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Journal of Veterinary Cardiology (2012) 14, 103e126

www.elsevier.com/locate/jvc

Pathology of myxomatous mitral valve disease


in the dog
Philip R. Fox, DVM, MSc

Caspary Research Institute, The Animal Medical Center, 510 East 62nd Street, New York, NY 10065, USA

Received 24 December 2011; received in revised form 3 February 2012; accepted 4 February 2012

KEYWORDS Abstract Mitral valve competence requires complex interplay between structures
Pathology; that comprise the mitral apparatus e the mitral annulus, mitral valve leaflets, chor-
Canine; dae tendineae, papillary muscles, and left atrial and left ventricular myocardium.
Mxyomatous mitral Myxomatous mitral valve degeneration is prevalent in the canine, and most adult
valve dogs develop some degree of mitral valve disease as they age, highlighting the
apparent vulnerability of canine heart valves to injury. Myxomatous valvular remo-
deling is associated with characteristic histopathologic features. Changes include
expansion of extracellular matrix with glycosaminoglycans and proteoglycans;
valvular interstitial cell alteration; and attenuation or loss of the collagen-laden fi-
brosa layer. These lead to malformation of the mitral apparatus, biomechanical
dysfunction, and mitral incompetence. Mitral regurgitation is the most common
manifestation of mxyomatous valve disease and in advanced stages, associated
volume overload promotes progressive valvular regurgitation, left atrial and left
ventricular remodeling, atrial tears, chordal rupture, and congestive heart failure.
Future studies are necessary to identify clinical-pathologic correlates that track
disease severity and progression, detect valve dysfunction, and facilitate risk strat-
ification. It remains unresolved whether, or to what extent, the pathobiology of
mxyomatous mitral valve degeneration is the same between breeds of dogs, between
canines and humans, and how these features are related to aging and genetics.
ª 2012 Elsevier B.V. All rights reserved.

Structural and functional basis of and mortality in the dog. Frequently used and
descriptive terminology preferred terms to describe this condition empha-
size its degenerative, pathologic features, such as
Chronic, acquired atrioventricular valve disease is “degenerative myxomatous mitral valve disease
the most common cause of cardiac morbidity (MMVD),” “chronic, degenerative valve disease,”
“myxomatous degeneration of the atrioventricular
E-mail address: Philip.fox@amcny.org. valves,” and “endocardiosis.”1e9 The term “mitral

1760-2734/$ - see front matter ª 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.jvc.2012.02.001
104 P.R. Fox

been reported to affect the mitral valve alone in


Abbreviations 62% of dogs; both mitral and tricuspid valves in
32.5%; and tricuspid valves alone in 1.3%.4 Mild
GAG glycosaminoglycans aortic insufficiency associated with thickened,
MMVD myxomatous mitral valve disease mxyomatous aortic valve leaflets is often detected
by echocardiography and color flow Doppler
echocardiography in older dogs.
valve prolapse” reflecting altered valvular motion, Typically, MMVD progresses over many years and
has been adapted from human nomenclature and morbidity is directly related to the magnitude of
applied by some investigators to describe canine valvular insufficiency and volume overload. The
MMVD.10e13 While mitral valve motion can be natural history is incompletely understood, and
affected by mxyomatous degeneration, the precise most data originates from retrospective studies
definition of prolapse in man and dogs is elusive, and relatively short-term clinical drug trials. This
and not all affected valves appear to prolapse. condition can be relatively benign in mildly
Indeed, echocardiography often reveals that affected dogs.16 In contrast, severely affected
a portion of remodeled, redundant valve tissue animals can develop congestive heart failure, and
extends across the annulus into the left atrium morbidities such as syncope, cardiac cachexia, and
during systole. Such protrusion may reflect thick- cough caused by marked left atrial dilation that
ened leaflets or stretched chordae tendineae and compresses the left main stem bronchus, can
can be detected across a range of disease stages. precede congestive signs in some cases. Heart
Other dogs may develop leaflets with redundant failure confers a grave long term prognosis and
qualities resembling ‘hooded,’ ‘domed, or ‘para- leads inexorably to cardiac morbidity and death.
chute-like’ morphologies which substantially Surgical options to repair affected valves are
‘billow’ (i.e., prolapse) into the left atrium during presently limited, and medical management does
systole. However, it remains unresolved how to best little to alter the development and progression of
assess the severity and clinical significance of valve pathologic changes. Thus, long term monitoring
pathology, how to optimally grade the degree of and therapy results in substantial cardiac
associated valvular regurgitation, and how these morbidity with high attendant medical costs.6e8,14
factors vary between breeds, stage of disease, and
aging.
The normal mitral valve complex

Epidemiology and natural history Mitral valve competence relies upon the structural
and functional performance of six basic components
The incidence and progression of MMVD is strongly that comprise the mitral valve apparatus: the
associated with age, breed, and gender.1e12,14e25 posterior left atrial wall, mitral valve annulus,
Prevalence of myxomatous valve disease varies mitral valve leaflets, chordae tendineae, left
between breeds, but may occur in more than 90 ventricular papillary muscles, and associated left
percent of small breeds older than 8 years of ventricular wall32e37 (Figs. 1 and 2). This apparatus
age.1,2,10,15,16,25 Younger animals can also be operates through complex interplay, with each
affected, particularly the Cavalier King Charles element acting both independently and synergisti-
spaniel and bull terrier breeds.12, 21e23,26e28 Males cally to maintain valve integrity. Intact mitral valve
may develop MMVD earlier than females.8,25 While chordae tendineae mediate efficient and forceful
myxomatous valve disease is most commonly ventricular contraction and optimize left ventric-
diagnosed in small to medium sized dogs,5,7e10,25 it ular systolic performance, underscoring the impor-
also occurs in large breeds6,8,9,16,23,29 including tance of valvular-ventricular interaction.38e40 The
dogs with dilated cardiomyopathy, where it functional roles of the leaflets and chordae tendi-
develops concomitantly, but is often over- neae are related to their histologic and biochemical
looked.28,30,31 Although etiology of MMVD is unre- composition, which determine the tensile and
solved, a heritable basis was reported in the compressive loads borne by these structures.41
Dachshund10 and Cavalier King Charles Spaniel26 The mitral valve consists of anterior (septal) and
breeds, suggesting a polygenic mode of inheri- posterior (parietal) leaflets. The juncture where
tance. Genetic mechanisms remain to be clarified. they are supported at their hinge points, at the
The left atrioventricular valve is most confluence of the left atrial and left ventricular
commonly affected, but MMVD can involve all wall, is referred to as the mitral annulus (Fig. 2
cardiac valves.1e4,16,25 Myxomatous change has [see also Figs. 4e7]). It is a dynamic structure,
Pathology of canine myxomatous mitral valve disease 105

Figure 1 Dorsolateral, trans-illuminated view of


a normal mitral valve apparatus from a two year old,
mongrel dog. Valve leaflets are attached to myocardial
tissue along the top of the frame, and via chordae ten-
dineae to a papillary muscle (P) below. Normal valve
leaflets appear as thin, clear, translucent structures
with flat edges. First-order (“marginal”) chordae tendi-
neae attach to free edges of the leaflet. Several thin,
first-order chordae are identified by the small, vertical
arrows. Thicker first-order chordae are seen immedi-
ately to their right. Second-order (“ventricular”) chor-
dae (broad arrow) insert on the undersurface of the
valve, just beyond the leaflet edge. Scale, mm.

whose size and shape are both altered during the Figure 2 Sagittal section through the left atrium and
left ventricle of an eight-month-old dog displaying
cardiac cycle42 and are challenging to demon-
normal mitral valve and subvalvular apparatus. Atrial
strate.34,43e46 This discontinuous fibrous ring and ventricular myocardium have been dissected away
consists of a network of elastin, dense collagen to show the structures that support the mitral valve
fibers,4,36,47 and scant cartilage; is thicker in some leaflets and comprise the mitral apparatus. The leaflets
areas than in others; and is part of what has been attach at the junction of atrial and ventricular myocar-
referred to as the cardiac or fibrous skeleton of the dium, denoting the mitral annulus. These normal valve
heart. This annuli fibrosi is variably developed. It leaflets are thin, clear, and translucent and the chordae
contributes support for each atrioventricular valve tendineae are smooth and symmetric. LA, left atrium;
orifice and each arterial ring (the aortic ring is W, left atrial posterior wall: LVPW, left ventricular
more developed than the pulmonic). The fibrous posterior wall; P, papillary muscle. Scale, mm.
skeleton acts to reinforce the myocardium inter-
nally, anchor the valve cusps, prevent excessive
dilation of valvular orifices, serve as a point of fibrous body), is situated at the intersection of the
insertion for atrial and ventricular myocyte atrioventricular membranous septum, mitral and
bundles, and buffer conduction of electrical tricuspid valve annulus, and aortic annulus, and is
impulses between atria and ventricles. 35,36,43,46,47 generally larger than the left trigone. Anatomi-
The fibrous base of the heart lies between the left cally, the anterior mitral valve leaflet extends
and right atrioventricular ostia along the caudal between these trigones and is in fibrous continuity
margin of the aortic root. Here, the anterior mitral with the dorsal aspect of the left and noncoronary
valve annulus is flanked by two major collagenous aortic valve cusps at the aortic root (Figs. 3e5); it
structures which may contain scant cartilage in the also forms part of the left ventricular outflow
dog, and comprise the left and right fibrous trig- tract. This extensive area of fibrous continuity that
ones (Fig. 3). 33,45e47 Ventrally, the left fibrous connects the mitral and aortic valves has been
trigone consists of fibrous tissue at the confluence termed the ‘aortic-mitral curtain. 48 There is no
of the anterior mitral valve-aortic valve juncture, fibrous ring in this location. From the fibrous trig-
located under the left coronary aortic leaflet. The ones, delicate collagenous bundles extend dorsally
right fibrous trigone (which when conjoined with from the endocardium on each side, part way
the membranous septum comprises the central around the mitral orifice.
106 P.R. Fox

posterior mitral leaflet attaches to the left atrial


and left ventricular endocardium at the region of
the atrioventricular junction.33,34 The posterior
annulus is formed by merging of the posterior
mitral valve leaflet at the junction of the left
ventricular inflow tract and left ventricular
posterior wall (Figs. 2 and 5).44
When considered 3-dimensionally, the overall
atrioventricular junction is nonplanar and approx-
imates a hyperbolic parabola. The geometric
shape of the mitral annulus in normal hearts
resembles a tilted riding saddle, with the “saddle
horn” of the mitral annulus located near the area
of aortic-mitral continuity. Its geometric peaks
occur anteriorly and posteriorly, and its valleys
occur medially and laterally at the commi-
sures.38,49,50 Curvature of the leaflets reduces
peak leaflet stress. This mechanical advantage
may be important during states that influence
annular size such as during left atrial and ventric-
ular contractility, left atrial-left ventricular pres-
sure differential, and is associated with mitral
valve leaflet stress.33,42,49e51 The mitral annular
shape narrows eccentrically through its lateral and
dorsal aspects. Systolic changes in annular length
Figure 3 Cross-sectional view of the cardiac base in the normal state are predominantly caused by
viewed from above, demonstrating anatomic relation-
changes in length of the dorsal (posterior) portion
ships. The left and right atria were removed just above
the atrioventricular valves. The mitral annulus is divided
of the ring rather than at the base of the anterior
into anterior and posterior portions. The anterior mitral leaflet,33,52,53 with greater systolic decrease in
annulus is flanked by the left (L) and right (R) trigones length than in width. The mitral annulus moves
(fibrous bodies) e the major collagenous structures of towards the ventricular apex during systole and
the mitral annular ring. The right fibrous trigone (central towards the atrium early in diastole.33,52e54 Under
fibrous body) represents the confluence of fibrous normal filling pressure, the average area of the
connective tissue associated with the dorsal aspect of canine mitral valve orifice at end-systole was re-
aortic root (Ao), anterior mitral valve (A), tricuspid valve ported to be 28% less than at end-diastole, but
(TV), and membranous septum. The left fibrous trigone when challenged by volume load, the mitral valve
represents fibrous tissue associated with the confluence orifice increased 30% over normal, favoring the
of the left margins of the aortic and anterior mitral
development of mitral regurgitation.53 Moreover,
valves. The anterior (ventral) mitral valve leaflet is sit-
uated between these trigones, along the inter-trigonal
data from three-dimensional models constructed
region, and is in direct fibrous continuity with the to examine the effect of annular dilation on valve
aortic root, the left, and noncoronary aortic valve cusps. leaflet and chordal dynamics, have demonstrated
The anterior mitral leaflet separates the left ventricular that annular dilation leads to delayed valve coap-
inflow from the outflow tract. The union of the anterior tation, increased regurgitation, and high leaflet
mitral annulus and aortic annulus is referred to as the and chordal stresses.50e58 These responses illus-
aortic-mitral curtain. The annulus is bordered by the left trate how regurgitant stroke volume from myxo-
circumflex branch of the coronary artery (C) and the matous mitral valve disease can lead to further
coronary sinus. This dog had severe myxomatous valve compromise of mitral valve apparatus and exac-
disease. A portion of right auricular appendage (RAu) erbate valvular insufficiency, supporting the
remains attached. P, posterior (caudal) mitral valve
concept of a ‘closed-loop’ degenerative process.
leaflet. Scale, mm.
The subvalvular apparatus helps to restrain mitral
valve leaflet motion during both systole and dias-
The dorsal one-third to one-half of the mitral tole.56,57 Adverse effects resulting from transecting
orifice, which extends from one side to the other chordae tendineae are well documented and may be
of the posterior mitral valve leaflet, is devoid of related to changes in left ventricular geometry. The
a true fibrous annulus, and whose fibromuscular intact mitral subvalvular apparatus functions to help
distribution may vary considerably.43e45 Here, the optimize left ventricular energetics and ventriculo-
Pathology of canine myxomatous mitral valve disease 107

Figure 4 Sagittal section at the level left ventricular inflow and outflow tracts from a young adult, mongrel dog. The
left panel shows the aortic root (Ao) enclosing the semilunar valves, comprising the sinus of valsalva. There is
continuity of the anterior mitral valve leaflet (straight white arrow) with the posterior aspect of the aortic root
(straight black arrow). Chordae tendineae have been cut and chordal remnants are apparent on the anterior mitral
leaflet. LA, left atrium. Center panel and right panel are photomicrographs taken from the gross section. Center panel
is stained using Alcian blue with H&E counterstain; right panel is stained with Weigert Van Gieson stain. Curved arrows
indicate left atrial wall myocardium which lies adjacent to, but does not constitute the basal portion of the anterior
mitral valve. In the right panel, the collagen of the fibrosa layer (stained red, white arrow) illustrates the
mitraleaortic continuity. Bars ¼ 2 mm.

vascular coupling, in addition to enhance left


ventricular systolic performance.58 Investigations
that have studied the relative importance of ante-
rior and posterior mitral chordae tendineae to
maintain global left ventricular performance, have
demonstrated that severing the anterior leaflet
chordae significantly reduced the slope of the
pressure-volume relation. The chordae of the
anterior and posterior mitral leaflets had an additive

Figure 6 Photomicrograph of the proximal third of the


posterior mitral valve leaflet from a three year old
Figure 5 Sagittal section through the left ventricular German shepherd dog. The valve consists of four layers.
inflow and outflow tracts as viewed from a slightly From the atrial to ventricular aspect (top to bottom of
ventral perspective of the subvalvular apparatus in a six- this frame), the atrialis (A) is a thin layer on the inflow
year-old Boxer dog. The anterior mitral valve leaflet side of the mitral leaflet and is lined by endothelial cells
(AMV) is in fibrous continuity with aortic valve (AoV) overlying elastin fibers; the spongiosa (S) is comprised of
leaflets. The supporting structure for the anterior mitral glycosaminoglycans, proteoglycans, and loose, fine
valve leaflet in this region is not exclusively the collagen fibers, and extends from the annulus to the free
myocardium, but is predominantly comprised of the edge of the leaflet; the fibrosa (F) comprises a dense,
extensive fibrous continuity between the anterior mitral circumferentially oriented layer of collagen fibers that
valve leaflet and the aortic valve (referred to as the continues with the annulus proximally, and the central
aorticemitral curtain, black arrow). The posterior mitral core of chordae tendineae distally; the ventricularis (V)
valve leaflet (P) attaches at the junction of the left faces the left ventricular chamber; it is a thin layer
atrial and left ventricular posterior walls (white arrow). similar to the atrialis that contains elastic and collagen
LA, left atrium; Ao, aorta; P, posterior mitral valve fibers covered by endothelium. CT, chorda tendinae.
leaflet LVW, left ventricular posterior wall. Scale, mm. H&E. Bar ¼ 200 mm.
108 P.R. Fox

was recorded at necropsy between annular


circumference (6.0, 7.0, 7.5, 8.0, 8.5, 9.0, and 9.5
cm) and body weight (10.8, 12.7, 14.6, 15.1, 17.1,
18.8, and 20.2 kg), respectively, in mongrel dogs.61
Normal atrioventricular valve leaflets appear as
thin, translucent structures without nodules or
thickening at the valve margins. The anterior
(septal) and posterior (parietal or mural) leaflets
are separated at their commissures. Cusps or
scallops are variably developed and can be indis-
tinct.Subsidiary cusps have been described for the
posterior leaflet, and are located at each end of
the leaflet.47 The mitral valve leaflet surface has
been described as having a rough zone near their
free margin where chordae tendineae attach, and
a smooth (membranous, or clear) zone towards the
annular junction.62 The leaflets appear from the
atrial aspect as smooth, relatively transparent,
and glistening (Fig. 1). From their ventricular
surface, they appear as fasciculated and irregular,
associated with attachments of second-order
chordae tendineae (Fig. 2). The left atrioventric-
ular valve is attached at its hinge point to the
fibrous skeleton or to the annular junction in areas
where a distinct fibrous ring is absent (Figs. 2, 4
and 5 [see also Fig. 7]).
Figure 7 Close up view of myxomatous mitral valve
The anterior mitral valve leaflet is larger and
leaflets from Fig. 5. The leaflet edges are slightly
longer than the posterior leaflet.4,17,18,63 The
rounded and thickened at their contact points (thin
arrows) consistent with Whitney type I pathology. anterior to posterior length ratio has been re-
Occasional, nodular thickening (broad arrow) is present ported as 1.7 to 1, 38 and 1.81  0.15 (mean -
along distal leaflet segments (this coalescence of  standard deviation).17 Anatomic measurements
thickened leaflet edge to form nodular changes (mean  standard deviation) of the mitral valve
conforms to Whitney type II lesions). Chordae tendineae measured from 21 normal dogs weighing between
a p p e a r g r o s s l y n o r m a l . M o s t o f t h e fi r s t - o r d e r 22 and 64 kg (median, 22 kg) reported anterior
(“marginal”) chordae have been cut. Second-order mitral valve length of 22.86  3.89 mm; posterior
(“ventral”) chordae are evident and insert under the mitral valve length, 15.24  3.05 mm; mitral valve
larger anterior mitral valve leaflet. Scale, mm. leaflet area, 749.85  207.17 mm2; and mitral
valve annulus area, 477.2  149.49 mm2. Body
influence upon global left ventricular systolic weight was moderately but significantly correlated
performance, though the contribution of the ante- with mitral valve annulus and mitral valve leaflet
rior chordae tends to be more important.59 Others area.63
investigating how the mitral apparatus affects left
ventricular systolic function by assessing mitral
annulus and papillary muscle mechanical coupling The chordae tendineae and papillary
and mitral annular contraction, report that mitral muscles
apparatus preservation significantly improved left
ventricular function, compared with conventional Effective closure of the mitral valve requires
mitral valve replacement.60 complex, temporal, and geometric coordination of
the left atrioventricular annulus, mitral leaflets,
and subvalvular apparatus. Each mitral valve
Gross features leaflet is adjoined to the anterior or posterior
papillary muscles or occasionally, directly to the
The mitral valve ventricular wall by fibrous chords, the chordae
tendineae. Together, these structures work in
The mitral valve circumference is larger than that a coordinated manner to prevent mitral valve
of the tricuspid valve.53 A nearly linear correlation prolapse and regurgitation. Intact chordae
Pathology of canine myxomatous mitral valve disease 109

mediate efficient ventricular contraction, enhance order chordae can originate from a common, bifur-
left ventricular systolic function by regional cating chorda; 3) third-order chordae arise from the
afterload reduction and preserving ventricular septal wall, insert similarly to second-order chor-
geometry, and enhance left ventricular perfor- dae, or towards the attached border of the valve,
mance. 38,50e52,54e58,60e75 and are uncommon in dogs. Chordae increase in
The mitral chordae tendineae generally branch thickness from the first-order (“marginal”) chordae,
and are of variable thickness. A number of different to those that are more centrally placed.70
terms have been reported to classify chordae ten- Each mitral leaflet receives chordae tendineae
dineae according to their insertion sites on mitral from both the anterior and posterior papillary
valve leaflets51,64e68 (Fig. 1 [see also Figs. 2, 5, and muscles. In a study of normal dogs weighing
7e11]): 1) first-order (“primary,” “marginal”) 12e64 kg, there was no significant difference
chordae are thin, arise from the papillary muscle, between the number of chordae tendineae origi-
insert on the free edges of the leaflets, and are most nating from the anterior and posterior papillary
common (some authors have designated first-order muscles, and the number of chordal branches from
[“marginal”] chordae that insert into the free each papillary muscle. On average, two to five
margin of the commissural regions, as “commis- branches originated from each chorda tendinae.
sural” chordae65); 2) second-order (“secondary,” However, a significantly higher number of chordae
“basal,” “principal,” “stay,” “ventricular,” or (predominantly second-order chordae) were
“strut”) chordae arise from the papillary muscle, attached to the anterior mitral valve leaflet.63
are generally larger than first-order chordae, and Different functional roles have been proposed for
insert just beyond on the undersurface (ventricular first- and second-order chordae tendineae.65,66
aspect) of valve leaflets, typically near the junction
of the smooth and rough zone. Both first and second-

Figure 9 Mitral valve apparatus dissected from a 4


year old mongrel dog. Valve leaflets are attached at the
top margin of the frame to the dark band of myocardial
tissue, and via chordae tendineae to a papillary muscle
in the lower right portion of the frame. The juncture
where they are supported at their hinge points denotes
the region of the mitral annulus. The anterior leaflet
(left side of the frame) is longer than the posterior
Figure 8 Dorsolateral view of myxomatous mitral leaflet. Leaflets are trans-illuminated to highlight vari-
valve leaflets that conform to Whitney types I and II ations in thickness and opacities. Areas of diffuse
pathology. Leaflet edges are rounded with variable and opacity are present and small nodular densities are
generally mild thickening, and there are areas with evident at leaflet edges (Whitney type I lesions), with
differing stages of opacity and irregularity (constituting some coalescing (Whitney type II lesions). The thick,
type I lesions). Small nodular densities are evident on black arrow indicates a second-order (“ventral”) chorda
some edges (white arrow) and in some sections, coalesce tendinae, and the thin black arrow below and slightly to
to form more pronounced lesions (black arrow) (type II the right illustrates smaller chordal divisions from this
lesions). All chordae tendineae in this frame are first- second-order chorda that attach to the leaflet margin.
order (“marginal”) chordae except for one second- The thin, black arrow at the lower left hand side of this
order (“ventral”) chorda (white arrow head). Chordae figure indicates a first-order (“marginal”) chorda tendi-
tendineae appear grossly unremarkable. Scale, mm. nae. Scale, mm.
110 P.R. Fox

Figure 11 Mitral valve apparatus dissected from a 12


year old, male, Maltese dog with severe MMVD con-
forming to Whitney type III pathology. A portion of
thickened anterior mitral valve leaflet is seen on the left
side of the frame. There are varying grades of nodular
coalescence. Prominent, diffuse leaflet thickening (thick
black arrow) and focal, smaller nodules at leaflet edges
Figure 10 Photomicrographs of posterior mitral valve (thin black arrow) flank less severely affected segments.
leaflet and second-order chordae tendineae from a 4 Chordae tendineae in this portion of the subvalvular
year old Boxer dog with MMVD (Whitney type II apparatus have maintained normal morphology. P,
pathology) and congenital subaortic stenosis. Left frame papillary muscle. Scale, mm.
is stained with H & E; right frame is stained with Masson
trichrome; Upper bars ¼ 2 mm, Lower bars ¼ 1 mm).
Myocytes extend from the basal left atrial posterior wall
(LAPW) to approximately half way to the mid-point of edges of leaflets are stiffer, have higher stress, and
the leaflet. The distal valve leaflet is slightly thickened buttress leaflet motion during valve closure to
and nodular densities are evident at their margins. The prevent prolapse. Sectioning normal first-order
fibrosa layer is intact but displays a degree of disruption chordae results in acute mitral regurgitation.
and fragmentation distally. Two second-order chordae Second-order chordae which insert on the ventric-
insert into the ventricular side of the leaflet. Their ular aspect of the valves are more elastic, bear less
collagen cores divide and a portion of each becomes stress, and promote mechanical coupling between
continuous with fibrosa, which courses towards the
the anterior mitral valve leaflets and left ventricular
annulus. Close inspection of the chorada tendinae within
each respective the box of interest shows compact,
wall. Sectioning these chordae does not produce
intact, relatively homogeneous, and longitudinally mitral regurgitation, but can impact ventricular
oriented collagen bundles, whose alignment is parallel geometry and systolic function.51,65,67,68,71 Second-
to the long axis of the chorda and in the direction of order chordae from the papillary muscles attach to
load. The chorda is covered with an endothelial cell dense collagen networks of the anterior mitral valve
layer. LVPW, left ventricular posterior wall. leaflet, which imparts fibrous continuity to the
cardiac skeleton through the trigones. Some authors
have referred to these as “strut” chordae, although
First-order anterior mitral valve leaflet chordae the distinction for this qualification is vague.36,44,51,
67,71,73,74
prevent leaflet prolapse and insufficiency. Second-
order anterior mitral valve chordae are thicker. There is substantial chordal-papillary variation
Their collagen bundles radiate from the insertion with wide geometrical variability in papillary
site to the mitral annulus trigones, acting as muscle morphology and origin. It is unclear
a tendon-like, anatomic interface between the whether this variation affects the state of
mitral annulus at the fibrous trigones and left papillary-annular continuity or left ventricular
ventricular myocardium at the papillary muscles, function.76,77 In general the ventral (anterior)
thus promoting valvular-ventricular interaction.39,66 papillary muscle originates in mid-region of the
Chordae vary with regard to their biomechanical anterior left ventricular wall, closer to the sub-
properties. First-order chordae which insert on free sinuosal interventricular groove; the dorsal
Pathology of canine myxomatous mitral valve disease 111

(posterior) papillary muscle originates from the with smaller quantities of collagen I, III, and VI.
apical region of the posterior wall, near the sub- The spongiosa contains moderate quantity of
sinuosal interventricular groove47, and both collagen VI and a smaller proportion of collagen I,
usually avoid the interventricular wall. Papillary III, laminin, and fibronectin. The fibrosa is
muscle bellies may be single and undivided, or composed predominately of collagen I, III, and VI
divided into one to three segments at their apex or with small amounts of collagen IV and fibronectin.
base.63 Papillary muscle dynamics may play a role The ventricularis contains small quantities of
to facilitate leaflet apposition.74 Shortening of the collagen I and III.
papillary muscle throughout left ventricular iso- The functional roles of the leaflets and chordae
volumic relaxation may contribute to mitral valve are related to their morphology, tissue mechanical
opening, while elongation of the papillary muscle properties, and the make-up and distribution of
during late diastole permits closure of the mitral these constituents.81,82 The closed mitral valve
valve leaflets.75 experiences both tensile and compressive loads.
Through their collagenous attachments, the
central, flat region of the anterior leaflet and the
Histomorphologic features chordae maintain tension. In contrast, the free
edge of the anterior mitral valve leaflet and the
The mitral valve posterior leaflet contain relatively less collagen,
have a thicker spongiosa layer, and undergo
Leaflets are heterogeneous, laminated, structures compressive forces.41,81,82 The central chorda
composed of four distinct layers (Fig. 6). These are tendinae region has higher elastic properties than
most prominent at their mid-portion. 4,15,24,36,78,79 the free edge of the anterior mitral valve leaflet
From the atrial to ventricular aspect, the atrialis and posterior valve leaflet. 83e85 Collagen fibers
comprises a thin layer of endothelial cells sup- are oriented towards the main loading forces in
ported by scattered collagen fibers, elastic fibers, the chordae86 and central portion of the anterior
fibroblasts, and smooth muscle cells; the spon- mitral leaflet,84 while fibers are less aligned in the
giosa, a layer rich in proteoglycans and glycos- free edge of the anterior mitral valve leaflet and
aminoglycans, extends from the annulus to the posterior leaflet.82
free edge of the leaflet, contains ground substance Cardiac muscle extends from the left atrial wall
embedding a loose collection of collagen, elastic into the atrioventricular valve leaflet and is inti-
fibers, fibroblasts, and Anichkov’s cells. The mately associated with the connective tissue
spongiosa of the proximal third of the anterior skeleton. Conceptually, the anterior mitral leaflet
leaflet contains adipose cells; the fibrosa is a dense can be subdivided into thirds based upon the
layer of compact collagen bundles with scattered degree that striated muscle spreads into the
fibroblasts that continues with the annulus proxi- valve.4,36 Myocytes are oriented along the long axis
mally, and central core of chordae tendineae of the leaflet, and small nerves and vessels are
distally; and the ventricularis, a thin layer similar present below endothelial cells in the basal third
to the atrialis but without smooth muscle cells. of the mitral valve, intermingled between the
Elastic fibers occur throughout the valve leaflets atrialis and spongiosa. The mid-third of the leaflet
and particularly, the sub-atrialis layer; collagenous contains relatively fewer myocytes which become
fibers have diameters ranging from 350 e 550 Å, increasingly separated as they course distally, and
while delicate, thinner fibers are present in ground the spongiosa layer appears as muscle fibers are
substance of the extracellular matrix.80 The lost. The distal third of the leaflet contains no
endothelial covering of the ventricular aspect of myocytes. The posterior mitral valve leaflet also
the mitral valve leaflet is continuous with that contains myocytes but these end abruptly at the
covering of chordae tendineae. The fibrous mid-valve region. This trait of myocyte distribution
valvular layer is continuous with the fibrous provides the basis for characterizing the posterior
cardiac skeleton. leaflet into a proximal and distal portion, the
Immunohistochemical features of the normal latter representing the segment devoid of myo-
canine mitral valve leaflet have been reported.24 cytes.4,24,36,87,88 Myocardial fibers located on the
The subendothelial basement membrane is atrial side of the mitral valve might influence the
comprised of moderate amounts of laminin and three-dimensional shape and dynamic geometry of
fibronectin, small amounts of collagen I, III, IV, and the mitral area and the anterior mitral valve.
VI, and heparin sulphate, and is generally thicker Thus, it is possible that anterior mitral valve
on the atrial aspect compared with the ventricular leaflet muscle contributes to valve closure and
side. The atrialis is comprised primarily of elastin competency.89
112 P.R. Fox

Chordae tendineae Lymphatics return interstitial fluid, proteins, and


electrolytes to the venous system. Drainage
There are three distinct cross-sectional layers.36 vessels follow branches of the coronary artery.
Single, flattened endothelial cells comprise the Lymphatic capillaries appear as a thin layer of
outer layer. A basal lamina separates the endo- endothelial cells and are present in subepicardial,
thelium from an area of loosely meshed collagen, myocardial, and subendocardial regions. They are
elastic fibers, scattered fibroblasts, dense more prevalent in the ventricles than atria and are
collagen bundles, and sparse nerves. A central distributed in dense networks that simulate
core is comprised of dense, wavy, closely packed a fishnet-like arrangement. Lymphatic vessels are
and aligned collagen bundles whose orientation is also present in all cusps of the atrioventricular
parallel to the long axis of the chorda and in the valves, in the sinoatrial node and atrioventricular
direction of load. Chordal fibroblasts synthesize
collagen, elastin, and other matrix proteins that
help mediate mechanical stress and loading
conditions. As chordae interface with the papil-
lary muscle, they fan out to encompass the tip,
project into and interdigitate with myocyte
bundles, and course between endocardial cells. At
the papillary-chordal junction is a region
comprised of loose collagen, elastic fibers and
lipid droplets. Collagen bundles penetrate and
arborize into the papillary muscle tip, whose
smaller branches contain both loosely arranged
collagen strands and denser, wavy bands, capil-
laries, and small nerves, and terminate in the
basal lamina of myocytes.36 Where the chordae
insert into the ventricular side of the leaflet,
chordal and leaflet endothelium are continuous
with each other. The collagen core of the chordae
divides such that the major portion becomes
continuous with fibrosa, and courses in a contin-
uous sweep towards the annulus. The collagen
fibers cross to produce a basket-weave effect at
the central zone of the leaflet. Some collagen
from the central core is oriented towards the
leaflet free edge, contributing to the fibrosa of
the smooth area of the leaflet.36

Vessels and nerves

Vessels are present in papillary muscles and mitral


valves. Numbers of thin walled arteries increase
from the proximal papillary muscle tip (18%) to the
base (48%); intermediate walled arteries decrease
from the papillary tip (56%) to the base (14%); and Figure 12 Mitral valve apparatus with severe myxo-
thick walled arteries decreased from the tip (62%) matous degeneration dissected from an 8 year old, male,
to the mid-portion (38%).90 In the porcine mitral Cavalier King Charles spaniel. Lesions conform to Whitney
valve, blood vessels course through longitudinal type IV pathology. The posterior mitral valve leaflet is
and circumferential directions, and the second- attached to atrial and ventricular myocardium at the
annular junction (upper frame, between arrows). The
order (strut) chordae of the anterior mitral valve
longer anterior mitral valve leaflet seen to the left is
leaflet have greater vascularization than other supported by the extensive fibrous continuity between it
chordae.91 and the aortic valve. There is gross distortion and
Vascular channels are present in the atrioven- ‘ballooning’ of the valve cusps and some of the chordae
tricular valves and myocardium. These comprise tendineae are thickened proximally (lower frame,
drainage vessels and lymphatic capillaries.4,36,88,92 arrow). The upper frame is trans-illuminated. Scale, mm.
Pathology of canine myxomatous mitral valve disease 113

system.93 They have been described in the anterior subendocardium and in the myocardium.96
mitral valve leaflet to extend from the free margin Lymphatic capillaries at the base of the chordae
to the annulus, and as delicate lymphatic capillary tendineae appear flattened in cross section, and
networks that extend in the subendocardium of from the sides project thorn-like branchlets
the atrial side of the valves. There is marked comprised of a single endothelial cell with
variability in intravalvular distribution between apposing marginal zones. Straight lymphatic
lymphatic capillaries and small blood vessels.94 capillaries terminate blindly at their end, appear-
Ultrastructural characteristics of lymphatic capil- ing as a single endothelial cell whose ultrastruc-
laries include interstitial spaces lined by irregular, ture resembles the spiny branchlets.
occasionally fenestrated endothelium, absence of Innervation has been recognized as an impor-
basal membrane, and absence of erythrocytes tant feature of mitral valve function in several
within the lumen.92 A relatively dense concentra- species. In dogs4,36,88 nerve fibers, mostly sympa-
tion of lymphatics also occur in the region of the thetic, occur prominently in the proximal zone of
papillary muscles. It has been suggested that these mitral valve leaflets, less commonly in the middle
channels may play a role in the development of of the valve, and are absent in the distal valve and
pathologic changes affecting the mitral valve chordae tendineae. In the proximal valve region,
apparatus and result in valve dysfunction.95 In large nerve fiber bundles course along the longi-
human papillary muscles lymphatic networks are tudinal axis of the leaflet and nerve trunks can
present in superficial and deep layers of the travel perpendicular to the long axis. Here, they

Figure 13 Sagittal section which has passed through the entire left heart, proximal ascending aorta, ventricular
septum, right ventricle, and portion of the right auricle, from a 14 year old, male, Cavalier King Charles Spaniel dog
with severe MMVD (Whitney type IV pathology). This plane corresponds to the right parasternal, long axis inflow-
outflow tomographic view that would be obtained by 2-dimensional echocardiography. Left panel illustrates the six
components of the mitral apparatus: the posterior left atrial wall (W), mitral valve leaflets (MV), mitral valve annulus
(white arrows illustrate the location of the annulus at the juncture where the mitral valve leaflets are supported at
their hinge points at the confluence of the left atrial and left ventricular posterior wall [LVPW]), chordae tendineae
(CT), papillary muscle (P), and associated LVPW. Scale, mm. Right panel is a subgross photograph of the corresponding
section. The direction of blood flow is indicated as follows: a downward pointing arrow illustrates inflow from the left
atrium (LA) into the left ventricle, and an arrow obliquely directed towards the 11:00 o’clock position illustrates the
direction of blood flowing from the left ventricular chamber, through the left ventricular outflow tract, into the aorta
(Ao). The short black arrow points to the fibrous connection between the anterior mitral valve leaflet and the aortic
root, where there is no discreet mitral annulus. A component of the tricuspid valve is evident just above the right
ventricle (RV). IVS, interventricular septum. Masson trichrome stain.
114 P.R. Fox

lie in association with myocytes in the spongiosa, between papillary muscle displacement on func-
where nerve branches innervate muscle bundles tional mitral regurgitation have shown that
within epimysium, perimysium, and endomysium. inducing apical posterolateral papillary muscle
Sparse nerve fibers may extend beyond the region displacement (simulating left ventricular dilation),
of cardiac myocytes, but have not been identified increased mitral regurgitation markedly, when the
at the free edge or distal portion of the valve, or in annulus was enlarged 1.75 times the normal size. 65
the chordae.

Gross features
Pathology of the mitral valve apparatus
associated with chronic myxomatous Mitral valve leaflets
degeneration
The severity and extent of MMVD lesions are age
Each component of the mitral valve apparatus plays dependent and vary widely.1e6,8,9,11,15,17e23,25,
26e29, 36,78,79,88,97e101
both independent and synergistic roles, contrib- There is substantial patho-
uting complex functions that maintain valve logic heterogeneity within affected valve leaflets,
competency. Pathologic changes that alter this particularly with mild to moderate degrees of
apparatus restrain valve mechanics, affect fluid myxomatous degeneration, while advanced changes
dynamics, and promote valvular insufficiency. result in diffuse valvular thickening and distortion.
32,65,66,73
Also important amongst these factors are Early valvular changes are most evident along
the tethering and coapting forces acting on mitral leaflet edges at the juncture of leaflet apposition,
valve leaflets, as well as forces that affect annular particularly where first-order (“marginal”) chordae
size, papillary muscle position, and trans-valvular attach. Myxomatous degeneration transforms
pressure. Annular dilation is a major determinant normal thin, translucent leaflets (Figs. 1, 2, and 4)
of mitral regurgitation. In vitro models designed to into opaque structures that become thickened in
investigate the pathophysiologic interaction their distal third, progressing to diffuse valve

Figure 14 Photomicrograph of the distal posterior mitral valve leaflet from a 12 year old, male, Maltese dog with
severe myxomatous valve disease (Whitney stage IV pathology), illustrating the most prominent structural features of
this condition- increased thickness of the spongiosa from glycosaminoglycan and proteoglycan deposition, and
degeneration of the fibrosa. Left frame (H & E; Bar ¼ 1 mm) and right frame (Masson trichrome; bar ¼ 1 mm) reveal
total loss of the leaflet’s normal layered arrangement. Collagen bundles in the fibrosa have undergone disintegration.
Only scattered remnants remain which are variably displaced throughout the thickened valve stroma, forming swirls
throughout the leaflet. These changes contribute to the gross appearance of increased opacities in the leaflet, and
focal nodular thickening in the leaflet edge. A large, second-order chorda tendinae associated with this leaflet
appears on the left side of the left frame. Center frame is higher magnification taken from the area of interest within
the box of the left frame. Markedly increased glycosaminoglycan deposition transforms the spongiosa into a relatively
granular appearing stroma, which contains stellate and spindle-shaped cells, and scant mononuclear infiltration
within the increased mxyomatous content. H & E; Bar ¼ 500 mm).
Pathology of canine myxomatous mitral valve disease 115

thickening, nodularity, and deformation. With Chordae tendineae


disease progression, valve leaflet edges may thicken
and roll inward, producing a rounded contour, while Degenerative changes occur in chordae tendineae
bulging towards the atrial aspect. Early lesions with chronic myxomatous valve disease (Figs. 12,
appear as thickened valve edges (Fig. 7), can prog- 17e19). Myxomatous remodeling of chordae can
ress to form nodular densities (Figs. 8e10), which affect valve function or lead to rupture and flail
coalesce to involve larger sections of leaflet as the leaflet. Chordae may become thickened proximal
disease progresses (Fig. 11). In advanced cases, to leaflet insertion or extend to involve the
myxomatous transformation causes distal portions majority of the chordae in some cases. Others can
of the leaflet to become markedly thickened display thickened, proximal segments which then
(Figs. 12e16) and protrude into the left atrium (Figs. taper over their mid-portion (Fig. 17). Some
12, 13, and 15). This feature has been variably affected dogs appear to have excessively long
described as “hooding,” “ballooning,” “bulging,” or chordae tendineae,97 but it is uncertain whether
“prolapsing,” although the distinctions underlying this represents pathologic change or morphologic
these terms, as well as the relationship to human variation.
‘mitral valve prolapse,’ are blurred. Chronic volume
overload may cause the annulus to dilate which
exacerbates valvular incompetency.
A simple classification scheme for grading the
severity of gross, myxomatous lesions has been
reported and is based upon the degree of leaflet
nodularity, thickening, and deformity15,100,101:
Type I lesions represent valve leaflets that contain
a few, small, discrete nodules in regions where
leaflets contact each other, with areas of opacity
in the proximal valve (Figs. 7 and 8); Type 2 lesions
represents leaflets with larger nodules which tend
to coalesce at the edges of valve contact, and
areas of diffuse opacity may be present (Figs.
7e10); Type 3 lesions comprise larger nodules
which have coalesced into irregular, plaque-like
deformities, and extend to involve proximal
portions of the chordae (Fig. 11); Type 4 lesions
denote gross distortion and ‘ballooning’ of the
valve cusps, and the chordae tendineae are
thickened proximally (Figs. 12e18). While this
‘Whitney’ classification scheme provides a quick
and convenient method to foster gross pathologic
description, it should be noted that MMVD repre-
sents a pathologic continuum in dogs. Disease
stages can overlap, lesions may vary considerably
in the same patient, and not all cases will fit
conveniently or homogeneously into these discrete
categories.
The ratio of anterior to posterior mitral valve
length has been demonstrated to be greater than 1
in both normal dogs and those with MMVD. Valve
length ratios (mean  standard deviation) reported Figure 15 Dorsolateral view from the left atrium
from 5 normal dogs and 25 dogs with Whitney looking downward, of severely myxomatous mitral
valves from the same dog in Fig. 13. Lesions correspond
grades 0 (normal) to 4 MMVD were 1.81 (0.15), 1.74
to Whitney stage IV pathology. Both anterior and
(0.14), 1.61 (0.12), and 1.52 (0.17), respectively,
posterior leaflets are markedly thickened and convexly
suggesting progressive lengthening of valve shaped, with rounded edges and contracted borders,
leaflets or chordae. Disease severity was statisti- and protrude into the left atrium. Chordae tendineae
cally correlated with degree of thickening of the were thickened. IAS, interatrial septum; LAPW, left
distal portion of both the anterior and posterior atrial posterior wall; LVPW, left ventricular posterior
leaflets.17 wall; IVS, interventricular septum. Scale, mm.
116 P.R. Fox

Histopathologic features containing glycosaminoglycans (GAG, formerly


described as acid mucopolysaccharides) and
Microscopic findings vary with the degree and proteoglycans, and proliferation of edematous
severity of myxomatous valvular degeneration. ground substance. The normal arrangement of
The histopathologic lesions predominate in the layered collagen in the fibrosa becomes disrupted
distal third of the valve leaflets and the incidence and attenuated. In advanced stages, it is difficult
and severity increase with age. Lesions include to recognize distinct spongiosa and fibrosa layers
progressive expansion of the spongiosa layer and (Figs. 14 and 16).
disruption of the fibrosa layer.4,15,17,20,24,36,78,97 A three tiered grading system has been reported
Such changes can be detected most readily along to describe mxyomatous valvular lesions, based
the region of leaflet apposition, and early lesions upon progressive histopathologic and immunohis-
may be accentuated in proximity to major chordal topathologic severity24: Mild MMVC is character-
attachment. The spongiosa valve layer becomes ized by activated stromal cells and proliferation of
thickened with increased extracellular matrix endothelium and fibroelastic tissue of the atrialis;

Figure 16 Photomicrographs from a sagittal section through the left atrium and left ventricle of a 15 year old,
neutered male, miniature schnauzer dog with severe MMVD (Whitney stage IV pathology). Images illustrate severe
mxyomatous degenerative changes in the posterior mitral valve leaflet and chorda tendinae. The top three frames are
stained with Alcian blue which stains glycosaminoglycans and acid mucopolysaccharides blue. It is counterstained
with H&E which colors nuclei black and cytoplasm with pink or red shades. The bottom three frames are stained with
Weigert Van Gieson designed to show collagen as pink-red, and muscle, cytoplasm, RBC and fibrin as gold to light
orange. Left upper and lower frames show a severely myxomatous posterior mitral leaflet whose distal segment is
grossly thickened and rounded (arrow). Jet lesions are present on the endocardial left atrial surface between the two
horizontal arrows on the lower left frame. These appear grossly as elevated, roughened, whitish-grey, fibrotic
surfaces that result from high velocity, turbulent, jets of mitral regurgitation that strike the endocardium.
Bars ¼ 2 mm. Middle upper and lower frames highlight the thickened and distorted distal mitral leaflet. They show
widespread deposition of glycosaminoglycan and acid mucopolysaccharides distending the fibrosa layer, and illustrate
loss of the fibrosa layer. Box identifies areas of higher magnification for the upper and lower right frames.
Bar ¼ 350 mm. Right upper and lower frames show an expanded, mxyomatous, relatively acellular region containing
fragmented and displaced collagen fibers and scattered, large, spindle-shaped stromal cells. Bar ¼ 40 mm.
Pathology of canine myxomatous mitral valve disease 117

Figure 17 Photomicrographs from same dog as Fig. 16 illustrating of a portion of the posterior mitral apparatus
stained with Weigert Van Gieson (collagen stains pink-red; muscle, cytoplasm, RBC and fibrin stains light orange).
Upper Left Frame. The posterior mitral valve hinge point attaches at the junction of the left atrial posterior wall
(LAPW) and left ventricular posterior wall (LVPW). The distal segment of the valve is grossly thickened, distorted, and
rounded. A jet lesion on the atrial endocardial wall appears as a long, irregularly thickened, fibrotic lesion. The box of
interest contains the mid-portion of the leaflet and a chorda tendinae that is magnified in the upper right frame.
Box ¼ 2 mm. Upper Right Frame. Myxomatous changes are evident and include light, fine, disrupted collagen strands
within an expanded extracellular matrix. The circle encompasses the proximal chorda at its attachment to the leaflet
edge. The chorda is distended, tapers abruptly, and is portrayed in higher magnification below, right. Bar ¼ 2 mm.
Lower Right Frame. Diffuse, mxyomatous degeneration and remodeling is present. The box of interest encloses
a section portrayed at higher magnification to the lower left. Lower Left Frame. Collagen bundles are disrupted,
loosely arranged, and contain many thin, attenuated fibers within an expanded, mxyomatous extracellular matrix.
Compare these changes with relatively normal histologic appearance in Fig. 10.
118 P.R. Fox

the basement membrane composed of collagen IV inactive-myofibroblasts (vimentin-positive cells)


and laminin of the atrialis is irregularly split; were reduced in mitral valve leaflets of dogs
increased collagen VI and laminin invades into the with myxomatous valve disease.102 Minimal
atrialis; nodular thickening of the fibrosa is seen, numbers of vimentin-positive cells, which are
associated with proteoglycan deposition, with located throughout normal valve leaflets, were
intact collagen bundles of the fibrosa; mildly found in distinctive myxomatous regions. A slight
increased extracellular components are present, increase in mast cell numbers was detected in
and spread into the atrialis; loss of normal collagen distal portions of myxomatous leaflets. Whether
I and III layers occurs and is replaced by loose, fine, such changes represent direct causeeeffect rela-
fibrillary networks in the atrialis and spongiosa. tionships between these cells, or whether they
Moderate MMVD is characterized by moderately represent reactions to the disease process,
increased GAG and proteoglycan deposition in the requires further study.
distal half of the valvular spongiosa, mild degen- Pathologic alterations involving the surface of
eration of collagen bundles in the fibrosa, but mitral valve leaflets have also been described.70,80
normal structure in the proximal half of the valve. Morphologic abnormalities comprise patchy,
Severe MMVD is characterized by severely endothelial injury that is most extensive at or near
increased GAG and proteoglycan deposition the leaflet edges, and extend more towards the
resulting in complete displacement of the fibrosa, ventricular side than the atrial aspect. Damaged
disrupted collagen bundles in the distal half of the zones include denuded areas exposing the sub-
valve, and fibroblastic proliferation in the atrialis endothelial basement membrane, or sub-
and fibrosa. endothelial matrix that contained elastin and
In moderate and severe MMVD, changes in the collagen strands and valvular interstitial cells.
extracellular matrix and connective tissue Endothelial injury may also extend from valve
components become substantial. They result in leaflets, to proximal chordae tendineae which can
significant reduction in connective tissue density exhibit swelling. At chorda-papillary junctions,
(Figs. 14, 16, 17), and these changes increase with chordal swelling with minimal endothelial cell loss
advanced age.17,24 Multifocal accumulations of is detectable. Mid-chordal regions appear to be
elastin and collagen IV occur in subendothelial least affected.83
regions, and laminin and collagen VI can be
detected in these areas. In nodular lesions fibro-
nectin occurred predominantly in marginal
regions, closely related to collagen VI. Collagen I
was present diffusely, while moderate amounts of
collagen III was present, predominantly in central
regions. Laminin, elastin and collagen IV were
associated with the basement membrane, and
mildly present in peripheral regions of severely
affected leaflets.24 Nodular valvular lesions were
characterized by large, relatively acellular,
central regions that are rich in proteoglycans,
collagen I and II, and a marginal, cellular, region
containing numerous, large spindle-shaped
stromal cells assumed to produce collagen I, IV,
fibronectin, and basal membrane components.24
Distal valve regions with myxomatous degenera- Figure 18 Sagittal section through the left atrium and
tive changes contained statistically fewer spindle- left ventricle from a 15 year old, neutered male,
shaped cell numbers compared to normal Pomeranian dog with severe MMVD (Whitney type IV
leaflets.17 Morphologic changes have been re- pathology), as viewed from a slightly subvalvular
ported to occur in valvular interstitial cells of perspective. The anterior mitral valve has been exteri-
orized to illustrate its thickened and irregularly dis-
mxyomatous valves. These included change in cell
torted first-order (“marginal”) chordae tendineae and
type from a quiescent fibroblast to eventually,
a ruptured chorda (black arrow). The thickened,
a mixed myofibroblast, or more smooth muscle rounded end of the ruptured chorda contrasts with the
cell phenotype.19,102 These changes may be asso- cleanly transected edge of a normal appearing chorda
ciated with a response to maintain mechanical (white arrow) attached to a thickened posterior mitral
valve function and tone.19 Activated myofibro- valve leaflet. LA, left atrium; LVW, left ventricular
blasts (a-SMA-positive cells) were increased and posterior wall; IVS, interventricular septum. Scale, mm.
Pathology of canine myxomatous mitral valve disease 119

Mitral valve innervation is altered in aged dogs


and in dogs with MMVD.88 Significant loss of
innervation was detected in association with
reduction in myocytes with and an increase in
adipocytes within mitral valvular leaflets. MMVD
may develop before reduced innervation with
advanced age. It is uncertain whether muscle loss
occurred secondary to loss of innervation, or
whether reduced innervation density was caused
by muscle loss.88

Cardiac sequelae associated with


chronic degenerative mitral valve
disease

Rupture of chordae tendineae

Mxyomatous degeneration of the mitral valve can


also involve chordae tendineae, and chordal
rupture is a well-recognized complication of this
disease.4,6e8,15,78,98e103 Rupture generally involves
first-order (marginal) chordae, and affected
ruptured structures are thickened and irregular
(particularly proximal to the valve leaflet) (Figs.
17e20). Affected chordae may taper to their
mid-portion (Fig. 17) and rupture at this junction
can be observed. Other chordae have diffuse
swelling from mxyomatous degeneration. Most
ruptures occur within the proximal third to half of
their length relative to the mitral valve leaflet.
Affected collagen bundles become hyalinized,
attenuated and disorganized, separated, and in
advanced cases, undergo disintegration with
deposition of lipid (Figs. 17 and 20).4
Factors that predispose human mxyomatous
chordae to rupture have been investigated.104
Measurements of extensibility and failure strain
recorded from both normal and mxyomatous
chordae tendineae showed that chordae from
myxomatous mitral valves were larger, heavier,
had significantly lower moduli, and failed at
significantly lower tensile stress and absolute
load, compared with normal chordae. Myxoma-
tous degeneration severely affected the
mechanical properties of mitral valve chordae,
and myxomatous chordae failed at loads that
Figure 19 Severely mxyomatous mitral valves (Whit-
were one-half of those of normal chordae.105
ney stage IV pathology) and ruptured chordae tendineae
in a two geriatric, small breed dogs. Upper Frame. Mitral
Local absence of tenomodulin, angiogenesis, and
valve viewed from above through the left atrium. Leaf-
lets are greatly thickened, rounded, and deformed. A
ruptured first-order (marginal) chorda tendinae (arrow) chorda tendinae (broad arrow) attached to the ante-
attached to the anterior leaflet is evident. Lower Frame. rior mitral valve leaflet. A small jet lesion is present
Sagittal section through the left atrium and left ventricle above the annulus (thin arrow). LVPW, left ventricular
displaying myxomatous leaflets and ruptured first-order posterior wall; LA, left atrial posterior wall. Scale, mm.
120 P.R. Fox

matrix metalloproteinase activation may The mitral subvalvular apparatus plays an


contribute to chordal rupture.106 Tenomodulin, an important role to maintain both valvular compe-
antiangiogenic factor expressed in the elastin-rich tence and left ventricular function. Severing chor-
subendothelial outer layer of normal chordae dae alters left ventricular geometry and reduces
tendineae, was absent in ruptured areas. These left ventricular systolic performance, highlighting
regions were associated with abnormal vessel the importance of valvulareventricular interac-
formation, vascular endothelial growth factor-A tion.39 Clinical outcome is affected by several
and matrix metalloproteinase expression, and factors including the type and location of chordal
inflammation, in comparison to normal or non- rupture, the geometry and size of the mitral valve
ruptured areas where these changes were not orifice, the size, function, and compliance of the
observed. left atrium, the status of left ventricular function,
Clinical diagnosis relies upon echocardiographic and heart rate.79, 99,106e108 Chordae tendineae
detection, but there are no necropsy-based echo- rupture does not always lead to fulminant heart
cardiographic criteria to reliably distinguish mitral failure and this lesion is sometimes detected as an
valve prolapse from flail leaflet caused by rupture incidental finding at necropsy.78 In fact, 58 percent
of a chorda tendinae in the dog. Thus, different of dogs with ruptured chordae tendineae assessed
echocardiographic criteria may influence ante by echocardiography survived greater than one
mortem reports of chordae tendineae rupture. year, and ruptured chordae tendineae have been
Nevertheless, a prevalence of approximately 16 detected in asymptomatic dogs who did not have
percent was reported in a retrospective study of heart failure.99
114 dogs with MMVD.99 Affected dogs tended to be
older (median 12.2 years; range, 6e17 years),
small breed (87% <10 kg, 11% 10e20 kg body Left atrial endocardial tear and rupture
weight), male dogs. Ruptured chordae tendineae
were detected in the anterior mitral valve leaflet Severe MMVD can generate high velocity jets of
in approximately 96 percent of recognized cases, mitral regurgitation that strike and injure left atrial
and prevalence was highest in dogs with ISACHC endocardium. These jets are usually obliquely
class III heart failure. directed, oriented opposite to the anterior mitral
valve leaflet, towards the posterior-dorsal or
posterior-lateral left atrial wall. Such jets may
traumatize the atrial endocardium and result in
focal, thickened, fibrotic, endocardial contact
lesions (known as ‘jet’ lesions). More advanced
cases can induce endocardial tears.78
Atrial tears range from acute partial thickness
tears, to chronic partial thickness tears with
replacement fibrosis, to full thickness atrial split-
ting which are typically acute or subacute. Histo-
pathologic changes include left atrial
endomyocardial degeneration, fibrosis and necrosis
with hemorrhage, fibrin, and acute or chronic-
active inflammation.109 Affected animals may
have multiple tears of variable thickness ranging
from small perforations, to extensive lesions (Figs.
Figure 20 Photomicrograph of a segment of ruptured 21 and 22). In a series of 30 affected dogs with
first-order (“marginal”) chorda tendinae that was left atrial tears, 17 of 30 were non-perforating,
attached to the anterior mitral valve, from a nine year while approximately one-third had hemopericar-
old cavalier King Charles spaniel with severe MMVD. The dium resulting from full thickness perforation.
rounded and enlarged, ruptured end contains fibrous These lesions have been described to be more
connective tissue and mxyomatous extracellular matrix.
common in older, male dogs, and Dachshunds and
The normal central core of compact collagen bundles
cocker spaniels may be overrepresented.110
has been remodeled and displays distorted and frag-
mented collagen fibers of varying thickness, separated Left atrial rupture with acute cardiac tampo-
by edematous ground substance and mxyomatous nade is an uncommon but catastrophic
matrix. These lesions are strikingly different from sequella.4,8,78,109e113 Factors associated with atrial
normal histologic architecture shown in Fig. 10. Masson tear include atrial wall mechanical strength,
trichrome. Magnification  20. distention and function.114e117 Acquired atrial
Pathology of canine myxomatous mitral valve disease
Figure 21 Gross and histological images from a sagittal section made through the left atrium and left ventricle, from a 10 year old, neutered female, standard
poodle with severe MMVD (Whitney stage IV) pathology. Anterior and posterior mitral valves are greatly thickened and distorted and protrude into the left atrium (LA).
There is severe dilation of the LA. White-appearing jet lesions are present above the mitral annulus (the raised feature of this lesion is not apparent from this
photograph). Partial thickness atrial tears are visible in the dorsal (black arrow) and caudal (white arrows) aspects of the LA wall. The dorsal-most atrial tear shows
exposed atrial myocardium between clear edges of a thickened, torn, endocardial surface. A larger and more chronic lesion is seen between the white arrows. It is
depressed and covered by whitish appearing fibrous connective tissue. The region enclosed in the box represents the photomicrograph in the central frame. IVS,
interventricular septum; LVPW, left ventricular posterior wall; Scale, mm. Central Frame. Photomicrograph showing the severely mxyomatous posterior mitral leaflet.
The distal half of the valve is greatly thickened by expansion of the spongiosa by extracellular matrix. Transmural fibrous replacement of torn atrial myocardium
(arrow) is evident. Bar ¼ 2 mm. Higher magnification of the section defined by the box placed on the ventricular aspect of the valve, shows loss of the fibrosa layer and
fragmented, disoriented collagen fibers (Bar ¼ 100 mm). Upper Right Frame. This section shows another sagittal section from an adjacent region. At this section
through the atrial tear, fibrous connective tissue has filled in the atrial tear which had extended midway through the atrial myocardium. W, left atrial posterior wall.
Bar ¼ 2 mm

121
122 P.R. Fox

Figure 22 Sagittal section from an 8 year old, female, mongrel dog with severe MMVD that conforms to a left
parasternal five chamber tomographic view as would be imaged by 2-dimensional echocardiography. A. Mitral valve
leaflets are severely thickened and deformed (Whitney type IV pathology). There is an extensive, obliquely oriented,
partial thickness, left atrial tear measuring approximately 4 cm in length. Box denotes region of interest for frame B.
LA, left atrium; LV, left ventricle; AV, aortic valve. Scale, mm. B. Photomicrograph showing LA posterior wall (LA) and
LV posterior wall (LVPW), and portion of the posterior mitral valve leaflet (arrow). Black box encompasses the upper
two-thirds of the left atrial tear and represents the area of interest for frame C. Alcian blue with H&E counterstain;
Bar ¼ 2 mm. C. The left atrial myocardial tear is extensive, nearly transmural, and measures 150 mm at its narrowest
thickness within the box. Alcian blue and H&E counterstain Bar ¼ 1 mm. D. Section of LA wall along the myo-
cardialeepicardial junction. Cardiomyocytes are separated by hemorrhage and edema, with myodegeneration and
necrosis. Hemorrhage is present between adipocytes. Alcian blue with H&E counterstain. Bar ¼ 50 mm. E. Section of
myocardium taken just below the region of the black box in frame C, displaying various stages of myocardiocyte
degeneration and necrosis. There is mild and focal hemorrhage. Alcian blue with H&E counterstain. Bar ¼ 100 mm. F
and G are photomicrographs of the same section outlined by the box in Frame A. Bars ¼ 2 mm. F. Arrows illustrate the
width of the atrial tear at this level which varied between 2.2 and 2.4 mm wide. Masson trichrome stain (collagen
stains light blue). Bar ¼ 2 mm. G, H, I and J are Weigert Van Gieson stain (collagen stains pink-red; muscle, cytoplasm,
RBC and fibrin stains light orange). A jet lesion appears as an irregularly thickened fibrotic region above the atrial rent
(Frames F, G, H and I). Endocardial fibrosis is present and is seen to extend to the upper and lower margins of the atrial
tear. I. Box of interest contains region of endocardium and myocardium towards the basal aspect of the LA caudal
wall, shown in higher magnification in frame J. Bar ¼ 2 mm. J. Endocardial thickening (Endo) is present. There is also
an extensive band of subendocardial repair comprising replacement fibrosis (stains red-pink), myocyte necrosis, and
scattered adipocytes. Bar ¼ 200 mm.

septal defects are an uncommon, sequel to atrial Myxomatous mitral valve degeneration is prevalent
septal rupture in dogs with MMVD.118 in the canine and by ten to twelve years of age, most
dogs have acquired some degree of mitral valve
disease. Clearly, canine heart valves are prone to
Conclusions injury. The gross pathologic features are associated
with histological remodeling that is characterized
The functional competence of the mitral valve relies by expansion of the extracellular matrix with
intimately upon effective interaction of the mitral glycosaminoglycans, proteoglycans; alterations in
apparatus, whose components include the mitral valvular interstitial cells; attenuation or loss of the
annulus and leaflets, the subvalvular apparatus, and collagen-laden fibrosa layer; and other
left atrial and left ventricular myocardium.32e35 changes.19,24,36,102,119 Such alterations lead to
Pathology of canine myxomatous mitral valve disease 123

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