In recent years, the utility of biomarkers in heart failure diagnosis and prognosis prediction had become much important than previous era. In this review article, we introduce several significant biomarkers in heart failure diagnosis and risk stratification. We also show some new biomarkers which would be available clinically in the future. Although biomarkers can be a great help in heart failure confirmation and treatment, clinical condition and physical findings are still the most important clue to approach a patient with high probability of heart failure. Synergism of the usefulness of biomarkers and clinical evaluation may lead patients with heart failure to a better outcome.
Heart failure (HF) is one of the leading cause of cardiovascular death worldwide. Also, the incidence and prevalence of the disease are both increasing gradually. In recent years, biomarkers are gaining greater attention for their utility in HF management. These biomarkers may reflect various pathophysiological aspects of HF, including myocardium stress, inflammation, oxidative stress, neurohormonal, and myocardial remodeling. In this review article, we will introduce some powerful and significant biomarkers for heart failure.
B-type natriuretic peptide (BNP)
BNP or its amino-terminal cleavage equivalent (NT-proBNP) is derived from a common 108-amino acid precursor peptide (proBNP108) that is generated by cardiomyocytes in the context of myocardial stretch. BNP has become the standard of care in the diagnosis of HF. There is accumulating evidence that BNP is also useful for screening, assessing prognosis, and titration of drug therapy in HF.
Once in the blood, BNP binds to the Natriuretic Peptide receptor A, causing increased intracellular cyclic guanosine monophosphate–dependent signaling cascade. The effects include diuresis, vasodilation, inhibition of renin and aldosterone production, and inhibition of cardiac and vascular myocyte growth. BNP and NT-proBNP are similar but are not interchangeable. BNP has a half-life of approximately 20 minutes and NT-proBNP has a half-life of 1 to 2 hours, which results in higher circulating and less ﬂuctuating NT-proBNP concentration.
In 2013 ACCF/AHA Guideline for the Management of Heart Failure , natriuretic peptide has gained the highest level of recommendation for clinical use for any biomarker in HF, especially in the setting of clinical uncertainty (class 1 recommendation, level of evidence A). There are two clinical scenarios represented in this indication. When patients present with signs and symptoms suspicious of HF (shortness of breath, fluid retention, peripheral edema, evidence of central congestion), elevated natriuretic peptide level provides confirmation of an underlying cardiac cause of these symptoms. Conversely, when there are alternative explanations or if the presentation is subtle and there is some degree of uncertainty, testing natriuretic peptide levels helps establish the diagnosis of HF when levels are higher than the cut-off values, and levels below the cutoff have a high negative predictive value. Furthermore, for patients with established HF, a deviation of natriuretic peptide levels (particularly an increase of more than 30%) may represent evolving destabilization that may warrant some medical adjustment, whereas an unchanged or reduced level may be taken as objective evidence of clinical stability. The consistent association between elevated natriuretic peptide levels and worse prognosis has led to the promise that intensification of medical therapy in those with elevated natriuretic peptide levels can lead to better outcomes . However, the rise in natriuretic peptide levels may caused by other reasons (eg, age, renal insufficiency) and still require interpretation in the clinical scenario.
In a recent study that utilized the NT-proBNP threshold, only half of patients were able to reach the target of less than 1000 pg/Ml . In the same study, the inability to reach less than 5000 pg/mL within 3 months after discharge clearly identified advanced, “nonresponsive” HF refractory to medical therapy and with a poor prognosis . This is an important point when assessing the clinical utility of biomarkers, as incremental prognostic values may not guarantee the feasibility or ultimate benefit of intensifying drug therapy according to specific biomarker targets.
Whether a care pathway guided by NT-proBNP measurements can lead to a consistent reduction in rates of hospitalization and mortality, it is reasonable to target those with elevated natriuretic peptide levels by reevaluating their treatment regimen to achieve optimal dosing of guideline-directed medical therapy (Class 2a recommendation, level of evidence B) . On the other hand, the usefulness of BNP and NT-proBNP in guiding therapy for acute decompensated HF (ADHF) is not well established (Class 2b recommendation, level of evidence C) .
Cardiac Troponin T or I
In patient with acute decompensated HF (ADHF), measurement of highly sensitive troponin (hsTn) is recommended by clinical practice guidelines as well as consensus statements . This is mainly to seek the presence of myocardial infarction as the precipitant of ADHF. Compared with conventional troponin assays, hsTn methods detect substantially more myocardial necrosis in patients with HF. Elevated hsTn in the context of ADHF provides important prognostic information and may play an integral role in the evaluation of HF syndromes. In a recent study, hsTnT was detected in 98% of participants among 202 patients with ADHF without acute myocardial infarction (compared with 56% as measured with a conventional TnT method). Elevated serum hsTnT concentration (above 20 pg/mL) identiﬁed a signiﬁcantly higher risk of death (HR=4.7; 95%CI, 1.6- 13.8; P=.005) . In another study, hsTnT was particularly useful among those whose conventional TnT was below 0.03 ng/Ml . Therefore, hsTnT provides valuable incremental prognostic information when conventional assay are normal.
Compared with baseline measurements alone, serially measured hsTn concentrations may inform treatment response and risk for future adverse events. In an analysis performed among 100 patients with ADHF, hsTnT decreased from day 1 to day 3 (P=.04) overall, but this reduction was driven by the group of patients achieving recompensation; in the subgroup of patients who remained decompensated, no signiﬁcant differences were observed in hsTnT from day 1 to day 3 (P=.96). Similarly, deterioration of hsTnI concentration from baseline to discharge may identify those at higher risk for future events. A discharge hsTnI of 23.25 ng/L or higher and BNP of 360 pg/mL or higher were both associated with increased risk for mortality and readmission (P=.003). Patients with increasing hsTnI during treatment had increased mortality compared with patients with stable or decreasing hsTnI (P=.047) . Finally, a favorable change in hsTnT concentrations may predict response to therapy with certain drugs for ADHF, such as serelaxin .
Protein ST2 belongs to the interleukin-1 (IL-1) receptor family with participates significantly in immunologic processes, as well as in the ﬁbrotic heart response to injury . There are two isoforms of ST2 protein: transmembrane (ST2L) and soluble, circulating (sST2) isoforms. Both sST2 and ST2L are induced in cardiomyocytes and ﬁbroblasts by biomechanical stress. ST2L plays an important role in immunologic processes through activated type 2 T-helper cells (Th2) and mast cells, but not expressed by type 1 helper T cells. Whereas the soluble isoform of ST2 (sST2) is considered a novel biomarker for cardiac strain because it lacks transmembrane and cytoplasmatic domain and can be detected in serum.
Through binding of its ligand (interleukin-33, which has anti-ﬁbrosis and anti-remodeling effects) to either ST2 ligand (ST2L) or a soluble “decoy receptor” version (sST2), the ST2 system represents an inducible pathway participant in mitigation of biomechanical stress. Clinically, concentrations of sST2 are predicted by a phenotype of cardiac decompensation and remodeling . Compared to other biomarkers, advantages of sST2 include that its concentration is not affected by age, renal function or body mass index .
In clinical practice, measurements of sST2 in subjects with HF should bring helpful insights into the biological process that leads to adverse outcomes. Higher concentrations of sST2 were associated with a greater likelihood of HF diagnosis. Also, concentrations of the marker were higher in patients who were dead at 1 year compared with survivors. An sST2 concentration greater than 0.20 ng/ml strongly predicted 1-year mortality in patients with and without HF .
In a study of 346 patients with acute HF from the PRIDE study examined the association between sST2 concentrations and clinical characteristics and prognosis. sST2 value correlated with the severity of HF assessed by NYHA, left ventricular ejection fraction, creatinine clearance, B-type natriuretic peptide, amino terminal B-type natriuretic peptide and C-reactive protein .
In summary, ST2 gene with ligand IL-33 modulate heart remodelling via effects on apoptosis, inflammation and ﬁbrosis. sST2 appears to be a biomarker for remodelling. The circulating level of sST2 is correlated with short and long-term post-discharge mortality in acute and chronic heart failure.
Growth differentiation factor (GDF)-15
GDF-15 belongs to the TGF-β cytokine superfamily, and participates in mitigation of myocardial stress and remodeling. GDF-15 expression is strongly induced in cardiomyocytes in response to metabolic stress such as cardiac ischemia or pressure overload. Accordingly, GDF-15 is elevated in acute MI and HF [15-17].
In a study which serum GDF-15 concentration was measured in 455 chronic HF patients, about 75% of the participants had GDF-15 levels above the upper limit of normal, and increasing GDF-15 concentration was associated with increasing symptom severity. Notably, higher GDF-15 values were associated with increased risk of death during a 2 years follow-up (10.0%, 9.4%, 33.4% and 56.2% respectively, p < 0.001). GDF-15 remained an independent predictor of mortality even after adjusting for various traditional risk factors that included NT-proBNP .
In another study, GDF-15 was measured at baseline and after 12 months of treatment with valsartan or placebo. About 85% of all patients had abnormal concentrations (> 1200 ng/L). BNP, hsCRP and hsTnT, GDF-15 was an independent predictor of death in a multiple-variable Cox regression model (HR 1.007, 95% CI 1.001–1.014). After 12 months, GDF-15 levels increased comparable in both groups (median increase 145 ng/L in the placebo group and 173 ng/L in the valsartan group, p=0.94) and such an increase was associated with increased risk of first morbid event and death . As many other novel markers, the promise of therapy guidance using GDF-15 is not yet realized.
Galectin-3 is a member of the lectin family and is found in many cells and tissues. It participates in the inﬂammatory cascade following cardiac injury and especially the process of ﬁbrosis formation. Galectin-3 was ﬁrst measured in the PRIDE study . Patients with HF had higher levels of galectin-3 compared with those without HF (median 9.2 ng/mL vs. 6.9 ng/mL, p < 0.001). According to the result, galectin-3 showed its superiority to predict 60-day mortality than NT-proBNP even after adjusting for traditional risk factors. Similar to previously discussed biomarkers, adding galectin-3 to NT-proBNP and other risk factors provided the best strategy for predicting prognosis in HF. Interestingly, de Boer and colleagues reported that galectin-3 was especially predictive of death in those subjects with HF with preserved left ventricular ejection fraction (HFpEF) .
In summary, galectin-3 appears to be a mediator of cardiac fibrosis, and is increased in acute and chronic heart failure. It could be used to better identify HF (especially HFpEF) patients with a high risk of readmission or death. In the future, maybe we could use galectin-3 concentration to identify asymptomatic patients with early evidence of cardiac fibrosis and prescribe targeted therapy to delay the onset of HF.
Adrenomedullin (ADM) was first isolated from pheochromocytoma cells in the adrenal medulla and has vasodilatory effects. In the later studies, ADM has been found in various organs including the heart, and appears to increased myocardial contractility. ADM release seems to be a compensatory mechanism in HF and correlate with decreasing LVEF, increasing pulmonary artery pressures and the presence of diastolic dysfunction [21,22]. Because serum ADM level is hard to detect, measuring the mid-regional portion of the stable pro-hormone of ADM, the MR-proADM, has been developed and used for further evaluation.
According to the BACH study, MR-proADM was a powerful prognostic factor for death at 90 days . Similarly, in the PRIDE study, MR-proADM had the best AUC for mortality at 1 year among 560 patients . In contrast with a strong correlation was observed between NT-proBNP and LVEF , MR-proADM correlated with age, creatinine and NYHA class, but not with LVEF . In summary, MR-proADM measurement provided a reliable predictor of cardiovascular death and heart failure.
Mediators of inflammation have been always studied intensively as potential biomarkers in HF because inflammation is an important process in HF. C-reactive protein (CRP) is the first inflammatory markers which was noted to be increased in chronic HF patients . Although recent studies confirmed CRP as a prognostic predictor in HF, it might be less suitable as a biomarker for HF because CRP is not specific to inflammatory processes in HF.
Interleukin-6 (IL-6) has also been studied as a biomarker of HF. IL-6 affects intercellular communications between cardiac myocytes and fibroblasts, and alterations in IL-6 concentrations are associated with changing of the cardiac extracellular matrix. The role of IL-6 to predict adverse outcome in HF may be useful, but just like CRP, IL-6 also lacks diagnostic specificity [27-28].
Tumor necrosis factor (TNF-α) contributes to the process of HF and also decreases myocardial contractility through several mechanisms. Serum TNF-α concentration could predict the development of HF in asymptomatic individuals as well as the progression in HF patients[27-28]. However, targeted-therapy for TNF-α blockade did not show better outcome .
Recently, a promising inflammatory biomarker, pentraxin 3 (PTX3), seems to play an important role in HF. According to a study with 196 HF patients, increased serum PTX3 level predicted outcome and was superior to CRP for this scenario . However, more investigation is still needed to demonstrate the clinical utility of PTX3.
Although inflammatory markers may provide some benefits for prognosis prediction, they are mostly nonspecific to HF. This character makes inflammation mediators less eligible for clinical application.
Despite inflammation process, oxidative stress also plays an important role in HF. Oxidative stress means an imbalance between the formation of reactive oxygen species (ROS) and endogenous antioxidant mechanisms. In normal situation, decreased serum ROS level has beneﬁcial effects and overproduction of ROS may result in pathological consequences, such as cell damage or death. In the heart, ROS can inﬂuence extracellular matrix remodelling through the activation of the matrix metalloproteinases (MMPs) , which are protease enzymes and could degrade all the matrix components of the heart. A recent report suggests that parameters of extracellular matrix remodeling may be especially of interest for prediction of development of HF with HfpEF .
Another interesting biomarker of oxidative stress is myeloperoxidase (MPO). MPO is released by stimulated neutrophils and leukocytes and related to the formation of reactive oxidants, free radicals, and nitric oxide–derived oxidants. Among patients with acutely decompensated HF, MPO concentrations > 99 pmol/L had been demonstrated to identify patients with a higher 1-year mortality rate . Another study suggested that MPO predicts the development of HF over 7 years in individuals 65 to 75 years old, especially in those without traditional risk factors or a history of HF . Increased uric acid level is associated with ROS formation and could be considered as a nonspeciﬁc indicator of enhanced oxidative stress.
In summary, ROS has multiple effects in the progression of HF and all these processes and mechanisms should be helpful in the clinical approach.
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Urocortin-1 (UCN-1) is a protein with vasodilation effect. According to some studies, UCN-1 level would increase in tachycardia and high cardiac output status, and subsequently result in general vasodilation [35-36]. The biomarker may be an independent predictor of prognosis in HF patients, but its final role is still not well-established .
Endothelin-1 (ET-1) is a mediator which results in vasoconstriction, activation of ROS, and ventricular remodeling. It was stimulated by inflammation process, angiotensin II release, and vascular shear force. A recent study concluded that ET-1 may associated with diastolic dysfunction and the prognosis in HF.Further studies are still needed to confirm the utility of ET-1 in clinical situation.
Arginine vasopressin (AVP) is a vasoconstrictive and antidiuretic hormone that is released from the hypothalamus in response to hypovolemia and changes in plasma osmolality. Because of compensation mechanism, serum AVP concentration is increased during heart failure status . However, AVP is hard to detect due to instability and short half-life and could not be an optimal biomarker. In order to overcome the difficulty of AVP measurement, the detection of C-terminal portion of pro-vasopressin (copeptin), a stable propeptide of AVP, has been studied recently. According to a study, copeptin predicts prognosis in HF independently from troponin or NT-proBNP . We still need more data to prove the clinical application of copeptin in heart failure care.
We have discussed several biomarkers in patients with heart failure in this review article. It is obviously that the number of these biomarkers increased dramatically in the past several years. Biomarkers offer convenient, objective, safe and biologically relevant insight that complements clinical ﬁndings of the HF patient. Using a multi-marker strategy could conﬁrm accurate diagnosis and risk stratiﬁcation of patients with heart failure.
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