Cardiac Infections

Cardiac Valves

Most cases of IE involve the cardiac valves. The normal atrioventricular mitral and tricuspid valves of the cardiac inflow tracts and the semilunar aortic and pulmonary valves of the outflow tracts share a common structure. They consist of a dense, avascular, collagenous core, termed the valvular fibrosa, which is contiguous with the fibrous skeleton of the heart, surrounded by a spongiosa that consists of a loose matrix of collagen, elastic fibers, and glycosaminoglycans. The valve surfaces are lined by endothelium. This topographic arrangement is critical to the normal function of the valves during the cardiac cycle. The cardiac ventricles fill with blood that passes through the open leaflets of atrioventricular valves during diastole, and the valves must remain tightly apposed during systole. Conversely, the semilunar valves must open during systole and remain competently closed during diastole. This is achieved by the elastic and deformable properties of the valves. Because the normal cardiac valve is normally avascular, stromal cells that contribute to the valvular fibrosa and spongiosa must dynamically maintain valvular structure.

With the mechanical wear and tear that accompanies age—valves must open and close almost 3 million times in the course of a 75-year lifetime—the normal configuration of the valve changes. Fibrosis is the most common complication of aging, whereas myxomatous change can result from altered hemodynamics (e.g., the functional insufficiency that follows dilatation of a valve ring) or genetically encoded defects (e.g., Marfan syndrome).

Mechanical degeneration leads to increased collagen deposition by valvular mesenchymal cells and to a relative decrease in the size of the spongiosa. In addition, shear forces produce focal endothelial denudation of the valvular surface, leading to the deposition of a platelet-fibrin coagulum that signals subendothelial fibrogenesis.

Valvular calcifications complicate both age-related fibrosis and postinflammatory valvulitis. The structural distortions produced by scarring are further enhanced by calcifications that grow by accretion to be nodular and bulky, leading to valvular stenosis and insufficiency. In some cases, concomitant foci of ossification also develop.

Rheumatic fever, an immunologic complication of group A Streptococcus infection, is the most common cause of valvulitis. Rheumatic fever causes a pancarditis that affects the cardiac valves, myocardium, and pericardium. Histiocytic inflammation is accompanied by neovascularization and fibrosis. In the case of the atrioventricular valves the chordae tendineae become scarred and foreshortened, promoting the late hemodynamic consequences of valvular distortion. The end result is a scarred valve that is predisposed to further deformation by dystrophic calcification and functionally to both stenosis and insufficiency.

Infective Endocarditis

IE results from the growth of microorganisms on the endocardial surfaces of the cardiac valves or vascular endothelium. Most infections are caused by bacteria that have been entrapped in a mesh of fibrin and platelets previously deposited along an injured endocardial surface. These deposits are termed vegetations. They are friable and grow by accretion to be potentially bulky, depending on the cause, location, and duration of the infection. In the absence of antimicrobial treatment, effective healing of vegetations does not occur, and the risk of infected platelet–thrombi dislodging and traveling into the circulation is substantial.

In the past, IE was termed “bacterial endocarditis,” but with increased recognition that nonbacterial species, including fungi and rickettsia, can also cause endocarditis, the term IE is currently preferred. Modifiers, such as acute, subacute, or chronic, refer to the clinical course of the disease; however, they are imprecise and do not correlate well with the underlying pathology. Instead, IE should be considered a spectral disorder that can exhibit either an aggressive or an indolent course, depending on the circumstances of infection.

The once-universal mortality associated with IE has been substantially reduced by improved diagnosis, antimicrobial treatment, and aggressive surgical intervention. The current mortality rate ranges from 10% to 30%. In the first half of the 20th century, most cases of IE were complications of rheumatic mitral valvular disease. However, with decreased prevalence of rheumatic valvular disease and increased aging of the population, the senile fibrocalcific aortic valve has become an increasingly common presentation. New sources of infection include intravenous drug use and the widespread iatrogenic use of intravenous catheterization. Host immunosuppression in patients receiving corticosteroids and other immunosuppressant agents, human immunodeficiency virus (HIV)-1 infection, diabetes, renal failure, alcoholism, and cirrhosis all substantially increase the risk for development of IE.

Cardiac and vascular prostheses are potential nidi for infection and present a continued risk for IE after implantation. Right-heart pacemaker implantation can lead to infection along the pacemaker leads and the tricuspid valve. S. aureus and Staphylococcus epidermidis are the most common pathogens in the early (first 60 days) and late periods, respectively, after implantation. Left-ventricular assist devices are currently used in the treatment of intractable left ventricular failure and as a bridge to cardiac transplantation. The prevalence of IE associated with these devices ranges from 15% to 44%, and the diagnosis can be difficult to establish noninvasively. Enterococcus and Staphylococcus spp. are the most common infective agents, but fungi and low-virulence organisms also cause disease.

Pathogenesis of Infective Endocarditis

Experimental models have demonstrated that a catheter introduced into the right side of the heart of a rabbit or rat can cause endothelial injury to the tricuspid valve. Endocardial injury greatly increases the risk of developing IE when coupled with subsequent exposure to circulating bacteria ( Fig. 9.1 ). Endothelial injury exposes basement membrane proteins, including laminin, fibronectin, and vitronectin, which serve as adhesion molecules for bacteria. Activation of platelets and thrombus formation further promote bacterial adhesion. Bacterial binding to thrombus is followed by a lag period of several hours before bacterial proliferation is detected.

The risk of developing experimental disease is a function of the virulence and size of the bacterial inoculum and whether the injurious catheter is left in place or removed. For bacterial inocula introduced after catheter removal, the risk of developing IE decreases progressively with time. The histopathology of the valve shows healing of the catheter-induced lesion by reendothelialization, which appears to protect against subsequent bacterial colonization.

Other animal models of IE that do not require an indwelling catheter have been developed. In the guinea pig, electrocoagulation of the aortic valve followed by inoculation with S. aureus or Coxiella burnetii yields IE. In addition, electrical stimulation of the cervical vagus nerve can result in injury of the mitral valve and predisposes to IE with subsequent bacterial challenge.

Specific microbial factors have been examined in the pathogenesis of IE. Resistance by an S. aureus to a thrombin-induced microbicidal protein promotes IE. Fibronectin-binding proteins expressed by S. aureus facilitate binding to fibronectin and act as invasins. Organisms that do not bind fibronectin show decreased propensity to cause IE. Gelatinase/type IV collagenase enhances the virulence of Streptococcus gordonii , and an aggregation substance expressed by Enterococcus (formerly Streptococcus ) faecalis increases virulence in the catheter injury model.

Biofilm formation plays a critical role in the pathogenesis of IE and has important consequences with respect to its treatment. Bacteria can survive as isolated, free-living planktonic organisms or as stationary colonies associated with a substratum. Four criteria have been proposed for the biofilm origin of infection: adherence of pathogenetic bacteria to a substratum; presence of bacteria in clusters or colonies associated with either an endogenous or a host-derived matrix; localized infection; and resistance to antibiotic therapy despite sensitivity of the planktonic organism. Most, if not all, cases of IE associated with prosthetic surfaces meet these criteria. Bacteria within biofilms produce extracellular polymeric substances (EPSs)—slime-producing glycocalices that limit the accessibility of host humoral and cellular defenses, as well as antibiotics, to the organisms that are embedded in the matrix. Biofilms confer other advantages to the bacterial colonies as well. If the availability of growth requirements is limited, biofilm bacteria can convert to a slow-growing, stationary state, so-called persisters. Water channels form within the biomass and serve as a circulatory system through which nutrients are shared and waste products released.

The activities of the biofilm are coordinated by redundant interbacterial genetic signals. The properties of the biofilm make it virtually impossible to eradicate infection as long as the stationary phase persists. Organisms can spread along surfaces by means of a ripple effect or, alternatively, as detached clumps of organisms that can break free of the substratum matrix and travel to distant sites in the circulating blood. These mechanisms explain the local and distant spread of infection in IE.