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Wednesday 14 November 2018
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Cardiac biomarkers: the power of innovation

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Cardiovascular diseases represent a global burden because of related high morbidity, high mortality and a significant impact on health economies.1 We all play a role in the fight against cardiovascular diseases, and laboratory tests are important to assist clinicians in the prevention, diagnosis and prognosis of cardiovascular diseases. Heart failure (HF) is the inability of the heart to respond to the circulatory demand of the organism. The main causes of HF are hypertension and ischaemic and valvular injuries, whereas toxic, metabolic or genetic origins are less common. In addition to the initial abnormality, secondary changes occur over the course, leading to multi-organ impairment.1,2 More than 20 million people worldwide are estimated to suffer from HF.1,2 HF is increasing because of an ageing population, as a result of the success in prolonging survival in patients having coronary events, and the success in postponing coronary events by effective prevention in those at high risk or those who have already survived a first event. There are several forms of HF (with reduced left ventricular ejection fraction or with preserved left ventricular ejection fraction) challenging both the diagnosis and the risk estimation pathways.1 Understanding HF and its related molecular pathways is fundamental because it allows the identification of potential new biomarkers for patients’ management and potential innovative therapeutic approaches.
 

HF and biomarkers

Most of the biomarkers with potential applications in diagnosis and prognosis derive from the neurohormonal response to the failing myocardium.2,3 Neurohormonal activation plays a significant role in myocardial and multi-organ adaptations to HF. The use of biomarkers for the diagnosis of suspected HF patients is part of daily procedures and testing for B-type natriuretic peptide (BNP) and the biologically inactive N-terminal fragment (Nt-proBNP) is included in guidelines of scientific societies. Biomarkers may also fulfil complementary information for the evaluation of disease severity, prognosis estimation and for treatment selection.1–3
 

Natriuretic peptides, the standard of care

Natriuretic peptides are the most recognised and used biomarkers for the diagnosis and monitoring of HF.1-3 
 
The natriuretic peptide family features three members: atrial natriuretic peptide (ANP); BNP; and C-type natriuretic peptide (CNP). BNP is synthesised in the ventricles as a 108- prohormone undergoing a cleavage generating the C-terminal 32 amino-acid active peptide (BNP) and the inactive N-terminal fragment (Nt-proBNP). BNP synthesis and release are essentially stimulated by a ventricular stretch due to pressure or volume overload. Natriuretic peptides are sensitive markers of cardiac dysfunction and useful biomarkers to rule out HF in emergency departments and have also value for risk stratification of HF because their circulating levels show strong negative correlations with left ventricular ejection fraction and are related to the disease severity (as determined using the NYHA classification). 
 

Emerging biomarkers

Many new players are emerging and biomarkers of cardiac remodelling could provide additional information to natriuretic peptides testing and help to develop more tailor-based strategies for treatment.2,3 As previously mentioned, the remodelling and fibrosis of the heart plays an important role in the progression of HF. Biomarkers related to cardiac hypertrophy, cardiac fibrosis and remodeling of the extracellular matrix could provide valuable information for the risk stratification of HF patients. Soluble ST2 and fibroblast growth factor 23 (FGF-23) are two good examples of biomarkers related to remodelling, and automated assays are emerging to facilitate their measurement in clinical laboratories.4–8 
 

Soluble ST2

Interleukin 33 (IL-33) is a member of the IL-1 cytokine family acting both as a cytokine and as an intracellular nuclear factor with transcriptional regulatory properties. IL-33 prevents the apoptosis of cardiomyocytes and improves cardiac function and survival after myocardial infarction through ST2 signalling.4,7 ST2 is a receptor encoded by IL1RL1 and for which differential splicing of the gene can produce a functional membrane-bound receptor (ST2L) or a soluble decoy receptor (sST2) able to quench the biological activity of IL-33. The increase of circulating sST2 levels is related to cardiac remodelling, fibrosis and HF, and measurement of sST2 could facilitate the risk stratification and treatment of HF with reduced ejection fraction as well as the diagnosis and prognosis of HF with preserved ejection fraction.4,7,9
 

FGF-23

FGF-23, a key regulator of the phosphorus homeostasis, is produced by osteocytes and binds to renal and parathyroid FGF-Klotho receptor heterodimers, resulting in phosphate excretion, decreased 1-a-hydroxylation of 25-hydroxyvitamin D and decreased parathyroid hormone (PTH) secretion.5,6 As for PTH, impaired homeostasis of cations and decreased glomerular filtration rate might contribute to the rise of FGF-23. The amino-terminal portion of FGF-23 (amino acids 1–24) may serve as a signal peptide allowing the secretion into the blood, and the carboxyl-terminal portion (amino acids 180–251) participates in its biological action. FGF-23 is also related to the risk of cardiovascular diseases and mortality.5,6 FGF-23 levels are independently associated with left ventricular mass index and hypertrophy as well as mortality in patients with chronic kidney disease. Increased circulating concentrations of FGF-23 are independently associated with the risk of developing HF in the community and with poor clinical outcome in HF patients, and assays for the measurement of circulating concentrations of the intact hormone (iFGF-23) and some against the C-terminal fragments of FGF-23 (Ct-FGF-23) are available. 
 

Perspectives from emerging technologies 

Progress around point of care testing (POCT) technologies is enormous, contributing to increasing their reliability and the number of tests available.2,7,10 The added value of POCT is increasingly evident for rapid diagnosis and might add value in primary care and pre-hospital settings. An example is illustrated by the integration of tele-cardiology units and central laboratories through cardiac markers performed with POCT technologies in the ambulance.10  These procedures can play an important role in the early diagnosis and treatment of acute coronary syndrome patients related to the pre-hospital phase. The performances of some POCT assays are now compatible with the enquiries of physicians for the management and monitoring of HF, and both BNP and NT-proBNP can be determined by POCT assays. The implementation of POCT will of course rely on interactions between laboratory specialists and users to respect the requirements of accreditation standards and to maximise the efficiency of POCT-based protocols.7,10
 
Beside the shift of paradigm for biomarker testing, recent progress in the area of mobile Health (mHealth) is also spectacular.10 MHealth describes the use of portable electronic devices with software applications to provide health services and manage patient information. With approximately five billion mobile phone users globally, mHealth technologies have the potential to greatly impact health research, health care, and health outcomes. Mobile phones, smartphones, and tablets are therefore exceptional means for the empowerment of patients with chronic illness. The use of mHealth technologies decreases the number of disease-related health outcomes in patients suffering from chronic diseases compared with regular care.10 In HF patients, mHealth aid in decreasing the length of stay in hospitals and in maintaining the activities of daily living. Studies involving patients with hypertension also demonstrated the ability of mHealth to reduce systolic and/or diastolic blood pressure.10
 
Innovations are also coming from the field of data mining and integration, which will allow the combination of clinical and biological features for a more accurate management of patients and will facilitate the identification of clusters of patients at higher risk or more suitable for selection for clinical trials.
 

Conclusions

To reach maximum potential, innovative biomarkers and emerging technologies will require a multidisciplinary assessment of technical, clinical and economical outcomes, meaning that the communication between specialists in laboratory medicine and other healthcare professionals will be needed to ensure an efficient translation into daily practice.
 

References

1 Timmis A et al. European Society of Cardiology: Cardiovascular Disease Statistics 2017. Eur Heart J 2018;39(7):508–79. 
2 Gruson D, Thys F, Verschuren F. Diagnosing destabilized heart failure in the emergency setting: current and future biomarker tests. Mol Diagn Ther 2011;15(6):327–40.
3 Gruson D, Ko G. Galectins testing: new promises for the diagnosis and risk stratification of chronic diseases? Clin Biochem 2012;45(10-11):719–26.
4 Gruson D et al. Increased soluble ST2 is a stronger predictor of long-term cardiovascular death than natriuretic peptides in heart failure patients with reduced ejection fraction. Int J Cardiol 2014;172(1):e250–2.
5 Gruson D et al. Comparison of fibroblast growth factor 23, soluble ST2 and Galectin-3 for prognostication of cardiovascular death in heart failure patients. Int J Cardiol 2015;189:185–7.
6 Gruson D et al. Head to head comparison of intact and C-terminal fibroblast growth factor 23 in heart failure patients with reduced ejection fraction. Int J Cardiol 2017;248:270–3.
7 Gruson D et al. Testing for soluble ST2 in heart failure patients: Reliability of a point of care method. Clin Lab 2017;63(1):141–5.
8 Lepoutre T et al. Measurement Nt-proBNP circulating concentrations in heart failure patients with a new point-of-care assay. Clin Lab 2013;59(7-8):831–5.
9 Gruson D et al. Increased soluble ST2 is a stronger predictor of long-term cardiovascular death than natriuretic peptides in heart failure patients with reduced ejection fraction. Int J Cardiol 2014;172(1):e250–2.
10 Gruson D, Ko G. Laboratory medicine and mobile health technologies at crossroads: Perspectives for the management of chronic diseases. Crit Rev Clin Lab Sci 2016;53(5):352–7.

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