Corresponding Author:
Prof GD Angelini, MD,MCh,FRCS, FMedSci
British Heart Foundation Professor of Cardiac Surgery,
Bristol Heart Institute
Bristol Royal Infirmary,
Upper Maudlin Street BS2 8HW
Bristol, UK
G.D.Angelini@bristol.ac.uk
Conflict of Interest: none
Funding: This work was supported by the British Heart Foundation and the
NIHR Biomedical Research Centre at University Hospitals Bristol and
Weston NHS Foundation Trust and the University of Bristol.
Key words: Mitral Plasticity, Endothelial-Mesenchymal Transition,
Valvular Interstitial Cells.
The pathophysiology of functional mitral regurgitation has traditionally
been described as being controlled by changes occurring in the left
ventricle. It was believed that changes in the left ventricle led to
changes in the orientation of the different components of the Mitral
Valve apparatus- leaflets, chorda tendinae and the papillary muscles. If
the orientation of the mitral valve apparatus was not satisfactory it
resulted in mitral regurgitation. Thus, the MV was portrayed as an
innocent bystander whose fate and functioning were in the hands of the
left ventricle.
However, in this excellent manuscript by Calafiore et
al1 this premise of the MV being an inert bystander
has been challenged. The authors have suggested that the MV is not an
inert structure but one that responds to changes and challenges in its
surroundings. Depending on its ability to respond to these changes
adequately or inadequately determines if the MV stays competent or
becomes incompetent. Its ability to respond to these changes is
determined by what the authors call- “Mitral Plasticity”. The authors
propose that Mitral Plasticity is an equally important determinant in
the pathophysiology of MR and not just the left ventricle as previously
believed. The authors also suggest that interventions for MR,
pharmacological or surgical, should therefore focus on modifying Mitral
Plasticity for a successful outcome.
The concept of Mitral valve plasticity is quite simple. It is the
ability of the Mitral valve to adapt to stresses imposed by the failing
left ventricle or to the turbulence created by a regurgitant jet of
MR.2,3 In response to these stresses the mitral valve
leaflet can increase its surface area thereby increasing the area of
coaptation resulting in reduction of MR. This does not happen in all
cases and in some there is incomplete adaptation or even mal-adaptation.
The mal-adaptation can lead to undesirable changes like thickening and
fibrosis of leaflets or chordae. While incomplete adaptation leads to
persistence of MR, mal-adaptation may lead to even exaggeration of MR.
However, Plasticity of Mitral valves is not a macroscopic phenomenon,
but a cellular concept whereby one type of cell can change into another
type depending on the need and still retain its ability to return to its
original type- otherwise referred as being able to “assume different
cellular phenotypes.”4 Plasticity of cells is a
normal developmental phenomenon and the concepts of adaptation and
mal-adaptation can be seen during wound repair and in cancer cells
respectively. This plasticity happens by conversion of epithelial cells
to mesenchymal cell, also known as Epithelial to Mesenchymal Transition
(EMT). The term transition denotes its reversibility as opposed to the
term transformation which is irreversible. The same phenomenon when seen
in endothelial cells is called Endothelial to Mesenchymal Transition
(EndMT). Transition to mesenchymal cells leads to formation of
myofibroblasts as well as smooth muscle cells.
This concept of EndMT is important because in the mitral valve the
leaflets are covered by endothelial cells on atrial as well as
ventricular sides.5 Therefore EndMT is central to
“plasticity” of mitral valves. In fact, the role of EndMT is paramount
in several other situations as well. Saphenous vein bypass graft failure
is the prime example of EndMT. Exposed to the stress of higher arterial
blood pressure after CABG, the venous endothelium undergoes a
mal-adaptive EndMT that results in smooth muscle cell hyperplasia and
eventually graft failure.6 Similarly EndMT affecting
the ventricular endothelium results in fibroelastosis. Coronary
atherosclerosis and cardiac transplant vasculopathy are other
pathologies that have been suggested to be influenced by
EndMT.6,7 Studies have reported that roughly 1% of
adult endothelial cells are capable of EndMT.8
The second important concept described by the authors is the role of
Valvular Interstitial Cells (VICs) in disease process. VICs are found in
all the layers of the valve and are responsible for the structural
integrity of the valve. They are normally quiescent but in disease
states these cells get activated. Simplistically speaking, mechanical
stress and inflammatory changes lead to EndMT which leads to activation
and generation of VICs.9 These VICs then regulate the
repair and remodelling through a complex interplay of various mediators
and pathways described by the authors.6
While the concept of Mitral Plasticity and how it may affect the degree
of MR is fascinating the more clinically relevant aspect is identifying
factors that can potentially influence plasticity. This will provide
clinicians the required knowledge to predict the degree of secondary MR
in a particular case. Even more importantly, from a therapeutic point of
view it may well be possible to intervene either pharmacologically or
surgically to complete or correct the adaptation. From a clinical
perspective it is therefore important to identify factors that initiate
and influence the process of Mitral Plasticity. The common clinical
scenarios which initiate Mitral Plasticity are mitral regurgitation,
myocardial infarctions and LV dilatation.2,3,10Following an infarction there can be asymmetric LV remodelling that
leads to tenting.11 LV dilatation displaces the
papillary muscles outwards also leading to tethering of the mitral
valve.3 The regurgitant jet of MR also stresses the
leaflet on the atrial side. The mitral valve responds to these stimuli
and increases its surface area.12 This adaptive
mechanism has been confirmed in animal models and other
studies.2,10,12
While the accepted theory is that Mitral Plasticity is an adaptive
response to LV remodelling it has also been noted that even with similar
degree of LV remodelling there can be dissimilar degrees of Mitral
Plasticity.3 This suggests that LV remodelling may be
responsible for initiating the Mitral Plasticity but there must be
factors which influence the degree of adaptation. Some of the clinically
relevant factors that have been recognized to influence the process of
plasticity include duration of diabetic control, hemoglobin levels and
smoking.3 These factors provide part of the
explanation why there is variability in this adaptive response.
This and knowledge of the factors that influence plasticity provide an
exciting opportunity to manipulate and modulate the process of Mitral
Plasticity. The management can thus be tailored to the response.
Pharmacological measures, for instance, can be taken to improve the
ability of the mitral valve to adapt adequately. Type of surgical repair
can be tailored depending on whether it is incomplete adaptation or
mal-adaptation that is the pathology behind the persistent MR.
In fact, work in this direction has already begun. It has been reported
that Angiotensin II receptors are found on the valvular endothelial
cells of the mitral valve which are stimulated by Angiotensin II to
initiate the process of EndMT. This response can be effectively blocked
by using Angiotensin II receptor blockers.13 This
property therefore has the potential to prevent excessive EndMT that may
result in fibrosis of the valve leaflets. However, as elegantly
described by the authors, EndMT is controlled by complex signalling
networks, and not all of them are completely
understood.14 Researchers working on tissue engineered
valves have taken cue from the fact that EMT is the first step for the
endocardial cushions to become a mature valve leaflet. As a result cell
types which can induce EMT are considered to be a great option for the
valve scaffolds.15 The principle of leaflet
augmentation in mitral valve repair is nothing but completing the
process of incomplete adaptation. The thickened retracted chords can be
seen as a mal-adaptation response and cutting the second order chords
have been used to treat the process of mal-adaptation with satisfactory
outcome.16
While the concept brought in by the authors is novel, even
revolutionary, realistically speaking we are still in the nascent stage
of this concept of “Mitral Plasticity” both from clinical as well as
cellular perspectives. In the current phase effort must be directed
towards better understanding of the process of EndMT and the interplay
between EndMT and VICs. Confirmatory mapping of the inhibitory and
activating signals for EndMT must be done before models to manipulate
EndMT and Mitral Plasticity can be reliably drawn. Clinically, further
studies would be required to identify co-morbid conditions that
influence “Mitral Plasticity” and only then can we think of
intervening pharmacologically to achieve desired outcomes. Surgical
interventions based on the concepts of Mitral Plasticity have to be done
in larger studies and only then convincing evidence can be gathered. It
is undoubtedly going to be a long hard road but one that is worth
travelling and the authors must be once again congratulated for taking
the first few steps.
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