The interactions between the human host and selected microorganisms that culminate in IE involve the vascular endothelium, hemostatic mechanisms, the host immune system, gross anatomic abnormalities in the heart, surface properties of microorganisms, and peripheral events that initiate bacteremia. Endothelial damage results in platelet-fibrin deposition, which in turn is more receptive to colonization by bacteria than is the intact endothelium. It is hypothesized that platelet-fibrin deposition occurs spontaneously in persons vulnerable to endocarditis and that these deposits, called nonbacterial thrombotic endocarditis (NBTE) are the sites at which micro organisms adhere during bacteremia to initiate IE. Bacteremia is the initiating event that ultimately converts NBTE to IE.  Bacteremia rates are highest for events that traumatize the oral mucosa, particularly the gingiva, and progressively decrease with procedures involving the genitourinary tract and the gastrointestinal tract.

The platelet-thrombin deposits are found at the valve closure-contact line on the atrial surfaces of the mitral and tricuspid valves and on the ventricular surfaces of the aortic and pulmonic valves, the sites of infected vegetations in patients with IE. Three hemodynamic circumstances may injure the endothelium, initiating NBTE: (1) a high velocity jet impacting endothelium (2) flow from a high to a low pressure chamber and (3) flow across a narrow orifice at high velocity.  Flow through a narrowed orifice, as a consequence of venturi's effect, deposits bacteria maximally at the low-pressure sink immediately beyond an orifice or at the site where a jet stream impacts a surface.

To cause IE, the organism must be able to persist and propagate on the endothelium. This requires resistance to host defenses. The complement-mediated bactericidal activity of serum limits the ability of susceptible aerobic gram-negative bacilli to cause IE. Those organisms that most frequently cause endocarditis adhere more vigorously in vitro to cardiac valves than do organisms that rarely cause IE.