Usefulness of Growth Differentiation Factor-15 (GDF-15) As A Marker for Patients with Possible MI and For Predicting Coronary Disease in Asymptomatic Patients
Cardiovascular disease remains the leading cause of death in the U.S., with coronary heart disease (CHD) accounting for 1 of every 6 deaths.(1) It is estimated that over 1.3 million Americans will have a new or recurrent acute coronary syndromes (ACS) and almost 800,000 will have new or recurrent strokes every year. Among individuals presenting with ACS, myocardial necrosis markers, troponins T and I, are clinically established markers to confirm the diagnosis, direct intensity of therapy, and provide powerful prognostic information in predicting recurrent CHD events and mortality.(2) In addition to myocardial necrosis markers, the natriuretic peptides, brain natriuretic peptide (BNP) and its amino-terminal fragment (NT-proBNP), also carry powerful prognostic information in predicting mortality,(3) and combining the natriuretic peptides and troponins together enhances the ability to predict mortality in this high-risk population with ischemic heart disease.(4) To date, these data support the concept that structural markers of myocardial damage or strain are perhaps the best prognostic markers in high risk patients with cardiovascular disease.
Finding novel circulating biomarkers that robustly predict CHD in asymptomatic individuals has been more challenging, yet the need for improved CHD risk prediction in the general population is great. Although many novel circulating markers are reported to be associated with increased CHD risk, almost none have consistently or robustly improved risk classification beyond traditional risk factors.(5, 6)
Growth differentiation factor-15 (GDF-15) is a novel circulating marker that has developed considerable enthusiasm for predicting mortality in high risk patients with ACS or CHF and may play a role in predicting and detecting atherosclerotic coronary disease. GDF-15 is a member of the transforming growth factor superfamily and is secreted from activated macrophages by stimulation from pro-inflammatory cytokines(7) as well as from human endothelial cells,(8) vascular smooth muscle cells, 8 and adipocytes.(9) Thus, it is reasonable to expect increased circulating levels of GDF-15 in individuals with atherosclerosis, a condition characterized by chronic inflammation and macrophage accumulation in lipid-laden arterial plaques.(10) This is supported by the observation that GDF-15 expression is increased in human atherosclerotic carotid artery specimens in response to oxidized LDL.(11) Whether GDF-15 contributes directly to atherosclerosis development has not been established.
The bulk of our understanding of the pathophysiologic role of GDF-15 in cardiovascular disease comes from pre-clinical data on its protective effects on the myocardium during stress. It is secreted from myocardial tissue in response to ischemia and reperfusion in murine models and is expressed in infarcted human myocardium.(12, 13) Infusion of recombinant GDF-15 into infarcted myocardium suppresses the inflammatory response, also suggesting a counter-regulatory cytokine role.(14) Based on these findings, most investigations of circulating GDF-15 levels in humans have been in high risk patients with heart failure or ACS. In these populations, increased levels of GDF-15 have been consistently associated with increased total and cardiovascular mortality, including patients with ST elevation MI,(15, 16) non-ST elevation MI,(17) and stable CHF (Table).(18)
Far fewer investigations have been reported on the association between circulating GDF-15 levels and non-fatal atherosclerotic disease end points. In the high-risk ACS and CHF populations, the associations with non-fatal MI have been inconsistent in contrast to the robust mortality signal (Table). In the FRISC-II study, which randomized patients with non-ST elevation MI into an invasive or conservative strategy, increasing levels of GDF-15 were associated with severity of coronary disease on angiogram. Almost a quarter of these patients had GDF-15 levels in the highest category (>1800 ng/L; n=493/2079), and almost half of these patients had three vessel or left main disease.(19) In this study, elevated GDF-15 levels were independently associated with the individual end point of recurrent MI (n=230; OR for 1 SD: 1.37 95%CI 1.06-1.76; p=0.015). However, in the AtheroGene study of patients with stable angina (n=1352) and acute coronary syndromes (n=877), GDF-15 > 1800 ng/L was associated with CHD mortality (~15% deaths, p<0.001) but not with non-fatal MI in either the stable angina (p=0.16) or ACS populations (p=0.28). Though the number of non-fatal MIs was low in this study, GDF-15 was strongly associated with CHD death in the ACS group with 49 events (p<0.001) but not with non-fatal MI with 52 events (p=0.28).(20) These findings suggest that circulating GDF-15 levels are a stronger risk marker for mortality than for non-fatal coronary events in high-risk populations. The only reported study assessing GDF-15 with non-fatal end points in a low-risk population comes from a nested case-control analysis within the Women's Health Study (median age 60), where GDF-15 levels above the 90th percentile were associated with a 2.7-fold increased risk of non-fatal MI and stroke.(21)
The relationship between GDF-15 levels and subclinical atherosclerosis has not been well studied. In the PIVUS study of Swedish community-dwelling seniors aged 70 (n=1016), increasing GDF-15 levels were associated with increased carotid intima media thickness in univariate analysis (rho=0.11; p<0.001) but lost significance when adjusted for risk factors (p=0.14).(22) However, increasing GDF-15 remained weakly but independently associated with carotid plaque burden after multivariate adjustment (p=0.03). In the Dallas Heart Study, composed of a younger population (median age 44; 50% African American) free of heart disease, increasing GDF-15 levels were independently associated with increased coronary calcium, a marker of coronary atherosclerosis and increased CHD risk (OR for GDF-15≥1800 ng/L: CAC>10: 2.1, 95% CI 1.2-3.7, p=0.01; CAC≥100: 2.6, 95%CI 1.4-4.9, p=0.002).(23) In this same study in low-risk individuals, GDF-15 ≥ 1800 ng/L was independently associated with a striking 3-fold increased adjusted risk in all-cause death (HR 3.5, 95%CI 2.1-5.9, p<0.0001) and a similar increase in cardiovascular death (HR 2.5, 95%CI 1.1-5.8, p=0.03). Intriguingly, in study populations free of disease, including the PIVUS and Dallas Heart studies mentioned above as well as the Rancho Bernado study of older healthy community dwellers (mean age 70),(24) GDF-15 levels were inversely correlated with total and LDL cholesterol, a finding that deserves further investigation if the signal for increased atherosclerotic risk holds in future studies.
Establishing associations between circulating levels of a marker and incident cardiovascular end points is the first and necessary step in determining its clinical utility in risk prediction. This has clearly been demonstrated with GDF-15 and both total and cardiovascular mortality but not with non-fatal coronary disease end points. The next step is to assess several metrics of biomarker performance in risk prediction as determined by discrimination (c-index), calibration (Hosmer-Lemeshow), and reclassification (Net Reclassification Index and Integrated Discrimination Index).(25) When these metrics have been applied to the performance of GDF-15 for predicting mortality, GDF-15 has consistently improved discrimination, calibration, and reclassification in patients presenting with chest pain(26) as well as in both middle-aged (Dallas Heart Study)(23) and elderly community-dwelling participants (Rancho Bernado Study)(22) from the general population. Similarly, addition of GDF-15 to the Global Registry of Acute Coronary Events (GRACE) score in 1122 patients with non-ST elevation MI resulted in improved discrimination, calibration, and reclassification for the combined end point of death or non-fatal MI.(27) In addition, GDF-15 appears to provide incremental information when added to risk prediction models for mortality that include traditional risk factors as well as troponin and natriuretic peptide markers, well-established markers of mortality across a spectrum of cardiovascular disease.
A recently published report from the international multicenter study, Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE), sheds new insights into the ability of GDF-15 to diagnose acute MI and predict outcomes in patients presenting to the emergency room with chest pain.(28) In this study, 646 unselected patients with chest pain but not on dialysis were followed for a mean of 26 months. Acute MI was the final diagnosis in 18% of the patients with a total of 55 deaths in follow up. GDF-15 levels were inferior in the diagnostic accuracy of detecting acute MI (C-index 0.69, 95%CI 0.64-0.74) compared to high-sensitivity troponin T (C-index 0.96, 95%CI 0.94-0.98, p<0.001) and BNP (C-index 0.74, 95%CI 0.69-0.80, p=0.02). However, GDF-15 was superior to both markers in predicting all-cause mortality as determined by the c-index and metrics of reclassification. Interestingly, both GDF-15 and high-sensitivity troponin T similarly predicted death or future acute MI in patients presenting with chest pain without AMI.
Taken together, these findings suggest that measurement of circulating levels of GDF-15 provides incremental improvement in mortality risk prediction in addition to traditional risk factors as well as troponins and natriuretic peptides in healthy individuals as well in patients with a spectrum of cardiovascular disease. Though several studies suggest an association between GDF-15 levels and subclinical and clinical atherosclerosis, these findings need to be confirmed in future studies and validated in populations with incident non-fatal coronary events. There does not appear to be a role for GDF-15 in diagnosing acute MI but its prognostic potential is preserved regardless of the etiology of chest pain, burden of risk factors, or spectrum of cardiovascular disease at baseline. Future studies will need to investigate the inverse relationship with total and LDL cholesterol as well as the impact of renal function on biological variation before measurement of GDF-15 will be useful in standard risk assessment algorithms.
Table: Studies of the association between GDF-15 and cardiovascular events |
||||
Study |
N |
Population |
End point(s) |
Outcome |
Acute Coronary Syndrome |
||||
Kempf, et al. |
741 |
STEMI |
Death (1 year) |
HR 1SD: 1.6 [1.1-2.1], p=0.005; c-index 0.75 |
Wollert, et al. (2007)(17) |
2081 |
NSTEMI |
Death (1 year) MI (30 days) |
HR 1SD: 1.5 [1.2-1.9], p<0.001; p=NS |
Wollert, et al. (2007)(19) |
2079 |
NSTEMI |
Death (2 years) MI (2 years) Coronary disease |
HR 1SD: 1.8 [1.2-2.6], p=0.002; HR 1SD: 1.4 [1.1-1.8], p=0.015; >1800 ng/L associated with 3-vz or left main |
Kempf, et al. (2009)(20) |
1352/ |
Stable Angina Acute Coronary Syndrome |
CHD death (3.6 years) CHD death (3.6 years) Recurrent MI |
HR 1SD: 2.4 [1.7-3.4], p<0.001 HR 1SD: 1.6 [1.2-2.1], p<0.001 P=NS |
Khan, et al. (2009)(16) |
1142 |
Post-MI |
Death or CHF (505 days) Death Heart Failure Recurrent MI |
HR 1 log unit: 1.8 [1.0-3.1], p=0.039; c-index 0.73 HR 1 log unit: 1.8 [1.1-3.2], p=0.03 HR 1 log unit: 1.6 [0.9-3.0], p=0.04 HR 1 log unit: 1.3 [0.8-2.1], p=NS |
Bonaca, et al. (2010)(29) |
3501 |
NSTEMI/STEMI |
Death or MI (2 years) Death Recurrent MI |
HR 1 log unit: 2.1 [1.6-2.9, p<0.001 HR 1 log unit: 3.0 [1.7-5.3, p<0.001 HR 1 log unit: 1.9 [1.3-1.7, p<0.001 No interaction with treatment group |
Widera, et al. (2011)(27) |
1122 |
NSTEMI |
Death or MI (6 months) |
Improved discrimination and reclassification when added to GRACE score + NT-proBNP |
Chest pain |
||||
Eggers, et al. (2008)(30) |
479 |
Chest pain |
Death or MI (6 months) |
HR 1 log unit: 2.7 [1.0-6.0], p=0.046 |
Eggers, et al. (2010)(26) |
453 |
Chest pain |
Death (5.8 years) |
HR 1SD: 2.1 [1.7-2.6], p<0.001; c-index 0.83 |
Schaub, et al. (2012)(28) |
646 |
Chest pain |
Diagnosis of MI Death |
c-index 0.69 (inferior to hs-cTnT and BNP) c-index 0.85 (superior to hs-cTnT and BNP) |
Healthy populations |
||||
Brown, et al. (2002)(21) |
514 |
Women's Health Study |
MI/stroke/ |
OR >90th%: 2.7 [1.6-4.9], p=0.0002 |
Lind, et al. (2009)(22) |
1004 |
Swedish healthy subjects age 70 |
CIMT Carotid plaque |
P=NS P=0.03 |
Daniels, et al. (2011)(24) |
1391 |
Healthy elderly – |
Death (11 years) CV death (11 years) |
HR 1SD: 1.5 [1.3-1.8], p<0.0001 HR 1 SD: 1.4 [1.1-1.8] |
Rohatgi, et al. (2012)(23) |
3219 |
Healthy – |
Death (7.3 years) CV death (7.3 years) CAC>10 CAC>100 |
HR 1SD: 2.4 [1.7-3.4], p<0.0001 HR 1SD: 1.8 [1.1-3.2], p=0.03 HR 1SD: 1.4 [1.1-1.8] HR 1SD: 1.7 [1.3-2.4] |
HR=Hazard ratio; OR=Odds ratio; SD=standard deviation; NS=not significant |
References
1. Members WG, Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB. Executive summary: Heart disease and stroke statistics—2012 update. Circulation 2012;125:188-197.
2. McCullough PA, Peacock WF, O'Neil B, de Lemos JA. Capturing the pathophysiology of acute coronary syndromes with circulating biomarkers. Rev Cardiovasc Med 2010;11 Suppl 2:S3-12.
3. Morrow DA, de Lemos JA, Sabatine MS, Murphy SA, Demopoulos LA, DiBattiste PM, McCabe CH, Gibson CM, Cannon CP, Braunwald E. Evaluation of b-type natriuretic peptide for risk assessment in unstable angina/non-st-elevation myocardial infarction: B-type natriuretic peptide and prognosis in tactics-timi 18. J Am Coll Cardiol 2003;41:1264-1272.
4. Scirica BM, Sabatine MS, Jarolim P, Murphy SA, de Lemos JL, Braunwald E, Morrow DA. Assessment of multiple cardiac biomarkers in non-st-segment elevation acute coronary syndromes: Observations from the merlin-timi 36 trial. Eur Heart J 2011;32:697-705.
5. Lloyd-Jones DM. Cardiovascular risk prediction: Basic concepts, current status, and future directions. Circulation 2010;121:1768-1777.
6. Helfand M, Buckley DI, Freeman M, Fu R, Rogers K, Fleming C, Humphrey LL. Emerging risk factors for coronary heart disease: A summary of systematic reviews conducted for the u.S. Preventive services task force. Ann Intern Med 2009;151:496-507.
7. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN. Mic-1, a novel macrophage inhibitory cytokine, is a divergent member of the tgf-beta superfamily. Proc Natl Acad Sci U S A 1997;94:11514-11519.
8. Secchiero P, Corallini F, Gonelli A, Dell'Eva R, Vitale M, Capitani S, Albini A, Zauli G. Antiangiogenic activity of the mdm2 antagonist nutlin-3. Circ Res 2007;100:61-69.
9. Ding Q, Mracek T, Gonzalez-Muniesa P, Kos K, Wilding J, Trayhurn P, Bing C. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes. Endocrinology 2009;150:1688-1696.
10. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999;340:115-126.
11. Schlittenhardt D, Schober A, Strelau J, Bonaterra GA, Schmiedt W, Unsicker K, Metz J, Kinscherf R. Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (gdf-15/mic-1) in oxldl-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res 2004;318:325-333.12. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006;98:351-360.
13. Xu J, Kimball TR, Lorenz JN, Brown DA, Bauskin AR, Klevitsky R, Hewett TE, Breit SN, Molkentin JD. Gdf15/mic-1 functions as a protective and antihypertrophic factor released from the myocardium in association with smad protein activation. Circ Res 2006;98:342-350.
14. Kempf T, Zarbock A, Widera C, Butz S, Stadtmann A, Rossaint J, Bolomini-Vittori M, Korf-Klingebiel M, Napp LC, Hansen B, Kanwischer A, Bavendiek U, Beutel G, Hapke M, Sauer MG, Laudanna C, Hogg N, Vestweber D, Wollert KC. Gdf-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 2011;17:581-588.
15. Kempf T, Bjorklund E, Olofsson S, Lindahl B, Allhoff T, Peter T, Tongers J, Wollert KC, Wallentin L. Growth-differentiation factor-15 improves risk stratification in st-segment elevation myocardial infarction. Eur Heart J 2007;28:2858-2865.
16. Khan SQ, Ng K, Dhillon O, Kelly D, Quinn P, Squire IB, Davies JE, Ng LL. Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction. Eur Heart J 2009.
17. Wollert KC, Kempf T, Peter T, Olofsson S, James S, Johnston N, Lindahl B, Horn-Wichmann R, Brabant G, Simoons ML, Armstrong PW, Califf RM, Drexler H, Wallentin L. Prognostic value of growth-differentiation factor-15 in patients with non-st-elevation acute coronary syndrome. Circulation 2007;115:962-971.
18. Kempf T, von Haehling S, Peter T, Allhoff T, Cicoira M, Doehner W, Ponikowski P, Filippatos GS, Rozentryt P, Drexler H, Anker SD, Wollert KC. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol 2007;50:1054-1060.
19. Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Allhoff T, Peter T, Siegbahn A, Venge P, Drexler H, Wallentin L. Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non st-elevation acute coronary syndrome. Circulation 2007;116:1540-1548.
20. Kempf T, Sinning JM, Quint A, Bickel C, Sinning C, Wild PS, Schnabel R, Lubos E, Rupprecht HJ, Munzel T, Drexler H, Blankenberg S, Wollert KC. Growth-differentiation factor-15 for risk stratification in patients with stable and unstable coronary heart disease: Results from the atherogene study. Circ Cardiovasc Genet 2009;2:286-292.
21. Brown DA, Breit SN, Buring J, Fairlie WD, Bauskin AR, Liu T, Ridker PM. Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: A nested case-control study. Lancet 2002;359:2159-2163.
22. Lind L, Wallentin L, Kempf T, Tapken H, Quint A, Lindahl B, Olofsson S, Venge P, Larsson A, Hulthe J, Elmgren A, Wollert KC. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: Results from the prospective investigation of the vasculature in uppsala seniors (pivus) study. Eur Heart J 2009;30:2346-2353.
23. Rohatgi A, Patel P, Das SR, Ayers CR, Khera A, Martinez-Rumayor A, Berry JD, McGuire DK, de Lemos JA. Association of growth differentiation factor-15 with coronary atherosclerosis and mortality in a young, multiethnic population: Observations from the dallas heart study. Clin Chem 2012;58:172-182.
24. Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: The rancho bernardo study. Circulation 2011;123:2101-2110.
25. Hlatky MA, Greenland P, Arnett DK, Ballantyne CM, Criqui MH, Elkind MSV, Go AS, Harrell FE, Jr., Howard BV, Howard VJ, Hsue PY, Kramer CM, McConnell JP, Normand S-LT, O'Donnell CJ, Smith SC, Jr., Wilson PWF, on behalf of the American Heart Association Expert Panel on Subclinical Atherosclerotic D, Emerging Risk F, the Stroke C. Criteria for evaluation of novel markers of cardiovascular risk. A scientific statement from the american heart association. Circulation 2009; 119:2408-16.
26. Eggers KM, Kempf T, Venge P, Wallentin L, Wollert KC, Lindahl B. Improving long-term risk prediction in patients with acute chest pain: The global registry of acute coronary events (grace) risk score is enhanced by selected nonnecrosis biomarkers. Am Heart J 2010;160:88-94.
27. Widera C, Pencina MJ, Meisner A, Kempf T, Bethmann K, Marquardt I, Katus HA, Giannitsis E, Wollert KC. Adjustment of the grace score by growth differentiation factor 15 enables a more accurate appreciation of risk in non-st-elevation acute coronary syndrome. Eur Heart J 2011.
28. Schaub N, Reichlin T, Twerenbold R, Reiter M, Steuer S, Bassetti S, Stelzig C, Wolf C, Winkler K, Haaf P, Meissner J, Drexler B, Mueller C. Growth differentiation factor-15 in the early diagnosis and risk stratification of patients with acute chest pain. Clin Chem 2012;58:441-449.
29. Bonaca MP, Morrow DA, Braunwald E, Cannon CP, Jiang S, Breher S, Sabatine MS, Kempf T, Wallentin L, Wollert KC. Growth differentiation factor-15 and risk of recurrent events in patients stabilized after acute coronary syndrome. Observations from prove it-timi 22. Arterioscler Thromb Vasc Biol 2011;31:203-10.
30. Eggers KM, Kempf T, Allhoff T, Lindahl B, Wallentin L, Wollert KC. Growth-differentiation factor-15 for early risk stratification in patients with acute chest pain. Eur Heart J 2008;29:2327-2335.
Keywords: Acute Coronary Syndrome, Cause of Death, Coronary Disease, Myocardial Infarction, Myocardial Ischemia, Natriuretic Peptide, Brain, Peptide Fragments, Stroke, Troponin, Troponin T
< Back to Listings