyocardial and intracoronary) and the intracoronary mode of delivery of BM-SCs therapy in the early and late periods after AMI.
American heart journal 03/2007; 153(2):212.e1-7. DOI:10.1016/j.ahj.2006.10.027 · 4.46 Impact Factor