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Current Heart Failure Reports
Published in: Current Heart Failure Reports 4/2017

01-08-2017 | Biomarkers of Heart Failure (W.H.W. Tang and J.L. Grodin, Section Editors)

Novel Biomarkers of Subclinical Cardiac Dysfunction in the General Population

Authors: Kamal Shemisa, Anish Bhatt, Daniel Cheeran, Ian J. Neeland

Published in: Current Heart Failure Reports | Issue 4/2017

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Abstract

Purpose of Review

Recognition of subclinical myocardial dysfunction offers clinicians and patients an opportunity for early intervention and prevention of symptomatic cardiovascular disease. We review the data on novel biomarkers in subclinical heart disease in the general population with a focus on pathophysiology, recent observational or trial data, and potential applicability and pitfalls for clinical use.

Recent Findings

High-sensitivity cardiac troponin and natriuretic peptide assays are powerful markers of subclinical cardiac disease. Elevated levels of these biomarkers signify subclinical cardiac injury and hemodynamic stress and portend an adverse prognosis. Novel biomarkers of myocardial inflammation, fibrosis, and abnormal contraction are gaining momentum as predictors for incident heart failure, providing new insight into pathophysiologic mechanisms of cardiac disease.

Summary

There has been exciting growth in both traditional and novel biomarkers of subclinical cardiac injury in recent years. Many biomarkers have demonstrated associations with relevant cardiovascular outcomes and may enhance the diagnostic and prognostic power of more conventional biomarkers. However, their use in “prime time” to identify patients with or at risk for subclinical cardiac dysfunction in the general population remains an open question. Strategic investigation into their clinical applicability in the context of clinical trials remains an area of ongoing investigation.
Literature
1.
Jneid H, Alam M, Virani SS, et al. Redefining myocardial infarction: what is new in the ESC/ACCF/AHA/WHF third universal definition of myocardial infarction? Methodist Debakey Cardiovasc J. 2013;9:169–72.CrossRefPubMedPubMedCentral
2.
Sato Y, Fujiwara H, Takatsu Y. Cardiac troponin and heart failure in the era of high-sensitivity assays. J Cardiol. 2012;60:160–7.CrossRefPubMed
3.
Missov E, Mair J. A novel biochemical approach to congestive heart failure: cardiac troponin T. Am Heart J. 1999;138:95–9.CrossRefPubMed
4.
Wallace TW, Abdullah SM, Drazner MH, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation. 2006;113:1958–65.CrossRefPubMed
5.
Daniels LB, Laughlin GA, Clopton P, et al. Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study. J Am Coll Cardiol. 2008;52:450–9.CrossRefPubMedPubMedCentral
6.
Latini R, Masson S, Anand IS, et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation. 2007;116:1242–9.CrossRefPubMed
7.
Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009;361:858–67.CrossRefPubMed
8.
Giannitsis E, Kurz K, Hallermayer K, et al. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56:254–61.CrossRefPubMed
9.
de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304:2503–12.CrossRefPubMed
10.
Saunders JT, Nambi V, de Lemos JA, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the atherosclerosis risk in communities study. Circulation. 2011;123:1367–76.CrossRefPubMedPubMedCentral
11.
deFilippi CR, de Lemos JA, Christenson RH, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA. 2010;304:2494–502.CrossRefPubMedPubMedCentral
12.
• Gore MO, Seliger SL, Defilippi CR, et al. Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. J Am Coll Cardiol. 2014;63:1441–8. This study highlights the significant age and sex variability in the distribution of values for hs-cTnT. It shows that implementing the current clinical abnormal cutoff value for hs-cTnT (99 th percentile of the population) equivalent to 0.014 μg/L may lead to widespread improper diagnosis of acute myocardial infarction.CrossRefPubMedPubMedCentral
13.
Drazner MH, Rame JE, Marino EK, et al. Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. J Am Coll Cardiol. 2004;43:2207–15.CrossRefPubMed
14.
Otsuka T, Kawada T, Ibuki C, et al. Association between high-sensitivity cardiac troponin T levels and the predicted cardiovascular risk in middle-aged men without overt cardiovascular disease. Am Heart J. 2010;159:972–8.CrossRefPubMed
15.
•• Neeland IJ, Drazner MH, Berry JD, et al. Biomarkers of chronic cardiac injury and hemodynamic stress identify a malignant phenotype of left ventricular hypertrophy in the general population. J Am Coll Cardiol. 2013;61:187–95. This study is the first to show a major interaction between left ventricular hypertrophy, hs-cTnT, and NT-proBNP on the outcome of heart failure and cardiovascular death in a community dwelling population. Asymptomatic individuals with LVH and either elevated hs-cTnT or NT-proBNP had a >4-fold higher risk for heart failure or cardiovascular death compared with persons without LVH or elevated biomarkers.CrossRefPubMed
16.
McEvoy JW, Chen Y, Rawlings A, et al. Diastolic blood pressure, subclinical myocardial damage, and cardiac events: implications for blood pressure control. J Am Coll Cardiol. 2016;68:1713–22.CrossRefPubMed
17.
Brouwers FP, de Boer RA, van der Harst P, et al. Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND. Eur Heart J. 2013;34:1424–31.CrossRefPubMed
18.
•• McEvoy JW, Chen Y, Ndumele CE, et al. Six-year change in high-sensitivity cardiac troponin T and risk of subsequent coronary heart disease, heart failure, and death. JAMA Cardiol. 2016;1:519–28. This study showed that temporal increases in hs-cTnT are strongly associated with incident heart failure independent of NT-pro BNP, suggesting that repeat measurements of this assay may further help to identify and risk stratify patients in the general population.CrossRefPubMed
19.
Volpe M, Rubattu S, Burnett J Jr. Natriuretic peptides in cardiovascular diseases: current use and perspectives. Eur Heart J. 2014;35:419–25.CrossRefPubMed
20.
Masson S, Latini R, Anand IS, et al. Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure Trial). J Am Coll Cardiol. 2008;52:997–1003.CrossRefPubMed
21.
Sanders-van Wijk S, Maeder MT, Nietlispach F, et al. Long-term results of intensified, N-terminal-pro-B-type natriuretic peptide-guided versus symptom-guided treatment in elderly patients with heart failure. Circ Heart Fail. 2014;7:131.CrossRefPubMed
22.
Gaggin HK, Mohammed AA, Bhardwaj A, et al. Heart failure outcomes and benefits of NT-proBNP-guided management in the elderly: results from the prospective, randomized ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) Study. J Card Fail. 2012;18:626–34.CrossRefPubMed
23.
Richards M, Nicholls MG, Espiner EA, et al. Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease. J Am Coll Cardiol. 2006;47:52–60.CrossRefPubMed
24.
Masson S, Latini R, Anand IS, et al. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the valsartan heart failure (Val-HeFT) data. Clin Chem. 2006;52:1528–38.CrossRefPubMed
25.
Betti I, Castelli G, Barchielli A, et al. The role of N-terminal PRO-brain natriuretic peptide and echocardiography for screening asymptomatic left ventricular dysfunction in a population at high risk for heart failure. The PROBE-HF Study. J Card Fail. 2009;15:377–84.CrossRefPubMed
26.
Mureddu GF, Tarantini L, Agabiti N, et al. Evaluation of different strategies for identifying asymptomatic left ventricular dysfunction and pre-clinical (stage B) heart failure in the elderly. Results from ‘PREDICTOR’, a population based-study in central Italy. Eur J Heart Fail. 2013;15:1102–12.CrossRefPubMed
27.
McKie PM, Cataliotti A, Lahr BD, et al. The prognostic value of N-terminal pro-B-type natriuretic peptide for death and cardiovascular events in healthy normal and stage A/B heart failure subjects. J Am Coll Cardiol. 2010;55:2140–7.CrossRefPubMedPubMedCentral
28.
Ballo P, Betti I, Barchielli A, et al. Prognostic role of N-terminal pro-brain natriuretic peptide in asymptomatic hypertensive and diabetic patients in primary care: impact of age and gender. Clin Res Cardiol. 2016;105:421–31.CrossRefPubMed
29.
Bansal N, Hyre Anderson A, Yang W, et al. High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and risk of incident heart failure in patients with CKD: the Chronic Renal Insufficiency Cohort (CRIC) Study. J Am Soc Nephrol. 2015;26:946–56.CrossRefPubMed
30.
Kistorp C, Raymond I, Pedersen F, et al. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA. 2005;293:1609–16.CrossRefPubMed
31.
Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350:655–63.CrossRefPubMed
32.
Smith JG, Newton-Cheh C, Almgren P, et al. Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation. J Am Coll Cardiol. 2010;56:1712–9.CrossRefPubMedPubMedCentral
33.
Kara K, Lehmann N, Neumann T, et al. NT-proBNP is superior to BNP for predicting first cardiovascular events in the general population: the Heinz Nixdorf Recall Study. Int J Cardiol. 2015;183:155–61.CrossRefPubMed
34.
Palmer G, Lipsky BP, Smithgall MD, et al. The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine. 2008;42:358–64.CrossRefPubMed
35.
Miyama N, Hasegawa Y, Suzuki M, et al. Investigation of major genetic polymorphisms in the renin-angiotensin-aldosterone system in subjects with young-onset hypertension selected by a targeted-screening system at university. Clin Exp Hypertens. 2007;29:61–7.CrossRefPubMed
36.
37.
Chen LQ, de Lemos JA, Das SR, et al. Soluble ST2 is associated with all-cause and cardiovascular mortality in a population-based cohort: the Dallas Heart Study. Clin Chem. 2013;59:536–46.CrossRefPubMed
38.
Aldous SJ, Richards AM, Troughton R, et al. ST2 has diagnostic and prognostic utility for all-cause mortality and heart failure in patients presenting to the emergency department with chest pain. J Card Fail. 2012;18:304–10.CrossRefPubMed
39.
Schlittenhardt D, Schober A, Strelau J, et al. Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res. 2004;318:325–33.CrossRefPubMed
40.
Rohatgi A, Patel P, Das SR, et al. Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: observations from the Dallas Heart Study. Clin Chem. 2012;58:172–82.CrossRefPubMed
41.
Chan MM, Santhanakrishnan R, Chong JP, et al. Growth differentiation factor 15 in heart failure with preserved vs. reduced ejection fraction. Eur J Heart Fail. 2016;18:81–8.CrossRefPubMed
42.
Baggen VJ, van den Bosch AE, Eindhoven JA, et al. Prognostic value of N-terminal pro-B-type natriuretic peptide, troponin-T, and growth-differentiation factor 15 in adult congenital heart disease. Circulation. 2017;135:264–79.CrossRefPubMed
43.
Wollert KC, Kempf T, Wallentin L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin Chem. 2017;63:140–51.CrossRefPubMed
44.
Wang TJ, Wollert KC, Larson MG, et al. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation. 2012;126:1596–604.CrossRefPubMed
45.
Huby AC, Antonova G, Groenendyk J, et al. Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation. 2015;132:2134–45.CrossRefPubMed
46.
Cavalera M, Wang J, Frangogiannis NG. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl Res. 2014;164:323–35.CrossRefPubMedPubMedCentral
47.
Sharma UC, Pokharel S, van Brakel TJ, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation. 2004;110:3121–8.CrossRefPubMed
48.
van Kimmenade RR, Januzzi JL Jr, Ellinor PT, et al. 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. 2006;48:1217–24.CrossRefPubMed
49.
Meijers WC, Januzzi JL, deFilippi C, et al. Elevated plasma galectin-3 is associated with near-term rehospitalization in heart failure: a pooled analysis of 3 clinical trials. Am Heart J. 2014;167:853–60. e4 CrossRefPubMed
50.
Ho JE, Liu C, Lyass A, et al. Galectin-3, a marker of cardiac fibrosis, predicts incident heart failure in the community. J Am Coll Cardiol. 2012;60:1249–56.CrossRefPubMedPubMedCentral
51.
52.
Ueland T, Yndestad A, Oie E, et al. Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation. 2005;111:2461–8.CrossRefPubMed
53.
di Giuseppe R, Biemann R, Wirth J, et al. Plasma osteoprotegerin, its correlates, and risk of heart failure: a prospective cohort study. Eur J Epidemiol. 2016;
54.
Ueland T, Jemtland R, Godang K, et al. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol. 2004;44:1970–6.CrossRefPubMed
55.
Andersen GO, Knudsen EC, Aukrust P, et al. Elevated serum osteoprotegerin levels measured early after acute ST-elevation myocardial infarction predict final infarct size. Heart. 2011;97:460–5.CrossRefPubMed
56.
Roysland R, Bonaca MP, Omland T, et al. Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes. Heart. 2012;98:786–91.CrossRefPubMedPubMedCentral
57.
Viswanathan K, Kilcullen N, Morrell C, et al. Heart-type fatty acid-binding protein predicts long-term mortality and re-infarction in consecutive patients with suspected acute coronary syndrome who are troponin-negative. J Am Coll Cardiol. 2010;55:2590–8.CrossRefPubMed
58.
Niizeki T, Takeishi Y, Arimoto T, et al. Heart-type fatty acid-binding protein is more sensitive than troponin T to detect the ongoing myocardial damage in chronic heart failure patients. J Card Fail. 2007;13:120–7.CrossRefPubMed
59.
O'Donoghue M, de Lemos JA, Morrow DA, et al. Prognostic utility of heart-type fatty acid binding protein in patients with acute coronary syndromes. Circulation. 2006;114:550–7.CrossRefPubMed
60.
Hoffmann U, Espeter F, Weiss C, et al. Ischemic biomarker heart-type fatty acid binding protein (hFABP) in acute heart failure—diagnostic and prognostic insights compared to NT-proBNP and troponin I. BMC Cardiovasc Disord. 2015;15:50.CrossRefPubMedPubMedCentral
61.
Kutsuzawa D, Arimoto T, Watanabe T, et al. Ongoing myocardial damage in patients with heart failure and preserved ejection fraction. J Cardiol. 2012;60:454–61.CrossRefPubMed
62.
Hartshorne DJ, Ito M, Erdodi F. Myosin light chain phosphatase: subunit composition, interactions and regulation. J Muscle Res Cell Motil. 1998;19:325–41.CrossRefPubMed
63.
Ding P, Huang J, Battiprolu PK, et al. Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo. J Biol Chem. 2010;285:40819–29.CrossRefPubMedPubMedCentral
64.
Gabrielli L, Winter JL, Godoy I, et al. Increased Rho-kinase activity in hypertensive patients with left ventricular hypertrophy. Am J Hypertens. 2014;27:838–45.CrossRefPubMed
65.
Ocaranza MP, Gabrielli L, Mora I, et al. Markedly increased Rho-kinase activity in circulating leukocytes in patients with chronic heart failure. Am Heart J. 2011;161:931–7.CrossRefPubMed
66.
Ungvari Z, Csiszar A. The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci. 2012;67:599–610.CrossRefPubMed
67.
Groban L, Pailes NA, Bennett CD, et al. Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. J Gerontol A Biol Sci Med Sci. 2006;61:28–35.CrossRefPubMed
68.
Faxen UL, Hage C, Benson L, et al. HFpEF and HFrEF display different phenotypes as assessed by IGF-1 and IGFBP-1. J Card Fail. 2016;
69.
Barroso MC, Kramer F, Greene SJ, et al. Serum insulin-like growth factor-1 and its binding protein-7: potential novel biomarkers for heart failure with preserved ejection fraction. BMC Cardiovasc Disord. 2016;16:199.CrossRefPubMedPubMedCentral
70.
Gandhi PU, Gaggin HK, Sheftel AD, et al. Prognostic usefulness of insulin-like growth factor-binding protein 7 in heart failure with reduced ejection fraction: a novel biomarker of myocardial diastolic function? Am J Cardiol. 2014;114:1543–9.CrossRefPubMed
71.
Metadata
Title
Novel Biomarkers of Subclinical Cardiac Dysfunction in the General Population
Authors
Kamal Shemisa
Anish Bhatt
Daniel Cheeran
Ian J. Neeland
Publication date
01-08-2017
Publisher
Springer US
Published in
Current Heart Failure Reports / Issue 4/2017
Print ISSN: 1546-9530
Electronic ISSN: 1546-9549
DOI
https://doi.org/10.1007/s11897-017-0342-z

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