Total adiponectin in indigenous Melanesians on Kitava.

OBJECTIVES: Experimental and small human studies have indicated that high total adiponectin levels have beneficial cardiometabolic effects. In contrast, however, high total adiponectin levels are also associated with higher all-cause and cardiovascular mortality in thoroughly adjusted epidemiological studies. To gain further insight into these seemingly contradictory results, we report results on total adiponectin from the indigenous Melanesian population of Kitava, Trobriand Islands, Papua New Guinea, where an apparent absence of cardiometabolic disease has been previously reported. METHODS: Fasting levels of serum total adiponectin were measured cross-sectionally in ≥40-year-old Kitavans (n = 102) and Swedish controls matched for age and sex (n = 108). Multivariable linear regression was used for the analysis of associations with total adiponectin when controlled for group, sex, smoking, hypertension and/or type 2 diabetes, age, and body mass index. RESULTS: Total adiponectin was lower for Kitavans compared to Swedish controls (Median [Mdn] 4.6 µg/mL, range 1.0-206 µg/mL and Mdn 9.7 µg/mL, range 3.1-104 µg/mL, respectively, r = .64, p < .001). Lower total adiponectin was associated with Kitavan group, male sex (only in Swedish controls), smoking (only in Kitavans and Swedish controls combined), younger age (not in Swedish controls), higher BMI, lower total, low-density lipoprotein, high-density lipoprotein (HDL) (only in Kitavans and Swedish controls combined), and non-HDL cholesterol, and higher anti-PC IgG (only in Kitavans and Swedish controls combined). CONCLUSION: Total adiponectin in Kitavans was significantly lower than in Swedish controls.

Galectin-4 levels in hospitalized versus non-hospitalized subjects with obesity: the Malmö Preventive Project.

BACKGROUND: Obesity is strongly associated with the development of cardiovascular disease (CVD). However, the heterogenous nature of obesity in CVD-risk is still poorly understood. We aimed to explore novel CVD biomarkers and their possible association with presumed unhealthy obesity, defined as hospitalized subjects with obesity (HO). METHODS: Ninety-two proteins associated with CVD were analyzed in 517 (mean age 67 ± 6 years; 33.7% women) individuals with obesity (BMI ≥30 kg/m2) from the Malmö Preventive Project cohort, using a proximity extension array technique from the Olink CVD III panel. Individuals with at least one recorded hospitalization for somatic disease prior to study baseline were defined as HO phenotypes. Associations between proteins and HO (n = 407) versus non-hospitalized subjects with obesity (NHO, n = 110), were analyzed using multivariable binary logistic regression, adjusted for traditional risk factors. RESULTS: Of 92 analyzed unadjusted associations between biomarkers and HO, increased levels of two proteins were significant at a false discovery rate < 0.05: Galectin-4 (Gal-4) and insulin-like growth factor-binding protein 1 (IGFBP-1). When these two proteins were included in logistic regression analyses adjusted for age and sex, Gal-4 remained significant. Gal-4 was independently associated with the HO phenotype in multivariable logistic regression analysis (OR 1.72; CI95% 1.16-2.54). Post-hoc analysis revealed that this association was only present in the subpopulation with diabetes (OR 2.26; CI95% 1.25-4.07). However, an interaction analysis was performed, showing no significant interaction between Gal-4 and prevalent diabetes (p = 0.16). CONCLUSIONS: In middle-aged and older individuals with obesity, increased Gal-4 levels were associated with a higher probability of HO. This association was only significant in subjects with diabetes only, further implying a role for Gal-4 in diabetes and its complications.

Longitudinal association between leisure-time physical activity and vascular elasticity indices.

AIM: We investigated the association between levels of leisure-time physical activity and vascular stiffness in a longitudinal observational study from a representative Swedish population. METHOD: A total of 2816 randomly selected individuals were examined at visit 1 (2002-2005, Men = 1400). After a mean follow-up of 9.7 ± 1.4 years, a representative sample of 1327 of the original participants were re-examined at visit 2. After excluding subjects with hypertension at baseline, 761 participants were included in the longitudinal analyses. Leisure-time physical (LTPA) activity was self-reported and dichotomized as high or low (level 3, 4 and level 1, 2, respectively). Large Arterial Elasticity Index (LAEI) and Small Arterial Elasticity Index (SAEI) were measured using the HDI/Pulse Wave™ CR2000. Multivariable general linear models were used to investigate the differences in changes SAEI and LAEI based on LTPA levels. RESULTS: At visit 1, and after adjustment for possible confounders, participants in the high LTPA group had better small artery elasticity (SAEI) (SAEI in low-level LTPA: 7.89 ± 0.11, SAEI in high-level LTPA: 8.32 ± 0.15, ΔSAEI: 0.42, CI: 0.07-0.78; p = 0.020). SAEI decreased between the two assessments (Visit 1: SAEI 8.01 ± 3.37 ml/mmHg; Δ SAEI: 1.4, CI 1.2-1.6, p < 0.001). Participants with a higher LTPA at visit 1 had significantly better SAEI at visit 2 (ΔSAEI: 0.44, CI 0.03-0.85, p = 0.037). No significant associations were observed between LAEI and LTPA after adjustments. CONCLUSIONS: High LTPA predicted higher small arterial compliance at visit 2 suggesting that positive effects of LTPA on arterial elasticity persists over time.

The 10-year incidence of hypertension across blood pressure categories in a population-based cohort in southwestern Sweden.

BACKGROUND: To explore the determinants of incident hypertension, and especially the impact of baseline blood pressure categories, in a representative Swedish population. METHODS: A 10-year longitudinal study of residents aged 30-74. Blood pressures were measured and categorized according to ESH guidelines with optimal blood pressure < 120/80 mmHg, normal 120-129/80-84 mmHg, and high normal 130-139/85-89 mmHg. Incident hypertension was defined as ongoing treatment or three consecutive blood pressure readings ≥ 140/ ≥ 90 mmHg (one or both) at follow-up, while those with ≥ 140 and/or ≥ 90 mmHg at only one or two visits were labelled as unstable. After excluding subjects with hypertension, ongoing blood pressure lowering medication or a previous CVD event at baseline, 1099 remained for further analyses. RESULTS: Sixteen (2.6%) subjects with optimal baseline blood pressure had hypertension at follow up. Corresponding numbers for subjects with normal, high normal and unstable blood pressure were 55 (19.4%), 50 (39.1%) and 46 (74.2%), respectively. Compared with subjects in optimal group those in normal, high normal and unstable blood pressure categories had significantly higher risk to develop manifest hypertension with odds ratios OR and (95% CI) of 7.04 (3.89-12.7), 17.1 (8.88-33.0) and 84.2 (37.4-190), respectively, with adjustment for age, BMI and family history for hypertension. The progression to hypertension was also independently predicted by BMI (p < 0.001), however, not by age. CONCLUSIONS: Subjects with high normal or unstable blood pressure should be identified in clinical practice, evaluated for global hypertension risk and offered personalized advice on lifestyle modification for early prevention of manifest hypertension and cardiovascular disease.

C-reactive protein in traditional melanesians on Kitava.

BACKGROUND: Population-based levels of the chronic low-grade systemic inflammation biomarker, C-reactive protein (CRP), vary widely among traditional populations, despite their apparent absence of chronic conditions associated with chronic low-grade systemic inflammation, such as type 2 diabetes, metabolic syndrome and cardiovascular disease. We have previously reported an apparent absence of aforementioned conditions amongst the traditional Melanesian horticulturalists of Kitava, Trobriand Islands, Papua New Guinea. Our objective in this study was to clarify associations between chronic low-grade systemic inflammation and chronic cardiometabolic conditions by measuring CRP in a Kitava population sample. For comparison purposes, CRP was also measured in Swedish controls matched for age and gender. METHODS: Fasting levels of serum CRP were measured cross-sectionally in ≥ 40-year-old Kitavans (N = 79) and Swedish controls (N = 83). RESULTS: CRP was lower for Kitavans compared to Swedish controls (Mdn 0.5 mg/L range 0.1-48 mg/L and Mdn 1.1 mg/L range 0.1-33 mg/L, respectively, r = .18 p = .02). Among Kitavans, there were small negative associations between lnCRP for CRP values < 10 and total, low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL) cholesterol. Among Swedish controls, associations of lnCRP for CRP values < 10 were medium positive with weight, body mass index, waist circumference, hip circumference and waist-hip ratio and low positive with triglyceride, total cholesterol-HDL cholesterol ratio, triglyceride-HDL cholesterol ratio and serum insulin. CONCLUSIONS: Chronic low-grade systemic inflammation, measured as CRP, was lower among Kitavans compared to Swedish controls, indicating a lower and average cardiovascular risk, respectively, for these populations.

Impact of heart failure and other comorbidities on mortality in patients with chronic obstructive pulmonary disease: a register-based, prospective cohort study.

BACKGROUND: Multimorbidity has already become common in primary care and will be a challenge in the future. Primary care in Sweden participates to a great extent in the care of patients with two severe, chronic conditions: chronic obstructive pulmonary disease (COPD) and heart failure. Both conditions are characterized by high mortality and often coexist. Age, sex, heart failure and other comorbidities are considered to be the major predictors of mortality in patients with COPD. We aimed to study the impact of heart failure, other comorbidities, age and sex on mortality in patients with COPD. METHODS: A register-based, prospective cohort study conducted in Blekinge County in Sweden with about 150,000 inhabitants. The study population was comprised of people aged ≥35 years. The data about diagnoses of COPD and heart failure came from the 2007 health care register, in which we found 984 individuals with a diagnosis of COPD. Date of death was collected from January 1st, 2008 -August 31st, 2015. The diagnosis-based Adjusted Clinical Groups (ACG) Case-Mix System 7.1 was used to describe comorbidity. Each individual was assigned one of six comorbidity levels called resource utilization bands (RUB) graded from 0 to 5. RESULTS: Estimated eight year mortality in patients with COPD and coexisting heart failure was seven times higher than in patients with COPD alone - odds ratio 7.06 (95% CI 3.88-12.84). Adjusting for age and male sex resulted in odds ratio 3.75 (95% CI 1.97-7.15). Further adjusting for other comorbidities resulted in odds ratio 3.26 (95% CI 1.70-6.25). The mortality was strongly associated with the highest comorbidity level - RUB 5 where the odds ratio was 5.19 (95% CI 2.59-10.38). CONCLUSION: Heart failure has an important impact on mortality in patients with COPD. The mortality in patients with COPD and coexisting heart failure was strongly associated with age, male sex and other comorbidities. Of those three predictors, only other comorbidities can be influenced. Heart failure and other comorbidities should be recognized early and properly treated in order to improve survival in patients with coexisting COPD and heart failure.

Antibodies against Phosphorylcholine among New Guineans Compared to Swedes: An Aspect of the Hygiene/Missing Old Friends Hypothesis.

BACKGROUND: We here study antibodies against phosphorylcholine (anti-PC) which we reported to be inversely associated with atherosclerosis, cardiovascular disease (CVD), and autoimmune conditions. In previous studies, we determined that this inverse association is more pronounced at low levels with high risk and at high levels, with decreased risk. We compare individuals from Kitava, New Guinea (with low risk of these conditions), with Swedish controls. METHODS: We studied a group of 178 individuals from Kitava (age 20-86), and compared those above age 40 (n = 108) with a group of age- and sex-matched individuals from a population based cohort in Sweden (n = 108). Traditional risk factors for CVD and fatty acids were determined. IgM, IgG, and IgA anti-PC were tested by enzyme-linked immunosorbent assay (ELISA). RESULTS: All anti-PC measures were significantly lower among Swedish controls as compared to Kitavans (p < 0.001), independent of traditional risk factors. Having low levels of anti-PC, defined as below 25th percentile of values among Swedish controls, was associated with this cohort after adjustment for other risk factors (OR 5.7, 95% CI 2.2-14.7 for IgM; OR 31.7, 95% CI 3.9-252 for IgA; and OR 11.1, 95% CI 2.4-51 for IgG). CONCLUSIONS: PC is highly exposed on microorganisms and helminths (common on Kitava) exposing much PC which humans and hominids may have been exposed to for millions of years. We propose that low anti-PC levels in the developed world could be a new aspect of the hygiene hypothesis, generating a pro-inflammatory and pro-atherosclerotic state.

Low concentrations of serum testosterone predict acute myocardial infarction in men with type 2 diabetes mellitus.

BACKGROUND: The aim of the present study was to investigate the associations between endogenous testosterone concentrations and the incidence of acute myocardial infarction (AMI) in men and women with and without type 2 diabetes. METHODS: The study comprised 1109 subjects ≥40 years of age (mean age 62 ± 12 years) participating in a baseline survey in Sweden in 1993-94. Information about smoking habits and physical activity was obtained using validated questionnaires. Serum concentrations of testosterone and sex hormone-binding globulin (SHBG) were obtained using radioimmunoassay. Diagnosis of type 2 diabetes was based on WHO's 1985 criteria. Individual patient information on incident AMI was ascertained by record linkage with national inpatient and mortality registers from baseline through 2011. RESULTS: The prevalence of type 2 diabetes at baseline was 10.0% in men and 7.5% in women. During a mean follow-up of 14.1 years (±5.3), there were 74 events of AMI in men and 58 in women. In age-adjusted Cox models, a significant inverse association between concentrations of testosterone and AMI-morbidity was found in men with type 2 diabetes (HR = 0.86 CI (0.75-0.98)). In a final model also including waist-to-hip ratio, systolic blood pressure, total cholesterol and active smoking, the association still remained statistically significant (HR = 0.754 CI (0.61-0.92)). CONCLUSION: Low concentrations of testosterone predicted AMI in men with type 2 diabetes independent of other risk factors. Trials with testosterone investigating the effect regarding cardiovascular outcome are still lacking. Future trials in this field should take into account a modification effect of diabetes.

Circulating concentrations of endothelin-1 predict coronary heart disease in women but not in men: a longitudinal observational study in the Vara-Skövde Cohort.

BACKGROUND: The vasoconstricting peptide endothelin-1 has been proposed to be a marker of cardiovascular disease. Our aim was to investigate whether circulating endothelin-1 levels predict coronary heart disease (CHD) in Sweden. METHODS: In 2002-2005, 2816 adult participants (30-74 years) were randomly selected from two municipalities in south-western Sweden. Cardiovascular risk factors and endothelin-1 levels were assessed at baseline, and incident CHD was followed-up in all participants through 2011. After exclusion of 50 participants due to known CHD at baseline and 21 participants because of unsuccessful analysis of endothelin-1, 2745 participants were included in the study. In total, 72 CHD events (52 in men and 20 in women) were registered during the follow-up time. RESULTS: We showed that baseline circulating endothelin-1 levels were higher in women with incident CHD than in women without CHD (3.2 pg/ml, SE: 0.36 vs 2.4 pg/ml, SE: 0.03, p = 0.003) whereas this difference was not observed in men (2.3 pg/ml, SE: 0.16 vs 2.3 pg/ml, SE: 0.04, p = 0.828). An age-adjusted Cox proportional regression analysis showed an enhanced risk of CHD with increasing baseline endothelin-1 levels in women (hazard ratio (HR) = 1.51, 95 % CI = 1.1-2.1, p = 0.015) but not in men (HR = 0.98, 95 % CI = 0.8-1.2, p = 0.854). Furthermore, the predictive value of endothelin-1 for incident CHD in women was still significant after adjustments for age, HOMA-IR, apolipoprotein (apo)B/apoA1 and smoking (HR = 1.53, CI = 1.1-1.2, p = 0.024). CONCLUSION: Circulating endothelin-1 levels may predict CHD in women.

Impaired artery elasticity predicts cardiovascular morbidity and mortality- A longitudinal study in the Vara-Skövde Cohort.

It is still debated whether arterial elasticity provides prognostic information for cardiovascular risk beyond blood pressure measurements in a healthy population. To investigate the association between arterial elasticity obtained by radial artery pulse wave analysis and risk for cardiovascular diseases (CVD) in men and women. In 2002-2005, 2362 individuals (men=1186, 50.2%) not taking antihypertensive medication were included. C2 (small artery elasticity) was measured using the HDI/Pulse Wave CR2000. Data on acute myocardial infarction or stroke, fatal or non-fatal, was obtained between 2002-2019. Cox- regression was used to investigate associations between C2 and future CVD, adjusting for confounding factors such as age, sex, systolic blood pressure, heart rate, HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LDL- cholesterol, CRP (C-Reactive Protein), alcohol consumption, smoking and physical activity. At baseline, the mean age of 46 ± 10.6 years and over the follow-up period, we observed 108 events 70 events in men [event rate: 5.9%], 38 in women [event rate: 3.2%]. In the fully adjusted model, and for each quartile decrease in C2, there was a significant increase in the risk for incident CVD by 36%. (HR = 1.36, 95% CI: 1.01-1.82, p = 0.041). The results were accentuated for all men (HR = 1.74, 95% CI: 1.21-2.50, p = 0.003) and women over the age of 50 years (HR = 1.70, 95% CI: 0.69-4.20). We showed a strong and independent association between C2 and CVD in men. In women after menopause, similar tendencies and effect sizes were observed.

Low sex hormone-binding globulin is associated with hypertension: a cross-sectional study in a Swedish population.

BACKGROUND: The aim of this study was to investigate the association of sex hormone-binding globulin (SHBG) and hypertension in a Swedish population. METHODS: The study is based on a random sample of a Swedish population of men and women aged 30-74 years (n=2,816). Total testosterone, oestradiol and SHBG were measured in 2,782 participants. Free androgen index was then calculated according to the formula FAI=100 × (Total testosterone)/SHBG. Hypertension was diagnosed according to JNC7. RESULTS: In men, but not in women, significant association between SHBG and both diastolic (diastolic blood pressure: ß=-0.143 p<0.001) and systolic blood pressure (systolic blood pressure ß=-0.114 p<0.001) was found. The association was still significant after adjusting for age, body mass index (BMI), homeostatic model assessment insulin resistance (HOMA-IR), triglycerides, high density lipoproteins (HDL) and C-reactive protein (CRP) (diastolic blood pressure: ß=-0.113 p<0.001; systolic blood pressure ß=-0.093 p=0.001). An inverse association was observed between SHBG and hypertension in both men (B=-0.024 p<0.001) and women (B=-0.022 p<0.001). The association was still significant in women older than 50 years after adjustments for age, BMI, physical activity, CRP and alcohol consumption (B=-0.014, p=0.008). CONCLUSION: In conclusion, these results show a strong association between SHBG and blood pressure independent of major determinants of high blood pressure. This association might be addressed to direct effects of SHBG in endothelial cells through the receptor for SHBG. If this is confirmed by other observational and experimental studies, it might become a new field for the development of therapies for lowering blood pressure.

Association between self-reported alcohol consumption and diastolic dysfunction: a cross-sectional study.

BACKGROUND AND OBJECTIVES: While alcohol consumption is associated with common risk factors for diastolic dysfunction the independent impact of low levels of alcohol consumption on this condition in a community setting is still unclear.Thus, the aim of this study was to explore this association in a representative population sample employing optimal echocardiographic techniques. DESIGN: Cross-sectional observational study in community-based population. SETTINGS, PARTICIPANTS AND METHODS: Participants between 30 and 75 years of age were consecutively invited to a physical examination, interview, conventional echocardiography, including Tissue Velocity Imaging. Diastolic dysfunction was defined according to the European Society of Cardiology criteria, excluding subjects with ejection fraction <45%, self-reported history of heart failure or atrial fibrillation on ECG. Self-reported alcohol intake using a validated questionnaire was categorised as no intake, low and medium-high intake. RESULTS: In total, 500 men and 538 women (mean age 55.4±13) were successfully examined. Diastolic dysfunction was identified in 16% (79/500) of the men and 13% (58/538) of the women. The multivariable adjusted model revealed a strong and independent association between alcohol intake and diastolic dysfunction. In fact, using no alcohol intake as reference, diastolic dysfunction was independently associated with alcohol consumption in a dose-dependent fashion; low consumption, OR 2.3 (95% CI 1.3 to 4.0) and medium-high consumption OR 3.1 (95% CI 1.6 to 6.2), respectively. CONCLUSION: There was a significant association between alcohol consumption and diastolic dysfunction starting already at low levels that was supported by a dose-dependent pattern. These results need confirmatory studies and are important in public health policies.

Prevalence, awareness, treatment, and control of hypertension: rule of thirds in the Skaraborg project.

OBJECTIVE: To describe the prevalence, awareness, and control of hypertension in a Swedish population during the early 2000s to address implications for care and prevention. DESIGN: A cross-sectional population survey. SETTING: Primary health care in Skaraborg, a rural part of western Sweden. SUBJECTS: Participants (n =2816) in a population survey of a random sample of men and women between 30 and 75 years of age in the municipalities of Vara (81% participation rate) and Skövde (70%), in western Sweden during 2001-2005. MAIN OUTCOME MEASURES: Anthropometric measures, blood pressure, leisure-time physical activity, current smoking, fasting glucose, and cholesterol. Hypertension was defined as ongoing treatment for hypertension, or three consecutive blood pressure readings ≥140 systolic and/or ≥90 mmHg diastolic. Hypertension was considered controlled when the blood pressure was <140/90 mm Hg (both). RESULTS: The prevalence of hypertension was 20% in both men and women with a steep increase by age. Among hypertensive subjects, 33% were unaware, 36% aware but uncontrolled, and 31% aware and controlled, with no statistically significant differences between men and women. Patients with diabetes had a higher awareness (87% vs. 64%, p <0.001), but the same control rate (56% vs. 44%, p =0.133), when compared with those without diabetes. CONCLUSION: A large proportion of subjects with hypertension are still unaware of their condition, or aware but not controlled. It is important to emphasize population-based prevention to reduce the prevalence of hypertension, to perform screening to increase awareness, and to improve implementation of expert guidelines in clinical practice to improve control.

High prevalence of type 2 diabetes in Iraqi and Swedish residents in a deprived Swedish neighbourhood--a population based study.

BACKGROUND: Immigrants from the Middle-East are at high risk of developing type 2 diabetes (T2D). The aim of the present survey was to measure, in a single deprived neighbourhood, the prevalence rates of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and T2D in residents originating from Iraq and to compare them to those in residents born in Sweden. An additional aim was to identify metabolic, lifestyle and socioeconomic risk factors associated with IFG/IGT and T2D in these residents. METHODS: The study was conducted February 1'st to March 31'st 2010. Men and women aged 45 to 65 years of Swedish or Iraqi origin, living in the neighbourhood of Rosengård, Malmö, Sweden, were randomly selected from the census register. Each participant signed a written informed consent form, underwent a physical examination and an oral glucose tolerance test (OGTT), provided blood samples and filled in a questionnaire. A total of 175 subjects participated (Swedish origin n = 79, Iraqi origin n = 96), reflecting an overall response rate of almost 60%. RESULTS: In total, 21.9% and 19.0% of the Iraqi and Swedish participants, respectively, suffered from T2D, while 24.0% of the Iraqi participants and 25.3% of the Swedish participants had IFG/IGT. There were no significant differences in prevalence rates relating to country of origin.Obesity (BMI ≥30 kg/m2) and sedentary leisure time physical activity were highly prevalent in both groups, while a family history of diabetes was more prevalent in participants from Iraq (49.2%) than in those from Sweden (22.8%) (p = 0.001).Being obese or having a sedentary leisure time were, independently associated with T2D (OR 5.43 (95% CI 2.10-14.02) and 2.89 (95% CI 1.03-8.10) respectively), while economic difficulties were independently associated with IFG/IGT (OR 2.55 (95% CI 1.06-6.15)) after adjustment for the confounding effects of other common risk factors for T2D. CONCLUSIONS: This study reveals a high prevalence of T2D, independently of country of origin (Iraq or Sweden), in a socially vulnerable area and additionally presents a risk factor profile that is markedly different from that of Sweden in general.

Diastolic dysfunction is associated with sedentary leisure time physical activity and smoking in females only.

OBJECTIVES: Left ventricular diastolic dysfunction with preserved systolic function (DD-PSF) is associated with an increased risk of morbidity and mortality. Population-based surveys studying the associations between DD-PSF and lifestyle-associated risk factors, such as leisure time physical activity (LTPA) and smoking, are scarce. Thus, the aims were to explore the associations between DD-PSF and LTPA and smoking, employing optimal echocardiographic techniques. DESIGN: Cross-sectional study conducted from 2001 to 2003. SETTING: The study was conducted in a random sample of a rural Swedish population. SUBJECTS: Men and women of 30-75 years of age were consecutively invited for conventional echocardiography and tissue velocity imaging (n = 1149). Structured questionnaires and physical examinations were conducted using standardized methods. MAIN OUTCOME MEASURES: DD-PSF was defined according to the European Society of Cardiology criteria excluding subjects with ejection fraction < 45%, or a self-reported history of heart failure. RESULTS: Complete information was available in 500 men and 538 women. In a multivariate model, DD-PSF was independently associated with sedentary LTPA and smoking in females; sedentary LTPA odds ratio (OR) 2.91, 95% confidence interval (CI) 1.02 to 8.27, and smoking OR 3.42, 95% CI 1.35 to 8.64. The probability of identifying DD-PSF in females with a sedentary LTPA was 37% and increased to 80% if they also had hypertension and were obese. CONCLUSIONS: Sedentary LTPA and smoking are independently associated with DD-PSF in females. Identification of a sedentary lifestyle in females increases the probability of diagnosing DD-PSF.

A diabetes-associated genetic variant is associated with diastolic dysfunction and cardiovascular disease.

AIMS: Although the epidemiological association between Type 2 diabetes and congestive heart failure (CHF) as well as cardiovascular disease (CVD) is well established, associations between diabetes-related single-nucleotide polymorphisms (SNPs), CHF, and CVD have been surprisingly inconclusive. Our aim is to examine if 43 diabetes-related SNPs were associated with prevalent diastolic dysfunction assessed by echocardiography and incident CVD and/or CHF. METHODS AND RESULTS: We genotyped 43 SNPs that previously reported genome-wide significant associations with Type 2 diabetes, in 1444 subjects from the population-based Malmö Preventive Project-Re-examination Study (MPP-RES) (mean age 68 years; 29% women, 36% prevalent diabetes) (discovery cohort) and in 996 subjects from the VARA cohort (mean age 51 years, 52% women, 7% prevalent diabetes) (replication cohort). Multivariable logistic regression was assessed. Genetic variants that reached significant association with diastolic dysfunction in both cohorts were then analysed for association with incident CVD/CHF in a larger sample of the MPP-RES cohort (3,407 cases and 11,776 controls, median follow up >30 years) using Cox regression analysis. A common variant at the HNF1B [major allele (T) coded, also the risk allele for diabetes] was the only SNP associated with increased risk of prevalent diastolic dysfunction in both the discovery [MPP-RES; odds ratio (OR) 1.21, P = 0.024), and the replication cohort (VARA; OR 1.38, P = 0.042]. Cox regression analysis showed that carriers of the T-allele of rs757210 had an increased risk of future CVD (HR 1.05, P = 0.042). No significant association was seen for incident CHF. CONCLUSIONS: The diabetes susceptibility locus HNF1B is associated with prevalent diastolic dysfunction in two independent Swedish cohorts as well as incident cardiovascular disease.

Proteomic exploration of common pathophysiological pathways in diabetes and cardiovascular disease.

AIMS: The epidemiological association between diabetes and cardiovascular disease is well established, but the pathophysiological link is complex and multifactorial. We investigated seven proteins, previously linked to incident diabetes mellitus, and their association with cardiovascular disease and mortality. METHODS AND RESULTS: Plasma samples from 1713 individuals from the Swedish population-based Malmö Preventive Project (mean age 67.4 ± 6.0 years; 29.1% women) were analysed with a proximity extension assay panel. Seven proteins [scavenger receptor cysteine rich type 1 protein M130 (CD163), fatty acid-binding protein 4 (FABP4), plasminogen activator inhibitor 1 (PAI), insulin-like growth factor-binding protein 2 (IGFB2), cathepsin D (CTSD), galectin-4 (GAL4), and paraoxonase-3 (PON3)] previously shown to be associated with incident diabetes were analysed for associations with all-cause mortality (ACM), cardiovascular mortality (CVM), incident coronary events (CEs), and incident heart failure (HF). After exclusion of prevalent cases of respective outcome, proteins that met Bonferroni-corrected significance were analysed in multivariable Cox regression models. Significant associations were identified between five proteins [GAL4 (hazard ratio; 95% confidence interval: 1.17-1.41), CTSD (1.15-1.37), CD163 (1.09-1.30), IGFBP2 (1.05-1.30), and FABP4 (1.04-1.29)] and ACM and four proteins [GAL4 (1.38-1.56), CTSD (1.14-1.43), CD163 (1.09-1.36), and IGFBP2 (1.03-1.35)] with CVM. Three proteins [GAL4 (1.14-1.57), CTSD (1.12-1.50), and FABP4 (1.05-1.55)] were significantly associated with incident CE and two [GAL4 (1.03-1.54) and CTSD (1.01-1.46)] were associated with incident HF after adjusting for traditional risk factors including N-terminal pro-brain natriuretic peptide. CONCLUSIONS: In a general Swedish population, four proteins previously shown to be associated with diabetes were associated with ACM and CVM. Three proteins were associated with incident CE. Finally, GAL4 and CTSD displayed novel associations with incident HF and were the only proteins associated with all outcomes.

Exploration of pathophysiological pathways for incident atrial fibrillation using a multiplex proteomic chip.

Objective: Atrial fibrillation (AF) is the most common arrhythmia and associated with increased morbidity and mortality. Its increasing prevalence calls for novel biomarkers to identify underlying pathophysiological mechanisms as well as patients at risk. Methods: Plasma samples from 1694 individuals from the Swedish population-based Malmö Preventive Project (mean age 69.5 years; 29.3% female; mean follow-up time 9.7±3.1 years) were analysed with the Olink proximity extension assay CVD III panel consisting of 92 proteins to identify proteins associated with incident AF or atrial flutter, referred to as incident AF. Incident cases of AF (n=278) were retrieved by linkage to the registers. Participants were followed until the first episode of AF or until censoring by death or emigration. Bonferroni-corrected multivariable Cox regression models adjusted for known risk factors were used to explore possible associations of the 92 proteins and incidence of AF. Results: Multivariable Cox regression analyses of 11 proteins associated with incident AF (mean follow-up time 9.7±3.1 years) after Bonferroni correction confirmed N-terminal pro-B-type natriuretic peptide (HR per 1 SD increment (95% CI) 1.80 (1.58 to 2.04); p=1.2×10-19) as risk marker of incident AF. Further, matrix metalloproteinase-2 (1.22 (1.07 to 1.39); p=0.002) and osteopontin (1.27 (1.12 to 1.44); p=2.7×10-4) were associated with incident AF at follow-up independently of traditional risk markers and NT-proBNP. Conclusion: In a general Swedish population, we confirmed the well-known association of NT-proBNP with incident AF and also identified matrix metalloproteinase-2 and osteopontin as novel risk markers for incident AF, independently of traditional risk factors and NT-proBNP.

Factors associated with multiple medication use in different age groups.

BACKGROUND: Multiple medicine use among elderly persons is likely to be the result of treatment regimens developed over a long period of time. By learning more about how multiple medication use develops, the quality of prescribing may be improved across the adult lifespan. OBJECTIVE: To describe patterns of multiple medicine use in the general Swedish population and its association with sociodemographic, lifestyle, and health status factors. METHODS: Data from a cross-sectional population health survey collected during 2001-2005 from 2816 randomly selected Swedish residents (age 30-75 y; response rate 76%) were analyzed. Multiple medicine use was restricted to prescription drugs and defined as the 75th percentile; that is, the 25% of the study group using the highest number of drugs per individual. RESULTS: Seventy-one percent of the respondents used some kind of drug, 51.5% used one or more prescription drug, 38.4% used one or more over-the-counter (OTC) medication, and 8.3% used one or more herbal preparation. The cutoff amounts defining multiple medicine use were: 2 or more medications for 30- to 49-year-olds, 3 or more for 50- to 64-year-olds, and 5 or more for 65- to 75-year-olds. No association between use of multiple medicines and use of OTC drugs or herbal preparations was found. When drugs were classified into therapeutic subgroups, 76.3% of those aged 30-49 years, 97.9% of those aged 50-64 years, and 100% of those aged 65-75 years were taking a unique combination of drugs. Multivariate analyses showed that diabetes and poor self-rated health were associated with multiple medicine use in all age cohorts. Female sex and hypertension were associated with multiple medicine use among those aged 30-49 and 50-64 years, current smoking among those aged 50-64 years, and obesity among those aged 65-75 years. CONCLUSIONS: Multiple medicine use was associated with morbidity and poor self-rated health across all age groups. The vast majority of users of multiple drugs are taking a unique combination of medications.

Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study.

BACKGROUND: Most studies on cortisol have focused on smaller, selected samples. We therefore aimed to sex-specifically study the diurnal cortisol pattern and explore its association with abdominal obesity in a large unselected population. METHODS: In 2001-2004, 1811 men and women (30-75 years) were randomly selected from the Vara population, south-western Sweden (81% participation rate). Of these, 1671 subjects with full information on basal morning and evening salivary cortisol and anthropometric measurements were included in this cross-sectional study. Differences between groups were examined by general linear model and by logistic and linear regression analyses. RESULTS: Morning and Delta-cortisol (morning - evening cortisol) were significantly higher in women than men. In both genders older age was significantly associated with higher levels of all cortisol measures, however, most consistently with evening cortisol. In women only, age-adjusted means of WHR were significantly lower in the highest compared to the lowest quartile of morning cortisol (p = 0.036) and Delta-cortisol (p < 0.001), respectively. Furthermore, when comparing WHR above and below the mean, the age-adjusted OR in women for the lowest quartile of cortisol compared to the highest was 1.5 (1.0-2.2, p = 0.058) for morning cortisol and 1.9 (1.3-2.8) for Delta-cortisol. All findings for Delta-cortisol remained after adjustments for multiple covariates and were also seen in a linear regression analysis (p = 0.003). CONCLUSION: In summary, our findings of generally higher cortisol levels in women than men of all ages are novel and the stronger results seen for Delta-cortisol as opposed to morning cortisol in the association with WHR emphasise the need of studying cortisol variation intra-individually. To our knowledge, the associations in this study have never before been investigated in such a large population sample of both men and women. Our results therefore offer important knowledge on the descriptive characteristics of cortisol in relation to age and gender, and on the impact that associations previously seen between cortisol and abdominal obesity in smaller, selected samples have on a population level.