oa Adaptation of the Mitral Valve to Chronic Ischemic Left Ventricular Failure in Swine

Mitral valve leaflets in patients with chronic heart failure are severely stiffened, larger and fibrotic; though the mechanisms underlying such biological remodeling are currently unknown. Chronic tethering of the valve leaflets by the enlarged left ventricle, and the presence of mitral regurgitation (MR), is hypothesized to trigger fibrotic pathways that induce such remodeling. In this study, we sought to develop a large animal model of chronic ischemic left ventricular failure in which moderate leaflet tethering and MR can be repeatedly induced, and the remodeling of the mitral valve can be assessed in vivo using echocardiography. Inferior wall myocardial infarction (IMI) was induced in 16 farm swine (30-35kg) using a percutaneous transfemoral approach. Coronary angiography was performed to selectively identify the marginal branches of the left circumflex artery perfusing the inferior left ventricular (LV) wall and the posterior papillary muscle (PPM), and then these regions were infarcted using a 2 mm balloon catheter and injection of 100% ethyl alcohol into the corresponding branch. Transthoracic 2D echocardiography (TTE) of the left heart was performed pre and post-IMI in all animals, at 4 weeks and at 8 weeks. MR percentage (MR jet/left atrial area), mitral leaflet length and thickness, and mitral annular geometry were measured. Leaflet length and thickness were measured at end diastole to assure measurements were taken in the maximal unloaded state. All animals survived the procedure without complications (0% mortality). At baseline, the swine had mild MR (10.7±8%) which significantly increased to 26.6±9% immediately post-op (p<0.05), declined slightly to 23.8±7.8% at 4 weeks, and increased to 32.2±13.9% at 8 weeks. Mitral annular diameter increased from 2.7±0.5 cm pre-op, to 3.1±0.5 cm post-op (p<0.05), then to 3.8±0.4 cm (p<0.005) and 3.9±0.6 cm (p<0.005), at 4 and 8 weeks, respectively. Posterior leaflet length was 1.8±0.2 cm pre-op, and then stabilized at 1.9±0.2 cm post-op, at 4 weeks, and at 8 weeks. Anterior leaflet length was 2.3±0.3 cm at baseline and increased with the increase in MR, to 2.5±0.4 cm post-op, 2.8±0.5 cm at 4 weeks (p<0.05), and 3.2±0.2 cm at 8 weeks (p<0.001). Posterior leaflet thickness increased from 0.36±0.05 cm at baseline, to 0.37±0.07 cm post-op, and then to 0.4±0.05 cm and 0.41±0.03 cm at 4 weeks and 8 weeks, respectively. Anterior leaflet thickness was 0.4±0.05 cm at baseline and post-operatively, and 0.47±0.03 cm (p<0.01) and 0.45±0.07 cm at 4 weeks and 8 weeks, respectively. Changes in mitral leaflet geometry correspond with changes in the mitral valvular apparatus after IMI in a chronic swine model. As the mitral annulus increases in diameter, significant lengthening is seen from the anterior leaflet, while the posterior leaflet remains relatively static and tethered. The anterior leaflet thickens by 4 weeks, while the posterior leaflet remains stable.