**2. Pathophysiology of septic emboli**

When discussing the pathophysiology of emboli of cardiac origin, one must consider both noninfective (Libman-Sacks or autoimmune, Marantic or related to wasting illnesses such as cancer) and infective (e.g., bacterial or fungal) endocarditis [19–21]. As an overarching theme, any condition that results in structural "damage or alteration" of cardiac valves has the potential to trigger an inflammatory reaction leading to the formation of valvular "vegetations" and thromboembolic complications [22]. In contrast to non-infectious valvular etiologies which lead to sterile emboli, IE has the potential to produce SE which typically are composed of a conglomerate of infectious organisms, inflammatory cells, platelets and fibrin [23]. In contrast to non-infectious emboli, SE have the potential to result in both vascular compromise and hematogenous spread of infection [24–26]. Evidence shows that as many as 50–82% of patients with IE may be affected by some form of SE, including both symptomatic and sub-clinical presentations [27–29]. In terms of valvular propensity for systemic (non-pulmonary) SE development, mitral valve is the most commonly involved [10, 30].

**1. Introduction**

150 Advanced Concepts in Endocarditis

The collective understanding of infective endocarditis (IE) has changed significantly since its early characterization by Sir William Osler [1, 2]. In most low-and-middle income countries, rheumatic fever accounts for approximately two-thirds of all endocarditis cases [3–5], whereas in developed countries it is responsible for less than 10% of instances [6]. Over the past decade the incidence of IE has been increasing, with a recent study showing an overall increase of >30% between 2000 and 2011 [7]. The American Heart Association identified IE

This surge in IE has been linked, in part, to recent medical advances, including increased use of implantable cardiac devices and a growing population of patients with chronic comorbidities [5, 9, 10]. Moreover, 10–35% of newly diagnosed cases of IE are thought to be healthcare associated infections, and hospital-acquired IE attributable to sources other than cardiac surgery is an emerging problem with mortality as high as 30–50% [11, 12]. The above observations can be explained, to some degree, by increases in antibiotic resistance including greater incidence of methicillin-resistant *Staphylococcus aureus* (MRSA), and higher prevalence of

In terms of intravenous drug use, injectable heroin has seen significant escalation [14, 15], with an associated incidence of IE growing by 58% between 2000 and 2013 [14]. In addition to the disease burden on individual patients and their families, the health-care system is further taxed with managing this difficult and expensive to treat population [14, 16]. Finally, it is important to recognize that recent years have seen IE presentations becoming more acute in nature, making diagnosis and treatment more challenging at times [5, 17, 18]. Among key complications of acute IE, the development of potentially devastating septic emboli (SE) may be seen. In this chapter, we will focus on the pathophysiology, diagnosis, and management of SE in the context of IE, using a systematic anatomic approach and outlining some of the most

recent developments in this fast-changing area of cardiovascular infectious disease.

When discussing the pathophysiology of emboli of cardiac origin, one must consider both noninfective (Libman-Sacks or autoimmune, Marantic or related to wasting illnesses such as cancer) and infective (e.g., bacterial or fungal) endocarditis [19–21]. As an overarching theme, any condition that results in structural "damage or alteration" of cardiac valves has the potential to trigger an inflammatory reaction leading to the formation of valvular "vegetations" and thromboembolic complications [22]. In contrast to non-infectious valvular etiologies which lead to sterile emboli, IE has the potential to produce SE which typically are composed of a conglomerate of infectious organisms, inflammatory cells, platelets and fibrin [23]. In contrast to non-infectious emboli, SE have the potential to result in both vascular compromise and hematogenous spread of infection [24–26]. Evidence shows that as many as 50–82% of patients with IE may be affected by some form of SE, including both symptomatic and sub-clinical

and associated complications as a major source of cardiovascular disability [8].

comorbidities in an increasingly aging population [2, 5, 12, 13].

**2. Pathophysiology of septic emboli**

The genesis of SE is predicated on the appearance of a thrombus in a critical cardiac (usually valvular, **Figure 1**) location. This is usually associated with the presence of infected pacemaker leads, prosthetic valve, or some form of anatomic (acquired or congenital) abnormality of the native valve [30]. Bacterial species that feature specific adhesion matrix molecules are particularly likely to attach onto the damaged valvular surfaces, endocardium, or exposed prosthetic material [30–32]. Simultaneous presence of inflamed tissue and microorganisms leads to further accumulation of fibrin-platelet-microorganism complexes, contributing to the growth of infectious vegetations [33, 34]. If fragments of such vegetations—in whole or in part—are released into the circulation, SE is said to have occurred [5, 31, 32]. Microorganisms most often implicated include *Staphylococci*, *Beta-hemolytic Streptococci*, *Haemophilus*, *Actinobacteria*, *Caridobacterium*, *Eikenella*, and *Kingella*. The latter 5 are often listed under the acronym, "HACEK", and are less likely to cause IE than *Staphylococci* and *Streptococci* [10, 32, 35, 36]. Identifying the causative organism is critical to instituting prompt treatment with the most appropriate antibiotics. It is important to recognize that SE may affect any organ system or anatomic location, although certain patterns of involvement tend to be more common than others. This chapter will review key clinical evidence and developments regarding the diagnosis and management of SE. The authors will organize the current discussion according to regional/anatomic considerations in order to systematize and simplify the review process.

**Figure 1.** An example of a large necrotic bacterial vegetation, leading to the replacement of the entire posterior mitral valve leaflet. A pustule can be seen in the immediate vicinity of the vegetation. Also note the normal-appearing leaflet, chorda tendinea, and papillary muscles of the anterior leaflet (labeled as ANT. MV).
