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
descriptive terminology
Chronic, acquired atrioventricular valve disease is
the most common cause of cardiac morbidity
E-mail address: Philip.fox@amcny.org.
and mortality in the dog. Frequently used and
preferred terms to describe this condition empha-
size its degenerative, pathologic features, such as
“degenerative myxomatous mitral valve disease
(MMVD),” “chronic, degenerative valve disease,”
“myxomatous degeneration of the atrioventricular
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
Abbreviations
GAG glycosaminoglycans
MMVD myxomatous mitral valve disease
valve prolapse” reflecting altered valvular motion,
has been adapted from human nomenclature and
applied by some investigators to describe canine
MMVD.10e13 While mitral valve motion can be
affected by mxyomatous degeneration, the precise
definition of prolapse in man and dogs is elusive,
and not all affected valves appear to prolapse.
Indeed, echocardiography often reveals that
a portion of remodeled, redundant valve tissue
extends across the annulus into the left atrium
during systole. Such protrusion may reflect thick-
ened leaflets or stretched chordae tendineae and
can be detected across a range of disease stages.
Other dogs may develop leaflets with redundant
qualities resembling ‘hooded,’ ‘domed, or ‘para-
chute-like’ morphologies which substantially
‘billow’ (i.e., prolapse) into the left atrium during
systole. However, it remains unresolved how to best
assess the severity and clinical significance of valve
pathology, how to optimally grade the degree of
associated valvular regurgitation, and how these
factors vary between breeds, stage of disease, and
aging.
Epidemiology and natural history
The incidence and progression of MMVD is strongly
associated with age, breed, and gender.1e12,14e25
Prevalence of myxomatous valve disease varies
between breeds, but may occur in more than 90
percent of small breeds older than 8 years of
age.1,2,10,15,16,25 Younger animals can also be
affected, particularly the Cavalier King Charles
spaniel and bull terrier breeds.12, 21e23,26e28 Males
may develop MMVD earlier than females.8,25 While
myxomatous valve disease is most commonly
diagnosed in small to medium sized dogs,5,7e10,25 it
also occurs in large breeds6,8,9,16,23,29 including
dogs with dilated cardiomyopathy, where it
develops concomitantly, but is often over-
looked.28,30,31 Although etiology of MMVD is unre-
solved, a heritable basis was reported in the
Dachshund10 and Cavalier King Charles Spaniel26
breeds, suggesting a polygenic mode of inheri-
tance. Genetic mechanisms remain to be clarified.
The left atrioventricular valve is most
commonly affected, but MMVD can involve all
cardiac valves.1e4,16,25 Myxomatous change has
P.R. Fox
been reported to affect the mitral valve alone in
62% of dogs; both mitral and tricuspid valves in
32.5%; and tricuspid valves alone in 1.3%.4 Mild
aortic insufficiency associated with thickened,
mxyomatous aortic valve leaflets is often detected
by echocardiography and color flow Doppler
echocardiography in older dogs.
Typically, MMVD progresses over many years and
morbidity is directly related to the magnitude of
valvular insufficiency and volume overload. The
natural history is incompletely understood, and
most data originates from retrospective studies
and relatively short-term clinical drug trials. This
condition can be relatively benign in mildly
affected dogs.16 In contrast, severely affected
animals can develop congestive heart failure, and
morbidities such as syncope, cardiac cachexia, and
cough caused by marked left atrial dilation that
compresses the left main stem bronchus, can
precede congestive signs in some cases. Heart
failure confers a grave long term prognosis and
leads inexorably to cardiac morbidity and death.
Surgical options to repair affected valves are
presently limited, and medical management does
little to alter the development and progression of
pathologic changes. Thus, long term monitoring
and therapy results in substantial cardiac
morbidity with high attendant medical costs.6e8,14
The normal mitral valve complex
Mitral valve competence relies upon the structural
and functional performance of six basic components
that comprise the mitral valve apparatus: the
posterior left atrial wall, mitral valve annulus,
mitral valve leaflets, chordae tendineae, left
ventricular papillary muscles, and associated left
ventricular wall32e37 (Figs. 1 and 2). This apparatus
operates through complex interplay, with each
element acting both independently and synergisti-
cally to maintain valve integrity. Intact mitral valve
chordae tendineae mediate efficient and forceful
ventricular contraction and optimize left ventric-
ular systolic performance, underscoring the impor-
tance of valvular-ventricular interaction.38e40 The
functional roles of the leaflets and chordae tendi-
neae are related to their histologic and biochemical
composition, which determine the tensile and
compressive loads borne by these structures.41
The mitral valve consists of anterior (septal) and
posterior (parietal) leaflets. The juncture where
they are supported at their hinge points, at the
confluence of the left atrial and left ventricular
wall, is referred to as the mitral annulus (Fig. 2
[see also Figs. 4e7]). It is a dynamic structure,
Pathology of canine myxomatous mitral valve disease
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
cardiac cycle42 and are challenging to demon-
strate.34,43e46 This discontinuous fibrous ring
consists of a network of elastin, dense collagen
fibers,4,36,47 and scant cartilage; is thicker in some
areas than in others; and is part of what has been
referred to as the cardiac or fibrous skeleton of the
heart. This annuli fibrosi is variably developed. It
contributes support for each atrioventricular valve
orifice and each arterial ring (the aortic ring is
more developed than the pulmonic). The fibrous
skeleton acts to reinforce the myocardium inter-
nally, anchor the valve cusps, prevent excessive
dilation of valvular orifices, serve as a point of
insertion for atrial and ventricular myocyte
bundles, and buffer conduction of electrical
impulses between atria and ventricles. 35,36,43,46,47
The fibrous base of the heart lies between the left
and right atrioventricular ostia along the caudal
margin of the aortic root. Here, the anterior mitral
valve annulus is flanked by two major collagenous
structures which may contain scant cartilage in the
dog, and comprise the left and right fibrous trig-
ones (Fig. 3). 33,45e47 Ventrally, the left fibrous
trigone consists of fibrous tissue at the confluence
of the anterior mitral valve-aortic valve juncture,
located under the left coronary aortic leaflet. The
right fibrous trigone (which when conjoined with
the membranous septum comprises the central
105
Figure 2 Sagittal section through the left atrium and
left ventricle of an eight-month-old dog displaying
normal mitral valve and subvalvular apparatus. Atrial
and ventricular myocardium have been dissected away
to show the structures that support the mitral valve
leaflets and comprise the mitral apparatus. The leaflets
attach at the junction of atrial and ventricular myocar-
dium, denoting the mitral annulus. These normal valve
leaflets are thin, clear, and translucent and the chordae
tendineae are smooth and symmetric. LA, left atrium;
W, left atrial posterior wall: LVPW, left ventricular
posterior wall; P, papillary muscle. Scale, mm.
fibrous body), is situated at the intersection of the
atrioventricular membranous septum, mitral and
tricuspid valve annulus, and aortic annulus, and is
generally larger than the left trigone. Anatomi-
cally, the anterior mitral valve leaflet extends
between these trigones and is in fibrous continuity
with the dorsal aspect of the left and noncoronary
aortic valve cusps at the aortic root (Figs. 3e5); it
also forms part of the left ventricular outflow
tract. This extensive area of fibrous continuity that
connects the mitral and aortic valves has been
termed the ‘aortic-mitral curtain. 48 There is no
fibrous ring in this location. From the fibrous trig-
ones, delicate collagenous bundles extend dorsally
from the endocardium on each side, part way
around the mitral orifice.
106
Figure 3 Cross-sectional view of the cardiac base
viewed from above, demonstrating anatomic relation-
ships. The left and right atria were removed just above
the atrioventricular valves. The mitral annulus is divided
into anterior and posterior portions. The anterior mitral
annulus is flanked by the left (L) and right (R) trigones
(fibrous bodies) e the major collagenous structures of
the mitral annular ring. The right fibrous trigone (central
fibrous body) represents the confluence of fibrous
connective tissue associated with the dorsal aspect of
aortic root (Ao), anterior mitral valve (A), tricuspid valve
(TV), and membranous septum. The left fibrous trigone
represents fibrous tissue associated with the confluence
of the left margins of the aortic and anterior mitral
valves. The anterior (ventral) mitral valve leaflet is sit-
uated between these trigones, along the inter-trigonal
region, and is in direct fibrous continuity with the
aortic root, the left, and noncoronary aortic valve cusps.
The anterior mitral leaflet separates the left ventricular
inflow from the outflow tract. The union of the anterior
mitral annulus and aortic annulus is referred to as the
aortic-mitral curtain. The annulus is bordered by the left
circumflex branch of the coronary artery (C) and the
coronary sinus. This dog had severe myxomatous valve
disease. A portion of right auricular appendage (RAu)
remains attached. P, posterior (caudal) mitral valve
leaflet. Scale, mm.
The dorsal one-third to one-half of the mitral
orifice, which extends from one side to the other
of the posterior mitral valve leaflet, is devoid of
a true fibrous annulus, and whose fibromuscular
distribution may vary considerably.43e45 Here, the
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
in the normal state are predominantly caused by
changes in length of the dorsal (posterior) portion
of the ring rather than at the base of the anterior
leaflet,33,52,53 with greater systolic decrease in
length than in width. The mitral annulus moves
towards the ventricular apex during systole and
towards the atrium early in diastole.33,52e54 Under
normal filling pressure, the average area of the
canine mitral valve orifice at end-systole was re-
ported to be 28% less than at end-diastole, but
when challenged by volume load, the mitral valve
orifice increased 30% over normal, favoring the
development of mitral regurgitation.53 Moreover,
data from three-dimensional models constructed
to examine the effect of annular dilation on valve
leaflet and chordal dynamics, have demonstrated
that annular dilation leads to delayed valve coap-
tation, increased regurgitation, and high leaflet
and chordal stresses.50e58 These responses illus-
trate how regurgitant stroke volume from myxo-
matous mitral valve disease can lead to further
compromise of mitral valve apparatus and exac-
erbate valvular insufficiency, supporting the
concept of a ‘closed-loop’ degenerative process.
The subvalvular apparatus helps to restrain mitral
valve leaflet motion during both systole and dias-
tole.56,57 Adverse effects resulting from transecting
chordae tendineae are well documented and may be
related to changes in left ventricular geometry. The
intact mitral subvalvular apparatus functions to help
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

Figure 5 Sagittal section through the left ventricular
inflow and outflow tracts as viewed from a slightly
ventral perspective of the subvalvular apparatus in a six-
year-old Boxer dog. The anterior mitral valve leaflet
(AMV) is in fibrous continuity with aortic valve (AoV)
leaflets. The supporting structure for the anterior mitral
valve leaflet in this region is not exclusively the
myocardium, but is predominantly comprised of the
extensive fibrous continuity between the anterior mitral
valve leaflet and the aortic valve (referred to as the
aorticemitral curtain, black arrow). The posterior mitral
valve leaflet (P) attaches at the junction of the left
atrial and left ventricular posterior walls (white arrow).
LA, left atrium; Ao, aorta; P, posterior mitral valve
leaflet LVW, left ventricular posterior wall. Scale, mm.
posterior mitral valve leaflet from a three year old
German shepherd dog. The valve consists of four layers.
From the atrial to ventricular aspect (top to bottom of
this frame), the atrialis (A) is a thin layer on the inflow
side of the mitral leaflet and is lined by endothelial cells
overlying elastin fibers; the spongiosa (S) is comprised of
glycosaminoglycans, proteoglycans, and loose, fine
collagen fibers, and extends from the annulus to the free
edge of the leaflet; the fibrosa (F) comprises a dense,
circumferentially oriented layer of collagen fibers that
continues with the annulus proximally, and the central
core of chordae tendineae distally; the ventricularis (V)
faces the left ventricular chamber; it is a thin layer
similar to the atrialis that contains elastic and collagen
fibers covered by endothelium. CT, chorda tendinae.
H&E. Bar ¼ 200 mm.
108
Figure 7 Close up view of myxomatous mitral valve
leaflets from Fig. 5. The leaflet edges are slightly
rounded and thickened at their contact points (thin
arrows) consistent with Whitney type I pathology.
Occasional, nodular thickening (broad arrow) is present
along distal leaflet segments (this coalescence of
thickened leaflet edge to form nodular changes
conforms to Whitney type II lesions). Chordae tendineae
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
(“marginal”) chordae have been cut. Second-order
(“ventral”) chordae are evident and insert under the
larger anterior mitral valve leaflet. Scale, mm.
influence upon global left ventricular systolic
performance, though the contribution of the ante-
rior chordae tends to be more important.59 Others
investigating how the mitral apparatus affects left
ventricular systolic function by assessing mitral
annulus and papillary muscle mechanical coupling
and mitral annular contraction, report that mitral
apparatus preservation significantly improved left
ventricular function, compared with conventional
mitral valve replacement.60
Gross features
The mitral valve
The mitral valve circumference is larger than that
of the tricuspid valve.53 A nearly linear correlation
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]).
The anterior mitral valve leaflet is larger and
longer than the posterior leaflet.4,17,18,63 The
anterior to posterior length ratio has been re-
ported as 1.7 to 1, 38 and 1.81  0.15 (mean -
 standard deviation).17 Anatomic measurements
(mean  standard deviation) of the mitral valve
measured from 21 normal dogs weighing between
22 and 64 kg (median, 22 kg) reported anterior
mitral valve length of 22.86  3.89 mm; posterior
mitral valve length, 15.24  3.05 mm; mitral valve
leaflet area, 749.85  207.17 mm2; and mitral
valve annulus area, 477.2  149.49 mm2. Body
weight was moderately but significantly correlated
with mitral valve annulus and mitral valve leaflet
area.63
The chordae tendineae and papillary
muscles
Effective closure of the mitral valve requires
complex, temporal, and geometric coordination of
the left atrioventricular annulus, mitral leaflets,
and subvalvular apparatus. Each mitral valve
leaflet is adjoined to the anterior or posterior
papillary muscles or occasionally, directly to the
ventricular wall by fibrous chords, the chordae
tendineae. Together, these structures work in
a coordinated manner to prevent mitral valve
prolapse and regurgitation. Intact chordae
Pathology of canine myxomatous mitral valve disease
mediate efficient ventricular contraction, enhance
left ventricular systolic function by regional
afterload reduction and preserving ventricular
geometry, and enhance left ventricular perfor-
mance. 38,50e52,54e58,60e75
The mitral chordae tendineae generally branch
and are of variable thickness. A number of different
terms have been reported to classify chordae ten-
dineae according to their insertion sites on mitral
valve leaflets51,64e68 (Fig. 1 [see also Figs. 2, 5, and
7e11]): 1) first-order (“primary,” “marginal”)
chordae are thin, arise from the papillary muscle,
insert on the free edges of the leaflets, and are most
common (some authors have designated first-order
[“marginal”] chordae that insert into the free
margin of the commissural regions, as “commis-
sural” chordae65); 2) second-order (“secondary,”
“basal,” “principal,” “stay,” “ventricular,” or
“strut”) chordae arise from the papillary muscle,
are generally larger than first-order chordae, and
insert just beyond on the undersurface (ventricular
aspect) of valve leaflets, typically near the junction
of the smooth and rough zone. Both first and second-
Figure 8 Dorsolateral view of myxomatous mitral
valve leaflets that conform to Whitney types I and II
pathology. Leaflet edges are rounded with variable and
generally mild thickening, and there are areas with
differing stages of opacity and irregularity (constituting
type I lesions). Small nodular densities are evident on
some edges (white arrow) and in some sections, coalesce
to form more pronounced lesions (black arrow) (type II
lesions). All chordae tendineae in this frame are first-
order (“marginal”) chordae except for one second-
order (“ventral”) chorda (white arrow head). Chordae
tendineae appear grossly unremarkable. Scale, mm.
109
order chordae can originate from a common, bifur-
cating chorda; 3) third-order chordae arise from the
septal wall, insert similarly to second-order chor-
dae, or towards the attached border of the valve,
and are uncommon in dogs. Chordae increase in
thickness from the first-order (“marginal”) chordae,
to those that are more centrally placed.70
Each mitral leaflet receives chordae tendineae
from both the anterior and posterior papillary
muscles. In a study of normal dogs weighing
12e64 kg, there was no significant difference
between the number of chordae tendineae origi-
nating from the anterior and posterior papillary
muscles, and the number of chordal branches from
each papillary muscle. On average, two to five
branches originated from each chorda tendinae.
However, a significantly higher number of chordae
(predominantly second-order chordae) were
attached to the anterior mitral valve leaflet.63
Different functional roles have been proposed for
first- and second-order chordae tendineae.65,66
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
leaflet. Leaflets are trans-illuminated to highlight vari-
ations in thickness and opacities. Areas of diffuse
opacity are present and small nodular densities are
evident at leaflet edges (Whitney type I lesions), with
some coalescing (Whitney type II lesions). The thick,
black arrow indicates a second-order (“ventral”) chorda
tendinae, and the thin black arrow below and slightly to
the right illustrates smaller chordal divisions from this
second-order chorda that attach to the leaflet margin.
The thin, black arrow at the lower left hand side of this
figure indicates a first-order (“marginal”) chorda tendi-
nae. Scale, mm.
110
Figure 10 Photomicrographs of posterior mitral valve
leaflet and second-order chordae tendineae from a 4
year old Boxer dog with MMVD (Whitney type II
pathology) and congenital subaortic stenosis. Left frame
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
the leaflet. The distal valve leaflet is slightly thickened
and nodular densities are evident at their margins. The
fibrosa layer is intact but displays a degree of disruption
and fragmentation distally. Two second-order chordae
insert into the ventricular side of the leaflet. Their
collagen cores divide and a portion of each becomes
continuous with fibrosa, which courses towards the
annulus. Close inspection of the chorada tendinae within
each respective the box of interest shows compact,
intact, relatively homogeneous, and longitudinally
oriented collagen bundles, whose alignment is parallel
to the long axis of the chorda and in the direction of
load. The chorda is covered with an endothelial cell
layer. LVPW, left ventricular posterior wall.
First-order anterior mitral valve leaflet chordae
prevent leaflet prolapse and insufficiency. Second-
order anterior mitral valve chordae are thicker.
Their collagen bundles radiate from the insertion
site to the mitral annulus trigones, acting as
a tendon-like, anatomic interface between the
mitral annulus at the fibrous trigones and left
ventricular myocardium at the papillary muscles,
thus promoting valvular-ventricular interaction.39,66
Chordae vary with regard to their biomechanical
properties. First-order chordae which insert on free
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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
(thin black arrow) flank less severely affected segments.
Chordae tendineae in this portion of the subvalvular
apparatus have maintained normal morphology. P,
papillary muscle. Scale, mm.
edges of leaflets are stiffer, have higher stress, and
buttress leaflet motion during valve closure to
prevent prolapse. Sectioning normal first-order
chordae results in acute mitral regurgitation.
Second-order chordae which insert on the ventric-
ular aspect of the valves are more elastic, bear less
stress, and promote mechanical coupling between
the anterior mitral valve leaflets and left ventricular
wall. Sectioning these chordae does not produce
mitral regurgitation, but can impact ventricular
geometry and systolic function.51,65,67,68,71 Second-
order chordae from the papillary muscles attach to
dense collagen networks of the anterior mitral valve
leaflet, which imparts fibrous continuity to the
cardiac skeleton through the trigones. Some authors
have referred to these as “strut” chordae, although
the distinction for this qualification is vague.36,44,51,
67,71,73,74
There is substantial chordal-papillary variation
with wide geometrical variability in papillary
muscle morphology and origin. It is unclear
whether this variation affects the state of
papillary-annular continuity or left ventricular
function.76,77 In general the ventral (anterior)
papillary muscle originates in mid-region of the
anterior left ventricular wall, closer to the sub-
sinuosal interventricular groove; the dorsal
Pathology of canine myxomatous mitral valve disease
(posterior) papillary muscle originates from the
apical region of the posterior wall, near the sub-
sinuosal interventricular groove47, and both
usually avoid the interventricular wall. Papillary
muscle bellies may be single and undivided, or
divided into one to three segments at their apex or
base.63 Papillary muscle dynamics may play a role
to facilitate leaflet apposition.74 Shortening of the
papillary muscle throughout left ventricular iso-
volumic relaxation may contribute to mitral valve
opening, while elongation of the papillary muscle
during late diastole permits closure of the mitral
valve leaflets.75
Histomorphologic features
The mitral valve
Leaflets are heterogeneous, laminated, structures
composed of four distinct layers (Fig. 6). These are
most prominent at their mid-portion. 4,15,24,36,78,79
From the atrial to ventricular aspect, the atrialis
comprises a thin layer of endothelial cells sup-
ported by scattered collagen fibers, elastic fibers,
fibroblasts, and smooth muscle cells; the spon-
giosa, a layer rich in proteoglycans and glycos-
aminoglycans, extends from the annulus to the
free edge of the leaflet, contains ground substance
embedding a loose collection of collagen, elastic
fibers, fibroblasts, and Anichkov’s cells. The
spongiosa of the proximal third of the anterior
leaflet contains adipose cells; the fibrosa is a dense
layer of compact collagen bundles with scattered
fibroblasts that continues with the annulus proxi-
mally, and central core of chordae tendineae
distally; and the ventricularis, a thin layer similar
to the atrialis but without smooth muscle cells.
Elastic fibers occur throughout the valve leaflets
and particularly, the sub-atrialis layer; collagenous
fibers have diameters ranging from 350 e 550 Å,
while delicate, thinner fibers are present in ground
substance of the extracellular matrix.80 The
endothelial covering of the ventricular aspect of
the mitral valve leaflet is continuous with that
covering of chordae tendineae. The fibrous
valvular layer is continuous with the fibrous
cardiac skeleton.
Immunohistochemical features of the normal
canine mitral valve leaflet have been reported.24
The subendothelial basement membrane is
comprised of moderate amounts of laminin and
fibronectin, small amounts of collagen I, III, IV, and
VI, and heparin sulphate, and is generally thicker
on the atrial aspect compared with the ventricular
side. The atrialis is comprised primarily of elastin
111
with smaller quantities of collagen I, III, and VI.
The spongiosa contains moderate quantity of
collagen VI and a smaller proportion of collagen I,
III, laminin, and fibronectin. The fibrosa is
composed predominately of collagen I, III, and VI
with small amounts of collagen IV and fibronectin.
The ventricularis contains small quantities of
collagen I and III.
The functional roles of the leaflets and chordae
are related to their morphology, tissue mechanical
properties, and the make-up and distribution of
these constituents.81,82 The closed mitral valve
experiences both tensile and compressive loads.
Through their collagenous attachments, the
central, flat region of the anterior leaflet and the
chordae maintain tension. In contrast, the free
edge of the anterior mitral valve leaflet and the
posterior leaflet contain relatively less collagen,
have a thicker spongiosa layer, and undergo
compressive forces.41,81,82 The central chorda
tendinae region has higher elastic properties than
the free edge of the anterior mitral valve leaflet
and posterior valve leaflet. 83e85 Collagen fibers
are oriented towards the main loading forces in
the chordae86 and central portion of the anterior
mitral leaflet,84 while fibers are less aligned in the
free edge of the anterior mitral valve leaflet and
posterior leaflet.82
Cardiac muscle extends from the left atrial wall
into the atrioventricular valve leaflet and is inti-
mately associated with the connective tissue
skeleton. Conceptually, the anterior mitral leaflet
can be subdivided into thirds based upon the
degree that striated muscle spreads into the
valve.4,36 Myocytes are oriented along the long axis
of the leaflet, and small nerves and vessels are
present below endothelial cells in the basal third
of the mitral valve, intermingled between the
atrialis and spongiosa. The mid-third of the leaflet
contains relatively fewer myocytes which become
increasingly separated as they course distally, and
the spongiosa layer appears as muscle fibers are
lost. The distal third of the leaflet contains no
myocytes. The posterior mitral valve leaflet also
contains myocytes but these end abruptly at the
mid-valve region. This trait of myocyte distribution
provides the basis for characterizing the posterior
leaflet into a proximal and distal portion, the
latter representing the segment devoid of myo-
cytes.4,24,36,87,88 Myocardial fibers located on the
atrial side of the mitral valve might influence the
three-dimensional shape and dynamic geometry of
the mitral area and the anterior mitral valve.
Thus, it is possible that anterior mitral valve
leaflet muscle contributes to valve closure and
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
thick walled arteries decreased from the tip (62%)
to the mid-portion (38%).90 In the porcine mitral
valve, blood vessels course through longitudinal
and circumferential directions, and the second-
order (strut) chordae of the anterior mitral valve
leaflet have greater vascularization than other
chordae.91
Vascular channels are present in the atrioven-
tricular valves and myocardium. These comprise
drainage vessels and lymphatic capillaries.4,36,88,92
Figure 12 Mitral valve apparatus with severe myxo-
matous degeneration dissected from an 8 year old, male,
Cavalier King Charles spaniel. Lesions conform to Whitney
type IV pathology. The posterior mitral valve leaflet is
attached to atrial and ventricular myocardium at the
annular junction (upper frame, between arrows). The
longer anterior mitral valve leaflet seen to the left is
supported by the extensive fibrous continuity between it
and the aortic valve. There is gross distortion and
‘ballooning’ of the valve cusps and some of the chordae
tendineae are thickened proximally (lower frame,
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
mitral valve leaflet to extend from the free margin
to the annulus, and as delicate lymphatic capillary
networks that extend in the subendocardium of
the atrial side of the valves. There is marked
variability in intravalvular distribution between
lymphatic capillaries and small blood vessels.94
Ultrastructural characteristics of lymphatic capil-
laries include interstitial spaces lined by irregular,
occasionally fenestrated endothelium, absence of
basal membrane, and absence of erythrocytes
within the lumen.92 A relatively dense concentra-
tion of lymphatics also occur in the region of the
papillary muscles. It has been suggested that these
channels may play a role in the development of
pathologic changes affecting the mitral valve
apparatus and result in valve dysfunction.95 In
human papillary muscles lymphatic networks are
present in superficial and deep layers of the
subendocardium and in the myocardium.96
Lymphatic capillaries at the base of the chordae
tendineae appear flattened in cross section, and
from the sides project thorn-like branchlets
comprised of a single endothelial cell with
apposing marginal zones. Straight lymphatic
capillaries terminate blindly at their end, appear-
ing as a single endothelial cell whose ultrastruc-
ture resembles the spiny branchlets.
Innervation has been recognized as an impor-
tant feature of mitral valve function in several
species. In dogs4,36,88 nerve fibers, mostly sympa-
thetic, occur prominently in the proximal zone of
mitral valve leaflets, less commonly in the middle
of the valve, and are absent in the distal valve and
chordae tendineae. In the proximal valve region,
large nerve fiber bundles course along the longi-
tudinal axis of the leaflet and nerve trunks can
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,
where nerve branches innervate muscle bundles
within epimysium, perimysium, and endomysium.
Sparse nerve fibers may extend beyond the region
of cardiac myocytes, but have not been identified
at the free edge or distal portion of the valve, or in
the chordae.
between papillary muscle displacement on func-
tional mitral regurgitation have shown that
inducing apical posterolateral papillary muscle
displacement (simulating left ventricular dilation),
increased mitral regurgitation markedly, when the
annulus was enlarged 1.75 times the normal size. 65

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

Microscopic findings vary with the degree and
severity of myxomatous valvular degeneration.
The histopathologic lesions predominate in the
distal third of the valve leaflets and the incidence
and severity increase with age. Lesions include
progressive expansion of the spongiosa layer and
disruption of the fibrosa layer.4,15,17,20,24,36,78,97
Such changes can be detected most readily along
the region of leaflet apposition, and early lesions
may be accentuated in proximity to major chordal
attachment. The spongiosa valve layer becomes
thickened with increased extracellular matrix
described as acid mucopolysaccharides) and
proteoglycans, and proliferation of edematous
ground substance. The normal arrangement of
layered collagen in the fibrosa becomes disrupted
and attenuated. In advanced stages, it is difficult
to recognize distinct spongiosa and fibrosa layers
(Figs. 14 and 16).
A three tiered grading system has been reported
to describe mxyomatous valvular lesions, based
upon progressive histopathologic and immunohis-
topathologic severity24: Mild MMVC is character-
ized by activated stromal cells and proliferation of
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
the basement membrane composed of collagen IV
and laminin of the atrialis is irregularly split;
increased collagen VI and laminin invades into the
atrialis; nodular thickening of the fibrosa is seen,
associated with proteoglycan deposition, with
intact collagen bundles of the fibrosa; mildly
increased extracellular components are present,
and spread into the atrialis; loss of normal collagen
I and III layers occurs and is replaced by loose, fine,
fibrillary networks in the atrialis and spongiosa.
Moderate MMVD is characterized by moderately
increased GAG and proteoglycan deposition in the
distal half of the valvular spongiosa, mild degen-
eration of collagen bundles in the fibrosa, but
normal structure in the proximal half of the valve.
Severe MMVD is characterized by severely
increased GAG and proteoglycan deposition
resulting in complete displacement of the fibrosa,
disrupted collagen bundles in the distal half of the
valve, and fibroblastic proliferation in the atrialis
and fibrosa.
In moderate and severe MMVD, changes in the
extracellular matrix and connective tissue
components become substantial. They result in
significant reduction in connective tissue density
(Figs. 14, 16, 17), and these changes increase with
advanced age.17,24 Multifocal accumulations of
elastin and collagen IV occur in subendothelial
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-
tive changes contained statistically fewer spindle-
shaped cell numbers compared to normal
leaflets.17 Morphologic changes have been re-
ported to occur in valvular interstitial cells of
mxyomatous valves. These included change in cell
type from a quiescent fibroblast to eventually,
a mixed myofibroblast, or more smooth muscle
cell phenotype.19,102 These changes may be asso-
ciated with a response to maintain mechanical
valve function and tone.19 Activated myofibro-
blasts (a-SMA-positive cells) were increased and
P.R. Fox
inactive-myofibroblasts (vimentin-positive cells)
were reduced in mitral valve leaflets of dogs
with myxomatous valve disease.102 Minimal
numbers of vimentin-positive cells, which are
located throughout normal valve leaflets, were
found in distinctive myxomatous regions. A slight
increase in mast cell numbers was detected in
distal portions of myxomatous leaflets. Whether
such changes represent direct causeeeffect rela-
tionships between these cells, or whether they
represent reactions to the disease process,
requires further study.
Pathologic alterations involving the surface of
mitral valve leaflets have also been described.70,80
Morphologic abnormalities comprise patchy,
endothelial injury that is most extensive at or near
the leaflet edges, and extend more towards the
ventricular side than the atrial aspect. Damaged
zones include denuded areas exposing the sub-
endothelial basement membrane, or sub-
endothelial matrix that contained elastin and
collagen strands and valvular interstitial cells.
Endothelial injury may also extend from valve
leaflets, to proximal chordae tendineae which can
exhibit swelling. At chorda-papillary junctions,
chordal swelling with minimal endothelial cell loss
is detectable. Mid-chordal regions appear to be
least affected.83
Figure 18 Sagittal section through the left atrium and
left ventricle from a 15 year old, neutered male,
Pomeranian dog with severe MMVD (Whitney type IV
pathology), as viewed from a slightly subvalvular
perspective. The anterior mitral valve has been exteri-
orized to illustrate its thickened and irregularly dis-
torted first-order (“marginal”) chordae tendineae and
a ruptured chorda (black arrow). The thickened,
rounded end of the ruptured chorda contrasts with the
cleanly transected edge of a normal appearing chorda
(white arrow) attached to a thickened posterior mitral
valve leaflet. LA, left atrium; LVW, left ventricular
posterior wall; IVS, interventricular septum. Scale, mm.
Pathology of canine myxomatous mitral valve disease
Figure 19 Severely mxyomatous mitral valves (Whit-
ney stage IV pathology) and ruptured chordae tendineae
in a two geriatric, small breed dogs. Upper Frame. Mitral
valve viewed from above through the left atrium. Leaf-
lets are greatly thickened, rounded, and deformed. A
ruptured first-order (marginal) chorda tendinae (arrow)
attached to the anterior leaflet is evident. Lower Frame.
Sagittal section through the left atrium and left ventricle
displaying myxomatous leaflets and ruptured first-order
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
were one-half of those of normal chordae.105
Local absence of tenomodulin, angiogenesis, and
chorda tendinae (broad arrow) attached to the ante-
rior mitral valve leaflet. A small jet lesion is present
above the annulus (thin arrow). LVPW, left ventricular
posterior wall; LA, left atrial posterior wall. Scale, mm.
120
matrix metalloproteinase activation may
contribute to chordal rupture.106 Tenomodulin, an
antiangiogenic factor expressed in the elastin-rich
subendothelial outer layer of normal chordae
tendineae, was absent in ruptured areas. These
regions were associated with abnormal vessel
formation, vascular endothelial growth factor-A
and matrix metalloproteinase expression, and
inflammation, in comparison to normal or non-
ruptured areas where these changes were not
observed.
Clinical diagnosis relies upon echocardiographic
detection, but there are no necropsy-based echo-
cardiographic criteria to reliably distinguish mitral
valve prolapse from flail leaflet caused by rupture
of a chorda tendinae in the dog. Thus, different
echocardiographic criteria may influence ante
mortem reports of chordae tendineae rupture.
Nevertheless, a prevalence of approximately 16
percent was reported in a retrospective study of
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
weight), male dogs. Ruptured chordae tendineae
were detected in the anterior mitral valve leaflet
in approximately 96 percent of recognized cases,
and prevalence was highest in dogs with ISACHC
class III heart failure.
Figure 20 Photomicrograph of a segment of ruptured
first-order (“marginal”) chorda tendinae that was
attached to the anterior mitral valve, from a nine year
old cavalier King Charles spaniel with severe MMVD. The
rounded and enlarged, ruptured end contains fibrous
connective tissue and mxyomatous extracellular matrix.
The normal central core of compact collagen bundles
has been remodeled and displays distorted and frag-
mented collagen fibers of varying thickness, separated
by edematous ground substance and mxyomatous
matrix. These lesions are strikingly different from
normal histologic architecture shown in Fig. 10. Masson
trichrome. Magnification  20.
P.R. Fox
The mitral subvalvular apparatus plays an
important role to maintain both valvular compe-
tence and left ventricular function. Severing chor-
dae alters left ventricular geometry and reduces
left ventricular systolic performance, highlighting
the importance of valvulareventricular interac-
tion.39 Clinical outcome is affected by several
factors including the type and location of chordal
rupture, the geometry and size of the mitral valve
orifice, the size, function, and compliance of the
left atrium, the status of left ventricular function,
and heart rate.79, 99,106e108 Chordae tendineae
rupture does not always lead to fulminant heart
failure and this lesion is sometimes detected as an
incidental finding at necropsy.78 In fact, 58 percent
of dogs with ruptured chordae tendineae assessed
by echocardiography survived greater than one
year, and ruptured chordae tendineae have been
detected in asymptomatic dogs who did not have
heart failure.99
Left atrial endocardial tear and rupture
Severe MMVD can generate high velocity jets of
mitral regurgitation that strike and injure left atrial
endocardium. These jets are usually obliquely
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.
21 and 22). In a series of 30 affected dogs with
left atrial tears, 17 of 30 were non-perforating,
while approximately one-third had hemopericar-
dium resulting from full thickness perforation.
These lesions have been described to be more
common in older, male dogs, and Dachshunds and
cocker spaniels may be overrepresented.110
Left atrial rupture with acute cardiac tampo-
nade is an uncommon but catastrophic
sequella.4,8,78,109e113 Factors associated with atrial
tear include atrial wall mechanical strength,
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
septal rupture in dogs with MMVD.118
Conclusions
The functional competence of the mitral valve relies
intimately upon effective interaction of the mitral
apparatus, whose components include the mitral
annulus and leaflets, the subvalvular apparatus, and
left atrial and left ventricular myocardium.32e35
Myxomatous mitral valve degeneration is prevalent
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
injury. The gross pathologic features are associated
with histological remodeling that is characterized
by expansion of the extracellular matrix with
glycosaminoglycans, proteoglycans; alterations in
valvular interstitial cells; attenuation or loss of the
collagen-laden fibrosa layer; and other
changes.19,24,36,102,119 Such alterations lead to
Pathology of canine myxomatous mitral valve disease
mitral valve/mitral apparatus malformation and
biomechanical dysfunction.120,121
Mitral regurgitation is the most common mani-
festation of mxyomatous valve disease. Accord-
ingly, there is need for better quantitative
echoDoppler methods to assess severity of mitral
regurgitation; for more accurate characterization
of pathology-verified imaging features; and to
understand how to recognize pathologic changes
that influence mitral dysfunction, characterize
disease severity, and stratify risk. It remains
unresolved whether, or to what extent, the
underlying pathologic process in MMVD is the same
between breeds of dogs, between canines and
humans, and how these features are related to
aging and genetic factors. Advances in under-
standing valve cell/matrix and molecular biology,
signaling transduction pathways, and gene activa-
tion sequences are essential in order to charac-
terize the fundamental pathobiology- and to
develop effective diagnostic and therapeutic
strategies for valve disease.120e123
Conflict of interest statement
The author has no conflicts of interest.
References
1. Detweiler DK, Luginbühl H, Buchanan JW, Patterson DF.
The natural history of acquired cardiac disability of the
dog. Ann N Y Acad Sci 1968;147:318e329.
2. Detweiler DK, Patterson DF. The prevalence and types of
cardiovascular disease in dogs. Ann N Y Acad Sci 1965;127:
481e586.
3. Das KM, Tashjian RJ. Chronic mitral valve disease in the
dog. Vet Med Small Anim Clin 1965;60:1209e1216.
4. Buchanan JW. Chronic valvular disease (endocardiosis) in
dogs. Adv Vet Sci Comp Med 1977;21:75e106.
5. Buchanan JW. Prevalence of cardiovascular disorders. In:
Fox PR, Sisson D, Moise NS, editors. Textbook of canine and
feline cardiology. Principles and clinical practice. 2nd ed.
Philadelphia: WB Saunders; 1999. p. 455e478.
6. Høier Olsen L, Häggström J, Petersen HD. Acquired valvular
heart disease. In: Ettinger SJ, Feldman EC, editors. 7th ed.,
Textbook of veterinary internal medicine, vol. 2 St Luis:
Saunders Elsevier; 2011. 1299e1219.
7. Haggstrom J, Hoglund H, Borgarelli M. An update on treat-
ment and prognostic indicators in canine myxomatous mitral
valve disease. J Small Anim Pract 2009;50(Suppl. 1):25e33.
8. Sisson D, Kvart C, Darke P. Acquired valvular heart disease
in dogs and cats. In: Fox PR, Sisson D, Moise NS, editors.
Textbook of canine and feline cardiology. Principles and
clinical practice. 2nd ed. Philadelphia: WB Saunders; 1999.
p. 536e565.
9. Borgarelli M, Haggstrom J. Canine degenerative myxoma-
tous mitral valve disease: natural history, clinical
123
presentation and therapy. Vet Clin North Am Small Anim
Pract 2010;40:651e663.
10. Olsen LH, Fredholm M, Pedersen HD. Epidemiology and
inheritance of mitral valve prolapse in Dachshunds. J Vet
Intern Med 1999;13:448e456.
11. Pedersen HD, Haggstrom J. Mitral valve prolapse in the
dog: a model of mitral valve prolapse in man. Cardiovasc
Res 2000;47:234e243.
12. Pedersen HD, Lorentzen KA, Kristensen BO. Echocardio-
graphic mitral valve prolapse in cavalier King Charles
spaniels: epidemiology and prognostic significance for
regurgitation. Vet Rec 1999;144:315e320.
13. Shah PM. Current concepts in mitral valve prolapse e
diagnosis and management. J Cardiol 2010;56:125e133.
14. Egenvall A, Bonnett BN, Olson P, Hedhammar A. Gender,
age, breed and distribution of morbidity and mortality in
insured dogs in Sweden during 1995 and 1996. Vet Rec
2000;146:519e525.
15. Whitney JC. Observation on the effect of age on the
severity of heart valve lesions in the dog. J Small Anim
Pract 1974;15:511e522.
16. Borgarelli M, Savarino P, Crosara S, Santilli RA,
Chiavegato D, Poggi M, Bellino C, La Rosa G, Zanatta R,
Haggstrom J, Tarducci A. Survival characteristics and
prognostic variables of dogs with mitral regurgitation
attributable to myxomatous valve disease. J Vet Intern
Med 2008;22:120e128.
17. Han RI, Black A, Culshaw G, French AT, Corcoran BM.
Structural and cellular changes in canine myxomatous
mitral valve disease: an image analysis study. J Heart
Valve Dis 2010;19:60e70.
18. Hadian M, Corcoran BM, Han RI, Grossmann JG,
Bradshaw JP. Collagen organization in canine myxomatous
mitral valve disease: an x-ray diffraction study. Biophys J
2007;93:2472e2476.
19. Black A, French AT, Dukes-McEwan J, Corcoran BM.
Ultrastructural morphologic evaluation of the phenotype
of valvular interstitial cells in dogs with myxomatous
degeneration of the mitral valve. Am J Vet Res 2005;66:
1408e1414.
20. Han RI, Black A, Culshaw GJ, French AT, Else RW,
Corcoran BM. Distribution of myofibroblasts, smooth
muscle-like cells, macrophages, and mast cells in mitral
valve leaflets of dogs with myxomatous mitral valve
disease. Am J Vet Res 2008;69:763e769.
21. Darke PGG. Valvular incompetence in cavalier King Charles
spaniels. Vet Rec 1987;120:365e366.
22. Beardow AW, Buchanan JW. Chronic mitral valve disease in
Cavalier King Charles Spaniels: 95 cases (1987-1991). J Am
Vet Med Assoc 1993;203:1023e1029.
23. Borgarelli M, Zini E, D’Agnolo G, Tarducci A, Santilli RA,
Chiavegato D, Tursi M, Prunotto M, Häggström J.
Comparison of primary mitral valve disease in German
Shepherd dogs and is small breeds. J Vet Cardiol 2004;6:
27e34.
24. Aupperle H, März I, Thielebein J, Kiefer B, Kappe A,
Schoon HA. Immunonhistochemical characterization of the
extracellular matrix in normal mitral valves and in chronic
valve disease (endocardiosis) in dogs. Res Vet Sci 2009;87:
277e283.
25. Olsen LH, Martinussen T, Pedersen HD. Early echocardio-
graphic predictors of myxomatous mitral valve disease in
Dachshunds. Vet Rec 2003;152:293e297.
26. Swenson L, Häggström J, Kvart C, Juneja RK. Relationship
between parental cardiac status in Cavalier King Charles
Spaniels and prevalence and severity of chronic valvular
124
disease in offspring. J Am Vet Med Assoc 1996;208:
2009e2012.
27. Häggström J, Hansson K, Kvart C, Swenson L. Chronic
valvular disease in the cavalier King Charles Spaniel in
Sweden. Vet Rec 1992;131:549e553.
28. O’Leary CA, Wilkie I. Cardiac valvular and vascular disease
in Bull Terriers. Vet Pathol 2009;46:1149e1155.
29. Borgarelli M, Tarducci A, Zanatta R, Haggstrom J.
Decreased systolic function and inadequate hypertrophy in
large and small breed dogs with chronic mitral valve
insufficiency. J Vet Intern Med 2007;21:61e67.
30. Basso C, Fox PR, Meurs KM, Towbin JA, Spier AW,
Calabrese F, Maron BJ, Thiene G. Arrhythmogenic right
ventricular cardiomyopathy causing sudden cardiac death
in boxer dogs: a new animal model of human disease.
Circulation 2004;109:1180e1185.
31. Hazlett MJ, Maxie MG, Allen DG, Wilcock BP. A retro-
spective study of heart disease in Doberman pinscher dogs.
Can Vet J 1983;24:205e210.
32. Perloff JK, Roberts WK. The mitral apparatus. Functional
anatomy of mitral regurgitation. Circulation 1972;46:
227e239.
33. Tsakiris AG, Von Bernuth G, Rastelli GC, Bourgeois MJ,
Titus JL, Wood EH. Size and motion of the mitral valve
annulus in anesthetized intact dogs. J Appl Physiol 1971;
30:611e618.
34. van Gils FA. The fibrous skeleton in the human heart:
embryological and pathogenetic considerations. Virchows
Arch A Pathol Anat Histol 1981;393:61e73.
35. Silverman ME, Hurst JW. The mitral complex: interaction
of the anatomy, physiology, and pathology of the mitral
annulus, mitral valve leaflets, chordae tendineae, and
papillary muscles. Am Heart J 1968;76:399e418.
36. Fenoglio Jr JJ, -Pham Tuan-Duc, Wit AL, Bassett AL,
Wagner BM. Canine mitral complex: ultrastructure and
electromechanical properties. Circ Res 1972;31:417e430.
37. Dasi LP, Sucosky P, de Zelicourt D, Sundareswaran K,
Jimenez J, Yoganathan AP. Advances in cardiovascular
fluid mechanics: bench to bedside. Ann N Y Acad Sci 2009;
1161:1e25.
38. Frater RWM, Ellis Jr FH. The anatomy of the canine mitral
valve: with notes on function and comparisons with other
mammalian mitral valves. J Surg Res 1961;1:171e179.
39. Sarris GE, Miller DC. Valvulareventricular interaction: the
importance of the mitral chordae tendineae in terms of
global left ventricular systolic function. J Card Surg 1988;
3:215e234.
40. Hansen DE, Cahill PD, Derby GC, Miller DC. Relative
contributions of the anterior and posterior mitral chordae
tendineae to canine global left ventricular systolic func-
tion. J Thorac Cardiovasc Surg 1987;93:45e55.
41. Grande-Allen KJ, Calabro A, Gupta V, Wight TN,
Hascall VC, Vesely I. Glycosaminoglycans and proteogly-
cans in normal mitral valve leaflets and chordae: associa-
tion with regions of tensile and compressive loading.
Glycobiology 2004;14:621e633.
42. Glasson JR, Komeda MK, Daughters GT, Niczyporuk MA,
Bolger AF, Ingels NB, Miller DC. Three-dimensional regional
dynamics of the normal mitral annulus during left
ventricular ejection. J Thorac Cardiovasc Surg 1996;111:
574e585.
43. Anderson RH, Wilcox BR. The anatomy of the mitral valve.
In: Wells FC, Shapiro LM, editors. Mitral valve disease.
Oxford, England: ButterwortheHeinemann; 1996. p. 4.
44. Berdais D, Zund G, Camenisch C, Schurr U, Turina MI,
Genoni M. Annulus fibrosus of the mitral valve: reality or
myth. J Card Surg 2007;22:406e409.
P.R. Fox
45. Schneider RJ, Perrin DP, Vasilyev NV, Marx GR, del Nido PJ,
Howe RD. Mitral annulus segmentation from 3D ultrasound
using graph cuts. IEEE Trans Med Imaging 2010;29:
1676e1687.
46. Fann JI, Ingles NB, Miller DC. Pathophysiology of mitral
valve disease. In: Cohn LH, editor. Cardiac surgery in the
adult. 3rd ed. New York: McGraw-Hill; 2008. p. 973e1012.
47. Evans HE. Miller’s anatomy of the dog. 3rd ed. Phila-
delphia: WB Saunders; 1993. p. 592e597.
48. Kumar N, Kumar M, Duran CM. A revised terminology for
recording surgical findings of the mitral valve. J Heart
Valve Dis 1995;4:70e75.
49. Glasson JR, Komeda M, Daughters 2nd GT, Bolger AF,
MacIsaac A, Oesterle SN, Ingels Jr NB, Miller DC. Three-
dimensional dynamics of the canine mitral annulus during
ischemic mitral regurgitation. Ann Thorac Surg 1996;62:
1059e1068.
50. Levine RA, Handschumacher MD, Sanfilippo AJ, Hagege AA,
Harrigan P, Marshall JE, Weyman AE. Three-dimensional
echocardiographic reconstruction of the mitral valve, with
implications for the diagnosis of mitral valve prolapse.
Circulation 1989;80:589e598.
51. Rodriguez F, Langer F, Harrington KB, Tibayan FA,
Zasio MK, Cheng A, Liang D, Daughters GT, Covell JW,
Criscione JC, Ingels NB, Miller DC. Importance of mitral
valve second-order chordae for left ventricular geometry,
wall thickening mechanics, and global systolic function.
Circulation 2004;110(11 Suppl. 1):115e122.
52. Tsakiris AG, Sturm RE, Wood EH. Experimental studies on
the mechanisms of closure of cardiac valves with use of
roentgen videodensitometry. Am J Cardiol 1973;32:
136e143.
53. Ross Jr J, Sonnenblick EH, Covell JW, Kaiser G, Spiro D.
The architecture of the heart in systole and diastole.
Technique of rapid fixation and analysis of left ventricular
geometry. Circ Res 1967;21:409e421.
54. Tsakiris AG, Gordon DA, Padiyar R, Fréchette D,
Labrosse C. The role of displacement of the mitral annulus
in left atrial filling and emptying in the intact dog. Can J
Physiol Pharmacol 1978;56:447e457.
55. Grewal J, Suri R, Mankad S, Tanaka A, Mahoney DW,
Schaff HV, Miller FA, Enriquez-Sarano M. Mitral annular
dynamics in myxomatous valve disease: new insights with
real-time 3-dimensional echocardiography. Circulation
2010;121:1423e1431.
56. Levine RA, Vlahakes GJ, Lefebvre X, Guerrero JL,
Cape EG, Yoganathan AP, Weyman AE. Papillary muscle
displacement causes systolic anterior motion of the
mitral valve. Experimental validation and insights into
the mechanism of subaortic obstruction. Circulation
1995;91:1189e1195.
57. Yellin EL, Peskin C, Yoran C, Koenigsberg M, Matsumoto M,
Laniado S, McQueen D, Shore D, Frater RW. Mechanisms of
mitral valve motion during diastole. Am J Physiol 1981;
241:H389eH400.
58. Yun KL, Niczyporuk MA, Sarris GE, Fann JI, Miller DC.
Importance of mitral subvalvular apparatus in terms of
cardiac energetics and systolic mechanics in the ejecting
canine heart. J Clin Invest 1991;87:247e254.
59. Hutchins GM, Moore GW, Skoog DK. The association of
floppy mitral valve with disjunction of the mitral annulus
fibrosus. N Engl J Med 1986;314:535e540.
60. Oe M, Asou T, Kawachi Y, Kishizaki K, Fukamachi K,
Sunagawa K, Tokunaga K. Effects of preserving mitral
apparatus on ventricular systolic function in mitral valve
operations in dogs. J Thorac Cardiovasc Surg 1993;106:
1138e1146.
Pathology of canine myxomatous mitral valve disease
61. Clark RE. Anatomic considerations in canine mitral valve
replacement. Am J Vet Res 1972;33:631e633.
62. Shimakura T, Ishihara S, Kawazoe K, Hashimoto A.
Anatomic features in mitral insufficiency and morphology
of the normal mitral valve. Jap J Thoracic Surgery 1978;31:
331e338.
63. Borgarelli M, Tursi M, Rosa GL, Savarino P, Galloni M. Anatomic,
histologic, and two-dimensional-echocardiographic evalua-
tion of mitral valve anatomy in dogs. Am J Vet Res 2011;72:
1186e1192.
64. Lam HC, Ranganathan N, Wigle ED, Silver MD. Morphology
of the human mitral valve, I: chordae tendineae: a new
classification. Circulation 1970;41:449e458.
65. Obadia JF, Casali C, Chassignolle JF, Janier M. Mitral sub-
valvular apparatus: different functions of primary and
secondary chordae. Circulation 1997;96:3124e3128.
66. Nielsen SL, Timek TA, Green GR, Dagum P, Daughters GT,
Hasenkam JM, Bolger AF, Ingels NB, Miller DC. Influence of
anterior mitral leaflet second-order chordae tendineae on
left ventricular systolic function. Circulation 2003;108:
486e491.
67. Lomholt M, Nielsen SL, Hansen SB, Andersen NT,
Hasenkam JM. Differential tension between secondary and
primary mitral chordae in an acute in-vivo porcine model.
J Heart Valve Dis 2002;11:337e345.
68. Kunzelman KS, Cochran RP. Mechanical properties of basal
and marginal mitral valve chordae tendineae. ASAIO Trans
1990;36:M405eM408.
69. Poglajen G, Harlander M, Gersak B. Ex vivo study of altered
mitral apparatus geometry in functional mitral regurgita-
tion. Heart Surg Forum 2010;13:E172eE176.
70. Nazari S, Carli F, Salvi S, Banfi C, Aluffi A, Mourad Z,
Buniva P, Rescigno G. Patterns of systolic stress distribu-
tion on mitral valve anterior leaflet chordal apparatus. A
structural mechanical theoretical analysis. J Cardiovasc
Surg (Torino) 2000;41:193e202.
71. Silbiger JJ, Bazaz R. Contemporary insights into the
functional anatomy of the mitral valve. Am Heart J 2009;
158:887e895.
72. He S, Lemmon Jr JD, Weston MW, Jensen MO, Levine RA,
Yoganathan AP. Mitral valve compensation for annular
dilatation: in vitro study into the mechanisms of functional
mitral regurgitation with an adjustable annulus model.
J Heart Valve Dis 1999;8:294e302.
73. David PE. Papillary muscle-annular continuity: is it
important? J Card Surg 1994;9:252e254.
74. Karas Jr S, Elkins R. Mechanism of function of the
mitral valve leaflets, chordae tendineae and left
ventricular papillary muscles in dogs. Circ Res 1970;26:
689e696.
75. Grimm AF, Lendrum BL, Lin HL. Papillary muscle short-
ening in the intact dog; a cinderadiographic study of
tranquilized dogs in the upright position. Circ Re 1975;36:
49e57.
76. Salter DR, Pellom GL, Murphy CE, Brunsting LA,
Goldstein JP, Morris 3rd JM, Wechsler AS. Papillary-annular
continuity and left ventricular systolic function after
mitral valve replacement. Circulation 1986;74(3 Pt 2):
I121e1129.
77. Dasi LP, Sucosky P, de Zelicourt D, Sundareswaran K,
Jimenez J, Yoganathan AP. Advances in cardiovascular
fluid mechanics: bench to bedside. Ann N Y Acad Sci 2009;
1161:1e25.
78. Liu S-K, Fox PR. Cardiovascular pathology. In: Fox PR,
Sisson D, Moise NS, editors. Textbook of canine and feline
cardiology. Principles and clinical practice. 2nd ed. Phil-
adelphia: WB Saunders; 1999. p. 817e844.
125
79. Corcoran BM, Black A, Anderson H, McEwan JD, French A,
Smith P, Devine C. Identification of surface morphologic
changes in the mitral valve leaflets and chordae tendineae
of dogs with myxomatous degeneration. Am J Vet Res
2004;65:198e206.
80. Ernst VE, Drommer W, Schneider P, Trautwein G. Ele-
tronenmikroskopische untersuchungen zur normalstruktur
der atrioventrikularklappen des hundes. Anat Anz 1973;
134:309e326.
81. Stevanella M, Krishnamurthy G, Votta E, Swanson JC,
Redaelli A, Ingels Jr NB. Mitral leaflet modeling: Impor-
tance of in vivo shape and material properties. J Biomech
2011;44:2229e2235.
82. Kunzelman KS, Cochran RP, Chuong C, Ring WS, Verrier ED,
Eberhart RD. Finite element analysis of the mitral valve.
J Heart Valve Dis 1993;2:326e340.
83. Clark RE. Stress-strain characteristics of fresh and frozen
human aortic and mitral leaflets and chordae tendineae.
Implications for clinical use. J Thorac Cardiovasc Surg
1973;66:202e208.
84. Kunzelman KS, Cochran RP. Stress/strain characteristics of
porcine mitral valve tissue: parallel versus perpendicular
collagen orientation. J Card Surg 1992;7:71e78.
85. May-Newman K, Yin FC. Biaxial mechanical behavior of
excised porcine mitral valve leaflets. Am J Physiol 1995;
269(4 Pt 2):H1319eH1327.
86. Millington-Sanders C, Meir A, Lawrence L, Stolinski C.
Structure of chordae tendineae in the left ventricle of the
human heart. J Anat 1998;192(Pt 4):573e581.
87. Rossi MA, Abreu MA, Santoro LB. Images in cardiovascular
medicine. Connective tissue skeleton of the human heart:
a demonstration by cell-maceration scanning electron
microscope method. Circulation 1998;97:934e935.
88. Culshaw GJ, French AT, Han RI, Black A, Pearson GT,
Corcoran BM. Evaluation of innervation of the mitral valves
and the effects of myxomatous degeneration in dogs. Am J
Vet Res 2010;71:194e202.
89. Timek TA, Lai DT, Dagum P, Tibayan F, Daughters GT,
Liang D, Berry GJ, Miller DC, Ingels Jr NB. Ablation of
mitral annular and leaflet muscle: effects on annular and
leaflet dynamics. Am J Physiol Heart Circ Physiol 2003;
285(4):H1668eH1674.
90. Gumusalan Y, Ozbag D, Ozden H, Saruhan BG, Demirant A.
The comparative investigation of left ventricle papillary
muscle arteries in different species. Saudi Med J 2006;27:
826e832.
91. Ritchie J, Warnock JN, Yoganathan AP. Structural charac-
terization of the chordae tendineae in native porcine
mitral valves. Ann Thorac Surg 2005;80:189e197.
92. Ullal SR, Kluge TH, Kerth WJ, Gerbode F. Anatomical
studies on lymph drainage of the heart in dogs. Ann Surg
1972;175:305e310.
93. Shimada T, Morita T, Oya M, Kitamura H. Morphological
studies of the cardiac lymphatic system. Arch Histol Cytol
1990;53(Suppl.):115e126.
94. Noguchi T, Shimada T, Nakamura M, Uchida Y, Shirabe J. The
distribution and structure of the lymphatic system in dog
atrioventricular valves. Arch Histol Cytol 1988;51:361e370.
95. Uhley HN, Leeds SE. Lymphatics of the canine papillary
muscles. Lymphology 1976;9:72e74.
96. Eliskova M, Oldrich E. How lymph is drained away from the
human papillary muscle: anatomical conditions. Cardi-
ology 1992;81:371e377.
97. Kogure K. Pathology of chronic mitral valvular disease in
the dog. Jpn J Vet Sci 1980;42:323e335.
98. Ettinger S, Buergelt CD. Ruptured chordae tendineae in
the dog. J Am Vet Med Assoc 1969;155:535e546.
126
99. Serres F, Chetboul V, Tissier R, Sampedrano CC, Gouni V,
Nicolle AP, Pouchelon JL. Chordae tendineae rupture in
dogs with degenerative mitral valve disease: prevalence,
survival, and prognostic factors (114 cases, 2001e2006).
J Vet Intern Med 2007;21:258e264.
100. Whitney JC. Cardiovascular pathology. J Small Anim Pract
1967;8:459e465.
101. Pomerance A, Whitney JC. Heart valve changes common to
man and dog: a comparative study. Cardiovasc Res 1970;4:
61e66.
102. Rabkin-Aikawa E, Farber M, Aikawa M, Schoen FJ. Dynamic
and reversible changes of interstitial cell phenotype
during remodeling of cardiac valves. J Heart Valve Dis
2004;13:841e847.
103. Jacobs GJ, Calvert CA, Mahaffey MB, Hall DG. Echocar-
diographic detection of flail left atrioventricular valve
cusp from ruptured chordae tendineae in 4 dogs. J Vet
Intern Med 1995t;9:341e346.
104. Barber JE, Ratliff NB, Cosgrove 3rd DM, Griffin BP, Vesely I.
Myxomatous mitral valve chordae. I: Mechanical proper-
ties. J Heart Valve Dis 2001;10:320e324.
105. Kimura N, Shukunami C, Hakuno D, Yoshioka M, Miura S,
Docheva D, Kimura T, Okada Y, Matsumura G, Shinoka T,
Yozu R, Kobayashi J, Ishibashi-Ueda H, Hiraki Y, Fukuda K.
Local tenomodulin absence, angiogenesis, and matrix
metalloproteinase activation are associated with the
rupture of the chordae tendineae cordis. Circulation 2008;
118:1737e1747.
106. Sasayama S, Takahashi M, Kawai C. Left atrial function in
acute mitral regurgitation. Factors which modify the
regurgitant volume. Herz 1981;6:156e165.
107. Sasayama S, Takahashi M, Osakada G, Hirose K,
Hamashima H, Nishimura E, Kawai C. Dynamic geometry of
the left atrium and left ventricle in acute mitral regurgi-
tation. Circulation 1979;60:177e186.
108. Yun KL, Fann JI, Rayhill SC, Nasserbakht F, Derby GC,
Handen CE, Bolger AF, Miller DC. Importance of the mitral
subvalvular apparatus for left ventricular segmental
systolic mechanics. Circulation 1990;82(5 Suppl):IV89e104.
109. Buchanan JW, Kelly AM. Endocardial splitting of the left
atrium in the dog with hemorrhage and hemopericardium.
J Am Vet Rad Soc 1964;5:28e39.
110. Buchanan JW. Spontaneous left atrial rupture in dogs. In:
Bloor CM, editor, Comparative pathophysiology of
Available online at www.sciencedirect.com
P.R. Fox
circulatory disturbances, vol. 22. New York: Plenum Press;
1976. p. 315.
111. Buchanan JW. Spontaneous left atrial rupture in dogs. Adv
Exp Med Biol 1972;22:315e334.
112. Stünzi H, Ammann-Mann M. Nontraumatic ruptures of the
heart atrium in the dog. Zentralbl Veterinarmed A 1973;
20:409e418.
113. Komitor DA. Left atrial rupture. Infrequent sequel t
chronic microvalvular insufficiency. Vet Med Small Anim
Clinic 1976;71:620e621.
114. Jugdutt BI. Effect of nitroglycerin and ibuprofen on left
ventricular topography and rupture threshold during
healing after myocardial infarction in the dog. Can J
Physiol Pharmacol 1988;66:385e395.
115. Jugdutt BI. Left ventricular rupture threshold during the
healing phase after myocardial infarction in the dog. Can J
Physiol Pharmacol 1987;65:307e316.
116. Sadanaga KK, McDonald MJ, Buchanan JW. Echocardiog-
raphy and surgery in a dog with left atrial rupture and
hemopericardium. J Vet Intern Med 1990;4:216e221.
117. McCarthy PM, Lee R, Foley JL, Phillips L, Kanayinkal T,
Francischelli DE. Occlusion of canine atrial appendage
using an expandable silicone band. J Thorac Cardiovasc
Surg 2010;140:885e889.
118. Peddle GD, Buchanan JW. Acquired atrial septal defects
secondary to rupture of the atrial septum in dogs with
degenerative mitral valve disease. J Vet Cardiol 2010;12:
129e134.
119. Grande-Allen KJ, Griffin BP, Ratliff NB, Cosgrove DM,
Vesely I. Glycosaminoglycan profiles of myxomatous mitral
leaflets and chordae parallel the severity of mechanical
alterations. J Am Coll Cardiol 2003;42:271e277.
120. Xu S, Grande-Allen KJ. The role of cell biology and leaflet
remodeling in the progression of heart valve disease.
Methodist Debakey Cardiovasc J 2010;6:2e7.
121. Schoen FJ. Mechanisms of function and disease of natural
and replacement heartvalves. Annu Rev Pathol 2012;7:
161e183.
122. Durbin AD, Gotlieb AI. Advances towards understanding
heart valve response to injury. Cardiovasc Pathol 2002;11:
69e77.
123. Mendelson K, Schoen FJ. Heart valve tissue engineering:
concepts, approaches, progress, and challenges. Ann Bio-
med Eng 2006;34:1799e1819.