Jaco H. Houtgraaf

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.

Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT).

There is evolving interest in the use of mesenchymal stem cells (MSC) in solid organ transplantation. Pre-clinical transplantation models show efficacy of MSC in prolonging graft survival and a number of clinical studies are planned or underway. At a recent meeting of the MISOT consortium (MSC In Solid Organ Transplantation) the advances of these studies were evaluated and mechanisms underlying the potential effects of MSC discussed. Continued discussion is required for definition of safety and eventually efficacy endpoints for MSC therapy in solid organ transplantation.

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.

Cardiac function in a long-term follow-up study of moderate and severe porcine model of chronic myocardial infarction

Background. Novel therapies need to be evaluated in a relevant large animal model that mimics the clinical course and treatment in a reasonable time frame. To reliably assess therapeutic efficacy, knowledge regarding the translational model and the course of disease is needed. Methods. Landrace pigs were subjected to a transient occlusion of the proximal left circumflex artery (LCx) (n = 6) or mid-left anterior descending artery (LAD) (n = 6) for 150 min. Cardiac function was evaluated before by 2D echocardiography or 3D echocardiography and pressure-volume loop analysis. At 12 weeks of follow-up the heart was excised for histological analysis and infarct size calculations. Results. Directly following AMI, LVEF was severely reduced compared to baseline in the LAD group (−17.1 ± 1.6%, P = 0.009) compared to only a moderate reduction in the LCx group (−5.9 ± 1.5%, P = 0.02) and this effect remained unchanged during 12 weeks of follow-up. Conclusion. Two models of chronic MI, representative for different patient groups, can reproducibly be created through clinically relevant ischemia-reperfusion of the mid-LAD and proximal LCx.