Vegetative Lesions

The inciting event in the development of IE is bacterial adherence to the disrupted endothelial surface of a cardiac valve. Mechanical lesions (e.g., subaortic stenosis or cardiac catheterization procedure) or inflammatory disease can promote bacterial seeding within the endothelium. During disruption of the endothelium, extracellular matrix proteins, thromboplastin, and tissue factor all trigger coagulation, and a coagulum forms on the damaged endothelium. This coagulum contains fibrinogen, fibrin, and platelet proteins and avidly binds bacteria. Inflammation induces endothelial cell expression of integrins that bind bacteria and fibronectin to the extracellular matrix. Some bacteria (e.g., Staphylococcus aureus) carry fibronectin-binding proteins and also can trigger active internalization by host cells. Organisms that commonly cause IE are those that have the greatest ability to adhere to damaged valves because they express special receptors called microbial surface components recognizing adhesive matrix molecules (MSCRAMMs); such organisms include Staphylococcus spp. and Streptococcus spp. These bacteria can trigger tissue factor production and induce platelet aggregation. Platelets release bactericidal proteins, but many of the bacteria that cause IE are resistant to these proteins. Bacteria such as S. aureus and Bartonella spp. may become internalized within the endothelial cells and escape detection by the immune system. Bartonella also evades the immune system by colonizing red blood cells without causing hemolysis. Additionally, bacteria can excrete enzymes that lead to destruction of valve tissue and proliferation of the vegetative lesion. The fibrinous vegetative lesion shields bacteria from the bloodstream and inflammatory cells and provides a formidable obstacle for antibiotic penetration.

Congestive Heart Failure

CHF develops subsequent to severe aortic or mitral valve insufficiency in dogs with IE of those valves. Rarely vegetations also create stenosis of the valve. Increased left ventricular end-diastolic pressure occurs secondary to severe valvular insufficiency and leads to elevated left atrial and pulmonary capillary wedge pressures and subsequent development of cardiogenic pulmonary edema once left ventricular end-diastolic pressure exceeds 20 to 25 mm Hg. Given the acute nature of the disease, often the left atrial pressure is elevated markedly in the absence of left atrial dilation, and cardiogenic pulmonary edema may develop despite a lack of overt signs of cardiomegaly on a radiograph or echocardiogram.

Immune-Mediated Disease

Patients with IE tend to develop high titers of antibodies against causative microorganisms, and there is continuous formation of circulating immune complexes consisting of immunoglobulin M (IgM) and IgG as well as C3 (complement). Factors such as rheumatoid factor may impair the ability of complement to solubilize immune complexes and may lead to formation of large immune complexes. Extracardiac disease manifestations are caused by immune complex deposition and further complement activation and tissue destruction in the glomerular basement membrane, joint capsule, or dermis. Levels of circulating immune complexes are greatly reduced shortly after antibiotic therapy in humans with IE. Immune-mediated disease is seen commonly in dogs with IE; polyarthritis and glomerulonephritis were observed in 6 of 8 dogs (75%) and 4 of 11 dogs (36%), respectively, in a study by MacDonald and colleagues (2004).

Cardiopulmonary Abnormalities

A murmur is auscultated in a majority of dogs with IE (89% to 96%), although one study reported a lower incidence of murmurs of 59% (41 of 70 dogs) (MacDonald et al, 2004; Sisson and Thomas, 1984; Sykes et al, 2006a). Clinical findings of a diastolic murmur and bounding femoral pulses should trigger a high level of suspicion of aortic valve IE, and further diagnostic testing should be pursued immediately as outlined in the following paragraphs. Fever often is present (50% to 74% of cases); however, dogs with Bartonella-associated IE are more likely to be afebrile. Arrhythmias are present in 40% to 70% of dogs and include in order of incidence ventricular arrhythmias, supraventricular tachycardia, third-degree atrioventricular block, and atrial fibrillation. The highest reported frequency of arrhythmias was in dogs with aortic IE, with 62% of dogs having ventricular arrhythmias (Sisson and Thomas, 1984). Third-degree atrioventricular block may occur with periannular abscess formation secondary to aortic valve IE. CHF is present in almost half of patients and is diagnosed by identification of perihilar to caudodorsal pulmonary infiltrates and pulmonary venous distention. Acute CHF, often with widespread pulmonary edema, occurs in the absence of significant left atrial enlargement in a majority of cases of IE (75%) (MacDonald et al, 2004). In a large case series of 71 dogs diagnosed with IE, CHF was more likely to develop in dogs with aortic valve involvement (Sykes et al, 2006b).

Other Systemic Sequelae

Thromboembolism (septic and aseptic) occurs in 70% to 80% of dogs with IE examined at pathology and in almost half of all clinical cases (MacDonald et al, 2004; Sykes et al, 2006a). Like people, dogs are more likely to experience thromboembolic disease with mitral valve IE (Sykes et al, 2006a). In people, the risk of thromboembolic disease is greatest with mitral valve IE, mobile vegetative lesions larger than 1 to 1.5 cm, or lesions that increase in size during antibiotic therapy (Macarie et al, 2004; Mügge et al, 1989). Infarction of the kidneys and spleen are most common in dogs, followed by infarction of the myocardium, brain, and peripheral arteries. Vascular encephalopathy occurs in approximately one third of people with IE but is uncommon in dogs. Recently a case series of four dogs with IE and vascular encephalopathy was described (Cook et al, 2005). Central nervous system thromboembolism most commonly occurs in the middle cerebral artery in both people and dogs and results in brain ischemia and possibly ischemic necrosis if persistent.

Arthrocentesis, cytologic analysis of joint fluid, and culture of joint fluid are indicated procedures for dogs with lameness or joint effusion. In a study of 71 dogs with IE, 35% of dogs had joint fluid analyzed, and 84% of these dogs had suppurative effusion (Sykes et al, 2006a). Septic inflammation is less common than immune-mediated polyarthritis.

Clinicopathologic Abnormalities

Complete blood count commonly reveals leukocytosis (78% to 89% of dogs with IE) with a mature neutrophilia and monocytosis. Mild to severe thrombocytopenia commonly is seen in over half of all cases. Mild nonregenerative anemia also is commonly seen (52% of dogs). Serum chemistry often shows hypoalbuminemia (95% of cases), elevated hepatic enzyme activity (70%), and acidosis. Azotemia is common (42% of dogs) and may be prerenal or renal. Renal infarction may be seen secondary to thromboembolic disease in IE and may cause severe azotemia. Urinalysis commonly reveals hematuria (62% of cases), proteinuria (62%), and cystitis (60%). Urine culture should be performed in all cases in an effort to identify possible offending microbes. Urine protein/creatinine ratio (UP/C) should be measured in dogs with proteinuria to establish if there is excess protein loss from the kidneys, which may lead to a hypercoagulable state due to loss of plasma antithrombin. In one study, an increased UP/C ratio was present in 77% of dogs in which it was measured and was moderate or severely elevated in 58% of these dogs. Anticoagulant or antiplatelet therapy may be indicated in patients with evidence of a hypercoagulable state but is not recommended empirically for dogs with IE.

Blood Culture

Blood culture before treatment with antibiotics is an essential tool to support the diagnosis of IE and to aid in proper selection of antimicrobial treatment. Unfortunately, many patients (78% in one study) have been treated with antibiotics before blood culture, which reduces the likelihood of a positive blood culture result. Three or four blood samples (5 to 10 ml) should be collected aseptically from different venous sites at least 30 minutes to 1 hour apart and submitted for aerobic and anaerobic culture. The use of lysis centrifugation tubes (Isolator/Isostat Microbial System) may increase diagnostic yield. For culture of Bartonella, a fastidious gram-negative intracellular bacterium, 2 ml of aseptically collected blood is placed in a plastic tube containing ethylenediaminetetraacetic acid (EDTA) (K₂EDTA blood tubes, Vacutainer systems) and frozen at −70° C (−94° F) until plated. Samples are plated on a specialized culture medium of heart infusion agar or Bartonella α-proteobacteria culture medium and incubated in 5% carbon dioxide for up to 4 weeks.

Bacterial Isolates

There is a high incidence of negative blood culture results in dogs with IE ranging from 60% to 70% (MacDonald et al, 2004; Sisson and Thomas, 1984) The most common bacterial isolates are Staphylococcus spp. (S. aureus, S. intermedius, coagulase-positive, and coagulase-negative), Streptococcus spp. (S. canis, S. bovis, and β-hemolytic), and Escherichia coli (Web Table 61-1). Other isolates cultured at the author’s hospital and reported in other case series include Pseudomonas spp., Erysipelothrix rhusiopathiae, Enterobacter spp., Pasteurella spp., Corynebacterium spp., and Proteus spp. Rare bacterial isolates include a Bordetella avium–like organism, Erysipelothrix tonsillarum, and Actinomyces turicensis.