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Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Competing Interests: The authors declare no conflict of interest.

Objective: Several studies report a cross-sectional association between metabolic syndrome and depression. Possibly, metabolic syndrome promotes onset or chronicity of depression. However, such a longitudinal link has not yet been confirmed. This study examines whether metabolic syndrome or its components are associated with onset and chronicity of depression., Method: Secondary analyses were performed on data from 823 participants (≥ 65 years of age) in the InCHIANTI study, a prospective, population-based cohort study of older persons. From 1998 to 2000, the study sample was randomly selected from the population registry of 2 sites in Italy using a multistage stratified sampling method. Baseline data collection consisted of a home interview and a medical evaluation at the study clinic. Follow-up for each participant occurred after 3 years and 6 years. Metabolic syndrome at baseline was defined as ≥ 3 of the following: abdominal obesity, high triglycerides, low high-density lipoprotein cholesterol, high blood pressure, and high fasting glucose. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale (CES-D) at baseline and after 3 and 6 years. Sample characteristics were compared between persons with and without depression at baseline using χ² and t statistics. Logistic regression analyses were conducted separately in persons with and without depression at baseline to test whether metabolic syndrome at baseline could predict onset and chronicity of depression at follow-up., Results: At baseline, 235 persons had metabolic syndrome, and 168 were depressed (CES-D score ≥ 20). Among persons not depressed at baseline, 26.0% developed depression. Higher waist circumference increased the odds of depression onset (adjusted OR per SD increase = 1.28; 95% CI, 1.05-1.56), but there was no association between other metabolic syndrome components and onset of depression. Among persons depressed at baseline, depression had a chronic character in 69.0% of persons without and 88.5% of persons with metabolic syndrome. Metabolic syndrome was associated with an almost 3-fold increase in the odds of chronicity of depression (adjusted OR = 2.66; 95% CI, 1.01-7.00), with almost every metabolic syndrome component contributing to this association., Conclusion: In late life, waist circumference, but not metabolic syndrome, predicted onset of depression. Depressed persons with metabolic syndrome were more likely to have persistent or recurrent depression. The latter may suggest that depression with metabolic abnormalities, which could be labeled metabolic depression, identifies a chronic subtype of depression., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Context: The stress hormone cortisol has been linked with unfavorable cardiovascular risk factors, but longitudinal studies examining whether high levels of cortisol predict cardiovascular mortality are largely absent., Objective: The aim of this study was to examine whether urinary cortisol levels predict all-cause and cardiovascular mortality over 6 yr of follow-up in a general population of older persons., Design and Setting: Participants were part of the InCHIANTI study, a prospective cohort study in the older general population with 6 yr of follow-up., Participants: We studied 861 participants aged 65 yr and older., Main Outcome Measure: Twenty-four-hour urinary cortisol levels were assessed at baseline. In the following 6 yr, all-cause and cardiovascular mortality was ascertained from death certificates. Cardiovascular mortality included deaths due to ischemic heart disease and cerebrovascular disease., Results: During a mean follow-up of 5.7 (sd = 1.2) yr, 183 persons died, of whom 41 died from cardiovascular disease. After adjustment for sociodemographics, health indicators, and baseline cardiovascular disease, urinary cortisol did not increase the risk of noncardiovascular mortality, but it did increase cardiovascular mortality risk. Persons in the highest tertile of urinary cortisol had a five times increased risk of dying of cardiovascular disease (hazard ratio = 5.00; 95% confidence interval = 2.02-12.37). This effect was found to be consistent across persons with and without cardiovascular disease at baseline (p interaction = 0.78)., Conclusions: High cortisol levels strongly predict cardiovascular death among persons both with and without preexisting cardiovascular disease. The specific link with cardiovascular mortality, and not other causes of mortality, suggests that high cortisol levels might be particularly damaging to the cardiovascular system.

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation., Competing Interests: Vincent Mooser and Dawn Waterworth are full-time employees of GlaxoSmithKline, a pharmaceutical company. Peter Vollenweider and Gerard Waeber received financial support from GlaxoSmithKline to build the CoLaus study. Daniel F Gudbjarsson, Unnur Styrkarsdottir, Hilma Holm, Unnur Thorsteinsdottir and Kari Stefansson are employees of deCODE genetics, a biotechnology company.

Context: Hypovitaminosis D and depressive symptoms are common conditions in older adults., Objective: We examined the relationship between 25-hydroxyvitamin D [25(OH)D] and depressive symptoms over a 6-yr follow-up in a sample of older adults., Design and Setting: This research is part of a population-based cohort study (InCHIANTI Study) in Tuscany, Italy., Participants: A total of 531 women and 423 men aged 65 yr and older participated., Main Outcome Measure: Serum 25(OH)D was measured at baseline. Depressive symptoms were assessed at baseline and at 3- and 6-yr follow-ups using the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D of 16 or higher. Analyses were stratified by sex and adjusted for relevant biomarkers and variables related to sociodemographics, somatic health, and functional status., Results: Women with 25(OH)D less than 50 nmol/liter compared with those with higher levels experienced increases in CES-D scores of 2.1 (P = 0.02) and 2.2 (P = 0.04) points higher at, respectively, 3- and 6-yr follow-up. Women with low vitamin D (Vit-D) had also significantly higher risk of developing depressive mood over the follow-up (hazard ratio = 2.0; 95% confidence interval = 1.2-3.2; P = 0.005). In parallel models, men with 25(OH)D less than 50 nmol/liter compared with those with higher levels experienced increases in CES-D scores of 1.9 (P = 0.01) and 1.1 (P = 0.20) points higher at 3- and 6-yr follow-up. Men with low Vit- D tended to have higher risk of developing depressed mood (hazard ratio = 1.6; 95% confidence interval = 0.9-2.8; P = 0.1)., Conclusion: Our findings suggest that hypovitaminosis D is a risk factor for the development of depressive symptoms in older persons. The strength of the prospective association is higher in women than in men. Understanding the potential causal pathway between Vit- D deficiency and depression requires further research.

Objectives: To examine whether performance in the Trail Making Test (TMT) predicts mobility impairment and mortality in older persons., Design: Prospective cohort study., Setting: Community-dwelling older persons enrolled in the Invecchiare in Chianti (InCHIANTI) Study., Participants: Five hundred eighty-three participants aged 65 and older and free of major cognitive impairment (Mini-Mental State Examination score >21) with baseline data on TMT performance. Of these, 427 performed the Short Physical Performance Battery (SPPB) for the assessment of lower extremity function at baseline and after 6 years. Of the initial 583 participants, 106 died during a 9-year follow-up., Measurements: The TMT Parts A and B (TMT-A and TMT-B) and SPPB were administered at baseline and 6-year follow-up. Impaired mobility was defined as an SPPB score less than 10. Vital status was ascertained over a 9-year follow-up., Results: InCHIANTI participants in the fourth quartile of the time to complete TMT-B minus time to complete TMT-A (TMT (B-A)) were significantly more likely to develop an SPPB score less than 10 during the 6-year follow-up than those in the first quartile (relative risk (RR)=2.4, 95% confidence interval (CI)=1.4-3.9, P=.001). After adjusting for potential confounders, these findings were substantially unchanged (RR=2.2, 95% CI=1.4-3.6, P=.001). Worse performance on the TMT was associated with significantly greater decline in SPPB score over the 6-year follow-up, after adjusting for age, sex, and baseline SPPB scores (beta=-0.01, standard error=0.003, P=.004). During the 9-year follow-up, 18.2% of the participants died. After adjustment for age and sex, the proportion of participants who died was higher in participants in the worst than the best performance quartile of TMT (B-A) scores (hazard ratio (HR)=1.7, 95% CI=1.0-2.9, P=.048). Results were similar in a parsimonious adjusted model (HR=1.8, 95% CI=1.0-3.2, P=.04)., Conclusion: Performance on the TMT is a strong, independent predictor of mobility impairment, accelerated decline in lower extremity function, and death in older adults living in the community. The TMT could be a useful addition to geriatric assessment.

Trajectories of health and functioning with age show extreme variability among different individuals. In frail, older persons the decline in functional reserve is accelerated and compensatory mechanisms start failing, with high risk of homeostasis disruption and consequent negative health outcomes. Frailty is currently conceptualized as an age-related alteration in physiology and pathology that results into a typical constellation of signs and symptoms. Although current attempts to identify frail, older individuals for clinical purposes is based on measures of mobility and motor performance, candidate biological markers that may be specific of the frailty syndrome start to emerge in the literature. Different theories have been drawn to describe the interaction of aging process and loss of ability in performance. One of these hypothesis is based on the progressive dysregulation that occur with age in the homeostatic network and the less efficiency and efficacy in its vital mechanism that allows at all levels integration, from mitochondrial function to societal and community adaptations.

Objectives: To test the hypothesis that, in older persons, sense of personal mastery, defined as the extent to which one regards one's life chance as being under one's own control, predicts change in lower extremity performance during a 6-year follow-up., Design: Prospective cohort study., Setting: Community based., Participants: Six hundred twenty-six participants aged 65 and older., Measurements: Personal mastery was assessed at baseline using Pearlin's mastery scale. Lower extremity performance was measured at baseline and at 6-year follow-up using the Short Physical Performance Battery (SPPB) of lower extremity function., Results: Higher sense of mastery was associated with a significantly less-steep decline in lower extremity performance. Participants in the two lowest quartiles of personal mastery had, respectively, a 2.6 (95% confidence interval (CI)=1.4-5.1, P=.01) and 3.2 (95% CI=1.6-6.6, P=.002) higher risk of experiencing a substantial decline (> or =3 points) in SPPB scores after 6 years as those in the highest quartile., Conclusions: Older individuals with poor sense of personal mastery are at high risk of accelerated lower extremity physical function decline. Whether interventions aimed at improving personal mastery may prevent disability remains unknown.

Background: Despite its implications for treatment strategies, the potential role of previous depression on the medical course after coronary heart disease (CHD) has not yet been thoroughly studied., Objective: The aim of this study was to determine whether the presence of major and minor depression, dysthymia, and demoralization in the years preceding the first myocardial infarction (MI) or angina, was associated with poor cardiac outcome at 2.5-year follow-up., Method: A group of 97 consecutive patients with acute CHD, admitted to a coronary-care unit, were studied while in remission from the acute phase of CHD. Various clinical depression measures were used to assess the occurrence or recurrence of mood disorders preceding the first episode of CHD (baseline visit) and at 2.5 years after the first interview., Results: Among the variables examined as potential cardiac risk factors, only dysthymia attained statistical significance., Discussion: Further research is needed to identify an effective treatment for dysthymic patients.

Background: the identification of modifiable risk factors for preventing disability in older individuals is essential for planning preventive strategies., Purpose: to identify cross-sectional correlates of disability and risk factors for the development activities of daily living (ADL) and instrumental ADL (IADL) disability in community-dwelling older adults., Methods: the study population consisted of 897 subjects aged 65-102 years from the InCHIANTI study, a population-based cohort in Tuscany (Italy). Factors potentially associated with high risk of disability were measured at baseline (1998-2000), and disability in ADLs and IADLs were assessed both at baseline and at the 3-year follow-up (2001-03)., Results: the baseline prevalence of ADL disability and IADL disability were, respectively, 5.5% (49/897) and 22.2% (199/897). Of 848 participants free of ADL disability at baseline, 72 developed ADL disability and 25 of the 49 who were already disabled had a worsening in ADL disability over a 3-year follow-up. Of 698 participants without IADL disability at baseline, 100 developed IADL disability and 104 of the 199 who already had IADL disability had a worsening disability in IADL over 3 years. In a fully adjusted model, high level of physical activity compared to sedentary state was significantly associated with lower incidence rates of both ADL and IADL disability at the 3-year follow-up visit (odds ratio (OR): 0.30; 95% confidence intervals (CI) 0.12-0.76 for ADL disability and OR: 0.18; 95% CI 0.09-0.36 for IADL disability). After adjusting for multiple confounders, higher energy intake (OR for difference in 100 kcal/day: 1.09; 95% CI 1.02-1.15) and hypertension (OR: 1.91; 95% CI 1.06-3.43) were significant risk factors for incident or worsening ADL disability., Conclusions: higher level of physical activity and lower energy intake may be protective against the development in ADL and IADL disability in older persons.

Aim: The purposes of this study are: (1) to evaluate symptomatology and psychological well-being, according to Ryff's theoretical model, of two groups of drug dependent patients in residential structures compared with a control; (2) to explore the impact of dual diagnosis, pharmacological therapy, duration of stay in structures and previous therapeutic experience as indicators on symptomatology and psychological well-being., Methods: The sample is formed by 61 drug-dependent patients and 65 controls. Each subject completed two self-administered scales: Kellner's Symptom Questionnaire-SQ and Ryff's Psychological Well-Being Scales-PWB. Differences in PWB and SQ mean scores between clinical and control subjects and within clinical group, for each specific variable, were analyzed using analysis of variance., Results: Clinical group had significantly lower levels of all six PWB dimensions and SQ scores compared to the controls. Dual diagnosis did not produce any significant effect on PWB and SQ general scores, except for the PWB dimension of positive social relations. Pharmacological therapy had a slightly significant effect only on PWB. No significant effects were found in terms of symptomatology and general well-being depending on duration of stay, except for purpose in life. Previous experience caused a significant result for psychological well-being, while no general effect on symptomatology was found., Discussion: We found that drug dependence is associated with high degree of symptomatology and the lack of positive psychological functioning in specific areas. Improving positive psychological functioning of this population could be a good way to intervene on specific problems which could interfere with treatment continuity.

Background: In the past decade, there has been an increasing awareness of both quality-of-life impairment and the negative prognostic role of depression in congestive heart failure (CHF) patients., Objective: The aims of this study were to evaluate distress, psychological well-being, and clinical and subclinical depression in 68 CHF outpatients at Bellaria Hospital in Bologna, Italy, at an initial assessment and at a 2-month routine follow-up visit., Results: Patients reported a high prevalence of somatic complaints, depression, and demoralization, and low scores on psychological well-being. Among the variables examined as potential risk factors for cardiovascular outcome events, based on rehospitalization and cardiac death, only minor depression attained statistical significance., Conclusion: Clinicians should thus assess minor depression among other psychological variables in these patients.

Background: We test the hypothesis that in older persons higher plasma levels of inflammatory markers predict the development of depressive symptoms during a 6-year follow-up., Method: This study is part of the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study, a prospective population-based study of older persons. The sample consisted of 991 participants, ages 65 years and older. Serum levels of C-reactive protein, interleukin (IL)-1beta, IL-1 receptor antagonist (ra), tumor necrosis factor-alpha, IL-6, IL-6 receptor, and IL-18 were measured. Depressive symptoms were assessed at baseline and at the 3- and 6-year follow-ups with the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D > 20. Potential confounders were baseline variables related to sociodemographic, somatic health, and functional status., Results: At baseline, IL-1ra levels were significantly higher (p = .004) in depressed compared with nondepressed participants. After adjustment for confounders, among subjects free of depression at baseline, those in the third and fourth IL-1ra quartiles compared with those in the lowest quartile had, respectively, a 2.32-fold (95% confidence interval: 1.21-4.42, p = .01) and 2.78-fold (95% confidence interval: 1.47-5.26, p = .002) higher risk of developing depressed mood during a 6-year follow-up., Conclusions: In old age, persons with high plasma levels of IL1-ra had a higher risk of developing depressive symptoms over time. These findings suggest a potential causal role for inflammation in the development of depressive symptoms in older persons.

A few studies have investigated the role of psychosocial variables on clinical outcomes in coronary artery bypass grafting patients. The aims of this prospective study were 1) to assess clinical and subclinical distress in a consecutive sample of patients who underwent coronary artery bypass grafting surgery at both a 1-month assessment and a 6- to 8-year follow-up visit; and 2) to investigate the relationship between psychological variables and coronary events. A consecutive series of 47 patients with recent coronary artery bypass grafting surgery was evaluated by means of observer-rated categories (both the Diagnostic and Statistical Manual [DSM] and the new Diagnostic Criteria for Psychosomatic Research [DCPR]), and self-rated scales such as the Psychosocial Index. Survival analysis was used to characterize the clinical course of patients at the 6- to 8-year follow-up. One month after surgery, at the first psychological assessment, 36% of patients received a psychiatric diagnosis, and almost half of the sample met the criteria for a DCPR cluster. At follow-up, only abnormal illness behavior scores varied significantly from those at the first evaluation. Among the variables examined as potential risk factors for coronary events, only minor depression attained statistical significance. Psychological evaluation of patients who underwent coronary artery bypass grafting surgery needs to incorporate both clinical (DSM) and subclinical (DCPR) methods of classification. Furthermore, the data suggest minor depression as a potential cardiac risk factor in coronary artery bypass grafting patients. The clinical approach to coronary artery bypass grafting patients should thus include not only major depressive symptoms but also minor depression.

Background: Several studies outlined the role of stressful life events in the pathogenesis of coronary heart disease. It has recently been emphasized the role of depression, both clinical and subclinical, in the course of myocardial infarction. The relationship between recent life events, major depression, depressive symptomatology and onset of acute coronary heart disease has been less considered., Methods: Ninety-seven consecutive patients with first episode of coronary heart disease and 97 healthy subjects matched for sociodemographic variables were included. All patients were interviewed by Paykel's interview for recent life events, a semistructured interview for determining the psychiatric diagnosis of mood disorders, a semistructured interview for demoralization. Patients were assessed while on remission from the acute phase. The time period considered was the year preceding the first episode of coronary heart disease, and the year before interview for controls., Results: Patients with acute coronary heart disease reported significantly more life events than control subjects (p < 0.001). All categories of events (except entrance events) were significantly more frequent. Thirty percent of patients were identified as suffering from a major depressive disorder; 9% of patients were suffering from minor depression, and 20% from demoralization. Even though there was an overlap between major depression and demoralization (12%), 17% of patients with major depression were not classified as demoralized and 7 % of patients with demoralization did not satisfy the criteria for major depression. Independently of mood disorders, patients have a higher (p < 0.001) mean number of life events than controls. With regard to life events, the same significant difference (p < 0.001) compared to controls applied to patients with and without mood disorders., Conclusions: Our findings emphasize the relationship between life events and acute coronary heart disease. These data, together with those regarding traditional cardiac risk factors, may have clinical and prognostic implications to be verified in longitudinal studies.

Background: While the effect of psychological stress and depression on the course of heart disease is commonly recognized, the relationship between recent life events, major depression, depressive symptomatology and the onset of acute coronary heart disease (CHD) has been less considered. The aim of this study was to investigate the presence of stressful life events, major and minor depression, recurrent depression and demoralization in the year preceding the occurrence of a first acute myocardial infarction (AMI) and/or a first episode of instable angina and to compare stressful life events, also related with mood disorders, in patients and healthy controls., Methods: 97 consecutive patients with a first episode of CHD (91 with AMI and 6 with instable angina) and 97 healthy subjects matched for sociodemographic variables were included. All patients were interviewed with Paykel's Interview for Recent Life Events, a semistructured interview for determining the psychiatric diagnosis of mood disorders (DSM-IV), a semistructured interview for demoralization (DCPR). Patients were assessed while on remission from the acute phase. The time period considered was the year preceding the first episode of CHD and the year before the interview for controls., Results: Patients with acute CHD reported significantly more life events than control subjects (p < 0.001). All categories of events (except entrance events) were significantly more frequent. 30% of patients were identified as suffering from a major depressive disorder; 9% of patients were suffering from minor depression, 20% from demoralization. Even though there was an overlap between major depression and demoralization (12%), 17% of patients with major depression were not classified as demoralized and 7% of patients with demoralization did not satisfy the criteria for major depression. Independently of mood disorders, patients had a higher (p < 0.001) mean number of life events than controls. With regard to life events, the same significant difference (p < 0.001) compared to controls applied to patients with and without mood disorders., Conclusions: Our findings emphasize, by means of reliable methodology, the relationship between life events and AMI. These data, together with those regarding traditional cardiac risk factors, may have clinical and prognostic implications to be verified in longitudinal studies.