Francisco Gude

Determinants of Serum Concentrations of Lipopolysaccharide-Binding Protein (LBP) in the Adult Population: The Role of Obesity

Background and Aim Assessment of serum concentration of lipopolysaccharide (LPS)-binding protein (LBP) has been suggested as a useful biomarker to indicate activation of innate immune responses to microbial products. We investigated LBP concentrations and associations with demographics, lifestyle factors, and common metabolic abnormalities in adults. We also examined if LBP concentrations were associated with common polymorphisms in genes coding for LBP (rs2232618), CD14 (rs2569190), and TLR4 (rs4986790), the molecules responsible for the innate immune response to LPS, or serum levels of soluble CD14 (sCD14) and proinflammatory cytokines. Methods Serum LBP was measured with a commercial immunoassay in a random sample of the adult population (n = 420, 45% males, age 18–92 years) from a single municipality. Results Serum LBP concentrations increased with age (P<0.001) and were higher in individuals who were overweight or obese than in normal-weight individuals (P<0.001). Similarly, LBP concentrations were higher in individuals with metabolic syndrome than in individuals without it (P<0.001). Among metabolic syndrome components, LBP concentrations were independently associated with abdominal obesity (P = 0.002) and low concentrations of HDL-cholesterol (P<0.001). Serum LBP concentrations tended to be independently associated with smoking (P = 0.05), but not with alcohol consumption. Likewise, there was not significant association between LBP concentrations and gene polymorphisms. Concentrations of LBP significantly correlated with serum levels of proinflammatory cytokines (IL-6 and IL-8), sCD14, and with liver enzymes. Conclusions Serum LBP concentrations increased with age. Overweight, obesity, and having metabolic syndrome (particularly, low HDL cholesterol levels) were associated with higher LBP concentrations. These findings are consistent with microbial exposure playing a role in these inflammatory, metabolic abnormalities.

Clinical characteristics and prognosis of hospitalised inpatients with heart failure and preserved or reduced left ventricular ejection fraction.

Objective: To determine the clinical and prognostic differences between patients with heart failure who had preserved or deteriorated systolic function, defined as a left ventricular ejection fraction of > 50% or < 50%, respectively, within two weeks of admission to hospital. Methods: The records of 229 patients with congestive heart failure were studied. There were 95 women and 134 men, mean (SD) age 66.7 (11.7) years, who had been admitted to a cardiology department for congestive heart failure in the period 1991 to 1994, and whose left ventricular systolic function had been evaluated echocardiographically within two weeks of admission. Data were collected on the main clinical findings, supplementary investigations, treatment, and duration of hospital admission. Follow up information was obtained in the spring of 1998 by searching the general archives of the hospital and by a telephone survey. Results: Left ventricular systolic function was preserved in 29% of the patients. The preserved and deteriorated groups differed significantly in the sex ratio (more women in the preserved group) and in the presence of a third heart sound, cardiomegaly, alveolar oedema, ischaemic cardiomyopathy, and treatment with angiotensin converting enzyme (ACE) inhibitors (all more in the deteriorated group). There were no significant differences in age, New York Heart Association functional class, rhythm disturbances, left ventricular hypertrophy, treatment with drugs other than ACE inhibitors, or survival. In the group as a whole, the survival rates after three months, one year, and five years were 92.6%, 80%, and 48.4%, respectively. Conclusions: In view of the unexpectedly poor prognosis of patients with congestive heart failure and preserved left ventricular systolic function, controlled clinical trials should be carried out to optimise their treatment.

Liver Disease in Heavy Drinkers With and Without Alcohol Withdrawal Syndrome

BACKGROUND Withdrawal syndrome is a hallmark of alcohol dependence. The characteristics of alcohol consumption, closely related to dependence, could influence the development of alcoholic liver disease. The study aimed to investigate if patients with severe alcohol withdrawal syndrome have a peculiar profile of liver disease. METHODS The study included 256 heavy drinkers (aged 19-75 years, 70.3% males) admitted to an Internal Medicine Department. Patients admitted for complications of liver disease were not included. Severe alcohol withdrawal syndrome (seizures, disordered perceptions, or delirium) developed in 150 patients (58.6%). Alcohol consumption (daily quantity, duration, and pattern [regular or irregular]) was assessed by questionnaire. Liver biopsy was performed in all cases. RESULTS Patients with alcohol withdrawal syndrome showed a lower prevalence of liver cirrhosis and a higher prevalence of alcoholic hepatitis than patients without it. The negative association of alcohol withdrawal syndrome with liver cirrhosis persisted after we adjusted for sex, daily intake, duration, and pattern of alcohol consumption. Alcoholic hepatitis was independently associated with the irregular pattern of alcohol consumption, which was closely associated with severe alcohol withdrawal syndrome. CONCLUSIONS The profile of liver injury is different in heavy drinkers who develop and who do not develop a severe alcohol withdrawal syndrome when admitted to the hospital.

Serum TNF-α levels in relation to alcohol consumption and common TNF gene polymorphisms

Tumor necrosis factor-alpha (TNF-alpha) mediates alcohol-induced organ dysfunction, including alcoholic hepatitis. Variations in the TNF-alpha gene may underlie the individual predisposition to alcoholic liver disease. Measurement of serum TNF-alpha levels has become a routine in clinical practice. The study was aimed at investigating the level of serum TNF-alpha levels in adults and analyzing its relationship with different levels of alcohol consumption, as well as the potential interaction between alcohol consumption and common TNF-alpha gene polymorphisms in relation to TNF-alpha levels and liver disease. Serum TNF-alpha was measured in a random sample of 459 individuals from a general adult population and in 137 hospital-admitted alcoholics. Three common TNF-alpha gene polymorphisms (-238G> A, -308G> A, and -857C> T) were investigated in 419 of these individuals. In the general adult population, the TNF-alpha levels were similar in alcohol abstainers and alcohol drinkers. Alcoholics admitted to the hospital showed the highest TNF-alpha levels, which were correlated with liver dysfunction. We found no evidence of an interaction between alcohol consumption and TNF-alpha gene polymorphisms in relation to TNF-alpha levels. Carriers of the TNF -238A allele tended to have a higher prevalence of advanced liver disease than -238G homozygotes, confirming previous reports. In conclusion, light-to-moderate drinking had no significant effect on the levels of serum TNF-alpha levels. Serum TNF-alpha levels are elevated in alcoholics independently of common TNF gene polymorphisms.

Insulin resistance index (HOMA-IR) levels in a general adult population: Curves percentile by gender and age. The EPIRCE study

AIMS To describe the distribution of HOMA-IR levels in a general nondiabetic population and its relationships with metabolic and lifestyles characteristics. METHODS Cross-sectional study. Data from 2246 nondiabetic adults in a random Spanish population sample, stratified by age and gender, were analyzed. Assessments included a structured interview, physical examination, and blood sampling. Generalized additive models (GAMs) were used to assess the effect of lifestyle habits and clinical and demographic measurements on HOMA-IR. Multivariate GAMs and quantile regression analyses of HOMA-IR were carried out separately in men and women. RESULTS This study shows refined estimations of HOMA-IR levels by age, body mass index, and waist circumference in men and women. HOMA-IR levels were higher in men (2.06) than women (1.95) (P=0.047). In women, but not men, HOMA-IR and age showed a significant nonlinear association (P=0.006), with increased levels above fifty years of age. We estimated HOMA-IR curves percentile in men and women. CONCLUSIONS Age- and gender-adjusted HOMA-IR levels are reported in a representative Spanish adult non-diabetic population. There are gender-specific differences, with increased levels in women over fifty years of age that may be related with changes in body fat distribution after menopause.

Long-term mortality of patients admitted to the hospital with alcohol withdrawal syndrome.

BACKGROUND Although it is well known that alcoholism increases long-term mortality, there is a paucity of data regarding long-term prognosis in alcoholic patients who have an episode of alcohol withdrawal syndrome (AWS). METHODS We studied a cohort of 1,265 individuals with severe AWS who were admitted to a single university hospital between 1996 and 2006. Median age was 49 years (range 18 to 89 years). A total of 1,085 (85.8%) were men. Median follow-up was 34 months (range 0 to 121 months). Survival of patients with AWS was compared with that of a reference cohort of 1,362 individuals from the same area. In addition, age- and sex-standardized mortality ratios were calculated using the general population from the region (Galicia, Spain) as the reference. RESULTS The risk of mortality was higher in the cohort of patients with AWS than in the reference cohort after adjusting for age, sex, and smoking (hazard ratio 12.7; 95% CI 9.1 to 17.6; p < 0.001). The standardized mortality ratio in patients with AWS was 8.6 (95% CI 7.7 to 9.7). Age, smoking, serum creatinine, serum bilirubin, and prothrombin time at baseline were independently associated with mortality among patients with AWS. CONCLUSIONS Long-term mortality is highly increased in patients who have a history of AWS. Liver and kidney dysfunction are independent predictors of long-term mortality in patients with AWS.

Atherosclerosis profile and microalbuminuria in essential hypertension

Whether microalbuminuria (MA) is the result of intrarenal hemodynamic changes induced by increased systemic blood pressure (BP) or a marker of capillary leakiness at the glomerular level that reflects more generalized atherosclerotic vascular damage is still debated. To address this question, 319 patients without diabetes, 154 men and 165 women aged 57 +/- 8.6 years (range, 37 to 73 years), but with essential hypertension (EH) never treated with drugs were enrolled onto the study. Using a multiple linear regression analysis, we analyzed the prevalence of MA and its relationship with BP level as well as with other risk factors for the development of atherosclerosis. MA was present in 40% of the population studied. A univariable analysis of ambulatory BP monitoring measurements showed that only 24-hour systolic BP (P = 0.04), daytime systolic BP (P = 0. 02), and 24-hour daytime and nighttime systolic BP load (P < 0.01) predicted the presence of MA, whereas all BP variability parameters significantly predicted it. Multivariable analysis showed that only a positive family history of hypertension (P < 0.001), BMI (P < 0. 001), glucose (P < 0.001), and 24-hour systolic BP coefficient of variation (P < 0.001) independently predicted MA. In summary, the prevalence of MA in our group of patients with EH was high, presumably as a consequence of the older mean age of the population and the selection criteria. Besides being a marker of concomitant cardiovascular damage, MA was associated with a worse pattern of atherosclerotic risk factors. Although its pathophysiological meaning remains to be completely clarified, MA seems to be more related to other atherosclerosis risk factors and presumably reflects a more diffuse vascular injury.

smoothHR: An R Package for Pointwise Nonparametric Estimation of Hazard Ratio Curves of Continuous Predictors

The Cox proportional hazards regression model has become the traditional choice for modeling survival data in medical studies. To introduce flexibility into the Cox model, several smoothing methods may be applied, and approaches based on splines are the most frequently considered in this context. To better understand the effects that each continuous covariate has on the outcome, results can be expressed in terms of splines-based hazard ratio (HR) curves, taking a specific covariate value as reference. Despite the potential advantages of using spline smoothing methods in survival analysis, there is currently no analytical method in the R software to choose the optimal degrees of freedom in multivariable Cox models (with two or more nonlinear covariate effects). This paper describes an R package, called smoothHR, that allows the computation of pointwise estimates of the HRs—and their corresponding confidence limits—of continuous predictors introduced nonlinearly. In addition the package provides functions for choosing automatically the degrees of freedom in multivariable Cox models. The package is available from the R homepage. We illustrate the use of the key functions of the smoothHR package using data from a study on breast cancer and data on acute coronary syndrome, from Galicia, Spain.

Pro B-type natriuretic peptide plasma value: A new criterion for the prediction of short- and long-term outcomes after transcatheter aortic valve implantation

BACKGROUND To determine the prognostic value of pro B-type natriuretic peptide (pro-BNP) to predict mortality after transcatheter aortic valve implantation (TAVI). Logistic EuroSCORE (LES) overestimates observed mortality after TAVI. A new risk score specific to TAVI is needed to accurately assess mortality and outcome. METHODS Eighty-five patients were included. Indications for TAVI were nonoperable or surgically high-risk patients (LES>20%). Pro-BNP was measured 24h before the procedure. Cox proportional hazards model was used to evaluate clinical factors. The predictive accuracy of these Cox models was determined by using time-dependent receiver operating characteristic (ROC) curves. RESULTS Pro-BNP levels (log-transformed) were significantly higher in non-survivors than in survivors at 30 days (3.36 ± 0.43 vs. 3.81 ± 0.43, p<0.004) and at the end of follow-up (3.34 ± 0.42 vs. 3.63 ± 0.48, p<0.011). Multivariate analysis revealed that only increased log pro-BNP levels were associated with higher mortality rate at short [hazard ratio (HR) (95% confidence intervals (CI)]=5.35 (1.74-16.5), p=0.003] and long-term follow-ups [HR=11 (CI: 1.51-81.3), p=0.018]. LES was not associated with increased mortality at either time point [HR=1.03 (CI: 0.95-1.10), p=0.483 and HR=1.03 (CI: 0.98-1.07), p=0.230, respectively]. At 30, 90, 180, and 365 days, the c-index was 0.72 for log pro-BNP and 0.63 for LES (p=0.044). CONCLUSION Pre-procedure log transform of plasma pro-BNP levels are an independent and strong predictor of short- and long-term outcomes after TAVI and are more discriminatory than LES.

Circulating levels of vascular endothelial markers in obstructive sleep apnoea syndrome. Effects of nasal continuous positive airway pressure

Introduction Obstructive sleep apnoea syndrome (OSAS) is an important risk factor in cardiovascular disorders. Although the exact mechanism remains to be elucidated, the endothelial dysfunction process seems to be implicated. Material and methods In order to test this hypothesis, blood circulating levels of endothelial markers were measured at baseline and 1 year after treatment with continuous positive airway pressure (CPAP). We studied 37 males using polysomnography: 20 subjects with OSAS and a 17-subject control group. An OSAS-validated sleep questionnaire covering the most important cardiovascular risk factors was applied to all subjects. Furthermore, patients received a complete general physical examination and biochemistry test with lipid profile. The specific markers measured were intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, endothelin-1, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1). Results Obstructive sleep apnoea syndrome patients presented higher circulating levels of ICAM-1, endothelin-1 and PAI-1 than the control group. On the other hand, no differences were found in E-selectin and vWF. After 1 year of CPAP treatment, there was a significant decrease in circulating levels of ICAM-1 and PAI-1. On the other hand, no differences were found in endothelin-1, E-selectin and vWF. Conclusions Obstructive sleep apnoea syndrome is associated with elevated levels of ICAM-1 and PAI-1 and these levels normalize after treatment with CPAP.