Pathology and Pathogenesis of Infective Endocarditis in Native Heart Valves
Pathology and Pathogenesis of Infective Endocarditis in Native Heart Valves
Pathology and Pathogenesis of Infective Endocarditis in Native Heart Valves
Symposium Article
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.
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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]
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
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
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
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