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. (2007)(15)	741	STEMI (ASSENT)	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 (GUSTO-IV)	Death (1 year) MI (30 days)	HR 1SD: 1.5 [1.2-1.9], p<0.001; c-index 0.76; p=NS
Wollert, et al. (2007)(19)	2079	NSTEMI (FRISC-II)	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; Significant interaction with treatment strategy >1800 ng/L associated with 3-vz or left main
Kempf, et al. (2009)(20)	1352/ 877	Stable Angina Acute Coronary Syndrome (AtheroGene)	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 (30% acute MI)	Death or MI (6 months)	HR 1 log unit: 2.7 [1.0-6.0], p=0.046 C-index 0.78
Eggers, et al. (2010)(26)	453	Chest pain (31% acute MI)	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 (18% acute MI)	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 (nested case control)	MI/stroke/ CV death	OR >90th%: 2.7 [1.6-4.9], p=0.0002
Lind, et al. (2009)(22)	1004	Swedish healthy subjects age 70 (PIVUS)	CIMT Carotid plaque	P=NS P=0.03
Daniels, et al. (2011)(24)	1391	Healthy elderly – mean age 70 (Rancho Bernado)	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 – mean age 44; 49% Black	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 CHD=coronary heart disease; CIMT=carotid intima media thickness; CV=cardiovascular; CAC=coronary calcium

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Keywords: Acute Coronary Syndrome, Cause of Death, Coronary Disease, Myocardial Infarction, Myocardial Ischemia, Natriuretic Peptide, Brain, Peptide Fragments, Stroke, Troponin, Troponin T

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