Peter Donndorf

Intramyocardial bone marrow stem cell transplantation during coronary artery bypass surgery: a meta-analysis.

OBJECTIVE Experimental and clinical studies have suggested that intramyocardial bone marrow stem cell transplantation combined with coronary artery bypass grafting might improve left ventricular function in the setting of chronic ischemic heart disease. We therefore conducted a systematic review and meta-analysis of available publications regarding the efficacy and safety of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting. METHODS The databases PUBMED, MEDLINE, Cochrane Controlled Trials Register, and ClinicalTrials.gov (all from their inception to May 2009) were searched for randomized controlled trials and cohort studies of intramyocardial bone marrow stem cell transplantation during coronary artery bypass grafting to treat ischemic heart disease. Six studies were included. RESULTS Compared with control groups, the bone marrow stem cell transplantation group showed a significant improvement of left ventricular ejection fraction from baseline to follow-up (5.40%; 95% confidence interval, 1.36-9.44; P = .009). Moreover, the overall change of left ventricular end-diastolic volume from baseline to follow-up favored the bone marrow stem cell therapy group (9.55 mL; 95% confidence interval, -2.82 to 21.92; P = .13). Major adverse cardiovascular events, including ventricular arrhythmia and the composite of other cardiovascular events, were not significantly different between the bone marrow stem cell therapy group and controls (relative risk for ventricular arrhythmia = 0.951; 95% confidence interval, 0.389-2.325; P = .913; relative risk for cardiovascular event = 1.134; 95% confidence interval, 0.28-4.6; P = .86). CONCLUSIONS Clinical evidence suggests that intramyocardial bone marrow stem cell transplantation in combination with coronary artery bypass grafting is associated with improvements of functional parameters in patients with chronic ischemic heart disease. Furthermore, surgical intramyocardial bone marrow stem cell transplantation seems to be safe.

Endothelial NOS is required for SDF-1α/CXCR4-mediated peripheral endothelial adhesion of c-kit+ bone marrow stem cells

In the era of intravascular approaches for regenerative cell therapy, the underlying mechanisms of stem cell migration to non-marrow tissue have not been clarified. We hypothesized that next to a local inflammatory response implying adhesion molecule expression, endothelial nitric oxide synthase (eNOS)-dependent signaling is required for stromal- cell-derived factor-1 alpha (SDF-1α)-induced adhesion of c-kit+ cells to the vascular endothelium. SDF-1α/tumor necrosis factor-alpha (TNF-α)-induced c-kit+-cell shape change and migration capacity was studied in vitro using immunohistochemistry and Boyden chamber assays. In vivo interaction of c-kit+ cells from bone marrow with the endothelium in response to SDF-1α/TNF-α stimulation was visualized in the cremaster muscle microcirculation of wild-type (WT) and eNOS (−/−) mice using intravital fluorescence microscopy. In addition, NOS activity was inhibited with N-nitro-L-arginine-methylester-hydrochloride in WT mice. To reveal c-kit+-specific adhesion behavior, endogenous leukocytes (EL) and c-kit+ cells from peripheral blood served as control. Moreover, intercellular adhesion molecule-1 (ICAM-1) and CXCR4 were blocked systemically to determine their role in inflammation-related c-kit+-cell adhesion. In vitro, SDF-1α enhanced c-kit+-cell migration. In vivo, SDF-1α alone triggered endothelial rolling—not firm adherence—of c-kit+ cells in WT mice. While TNF-α alone had little effect on adhesion of c-kit+ cells, it induced maximum endothelial EL adherence. However, after combined treatment with SDF-1α+TNF-α, endothelial adhesion of c-kit+ cells increased independent of their origin, while EL adhesion was not further incremented. Systemic treatment with anti-ICAM-1 and anti-CXCR4-monoclonal antibody completely abolished endothelial c-kit+-cell adhesion. In N-nitro-L-arginine-methylester-hydrochloride-treated WT mice as well as in eNOS (−/−) mice, firm endothelial adhesion of c-kit+ cells was entirely abrogated, while EL adhesion was significantly increased. The chemokine SDF-1α mediates firm adhesion c-kit+ cells only in the presence of TNF-α stimulation via an ICAM-1- and CXCR4-dependent mechanism. The presence of eNOS appears to be a crucial and specific factor for firm c-kit+-cell adhesion to the vascular endothelium.

Validating intramyocardial bone marrow stem cell therapy in combination with coronary artery bypass grafting, the PERFECT Phase III randomized multicenter trial: study protocol for a randomized controlled trial

BackgroundFor the last decade continuous efforts have been made to translate regenerative cell therapy protocols in the cardiovascular field from ‘bench to bedside’. Successful clinical introduction, supporting safety, and feasibility of this new therapeutic approach, led to the initiation of the German, Phase III, multicenter trial - termed the PERFECT trial (ClinicalTrials.gov Identifier: NCT00950274), in order to evaluate the efficacy of surgical cardiac cell therapy on left ventricular function.Methods/DesignThe PERFECT trial has been designed as a prospective, randomized, double-blind, placebo controlled, multicenter trial, analyzing the effect of intramyocardial CD 133+ bone marrow stem cell injection in combination with coronary artery bypass grafting on postoperative left ventricular function. The trial includes patients aged between 18 and 79 years presenting with a coronary disease with indication for surgical revascularization and reduced global left ventricular ejection fraction as assessed by cardiac magnet resonance imaging. The included patients are treated in the chronic phase of ischemic cardiomyopathy after previous myocardial infarction.DiscussionPatients undergoing coronary artery bypass grafting in combination with intramyocardial CD133+ cell injection will have a higher LV ejection fraction than patient who undergo CABG alone, measured 6 months after the operation.Trial registrationClinicalTrials.gov Identifier: NCT00950274

Stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease.

Chronic ischemic heart disease remains a major cause of morbidity and mortality worldwide. Although revascularisation strategies and pharmaceutical therapy are able to delay ventricular remodelling, until today no therapeutic strategy is available that might prevent or even reverse this process of remodelling and consequent ventricular failure. In the recent past, experimental and clinical studies have demonstrated the capacity of bone marrow stem cells in cardiac repair and regeneration of compromised heart muscle. Several clinical trials showed the safety and efficacy of autologous bone marrow stem cell transplantation in the patients with acute myocardial infarction or chronic ischemic heart disease. Today the therapeutic strategy of cell administration during cardiac surgery or coronary artery intervention is entering the clinical practice. In the following Review we will highlight biological as well as methodological backgrounds, indications and clinical results of cardiac stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease.

HMGB-1 induces c-kit+ cell microvascular rolling and adhesion via both toll-like receptor-2 and toll-like receptor-4 of endothelial cells.

High‐mobility group box 1 (HMGB‐1) is a strong chemo‐attractive signal for both inflammatory and stem cells. The aim of this study is to evaluate the mechanisms regulating HMGB‐1–mediated adhesion and rolling of c‐kit+ cells and assess whether toll‐like receptor‐2 (TLR‐2) and toll‐like receptor‐4 (TLR‐4) of endothelial cells or c‐kit+ cells are implicated in the activation of downstream migration signals to peripheral c‐kit+ cells. Effects of HMGB‐1 on the c‐kit+ cells/endothelial interaction were evaluated by a cremaster muscle model in wild‐type (WT), TLR‐2 (−/−) and Tlr4 (LPS‐del) mice. The mRNA and protein expression levels of endothelial nitric oxide synthase were determined by quantitative real‐time PCR and immunofluorescence staining. Induction of crucial adhesion molecules for rolling and adhesion of stem cells and leukocytes were monitored in vivo and in vitro. Following local HMGB‐1 administration, a significant increase in cell rolling was detected (32.4 ± 7.1% in ‘WT’ versus 9.9 ± 3.2% in ‘control’, P < 0.05). The number of firmly adherent c‐kit+ cells was more than 13‐fold higher than that of the control group (14.6 ± 5.1 cells/mm2 in ‘WT’ versus 1.1 ± 1.0 cells/mm2 in ‘control’, P < 0.05). In knockout animals, the fraction of rolling cells did not differ significantly from control levels. Firm endothelial adhesion was significantly reduced in TLR‐2 (−/−) and Tlr4 (LPS‐del) mice compared to WT mice (1.5 ± 1.4 cells/mm2 in ‘TLR‐2 (−/−)’ and 2.4 ± 1.4 cells/mm2 in ‘Tlr4 (LPS‐del)’ versus 14.6 ± 5.1 cells/mm2 in ‘WT’, P < 0.05). TLR‐2 (−/−) and Tlr4 (LPS‐del) stem cells in WT mice did not show significant reduction in rolling and adhesion compared to WT cells. HMGB‐1 mediates c‐kit+ cell recruitment via endothelial TLR‐2 and TLR‐4.

Comparing microvascular alterations during minimal extracorporeal circulation and conventional cardiopulmonary bypass in coronary artery bypass graft surgery: A prospective, randomized study

OBJECTIVES Minimal extracorporeal circulation (MECC) has been introduced in coronary artery bypass graft (CABG) surgery, offering clinical benefits owing to reduced hemodilution and no blood-air interface. Yet, the effects of MECC on the intraoperative microvascular perfusion in comparison with conventional extracorporeal circulation (CECC) have not been studied so far. METHODS The current study aimed to analyze alterations in microvascular perfusion at 4 predefined time points (T1-T4) during on-pump CABG using orthogonal polarization spectral imaging. Forty patients were randomized for being operated on with either MECC or CECC. Changes in functional capillary density (FCD), blood flow velocity, and vessel diameter were analyzed by a blinded investigator. RESULTS After start of extracorporeal circulation (ECC) and aortic crossclamping (T2), both groups showed a significant drop of FCD, with a significantly higher FCD in the MECC group (206.8 ± 33.6 cm/cm² in CECC group versus 217.8 ± 35.3 cm/cm² in MECC group; P = .034). In the late phase of the ECC (T3), FCD in the MECC group was already recovered, whereas FCD in the CECC group was still significantly depressed (223.1 ± 35.6 cm/cm² in MECC group; P = .100 vs T1; 211.1 ± 36.9 cm/cm² in CECC group; P = .017 vs T1). After termination of ECC (T4), FCD recovered in both groups to baseline. Blood flow velocity tended to be higher in the MECC group, with a significant intergroup difference after aortic crossclamping (T2). CONCLUSIONS Orthogonal polarization spectral imaging data reveal an impairment of microvascular perfusion during on-pump CABG. Changes in FCD indicate a faster recovery of the microvascular perfusion in MECC during the reperfusion period. Beneficial recovery of microvascular organ perfusion could partly explain the perioperative advantages reported for MECC.

Update on cardiac stem cell therapy in heart failure.

Purpose of review Presentation of the current status of cardiac stem cell therapy for the treatment of ischaemic heart failure by highlighting recent clinical results and introducing ongoing trials. Furthermore, necessary upcoming procedural adjustments are discussed. Recent findings During the last decade, stem cell application in the setting of ischaemic heart failure has been evaluated in phase I and II clinical trials, proving safety and feasibility of this approach. Functional results gained so far indicate moderate benefits. However, conclusive evaluation of cell therapy will not be possible before completion of ongoing phase III multicentre trials. Moreover, questions regarding the optimal cell population for treatment in a chronic setting and the favourable time-point of cell delivery have not been ultimately answered. Summary Cell therapy for the treatment of ischaemic heart failure needs to be evaluated separately from the setting of acute myocardial infarction. In parallel with upcoming clinical evaluation in large-scale trials, further optimization of the ‘cell product’ regarding the favourable cell type and periprocedural processing, as well as route and time-point of application, is mandatory.

CD133-Positive Cells for Cardiac Stem Cell Therapy: Current Status and Outlook

Ischemic heart disease represents one major cause of death in developed countries. Ten years ago, cardiac application of bone marrow-derived progenitor cells was introduced as a new therapeutic strategy with the aim of restoring the function of ischemic myocardium. Among other cell populations, CD133(+) bone marrow stem cells form a major subpopulation of progenitor cells studied in this context. Following promising preclinical evidence, both cardiac surgeons and interventional cardiologists have applied CD133(+) cells in setting of chronic ischemic heart failure as well as acute myocardial infarction within phase I and II clinical trials. This chapter summarizes the rationale for the use of this stem cell subpopulation in the field of regenerative cardiac therapy strategies and gives an overview on the current clinical evidence as well as upcoming phase III trials.

Chirurgische intramyokardiale Stammzelltherapie bei chronischer Myokardischämie

Chronic ischemic heart disease patients are already being treated worldwide with bone marrow stem cells both in the context of clinical studies and in therapy trials. By combining this therapy with established revascularization procedures such as bypass surgery, a high level of patient safety can be achieved. To date, no stem cell-related cardiac complications following intramyocardial injection of bone marrow-derived stem cells during CABG (coronary artery bypass graft) surgery have been reported. The functional advantage conferred by surgical bone marrow stem cell therapy is a 7.2% increase in LVEF (left ventricular ejection fraction) compared to controls. Randomized placebo-controlled trials, like the German trial PERFECT, are needed to obtain a more evidence-based assessment of this therapy.ZusammenfassungDie Therapie der chronisch-ischämischen Herzkrankheit mit Stammzellen aus dem Knochenmark wird im Rahmen klinischer Studien und als Therapieversuch weltweit bereits an Patienten angewendet. Durch Kombination mit etablierten Verfahren zur Revaskularisation wie der Bypasschirurgie kann ein hohes Maß an Patientensicherheit erreicht werden. Dabei sind bisher keine negativen stammzellbedingten kardialen Ereignisse nach Verwendung von Knochenmarkstammzellen dokumentiert worden. Der funktionelle Vorteil einer chirurgischen Zelltherapie unter Verwendung von Knochenmarkstammzellen beträgt, bezogen auf die linksventrikuläre Ejektionsfraktion, 7,2% im Vergleich zu den Kontrollpatienten. Randomisierte, plazebokontrollierte Studien wie die deutsche Studie PERFECT sind notwendig, um den Effekt dieser Therapie wissenschaftlich mit hoher Evidenz beurteilen zu können.AbstractChronic ischemic heart disease patients are already being treated worldwide with bone marrow stem cells both in the context of clinical studies and in therapy trials. By combining this therapy with established revascularization procedures such as bypass surgery, a high level of patient safety can be achieved. To date, no stem cell-related cardiac complications following intramyocardial injection of bone marrow-derived stem cells during CABG (coronary artery bypass graft) surgery have been reported. The functional advantage conferred by surgical bone marrow stem cell therapy is a 7.2% increase in LVEF (left ventricular ejection fraction) compared to controls. Randomized placebo-controlled trials, like the German trial PERFECT, are needed to obtain a more evidence-based assessment of this therapy.

Mobilization of Bone Marrow-Derived Endothelial Progenitor Cells following Finnish Sauna: A Pilot Study

Background: Sauna bathing is claimed to provide benefits for patients suffering from cardiovascular diseases. The current study aims at analyzing the induction of potential regenerative processes by quantifying the mobilization of bone marrow-derived stem cells into the peripheral blood of healthy adults following Finnish sauna. Materials and Methods: Twenty healthy unbiased male volunteers (20-30 years old) were exposed to a Finnish sauna bath (3 × 10 min, 90°C). Venous blood samples were drawn before (baseline), immediately, and 6 h as well as 24 h after the sauna bath. Blood analysis included isolation of mononuclear cells, cell staining with mononuclear antibodies, and fluorescence-activated cell sorting (FACS). For baseline and 24 h post-sauna samples colony-forming unit-Hill assays were applied to quantify endothelial progenitor cells (EPC). Results: Flow cytometry revealed an upregulation of circulating CD45+/CD309+ progenitor cells immediately after the sauna bath, however without reaching statistical significance. Circulating cell numbers of the CD45+CD34+, CD45+CD34+CD133+, and CD45+CD34+CD117+ populations did not show clear enhancements following sauna. EPC colony formation tended to be enhanced after sauna as compared to baseline values. Conclusion: Peripheral EPC numbers exhibited a moderate increase following Finnish sauna in a cohort of healthy young men. Furthermore, sauna bathing tended to increase EPC colony-forming capacity. These rather weak responses to thermotherapy might indicate a ceiling effect. In individuals exhibiting cardiovascular risk factors the effects may be more pronounced.