Blood transfusion and ischaemic outcomes according to anemia and bleeding in patients with non-ST-segment elevation acute coronary syndromes: Insights from the TAO randomized clinical trial.

BACKGROUND: The benefits and risks of blood transfusion in patients with acute myocardial infarction who are anemic or who experience bleeding are debated. We sought to study the association between blood transfusion and ischemic outcomes according to haemoglobin nadir and bleeding status in patients with NST-elevation myocardial infarction (NSTEMI). METHODS: The TAO trial randomized patients with NSTEMI and coronary angiogram scheduled within 72h to heparin plus eptifibatide versus otamixaban. After exclusion of patients who underwent coronary artery bypass surgery, patients were categorized according to transfusion status considering transfusion as a time-varying covariate. The primary ischemic outcome was the composite of all-cause death or MI within 180 days of randomization. Subgroup analyses were performed according to pre-transfusion hemoglobin nadir and bleeding status. RESULTS: 12,547 patients were enrolled. Among these, blood transfusion was used in 489 (3.9%) patients. Patients who received transfusion had a higher rate of death or MI (29.9% vs. 8.1%, p<0.01). This excess risk persisted after adjustment on GRACE score and nadir of hemoglobin (HR 3.36 95%CI 2.63-4.29 p<0.01). Subgroup analyses showed that blood transfusion was associated with a higher risk in patients without overt bleeding (adjusted HR 6.25 vs. 2.85; p-interaction 0.001) as well as in those with hemoglobin nadir > 9.0 g/dl (HR 4.01; p-interaction<0.0001). CONCLUSION: In patients with NSTEMI, blood transfusion was associated with an overall increased risk of ischaemic events. However, this was mainly driven by patients without overt bleeding and those hemoglobin nadir > 9.0g/dl. This suggests possible harm of transfusion in those groups.

Loop diuretics decrease the renal elimination rate and increase the plasma levels of trimethylamine-N-oxide.

AIMS: Trimethylamine-N-oxide (TMAO) is a novel cardiovascular risk marker. We explored the association of commonly used cardiovascular medications with TMAO levels in patients and validated the identified associations in mice. METHODS: Detailed history of drug treatment was recorded in 300 patients with cardiovascular disease without diabetes in an observational, cross-sectional study. Animal study was performed in CD1 mice. RESULTS: Median plasma TMAO (interquartile range) level was 2.144 (1.570-3.104) µmol l-1 . Among nine cardiovascular drug groups, the use of loop diuretics (0.510 ± 0.296 in users vs. 0.336 ± 0.272 in nonusers, P = 0.008) and mineralocorticoid receptor antagonists (0.482 ± 0.293 in users vs. 0.334 ± 0.272 in nonusers, P = 0.007) was associated with increased log-TMAO. Acute concomitant administration of furosemide or torasemide with TMAO in mice significantly influenced TMAO pharmacokinetic profile and almost doubled the plasma TMAO area under the curve. Furosemide decreased the TMAO excretion rate by 1.9-fold during the first 30 min after administration and increased TMAO concentrations in kidney, heart and liver, suggesting the interaction of furosemide and TMAO with efflux transporters. The concentrations of TMAO in blood plasma after the administration of the organic anion transporter inhibitor probenecid were not different from those of the control group, suggesting an effect not mediated by organic anion transporters. CONCLUSIONS: Loop diuretics increased plasma TMAO concentration by decreasing its urinary excretion rate. Loop diuretic use should be considered a potential confounder in TMAO studies.

Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels.

Recent studies have revealed strong associations between systemic trimethylamine N-oxide (TMAO) levels, atherosclerosis and cardiovascular risk. In addition, plasma L-carnitine levels in patients with high TMAO concentrations predicted an increased risk for cardiovascular disease and incident major adverse cardiac events. The aim of the present study was to investigate the relation between TMAO and L-carnitine plasma levels and diabetes. Blood plasma samples were collected from 12 and 20 weeks old db/db mice and patients undergoing percutaneous coronary intervention. Diabetic compared to non-diabetic db/L mice presented 10-fold higher TMAO, but lower L-carnitine plasma concentrations at 12 weeks of age. After 8 weeks of observation, diabetic db/db mice had significantly increased body weight, insulin resistance and TMAO concentration in comparison to non-diabetic control. In 191 patients undergoing percutaneous coronary intervention the median (interquartile range) plasma concentration of TMAO was 1.8 (1.2-2.6) µmol/L. Analysis of the samples showed a bivariate association of TMAO level with age, total cholesterol and L-carnitine. The multivariate linear regression analysis revealed that, in addition to L-carnitine as the strongest predictor of log transformed TMAO (p<0.001), the parameters of age, diabetes status and body mass index (BMI) were independently associated with increased log transformed TMAO levels (p<0.01).Our data provide evidence that age, diabetes and BMI are associated with higher TMAO levels independently of L-carnitine. These data support the hypothesis of TMAO as a cardiovascular risk marker and warrant further investigation of TMAO for diabetes research applications.

Common haplotype of interleukin-6 gene is associated with chronic total occlusions of coronary arteries.

AIM: Genetic polymorphisms in genes coding for cytokines may predispose patients to coronary artery disease and chronic total occlusion (CTO) of coronary arteries. The aim of the study was to evaluate association of common genetic variations of interleukins (IL) with CTOs. METHODS: We reviewed coronary angiograms and evaluated presence of CTOs in 684 consecutive patients with no history of revascularization. The following genetic variations were analyzed: IL-1B +3954 C>T, IL-1B -511 C>T, IL-1RN VNTR and haplotypes of IL-6 encompassing IL-6 -596 G>A, IL-6 -572 G>C, IL-6 -373 AnTn and IL-6 -174 G>C polymorphisms. RESULTS: In 254 patients (37.1%) CTO of at least one artery was found. We observed nine IL-6 haplotypes, of which five were common (>1%) and one (GG9/12G, n=8) was not previously reported in literature. The most prevalent IL-6 haplotype (AG8/12C or Hap*1, 49.5%) correlated with CTOs, that were present in 31.5%, 36.5% and 44.5% of patients with none, one and two Hap*1, respectively (OR [95%CI] 1.252 [0.844-1.856] and 1.746 [1.104-2.762] for heterozygots and homozygots, respectively). In multivariate analysis this association became non-significant (OR [95%CI] 1.202 [0.805-1.796] and 1.529 [0.955-2.450]). In subgroup analysis Hap*1 was, however, associated with CTOs in the left anterior descending artery (p for trend 0.032) and the left circumflex artery (P=0.047), but not in the right coronary artery (p=0.799). In multivariate analysis CTOs of the left coronary arteries were associated only with total cholesterol (OR [95%CI] 1.170 [1.020-1.341]) and Hap*1 (OR [95%CI] 1.469 [0.914-2.361] and 1.970 [1.151-3.372] for heterozyogots and homozygots, respectively). CONCLUSION: Our study suggests that common IL-6 haplotype (AG8/12C or Hap*1) is associated with development of CTOs in left coronary arteries.

Left main coronary artery disease in 2011: CABG or PCI?

Left main coronary artery disease, present in 5-9% of patients with angina pectoris, is associated with high mortality risk when treated medically. For several decades coronary artery bypass grafting (CABG) has been regarded as the treatment choice for unprotected left main coronary artery (ULMCA) disease patients. However, proximal location and large caliber of the left main has set challenge for interventional cardiologists. Recent clinical guidelines have stated that elective percutaneous coronary intervention (PCI) can be considered for patients with ULMCA disease, although suggesting that the aggregated evidence favors CABG. A number of registry reports, as well as a substudy from a large, randomized trial, have indicated that PCI may be an acceptable alternative to CABG in some patients with ULMCA stenosis. PCI already offers tangible short-term advantages over CABG as it is less invasive, reduces hospitalization duration, avoids the disability of surgical recovery, and allows patients to subsequently have CABG if necessary.

[Interventional cardiology in Latvia from 1993 to 2003]. / Invasive Kardiologie in Lettland von 1993 bis 2003.

A nationale programme for combatting cardiovascular diseases is being implemented in Letvia. A milestone was reached in 1993 with the establishment of a Letvian Centre for Cardiology. Within 10 years the only cardiac catheterization unit in the country has developed into a centre of excellence. But to meet the cardiological needs for all of Letvia requires at least three additional units for left heart catheterization and one for paediatric a cardiac catheterization.

Immune activation and degradation of tryptophan in coronary heart disease.

BACKGROUND: Inflammation and immune activation appear to be important in the pathogenesis of coronary heart disease (CHD). Cytokine interferon-gamma, which is released during cell-mediated immune responses, induces indoleamine (2,3)-dioxygenase (IDO), an enzyme degrading tryptophan to kynurenine. Therefore, immune stimulation is commonly associated with an increased kynurenine to tryptophan ratio (kyn trp-1) indicative for activated indoleamine (2,3)-dioxygenase and a measurable decline of tryptophan. METHODS: Blood concentrations of kynurenine and free tryptophan and the kynurenine to tryptophan ratio were examined in 35 patients with coronary heart disease verified by coronary angiography and compared with healthy controls. Patients were observed before percutaneous transluminal coronary angioplasty (21 patients: one with artery disease, nine with 2- or 3-artery disease, and five with restenosis). RESULTS AND CONCLUSIONS: Decreased tryptophan concentrations were found in a significant proportion of coronary heart disease patients and coincided with increased kyn trp-1 and also with increased neopterin concentrations, indicating an activated cellular immune response. We conclude that in coronary heart disease immune activation is associated with an increased rate of tryptophan degradation and thereby lowered tryptophan levels. Results may provide a basis for a better understanding of the pathogenesis of mood disturbances and depression in coronary heart disease patients.

Plasma HDL-cholesterol has an effect on nitric oxide production and arachidonic acid metabolism in the platelet membranes of coronary heart disease patients without LDL-hypercholesterolemia.

AIM: To evaluate nitric oxide (NO) production and [3H]arachidonic acid (AA) incorporation into platelet membranes of coronary artery disease (CAD) patients with/without HDL-hypocholesterolemia. MATERIAL: 16 healthy controls (C), 14 CAD patients with plasma HDL-hypocholesterolemia (nCAD) and 14--without HDL-hypocholesterolemia (nCAD). All subjects were without peripheral vascular disease and hypertension. The groups were matched for age, sex, BMI. The diagnosis of CAD was substantiated by coronary angiography. METHODS: Nitric oxide end products xNO (NO2- plus NO3-) levels in the platelet membranes were measured using anion-exchange chromatography. [3H]AA release from labelled platelets was studied by the method of Neufeld and Majerus; radioactivity was measured by liquid scintillation counting. Levels of plasma HDL-cholesterol (HDL-Ch) and triglycerides were enzymatically determined. RESULTS: Significant increase (mean +/- SD; Mann-Whitney U test) of [3H]AA incorporation into platelet membrane phospholipids was noted in CAD patients in comparison with healthy subjects (p < 0.001). A correlation (multiple regression analysis) was established between HDL-C level and [3H]AA (r = -0.58, p < 0.05, n = 28); and between HDL-Ch and NOx levels (r = 0.76, p < 0.05, n = 28) in CAD patients. CAD patients had lower NOx than healthy subjects (p < 0.0001), NOx was lower in the group with decreased HDL-Ch concentration (wCAD 36 +/- 5 vs. nCAD 42.3 +/- 6 mumol/mg, p < 0.002). CONCLUSIONS: CAD patients show decreased ability to produce platelet-derived NO that leads to higher platelet sensitivity to aggregating stimuli. Decreased plasma HDL-Ch may affect AA metabolism and NO production in the platelet membranes of CAD patients without LDL-hypercholesterolemia.

Colorimetric quantitation of albumin in microliter volumes of serum.

Various non-immunochemical approaches to the quantitation of albumin in serum are reviewed. Salt fractionation techniques are unreliable, with substantial errors in estimating hypoalbuminemic states. Electrophoresis displays biases owing to irregular dye-binding or to densitometric scanning of irregular globulin bands. Currently, the most reliable colorimetric procedure for albumin quantitation is the rapid reaction with bromcresol green. By measuring final absorbance within fifteen seconds of mixing serum with reagent, the interference of globulins is eliminated. A microscale (5 microliter serum) rapid reaction for albumin assay has been developed; it can be readily automated on kinetic or centrifugal analyzers.