Transforming Growth Factor-β Genes Are Upregulated And Collagen Synthesis Is Elevated In Mitral Valve Leaflets After Undersizing Mitral Annuloplasty To Repair Ischemic Mitral Regurgitation
Alicja Sielicka, Daniella Espiritu, Weiwei Shi, Vinod H. Thourani, Robert A. Guyton, Eric Sarin, Muralidhar Padala.
Emory University, Atlanta, GA, USA.
OBJECTIVE: Undersizing ring annuloplasty (URA) is a commonly used surgical technique to repair functional mitral regurgitation (FMR). It acutely restores valve competence but at the expense of poor leaflet kinematics, with anterior leaflet hyperextension & posterior leaflet immobility after the repair (Fig-A). Repair failure and recurrence of FMR after URA occurs in 64% of the patients within 2 years after repair. We sought to investigate if poor mitral valve kinematics after URA induce fibrotic remodeling of the leaflets, and if a repair that better preserves leaflet mechanics (papillary muscle approximation (PMA)) would inhibit this process.
METHODS: 30 Yorkshire pigs were induced with an inferior myocardial infarction (Fig-B) and allowed 2.5 months to develop >2+ FMR (Fig-C1). Pigs were then randomized to four mitral repair groups- (G1,n=5) sham/no repair; (G2,n=7) URA (Fig-C2); (G3, n=6)PMA (Fig-C3); (G4, n=12) URA+PMA. Leaflet kinematics were measured pre-op, post-op and at 3 months post-repair (termination point). Mitral valve tissue was collected for gene expression and protein quantification studies.
RESULTS: Anterior leaflet hyper-extension was observed in URA and URA+PMA, while posterior leaflet immobility was observed in URA. TGF-β genes were upregulated in URA group, and suppressed in PMA and URA+PMA. However, TGF-β protein levels were elevated in all the groups compared to sham (Fig-D). Collagen synthesis genes were upregulated in the anterior leaflets of URA and URA+PMA, and in the posterior leaflet of the URA group only(Fig-E1). Prolyl 4 hydroxylase (P4HA1) and heat shock protein 47 (HSP47) involved in collagen 1 biosynthesis were elevated in both leaflets in the URA and URA+PMA groups, and procollagen 1C was elevated in the anterior and posterior leaflets of the URA group only (Fig-E2-4).
CONCLUSIONS: Undersizing mitral annuloplasty was associated with pro-fibrotic remodeling of mitral leaflets, potentially from abnormal leaflet mechanics. Elevated leaflet stretch in tandem with TGF-β may enhance leaflet fibrosis and potentially cause repair failure. Repairs that better restore leaflet stresses may inhibit this adverse leaflet remodeling process.
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