Abstract 1604: Improved Cardiac Function after Expression of the Human Elastin Gene in the Infarcted Myocardium
Rationale: After a myocardial infarction, necrosed cardiomyocytes are replaced by fibrotic tissue. Subsequent thinning and expansion of this non-elastic scar contributes to cardiac dilatation and congestive heart failure. We attempted to restore the elastic properties of the scar by implanting the infarct area with cells expressing elastin.
Methods: Full-length elastin cDNA was generated by PCR using the human lung cDNA library, and then transfected (in adenoviral vector) into rat bone marrow stromal cells (BMSCs). Western blot and immuno-staining confirmed expression of elastin protein. Seven days after coronary artery ligation, BMSCs transfected with genes for either adeno-elastin (BMSC+Elastin) or adeno-green fluorescence protein (BMSC), or media (control group) were injected into the infarct area of adult rats (n=8/group).
Results: Over 8 weeks following cell or media implantation, cardiac function (fractional shortening by echocardiography), ventricular volumes, and load independent indices of cardiac function (end systolic and diastolic volumes, preload recruitable stroke work and end systolic elastance by pressure-volume catheter), were all significantly better preserved in both BMSC groups (p<0.05 vs. media), with further improvements in the BMSC+Elastin group (p<0.05 vs. BMSC group). Biochemical analysis detected over-expression of recombinant elastin, and histological examination revealed that collagen fiber length and diameter were preserved in the scar tissue. Myocardial birefringence determined by polarized light (linear retardance of the tissue structure) was significantly highest in the infarct area of the BMSC+Elastin group (p<0.05 compared to BMSC and media groups). Elastin over-expression by cell-based gene therapy restored the elastic matrix structure in the scar tissue, stabilized the infarct and prevented ventricular dilatation, producing the smallest (p<0.05) scar size and surface area in the BMSC+Elastin group.
Conclusions: Over-expression of elastin in transplanted BMSCs contributed to the alignment and organization of an elastic extracellular matrix structure, which prevented cardiac dilatation and dysfunction. Elastin plays a key role in the remodeling of the extracellular matrix.