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.