Mathews Journal of Cardiology

2572-6420

Previous Issues Volume 3, Issue 1 - 2018

Short CommunicationPDF  

Influence of Serum Biomarkers in the Diagnostic, Prognostic and Therapeutic Management of Patients with Heart Failure

Osmar Antonio Centurión1,2, Christian O. Chávez-Alfonso1 , Laura Beatriz García1,2, Judith María Torales1,2

1Division of Cardiovascular Medicine, Clinic Hospital, Asuncion National University (UNA), San Lorenzo, Paraguay.
2Department of Health Sciences Investigation. Sanatorio Metropolitano. Fernando de la Mora. Paraguay.

Corresponding Author: Osmar Antonio Centurión, Division of Cardiovascular Medicine, Clinic Hospital, Asuncion National University (UNA), San Lorenzo, Paraguay, Tel: + (595) 971 354444; E-Mail: osmarcenturion@hotmail.com

Received Date:  21 Sep 2018  
Accepted Date:  24 Sep 2018  
Published Date: 25 Sep 2018

Copyright © 2018 Centurión OA

Citation: Centurión OA, Chávez-Alfonso C, García LB and Torales JM. (2018). Influence of Serum Biomarkers in the Diagnostic, Prognostic and Therapeutic Management of Patients with Heart Failure Mathews J Cardiol. 3(1): 017.

 

ABSTRACT

Heart failure (HF) is a clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intra-cardiac pressures at rest or during stress. HF continues to be a significant cause of morbidity and mortality worldwide, and over a half of patients with acute HF admitted to the hospital have a history of coronary heart disease. In addition, a substantial proportion of hospitalized patients with coronary heart disease develop acute HF during the hospital stay, and have a worse prognosis in those patients who develop acute HF at the initial presentation. Given the diversity of clinical presentations, several different physio-pathological mechanisms along with triggering factors of circulatory decompensation are involved. The improvement in clinical assessment of HF patients by the utilization of noninvasive and biologically meaningful serum biomarkers has considerably paved the way on HF diagnostic and therapeutic management. Indeed, serum biomarkers allow safe, objective, and biologically relevant insight that complements clinical findings of HF patients. They are useful for determining diagnosis, prognosis, or therapy decision making. There are different biomarkers that can be measured during the evolution of HF, as well as, several pathways involved in HF progression. Therefore, it may be rational to utilize a multi-biomarker measurement approach to individualize the diagnosis, prognosis and therapeutic management in patients with heart failure.

KEYWORDS

Heart failure; Serum biomarkers; Natriuretic peptides; Galectin; MicroRNA.

 

INTRODUCTION

The number of heart failure (HF) patients is around 23 million people worldwide and it is expected to grow as the population ages due to improved survival and advanced therapies for cardiovascular diseases [1-3]. HF is a clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intra-cardiac pressures at rest or during stress [4-7]. HF continues to be a significant cause of morbidity and mortality worldwide, and over a half of patients with acute HF admitted to the hospital have a history of coronary heart disease [8-15]. Acute coronary syndrome complicated by acute HF leads to a severalfold increase in hospital mortality compared to those without acute HF. In addition, a substantial proportion of hospitalized patients with coronary heart disease develop acute HF during the hospital stay, and have a worse prognosis in those patients who develop acute HF at the initial presentation [16-20]. Given the diversity of clinical presentations, several different physio-pathological mechanisms along with triggering factors of circulatory decompensation are involved.

The improvement in clinical assessment of HF patients by the utilization of noninvasive and biologically meaningful serum biomarkers has considerably paved the way on HF diagnostic and therapeutic management. Therefore, we analyzed the role of several serum biomarkers in different ways, namely, to predict the onset of future episodes of HF, to identify the presence of early or decompensated HF, to risk stratify affected patients, and to guide HF treatment

THE NATRIURETIC PEPTIDES

The natriuretic peptides represent the gold standard for biomarkers in HF. The understanding about the biology of the natriuretic peptides, and their clinical use has grown exponentially since their introduction. Several structurally similar natriuretic peptides have been identified: atrial natriuretic peptide (ANP), urodilantin (an isoform of ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide and Dendroaspis natriuretic peptide [21]. ANP and BNP are produced in the myocytes of the atria and ventricles, respectively in response to myocardial stretch due to pressure or volume overload [22, 23]. The biological functions of these natriuretic peptides include natriuresis, diuresis, and vasodilation [24-26]. During HF because of myocardial stretch, the induction of the BNP gene results in the production and secretion of prohormone proBNP1–108. This is cleaved into the biologically active BNP, as well as, NT-proBNP which is biologically inert, but biochemically more stable. Both fragments are detected in plasma [27]. The Breathing Not Properly Study measured BNP levels in 1586 patients with acute dyspnea [28]. Those patients with clinically diagnosed HF had higher BNP levels compared with those without HF (mean 675±450 vs 110±225 pg/mL, p<0.001). BNP was the best single predictor of a final diagnosis of HF compared to other clinical findings [28]. NTproBNP is cleared via different mechanisms and has a longer half-life than BNP (70 min vs. 20 min). The use of NT-proBNP in the diagnosis of acutely decompensated HF was first demonstrated in the ProBNP Investigation of Dyspnea in the PRIDE Study [29]. Later on, the International collaborative of NT-proBNP (ICON) study investigated 1256 acutely dyspneic patients [30]. They found that decompensated HF patients had higher NT-proBNP concentrations, compared to those patients without HF (4639 vs. 108 pg/mL, p<0.001) [30]. The use of BNP and NT-proBNP for the diagnosis of HF has dramatically impacted the standard of care in HF and the therapeutic management. All major societies worldwide recommend the use of BNP or NT-proBNP for the diagnosis of HF in their clinical practice guidelines [31, 32].

OTHER SERUM BIOMARKERS IN HEART FAILURE

Several different serum biomarkers have been studied, such as mid-regional pro atrial natriuretic peptide (MR-proANP), mid-regional pro adrenomedullin (MR-proADM), highly sensitive troponins, soluble ST2 (sST2), growth differentiation factor (GDF)-15, Galectin-3, and microRNA, show potential in evaluate HF diagnosis, prognosis and treatment [21-38].

Adrenomedullin (ADM) is another serum biomarker that can be very useful in HF [33-36]. Circulating levels of ADM are elevated in HF and correlate with decreasing left ventricular ejection fraction, increasing pulmonary artery pressures and the presence of diastolic dysfunction and restrictive filling patterns [35, 36]. ADM was initially found in pheochromocytoma cells in the adrenal medulla and has potent vasodilatory effects. ADM has been also found in other organs including the heart increasing myocardial contractility through a cyclic AMP-independent mechanism [33, 34]. A commercial assay measuring the mid-regional portion of the stable prohormone of ADM, MR-proADM, has been developed and used to explore its role in HF. In the BACH study, MR-proADM was found to have strong prognostic value for death at 90 days [37]. This prognostic value was further corroborated in the PRIDE study [38].

Although cardiac troponins have been used for the diagnostic evaluation for acute coronary syndromes, they are also elevated in HF [39]. Xue et al. demonstrated that concentrations of highly sensitive troponin I (hsTnI) were frequently elevated in patients with acutely decompensated HF [40]. hsTnI typically rose or remained elevated in subjects with impending complications. On the other hand, ST2, another serum biomarker was found to have prognostic value in patients with acutely decompensated HF [41, 42]. ST2 was found to have immunomodulatory function as a cell-surface marker of T helper type 2 lymphocytes. ST2 was found in the context of cell proliferation, inflammatory states and autoimmune diseases [43]. However, the ST2 system is also induced in mechanical strain of cardiac fibroblasts or cardiomyocytes, and it may be involved in cardiac remodeling and fibrosis in HF [44]. A soluble “decoy receptor” version (sST2) was studied in 593 patients presenting with acute dyspnea [41, 42]. It was demonstrated a concentration-dependent relationship between sST2 and many clinical markers of HF severity including left ventricular ejection fraction and NYHA functional classification. An elevated sST2 was prognostic in acutely decompensated HF patients (HR=9.3, p=0.003), and in all dyspnea patients (HR=5.6, p<0.001) in multivariable analyses.

Another interesting serum biomarker that has a role in HF is GDF-15 which is a member of the transforming growth factor-β cytokine superfamily. GDF-15 is induced in cardiomyocytes in response to metabolic stress such as in pressure overload states, hence, it is elevated in HF [45-53]. The ValHeFT study which included 1734 patients demonstrated the utility of GDF-15 [50]. This serum biomarker was measured at baseline and after 12 months of treatment with the angiotensin receptor blocker valsartan or placebo. In 85% of the patients there were abnormal concentrations greater than 1200 ng/L associated with features of advanced HF. Moreover, GDF15 was an independent predictor of death (HR 1.007, 95% CI 1.001–1.014) in a multiple-variable Cox regression model that included clinical risk factors, BNP, high-sensitivity C-reactive protein and hsTnT [50].

Galectin-3 is a macrophage product member of the lectin family which is related to the inflammatory cascade following cardiac injury [51]. Galectin-3 was first measured in patients from the PRIDE study [52]. 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). Galectin-3’s ability to predict 60-day mortality was superior to NT-proBNP even after adjusting for traditional risk factors. However, similar to other serum biomarkers of prognosis mentioned above, adding galectin-3 to NT-proBNP and other risk factors provided the best strategy for predicting prognosis in HF [52].

In addition, there is also interesting data on functional microRNA (miRNA) from clinical studies which reported that a variety of miRNA play a role in pathogenic mechanisms leading to heart failure, such as remodeling, hypertrophy, apoptosis, and hypoxia [54, 55]. There is strong evidence that miRNAs play a role in the onset and progression of heart failure, and because of their stability in plasma, miRNAs are interesting potential novel biomarkers in heart failure [56-58].

 

CONCLUSION

In conclusion, serum biomarkers allow safe, objective, and biologically relevant insight that complements clinical findings of HF patients. They are useful for determining diagnosis, prognosis, or therapy decision making. There are different biomarkers that can be measured during the evolution of HF, as well as, several pathways involved in HF progression. Therefore, it may be rational to utilize a multi-biomarker measurement approach to individualize the diagnosis, prognosis and therapeutic management in patients with heart failure.

 

REFERENCES

  1. McMurray JJ, Petrie MC, Murdoch DR and Davie AP. (1998). Clinical epidemiology of heart failure: public and private health burden. Eur Heart J. 19 (Suppl. P): 9-16.
  2. Rohde LE, Beck-da-Silva L, Goldraich L, Grazziotin TC, et al. (2004). Reliability and prognostic value of traditional signs and symptoms in outpatients with congestive heart failure. Can J Cardiol. 20(7): 697-702.
  3. Maisel AS, Peacock WF, McMullin N, Jessie R, et al. (2008). Timing of immunoreactive B-type natriuretic peptide levels and treatment delay in acute decompensated heart failure: an ADHERE (Acute Decompensated Heart Failure National Registry) analysis. J Am Coll Cardiol. 52(7): 534- 540.
  4. Ponikowski P, Voors AA, Anker SD, Bueno H, et al. (2016). 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure. Rev Esp Cardiol. 69(12): 1167.
  5. Martindale JL, Wakai A, Collins SP, Levy PD, et al. (2016). Diagnosing Acute Heart Failure in the Emergency Department: A Systematic Review and Meta-analysis. Acad Emerg Med. 23(3): 223-242.
  6. AlHabib KF, Elasfar AA, Alfaleh H, Kashour T, et al. (2014). Clinical features, management, and short- and long-term outcomes of patients with acute decompensated heart failure: phase I results of the HEARTS database. Eur J Heart Fail. 16(4): 461-469.
  7. Fonarow GC, Abraham WT, Albert NM, Gattis SW, et al. (2007). OPTIMIZE-HF Investigators and Hospitals. Influence of a Performance-Improvement Initiative on Quality of Care for Patients Hospitalized With Heart Failure Results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). Arch Intern Med. 167(14): 1493-1502.
  8. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, et al. (2006). EuroHeart Survey Investigators; Heart Failure Association, European Society of Cardiology. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 27(22): 2725-2736.
  9. Steg PG, Dabbous OH, Feldman LJ, Cohen-Solal A, et al. (2004). Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation. 109(4): 494-499.
  10. AlFaleh H, Elasfar AA, Ullah A, AlHabib KF, et al. (2016). Acute heart failure with and without acute coronary syndrome: clinical correlates and prognostic impact (From the HEARTS registry). BMC Cardiovasc Disord. 16: 98.
  11. Tarvasmäki T, Harjola VP, Nieminen MS, Siirilä-Waris K, et al. (2014). for the FINN-AKVA Study Group. Acute heart failure with and without concomitant acute coronary syndromes: patient characteristics, management, and survival. J Card Fail. 20(10): 723-730.
  12. Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, et al. (2016 ). Heart Failure Association (HFA) of the European Society of Cardiology (ESC). European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-year follow-up outcomes and differences across regions. Eur J Heart Fail. 18(6): 613-625.
  13. Felker GM, Mentz RJ, Teerlink JR, Voors AA, et al. (2015). Serial high sensitivity cardiac troponin T measurement in acute heart failure: insights from the RELAX-AHF study. Eur J Heart Fail. 17(12): 1262-1270.
  14. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, et al. (2014). for American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons; American Association for Clinical Chemistry. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 64(24): e139-228.
  15. Ibanez B, James S, Agewall S, Antunes MJ, et al. (2018). 2018 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 39(2): 119-177.
  16. Roffi M, Patrono C, Collet JP, Mueller C, et al. (2015). 2015 ESC Guidelines for the Management of Acute Coronary Syndromes in Patients Presenting Without Persistent STsegment Elevation. Rev Esp Cardiol. 68(12): 1125.
  17. Mebazaa A, Yilmaz MB, Levy P, Ponikowski P, et al. (2015). Recommendations on pre-hospital & early hospital management of acute heart failure: a consensus paper from the Heart Failure Association of the European Society of Cardiology, the European Society of Emergency Medicine and the Society of Academic Emergency Medicine. Eur J Heart Fail. 17(6): 544-558.
  18. Prins KW, Neill JM, Tyler JO and Eckman PM. (2015). Duval S. Effects of Beta-Blocker Withdrawal in Acute Decompensated Heart Failure: A Systematic Review and MetaAnalysis. JACC Heart Fail. 3(8): 647-653.
  19. King JB, Bress AP, Reese AD and Munger MA. (2015). Neprilysin inhibition in heart failure with reduced ejection fraction: a clinical review. Pharmacother J Hum Pharmacol Drug Ther. 35(9): 823-837.
  20. McMurray JJ, Packer M, Desai AS, Gong J, et al. (2013). PARADIGM-HF Committees and Investigators. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 15(9): 1062-1073.
  21. Cea LB. (2005). Natriuretic peptide family: new aspects. Curr Med Chem Cardiovasc. Hematol Agents. 3(2): 87-98.
  22. Mukoyama M, Nakao K, Hosoda K, Suga S, et al. (1991). Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest. 87(4): 1402-1412.
  23. Kinnunen P, Vuolteenaho O and Ruskoaho H. (1993). Mechanisms of atrial and brain natriuretic peptide release from rat ventricular myocardium: effect of stretching. Endocrinology. 132(5): 1961-1970.
  24. Cody RJ, Atlas SA, Laragh JH, Kubo SH, et al. (1986). Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion J Clin Invest. 78(5): 1362-1374.
  25. Marcus LS, Hart D, Packer M, Yushak M, et al. (1996). Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure. A double-blind, placebo-controlled, randomized crossover trial, Circulation. 94(12): 3184-3189.
  26. Hunt PJ, Richards AM, Nicholls MG, Yandle TG, et al. (1997). Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol. 47(3): 287-296.
  27. Tateyama H, Hino J, Minamino N, Kangawa K, et al. (1992). Concentrations and molecular forms of human brain natriuretic peptide in plasma, Biochem. Biophys. Res Commun.185(2): 760-767.
  28. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, et al. (2002). Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl. J. Med. 347(3): 161-167.
  29. Januzzi JL Jr, Camargo CA, Anwaruddin S, Baggish AL, et al. (2005). The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol. 95(8): 948-954.
  30. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, et al. (2006). NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J. 27(3): 330-337.
  31. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, et al. (2012). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC. Eur Heart J. 30(14): 1787-1847.
  32. Lindenfeld J, Albert NM, Boehmer JP, Collins SP, et al. (2010). HFSA 2010 comprehensive heart failure practice guideline. J Card Fail. 16(6): e1-e194.
  33. Kitamura K. (1998). Adrenomedullin and related peptides. Nihon Yakurigaku Zasshi. 112(3): 137-146.
  34. Ikeda U, Kanbe T, Kawahara Y, Yokoyama M, et al. (1996). Adrenomedullin augments inducible nitric oxide synthase expression in cytokine-stimulated cardiac myocytes. Circulation. 94(10): 2560- 2565.
  35. Nishikimi T, Saito Y, Kitamura K, Ishimitsu T, et al. (1995). Increased plasma levels of adrenomedullin in patients with heart failure. J Am Coll Cardiol. 26(6): 1424-1431.
  36. Yu CM, Cheung BM, Leung R, Wang Q, et al. (2001). Increase in plasma adrenomedullin in patients with heart failure characterised by diastolic dysfunction. Heart. 86(2): 155-160.
  37. Thygesen K, Alpert JS and White HD. (2007). Universal definition of myocardial infarction, J Am Coll Cardiol. 50(22): 2173-2195.
  38. Xue Y, Clopton P, Peacock WF and Maisel AS. (2011). Serial changes in high-sensitive troponin I predict outcome in patients with decompensated heart failure. Eur J Heart Fail. 13(1): 37-42.
  39. Xu D, Chan WL, Leung BP, Huang F, et al. (1998). Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J Exp Med. 187(5): 787-794.
  40. Weinberg EO, Shimpo M, De Keulenaer GW, MacGillivray D, et al. (2002). Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation. 106(23): 2961-2966.
  41. Januzzi JL Jr, Peacock WF, Maisel AS, Chae CU, et al. (2007). Measurement of the interleukin family member ST2 in patients with acute dyspnea: results from the PRIDE (ProBrain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study. J Am Coll Cardiol. 50(7): 607-613.
  42. Rehman SU, Mueller T and Januzzi JL Jr. (2008). Characteristics of the novel interleukin family biomarker ST2 in patients with acute heart failure. J Am Coll Cardiol. 52: 1458-1465.
  43. Kempf T, Eden M, Strelau J, Naguib M, et al. (2006). The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res. 98(3): 351-360.
  44. Xu J, Kimball TR, Lorenz JN, Brown DA, et al. (2006). GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res. 98(3): 342- 350.
  45. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, et al. (1997). MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc. Natl. Acad Sci. 94(21): 11514-11519.
  46. Kempf T and Wollert KC. (2009). Growth-differentiation factor-15 in heart failure. Heart Fail Clin. 5(4): 537-547.
  47. Kempf T, von Haehling S, Peter T, Allhoff T, et al. (2007). Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol. 50(11): 1054-1060.
  48. Wollert KC, Kempf T, Peter T, Olofsson S, et al. (2007). Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation. 115(8): 962-971.
  49. Kempf T, Bjorklund E, Olofsson S, Lindahl B, et al. (2007). Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J. 28(23): 2858-2865.
  50. Anand LS, Kempf T, Rector TS, Tapken H, et al. (2010). Serial measurement of growth-differentiation factor-15 in heart failure: relation to disease severity and prognosis in the Valsartan Heart Failure Trial. Circulation. 122(14): 1387-1395.
  51. Dumic J, Dabelic S and Flogel M. (2006). Galectin-3: an open-ended story. Biochimica et biophysica Acta. 1760(4): 616-635.
  52. Van Kimmenade RR, Januzzi JL Jr, Ellinor PT, Sharma UC, et al. (2006). Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure. J Am Coll Cardiol. 48(6): 1217-1224.
  53. Sulo G, Igland J, Nygard O, Vollset SE, et al. (2017). Prognostic Impact of In-Hospital and Postdischarge Heart Failure in Patients With Acute Myocardial Infarction: A Nationwide Analysis Using Data From the Cardiovascular Disease in Norway (CVDNOR) Project. J Am Heart Assoc. 6(3). pii: e005277.
  54. Tijsen AJ, Pinto YM and Creemers EE. (2012). Non-cardiomyocyte microRNAs in heart failure. Cardiovasc Res. 93(4): 573-582.
  55. Thum T, Galuppo P, Wolf C, Fiedler J, et al. (2007). Bauersachs J. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 116(3): 258-267.
  56. Watson CJ, Gupta SK, O’Connell E, Thum S, et al. (2015). MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. Eur J Heart Fail. 17(14): 405-415.
  57. Wong LL, Armugam A, Sepramaniam S, Karolina DS, et al. (2015). Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail. 17(4): 393-404.
  58. Ellis KL, Cameron VA, Troughton RW, Frampton CM, et al. (2013). Circulating microRNAs as candidate markers to distinguish heart failure in breathless patients. Eur J Heart Fail. 15(10): 138-1147.

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