Atypical Sympathetic Ophthalmia Presenting with Ocular Pain Associated with Posterior Scleral Involvement.

PURPOSE: To describe an atypical case of sympathetic ophthalmia. Design: Case report. RESULTS: A 37 -year-old female presented a 3-day long acute left retroocular pain and photophobia, 1 month after having undergone evisceration of the fellow eye. Upon exploration, the patient presented conjunctival injection, macular retinal folds with peripapillary subretinal fluid, and hypocyanescent choroidal spots on indocyanine green angiography. A sympathetic ophthalmia with a reactive posterior scleritis involvement was diagnosed. The patient underwent treatment with prednisone, mycophenolate, and cyclosporine with slowly tapering, presenting a total recovery over the years. CONCLUSION: Sympathetic ophthalmia may present itself atypically as ocular pain with little vision loss secondarily to a mild panuveitis with reactive scleral involvement.

Compression stockings attenuate the expression of proteins associated with vascular damage in human varicose veins.

OBJECTIVE: The objective of this study was to analyze whether compression stocking therapy in the human varicose vein wall may change the levels of biomarkers associated with vein insufficiency. METHODS: Dilated collateral varicose vein samples were obtained from patients showing chronic venous disease (class 2 of the Clinical, Etiology, Anatomy, and Pathophysiology classification). Before elective surgery, 12 patients underwent compression stocking therapy (for 1 month) and 9 patients did not (control group). Expression levels of biomarkers associated with endothelial functionality (nitric oxide synthase 3), inflammation (interleukin-6, interleukin-10), oxidative stress (Gp91phox subunit of NADPH oxidase), and coagulation (factor Xa) were determined. P-selectin, an inflammatory and thrombosis-related biomarker, was also measured. RESULTS: Compression stockings increased the content of nitric oxide synthase 3 (control, 16.48 [16.04-17.40] AU; compression, 83.71 [67.70-91.85] AU; P < .001) in the varicose vein wall that was accompanied by reduction of both interleukin-6 levels (control, 38.72 [33.48-48.52] pg/µg protein; compression, 14.49 [11.05-17.41] pg/µg protein; P = .001) and the expression of Gp91phox subunit of NADPH oxidase (control, 63.24 [53.79-77.03] AU; compression, 36.85 [35.66-52.27] AU; P < .010). P-selectin (control, 77.37 [61.86-85.00] AU; compression, 54.31 [49.60-67.50] AU; P = .017) and factor Xa (control, 90.78 [75.02-100.00] AU; compression, 14.50 [13.77-36.20] AU; P < .001) were also reduced in the varicose vein wall of compression stocking-treated patients. However, P-selectin lost its statistical significance after adjustment by dyslipidemia. CONCLUSIONS: In the varicose vein wall, compression stocking therapy improved the content levels of biomarkers associated with endothelial functionality, inflammation, oxidative stress, and coagulation.

Platelet Apoptotic Response May Be Associated With the Capacity of Aspirin to Inhibit Platelets.

An inadequate platelet response to aspirin (ASA) has been identified in some patients under chronic ASA treatment. The aim of this study was to analyze if ASA-sensitive and ASA-resistant platelets have differences in their apoptotic capability. Clinically stable ischemic coronary patients who had been taking ASA (100 mg/d) for at least 9 months before inclusion were divided into ASA-resistant (n = 11) and ASA-sensitive (n = 13) groups as defined by the PFA-100 test. Platelets from ASA-sensitive patients showed higher expression of the proapoptotic proteins Bak and Bax than those from ASA-resistant patients, although only Bak protein remained different when the results were adjusted by age. In resting platelets, neither caspase-3 activity nor cytosolic cytochrome C levels were different between both experimental groups. Stimulation of platelets with calcium ionophore (10 nmol/L, A23187) increased caspase-3 activity (1.91-fold higher; P < 0.05) and cytosolic cytochrome C levels (1.84-fold higher; P < 0.05) to a higher degree in ASA-sensitive than in ASA-resistant platelets. In conclusion, ASA-sensitive platelets seem to be better prepared to undergo apoptosis during robust platelet activation.

Factor Xa Inhibition by Rivaroxaban Modified Mitochondrial-Associated Proteins in Human Abdominal Aortic Aneurysms.

BACKGROUND: The presence of intraluminal thrombus and mitochondrial dysfunction in human abdominal aortic aneurysms (AAAs) have been associated with aneurysmal growth and rupture. The objective of the study was to study if endogenous factor Xa (FXa) may modulate mitochondrial functionality and expression of proteins associated with mitophagy in human AAAs. METHODS: AAA sites with intraluminal thrombus were obtained from 6 patients undergoing elective AAA surgery repair. Control samples were collected from 6 organ donors. The effect of FXa was analyzed by in vitro incubation of AAA with 50 nmol/L rivaroxaban, an oral FXa inhibitor. RESULTS: The enzymatic activities of citrate synthase, a biomarker of mitochondrial density, and cytochrome C oxidase, a biomarker of mitochondrial respiratory chain functionality, were significantly reduced in the AAA sites with respect to the healthy aorta (citrate synthase activity in µU/min/µg protein: control: 3.51 ± 0.22 vs. AAA: 0.37 ± 0.15.; P < 0.01; cytochrome C oxidase activity in µOD/min/µg protein: control: 8.05 ± 1.57 vs. AAA: 3.29 ± 1.05; P < 0.05). The addition of rivaroxaban to AAA reverted the activity of both citrate synthase and cytochrome C oxidase to similar values to control. Mitochondrial Drp-1 expression was higher in AAA sites than in either control aortas or rivaroxaban-incubated AAA sites. Cytosolic content of Drp-1 phosphorylated at Ser637, mitochondrial Parkin, and mitochondrial PINK1-Parkin interaction were significantly reduced in the AAA sites with respect to control aortas. For all these parameters, rivaroxaban-incubated AAA showed similar values compared with control aortas. CONCLUSIONS: In human AAA, rivaroxaban improved mitochondrial functionality that was associated with changes in proteins related to mitophagy. Its opens possible new effects of endogenous FXa on the mitochondria in the human AAA site.

Decision tree learning to predict overweight/obesity based on body mass index and gene polymporphisms.

The new technologies for data analysis, such as decision tree learning, may help to predict the risk of developing diseases. The aim of the present work was to develop a pilot decision tree learning to predict overweight/obesity based on the combination of six single nucleotide polymorphisms (SNP) located in feeding-associated genes. Genotype study was performed in 151 healthy individuals, who were anonymized and randomly selected from the TALAVERA study. The decision tree analysis was performed using the R package rpart. The learning process was stopped when 15 or less observation was found in a node. The participant group consisted of 78 men and 73 women, who 100 individuals showed body mass index (BMI) ≥ 25 kg/m2 and 51 BMI < 25 kg/m2. Chi-square analysis revealed that individuals with BMI ≥ 25 kg/m2 showed higher frequency of the allelic variation Ala67Ala in AgRP rs5030980 with respect to those with BMI <25 kg/m2. However, the variant Thr67Ala in AgRP rs5030980 was the most frequently found in individuals with BMI <25 kg/m2. There were no statistical differences in the other analyzed SNPs. Decision tree learning revealed that carriers of the allelic variants AgRP (rs5030980) Ala67Ala, ADRB2 (rs1042714) Gln27Glu or Glu27Glu, INSIG2 (rs7566605) 73 + 9802 with CC or GG genotypes and PPARG (rs1801282) with the allelic variants of Ala12Ala or Pro12Pro, will most likely develop overweight/obesity (BMI ≥ 25 kg/m2). Moreover, the decision tree learning indicated that age and gender may change the developed three decision learning associated with overweight/obesity development. The present work should be considered as a pilot demonstrative study to reinforce the broad field of application of new data analysis technologies, such as decision tree learning, as useful tools for diseases prediction. This technology may achieve a potential applicability in the design of early strategies to prevent overweight/obesity.

Relationship Between Erectile Dysfunction, Diabetes and Dyslipidemia in Hypertensive-Treated Men.

PURPOSE: PRESIDEN study is a large study to analyze the erectile dysfunction (ED) incidence in Spanish population. The present study is a pilot sub-analysis from PRESIDEN to determine if ED or plasma testosterone (TST) level in controlled hypertensive patients may be associated with comorbidities and/or plasma nitrite+nitrate and antioxidant capacity. MATERIALS AND METHODS: Forty-four hypertensive individuals were aleatory selected from PRESIDEN study, matching by age (28 showing ED and 16 without ED). RESULT: Diabetes was present in 28.57% of ED patients and in 18.75% of patients without ED. In patients with and without ED, increasing age showed tendency of higher frequency of an additional comorbidity (diabetes or dyslipemia) (P = .09). Apparently, plasma TST levels were lower in older ED patients compared to younger patients with and without ED, although it did not reach statistical significance (P = .69). Older ED patients also showed lower TST levels than older patients without ED, although it was not statistical significant (16.15 ± 2.84 vs 13.91± 2.77; P = .69). Dyslipidemia was showed by 52.17% with lower TST (? nmol/L) while 23.80% of patients with plasma TST levels > 15 nmol/L had dyslipidemia. The percentage of ED patients was similar between patients with low and high TST levels. CONCLUSION: More ED hypertensive patients seem to show two comorbidities (diabetes and dyslipidemia) than hypertensivepatients without ED. Younger patients with ED tended to show more commonly diabetes than older ED patients. Plasma TST levels were not associated with more prevalence of ED but lower plasma TST levels showed tendency to higher prevalence of dyslipidemia.

Evaluación de la validez de las funciones SCORE de bajo riesgo y calibrada para población española en las cohortes FRESCO / Validity assessment of low-risk SCORE function and SCORE function calibrated to the Spanish population in the FRESCO cohorts

Introducción y objetivos. Estudiar la validez de la función SCORE original de bajo riesgo sin y con colesterol unido a lipoproteínas de alta densidad y SCORE calibrada en población española. Métodos. Análisis agrupado con datos individuales de 12 estudios de cohorte de base poblacional. Se incluyó a 30.919 participantes de 40-64 años sin enfermedades cardiovasculares en el momento del reclutamiento, que se siguieron durante 10 años para la mortalidad cardiovascular contemplada en el proyecto SCORE. La validez de las funciones se analizó mediante el área bajo la curva ROC (discriminación) y el test de Hosmer-Lemeshow (calibración), respectivamente. Resultados. Se dispuso de 286.105 personas/año. La mortalidad a 10 años por causas cardiovasculares fue del 0,6%. La razón de casos esperados/observados fue de 9,1, 6,5 y 9,1 en varones y de 3,3, 1,3 y 1,9 en mujeres con las funciones SCORE original de bajo riesgo sin y con colesterol unido a lipoproteínas de alta densidad y SCORE calibrada, respectivamente; diferencias estadísticamente significativas con el test de calibración de Hosmer-Lemeshow entre la mortalidad predicha con SCORE y la observada (p < 0,001 en ambos sexos y en todas las funciones). Las áreas bajo la curva ROC con SCORE original fueron 0,68 en varones y 0,69 en mujeres. Conclusiones. Todas las versiones de las funciones SCORE disponibles en España sobreestiman significativamente la mortalidad cardiovascular observada en la población española. A pesar de la aceptable capacidad de discriminación, la predicción del número de acontecimientos cardiovasculares mortales (calibración) fue significativamente imprecisa (AU)

Introduction and objectives. To assess the validity of the original low-risk SCORE function without and with high-density lipoprotein cholesterol and SCORE calibrated to the Spanish population. Methods. Pooled analysis with individual data from 12 Spanish population-based cohort studies. We included 30 919 individuals aged 40 to 64 years with no history of cardiovascular disease at baseline, who were followed up for 10 years for the causes of death included in the SCORE project. The validity of the risk functions was analyzed with the area under the ROC curve (discrimination) and the Hosmer-Lemeshow test (calibration), respectively. Results. Follow-up comprised 286 105 persons/y. Ten-year cardiovascular mortality was 0.6%. The ratio between estimated/observed cases ranged from 9.1, 6.5, and 9.1 in men and 3.3, 1.3, and 1.9 in women with original low-risk SCORE risk function without and with high-density lipoprotein cholesterol and calibrated SCORE, respectively; differences were statistically significant with the Hosmer-Lemeshow test between predicted and observed mortality with SCORE (P < .001 in both sexes and with all functions). The area under the ROC curve with the original SCORE was 0.68 in men and 0.69 in women. Conclusions. All versions of the SCORE functions available in Spain significantly overestimate the cardiovascular mortality observed in the Spanish population. Despite the acceptable discrimination capacity, prediction of the number of fatal cardiovascular events (calibration) was significantly inaccurate (AU)

Interaction between cardiovascular risk factors and body mass index and 10-year incidence of cardiovascular disease, cancer death, and overall mortality.

The effect of above-normal body mass index (BMI) on health outcomes is controversial because it is difficult to distinguish from the effect due to BMI-associated cardiovascular risk factors. The objective was to analyze the impact on 10-year incidence of cardiovascular disease, cancer deaths and overall mortality of the interaction between cardiovascular risk factors and BMI. We conducted a pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79years old at basal examination. Body mass index was measured at baseline being the outcome measures ten-year cardiovascular disease, cancer and overall mortality. Multivariable analyses were adjusted for potential confounders, considering the significant interactions with cardiovascular risk factors. We included 54,446 individuals (46.5% with overweight and 27.8% with obesity). After considering the significant interactions, the 10-year risk of cardiovascular disease was significantly increased in women with overweight and obesity [Hazard Ratio=2.34 (95% confidence interval: 1.19-4.61) and 5.65 (1.54-20.73), respectively]. Overweight and obesity significantly increased the risk of cancer death in women [3.98 (1.53-10.37) and 11.61 (1.93-69.72)]. Finally, obese men had an increased risk of cancer death and overall mortality [1.62 (1.03-2.54) and 1.34 (1.01-1.76), respectively]. In conclusion, overweight and obesity significantly increased the risk of cancer death and of fatal and non-fatal cardiovascular disease in women; whereas obese men had a significantly higher risk of death for all causes and for cancer. Cardiovascular risk factors may act as effect modifiers in these associations.

Validity Assessment of Low-risk SCORE Function and SCORE Function Calibrated to the Spanish Population in the FRESCO Cohorts.

INTRODUCTION AND OBJECTIVES: To assess the validity of the original low-risk SCORE function without and with high-density lipoprotein cholesterol and SCORE calibrated to the Spanish population. METHODS: Pooled analysis with individual data from 12 Spanish population-based cohort studies. We included 30 919 individuals aged 40 to 64 years with no history of cardiovascular disease at baseline, who were followed up for 10 years for the causes of death included in the SCORE project. The validity of the risk functions was analyzed with the area under the ROC curve (discrimination) and the Hosmer-Lemeshow test (calibration), respectively. RESULTS: Follow-up comprised 286 105 persons/y. Ten-year cardiovascular mortality was 0.6%. The ratio between estimated/observed cases ranged from 9.1, 6.5, and 9.1 in men and 3.3, 1.3, and 1.9 in women with original low-risk SCORE risk function without and with high-density lipoprotein cholesterol and calibrated SCORE, respectively; differences were statistically significant with the Hosmer-Lemeshow test between predicted and observed mortality with SCORE (P < .001 in both sexes and with all functions). The area under the ROC curve with the original SCORE was 0.68 in men and 0.69 in women. CONCLUSIONS: All versions of the SCORE functions available in Spain significantly overestimate the cardiovascular mortality observed in the Spanish population. Despite the acceptable discrimination capacity, prediction of the number of fatal cardiovascular events (calibration) was significantly inaccurate.

Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis.

OBJECTIVE: Diabetes is a common cause of shortened life expectancy. We aimed to assess the association between diabetes and cause-specific death. RESEARCH DESIGN AND METHODS: We used the pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79 years old. Diabetes status was self-reported or defined as glycemia >125 mg/dL at baseline. Vital status and causes of death were ascertained by medical records review and linkage with the official death registry. The hazard ratios and cumulative mortality function were assessed with two approaches, with and without competing risks: proportional subdistribution hazard (PSH) and cause-specific hazard (CSH), respectively. Multivariate analyses were fitted for cardiovascular, cancer, and noncardiovascular noncancer deaths. RESULTS: We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63-2.52) and PSH = 1.99 (1.60-2.49) in men; and CSH = 2.28 (1.75-2.97) and PSH = 2.23 (1.70-2.91) in women; 2) cancer death, CSH = 1.37 (1.13-1.67) and PSH = 1.35 (1.10-1.65) in men; and CSH = 1.68 (1.29-2.20) and PSH = 1.66 (1.25-2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23-1.91) and PSH = 1.50 (1.20-1.89) in men; and CSH = 1.89 (1.43-2.48) and PSH = 1.84 (1.39-2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes. CONCLUSIONS: Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes. The use of CSH and PSH provides a comprehensive view of mortality dynamics in a population with diabetes.

On the problem of type 2 diabetes-related mortality in the Canary Islands, Spain. The DARIOS Study.

AIMS: To compare diabetes-related mortality rates and factors associated with this disease in the Canary Islands compared with other 10 Spanish regions. METHODS: In a cross-sectional study of 28,887 participants aged 35-74 years in Spain, data were obtained for diabetes, hypertension, dyslipidemia, obesity, insulin resistance (IR), and metabolic syndrome. Healthcare was measured as awareness, treatment and control of diabetes, dyslipidemia, and hypertension. Standardized mortality rate ratios (SRR) were calculated for the years 1981 to 2011 in the same regions. RESULTS: Diabetes, obesity, and hypertension were more prevalent in people under the age of 64 in the Canary Islands than in Spain. For all ages, metabolic syndrome and insulin resistance (IR) were also more prevalent in those from the Canary Islands. Healthcare parameters were similar in those from the Canary Islands and the rest of Spain. Diabetes-related mortality in the Canary Islands was the highest in Spain since 1981; the maximum SRR was reached in 2011 in men (6.3 versus the region of Madrid; p<0.001) and women (9.5 versus Madrid; p<0.001). Excess mortality was prevalent from the age of 45 years and above. CONCLUSIONS: Diabetes-related mortality is higher in the Canary Islands population than in any other Spanish region. The high mortality and prevalence of IR warrants investigation of the genetic background associated with a higher incidence and poor prognosis for diabetes in this population. The rise in SRR calls for a rapid public health policy response.

Serum biomarkers in uncontrolled no heart-beating donors may identify kidneys that will never work after transplantation.

BACKGROUND/AIMS: Kidneys from uncontrolled non heart-beating donors achieve a good level of renal function after transplantation. However, a number of them will never function in the recipient. Our aim was to determine if serum biomarkers associated with platelet activity, inflammation and the nitric oxide system in uncontrolled non heart-beating donors may help to predict no renal function recovery after renal transplantation. METHODS: Serum levels of interleukin (IL)-6, IL-10, intercellular cell adhesion molecule-1 (ICAM-1), cyclic guanosine monophosphate (cGMP), nitrite + nitrate and platelet factor-4 (PF4) were measured using enzyme-linked immunosorbent assay (ELISA) kits in 88 uncontrolled non heart-beating donors divided according to the renal functionality achieved in the recipients into functional (n = 76) and non functional (n = 12). RESULTS: Kidneys from donors with higher IL-6 levels (>900 pg/ml) were functional after transplantation. Serum cGMP levels below 372.3 fmol/l were also associated with kidneys that recovered the renal function. However, serum levels of PF4 showed the best correlation with recovery of renal functional in the recipients since they were significantly lower in the donors whose kidneys functioned after transplantation. CONCLUSIONS: Serum PF4 levels in uncontrolled non heart-beating donors may be a good predictor for kidneys that never will reach functional recovery. Some serum cGMP, IL-6 and IL-10 levels may simply help identify kidneys that will function after transplantation.

Clinical Manifestations and Outcomes of Syphilis-associated Uveitis in Northern Spain.

PURPOSE: To describe the clinical characteristics and to assess visual prognosis of patients with syphilis-associated uveitis in northern Spain. METHODS: Retrospective review of clinical records in eight general uveitis referral centers. RESULTS: Since the year 2000, 50 patients have been diagnosed: 31 men and 19 women; median age was 41 (19-76) years. A total of 34% were co-infected with HIV and 24% presented systemic manifestations of syphilis. Median initial visual acuity and vision at last visit in 93 affected eyes was 20/50 (20/20-20/2000) and 20/22 (20/20-20/2000), respectively (p < .0001). The most frequent manifestation was papillitis (33.3%). Fifty percent of eyes with macular edema on admission presented worsening of visual acuity at last visit, whereas frequency of worsening in eyes without edema was 7.1% (p = 0.009). CONCLUSIONS: In our series, patients with syphilitic uveitis were more usually middle-aged men and were frequently co-infected with HIV. Although most patients showed posterior segment involvement, visual prognosis was good.

La ecuación ERICE: la nueva ecuación autóctona de riesgo cardiovascular para una población mediterránea envejecida y de bajo riesgo en España / The ERICE-score: the new native cardiovascular score for the low-risk and aged mediterranean population of Spain

Introducción y objetivos En España no existen unas cohortes poblacionales suficientemente grandes para hacer predicciones precisas del riesgo cardiovascular. Las ecuaciones de Framingham y EuroSCORE calibradas son las más utilizadas en España. El objetivo es desarrollar la primera ecuación de predicción autóctona para estimar con precisión el riesgo cardiovascular individual en España. Métodos Análisis conjunto de siete cohortes españolas de población de mediana edad y anciana. La población del estudio -11.800 personas (6.387 mujeres)- aportó un total de 107.915 personas-año de seguimiento y 1.214 eventos cardiovasculares (633 de ellos, mortales). Se efectuó un análisis de regresión de Cox para examinar la contribución de los diferentes factores al riesgo de cualquier evento cardiovascular (mortal y no mortal). Resultados La edad fue el principal factor de riesgo de eventos cardiovasculares. La presión arterial sistólica, la diabetes mellitus, el tabaquismo y el tratamiento antihipertensivo fueron factores predictivos fuertemente asociados con el riesgo cardiovascular. En cambio, la contribución del colesterol total sérico fue pequeña, especialmente en los mayores de 70 años. El modelo final de riesgo mostró un buen poder discriminatorio (estadístico C = 0,789 en varones y C = 0,816 en mujeres). Conclusiones ERICE es una nueva ecuación de riesgo cardiovascular genuinamente española obtenida a partir del riesgo concurrente individual de los participantes en varias cohortes. La ecuación ERICE ofrece una estimación directa y fiable del riesgo cardiovascular total teniendo en cuenta factores como la diabetes mellitus y el tratamiento farmacológico de los factores de riesgo cardiovascular, habitualmente no incluidos en otras ecuaciones (AU)

Introduction and objectives In Spain, data based on large population-based cohorts adequate to provide an accurate prediction of cardiovascular risk have been scarce. Thus, calibration of the EuroSCORE and Framingham scores has been proposed and done for our population. The aim was to develop a native risk prediction score to accurately estimate the individual cardiovascular risk in the Spanish population. Methods Seven Spanish population-based cohorts including middle-aged and elderly participants were assembled. There were 11 800 people (6387 women) representing 107 915 person-years of follow-up. A total of 1214 cardiovascular events were identified, of which 633 were fatal. Cox regression analyses were conducted to examine the contributions of the different variables to the 10-year total cardiovascular risk. Results Age was the strongest cardiovascular risk factor. High systolic blood pressure, diabetes mellitus and smoking were strong predictive factors. The contribution of serum total cholesterol was small. Antihypertensive treatment also had a significant impact on cardiovascular risk, greater in men than in women. The model showed a good discriminative power (C-statistic = 0.789 in men and C = 0.816 in women). Ten-year risk estimations are displayed graphically in risk charts separately for men and women. Conclusions The ERICE is a new native cardiovascular risk score for the Spanish population derived from the background and contemporaneous risk of several Spanish cohorts. The ERICE score offers the direct and reliable estimation of total cardiovascular risk, taking in consideration the effect of diabetes mellitus and cardiovascular risk factor management. The ERICE score is a practical and useful tool for clinicians to estimate the total individual cardiovascular risk in Spain (AU)

The ERICE-score: the new native cardiovascular score for the low-risk and aged Mediterranean population of Spain.

INTRODUCTION AND OBJECTIVES: In Spain, data based on large population-based cohorts adequate to provide an accurate prediction of cardiovascular risk have been scarce. Thus, calibration of the EuroSCORE and Framingham scores has been proposed and done for our population. The aim was to develop a native risk prediction score to accurately estimate the individual cardiovascular risk in the Spanish population. METHODS: Seven Spanish population-based cohorts including middle-aged and elderly participants were assembled. There were 11800 people (6387 women) representing 107915 person-years of follow-up. A total of 1214 cardiovascular events were identified, of which 633 were fatal. Cox regression analyses were conducted to examine the contributions of the different variables to the 10-year total cardiovascular risk. RESULTS: Age was the strongest cardiovascular risk factor. High systolic blood pressure, diabetes mellitus and smoking were strong predictive factors. The contribution of serum total cholesterol was small. Antihypertensive treatment also had a significant impact on cardiovascular risk, greater in men than in women. The model showed a good discriminative power (C-statistic=0.789 in men and C=0.816 in women). Ten-year risk estimations are displayed graphically in risk charts separately for men and women. CONCLUSIONS: The ERICE is a new native cardiovascular risk score for the Spanish population derived from the background and contemporaneous risk of several Spanish cohorts. The ERICE score offers the direct and reliable estimation of total cardiovascular risk, taking in consideration the effect of diabetes mellitus and cardiovascular risk factor management. The ERICE score is a practical and useful tool for clinicians to estimate the total individual cardiovascular risk in Spain.

Identification of a new locus and validation of previously reported loci showing differential methylation associated with smoking. The REGICOR study.

Smoking increases the risk of many diseases and could act through changes in DNA methylation patterns. The aims of this study were to determine the association between smoking and DNA methylation throughout the genome at cytosine-phosphate-guanine (CpG) site level and genomic regions. A discovery cross-sectional epigenome-wide association study nested in the follow-up of the REGICOR cohort was designed and included 645 individuals. Blood DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip. Smoking status was self-reported using a standardized questionnaire. We identified 66 differentially methylated CpG sites associated with smoking, located in 38 genes. In most of these CpG sites, we observed a trend among those quitting smoking to recover methylation levels typical of never smokers. A CpG site located in a novel smoking-associated gene (cg06394460 in LNX2) was hypomethylated in current smokers. Moreover, we validated two previously reported CpG sites (cg05886626 in THBS1, and cg24838345 in MTSS1) for their potential relation to atherosclerosis and cancer diseases, using several different approaches: CpG site methylation, gene expression, and plasma protein level determinations. Smoking was also associated with higher THBS1 gene expression but with lower levels of thrombospondin-1 in plasma. Finally, we identified differential methylation regions in 13 genes and in four non-coding RNAs. In summary, this study replicated previous findings and identified and validated a new CpG site located in LNX2 associated with smoking.

Effects of factor Xa on the expression of proteins in femoral arteries from type 2 diabetic patients.

AIM: Further to its pivotal role in haemostasis, factor Xa (FXa) promotes effects on the vascular wall. The purpose of the study was to evaluate if FXa modifies the expression level of energy metabolism and oxidative stress-related proteins in femoral arteries obtained from type 2 diabetic patients with end-stage vasculopathy. METHODS: Femoral arteries were obtained from 12 type 2 diabetic patients who underwent leg amputation. Segments from the femoral arteries were incubated in vitro alone and in the presence of 25 nmol l(-1) FXa and 25 nmol l(-1) FXa + 50 nmol l(-1) rivaroxaban. RESULTS: In the femoral arteries, FXa increased triosephosphate isomerase and glyceraldehyde-3-phosphate dehydrogenase isotype 1 expression but decreased pyruvate dehydrogenase expression. These facts were accompanied by an increased content of acetyl-CoA. Aconitase activity was reduced in FXa-incubated femoral arteries as compared with control. Moreover, FXa increased the protein expression level of oxidative stress-related proteins which was accompanied by an increased malonyldialdehyde arterial content. The FXa inhibitor, rivaroxaban, failed to prevent the reduced expression of pyruvate dehydrogenase induced by FXa but reduced acetyl-CoA content and reverted the decreased aconitase activity observed with FXa alone. Rivaroxaban + FXa but not FXa alone increased the expression level of carnitine palmitoyltransferase I and II, two mitochondrial long chain fatty acid transporters. Rivaroxaban also prevented the increased expression of oxidative stress-related proteins induced by FXa alone. CONCLUSIONS: In femoral isolated arteries from type 2 diabetic patients with end-stage vasculopathy, FXa promoted disruption of the aerobic mitochondrial metabolism. Rivaroxaban prevented such effects and even seemed to favour long chain fatty acid transport into mitochondria.

Nitric oxide from mononuclear cells may be involved in platelet responsiveness to aspirin.

BACKGROUND: Several mechanisms have been proposed to explain why some platelets have a reduced response to aspirin (ASA). Among them, it was reported an increased circulating level of vitamin-D-binding protein (DBP). In addition, nitric oxide (NO) released from mononuclear cells was involved in the antiplatelet effects of ASA. The aim was to analyse the relationship between platelet response to ASA and both NO generation and vitamin-D-binding protein content in mononuclear cells. MATERIALS AND METHODS: Mononuclear cells were obtained from patients with stable coronary artery disease that were divided by a platelet functionality test (PFA-100) as ASA-sensitive (n=23) and ASA resistant (n=27). RESULTS: Both the release of NO (determined by nitrite+nitrate concentration) and the expression of endothelial-type NO synthase (eNOS) were higher in mononuclear cells from ASA sensitive as compared with those from ASA-resistant patients. There was a positive correlation between either the release of NO and the expression of eNOS protein in mononuclear cells with the ability of ASA to inhibit platelet activity. DBP content in mononuclear cells was higher in ASA resistant than in ASA sensitive. The level of DBP content in mononuclear cells was negatively associated with the ability of ASA to inhibit platelets. However, in vitro experiments suggested that there was no association between DBP and NO production by mononuclear cells. CONCLUSIONS: Mononuclear cells from patients with platelets with lower responsiveness to ASA showed a reduced ability to produce NO.