Growth Differentiation Factor-15 and Clinical Outcomes in Japanese Patients With Ischemic Heart Disease

Background Despite a reduction in the rate of thrombotic events, ischemic heart disease (IHD) remains a key medical problem associated with high major bleeding and mortality in Asian patients with IHD. Growth differentiation factor (GDF)-15, a stress-response cytokine belonging to the transforming growth factor beta superfamily, is reportedly associated with poor clinical outcomes in Western patients with IHD. However, the clinical significance of GDF-15 in Asian patients with IHD has not yet been fully elucidated. Objectives The aim of the present study was to examine the impact of serum GDF-15 on clinical outcomes in Japanese patients with IHD. Methods Serum GDF-15 levels were evaluated in 632 consecutive patients with IHD. All patients were followed up for a median period of 2.8 years. The primary endpoint was the all-cause mortality rate. Secondary endpoints were major adverse cardiovascular events (MACE), heart failure (HF)–related rehospitalization, bleeding, and thrombotic events. Results Serum GDF-15 levels were elevated in acute coronary syndrome, severe coronary artery disease, and the major Japanese version of the high bleeding risk criteria. Multivariate Cox proportional hazards regression analysis demonstrated that GDF-15 was an independent predictor of all-cause mortality, MACE, HF-related rehospitalizations, and bleeding events after adjusting for confounding risk factors but not for thrombotic events. Adding GDF-15 to risk factors significantly improved the net reclassification index and integrated discrimination improvement for all-cause deaths, MACE, HF-related rehospitalization, and bleeding events. Conclusions Serum GDF-15 could be a feasible marker for major bleeding and adverse clinical outcomes in Japanese patients with IHD.

I schemic heart disease (IHD) is a leading cause of death worldwide. Because of advances in revascularization and antithrombotic medicine, the thrombotic event rate has decreased significantly among patients with IHD who undergo revascularization. 1 However, mortality in patients with IHD who undergo revascularization remains high. Therefore, early identification and risk stratification of patients at high risk for all-cause death are of critical importance.
Bleeding events in patients with IHD are associated with high mortality risk. 2 such as oxidative stress, inflammation, and mechanical stress in various tissues, and is released into circulation. 7,8 As circulating GDF-15 is reportedly elevated in advanced age, cancer, and cardiovascular disease, 9 it is considered a stress-response cytokine.
Accumulating evidence has demonstrated that GDF-15 can help predict mortality, major adverse cardiovascular events (MACE), and HF hospitalizations in patients with IHD. [10][11][12][13] Moreover, GDF-15 is associated with major bleeding in patients with AF across different geographic areas, including Asia. 14,15 GDF-15 measurement is used clinically for risk    Values are mean AE SD, n (%), n, or median (IQR). a P < 0.05 vs first tertile. b P < 0.05 vs second tertile by analysis of variance with Tukey's post hoc test. c P < 0.05 vs first tertile. d P < 0.05 vs second tertile by Steel-Dwass test.
AF-bleeding score is composed of age, TnT, hemoglobin, GDF-15, and previous bleeding. 15 The ABC-AFbleeding score was evaluated using an online calculator.
CARDIOVASCULAR RISK FACTORS. Hypertension was defined as systolic blood pressure $140 mm Hg, diastolic blood pressure $90 mm Hg, or antihypertensive medication use. Diabetes mellitus was defined as a fasting blood glucose level $126 mg/dL, glycated hemoglobin $6.5%, or antidiabetic medication use.  BNP is also a prognostic marker for IHD, so we   severe coronary artery disease, such as left main trunk lesions and 3-vessel disease (Figures 2A and 2B).
Furthermore, serum GDF-15 levels were higher in patients with ACS than in those with CCS ( Figure 2C). Figures 2D to 2I During the follow-up period, 78 all-cause deaths occurred in this study. As shown in Figure 3A,  Figure 3B).     Figures 5A to 5C). The more severe the CKD, the higher the risk for bleeding events in patients with IHD. 6 A high GDF-15 level was reportedly associated with the progression and incidence of CKD and mortality in patients undergoing hemodialysis. [23][24][25] Anemia involved in renal dysfunction and chronic inflammation is reportedly associated with high GDF-15 levels, while iron deficiency anemia is not. 26,27 In the present study, AF was the primary reason for the anticipated use of long-term oral anticoagulation. It has been reported that plasma and atrial tissue expression of GDF-15 are higher in patients with AF than in those with sinus rhythm. 31 GDF-15 is also related to clinical outcomes, including mortality, major bleeding, and stroke, in patients with AF. 14 PVD is a common comorbidity in patients with IHD.

DISCUSSION
De Haan et al 32 demonstrated that serum GDF-15 level was correlated with the severity of PVD and was significantly associated with major amputation and all-cause mortality in patients with PVD.
We found that serum GDF-15 levels increased with increasing HBR risk, suggesting that serum GDF-15 levels, in part, reflect the accumulation of HBRs. As the significant association between serum GDF-15 and bleeding events was maintained in the multivariate    Serum GDF-15 could serve as a discriminatory factor between thrombotic and bleeding risk and is a feasible marker for major bleeding and adverse clinical outcomes in Asian patients with IHD.