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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.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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All topics are updated as new evidence becomes available and our peer review process is
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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

Extremely high concentrations of bacteria (eg. 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. section on 'Surgical considerations'. Clumps of bacteria. following therapy and during the healing process. ●Detection of microorganisms does not imply treatment failure in patients undergoing surgery prior to completion of antimicrobial therapy.extrinsic clotting pathway. Vegetations are avascular structures. 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. red blood cell debris. and monocytes are generally observed deep within the vegetation. In one study comparing vegetation histology of infected prosthetic valves and sterile (but dysfunctional) native valves. and activated endothelial cells continue to express further local deposition of fibronectin. The surface generally consists of fibrin and varying numbers of leukocytes. giant cells containing phagocytosed bacteria may also be seen. 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. such results may reflect persistence of viable organisms deep within the vegetation [6]. capillaries and fibroblasts appear. These processes culminate in a macroscopic excrescence or vegetation. such findings likely represent persistence of nonviable bacterial debris within the vegetation. histiocytes. 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]. and dense clusters of bacteria. the former demonstrated microorganisms and inflammatory infiltrates containing neutrophils. respectively). platelets. microorganisms were not present [4]. Effect of therapy — Following treatment of endocarditis. while the latter demonstrated inflammatory adherent thrombi containing mostly lymphocytes and macrophages. some of these organisms exist in a state of reduced metabolic activity. although in some cases. 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. vegetations may disappear or persist.) Histopathologic features — A mature vegetation is an amorphous collection of fibrin. Evaluation of vegetations with polymerase chain reaction (PCR) may demonstrate the presence of bacterial DNA months to years after completion of appropriate therapy. adherent monocytes release a variety of cytokines. . Bacterial growth occurs within cells and within the matrix of fibronectin inside vegetations. clearance of dead organisms via lysis or phagocytosis may take months. 109 to 1011CFU/gram of tissue) may accumulate deep within vegetations. leukocytes. The only reliable method to determine the efficacy of treatment in such cases is culture of the excised tissue. (See "Surgery for native valve endocarditis".

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

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