5.7 High-mobility group box 1 protein (HMGB1)

HMGB1 is a pleiotropic cytokine that has been implicated in the pathophysiology of systemic inflammatory response syndrome (SIRS) and sepsis. HMGB1 is measurable in the systemic circulation in response to severe injury. This protein has the propensity to bind to a variety of inflammatory mediators such as lipopolysaccharide and pro-inflammatory cytokines, including IL-1. The role of HMGB1 as an endogenous molecule facilitates immune responses and has an important role in homeostasis between tissue and disease. HMGB1 is implicated in the pathophysiology of a variety of inflammatory diseases, and it has been found that variation in the HMGB1 gene is associated with mortality in patients with systemic inflammatory response syndrome [58]. Kornblit et al. performed a long-term, 4-year study comparing HMGB1 sequencing data in 239 intensive care unit (ICU) patients with HMGB1 blood levels and clinical outcomes. The promoter variant ˜1377delA was associated with a markedly reduced long-term survival rate after ICU admission in SIRS patients. There was also a significant interaction with a polymorphism within the coding region of the HMGB1 gene at position 982 (C > T) in exon 4; carriers had an increased frequency of early death from infection [59].

### 5.8 Toll-like receptor 2 (TLR2)

TLRs are a group of pattern recognition receptors. They play important roles in regulating inflammatory reactions and activating adaptive immune response to eliminate infective pathogens [60]. TLR2, a key member of TLR family, can recognize a variety of bacterial lipoproteins. The mechanism of TLR2-recognizing lipoproteins has been elucidated; after TLR2 recognizes lipoproteins, it activates MyD88 adaptor-like protein and initiates a signaling pathway, which induces further immune response [61]. This evidence puts TLR2 gene as an appealing candidate for determining sepsis risk. In a recent meta-analysis, Gao et al. [62] analyzed a total of 12 studies (11 records) with 898 cases and 1517 controls examined to determine the association between the TLR2 Arg753Gln polymorphism and sepsis risk. The combined results of the overall comparison indicated that there were significant associations between the TLR2 Arg753Gln polymorphism and sepsis risk under the allele comparison model and the dominant model, respectively (for A vs. G, OR 1.76, 95% CI 1.05–2.95, p = 0.03; for AA/GA vs. GG, OR 1.92, 95% CI 1.11–3.32, p = 0.02).

#### 5.9 Genome-wide association study

Rautanen et al. [63] did a genome-wide association study in three independent cohorts of white adult patients admitted to ICU with sepsis, severe sepsis, or septic shock due to pneumonia or intra-abdominal infection (n = 2534 patients). The primary outcome was 28-day survival. Results for the three cohorts of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients. The most significantly associated SNPs were genotyped in a further 538 white patients with sepsis due to pneumonia (an independent fourth cohort), of whom 106 died. In the genome-wide meta-analysis of three independent pneumonia cohorts, common variants in the FER gene were strongly associated with survival (p = 9°7 ˛ 10–8; OR 0°52 [95% CI 0°41–0°66]). Genotyping of the additional fourth cohort strengthened the evidence for association with survival (p = 5°6 ˛ 10–8; OR 0°56 [0°45– 0°69]).

Infective Endocarditis: Inflammatory Response, Genetic Susceptibility, Oxidative Stress… DOI: http://dx.doi.org/10.5772/intechopen.84908

#### 5.10 The evidence in infective endocarditis

There are many risk factors described for the development of IE; nevertheless up to 30–50% of patients with this diagnosis does not have any known risk factor [64]. Therefore, as in sepsis per se, there is thought to be immunogenetic influences that affect the risk of development and outcomes in IE. However, in comparison to sepsis, evidence of the immunogenetic influence on the susceptibility and outcomes of IE is less robust. Golovkin et al. [65] hypothesized that inherited variation in TLR and triggering receptor expressed on myeloid cells (TREMs) genes may affect individual susceptibility to IE. They conducted a specific SNP study in which the distribution of genotypes and alleles of the TLR1, TLR2, TLR4, TLR6, and TREM-1 gene polymorphisms was investigated in 110 Caucasian subjects with IE and 300 matched healthy blood donors. ORs with 95% CI were calculated. They found that C/C genotype of the rs3775073 polymorphism within TLR6 gene was associated with a decreased risk of IE (OR = 0.51, 95% CI = 0.26–0.97, p = 0.032) according to the recessive model; however, there was no association between the other investigated SNPs within TLR andTREM-1 genes and IE.

Moreau et al. [66] conducted a GWAS of 67 patients with definite native valve S. aureus IE (cases) and 72 matched native valve patients with S. aureus bacteremia but without IE (controls). Unfortunately, no SNPs were significantly associated with S. aureus IE at the genome-wide level (p <sup>&</sup>lt; <sup>5</sup> ˜ <sup>10</sup>°<sup>8</sup> ). Four suggestive SNPs (p < 0.00001) were located on one locus on chromosome 3, near the genes CLDN11 and SLC7A14. For all, the frequency of the minor allele was lower in cases than in controls, suggesting a protective effect against S. aureus IE. The same association was observed using an independent Danish verification cohort of Staphylococcus aureus bacteremia with (n = 57) and without (n = 123) IE. An ex vivo analysis of aortic valve tissues revealed that S. aureus IE associated SNPs mentioned above were associated with significantly higher mRNA expression levels of SLC7A14, which is a cationic amino acid transporter protein. These results suggest an IE-protective effect of SNPs on chromosome 3 during S. aureus bacteremia. The authors concluded that the effects of protective minor alleles may be mediated by increasing expression levels of SLC7A14 in valve tissues.

#### 6. Inflammation and oxidative stress

The modern mitochondria have an evolution of more than a billion years, originating as an invading Eubacterium in early eukaryotic cells. The knowledge of the structure, functionality, and the similarities of the DNA between mitochondria and bacteria strongly prove the endosymbiotic origin of the mitochondria. Of the 1000 or more mitochondrial proteins, only 13 are encoded by the mitochondrial genome, the rest is transcribed and translated into the nuclear genome and transported to the inner mitochondrial membrane [67].

In the heart the populations of mitochondria include subsarcolemmal mitochondria, which are more susceptible to injury. Subsarcolemmal mitochondria provide energy for membrane-related processes, including signal transduction, ion exchange, and substrate transport, whereas the intermyofibrillar mitochondria more directly support muscle contraction [68].

The mitochondrial oxidative phosphorylation process is responsible for the conversion of macronutrient energy (e.g., glucose, fatty acids, and amino acids) into ATP through a set of coordinated and highly coupled reactions where the macronutrients are oxidized and the oxygen is reduced to water and adenosine diphosphate (ADP) is phosphorylated to ATP.
