Carotid atherosclerosis in virologically suppressed HIV patients: comparison with a healthy sample and prediction by cardiovascular risk equations.

OBJECTIVES: To compare the prevalence of carotid atherosclerosis in virologically suppressed HIV patients with that of a community sample, and to evaluate the capacity of various cardiovascular risk (CVR) equations for predicting carotid atherosclerosis. METHODS: This was a cross-sectional study with two randomly selected groups: HIV patients from an HIV unit and a control group drawn from the community. Participants were matched by age (30-80 years) and sex without history of cardiovascular disease. Carotid plaque, common carotid intima-media thickness (cc-IMT) and subclinical atherosclerosis (carotid plaque and/or cc-IMT > 75th percentile) were assessed by carotid ultrasound. The Systematic Coronary Risk Evaluation (SCORE), Framingham, REGICOR, reduced Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D), and COMVIH equations were applied, and their abilities to predict carotid plaque were compared using the area under the curve (AUC). RESULTS: Each group included 379 subjects (77.8% men, age 49.7 years). Duration of antiretroviral therapy was 15.5 years. There were no differences between the groups for carotid plaque (HIV, 33.2%; control, 31.3%), mean cc-IMT (HIV, 0.63 mm; control, 0.61 mm) or subclinical atherosclerosis (HIV, 42.9%; control, 47.9%). Thymidine analogues were independently associated with subclinical atherosclerosis in HIV-infected patients. CVR equations revealed AUCs between 0.715 and 0.807 for prediction of carotid plaque; prediction was better in the control group and did not improve when HIV-adapted scales were used. CONCLUSIONS: The features of carotid atherosclerosis did not differ between the HIV-infected and the control group, although CVR equations were more predictive for carotid plaque in controls than in HIV-infected patients. HIV-specific equations did not improve prediction.

Electronegative LDL induces priming and inflammasome activation leading to IL-1ß release in human monocytes and macrophages.

BACKGROUND: Electronegative LDL (LDL(−)), a modified LDL fraction found in blood, induces the release of inflammatory mediators in endothelial cells and leukocytes. However, the inflammatory pathways activated by LDL(−) have not been fully defined. We aim to study whether LDL(−) induced release of the first-wave proinflammatory IL-1ß in monocytes and monocyte-derived macrophages (MDM) and the mechanisms involved. METHODS: LDL(−) was isolated from total LDL by anion exchange chromatography. Monocytes and MDM were isolated from healthy donors and stimulated with LDL(+) and LDL(−) (100 mg apoB/L). RESULTS: In monocytes, LDL(−) promoted IL-1ß release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1ß release induced by LDL(−) than by native LDL. LDL(−)-induced IL-1ß release involved activation of the CD14-TLR4 receptor complex. LDL(−) induced priming, the first step of IL-1ß release, since it increased the transcription of pro-IL-1ß (8-fold) and NLRP3 (3-fold) compared to native LDL. Several findings show that LDL(−) induced inflammasome activation, the second step necessary for IL-1ß release. Preincubation of monocytes with K+ channel inhibitors decreased LDL(−)-induced IL-1ß release. LDL(−) induced formation of the NLRP3-ASC complex. LDL(−) triggered 2-fold caspase-1 activation compared to native LDL and IL-1ß release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD. In MDM, LDL(−) promoted IL-1ß release, which was also associated with caspase-1 activation. CONCLUSIONS: LDL(−) promotes release of biologically active IL-1ß in monocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation. SIGNIFICANCE: By IL-1ß release, LDL(−) could regulate inflammation in atherosclerosis.

Metabolic syndrome in Mediterranean women with polycystic ovary syndrome: when and how to predict its onset.

Polycystic ovary syndrome (PCOS) is associated with the metabolic syndrome (MetS). The metabolic disorders are not universal and may vary with race, age and phenotype. Our purpose was to determine the clinical and biochemical characteristics of Mediterranean PCOS women with MetS, compare them with non-MetS PCOS patients, and assess the ability of clinical data and biochemical tests to predict these abnormalities within our population. A total of 218 subjects, 196 PCOS women and 22 controls, undergo a physical examination and laboratory evaluation for a diagnosis of MetS. MetS was categorized according to NCEP ATP III guidelines. PCOS patients were analyzed separately and compared in three subgroups: three or more MetS criteria, two criteria, one or no criteria. The overall prevalence of MetS was 21.4%. Women with MetS had higher glucose (G) levels than PCOS women with two criteria (5.7 ± 1.5 vs 5 ± 0.4, p < 0.05). Both groups were comparable for all the other parameters. Waist circumference (WC), body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP), bioavailable testosterone (uT), triglycerides (TG) and insulin (I) levels were significantly higher and sex hormone-binding globulin (SHBG) levels, high-density lipoprotein (HDL), HOMA and QUICKI indexes significantly lower in both groups, MetS and patients with two criteria, compared with women with one or no criteria and the control group. WC, HDL and TG were the best predictors of PCOS patients at risk for MetS. In conclusion, we recommend considering PCOS patients with two criteria of MetS as having the same risk as patients with the full syndrome. Waist circumference with HDL and triglycerides is an efficient combined test to identify PCOS women at risk for metabolic and cardiovascular diseases.

Diagnostic performance of high sensitive troponin in non-ST elevation acute coronary syndrome. / Rendimiento diagnóstico de la troponina de alta sensibilidad en el síndrome coronario agudo sin elevación del segmento ST.

OBJECTIVE: To assess the diagnostic performance of high-sensitivity troponin T (hs-TnT) in patients with suspected non-ST elevation acute coronary syndrome (NSTE-ACS); confirm whether it shortens the time to diagnosis; and analyze the clinical consequences derived from its use. METHOD: A prospective, longitudinal observational study was carried out in 5 emergency care departments. Patients seen for chest pain with suspected of NSTE-ACS were consecutively included. Patient care followed the internal protocols of the center, based on the consensus guidelines of the European Society of Cardiology. Serial conventional cardiac troponin (cTn) and hs-TnT determinations were made. RESULTS: A total of 351 patients were included in the study. A final diagnosis of acute myocardial infarction (AMI) was established in 77 patients, with unstable angina in 102, and no acute coronary syndrome in 172 patients. The hs-TnT values were above percentile 99% in a large number of patients without AMI. In the initial determination, the diagnostic sensitivity of the hs-TnT was significantly greater than that of cTn (87.0% vs. 42.9%), which led to a negative predictive value of 95.1%. CONCLUSIONS: High-sensitivity troponin T improves diagnostic performance compared with conventional troponin assay, shortens the time to diagnosis, and identifies a larger number of patients with smaller myocardial infarctions.

Potential of mid-infrared spectroscopy to aid the triage of patients with acute chest pain.

A total of 1,429 serum samples from 389 consecutive patients with acute chest pain were analyzed with the goal to aid the rapid diagnosis of acute myocardial infarction. To the best of our knowledge this is the largest and most comprehensive study on mid-infrared spectroscopy in cardiology. We were able to identify those signatures in the mid-infrared spectra of the samples, which were specific to either acute myocardial infarction or chest pain of other origin (angina pectoris, oesophagitis, etc). These characteristic spectral differences were used to distinguish between the cause of the donor's acute chest pain using robust linear discriminant analysis. A sensitivity of 88.5% and a specificity of 85.1% were achieved in a blind validation. The area under the receiver operating characteristics curve amounts to 0.921, which is comparable to the performance of routine cardiac laboratory markers within the same study population. The biochemical interpretation of the spectral signatures points towards an important role of carbohydrates and potentially glycation. Our studies indicate that the "Diagnostic Pattern Recognition (DPR)" method presented here has the potential to aid the diagnostic procedure as early as within the first 6 hours after the onset of chest pain.

Does Whole-Blood Neutrophil Gelatinase-Associated Lipocalin Stratify Acute Kidney Injury in Critically Ill Patients?

PURPOSE: To analyse the capacity of whole-blood NGAL (wbNGAL) to stratify AKI in critically ill patients with and without sepsis. METHODS: Whole-blood NGAL was measured with a point-of-care device at admission and 48 hours later in patients admitted to a general ICU. Patients were classified by the AKIN and KDIGO classifications at admission and 24 and 48 hours. We performed an ROC curve analysis. wbNGAL values at admission were compared in patients with sepsis and septic shock. RESULTS: The study included 100 consecutively admitted patients (40 female) with mean age 59.1 ± 17.8 years. Thirty-three patients presented AKI at admission, and 10 more developed it in the next 48 h. Eighteen patients had AKI stage 3, 14 of them at admission. Nine patients required renal replacement therapy. According to KDIGO at admission, wbNGAL values were 78 µg/L (60-187) in stage 0 (n = 67), 263 µg/L (89-314) in stage 1 (n = 8), 484 µg/L (333-708) in stage 2 (n = 11), and 623 µg/L (231-911) in stage 3 (n = 14), p = 0.0001 for trend. Ten patients did not complete 48 hours of study: 6 of 10 were discharged (initial wbNGAL 130 µg/L (60-514)) and 4 died (773 µg/L (311-1010)). The AUROC curve of wbNGAL to predict AKI was 0.838 (95% confidence interval 0.76-0.92, p = 0.0001), with optimal cut-off value of 178 µg/L (sensitivity 76.7%, specificity 78.9%, p < 0.0001). At admission, twenty-nine patients had sepsis, of whom 20 were in septic shock. wbNGAL concentrations were 81 µg/L (60-187) in patients without sepsis, 481 (247-687) in those with sepsis, and 623.5 µg/L (361-798) in the subgroup of septic shock (p < 0.0001). CONCLUSIONS: Whole-blood NGAL concentration at ICU admission was a good stratifier of AKI in critically ill patients. However, wbNGAL concentrations were higher in septic patients irrespective of AKI occurrence.

The effects of liposuction removal of subcutaneous abdominal fat on lipid metabolism are independent of insulin sensitivity in normal-overweight individuals.

BACKGROUND: Abdominal fat (both visceral and subcutaneous) accumulation is associated with an increased risk of developing insulin resistance. The latter stands as the basis upon which diabetes, hypertension, and atherogenic dyslipidemia tend to build up. Hence, abdominal liposuction (AL) could theoretically hold metabolic benefits. We undertook the present study to assess the effects of AL on carbohydrate and lipid metabolism. METHODS: This is a prospective study including 20 healthy volunteers (M2/F18) aged 39.6 +/- 7.7 years old (24-52), body mass index (BMI) = 25.3 +/- 4.7 kg/m(2) (19.8-36) who underwent AL. Before and 4 months after AL, we measured glucose and insulin concentrations, HOMA index [glucose (mM) x IRI (microUI/l)/22.5], free fatty acids (FFA), glycerol, total cholesterol and triglycerides, high-density lipoprotein (HDL)-cholesterol (HDL-c), low-density lipoprotein (LDL)-cholesterol (LDL-c), very low-density lipoprotein (VLDL)-cholesterol (VLDL-c) and apolipoproteins (apo) B, AI and AII, adiponectin (Adp), and ultra-sensitive C-reactive protein (CRP). RESULTS: Lipo-aspirate averaged 5.494 +/- 5.297 cc (600-19.000). Weight, BMI, and waist circumference decreased significantly 4 months after surgery by 4.6, 4.6 and 5.9%, respectively. There were significant decrements in FFA (-35%, p < 0.0001), glycerol (-63%, p < 0.0005), VLDL-c (-15.2%; p < 0.001), and triglycerides (-21.3%, p < 0.002), an increase in HDL-c (+10%, p < 0.03), Apo AI (+10.1%, p < 0.02), and Apo AII (+11.8%, p < 0.001). Total cholesterol, LDL-c, ApoB, and the LDL-c/ApoB ratio raised by +15% (p < 0.0005), +27.3% (p < 0.000), +15.1% (p < 0.008) and +2.76% (p < 0.008), respectively. Glucose, insulin, the HOMA index, Adp, and CRP were not significantly altered after AL. CONCLUSION: AL in healthy normal weight or slightly overweight subjects improves the major lipoprotein components of obesity-associated dyslipidemia. This improvement occurs independent of insulin sensitivity.

Cell-cycle arrest biomarkers in urine to predict acute kidney injury in septic and non-septic critically ill patients.

PURPOSE: To analyse the usefulness of the composite index of the tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) as urinary biomarkers for the early prediction of AKI in septic and non-septic patients. METHODS: This is a prospective, observational study including patients admitted to ICU from acute care departments and hospital length of stay <48 h. The main exclusion criteria were pre-existing eGFR <30 mL/min/1.73 m2 and hospitalisation 2 months prior to current admission. The [TIMP-2]·[IGFBP7] index was analysed twice, within the first 12 h of ICU admission. RESULTS: The sample included 98 patients. AKI incidence during ICU stay was 50%. Sepsis was diagnosed in 40.8%. Baseline renal variables were comparable between subgroups except for a higher baseline eGFR in non-septic patients. Patients were stratified based on the presence of AKI and their highest level of [TIMP-2]·[IGFBP7] within the first 12 h of stay. [TIMP-2]·[IGFBP7] index values were dependent on the incidence of AKI but not of sepsis. [TIMP-2]·[IGFBP7] values were significantly related to AKI severity according to AKIN criteria (p < 0.0001). The AUROC curve to predict AKI of the worst [TIMP-2]·[IGFBP7] index value was 0.798 (sensitivity 73.5%, specificity 71.4%, p < 0.0001). Index values below 0.8 ruled out any need for renal replacement (NPV 100%), whereas an index >0.8 predicted a rate of AKI of 71% and AKIN ≥ 2 of 62.9%. CONCLUSIONS: In our study, urinary [TIMP-2]·[IGFBP7] was an early predictor of AKI in ICU patients regardless of sepsis. Besides, index values <0.8(ng/mL)2/1000 ruled out the need for renal replacement.

Consensus document and recommendations on the use of natriuretic peptides in clinical practice. / Documento de consenso y recomendaciones sobre el uso de los péptidos natriuréticos en la práctica clínica.

Natriuretic peptides are a useful laboratory tool for the diagnosis, prognosis and treatment of patients with heart failure. Natriuretic peptides are used in various healthcare settings (consultations, emergency department, hospitalization, laboratory) and by various primary care and specialised professionals. However, their use in clinical practice is still scare and uneven. Properly using and interpreting natriuretic peptides in clinical practice requires a minimum of prelaboratory (pathophysiology), laboratory (methods) and postlaboratory (interpretation and integration of clinical data) expertise. The objective of this consensus document, developed by several scientific societies, is to update the necessary concepts and expertise on natriuretic peptides that enable its application in the diagnosis, prognosis and treatment of heart failure, in various healthcare environments.

Prognostic Value of High-Sensitivity Troponin-T to Identify Patients at Risk of Left Ventricular Graft Dysfunction After Heart Transplantation.

Primary graft dysfunction after heart transplantation (HTx) has a very high mortality rate, especially if the left ventricle (PGD-LV) is involved. Early diagnosis is important to select the appropriate therapy to improve prognosis. The value of high-sensitivity troponin T (HS-TNT) measurement obtained at patient arrival at the intensive care unit was analyzed in 71 HTx patients. Mild or moderate PGD-LV was defined by hemodynamic compromise with one of the following criteria: left ventricular ejection fraction <40%, hemodynamic compromise with right atrial pressure >15 mm Hg, pulmonary capillary wedge pressure >20 mm Hg, cardiac index <2.0 L/min/m2, hypotension (mean arterial pressure <70 mm Hg), and need for high-dose inotropes (inotrope score >10) or newly placed intra-aortic balloon pump. The mean recipient age was 54 ± 12 years (73% men), and donor age was 47 ± 11 years. Ischemic time was 200 ± 51 minutes, and coronary bypass time was 122 ± 31 minutes. Nine (13%) HTx patients were diagnosed with PGD-LV post-HTx, 8 with biventricular dysfunction. Four patients died, 2 with PGD-LV (22%) and 2 without PGD (4%). Mean HS-TNT before HTx was 158 ± 565 ng/L, and post-HT was 1621 ± 1269 ng/L. The area under the curve (receiver-operator characteristic) of HS-TNT to detect patients at risk of PGD-LV was 0.860 (P < .003). A cutoff value of HS-TNT >2000 ng/L had a sensitivity of 75% and specificity of 87% to identify patients at risk of PGD-LV. Multivariate analysis identified HS-TNT >2000 ng/L (P < .02) and coronary bypass-time (P < .01) as independent predictors of PGD-LV. HS-TNT >2000 ng/L at intensive care admission after HT and prolonged coronary bypass time were the most powerful predictors of PGD-LV. HS-TNT may be helpful for early detection of HTx patients at risk of PGD-LV.

Increased production of very-low-density lipoproteins in transgenic mice overexpressing human apolipoprotein A-II and fed with a high-fat diet.

We investigated the mechanisms that lead to combined hyperlipidemia in transgenic mice that overexpress human apolipoprotein (apo) A-II (line 11.1). The 11.1 transgenic mice develop pronounced hypertriglyceridemia, and a moderate increase in free fatty acid (FFA) and plasma cholesterol, especially when fed a high-fat/high-cholesterol diet. Post-heparin plasma lipoprotein lipase and hepatic lipase activities (using artificial or natural autologous substrates), the decay of plasma triglycerides with fasting, and the fractional catabolic rate of the radiolabeled VLDL-triglyceride (both fasting and postprandial) were similar in 11. 1 transgenic mice and in control mice. In contrast, a 2.5-fold increase in hepatic VLDL-triglyceride production was observed in 11. 1 transgenic mice in a period of 2 h in which blood lipolysis was inhibited. This increased synthesis of hepatic VLDL-triglyceride used preformed FFA rather than FFA of de novo hepatic synthesis. The 11.1 transgenic mice also presented reduced epididymal/parametrial white adipose tissue weight (1.5-fold), increased rate of epididymal/parametrial hormone-sensitive lipase-mediated lipolysis (1.2-fold) and an increase in cholesterol and, especially, in triglyceride liver content, suggesting an enhanced mobilization of fat as the source of preformed FFA reaching the liver. Increased plasma FFA was reverted by insulin, demonstrating that 11.1 transgenic mice are not insulin resistant. We conclude that the overexpression of human apoA-II in transgenic mice induces combined hyperlipidemia through an increase in VLDL production. These mice will be useful in the study of molecular mechanisms that regulate the overproduction of VLDL, a situation of major pathophysiological interest since it is the basic mechanism underlying familial combined hyperlipidemia.

Optimization of glycemic control by insulin therapy decreases the proportion of small dense LDL particles in diabetic patients.

Small dense LDL particles (B phenotype) are considered to be more atherogenic than large buoyant LDL particles. The influence of glycemic control on LDL particle size and density is still under debate. The aim of this study was to determine LDL subfraction phenotype in both IDDM and NIDDM patients in poor glycemic control compared with that of respective matched control groups. In addition, we evaluated the effect of a 3-month period of optimized glycemic control on this parameter. Thirty-seven IDDM patients and 33 NIDDM patients, together with two respective age-, sex-, and BMI-matched control groups were studied. Non-A phenotype prevalence in IDDM patients before (19%) and after blood glucose optimization (11%) was similar to that of their control group (12%). However, NIDDM patients displayed a higher proportion of the non-A phenotype (51%) than did the control group (28%), but it became closer (30%, P < 0.05) after glycemic control improved. All subjects with non-A phenotype that changed to A phenotype showed triglyceride levels below 1.63 mmol/l and a greater decrease in HbA1c than did subjects whose phenotype did not change (4.9 +/- 1.5 vs. 3.1 +/- 1.4%, P < 0.05). A higher proportion of small dense LDL was observed in NIDDM women than in nondiabetic women (LDL5 10.0 +/- 4.8 vs. 6.3 +/- 1.5%, LDL6 6.1 +/- 2.2 vs. 4.2 +/- 0.8%, P < 0.05) during both stages of glycemic control, but no differences were observed between NIDDM and nondiabetic men. In conclusion, these findings provide new evidence for the relevance of near-normal glycemic control in the prevention of macrovascular disease and could contribute to an explanation of the loss of protection for cardiovascular disease in diabetic women.

Electronegative LDL from normolipemic subjects induces IL-8 and monocyte chemotactic protein secretion by human endothelial cells.

The presence in plasma of an electronegative LDL subfraction [LDL(-)] cytotoxic for endothelial cells (ECs) has been reported. We studied the effect of LDL(-) on the release by ECs of molecules implicated in leukocyte recruitment [interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1)] and in the plasminogen activator inhibitor-1 (PAI-1). LDL(-), isolated by anion-exchange chromatography, differed from nonelectronegative LDL [LDL(+)] in its higher triglyceride, nonesterified fatty acid, apoprotein E and apoprotein C-III, and sialic acid contents. No evidence of extensive oxidation was found in LDL(-); its antioxidant and thiobarbituric acid-reactive substances contents were similar to those of LDL(+). However, conjugated dienes were increased in LDL(-), which suggests that mild oxidation might affect these particles. LDL(-) increased, in a concentration-dependent manner, the release of IL-8 and MCP-1 by ECs and was a stronger inductor of both chemokines than oxidized LDL (oxLDL) or LDL(+). PAI-1 release increased slightly in ECs incubated with both LDL(-) and oxLDL but not with LDL(+). However, no cytotoxic effects of LDL(-) were observed on ECs. Actinomycin D inhibited the release of IL-8 and MCP-1 induced by LDL(-) and oxLDL by up to 80%, indicating that their production is mediated by protein synthesis. Incubation of ECs with N:-acetyl cysteine inhibited production of IL-8 and MCP-1 induced by LDL(-) and oxLDL by >50%. The free radical scavenger butylated hydroxytoluene slightly inhibited the effect of oxLDL but did not modify the effect of LDL(-). An antagonist (BN-50730) of the platelet-activating factor receptor inhibited production of both chemokines by LDL(-) and oxLDL in a concentration-dependent manner. Our results indicate that LDL(-) shows proinflammatory activity on ECs and may contribute to early atherosclerotic events.

Quantitative effect of glycaemic improvement on the components of diabetic dyslipidaemia: a longitudinal study.

In order to assess the effect of glycaemic improvement on lipoprotein concentrations, we studied 73 type 2 diabetic subjects before (HbA1c 10.1 (6.2-16)%) and after (HbA1c 6.6 (3.8-8.0)%) glycaemic improvement. Total triglyceride and cholesterol (c), LDLc, HDLc, non-HDLc and apolipoproteins AI (apoAI) and B (apoB) were measured. Bivariate correlations and step-wise, multivariate analysis were performed to find predictors of change in the different components of diabetic dyslipidaemia. Changes in HDLc (r = -0.358, P = 0.001), apoAI (r = -0.355, P = 0.003), apoAI/apoB ratio (r = -0.333, P = 0.005), weight (r = -0.245, P = 0.046) and BMI (r = -0.253, P = 0.039) correlated with that of HbA1c, but, in multivariate analysis, only changes in HDLc, apoAI and apoAI/apoB ratio were predicted by the decrease in HbA1c. For the median observed change in HbA1c (-3.3 percentage-points), the estimated changes were +0.14 mmol/l, +0.12 g/l and +0.20 for HDLc, apoAI and apoAI/apoB ratio, respectively, accounting for 81, 92 and 80% of the observed changes. In conclusion, for the component of diabetic dyslipidaemia for which less therapeutic tools are available, glycaemic improvement is most effective.

Susceptibility of plasma low- and high-density lipoproteins to oxidation in patients with severe hyperhomocysteinemia.

A moderate increase in plasma homocysteine is increasingly considered an important risk factor of atherosclerosis and thrombosis. However, the mechanisms by which hyperhomocysteinemia induces vascular disease are not well defined. In vitro studies suggest that cysteine and homocysteine can induce oxidative modification of low-density lipoproteins (LDL). This suggestion is relevant because lipoprotein oxidation is thought to play a key role in the development of atherosclerosis and in the triggering of thrombotic events. An attractive model to study this topic is provided by patients with classical homocystinuria, an inherited disease characterized by severe hyperhomocysteinemia and a high incidence of thromboembolisms. We investigated the existence of oxidized LDL and the susceptibility to oxidation of the plasma cholesterol-rich lipoproteins in six patients with severe hyperhomocysteinemia, most likely due to classical homocystinuria, and compared the results with matched controls. The proportion of electronegative LDL and the concentration of thiobarbituric acid reactive substances in native LDL and high-density lipoproteins (HDL) did not differ between patients and controls, suggesting that the proportion of modified lipoproteins is not increased in patients with severe hyperhomocysteinemia. The susceptibility to oxidative modification of plasma LDL and HDL was also similar in the two groups, although the patients had homocysteine levels 18.3-fold higher than controls. Thus, increased oxidative modification is not likely to be a relevant mechanism in explaining their high incidence of vascular disease. A possible explanation for the lack of increased susceptibility to oxidation, as would be expected for the metabolic blockade that cause classical homocystinuria, is the 4.1-fold decrease in the concentration of cysteine in the plasma of patients. As a result the total concentration of homocysteine plus cysteine was slightly lower in patients than in controls. This interpretation implies that more studies are needed on lipoprotein susceptibility to oxidation in patients in which both plasma homocysteine and cysteine concentrations are increased. This metabolic situation may be frequent in the population with moderate hyperhomocysteinemia and vascular disease.

Determinants of plasma homocyst(e)ine in patients with nephrotic syndrome.

Hyperhomocyst(e)inemia is an independent risk factor for atherothrombosis in several clinical settings in which renal function is impaired, but its prevalence in the nephrotic syndrome has not been investigated in detail, even though this syndrome provides an excellent model in which to study a possible link between albuminuria, proteinuria, and hyperhomocyst(e)inemia. We obtained plasma and urine from 27 patients with biopsy-confirmed membranous glomerulonephritis presenting nephrotic syndrome and 27 matched controls and determined the concentrations of homocyst(e)ine and proteins considered putative markers of glomerular and tubular function. Hyperhomocyst(e)inemia, defined as the mean +SD of the plasma homocyst(e)ine concentration of the controls [plasma homocyst(e)ine concentration >10.8 micromol/l] was present in 26% of the patients with nephrotic syndrome but in only 7.4% of the controls. Furthermore, the degree of hyperhomocyst(e)inemia was more severe in the nephrotic patients than in the controls. The existence of renal failure, tubular damage, and, interestingly, relatively well conserved glomerular function barrier were the main predictors of increased levels of plasma homocyst(e)ine. In conclusion, hyperhomocyst(e)inemia is a frequent cardiovascular risk factor present in patients with nephrotic syndrome and renal failure, but it is not directly associated with proteinuria.

Plasma lipoprotein(a) levels are not influenced by glycemic control in type 1 diabetes.

OBJECTIVE: To determine the influence of glycemic control improvement with intensive therapy on lipoprotein(a) [Lp(a)] concentrations in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 105 poorly controlled type 1 diabetic patients (60 men, 45 women) without diabetic complications participated in a longitudinal study performed in a tertiary referral center, to compare lipid, lipoprotein, and Lp(a) levels before and after 3 months of intensive therapy with multiple insulin doses. Lp(a) levels were measured by the Terumo method. Differences between the two periods were assessed by the paired t test and Wilcoxon's test. RESULTS: After 3 months of intensive therapy, all patients exhibited improved glycemic control. HbA1c decreased from 8.9 +/- 2.4 to 6.5 +/- 1.6% (P < 0.0001), being < or =6% in 47% of patients. However, although a more favorable lipoprotein profile was obtained, no changes in Lp(a) concentrations were observed in the whole group of patients (16.7 +/- 17.3 vs. 17.2 +/- 17.7 mg/dl) or in patients with baseline Lp(a) levels above 30 mg/dl (47.1 +/- 14.8 vs. 47.4 +/- 18.9 mg/dl) or below 30 mg/dl (9.6 +/- 7.3 vs. 10.2 +/- 6.7 mg/dl). In addition, patients reaching HbA1c < or =6 or >6% presented similar Lp(a) levels (19.7 +/- 18.0 vs. 15.0 +/- 17.4 mg/dl), and changes in Lp(a) did not correlate with those observed in HbA1c. CONCLUSIONS: These data demonstrate that the improvement of glycemic control does not influence plasma Lp(a) concentrations in type 1 diabetic patients independently of baseline Lp(a) levels and the degree of glycemic control.

Cost-Effectiveness of Highly Sensitive Cardiac Troponin T to Rule Out Acute Rejection After Heart Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) remains the gold standard for detecting acute rejection (AR) after heart transplantation (HTx). Non-invasive detection of AR thus far remains a challenge. Several studies have demonstrated that highly sensitive cardiac troponin T (hs-cTnT) concentrations have a low positive predictive value for diagnosing AR. Nevertheless, hs-cTnT proved to be useful for ruling out AR after HTx. An hs-cTnT concentration <17 ng/L, a value close to that used for rule-in or rule-out myocardial infarction, was associated with a 100% negative predictive value of AR. However, the cost-effectiveness of a strategy with the use of hs-cTnT for ruling out AR in HTx patients remains to be proven. METHODS: The cost-effectiveness of hs-cTnT determination for ruling out AR was assessed, comparing the costs of hs-cTnT measurements in 305 blood samples obtained at the time of EMB. Eighteen samples were excluded because the EMB was not assessable. RESULTS: Hs-cTnT determination cost 16.00€ per sample, whereas EMB cost 1752.00€ per biopsy; cost estimations included direct and indirect (30%) charges. Thirty-nine (13.6%) of the 287 blood samples presented hs-cTnT concentrations <17 ng/L; in none of them was an AR >2R degree found in the EMB. The cost of the assessment in the 287 blood samples and biopsies was of 4592.00€ for hs-cTnT and 502,824.00€ for EMB. Hs-cTnT systematic measurement would have avoided 39 EMB, with a saving of 68,328.00€, which represents the 13.5% of the total budget expended in these cases. CONCLUSIONS: The use of hs-cTnT values to rule out the need of EMB for AR diagnosis after HTx appears to be a cost-effective procedure.

Circulating soluble low-density lipoprotein receptor-related protein 1 (sLRP1) concentration is associated with hypercholesterolemia: A new potential biomarker for atherosclerosis.

BACKGROUND: There is clinical interest in identifying novel lipid biomarkers for evaluating cardiovascular risk and targeting lipid-lowering treatment. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in the dysregulated cholesterol transfer from modified lipoproteins to human coronary vascular smooth muscle cells (hVSMCs), promoting hVSMC-derived foam cell formation. LRP1 has a soluble and circulating form (sLRP1) generated from LRP1. Cholesterol modulates the release of the soluble form of LRP1. Using in vitro, ex vivo and patient-based approaches, we tested the association between circulating sLRP1 concentrations and hypercholesterolemia and the potential of sLRP1 as a biomarker of atherosclerosis. METHODS AND RESULTS: Circulating sLRP1 concentrations were higher in severe hypercholesterolemia compared to moderate hypercholesterolemia or normocholesterolemia (Study 1). Circulating sLRP1 was significantly associated with established pro-atherogenic lipid parameters in two different hypercholesterolemic populations (Studies 2 and 3). sLRP1 concentrations decreased after statin treatment and increased after statin withdrawal (Study 3). In vitro experiments showed that native LDL, aggregated LDL and VLDL+IDL lipoproteins induced the release of sLRP1 from hVSMC. sLRP1 levels were increased in the conditioned medium of coronary atherosclerotic plaque areas extracted from patients compared to non-atherosclerotic areas of the same coronary artery and patient. Circulating sLRP1 concentrations were independently associated with the occurrence of carotid atherosclerosis in a hypercholesterolemic population (Study 2). The later association was higher than that observed for other classical or novel lipid parameters. CONCLUSIONS: Circulating sLRP1 is a new lipid-related parameter potentially useful as a biomarker for atherosclerosis.

Rendimiento diagnóstico de la troponina de alta sensibilidad en el síndrome coronario agudo sin elevación del segmento ST / Diagnostic performance of high sensitive troponin in non-ST elevation acute coronary syndrome

Objetivo: Los objetivos del estudio son evaluar el rendimiento diagnóstico de la troponina cardiaca T de alta sensibilidad (TnTc-hs) en pacientes con sospecha de síndrome coronario agudo sin elevación del segmento ST (SCASEST), confirmar si permite acortar el tiempo hasta el diagnóstico y analizar las consecuencias clínicas derivadas de su utilización. Método: Se trata de un estudio observacional, longitudinal y prospectivo, realizado en 5 servicios de urgencias hospitalarias. Se incluyó de forma consecutiva a los pacientes que acudían por dolor torácico sospechoso de SCASEST. El manejo del paciente y el tratamiento aplicado siguieron los protocolos internos basados en las guías de consenso de la Sociedad Europea de Cardiología. Se realizaron determinaciones seriadas de Tnc convencional (4ªG) y de TnTc-hs. Resultados: Se incluyó en el estudio a 351 pacientes. El diagnóstico final de infarto agudo de miocardio (IAM) se estableció en 77 pacientes del total, angina inestable en 102 y 172 fueron pacientes diagnosticados como sin síndrome coronario agudo. Los valores de TnTc-hs estaban por encima del p99 en un alto número de pacientes sin IAM. En la determinación inicial del paciente, la sensibilidad diagnóstica de la TnTc-hs fue significativamente superior a la de la TnTc 4ªG (87,0 vs. 42,9%), lo que comportó un valor predictivo negativo del 95,1%. Conclusiones: La TnTc-hs mejora el rendimiento diagnóstico al compararla con el ensayo de Tnc convencional, acorta el tiempo hasta el diagnóstico y reconoce mayor número de pacientes con IAM más pequeños

Objective: To assess the diagnostic performance of high-sensitivity troponin T (hs-TnT) in patients with suspected non-ST elevation acute coronary syndrome (NSTE-ACS); confirm whether it shortens the time to diagnosis; and analyze the clinical consequences derived from its use. Method: A prospective, longitudinal observational study was carried out in 5 emergency care departments. Patients seen for chest pain with suspected of NSTE-ACS were consecutively included. Patient care followed the internal protocols of the center, based on the consensus guidelines of the European Society of Cardiology. Serial conventional cardiac troponin (cTn) and hs-TnT determinations were made. Results: A total of 351 patients were included in the study. A final diagnosis of acute myocardial infarction (AMI) was established in 77 patients, with unstable angina in 102, and no acute coronary syndrome in 172 patients. The hs-TnT values were above percentile 99% in a large number of patients without AMI. In the initial determination, the diagnostic sensitivity of the hs-TnT was significantly greater than that of cTn (87.0% vs. 42.9%), which led to a negative predictive value of 95.1%. Conclusions: High-sensitivity troponin T improves diagnostic performance compared with conventional troponin assay, shortens the time to diagnosis, and identifies a larger number of patients with smaller myocardial infarctions