FIGURES
Fig. 1 – Patients with idiopathic dilated cardiomyopathy, severely
dilated hearts, displaced papillary muscles and mild MR. Balanced mitral
adaptation, with longer leaflets and chords.
Legend. EDV, end diastolic volume; EDD, end diastolic dimension; EF,
ejection fraction; IPd, interpapillary distance; AML, anterior mitral
leaflet; PML, posterior mitral leaflet; MR, mitral regurgitation.
Fig. 2 – Patient with idiopathic dilated cardiomyopathy, severely
dilated heart, dispiace papillary muscles and severe MR. Unbalanced
mitral adaptation, with nor elongated leaflets and tethered chords.
Legend. EDV, end diastolic volume; EDD, end diastolic dimension; EF,
ejection fraction; IPd, interpapillary distance; AML, anterior mitral
leaflet; PML, posterior mitral leaflet; MR, mitral regurgitation.
Fig. 3 – Patients with ischemic cardiomyopathy after an anterior AMI,
not dilated heart and distance between the papillary muscles within the
range. A and B, mild MR: C and D, severe MR.
Legend. AMI, acute myocardial infarction; EDV, end diastolic volume;
EDD, end diastolic dimension; EF, ejection fraction; AML, anterior
mitral leaflet; PML, posterior mitral leaflet; MR, mitral regurgitation.
Fig. 4 – The leaflet consists of four layers, the atrialis and the
ventricularis, both of which are thin elastin-rich layers, the
spongiosa, which consists mainly of GAGs and collagen, and the fibrosa,
the main load-bearing layer, composed of circumferentially oriented
collagen fibers. In a stressed valve, or in a valve stimulated by TGF-β,
the endothelial cells undergo EndMT, increasing the number of
matrix-producing cells.
Legend. GAGs, glycosaminoglycans; TGF-β; transforming growth factor β;
EndMT, endothelial-to-mesenchimal transition; VIC, valve interstitial
cell.
From Levine et al47, with permission.
Fig. 5 – Scanning electron micrograph of external aspect of the
endothelial cells of the chorda, obtained from a 23-y-old subject
(x3170). (B ) The elastic fibers, situated underneath the
endocardium which was removed (x1720). (C ) Interior of a split
chorda. Waves of collagen fibrils with similar dimensions (10.7 µm) to
the reflections shown in A and undulations in B (x3260).
From Millington-Sanders and Stolinski7, with
permission.
Fig. 6 – Diagrammatic representation of other pathways involved in
EndMT regulation. Molecular signaling pathways beside the TGF-β pathways
that induce or inhibit the EndMT process. These include endothelin
(ET)-1, NOTCH, caveolin (CAV)-1, Wnt, high glucose, and hypoxia
inducible factor (HIF)-1α pathways. Shear stress forces (represented by
undulating arrows) induce EndMT through several different molecular
mechanisms. One mechanism is initiated by the mechanical force-induced
release and liberation of TGF-β from the latency associated peptide
(LAP) followed by activation of the TGF-β canonical pathway. Legend.
EndMT, endothelial-to-mesenchymal transcription; TGF-β, transforming
growth factor-β.
From Piera-Velazquez and Jimenez48, with permission.
Fig. 7 – Myofibroblasts play a central role in in the progression of
fibrotic disease in the heart. One important mechanism yielding MyoFBs
is EndMT (A), by which endothelial cells lose their endothelial markers.
Valvular interstitial cells and cardiac fibroblasts can differentiate
into MyoFBs in response to high mechanical strain (B) with the
degradation of initial ECM and a corresponding decrease in tissue
stiffness. Quiescent VICs and CFs can also differentiate into MyoFBs in
response to high mechanical stress (C), caused by both increased tissue
stiffness and increased tissue forces. MyoFBs increase the overall
stress in the environment by producing excess ECM and contracting
existing ECM through increased cellular contractility. MyoFBs also
release profibrotic signaling factors, including TGF-β1and Wnt, that
promote further MyoFB differentiation and tissue stiffening. This forms
a positive feedback loop leading to progressively worsening fibrosis.
Legend. MyoFBs, myofibroblasts; ECM, exracellular matrix; VICs, valve
interstitial cells; CFs, cardiac fibroblasts; TGF-β1, transforming
growth factor-β1; Wnt, wingless Int-1; EC, endothelial cell; EndMT,
endothelial-to-mesenchimal transition; FGF, fibroblast growth factor;
α-SMA, smooth muscle α-actin.
From Schroer and Merryman49, with permission.
Fig. 8 – A, anterior leaflet of a never-pregnant heifer. B , anterior
leaflet of a cow in early phase of pregnancy (110 days). C, anterior
leaflet of a cow in the late phase of pregnancy (240 days). Collagen
fibers are crimped in heifers, but lose crimp in early pregnancy. Cells
are notably deformed, possibly becoming activated VICs. In late
pregnancy crimping is restored, but the period is almost the double than
in heifer. D, schematic of the possible mechanism of valvular growth via
the serial addition of collagenous fibrillar material as well as the
deposition of new collagen fibres. As existing fibres elongate, their
crimp amplitude and slack are gradually restored, relieving VICs
compression and restoring normal homeostatic function.
Legend. VICs. Valvular interstitial cells.
From Rego et al23, with permission
Fig. 9 – Cellular deformation demonstrate nonlinear tissue
micromechanics at higher strain levels. Mitral valve interstitial cells
from the fibrosa layer from samples stretched at different strain levels
(increasing from left to right). Scale bar: 5 µm.
Legend. T, transmural/thickness; C, circumferential; NOI, normalized
orientation index. A NOI value of 100% represents a highly oriented
fibre network, whereas a NOI value of 0% represents a more randomly
oriented network.
From Ayoub et al24, with permission.
Fig. 10 – Patients with dilated cardiomyopathy due to severe aortic
regurgitation. The heart is severely dilated heart, but MR is mild.
Balanced mitral adaptation, with longer leaflets and chords.
Legend. EDV, end diastolic volume; EDD, end diastolic dimension; EF,
ejection fraction; IPd, interpapillary distance; AML, anterior mitral
leaflet; PML, posterior mitral leaflet; MR, mitral regurgitation.
Fig. 11 – 3D reconstruction of the mitral annulus and leaflets in
systole. Severe chronic IMR. A, preoperatively the tenting volume is
high and the AL is directed toward the apex because of tethering of the
second‐order chords. B, postoperatively the tenting volume is minimal
and the AL reaches easily the PL because of the increased length and the
lack of tethering. The PL is positioned vertically.
Legend. 3D, three‐dimensional; AL, anterior leaflet; IMR, ischemic
mitral regurgitation; PL, posterior leaflet
From Calafiore et al45, with permission.
Fig. 12 – Patient with severe dilated cardiomyopathy. A, severe MR,
with a long AL and tethering of the second order chords (B, red arrow).
3D reconstruction of mitral annulus and leaflets in systole. C, the AL
is moved toward the apex and the second order chords are tethered (red
arrow). D, after mitral annuloplasty and second order cutting through
aortotomy, the AL coapts with the PL with a coaptation length of 9 mm.
Chordal tethering disappeared.
Legend. MR, mitral regurgitation; AL, anterior leaflet; PL, posterior
leaflet.
Fig. 13 – Failure after isolated restrictive mitral annuloplasty for
ischaemic mitral regurgitation. (A) Transthoracic echocardiography. The
anterior leaflet is short (21 mm) and tethered (red arrow) and is not
able to coapt with the posterior leaflet. There is moderate mitral
regurgitation. (B and C) Transoesophageal echocardiography. There is a
significant tenting volume, which pushes the mitral valve inside the
left ventricle. The anterior leaflet has reduced mobility and cannot
coapt with the posterior leaflet due to chordal tethering.
From Calafiore et al50, with permission.