The inclusion criteria were: (a) animal or human studies; (b) biomarkers used in both ischemic heart disease and kidney disease; (c) original study or meta-analysis; (d) English or Portuguese language; (e) published in the previous 20 years. The exclusion criteria were: (a) duplicated studies; (b) commentaries or editorials. The articles were considered to be of high quality if they had been indexed in MEDLINE and published in journals with an acceptable impact factor.

Elevated levels of NGAL, a member of the lipocalin iron-carrier protein family, have been associated with ischemic and nephrotoxic kidney injury.3 It is measured using latex particles of sensitized anti-NGAL antibody, assessed in blood or urine samples, using validated kits. NGAL was assessed as a prognostic marker in 76 survivors of cardiac arrest, high levels indicating worse outcome, the optimal time point for predicting long-term outcomes being on the third day of the event. However, NGAL had a low predictive value alone, and according to the authors should be used together with other predictors of prognosis.4

FGF23 is a protein that participates in phosphate and vitamin D metabolism. It can be measured using an ELISA kit. In a cross-sectional study of 177 patients with CKD who underwent cardiac catheterization, FGF23 levels were shown to be associated with severity of CAD after adjusting for traditional risk factors.5

Another study analyzed 833 patients with stable CAD who had 402 events (death or cardiovascular event) during a median follow-up of six years. After adjustment for traditional risk factors, patients with levels in the highest tertile had a two-fold higher risk of death or cardiovascular events.6

Klotho is a co-receptor associated with FGF23. In a study of 956 patients, Klotho deficiency was associated with the occurrence of occult atherosclerotic disease.7 In another report, reduced Klotho gene expression in the aorta was also associated with CAD severity.

TIMP-2 induces cell-cycle arrest. There have been few reports on the measurement of this biomarker in cardiovascular disease. TIMP-2 levels can be measured by NephroCheck® (Astute Medical), the commercial name of a combination of two urinary biomarkers, TIMP-2 and insulin-like growth factor-binding protein 7 (IGFBP7), expressed as [TIMP-2]·[IGFBP7], that can be used to identify patients at high risk of AKI. In 2014, the FDA approved marketing of NephroCheck® to measure urinary [TIMP-2]·[IGFBP7] and to determine if certain critically-ill patients are at risk of developing moderate to severe AKI. Regarding cardiovascular implications, studies on TIMP-2 are experimental and focus on the pathophysiology of angiogenesis and atherosclerosis. An experimental study showed that mice with genetic alterations in the TIMP2 gene (-/-) had decreased matrix metalloproteinase (MMP)-2 expression and increased anti-angiogenic factors, which resulted in abnormal ventricular remodeling and severe heart failure.8 Additional evidence to support the role of TIMP-2 in protecting against CAD comes from studies examining poly(ADP-ribose) polymerase (PARP) and apolipoprotein E (ApoE) genes. Mice with a genetic deficiency in PARP fed an atherogenic diet demonstrated an increase in TIMP-2 expression, counteracting the deleterious effects of MMP activation.9 A study in APOE -/- knockout mice demonstrated that TIMP-2 plays a greater protective role than TIMP-1 during the pathogenesis of atherosclerosis, in part by suppressing MMP-14-dependent monocyte/macrophage accumulation in atherosclerotic plaques.10 A study involving 67 patients with ACS (24 controls) concluded that increased TIMP-2 expression disturbs the equilibrium of the MMP/TIMP inhibition system and, as a consequence, contributes to atherosclerotic plaque destabilization and the occurrence of ACS.11

Syndecans are an important family of cell surface heparan sulfate proteoglycans. Syndecan 1 (SDC1 or sCD138) can be measured using the sCD138 ELISA kit, a solid phase sandwich ELISA for the in-vitro qualitative and quantitative determination of sCD138 in supernatants, buffered solutions or serum and plasma samples. This assay will recognize both natural and recombinant human sCD138. In adult tissues, SDC1 is predominantly expressed by simple and stratified epithelia.12 In an experimental study with rats, SDC1 levels were elevated in rats with induced MI.12 Another experimental study demonstrated that increased SDC1 expression in MI protects against an excessive inflammatory response, reducing cardiac dilatation and ventricular dysfunction post-MI.13

IL-6 is a 26-kDa pleiotropic immunomodulatory cytokine secreted by a variety of cell types that plays a critical role in many inflammatory processes. ELISA kits for the measurement of human or mouse IL-6 are available from a number of companies, although IL-6 is not usually measured in clinical practice. IL-6 is associated with atherosclerotic disease, as shown in a subanalysis of the STABILITY trial that studied 14 611 patients with stable chronic CAD and identified an association of IL-6 with the risk of major adverse cardiovascular events, cardiovascular death, MI, all-cause mortality, and hospital admission for heart failure.14 Serum IL-6>1 pg/ml in patients with chest pain and intermediate risk (according to the Atherosclerotic Cardiovascular Disease risk score) referred for coronary angiography was predictive of significant CAD.15 Measurement of IL-6 may be useful to reclassify intermediate risk patients into higher risk categories. Studies on IL-6 receptors suggest that IL-6 blockade could provide an innovative therapeutic approach to coronary heart disease prevention, but robust clinical trials and genetic testing in large populations are required to validate and prioritize new therapeutic targets.14,15

Studies have demonstrated the potential role of galectin-3, a protein in the lectin family, as a biomarker in patients with heart failure.16 It can be measured by quantitative sandwich enzyme immunoassay, for which kits have been approved by the FDA. For patients with CAD, elevated levels six hours post-MI were correlated with adverse clinical events at 30 days.17 Another study found no relationship between galectin-3 levels and cardiovascular events but did find an association with new-onset atrial fibrillation and new diagnosis of heart failure.18 The GIPS-III study analyzed 263 patients and found that galectin-3 was an independent predictor of left ventricular ejection fraction four months post-MI.19

Plasma-soluble VCAM-1 and ICAM-1 can be measured using commercially available ELISA kits. A meta-analysis of 18 studies with 3546 cases found that the K469E polymorphism of the ICAM1 gene increases the risk of developing CAD.20 Another study involving this polymorphism and a second polymorphism, G2412, found no association between these genetic alterations and the occurrence of CAD and MI. In a subgroup of 2880 patients from the MESA study in whom ICAM-1 and VCAM-1 polymorphisms were analyzed, the authors found that ICAM-1 gene polymorphisms were associated with increased circulating ICAM-1 levels, but not with these patients’ coronary calcium score, exemplifying the conflicting results in the literature on these genetic polymorphisms.21 Another interesting study, which measured circulating ICAM-1 and VCAM-1 levels and assessed degree of restenosis in 15 patients with stable angina before and six months after bare-metal stent implantation, concluded that elevated circulating levels of VCAM-1, but not of ICAM-1, were correlated with stent restenosis.22 Circulating ICAM-1 and VCAM-1 levels were measured in a study that included 75 patients with CAD, in which only VCAM-1 was shown to be a powerful predictor of major events in patients with ACS.23 In a subgroup of the PRIME study in which patients who experienced an acute event during five-year follow-up were compared with controls, high ICAM-1 levels predicted future cardiac events. Elevated circulating ICAM-1, VCAM-1 and E-selectin levels have also been observed in patients with coronary slow-flow; these could be indicators of inflammation and endothelial activation.24,25