Early evaluation of genetically engineered mesenchymal stromal stem cell therapy for prevention of left ventricular dysfunction in pigs (2009)

&lt;sec&gt;&lt;st&gt;Introduction&lt;/st&gt; Heart Failure &amp;lpar;HF&amp;rpar; is still associated with a poor prognosis, with almost 50&amp;percnt; of patients dying within 5 years of diagnosis. Glucagon-like peptide-1 &amp;lpar;GLP-1&amp;rpar; is a naturally occurring gut incretin hormone that stimulates insulin secretion and has anti-apoptotic properties. Infusion of GLP-1 after successful primary angioplasty has previously been shown to reduce left ventricular systolic dysfunction &amp;lpar;LVSD&amp;rpar;. We hypothesised that a prolonged delivery of GLP-1 from cells at the time of a myocardial infarction would improve left ventricular function and significantly reduce infarct size in a porcine model of early left ventricular dysfunction. We have previously shown that bead embolisation of porcine coronary arteries creates a reproducible infarct and left ventricular dysfunction. In order to evaluate the effects of locally delivered GLP-1 on the size and nature of the infarct, GLP-1-secreting CellBeads were compared with control &amp;lpar;non-GLP-1-secreting beads&amp;rpar; 4 weeks following delivery. &lt;/sec&gt;&lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; Human mesenchymal stromal cells immortalised and engineered to produce GLP-1 were encapsulated into alginate beads in order to immuno-isolate the cells &amp;lpar;GLP-1 CellBeads&amp;rpar;. These beads were selectively delivered to branches of the left anterior descending coronary artery in Yorkshire white pigs &amp;lpar;n &amp;hairsp;&amp;equals;&amp;hairsp; 6&amp;rpar;, with the control group receiving cell-free alginate beads &amp;lpar;n &amp;hairsp;&amp;equals;&amp;hairsp; 6&amp;rpar;. Four weeks after intervention, hearts were explanted for morphometric quantification of infarcted surface area and histological analysis. &lt;/sec&gt;&lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; Acute animal loss was two in the treatment and one in the control group. In the surviving animals, transthoracic echocardiography confirmed the onset of mild LVSD in both groups &amp;lpar;ejection fraction &amp;lpar;EF&amp;rpar; 44.0 ± 1.2 vs 43.4 ± 1.1; CellBead vs control, p&amp;hairsp;&amp;equals;&amp;hairsp;NS&amp;rpar;. Four weeks after intervention, repeat echocardiography demonstrated normal left ventricular function in the treatment &amp;lpar;CellBead&amp;rpar; but not the control group &amp;lpar;EF 49.7 ± 1 vs 41.2 ± 2.2, p&lt;0.01&amp;rpar;. Left ventricular surface area morphometry showed significantly decreased infarction area in the treatment &amp;lpar;CellBead&amp;rpar; group, compared with the control group &amp;lpar;4.7 ± 2.1&amp;percnt; vs 21.8 ± 4.8&amp;percnt;; p&lt;0.018&amp;rpar;. Histological analysis showed similar patterns of fibrosis and moderately enhanced inflammation in the treatment group. Further work is aimed at investigating the effect of GLP-1 CellBeads on calcium regulatory proteins, apoptosis and angiogenesis. &lt;/sec&gt;&lt;sec&gt;&lt;st&gt;Summary and Conclusions&lt;/st&gt; Delivery of alginate-encapsulated mesenchymal stromal cells expressing GLP-1 &amp;lpar;GLP-1 CellBeads&amp;rpar; reduces infarct size and improves left ventricular function in a porcine model of early left ventricular dysfunction. GLP-1 CellBeads are currently under clinical evaluation in human patients in the area of stroke. Promising preclinical data from this embolisation model suggests the antiapoptotic properties of locally delivered GLP-1 could be of benefit to patients post-acute myocardial infarction. &lt;/sec&gt;