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Prognostic Significance of Adrenomedullin in Patients With Heart Failure and With Myocardial Infarction
Prognostic Significance of Adrenomedullin in Patients With Heart Failure and With Myocardial Infarction Matthew F. Yuyun, MD, MPhil, PhDa,*, Hafid K. Narayan, MDa,b, and Leong L. Ng, MDa,b We undertook this systematic review to determine the prognostic significance of adrenomedullin (ADM) in patients with heart failure and acute myocardial infarction (AMI). Given the difficulty in measuring mature ADM, its surrogate, midregional proadrenomedullin (MRproADM) has been used in most studies. Systematic search of original published studies through MEDLINE and the Cochrane Collaboration databases restricted to reports in English from January 1, 1993, to June 30, 2014, in humans was undertaken. Heterogeneity of studies prohibited a meta-analysis. In patients with heart failure, the area under the curve for prediction of mortality by MRproADM ranged from 0.68 to 0.81 (95% confidence intervals [CI] 0.63 to 0.91) across studies. One nmol/l increase in MRproADM was associated with hazard ratios (HRs) ranging from 1.77 to 2.79 (95% CI 1.29 to 5.95) for death in patients with heart failure. In patients with AMI, the area under the curve for MRproADM predicting MACE ranged from 0.64 to 0.80 (CI 0.51 to 0.87) across studies and death 0.79 to 0.84 (CI 0.73 to 0.90). One nmol/l increase in MRproADM was associated with HR for MACE ranging from 1.78 to 4.10 (CI 1.20 to 10.12), whereas log10 of MRproADM had HRs of 3.63 to 9.75 (CI 1.48 to 26.16) for MACE and 4.86 to 16.68 (CI 4.56 to 60.99) for death across studies in patients with AMI. In conclusion, adrenomedullin is an independent predictor of death in patients with heart failure and of MACE and death in patients who have suffered an AMI. Quantification of this peptide might contribute to improved risk stratification in settings of heart failure and myocardial infarction. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:986e991) Adrenomedullin (ADM) is produced from a large peptide precursor molecule (preproadrenomedullin) which consists of 185 amino acids through a 2-staged enzymatic process into the mature form with 52 amino acids.1 The gene encoding for adrenomedullin is located within the short arm of chromosome 11.2 Measurement of mature ADM as biomarker has been previously hampered by its short plasma half-life of 22 1.6 minutes, the presence of a binding protein called human adrenomedullin-binding protein (AMBP-1) identified as complement factor H,3 and the immediate binding of ADM to local receptors, which had rendered its accurate measurement difficult to achieve.3,4 A possible solution to this problem came from the development of assays to identify midregional proadrenomedullin (MRproADM), which is a more stable nonfunctional fragment of initial precursor peptide, consisting of 45 to 92 amino acids. MRproADM is secreted in stoichiometric amounts to mature ADM and therefore acts as a reliable surrogate of ADM levels.4 To the best of our knowledge, no study has undertaken a systematic review or meta-analysis of ADM and incident major cardiovascular
a Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom and bDepartment of Cardiovascular Sciences, National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Manuscript received October 5, 2014; revised manuscript received and accepted January 6, 2015. See page 990 for disclosure information. *Corresponding author: Tel: (44) 116 250 2449; fax: (44) 116 252 3108. E-mail address: [email protected] (M.F. Yuyun).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.01.027
events or mortality in patients with heart failure or acute myocardial infarction (AMI). We therefore undertook this systematic review with the hope of including a meta-analysis if possible, to determine the prognostic significance of ADM in patients with heart failure and post-AMI. Methods The method was guided by Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).5 The inclusion criteria were prospective studies published in adult patients with acute or chronic heart failure or AMI or patients presenting with acute dyspnea or acute chest pain or stable or unstable angina. In addition, they must have had adrenomedullin measured at baseline and related to major adverse cardiovascular events (MACE) or mortality. Excluded were review articles, pediatric studies, and animal studies. A systematic search of studies was carried out on original published studies using PubMed (MEDLINE) and the Cochrane Collaboration databases using key words and MeSH terms. For patients with heart failure, the MeSH terms or key words were (“Adrenomedullin” OR “ADM” OR “MRproADM”) AND “Heart Failure.” For patients with myocardial infarction, these were (“Myocardial Infarction” OR “Angina Pectoris” OR “Angina, Stable” OR “Angina, Unstable”) AND (“Adrenomedullin” OR “ADM” OR “MRproADM”). Searches of references of published reports obtained from the aforementioned systematic search were also undertaken. The search was restricted to reports published in English from January 1, 1993, to June 30, 2014, in humans. Figure 1 shows the flow chart for selection for this systematic review. www.ajconline.org
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Figure 1. Flowchart of search of studies and identification of relevant English-language studies on of adrenomedullin and death in patients with heart failure and adrenomedullin and MACE and death in patients with myocardial infarction (January 1, 1993, to June 30, 2014).
The main outcome measure of this systematic review for patients with heart failure was death. The outcome measure for patients with myocardial infarction was MACE as primary end point measure, with death as secondary end point. The end point, MACE, was defined variably across studies as a composite of myocardial infarction, stroke, hospitalization for heart failure, and all-cause mortality, although in some studies not all these components were present. Two authors independently perused all the relevant titles and abstracted data from selected reports with any disagreements settled by a consensus or opinion from other co-authors. Some studies had very small sample sizes, but we included given the small number of studies. Because of the high level of heterogeneity across studies, no quantitative pooling of results from various studies through a meta-analysis was undertaken. This heterogeneity was mainly due to the discrepancy in type of adrenomedullin measured (mature ADM vs its surrogate MRproADM), discrepancy in units of ADM used by different studies, the varying use of ADM as a continuous and a categorical variable across studies, the different cutoffs of ADM when used as a categorical variable, and differing logarithmic transformations or unit change of ADM when used as a continuous variable in various statistical models. Results Table 1 lists studies which looked at the relation between ADM and mortality in patients with heart failure. We
identified 14 studies in total, and these were mainly cohort studies. Baseline plasma levels of MRproADM were significantly higher in patients who died during follow-up compared with the levels of those who survived. The area under the curve (AUC) for adrenomedullin predicting mortality was only reported for 12 studies using MRproADM in patients with heart failure, and this ranged from 0.68 to 0.81 (95% confidence interval [CI] 0.63 to 0.91) across studies. Overall, the earlier studies using mature adrenomedullin demonstrated a statistically significant association from hazard ratios (HRs) and 95% CIs with all-cause mortality.6,7 Subsequent studies using MRproADM showed similar results. When taken as a continuous variable, a 1 nmol/l increase in MRproADM was associated with HRs ranging from 1.77 to 2.79 (95% CI 1.29 to 5.95) for death in patients with heart failure. When taken as a log10 of MRproADM measured in nanomoles per liter, the HRs ranged from 1.82 to 10.26 for death (95% CI 1.26 to 80.50). Various cutoffs were used for categorical adrenomedullin as presented in Table 1, and these included upper tertile, receiver operating characteristic optimal cutoff, and above the median value. Only one study showed a negative result of MRproADM on mortality in heart failure patients.8 Table 2 depicts studies which looked at the relation between adrenomedullin and MACE in patients with acute coronary syndrome. We identified 9 cohort studies in total. Baseline plasma levels of MRproADM were significantly higher in patients who experienced a MACE during followup compared with the levels of those who did not. The
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Table 1 Studies showing the predictive effect of adrenomedullin on all-cause mortality in patients with heart failure Year
Sample size
Number of Deaths
Pousset6 Richards7 Gegenhuber8 Adlbrecht9 Potocki10 Masson11 Neuhold12 Haehling13 Maisel14 Shah15
2000 2001 2007 2009 2009 2010 2010 2010 2011 2012
117 297 137 786 287 acute dyspnoea 54% AHF 1237 181 501 568 AHF 560 acute dyspnoea 180 AHF
14 35 41 233 77 332 36 70 65 189
1.56 3.92 2.11 1.77 10.46 1.91 2.79 1.82 2.4 1.51
15 252 195
8.5 (2.50-28.50) 2.37 (1.66-3.38) 2.307 (P<0.001)
21
NA
Cinar16 2012 154 acute dyspnoea 42.2 % AHF 424 Bosselmann17 2013 Xue18 2013 724 Travaglino19
2014
441 acute dyspnoea 162 AHF
HR (95% CI)
AUC (95% CI or p-value)
(1.05-2.32) (1.76-8.70) (0.93-4.77) (1.41-2.22) (1.26-80.50) (1.29-2.82) (1.29-5.95) (1.24-2.66) (1.40-4.40) (1.03-2.20)
Duration follow-up
Measure of Adrenomedullin
Primary endpoint
Modelled adrenomedullin
237 days 300 days 365 days 24 Months 1 year 3.9 yrs 24 months 1 year 90 days 4 years
Mature ADM Mature ADM MRproADM MRproADM MRproADM MRproADM MRproADM MRproADM MRproADM MRproADM
Death, cardiac transplant Death, HF hospitalization Death Death Death Death Death Death Death Death
0.81 (0.71-0.91) NA 0.68 (P<0.00001)
30 days 4.9 years 6 years
MRproADM MRproADM MRproADM
Death Death Death
0.66 (p<0.001)
90 days
MRproADM
Death
1 SD increase, pg/ml Above median, pmol/l Upper tertile > 1.23, nmol/l Continuous, 1 nmol/l Log10 MRproADM, nmol/l Upper tertile >/¼ 0.88 ,nmom/l Continuous, 1 nmol/l Log10 MRproADM, nmol/l Log10 MRproADM, nmol/l ROC curve optimal cut-off value of 0.77, nmol/l Cut-off 1.5, nmol/l Continuous 1 nmol/l ROC curve optimal cut-off value of 0.72, nmol/l AUC for baseline MRproADM, nmol/l
0.71 0.75 0.70 0.72 0.67 0.77
NA NA (0.63-0.79) NA (0.69-0.81) (0.67-0.74) NA (0.67-0.76) (NA) (p<0.001)
ADM ¼ adrenomedullin; AHF ¼ acute heart failure; AUC ¼ area under the curve; CI ¼ confidence interval; HF ¼ heart failure; HR ¼ hazard ratio; MRproADM ¼ mid-regional adrenomedullin; NA ¼ not applicable; ROC curve ¼ receiver operator characteristic curve; SD ¼ standard deviation. Table 2 Studies showing the predictive effect of adrenomedullin on major adverse cardiovascular events (MACE) in acute myocardial infarction patients Author
Year
Sample size
MACE
Khan20 Behnes21 Dhillon22 Walter23 Klip24
2007 2008 2010 2010 2011
983 30 745 30 214
150 11 262 11 61
Dzielinska25 Wild26 Wild26 Meune27
2011 2012 2012 2012
127 1355 stable angina 885 ACS 1247 acute chest pain
12 90 102 21
Tzikas28
2013
1386 acute chest pain
132
HR MACE (95% CI) 3.63 2.80 9.75 2.80 1.78
(1.48-8.90) (1.20-6.90) (3.60-26.16) (1.20-6.90) (0.94-3.35)
2.12 (1.18-3.81) 3.40 (1.06-10.92) 4.10 (1.66-10.12) 8.70 (1.10-69.4) 3rd quartile to 1st & 10.90 (1.40-85.4) 4th quartile to 1st 1.26 (1.06-1.49)
AUC (95 % CI)
Duration of follow-up
Measure of Adrenomedullin
(0.72-0.81) (0.51-0.86) (0.67-0.77) (0.51-0.86) (0.58-0.75)
2.1 years 10 months 2 years 10 months 2.5 years
MRproADM MRproADM MRproADM MRproADM MRproADM
NA 0.64 (0.57-0.71) 0.64 (0.57-0.70) 0.71 (0.62-0.81)
6 months 3.6 years 3.6 years 22 Months
Mature ADM MRproADM MRproADM MRproADM
0.80 (0.73-0.87)
6 months
MRProADM
0.77 0.71 0.72 0.71 0.66
Primary endpoint Death, HF Death, HF, PCI, CABG Death, HF, AMI Death, HF, PCI, CABG Death, AMI, Stroke, resuscitated CA Death, AMI, Stroke Nonfatal AMI or CVD death Nonfatal AMI or CVD death Death, AMI
Death, AMI, Revascularization, Stroke, HF
Modelled adrenomedullin Log Base10 MRproADM, nmol/l Continuous 1, nmol/l Log Base10 MRproADM, nmol/l Continuous, 1 nmol/l Doubling of MRproADM, nmol/l Every 10 pmol/l increase Continuous, 1 nmol/l Continuous 1 nmol/l 3rd quartile compared to 1st, nmol/l & 4th quartile compared to 1st, nmol/l 1 SD log-transformed MRproADM, nmol/l
ACS ¼ acute coronary syndrome; ADM ¼ adrenomedullin; AMI ¼ acute myocardial infarction; AUC ¼ area under the curve; CA ¼ cardiac arrest; CABG ¼ coronary artery bypass grafting; CI ¼ confidence interval; CVD ¼ cardiovascular diseases; HF ¼ heart failure; HR ¼ hazard ratio; MACE ¼ major adverse cardiovascular events; MRproADM ¼ mid-regional adrenomedullin; NA ¼ not applicable; PCI ¼ percutaneous coronary intervention; SD ¼ standard deviation.
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Author
ADM ¼ adrenomedullin; AMI ¼ acute myocardial infarction; AUC ¼ area under the curve; CA ¼ cardiac arrest; CI ¼ confidence interval; HF ¼ heart failure; HR ¼ hazard ratio; MRproADM ¼ mid-regional adrenomedullin; NA ¼ not applicable.
Death, HF Continuous, 1 pmol/l Death, HF Above median, pmol/l Cardiovascular death Continuous, 1 pmol/l Death Continuous 1, fmol/l Death, HF Log Base10 MRproADM, nmol/l Death, HF, AMI Log Base10 MRproADM, nmol/l Death, AMI, Stroke, resuscitated CA Doubling of MRproADM, nmol/l Death Continuous, 1 nmol/l Mature ADM Mature ADM Mature ADM Mature ADM MRproADM MRproADM MRproADM MRproADM (not significant) NA 2 4 month (1.76-8.70) NA 18 months (1.01-1.08) NA 25 months (1.06-107.06) NA 90 days (p¼0.001) NA 2.1 years (4.56-60.99) 0.79 (0.74-0.84) 2 years (1.38-5.49) 0.81 (0.73-0.90) 2.5 years (1.81-4.33) 0.84 (0.81-0.86) 2 years 1998 121 2001 297 1999 113 2005 124 2007 983 2010 745 2011 214 2013 1179 Acute chest pain Richards29 Richards7 Nagaya30 Katayama31 Khan20 Dhillon22 Klip24 Haaf32
27 35 16 9 101 120 31 79
1.21 3.92 1.04 10.63 4.86 16.68 3.51 2.79
Measure of Adrenomedullin Duration follow-up AUC (95% CI) HR Death (95% CI or P value) Number of Deaths Sample size Year Author
Table 3 Studies showing the predictive effect of adrenomedullin on all-cause mortality in acute myocardial infarction patients
Primary endpoint
Modelled adrenomedullin
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AUC for MRproADM predicting MACE ranged from 0.64 to 0.80 (95% CI 0.51 to 0.87) across studies in patients with AMI. When taken as a continuous variable, 1 nmol/L increase in MRproADM was associated with HRs for MACE ranging from 1.78 to 4.10 (95% CI 1.20 to 10.12), whereas log10 of MRproADM had HRs of 3.63 to 9.75 (95% CI 1.48 to 26.16) for MACE across studies in patients with AMI. Only 1 study showed a negative result of MRproADM on MACE in patients with AMI.24 This review also identified studies which have shown that MRproADM significantly enhances the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI) when added to other risk markers such as brain natriuretic peptide and the GRACE score in patients with AMI.22,24 For example, 1 study showed an NRI of 34.1% (range 18.6% to 49.5%) for 30-day mortality when MRproADM was added to the GRACE score.22 Table 3 depicts studies which looked at the relation between adrenomedullin and death in patients with AMI. We identified 8 cohort studies in total. The AUC for MRproADM predicting death ranged from 0.79 to 0.84 (95% CI 0.73 to 0.90) across studies in patients with AMI. When taken as a log10 of MRproADM measured in nanomoles per liter, death was associated with HRs ranging from 4.86 to 16.68 (95% CI 4.56 to 60.99) across studies in patients with AMI. One study showed a negative result of MRproADM on mortality in patients with AMI.29 Discussion This systematic review has demonstrated that ADM is an independent predictor of death in patients with heart failure. An expanding number of studies have shown diagnostic and prognostic significance of ADM in patients with heart failure. Initial cross-sectional studies demonstrated that ADM levels were significantly raised in patients with established heart failure compared with controls. ADM is elevated in heart failure proportionally to the severity of the disease assessed by New York Heart Association class and to the degree of left ventricular impairment.13,24 ADM also has diagnostic and prognostic value alongside the natriuretic peptides in acute dyspnea and in chronic heart failure9,11e16,18,19 and diastolic dysfunction.33 In post-AMI patients with new heart failure,24 patients with established heart failure,13,17 and patients presenting with acute dyspnea in emergency settings,10,14e16 MRproADM has been shown to have independent prognostic significance for major adverse cardiovascular outcomes. It is also predictive of adverse outcomes in community patients with symptoms of heart failure.34 Our findings therefore highlight the possible usefulness of ADM as a risk-stratifying measure in patients with heart failure. This systematic review has shown that ADM is independently predictive of MACE in patients who have suffered an AMI and strongly support the results of various individual studies. ADM is a known independent predictor of future MACE in coronary disease. It significantly predicts fatal and nonfatal cardiovascular events and all-cause mortality in patients with stable angina,26,35e37 patients with acute coronary syndromes,20e26,29e31 and patients presenting with acute chest pain.27,28,32 Our findings corroborate the aforementioned observations and help to enhance the importance
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of ADM as prognostic marker in acute coronary syndromes independent of other established risk markers such as the GRACE score and BNP. Initial studies used free mature ADM to relate to cardiovascular outcomes,29e31 whereas more recent studies have used the surrogate MRproADM to study this relation.20,22,24,26e28,32,35 We have reported on the few results for mature ADM. Although we acknowledge that the reliability of some of these results might be questionable because of known problems with mature ADM detection given its short half-life, the studies using mature ADM did show a consistent significant prognostic effect on outcomes. Most studies identified in this systematic review used MRproADM, which given the reliability of its measurement should remain the main contemporary method of detecting this peptide. There were only 3 negative studies identified in this systematic review for ADM and some outcomes (mortality in heart failure,8 MACE in AMI,24 and death in AMI29), and these could be attributed to small sample sizes or broadening of composite end point to include softer outcomes or shorter duration of follow-up of the studies. An NRI and an IDI have been observed with the addition of MRproADM into risk assessment models of mortality in patients with acute coronary syndromes.22,24 Abundant evidence has accrued suggesting the important role ADM might be playing in cardiovascular disease. ADM plasma levels are increased in atherosclerosis in coronary and peripheral circulation, and there is augmented expression with severity of plaque formation or stenosis and degree of ischemic heart disease syndromes, for example less expression in patients with stable angina compared with unstable angina. ADM is significantly raised in AMI and correlates with severity of AMI.38 ADM levels in AMI are independently associated with subacute left ventricular systolic dysfunction through ejection fraction measurements.31 Intravenous ADM infusion to patients with AMI significantly reduces infarct size and prospectively reduces regional wall motion abnormality on cardiac magnetic resonance imaging. ADM levels in community patients with preexisting cardiovascular disease are predictive of longterm adverse cardiovascular outcomes.39 ADM is associated with degree of systemic hypertension and pulmonary hypertension and also correlates with functional outcomes in patients with ischemic stroke. ADM plasma levels increase with increasing degree of renal impairment.2 Actions of adrenomedullin are generally protective to organs and tissues, from vasodilation, natriuresis, diuresis, to anti-inflammation.2 The receptors of ADM are a complex of receptor activityemodifying proteins and calcitonin receptor-like receptor.40 The mechanisms of action of ADM are believed so far to be through the generation of nitric oxide through nitric oxideecyclic guanine monophosphate pathway or through increased intracellular cyclic adenosine monophosphate which activates protein kinase A which then activates nitric oxide synthase or through phosphatidylinositol 3-kinase activation and Akt phosphorylation resulting in enhanced stimulation of endothelial nitric oxide synthase.2,38 The marked heterogeneity mainly due to discrepancy in adrenomedullin measurements across studies prohibited the quantitative combination of data through a meta-analysis. This was a major limitation of the systematic review.
Another limitation was the small sample size of some studies and the small number of outcome events in some studies. The variability in study design when including several studies, specifically regarding the definition of MACE as outcome which varied across studies, remains a challenge that needs to be considered when performing a systematic review. Disclosures The authors have no conflicts of interest to disclose. 1. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromacytoma. Biochem Biophys Res Commun 1993;192: 553e560. 2. Ishimitsu T, Ono H, Minami J, Matsuoka H. Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders. Pharmacol Ther 2006;111:909e927. 3. Pio R, Martinez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, Elsasser TH, Cuttitta F. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 2001;276:12292e12300. 4. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 2004;25:1369e1372. 5. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. 6. Pousset F, Masson F, Chavirovskaia O, Isnard R, Carayon A, Golmard JL, Lechat P, Thomas D, Komajda M. Plasma adrenomedullin, a new independent predictor of prognosis in patients with chronic heart failure. Eur Heart J 2000;21:1009e1014. 7. Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N, Murphy J, Espiner EA, Frampton C, Yandle TG. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. J Am Coll Cardiol 2001;37:183A. 8. Gegenhuber A, Struck J, Dieplinger B, Poelz W, Pacher R, Morgenthaler NG, Bergmann A, Haltmayer M, Mueller T. Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and copeptin to predict 1-year mortality in patients with acute destabilized heart failure. J Card Fail 2007;13:42e49. 9. Adlbrecht C, Huelsmann M, Strunk G, Berger R, Moertl D, Struck J, Morgenthaler NG, Bergmann A, Jakowitsch J, Maurer G, Lang IM, Pacher R. Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients. Eur J Heart Fail 2009;11:361e366. 10. Potocki M, Breidthardt T, Reichlin T, Morgenthaler NG, Bergmann A, Noveanu M, Schaub N, Uthoff H, Freidank H, Buser L, Bingisser R, Christ M, Mebazaa A, Mueller C. Midregional pro-adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study. Crit Care 2009;13:R122. 11. Masson S, Latini R, Carbonieri E, Moretti L, Rossi MG, Ciricugno S, Milani V, Marchioli R, Struck J, Bergmann A, Maggioni AP, Tognoni G, Tavazzi L; Investigators G-H. The predictive value of stable precursor fragments of vasoactive peptides in patients with chronic heart failure: data from the GISSI-heart failure (GISSI-HF) trial. Eur J Heart Fail 2010;12:338e347. 12. Neuhold S, Huelsmann M, Strunk G, Struck J, Adlbrecht C, Gouya G, Elhenicky M, Pacher R. Prognostic value of emerging neurohormones in chronic heart failure during optimization of heart failure-specific therapy. Clin Chem 2010;56:121e126. 13. von Haehling S, Filippatos GS, Papassotiriou J, Cicoira M, Jankowska EA, Doehner W, Rozentryt P, Vassanelli C, Struck J, Banasiak W, Ponikowski P, Kremastinos D, Bergmann A, Morgenthaler NG, Anker SD. Mid-regional pro-adrenomedullin as a novel predictor of mortality in patients with chronic heart failure. Eur J Heart Fail 2010;12: 484e491. 14. Maisel A, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Mockel M, Hogan C, Wu AH, Richards M, Clopton P, Filippatos GS, Di
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artery disease: results from the AtheroGene study. Clin Chem 2012;58: 226e236. Meune C, Balmelli C, Twerenbold R, Reiter M, Reichlin T, Ziller R, Drexler B, Stelzig C, Freese M, Wolf C, Haaf P, Osswald S, Mueller C. Utility of 14 novel biomarkers in patients with acute chest pain and undetectable levels of conventional cardiac troponin. Int J Cardiol 2013;167:1164e1169. Tzikas S, Keller T, Ojeda FM, Zeller T, Wild PS, Lubos E, Kunde J, Baldus S, Bickel C, Lackner KJ, Munzel TF, Blankenberg S. MR-proANP and MR-proADM for risk stratification of patients with acute chest pain. Heart 2013;99:388e395. Richards AM, Nicholls MG, Yandle TG, Frampton C, Espiner EA, Turner JG, Buttimore RC, Lainchbury JG, Elliott JM, Ikram H, Crozier IG, Smyth DW. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 1998;97:1921e1929. Nagaya N, Nishikimi T, Uematsu M, Yoshitomi Y, Miyao Y, Miyazaki S, Goto Y, Kojima S, Kuramochi M, Matsuo H, Kangawa K, Nonogi H. Plasma adrenomedullin as an indicator of prognosis after acute myocardial infarction. Heart 1999;81:483e487. Katayama T, Nakashima H, Honda Y, Suzuki S, Yano K. Relationship between adrenomedullin and left-ventricular systolic function and mortality in acute myocardial infarction. Angiology 2005;56: 35e42. Haaf P, Twerenbold R, Reichlin T, Faoro J, Reiter M, Meune C, Steuer S, Bassetti S, Ziller R, Balmelli C, Campodarve I, Zellweger C, Kilchenmann A, Irfan A, Papassotiriou J, Drexler B, Mueller C. Mid-regional pro-adrenomedullin in the early evaluation of acute chest pain patients. Int J Cardiol 2013;168:1048e1055. Xue Y, Taub P, Fard A, Iqbal NM, Nguyen H, Clopton P, Maisel AS. Elevated mid-region pro-adrenomedullin is associated with increased mortality in stable outpatients with diastolic dysfunction. Eur Heart J 2011;32:907e908. 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;19:31e39. Schnabel RB, Schulz A, Messow CM, Lubos E, Wild PS, Zeller T, Sinning CR, Rupprecht HJ, Bickel C, Peetz D, Cambien F, Kempf T, Wollert KC, Benjamin EJ, Lackner KJ, Munzel TF, Tiret L, Vasan RS, Blankenberg S. Multiple marker approach to risk stratification in patients with stable coronary artery disease. Eur Heart J 2010;31:3024e3031. Sabatine MS, Morrow DA, de Lemos JA, Omland T, Sloan S, Jarolim P, Solomon SD, Pfeffer MA, Braunwald E. Evaluation of multiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease. Circulation 2012;125:233e240. Nishida H, Horio T, Suzuki Y, Iwashima Y, Kamide K, Kangawa K, Kawano Y. Plasma adrenomedullin as an independent predictor of future cardiovascular events in high-risk patients: comparison with C-reactive protein and adiponectin. Peptides 2008;29:599e605. Kato J, Tsuruda T, Kita T, Kitamura K, Eto T. Adrenomedullin: a protective factor for blood vessels. Arterioscler Thromb Vasc Biol 2005;25:2480e2487. 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. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA 2009;302:49e57. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 1998;393: 333e339.
a Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom and bDepartment of Cardiovascular Sciences, National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. Manuscript received October 5, 2014; revised manuscript received and accepted January 6, 2015. See page 990 for disclosure information. *Corresponding author: Tel: (44) 116 250 2449; fax: (44) 116 252 3108. E-mail address: [email protected] (M.F. Yuyun).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.01.027
events or mortality in patients with heart failure or acute myocardial infarction (AMI). We therefore undertook this systematic review with the hope of including a meta-analysis if possible, to determine the prognostic significance of ADM in patients with heart failure and post-AMI. Methods The method was guided by Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).5 The inclusion criteria were prospective studies published in adult patients with acute or chronic heart failure or AMI or patients presenting with acute dyspnea or acute chest pain or stable or unstable angina. In addition, they must have had adrenomedullin measured at baseline and related to major adverse cardiovascular events (MACE) or mortality. Excluded were review articles, pediatric studies, and animal studies. A systematic search of studies was carried out on original published studies using PubMed (MEDLINE) and the Cochrane Collaboration databases using key words and MeSH terms. For patients with heart failure, the MeSH terms or key words were (“Adrenomedullin” OR “ADM” OR “MRproADM”) AND “Heart Failure.” For patients with myocardial infarction, these were (“Myocardial Infarction” OR “Angina Pectoris” OR “Angina, Stable” OR “Angina, Unstable”) AND (“Adrenomedullin” OR “ADM” OR “MRproADM”). Searches of references of published reports obtained from the aforementioned systematic search were also undertaken. The search was restricted to reports published in English from January 1, 1993, to June 30, 2014, in humans. Figure 1 shows the flow chart for selection for this systematic review. www.ajconline.org
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Figure 1. Flowchart of search of studies and identification of relevant English-language studies on of adrenomedullin and death in patients with heart failure and adrenomedullin and MACE and death in patients with myocardial infarction (January 1, 1993, to June 30, 2014).
The main outcome measure of this systematic review for patients with heart failure was death. The outcome measure for patients with myocardial infarction was MACE as primary end point measure, with death as secondary end point. The end point, MACE, was defined variably across studies as a composite of myocardial infarction, stroke, hospitalization for heart failure, and all-cause mortality, although in some studies not all these components were present. Two authors independently perused all the relevant titles and abstracted data from selected reports with any disagreements settled by a consensus or opinion from other co-authors. Some studies had very small sample sizes, but we included given the small number of studies. Because of the high level of heterogeneity across studies, no quantitative pooling of results from various studies through a meta-analysis was undertaken. This heterogeneity was mainly due to the discrepancy in type of adrenomedullin measured (mature ADM vs its surrogate MRproADM), discrepancy in units of ADM used by different studies, the varying use of ADM as a continuous and a categorical variable across studies, the different cutoffs of ADM when used as a categorical variable, and differing logarithmic transformations or unit change of ADM when used as a continuous variable in various statistical models. Results Table 1 lists studies which looked at the relation between ADM and mortality in patients with heart failure. We
identified 14 studies in total, and these were mainly cohort studies. Baseline plasma levels of MRproADM were significantly higher in patients who died during follow-up compared with the levels of those who survived. The area under the curve (AUC) for adrenomedullin predicting mortality was only reported for 12 studies using MRproADM in patients with heart failure, and this ranged from 0.68 to 0.81 (95% confidence interval [CI] 0.63 to 0.91) across studies. Overall, the earlier studies using mature adrenomedullin demonstrated a statistically significant association from hazard ratios (HRs) and 95% CIs with all-cause mortality.6,7 Subsequent studies using MRproADM showed similar results. When taken as a continuous variable, a 1 nmol/l increase in MRproADM was associated with HRs ranging from 1.77 to 2.79 (95% CI 1.29 to 5.95) for death in patients with heart failure. When taken as a log10 of MRproADM measured in nanomoles per liter, the HRs ranged from 1.82 to 10.26 for death (95% CI 1.26 to 80.50). Various cutoffs were used for categorical adrenomedullin as presented in Table 1, and these included upper tertile, receiver operating characteristic optimal cutoff, and above the median value. Only one study showed a negative result of MRproADM on mortality in heart failure patients.8 Table 2 depicts studies which looked at the relation between adrenomedullin and MACE in patients with acute coronary syndrome. We identified 9 cohort studies in total. Baseline plasma levels of MRproADM were significantly higher in patients who experienced a MACE during followup compared with the levels of those who did not. The
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Table 1 Studies showing the predictive effect of adrenomedullin on all-cause mortality in patients with heart failure Year
Sample size
Number of Deaths
Pousset6 Richards7 Gegenhuber8 Adlbrecht9 Potocki10 Masson11 Neuhold12 Haehling13 Maisel14 Shah15
2000 2001 2007 2009 2009 2010 2010 2010 2011 2012
117 297 137 786 287 acute dyspnoea 54% AHF 1237 181 501 568 AHF 560 acute dyspnoea 180 AHF
14 35 41 233 77 332 36 70 65 189
1.56 3.92 2.11 1.77 10.46 1.91 2.79 1.82 2.4 1.51
15 252 195
8.5 (2.50-28.50) 2.37 (1.66-3.38) 2.307 (P<0.001)
21
NA
Cinar16 2012 154 acute dyspnoea 42.2 % AHF 424 Bosselmann17 2013 Xue18 2013 724 Travaglino19
2014
441 acute dyspnoea 162 AHF
HR (95% CI)
AUC (95% CI or p-value)
(1.05-2.32) (1.76-8.70) (0.93-4.77) (1.41-2.22) (1.26-80.50) (1.29-2.82) (1.29-5.95) (1.24-2.66) (1.40-4.40) (1.03-2.20)
Duration follow-up
Measure of Adrenomedullin
Primary endpoint
Modelled adrenomedullin
237 days 300 days 365 days 24 Months 1 year 3.9 yrs 24 months 1 year 90 days 4 years
Mature ADM Mature ADM MRproADM MRproADM MRproADM MRproADM MRproADM MRproADM MRproADM MRproADM
Death, cardiac transplant Death, HF hospitalization Death Death Death Death Death Death Death Death
0.81 (0.71-0.91) NA 0.68 (P<0.00001)
30 days 4.9 years 6 years
MRproADM MRproADM MRproADM
Death Death Death
0.66 (p<0.001)
90 days
MRproADM
Death
1 SD increase, pg/ml Above median, pmol/l Upper tertile > 1.23, nmol/l Continuous, 1 nmol/l Log10 MRproADM, nmol/l Upper tertile >/¼ 0.88 ,nmom/l Continuous, 1 nmol/l Log10 MRproADM, nmol/l Log10 MRproADM, nmol/l ROC curve optimal cut-off value of 0.77, nmol/l Cut-off 1.5, nmol/l Continuous 1 nmol/l ROC curve optimal cut-off value of 0.72, nmol/l AUC for baseline MRproADM, nmol/l
0.71 0.75 0.70 0.72 0.67 0.77
NA NA (0.63-0.79) NA (0.69-0.81) (0.67-0.74) NA (0.67-0.76) (NA) (p<0.001)
ADM ¼ adrenomedullin; AHF ¼ acute heart failure; AUC ¼ area under the curve; CI ¼ confidence interval; HF ¼ heart failure; HR ¼ hazard ratio; MRproADM ¼ mid-regional adrenomedullin; NA ¼ not applicable; ROC curve ¼ receiver operator characteristic curve; SD ¼ standard deviation. Table 2 Studies showing the predictive effect of adrenomedullin on major adverse cardiovascular events (MACE) in acute myocardial infarction patients Author
Year
Sample size
MACE
Khan20 Behnes21 Dhillon22 Walter23 Klip24
2007 2008 2010 2010 2011
983 30 745 30 214
150 11 262 11 61
Dzielinska25 Wild26 Wild26 Meune27
2011 2012 2012 2012
127 1355 stable angina 885 ACS 1247 acute chest pain
12 90 102 21
Tzikas28
2013
1386 acute chest pain
132
HR MACE (95% CI) 3.63 2.80 9.75 2.80 1.78
(1.48-8.90) (1.20-6.90) (3.60-26.16) (1.20-6.90) (0.94-3.35)
2.12 (1.18-3.81) 3.40 (1.06-10.92) 4.10 (1.66-10.12) 8.70 (1.10-69.4) 3rd quartile to 1st & 10.90 (1.40-85.4) 4th quartile to 1st 1.26 (1.06-1.49)
AUC (95 % CI)
Duration of follow-up
Measure of Adrenomedullin
(0.72-0.81) (0.51-0.86) (0.67-0.77) (0.51-0.86) (0.58-0.75)
2.1 years 10 months 2 years 10 months 2.5 years
MRproADM MRproADM MRproADM MRproADM MRproADM
NA 0.64 (0.57-0.71) 0.64 (0.57-0.70) 0.71 (0.62-0.81)
6 months 3.6 years 3.6 years 22 Months
Mature ADM MRproADM MRproADM MRproADM
0.80 (0.73-0.87)
6 months
MRProADM
0.77 0.71 0.72 0.71 0.66
Primary endpoint Death, HF Death, HF, PCI, CABG Death, HF, AMI Death, HF, PCI, CABG Death, AMI, Stroke, resuscitated CA Death, AMI, Stroke Nonfatal AMI or CVD death Nonfatal AMI or CVD death Death, AMI
Death, AMI, Revascularization, Stroke, HF
Modelled adrenomedullin Log Base10 MRproADM, nmol/l Continuous 1, nmol/l Log Base10 MRproADM, nmol/l Continuous, 1 nmol/l Doubling of MRproADM, nmol/l Every 10 pmol/l increase Continuous, 1 nmol/l Continuous 1 nmol/l 3rd quartile compared to 1st, nmol/l & 4th quartile compared to 1st, nmol/l 1 SD log-transformed MRproADM, nmol/l
ACS ¼ acute coronary syndrome; ADM ¼ adrenomedullin; AMI ¼ acute myocardial infarction; AUC ¼ area under the curve; CA ¼ cardiac arrest; CABG ¼ coronary artery bypass grafting; CI ¼ confidence interval; CVD ¼ cardiovascular diseases; HF ¼ heart failure; HR ¼ hazard ratio; MACE ¼ major adverse cardiovascular events; MRproADM ¼ mid-regional adrenomedullin; NA ¼ not applicable; PCI ¼ percutaneous coronary intervention; SD ¼ standard deviation.
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Author
ADM ¼ adrenomedullin; AMI ¼ acute myocardial infarction; AUC ¼ area under the curve; CA ¼ cardiac arrest; CI ¼ confidence interval; HF ¼ heart failure; HR ¼ hazard ratio; MRproADM ¼ mid-regional adrenomedullin; NA ¼ not applicable.
Death, HF Continuous, 1 pmol/l Death, HF Above median, pmol/l Cardiovascular death Continuous, 1 pmol/l Death Continuous 1, fmol/l Death, HF Log Base10 MRproADM, nmol/l Death, HF, AMI Log Base10 MRproADM, nmol/l Death, AMI, Stroke, resuscitated CA Doubling of MRproADM, nmol/l Death Continuous, 1 nmol/l Mature ADM Mature ADM Mature ADM Mature ADM MRproADM MRproADM MRproADM MRproADM (not significant) NA 2 4 month (1.76-8.70) NA 18 months (1.01-1.08) NA 25 months (1.06-107.06) NA 90 days (p¼0.001) NA 2.1 years (4.56-60.99) 0.79 (0.74-0.84) 2 years (1.38-5.49) 0.81 (0.73-0.90) 2.5 years (1.81-4.33) 0.84 (0.81-0.86) 2 years 1998 121 2001 297 1999 113 2005 124 2007 983 2010 745 2011 214 2013 1179 Acute chest pain Richards29 Richards7 Nagaya30 Katayama31 Khan20 Dhillon22 Klip24 Haaf32
27 35 16 9 101 120 31 79
1.21 3.92 1.04 10.63 4.86 16.68 3.51 2.79
Measure of Adrenomedullin Duration follow-up AUC (95% CI) HR Death (95% CI or P value) Number of Deaths Sample size Year Author
Table 3 Studies showing the predictive effect of adrenomedullin on all-cause mortality in acute myocardial infarction patients
Primary endpoint
Modelled adrenomedullin
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AUC for MRproADM predicting MACE ranged from 0.64 to 0.80 (95% CI 0.51 to 0.87) across studies in patients with AMI. When taken as a continuous variable, 1 nmol/L increase in MRproADM was associated with HRs for MACE ranging from 1.78 to 4.10 (95% CI 1.20 to 10.12), whereas log10 of MRproADM had HRs of 3.63 to 9.75 (95% CI 1.48 to 26.16) for MACE across studies in patients with AMI. Only 1 study showed a negative result of MRproADM on MACE in patients with AMI.24 This review also identified studies which have shown that MRproADM significantly enhances the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI) when added to other risk markers such as brain natriuretic peptide and the GRACE score in patients with AMI.22,24 For example, 1 study showed an NRI of 34.1% (range 18.6% to 49.5%) for 30-day mortality when MRproADM was added to the GRACE score.22 Table 3 depicts studies which looked at the relation between adrenomedullin and death in patients with AMI. We identified 8 cohort studies in total. The AUC for MRproADM predicting death ranged from 0.79 to 0.84 (95% CI 0.73 to 0.90) across studies in patients with AMI. When taken as a log10 of MRproADM measured in nanomoles per liter, death was associated with HRs ranging from 4.86 to 16.68 (95% CI 4.56 to 60.99) across studies in patients with AMI. One study showed a negative result of MRproADM on mortality in patients with AMI.29 Discussion This systematic review has demonstrated that ADM is an independent predictor of death in patients with heart failure. An expanding number of studies have shown diagnostic and prognostic significance of ADM in patients with heart failure. Initial cross-sectional studies demonstrated that ADM levels were significantly raised in patients with established heart failure compared with controls. ADM is elevated in heart failure proportionally to the severity of the disease assessed by New York Heart Association class and to the degree of left ventricular impairment.13,24 ADM also has diagnostic and prognostic value alongside the natriuretic peptides in acute dyspnea and in chronic heart failure9,11e16,18,19 and diastolic dysfunction.33 In post-AMI patients with new heart failure,24 patients with established heart failure,13,17 and patients presenting with acute dyspnea in emergency settings,10,14e16 MRproADM has been shown to have independent prognostic significance for major adverse cardiovascular outcomes. It is also predictive of adverse outcomes in community patients with symptoms of heart failure.34 Our findings therefore highlight the possible usefulness of ADM as a risk-stratifying measure in patients with heart failure. This systematic review has shown that ADM is independently predictive of MACE in patients who have suffered an AMI and strongly support the results of various individual studies. ADM is a known independent predictor of future MACE in coronary disease. It significantly predicts fatal and nonfatal cardiovascular events and all-cause mortality in patients with stable angina,26,35e37 patients with acute coronary syndromes,20e26,29e31 and patients presenting with acute chest pain.27,28,32 Our findings corroborate the aforementioned observations and help to enhance the importance
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of ADM as prognostic marker in acute coronary syndromes independent of other established risk markers such as the GRACE score and BNP. Initial studies used free mature ADM to relate to cardiovascular outcomes,29e31 whereas more recent studies have used the surrogate MRproADM to study this relation.20,22,24,26e28,32,35 We have reported on the few results for mature ADM. Although we acknowledge that the reliability of some of these results might be questionable because of known problems with mature ADM detection given its short half-life, the studies using mature ADM did show a consistent significant prognostic effect on outcomes. Most studies identified in this systematic review used MRproADM, which given the reliability of its measurement should remain the main contemporary method of detecting this peptide. There were only 3 negative studies identified in this systematic review for ADM and some outcomes (mortality in heart failure,8 MACE in AMI,24 and death in AMI29), and these could be attributed to small sample sizes or broadening of composite end point to include softer outcomes or shorter duration of follow-up of the studies. An NRI and an IDI have been observed with the addition of MRproADM into risk assessment models of mortality in patients with acute coronary syndromes.22,24 Abundant evidence has accrued suggesting the important role ADM might be playing in cardiovascular disease. ADM plasma levels are increased in atherosclerosis in coronary and peripheral circulation, and there is augmented expression with severity of plaque formation or stenosis and degree of ischemic heart disease syndromes, for example less expression in patients with stable angina compared with unstable angina. ADM is significantly raised in AMI and correlates with severity of AMI.38 ADM levels in AMI are independently associated with subacute left ventricular systolic dysfunction through ejection fraction measurements.31 Intravenous ADM infusion to patients with AMI significantly reduces infarct size and prospectively reduces regional wall motion abnormality on cardiac magnetic resonance imaging. ADM levels in community patients with preexisting cardiovascular disease are predictive of longterm adverse cardiovascular outcomes.39 ADM is associated with degree of systemic hypertension and pulmonary hypertension and also correlates with functional outcomes in patients with ischemic stroke. ADM plasma levels increase with increasing degree of renal impairment.2 Actions of adrenomedullin are generally protective to organs and tissues, from vasodilation, natriuresis, diuresis, to anti-inflammation.2 The receptors of ADM are a complex of receptor activityemodifying proteins and calcitonin receptor-like receptor.40 The mechanisms of action of ADM are believed so far to be through the generation of nitric oxide through nitric oxideecyclic guanine monophosphate pathway or through increased intracellular cyclic adenosine monophosphate which activates protein kinase A which then activates nitric oxide synthase or through phosphatidylinositol 3-kinase activation and Akt phosphorylation resulting in enhanced stimulation of endothelial nitric oxide synthase.2,38 The marked heterogeneity mainly due to discrepancy in adrenomedullin measurements across studies prohibited the quantitative combination of data through a meta-analysis. This was a major limitation of the systematic review.
Another limitation was the small sample size of some studies and the small number of outcome events in some studies. The variability in study design when including several studies, specifically regarding the definition of MACE as outcome which varied across studies, remains a challenge that needs to be considered when performing a systematic review. Disclosures The authors have no conflicts of interest to disclose. 1. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromacytoma. Biochem Biophys Res Commun 1993;192: 553e560. 2. Ishimitsu T, Ono H, Minami J, Matsuoka H. Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disorders. Pharmacol Ther 2006;111:909e927. 3. Pio R, Martinez A, Unsworth EJ, Kowalak JA, Bengoechea JA, Zipfel PF, Elsasser TH, Cuttitta F. Complement factor H is a serum-binding protein for adrenomedullin, and the resulting complex modulates the bioactivities of both partners. J Biol Chem 2001;276:12292e12300. 4. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an adrenomedullin precursor fragment in plasma of sepsis patients. Peptides 2004;25:1369e1372. 5. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. 6. Pousset F, Masson F, Chavirovskaia O, Isnard R, Carayon A, Golmard JL, Lechat P, Thomas D, Komajda M. Plasma adrenomedullin, a new independent predictor of prognosis in patients with chronic heart failure. Eur Heart J 2000;21:1009e1014. 7. Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N, Murphy J, Espiner EA, Frampton C, Yandle TG. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. J Am Coll Cardiol 2001;37:183A. 8. Gegenhuber A, Struck J, Dieplinger B, Poelz W, Pacher R, Morgenthaler NG, Bergmann A, Haltmayer M, Mueller T. Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and copeptin to predict 1-year mortality in patients with acute destabilized heart failure. J Card Fail 2007;13:42e49. 9. Adlbrecht C, Huelsmann M, Strunk G, Berger R, Moertl D, Struck J, Morgenthaler NG, Bergmann A, Jakowitsch J, Maurer G, Lang IM, Pacher R. Prognostic value of plasma midregional pro-adrenomedullin and C-terminal-pro-endothelin-1 in chronic heart failure outpatients. Eur J Heart Fail 2009;11:361e366. 10. Potocki M, Breidthardt T, Reichlin T, Morgenthaler NG, Bergmann A, Noveanu M, Schaub N, Uthoff H, Freidank H, Buser L, Bingisser R, Christ M, Mebazaa A, Mueller C. Midregional pro-adrenomedullin in addition to b-type natriuretic peptides in the risk stratification of patients with acute dyspnea: an observational study. Crit Care 2009;13:R122. 11. Masson S, Latini R, Carbonieri E, Moretti L, Rossi MG, Ciricugno S, Milani V, Marchioli R, Struck J, Bergmann A, Maggioni AP, Tognoni G, Tavazzi L; Investigators G-H. The predictive value of stable precursor fragments of vasoactive peptides in patients with chronic heart failure: data from the GISSI-heart failure (GISSI-HF) trial. Eur J Heart Fail 2010;12:338e347. 12. Neuhold S, Huelsmann M, Strunk G, Struck J, Adlbrecht C, Gouya G, Elhenicky M, Pacher R. Prognostic value of emerging neurohormones in chronic heart failure during optimization of heart failure-specific therapy. Clin Chem 2010;56:121e126. 13. von Haehling S, Filippatos GS, Papassotiriou J, Cicoira M, Jankowska EA, Doehner W, Rozentryt P, Vassanelli C, Struck J, Banasiak W, Ponikowski P, Kremastinos D, Bergmann A, Morgenthaler NG, Anker SD. Mid-regional pro-adrenomedullin as a novel predictor of mortality in patients with chronic heart failure. Eur J Heart Fail 2010;12: 484e491. 14. Maisel A, Mueller C, Nowak RM, Peacock WF, Ponikowski P, Mockel M, Hogan C, Wu AH, Richards M, Clopton P, Filippatos GS, Di
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