Abstract 13448: Impact of Diabetes on Growth Differentiation Factor 15 and Mortality in Patients With Stable Coronary Artery Disease: The ANOX Study

Background: Diabetes mellitus (DM) is still significantly associated with the risk of mortality in the general population. Higher circulating growth differentiation factor 15 (GDF-15) levels are associated with the risk of mortality in the general population, in patients with DM, and in those with coronary artery disease (CAD). However, whether GDF-15 levels differ according to the diabetic status and whether DM modifies the relationship between GDF-15 and mortality in patients with stable CAD are unclear. Methods: Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between diabetic status and GDF-15 and the impact of DM on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 797 DM and 663 non-DM patients enrolled in the ANOX Study. Results: The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with DM exhibited significantly higher levels of GDF-15 compared to those without DM (median [interquartile range], 1472 [1049-2258] vs. 1274 [868-1874] pg/mL, respectively; P <0.001). Stepwise multiple linear regression analysis revealed that the log-transformed (Ln-) GDF-15 level was independently associated with higher age, DM, current smoking, lower estimated glomerular filtration rate, anemia, no use of aspirin, Ln-N-terminal pro-natriuretic peptide, and Ln-high-sensitivity C-reactive protein ( P <0.005 for all). In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders (hazard ratio per 1-SD increase [HR], 1.51; 95% confidence interval [CI], 1.33-1.71). This association was still significant in patients with DM (HR, 1.52; 95% CI, 1.30-1.79) and in those without DM (HR, 1.57; 95% CI, 1.25-1.96). However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in the entire cohort and in patients with DM, but not in those without DM. Conclusions: Higher levels of GDF-15 were independently associated with DM in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with DM.

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Abstract 13423: Impact of Anemia on Growth Differentiation Factor 15 and Mortality in Patients With Stable Coronary Artery Disease: The ANOX Study

Circulation ◽

10.1161/circ.142.suppl_3.13423 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Moritake Iguchi ◽

masahiro suzuki ◽

Morihiro Matsuda ◽

Yoichi Ajiro ◽

Tsuyoshi Shinozaki ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Transforming Growth Factor ◽

Stable Coronary Artery Disease ◽

Linear Regression Analysis ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Artery Disease ◽

Stable Cad ◽

The Impact

Background: Growth differentiation factor 15 (GDF-15) is a stress responsive cytokine of the transforming growth factor superfamily. Circulating levels of GDF-15 are elevated in various conditions including anemia and stable coronary artery disease (CAD), and associated with the risk of mortality in patients with stable CAD. However, whether anemia modifies the relationship between GDF-15 and mortality in patients with stable CAD is unknown. Methods: Using data from a multicenter, prospective cohort of 1460 patients with stable CAD, we assessed the association between anemic status and GDF-15 and the impact of anemia on the association between GDF-15 levels and the risk of all-cause death. GDF-15 was measured in 564 anemic and 896 non-anemic patients enrolled in the ANOX Study. Results: The mean age (standard deviation [SD]) of the patients was 71.7 (9.4) years; 74.4% were men. Patients with anemia exhibited significantly higher levels of GDF-15 compared to those without anemia (median [interquartile range], 1953 [1302-3110] vs. 1175 [838-1579] pg/mL, respectively; P <0.001). Stepwise multiple linear regression analysis revealed that the log-transformed (Ln-) GDF-15 level was independently associated with higher age, diabetes, current smoking, lower estimated glomerular filtration rate, anemia, no use of aspirin, Ln-N-terminal pro-natriuretic peptide, and Ln-high-sensitivity C-reactive protein ( P <0.005 for all). In the entire patient cohort, the GDF-15 level was significantly associated with all-cause death after adjusting for potential clinical confounders (hazard ratio per 1-SD increase [HR], 1.51; 95% confidence interval [CI], 1.33-1.71). This association was still significant in patients with anemia (HR, 1.71; 95% CI, 1.44-2.05) and in those without anemia (HR, 1.44; 95% CI, 1.21-1.71). However, GDF-15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in the entire cohort and in patients with anemia, but not in those without anemia. Conclusions: Higher levels of GDF-15 were independently associated with anemia in patients with stable CAD. The prognostic value of GDF-15 on mortality was pronounced in patients with anemia.

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Abstract 5016: Growth-Differentiation Factor-15 is an Independent Predictor of Cardiovascular Events and Mortality in Patients with Stable Coronary Artery Disease

Circulation ◽

10.1161/circ.118.suppl_18.s_1132 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Tibor Kempf ◽

Jan-Malte Sinning ◽

Anja Quint ◽

Christoph Bickel ◽

Christoph Sinning ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Independent Predictor ◽

Troponin T ◽

Receiver Operating Curve ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

All Cause Mortality ◽

Artery Disease ◽

Stable Cad

Circulating levels of the TGF β-related cytokine, growth-differentiation factor-15 (GDF-15), provide independent prognostic information in patients with unstable coronary artery disease (CAD). To explore the prognostic utility of GDF-15 in patients with stable CAD, we analyzed the relation of GDF-15 to mortality and cardiovascular (CV) events in the AtheroGene registry which enrolled consecutive patients with stable angina and at least one stenosis >30% in a larger coronary artery. Patients were followed for a median of 3.6 years. Serum samples for measurement of GDF-15 along with other biomarkers were available from 1352 patients. Two pre-specified cutoff points (1200 and 1800 ng/L) were used to identify different risk groups. 55.9%, 26.4%, and 17.7% of the patients presented with GDF-15 values <1200 ng/L, between 1200 and 1800 ng/L, and >1800 ng/L, respectively. Increasing levels of GDF-15 were related to age (P<0.001), hypertension (P=0.01), diabetes mellitus (P<0.001), low HDL cholesterol (P<0.001), and the extent of CAD (P=0.001). Moreover, significant relations to hsCRP, troponin T, NT-proBNP, and reduced renal function (GFR) were observed (all P<0.001). Increasing levels of GDF-15 were associated with an increased risk of all-cause mortality (P<0.001, log-rank test), CV mortality (P<0.001), and CV events (P<0.001). Receiver operating curve analyses confirmed GDF-15 as a strong marker of 2-year adverse outcomes (area under the curve for all-cause mortality, 0.79; CV mortality, 0.81; CV events, 0.70). By multiple Cox regression analysis, GDF-15 emerged as an independent predictor of all-cause mortality (HR 2.1 per one standard deviation of lnGDF-15 [95% CI 1.6 –2.8], P<0.001), CV mortality (HR 2.2 [95% CI 1.5–3.3], P<0.001), and CV events (HR 1.7 [95% CI 1.3–2.4], P=0.001) after adjustment for baseline characteristics, clinical variables, LDL/HDL ratio, hsCRP, troponin T, NT-proBNP, and GFR. Patients with a GDF-15 level above 1800 ng/L had a highly elevated risk of CV mortality even in the fully adjusted model (HR 5.2 [95% CI 1.6 –16.1], P=0.005). These data identify GDF-15 as a powerful and independent biomarker of mortality and CV events in patients with stable CAD.

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Impact of Smoking Status on Growth Differentiation Factor 15 and Mortality in Patients With Suspected or Known Coronary Artery Disease: The ANOX Study

Journal of the American Heart Association ◽

10.1161/jaha.120.018217 ◽

2020 ◽

Vol 9 (22) ◽

Author(s):

Hiromichi Wada ◽

Masahiro Suzuki ◽

Morihiro Matsuda ◽

Yoichi Ajiro ◽

Tsuyoshi Shinozaki ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Smoking Status ◽

Linear Regression Analysis ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Former Smokers ◽

Artery Disease ◽

Never Smokers ◽

The Impact

Background Whether circulating growth differentiation factor 15 (GDF‐15) levels differ according to smoking status and whether smoking modifies the relationship between GDF‐15 and mortality in patients with coronary artery disease are unclear. Methods and Results Using data from a multicenter, prospective cohort of 2418 patients with suspected or known coronary artery disease, we assessed the association between smoking status and GDF‐15 and the impact of smoking status on the association between GDF‐15 and all‐cause death. GDF‐15 was measured in 955 never smokers, 1035 former smokers, and 428 current smokers enrolled in the ANOX Study (Development of Novel Biomarkers Related to Angiogenesis or Oxidative Stress to Predict Cardiovascular Events). Patients were followed up during 3 years. The age of the patients ranged from 19 to 94 years; 67.2% were men. Never smokers exhibited significantly lower levels of GDF‐15 compared with former smokers and current smokers. Stepwise multiple linear regression analysis revealed that the log‐transformed GDF‐15 level was independently associated with both current smoking and former smoking. In the entire patient cohort, the GDF‐15 level was significantly associated with all‐cause death after adjusting for potential clinical confounders. This association was still significant in never smokers, former smokers, and current smokers. However, GDF‐15 provided incremental prognostic information to the model with potential clinical confounders and the established cardiovascular biomarkers in never smokers, but not in current smokers or in former smokers. Conclusions Not only current, but also former smoking was independently associated with higher levels of GDF‐15. The prognostic value of GDF‐15 on mortality was most pronounced in never smokers among patients with suspected or known coronary artery disease.

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Impact of anemia on the relationships of growth differentiation factor 15 with mortality and cardiovascular events in patients with suspected or known coronary artery disease: the ANOX study

European Heart Journal ◽

10.1093/ehjci/ehaa946.2934 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Wada ◽

M Suzuki ◽

M Matsuda ◽

Y Ajiro ◽

T Shinozaki ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Troponin I ◽

Public Institution ◽

Funding Source ◽

Growth Differentiation Factor 15 ◽

Differentiation Factor ◽

Artery Disease ◽

The Impact

Abstract Background Growth differentiation factor 15 (GDF-15) is a stress-responsive cytokine that plays an important role in the regulation of the inflammatory response, growth and cell differentiation. An elevated GDF-15 was found in various conditions including anemia and stable coronary artery disease (CAD), and it was reported to predict mortality and cardiovascular (CV) events in general population and in patients with established CAD. However, the impact of anemia on the relationships of GDF-15 with mortality and CV events in patients with suspected or known CAD is unclear. Methods Serum GDF-15 levels were measured in 2,418 patients with suspected or known CAD undergoing elective coronary angiography, enrolled in the development of novel biomarkers related to angiogenesis or oxidative stress to predict CV events (ANOX) study, and followed up for 3 years. Anemia was defined as a hemoglobin level of less than 13 g/dL in men and <12 g/dL in women. Patients were divided into 2 groups according to the presence (anemic, n=882) or absence (non-anemic, n=1,536) of anemia. The primary outcome was all-cause death. The secondary outcomes were CV death, and major adverse CV events (MACE) defined as a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Results During the follow-up, 164 anemic and 90 non-anemic patients died from any cause, 64 anemic and 24 non-anemic patients died from CV disease, and 96 anemic and 69 non-anemic patients developed MACE. After adjustment for established risk factors, GDF-15 levels were significantly associated with all-cause death (hazard ratio [HR] for 1-SD increase, 1.75; 95% confidence interval [CI], 1.51–2.04), CV death (HR, 1.67; 95% CI, 1.30–2.13), and MACE (HR, 1.46; 95% CI, 1.18–1.81) in anemic, while GDF-15 levels were also significantly associated with all-cause death (HR, 1.47; 95% CI, 1.27–1.69), CV death (HR, 1.56; 95% CI, 1.18–1.99), and MACE (HR, 1.25; 95% CI, 1.004–1.50) in non-anemic patients. Even after incorporation of N-terminal pro-brain natriuretic peptide, contemporary sensitive cardiac troponin I, and high-sensitivity C-reactive protein into a model with established risk factors, the addition of GDF-15 levels further improved the prediction of all-cause death (P<0.001 for continuous net reclassification improvement [NRI], P<0.001 for integrated discrimination improvement [IDI]), CV death (P=0.026 for NRI, P=0.023 for IDI), and MACE (P=0.025 for NRI, P=0.042 for IDI) in anemic, whereas it did not improved the prediction of all-cause death (P=0.072 for NRI, P=0.079 for IDI), CV death (P=0.289 for NRI, P=0.179 for IDI) or MACE (P=0.397 for NRI, P=0.230 for IDI) in non-anemic patients. Conclusions The GDF-15 level significantly improved the prediction of all-cause death, CV death, and MACE in anemic, but not in non-anemic patients with suspected or known CAD. The relationships of GDF-15 with mortality and CV events seem to be remarkable in the presence of anemia. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The ANOX study is supported by a Grant-in-Aid for Clinical Research from the National Hospital Organization.

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