Renate de Jong

First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction.

To the Editor: In preclinical animal models of acute myocardial infarction (AMI), administration of freshly isolated adipose tissue–derived regenerative cells (ADRCs) immediately after the AMI improved left ventricular (LV) function and myocardial perfusion ([1,2][1]). The predominant working

Intracoronary Stem Cell Infusion After Acute Myocardial Infarction A Meta-Analysis and Update on Clinical Trials

Background—Several cell-based therapies for adjunctive treatment of acute myocardial infarction have been investigated in multiple clinical trials, but the benefits still remain controversial. This meta-analysis aims to evaluate the efficacy of bone marrow–derived mononuclear cell (BMMNC) therapy in patients with acute myocardial infarction, but also explores the effect of newer generations of stem cells. Methods and Results—A random-effects meta-analysis was performed on randomized controlled trials investigating the effects of stem cell therapy in patients with acute myocardial infarction that were published between January 2002 and September 2013. The defined end points were left ventricular (LV) ejection fraction, LV end-systolic and end-diastolic volumes, infarct size, and major adverse cardiac and cerebrovascular event rates. Also, several subgroup analyses were performed on BMMNC trials. Overall, combining the results of 22 randomized controlled trials (RCTs), LV ejection fraction increased by +2.10% (95% confidence interval [CI], 0.68–3.52; P=0.004) in the BMMNC group as compared with controls, evoked by a preservation of LV end-systolic volume (−4.05 mL; 95% CI, −6.91 to −1.18; P=0.006) and a reduction in infarct size (−2.69%; 95% CI, −4.83 to −0.56; P=0.01). However, there is no effect on cardiac function, volumes, or infarct size, when only RCTs (n=9) that used MRI-derived end points were analyzed. Moreover, no beneficial effect could be detected on major adverse cardiac and cerebrovascular event rates after BMMNC infusion after a median follow-up duration of 6 months. Conclusions—Intracoronary infusion of BMMNC is safe, but does not enhance cardiac function on MRI-derived parameters, nor does it improve clinical outcome. New and possibly more potent stem cells are emerging in the field, but their clinical efficacy still needs to be defined in future trials.

Treatment with OPN-305, a humanized anti-toll-like receptor-2 antibody, reduces myocardial ischemia/reperfusion injury in pigs

Background— Toll-like receptor (TLR)-2 is an important mediator of innate immunity and ischemia/reperfusion-induced cardiac injury. We have previously shown that TLR2 inhibition reduces infarct size and improves cardiac function in mice. However, the therapeutic efficacy of a clinical grade humanized anti-TLR2 antibody, OPN-305, in a large-animal model remained to be addressed. Methods and Results— Pigs (n=38) underwent 75 minutes ischemia followed by 24 hours of reperfusion. Saline or OPN-305 (12.5, 6.25, or 1.56 mg/kg) was infused intravenously 15 minutes before reperfusion. Cardiac function and geometry were assessed by echocardiography. Infarct size was calculated as the percentage of the area at risk and by serum Troponin-I levels. Flow cytometry analysis revealed specific binding of OPN-305 to porcine TLR2. In vivo, OPN-305 exhibited a secondary half-life of 8±2 days. Intravenous administration of OPN-305 before reperfusion significantly reduced infarct size (45% reduction, P=0.041) in a dose-dependent manner. In addition, pigs treated with OPN-305 exhibited a significant preservation of systolic performance in a dose-dependent fashion, whereas saline treatment completely diminished the contractile performance of the ischemic/reperfused myocardium. Conclusions— OPN-305 significantly reduces infarct size and preserves cardiac function in pigs after ischemia/reperfusion injury. Hence, OPN-305 is a promising adjunctive therapeutic for patients with acute myocardial infarction.

Clinical Study Using Adipose-Derived Mesenchymal-Like Stem Cells in Acute Myocardial Infarction and Heart Failure

Adipose tissue represents an abundant, accessible source of regenerative cells that can be easily obtained in sufficient amount for therapy. Adipose-derived regenerative cells (ADRC) are comprised of leukocytes, smooth muscles, endothelial cells, and mesenchymal stem cells. In contrast to bone-marrow-derived MSC, the abundance of adipose tissue in patients and the higher frequency per unit mass of regenerative cells allow for the isolation of cells in therapeutic meaningful amounts in less than 2h after donor tissue acquisition.Harvest of adipose tissue can thus follow primary PCI, allowing efficient treatment within 24h. This obviates the need for extensive cell culturing in GMP clean room facilities and makes ADSCs a promising and practical autologous cell source. In the following chapter, we will describe the liposuction procedure for stem cell harvest, two cell delivery techniques, and pressure/volume loop analysis for the follow-up of our patients enrolled in the clinical studies.

Intracoronary Infusion of Encapsulated Glucagon-Like Peptide-1–Eluting Mesenchymal Stem Cells Preserves Left Ventricular Function in a Porcine Model of Acute Myocardial Infarction

Background—Engraftment and survival of stem cells in the infarcted myocardium remain problematic in cell-based therapy for cardiovascular disease. To overcome these issues, encapsulated mesenchymal stem cells (eMSCs) were developed that were transfected to produce glucagon-like peptide-1, an incretin hormone with known cardioprotective effects, alongside MSC endogenous paracrine factors. This study was designed to investigate the efficacy of different doses of intracoronary infusion of eMSC in a porcine model of acute myocardial infarction (AMI). Methods and Results—One hundred pigs were subjected to a moderate AMI (posterolateral AMI; n=50) or a severe AMI (anterior AMI; n=50), whereupon surviving animals (n=36 moderate, n=33 severe) were randomized to receive either intracoronary infusion of 3 incremental doses of eMSC or Ringers’ lactate control. Cardiac function was assessed using invasive hemodynamics, echocardiography, and histological analysis. A trend was observed in the moderate AMI model, whereas in the severe AMI model, left ventricular ejection fraction improved by +9.3% (P=0.004) in the best responding eMSC group, because of a preservation of left ventricular end-systolic volume. Arteriolar density increased 3-fold in the infarct area (8.4±0.9/mm2 in controls versus 22.2±2.6/mm2 in eMSC group; P<0.001). Although not statistically significant, capillary density was 30% higher in the border zone (908.1±99.7/mm2 in control versus 1209.0±64.6/mm2 in eMSC group; P=ns). Conclusions—eMSCs enable sustained local delivery of cardioprotective proteins to the heart, thereby enhancing angiogenesis and preserving contractile function in an animal AMI model.

Invasive surgery reduces infarct size and preserves cardiac function in a porcine model of myocardial infarction

Reperfusion injury following myocardial infarction (MI) increases infarct size (IS) and deteriorates cardiac function. Cardioprotective strategies in large animal MI models often failed in clinical trials, suggesting translational failure. Experimentally, MI is induced artificially and the effect of the experimental procedures may influence outcome and thus clinical applicability. The aim of this study was to investigate if invasive surgery, as in the common open chest MI model affects IS and cardiac function. Twenty female landrace pigs were subjected to MI by transluminal balloon occlusion. In 10 of 20 pigs, balloon occlusion was preceded by invasive surgery (medial sternotomy). After 72 hrs, pigs were subjected to echocardiography and Evans blue/triphenyl tetrazoliumchloride double staining to determine IS and area at risk. Quantification of IS showed a significant IS reduction in the open chest group compared to the closed chest group (IS versus area at risk: 50.9 ± 5.4% versus 69.9 ± 3.4%, P = 0.007). End systolic LV volume and LV ejection fraction measured by echocardiography at follow‐up differed significantly between both groups (51 ± 5 ml versus 65 ± 3 ml, P = 0.033; 47.5 ± 2.6% versus 38.8 ± 1.2%, P = 0.005). The inflammatory response in the damaged myocardium did not differ between groups. This study indicates that invasive surgery reduces IS and preserves cardiac function in a porcine MI model. Future studies need to elucidate the effect of infarct induction technique on the efficacy of pharmacological therapies in large animal cardioprotection studies.