Therapeutic implications
The different anatomical pictures that result from MV plasticity can provide many anatomical aspects. The most favorable is a balanced adaptation , with long leaflets and long chords, with absent or mild MR. On the other extreme there is an unbalanced adaptation , where leaflet area and length are not adequate to respond to increased annular area and changed LV geometry. Leaflets are fibrotic and chords are thick and retracted, with resulting moderate or severe MR. In the middle there are many possibilities, with different anatomical aspects and MR grade. Among them, it is worthy noting that we can have partial adaptation , such as long leaflets and tethered chords or relatively short and thick leaflets and normal or long chords. Then the necessity to look carefully at the anatomy of the MV apparatus, which can change from case to case.
The comprehension, even if partial, of the mechanisms of adaptation of the MV led to the search of pharmacological prevention of a possible maladaptive evolution of the process. Given the role of angiotensin II as TGF-β activator after MI, the use of losartan, a selective inhibitor of angiotensin II receptor-1, was explored successfully both in vitro37 and in an animal model38. In this latter experiment profibrotic changes of tethered MV leaflets post-MI were modulated by losartan without eliminating adaptive growth. Losartan decreases production of TGF-β and its receptor and angiotensin II-induced release of latent TGF-β39. It blocks the interaction of angiotensin II with its AT1 receptor, decreasing TGF-β signaling18. Losartan inhibits angiotensin II-induced expression of endoglin, which promotes the fibrogenic effects of TGF-β19. Through such effects on the MV, losartan can potentially inhibit fibrosis40, while maintaining adaptive leaflet growth with flexible leaflet closure.
In a clinical study on 40 patients with 2 serial echocardiograms (6 days and 12 years) after an inferior MI, leaflet thickness increased over time and was correlated with MR. Most of the patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. In the subgroup taking high dose, late echocardiogram showed thinner leaflets than in patients where small dose was used34. In another study on patients with end stage renal disease, losartan more effectively suppressed myocardial fibrosis than did enalapril or amlodipine despite a comparable antihypertensive effect among the three drugs41.
The length of the leaflets can be used as a predictor of the reversibility of untreated mild or moderate IMR after CABG . Yoshida et al.42 found that the estimated coaptation length was a determinant of MR improvement after 2.9 years from surgery, with a cutoff of 6.5 mm. In patients where MR improved, leaflets were longer than in patients where MR did not improve.
Finally, understanding the mechanisms of mitral plasticity can provide a new paradigm in surgical treatment of IMR. Surgical repair with reductive mitral annuloplasty alone imposes abnormal biomechanics on the MV. Serial cardiac computed tomography 1 to 5 years postoperatively demonstrated that MV leaflet thickening occurred in 69% of 45 patients43. Patients with thicker leaflets also presented with elevated transmitral pressure gradients, indicating progressive valve stenosis. In a swine experimental model of moderate IMR pathogenic biological changes in the MV leaflets were demonstrated within a short period of 3 months. Collagen levels were elevated in these stressed leaflets and the profibrotic changes in the valve paralleled increase in TGF-β44. Surgical repair with restrictive mitral annuloplasty alone frequently do not restore physiological leaflet configuration and, if mechanical strains remains elevated, pathogenic changes in valve leaflets can be induced.
The role of reparative surgery should be to “take up where the nature left” and complete the process of adaption by intervening at different levels on the MV and mimicking the natural adaptive mechanism. We have termed this surgical approach “surgical mitral plasticity”45. To complete what nature could not, the AL has to be augmented and lengthened (by an autologous glutaraldehyde-treated or heterologous pericardial patch or any biological patch) and the second order chords have to be cut to increase the effective AL length and area (fig. 11). It is worth emphasizing the necessity of second-order chords transection, as the fibrotic process, once started, can be progressive46. Moreover, by eliminating apical tethering, the AL can recover its normal curvature by removal, or reduction, of the tenting area. In selected cases, when the AL is sufficiently long, it is not necessary to augment it, but chordal cutting, performed through aortotomy, is sufficient (fig. 12). This maneuver causes an important reduction of leaflets stress27. Restrictive mitral annuloplasty should then complete the repair. None of these technique is new, but the rationale behind is. We prefer to target the surgical augmentation on the AL as the PL, after restrictive mitral annuloplasty, is positioned vertically, representing a doorjamb for the AL which, as recovers its length and mobility, is able to close the annular area with a long coaptation length.
Mechanisms of failure after isolated annuloplasty can be due to shortness and thickness of the AL, with persistent chordal tethering and critical tenting area (fig. 13). Many techniques to be added to isolated restrictive mitralo annuloplasty have been described and are currently used to improve results of MV repair. A longer follow up and a critical review of the results will give us a guide to correct secondary MR, a disease more complex than perceived.