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).