Diabetes and baseline glucose are associated with inflammation, left ventricular function and short- and long-term outcome in acute coronary syndromes: role of the novel biomarker Cyr 61

Abstract

Background: Hyperglycemia in the setting of an acute coronary syndrome (ACS) impacts short term outcomes, but little is known about longer term effects. We therefore designed this study to firstly determine the association between hyperglycemia and short term and longer term outcomes in patients presenting with ACS and secondly evaluate the prognostic role of diabetes, body mass index (BMI) and the novel biomarker Cyr61 on outcomes.

Methods: The prospective Special Program University Medicine-Acute Coronary Syndrome (SPUM-ACS) cohort enrolled 2168 patients with ACS between December 2009 and October 2012, of which 2034 underwent PCI (93.8%). Patients were followed up for 12 months. Events were independently adjudicated by three experienced cardiologists. Participants were recruited from four tertiary hospitals in Switzerland: Zurich, Geneva, Lausanne and Bern. Participants presenting with acute coronary syndromes and who underwent coronary angiography were included in the analysis. Patients were grouped according to history of diabetes (or HbA1c greater than 6%), baseline blood sugar level (BSL; < 6, 6-11.1 and > 11.1 mmol/L) and body mass index (BMI). The primary outcome was major adverse cardiac events (MACE) which was a composite of myocardial infarction, stroke and all-cause death. Secondary outcomes included the individual components of the primary endpoint, revascularisations, bleeding events (BARC classification) and cerebrovascular events (ischaemic or haemorrhagic stroke or TIA).

Results: Patients with hyperglycemia, i.e. BSL ≥ 11.1 mmol/L, had higher levels of C-reactive protein (CRP), white blood cell count (WBC), creatinine kinase (CK), higher heart rates and lower left ventricular ejection fraction (LVEF) and increased N-terminal pro-brain natriuretic peptide. At 30 days and 12 months, those with BSL ≥ 11.1 mmol/L had more MACE and death compared to those with BSL < 6.0 mmol/L or 6.0-11.1 mmol/L (HR-ratio 4.78 and 6.6; p < 0.001). The novel biomarker Cyr61 strongly associated with high BSL and STEMI and was independently associated with 1 year outcomes (HR 2.22; 95% CI 1.33-3.72; Tertile 3 vs. Tertile 1).

Conclusions and relevance: In this large, prospective, independently adjudicated cohort of in all comers ACS patients undergoing PCI, both a history of diabetes and elevated entry glucose was associated with inflammation and increased risk of MACE both at short and long-term. The mediators might involve increased sympathetic activation, inflammation and ischemia as reflected by elevated Cyr61 levels leading to larger levels of troponin and lower LVEF. Trial registration Clinical Trial Registration Number: NCT01000701. Registered October 23, 2009.

Keywords: Acute coronary syndromes; Diabetes; Glucose; Inflammation; Major cardiovascular and cerebrovascular events; Mortality.

Conflict of interest statement

MR has received institutional research grants from Abbott Vascular, Boston Scientific, Terumo, Medtronic, and Biotronik; RK has received advisory board fees from Novartis; FM has received research grants to the institution from Amgen, AstraZeneca, Boston Scientific, Biotronik, Medtronic, MSD, Eli Lilly and St. Jude Medical including speaker or consultant fees; LR received speaker fees and research grants to the institution from St. Jude Medical; SW has received research grants to the institution from Abbott, Boston Scientific, Biosensors, Biotronik, the Medicines Company, Medtronic and St. Jude Medical and honoraria from Abbott, Astra Zeneca, Eli Lilly, Boston Scientific, Biosensors, Biotronik, Medtronic and Edwards; FN is serving as a consultant for Abbott, Edwards Lifesciences and Medtronic; AvE received speaker or consultant fees from Amgen, MSD, and Sanofi-Aventis; TFL received research grants to the institution from AstraZeneca, Bayer Healthcare, Biosensors, Biotronik, Boston Scientific, Eli Lilly, Medtronic, MSD, Merck, Roche and Servier, including speaker fees by some of them. CMM received research grants to the institution from Eli Lilly, AstraZeneca, Roche, Amgen and MSD including speaker or consultant fees.

Figures

Fig. 1

Box plots of selected variables and biomarkers according to glucose level at baseline. Differences between groups analysed using either ANOVA or Kruskal–Wallis tests

Fig. 2

a Kaplan–Meier curves of major adverse cardiovascular events (MACE) in diabetics versus non-diabetics in the first 30 days. b Landmark survival curves (30 days to 1 year) of major adverse cardiovascular events in diabetics versus non-diabetics

Fig. 3

a Kaplan–Meier survival curves of mortality in diabetics versus non-diabetics in the first 30 days. b Landmark survival analysis using Kaplan–Meier survival curves to assess mortality in diabetics versus non-diabetics from 30 to 365 days

Fig. 4

a Kaplan–Meier curves of MACE in ACS patients within 30 days according to plasma glucose levels on presentation. b Landmark survival analysis using Kaplan–Meier survival curves comparing outcomes from 30 days to 1 year according to plasma glucose levels on presentation

Fig. 5

Box plot demonstrating change in Cyr61 levels as glucose increases, stratified by infarct type (STEMI vs. NSTEMI/UA)