Minimised closed circuit coronary artery bypass grafting in the elderly is associated with lower levels of organ-specific biomarkers: a prospective randomised study.

BACKGROUND: Restrictive fluid management may protect organ function and improve postoperative outcome in elderly coronary artery bypass grafting (CABG) patients. OBJECTIVE: We assessed organ-specific biomarker release to study the contribution of a fluid restrictive closed circuit concept to organ protection in elderly CABG patients. Cardiac, respiratory and abdominal organ injury was measured during and following minimal fluid coronary artery bypass grafting (mCABG), off-pump coronary artery bypass (opCAB) surgery and conventional CABG with high volume prime and cold crystalloid cardioplegia (cCABG). The results were related to differences in clinical outcome. DESIGN: Prospective randomised trial. SETTING: Dutch tertiary single centre study. PATIENTS: Sixty patients over 70 years of age (38 men and 22 women) were randomised to one of the three different techniques. Inclusion criteria were as follows: first time CABG, elective surgery, ejection fraction more than 30% and multivessel disease. Acetylsalicylic acid and clopidogrel administration or requiring less than three distal anastomoses were an exclusion. MAIN OUTCOME MEASURES: Organ-specific markers of the heart--heart fatty acid binding protein (HFABP), troponin T, pro-brain natriuretic peptide (pro-BNP) and creatinine phosphokinase (CPK), lung clara cell 16 protein, pneumoprotein (CC16), intestinal fatty acid binding protein (IFABP) and liver glutathione S-transferase (α-GST)--were measured perioperatively. Postoperative PaO2 levels, ventilation time, blood product consumption and adverse events were noted. RESULTS: Myocardial organ-specific biomarker troponin T showed significantly lower median levels during mCABG compared with the cCABG and opCAB groups [troponin 0.25 mg l(-1) (interquartile range, IQR 0.18 to 0.40), 0.39 mg l(-1) (IQR 0.23 to 0.49) and 0.36 mg l(-1) (IQR 0.23 to 0.50), respectively (P<0.003)]. HFABP, IFABP and α-GST levels were significantly higher during cCABG compared with opCAB and mCABG [HFABP 38.6 mg l(-1) (IQR 29.6 to 47.1), 23.3 mg l(-1) (IQR 16.5 to 31.0) and 21.1 mg l(-1) (IQR 15.7 to 28.8; P<0.001), IFABP 0.57 mg l(-1) (IQR 0.37 to 1.11), 0.44 mg l(-1) (IQR 0.16 to 0.74) and 0.37 mg l(-1) (IQR 0.13 to 1.05; P<0.02) and α-GST 11.5 mg l(-1) (IQR 7.7 to 15.7), 7.0 mg l(-1) (IQR 4.5 to 13.8) and 7.3 mg l(-1) (IQR 6.2 to 11.2), respectively (P<0.009)]. There was a trend towards higher median CC16 levels in the cCABG group (P<0.07). CPK and pro-BNP were not significantly different. On the first postoperative day, PaO2 levels and duration of mechanical ventilation were significantly improved, and there was lower use of blood products in the mCABG group than in the cCABG and opCAB groups (P<0.05). CONCLUSION: Following mCABG with low volume myocardial preservation and restrictive fluid management, early respiratory performance was improved and consumption of blood products reduced compared with opCAB and cCABG.

Impact of different surgical strategies on perioperative protein S100ß release in elderly patients undergoing coronary artery bypass grafting.

OBJECTIVE: This study was designed to compare neurological injury-associated protein S100ß release during three different treatment modalities, minimized closed circuit coronary artery bypass grafting (CABG) (MCABG), off-pump CABG (OPCAB), and conventional CABG (CCABG), comprising high-volume prime and cold crystalloid cardioplegia. Our working hypothesis was that fluid restriction as provided by MCABG may decrease neurological injury-associated protein S100ß release. METHODS: In this prospective trial, in a tertiary center, 30 surgical patients (aged >70 years, 25 men and 5 women) undergoing first-time elective CABG were enrolled. The inclusion criteria were three-vessel disease and elective surgery. The exclusion criteria were left ventricular ejection fraction of less than 30%, use of clopidogrel, carotid disease, or needing fewer than three distal anastomoses. Protein S100ß concentrations, hematocrit (Ht) levels, and PO2 levels were measured after induction of anesthesia, 10 minutes after reperfusion, upon arrival at the intensive care unit, 3 hours postoperatively at the intensive care unit, and the next morning. Statistics consisted of areas under the curve, peak levels, and correlation and variance tests. RESULTS: A significant negative correlation was found indicating higher S100ß release at lower Ht levels and at lower PO2 levels in all study groups. The lowest S100ß variance was measured during MCABG (Wilks Λ P = 0.052). The perioperative Ht was significantly higher in the MCABG group and in the OPCAB group compared with the CCABG group (P = 0.04 vs P < 0.01). At all time points, the S100ß protein concentration showed no significant differences between the different surgical techniques. The mean (95% confidence interval) values of S100 area under the curve were the following: CCABG, 2.3 (1.06-3.5); MCABG, 1.44 (0.6-2.21); and OPCAB, 1.87 (1.5-2.19) [independent nonparametric Kruskal-Wallis test (P = 0.13)]. The mean (95% confidence interval) peak S100 values (calculated as the maximum value seen in a patient during the research period) were the following: CCABG, 1.07 (0.4-1.68); MCABG, 0.59 (0.28-0.90); and OPCAB, 0.83 (0.59-1.06) [independent nonparametric Kruskal-Wallis test (P = 0.22)]. CONCLUSIONS: Despite similar perioperative S100ß protein release for all techniques studied, higher Ht and PO2 levels correlated with lower S100ß release within all study groups. The low S100ß variance during the fluid restrictive MCABG technique may be due to more efficient oxygen transport to the brain provided by significantly higher perioperative Ht levels. Further prospective data are required to better understand this complex issue.

Myocardial oxidative stress, and cell injury comparing three different techniques for coronary artery bypass grafting.

OBJECTIVE: Oxidative stress as a result of reperfusion injury is a known causative factor of cardiac muscle injury. In the peripheral blood as well in the coronary sinus, oxidative stress parameters and cardiac biomarkers were measured to investigate the different levels of oxidative stress during three different CABG techniques; MCABG (with minimal prime volume and warm blood cardioplegia) that was newly introduced in our hospital, versus OPCAB, versus our current standard, conventional CABG (CCABG, consisting of high volume prime and cold crystalloid cardioplegia). Concomitantly, cardiac biomarkers were measured to detect myocardial cell injury. METHODS: Thirty patients scheduled for CABG with the intention to treat three-vessel disease were randomly assigned for CCABG, MCABG or OPCAB. Perioperatively, plasma levels of malondialdehyde (MDA) as a marker of oxidative stress, and the allantoin/uric acid ratio (A/U ratio) as a marker of antioxidant activity were measured in the ascending aorta (Aa), and in the coronary sinus (Cs), simultaneously. Additionally peripheral (Aa) blood levels of heart fatty acid binding protein (HFABP), troponin T, CPK and CKMB as markers of myocardial injury were obtained. RESULTS: The MCABG group had significantly lower MDA levels in the Cs compared to the CCABG group, respectively, to the OPCAB group (p=0.04 and p=0.03). At all time points the A/U ratio in the CCABG group remained significantly higher in the Cs as well in the Aa samples compared to the MCABG and the OPCAB group (p<0.001, respectively, p<0.001, for both groups). HFABP and troponin T showed consistent curves compared to the CPK figure over time in all groups. CONCLUSION: In this study coronary sinus blood levels of oxidative stress parameters were consistently higher compared to peripheral blood levels. The levels were lowest in the MCABG study group. In this group also the lowest levels cardiac biomarkers of myocardial injury were found.

Perioperative microemboli and platelet aggregation in patients undergoing carotid endarterectomy.

In carotid endarterectomy (CEA) patients, platelet aggregation is increased despite heparinization. We investigated whether this phenomenon correlates with the occurrence of perioperative microemboli. Of 27 CEA patients, 18 (67%) used aspirin and 9 also used clopidogrel. Blood was collected at multiple time points before, during, and after CEA. Platelet aggregation and P-selectin expression were determined. Transcranial Doppler monitoring was used to measure microemboli. Platelet aggregation showed a significant increase 5 minutes postheparinization compared with preheparinization (19.7 +/- 2.8% vs 8.9 +/- 0.9% in the aspirin group and 22.5 +/- 4.4% vs 8.7 +/- 1.2% in the clopidogrel group; p < .01 and p < .05, respectively). P-selectin expression showed a tendency to increase postheparinization in both groups (p = .07 and p = .09, respectively). The number of microemboli ranged from 0 to 50. Clopidogrel patients displayed fewer microemboli than aspirin patients (4.1 +/- 2.3 vs 17.6 +/- 18.2; p < .01). Patients with a high number of microemboli displayed had a tendency toward higher baseline platelet aggregation than patients with a low number of microemboli (p = .08). In conclusion, platelet aggregation is transiently increased during CEA despite the administration of antiplatelet agents. Clopidogrel is associated with a decreased number of perioperative microemboli. The exact relationships between these findings, postoperative microemboli formation, and the risk for thromboembolic complications after CEA remain to be determined.

ACE I/D-corrected Z-scores to identify normal and elevated ACE activity in sarcoidosis.

BACKGROUND: The value of elevated serum angiotensin-converting enzyme (ACE) activity in the diagnosis and follow-up in sarcoidosis is a matter of ongoing debate. This may be at least related to the insertion (I)/deletion (D) polymorphism in the ACE gene (ACE I/D). ACE activity is influenced by the ACE I/D polymorphism. As a consequence, the use of one reference interval instead of three genotype-specific reference intervals for ACE activity may lead to a less precise interpretation of ACE activity. METHODS: In order to assess whether determination of ACE activity indeed requires the ACE I/D genotype to be taken into account, we established ACE I/D-corrected reference intervals in healthy, Caucasian volunteers (n=200). In addition, ACE activities in ACE I/D genotyped patients suspected of or having sarcoidosis (n=129) were expressed as the Z-score related to ACE I/D-corrected reference intervals. RESULTS: Comparison of the Z-score with ACE activity in which ACE I/D is ignored rendered 8.5% misclassification of 'elevated' versus 'normal' ACE or vice versa. CONCLUSIONS: Our data demonstrate a convenient way to circumvent the use of three reference intervals by introducing a Z-score for ACE activity. It also illustrates the need to re-investigating the possible clinical value of serum ACE activity in sarcoidosis by considering ACE I/D.

Plasma matrix metalloproteinase-9 and ACE-inhibitor-induced improvement of urinary albumin excretion in non-diabetic, microalbuminuric subjects.

INTRODUCTION: Elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been suggested to precede the development of microalbuminuria. As angiotensin-converting enzyme (ACE) inhibitors effectively reduce urinary albumin excretion (UAE), in the present study we have investigated the potential association of plasma MMP-9 levels with UAE and treatment effects of ACE-inhibition. MATERIAL AND METHODS: In a placebo-controlled randomised trial we determined plasma MMP-9 levels at baseline and after three months of randomisation to either placebo (n=202) or fosinopril (20 mg/day, n=204) treatment. RESULTS: Baseline plasma MMP-9 levels were not related to baseline UAE (r=-0.008, p=0.871). Three months of fosinopril treatment effectively reduced UAE compared to placebo treatment (-10.4+/-2.4 vs. 1.8+/-1.3 mg/24 hours, p<0.001, respectively). However, fosinopril treatment failed to significantly change plasma MMP-9 levels compared to placebo (-0.47+/-7.68 vs. 0.06+/-9.20, p=0.646, respectively). In addition, the change in UAE was not related with change in MMP-9 levels. CONCLUSION: The effective reduction of UAE with fosinopril was not related to plasma MMP-9 levels.

Expression of priming-associated cellular markers on neutrophils during an exacerbation of COPD.

Chronic inflammation of the airways is a hallmark of chronic obstructive pulmonary disease (COPD). We investigated the kinetics of priming of inflammatory cells in peripheral blood during exacerbations of COPD and during the resolution phase. Modulation of the leukocyte compartment as a consequence of systemic activation by cytokines/chemokines was determined by measuring the expression of priming-associated epitopes by novel antibodies designated A17 and A27. Furthermore, H2O2 was determined in breath condensate as a read out for local inflammation. Leukocytes were obtained from COPD patients (GOLD II-IV) during and after an exacerbation of their disease. During an exacerbation the expression of priming epitopes on leukocytes was increased. This priming phenotype disappeared upon treatment with intravenous corticosteroids. Similarly, H2O2 levels in breath condensate were also increased during an exacerbation and decreased upon treatment. We conclude that the activation status of neutrophils in the systemic compartment can be used as a read-out for systemic innate immune signals involved in the pathogenesis of COPD. The correlation between H2O2 in exhaled air with A27 priming on neutrophils showed that local inflammation has systemic effects on cells of the innate immune system.

The mucin-1 568 adenosine to guanine polymorphism influences serum Krebs von den Lungen-6 levels.

Krebs von den Lungen (KL)-6 offers a new perspective as a disease marker in pulmonary diseases. The aim of this study was to analyze whether serum KL-6 levels are dependent on the functional adenosine to guanine mucin-1 (MUC1) gene polymorphism at nucleotide position 568 in a well-characterized white population. Polymorphisms were determined in 327 healthy, white individuals and 74 patients with sarcoidosis, using a PCR-sequence-specific primer assay. The serum KL-6 levels were measured by ELISA. Significant differences between serum KL-6 levels of healthy subjects who were grouped according to MUC1 568 genotype were observed (P<0.0001) (mean+/-SEM): AA (195.2+/-9.9 U/ml; 95% confidence interval [CI], 175.7-214.8), AG (246.0+/-8.6 U/ml; 95% CI, 229.0-263.1), and GG (302.6+/-11.8 U/ml; 95%CI, 279.3-326.0). In the patients with sarcoidosis, the results were (mean+/-SD): AA (550.1+/-411.7; 95% CI, 380.2-720.1), AG (716.3+/-452.4; 95% CI, 547.4-885.2), GG (1,151.0+/-1122; 95% CI, 610.1-1692.0); P=0.02. Comparison of the KL-6 levels in which the 568 genotype was ignored rendered 6 out of 74 (7.5%) misclassifications of "elevated" versus "normal" KL-6 levels or vice versa. In conclusion, the MUC1 568 A to G polymorphism may be of interest for diagnostic purposes because our study delivered in vivo evidence that it contributes to interindividual variations in KL-6 levels.

Malondialdehyde in plasma, a biomarker of global oxidative stress during mini-CABG compared to on- and off-pump CABG surgery: a pilot study.

In contrast to conventional on-pump coronary artery bypass grafting only mild increase of parameters of oxidative stress is reported during and after off-pump coronary artery bypass grafting. In an attempt to reduce the side effects of extra corporeal circulation the mini- extra corporeal circulation concept was introduced. In this study peroperative oxidative stress biomarkers were compared using three different techniques for CABG (conventional, mini and off-pump). It concerns a prospective randomized pilot study of 60 aged patients (70+ years) divided over 3 study groups. During the peroperative time points there was a significant increase in the mean concentration of uric acid for the CCABG group. On arrival at the intensive care unit the mean concentrations decreased significantly. During the per-operative period all groups showed significant increase in the concentration of malondialdehyde, however, this increase was the steepest for the CCABG group. On arrival at the intensive care unit the mean concentration decreased significantly for all groups. We found only mild organ ischemia/reperfusion injury and oxidative stress in the OPCAB group and the MCABG group with respect to the CCABG group.

Validation of a new method to measure hydrogen peroxide in exhaled breath condensate.

Inflammatory processes in the lung can or will elicit oxidative stress. The degree of oxidative stress can be determined by measuring hydrogen peroxide (H(2)O(2)) concentration in exhaled breath condensate (EBC) but the methods to measure H(2)O(2) are all rather time consuming and only reliable and/or accurate in the hand of skilled technicians in a dedicated laboratory. We tested a new commercial device (Ecocheck), developed to offer a less time-consuming method to measure H(2)O(2). We validated this new method according the NCCLS EP10-A2 protocol. The validation shows that the imprecision in the low range is high (28.4%) and declines with higher concentrations of H(2)O(2) (up to 6.6%). The Ecocheck is "an easy to use" measuring device for routine measurements getting quick results without the need for skilled technicians to determine H(2)O(2) concentrations.

Markers of inflammation and oxidative stress in exacerbated chronic obstructive pulmonary disease patients.

COPD is characterised by damage to small airways due to an inflammatory process as well as an imbalance between oxidants and antioxidants. Several cytokines and cell adhesion molecules enhancing a mainly neutrophilic inflammation have been associated with COPD. The aim of the study was to investigate whether inflammation or oxidative markers gave an indication of the course of COPD during an exacerbation. Fourteen patients with moderate to severe COPD admitted to the St. Antonius Hospital because of an exacerbation have been monitored during treatment with prednisolone 50 mg intravenously during 24 h at admission, reduced to 25 mg at day 3 and tapered off with oral prednisolone at day 7. On three separate occasions, day 1, 3 and 7, H2O2 in exhaled air, IL-8 and the soluble cell adhesion molecule sICAM and sE-selectin in serum were measured. We compared the patients at day 1 with healthy controls (in both non-smokers and smokers). Furthermore, we examined the changes from the study group in time during therapy. At admission all the markers were raised in comparison with the control groups. During treatment H2O2 concentrations in breath condensate declined significantly (P<0.001) as well as IL-8 and sICAM in serum (P=0.002, respectively, P<0.001). There was no significant change in sE-selectin (P=0.132). No significant improvement has been found in spirometry. These data suggest that the markers H2O2 in exhaled air, IL-8 and sICAM in serum are suitable markers in monitoring exacerbated COPD.

High-dose aspirin in addition to daily low-dose aspirin decreases platelet activation in patients before and after percutaneous coronary intervention.

BACKGROUND: Activated platelets play a major role in acute vessel closure after coronary angioplasty. Although aspirin is the routine therapy during angioplasty, it only incompletely prevents acute closure. This might be due to suboptimal dosing. OBJECTIVE: First, to study the effect of additional high-dose aspirin on platelet activation during coronary angioplasty. Second, to assess the potential of the new PFA-100 analyzer to evaluate the effect of different doses of aspirin in patients undergoing angioplasty. METHODS: Fifty-one patients on 100 mg aspirin/day for at least 1 month were randomized to continuation of 100 mg aspirin/day only (Group A=24 patients), or to this regime plus a bolus of 1000 mg of aspirin given 1 day before angioplasty (Group B=27 patients). Results were compared with 15 controls. Platelet function was measured before angioplasty by the PFA-100 analyzer; platelet activation was measured by flow cytometry just before and 1 h after angioplasty. RESULTS: At baseline, Group A had significantly more activated platelets than the control group (P<.001). High-dose aspirin in Group B resulted in significantly lower platelet activation as compared with both controls (P<.001) and Group A (P<.001). During angioplasty, the number of activated platelets decreased significantly in Group A (P<.001), while there was no change in Group B (P=.6). The PFA-100 analyzer was unable to detect differences between the two treatment groups. CONCLUSIONS: The addition of high-dose aspirin to daily low-dose aspirin, 1 day before coronary angioplasty, significantly reduced the platelet activation state before and after intervention. The PFA-100 analyzer did not detect differences in the effect of low- versus high-dose aspirin on platelet function.

Pretreatment with oral anticoagulants decreases platelet activation in patients before and after percutaneous coronary intervention.

BACKGROUND: Platelet activation plays a major role in acute vessel closure after coronary angioplasty. In the randomized Balloon Angioplasty and Anticoagulation Study (BAAS), pretreatment with oral anticoagulants in addition to aspirin resulted in a 47% reduction of acute complications as compared with aspirin alone. This result may suggest a direct effect of oral anticoagulants on platelet activation. METHODS AND RESULTS: Patients were randomized to aspirin alone (group A, n = 26) or to aspirin plus oral anticoagulants started one week before angioplasty (group B, n = 26). Platelet response tests were performed 1 hour before (baseline) and 1 hour after intervention and on day 1. Platelet activation was measured by flow cytometry, as the number of antibody-positive platelets per 10,000 counted. Platelet function was evaluated with use of the PFA-100 analyzer. In group B, the median number of P-selectin-positive platelets was lower before (28 vs. 54, P = 0.018) and after (13 vs. 24, P = 0.377) angioplasty than in group A. Also the median decrease in the number of P-selectin-positive platelets during angioplasty was lower in group B (delta = 4) than in group A (delta = 30, P = 0.022). No further significant change was observed in platelet activation on day 1 in the two groups. The ability of platelets to become stimulated as measured with the PFA-100 analyzer was not affected by oral anticoagulants. CONCLUSIONS: Pretreatment with oral anticoagulants resulted in less activated platelets before and after coronary angioplasty, which is in agreement with its clinical effect of reducing procedural complications. Platelet function was not affected by oral anticoagulants.