Valvular disease

Basic Science and Forensic
Pathology Aspects of Valvular Heart
Disease
Luchenga Adam Mucheleng’anga
Clinical Fellow of Forensic Pathology
University of Toronto.

Disclaimer
This is not original work as it is book lifted from the
books listed at the end. This material is study notes
The PowerPoint is meant to ease the learning
process.

• THE BASIC SCIENCE OF VALVULAR
HEART DISEASE

The Basic
Science of
Valvular
Heart Disease
• Valvular Heart Disease
• Valvular disease can come to clinical
attention due to stenosis, insufficiency
(synonyms: regurgitation or incompetence),
or both.
• Stenosis is the failure of a valve to open
completely, which impedes forward ﬂow.
• Insufficiency results from failure of a valve
to close completely, thereby allowing
reversed ﬂow.
• These abnormalities can be present alone or
coexist, and may involve only a single valve,
or more than one valve.

The Basic
Science of
Valvular
Heart
Disease
VALVULAR HEART DISEASE FUNCTIONAL
REGURGITATION IS USED TO
DESCRIBE THE
INCOMPETENCE OF A VALVE
STEMMING FROM AN
ABNORMALITY IN ONE OF
ITS SUPPORT STRUCTURES,
AS OPPOSED TO A PRIMARY
VALVE DEFECT.
FOR EXAMPLE, DILATION OF
THE RIGHT OR LEFT
VENTRICLE CAN PULL THE
VENTRICULAR PAPILLARY
MUSCLES DOWN AND
OUTWARD, THEREBY
PREVENTING PROPER
CLOSURE OF OTHERWISE
NORMAL MITRAL OR
TRICUSPID LEAﬂETS.
FUNCTIONAL MITRAL VALVE
REGURGITATION IS
PARTICULARLY COMMON
AND CLINICALLY
IMPORTANT IN IHD, AS
WELL AS IN DILATED
CARDIOMYOPATHY.

The Basic
Science of
Valvular
Heart
Disease
Valvular Heart Disease The clinical
consequences of valve
dysfunction vary
depending on the valve
involved, the degree of
impairment, the tempo
of disease onset, and
the rate and quality of
compensatory
mechanisms.
For example, sudden
destruction of an aortic
valve cusp by infection
(infective endocarditis)
can cause acute,
massive, and rapidly
fatal regurgitation.
In contrast, rheumatic
mitral stenosis typically
develops indolently over
years, and its clinical
effects can be well
tolerated for extended
periods.
Certain conditions can
complicate valvular
heart disease by
increasing the demands
on the heart; for
example, the increased
output demands of
pregnancy can
exacerbate valve
disease and lead to
unfavourable maternal
or fetal outcomes.

The Basic
Science of
Valvular
Heart
Disease
Valvular Heart Disease
Valvular stenosis or insufficiency often produces
secondary changes, both proximal and distal to the
affected valve, particularly in the myocardium.
Generally, valvular stenosis leads to pressure
overload cardiac hypertrophy, whereas mitral or
aortic valvular insufficiency leads to volume
overload; both situations can culminate in heart
failure.
In addition, the ejection of blood through narrowed
stenotic valves can produce high speed “jets” of
blood that injure the endocardium where they
impact.

The Basic
Science of
Valvular
Heart
Disease
Valvular abnormalities can be congenital or acquired.
Acquired valvular stenosis has relatively few causes; it is
almost always a consequence of a remote or chronic injury of
the valve cusps that declares itself clinically only after many
years.
In contrast, acquired valvular insufficiency can result from
intrinsic disease of the valve cusps or damage to or distortion
of the supporting structures (e.g., the aorta, mitral annulus,
tendinous cords, papillary muscles, ventricular free wall).
Thus, valvular insufficiency has many causes and may appear
acutely, as with rupture of the cords, or chronically in
disorders associated with leaﬂet scarring and retraction.

The Basic
Science of
Valvular
Heart
Disease
The most frequent causes of the major
functional valvular lesions are:
Aortic stenosis: calcification and sclerosis of
anatomically normal or congenitally bicuspid
aortic valves
Aortic insufficiency: dilation of the ascending
aorta, often secondary to hypertension and/or
aging
Mitral stenosis: rheumatic heart disease
Mitral insufficiency: myxomatous degeneration
(mitral valve prolapse)

The Basic
Science of
Valvular
Heart Disease
• Calcific Valvular Degeneration
• Heart valves are subjected to
high levels of repetitive
mechanical stress, particularly at
the hinge points of the cusps and
leaﬂets; this is a consequence of
• 30 to 40 million or more
cardiac contractions per
year
• Substantial tissue
deformations during each
contraction
• Transvalvular pressure
gradients in the closed
phase of each contraction
of approximately 120 mm
Hg for the mitral and 80
mm Hg for the aortic
valve.
• It is therefore not surprising that
these delicate structures can
suffer cumulative damage and
calcification that lead to clinically
important dysfunction.

The Basic Science of Valvular Heart
Disease
• Heart valves are subjected to high levels of repetitive mechanical stress,
particularly at the hinge points of the cusps and leaﬂets; this is a
consequence of
• 30 to 40 million or more cardiac contractions per year
• Substantial tissue deformations during each contraction
• Transvalvular pressure gradients in the closed phase of each
contraction of approximately 120 mm Hg for the mitral and 80 mm
Hg for the aortic valve.
• It is therefore not surprising that these delicate structures can suffer
cumulative damage and calcification that lead to clinically important
dysfunction.
• Calcifc Aortic Stenosis
• The most common of all valvular abnormalities, calcifc

The Basic
Science of
Valvular
Heart
Disease
Calcific Valvular Degeneration
Calcific Aortic Stenosis
The most common of all valvular abnormalities, calcific aortic
stenosis is usually the consequence of age-associated “wear
and tear” of either anatomically normal valves or congenitally
bicuspid valves (in approximately 1% of the population).
The prevalence of aortic stenosis is estimated at 2% and is
increasing as the general population ages.
Aortic stenosis of previously normal valves (termed senile
calcific aortic stenosis) usually comes to clinical attention in the
seventh to ninth decades of life, whereas stenotic bicuspid
valves tend to become clinically significant 1 to 2 decades
earlier.

The Basic
Science of
Valvular
Heart
Disease
Aortic valve calcification is likely a consequence of recurrent
chronic injury due to hyperlipidaemia, hypertension,
inﬂammation, and other factors similar to those implicated in
atherosclerosis.
Bicuspid valves incur greater mechanical stress than normal
tricuspid valves, which may explain their accelerated stenosis.
The chronic progressive injury leads to valvular degeneration
and incites the deposition of hydroxyapatite (the same
calcium salt found in bone).
Although this model provides a good starting point for
understanding calcific degeneration, it is increasingly clear
that the valve injury of calcific aortic stenosis differs in some
important respects from atherosclerosis.

The Basic
Science of
Valvular
Heart
Disease
Most notably, the abnormal valves
contain cells resembling osteoblasts that
synthesize bone matrix proteins and
promote the deposition of calcium salts.
Moreover, interventions that improve
atherosclerotic risk (e.g., statins), do not
appear to significantly impact valvular
calcific degeneration.

The Basic
Science of
Valvular
Heart
Disease
MORPHOLOGY
The gross morphologic hallmark of nonrheumatic, calcific
aortic stenosis (involving either tricuspid or bicuspid valves)
is mounded calcified masses within the aortic cusps that
ultimately protrude through the outﬂow surfaces into the
sinuses of Valsalva, and prevent cuspal opening.
The free edges of the cusps are usually not involved.

Calcific aortic
stenosis of a
previously normal
valve (viewed from
aortic aspect).
Nodular masses
of calcium are
heaped up
within the
sinuses of
Valsalva (arrow).
Note that the
commissures are
not fused, as
occurs with
post-rheumatic
aortic valve
stenosis

The Basic
Science of
Valvular
Heart
Disease
MORPHOLOGY
Microscopically, the layered architecture of the valve is
largely preserved.
The calcific process begins in the valvular fibrosa on
the outflow surface of the valve, at the points of
maximal cusp flexion (near the margins of attachment).
Inflammation is variable, and metaplastic bone (and even
bone marrow) may be seen.

The Basic
Science of
Valvular
Heart
Disease
MORPHOLOGY
In aortic stenosis, the functional valve area is
decreased by large nodular calcific deposits that can
eventually cause measurable outﬂow obstruction; this
subjects the left ventricular myocardium to progressively
increasing pressure overload.
In contrast to rheumatic (and congenital) aortic stenosis,
commissural fusion is not usually seen.

Surgically resected
specimen of
rheumatic aortic
stenosis,
demonstrating
thickening and
distortion of the
cusps with
commissural fusion

The Basic
Science of
Valvular
Heart
Disease
• Calcific Aortic Stenosis
• MORPHOLOGY
• The mitral valve is generally
normal, although some patients
may have direct extension of
aortic valve calcific deposits
onto the anterior mitral leaﬂet.
• In contrast, virtually all
patients with rheumatic aortic
stenosis also have concomitant
and characteristic structural
abnormalities of the mitral
valve.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
In calcific aortic stenosis (superimposed on a previously normal or
bicuspid aortic valve), the obstruction to left ventricular outﬂow leads to
gradual narrowing of the valve orifice (valve area approximately 0.5 to 1
cm2 in severe aortic stenosis; normal approximately 4 cm2) and an
increasing pressure gradient across the calcified valve, reaching 75 to 100
mm Hg in severe cases.
Left ventricular pressures rise to 200 mm Hg or more in such instances,
producing concentric left ventricular (pressure overload) hypertrophy.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
The hypertrophied myocardium tends to be ischemic
(as a result of diminished microcirculatory perfusion,
often complicated by coronary atherosclerosis), and
angina pectoris may occur.
Both systolic and diastolic myocardial function may
be impaired; eventually, cardiac decompensation and
CHF can ensue.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
The onset of symptoms (angina, CHF, or syncope) in
aortic stenosis heralds cardiac decompensation and
carries an extremely poor prognosis.
If untreated, most patients with aortic stenosis will die
within 5 years of developing angina, within 3 years of
developing syncope, and within 2 years of CHF onset.
Treatment requires surgical valve replacement, as
medical therapy is ineffective in severe symptomatic
aortic stenosis.

The Basic
Science of
Valvular
Heart
Disease
Calcific Stenosis of Congenitally Bicuspid Aortic
Valve
Bicuspid aortic valve (BAV) is a developmental
abnormality with prevalence in the population of
approximately 1%.
Some cases of BAV show familial clustering, often
with associated aorta or left ventricular outﬂow
tract malformations.
While the heritability of BAV is well-established,
and three loci on chromosomes 18q, 5q, and 13q
have been identified in kindred studies, the
specific genes that are responsible for the disorder
remain largely unknown.

The Basic
Science of
Valvular
Heart
Disease
Calcific Stenosis of Congenitally Bicuspid Aortic Valve
Thus far, only loss-of-function mutations in NOTCH1
(mapping to chromosome 9q34.3) have been specifically
associated with BAV in a few families; tantalizingly,
modulation of Notch activity in animal models also impacts
valvular calcification.
In a congenitally bicuspid aortic valve, there are only two
functional cusps, usually of unequal size, with the larger
cusp having a midline raphe, resulting from incomplete
commissural separation during development; less
frequently the cusps are of equal size and the raphe is
absent.
The raphe is frequently a major site of calcific deposits.

The Basic
Science of
Valvular
Heart
Disease
Calcific Stenosis of Congenitally Bicuspid Aortic Valve
Once stenosis is present, the clinical course is similar to
that described earlier for calcific aortic stenosis.
Valves that become bicuspid because of an acquired
deformity (e.g., rheumatic valve disease) have a fused
commissure that produces a conjoined cusp that is
generally twice the size of the nonconjoined cusp.
BAVs may also become incompetent as a result of aortic
dilation, cusp prolapse, or infective endocarditis.
The mitral valve is generally normal in patients with a
congenitally bicuspid aortic valve.

The Basic
Science of
Valvular
Heart
Disease
Calcific Stenosis of Congenitally Bicuspid Aortic
Valve
Although BAV is usually asymptomatic early in life,
late complications include aortic stenosis or
regurgitation, infective endocarditis, and aortic
dilation and/or dissection.
In particular, BAVs are predisposed to progressive
calcification, similar to that occurring in aortic
valves with initially normal anatomy; calcified BAV
comprise approximately 50% of cases of aortic
stenosis in adults.
Structural abnormalities of the aortic wall also
commonly accompany BAV, even when the valve is
hemodynamically normal, and this may potentiate
aortic dilation or aortic dissection.

Calcific aortic
stenosis of a
congenitally
bicuspid valve.
One cusp has
a partial
fusion at its
centre, called
a raphe (arrow).

The Basic
Science of
Valvular
Heart
Disease
Mitral Annular Calcification
As opposed to the predominantly cuspal
involvement in aortic valve calcification,
degenerative calcific deposits in the mitral valve
typically develop in the fibrous annulus.
Grossly, these appear as irregular, stony hard,
occasionally ulcerated nodules (2 to 5 mm in
thickness) at the base of the leaﬂets.
Mitral annular calcification usually does not affect
valvular function.

Mitral annular calcification, with calcific nodules at the base
(attachment margin) of the anterior mitral leaﬂet (arrows).
Cut section of myocardium showing the lateral wall with dense
calcification that extends into the underlying myocardium (arrow).

The Basic Science of Valvular
Heart Disease
Mitral Annular Calcifcation
However, in exceptional cases it can lead to:
• Regurgitation by interfering with physiologic contraction of the
valve ring
• Stenosis by impairing opening of the mitral leaﬂets
• Arrhythmias and occasionally sudden death by penetration of
calcium deposits to a depth sufficient to impinge on the
atrioventricular conduction system.

The Basic
Science of
Valvular
Heart
Disease
Mitral Annular Calcification
Because calcific nodules may also provide a site for thrombus
formation, patients with mitral annular calcification have an
increased risk of embolic stroke, and the calcific nodules can
become a nidus for infective endocarditis.
Heavy calcific deposits are sometimes visualized on
echocardiography or seen as distinctive, ring-like opacities on
chest radiographs.
Mitral annular calcification is most common in women older
than age 60 and individuals with mitral valve prolapse.

The Basic
Science of
Valvular
Heart
Disease
Mitral Valve Prolapse (Myxomatous
Degeneration of the Mitral Valve)
In mitral valve prolapse (MVP), one
or both mitral valve leaﬂets are
“ﬂoppy” and prolapse, or balloon
back, into the left atrium during
systole.
Most often an incidental finding on
physical examination, but in a small
minority of affected individuals may
lead to serious complications.

The Basic
Science of
Valvular
Heart
Disease
Mitral Valve Prolapse (Myxomatous Degeneration
of the Mitral Valve)
Pathogenesis.
The etiologic basis for the changes that weaken
the valve leaﬂets and associated structures is
unknown in most cases.
Uncommonly, MVP is associated with heritable
disorders of connective tissue including Marfan
syndrome, caused by fbrillin-1 (FBN-1) mutations.
Fibrillin-1 defects alter cell-matrix interactions and
dysregulate TGF-β signaling.

The Basic
Science of
Valvular
Heart
Disease
Mitral Valve Prolapse (Myxomatous Degeneration of the
Mitral Valve)
Pathogenesis.
Interestingly, mice with mutated FBN-1 develop a form of
mitral valve prolapse that is prevented by TGF-β inhibitors,
indicating that excess TGF-β activity can cause the
characteristic structural laxity and myxomatous changes.
Whether similar mechanisms contribute to sporadic MVP is
unknown.
Genetic linkage analyses have also mapped inherited forms
of MVP to loci involved in the remodelling of valvular
extracellular matrix and cell cell adhesion.

The Basic
Science of
Valvular
Heart
Disease
Mitral Valve Prolapse (Myxomatous Degeneration of the
Mitral Valve)
Clinical Features.
Most individuals diagnosed with MVP are asymptomatic;
in such cases, the condition is discovered incidentally by
auscultation of mid-systolic clicks, sometimes followed by
a mid to late systolic murmur.
The diagnosis is confirmed by echocardiography.
A minority of patients have chest pain mimicking angina
(although not exertional in nature), and a subset has
dyspnea, presumably related to valvular insufficiency.

The Basic
Science of
Valvular
Heart
Disease
Mitral Valve Prolapse
(Myxomatous Degeneration of
the Mitral Valve)
Clinical Features.
Although the great majority of
persons with MVP have no
untoward effects, approximately
3% develop one of four serious
complications:
infective endocarditis
mitral insufficiency, sometimes
with chordal rupture
stroke or other systemic infarct,
resulting from embolism of
leaﬂet thrombi;
arrhythmias, both ventricular
and atrial.

The Basic
Science of
Valvular
Heart
Disease
Mitral Valve Prolapse (Myxomatous Degeneration
of the Mitral Valve)
Clinical Features.
Rarely, MVP is the only finding in sudden cardiac
death.
The risk of serious complications is very low in MVP
discovered incidentally in young asymptomatic
patients; the risk is higher for men, older patients,
and those with arrhythmias or mitral regurgitation.
Valve repair or replacement surgery can be done for
symptomatic patients or those with increased risk
for significant complications.

The Basic
Science of
Valvular
Heart
Disease
Rheumatic Fever and Rheumatic Heart Disease
Rheumatic fever (RF) is an acute, immunologically
mediated, multisystem inﬂammatory disease classically
occurring a few weeks after an episode of group A
streptococcal pharyngitis; occasionally, RF can follow
streptococcal infections at other sites, such as the skin.
Acute rheumatic carditis is a common manifestation of
active RF and may progress over time to chronic
rheumatic heart disease (RHD), mainly manifesting as
valvular abnormalities.
RHD is characterized principally by deforming fibrotic
valvular disease, particularly involving the mitral valve;
indeed, RHD is virtually the only cause of mitral stenosis.

The Basic
Science of
Valvular
Heart
Disease
Pathogenesis.
Acute rheumatic fever results from host immune responses to
group A streptococcal antigens that cross-react with host
proteins.
In particular, antibodies and CD4+ T cells directed against
streptococcal M proteins can also in some cases recognize
cardiac self-antigens.
Antibody binding can activate complement, as well as recruit
Fc-receptor bearing cells (neutrophils and macrophages);
cytokine production by the stimulated T cells leads to
macrophage activation (e.g., within Aschoff bodies).
Damage to heart tissue may thus be caused by a combination
of antibody- and T cell–mediated reactions.

The Basic
Science of
Valvular
Heart
Disease
Morphology
During acute RF, focal inﬂamatory lesions are
found in various tissues.
Distinctive lesions occur in the heart, called
Aschoff bodies, consisting of foci of T
lymphocytes, occasional plasma cells, and plump
activated macrophages called Anitschkow cells
(pathognomonic for RF).
These macrophages have abundant cytoplasm
and central round-to-ovoid nuclei (occasionally
binucleate) in which the chromatin condenses
into a central, slender, wavy ribbon (hence the
designation “caterpillar cells”).

The Basic
Science of
Valvular
Heart
Disease
Morphology
During acute RF, diffuse inﬂammation and
Aschoff bodies may be found in any of the
three layers of the heart, resulting in pericarditis,
myocarditis, or endocarditis (pancarditis).
Inﬂammation of the endocardium and the left-
sided valves typically results in fibrinoid necrosis
within the cusps or tendinous cords.
Overlying these necrotic foci and along the lines
of closure are small (1 to 2 mm) vegetations,
called verrucae.

The Basic
Science of
Valvular
Heart
Disease
Morphology
Thus, RHD is one of the forms of
vegetative valve disease, each of which
exhibit their own characteristic
morphologic features .
Subendocardial lesions, perhaps exacerbated
by regurgitant jets, can induce
irregular thickenings called MacCallum
plaques, usually in the left atrium.

The rheumatic fever
phase of rheumatic
heart disease (RHD)
is marked by small,
warty vegetations
along the lines of
closure of the
valve leaﬂets

The Basic
Science of
Valvular
Heart
Disease
Morphology
The cardinal anatomic changes of the mitral valve in
chronic RHD are leaﬂet thickening, commissural fusion and
shortening, and thickening and fusion of the tendinous cords.
In chronic disease the mitral valve is virtually
always involved.
The mitral valve is affected in isolation in roughly
two thirds of RHD, and along with the aortic valve
in another 25% of cases.
Tricuspid valve involvement is infrequent, and the
pulmonary valve is only rarely affected.

Thickening tendineae.
Note
neovascularization
of anterior mitral
leaﬂet
(arrow).

The Basic
Science of
Valvular
Heart
Disease
Morphology
Tricuspid valve involvement is infrequent, and the
pulmonary valve is only rarely affected.
Because of the increase in calcific aortic stenosis
and the reduced frequency of RHD, rheumatic aortic
stenosis now accounts for a small fraction of
cases of acquired aortic stenosis.
In rheumatic mitral stenosis, calcification and fibrous
bridging across the valvular commissures create “fish
mouth” or “buttonhole” stenoses.

The Basic
Science of
Valvular
Heart
Disease
• Rheumatic Fever and
Rheumatic Heart Disease
• Morphology
• With tight mitral
stenosis, the left
atrium progressively
dilates and may
harbor mural thrombi
that can embolize.
• Long-standing congestive
changes in the lungs
may induce pulmonary
vascular and
parenchymal changes;
over time, these can
lead to right
ventricular hypertrophy.
• The left ventricle is
largely unaffected by
isolated pure mitral
stenosis.

The Basic
Science of
Valvular
Heart
Disease
Morphology
Microscopically, valves show organization of
the acute inflammation, with post-
inflammatory neovascularization and
transmural fibrosis that obliterate the
leaflet architecture.
Aschoff bodies are rarely seen in surgical
specimens or autopsy tissue from patients
with chronic RHD, as a result of the long
intervals between the initial insult and
the development of the chronic deformity.

Acute rheumatic mitral
valvulitis superimposed
on chronic rheumatic
heart disease.
Small vegetations
(verrucae) are visible
along the line of
closure of the mitral
valve leaﬂet (arrows).
Previous episodes of
rheumatic valvulitis
have caused fibrous
thickening and fusion of
the chordae tendineae.

Microscopic appearance
of an Aschoff body in
a patient with acute
rheumatic carditis.
The myocardium
exhibits a
circumscribed nodule
of mixed mononuclear
inﬂammatory cells with
associated necrosis;
within the
inﬂammation, large
activated macrophages
show prominent
nucleoli, as well as
chromatin condensed
into long, wavy
ribbons (caterpillar
cells; arrows).

The Basic
Science of
Valvular
Heart
Disease
• Rheumatic Fever and
Rheumatic Heart Disease
• Clinical Features.
• RF is characterized by a
constellation of findings:
• Migratory
polyarthritis of the
large joints
• Pancarditis
• Subcutaneous
nodules
• Erythema
marginatum of the
skin
• Sydenham chorea, a
neurologic disorder
with involuntary
rapid, purposeless
movements.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
The diagnosis is established by the so-called Jones criteria: evidence of a
preceding group A streptococcal infection, with the presence of two of
the major manifestations listed earlier or one major and two minor
manifestations (non-specific signs and symptoms that include fever,
arthralgia, or elevated blood levels of acute phase reactants).
Acute RF typically appears 10 days to 6 weeks after a group A
streptococcal infection in about 3% of patients.
It occurs most often in children between ages 5 and 15, but first attacks
can occur in middle to later life.

The Basic
Science of
Valvular
Heart
Disease
Arthritis typically begins with migratory polyarthritis (accompanied by fever)
in which one large joint after another becomes painful and swollen for a
period of days and then subsides spontaneously, leaving no residual
disability.
The predominant clinical manifestations are carditis and arthritis, the latter
more common in adults than in children.
Although pharyngeal cultures for streptococci are negative by the time the
illness begins, antibodies to one or more streptococcal enzymes, such as
streptolysin O and DNase B, can be detected in the sera of most patients with
RF.
Clinical Features.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
Clinical features related to acute carditis include pericardial
friction rubs, tachycardia, and arrhythmias.
Myocarditis can cause cardiac dilation that may culminate in
functional mitral valve insufficiency or even heart failure.
Approximately 1% of affected individuals die of fulminant RF
involvement of the heart.
After an initial attack there is increased vulnerability to
reactivation of the disease with subsequent pharyngeal
infections, and the same manifestations are likely to appear
with each recurrent attack.

The Basic
Science of
Valvular
Heart
Disease
Rheumatic Fever and
Rheumatic Heart
Disease
Clinical Features.
Damage to the valves is
cumulative.
Turbulence induced by
ongoing valvular
deformities leads to
additional fibrosis.
Clinical manifestations
appear years or even
decades after the initial
episode of RF and
depend on which
cardiac valves are
involved.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
In addition to various cardiac murmurs, cardiac hypertrophy
and dilation, and heart failure, individuals with chronic RHD
may suffer from arrhythmias (particularly atrial fibrillation in
the setting of mitral stenosis), thromboembolic
complications, and infective endocarditis.
The long-term prognosis is highly variable.
Surgical repair or prosthetic replacement of diseased valves
has greatly improved the outlook for persons with RHD.

The Basic
Science of
Valvular
Heart
Disease
Infective Endocarditis
Infective endocarditis (IE) is a microbial infection of the
heart valves or the mural endocardium that leads to the
formation of vegetations composed of thrombotic debris
and organisms, often associated with destruction of the
underlying cardiac tissues.
The aorta, aneurysms, other blood vessels, and
prosthetic devices can also become infected.
Although fungi and other classes of microorganisms can
be responsible, most infections are bacterial (bacterial
endocarditis).

The Basic
Science of
Valvular
Heart
Disease
Prompt diagnosis, identification of the offending
agent, and effective treatment of IE is important in
limiting morbidity and mortality.
Traditionally, IE has been classified on clinical
grounds into acute and subacute forms.
This subdivision reﬂects the range of the disease
severity and tempo, which are determined in large
part by the virulence of the infecting microorganism
and whether underlying cardiac disease is present.

The Basic
Science of
Valvular
Heart
Disease
Acute infective endocarditis is typically caused by
infection of a previously normal heart valve by a highly
virulent organism (e.g., Staphylococcus aureus) that
rapidly produces necrotizing and destructive lesions.
These infections may be difficult to cure with antibiotics
alone, and usually require surgery.
Despite appropriate treatment, death can ensue within
days to weeks.

The Basic
Science of
Valvular
Heart
Disease
In contrast, subacute IE is characterized
by organisms with lower virulence (e.g.,
viridans streptococci) that cause
insidious infections of deformed valves
with overall less destruction.
In such cases the disease may pursue a
protracted course of weeks to months,
and cures can be achieved with
antibiotics.

The Basic
Science of
Valvular
Heart
Disease
Pathogenesis.
Although highly virulent organisms can infect previously
normal valves, a variety of cardiac and vascular abnormalities
increase the risk of developing IE.
Rheumatic heart disease with valvular scarring has historically
been the major antecedent disorder; as RHD becomes less
common, it has been supplanted by mitral valve prolapse,
degenerative calcific valvular stenosis, bicuspid aortic valve
(whether calcified or not), artificial (prosthetic) valves, and
unrepaired and repaired congenital defects.

The Basic
Science of
Valvular
Heart
Disease
Pathogenesis.
The causal organisms differ among the major high-risk groups.
Endocarditis of native but previously damaged or otherwise
abnormal valves is caused most commonly (50% to 60% of
cases) by Streptococcus viridans, a normal component of the
oral cavity ﬂora.
In contrast, more virulent S. aureus organisms commonly found
on the skin can infect either healthy or deformed valves and
are responsible for 20% to 30% of cases overall; notably, S.
aureus is the major offender in IE among intravenous drug
abusers.

The Basic
Science of
Valvular
Heart
Disease
Pathogenesis.
Other bacterial causes include enterococci and the
so-called HACEK group (Haemophilus,
Actinobacillus, Cardiobacterium, Eikenella, and
Kingella), all commensals in the oral cavity.
Prosthetic valve endocarditis is caused most
commonly by coagulase-negative staphylococci
(e.g., S. epidermidis).
Other agents causing endocarditis include gram-
negative bacilli and fungi.

The Basic
Science of
Valvular
Heart
Disease
Pathogenesis.
In about 10% of all cases of endocarditis, no organism
can be isolated from the blood (“culture negative”
endocarditis); reasons include prior antibiotic therapy,
difficulties in isolating the offending agent, or because
deeply embedded organisms within the enlarging
vegetation are not released into the blood.
Foremost among the factors predisposing to endocarditis
are those that cause microorganism seeding into the
blood stream (bacteremia or fungemia).

The Basic
Science of
Valvular
Heart
Disease
Pathogenesis.
The source may be an obvious infection
elsewhere, a dental or surgical procedure, a
contaminated needle shared by intravenous drug
users, or seemingly trivial breaks in the epithelial
barriers of the gut, oral cavity, or skin.
In patients with valve abnormalities, or with
known bacteremia, IE risk can be lowered by
antibiotic prophylaxis.

The Basic
Science of
Valvular
Heart
Disease
Morphology
Vegetations on heart valves are the classic
hallmark of IE; these are friable, bulky,
potentially destructive lesions containing fibrin,
inﬂammatory cells, and bacteria or other
organisms (Figs. 12-24 and 12-25).
The aortic and mitral valves are the
most common sites of infection, although
the valves of the right heart may also be
involved, particularly in intravenous drug
abusers.

Infective
endocarditis (IE)
is characterized
by large, irregular
masses on the
valve cusps that
can extend onto
the chordae.

Endocarditis of mitral
valve (subacute, caused
by Streptococcus viridans).
The large, friable
vegetations are denoted
by arrows.

Acute endocarditis of
congenitally bicuspid
aortic valve (caused by
Staphylococcus aureus) with
extensive cuspal
destruction and ring
abscess (arrow).

The Basic
Science of
Valvular
Heart
Disease
Morphology
Vegetations can be single or multiple
and may involve more than one valve;
they can occasionally erode into the
underlying myocardium and produce an
abscess (ring abscess).
Vegetations are prone to embolization;
because the embolic fragments often contain
virulent organisms, abscesses frequently develop
where they lodge, leading to sequelae such
as septic infarcts or mycotic aneurysms.

The Basic
Science of
Valvular
Heart
Disease
Morphology
The vegetations of subacute endocarditis
are associated with less valvular destruction
than those of acute endocarditis, although
the distinction can be subtle.
Microscopically, the vegetations of subacute
IE typically exhibit granulation tissue at
their bases indicative of healing.
With time, fibrosis, calcification, and a
chronic inﬂammatory infiltrate can develop.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
Acute endocarditis has a stormy onset with rapidly
developing fever, chills, weakness, and lassitude.
Although fever is the most consistent sign of IE, it
can be slight or absent, particularly in older adults,
and the only manifestations may be non-specific
fatigue, loss of weight, and a ﬂulike syndrome.
Murmurs are present in 90% of patients with left-
sided IE, either from a new valvular defect or from
a pre-existing abnormality.

The Basic
Science of
Valvular
Heart
Disease
Clinical Features.
The so-called modified Duke criteria facilitate
evaluation of individuals with suspected IE that
takes into account predisposing factors, physical
findings, blood culture results, echocardiographic
findings, and laboratory information.
Complications of IE generally begin within the first
few weeks of onset, and can include glomerular
antigen antibody complex deposition causing
glomerulonephritis.

Diagnostic
Criteria
for
Infective
Endocarditis

The Basic
Science of
Valvular
Heart
Disease
• Infective Endocarditis
• Clinical Features.
• Earlier diagnosis and
effective treatment has
nearly eliminated some
previously common clinical
manifestations of long-
standing IE
• For example:
• Microthromboemboli
• Janeway lesions
• Osler nodes
• Roth spots

The Basic
Science of
Valvular
Heart
Disease
Noninfected Vegetations
Noninfected (sterile) vegetations
occur in nonbacterial thrombotic
endocarditis and the endocarditis
of systemic lupus erythematosus
(SLE), called Libman-Sacks
endocarditis.

The Basic
Science of
Valvular
Heart
Disease
Nonbacterial Thrombotic Endocarditis
Nonbacterial thrombotic endocarditis (NBTE) is
characterized by the deposition of small sterile
thrombi on the leaflets of the cardiac valves.
The lesions are 1 to 5 mm in size, and occur as
single or multiple vegetations along the line of
closure of the leaflets or cusps.
Histologically, they comprise bland thrombi that are
loosely attached to the underlying valve; the
vegetations are not invasive and do not elicit any
inflammatory reaction.

Nonbacterial
thrombotic
endocarditis
(NBTE) typically
exhibits small,
bland
vegetations,
usually attached
at the line
of closure.
One or many
may be
present.

Nearly complete row of
thrombotic vegetations
along the line of
closure of the mitral
valve leaﬂets (arrows).

Photomicrograph of
NBTE, showing
bland thrombus,
with virtually no
inﬂammation in the
valve cusp (c) or
the thrombotic
deposit (t).
The thrombus is
only loosely
attached to the
cusp(arrow).

The Basic
Science of
Valvular
Heart
Disease
Thus, although the local effect of the vegetations is
usually trivial, they can be the source of systemic
emboli that produce significant infarcts in the brain,
heart, or elsewhere.
NBTE is often encountered in debilitated patients,
such as those with cancer or sepsis—hence the
previous term marantic endocarditis (root word
marasmus, relating to malnutrition).
It frequently occurs concomitantly with deep
venous thromboses, pulmonary emboli, or other
findings suggesting an underlying systemic
hypercoagulable state.

The Basic
Science of
Valvular
Heart
Disease
Indeed, there is a striking association with
mucinous adenocarcinomas, potentially relating to
the procoagulant effects of tumor-derived mucin or
tissue factor that can also cause migratory
thrombophlebitis (Trousseau syndrome).
Endocardial trauma, as from an indwelling catheter,
is another well-recognized predisposing condition,
and right-sided valvular and endocardial thrombotic
lesions frequently track along the course of
pulmonary artery catheters.

The Basic
Science of
Valvular
Heart
Disease
Endocarditis of Systemic Lupus Erythematosus (Libman-Sacks
Disease)
Mitral and tricuspid valvulitis with small, sterile vegetations,
called Libman-Sacks endocarditis, is occasionally encountered
in systemic lupus erythematosus.
Due to the use of steroids, the incidence of this complication
has been greatly reduced.
The lesions are small (1 to 4 mm in diameter), single or
multiple, sterile, pink vegetations with a warty (verrucous)
appearance. They may be located on the under-surfaces of the
atrioventricular valves, on the valvular endocardium, on the
chords, or on the mural endocardium of atria or ventricles.

The Basic
Science of
Valvular
Heart
Disease
Endocarditis of Systemic Lupus Erythematosus
(Libman-Sacks Disease)
Histologically the vegetations consist of a finely
granular, fibrinous eosinophilic material containing
cellular debris including nuclear remnants.
Vegetations are often associated with an intense
valvulitis, characterized by fibrinoid necrosis of the
valve substance and reﬂecting the activation of
complement and recruitment of Fc-receptor-
bearing cells.

The Basic
Science of
Valvular
Heart
Disease
Endocarditis of Systemic Lupus Erythematosus
(Libman-Sacks Disease)
Thrombotic heart valve lesions with sterile
vegetations or rarely fibrous thickening can occur
in the setting of the antiphospholipid syndrome,
which can also induce a hypercoagulable state.
The mitral valve is more frequently involved than
the aortic valve, and regurgitation is the usual
functional abnormality.

Libman-Sacks
endocarditis (LSE)
has small or
medium-sized
vegetations on
either or both
sides of the
valve leaﬂets.

• THE FORENSIC ASPECT VALVULAR
HEART DISEASE

Valvular
heart
disease
The most common valvular
abnormalities associated with sudden
death involve the aortic valve and, in
particular, aortic outflow tract
stenosis.
Spontaneous bacterial endocarditis is
seen on occasion, although
endocarditis associated with
intravenous drug abuse may be seen
more frequently in larger centers.
Mitral valve prolapse, although said
to be present in about 2 percent of
the population, is actually quite rare
as a cause of sudden death.

Valvular
heart
disease
A 63-year-old male was driving a
taxicab when he pulled over to the
side of a roadway, collapsed, and
died.
Autopsy revealed a hypertrophied
and dilated left ventricle caused by
congenitally bicuspid stenosis of the
aortic valve.
The residual valve orifice would not
admit the tip of a small finger,
which is a common finding in aortic
valvular stenosis of any etiology.

Valvular
heart
disease
Aortic valve stenosis
Examination of the aortic
valve from above is the best
way to establish the etiology
of aortic valvular stenosis.
The congenitally bicuspid
aortic valve has two cusps,
one of which is slightly larger
than the other.
The slightly larger cusp often
has a partially calcified ridge,
the median raphe, extending
across its midpoint.
The median raphe can be
mistaken for the fused edges
of two adjoining valve cusps,
as seen in acquired post-
inflammatory aortic valvular
stenosis.
Unlike post-inflammatory
fusion, however, the median
raphe does not extend to the
free edge of the valve cusp
and does not extend up to the
height of the valve
commissures on the aortic
wall.

Valvular
heart
disease
• Aortic valve stenosis
• Congenitally bicuspid aortic
valves, which occur in
approximately 2 percent of
all births, are the most
common congenital
abnormality of the heart
valves.
• They can be seen as
incidental findings in
children and young adults,
but are not usually stenotic.
• Stenosis of the valve
develops with calcification of
its cusps over time, such that
sudden death due to
congenitally bicuspid
valvular stenosis is usually
seen in individuals between
60 and 75 years of age.

Valvular
heart
disease
Acquired post-inflammatory aortic valvular
stenosis , the second most common cause
of aortic valvular stenosis, is usually seen
as a cause of sudden death in individuals
between 50 and 60 years of age.
When viewed from above, the valve will
exhibit varying degrees of fusion of its
commissures.

• Acquired post-inflammatory
aortic valvular stenosis

Valvular
heart
disease
In some cases, two cusps can be fused in such
a manner that the valve appears quite similar
to a congenitally bicuspid valve.
One of the cusps will be twice the size of the
second cusp on a post-inflammatory valve.
Unlike the median raphe of the congenitally
bicuspid valve, fusion of the cusps extends up
to the free edge of the valve and extends up
to the full height of the valvular commissures.

Valvular
heart
disease
In the absence of associated mitral valve disease,
isolated post-inflammatory aortic valvular stenosis is
no longer thought to be rheumatic in origin, but rather
is thought to be the result of some other inflammatory
process, the etiology of which remains unknown.
Senile calcific aortic valvular stenosis is usually seen in
individuals over 70 years of age.
The commissures of the valve are generally free of
adhesions, but deposits of calcium are found on the
aortic surfaces of the cusps.

Senile
calcific
aortic
valvular
stenosis

Valvular
heart
disease
The calcification produces reduced mobility of the
cusps, resulting in valvular stenosis.
Although the stenosis may be associated with left
ventricular hypertrophy, the advanced age of
individuals with senile calcific valvular stenosis is
such that there are often other lethal natural
disease processes present.
Thus, it is often difficult to attribute the sole cause
of a sudden death to senile calcific aortic valvular
disease.

Valvular heart
disease
• Membranous subaortic stenosis
• Membranous subaortic stenosis, an uncommon
cause of left ventricular outflow tract obstruction,
is usually detected clinically in children and
adolescents.
• The subaortic membrane is usually a thin or broad
“discrete” band of fibroelastic tissue, or can be a
broader fibromuscular band referred to as tunnel
subaortic stenosis.
• The aortic valve itself may be normal, but may
also exhibit thickening of its cusps, which
predisposes it to the development of infection or
insufficiency

Valvular
heart
disease
Supravalvular aortic stenosis
Can take the form of
membranous stenosis, an
hourglass deformity, or
hypoplasia of the ascending
aorta, is a decidedly rare cause
of sudden death in adults.

Valvular heart disease
• Supravalvular aortic stenosis
• A 42-year old male collapsed during an exercise
class.
• All attempts at resuscitation were unsuccessful.
• He had a history of an aortic valve lesion of
unknown etiology since the age of 16.
• He had been investigated 1 year previously for
syncopal episodes while running and for
shortness of breath on exertion.

• Supravalvular aortic stenosis
• He was told to modify his exercise program, but he was running 6 miles
a day and participating in four exercise classes per week at the time of
his death.
• At autopsy, there was left ventricular hypertrophy and dilatation
together with the presence of a thin fibrous membrane extending
around the circumference of the left ventricular outflow tract below the
aortic valve.

Thin fibrous
membrane
extending
around the
circumference
of the left
ventricular
outflow tract
below the
aortic valve.

Valvular
heart
disease
• Infective endocarditis
• A rare cause of sudden death, although it may be
seen more commonly in chronic intravenous drug
abusers.
• In those cases not related to drug abuse, one will
often find abnormal heart valves with
superimposed infection by bacterial organisms,
such as alpha-hemolytic Streptococcus viridans,
which tend to produce a subacute clinical
presentation (i.e., so-called subacute bacterial
endocarditis).
• More clinically aggressive organisms, such as
Staphylococcus aureus, can infect normal cardiac
valves and will usually create a more acute clinical
picture.
• On occasion, however, organisms usually associated
with subacute disease will infect normal valves.

Valvular
heart
disease
Infective endocarditis
In those instances where infective
endocarditis is found involving the tricuspid
and pulmonary valves, careful attention
should be paid to either historical or autopsy
evidence of intravenous drug abuse.
Cultures and Gram stains of the vegetations
should be taken in all cases of infective
endocarditis.

Valvular
heart
disease
• Infective endocarditis
• A 44-year-old male
presented to hospital with a
1-week history of left lower
quadrant abdominal pain
associated with anorexia.
• He had a history of chronic
ethanol abuse and
homozygous hemoglobin C
disease.
• Shortly after his admission,
he became bradycardic and
hypotensive.
• He deteriorated rapidly and
died shortly thereafter.
• At autopsy, the left and right
coronary ostia were located
adjacent to each other
above the left coronary cusp.

The vegetation on the left
coronary cusp extended
upward into the left main
coronary artery

Gram-positive cocci were
found in the vegetations
(Gram stain).

Mycotic aneurysms
were found in the
right coronary artery
and the right middle
cerebral artery

Valvular
heart
disease
INFECTIVE ENDOCARDITIS
AN ANTEMORTEM BLOOD
CULTURE GREW
ALPHAHEMOLYTIC
STREPTOCOCCUS VIRIDANS.

Valvular
heart
disease
Mitral valve prolapse
Mitral valve prolapse is the most common congenital heart disease,
occurring in approximately 5 percent of persons over 15 years of
age.
It occurs at a higher frequency in individuals with Marfan’s
syndrome.
Features of mitral valve prolapse, which include a redundant
“accordion”-like widening of the valve leaflets, excessive length of
the posterior valve leaflet, thickening of the central spongiosa
portion of the valve leaflets with excessive deposits of acid
mucopolysaccharide material, and thickening and rupture of
chordae tendineae, are usually incidental findings in cases where
there is another obvious cause of death.

Mitral valve prolapse
On very rare occasions,
mitral valve prolapse
will be the only
anatomic abnormality
present to account for
a sudden death.
Some individuals with
mitral valve prolapse
experience chest pain
and/or cardiac
arrhythmias, although
the anatomic basis for
this is not understood
(referred to
eponymously as
Barlow’s syndrome).
There is also a higher
rate of infective
endocarditis involving
these valves.
A 40-year-old female
collapsed suddenly and
died while shopping.
Clinically she was
known to have mitral
valve prolapse.

At autopsy, the
mitral valve,
when viewed
from above,
was noted to
have thickened
and redundant
leaflets

Individual
chordae
tendineae
were
ruptured

Histologic sections
confirmed the
presence of
excessive acid
mucopoly-
saccharide
material within the
central spongiosa
of the leaflets

Do
Examine the cardiac valves (especially
the aortic and mitral valves) from above
prior to opening.
Try to establish the underlying pathology
of a stenotic aortic valve, rather than just
attributing a death to “aortic stenosis.”
Obtain cultures and Gram stains of the
vegetations in cases of infective
endocarditis in order to properly identify
the responsible organism.
Don’t
Assume that mitral valve prolapse must
be the cause of a sudden natural death
when it is identified at autopsy: It is the
most common congenital heart disease,
but is a rare cause of sudden death; and,
as always, this autopsy finding must be
considered in conjunction with the
history, scene, and circumstances of the
death before drawing a conclusion about
the cause of death.

• Pathologic basis of disease
• ISBN 978-1-4557-2613-4
• I. Kumar, Vinay, 1944- editor. II. Abbas, Abul K., editor. III. Aster,
Jon C., editor.

• Forensic Pathology, Principles and Practice
• David Dolinak, M.D.
• Evan W. Matshes, M.D.
• Emma O. Lew, M.D.

Valvular disease

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