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Page 10 of 19 Cervantes-Gracia et al. Vessel Plus 2020;4:27 I http://dx.doi.org/10.20517/2574-1209.2020.22

chemokines and adhesion molecule synthesis in damaged myocardium and causing additional leukocyte
[149]
infiltration in mice .

Toll-like receptors (TLRs) may be key to understanding heart failure. TLR4 deficiency is associated with
[150]
decreased in size of damage by infarct and reduction of systemic inflammation in mice . In humans, the
[151]
activation of TLR4 in monocytes is associated with the development of cardiac failure after AMI [Figure 3] .
By contrast, deficiencies in the function of TLR2 were found to reduce myocardial fibrosis and improve
[152]
ventricular remodeling after AMI in a murine model .

Atherosclerosis is often described as a chronic inflammatory process. Deregulation in the endothelium is
mediated by cell adhesion molecules, such as ICAM1, P-selectin and VCAM1. Additionally, the secretion
of cytokines has a role in atherogenesis, namely IL-1, IL-6, TNF, IL-4, IL-10 and IL-13 [Figure 3]. The
detection of some of these molecules in plasma has identified associations that could help to predict
atherosclerosis severity. Moreover, the identification of cell types through flow cytometry has proven to
14+
16++
be a promising predictor for atherogenic levels of severity. The amount CD CD monocytes present in
16+
circulation has been found to be inversely correlated to plasma HDL levels while CD monocytes levels
[153]
are proportional to severe atherosclerosis [Figure 3] .
CVD AND CIN BIOMARKERS
The identification of rapid, predictive biomarkers for CIN is essential as current targets are relatively slow
to be useful, or the assays are just too expensive to be launched in a clinical setting. Some of the postulated
biomarkers for CIN and CVD are shown on Table 1. An early predictive biomarker of AKI is human
neutrophil gelatinease-associated lipocalin (NGAL). NGAL is a small protein of the lipocalin superfamily
that was initially identified from the supernatant of activated human neutrophils in 1993. Successive studies
have recognized renal NGAL as a unique, specific biomarker for the early detection of AKI in critically ill
patients and after CM administration. Urinary and serum levels of NGAL increase well before the increase
of serum creatinine levels (~2 h). As a result, NGAL is increasingly studied as a marker of AKI [154-157] .
Another proposed sensitive, early, non-invasive biomarker for AKI kidney injury is urinary neutrophil
gelatinase-associated lipocalin (uNGAL) also known as lipocalin-2. uNGAL is an iron-transporting
protein that rapidly accumulates in the urine and kidney tubules after nephrotoxic and ischemic insults.
[158]
Zappitelli et al. concluded that uNGAL is an effective predictor of AKI which is triggered in advance of
increases in serum creatinine concentration. Despite these findings, the use of uNGAL is still experimental.

Liver type fatty acid binding protein (L-FABP) is an intracellular lipid chaperone and is expressed in renal
proximal tubule cells and secreted into the urine in response to hypoxia caused by a decrease in peritubular
capillary blood flow. Although L-FABP concentration is significantly increased in CIN patients after
24 hours, the specificity of this biomarker for CIN is low on account of a range of potential confounders .
[159]
Tissue plasminogen activator (tPA), a part of the serine protease family, is a plasma protein involved in the
breakdown of blood clots and a key fibrinolytic agent that takes part in the recruitment of inflammatory
cells. Some other roles of tPA involve the turnover of extracellular matrix components via activation of
matrix metalloproteinases and immune-modulatory functions. Plasminogen activator inhibitor-1 is the
main physiological inhibitor of endogenous fibrinolysis which functions through the inhibition of tPA
[162]
and the urokinase type activator (uPA) [160,161] . A recent study reported a relationship between increased
serum tPA levels with an increased rate of mortality of dialysis-dependent AKI (AKI-D) patients. Elevated
tPA expression has been detected in the proximal tubular epithelial cells of ischemic kidneys, in animal
models. Removing tPA by antisense treatment had reduced the influx of neutrophils and helped protect
renal function during ischemia-reperfusion injury. This suggests tPA inhibition as a novel strategy to
[163]
improve ischemic AKI . Many additional studies have also implied the involvement of tPA in the process
of kidney fibrosis that leads to progression of CKD [164-166] .