Genetic screening of hypertensive patients with aldosterone hypersecretion under conditions of stress.

PURPOSE: Although ACTH is considered a secondary regulator of aldosterone production, patients with apparent essential hypertension have been treated with mineralocorticoid receptor antagonists (MRAs). In this study, we aimed to identify potentially damaging variants that might be implicated in the phenotype of a well-characterized cohort of 21 hypertensive patients without PA but with stress-induced aldosterone hypersecretion. The patients' blood pressure was normalized though MRA administration. METHODS: Genetic screening was performed through whole-exome sequencing (WES), and variants in PA-associated or in ion-channels of aldosterone-regulating genes were prioritized. Variants with population frequency < 0.01, predicted to alter protein structure and classified as likely pathogenic by in silico tools, were retained. RESULTS: Qualifying variants were identified in nine of the 21 patients screened. Seven patients were carriers of six potentially damaging variants in six genes associated with PA (KCNK9, KCNK5, ATP13A3, SLC26A2, CACNA1H, and CACNA1D). A novel variant in the KCNK9 gene (p.V221M) is reported. Our analysis revealed two variants in two novel susceptibility genes for aldosterone hypersecretion, namely, KCNK16 (p.P255H) and CACNA2D3 (p.V557I). CONCLUSION: WES revealed potentially damaging germline variants in genes participating in aldosterone synthesis/regulating pathways in 9/21 patients of our cohort. The variants identified might play a role in aldosterone hypersecretion under conditions of stress. The potential pathogenicity of these variants should be examined in future functional studies.

Sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for type 2 diabetes: a narrative review with emphasis on data from Europe.

BACKGROUND: Type 2 diabetes mellitus (T2DM) comprises the vast majority of all diabetes cases in adults, with alarmingly increasing prevalence over the past few decades worldwide. A particularly heavy healthcare burden of diabetes is noted in Europe, where 8.8% of the population aged 20-79 years is estimated to have diabetes according to the International Diabetes Federation. Multiple risk factors are implicated in the pathogenesis of T2DM with complex underlying interplay and intricate gene-environment interactions. Thus, intense research has been focused on studying the role of T2DM risk factors and on identifying vulnerable groups for T2DM in the general population which can then be targeted for prevention interventions. METHODS: For this narrative review, we conducted a comprehensive search of the existing literature on T2DM risk factors, focusing on studies in adult cohorts from European countries which were published in English after January 2000. RESULTS: Multiple lifestyle-related and sociodemographic factors were identified as related to high T2DM risk, including age, ethnicity, family history, low socioeconomic status, obesity, metabolic syndrome and each of its components, as well as certain unhealthy lifestyle behaviors. As Europe has an increasingly aging population, multiple migrant and ethnic minority groups and significant socioeconomic diversity both within and across different countries, this review focuses not only on modifiable T2DM risk factors, but also on the impact of pertinent demographic and socioeconomic factors. CONCLUSION: In addition to other T2DM risk factors, low socioeconomic status can significantly increase the risk for prediabetes and T2DM, but is often overlooked. In multinational and multicultural regions such as Europe, a holistic approach, which will take into account both traditional and socioeconomic/socioecological factors, is becoming increasingly crucial in order to implement multidimensional public health programs and integrated community-based interventions for effective T2DM prevention.

Olive oil consumption and 10-year (2002-2012) cardiovascular disease incidence: the ATTICA study.

PURPOSE: Olive oil, being rich in mono-unsaturated fatty acids and anti-inflammatory compounds, may have protective effects against cardiovascular disease (CVD). The aim of the present work was to examine the association of olive oil consumption with the 10-year CVD incidence in adults without pre-existing CVD. METHODS: The ATTICA Study is a prospective, population-based study conducted in the greater metropolitan area of Athens (Attica, Greece). During 2001-2002, 3042 CVD-free adults (1514 men and 1528 women) were voluntarily recruited to the ATTICA study. Among various dietary habits, consumption of olive oil and other fats/oils was assessed at baseline; participants were classified into three groups (no use; mixed use; and exclusive use of olive oil). In 2011-2012, the 10-year study follow-up was performed, recording the fatal/non-fatal CVD incidence in 2020 participants (mean follow-up duration: 8.41 years). RESULTS: After controlling for various covariates, an inverse association between exclusive olive oil use and the risk of developing CVD was observed (relative risk 0.07, 95% CI: 0.01-0.66) compared to those not consuming olive oil. Further adjustment for fibrinogen plasma levels (among various inflammatory markers) showed a significant mediation effect on the previous association. CONCLUSIONS: These findings support exclusive olive oil consumption, a key component of the Mediterranean diet, for the primary CVD prevention, in adults without pre-existing disease. Circulating fibrinogen levels appear to play a mediating role in this relationship.

Beer, wine consumption, and 10-year CVD incidence: the ATTICA study.

BACKGROUND/OBJECTIVES: Low/moderate alcohol consumption seems to be protective against cardiovascular disease (CVD). This study aimed to investigate the association of wine/beer consumption with the 10-year CVD incidence. SUBJECTS/METHODS: During 2001-2002, 3042 CVD-free adults consented to participate in the ATTICA study; of them 2583 completed the 10-year follow-up (85% participation rate), but precise information about fatal/nonfatal CVD incidence (myocardial infarction, angina pectoris, cardiac ischemia, heart failure, chronic arrhythmias, and stroke) was available in 2020 participants (overall retention rate 66%). Alcohol/ethanol intake and the alcoholic beverages consumed were assessed; participants were categorized into three groups (no use; ≤1 glass/week; >1 glass/week). RESULTS: Alcohol drinking was reported by 56% of the participants who did not develop a CVD event and 49% of those who had (p = 0.04); whereas ethanol intake was 14 ± 16 g among those who did not had an event vs. 21 ± 18 g among those who had a CVD event (p < 0.001). A strong inverse and similar association between low wine/beer intake (≤1 glass/week) and the risk of developing CVD was observed [HR: 0.40, 95% confidence interval (CI): 0.17-0.98; and HR: 0.43, 95% CI: 0.20-0.93, respectively], as compared to abstention. No significant association was found in participants exceeding drinking 1 glass/week compared with abstainers. Compared to <2 g/day ethanol intake, participants who reported 2-10, 10-20, and >20 g/day had CVD-risk HRs (95% CI) of 0.60 (0.40-0.98), 1.22 (0.60-1.14), and 1.81 (0.70-4.61), respectively. CONCLUSIONS: This study revealed similar results of low wine/beer consumption against CVD incidence, mainly due to its implication on low-grade chronic inflammation.

Lipid accumulation product in relation to 10-year cardiovascular disease incidence in Caucasian adults: The ATTICA study.

BACKGROUND AND AIMS: The lipid accumulation product (LAP) is an index describing lipid over-accumulation based on waist circumference (WC) and fasting triglycerides, and can outperform the body mass index (BMI) in recognizing cardiovascular disease (CVD) risk. We aimed to explore the association of LAP with long-term CVD risk and compare its CVD-predictive value against common anthropometric indices/ratios of obesity. METHODS: ATTICA is a prospective, population-based cohort that recruited 3042 adults without pre-existing CVD from the Greek general population (age 18-89 years; 1514 men). The 10-year study follow-up (2011-2012) captured the fatal/non-fatal CVD incidence in 2020 participants (50% men). Baseline LAP (cm·mmol/L) was calculated and analyzed in relation to the 10-year CVD incidence. RESULTS: In total, 317 CVD cases (15.7%) were documented during the follow-up. Baseline LAP showed a significant positive association with the 10-year CVD incidence, even after adjusting for hypertension, diabetes, hypercholesterolemia, smoking, physical activity, Mediterranean diet adherence, and key pro-inflammatory biomarkers (Hazard Ratios per 10 cm·mmol/L of LAP ranging from 1.1 to 1.21, p = 0.04). Moreover, LAP predicted the 10-year CVD study incidence better than common obesity indices (BMI, WC, waist-to-hip, waist-to-height ratio). CONCLUSIONS: These findings support a positive association between LAP and long-term CVD incidence in CVD-free Caucasian adults from the general population.

J-shaped relationship between habitual coffee consumption and 10-year (2002-2012) cardiovascular disease incidence: the ATTICA study.

PURPOSE: The purpose of this work was to evaluate the association between coffee consumption and 10-year cardiovascular disease (CVD) incidence in the ATTICA study, and whether this is modified by the presence or absence of metabolic syndrome (MetS) at baseline. METHODS: During 2001-2002, 3042 healthy adults (1514 men and 1528 women) living in the greater area of Athens were voluntarily recruited to the ATTICA study. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Coffee consumption was assessed by a validated food-frequency questionnaire at baseline (abstention, low, moderate, heavy). Incidence of fatal or non-fatal CVD event was recorded using WHO-ICD-10 criteria and MetS was defined by the National Cholesterol Education Program Adult Treatment panel III (revised) criteria. RESULTS: Overall, after controlling for potential CVD risk factors, the multivariate analysis revealed a J-shaped association between daily coffee drinking and the risk for a first CVD event in a 10-year period. Particularly, the odds ratio for low (<150 ml/day), moderate (150-250 ml/day) and heavy coffee consumption (>250 ml/day), compared to abstention, were 0.44 (95% CI 0.29-0.68), 0.49 (95% CI 0.27-0.92) and 2.48 (95% CI 1.56-1.93), respectively. This inverse association was also verified among participants without MetS at baseline, but not among participants with the MetS. CONCLUSIONS: These data support the protective effect of drinking moderate quantities of coffee (equivalent to approximately 1-2 cups daily) against CVD incidents. This protective effect was only significant for participants without MetS at baseline.

Adiponectin circulating levels and 10-year (2002-2012) cardiovascular disease incidence: the ATTICA Study.

PURPOSE: Adiponectin is an adipokine with anti-inflammatory and cardiovascular-protective properties. Existing epidemiological evidence is conflicting on the exact relationship between adiponectin and long-term cardiovascular disease (CVD) risk. Our aim was to prospectively assess whether circulating adiponectin is associated with long-term incident CVD. METHODS: A population-based, prospective study in adults (>18 years) without previous CVD history (ATTICA study). Circulating total adiponectin levels were measured at baseline (2001-2002) in a sub-sample (n = 531; women/men: 222/309; age: 40 ± 11 years) of the ATTICA cohort and complete 10-year follow-up data were available in 366 of these participants (women/men: 154/212; age: 40 ± 12 years). RESULTS: After adjusting for multiple factors, including age, sex, body mass index, waist circumference, smoking, physical activity, Mediterranean diet adherence, hypertension, diabetes, and hypercholesterolemia, our logistic regression analysis indicates that an increase in circulating total adiponectin levels by 1 unit was associated with 36% lower CVD risk (relative risk [RR]: 0.64, 95% confidence interval [CI] 0.42-0.96; p = 0.03). Further adjusting for interleukin-6 plasma levels had no significant impact (RR: 0.60, 95% CI 0.38-0.94; p = 0.03), while additional adjustment for circulating C-reactive protein (CRP) modestly attenuated this association (RR: 0.63, 95% CI 0.40-0.99; p = 0.046). CONCLUSIONS: In our study, elevated circulating total adiponectin levels were associated with lower 10-year CVD risk in adults without previous CVD, independently of other established CVD risk factors. This association appeared to be modestly attenuated by CRP, yet was not mediated by interleukin-6 which is the main endocrine/circulating pro-inflammatory cytokine.

Effects of a hops (Humulus lupulus L.) dry extract supplement on self-reported depression, anxiety and stress levels in apparently healthy young adults: a randomized, placebo-controlled, double-blind, crossover pilot study.

OBJECTIVE: The Humulus lupulus L. plant (hops) is used as a herbal medicinal product for anxiety/mood disorders. Our aim was to study the effects of a hops dry extract on self-reported depression, anxiety and stress levels in young adults. DESIGN: Apparently healthy young adults from our university completed the Depression Anxiety Stress Scale-21 (DASS-21) and those reporting at least mild depression, anxiety and stress were invited to complete the study intervention. This followed a randomized (1:1), placebo-controlled, double-blind, crossover design with two 4-week intervention periods (Melcalin hops or placebo; two 0.2 gr capsules once daily) separated by a 2-week wash-out. Anthropometric measurements, DASS-21 assessments and measurements of morning cortisol plasma levels were performed at the beginning and the end of the 4-week treatment periods. RESULTS: 36 participants (Females/Males: 31/5; age: 24.7±0.5 years) completed the study intervention (attrition: 6/42). No significant changes in body weight and composition or morning circulating cortisol were noted with the hops or placebo. Significantly decreased DASS-21 anxiety, depression and stress scores were documented with hops (9.2±7.3 vs. 5.1±5.9, 11.9±7.9 vs. 9.2±7.4, and 19.1±8.1 vs. 11.6±8.1; all p values <0.05), which were significantly greater compared to those caused by the placebo (all p values <0.05). CONCLUSION: In otherwise healthy young adults reporting at least mild depression, anxietyand stress symptoms, daily supplementation with a hops dry extract can significantly improve all these symptoms over a 4-week period. These beneficial effects agree with the indication of hops for anxiety/mood disorders and restlessness, as approved by the German Commission E.

Modeling anthropometric indices in relation to 10-year (2002-2012) incidence of cardiovascular disease, among apparently healthy individuals: The ATTICA study.

AIMS: Body fat accumulation is implicated in the development of cardiovascular disease (CVD). Our objective was to explore potential associations between anthropometric indices and the 10-year CVD incidence in Greek adults without previous CVD. METHODS: During 2001-2, we enrolled 3042 adults without CVD from the general population of Attica, Greece. In 2011-2, the 10-year study follow-up was performed, recording the CVD incidence in 1958 participants with baseline body mass index (BMI) ≥18.5kg/m2. RESULTS: The study 10-year CVD incidence was 15.8%, exhibiting a gradual increase according to the baseline body mass index (BMI) category. Baseline BMI ≥30kg/m2 was related with significantly higher 10-year CVD risk compared to BMI <25kg/m2, even after adjustment for age and other known CVD risk factors. Baseline BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio and waist-to-hip-to-height ratio were independently associated with the 10-year CVD risk in multi-adjusted models. Gender-specific analyses showed that these associations were more evident in men compared to women, with baseline BMI exhibiting an independent association with the 10-year CVD incidence in men. CONCLUSIONS: Our results indicate that even simple anthropometric indices exhibit independent associations with CVD risk in a representative sample of the Greek general population without previous CVD.

Association of depression and anxiety status with 10-year cardiovascular disease incidence among apparently healthy Greek adults: The ATTICA Study.

Background Chronic stress frequently manifests with anxiety and/or depressive symptomatology and may have detrimental cardiometabolic effects over time. As such, recognising the potential links between stress-related psychological disorders and cardiovascular disease (CVD) is becoming increasingly important in cardiovascular epidemiology research. The primary aim of this study was to explore prospectively potential associations between clinically relevant depressive symptomatology and anxiety levels and the 10-year CVD incidence among apparently healthy Greek adults. Design A population-based, health and nutrition prospective survey. Methods In the context of the ATTICA Study (2002-2012), 853 adult participants without previous CVD history (453 men (45 ± 13 years) and 400 women (44 ± 18 years)) underwent psychological evaluations through validated, self-reporting depression and anxiety questionnaires. Results After adjustment for multiple established CVD risk factors, both reported depression and anxiety levels were positively and independently associated with the 10-year CVD incidence, with depression markedly increasing the CVD risk by approximately fourfold (adjusted odds ratio (95% confidence interval) 3.6 (1.3, 11) for depression status; 1.03 (1.0, 1.1) for anxiety levels). Conclusions Our findings indicate that standardised psychological assessments focusing on depression and anxiety should be considered as an additional and distinct aspect in the context of CVD preventive strategies that are designed and implemented by health authorities at the general population level.

Anti-inflammatory diet and 10-year (2002-2012) cardiovascular disease incidence: The ATTICA study.

BACKGROUND/OBJECTIVES: The aim of the present work was to evaluate the association between the inflammatory potential of the diet and the 10-year cardiovascular disease (CVD) incidence in the ATTICA Study, and whether this is modified by the baseline presence or absence of metabolic syndrome (MetS). METHODS: During 2001-2002, 3042 healthy adults (1514 men and 1528 women) living in the greater area of Athens were voluntarily recruited to the ATTICA study. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Incidence of fatal or non-fatal CVD event was recorded using WHO-ICD-10 criteria and MetS was defined by the National Cholesterol Education Program Adult Treatment panel III (revised) definition. A proxy dietary anti-inflammatory index (D-AII) score computed using participants' diet records. RESULTS: The 10-year fatal or non-fatal CVD event rate was 157 cases/1000 participants. After adjusting for several confounding factors, an anti-inflammatory diet, as expressed by higher DII scores, was borderline associated with 10-year CVD incidence (OR3rd tertile vs. 1st tertile=0.98, 95%CI: 0.96-1.01). This inverse association was also verified among participants without MetS at baseline (OR3rd tertile vs. 1st tertile=0.97, 95%CI: 0.94-0.99), but not among participants with the MetS. CONCLUSIONS: Results of the present work verified the protective effect of an anti-inflammatory diet towards the 10-year CVD incidence among participants without MetS. In contrast, the presence of MetS already at baseline seemed to impede this anti-inflammatory diet protective effect, which underlines the independent importance of MetS on CVD risk.

European Guidelines for Obesity Management in Adults.

Obesity is a chronic metabolic disease characterised by an increase of body fat stores. It is a gateway to ill health, and it has become one of the leading causes of disability and death, affecting not only adults but also children and adolescents worldwide. In clinical practice, the body fatness is estimated by BMI, and the accumulation of intra-abdominal fat (marker for higher metabolic and cardiovascular disease risk) can be assessed by waist circumference. Complex interactions between biological, behavioural, social and environmental factors are involved in regulation of energy balance and fat stores. A comprehensive history, physical examination and laboratory assessment relevant to the patient's obesity should be obtained. Appropriate goals of weight management emphasise realistic weight loss to achieve a reduction in health risks and should include promotion of weight loss, maintenance and prevention of weight regain. Management of co-morbidities and improving quality of life of obese patients are also included in treatment aims. Balanced hypocaloric diets result in clinically meaningful weight loss regardless of which macronutrients they emphasise. Aerobic training is the optimal mode of exercise for reducing fat mass while a programme including resistance training is needed for increasing lean mass in middle-aged and overweight/obese individuals. Cognitive behavioural therapy directly addresses behaviours that require change for successful weight loss and weight loss maintenance. Pharmacotherapy can help patients to maintain compliance and ameliorate obesity-related health risks. Surgery is the most effective treatment for morbid obesity in terms of long-term weight loss. A comprehensive obesity management can only be accomplished by a multidisciplinary obesity management team. We conclude that physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment. Treatment should be based on good clinical care, and evidence-based interventions; should focus on realistic goals and lifelong multidisciplinary management.

Stress and inflammatory biomarkers and symptoms are associated with bioimpedance measures.

BACKGROUND: This large cross-sectional, multi-centre study evaluated the association of body composition measurements by a novel dual frequency bioimpedance device (BIA-ACC) with chronic stress/inflammation biomarkers and the presence of medically unexplained symptoms (MUS). MATERIALS AND METHODS: Participants were adult Caucasians of both sexes and included 10,416 lean subjects with no MUS (Group A), 58,710 lean subjects with MUS (Group B) and 30,445 overweight/obese subjects with no MUS and excessive fat mass (FM) (Group C). RESULTS: Total body extracellular water (ECW) was higher, while intracellular water (ICW) was lower in Group B than both other groups (P < 0.01). Group A had significantly lower FM and higher skeletal mass (SK) and phase angle (PA) than Group B and lower circulating high sensitivity (hs) CRP levels than both other groups. hsCRP was higher in Group C than Group A though (P < 0.01). Salivary cortisol in Group B was lower in the morning and higher in the evening than both other groups (P < 0.001), indicating circadian rhythm obliteration or reversal in this group. ECW correlated positively with serum hsCRP and 8 p.m. salivary cortisol, but negatively with 8 a.m. salivary cortisol, while PA correlated positively with 8 a.m. and negatively with 8 p.m. salivary cortisol and serum hsCRP. Both 8 a.m. and 8 p.m. salivary cortisol and serum hsCRP were associated with the presence of MUS and BIA-ACC measurements, including ECW, ICW, FM, SK and PA. CONCLUSIONS: MUS is an index of chronic stress and inflammation and BIA-ACC may provide a useful, bloodless and rapid tool in the clinical setting, distinguishing patients with chronic stress/inflammation from healthy subjects and monitoring their response to treatment.

Criteria for EASO-collaborating centres for obesity management.

Obesity is recognised as a global epidemic and the most prevalent metabolic disease world-wide. Specialised obesity services, however, are not widely available in Europe, and obesity care can vary enormously across European regions. The European Association for the Study of Obesity (EASO, www.easo.org) has developed these criteria to form a pan-European network of accredited EASO-Collaborating Centres for Obesity Management (EASO-COMs) in accordance with accepted European and academic guidelines. This network will include university, public and private clinics and will ensure that the obese and overweight patient is managed by a holistic team of specialists and receives comprehensive state-ofthe-art clinical care. Furthermore, the participating centres, under the umbrella of EASO, will work closely for quality control, data collection, and analysis as well as for education and research for the advancement of obesity care and obesity science.

Stress hormones: physiological stress and regulation of metabolism.

Stress, defined as a state of threatened homeostasis, mobilizes a complex spectrum of adaptive physiologic and behavioral responses that aim to re-establish the challenged body homeostasis. The hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) constitute the main effector pathways of the stress system, mediating its adaptive functions. In western societies, indices of stress correlate with increasing rates of both obesity and metabolic syndrome which have reached epidemic proportions. Recent data indicate that chronic stress, associated with mild hypercortisolemia and prolonged SNS activation, favors accumulation of visceral fat and contributes to the clinical presentation of visceral obesity, type 2 diabetes, and related cardiometabolic complications. Reciprocally, obesity promotes a systemic low-grade inflammation state, mediated by increased adipokine secretion, which can chronically stimulate the stress system.

Peripheral mononuclear cell resistin mRNA expression is increased in type 2 diabetic women.

Resistin has been shown to cause insulin resistance and to impair glucose tolerance in rodents, but in humans its physiological role still remains elusive. The aim of this study was to examine whether resistin mRNA expression in human peripheral mononuclear cells (PBMCs) and its corresponding plasma levels are altered in type 2 diabetes. Resistin mRNA levels were easily detectable in human PBMC, and found to be higher in DM2 compared to healthy women (P = .05). Similarly, mononuclear mRNA levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6 were all significantly higher in DM2 compared to control women (P < .001). The corresponding plasma resistin levels were slightly, but not significantly, increased in DM2 women (P = .051), and overall, they correlated significantly with BMI (r = 0.406, P = .010) and waist circumference (r = 0.516, P = .003), but not with fasting insulin levels or HOMA-IR. Resistin mRNA expression is increased in PBMC from DM2 women, together with increased expression of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6, independent of obesity. These results suggest that resistin and cytokines might contribute to the low-grade inflammation and the increased atherogenic risk observed in these patients.