Pathogenesis of vegetation formation in infective endocarditis

Author
Daniel J Sexton, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures: Daniel J Sexton, MD Grant/Research/Clinical Trail Support: Cubist [C. difficile infection
(Fidaxomycin)]. Consultant/Advisory Boards: Johnson & Johnson [Pelvic mesh-related infection]; Sterilis [Medical
waste disposal systems]; Magnolia Medical Technologies [Intravenous devices]. Other Financial Interest:
National Football League [Infection control program]. Equity Ownership/Stock Options: Magnolia Medical
Technologies [Intravenous devices]. Stephen B Calderwood, MD Patent Holder: Vaccine Technologies Inc.
[Vaccines (Cholera vaccines)]. Equity Ownership/Stock Options: Pulmatrix [Inhaled antimicrobials]; PharmAthene
[Anthrax (Anti-protective antigen monoclonal antibody)]. Elinor L Baron, MD, DTMH Nothing to disclose.
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Literature review current through: Mar 2015. | This topic last updated: Jan 10, 2014.
INTRODUCTION Infective endocarditis arises when an adherent platelet-fibrin nidus
becomes secondarily infected and produces vegetations, which in turn may directly damage the
endocardial tissue and/or valves. The pathogenesis of infective endocarditis will be reviewed
here.
Other aspects of infective endocarditis, including clinical consequences of vegetation formation,
are discussed separately. (See "Epidemiology, risk factors and microbiology of infective
endocarditis" and "Epidemiology, clinical manifestations, and diagnosis of prosthetic valve
endocarditis" and "Infective endocarditis in injection drug users" and "Infective endocarditis in
children" and "Clinical manifestations and diagnosis of infective endocarditis" and"Antimicrobial
therapy of native valve endocarditis" and "Antimicrobial therapy of prosthetic valve
endocarditis" and "Surgery for native valve endocarditis"and "Complications and outcome of
infective endocarditis".)
PATHOGENESIS
Vegetation formation The endothelial lining of the heart and its valves is normally resistant
to infection with bacteria and fungi. Experiments in animal models have demonstrated that a
sequence of interrelated events must occur before microbes can establish an infective nidus or
vegetation on the endocardium:
The initial step in the establishment of a vegetation is endocardial injury, followed by
focal adherence of platelets and fibrin. Some organisms with high virulence are capable of
infecting normal human heart valves, such as Staphylococcus aureus.
The initially sterile platelet-fibrin nidus becomes secondarily infected by microorganisms
circulating in the blood, either from a distant source of focal infection, or as a result of
transient bacteremia from a mucosal or skin source [1,2].
It is likely that the pathogenesis of vegetation formation varies depending on the infecting
organism. In most instances, colonization of the platelet-fibrin aggregate is an initial event.
Subsequent microbial growth results in further activation of the coagulation system via the

extrinsic clotting pathway, adherent monocytes release a variety of cytokines, and

activated endothelial cells continue to express further local deposition of fibronectin. These
processes culminate in a macroscopic excrescence or vegetation. Bacterial growth occurs
within cells and within the matrix of fibronectin inside vegetations, making it difficult for
host immune responses to control or eradicate the ongoing infection (figure 1 and figure 2)
[3]
The significance of vegetation size is discussed further separately. (See "Surgery for native
valve endocarditis", section on 'Surgical considerations'.)
Histopathologic features A mature vegetation is an amorphous collection of fibrin, platelets,
leukocytes, red blood cell debris, and dense clusters of bacteria. The surface generally consists
of fibrin and varying numbers of leukocytes. Clumps of bacteria, histiocytes, and monocytes are
generally observed deep within the vegetation; giant cells containing phagocytosed bacteria
may also be seen. Extremely high concentrations of bacteria (eg, 109 to 1011CFU/gram of
tissue) may accumulate deep within vegetations; some of these organisms exist in a state of
reduced metabolic activity. Vegetations are avascular structures; following therapy and during
the healing process, capillaries and fibroblasts appear.
In one study comparing vegetation histology of infected prosthetic valves and sterile (but
dysfunctional) native valves, the former demonstrated microorganisms and inflammatory
infiltrates containing neutrophils, while the latter demonstrated inflammatory adherent thrombi
containing mostly lymphocytes and macrophages; microorganisms were not present [4].
Effect of therapy Following treatment of endocarditis, vegetations may disappear or persist.
A retrospective histopathology study among 480 patients with endocarditis who underwent
valve replacement or repair noted the following findings [5]:
Valvular specimens from patients undergoing surgery prior to completion of antimicrobial
therapy demonstrated microorganisms by gram stain and/orhistologic examination in most
cases (81 and 67 percent, respectively).
Detection of microorganisms does not imply treatment failure in patients undergoing
surgery prior to completion of antimicrobial therapy. The only reliable method to determine
the efficacy of treatment in such cases is culture of the excised tissue; clearance of dead
organisms via lysis or phagocytosis may take months.
Evaluation of vegetations with polymerase chain reaction (PCR) may demonstrate the presence
of bacterial DNA months to years after completion of appropriate therapy; such findings likely
represent persistence of nonviable bacterial debris within the vegetation, although in some
cases, such results may reflect persistence of viable organisms deep within the vegetation [6].
Host factors
Endocardial injury It is virtually impossible to induce endocarditis in experimental animals
unless the valvular endocardium is first traumatized with a polyethylene catheter inserted into
the right or left side of the heart [1]. A corollary to this observation is that animals with prior
catheter-induced valvular lesions that are injected with bacteria such as viridans streptococci
(which have the inherent ability to adhere to fibrin-platelet matrices on damaged endocardium)
predictably develop a vegetation at the site of valve injury within a few days. Similar lesions
probably occur naturally in bacteremic humans with congenital or acquired cardiac lesions that
induce continuous endocardial trauma via regurgitant flow or high pressure jets of blood through
stenotic lesions.

Vegetation sites Vegetations tend to develop at sites where blood travels from an area of
high pressure through a narrow orifice into an area of lower pressure. The explanation for this
phenomenon can be deduced from in vitro experiments demonstrating the physics of turbulent
flow. As an example, it has been observed that, following injection of nebulized bacteria into an
air stream passing through an agar-coated tube, the highest concentration of bacteria is found
in the low pressure area immediately distal to the narrowing [7]. The propensity for vegetations
to form at specific sites may be correlated with a decrease in lateral pressure downstream from
the regurgitant flow, which causes a decrease in the perfusion of the intimal lining at these sites
[8]:
In the setting of preexisting valvular disease, vegetations are usually located on the atrial
surface of incompetent atrioventricular valves or the ventricular surface of incompetent
semilunar valves.
In the setting of ventricular septal defect, vegetations tend to develop on the orifice of the
defect, on the right ventricular side of the opening, and/orsecondarily on the tricuspid and
pulmonic valves [9].
In the setting of aortic insufficiency, vegetations may localize to the chordae tendineae of
the anterior leaflet of the mitral valve
In the setting of mitral regurgitation, vegetations may develop on the wall of the left
atrium, where the regurgitant jet strikes the atrial wall and results in endocardial thickening
(MacCallum's patch).
Pathogen factors
Source of infection The bacterial source for endocarditis may be readily discernible (such
as a dental abscess, infected skin lesion, or infected vascular catheter), or there may be no
clear history of antecedent infection. In such cases, the source is frequently attributed to minor
trauma of the oropharyngeal, gastrointestinal, or genitourinary mucosa.
Endocarditis in injection drug users is presumed to be a consequence of bacterial contamination
of material injected, of injection equipment, and/or of the skin surface at the injection site.
Microbial adherence Microbial adherence is a crucial event in the pathogenesis of
endocarditis. Organisms typically associated with endocarditis have the capacity to adhere
avidly to valve tissue; these include S. aureus, viridans streptococci, enterococci,
and Pseudomonas aeruginosa [10]. Bacterial adherence to a platelet-fibrin nidus involves a
complex interaction of microbial cell wall components. The mechanism of adherence is poorly
understood and may vary among different organisms.
In vitro models have provided some data regarding the pathogenesis of adherence:
The relative frequency with which different species of bacteria cause endocarditis in
humans has been correlated with their ability to cause endocarditis in rabbits [8]. In this
experimental model, the amount of dextran produced by the cell wall of streptococci grown
in broth is proportional to the intrinsic ability of various streptococcus species to cause
endocarditis, suggesting the importance of the interaction between dextran and the
valvular endothelium [11].
Intrinsic binding affinity to fibronectin appears to be a contributing pathogenic factor; in
rats, S. aureus mutants with diminished capacity to bind fibronectin had reduced ability to
cause endocarditis compared with parent strains with higher fibronectin binding affinity [12].

Glucosyltransferases (GTFs), proteins made by viridans streptococci, have the ability to

convert sucrose into polysaccharides which in turn may act as "modulins" to induce
various cytokines that in turn recruit leukocytes to vegetations [13].
Other potential mediators of microbial adherence include fibrinogen, laminin, and type 4
collagen. Bacterial-platelet interactions appear to be important in the development and
enlargement of a vegetation.
SUMMARY
In general, the initial step in the establishment of a vegetation is endocardial injury,
followed by focal adherence of platelets and fibrin. The initially sterile platelet-fibrin nidus
becomes secondarily infected by microorganisms circulating in the blood. Microbial growth
results in the secondary accumulation of more platelets and fibrin and further activation of
the coagulation system via the extrinsic clotting pathway. (See 'Vegetation
formation'above.)
A mature vegetation is an amorphous collection of fibrin, platelets, leukocytes, red blood
cell debris, and dense clusters of bacteria. The surface generally consists of fibrin and
varying numbers of leukocytes. Clumps of bacteria, histiocytes, and monocytes are
generally observed deep within the vegetation; giant cells containing phagocytosed
bacteria may also be seen. (See 'Histopathologic features' above.)
Detection of microorganisms on histopathology examination of an excised valve does not
imply treatment failure; clearance of dead organisms via lysis or phagocytosis may take
months. Similarly, detection of bacterial DNA via PCR months to years after completion of
appropriate therapy likely reflects persistence of nonviable bacterial debris within the
vegetation. (See 'Effect of therapy' above.)
Vegetations tend to develop at sites where blood travels from an area of high pressure
through a narrow orifice into an area of lower pressure. (See'Vegetation sites' above.)
The bacterial source for endocarditis may be readily discernible (such as a dental
abscess, infected skin lesion or infected vascular catheter), or there may be no clear
history of antecedent infection. In such cases, the source is frequently attributed to minor
trauma of the oropharyngeal, gastrointestinal, or genitourinary mucosa. (See 'Source of
infection' above.)