The ventricular assist device (LVAD) has become a major form of therapy for patients with congestive heart failure. Originally introduced as a bridge to cardiac transplantation, it has recently been approved for """"""""destination therapy"""""""": a means to improve survival and the quality of life in patients with heart failure refractory to medical therapy. A serious limitation to the prolonged use of LVADs has been the high incidence of device-related infections. These infections, ranging from driveline infections to device-associated endocarditis, occur in 28-48% of patients and entail significant morbidity and mortality. A combination of factors is responsible for the high incidence of infection, including immunocompromised hosts, lengthy hospitalizations with numerous invasive procedures, and the long-term presence of a large prosthetic device. While the nature of LVAD-associated infections has been well described, less attention has been devoted to their epidemiology and pathogenesis. Critical to the initiation of most bacterial infections is the colonization step where bacteria adhere to the host cellular or extracellular matrix. For Staphylococcus aureus, a primary pathogen in these infections, a family of structurally related surface proteins facilitates this initial step. The importance of these proteins has been demonstrated in a number of experimental models of infection. The contribution of these proteins to LVAD infections has not been previously investigated. If left ventricular assist devices (LVADs) are to become a more established form of therapy, the incidence of infections must be reduced. The goals of this proposal are to perform clinical trials that will investigate the pathogenesis of these infections while assessing promising strategies for preventing them. The proposal will focus on S. aureus because of its prominence as a pathogen in this setting and its unique virulence. The most lethal of the LVAD infections -- """"""""pump endocarditis"""""""" -- will be a particular focus.
Our specific aims are summarized below. 1) Develop clinical intervention strategies to prevent LVAD-related infections. 2) Characterize the nature of S. aureus - LVAD surface interactions by identifying both the S. aureus adhesins and the LVAD cellular and matrix surface components that mediate these interactions in vitro. 3) Examine the role of specific S. aureus adhesins in a mouse model of prosthetic intravascular infection.
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