Cysteinyl leukotriene signaling aggravates myocardial hypoxia in experimental atherosclerotic heart disease

Cysteinyl-leukotrienes (cys-LT) are powerful spasmogenic and immune modulating lipid mediators involved in inflammatory diseases, in particular asthma. Here, we investigated whether cys-LT signaling, in the context of atherosclerotic heart disease, compromises the myocardial microcirculation and its response to hypoxic stress. To this end, we examined Apoe(-/-) mice fed a hypercholesterolemic diet and analysed the expression of key enzymes of the cys-LT pathway and their receptors (CysLT1/CysLT2) in normal and hypoxic myocardium as well as the potential contribution of cys-LT signaling to the acute myocardial response to hypoxia. METHODS AND PRINCIPAL FINDINGS: Myocardial biopsies from Apoe(-/-) mice demonstrated signs of chronic inflammation with fibrosis, increased apoptosis and expression of IL-6, as compared to biopsies from C57BL/6J control mice. In addition, we found increased leukotriene C(4) synthase (LTC(4)S) and CysLT1 expression in the myocardium of Apoe(-/-) mice. Acute bouts of hypoxia further induced LTC(4)S expression, increased LTC(4)S enzyme activity and CysLT1 expression, and were associated with increased extension of hypoxic areas within the myocardium. Inhibition of cys-LT signaling by treatment with montelukast, a selective CysLT1 receptor antagonist, during acute bouts of hypoxic stress reduced myocardial hypoxic areas in Apoe(-/-) mice to levels equal to those observed under normoxic conditions. In human heart biopsies from 14 patients with chronic coronary artery disease mRNA expression levels of LTC(4)S and CysLT1 were increased in chronic ischemic compared to non-ischemic myocardium, constituting a molecular basis for increased cys-LT signaling. CONCLUSION: Our results suggest that CysLT1 antagonists may have protective effects on the hypoxic heart, and improve the oxygen supply to areas of myocardial ischemia, for instance during episodes of sleep apnea

Total and Subtypes of Dietary Fat Intake and Its Association with Components of the Metabolic Syndrome in a Mediterranean Population at High Cardiovascular Risk

Background: The effect of dietary fat intake on the metabolic syndrome (MetS) and in turn on cardiovascular disease (CVD) remains unclear in individuals at high CVD risk. Objective: To assess the association between fat intake and MetS components in an adult Mediterranean population at high CVD risk. Design: Baseline assessment of nutritional adequacy in participants (n = 6560, men and women, 55-75 years old, with overweight/obesity and MetS) in the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial. Methods: Assessment of fat intake (total fat, monounsatured fatty acids: MUFA, polyunsaturated fatty acids: PUFA, saturated fatty acids: SFA, trans-fatty acids: trans-FA, linoleic acid, α-linolenic acid, and ω-3 FA) using a validated food frequency questionnaire, and diet quality using 17-item Mediterranean dietary questionnaire and fat quality index (FQI). Results: Participants in the highest quintile of total dietary fat intake showed lower intake of energy, carbohydrates, protein and fiber, but higher intake of PUFA, MUFA, SFA, TFA, LA, ALA and ω-3 FA. Differences in MetS components were found according to fat intake. Odds (5th vs. 1st quintile): hyperglycemia: 1.3-1.6 times higher for total fat, MUFA, SFA and ω-3 FA intake; low high-density lipoprotein cholesterol (HDL-c): 1.2 higher for LA; hypertriglyceridemia: 0.7 lower for SFA and ω-3 FA intake. Conclusions: Dietary fats played different role on MetS components of high CVD risk patients. Dietary fat intake was associated with higher risk of hyperglycemia

Relationship between olive oil consumption and ankle-brachial pressure index in a population at high cardiovascular risk

The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome. Methods: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure. Results: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48]). Conclusions: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed

Effect of a mediterranean diet intervention on dietary glycemic load and dietary glycemic index: the predimed study

Objective. To compare the one year effect of two dietary interventions with MeDiet on GL and GI in the PREDIMED trial. Methods. Participants were older subjects at high risk for cardiovascular disease. This analysis included 2866 nondiabetic subjects. Diet was assessed with a validated 137-item food frequency questionnaire (FFQ). The GI of each FFQ item was assigned by a 5-step methodology using the International Tables of GI and GL Values. Generalized linear models were fitted to assess the relationship between the intervention group and dietary GL and GI at one year of follow-up, using control group as reference. Results. Multivariate-adjusted models showed an inverse association between GL and MeDiet + extra virgin olive oil (EVOO) group: β = -8.52 (95% CI: -10.83 to -6.20) and MeDiet + Nuts group: β = -10.34 (95% CI: -12.69 to -8.00), when comparing with control group. Regarding GI, β = -0.93 (95% CI: -1.38 to -0.49) for MeDiet + EVOO, β = -1.06 (95% CI: -1.51 to -0.62) for MeDiet + Nuts when comparing with control group. Conclusion. Dietary intervention with MeDiet supplemented with EVOO or nuts lowers dietary GL and GI

Seafood Consumption, Omega-3 Fatty Acids Intake, and Life-Time Prevalence of Depression in the PREDIMED-Plus Trial

Background: The aim of this analysis was to ascertain the type of relationship between fish and seafood consumption, omega-3 polyunsaturated fatty acids (ω-3 PUFA) intake, and depression prevalence. Methods: Cross-sectional analyses of the PREDIMED-Plus trial. Fish and seafood consumption and ω-3 PUFA intake were assessed through a validated food-frequency questionnaire. Self-reported life-time medical diagnosis of depression or use of antidepressants was considered as outcome. Depressive symptoms were collected by the Beck Depression Inventory-II. Logistic regression models were used to estimate the association between seafood products and ω-3 PUFA consumption and depression. Multiple linear regression models were fitted to assess the association between fish and long-chain (LC) ω-3 PUFA intake and depressive symptoms. Results: Out of 6587 participants, there were 1367 cases of depression. Total seafood consumption was not associated with depression. The odds ratios (ORs) (95% confidence intervals (CIs)) for the 2nd, 3rd, and 4th quintiles of consumption of fatty fish were 0.77 (0.63–0.94), 0.71 (0.58–0.87), and 0.78 (0.64–0.96), respectively, and p for trend = 0.759. Moderate intake of total LC ω-3 PUFA (approximately 0.5–1 g/day) was significantly associated with a lower prevalence of depression. Conclusion: In our study, moderate fish and LC ω-3 PUFA intake, but not high intake, was associated with lower odds of depression suggesting a U-shaped relationship

Dietary diversity and nutritional adequacy among an older Spanish population with Metabolic Syndrome in the PREDIMED-Plus study: a cross-sectional analysis

Dietary guidelines emphasize the importance of a varied diet to provide an adequate nutrient intake. However, an older age is often associated with consumption of monotonous diets that can be nutritionally inadequate, increasing the risk for the development or progression of diet-related chronic diseases, such as metabolic syndrome (MetS). To assess the association between dietary diversity (DD) and nutrient intake adequacy and to identify demographic variables associated with DD, we cross-sectionally analyzed baseline data from the PREDIMED-Plus trial: 6587 Spanish adults aged 55–75 years, with overweight/obesity who also had MetS. An energy-adjusted dietary diversity score (DDS) was calculated using a 143-item validated semi-quantitative food frequency questionnaire (FFQ). Nutrient inadequacy was defined as an intake below 2/3 of the dietary reference intake (DRI) forat least four of 17 nutrients proposed by the Institute of Medicine (IOM). Logistic regression models were used to evaluate the association between DDS and the risk of nutritionally inadequate intakes. In the higher DDS quartile there were more women and less current smokers. Compared with subjects in the highest DDS quartile, those in the lowest DDS quartile had a higher risk of inadequate nutrient intake: odds ratio (OR) = 28.56 (95% confidence interval (CI) 20.80–39.21). When we estimated food varietyfor each of the food groups, participants in the lowest quartile had a higher risk of inadequate nutrient intake for the groups of vegetables, OR = 14.03 (95% CI 10.55–18.65), fruits OR = 11.62 (95% CI 6.81–19.81), dairy products OR = 6.54 (95% CI 4.64–9.22) and protein foods OR = 6.60 (95% CI 1.96–22.24). As DDS decreased, the risk of inadequate nutrients intake rose. Given the impact of nutrient intake adequacy on the prevention of non-communicable diseases, health policies should focus on the promotion of a healthy varied diet, specifically promoting the intake of vegetables and fruit among population groups with lower DDS such as men, smokers or widow(er)s. View Full-Tex

Blocking cysteinyl leukotriene signalling ameliorates myocardial hypoxia in chronic ischemic heart disease

Background: The involvement of cysteinyl leukotrienes (cys-LTs) and their receptors (CysLTs receptor) in the pathologic response to chronic cardiac ischemia and during bouts of ischemia remains an unresolved question. Objective: We investigated the expression of cys-LT pathway components in normal and ischemic myocardium and the potential benefits of interrupting cys-LT signalling during bouts of ischemia. Methods and Results: Heart biopsies were collected from C57BL/6J control mice and Apoe-/- mice fed a hypercholesterolemic diet for 1 year and subjected to an hypoxic stimulus for 30 minutes. Contribution of leukotriene signalling to cardiac ischemia induced by hypoxia was evaluated by administration of montelukast, a selective CysLT1 receptor antagonist. We also used a unique collection of human heart biopsies obtained from normal and chronic ischemic areas of the myocardium of 14 patients with chronic coronary artery disease. Here we report that in myocardium of Apoe-/- mice, leukotriene C4 synthase (LTC4S) and CysLT1 are upregulated compared to C57BL/6J. Acute hypoxia further induced LTC4S expression and enzyme activity along with increased CysLT1 expression. Similar mRNA expression patterns of LTC4S and CysLT1 were observed in non-ischemic versus chronic ischemic human myocardium. Treatment of Apoe-/- mice with montelukast, during acute hypoxic stress, ameliorated myocardial hypoxic load to levels equal to those observed under normoxia. Conclusions: The data show an increased leukotriene signalling in chronic ischemic myocardium. In an experimental Apoe-/- model of ischemic cardiomyopathy, inhibition of leukotriene signalling ameliorates hypoxic damage to the myocardium suggesting a possible beneficial effect of antileukotriene drugs on the ischemic heart. Figure 1: LTC4S and CysLT1 are upregulated in cardiac tissue of Apoe-/- mice In the -/-Apoe-/- heart levels of LTC4S and CysLT1 are significantly upregulated as compared to control C57BL/6J mice (Panel A). Acute hypoxic stress in Apoe-/- mice increases the cardiac expression of LTC4S (p<0.05) and CysLT1 (p=0.06) compared to normoxic conditions (Panel B). Each experiment was run in duplicate and changes in mRNA levels were expressed as \u394\u394Ct values. Values are mean \ub1 SD. *, p<0.05; **, p<0.01. References. [1] Gabrielsen A, Lawler PR, Yongzhong W, et al., Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium. J Mol Cell Cardiol. 42, 870-83, 2007. [2] Steffens S, Montecucco F, Mach F., The inflammatory response as a target to reduce myocardial ischaemia and reperfusion injury. Thromb Haemost,102, 240-7, 2009

Nut Consumptions as a Marker of Higher Diet Quality in a Mediterranean Population at High Cardiovascular Risk

Background: Nut consumption has been associated with improved nutrient adequacy and diet quality in healthy adult populations but this association has never been explored in individuals at high cardiovascular risk. Objective: to assess the associations between consumption of nuts and nutrient adequacy and diet quality in a Mediterranean population at high cardiovascular risk. Design: baseline assessment of nutritional adequacy in participants (n = 6060, men and women, with ages 55⁻75 years old, with overweight/obesity and metabolic syndrome) in the PREDIMED-PLUS primary cardiovascular prevention randomized trial. Methods: nut intake was assessed using a validated food frequency questionnaire. Participants who reported consuming zero quantity of nuts were classified as 'non-nut consumers'. 'Nut consumers' were participants who reported consuming any quantity of nuts. Nineteen micronutrients were examined (vitamins B1, B2, B3, B6, B12, A, C, D, E and folic acid; Ca, K, P, Mg, Fe, Se, Cr, Zn, and iodine). The proportion of micronutrient inadequacy was estimated using the estimated average requirements (EAR) or adequate intake (AI) cut-points. Diet quality was also assessed using a 17-item Mediterranean dietary questionnaire (Mediterranean diet score, MDS), a carbohydrate quality index (CQI) and a fat quality index (FQI). Results: eighty-two percent of participants were nut consumers (median of nut consumption 12.6 g/day; interquartile range: 6.0⁻25.2). Nut consumers were less likely to be below the EAR for vitamins A, B1, B2, B6, C, D, E, folic acid, and Ca, Mg, Se and Zn than non-nut consumers. Nut consumers were also more likely to be above the AI for K and Cr than non-nut consumers. Nut consumers had lower prevalence of inadequate micronutrient intakes, but also higher CQI, higher FQI, and better scores of adherence to the Mediterranean diet (Mediterranean diet score, MDS). Conclusions: nut consumers had better nutrient adequacy, diet quality, and adherence to the MedDiet than those non-nut consumers

Quantitative MRI analysis of brain volume changes due to controlled cortical impact

More than 85% of reported brain traumas are classified clinically as “mild” using GCS; qualitative MRI findings are scarce and provide little correspondence to clinical symptoms. Our goal, therefore, was to establish in-vivo sequellae of traumatic brain injury following lower and higher levels of impact to the frontal lobe using quantitative MRI analysis and a mechanical model of penetrating impact injury. To investigate time-based morphological and physiological changes of living tissue requires a surrogate for the human central nervous system. The present model for TBI was a systematically varied and controlled cortical impact on deeply-anaesthetized Sprague Dawley rats designed to mimic different injury severities. Whole-brain MRI scans were performed on each rat prior to either a lower or a higher level of impact and then at hourly intervals for five hours post-impact. Both brain volume and specific anatomical structures were segmented from MR images for inter-subject comparisons post-registration. Animals subjected to lower and higher impact levels exhibited elevated intracranial pressure (ICP) in the low compensatory reserve (i.e., nearly exhausted) and terminal disturbance (i.e., exhausted) ranges, respectively. There was a statistically-significant drop in cerebrospinal fluid of 35% in the lower impacts and 65% in the higher impacts at Hr5 in comparison to the sham control. There was a corresponding increase in corpus callosum volume starting from Hr1 of 60-110% and 30-40% following the lower and higher impact levels, respectively. A statistically significant change in the abnormal tissue from Hr2 to Hr5 was observed for both impact levels, with greater significance for higher impacts. Furthermore, a statistically significant difference between the lower impacts and the sham controls occurred at Hr3. These results are statistically substantiated by a fluctuation in the physical size of the corpus callosum, a decrease in the volume of CSF, and elevated levels of atrophy in the cerebral cortex.Science Foundation IrelandHigher Education AuthorityOther funderEnterprise Irelandti, ke, ab - TS 02.1

Effect of a mediterranean diet intervention on dietary glycemic load and dietary glycemic index: the predimed study

Objective. To compare the one year effect of two dietary interventions with MeDiet on GL and GI in the PREDIMED trial. Methods. Participants were older subjects at high risk for cardiovascular disease. This analysis included 2866 nondiabetic subjects. Diet was assessed with a validated 137-item food frequency questionnaire (FFQ). The GI of each FFQ item was assigned by a 5-step methodology using the International Tables of GI and GL Values. Generalized linear models were fitted to assess the relationship between the intervention group and dietary GL and GI at one year of follow-up, using control group as reference. Results. Multivariate-adjusted models showed an inverse association between GL and MeDiet + extra virgin olive oil (EVOO) group: β = -8.52 (95% CI: -10.83 to -6.20) and MeDiet + Nuts group: β = -10.34 (95% CI: -12.69 to -8.00), when comparing with control group. Regarding GI, β = -0.93 (95% CI: -1.38 to -0.49) for MeDiet + EVOO, β = -1.06 (95% CI: -1.51 to -0.62) for MeDiet + Nuts when comparing with control group. Conclusion. Dietary intervention with MeDiet supplemented with EVOO or nuts lowers dietary GL and GI