Biomarkers for Heart Failure Prognosis: Proteins, Genetic Scores and Non-coding RNAs PDF

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REVIEW published: 23 November 2020 doi: 10.3389/fcvm.2020.601364 Biomarkers for Heart Failure Prognosis: Proteins, Genetic Scores and Non-coding RNAs Apurva Shrivastava 1,2 , Tina Haase 1,2 , Tanja Zeller 1,2 and Christian Schulte 1,2,3* 1 Clinic for Cardiology, University Heart and Vascular Center, University Medical Center Eppendorf, Hamburg, Germany, 2 German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Kiel/Luebeck, University Medical Center Eppendorf, Hamburg, Germany, 3 King’s British Heart Foundation Centre, King’s College London, London, United Kingdom Heart failure (HF) is a complex disease in which cardiomyocyte injury leads to a cascade of inflammatory and fibrosis pathway activation, thereby causing decrease in cardiac function. As a result, several biomolecules are released which can be identified easily in circulating body fluids. The complex biological processes involved in the development and worsening of HF require an early treatment strategy to stop deterioration of cardiac function. Circulating biomarkers provide not only an ideal platform to detect subclinical changes, their clinical application also offers the opportunity to monitor disease treatment. Many of these biomarkers can be quantified with high sensitivity; Edited by: allowing their clinical application to be evaluated beyond diagnostic purposes as potential Alexander E. Berezin, Zaporizhia State Medical tools for HF prognosis. Though the field of biomarkers is dominated by protein molecules, University, Ukraine non-coding RNAs (microRNAs, long non-coding RNAs, and circular RNAs) are novel and Reviewed by: promising biomarker candidates that encompass several ideal characteristics required Kenichi Hongo, Jikei University School of in the biomarker field. The application of genetic biomarkers as genetic risk scores in Medicine, Japan disease prognosis, albeit in its infancy, holds promise to improve disease risk estimation. Alberto Aimo, Despite the multitude of biomarkers that have been available and identified, the majority Sant’Anna School of Advanced Studies, Italy of novel biomarker candidates are not cardiac-specific, and instead may simply be a *Correspondence: readout of systemic inflammation or other pathological processes. Thus, the true value Christian Schulte of novel biomarker candidates in HF prognostication remains unclear. In this article, we [email protected] discuss the current state of application of protein, genetic as well as non-coding RNA Specialty section: biomarkers in HF risk prognosis. This article was submitted to Keywords: biomarker, heart failure, prognosis, protein biomarker, NT-proBNP, non-coding RNA, genetic risk score Heart Failure and Transplantation, a section of the journal Frontiers in Cardiovascular Medicine INTRODUCTION Received: 31 August 2020 Accepted: 14 October 2020 Heart failure (HF) is a complex cardiovascular disease (CVD) in which the heart’s functional Published: 23 November 2020 capacity is reduced, leading to failure in meeting the body’s blood and oxygen demand (1). The Citation: most common risk factors are age, sex, environmental risk factors, genetic disposition, and diseases Shrivastava A, Haase T, Zeller T and such as diabetes, hypertension, coronary artery disease, and atrial fibrillation. HF is described Schulte C (2020) Biomarkers for Heart Failure Prognosis: Proteins, Genetic as a global pandemic as it affects ∼26 million people worldwide (2). In North America and Scores and Non-coding RNAs. Europe, >80% of HF cases comprise of people who are ≥65 years old (2–5). Survival rate of Front. Cardiovasc. Med. 7:601364. HF patients is poor with 2–17% of HF patients dying while in hospital, 17–45% patients die doi: 10.3389/fcvm.2020.601364 within 1-year of admission and the majority dies within 5-years of admission (6). Due to the high Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 November 2020 | Volume 7 | Article 601364 Shrivastava et al. Biomarkers for Heart Failure Prognosis mortality rates associated with HF, early diagnosis of the first In this review article, we elucidate the role of the most subclinical signs is essential to prevent severe outcomes. prominent circulating protein biomarkers which show promising HF is a multi-system disorder which is characterized by results in HF prognosis. In addition, we provide details on a decrease in functional capacity of the heart. Reduced genetic biomarkers and polygenic risk scores that are currently cardiac output due to impairment in left ventricular function being developed along with details about emerging evidence on leads to an activation of the neuro-hormonal system. This, circulating non-coding RNA biomarkers. in turn, stimulates the renin-angiotensin-aldosterone system leading to increased concentrations of renin, angiotensin II and PROTEIN-BASED BIOMARKERS aldosterone, each of which causes salt and water retention, vasoconstriction, and enhanced sympathetic activity. Prolonged Protein biomarkers are released into the circulation and can exposure to neuro-hormonal activation leads to dilation and be detected using various assays. Protein biomarkers that have structural changes in the myocardium and fibrosis, thereby entered the prognostic field for HF are either released from further worsening cardiac output (7). The severity of HF is graded the heart exhibiting its value of tissue-specific damage, or in accordance to the New York Heart Association (NYHA) are released from other cells as a systemic response to HF classification I, II, III, and IV. This gradation is based on patient (Figure 2). In addition to tissue specificity, the half-life of protein clinical symptoms and effect of HF on their physical mobility. biomarkers is often the crucial factor for its potential use as This definition also takes into account the decrease in the left a biomarker (Table 1). The ease of measurement of circulating ventricular ejection fraction (LVEF), classifying HF as either protein biomarkers and the speed of assay results make them HF with preserved ejection fraction (HFpEF; LVEF ≥50%) or invaluable to HF diagnosis and prognosis. HF with reduced ejection fraction (HFrEF, LVEF 200 nucleotides in length patients suffering from severe MI (74), introducing a potential (198). There is thus far no agreement on sub-classification for detectability bias in quantification efforts; (2) up to date there are these RNAs. A recent review summarized different characteristic no harmonized methods with respect to miRNA quantification, features that could be used for this purpose, comprising of their which is particularly problematic for miRNA quantification in length, their relation to protein-coding genes or their relation low-RNA-yield samples such as plasma and serum in terms of to DNA/promoter elements (199). Unlike miRNAs, lncRNAs comparability of the results (78); (3) Only few large-scale studies are mainly located within the nucleus or in mitochondria have been conducted assessing the prognostic properties of (200, 201) (Figure 4) and their biosynthesis seems to largely miRNAs in CVD and their common interpretation of the results overlap with that of mRNAs with regards to their transcription, is, that not single miRNAs, but instead miRNA combinations polyadenylation, capping, and splicing (202). For the majority comprise prognostic potential as biomarker (194, 195). of identified lncRNAs, the function remains unclear. Nuclear Detailed reviews of specific cardiac-enriched (187) and other lncRNAs are involved in regulation of neighboring loci through miRNAs (196) involved in HFrEF and HFpEF (172) are beyond transcriptional regulation or by inhibiting expression of a gene the scope of this article and can be found elsewhere. Using miR- through sequestration of transcription factors (203). Conversely, 1 as an example, it can be seen that miRNAs are important other lncRNAs were shown to enhance transcription of genes. biological players in the development of HF and are suggested lncRNAs are more tissue-specific than protein coding genes (200) as promising circulating biomarker in HF prognostication, while and compared with miRNAs, many more transcripts have been Frontiers in Cardiovascular Medicine | www.frontiersin.org 11 November 2020 | Volume 7 | Article 601364 Shrivastava et al. Biomarkers for Heart Failure Prognosis identified (204). They have emerged as mediators of protein proven to be expressed in a tissue- and developmental-specific translation (205). Data is available suggesting key regulatory context (214, 215). They can either emerge from exons or roles of lncRNAs in cardiac and vascular tissue with respect to introns of primary gene transcripts (pre-mRNA) (215, 216) CVD (205). Both, miRNAs and lncRNAs are potent regulators of and are products of alternative splicing in a head-to-tail translation and their expression influences protein levels, while fashion known as “back-splicing” (214) (Figure 4). circRNAs at the same time these two ncRNA species influence each other’s are resistant to degradation by the exonuclease RNase R—a expression (206). type of RNase that cleaves linear RNA. RNase R treatment Several lncRNAs are also readily detected in the circulation. can therefore be used to enrich circRNAs over their linear This indicates the presence of protective mechanisms against counterparts (217, 218). In combination with the use of divergent RNase-mediated degradation, for which the mechanisms show primers in polymerase chain reaction (PCR) amplification, overlap with those of miRNAs (198). The plasma level of Long this approach yields high specificity for the detection of Intergenic ncRNA Predicting CArdiac Remodeling (LIPCAR) circular transcripts. was found to predict adverse cardiac remodeling and death in Functionally, circRNAs appear to influence gene expression in the aftermath of MI, imposing an increased risk for ischemic different ways. They act as potent miRNA sponges—decreasing cardiomyopathy and HF (201). Thus, LIPCAR has potential as the inhibitory effect of miRNAs on protein synthesis (219). a circulating biomarker for HF prognostication, but has not yet More recently, circRNAs were reported to be translated into been evaluated in a clinical trial. Myosin Heavy Chain Associated proteins (220). At the same time, their expression is regulated RNA Transcripts (MHRT) levels were found dysregulated in by proteins such as RNA-binding proteins. circRNAs appear to plasma depending on the SNP alleles (rs7140721, rs3729829, and influence gene expression by competing with splicing of their rs3729825) in chronic HF patients. Significant difference in risk linear counterparts (173, 218, 221). circRNA expression has been of mortality was observed based on these SNP genotypes (p < mapped in different tissue types and it is now clear that they can 0.001) indicating an association of these SNPs with chronic HF be reliably detected in a tissue- and cell-specific manner, whilst risk and prognosis (207). The latter might provide a way to also showing a certain degree of conservation across species link a single circulating molecule/biomarker with genetic risk (173, 222). prediction, while additional evaluation of this interesting link Bearing in mind the vast opportunities for disease detection remains to be further explored. lncRNA H19 was discovered and possibly treatment offered by miRNAs, efforts have been to be down-regulated in failing hearts from mice and was undertaken to evaluate circRNAs for their applicability as validated in pig and human hearts (208). The authors were biomarkers and disease modifiers. A growing number of studies further able to prove H19’s essential HF-reversing effect. While have reported the involvement of circRNAs across features these findings are backed-up by similar results on cardiac tissue of CVD, indicating diagnostic potential as well as potential level (209), validation of H19 as a circulating biomarker for relevance as regulators of biology (223). Sequencing data revealed HF prognostication is still pending. These findings indicate the more than 15,000 circRNAs present in the human heart, some potential use of lncRNAs as prognostic circulating biomarkers for in high abundance (224). A number of studies have described CVD—similar to some miRNAs. cardiac circRNAs to be involved in MI-related apoptosis in the lncRNAs are promising RNA molecules with good myocardium (225, 226) and circRNA MICRA was identified characteristics as circulating biomarkers for CVD such as to predict left ventricular dysfunction in MI patients (227). detectability in the circulation and distinct biological function in The results were validated in a different study where circRNA the heart. Their general exploration as circulating biomarkers is MICRA was reported to improve risk stratification of post- still in its infancy and more interesting results can be expected in MI patients (228). Recently, cardiac circRNAs were assessed for the near future. their detectability in the circulation after MI in a controlled stepwise approach (74). Interestingly, none of the screened and circRNAs validated circRNAs were identified as well-enough detectable The first single-stranded DNA product (replicating form of in neither plasma nor serum to be used as circulating cell-free DNA) that was shown to have a circular shape was described biomarkers. The findings question the validity of quantifying by Chandler et al. in 1964 (210), whereas the first circular circulating circRNAs in cell-free body liquids using currently RNA was described a decade later in plant viroids (211). Before available technology. In fact, when studying literature regarding circular RNAs were first described in humans in 1993, RNA circulating circRNAs including the abovementioned studies species were identified, where “exons were joined accurately regarding circRNA MICRA, an interesting fact can be observed: at consensus splice sites, but in an order different from that all circulating circRNA biomarker studies report their findings in present in genomic DNA”(212). These “scrambled exons” were whole blood samples—containing a large number of circulating described as stable and situated in the cellular cytoplasm (213). cells instead of cell-free serum or plasma. The use of whole Only during the past decade however, novel RNA analysis blood samples in the assessment of disease biomarkers yields tools such as biochemical enrichment strategies and high- a risk of confounding by cells such as platelets and leukocytes. throughput deep sequencing methods have allowed for large Thus, the assessment of circRNAs as circulating biomarkers in numbers of circRNAs to be detected (214). circRNAs are CVD currently suffers from detectability problems and efforts to a stable RNA species, endogenous to mammalian cells and improve detectability are needed to further evaluate this issue. Frontiers in Cardiovascular Medicine | www.frontiersin.org 12 November 2020 | Volume 7 | Article 601364 Shrivastava et al. Biomarkers for Heart Failure Prognosis TABLE 2 | Characteristics of a biomarker. Characteristics of a biomarker Protein biomarkers Genetic biomarkers Non-coding RNA biomarkers Pathophysiological reliability Stability - of biomolecule in body fluids Accessability - through routine clinical procedures Added value - does the biomarker improve standard clinical evaluation/risk stratification? Detectability - is the biomarker stably detectable in target phenotype? Diagnostic and/or prognostic validation - can the biomarker differentiate affected vs. non-affected individuals? Consensual agreement - are the quantification techniques standardized? Reference values - are they available and reliable? Comparability - of results across centers Gender specificity Tested in various ethnicities Protein biomarkers are the most widely used, largely due to methodological advances in their quantification methods and consensual agreement on their detection techniques. Genetic risk scores have the advantage of gender specificity tested across various ethnicities. ncRNAs specifically lack consensual agreement on the quantification methods, reference values and thus comparability of results. DISCUSSION implementation into clinical routine at the current stage. ncRNAs can be stably detected in the circulation and their potential The identification and further exploration of biomolecules as circulating biomarkers has been recognized. Several ncRNAs suitable as biomarkers for specific disease is a complex process, have been studied in the context of CVD. miRNAs, lncRNAs, which requires numerous prerequisites to be met such as and circRNAs are the most promising ncRNA species being detectability in the circulation, reliable quantification methods, evaluated for their biomarker potential. Several of them are pathophysiologic relation to the suspected disease, and many expressed in a cell type- and tissue-specific manner and are more (Table 2). Proteins have been evaluated as circulating involved in distinct physiological and pathological processes, biomarkers for quite a long time and their quantification raising hopes for them to evolve as helpful in diagnosis and methods are established. They have also been analyzed for their prognosis of CVD and HF. Currently, application of ncRNAs applicability in heart failure prognosis with promising results in clinical settings is hampered by methodological issues such already available. Nevertheless, validation of existing results is as lack of harmonized quantification methods and suboptimal crucial and has only just begun in this respect. Interestingly, the detectability in the circulation of some transcripts. added value of promising protein biomarkers on top of classic With respect to HF prognostication, currently the best data is risk factors still remains limited. Therefore, the exploration of available for NT-proBNP, which has been used in the diagnosis alternative biomarkers is a focus of current biomarker research. of HF for decades. Its value in HF prognostication has recently Alternatives such as genetic risk scores and also ncRNAs have been recognized and validation of currently available results caught scientists’ attention for a few years. Genetic biomarkers seems to be only a matter of time. NT-proBNP has been provide a promising platform to improve mid- and long-term included into the ESC and AHA guidelines not only because prognostication of HF, in particular with regards to improving it provides insights into the severity of cardiac damage, but individualized approaches of risk evaluation. On the other hand, also because current assays allow its detection even at small the current laboratory methodology for their determination amounts. But importantly, there is still need for validation of is complex, expensive, and time-consuming, limiting their sensitivity and specificity. Large-scale population-based cohort Frontiers in Cardiovascular Medicine | www.frontiersin.org 13 November 2020 | Volume 7 | Article 601364 Shrivastava et al. Biomarkers for Heart Failure Prognosis studies applying state-of-the-art laboratory methodology will AUTHOR CONTRIBUTIONS give the opportunity to identify additional prognostic biomarkers such as genetic biomarkers and validate existing biomarkers for AS, TH, and CS wrote the manuscript. TZ and CS edited the the prognosis of HF. Tissue-specificity seems to play a major role manuscript, figures and tables. All authors were responsible for in the application of biomolecules as biomarkers when assessing overall editing of the manuscript. All authors contributed to the single markers and it is not surprising that NT-proBNP, as one article and approved the submitted version. of only few heart-specific markers, ranks high in the list of biomarker candidates for HF prognostication. On the other hand, FUNDING given the complex etiology of HF, up until now trials failed to identify single biomarkers in the prognostic assessment of TZ is funded by the German Center for Cardiovascular patients with HF. This stretches the importance of the idea to Research (DZHK). CS was funded by a research fellowship identify complementary biomarkers in order to define biomarker by the Deutsche Forschungsgemeinschaft (DFG) (SCHU panels as a promising way of improving prognostication of 2983/1-1 and SCHU 2983/2-1). TH is funded by Grant multifactorial disease entities such as HF and argues to include No. 8/18 from the Ernst und Berta Grimmke-Stiftung and non-organ-specific molecules, which may provide a readout of the Research Promotion Fund of the Faculty of Medicine systemic disease, such as i.e., inflammation, in the seek for (FFM) of the University Medical Center Eppendorf, biomarkers in HF. Hamburg (UKE). REFERENCES 12. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by 1. National Heart Lung and Blood Institute. What Is Heart Failure? Maryland, echocardiography in adults: an update from the American society of MD: Nhlbi (2015). Available online at: https://www.nhlbi.nih.gov/health- echocardiography and the European Association of cardiovascular imaging. topics/heart-failure. J Am Soc Echocardiogr. (2015) 28:1–39.e14. doi: 10.1016/j.echo.2014. 2. 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