Lifestyle and biological factors influence the relationship between mental health and low-grade inflammation.

Mental health modulates the risk of common chronic conditions. Although inflammation is thought to partly explain this link, its relation with mental health is still unclear and largely unexplored. We investigated three scales assessing psychological resilience (CD-RISC), depression symptoms (PHQ9-6) and mental wellbeing (SF36-MCS) in an Italian adult population cohort (Nmax = 16,952). This showed a slightly higher frequency of men, more educated and younger participants, compared to samples with incomplete questionnaires. We performed stepwise generalized linear models to test the association between each scale and INFLA-score, a composite blood-based inflammation index. At each step, a class of potential mediators was included in the model, namely health conditions, lifestyle factors, or both (full model). Full model analysis was also conducted on single blood markers involved in the inflammatory process. In the baseline model, we observed significant associations of PHQ9-6 (standardized ß(SE) = 0.024(0.009), p = 8.9 × 10-3) and SF36-MCS (ß(SE) = -0.021(0.008), p = 7 × 10-3) with INFLA-score. These associations survived adjustment for health conditions but not for lifestyle factors, which explained 81% and 17% of the association with PHQ9-6 and SF36-MCS. Significant associations (p < 4.2 × 10-3) after mediator adjustment were observed for single low-grade inflammation markers, including platelet distribution width (with PHQ9-6 and CD-RISC), granulocyte- and neutrophil-to-lymphocyte ratios, monocyte and lymphocyte fractions (with SF36-MCS). After imputation of missing data, we observed substantially consistent associations. These findings suggest that the relationship between mental health and low-grade inflammation is largely influenced by lifestyle. However, the associations with specific biomarkers related to inflammation are partly independent and might be explained by biological factors.

Impact of combined healthy lifestyle factors on survival in an adult general population and in high-risk groups: prospective results from the Moli-sani Study.

BACKGROUND: There is poor knowledge on the association between combined lifestyles with mortality risk among individuals at high risk, and little is known on the biological mechanisms that could be on the pathway. METHODS: Longitudinal analysis on 22 839 individuals from the Moli-sani Study (Italy, 2005-2010). Among them, we identified 5200 elderly individuals (≥65 year), 2127 subjects with diabetes and 1180 with cardiovascular disease (CVD) at baseline. A healthy lifestyle score (HLS) was calculated, allocating 1 point for each of the following: abstention from smoking; adherence to Mediterranean diet; physical activity; absence of abdominal obesity. Hazard ratios (HR) with 95% confidence intervals (95%CI) were calculated by multivariable Cox regression and competing risk models. RESULTS: During 8.2 years of follow-up, 1237 deaths occurred. In the general population, adherence to all four healthy lifestyles, compared with none or 1, was associated with lower risk of all-cause (HR = 0.53; 95%CI:0.39-0.72), CVD (HR = 0.54; 0.32-0.91), cancer (HR = 0.62; 0.39-1.00) and mortality from other causes (HR = 0.39; 0.19-0.81). A 1-point increase in HLS was associated with 20%, 22% and 24% lower risk of total mortality among the elderly, in subjects with diabetes or CVD, respectively. Traditional (e.g. blood lipids), inflammatory (e.g. C-reactive protein) and novel biomarkers (e.g. markers of cardiac damage) accounted for up to 24% of the association of HLS with all-cause mortality risk in the general population. CONCLUSIONS: The impact of combined four healthy lifestyles on survival was considerable, both in the general population and among high-risk subgroups. Inflammatory and novel biomarkers of CVD risk explained a substantial proportion of this association.

Serum vitamin D deficiency and risk of hospitalization for heart failure: Prospective results from the Moli-sani study.

BACKGROUND AND AIMS: Evidence indicates that Vitamin D deficiency may be associated with increased risk of cardiovascular disease, although findings on risk of heart failure (HF) are controversial. We investigated the relationship between serum Vitamin D and the incidence of hospitalization for HF in a large prospective cohort of Italian adults. METHODS AND RESULTS: 19,092 (49% men, age range 35-99 years) HF-free individuals from the Moli-sani study, with complete data on serum Vitamin D (25-hydroxyvitamin) levels and incident hospitalized HF, were analysed. The cohort was followed up for a median of 6.2 years. Baseline serum Vitamin D levels were categorized in deficient (<10 ng/mL), insufficient (10-29 ng/mL), and normal (≥30 ng/mL) Incident cases of hospitalization for HF were identified by linkage with the regional hospital discharge registry. Hazard ratios (HRs) were calculated using Cox-proportional hazard models. The prevalence of normal, insufficient or deficient levels of Vitamin D was 12.2%, 79.6% and 8.2%, respectively. During follow-up, 562 admissions to hospital for HF were identified. The incidence of HF was 1.6%, 2.9% and 5.3%, respectively in subjects with normal, insufficient and deficient levels of Vitamin D. After multivariable analysis, individuals with deficiency of Vitamin D had a higher risk of hospitalization for HF (HR: 1.61, 95%CI: 1.06-2.43) than those with normal levels. Further adjustment for subclinical inflammation did not substantially change the association between Vitamin D deficiency and HF. CONCLUSION: Deficiency of Vitamin D was associated, independently of known HF risk factors, with an increased risk of hospitalization for HF in an Italian adult population.

Fish intake is associated with lower cardiovascular risk in a Mediterranean population: Prospective results from the Moli-sani study.

BACKGROUND AND AIMS: Fish consumption reportedly reduces the risk of heart disease, but the evidence of cardiovascular advantages associated with fish intake within Mediterranean cohorts is limited. The aim of this study was to test the association between fish intake and risk of composite coronary heart disease (CHD) and stroke in a large population-based cohort adhering to Mediterranean Diet. METHODS AND RESULTS: Prospective analysis on 20,969 subjects free from cardiovascular disease at baseline, enrolled in the Moli-sani study (2005-2010). Food intake was recorded by the Italian version of the EPIC food frequency questionnaire. Hazard ratios were calculated by using multivariable Cox-proportional hazard models. During a median follow-up of 4.3 years, a total of 352 events occurred (n of CHD = 287 and n of stroke = 66). After adjustment for a large panel of covariates, fish intake ≥4 times per week was associated with 40% reduced risk of composite CHD and stroke (HR = 0.60; 95%CI 0.40-0.90), and with 40% lower risk of CHD (HR = 0.60; 95%CI 0.38-0.94) as compared with subjects in the lowest category of intake (<2 times/week). A similar trend of protection was found for stroke risk although results were not significant (HR = 0.62; 95%CI 0.26-1.51). When fish types were considered, protection against the composite outcome and CHD was confined to fatty fish intake. CONCLUSIONS: Fish intake was associated with reduced risk of composite fatal and non-fatal CHD and stroke in a general Mediterranean population. The favourable association was likely to be driven by fatty fish.

Heritability, genetic correlation and linkage to the 9p21.3 region of mixed platelet-leukocyte conjugates in families with and without early myocardial infarction.

BACKGROUND AND AIMS: Variations in mixed platelet-leukocyte conjugate formation in human whole blood could be genetically determined. We quantified platelet and leukocyte activation and interaction in families with or without early myocardial infarction and evaluated their heritability, genetic correlation and linkage to the 9p21.3 region. METHODS AND RESULTS: The study population included 739 subjects (≥ 15 years old) from 54 large pedigrees, 23 with and 31 without familial myocardial infarction. Mixed platelet-leukocyte conjugates and markers of platelet or leukocyte activation (P-selectin, CD11b and L-selectin surface expression) were measured both before and after in vitro blood stimulation with collagen-ADP. All traits had significant genetic components (17.5-65.3% of the phenotypic variability), while shared household effects (0-39.6%) and environmental covariates (0-10.2%) tended to be smaller. Stimulated platelet-polymorphonuclear leukocyte (PMN) and platelet-monocyte conjugates showed the highest linkage to the 9p21.3 region (LOD = 0.94 and 1.33, respectively; empirical p value = 0.017 and 0.009). PMN markers resulted strongly genetically correlated between them in bivariate analysis among pairs of quantitative traits. CONCLUSION: This study supports a genetic regulation of human mixed platelet-leukocyte conjugates.

Typical breakfast food consumption and risk factors for cardiovascular disease in a large sample of Italian adults.

BACKGROUND AND AIMS: The overall consumption of foods most frequently consumed in a typical Italian breakfast might be associated with a better cardiovascular risk profile in Italian adults. METHOD SAND RESULTS: 18,177 subjects (53,2% women), aged ≥ 35 yrs, randomly selected from the Moli-sani Project population were studied. The European Prospective Investigation into Cancer and Nutrition (EPIC) FFQ was used for dietary assessment. To derive breakfast pattern, an "a priori" approach was used: firstly, foods typical of the Italian breakfast were selected: milk, coffee, tea, yogurt, crispbread/rusks, breakfast cereals, brioche, biscuits, honey, sugar and jam. The breakfast score was obtained adding the amounts of all selected foods, expressed in grams/day, previously standardized to mean zero and standard deviation 1. Subjects showing a higher breakfast score appeared to be younger, more frequently women or smokers, with higher social status but less likely practicing physical activity. After multivariable analyses, subjects with a higher breakfast food consumption had a lower risk to have high body mass index, abdominal obesity, systolic and diastolic blood pressure, blood glucose, triglycerides, total cholesterol (P < 0.0001 for all) and C Reactive Protein (P = 0.022). The associations were unrelated to age, sex, smoking, obesity, physical activity and social status. Subjects with a higher food breakfast score also showed a better physical healthy status score, a lower risk of metabolic syndrome (OR = 0.63; 0.55-0.72 95% CI) and of future CVD (P < 0.0001 for both women and men). CONCLUSION: Consumption of typical Italian breakfast foods positively affects CVD risk profile in an adult Italian population.

Dietary patterns, cardiovascular risk factors and C-reactive protein in a healthy Italian population.

BACKGROUND AND AIMS: Dietary habits have been associated with cardiovascular disease (CVD) risk factors. This study aimed at evaluating the association of non-predefined dietary patterns with CVD risk profile and C-reactive protein (CRP). METHODS AND RESULTS: We analyzed 7646 healthy subjects from the Moli-sani project, an on-going cross-sectional cohort study of men and women aged >or=35, randomly recruited from a general Italian population. The Italian EPIC food frequency questionnaire was used. Food patterns were generated using principal factor analysis (PFA) and reduced rank regression (RRR). Three dietary patterns were identified by PFA. The "Olive Oil and Vegetables" pattern, characterized by high intake of olive oil, vegetables, legumes, soups, fruits and fish, was associated with relatively lower values of glucose, lipids, CRP, blood pressure and individual global CVD risk score. The "Pasta and Meat" pattern, characterized by high intake of pasta, tomato sauce, red meat, animal fats and alcohol, was positively associated with glucose, lipids, CRP and CVD risk score. The "Eggs and Sweets" pattern, characterized by positive loadings of eggs, processed meat, margarines, butter, sugar and sweets, was associated with high values of CRP. The first RRR pattern was similar to the "Pasta and Meat" pattern both in composition and association with CVD risk profile. CONCLUSIONS: In a large healthy Italian population, non-predefined dietary patterns including foods considered to be rather unhealthy, were associated with higher levels of cardiovascular risk factors, CRP and individual global CVD risk, whereas a "prudent-healthy" pattern was associated with lower levels.

Alcohol-free red wine prevents arterial thrombosis in dietary-induced hypercholesterolemic rats: experimental support for the 'French paradox'.

The concept of the 'French paradox' has been recently challenged. As it is difficult in a short period to produce direct clinical evidence of the protective effect of red wine on thrombosis, we evaluated such a possibility in an experimental model mimicking the conditions of the 'French paradox'. Normolipidemic rats (FNL) were fed a standard diet or a 2% cholesterol-rich-diet (Ch-rich-diet) for 5 months: the latter was given either alone (FNL + D) or in combination with 'alcohol-free' red wine (FNL + D + 5 W). Arterial thrombosis was measured as the occlusion time (OT) of an artificial prosthesis inserted into the abdominal aorta. Lipid levels, platelet adhesion to fibrillar collagen, factor VII (FVII) clotting activity and fibrinogen levels were also measured. Compared to animals fed a standard diet, Ch-rich diet induced in FNL rats a several-fold increase in lipids and FVII levels with a concomitant significant increase in both thrombotic tendency (shortening of the OT) and platelet adhesion. 'Alcohol-free' red wine supplementation almost completely reverted the prothrombotic effect of the Ch-rich-diet. Indeed, the OT was prolonged from 78 +/- 3 to 122 +/- 10 h (P < 0.01), while platelet adhesion to fibrillar collagen was reduced from 49 +/- 3.5% to 30 +/- 2.8%. Neither the increase in lipid levels induced by Ch-rich diet nor FVII or fibrinogen levels were modified by wine supplementation. In conclusion, in experimental animals, this study supports the concept of the 'French paradox' that regular consumption of wine (rather than alcohol) was able to prevent arterial thrombosis associated with dietary-induced hypercholesterolemia, an effect mediated by downregulation of platelet function.

Orange juice intake during a fatty meal consumption reduces the postprandial low-grade inflammatory response in healthy subjects.

BACKGROUND AND AIMS: Evidence associates polyphenol-rich foods to reduction of low-grade inflammation and mortality for cardiovascular disease, the mechanisms underlying such effects being still unclear. Consumption of a fatty meal by healthy volunteers induces rapid and reversible low-grade inflammation. The aim of the present study was to evaluate the effect of orange juice on cellular modifications induced by a fatty meal. METHODS AND RESULTS: 18 apparently healthy subjects consumed a fatty meal, during which they drunk orange juice, either blond or red, or water, according to a randomized cross-over design. Two hours after the end of the fatty meal, both white blood cell (WBC) and platelet counts significantly increased (12.5 and 5%, respectively), while mean platelet volume decreased and a 25% release of myeloperoxidase (MPO) from polymorphonuclear leukocyte occurred. Both juices significantly prevented WBC increase and MPO degranulation, in respect to control. Triglycerides significantly increased (42%) after the fatty meal, but at a lower extent when red orange juice was consumed with the meal (20%), in respect to blond orange juice or control. This effect was statistically significant in the subgroup of 8 subjects with hypertriglyceridemia. Vascular stiffness (augmentation index), measured by Endo-PAT2000, significantly decreased after the meal only in conjunction with red orange juice. CONCLUSION: In healthy subjects the concomitant intake of orange juice may prevent the low-grade inflammatory reaction induced by a fatty meal, at cellular and possibly at vascular function levels. The relative role of different polyphenols on the observed effects of orange juices remains to be established.

Enhanced vascular plasminogen activator (t-PA) release by epinephrine in aged rats.

Adrenergic stimulation induces an acute fibrinolytic response in the vascular wall and can play an important role in limiting thrombus growth. The incidence of thrombotic disease increases with age. As many adrenergic functions are affected by aging, the vascular response to adrenergic stimulation was studied in young (3 +/- 1 months) and aged (18 +/- 3 months) rats, using an experimental model of vascular perfusion. Five min epinephrine (EPI) infusion (0.15-25 microM) induced a dose-dependent increase in tissue-type plasminogen activator (t-PA) release and in perfusion pressure, in both young and aged rats. In the latter, however, the basal activity of t-PA was significantly higher than in young animals (0.22 +/- 0.02 vs 0.13 +/- 0.01 U/ml; means +/- SE; p < 0.01, n = 40) and EPI infusion induced a significantly higher increase in t-PA activity (0.78 +/- 0.06 vs 0.47 +/- 0.08 U/ml, p < 0.01, for 6.25 microM EPI). The response was characterized by a delayed onset. In contrast, the increase in the perfusion pressure by EPI was significantly lower in aged that in young rats, its basal levels being normal. To evaluate whether the increased vascular response of t-PA was peculiar for adrenergic stimulation, we infused platelet activating factor (PAF), an inducer of t-PA release, not related to catecholamines. PAF, during five-minute infusion induced a rapid and dose-dependent (100-1250 pM) increase in t-PA release, to the same extent in both young and aged rats. In conclusion, basal t-PA secretion was increased in aged rats probably as a response of vascular endothelium to chronic stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental arterial thrombosis in genetically or diet induced hyperlipidemia in rats--role of vitamin K-dependent clotting factors and prevention by low-intensity oral anticoagulation.

To investigate the relationship among lipids, coagulation and thrombosis in the absence of atherosclerosis, spontaneous or dietary-induced hyperlipidemic (FHL) rats were studied. FHL showed higher levels of coagulation factors VII, IX, X, VIII and XII and a shortening of the occlusion time (OT) of an artificial arterial prosthesis as compared with normolipidemic (FNL) animals. Damage of abdominal aorta of FHL was followed by increased fibrin deposition in the vascular intima as compared to FNL. After 5 months of cholesterol-rich diet FNL showed increased cholesterol, triglycerides and factor II, VII, IX, X, XII levels. A significant shortening of the OT and increased fibrin deposition was also observed. Two-month diet withdrawal restored the initial condition. Warfarin treatment, at a dose decreasing vitamin K-dependent factor to levels found in FNL, prolonged the OT and reduced fibrin deposition, without modifying F XII or changing lipid profile. An increase in the activated form of F VII was observed. In contrast, no difference was found in F VII clearance. High lipid levels favour the process of thrombus formation by increasing the activation of vitamin K-dependent coagulation factors. Low-dose warfarin treatment reverts the prothrombotic effect of hyperlipidemia.

Effect of aspirin on the fibrinolytic response in perfused rat hindquarters.

The role of aspirin on tissue plasminogen activator (t-PA) release was studied in rats after experimental venous occlusion. For this purpose, we developed a new experimental model which combines a vascular perfusion system (isolated rat hindquarters) with vascular stimulation, namely the application of venous stasis. Application of venous stasis for 30 min induced the release of t-PA from the vascular endothelium into the perfusate (from 0.19 +/- 0.05 to 0.39 +/- 0.05 UI/ml), reaching a peak 90 s after reperfusion. Aspirin administered to rats 60 min before the experiments (100 mg/kg i.v.), or dissolved in Tyrode solution (100 microM), suppressed 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) synthesis (0.38 +/- 0.09 in control and < 0.01 and 0.15 +/- 0.09 ng/ml, respectively, in aspirin-treated groups) but did not prevent the increase in fibrinolytic activity after venous occlusion (from 0.20 +/- 0.04 to 0.38 +/- 0.06 and from 0.07 +/- 0.03 to 0.27 +/- 0.03 IU/ml, respectively, in the aspirin-treated group). Our results suggest that the increase in fibrinolytic activity after experimental venous occlusion in isolated rat hindlegs is modulated by mechanism(s) other than the cyclooxygenase pathway in the vascular wall.

Morphological and hemostatic changes in rats with abdominal arterial prosthesis.

We evaluated the changes over time in hemostatic factors during ongoing arterial thrombosis in rats, as induced by a loop-shaped aortic prosthesis. Moreover, we investigated this condition by inspecting in parallel local thrombus growth, systemic vascular prostacyclin and t-PA production. One minute after loop insertion, activated platelets spread on the internal surface of the prosthesis and 24 hrs later numerous platelet aggregates supported by a fibrin network could be observed. However, no evidence for platelet activation could be concomitantly found in peripheral blood. A sustained increased in PGI2 formation was detected together with a progressive increase in plasma fibrinolytic activity during thrombus growth. The levels of fibrinogen as well as antithrombin III (ATIII) and heparin cofactor II (HCII) activities were steadily increased in loop-bearing animals. In conclusion, the dynamic phases of thrombus formation, in an aortic prosthesis, produce changes in vascular function and in hemostatic factors at the level of systemic blood.

Mushroom and dietary selenium intakes in relation to fasting glucose levels in a free-living Italian adult population: the Moli-sani Project.

AIM: Mushrooms are known to be a major food source of selenium, a mineral associated with diabetes prevalence. This study aimed to evaluate the relationship between mushroom and dietary selenium intakes and blood glucose levels in a free-living adult Italian population. METHODS: A total of 6879 men and 6891 women (aged 53.1±11.0years) with neither diabetes nor on special diets were analyzed from the population randomly recruited for the Moli-sani study. The European Prospective Investigation into Cancer and Nutrition (EPIC) food frequency questionnaire was used for dietary assessment. Fasting blood glucose (FBG) levels were measured from fasting serum samples, and diabetes prevalence was determined according to American Diabetes Association diagnostic criteria. RESULTS: In men, an increase of one (30-g) portion/week in mushroom consumption was associated with a 0.43-0.55mmol/L increase in FBG at different levels of adjustment (P<0.05). In both men and women, dietary selenium was positively associated with blood glucose in both unadjusted and fully adjusted models (P<0.05 for all). Both mushroom and dietary selenium intakes were independently associated with blood glucose on multivariate analyses. In addition, high intakes of both were associated with higher diabetes prevalence in men and women (OR>1, P<0.05). CONCLUSION: The association of mushroom and selenium intakes with FBG suggests that mushroom and selenium might each independently increase the risk of diabetes. However, prospective studies are now necessary to confirm this hypothesis.

Consumption of healthy foods at different content of antioxidant vitamins and phytochemicals and metabolic risk factors for cardiovascular disease in men and women of the Moli-sani study.

BACKGROUND/OBJECTIVES: To categorize healthy food groups into categories of low-antioxidant (LAC) or high-antioxidant vitamins and phytochemicals content (HAC) and comparatively associate them with metabolic risk factors for cardiovascular disease (CVD). SUBJECTS/METHODS: A total of 6879 women (55±12 years) and 6892 men (56 ± 12 years) were analyzed from the Moli-sani cohort, randomly recruited from the general population. The European Prospective Investigation into Cancer and Nutrition Food Frequency Questionnaire was used for dietary assessment. The antioxidant content of each food group was evaluated using Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione and United States Department of Agriculture (USDA) food composition tables. Healthy foods, according to a Mediterranean dietary pattern, were categorized into HAC or LAC; total food antioxidant content (FAC) score was constructed for a comparative evaluation of the consumption of these two groups. RESULTS: In men, an increase in FAC score, which represents an increased consumption of HAC with respect to LAC foods, was associated with a decrease in systolic blood pressure, diastolic blood pressure and C-reactive protein (CRP) (ß=-0.5, P=0.02, ß=-0.3, P=0.02 and ß=-0.03, P=0.03, respectively). Logistic regression analyses showed that in men 15% (30 units) increase in FAC score was associated with 6% decrease in the likelihood of having hypertension (odds ratio (OR)=0.94, 95% confidence interval (CI) 0.91-0.98) and 3% decrease in the likelihood of having a high CRP risk level (OR=0.97, 95% CI 0.94-0.99). No significant associations were observed in women. CONCLUSIONS: A possible greater protective role of healthy HAC as compared with healthy LAC foods on hypertension and inflammation was detected in men. These results stress the importance of studying healthy foods according to their content in antioxidant vitamins and phytochemicals, in primary prevention of CVD.

Total dietary antioxidant capacity and lung function in an Italian population: a favorable role in premenopausal/never smoker women.

BACKGROUND/OBJECTIVES: Antioxidant-rich foods may favorably influence lung function. We examined possible associations between the total dietary antioxidant capacity (TAC) and pulmonary function in a healthy Italian population. SUBJECTS/METHODS: Until May 2009, 22,300 persons were randomly recruited from the general population in the Moli-sani project. A sample only including healthy women (5824) and men (5848) was analyzed. TAC was measured in foods by three different assays and the ferric reducing-antioxidant power (FRAP) assay was selected as the better indicator of dietary TAC. The European Investigation into Cancer and Nutrition Food Frequency Questionnaire was used for dietary assessment. The association between quintiles of dietary FRAP and pulmonary indexes was assessed using analysis of variance separately for men and women. RESULTS: After adjustment for confounders, women in the highest quintile of FRAP intake had +39 ml forced expiratory volume in the first second (FEV(1)) and +54 ml forced vital capacity, compared with those in the lowest quintile (P for trend ≤0.006). Stratified analysis showed that this relationship only occurred in women who were premenopausal/never smokers. In this subgroup, the observed effect of higher FRAP intake on FEV(1) was equivalent to an improvement in pulmonary age of 3.3 years. In men, all significant associations between pulmonary function and TAC were lost after adjustment for confounding. CONCLUSIONS: Dietary TAC may have a favorable role in respiratory health, particularly in premenopausal/never smoker women.