Pathology and Pathogenesis of Infective Endocarditis in Native Heart Valves

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Cardiovascular Pathology 15 (2006) 256 – 263

Symposium Article

Pathology and pathogenesis of infective endocarditis in native heart valvesB


Gaetano Thiene4, Cristina Basso
Institute of Pathological Anatomy, University of Padua Medical School, Padua, Italy
Received 22 March 2006; received in revised form 25 May 2006; accepted 26 May 2006

Abstract

Infective endocarditis is an endovascular microbial infection of cardiovascular structures, including large intrathoracic vessels and
intracardiac foreign bodies.
The characteristic lesions consist of vegetations composed of platelets, fibrin, microorganisms, and inflammatory cells, as well as leaflet
disruption. The commonly accepted pathogenetic theory is herein reported, from endothelial injury with deposition of noninfective sterile
thrombotic vegetations to transient bacteremia with microorganism adhesion (injury-thrombus-infection theory). This review addresses the
pathology of native valve endocarditis, including local (valvular and perivalvular destruction) and distal (embolism, metastatic infection, and
septicemia) complications. Old and new cardiac conditions and patients at risk, predisposing to the occurrence of infective endocarditis, are
then discussed. Particular emphasis is given to hidden bicuspid aortic valve and the need of early carrier identification for prophylaxis.
D 2006 Elsevier Inc. All rights reserved.

Keywords: Valves; Infective endocarditis; Risk factors; Microbiology

1. Definition since they serve as a predisposing milieu for bacterial


sticking on valve surfaces [3]. Endothelial injury and
Endocarditis is an endovascular microbial infection of erosion is the most plausible factor leading to platelet
intracardiac structures facing the blood, including infections deposition. The rarity of endocarditis, despite frequent
of the large intrathoracic vessels (Fig. 1) and intracardiac transient bacteremia, indicates that the intact endothelium
foreign bodies [1]. Formerly known as bacterial endocardi- is resistant to colonization by microorganisms.
tis, endocardial infections are currently named infective Hemodynamic and mechanical stress seems to play an
endocarditis in order to include both bacterial and fungal important role in the development of initial lesions and
microorganisms. As a consequence, sterile thrombotic location of the infection [4]. The predilection site of infective
lesions (thrombotic nonbacterial endocarditis) should be endocarditis is the area of valve’s line closure due to the
termed noninfective endocarditis [2]. impact of the pressure, a matter that accounts for the pre-
valent involvement of the left-sided valves. Altered hemo-
2. Pathogenesis and predisposition dynamics, due to preexisting valve damage, may predispose
to endothelial damage and platelet deposition, thus increas-
Sterile thrombotic vegetations are considered the crucial ing the likelihood of endocarditis during bacteremia. Entry
lesions underlying the development of infective endocarditis of microorganisms into circulation, due to focal infection or
trauma, ultimately converts thrombotic nonbacterial (non-
B
This article is based on a presentation at the Society for infective) endocarditis into infective endocarditis. Events
Cardiovascular Pathology Companion Meeting at the United States and that traumatize the oral mucosa, particularly the gingiva,
Canadian Academy of Pathology, Atlanta, GA, February 2006.
and the genitourinary and gastrointestinal tracts, are asso-
4 Corresponding author. Institute of Pathological Anatomy, University
of Padua Medical School, Via A. Gabelli, 61 35100 Padua, Italy. Tel.: +39 ciated with an increased risk of bacteremia. The adher-
49 8272283; fax: +39 49 8272284. ence propensity of some microorganisms to nonbacterial
E-mail address: gaetano.thiene@unipd.it (G. Thiene). thrombotic deposits plays a major role, and fibronectin

1054-8807/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.carpath.2006.05.009
G. Thiene, C. Basso / Cardiovascular Pathology 15 (2006) 256–263 257

Fig. 1. Mycotic aneurysm of the ascending aorta: (A) gross view, (B) histology.

(a glycoprotein that is the main surface constituent of endocarditis, to the best of our knowledge, does not exist.
mammalian cells), lamin, and von Willebrand factor have Fungal infections are mostly indolent, may be culture
been identified as important host factors in this process [5,6]. negative, and are common in patients with prosthetic
Gram-positive microorganisms have the propensity to adhere valves [10] or intracardiac catheters, intravenous drug
to valvular surfaces, whereas gram-negative ones adhere abusers, those who are immunosuppressed, or those who
very little. This accounts for the predominance of gram- are receiving cytotoxic agents [2]. Candida is the most
positive microorganisms as etiologic agents in endocarditis frequent infective fungal agent, followed by Aspergillus and
[7]. Bacterial factors, like dextran produced by viridans Histoplasma species. Although hematoxylin–eosin may be
streptococci, have been identified as promoting adherence to
heart valves [8], and dextranase has been used as adjunctive
therapy to antibiotics in experimental streptococcal endo-
carditis. Decrease of host defense mechanisms most prob-
ably plays a major role as well. The local blood flow pattern
changes, as a result of alteration of the valve’s geometry,
concur to thrombus formation (noninfective thrombotic
endocarditis), microorganism adhesion during bacteremia,
and onset of infective endocarditis (injury-thrombus-infec-
tion theory). The microorganisms then can grow and induce
further thrombus formation and neutrophil chemotaxis
(Fig. 2). Thus, underlying valve disease with deformed
leaflets is the main risk factor of infective endocarditis.
Likewise, jet or friction lesions of the endocardium, as seen
on the left ventricular outflow tract in aortic incompetence
and hypertrophic cardiomyopathy, are a well-known site of
infective colonization.
However, studies of experimental endocarditis showed
that injury to the endocardium and vascular endothelium
may serve as a focus of infection even before the develop-
ment of sterile thrombotic vegetations [9].
Most gram-positive bacteria are resistant to the bacter-
icidal activity of the serum, whereas gram-negative ones
are not. This explains why gram-positive bacteria are
more likely to be a cause of infective endocarditis. Viral Fig. 2. Pathogenetic theory of infective endocarditis.
258 G. Thiene, C. Basso / Cardiovascular Pathology 15 (2006) 256–263

Table 1 Table 3
Infective endocarditis: distal complications Duke Criteria for diagnosis of infective endocarditis: two major or one
Side Complications major plus three minor, or five minor criteria are required [17]

Right Lung infarcts, abcesses Major Minor


Pneumonia Positive blood culture Predisposing heart condition or
Left Systemic infarcts intravenous drug use
Myocarditis Evidence of endocardial involvement Fever N388C
Pericarditis Positive echocardiogram Vascular phenomena
Meningitis New valvular regurgitation Immunological phenomena
Pyelonephritis Microbiological evidence a
Glomerulonephritis Echocardiogram a
Splenic abscess a
Consistent with infective endocarditis but not meeting major criteria.
Multiorgan failure
Mycotic aneurysms
accidents occur in nearly 10% of infective left-sided
endocarditis, and a similar incidence was found in patients
enough, employment of special stains (Gram) are necessary receiving and not receiving anticoagulants [14]. Paradox-
to distinguish gram-positive (most frequent) from gram- ycal emboli may occur in congenital heart disease with
negative (rare) microorganisms. Gomori methenamine right-to-left shunt.
silver, Groccot, or PAS is best to stain fungi. As the Metastatic infection may lead to apostematous meningi-
vegetations become indolent and chronic, organization with tis, myocarditis, and pyelonephritis. Splenic abscesses are
calcification occurs and infective agents become difficult to at risk of rupture; thus, abdominal computed tomography is
be demonstrated. Following treatment with antibiotics, indicated to monitor splenic involvement [15]. Septicemia
bacteria may lose their liability to Gram stain and the may stimulate disseminated intravascular coagulation.
histologic diagnosis of infection becomes intriguing [11]. In Deposition of circulating complexes may account for
this case, gross features of cusp disruption and perforation diffuse or focal glomerulonephritis. Mycotic aneurysms
are per se diagnostic of previous infection.

3. Pathology and complications of native


valve endocarditis

The pathology of infective endocarditis may be local,


including valvular and perivalvular destruction [12],
or distal, due to detachment of septic vegetations with
embolism, metastatic infection, and septicemia [2].
As far as the distal complications are concerned (Table 1),
they differ whether endocarditis is right sided or left sided
and whether emboli from vegetations are septic or bland.
Right-sided endocarditis can be complicated by pulmonary
artery embolism and infarcts, pneumonia, and lung
abscesses. Left-sided endocarditis can be complicated by
systemic embolism and by cerebral, myocardial, kidney,
splenic, and intestinal infarcts and/or abscesses. Embolic
events are the most common extracardiac complication
associated with infective endocarditis, with the incidence
ranging from 22% to 43% [13]. Valvular vegetations seem
to be a significant risk factor for embolism only in case of
infection with Streptococcus viridans [13]. Cerebrovascular

Table 2
Infective endocarditis: local complications
Aortic valve Mitral valve
Vegetations ++ +++
Perforations ++ ++
Aneurysms of Valsalva sinuses, ++ Fig. 3. Gross view and drawing of an infective endocarditis of the aortic
annular abscesses, tunnel, fistulae valve with perforation and tearing of the leaflets in the absence of
Chordal rupture + significant vegetations.
G. Thiene, C. Basso / Cardiovascular Pathology 15 (2006) 256–263 259

Fig. 4. Annular abscess complicating endocarditis of aortic valve: spread of infection from the right coronary sinus into the ventricular septum (A) and into the
right atrium (B).

may involve both the large–medium size arteries and the of various size, which in the acute phase consist of
small vessels [16]. septic thrombus entrapping microorganisms and neutro-
Local complications of infective endocarditis occur in the philic infiltrates. Sometimes, they are too small that they
valve itself or in the perivalvular region, and they also vary, are overlooked by the pathologist. Echocardiography can
whether atrioventricular or semilunar valves are affected demonstrate only lesions 2 –3 mm or more in size. Nowa-
(Table 2). Vegetations are usually attached to the atrial aspect days, evidence of endocardial involvement through echo-
of atrioventricular valves and to the ventricular aspect of cardiography plays a major role in in vivo diagnosis, even
semilunar valves, at the valve line closure. Infective in the absence of positive blood culture [17] (Table 3).
endocarditis of the aortic valve may present with vegetations A molecular approach, by employing polymerase chain

Fig. 5. Ulcero-vegetative infective endocarditis of the aortic valve (A) with kiss lesion on the anterior leaflet of the mitral valve, accounting for perforation and
aneurysm (B).
260 G. Thiene, C. Basso / Cardiovascular Pathology 15 (2006) 256–263

reaction in either an excised valve or blood, may improve the Table 5


Infective endocarditis: underlying heart disease in 186 Indian patients [22]
microbiological diagnosis of infective valve endocarditis
[18]. Cusp disruption with loss of substance accounts for n (%)
tearing, fraying, perforation, and bulging, especially when Rheumatic heart disease 79 (42)
the microorganism is staphylococcus, even in the absence Congenital heart disease a 62 (33)
Normal valve 17 (9)
of vegetations (Fig. 3). Valve incompetence with left ven-
Uncertain etiology 24 (13)
tricular decompensation and congestive heart failure is the Floppy mitral valve 2 (1)
usual hemodynamic complication. It may be associated with Prosthetic valve 2 (1)
stenosis, if vegetations are remarkable, as in the case of a
Bicuspid aortic valve in 25 patients.
fungal infections. In subacute-chronic phase, microorgan-
isms may disappear, granulomatous inflammation including thick edges, cusp aneurysms, ruptured chordae tendineae,
giant cells occurs, and vegetations may transform into coarse and healed fistulae. Neovascularization, granulomatous
calcific deposits. Local spread of infection includes exten- inflammation, and calcification with disappearance of
sion to the aortic wall, which may lead to development of microorganisms are the histologic hallmarks.
Valsalva sinus aneurysms, ring abscess, tunnels, and fistulae
to the surrounding cardiac chambers (right and left atria,
right and left ventricles; Fig. 4), as well as pericardial cavity 4. Cardiac conditions/patients at risk
itself with cardiac rupture and tamponade. Transesophageal
echocardiography is highly accurate in the detection of A large spectrum of heart diseases may predispose the
complications such as paravalvular abscesses or mycotic onset of infective endocarditis, in which antimicrobial
aneurysms. Aortic root complications carry an increased prophylaxis is recommended (Table 4).
operative mortality and a high incidence of postoperative Rheumatic valve disease, particularly mitral and aortic
regurgitation [19]. Extension of the infective endocarditis valve steno-incompetence, has been considered for years as
from the aortic to the mitral valve occurs through mitro- the major risk factor. In the 1970s, rheumatic valve disease
aortic fibrous continuity. A marker of such complication is was the predisposing lesion for infective endocarditis,
the development of a septic aneurysm in the anterior leaflet accounting for 20% to 25% of cases [20], whereas in the
of the mitral valve (satellite infection or kiss lesion), with or 1980s, it dropped to 7–10% [21]. Sterile thrombus
without perforation (Fig. 5). Involvement of the atrioven- formation on the surface of deformed valves, due to altered
tricular conduction system may account for atrioventricular blood flow dynamics and endothelial injury, is the main
block, and extension to the membranous septum with rupture mechanism not only for microbial settlement but also for
may induce acquired ventricular septal defect. valve disease progression. Although the frequency of
Apart from cusp vegetations and perforations, which do rheumatic valve disease has diminished in Europe and
not differ substantially from those occurring at semilunar North America, it is still endemic in Third World countries
valve level, infective endocarditis of atrioventricular valves where it represents by far the leading predisposing factor for
are peculiar in so far as the subvalvular apparatus (chordae infective endocarditis, especially in children [22] (Table 5).
tendineae and papillary muscle) may be also affected. With the increase in life expectancy, nowadays, degen-
Chordal rupture may be observed in the setting of infective erative heart diseases are becoming the most common
disruption. Papillary muscle rupture may also occur, either acquired condition at risk of infective endocarditis.
due to septic localization on the tip or due to myocardial Mitral valve prolapse has emerged as the predominant
necrosis because of coronary embolism. Perivalvular exten- predisposing structural abnormality and accounts for 7–30%
sion of the infection and ring abscesses are exceptional at
the atrioventricular valve level.
Healed endocarditis is marked by indentation of the free
margin and/or perforation of the body of the cusps with

Table 4
Cardiac conditions in which antimicrobial prophylaxis is indicated [1]
Prosthetic heart valves a
Complex congenital cyanotic heart diseases a
Previous infective endocarditis a
Surgically constructed systemic or pulmonary conduits a
Acquired valvular heart diseases
Mitral valve prolapse with valvular regurgitation or severe valve thickening
Non-cyanotic congenital heart diseases (except for secundum type ASD),
including bicuspid aortic valves
Hypertrophic cardiomyopathy
a
High-risk group (see text). Fig. 6. Ulcero-vegetative infective endocarditis in mitral valve prolapse.
G. Thiene, C. Basso / Cardiovascular Pathology 15 (2006) 256–263 261

of native valve infective endocarditis in Western countries


[23 –25]. The risk is almost entirely confined to patients with
mitral prolapse and regurgitation (Fig. 6), particularly in
those with valve redundancy and thickened mucoid leaflets
[26]. The incidence of infective endocarditis in this subgroup
of patients with mitral valve prolapse is 10 times than that
noted in the general population or in patients with mitral
prolapse and no murmur but 100-fold less than that among
patients with rheumatic valve disease. The infection is
presumed to develop in association with tiny thrombi, often
found attached to the atrial aspect of the thickened prolapsing
leaflets or at the base of the prolapsing posterior leaflet [2].
Incidentally, these thrombi may be a possible source of
emboli, causing transient ischemic attacks. Infective endo-
carditis of prolapsing mitral valve may lead to chordal
rupture. Only histologic evidence of microorganisms,
inflammatory infiltrates, and/or neovascularization may
distinguish chordal rupture secondary to infection from
spontaneous rupture, complicating myxoid degeneration.
Dystrophic calcification of the mitral valve annulus is
quite a common finding at autopsy in elderly patients. It
usually accounts for mitral incompetence due to lack of
sphincteric contraction of the annulus and impaired valve
orifice closure. Vegetations of infective endocarditis are
found on the base of the posterior (mural) leaflet rather than
relative to its line of closure and are often associated with
leaflet ulceration. The infection develops in the atrial aspect
of the leaflet, raised by the calcium mass, thus producing
vegetations on the atrial surface. The infection may spread Fig. 8. Infective endocarditis complicating hypertrophic cardiomyopathy:
(A) the anterior mitral leaflet shows perforation and vegetations, (B) view
of the left ventricular outflow tract with septal asymmetrical hypertrophy
and subaortic stenosis: the septic lesion developed within the subaortic
plaque. Also, the aortic cusps are involved.

to the calcified tissue in the annulus, resulting into a ring


abscess [27].
At the aortic valve level, acquired degenerative disease
may present either in the form of aortic stenosis due to
dystrophic calcification of the leaflets or in the form of
aortic incompetence due to annuloaortic ectasia (including
Marfan syndrome) with elastic fragmentation and cystic
medial necrosis of the aortic wall and floppy semilunar
valves. In the latter condition, progressive dilatation of the
aortic root forces the semilunar valves to come into contact
during diastole at the free margin, which then thickens with
drumstick appearance. Endothelial erosion at this level may
account for noninfective thrombotic deposits, which serve
as an implant site of infection during bacteremia.
The bicuspid aortic valve, although being the most
common congenital defect (0.5 –2% in the general popula-
tion) [28], may be classified in between congenital and
acquired disorders [29]. In fact, because of progressive
dystrophic calcification, it represents the second-leading
Fig. 7. Infective endocarditis of the aortic valve: (A) vegetations of a cause of acquired aortic stenosis in the elderly, following
bicuspid aortic valve, (B) histology with gram-positive, cocci-like micro- senile dystrophic calcification of a trifoliate aortic valve.
organisms. Infective endocarditis may superimpose not only to the
262 G. Thiene, C. Basso / Cardiovascular Pathology 15 (2006) 256–263

Fig. 9. Infective endocarditis occurring in an apparently normal aortic valve: (A) gross view of vegetations in the aortic valve, (B) light microscopy shows
cocci-like microorganisms, fibrin, and neutrophilic infiltrates.

stenotic, symptomatic bicuspid valve in the adults and risk factor of endocarditis in 75– 90% in children, 10–20% in
elderly but also in the bicuspid valve of the young, when the young, and 8–10% in adults [33]. Ventricular septal
the bifoliate condition is silent, the valve is still normally defect, tetralogy of Fallot, bicuspid aortic valve, discrete
functioning, and infective endocarditis may represent the subaortic stenosis, patent ductus arteriosus, and coarctation
first manifestation of the disease [30]. Wear-and-tear mecha- of the aorta are the most common predisposing defects.
nisms of the unnaturally closing bileaflet valve accounts for Secundum atrial septal defect is not associated with increased
predisposition to infection (Fig. 7). risk of endocarditis, probably because of the left-to-right
Hypertrophic cardiomyopathy, an inherited heart muscle shunt at low pressure (Table 4). Ventricular septal defect is at
disease with altered genes encoding defective sarcomeric particular risk if small or associated with aortic regurgitation.
proteins, may complicate with infective endocarditis in In case of isthmal coarctation and patent ductus arteriosus,
5 –9% of the cases [31], especially in those with subaortic the infection may involve the great vessels themselves.
stenosis [32]. Hemodynamic and anatomic alterations of the Finally, native valve endocarditis may develop upon
left ventricular outflow tract, with contact between the ven- normal valves in up to 30% of cases (Fig. 9). Early dege-
tricular septal bulging and the anterior leaflet of the mitral nerative changes (floppiness) may preexist, as to cast doubts
valve due to systolic anterior motion, cause microtrauma- on the true normality in most of these cases. Whether such
tisms, which result into endocardial lesions (plaques), and valves are indeed normal has been questioned: b the
may represent the nidus for thrombus deposition and micro- recorded incidence of bacterial endocarditis on previously
bial seeding during bacteremia (Fig. 8). Both aortic and normal valves begs the question of what is normality for a
mitral valve leaflets may be involved. valveQ [34]. Risk factors like intravenous drug use, habitual
Congenital heart diseases have been historically associ- alcoholism, and immunodeficiencies may play a major role
ated with infective endocarditis. They are the predisposing in otherwise normally structured hearts. Intravenous drug
users can introduce several microorganisms of the skin flora
such as cocci and fungi. Right-sided heart structures are
typically involved in this setting, particularly the tricuspid
valve and even the eustachian valve [35] (Fig. 10). Hidden
bicuspid aortic valve is particularly at risk in drug addicts.
Among neonates, infective endocarditis typically affects
the tricuspid valve of a structurally normal heart. It is likely
that many of these cases develop as a consequence of
infected intravenous right-sided catheters [2].

5. Conclusions

From the clinical viewpoint, it is of utmost importance


that infective endocarditis is considered early in every
Fig. 10. Polypous fungal infective vegetation of the tricuspid valve in a patient with fever or septicemia and cardiac murmurs and
drug addict. that echocardiography is applied without any delay.
G. Thiene, C. Basso / Cardiovascular Pathology 15 (2006) 256–263 263

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