ABSTRACT
In secondary mitral regurgitation, the concept that the mitral valve
(MV) is an innocent bystander, has been challenged by many studies in
the last decades. The MV is a living structure with an intrinsic
plasticity that reacts to changes in stretch or in mechanical stress
activating bio-humoral mechanisms that have, as purpose, the adaptation
of the valve to the new environment. If the adaptation is balanced, the
leaflets increase both surface and length and the chordae tendinae
lengthen: the result is a valve with different characteristics, but able
to avoid or to limit the regurgitation. However, if the adaptation is
unbalanced, the leaflets and the chords do not change their size, but
become stiffer and rigid, with moderate or severe regurgitation. These
changes are mediated mainly by a cytokine, the transforming growth
factor β (TGF-β), which is able to promote the changes that the MV needs
to adapt to a new hemodynamic environment. In general, mild TGF-β
activation facilitates leaflet growth, excessive TGF-β activation, as
after a myocardial infarction, results in profibrotic changes in the
leaflets, with increased thickness and stiffness. The MV is then a
plastic organism, that reacts to the external stimuli, trying to
maintain its physiologic integrity. This review has the goal to unveil
the secret life of the MV, to understand which stimuli can trigger its
plasticity and to explain why the equation “large heart=moderate/severe
mitral regurgitation” and “small heart=no/mild mitral regurgitation”
does not work into the clinical practice.
Keywords. Mitral valve; Mitral regurgitation; ischemic adaptation;
ischemia; left ventricle.
For decades the diseases that can affect the mitral valve (MV) were
considered to follow a precise scheme: infectious, inflammatory,
congenital, degenerative, etc. In case of secondary mitral regurgitation
(MR), the valve and its chords were supposed to remain “normal”, while
the regurgitation was due to geometric changes of the left ventricle
(LV). If this were true, MR grade had to be directly proportional to the
displacement grade of the papillary muscles (PMs). However, in the
clinical setting some patients with large hearts and severely displaced
PMs have sometimes absent/mild MR (fig. 1) and sometimes severe MR (fig.
2). On the other side, other patients, in spite of normal volumes and
similar interpapillary distance, have either absent/mild or
moderate/severe MR (fig. 3).
However, during the same time frame many studies slowly started to show
that the MV was not only a passive bystander of the morphologic changes
of LV geometry, but was able to induce structural modifications in
response to external stimuli.
In human hearts with ischemic and non-ischemic dilated cardiomyopathy,
Hueb et al.1, in a study aimed to analyze annular
modifications, found that, compared with cardiomyopathy, by 24% if
ischemic and by 50% if non-ischemic. The degree of ante-mortem MR was
not reported. In transplant recipients, Grande-Allen et
al.2 demonstrated that mitral leaflets and chordae
tendinae were fibrotic and showed significant changes in the
extracellular matrix (ECM), with more cellularity and collagen than
normal. The ALs and the PLs were longer (+28% and +26% respectively)
and thicker (+26% both) than normal. The leaflets and the chords were
biochemically different from normal and were stiffer, less extensible
and less viscous than controls, due to a dysfunctional remodeling in
these subset of patients3.
These studies demonstrate that the MVs and the chords of patients with
end-stage dilated ischemic or non-ischemic cardiomyopathy changed
morphology and composition, in a process that we can term “adaptation
to disease”. Then the MV is not a structure that remains inert if the
environment around it changes, but is able to modify its shape and its
characteristics in the attempt to react to different geometry and stress
distribution to avoid or to reduce regurgitation. Under this aspect the
MV is a living organism, capable to respond to external stimuli due to
its intrinsic plasticity (a term that defines the adaptability of a
living structure to changes in its environment) in order to counteract
any change that can impair its function (regurgitation). Mitral
plasticity can be balanced (adaptation is complete and MR is absent or
mild, as in fig. 1 and 3, A and B) or unbalanced (adaptation is
uncomplete and is unable to control the MR degree, that progresses to
moderate or severe, as in fig. 2 and 3, C and D).