Based on 100 variables prospectively recorded during a 15-year period, a model for live birth prediction after strict SET was constructed and showed excellent calibration in internal validation. For the first time, female height qualified as a predictor of live birth after IVF/ICSI.

Background Identification of patients with stable coronary heart disease who are at significant residual risk could be helpful for targeted prevention. Our aim was to determine the prognostic value of the recently introduced ceramide‐ and phospholipid‐based risk score, the Cardiovascular Event Risk Test ( CERT 2), in patients with stable coronary heart disease on optimal medical therapy and to identify biological processes that contribute to the CERT 2 score. Methods and Results Plasma samples (n=11 222) obtained from the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial were analyzed using a tandem liquid chromatography‐mass spectrometry method. STABILITY was a trial in patients with stable coronary heart disease randomized to the lipoprotein‐associated phospholipase A2 inhibitor darapladib or placebo on optimized medical therapy at baseline, with a median follow‐up of 3.7 years. Hazard ratios per SD for the CERT 2 risk score were 1.32 (95% CI, 1.25–1.39) for major adverse cardiovascular event, 1.47 (95% CI, 1.35–1.59) for cardiovascular death, 1.32 (95% CI, 1.16–1.49) for stroke, 1.23 (95% CI, 1.14–1.33) for myocardial infarction, and 1.56 (95% CI, 1.39–1.76) for hospitalization due to heart failure, when adjusted for traditional cardiovascular risk factors. CERT 2 showed correlation ( P <0.001, r >0.2) with inflammatory markers high‐sensitivity C‐reactive protein, interleukin 6, the heart failure marker N‐terminal pro‐B‐type natriuretic peptide, and low‐density lipoprotein cholesterol. After also adjusting for levels of other prognostic biomarkers, the CERT 2 score was still independently related to the risk of cardiovascular death but not to nonfatal events. Conclusions The CERT 2 risk score can detect residual risk in patients with stable coronary heart disease and is associated with biomarkers indicating inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia. REGISTRATION URL : https://www.clini​caltr​ials.gov . Unique identifier: NCT 00799903.

Background There are limited data on how the combination of diabetes mellitus ( DM ) and chronic kidney disease ( CKD ) affects cardiovascular outcomes as well as response to different P2Y 12 receptor antagonists, which represented the aim of the present investigation. Methods and Results In this post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized acute coronary syndrome patients to ticagrelor versus clopidogrel, patients (n=15 108) with available DM and CKD status were classified into 4 groups: DM +/ CKD + (n=1058), DM +/ CKD − (n=2748), DM −/ CKD + (n=2160), and DM −/ CKD − (n=9142). The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke at 12 months. The primary safety end point was PLATO major bleeding. DM +/ CKD + patients had a higher incidence of the primary end point compared with DM −/ CKD − patients (23.3% versus 7.1%; adjusted hazard ratio 2.22; 95% CI 1.88–2.63; P <0.001). Patients with DM +/ CKD − and DM −/ CKD + had an intermediate risk profile. The same trend was shown for the individual components of the primary end point and for major bleeding. Compared with clopidogrel, ticagrelor reduced the incidence of the primary end point consistently across subgroups ( P ‐interaction=0.264), but with an increased absolute risk reduction in DM +/ CKD +. The effects on major bleeding were also consistent across subgroups ( P ‐interaction=0.288). Conclusions In acute coronary syndrome patients, a gradient of risk was observed according to the presence or absence of DM and CKD , with patients having both risk factors at the highest risk. Although the ischemic benefit of ticagrelor over clopidogrel was consistent in all subgroups, the absolute risk reduction was greatest in patients with both DM and CKD . Clinical Trial Registration URL : http://www.clinicatrials.gov . Unique identifier: NCT 00391872.

Objective: The chemokine C-X-C motif ligand 16 (CXCL16) is a scavenger receptor for oxidized low-density lipoproteins and involved in inflammation at sites of atherosclerosis. This study aimed to investigate the association of CXCL16 with clinical outcome in patients with acute coronary syndrome (ACS). Approach and Results: Serial measurements of CXCL16 were performed in a subgroup of 5142 patients randomized in the PLATelet inhibition and patient Outcome (PLATO) trial. Associations between CXCL16 and a composite of cardiovascular (CV) death, spontaneous myocardial infarction (sMI) or stroke, and the individual components were assessed by multivariable Cox regression analyses. The hazard ratio (HR) per 50% increase in admission levels of CXCL16 analyzed as continuous variable was 1.64 (95% confidence interval [95%CI]: 1.44-1.88), p<0.0001. This association remained statistically significant after adjustment for randomized treatment, clinical variables, C-reactive protein, leukocytes, cystatin C, NT-proBNP, troponin T, Growth Differentiation Factor 15 and other biomarkers; HR 1.23 [1.05-1.45], p=0.0126. The admission level of CXCL16 was independently associated with CV death (1.50 [1.17-1.92], p=0.0014), but not with ischemic events alone, in fully adjusted analyses. No statistically independent association was found between CXCL16 measured at 1-month, or change in CXCL16 from admission to 1month, and clinical outcomes. Conclusions: In patients with ACS, admission level of CXCL16 is independently related to adverse clinical outcomes, mainly driven by an association to CV death. Thus, CXCL16 measurement may enhance risk stratification in patients with this condition.

Pentraxin-3 vs. C-reactive protein and other prognostic biomarkers in acute coronary syndromes: A substudy of the PLATelet inhibition and patients Outcomes (PLATO) trial.

BackgroundWe aimed to assess associations between circulating IL‐18 concentrations and cardiovascular outcomes in patients with acute coronary syndromes (ACS).Hypothesis and MethodsPlasma IL‐18 concentrations were measured at admission, discharge, 1 month, and 6 months in patients with ACS in the PLATelet inhibition and patient Outcomes (PLATO) trial. Associations with outcomes were evaluated with Cox regression models on the composite of CV death, spontaneous myocardial infarction (sMI), or stroke; and on CV death or sMI separately, including adjustment for clinical risk factors and biomarkers (cTnT‐hs, NT‐proBNP, cystatin C, CRP‐hs, and GDF‐15).ResultsMedian IL‐18 concentrations at baseline, discharge, 1 month, and 6 months were 237, 283, 305, and 320 ng/L (n = 16 636). Male sex, obesity, diabetes, and plasma levels of cystatin C, GDF‐15, and CRP‐hs were independently associated with higher IL‐18 levels. Higher baseline IL‐18 levels were associated with the composite endpoint and with CV death (hazard ratio [HR] 1.05, 95% confidence interval [95% CI] 1.02‐1.07 and HR 1.10, 95% CI 1.06‐1.14, respectively, per 25% increase of IL‐18 levels). Associations remained significant after adjustment for clinical variables but became non‐significant after adjustment for all biomarkers (HR 1.01, 95% CI 0.98‐1.04 and HR 1.04, 95% CI 1.00‐1.08, respectively). There were no associations with sMI.ConclusionsIn ACS patients, IL‐18 concentrations increased after the acute event and remained increased for 6 months. Baseline IL‐18 levels were significantly associated with CV mortality, independent of clinical characteristics and indicators of renal/cardiac dysfunction but this association was attenuated after adjustment for multiple biomarkers.

IMPORTANCEInflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease.OBJECTIVE To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function. DESIGN, SETTING, AND PARTICIPANTSThis multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020.EXPOSURES Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs Ն2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [Ն90 mL/min/1.73 m 2 ], mildly decreased eGFR level [60-90 mL/min/1.73 m 2 ], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m 2 ]).MAIN OUTCOMES AND MEASURES Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. RESULTSThis substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (Ն2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]). CONCLUSIONS AND RELEVANCEIn patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.

Background: Inflammation plays a major role in the pathophysiology of coronary artery disease. We aimed to determine whether baseline inflammatory markers were associated with clinical outcomes and the observed superiority of ticagrelor compared to clopidogrel in patients with acute coronary syndromes in the PLATO study. Methods: Blood samples were collected from 16,400 patients within 24 hours of the onset of acute coronary syndrome, at the time of random assignment to ticagrelor or clopidogrel in the PLATO study and prior to invasive procedures. The differential white blood cell count and plasma levels of C-reactive protein, interleukin-6 and interleukin-10 were determined and their relationships with clinical outcomes were assessed according to quartiles and using continuous models. The substudy primary endpoint was a composite of cardiovascular death and myocardial infarction. Results: Compared to the lowest quartile, the risk of the primary endpoint was significantly elevated in patients in the highest quartile of white blood cell count (hazard ratio (HR) 1.30; P=0.01), neutrophil count (HR 1.33; P=0.007), monocyte count (HR 1.24; P=0.004), C-reactive protein (HR 1.93; P<0.001) and interleukin-6 (HR 2.29; P<0.001). This was predominantly driven by an association with cardiovascular death. Following adjustment for clinical characteristics, troponin, cystatin C and N-terminal pro-brain-type natriuretic peptide, only white blood cell count and neutrophil count maintained a significant association with the primary endpoint. Ticagrelor had a consistent relative cardiovascular benefit compared to clopidogrel in each quartile of each of the inflammatory markers. Conclusions: Acute coronary syndrome patients with elevated levels of baseline inflammatory markers are at increased risk of adverse cardiovascular events, particularly cardiovascular death. The consistent cardiovascular benefit of ticagrelor compared to clopidogrel tended to confer a greater absolute risk reduction in patients with the highest levels of inflammatory markers, as they were at highest risk.