AGE

, 36:9660 | Cite as

Plasma NT-proBNP as predictor of change in functional status, cardiovascular morbidity and mortality in the oldest old: the Leiden 85-plus study

  • Petra G. van Peet
  • Anton J.M. de Craen
  • Jacobijn Gussekloo
  • Wouter de Ruijter
Article

Abstract

In the aging society, it is important to identify very old persons at high risk of functional decline, cardiovascular disease and mortality. However, traditional risk markers lose their predictive value with age. We investigated whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels predict change in functional status, cardiovascular morbidity and mortality in very old age. Here we present an observational prospective cohort study (Leiden 85-plus Study, 1997–2004) in a population-based sample of 560 individuals aged 85 years with a 5-year complete follow-up for functional status, cardiovascular morbidity and cause-specific mortality. Median NT-proBNP for men was 351 pg/ml (cutoff values for low-medium tertiles 201 pg/ml and medium-high tertiles 649 pg/ml) and, for women, 297 pg/ml (cutoffs 204 and 519 pg/ml, respectively). During the 5-year follow-up, participants with high NT-proBNP had an accelerated cognitive decline and increase of activities of daily living (ADL) disability over time (all at p < 0.01) and an increased risk of incident heart failure [hazard ratio (HR) 3.3 (95 % confidence interval (CI) 1.8–6.1)], atrial fibrillation [HR 4.1 (2.0–8.7)], myocardial infarction [HR 2.1 (1.2–3.7)], stroke [HR 3.4 (1.9–6.3)], cardiovascular mortality [HR 5.5 (3.1–10)], non-cardiovascular mortality [HR 2.0 (1.4–3.0)] and all-cause mortality [HR 2.9 (2.1–4.0)], independent of other known risk markers. All results remained similar after exclusion of participants with heart failure at baseline. In very old age, high-NT-proBNP levels predict accelerated cognitive and functional decline, as well as cardiovascular morbidity and mortality. Results suggest that NT-proBNP can help clinicians to identify very old people at high risk of functional impairment and incident cardiovascular morbidity.

Keywords

Aged 80 years and over Pro-brain natriuretic peptide Activities of daily living Cognition Cardiovascular disease Cardiovascular morbidity Cardiovascular mortality Prediction Prevention 

Abbreviations

ADL

Activities of daily living

AF

Atrial fibrillation

AUC

Area under the curve

BNP

B-type natriuretic peptide

CI

Confidence interval

CRP

C-reactive protein

CVD

Cardiovascular disease

GDS

Geriatric Depression Scale

HCY

Homocysteine

HF

Heart failure

HR

Hazard ratio

ICD

International Classification of Diseases

MDRD

Estimated GFR (eGFR) using the Modification of Diet in Renal Disease formula

MI

Myocardial infarction

MMSE

Mini-Mental State Examination

NRI

Net reclassification improvement

NT-proBNP

N-terminal pro-B-type natriuretic peptide

SE

Standard error

TIA

Transient ischemic attack

Notes

Acknowledgments

The Leiden 85-plus Study was partly funded by an unrestricted grant from the Dutch Ministry of Health, Welfare and Sports.

Conflict of interest

The funder played no role in study design, collection, analysis and interpretation of data, writing of the report, and in the decision to submit the article for publication. All researchers were independent from the funder and have no conflicts of interest.

Supplementary material

11357_2014_9660_MOESM1_ESM.docx (48 kb)
Table 5 (online supplementary table) Association between NT-proBNP at age 85 years and (changes in) functional status in participants aged 85 through 90 years (n=560) adjusted for blood pressure, total cholesterol, HDL-cholesterol, history of diabetes, current smoking, BMI, MDRD and medication for hypertension (upper 2 rows), and adjusted for all these plus for prevalent cardiovascular disease (middle 2 rows) and for prevalent cerebrovascular disease (lower 2 rows), respectively. (DOCX 48 kb)
11357_2014_9660_MOESM2_ESM.docx (21 kb)
Table 6 (Online supplementary table). Five-year risk of cardiovascular morbidity and mortality depending on plasma NT-proBNP level at 85 years (n=560), adjusted for blood pressure, total cholesterol, HDL-cholesterol, history of diabetes, current smoking, BMI, MDRD and medication for hypertension. (DOCX 21 kb)
11357_2014_9660_MOESM3_ESM.docx (22 kb)
Table 7 (Online supplementary table). Five-year risk of cardiovascular morbidity and mortality depending on plasma NT-proBNP level at 85 years (n=560), adjusted for blood pressure, total cholesterol, HDL-cholesterol, history of diabetes, current smoking, BMI, MDRD, medication for hypertension plus for prevalent cardiovascular disease (DOCX 21 kb)

References

  1. Alehagen U, Goetze JP, Dahlstrő¦m U (2007) Reference intervals and decision limits for B-type natriuretic peptide (BNP) and its precursor (NT-proBNP) in the elderly. Clinica Chimica Acta 382:8–14CrossRefGoogle Scholar
  2. Beleigoli AM, Ribeiro AL, Diniz MdF, Lima-Costa MF, Boersma E (2013a) Comparing the value of BNP in predicting mortality among community-dwelling elderly with and without overweight/obesity: the Bambuï (Brazil) Cohort Study of Aging. Int J Cardiol 168(4):4364-4366Google Scholar
  3. Beleigoli AM, Boersma E, Diniz MF, Vidigal PG, Lima-Costa MF, Ribeiro AL (2013b) C-reactive protein and B-type natriuretic peptide yield either a non-significant or a modest incremental value to traditional risk factors in predicting long-term overall mortality in older adults. PLoSOne 8:e75809PubMedCentralPubMedCrossRefGoogle Scholar
  4. Campbell DJ (2008) Can measurement of B-type natriuretic peptide levels improve cardiovascular disease prevention? Clin Exp Pharmacol Physiol 35:442–446PubMedCrossRefGoogle Scholar
  5. Cantril H (1965) The pattern of human concerns. Rutgers University Press, New Brunswick (NJ)Google Scholar
  6. Daniels LB, Laughlin GA, Kritz-Silverstein D, Clopton P, Chen WC, Maisel AS, Barrett-Connor E (2011) Elevated natriuretic peptide levels and cognitive function in community-dwelling older adults. AmJ Med 124:670–678PubMedCentralPubMedCrossRefGoogle Scholar
  7. de Craen AJ, Heeren TJ, Gussekloo J (2003) Accuracy of the 15-item geriatric depression scale (GDS-15) in a community sample of the oldest old. Int J Geriatr Psychiatry 18:63–66PubMedCrossRefGoogle Scholar
  8. de Ruijter W, Westendorp RG, Assendelft WJ, den Elzen WP, de Craen AJ, le Cessie S, Gussekloo J (2009) Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study. BMJ 338:a3083PubMedCentralPubMedCrossRefGoogle Scholar
  9. DeFilippi C, van Kimmenade RR, Pinto YM (2008) Amino-terminal pro-B-type natriuretic peptide testing in renal disease. Am J Cardiol 101:82–88PubMedCrossRefGoogle Scholar
  10. Di Angelantonio E, Chowdhury R, Sarwar N, Ray KK, Gobin R, Saleheen D, Thompson A, Gudnason V, Sattar N, Danesh J (2009) B-type natriuretic peptides and cardiovascular risk: systematic review and meta-analysis of 40 prospective studies. Circulation 120:2177–2187PubMedCrossRefGoogle Scholar
  11. Eggers KM, Venge P, Lind L (2013) Prognostic usefulness of the change in N-terminal pro B-type natriuretic peptide levels to predict mortality in a single community cohort aged >/=70 years. Am J Cardiol 111:131–136PubMedCrossRefGoogle Scholar
  12. Feinkohl I, Sattar N, Welsh P, Reynolds RM, Deary IJ, Strachan MW, Price JF (2012) Association of N-terminal pro-brain natriuretic peptide with cognitive function and depression in elderly people with type 2 diabetes. PLoSOne 7:e44569PubMedCentralPubMedCrossRefGoogle Scholar
  13. Garcia BH, Smabrekke L, Trovik T, Giverhaug T (2013) Application of the MAT-CHDSP to assess guideline adherence and therapy goal achievement in secondary prevention of coronary heart disease after percutaneous coronary intervention. EurJ ClinPharmacol 69:703–709PubMedCrossRefGoogle Scholar
  14. Groenning BA, Raymond I, Hildebrandt PR, Nilsson JC, Baumann M, Pedersen F (2004) Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population. Heart 90:297–303PubMedCentralPubMedCrossRefGoogle Scholar
  15. Hiltunen M, Kerola T, Kettunen R, Hartikainen S, Sulkava R, Vuolteenaho O, Nieminen T (2013) The prognostic capacity of B-type natriuretic peptide on cognitive disorder varies by age. Ann Med 45:74–78PubMedCrossRefGoogle Scholar
  16. Kalantarian S, Stern TA, Mansour M, Ruskin JN (2013) Cognitive impairment associated with atrial fibrillation: a meta-analysis. Ann Intern Med 158:338–346PubMedCrossRefGoogle Scholar
  17. Kavousi M, Elias-Smale S, Rutten JH, Leening MJ, Vliegenthart R, Verwoert GC, Krestin GP, Oudkerk M, de Maat MP, Leebeek FW, Mattace-Raso FU, Lindemans J, Hofman A, Steyerberg EW, van der Lugt A, van den Meiracker AH, Witteman JC (2012) Evaluation of newer risk markers for coronary heart disease risk classification: a cohort study. Ann Intern Med 156:438–444PubMedCrossRefGoogle Scholar
  18. Kerola T, Nieminen T, Hartikainen S, Sulkava R, Vuolteenaho O, Kettunen R (2010) B-type natriuretic peptide as a predictor of declining cognitive function and dementia–a cohort study of an elderly general population with a 5-year follow-up. Ann Med 42:207–215PubMedCrossRefGoogle Scholar
  19. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P (2005) N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA: J Am Med Assoc 293:1609–1616CrossRefGoogle Scholar
  20. Koopman C, Vaartjes I, Heintjes EM, Spiering W, van Dis I, Herings RM, Bots ML (2013) Persisting gender differences and attenuating age differences in cardiovascular drug use for prevention and treatment of coronary heart disease, 1998–2010. Eur.Heart JGoogle Scholar
  21. Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC Jr, Hoffman E, Goto S, Ohman EM, Bhatt DL (2013) Adherence to secondary prevention medications and four-year outcomes in outpatients with atherosclerosis. AmJ Med 126:693–700PubMedCrossRefGoogle Scholar
  22. Laslett LJ, Alagona P Jr, Clark BA III, Drozda JP Jr, Saldivar F, Wilson SR, Poe C, Hart M (2012) The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol 60:S1–S49PubMedCrossRefGoogle Scholar
  23. Linssen GC, Bakker SJ, Voors AA, Gansevoort RT, Hillege HL, de Jong PE, van Veldhuisen DJ, Gans RO, de Zeeuw D (2010) N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population. EurHeart J 31:120–127PubMedCrossRefGoogle Scholar
  24. Longstreth WT Jr, Kronmal RA, Thompson JL, Christenson RH, Levine SR, Gross R, Brey RL, Buchsbaum R, Elkind MS, Tirschwell DL, Seliger SL, Mohr JP, deFilippi CR (2013) Amino terminal pro-B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy. StrokeGoogle Scholar
  25. Macfarlane PW, Latif S (1996) Automated serial ECG comparison based on the Minnesota code. J Electrocardiol 29(Suppl):29–34PubMedCrossRefGoogle Scholar
  26. Maisel AS, Daniels LB (2012) Breathing not properly 10 years later: what we have learned and what we still need to Learn. J Am Coll Cardiol 60:277–282PubMedCrossRefGoogle Scholar
  27. Marz W, Tiran B, Seelhorst U, Wellnitz B, Bauersachs J, Winkelmann BR, Boehm BO (2007) N-terminal pro-B-type natriuretic peptide predicts total and cardiovascular mortality in individuals with or without stable coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health Study. Clin Chem 53:1075–1083PubMedCrossRefGoogle Scholar
  28. Melander O, Newton-Cheh C, Almgren P, Hedblad B, Berglund G, Engstrom G, Persson M, Smith JG, Magnusson M, Christensson A, Struck J, Morgenthaler NG, Bergmann A, Pencina MJ, Wang TJ (2009) Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA: J Am Med Assoc 302:49–57CrossRefGoogle Scholar
  29. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD et al (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2197–2223PubMedCrossRefGoogle Scholar
  30. Nadir MA, Rekhraj S, Wei L, Lim TK, Davidson J, MacDonald TM, Lang CC, Dow E, Struthers AD (2012) Improving the primary prevention of cardiovascular events by using biomarkers to identify individuals with silent heart disease. J Am Coll Cardiol 60:960–968PubMedCrossRefGoogle Scholar
  31. Olsen MH, Hansen TW, Christensen MK, Gustafsson F, Rasmussen S, Wachtell K, Ibsen H, Torp-Pedersen C, Hildebrandt PR (2007) N-terminal pro-brain natriuretic peptide, but not high sensitivity C-reactive protein, improves cardiovascular risk prediction in the general population. Eur Heart J 28:1374–1381PubMedCrossRefGoogle Scholar
  32. Patton KK, Ellinor PT, Heckbert SR, Christenson RH, DeFilippi C, Gottdiener JS, Kronmal RA (2009) N-terminal pro-B-type natriuretic peptide is a major predictor of the development of atrial fibrillation: the Cardiovascular Health Study. Circulation 120:1768–1774PubMedCrossRefGoogle Scholar
  33. Pencina MJ, d’Agostino RB, Vasan RS (2010) Statistical methods for assessment of added usefulness of new biomarkers. Clin Chem Lab Med 48:1703–1711PubMedCentralPubMedCrossRefGoogle Scholar
  34. Pencina MJ, D’Agostino RB Sr, Steyerberg EW (2011) Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 30:11–21PubMedCentralPubMedCrossRefGoogle Scholar
  35. Perreault S, Yu AY, Cote R, Dragomir A, White-Guay B, Dumas S (2012) Adherence to antihypertensive agents after ischemic stroke and risk of cardiovascular outcomes. Neurology 79:2037–2043PubMedCentralPubMedCrossRefGoogle Scholar
  36. Pikula A, Beiser AS, Decarli C, Himali JJ, Debette S, Au R, Selhub J, Toffler GH, Wang TJ, Meigs JB, Kelly-Hayes M, Kase CS, Wolf PA, Vasan RS, Seshadri S (2012) Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the framingham offspring study. Circulation 125:2100–2107PubMedCentralPubMedCrossRefGoogle Scholar
  37. Rienstra M, McManus DD, Benjamin EJ (2012) Novel risk factors for atrial fibrillation: useful for risk prediction and clinical decision making? Circulation 125:e941–e946PubMedCentralPubMedCrossRefGoogle Scholar
  38. Rutten FH, Hoes AW (2008) B-type natriuretic peptide assays for detecting heart failure in the elderly: same value as those in the younger? Int J Cardiol 125:161–165PubMedCrossRefGoogle Scholar
  39. Satagopan JM, Ben-Porat L, Berwick M, Robson M, Kutlerand D, Auerbach AD (2004) A note on competing risks in survival data analysis. Br J Cancer 91(7):1229–1235PubMedCentralPubMedCrossRefGoogle Scholar
  40. Schnabel RB, Aspelund T, Li G, Sullivan LM, Suchy-Dicey A, Harris TB, Pencina MJ, D’Agostino RB Sr, Levy D, Kannel WB, Wang TJ, Kronmal RA, Wolf PA, Burke GL, Launer LJ, Vasan RS, Psaty BM, Benjamin EJ, Gudnason V, Heckbert SR (2010) Validation of an atrial fibrillation risk algorithm in whites and African Americans. Arch Intern Med 170:1909–1917PubMedCentralPubMedCrossRefGoogle Scholar
  41. Suwa M, Ito T (2009) Correlation between cognitive impairment and left ventricular diastolic dysfunction in patients with cardiovascular diseases. Int J Cardiol 136:351–354PubMedCrossRefGoogle Scholar
  42. Tombaugh TN, McIntyre NJ (1992) The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 40:922–935PubMedGoogle Scholar
  43. Ueda R, Yokouchi M, Suzuki T, Otomo E, Katagiri T (2003) Prognostic value of high plasma brain natriuretic peptide concentrations in very elderly persons. Am J Med 114:266–270PubMedCrossRefGoogle Scholar
  44. Uthoff H, Staub D, Socrates T, Meyerhans A, Bundi B, Schmid HP, Frauchiger B (2010) PROCAM-, FRAMINGHAM-, S. Vasa 39:325–333PubMedCrossRefGoogle Scholar
  45. Vaes B, de Ruijter W, Degryse J, Westendorp RG, Gussekloo J (2009a) Clinical relevance of a raised plasma N-terminal pro-brain natriuretic peptide level in a population-based cohort of nonagenarians. J Am Geriatr Soc 57:823–829PubMedCrossRefGoogle Scholar
  46. Vaes B, de Ruijter W, Gussekloo J, Degryse J (2009b) The accuracy of plasma natriuretic peptide levels for diagnosis of cardiac dysfunction and chronic heart failure in community-dwelling elderly: a systematic review. Age Ageing 38:655–662PubMedCrossRefGoogle Scholar
  47. Valle R, Aspromonte N, Barro S, Canali C, Carbonieri E, Ceci V, Chinellato M, Gallo G, Giovinazzo P, Ricci R, Milani L (2005) The NT-proBNP assay identifies very elderly nursing home residents suffering from pre-clinical heart failure. Eur J Heart Fail 7:542–551PubMedCrossRefGoogle Scholar
  48. van Peet PG, Drewes YM, de Craen AJ, Gussekloo J, de Ruijter W (2013a) NT-proBNP best predictor of cardiovascular events and cardiovascular mortality in secondary prevention in very old age: the Leiden 85-plus Study. PLoSOne 8:e81400PubMedCentralPubMedCrossRefGoogle Scholar
  49. van Peet PG, Drewes YM, de Craen AJ, Westendorp RG, Gussekloo J, de Ruijter W (2013b) Prognostic value of cardiovascular disease status: the Leiden 85-plus study. Age (Dordr) 35:1433–1444CrossRefGoogle Scholar
  50. Verduijn M, Grootendorst DC, Dekker FW, Jager KJ, le Cessie S (2011) The analysis of competing events like cause-specific mortality–beware of the Kaplan-Meier method. Nephrol Dial Transplant 26:56–61PubMedCrossRefGoogle Scholar
  51. Wallen T, Landahl S, Hedner T, Nakao K, Saito Y (1997) Brain natriuretic peptide predicts mortality in the elderly. Heart 77:264–267PubMedCentralPubMedCrossRefGoogle Scholar
  52. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS (2004) Plasma natriuretic peptide levels and the risk of cardiovascular events and death. NEnglJMed 350:655–663PubMedCrossRefGoogle Scholar
  53. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, Jacques PF, Rifai N, Selhub J, Robins SJ, Benjamin EJ, d’Agostino B, Vasan RS (2006) Multiple biomarkers for the prediction of first major cardiovascular events and death. NEnglJMed 355:2631–2639PubMedCrossRefGoogle Scholar
  54. Wannamethee SG, Welsh P, Lowe GD, Gudnason V, Di AE, Lennon L, Rumley A, Whincup PH, Sattar N (2011) N-terminal pro-brain natriuretic Peptide is a more useful predictor of cardiovascular disease risk than C-reactive protein in older men with and without pre-existing cardiovascular disease. J Am Coll Cardiol 58:56–64PubMedCrossRefGoogle Scholar
  55. Weber M, Hamm C (2006) Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine. Heart 92:843–849PubMedCentralPubMedCrossRefGoogle Scholar
  56. Welsh P, Doolin O, Willeit P, Packard C, Macfarlane P, Cobbe S, Gudnason V, Di Angelantonio E, Ford I, Sattar N (2013) N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular events: results from 15-year follow-up of WOSCOPS. Eur. Heart J 34:443–450CrossRefGoogle Scholar
  57. Zethelius B, Berglund L, Sundstrom J, Ingelsson E, Basu S, Larsson A, Venge P, Arnlov J (2008) Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. NEnglJMed 358:2107–2116PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • Petra G. van Peet
    • 1
  • Anton J.M. de Craen
    • 2
  • Jacobijn Gussekloo
    • 1
  • Wouter de Ruijter
    • 1
  1. 1.Department of Public Health and Primary CareLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of Gerontology and GeriatricsLeiden University Medical CenterLeidenThe Netherlands

Personalised recommendations