Infective endocarditis complicated by embolic events: Pathogenesis and predictors

Abstract Background Infective endocarditis (IE) continues to be associated with great challenges. Embolic events (EE) are frequent and life‐threatening complications in IE patients. It remains challenging to predict and assess the embolic risk in individual patients with IE accurately. Hypothesis Accurate prediction of embolization is critical in the early identification and treatment of risky and potentially embolic lesions in patients with IE. Methods We searched the PubMed, Web of Science, and Google Scholar databases using a range of related search terms, and reviewed the literatures about the pathogenesis and embolic predictors of IE. Results The development of IE and its complications is widely accepted as the result of complex interactions between microorganisms, valve endothelium, and host immune responses. The predictive value of echocardiographic characteristics is the most powerful for EE. In addition, both easily obtained blood biomarkers such as C‐reactive protein, mean platelet volume, neutrophil‐to‐lymphocyte ratio, anti‐β2‐glycoprotein I antibodies, D‐Dimer, troponin I, matrix metalloproteinases, and several microbiological or clinical characteristics might be promising as potential predictors of EE. Conclusion Our review provides a synthesis of current knowledge regarding the pathogenesis and predictors of embolism in IE along with a review of potentially emerging biomarkers.

seemingly unfavorable environment as the cardiac valves. Insufficient understanding of the specific underlying mechanisms involved in the pathogenesis of IE is one of the barriers to improving the management of IE and associated EE.
In this review, we focused on the pathophysiology of IE and potential predictors of embolic complications.

| METHODS
We searched the PubMed, Web of Science, and Google Scholar databases using a range of search terms, including "endocarditis," "emboli," "mechanism," "pathogenesis," "predict*," "risk factor," together with "right" or "left," "prosthetic," or "native." We reviewed journals published in English primarily from the past 20 years. However, the search also included highly regarded older publications. We searched the reference lists of the articles identified using this search strategy and selected additional articles that were used to explain some concepts in more detail.

| EMBOLISM COMPLICATIONS ASSOCIATED WITH IE
Currently, the imaging methods used to assess EE primarily include ultrasound, MRI, CT, and PET-CT. The brain is the most common site of embolization, followed by solid organs, including the spleen, kidney, and lung. Less common sites of embolization included peripheral arteries, coronary circulation, and eyes. 4 Appropriate antimicrobial therapy remains the preferred treatment to prevent EE. 3 However, there is no evidence to suggest that prolonged antimicrobial treatment can effectively reduce the incidence of EE. Guidelines recommend that the selection of antibiotics should be based on the sensitivity of the newly isolated bacteria, and the duration of antibacterial treatment is usually 2-6 weeks. 3 Patients with IE might also benefit from early surgery during the first several days following the initiation of antibiotic therapy because the risk of EE is highest at that time. According to the 2015 ESC guidelines, the primary indications for the use of surgery to prevent EE are the presence of persistent vegetations >10 mm and one or more previous episodes of EE despite appropriate antibiotic therapy. 3

| Vegetation and bacteremia
Frequently, IE is initiated by an endothelial injury that results in exposure of the subendothelial extracellular matrix that activates platelets and causes the formation of a fibrin-platelet clot. 5 The sterile cardiac lesion consists primarily of platelets and fibrin and is called nonbacterial thrombotic endocarditis (NBTE). The pathogenesis of NBTE involves injured or inflamed endothelium, combined with a hypercoagulable state. 6 Because the vegetations in NBTE are friable, systemic EE occurs more frequently in NBTE than in IE. Trousseau's syndrome has been reported as being associated with endocarditis, and NBTE can be the first presentation that leads to the diagnosis of Trousseau's syndrome.
Subsequently, microorganisms in the blood adhere to the fibrin-platelet clot to initiate vegetation formation. Pathogenesis also includes critical components of innate immunity and patternrecognition receptors on the surfaces of epithelial cells, leukocytes, and platelets that recognize the bacteria. 5

| Activation of coagulation and the complement and innate immune system
Coagulation has been proposed to be "at the heart" of IE. 5 The coagulation system activates the complement system in several different ways. 7 Thrombin, the cleavage product that forms as a result of the coagulation cascade, plays a fundamental role in hemostasis and bridges clotting and inflammation. The strong association between the coagulation and the innate immune system, which is referred to as immunothrombosis, 5 is maintained in a delicate balance in healthy people. When this balance is disrupted, a range of diseases, especially IE, can occur.

| Factors responsible for the valve's susceptibility to infection
Tissue destruction and inflammation are responsible for the valve's susceptibility to infection. Mechanical damage or inflammation of the cardiac endothelium, combined with an enhanced coagulation state and an imbalanced innate immune system, leads to platelet-fibrin aggregates in an environment that proves suitable for deposition. The deposition of these aggregates makes the valve more vulnerable to pathogens ( Figure 1).

| Valve colonization
Bacterial adhesion to damaged or inflamed valves is the initial step in valve colonization and ensuing vegetation formation and maturation.
In this process, most endocarditis pathogens need to overcome the strong shear forces present in the chambers of the heart by binding and activating platelets and using them like bridges. 8 In addition to platelets, Staphylococcus aureus produces von Willebrand factorbinding protein (vWFbp) that binds to the A1 domain of vWF directly and expresses two types of fibronectin-binding proteins (FnBPs), which allows the bacteria to interact with fibronectin. 9 For S. aureus, proliferation and formation of a biofilm is an excellent survival strategy that is employed after relatively weak initial adhesion. The expression of FnBPs is critical for valvular colonization since they assist with the initial adherence to the valves, control endothelial cell invasion, and aid in shielding S. aureus from the immune system. 10

| Prosthetic valve IE
Prosthetic valve IE has been recognized as the most severe form of IE. Here we primarily provide information concerning the mechanism underlying IE associated with the prosthetic aortic valve. High turbulent shear stress exists in the vicinity of mechanical aortic heart valves, which promotes platelet activation and aggregation. The high stress increases the chances for cell damage, while regions of flow stagnation and flow separation promote the deposition of damaged cell elements, which leads to NBTE. 8 Aortic regurgitation caused by an incomplete seal around the aortic valve leaflets can explain the abnormal high turbulent shear stress near the prosthetic valve. 11 Also, incomplete valvular seals create suitable spaces for thrombus formation, and the implanted cardiac device itself can serve as a nidus for infection. 12 Because microbial surface components recognize adhesive matrix molecules, methicillin-resistant Staphylococcus aureus (MRSA) can colonize the fibrin-platelet matrices of NBTE and even adhere to normal or minimally injured endothelium. The presence of cardiac prostheses is conducive to the adhesion of MRSA to the valve via biofilm formation, which facilitates prosthetic valve IE.

| Right-sided IE
Right-sided IE is strongly associated with IV drug abuse, although cardiac implanted electronic device infections, indwelling lines, and uncorrected congenital heart disease also are risk factors. 13 Repeat IV drug abusers tend to have cumulative subclinical endothelial injuries due to multiple inoculations of small bacterial loads. Also, certain substances in IV drugs can cause direct endothelial damage leading to vegetation formation. Addictive drugs, such as cocaine, can induce pulmonary hypertension through sympathomimetic actions, resulting in increased pressure gradients and turbulence, which increases the valve's vulnerability to pathogens. 14 Moreover, the proposed pathogenesis also involves immune complex formation and deposition mainly on the tricuspid valve due to antibody-inducing antigenic   Also, RT3DTEE exhibited better embolization prediction performance than 2DTEE. The best cutoff points related to increased risk for EE during infection when using RT3DTEE and 2DTEE assessments were the maximum length of vegetation ≥16.4 and ≥9.5 mm, respectively. 17

| Vegetation mobility
The incidence of EE was significantly higher in patients exhibiting mobile vegetations. It is not surprising that mobile vegetation can lead to a higher risk of EE, which has been proven by multiple studies over the past several years. 18

| Vegetation location
A meta-analysis reviewing 23 studies proved that a higher EE risk existed in IE patients with vegetations on the mitral valve versus the aortic valve. 18 Another study noted that vegetations attached to the anterior mitral leaflet were associated with a higher incidence of embolism. 19 The authors proposed that the anterior leaflet, which is the larger of the two mitral leaflets, can destabilize attached vegetations due to more rapid and forceful movement during valve closure. 19 Furthermore, compared with the more "aggressive" S. aureus, Streptococcus viridans is associated with a higher incidence of mitral endocarditis. Also, the more gradual progression of infection seen with can result in larger vegetations before symptoms appear.
Increased EE, especially pulmonary embolism, is an outstanding

| Mean platelet volume
Both endothelial damage and specific pathogens can initiate platelet activation in IE progression. Activated platelet surface receptors, such as the FcγRIIa receptor and GPIIb/IIIa, play a significant role in the process of bacteria binding to platelets. Therefore, mean platelet volume (MPV), which is associated with platelet function and activation, has achieved increased attention due to its predictive potential for the occurrence of embolism complications in IE patients. Increased MPV has been detected in patients who experienced EE compared to those who did not experience EE. 25 Also, MPV greater than 8.6 fL has proven to be a strong independent predictor of EE. 25 Thus, to some extent, antiplatelet therapy might reduce the risk of IE patients experiencing embolization. However, whether antiplatelet therapy is needed and effective for all IE patients is still controversial.

| Neutrophil-to-lymphocyte ratio
The neutrophil-to-lymphocyte ratio (NLR) can predict the severity and extent of cardiovascular disease. The NLR can be obtained immediately from a complete blood count. A retrospective study reported that an NLR above 3.045 measured on admission, exhibited a 73.3% sensitivity and a 51.9% specificity for predicting embolization. 26 Neutrophils and lymphocytes are of considerable importance in the inflammatory reaction associated with infection. While the NLR can provide considerable information concerning disease severity compared to conventional biomarkers, the potential association of NLR with EE needs additional exploration.

| Anti-β2-glycoprotein I antibodies
Anti-β2-glycoprotein I (β2GPI) antibodies have been reported to enhance activation of the coagulation system and platelets, which increases the risk for thrombosis and vegetation development in patients with IE. For individuals diagnosed with IE, EE occurred more frequently over time among patients expressing anti-β2GPI IgM, while patients who exhibited both anti-β2GPI IgM and anti-cardiolipin (aCL) IgM had a higher risk for cerebral embolism. 27

| D-dimer
D-dimer (DD) is a cross-linked dimer resulting from the degradation of fibrin. DD is used as a biomarker to indicate serum coagulation levels, fibrin turnover, and the autoimmune inflammatory response.
Since fibrin primarily results from activation of the coagulation cascade, which commonly occurs in IE-related tissue destruction, DD levels may be valuable in predicting EE risk. An elevated DD level might be a meaningful predictor for embolism as a consequence of increased fibrin turnover. In a recent study, D-dimer levels ≥3393 μg/L were significantly associated with the incidence of ischemic stroke in patients with IE. 28

| Troponin I
Troponin I (TnI) is an extremely sensitive biochemical marker for myocardial injury. TnI is frequently elevated in IE due to the presence of microbial infection and inflammation. There were statistically significant associations between elevated TnI levels and lethal complications, including central nervous system (CNS) events and major arterial embolism. 29 In that study, the prevalence of increased TnI in IE patients with embolism might be due to coronary septic embolization with subsequent myocardial injury and the release of TnI. However, severe infection or sepsis also can cause an elevated TnI.
Therefore, the association between TnI and embolism needs additional investigation. infections compared to other pathogens. 32 A recent systematic review of fungal endocarditis also reported a high embolic rate in patients infected by fungi. 33 Another study showed that infection with Staphylococcus spp. also increased the risk of EE. 18 5.7 | Accepted clinical characteristics

| Time-dependent factors
The majority of IE patients experience their first EE before or on the day of hospital admission, and before or on the day of echocardiography. 34 The study showed that echocardiographic characteristics were time-sensitive predictors of embolisms. 34

| Skin manifestations
According to one study, patients with skin manifestations (Osler's nodes, Janeway lesions, purpura, and splinter and conjunctival hemorrhages) presented a higher rate of IE-related cerebral emboli. Janeway lesions also were associated with more extracerebral emboli.
Consequently, the presence of these cutaneous lesions might indicate an active embolic process that is responsible for systemic complications. 37

| Conduction abnormalities
Patients with cardiac conduction abnormalities exhibited a significantly higher risk of experiencing in-hospital EE compared to patients without such abnormalities. 38 However, an appropriate explanation for the association between conduction abnormalities and a higher risk of EE is unknown.

| CONCLUSIONS
Our review presents several novel findings on the pathogenesis of IE and its embolization complications. Among the abovementioned predictors of EE discussed in this review, the predictive value of echocardiographic characteristics is the most powerful.
Easily obtained blood biomarkers also have promising prospects as

CONFLICT OF INTEREST
The authors declare no potential conflict of interest.

AUTHOR CONTRIBUTIONS
Wangling Hu: conceptualization and preparation of the original draft.
Xindi Wang: preparation of the original draft. Guanhua Su: review and editing of the writing and funding acquisition.

DATA AVAILABILITY STATEMENT
The data used to support the findings of this study are available from the corresponding author upon request.