Accepted Manuscript
Prognostic value of osteoprotegerin in acute heart failure
Fernando Friões, MD, Olga Laszczynska, MSc, Pedro-Bernardo Almeida, MD, Nuno Silva, MSc, João-Tiago Guimarães, MD, PhD, Torbjørn Omland, MD, PhD, MPH, Ana Azevedo, MD, PhD, Paulo Bettencourt, MD, PhD
PII: S0828-282X(15)00279-2
DOI: 10.1016/j.cjca.2015.04.003 Reference: CJCA 1646
To appear in: Canadian Journal of Cardiology
Received Date: 12 January 2015 Revised Date: 3 April 2015 Accepted Date: 3 April 2015
Please cite this article as: Friões F, Laszczynska O, Almeida P-B, Silva N, Guimarães J-T, Omland T, Azevedo A, Bettencourt P, Prognostic value of osteoprotegerin in acute heart failure, Canadian Journal of Cardiology (2015), doi: 10.1016/j.cjca.2015.04.003.
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1Prognostic value of osteoprotegerin in acute heart failure
Fernando Friões, MD (1,2); Olga Laszczynska, MSc (3); Pedro-Bernardo Almeida, MD (4); Nuno Silva, MSc (5); João-Tiago Guimarães, MD, PhD (3,5,6); Torbjørn Omland, MD, PhD, MPH (7,8); Ana Azevedo, MD, PhD (3,9); Paulo Bettencourt, MD, PhD (1,2).
1- Department of Internal Medicine, São João Hospital Centre, Porto, Portugal;
2- Department of Medicine, University of Porto Medical School, Porto, Portugal;
3- EPIUnit-Institute of Public Health, University of Porto (ISPUP), Porto, Portugal;
4- Department of Cardiology, São João Hospital Centre, Porto, Portugal;
5- Department of Pathology, São João Hospital Centre, Porto, Portugal;
6- Department of Biochemistry, University of Porto Medical School, Porto, Portugal;
7- Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway;
8- Center for Heart Failure Research and K.G. Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway;
9- Department of Clinical Epidemiology, Predictive Medicine and Public Health, University of Porto Medical School, Porto, Portugal;
Short title: Osteoprotegerin in acute heart failure.
Word count: 4424.
Corresponding author: Fernando Friões
Serviço de Medicina Interna – Centro Hospitalar de São João; Alameda Prof. Hernâni Monteiro
4200-319 Porto, Portugal
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2 Brief SummaryIn a prospective study involving 338 patients, plasma levels of osteoprotegerin at discharge of a hospital admission for acute heart failure were associated with higher all-cause mortality or readmission for worsening heart failure during a 6-month period, independently of known morbimortality markers such as age, diabetes, ischaemic aetiology, BNP, NYHA class, renal function, C-reactive protein and the presence or severity of left ventricle systolic dysfunction.
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3 ABSTRACTBackground: Osteoprotegerin (OPG) is promising as a predictor of adverse prognosis in patients with acute coronary syndromes and chronic heart failure. Its prognostic value in acute heart failure (AHF) is unknown. The aim of this study was to assess the prognostic value provided by serum OPG levels at discharge of an admission for AHF.
Methods: In a prospective study, we enrolled 338 patients consecutively admitted with AHF to the Internal Medicine Department of a tertiary care university hospital in Porto, between March 2009 and December 2010. OPG was measured using a commercial enzyme-linked immunosorbent assay, and analysed both as a continuous variable and categorized by quartiles. Patients were followed for up to six months after discharge to ascertain the occurrence of all-cause death or hospital readmission due to AHF.
Results: During follow-up, 119 patients died or were readmitted due to AHF. A graded increase in the risk of the combined endpoint was observed across quartiles of OPG. At 6 months, the cumulative risk of the endpoint was 25% for the first and 50% for the fourth quartile. The multivariable-adjusted risk of death or AHF hospitalization
increased progressively across categories of OPG up to a statistically significant 2.44-fold increase in risk in the highest category (p value for linear trend=0.002), by 5% per 10 pg/mL increase in OPG.
Conclusions: Serum OPG was directly associated with a higher probability of death or readmission for AHF within 6 months, irrespective of other known prognostic markers, both in preserved and reduced ejection fraction.
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4 INTRODUCTIONInitially associated with bone mineral density regulation [1], a growing body of evidence suggests that osteoprotegerin (OPG) plays an important role as a mediator in vascular remodelling and atherosclerotic disease [2-4]. Accordingly, OPG has emerged as a promising biomarker of cardiovascular morbidity and mortality [5-11].
A member of the tumour necrosis factor (TNF) superfamily, OPG interacts with the receptor activator of nuclear factor κB (RANK) and its ligand (RANKL), and also with the TNF-related apoptosis-inducing ligand (TRAIL), acting as a decoy receptor for both ligands and antagonizing their effects, i.e. cytokine release, monocyte
transmigration and apoptosis [12-13]. Since persistent inflammation has emerged as an important mechanism in the development and progression of chronic heart failure (CHF) [14-16] and further motivated by the disappointing results from anti-TNF trials [17-18], the role OPG plays in the development and progression of heart failure has been the object of both basic and clinical research [19-21]. These data suggest that OPG is a useful predictor for mortality [22] and hospitalization for worsening heart failure [23], supporting the theory that OPG/RANK/RANKL axis may represent a new and promising target for heart failure therapy.
Compared to CHF, acute heart failure (AHF) is a far less understood clinical entity, with diverse clinical presentations and corresponding therapeutic approaches [24]. AHF is a major health problem worldwide and is the most frequent cause of hospital admission in patients older than 65 years, accounting for 60% of all
expenditures of heart failure treatment [25-28]. Despite therapeutic interventions, AHF is still associated with an ominous prognosis [29-30]. So far, sparse data exists
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5prognostic value provided by OPG serum levels at discharge, in patients admitted to a tertiary-care hospital because of AHF.
MATERIAL AND METHODS
Study sample
In a prospective study on the prognosis of AHF, we enrolled all patients
consecutively admitted with the diagnosis of AHF to the Internal Medicine Department of Hospital de São João, a public tertiary care university hospital in Porto, between March 2009 and December 2010. Heart failure diagnosis was based on the European Society of Cardiology criteria [24], and both reduced and preserved ejection fraction patients were included. Patients were eligible whether AHF was de novo or an exacerbation of CHF with an increase in at least one New York Heart Association (NYHA) functional class. Patients with an acute coronary syndrome and patients on chronic renal function replacement therapy were excluded. Thirty patients died during the index hospitalization. Of the 612 who were discharged alive, a consecutive
subsample of 401 had OPG measured in serum collected before discharge. One patient was lost to follow-up and 62 further patients had missing data on variables included in the final multivariate model, leaving 338 for the current analysis.
Study design and procedures
Demographic and clinical data were recorded by the research team, based on interviews to the patients and on hospital records.
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6An echocardiogram was performed within 72 hours of admission. All images were obtained using standard ultrasound equipment (System 6, GE Vingmed, Horten,
Norway) with a 2.5-MHz probe. Left ventricular ejection fraction was calculated by the biplane Simpson's method. Patients were classified as heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF), using 45% as cut-off.
Fasting venous blood samples were collected between 8 and 9 a.m. on the last hospitalization day. Specimens were centrifuged for 10 minutes at 3000 × g within two hours after laboratory arrival. Glomerular filtration rate was estimated according to the Modification of Diet in Renal Disease (MDRD) formula [31]. Serum OPG (pg/mL) was assayed in 2013, in serum stored at -80ºC, using enzyme-linked immunosorbent assay kits (MicroVue-Quidel Corporation, San Diego, USA). The lower limit of detection is 8 pg/ml, and the within-run and the run-to-run variation was 2.1%-3.5% and 4.2%-6.1%, respectively.
Patients received standard treatment according to the attending physicians, and the timing of discharge was at their discretion.
The endpoint in the analysis was all-cause death or readmission due to AHF. Patients were followed for up to six months after discharge. Information about the endpoint was obtained from hospital records and telephone contact with the patients.
Ethical standards
The study protocol conforms to the ethical principles of the 1964 Declaration of Helsinki and its later amendments, the local ethics committee approved the study and patients provided written informed consent prior to their inclusion in the study.
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7 Statistical analysisContinuous variables are presented as mean (standard deviation) if normally distributed or median (interquartile range) if skewed. Categorical variables are presented as proportions. The Kruskal-Wallis test was used to compare numerical variables and Pearson Chi-square test for categorical variables.
We used the Kaplan-Meier method to estimate the risk of all-cause death or readmission due to AHF within six months, according to quartiles of serum OPG. Cox regression models were used to quantify the association between serum OPG and the six-month risk of the endpoint. The potential confounders were selected departing from previous knowledge [32-34] to list variables expected to predict worse prognosis in this population, and then kept in the model if either they had a significant effect on the outcome or they changed the regression coefficient for the effect of OPG by more than 10%.
Statistical analyses were performed using Stata version 11.1 for Windows (StataCorp LP, College Station, TX). P values lower than 0.05 were considered statistically significant.
RESULTS
Overall, of the 338 patients with AHF, 33 (9.8%) had heart failure de novo and the remaining had a decompensation of CHF. There were 180 (53.2%) women; the average age was 76 years. All patients were Caucasian. Serum OPG ranged from 39.6
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8to 506.7 pg/ml, with a median value of 146.2 pg/ml. Table 1 depicts the patients’ characteristics by quartiles of serum OPG. Age increased strongly and significantly by 10 years, on average, from the first to the fourth quartile. OPG was also positively associated with NYHA class at discharge, with a 4-fold increase in the proportion discharged in NYHA class III-IV from the first to the fourth quartile. Serum BNP
increased and estimated glomerular filtration rate decreased with the increase in OPG, both in a graded way. C-reactive protein showed a direct association with OPG. There were no important differences in the drug therapy prescribed at discharge according to OPG [Table 1]. OPG levels were not different in the 12 patients with moderate to severe aortic stenosis.
The combined endpoint all-cause death or hospital readmission for AHF was observed in 119 patients. As shown in Figure 1, after approximately 1 month post-discharge from the index hospitalization, the estimated survival curves separate and a graded increase in the risk of the endpoint is observed across the quartiles of OPG. At 6 months, the cumulative risk of the endpoint is 25% for the first and 50% for the fourth quartile.
When adjusting for potential confounders, the risk of death or AHF
hospitalization increased progressively across categories of OPG up to a statistically significant 2.44-fold increase in risk in the highest category (p value for linear
trend=0.002). The graded effect translated into a statistically significant increase in risk of the endpoint by 5% per 10 pg/mL of OPG [Table 2].
The association between OPG and the combined endpoint stratifying by preserved versus reduced ejection fraction is presented in Table 2. There was no significant difference in the prognostic effect of OPG between these groups (hazard ratio (95% confidence interval) = 1.04 (1.01-1.08) in HFpEF versus 1.06 (1.01-1.11) in HFrEF, p for interaction=0.792).
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9 Sensitivity analysesAfter exclusion of 126 patients whose decompensation was due to an infection, the hazard ratio for the composite endpoint was 1.99 (0.86-4.63), 2.04 (0.92-4.55) and 2.74 (1.20-6.25) across the 2nd, 3rd and 4th quartiles, respectively, compared to the first, p for trend=0.023.
When excluding 33 patients with de novo heart failure, the hazard ratio for the composite endpoint was 1.36 (0.72-2.56), 1.37 (0.74-2.56) and 2.13 (1.15-3.92) across the 2nd, 3rd and 4th quartiles, respectively, compared to the first, p for trend=0.014.
DISCUSSION
Plasma levels of OPG at discharge after hospital admission for AHF were related to higher any-cause mortality or admission for worsening heart failure during a 6-month period, independently of known morbimortality markers such as age, diabetes, ischaemic aetiology, BNP, NYHA class, renal function, C-reactive protein and the presence or severity of left ventricle systolic dysfunction.
OPG, formerly known as osteoclastogenesis inhibitory factor, was initially thought to be exclusively related to bone metabolism [1]. Nevertheless, it rapidly became a point of interest in all pathways where the handling of calcium can be disturbed, such as atherosclerosis and chronic renal failure [35-36]. Thus, the
contribution of OPG to a more accurate risk stratification in the cardiovascular diseases continuum is being noted, with several studies associating OPG to the progression of
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10asymptomatic atherosclerosis and to the severity of coronary disease [7, 10, 37], and predicting a higher mortality and cardiovascular morbidity in patients with acute myocardial infarction [8-11, 38].
In the specific setting of HF, several biochemical pathways are activated (neurohumoral activation, oxidative stress, matrix remodelling, myocardial stress, myocyte injury, inflammation, renal dysfunction) working together, leading to the disruption and/or perpetuation of the syndrome and providing a myriad of biological substances potentially useful as biomarkers [39]. Acting as a decoy receptor for some pro-inflammatory cytokines, OPG reflects the inflammatory status as well as it protects cells (including myocytes) from apoptotic stimuli and is related to hemodynamic and neurohumoral disease severity [20]. Nevertheless, the results of two studies using cohorts derived from two major clinical trials in CHF that assessed its potential as a biomarker are somewhat discrepant from each other: OPG was associated with all-cause mortality and cardiovascular hospitalizations (despite modest significance) in a sub-analysis of the Gruppo Italiano per lo Studio della Sopravivenza nell’Infarto Miocardico – Heart Failure trial [22], whereas in the Controlled Rosuvastatin
Multinational Trial in Heart Failure OPG levels were only related to hospitalization for worsening heart failure, not adding predictive information on what concerns to all-cause mortality or the combined end-point of cardiovascular death, nonfatal myocardial
infarction or nonfatal stroke [23].
Concerning the more recent field of AHF, OPG was once previously evaluated as a prognostic tool but only in the specific setting of HFpEF [40]. Our study went beyond the item of ventricular function, showing results that supports OPG as a useful marker for prognostic assessment within 6 months after an AHF hospital admission, irrespective of the left ventricle ejection fraction [Table 2]. Interestingly, as observed in the Kaplan-Meier curves for quartiles of serum OPG [Fig. 1], prognosis seems to be
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11well stratified only about one month after discharge from hospital, a situation not much different from studies evaluating OPG after acute myocardial infarction [11, 37], suggesting a similitude of mechanisms in these two settings, involving ischemia, inflammation, myocardial fibrosis, matrix degradation and remodelling, and leading to new or aggravated cardiac dysfunction [41].
Since OPG is a reliable indicator of the OPG/RANK/RANKL axis, and thereby, a marker of inflammation, it could be elevated in infectious situations, a major problem and a frequent cause of decompensation in the AHF setting. When excluding from the analysis patients whose precipitant factor was an infection, the conclusions remained the same.
Besides being a promising predictor of prognosis, and taking into account the mechanisms represented by the OPG/RANK/RANKL axis, and the fact that OPG acts, in fact, as a cell protector from pro-inflammatory cytokine aggression and apoptosis induction, efforts are being made to a targeted intervention. Whereas there are some promising results in treating postmenopausal osteoporosis and bone metastasis from solid tumours using denosumab, a monoclonal antibody against RANKL [42-43], no data is available concerning its clinical use in cardiovascular disorders, including heart failure.
Strengths and limitations
Our medium-sized cohort of AHF patients admitted consecutively to an Internal Medicine Department of a tertiary-care hospital, reflects the description of major
registries on the subject [29-30], representing an elderly population (75% older than 70 years), with about half of individuals being women (53%), diabetics (45%) or with heart failure of ischaemic aetiology (49%), and having heart failure with preserved ejection fraction in a substantial proportion of cases (40%). Besides, this was a prospective
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12study with a robust end-point (all-cause mortality or admission for worsening heart failure) and information provided/validated by two independent observers, making systematic misclassification unlikely.
Nevertheless, the association between OPG and outcome could be partly due to unspecific associations between inflammation and non-cardiovascular diseases and, as an observational study, a causal role for OPG cannot be established at this point.
CONCLUSION
Higher OPG is associated with a higher risk of death and readmission for AHF within 6 months after discharge from an index hospitalization due to AHF.
Acknowledgements
We thank all collaborators in this study, specially the medical and nursing staff of the Department of Internal Medicine of the São João Hospital Centre.
Funding sources
This study was supported by a grant from Fundação para a Ciência e Tecnologia, Lisbon, Portugal (PIC/IC/82773/2007).
Disclosures
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13 REFERENCES1. Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997 Apr 18; 89(2):309-19.
2. Kiechl S, Werner P, Knoflach M, Furtner M, Willeit J, Schett G. The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. Expert Rev Cardiovasc Ther. 2006 Nov; 4(6):801-11.
3. Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circ Res 2004 Nov 26; 95(11):1046-57.
4. Sandberg WJ, Yndestad A, Øie E et al. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol 2006 Apr; 26(4):857-63. 5. Kalaycıoğlu E, Gökdeniz T, Aykan AÇ et al. Osteoprotegerin is associated
with subclinical left ventricular systolic dysfunction in diabetic hypertensive patients: a speckle tracking study. Can J Cardiol 2014 Dec;30(12):1529-34. 6. Crisafulli A, Micari A, Altavilla D et al. Serum levels of osteoprotegerin and
RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond) 2005 Oct;109(4):389-95.
7. Jono S, Ikari Y, Shioi A et al. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002 Sep 3; 106(10):1192-4.
8. Lindberg S, Jensen JS, Hoffmann S et al. Osteoprotegerin levels change during STEMI and reflect cardiac function. Can J Cardiol 2014 Dec;30(12):1523-8.
9. Omland T, Ueland T, Jansson AM et al. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol 2008 Feb 12; 51(6):627-33.
10. Lieb W, Gona P, Larson MG et al. Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality. Arterioscler Thromb Vasc Biol 2010 Sep; 30(9):1849-54.
11. Pedersen S, Mogelvang R, Bjerre M et al. Osteoprotegerin predicts long-term outcome in patients with ST-segment elevation myocardial infarction
M
AN
US
CR
IP
T
AC
CE
PT
ED
14treated with primary percutaneous coronary intervention. Cardiology 2012; 123(1):31-8.
12. Ware CF. The TNF superfamily. Cytokine Growth Factor Rev 2003 Jun-Aug; 14(3-4):181-4.
13. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003 Sep;3(9):745-56.
14. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990 Jul 26; 323(4):236-41.
15. Kelly RA, Smith TW. Cytokines and cardiac contractile function. Circulation 1997 Feb 18; 95(4):778-81.
16. Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002 Nov 29; 91(11):988-98.
17. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003 Jul 1; 107(25):3133-40.
18. Mann DL, McMurray JJ, Packer M et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004 Apr 6; 109(13):1594-602.
19. Liu W, Feng W, Wang F et al. Osteoprotegerin/RANK/RANKL axis in cardiac remodelling due to immune-inflammatory myocardial disease. Exp Mol Pathol 2008 Jun; 84(3):213-7.
20. Ueland T, Yndestad A, Øie E et al. Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation 2005 May 17; 111(19):2461-8.
21. Putko BN, Yogasundaram H, Oudit GY. Cardiovascular pathophysiology: is it a Tumour Necrosis Factor Superfamily affair? Can J Cardiol 2014 Dec;30(12):1492-5.
22. Røysland R, Masson S, Omland T et al. Prognostic value of osteoprotegerin in chronic heart failure: The GISSI-HF trial. Am Heart J 2010 Aug; 160(2):286-93.
M
AN
US
CR
IP
T
AC
CE
PT
ED
1523. Ueland T, Dahl CP, Kjekshus J et al. Osteoprotegerin predicts progression of chronic heart failure: results from CORONA. Circ Heart Fail 2011 Mar;4(2):145-52.
24. McMurray JJ, Adamopoulos S, Anker SD et al. 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 (HFA) of the ESC. Eur J Heart Fail 2012 Aug; 14(8):803-69.
25. Lloyd-Jones D, Adams RJ, Brown TM et al. Heart disease and stroke statistics – 2010 update: a report from the American Heart Association. Circulation 2010 Feb 23; 121(7):e46-215.
26. Maggioni AP, Dahlström U, Filippatos G et al. EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2010 Oct;12(10):1076-84.
27. Damasceno A, Mayosi BM, Sani M et al. The causes, treatment, and outcome of acute heart failure in 1006 Africans from 9 countries: results of the Sub-Saharan Africa Survey of Heart Failure. Arch Intern Med 2012 Oct 8; 172(18):1386-94.
28. Go AS, Mozaffarian D, Roger VL et al. Heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation 2014 Jan 21; 129(3):e28-292.
29. Adams KF Jr, Fonarow GC, Emerman CL et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005 Feb; 149(2):209-16.
30. Nieminen MS, Brutsaert D, Dickstein K et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J 2006 Nov; 27(22):2725-36.
31. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999 Mar 16; 130(6):461-70.
M
AN
US
CR
IP
T
AC
CE
PT
ED
1632. Gheorghiade M, Zannad F, Sopko G et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005 Dec 20; 112(25):3958-68.
33. Siirila-Waris K, Lassus J, Melin J, et al. Characteristics, outcomes, and predictors of 1-year mortality in patients hospitalized for acute heart failure. Eur Heart J 2006; 27: 3011-7.
34. Maggioni AP, Dahlström U, Filippatos G et al. EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey /ESC-HF Pilot). Eur J Heart Fail. 2013 Jul; 15(7):808-17.
35. Kiechl S, Schett G, Wenning G et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004 May 11; 109(18):2175-80.
36. Nitta K, Akiba T, Uchida K et al. The progression of vascular calcification and serum osteoprotegerin levels in patients on long-term hemodialysis. Am J Kidney Dis 2003 Aug; 42(2):303-9.
37. Abedin M, Omland T, Ueland T et al. Relation of osteoprotegerin to coronary calcium and aortic plaque (from the Dallas Heart Study). Am J Cardiol 2007 Feb 15; 99(4):513-8.
38. Ueland T, Jemtland R, Godang K et al. Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol 2004 Nov 16; 44(10):1970-6.
39. Braunwald E. Heart failure. JACC Heart Fail. 2015 Feb; 3(2):97-107.
40. Aramburu-Bodas O, García-Casado B, Salamanca-Bautista P et al. Relationship between osteoprotegerin and mortality in decompensated heart failure with preserved ejection fraction. J Cardiovasc Med (Hagerstown). 2014 Dec 2. [Epub ahead of print]
41. Ueland T, Yndestad A, Dahl CP, Gullestad L, Aukrust P. TNF revisited: osteoprotegerin and TNF-related molecules in heart failure. Curr Heart Fail Rep 2012 Jun; 9(2):92-100.
42. Leder BZ, Tsai JN, Uihlein AV et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): a randomized controlled trial. J Clin Endocrinol Metab. 2014 May; 99(5):1694-700.
M
AN
US
CR
IP
T
AC
CE
PT
ED
1743. Rolfo C, Raez LE, Russo A et al. Molecular target therapy for bone metastasis: starting a new era with denosumab, a RANKL inhibitor. Expert Opin Biol Ther 2014 Jan; 14(1):15-26.
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18Table 1. Patient baseline characteristics by quartiles of serum OPG at hospital discharge. First quartile <108.3 pg/ml Second quartile 108.3-146.2 pg/ml Third quartile 146.3-184.8 pg/ml Fourth quartile 184.9-506.7 pg/ml P N 83 86 84 85 Female, % 44.6 59.3 56.0 52.9 0.260
Age (years), mean (standard deviation) 69.9 (11.7) 76.0 (9.4) 77.1 (11.5) 80.0 (11.0) <0.001
Diabetes mellitus, % 33.7 53.5 40.5 50.6 0.036
Ischemic etiology, % 41.0 57.0 46.4 50.6 0.200
Ejection fraction (%), mean (standard deviation)* 35 (19) 35 (15) 40 (17) 42 (17) 0.033
Left ventricular systolic function, % 0.034
Preserved 33.7 36.0 45.2 44.7
Mildly depressed 8.4 3.5 9.5 3.5
Moderately depressed 10.8 23.3 8.3 21.2
Severely depressed 47.0 37.2 36.9 30.6
Atrial fibrillation, % 47.0 45.9 47.6 51.8 0.879
NYHA class III-IV at discharge, % 7.2 16.3 23.8 27.1 0.005
BNP at discharge (pg/ml), median (P25-P75) 441 (230-1089) 588 (240-1565) 664 (300-1091) 927 (482-1615) 0.003 eGFR – MDRD (mL/min/1.73 m2), median (P25-P75) 56.9 (42.0-68.5) 47.9 (32.9-58.9) 47.5 (38.4-58.6) 41.4 (28.5-53.7) <0.001
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19 C-reactive protein at discharge (mg/l), median(P25-P75)
9.2 (4.0-18.2) 12.3 (7.4-25.4) 13.6 (7.4-25.8) 13.2 (8.3-28.9) 0.029
Use of inotropic drugs during hospital admission, % 4.8 10.5 3.6 10.6 0.168
Beta-blocker prescribed at discharge, % 80.7 77.9 76.2 76.5 0.891
ACEi/ARB prescribed at discharge, % 83.1 82.6 76.2 78.8 0.637
Spironolactone prescribed at discharge, % 20.5 26.7 26.2 27.1 0.732
Loop diuretic prescribed at discharge, % 93.9 92.9 98.8 95.3 0.300
Statin prescribed at discharge, % 67.1 73.6 65.1 57.6 0.230
ACEi, Angiotensin converting enzyme-inhibitor; ARB, Angiotensin II receptor-blocker; BNP, B-type natriuretic peptide; eGFR-MDRD, estimated glomerular filtration rate (Modification of Diet in Renal Disease study equation); P25-P75, 25th percentile-75th percentile.
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20Table 2. Multivariate Cox regression analysis for the association of serum OPG with all-cause death or hospital readmission due to heart failure within 6 months
after discharge from the index hospitalization for acute heart failure.
Hazard ratio* (95% confidence interval) Overall HFpEF HFrEF
Quartiles of serum OPG
1 <108.3 pg/ml 1 1 1
2 108.3-146.2 pg/ml 1.44 (0.78-2.70) 3.27 (0.85-12.54) 0.97 (0.47-2.03)
3 146.3-184.8 pg/ml 1.73 (0.94-3.20) 1.80 (0.47-6.95) 1.78 (0.89-3.58)
4 184.9-506.7 pg/ml 2.44 (1.33-4.49) 4.52 (1.28-15.94) 1.58 (0.76-3.29)
P value for linear trend 0.002 0.030 0.088
Serum OPG (continuous), per 10 pg/mL
1.05 (1.03-1.08) 1.04 (1.01-1.08) 1.06 (1.01-1.11)
* adjusted for age (continuous), diabetes (yes/no), ischaemic aetiology for heart failure (yes/no), left ventricular systolic dysfunction (preserved, mild, moderate, severe depression), New York Heart Association functional class at discharge (I-II/III-IV), estimated glomerular filtration rate at discharge (≥90, 60-89.9, 30-59.9, <30 mL/min/1.73 m2), serum B-type natriuretic peptide at discharge (continuous) and C-reactive protein at discharge (continuous). P value for interaction between OPG and preserved versus reduced ejection fraction=0.792.
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21Figure titles and legends
Fig. 1 Prognosis according to osteoprotegerin quartiles
Cumulative survival free of hospitalization for heart failure, within 6 months after the index hospitalization for acute heart failure, estimated by the Kaplan-Meier method, by quartiles of serum OPG at hospital discharge.
