Comparative prognostic value of postprocedural creatine kinase myocardial band and high-sensitivity troponin T in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.

OBJECTIVES: We aimed to assess the prognostic value of postprocedural creatine kinase myocardial band (CK-MB) and cardiac troponin (cTn) in patients with non-ST-segment elevation myocardial infarction (NSTEMI). BACKGROUND: Whether postprocedural CK-MB or cTn is a better biomarker to stratify the risk after percutaneous coronary intervention (PCI) remains unknown. METHODS: This study included 2,077 patients with NSTEMI undergoing early PCI. Peak postprocedural values of CK-MB and high-sensitivity cTn T (hs-cTnT) were analyzed. The primary outcome was 3-year mortality. RESULTS: The median values of peak postprocedural CK-MB and hs-cTnT were 18.3 U L-1 and 0.140 µg L-1 , respectively. Overall, 211 patients died during follow-up. There were 129 deaths in patients with CK-MB >the median value and 82 deaths in those with CK-MB ≤the median value (Kaplan-Meier estimates of 3-year mortality, 18.9% and 14.0%, respectively; hazard ratio [HR] = 1.52, 95% confidence interval [CI] 1.16-2.01; P < 0.001). There were 134 deaths in patients with hs-cTnT >the median value and 77 deaths in patients with hs-cTnT ≤the median value (Kaplan-Meier estimates of 3-year mortality, 19.9% and 13.2%, respectively; HR = 1.90 [1.44-2.52]; P < 0.001). After adjustment, peak postprocedural CK-MB (adjusted HR = 1.05 [1.02-1.07], P < 0.001 for each 24 U L-1 increment) and hs-cTnT (adjusted HR = 1.12 [1.01-1.25], P = 0.037 for each unit higher log hs-cTnT) remained independently associated with the risk of 3-year mortality. The C-statistic(s) of the model with CK-MB and hs-cTnT were 0.789 [0.757-0.817] and 0.793 [0.762-0.821], respectively (P = 0.585). CONCLUSION: In patients with NSTEMI undergoing early PCI, peak postprocedural CK-MB and hs-cTnT are independently associated with the risk of 3-year mortality. © 2017 Wiley Periodicals, Inc.

Neutrophil gelatinase-associated lipocalin reflects inflammation and is not a reliable renal biomarker in neonates and infants after cardiopulmonary bypass: a prospective case-control study.

Introduction Acute kidney injury is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Neutrophil gelatinase-associated lipocalin has been suggested to be a promising early biomarker of impending acute kidney injury. On the other hand, neutrophil gelatinase-associated lipocalin has been shown to be elevated in systemic inflammatory diseases without renal impairment. In this secondary analysis of data from our previous study on acute kidney injury after infant cardiac surgery, our hypothesis was that neutrophil gelatinase-associated lipocalin may be associated with surgery-related inflammation. METHODS: We prospectively enrolled 59 neonates and infants undergoing cardiopulmonary bypass surgery for CHD and measured neutrophil gelatinase-associated lipocalin in plasma and urine and interleukin-6 in the plasma. Values were correlated with postoperative acute kidney injury according to the paediatric Renal-Injury-Failure-Loss-Endstage classification. RESULTS: Overall, 48% (28/59) of patients developed acute kidney injury. Of these, 50% (14/28) were classified as injury and 11% (3/28) received renal replacement therapy. Both plasma and urinary neutrophil gelatinase-associated lipocalin values were not correlated with acute kidney injury occurrence. Plasma neutrophil gelatinase-associated lipocalin showed a strong correlation with interleukin-6. Urinary neutrophil gelatinase-associated lipocalin values correlated with cardiopulmonary bypass time. CONCLUSION: Our results suggest that plasma and urinary neutrophil gelatinase-associated lipocalin values are not reliable indicators of impending acute kidney injury in neonates and infants after cardiac surgery with cardiopulmonary bypass. Inflammation may have a major impact on plasma neutrophil gelatinase-associated lipocalin values in infant cardiac surgery. Urinary neutrophil gelatinase-associated lipocalin may add little prognostic value over cardiopulmonary bypass time.

Alkaline phosphatase and prognosis in patients with coronary artery disease.

BACKGROUND: The evidence on the association between alkaline phosphatase (ALP) and prognosis of patients with coronary artery disease (CAD) is limited. The aim of this study was to assess the association of ALP with the risk of mortality or coronary events in patients with CAD. MATERIALS AND METHODS: The study included 5540 patients with angiography-proven CAD treated with catheter-based coronary revascularization. Baseline ALP measurements were available for analysis in all patients. Patients were divided into three groups: a group with an ALP activity in the 1st tertile (ALP ≤ 65·5 U/L; n = 1855), a group with an ALP activity in the 2nd tertile (ALP > 65·5 to 85·7 U/L; n = 1839) and a group with an ALP in the 3rd tertile (ALP > 85·7 U/L; n = 1846). The primary outcome was all-cause mortality at 3-year follow-up. RESULTS: All-cause deaths (number [Kaplan-Meier estimates]) occurred in 443 patients: 117 (7·2%), 130 (8·1%) and 196 deaths (11·8%) among patients of the 1st, 2nd and 3rd ALP tertiles (unadjusted hazard ratio [HR] = 1·33, 95% confidence interval [CI]: 1·19 to 1·50; P < 0·001, calculated per tertile increment in the ALP activity). After adjustment in multivariable Cox proportional hazards model, ALP was independently associated with the risk of all-cause mortality (adjusted HR = 1·33 [1·18-1·51], P < 0·001, calculated per unit increment in log ALP). The multivariable model for all-cause mortality with baseline variables without ALP had a C statistic of 0·820 [0·797-0·843] which increased to 0·825 [0·804-0·849] after ALP inclusion; delta C statistic 0·005 [0·001-0·011]; P < 0·001. CONCLUSIONS: In patients with CAD, elevated ALP activity was independently associated with the risk of 3-year all-cause mortality.

Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery.

AIM: Tranexamic acid (TXA) continues to be one of the antifibrinolytics of choice during paediatric cardiac surgery. However, in infants less than 1 year of age, the optimal dosing based on pharmacokinetic (PK) considerations is still under discussion. METHODS: Forty-three children less than 1 year of age were enrolled, of whom 37 required the use of cardiopulmonary bypass (CPB) and six were operated on without CPB. Administration of 50 mg kg-1 TXA intravenously at the induction of anaesthesia was followed by 50 mg kg-1 into the CPB prime in the CPB group. Plasma concentrations of TXA were analysed by gas chromatography-mass spectrometry. PK data were investigated using nonlinear mixed-effect models. RESULTS: A two-compartment model was fitted, with the main covariates being allometrically scaled bodyweight, CPB, postmenstrual age (PMA). Intercompartmental clearance (Q), peripheral volume (V2), systemic clearance, (CL) and the central volume (V1) were calculated. Typical values of the PK parameter estimates were as follows: CL = 3.78 [95 % confidence interval (CI) 2.52, 5.05] l h-1 ; central volume of distribution = 13.6 (CI 11.7, 15.5) l; Q = 16.3 (CI 13.5, 19.2) l h-1 ; V2 = 18.0 (CI 16.1, 19.9) l. Independently of age, 10 mg kg-1 TXA as a bolus, a subsequent infusion of 10 mg kg-1 h-1 , then a 4 mg kg-1 bolus into the prime and a reduced infusion of 4 mg kg-1 h-1 after the start of CPB are required to maintain TXA concentrations continuously above 20 µg ml-1 , the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the '10-10-4-4 rule'). CONCLUSIONS: The introduction of a modified dosing regimen using a starting bolus followed by an infusion and a CPB prime bolus would prohibit the potential risk of seizures caused by high peak concentrations and also maintain therapeutic plasma concentration above 20 µg ml-1 .

Association of progression or regression of coronary artery atherosclerosis with long-term prognosis.

BACKGROUND: The association between coronary atherosclerosis progression or regression and long-term prognosis remains poorly defined. We assessed the association of atherosclerosis progression or regression with long-term mortality and factors that promote angiographic progression or regression of coronary atherosclerosis in patients with angiographically proven coronary artery disease. METHODS: The study included 605 patients with coronary artery disease who underwent coronary angiography at baseline and at 2 years later. Pan-coronary artery tree quantitative coronary angiography was performed. Of 6259 coronary segments (10.3 lesions per patient) analyzed, 1790 non-stented segments with ≥25% diameter stenosis at baseline were included. Atherosclerosis progression or regression was defined as a decrease or increase in the mean minimal lumen diameter (MLD) of the non-stented segments of ≥0.2 mm in the 2-year angiography compared to baseline angiography. The primary outcome was all-cause mortality. RESULTS: Based on the change in mean MLD between baseline and 2-year angiography, patients were divided into 3 groups: the group with progression of atherosclerosis (n=53; 8.8%), the group with no progression or regression of atherosclerosis (n=472; 78.0%) and the group with regression of atherosclerosis (n=80; 13.2%). There were 126 deaths over 8-year follow-up: 17 deaths among patients with progression, 103 deaths among patients with no progression/regression and 6 deaths among patients with regression (Kaplan-Meier estimates of mortality, 37.5%, 25.2% and 8.9%, respectively; adjusted hazard ratio=1.16, 95% confidence interval 1.05 to 1.29, P=.004 for 0.1 mm reduction in mean MLD). CONCLUSIONS: Progression or regression of coronary atherosclerosis in non-treated coronary segments was significantly associated with 8-year mortality.

Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants.

Stimulators of the soluble guanylyl cyclase (sGC) are emerging therapeutic agents in cardiovascular diseases. Genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease. Studies investigating sGC stimulators in subjects with CAD and carrying risk-related variants in sGC are, however, lacking. Here, we functionally investigate the impact of coding GUCY1A3 variants on sGC activity and the therapeutic potential of sGC stimulators in vitro. In addition to a known loss-of-function variant, eight coding variants in GUCY1A3 were cloned and expressed in HEK 293 cells. Protein levels and dimerization capability with the ß1 subunit were analysed by immunoblotting and co-immunoprecipitation, respectively. All α1 variants found in MI patients dimerized with the ß1 subunit. Protein levels were reduced by 72 % in one variant (p < 0.01). Enzymatic activity was analysed using cGMP radioimmunoassay after stimulation with a nitric oxide (NO) donor. Five variants displayed decreased cGMP production upon NO stimulation (p < 0.001). The addition of the sGC stimulator BAY 41-2272 increased cGMP formation in all of these variants (p < 0.01). Except for the variant leading to decreased protein level, cGMP amounts reached the wildtype NO-induced level after addition of BAY 41-2272. In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a sGC stimulator in vitro. These results might therefore represent the starting point for discovery of novel treatment strategies for patients at risk with coding GUCY1A3 variants.

Impact of immature platelets on platelet response to ticagrelor and prasugrel in patients with acute coronary syndrome.

AIMS: The influence of reticulated platelets (RPs) on platelet inhibition by ticagrelor when compared with prasugrel is unknown. We aimed to determine the influence of RPs on adenosine diphosphate- (ADP-) induced platelet aggregation in patients with acute coronary syndrome who were randomly assigned to receive either ticagrelor or prasugrel for P2Y12 receptor inhibition. METHODS AND RESULTS: One hundred and twenty-four patients were prospectively enrolled. The immature platelet fraction (IPF) was measured by an automated haematoanalyzer and platelet aggregation was assessed by multiple electrode aggregometry. In a subgroup of patients (n = 28) ADP-induced P-selectin expression was measured in dependence of the time point of study drug intake in RPs that were discriminated from mature platelets by thiazole-orange (TO) staining. The primary endpoint was the correlation of platelet aggregation and IPF in ticagrelor- vs. prasugrel-treated patients. Platelet aggregation significantly correlated with IPF in patients who received prasugrel (r = 0.41, P < 0.001). In contrast, no correlation between IPF and platelet aggregation was observed in ticagrelor-treated patients (r = 0.08, P = 0.51, P for difference of correlation coefficients P = 0.05). Within the TO-positive RP fraction, P-selectin expression was significantly higher in prasugrel when compared with ticagrelor-treated individuals (prasugrel 18.6 ± 16.0% vs. ticagrelor 11.5 ± 6.0%, P = 0.047). A time-dependent P-selectin expression was observed in prasugrel but not in ticagrelor-treated patients (prasugrel early 11.9 ± 9.4% vs. late 26.3 ± 19.0%, P = 0.031, ticagrelor early 9.6 ± 4.9% vs. late 13.5 ± 6.6%, P = 0.127). CONCLUSION: Reticulated platelets show a greater impact on platelet reactivity in response to prasugrel when compared with ticagrelor.

Decreased prevalence of cardiac arrhythmias during and after vigorous and prolonged exercise in healthy male marathon runners.

BACKGROUND: Vigorous exercise such as marathon running results in an increased risk of sudden cardiac death. Malignant arrhythmias seem to be the primary cause. However, continuous electrocardiographic monitoring for detection of arrhythmias during a marathon race has not been performed yet. METHODS: Twenty male marathon runners (age 45 ± 8 years) free of cardiovascular disease underwent 24-hour Holter monitoring 5 weeks before a marathon race (baseline). Subsequently, wireless Holter monitoring started immediately before the race, recorded up to 70 hours postrace. Electrocardiograms were analyzed for the presence of arrhythmias. Additionally, cardiac troponin, interleukin-6 (IL-6), and electrolytes were assessed prerace and postrace. RESULTS: At baseline Holter recordings, runners showed a median of 9 (interquartile range 3-25) atrial premature complexes (APCs) and 4 (2-16) ventricular premature complexes (VPCs) per 100,000 beats. Compared to baseline, the number of APCs decreased significantly during and 1 hour after the marathon race (0 [0-3] and 0 [0-0], all P < .001) as well as the number of VPCs during the race (0 [0-0], P = .008). No malignant arrhythmias occurred. Mean postrace levels for troponin and IL-6 were significantly augmented after the race (prerace to postrace: troponin 4 times, IL-6 17 times, all P < .001); however, no significant influence of these biomarkers or electrolytes on the prevalence of arrhythmias was observed (all P > .05). CONCLUSIONS: In this cohort of male runners free of cardiovascular disease, the prevalence of arrhythmias during and after a marathon race was decreased. Arrhythmogenic risk was independent of changes in biomarkers assessing cardiac injury, inflammation, and changes in electrolytes.

Prognostic Value of Plasma B-Type Natriuretic Peptide in the Long-Term Follow-up of Patients With Transposition of the Great Arteries With Morphologic Right Systemic Ventricle After Atrial Switch Operation.

BACKGROUND: B-type natriuretic peptide (BNP) is an established marker for heart failure assessment, but the prognostic quality of BNP after atrial switch operation (ASO) has not yet been elucidated. METHODS AND RESULTS: In 89 patients (median age, 24 years; range, 15-35 years) after ASO, BNP was measured. During a 48-months follow-up we focused on critical cardiac events, defined as decompensation, sudden cardiac death or need for heart transplantation. BNP was considerably lower in 81 patients in functional class (FC) I/II (median, 35 pg/ml; range, 3-586 pg/ml) than in 6 patients in FC III/IV (median, 246 pg/ml; range, 14-1,150 pg/ml, P≤0.073). BNP was significantly higher after Mustard than after Senning procedure (P≤0.030). There was no significant difference in BNP between simple or complex transposition of the great arteries (TGA) (P≤0.44). Eleven subjects (13%, 95% CI: 7-22%) had a critical cardiac event within 48 months. On ROC analysis BNP had a high predictive value regarding discrimination of patients with and without critical events (area under the ROC curve, 0.90; 95% CI: 0.76 to >0.99, P<0.001). The cut-off was 85 pg/ml (sensitivity, 88%; specificity, 85%). Additionally, estimated event-free-survival was longer after Senning than after Mustard procedure (P≤0.017). There was no significant difference in outcome between patients with simple or complex TGA with regard to occurrence of critical events. CONCLUSIONS: BNP is a sensitive and specific prognostic marker for critical cardiac events after ASO.

Intraoperative renal near-infrared spectroscopy indicates developing acute kidney injury in infants undergoing cardiac surgery with cardiopulmonary bypass: a case-control study.

INTRODUCTION: Acute kidney injury (AKI) is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Renal near-infrared spectroscopy (NIRS) is used to evaluate regional oximetry in a non-invasive continuous real-time fashion, and reflects tissue perfusion. The aim of this study was to evaluate the relationship between renal oximetry and development of AKI in the operative and post-operative setting in infants undergoing cardiopulmonary bypass surgery. METHODS: In this prospective study, we enrolled 59 infants undergoing cardiopulmonary bypass surgery for congenital heart disease for univentricular (n = 26) or biventricular (n = 33) repair. Renal NIRS was continuously measured intraoperatively and for at least 24 hours postoperatively and analysed for the intraoperative and first 12 hours, first 24 hours and first 48 hours postoperatively. The renal oximetry values were correlated with the paediatric risk, injury, failure, loss, end (pRIFLE) classification for AKI, renal biomarkers and the postoperative course. RESULTS: Twenty-eight (48%) infants developed AKI based on pRIFLE classification. Already during intraoperative renal oximetry and further in the first 12 hours, 24 hours and 48 hours postoperatively, significantly lower renal oximetry values in AKI patients compared with patients with normal renal function were recorded (P < 0.05). Of the 28 patients who developed AKI, 3 (11%) needed renal replacement therapy and 2 (7%) died. In the non-AKI group, no deaths occurred. Infants with decreased renal oximetry values developed significantly higher lactate levels 24 hours after surgery. Cystatin C was a late parameter of AKI, and neutrophil gelatinase-associated lipocalin values were not correlated with AKI occurrence. CONCLUSION: Our results suggest that prolonged low renal oximetry values during cardiac surgery correlate with the development of AKI and may be superior to conventional biochemical markers. Renal NIRS might be a promising non-invasive tool of multimodal monitoring of kidney function and developing AKI in infants undergoing cardiac surgery with cardiopulmonary bypass.

Predictors of antiplatelet response to prasugrel during maintenance treatment.

Insufficient P2Y12 receptor inhibition is associated with a higher risk of thrombotic events after percutaneous coronary intervention (PCI). The third generation thienopyridine prasugrel achieves stronger platelet inhibition as compared to its predecessor clopidogrel. Little is known about predictors of prasugrel drug responsiveness. The aim of this study was to explore predictors of prasugrel responsiveness in patients with a recent PCI on prasugrel maintenance dose (MD) treatment. In a registry of PCI-treated patients (n = 163, recruited between August 2009 and March 2012) on prasugrel MD treatment, the ADP-induced platelet aggregation (PA) was assessed on a Multiplate analyzer. The mean (interquartile range (IQR)) ADP-induced PA on prasugrel MD treatment was 206 (138-331) AU × min. Obese (defined by a body mass index (BMI) ≥ 30) patients (n = 42) (303 [192-467] vs. 187 [117-305] AU × min, p = 0.0001), patients (n = 70) with a history of clopidogrel low responsiveness (278 [161-409] vs. 192 [126-282] AU × min, p = 0.002) and patients (n = 18) on a low (5 mg) prasugrel MD (483 [252-798] vs. 198 [133-313] AU × min; p = 0.0001) showed higher PA values on prasugrel MD as compared to the remaining patients. In a multivariable linear regression model, the latter three variables were independently associated with higher PA values on prasugrel MD treatment. In summary response variability is observed in patients on prasugrel MD treatment. Obesity, a history of clopidogrel low responsiveness and a reduced prasugrel MD of 5 mg are independent predictors of an attenuated response to prasugrel treatment. Further studies are needed to explore clinical implications of this observation.

Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners.

We determined the prognostic value of transient increases in high-sensitive serum troponin I (hsTnI) during a marathon and its association with traditional cardiovascular risk factors and imaging-based risk markers for incident coronary events and all-cause mortality in recreational marathon runners. Baseline data of 108 marathon runners, 864 age-matched controls and 216 age- and risk factor-matched controls from the general population were recorded and their coronary event rates and all-cause mortality after 6 ± 1 years determined. hsTnI was measured in 74 marathon finishers before and after the race. Other potential predictors for coronary events, i.e., Framingham Risk Score (FRS), coronary artery calcium (CAC) and presence of myocardial fibrosis as measured by magnetic resonance imaging-based late gadolinium enhancement (LGE), were also assessed. An increase beyond the 99 % hsTnI-threshold, i.e., 0.04 µg/L, was observed in 36.5 % of runners. FRS, CAC, or prevalent LGE did not predict hsTnI values above or increases in hsTnI beyond the median after the race, nor did they predict future events. However, runners with versus without LGE had higher hsTnI values after the race (median (Q1/Q3), 0.08 µg/L (0.04/0.09) versus 0.03 µg/L (0.02/0.06), p = 0.039), and higher increases in hsTnI values during the race (median (Q1/Q3), 0.05 µg/L (0.03/0.08) versus 0.02 µg/L (0.01/0.05), p = 0.0496). Runners had a similar cumulative event rate as age-matched or age- and risk factor-matched controls, i.e., 6.5 versus 5.0 % or 4.6 %, respectively. Event rates in runners with CAC scores <100, 100-399, and ≥400 were 1.5, 12.0, and 21.4 % (p = 0.002 for trend) and not different from either control group. Runners with coronary events had a higher prevalence of LGE than runners without events (57 versus 8 %, p = 0.003). All-cause mortality was similar in marathon runners (3/108, 2.8 %) and controls (26/864, 3.0 % or 5/216, 2.4 %, respectively). Recreational marathon runners with prevalent myocardial fibrosis develop higher hsTnI values during the race than those without. Increasing coronary artery calcium scores and prevalent myocardial fibrosis, but not increases in hsTnI are associated with higher coronary event rates. All-cause mortality in marathon runners is similar to that in risk factor-matched controls.

Prediction of contrast-induced nephropathy in patients with serum creatinine levels in the upper normal range by cystatin C: a prospective study in 374 patients.

OBJECTIVE: Preexisting renal impairment is a risk factor for contrast-induced nephropathy (CIN). In patients with creatinine in the upper normal level, cystatin C might be a more sensitive predictor of CIN than creatinine. Therefore, in this study, we investigated the usefulness of cystatin C to predict CIN. SUBJECTS AND METHODS: In 400 consecutive patients with creatinine baseline levels between 0.8 and 1.3 mg/dL undergoing coronary angiography (n = 200) or CT (n = 200), baseline values of cystatin C, creatinine, blood urea nitrogen (BUN) and risk factors of CIN were determined. Creatinine was also assessed 24 and 48 hours after contrast administration. RESULTS: Creatinine significantly (p < 0.001) increased after 24 hours and 48 hours compared with baseline (1.06 ± 0.28 and 1.07 ± 0.28 vs 0.99 ± 0.18 mg/dL). Fifty-three of 373 evaluable patients (14.2%) had an increase in creatinine of ≥ 25% or ≥ 0.5 mg/dL within 48 hours. CIN according to this definition was significantly more frequent after intraarterial contrast administration (38/190, 20%) compared with IV contrast administration (15/183, 8.2%; p = 0.001). CIN was predicted by baseline cystatin C (area under the receiver operating characteristic [ROC] curve [AUC], 0.715; p < 0.001), whereas creatinine, creatinine clearance, and BUN were not predictive. The best predictive capabilities were provided by cystatin C/creatinine-ratio (AUC, 0.826; p < 0.001). Multivariate regression analysis showed that intraarterial contrast administration (p = 0.002) and higher baseline cystatin C (p < 0.001) combined with low creatinine (p = 0.044) were independently associated with higher increases in creatinine within 48 hours after contrast administration. CONCLUSION: CIN in patients with creatinine within the upper normal range is significantly more frequent after intraarterial than after IV contrast administration. In these patients, renal impairment after contrast administration is independently predicted by cystatin C and cystatin C/creatinine-ratio, whereas BUN and creatinine were not predictive.

Comparative prognostic value of C-reactive protein & fibrinogen in patients with coronary artery disease.

BACKGROUND & OBJECTIVES: The comparative prognostic value of C-reactive protein (CRP) and fibrinogen for cardiovascular events has been inconclusively investigated. t0 his study was carried out to compare the prognostic value of CRP versus fibrinogen in patients with coronary artery disease (CAD). METHODS: The study included 13,100 patients with coronary angiography-confirmed CAD. Plasma CRP and fibrinogen levels were measured before angiography in all patients. The levels of CRP>3 mg/l and fibrinogen>350 mg/dl were considered as elevated. The primary outcome was 1-year all-cause mortality. RESULTS: Patients were divided into four groups: patients with CRP≤3 mg/l and fibrinogen ≤350 mg/dl (n=4206); patients with CRP≤3 mg/l and fibrinogen >350 mg/dl (n=3132); patients with CRP>3 mg/l and fibrinogen ≤ 350 mg/dl (n=1273) and CRP >3 mg/l and patients with fibrinogen >350 mg/dl (n=4489). There were 634 deaths: 75 deaths in patients with CRP ≤3 mg/l and fibrinogen ≤350 mg/dl, 91 deaths in patients with CRP ≤3 mg/l and fibrinogen >350 mg/dl, 87 deaths in patients with CRP >3 mg/l and fibrinogen ≤350 mg/dl and 381 deaths in patients with CRP >3 mg/l and fibrinogen >350 mg/dl (Kaplan-Meier estimates of all-cause mortality, 1.8, 3.0, 7.0 and 8.7 %, log-rank test P<0.001). The multivariate analysis showed that CRP [adjusted hazard ratio (HR)=1.31, 95% confidence interval (CI) 1.18-1.45, for each standard deviation increase in the logarithmic scale] but not fibrinogen [adjusted HR=0.99 (0.90-1.09), for each standard deviation increase in the logarithmic scale] was an independent correlate of mortality. INTERPRETATION & CONCLUSIONS: The findings indicated that in patients with CAD, CRP was a better predictor of mortality than fibrinogen and offered prognostic information beyond that provided by the conventional cardiovascular risk factors.

Uric acid and prognosis in angiography-proven coronary artery disease.

BACKGROUND: The optimal uric acid (UA) level associated with the lowest mortality and the strength of association between UA and mortality in various subgroups of patients with coronary artery disease (CAD) are unknown. MATERIALS AND METHODS: This study included 13 273 patients with angiographic confirmation of CAD and UA measurements available. The primary outcome analysis was 1-year mortality. RESULTS: Based on the receiver operating characteristic curve analysis, the best cut-off of UA for mortality prediction was 7·11 mg/dL. Using this cut-off, patients were divided into two groups: the group with UA ≤ 7·11 mg/dL (n = 9075) and the group with UA > 7·11 mg/dL (n = 4198). Cardiac mortality was 6·3% (256 deaths) in patients with UA > 7·11 mg/dL and 2·3% (201 deaths) in patients with UA ≤ 7·11 mg/dL [hazard ratio (HR) = 2·82, 95% confidence interval (CI) 2·36-3·36; P < 0·001]. After adjustment for cardiovascular risk factors, UA remained an independent correlate of cardiac mortality (HR = 1·20, 95% CI 1·08-1·34; P = 0·001, for each standard deviation increase in the logarithmic scale of UA). The relationship between cardiac or all-cause mortality and UA showed a J-shaped pattern with lowest mortality in patients with UA between 5·17 and 6·76 mg/dL. UA predicted mortality across all subgroups of patients, with strongest association in women and patients without arterial hypertension. CONCLUSIONS: UA predicted an increased risk of cardiac mortality across all subgroups of patients with CAD. The association between UA and cardiac or all-cause mortality had a 'J-shaped' pattern with lowest risk of death in patients with UA levels between 5·17 and < 6·76 mg/dL.

Prognostic value of uric acid in patients with Type 2 diabetes mellitus and coronary artery disease.

Studies investigating the prognostic role of UA (uric acid) in patients with Type 2 diabetes mellitus have given conflicting findings. We undertook the present study to assess the association between UA and outcome in patients with Type 2 diabetes mellitus and CAD (coronary artery disease). The study included 3705 patients with diabetes mellitus and angiography-proven CAD. UA was measured before coronary angiography. The primary outcome was 1-year all-cause mortality. The UA concentration [median (25th-75th quartiles)] was 6.44 mg/dl (5.40-7.70 mg/dl). There were 264 deaths (7.1%) during follow-up: 45 deaths in patients of the first UA quartile, 43 deaths in patients of the second UA quartile, 51 deaths in patients of the third UA quartile and 125 deaths in patients of the fourth UA quartile {Kaplan-Meier estimates of mortality, 5.1, 4.8, 5.6 and 14.0% respectively; unadjusted HR (hazard ratio), 2.81 [95% CI (confidence interval), 2.21-3.58]; P<0.001 for fourth quartile compared with first-third quartiles combined}. In the multivariable analysis, UA predicted all-cause mortality with an adjusted HR of 1.29 (95% CI, 1.12-1.48; P<0.001), for each S.D. increase in the logarithmic scale of UA level. The inclusion of UA in the multivariable model alongside known cardiovascular risk factors and other relevant variables increased the discriminatory power of the model regarding prediction of all-cause mortality [absolute and relative IDI (integrated discrimination improvement) 0.034 and 20.5% respectively; P<0.001]. In conclusion, in patients with Type 2 diabetes mellitus and confirmed CAD, elevated levels of UA predict mortality independently of known cardiovascular risk factors.

The influence of antithrombin substitution on heparin sensitivity and activation of hemostasis during coronary artery bypass graft surgery: a dose-finding study.

BACKGROUND: Cardiopulmonary bypass is associated with a high degree of hemostatic system activation. Supplementation of antithrombin (AT) may attenuate this activation and increase a patient's susceptibility to heparin. However, the appropriate dosage of AT has not been defined. We sought to determine the dosage of AT concentrate necessary to achieve >100% AT activity at the end of cardiac surgery and the influence of AT on heparin sensitivity. METHODS: Forty-one patients were included. Thirty consecutive patients undergoing primary coronary artery bypass graft surgery with cardiopulmonary bypass were assigned to 3 groups of increasing dosages of AT concentrate. Eleven additional patients served as controls. AT activity and molecular markers of thrombin generation were determined, and heparin sensitivity was calculated. RESULTS: A median amount of 36.5 U (19.0; 42.8), 47.0 U (41.3; 61.6), and 50.0 U (47.4; 66.6) AT concentrate/kilogram body weight in the low, medium, and high AT group, respectively, was administered. At the end of surgery, AT activity with substitution was 84% (77; 111), 110% (92; 120), and 104% (97; 120) (median [25th; 75th percentile]), respectively, compared with 63% (49; 79) in controls (P < 0.05 all substitution groups versus control). Heparin sensitivity increased from 1.29 (1.17; 1.66) s/U heparin/kg in the control group to 2.02 (1.43; 3.65), 2.56 (1.52; 3.64), 1.72 (1.24; 2.66) s/U heparin/kg in the groups with substitution (P < 0.05 all substitution groups versus control). Compared with preoperative values, AT activity decreased during the postoperative period in all patients with a nadir on postoperative day 3 (P < 0.05 compared with baseline except for the medium AT group). Corresponding to this decrease, an increase in prothrombin fragment 1+2 and d-dimer could be observed postoperatively. DISCUSSION: High dosages of AT were required to preserve physiologic AT activity during coronary artery bypass graft surgery and to significantly enhance heparin sensitivity, respectively. However, a significant decrease in AT activity, accompanied by high levels of thrombin generation, was encountered up to 5 days postoperatively.

The perioperative course of factor XIII and associated chest tube drainage in newborn and infants undergoing cardiac surgery.

BACKGROUND: Perioperative acquired factor XIII deficiency has been looked upon as a potential cause of postoperative bleeding in adult cardiac surgery. METHODS: Forty-four infants were prospectively studied for the time course of factor XIII in plasma and the effect on chest tube drainage (CTD) and transfusion requirements in the first 24 h after surgery. A reconstituted blood prime (RBP) with fresh-frozen plasma (FFP) and packed red blood cells (PRBC) was used. Samples were taken at baseline, after cardiopulmonary bypass and upon arrival in the ICU. Differences in blood loss and transfusion requirements based on a cutoff value of 70% factor XIII activity at the time of ICU admission were also calculated. RESULTS: Baseline factor XIII activity was 79%, decreased to 71% after CPB (P = 0.102) and increased back up to 77% at ICU arrival (P = 0.708). There was no significant correlation between factor XIII, CTD, age, cyanosis, platelet count, and transfusion requirements at any time point. Only preoperative fibrinogen levels correlated significantly with factor XIII activity. Perioperative blood transfusions (PRBC P = 0.712, FFP P = 0.909, platelets P = 0.807) and chest tube losses (P = 0.424 at 6 h and P = 0.215 at 24 h) were not significantly different above or below a 70% factor XIII activity at ICU arrival. CONCLUSION: Factor XIII activity in infants with congenital heart defects is within the lower range of normal adults, independent of patient's age and the presence of cyanosis. Reconstituted blood prime maintains factor XIII activity at sufficient levels during pediatric cardiac surgery. We could not detect a correlation between FXIII and CTD.

Neither moxifloxacin nor cefuroxime produces significant attenuation of inflammatory mediator release in patients exposed to cardiopulmonary bypass: a randomized controlled trial.

OBJECTIVES: In vitro and experimental studies in animals have established the anti-inflammatory effects of moxifloxacin. Cardiopulmonary bypass (CPB) leads to an inflammatory response. The aim of this study was to assess whether the inflammatory cytokine response to CPB is reduced with a perioperative antibiotic prophylaxis, either moxifloxacin or cefuroxime (the standard prophylaxis). PATIENTS AND METHODS: Twenty-eight patients scheduled for elective coronary artery bypass grafting with CPB were randomly assigned to receive either moxifloxacin or cefuroxime as the perioperative antibiotic prophylaxis. Interleukin (IL)-6, -8, -10 and tumour necrosis factor-α (TNF-α) serum concentrations were determined at eight time points before and after CPB. RESULTS: In both groups, all cytokine concentrations significantly increased after the start of CPB. There were no statistically significant differences between the moxifloxacin and cefuroxime groups at any point; IL-6 concentrations [median (interquartile range)] 240 min after CPB, the primary endpoint, were 364 (192-598) and 465 (325-906) pg/mL (P = 0.323), respectively. CONCLUSIONS: Neither moxifloxacin nor cefuroxime produced significant attenuation of the inflammatory cytokine response to CPB. The reasons why moxifloxacin did not have significant anti-inflammatory effects in this unique clinical situation may be: (i) the inflammatory response to CPB may be different from that of infectious disease states that were used to establish the immunomodulatory effects of moxifloxacin; and (ii) a single intravenous dose, which was used in this investigation, may not lead to high enough plasma and intracellular concentrations.

Association of midregional proadrenomedullin with coronary artery stenoses, soft atherosclerotic plaques and coronary artery calcium.

Midregional proadrenomedullin (MR-proADM) is elevated in patients with heart failure and myocardial infarction. The aim of this study was to evaluate the association of MR-proADM with the grade of coronary artery stenosis, presence of coronary artery soft plaques and coronary artery calcification score (CACS), determined by 64-multislice computed tomography (MSCT) in patients without known prior cardiovascular disease. This retrospective study included 107 patients undergoing MSCT for confirmation (or exclusion) of coronary artery disease. MR-proADM levels were measured in all patients. The assessment of coronary artery stenoses, CACS and soft coronary plaques was made by MSCT using known criteria. The MR-proADM [median (25th-75th percentiles)] level was 0.33 (0.21-0.43) nmol/l. The MR-proADM level was 0.28 (0.22-0.40) nmol/l in patients with coronary stenoses ≥50% (n = 23) versus 0.33 (0.27-0.40) nmol/l in patients with coronary stenoses <50% (n = 83, P = 0.59), 0.33 (0.26-0.40) nmol/l in patients with soft plaques (n = 56) versus 0.33 (0.25-0.41) nmol/l in patients without soft plaques (n = 50, P = 0.73) and 0.33 (0.25-0.39) nmol/l in patients with CACS <200 (n = 81) versus 0.32 (0.26-0.44) nmol/l in patients with CACS ≥200 (n = 26, P = 0.77). In multivariate analysis, the MR-proADM level was a significant correlate of coronary artery stenoses [odds ratio (OR) = 0.93; 95% confidence interval (CI) 0.86-0.99; P = 0.026] and soft plaques (OR = 0.94; 95% CI 0.90-0.99; P = 0.015) but not of CACS (OR = 0.98; 95% CI 0.93-1.03; P = 0.36). A decreased MR-proADM level is an independent correlate of the presence of coronary artery disease and of soft atherosclerotic plaques. Patients with decreased MR-proADM levels may need invasive examinations to diagnose more severe forms of coronary artery disease.