Growth Differentiation Factor 15 at 1 Month After an Acute Coronary Syndrome Is Associated With Increased Risk of Major Bleeding

Background: Growth differentiation factor (GDF)-15, a stress responsive cytokine, is associated with the risk of CV events after an acute coronary syndrome (ACS). Unlike other established cardiac biomarkers, the level of GDF-15 remains elevated in sub-acute phase after ACS and gradually decreases over time. We evaluated the prognostic utility of GDF-15 in patients after ACS accounting for established markers and risk predictors. Methods: GDF-15 (R&D Systems) and other established cardiac biomarkers (BNP, hsCRP and hsTnI) were measured at baseline in a randomly selected cohort of 4,968 patients enrolled within 30 days of hospitalization with ACS (median=14d) in SOLID-TIMI 52. Previously defined cutpoints were applied for GDF-15 concentration: <1200 (n=3451), 1200-1800 (n=919), and > 1800 ng/L (n=598). Analyses were adjusted for established risk predictors, days from the ACS event and other markers. MACE was defined as CV death, MI or stroke. Median follow-up was 2.5 years. Results: Patients with higher GDF-15 tended to be older, more likely to have diabetes, hypertension, history of revascularization, and CKD at baseline. Higher baseline levels of GDF-15 identified patients with higher rates of MACE as well as each individual element (p-trend <0.001 for all endpoints, Fig). The rate of MI was ∼2-fold higher in those with GDF-15 concentration >1800ng/L compared to patients with GDF-15 concentration <1200 ng/L. After adjustment for clinical predictors and other markers, GDF-15 was independently associated with the risk of MACE (HR 1.4, 95% CI 1.1-1.7; HR 1.8, 95% CI 1.4-2.3 for GDF-15 1200-1800, >1800, respectively). Individuals with GDF-15 >1800 ng/L had an increased risk of MI (adj HR 1.4, 95% CI 1.1-2.0) and stroke (adj HR 2.3, 95% CI 1.3-3.9). Conclusion: In patients after ACS, GDF-15 concentration is associated with the risk of MACE including MI and stroke independent of traditional risk factors and risk markers.

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The safety of morphine use in acute coronary syndrome: a meta-analysis

Heart Asia ◽

10.1136/heartasia-2018-011142 ◽

2019 ◽

Vol 11 (1) ◽

pp. e011142 ◽

Cited By ~ 1

Author(s):

Rugheed Ghadban ◽

Tariq Enezate ◽

Joshua Payne ◽

Haytham Allaham ◽

Ahmad Halawa ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Major Bleeding ◽

Pain Control ◽

Controlled Trial ◽

Cochrane Central Register ◽

Minor Bleeding ◽

Coronary Syndrome ◽

Increased Risk ◽

Significant Difference ◽

All Cause Mortality

BackgroundMorphine is widely used for pain control in patients with acute coronary syndrome (ACS). Several studies have questioned the safety of morphine in this setting with a concern of interaction with and reduced efficacy of antiplatelet agents.ObjectiveThis study aims to systematically review the safety of morphine use in ACS.MethodsMEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were queried from inception through April 2018. Studies comparing morphine to nonmorphine use in ACS were included. Study endpoints included: in-hospital myocardial infarction (MI), all-cause mortality, stroke, major bleeding, minor bleeding and dyspnoea.ResultsA total of 64 323 patients with ACS were included from eight studies, seven of which were observational studies and one was a randomised controlled trial. The use of morphine was associated with increased risk of in-hospital recurrent MI (OR 1.30, 95% CI 1.18 to 1.43, p < 0.00001). There was, however, no significant difference in terms of all-cause mortality (OR 0.87, 95% CI 0.62 to 1.22, p = 0.44), stroke (OR 0.81, 95% CI 0.39 to 1.66, p = 0.57), major bleeding (OR 0.49, 95% CI 0.24 to 1.00, p = 0.05), minor bleeding (OR 0.98, 95% CI 0.41 to 2.34, p = 0.97), or dyspnoea (OR 0.55, 95% CI 0.16 to 1.83, p = 0.33).ConclusionThe use of morphine for pain control in ACS was associated with an increased risk of in-hospital recurrent MI. Randomised clinical trials are needed to further investigate the safety of morphine in ACS.

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Identification of Follistatin-Like 1 by Expression Cloning as an Activator of the Growth Differentiation Factor 15 Gene and a Prognostic Biomarker in Acute Coronary Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2012.182816 ◽

2012 ◽

Vol 58 (8) ◽

pp. 1233-1241 ◽

Cited By ~ 33

Author(s):

Christian Widera ◽

Evangelos Giannitsis ◽

Tibor Kempf ◽

Mortimer Korf-Klingebiel ◽

Beate Fiedler ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Biomarker Discovery ◽

Prognostic Biomarker ◽

Cardiovascular Death ◽

Luciferase Reporter ◽

Expression Cloning ◽

Mouse Heart ◽

Growth Differentiation Factor 15 ◽

Coronary Syndrome ◽

Differentiation Factor

Abstract BACKGROUND Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine and biomarker that is produced after myocardial infarction and that is related to prognosis in acute coronary syndrome (ACS). We hypothesized that secreted proteins that activate GDF15 production may represent new ACS biomarkers. METHODS We expressed clones from an infarcted mouse heart cDNA library in COS1 cells and assayed for activation of a luciferase reporter gene controlled by a 642-bp fragment of the mouse growth differentiation factor 15 (GDF15) gene promoter. We measured the circulating concentrations of follistatin-like 1 (FSTL1) and GDF15 in 1369 patients with ACS. RESULTS One cDNA clone that activated the GDF15 promoter–luciferase reporter encoded the secreted protein FSTL1. Treatment with FSTL1 activated GDF15 production in cultured cardiomyocytes. Transgenic production of FSTL1 stimulated GDF15 production in the murine heart, whereas cardiomyocyte-selective deletion of FSTL1 decreased production of GDF15 in cardiomyocytes, indicating that FSTL1 is sufficient and required for GDF15 production. In ACS, FSTL1 emerged as the strongest independent correlate of GDF15 (partial R2 = 0.26). A total of 106 patients died of a cardiovascular cause during a median follow-up of 252 days. Patients with an FSTL1 concentration in the top quartile had a 3.7-fold higher risk of cardiovascular death compared with patients in the first 3 quartiles (P < 0.001). FSTL1 remained associated with cardiovascular death after adjustment for clinical, angiographic, and biochemical variables. CONCLUSIONS Our study is the first to use expression cloning for biomarker discovery upstream of a gene of interest and to identify FSTL1 as an independent prognostic biomarker in ACS.

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