Abstract
Background:
The precursor peptide of atrial natriuretic peptide (MR-proANP) has a physiological role in fluid homeostasis and is associated with mortality and adverse clinical outcomes in heart failure patients. Little is known about the prognostic potential of this peptide for long-term mortality prediction in community-dwelling patients. We evaluated associations of MR-proANP levels with 10-year all-cause mortality in patients visiting their general practitioner for a respiratory tract infection.
Methods:
In this post-hoc analysis including 359 patients (78.5%) of the original trial, we calculated cox regression models and area under the receiver operating characteristic curve (AUC) to assess associations of MR-proANP blood levels with mortality and adverse outcome including death, pulmonary embolism, and major adverse cardiac or cerebrovascular events.
Results:
After a median follow-up of 10.0 years, 9.8% of included patients died. Median admission MR-proANP levels were significantly elevated in non-survivors compared to survivors (80.5 pmol/L, IQR 58.6–126.0; vs. 45.6 pmol/L, IQR 34.2–68.3; p<0.001) and associated with 10-year all-cause mortality (age-adjusted HR 2.0 [95% CI 1.3–3.1, p=0.002]; AUC 0.79). Results were similar for day 7 blood levels and also for the prediction of other adverse outcomes.
Conclusions:
Increased MR-proANP levels were associated with 10-year all-cause mortality and adverse clinical outcome in a sample of community-dwelling patients. If diagnosis-specific cut-offs are confirmed in future studies, this marker may help to direct preventive measures in primary care.
Acknowledgments
We are grateful to the physicians, their staff and patients who participated in the PARTI trial and the follow-up data collection. We would also like to thank the staff of the central laboratory of the University Hospital Basel for their assistance and technical support.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Mr. Odermatt and Ms. Lara Hersberger contributed equally to this study. Mr. Odermatt, Ms. Hersberger and Dr. Schuetz had full access to all of the data in the study and take responsibility for the integrity of the data, performed the statistical work, and drafted the manuscript. All authors helped to interpret the findings, read and revised the manuscript critically for important intellectual content, and approved the final version of the manuscript.
Research funding: The investigator-initiated PARTI trial was sponsored by a grant from the Swiss National Science Foundation (3300C0-107772) and by the Association for the Promotion of Science and Postgraduate Training of the University Hospital Basel. B.r.a.h.m.s. AG provided assay and kit material related to the study. Dr. Schuetz and Dr. Christ-Crain were supported by funds of the Freiwillige Akademische Gesellschaft, the Department of Endocrinology, Diabetology and Clinical Nutrition, and the Department of Clinical Chemistry, all Basel, Switzerland. Drs. Christ-Crain, Mueller and Schuetz, received support from B.r.a.h.m.s. to attend meetings and fulfilled speaking engagements. Drs. Schuetz, Christ-Crain and Mueller received support from bioMérieux to attend meetings and fulfilled speaking engagements. Dr. Mueller has served as a consultant and received research support from B.r.a.h.m.s. and bioMérieux. Heiner C. Bucher has received research support from B.r.a.h.m.s.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, et al. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care 2010;14:R106.10.1186/cc9055Search in Google Scholar PubMed PubMed Central
2. Schuetz P. “Personalized” sepsis care with the help of specific biomarker levels on admission and during follow up: are we there yet? Clin Chem Lab Med 2015;53:515–7.10.1515/cclm-2014-1246Search in Google Scholar PubMed
3. Schuetz P, Hausfater P, Amin D, Amin A, Haubitz S, Faessler L, et al. Biomarkers from distinct biological pathways improve early risk stratification in medical emergency patients: the multinational, prospective, observational TRIAGE study. Crit Care 2015;19:377.10.1186/s13054-015-1098-zSearch in Google Scholar PubMed PubMed Central
4. Kutz A, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, et al. Prognostic value of procalcitonin in respiratory tract infections across clinical settings. Crit Care 2015;19:74.10.1186/s13054-015-0792-1Search in Google Scholar PubMed PubMed Central
5. Alan M, Grolimund E, Kutz A, Christ-Crain M, Thomann R, Falconnier C, et al. Clinical risk scores and blood biomarkers as predictors of long-term outcome in patients with community-acquired pneumonia: a 6-year prospective follow-up study. J Intern Med 2015;278:174–84.10.1111/joim.12341Search in Google Scholar PubMed
6. Ahluwalia N, Blacher J, Szabo de Edelenyi F, Faure P, Julia C, Hercberg S, et al. Prognostic value of multiple emerging biomarkers in cardiovascular risk prediction in patients with stable cardiovascular disease. Atherosclerosis 2013;228:478–84.10.1016/j.atherosclerosis.2013.03.017Search in Google Scholar PubMed
7. Lindberg S, Jensen JS, Pedersen SH, Galatius S, Goetze JP, Mogelvang R. MR-proANP improves prediction of mortality and cardiovascular events in patients with STEMI. Eur J Prev Cardiol 2015;22:693–700.10.1177/2047487314538856Search in Google Scholar PubMed
8. O'Malley RG, Bonaca MP, Scirica BM, Murphy SA, Jarolim P, Sabatine MS, et al. Prognostic performance of multiple biomarkers in patients with non-ST-segment elevation acute coronary syndrome: analysis from the MERLIN-TIMI 36 trial (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction 36). J Am Coll Cardiol 2014;63:1644–53.10.1016/j.jacc.2013.12.034Search in Google Scholar PubMed
9. Gaggin HK, Januzzi JL, Jr. Natriuretic peptides in heart failure and acute coronary syndrome. Clin Lab Med 2014;34:43–58, vi.10.1016/j.cll.2013.11.007Search in Google Scholar PubMed
10. Seronde MF, Gayat E, Logeart D, Lassus J, Laribi S, Boukef R, et al. Comparison of the diagnostic and prognostic values of B-type and atrial-type natriuretic peptides in acute heart failure. Int J Cardiol 2013;168:3404–11.10.1016/j.ijcard.2013.04.164Search in Google Scholar PubMed
11. Aiura K, Ueda M, Endo M, Kitajima M. Circulating concentrations and physiologic role of atrial natriuretic peptide during endotoxic shock in the rat. Crit Care Med 1995;23:1898–906.10.1097/00003246-199511000-00017Search in Google Scholar PubMed
12. Ruiz-Gonzalez A, Esquerda A, Porcel JM, Bielsa S, Valencia H, Cao G, et al. A pilot study on the diagnostic accuracy of proadrenomedullin and proatrial natriuretic Peptide in lower respiratory tract infections. Open Respir Med J 2014;8:22–7.10.2174/1874306401408010022Search in Google Scholar PubMed PubMed Central
13. Reinstadler SJ, Feistritzer HJ, Klug G, Mayr A, Huybrechts L, Hammerer-Lercher A, et al. Biomarkers of hemodynamic stress and aortic stiffness after STEMI: a cross-sectional analysis. Dis Markers 2015;2015:717032.10.1155/2015/717032Search in Google Scholar PubMed PubMed Central
14. Khan SQ, Dhillon O, Kelly D, Squire IB, Struck J, Quinn P, et al. Plasma N-terminal B-Type natriuretic peptide as an indicator of long-term survival after acute myocardial infarction: comparison with plasma midregional pro-atrial natriuretic peptide: the LAMP (Leicester Acute Myocardial Infarction Peptide) study. J Am Coll Cardiol 2008;51:1857–64.10.1016/j.jacc.2008.01.041Search in Google Scholar PubMed
15. Katan M, Fluri F, Schuetz P, Morgenthaler NG, Zweifel C, Bingisser R, et al. Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke. J Am Coll Cardiol 2010;56:1045–53.10.1016/j.jacc.2010.02.071Search in Google Scholar PubMed
16. Duszyniska W, Lipinska-Gediga M, Domoslawski P, Kaiser T, Durek G, Bednarz W. [Haemorrhagic shock complicating acute pancreatitis]. Anestezjol Intens Ter 2011;43:36–9.Search in Google Scholar
17. Haviv M, Haver E, Lichtstein D, Hurvitz H, Klar A. Atrial natriuretic peptide in children with pneumonia. Pediatr Pulmonol 2005;40:306–9.10.1002/ppul.20233Search in Google Scholar PubMed
18. Vesely DL. Atrial natriuretic peptide prohormone gene expression: hormones and diseases that upregulate its expression. IUBMB Life 2002;53:153–9.10.1080/15216540212336Search in Google Scholar PubMed
19. de Bold AJ, de Bold ML. Determinants of natriuretic peptide production by the heart: basic and clinical implications. J Investig Med 2005;53:371–7.10.2310/6650.2005.53710Search in Google Scholar PubMed
20. Dietz JR. Mechanisms of atrial natriuretic peptide secretion from the atrium. Cardiovasc Res 2005;68:8–17.10.1016/j.cardiores.2005.06.008Search in Google Scholar PubMed
21. Frontzek K, Fluri F, Siemerkus J, Muller B, Gass A, Christ-Crain M, et al. Isolated insular strokes and plasma MR-proANP levels are associated with newly diagnosed atrial fibrillation: a pilot study. PLoS One 2014;9:e92421.10.1371/journal.pone.0092421Search in Google Scholar PubMed PubMed Central
22. van Hateren KJ, Landman GW, Kleefstra N, Groenier KH, Struck J, Navis GJ, et al. The midregional fragment of pro-A-type natriuretic peptide, blood pressure, and mortality in a prospective cohort study of patients with type 2 diabetes (ZODIAC-25). Diabetes Care 2013;36:1347–52.10.2337/dc12-0428Search in Google Scholar PubMed PubMed Central
23. Buckley MG, Marcus NJ, Yacoub MH. Cardiac peptide stability, aprotinin and room temperature: importance for assessing cardiac function in clinical practice. Clin Sci (Lond) 1999;97:689–95.10.1042/CS19990194Search in Google Scholar
24. Guertler C, Wirz B, Christ-Crain M, Zimmerli W, Mueller B, Schuetz P. Inflammatory responses predict long-term mortality risk in community-acquired pneumonia. Eur Respir J 2011;37:1439–46.10.1183/09031936.00121510Search in Google Scholar PubMed
25. Kruger S, Ewig S, Kunde J, Hartmann O, Suttorp N, Welte T, et al. Pro-atrial natriuretic peptide and pro-vasopressin for predicting short-term and long-term survival in community-acquired pneumonia: results from the German Competence Network CAPNETZ. Thorax 2010;65:208–14.10.1136/thx.2009.121178Search in Google Scholar PubMed
26. Kruger S, Papassotiriou J, Marre R, Richter K, Schumann C, von Baum H, et al. Pro-atrial natriuretic peptide and pro-vasopressin to predict severity and prognosis in community-acquired pneumonia: results from the German competence network CAPNETZ. Intensive Care Med 2007;33:2069–78.10.1007/s00134-007-0895-5Search in Google Scholar PubMed
27. Muller B, Suess E, Schuetz P, Muller C, Bingisser R, Bergmann A, et al. Circulating levels of pro-atrial natriuretic peptide in lower respiratory tract infections. J Intern Med 2006;260:568–76.10.1111/j.1365-2796.2006.01722.xSearch in Google Scholar PubMed
28. von Haehling S, Jankowska EA, Morgenthaler NG, Vassanelli C, Zanolla L, Rozentryt P, et al. Comparison of midregional pro-atrial natriuretic peptide with N-terminal pro-B-type natriuretic peptide in predicting survival in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1973–80.10.1016/j.jacc.2007.08.012Search in Google Scholar PubMed
29. Moertl D, Berger R, Struck J, Gleiss A, Hammer A, Morgenthaler NG, et al. Comparison of midregional pro-atrial and B-type natriuretic peptides in chronic heart failure: influencing factors, detection of left ventricular systolic dysfunction, and prediction of death. J Am Coll Cardiol 2009;53:1783–90.10.1016/j.jacc.2009.01.057Search in Google Scholar PubMed
30. Miller WL, Hartman KA, Grill DE, Struck J, Bergmann A, Jaffe AS. Serial measurements of midregion proANP and copeptin in ambulatory patients with heart failure: incremental prognostic value of novel biomarkers in heart failure. Heart 2012;98:389–94.10.1136/heartjnl-2011-300823Search in Google Scholar PubMed PubMed Central
31. Alehagen U, Dahlstrom U, Rehfeld JF, Goetze JP. Pro-A-type natriuretic peptide, proadrenomedullin, and N-terminal pro-B-type natriuretic peptide used in a multimarker strategy in primary health care in risk assessment of patients with symptoms of heart failure. J Card Fail 2013;19:31–9.10.1016/j.cardfail.2012.11.002Search in Google Scholar PubMed
32. Zabarovskaja S, Hage C, Linde C, Daubert JC, Donal E, Gabrielsen A, et al. Adaptive cardiovascular hormones in a spectrum of heart failure phenotypes. Int J Cardiol 2015;189:6–11.10.1016/j.ijcard.2015.03.381Search in Google Scholar PubMed
33. Vazquez M, Jockers K, Christ-Crain M, Zimmerli W, Muller B, Schuetz P. MR-pro-atrial natriuretic peptide (MR-proANP) predicts short- and long-term outcomes in respiratory tract infections: a prospective validation study. Int J Cardiol 2012;156:16–23.10.1016/j.ijcard.2010.10.037Search in Google Scholar PubMed
34. Kruger S, Ewig S, Giersdorf S, Hartmann O, Suttorp N, Welte T, et al. Cardiovascular and inflammatory biomarkers to predict short- and long-term survival in community-acquired pneumonia: Results from the German Competence Network, CAPNETZ. Am J Respir Crit Care Med 2010;182:1426–34.10.1164/rccm.201003-0415OCSearch in Google Scholar PubMed
35. Then C, Kowall B, Lechner A, Meisinger C, Heier M, Koenig W, et al. Plasma MR-proANP levels are associated with carotid intima-media thickness in the general community: the KORA F4 study. Atherosclerosis 2013;230:235–41.10.1016/j.atherosclerosis.2013.07.047Search in Google Scholar PubMed
36. Eggers KM, Venge P, Lind L. Mid-regional pro-atrial natriuretic peptide levels in the elderly: clinical and prognostic implications, and comparison to B-type natriuretic peptides. Clin Chim Acta 2013;419:62–6.10.1016/j.cca.2013.01.020Search in Google Scholar PubMed
37. Hobbelt AH, Siland JE, Geelhoed B, Van Der Harst P, Hillege HL, Van Gelder IC, et al. Clinical, biomarker, and genetic predictors of specific types of atrial fibrillation in a community-based cohort: data of the PREVEND study. Europace 2016 Mar 7. pii: euw016. [Epub ahead of print].10.1093/europace/euw016Search in Google Scholar PubMed PubMed Central
38. Melander O, Newton-Cheh C, Almgren P, Hedblad B, Berglund G, Engstrom G, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. J Am Med Assoc 2009;302:49–57.10.1001/jama.2009.943Search in Google Scholar PubMed PubMed Central
39. van Hateren KJ, Alkhalaf A, Kleefstra N, Groenier KH, de Jong PE, de Zeeuw D, et al. Comparison of midregional pro-A-type natriuretic peptide and the N-terminal pro-B-type natriuretic peptide for predicting mortality and cardiovascular events. Clin Chem. 2012;58:293–7.10.1373/clinchem.2011.166348Search in Google Scholar PubMed
40. Briel M, Schuetz P, Mueller B, Young J, Schild U, Nusbaumer C, et al. Procalcitonin-guided antibiotic use vs a standard approach for acute respiratory tract infections in primary care. Arch Intern Med 2008;168:2000–7; discussion 7–8.10.1001/archinte.168.18.2000Search in Google Scholar PubMed
41. Briel M, Christ-Crain M, Young J, Schuetz P, Huber P, Periat P, et al. Procalcitonin-guided antibiotic use versus a standard approach for acute respiratory tract infections in primary care: study protocol for a randomised controlled trial and baseline characteristics of participating general practitioners [ISRCTN73182671]. BMC Fam Pract 2005;6:34.10.1186/1471-2296-6-34Search in Google Scholar PubMed PubMed Central
42. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011;171:1322–31.10.1001/archinternmed.2011.318Search in Google Scholar PubMed
43. Odermatt J, Bolliger R, Hersberger L, Ottiger M, Christ-Crain M, Briel M, et al. Copeptin predicts 10-year all-cause mortality in community patients: a 10-year prospective cohort study. Clin Chem Lab Med 2016;54:1681–90.10.1515/cclm-2016-0151Search in Google Scholar PubMed
44. Morgenthaler NG, Struck J, Thomas B, Bergmann A. Immunoluminometric assay for the midregion of pro-atrial natriuretic peptide in human plasma. Clin Chem 2004;50:234–6.10.1373/clinchem.2003.021204Search in Google Scholar PubMed
45. Nowak A, Breidthardt T, Christ-Crain M, Bingisser R, Meune C, Tanglay Y, et al. Direct comparison of three natriuretic peptides for prediction of short- and long-term mortality in patients with community-acquired pneumonia. Chest 2012;141:974–82.10.1378/chest.11-0824Search in Google Scholar PubMed
46. Saritas T, Tascilar E, Abaci A, Yozgat Y, Dogan M, Dundaroz R, et al. Importance of plasma N-terminal pro B-type natriuretic peptide, epicardial adipose tissue, and carotid intima-media thicknesses in asymptomatic obese children. Pediatr Cardiol 2010;31:792–9.10.1007/s00246-010-9705-xSearch in Google Scholar PubMed
47. Sabatine MS, Morrow DA, de Lemos JA, Omland T, Sloan S, Jarolim P, et al. Evaluation of multiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease. Circulation 2012;125:233–40.10.1161/CIRCULATIONAHA.111.063842Search in Google Scholar PubMed PubMed Central
48. Daniels LB, Clopton P, Potocki M, Mueller C, McCord J, Richards M, et al. Influence of age, race, sex, and body mass index on interpretation of midregional pro atrial natriuretic peptide for the diagnosis of acute heart failure: results from the BACH multinational study. Eur J Heart Fail 2012;14:22–31.10.1093/eurjhf/hfr157Search in Google Scholar PubMed
49. Heining L, Giesa C, Ewig S. MR-proANP, MR-proADM, and PCT in Patients Presenting with Acute Dyspnea in a Medical Emergency Unit. Lung 2016;194:185–91.10.1007/s00408-015-9837-0Search in Google Scholar PubMed
50. Richards M, Di Somma S, Mueller C, Nowak R, Peacock WF, Ponikowski P, et al. Atrial fibrillation impairs the diagnostic performance of cardiac natriuretic peptides in dyspneic patients: results from the BACH Study (Biomarkers in ACute Heart Failure). JACC Heart Fail 2013;1:192–9.10.1016/j.jchf.2013.02.004Search in Google Scholar PubMed
51. von Haehling S, Papassotiriou J, Hartmann O, Doehner W, Stellos K, Geisler T, et al. Mid-regional pro-atrial natriuretic peptide as a prognostic marker for all-cause mortality in patients with symptomatic coronary artery disease. Clin Sci (Lond) 2012;123:601–10.10.1042/CS20120216Search in Google Scholar PubMed
52. Lainscak M, von Haehling S, Anker SD. Natriuretic peptides and other biomarkers in chronic heart failure: from BNP, NT-proBNP, and MR-proANP to routine biochemical markers. Int J Cardiol 2009;132:303–11.10.1016/j.ijcard.2008.11.149Search in Google Scholar PubMed
Supplemental Material:
The online version of this article offers supplementary material (DOI: https://doi.org/10.1515/cclm-2016-0760).
©2017 Walter de Gruyter GmbH, Berlin/Boston
