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The present study aims to describe accelerometer-assessed physical activity (PA) patterns and fulfillment of PA recommendations in a large sample of middle-aged men and women, and to study differences between subgroups of socio-demographic, socio-economic, and lifestyle-related variables. A total of 27 890 (92.5% of total participants, 52% women, aged 50–64 years) middle-aged men and women with at least four days of valid hip-worn accelerometer data (Actigraph GT3X+, wGT3X+ and wGT3X-BT) from the Swedish CArdioPulmonary bioImage Study, SCAPIS, were included. In total, 54.5% of daily wear time was spent sedentary, 39.1% in low, 5.4% in moderate, and only 0.1% in vigorous PA. Male sex, higher education, low financial strain, born in Sweden, and sedentary/light working situation were related to higher sedentary time, but also higher levels of vigorous PA. High BMI and having multiple chronic diseases associated strongly with higher sedentary time and less time in all three PA intensities. All-year physically active commuters had an overall more active PA pattern. The proportion fulfilling current PA recommendations varied substantially (1.4% to 92.2%) depending on data handling procedures and definition used. Twenty-eight percent was defined as having an “at-risk” behavior, which included both high sedentary time and low vigorous PA. In this large population-based sample, a majority of time was spent sedentary and only a fraction in vigorous PA, with clinically important variations between subgroups. This study provides important reference material and emphasizes the importance of a comprehensive assessment of all aspects of the individual PA pattern in future research and clinical practice.

The carotid-to-femoral pulse wave velocity, determined by pulse transit time (PTT) and distance, is a well-established measure of arterial stiffness and predicts adverse outcomes. However, its predictive value decreases with aging. To explore new risk indicator in the elderly, we investigated if the variation of carotid-to-femoral pulse wave velocity, registered as beat-to-beat variability of carotid-to-femoral PTT (cf-PTT), could predict outcome. Totally 3015 (median age, 72.4 years; 39.6% men) and 1181 (75.6 years; 42.2% men) subjects from communities of Malmö, Sweden, and Shanghai, China, were analyzed, respectively. Continuous pulse waves for 10 seconds were recorded sequentially at carotid and femoral arterial sites with applanation tonometry (SphygmoCor, Atcor, Australia). During a median of 6.6 and 10.2 years, 389 and 427 deaths occurred in the Malmö and Shanghai cohorts, respectively. Each one-SD increase in the log-transformed coefficient of variation of cf-PTT was associated with 24% (95% CI, 13%–37%) and 21% (10%–33%) increased risk for all-cause mortality in the Malmö and Shanghai subjects, and 60% (33%–91%) for cardiovascular mortality in the Malmö subjects. Adding the coefficient of variation of cf-PTT to the models including conventional risk factors and carotid-to-femoral pulse wave velocity significantly ( P

As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18–71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms. Electronic supplementary material The online version of this article (10.1007/s10654-020-00695-4) contains supplementary material, which is available to authorized users.

Although the causality of the obesity--hypertension association is established, the potential for prevention is not. We hypothesized that weight gain between early adulthood and mid-life is associated with higher mid-life blood pressure.We investigated the hypothesis using a large contemporaneous population-based mid-life cohort of men and women aged 50-64 years. Recalled body weight at age 20 years was self-reported, and mid-life body weight and office blood pressures were measured in accordance with a detailed protocol.On average, men had gained 14.9 (95% CI 14.6-15.2) kg of weight, and women 14.6 (95% CI 14.4-14.9) kg, between age 20 years and the mid-life examination, corresponding to 0.40 (95% CI 0.39-0.41) kg/year for men and women. Both weight at age 20 years and weight at the mid-life examination were associated with mid-life blood pressures. On average, a 10 kg weight increase between age 20 years and mid-life was associated with 2.2 (95% CI 0.9-3.5) mmHg higher systolic and 1.7 (95% CI 0.9-2.5) mmHg higher diastolic mid-life blood pressure in men, and 3.2 (2.5-4.0) mmHg higher systolic and 2.4 (1.9-2.9) mmHg higher diastolic mid-life blood pressure in women. Mid-life weight was more closely associated than weight at age 20 years with mid-life blood pressure. For a given mid-life weight, blood pressure was higher in persons with higher weight gain from age 20 years.In sum, weight gain between early adulthood and mid-life was associated with higher mid-life blood pressure. The magnitude of the association indicates a potentially great public health impact of strategies to prevent weight gain throughout adulthood.

Background The cardiovagal function can be assessed by quantification of respiratory sinus arrhythmia (RSA) during a deep breathing test. However, population studies of RSA and coronary atherosclerosis are lacking. This population‐based study examined the relationship between RSA during deep breathing and coronary atherosclerosis, assessed by coronary artery calcium score (CACS). Methods and Results SCAPIS (Swedish Cardiopulmonary Bioimage Study) randomly invited men and women aged 50 to 64 years from the general population. CACS was obtained from computed tomography scanning, and deep breathing tests were performed in 4654 individuals. Expiration–inspiration differences (E‐Is) of heart rates were calculated, and reduced RSA was defined as E‐I in the lowest decile of the population. The relationship between reduced RSA and CACS (CACS≥100 or CACS≥300) was calculated using multivariable‐adjusted logistic regression. The proportion of CACS≥100 was 24% in the lowest decile of E‐I and 12% in individuals with E‐I above the lowest decile ( P P P =0.001) for CACS≥100 and 1.28 ( P =0.001) for CACS≥300. Conclusions Low RSA during deep breathing is associated with increased coronary atherosclerosis as assessed by CACS, independently of traditional cardiovascular risk factors. Cardiovagal dysfunction could be a prevalent and modifiable risk factor for coronary atherosclerosis in the general population.

BackgroundLow resting heart rate and premature atrial contractions (PACs) predict incident atrial fibrillation (AF) and could be interdependent, since PACs occur in the gaps between normal beats.ObjectiveTo study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort.MethodsIn the Malmö Diet and Cancer study, 24hECGs were performed in 377 AF-free subjects. The endpoint was clinical AF retrieved from national hospital (mean follow-up 17 years). The interaction between increased supraventricular activity (SVA) top quartile of either PACs/hour or supraventricular tachycardias/hour) and mean heart rate (mHR) as regards AF risk was assessed in multivariable Cox regression analyses adjusted for age, sex, height, BMI, systolic blood pressure, antihypertensive medication, smoking and homeostasis model assessment of insulin resistance.ResultsThere were 80 (21%) incident cases of AF. Below median mHR (80 bpm/75 bpm for women/men) was associated with increased AF incidence (HR: 1.89, 95% CI 1.18 to 3.02, p=0.008). There was no correlation between mHR and SVA (p=0.6) or evidence of a multiplicative interaction between these factors for AF risk (p for interaction=0.6) In the group with both increased SVA and below median mHR (17% of the population) the relative risk of AF was very high (HR 4.5, 95% CI 2.2 to 9.1, p=0.001).ConclusionLow mHR at 24hECG independently predicts AF, but there is no association between mHR and SVA, and these factors are independent as regards AF risk. Subjects with both low mHR and increased SVA have high AF risk.

Background Circulating C3 has been associated with diabetes and hypertension, which are the leading causes of chronic kidney disease (CKD). C3 activation is considered to contribute to several renal diseases. Here we examined whether elevated C3 concentration is associated with hospitalization due to CKD in the general population, and whether this relationship is mediated by factors such as diabetes and hypertension. Methods Baseline plasma C3 was quantified in 4552 participants, without previous hospital admission due to CKD, from the Malmö Diet and Cancer cohort study. Incidence of first hospitalization due to CKD (main diagnosis) was investigated in relation to C3 levels using Cox proportional hazards regression models after a mean follow-up of 19.2 ± 4.16 years. Traditional risk factors of CKD including diabetes, blood pressure, C-reactive protein and baseline renal function were considered in adjustments and sensitivity analyses. Results During the follow-up period, 94 subjects were admitted to hospital due to CKD. After multivariate adjustment, the hazard ratios (95% confidence interval) for hospitalization from CKD across quartiles of C3 were 1.00 (reference), 1.68 (0.69, 4.13), 2.71 (1.15, 6.39), and 3.16 (1.36, 7.34) (p for trend = 0.003). Results were generally consistent across different sensitivity analyses. Conclusions These findings indicate that C3 is associated with incidence of first hospitalization due to CKD in the general population. The observed relationship cannot be entirely attributed to hyperglycemia and hypertension.

Background: The general population is ubiquitously exposed to the toxic metal cadmium through the diet and smoking. Cadmium exposure is associated with increased morbidity and mortality in myocardial infarction and stroke. Atherosclerosis is the main underlying mechanism of myocardial infarction. However, associations between cadmium and coronary artery atherosclerosis have not been examined. Objectives: Our study sought to examine the hypothesis that blood cadmium (B-Cd) is positively associated with coronary artery calcification, as a measure of coronary artery atherosclerosis in the population-based Swedish SCAPIS study. Methods: Our analysis included 5,627 individuals (51% women), age 50–64 y, enrolled from 2013 to 2018. The coronary artery calcium score (CACS) was obtained from computed tomography. Blood cadmium was determined by inductively coupled plasma mass spectrometry (ICP-MS). Associations between B-Cd and coronary artery calcium score (CACS Agatston score) were evaluated using prevalence ratios (PRs) in models adjusted for sex, age, smoking, hypertension, diabetes, low-density cholesterol/high-density cholesterol ratio, and family history. Results: The median B-Cd concentration was 0.24μg/L. The prevalence of positive coronary artery calcium (CACS>0) was 41% and the prevalence of CACS≥100 was 13%. Relative to the lowest quartile (Q) of B-Cd (0 (PR 1.1; 95% CI: 1.0, 1.3), and a greater relative increase in CACS≥100 (PR 1.6; 95% CI: 1.3, 2.0). When restricted to 2,446 never-smokers, corresponding PRs were 1.1 (95% CI 0.9, 1.3) for CACS>0 (63 cases in Q4) and 1.7 (95% CI 1.1, 2.7) for CACS≥100 (17 cases in Q4). Discussion: Blood cadmium in the highest quartile was associated with CACS in a general population sample with low to moderate cadmium exposure. This supports the hypothesis that atherosclerosis is an important mechanism underlying the associations between cadmium and incident cardiovascular disease. The findings suggest that public health measures to reduce cadmium exposure are warranted. https://doi.org/10.1289/EHP8523

Background: Arterial ageing is characterised by degradation of elastic fibres and increased stiffness of elastic arteries. Although low lung function and arterial stiffness are strongly related to age, the association between lung function and arterial ageing has not been widely explored. We used a large population-based study of 50-64 year olds to assess the association between lung function (measured by spirometry and CO diffusing capacity (D-LCO)) and arterial stiffness (measured by carotid-femoral pulse-wave velocity (c-f PWV)). Methods: Participants from the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort with information on spirometry (n = 8941) and D-LCO (n = 8616) were included. General linear models (lung function quartiles) and linear regression was used to determine the association between lung function and c-f PWV. Results: FEV1 (L), FVC (L), D-LCO (mmol/(min kPa)) and D-LCO/V-A (mmol/(min kPa L)) were significantly and inversely associated with c-f PWV after adjustments; mean PWV (m/s) in Q1 (highest lung function) vs Q4: FEV1; 8.45 vs 8.60, p-value 0.001; FVC; 8.45 vs 8.57, p-value 0.018; D-LCO; 8.46 vs 8.60, p-value 0.002; and D-LCO/V-A; 8.47 vs 8.58, p-value 0.001. In sex-stratified analyses, significant findings were reflected for FEV1 and D-LCO in men only. The results remained significant for D-LCO in all never smokers and in all participants without COPD or airflow limitation on spirometry. Conclusions: A reduction in spirometry and D-LCO is associated with elevated arterial stiffness in middle-aged men. A reduction in D-LCO is associated with higher c-f PWV even in never smokers and in those without COPD or airflow limitation on spirometry. Funding Agencies|Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation [2014-0047]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [822-2013-2000, 2019-01236]; VINNOVA (Swedens Innovation agency)Vinnova [2012-04476]; Linoping University and University Hospital; Lund University; Swedish Heart and Lung FoundationSwedish Heart-Lung Foundation [2020-0173]; Skane University Hospital; Swedish Heart and Lung FoundationSwedish Heart-Lung Foundation

Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder with poorly understood etiology and underlying pathophysiology. Since cardiovascular morbidity has been linked to growth hormone (GH), we studied GH levels in patients with POTS. We conducted an age-sex-matched case–control study in patients with POTS (age 31 ± 9 years; n = 42) and healthy controls (32 ± 9 years; n = 46). Plasma GH levels were measured using high-sensitivity chemiluminescence sandwich immunoassay. The burden of orthostatic intolerance symptoms was assessed by the Orthostatic Hypotension Questionnaire (OHQ), consisting of a symptom assessment scale (OHSA) and a daily activity scale (OHDAS). POTS patients had significantly higher composite OHQ score than controls, more symptoms and less activity. Supine heart rate and diastolic blood pressure (BP), but not systolic BP, were significantly higher in POTS. Median plasma GH levels were significantly lower in POTS (0.53 ng/mL) than controls (2.33 ng/mL, p = 0.04). GH levels were inversely related to OHDAS in POTS and supine systolic BP in POTS and controls, but not heart rate neither group. POTS is associated with lower GH levels. Impairment of daily life activities is inversely related with GH in POTS. A higher supine diastolic BP is inversely associated with GH levels in POTS and healthy individuals.

Supplemental Digital Content is available in the text., Background: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population. Methods: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data. Results: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort equation, 9.2% had CCTA-verified atherosclerosis. Prevalence estimates had excellent external validity and changed marginally when adjusted to the age-matched Swedish background population. Conclusions: Using CCTA in a large, random sample of the general population without established disease, we showed that silent coronary atherosclerosis is common in this population. High CAC scores convey a significant probability of substantial stenosis, and 0 CAC does not exclude atherosclerosis, particularly in those at higher baseline risk.

Background It is not clear if the European Systematic Coronary Risk Evaluation algorithm is useful for identifying prevalent subclinical atherosclerosis in a population of apparently healthy individuals. Our aim was to explore the association between the risk estimates from Systematic Coronary Risk Evaluation and prevalent subclinical atherosclerosis. Design The design of this study was as a cross-sectional analysis from a population-based study cohort. Methods From the general population, the Swedish Cardiopulmonary Bioimage Study randomly invited individuals aged 50-64 years and enrolled 13,411 participants mean age 57 (standard deviation 4.3) years; 46% males between November 2013-December 2016. Associations between Systematic Coronary Risk Evaluation risk estimates and coronary artery calcification and plaques in the carotid arteries by using imaging data from a computed tomography of the heart and ultrasonography of the carotid arteries were examined. Results Coronary calcification was present in 39.5% and carotid plaque in 56.0%. In men, coronary artery calcium score amp;gt;0 ranged from 40.7-65.9% and presence of carotid plaques from 54.5% to 72.8% in the age group 50-54 and 60-65 years, respectively. In women, the corresponding difference was from 17.1-38.9% and from 41.0-58.4%. A doubling of Systematic Coronary Risk Evaluation was associated with an increased probability to have coronary artery calcium score amp;gt;0 (odds ratio: 2.18 (95% confidence interval 2.07-2.30)) and to have amp;gt;1 carotid plaques (1.67 (1.61-1.74)). Conclusion Systematic Coronary Risk Evaluation estimated risk is associated with prevalent subclinical atherosclerosis in two major vascular beds in a general population sample without established cardiovascular disease or diabetes mellitus. Thus, the Systematic Coronary Risk Evaluation risk chart may be of use for estimating the risk of subclinical atherosclerosis. Funding Agencies|Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation [2019-0012]; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation [2014-0047]; Swedish Research CouncilSwedish Research Council [822-2013-2000]; VINNOVA (Swedens Innovation agency)Vinnova [2012-04476]; University of Gothenburg; Sahlgrenska University Hospital; Karolinska InstitutetKarolinska Institutet; Karolinska University HospitalKarolinska Institutet; Linkoping University; University Hospital; Lund University; Skane University Hospital; Swedish Heart Lung FoundationSwedish Heart-Lung Foundation; Swedish government [ALFGBG-718851, ALF-VLL-548791, ALF-LIO-700841]; county councils, the ALF-agreement [ALFGBG-718851, ALF-VLL-548791, ALF-LIO-700841]; AFA Insurance [160334]

Even though abdominal aortic aneurysm (AAA) and coronary heart disease (CHD) are both related to atherosclerosis, there could be important differences in risk factors. Based on Malmö Diet and Cancer Cohort, the incidence of AAA and CHD was followed prospectively. Cox regression was used to calculate the association of each factor with AAA and CHD and hazards ratio were compared using a modified Lunn-McNeil method; 447 participants developed AAA and 3129 developed CHD. After multivariate adjustments, smoking, antihypertensive medications, lipid-lowing medications, systolic and diastolic blood pressures, apolipoprotein (Apo) A1 (inversely), ApoB, ApoB/ApoA1 ratio, total leukocyte count, neutrophil count, and neutrophil to lymphocyte ratio were associated with the risks of both AAA and CHD. When comparing risk factor profiles for the 2 diseases, smoking, diastolic blood pressure, ApoA1, and ApoB/ApoA1 ratio had stronger associations with risk of AAA than with risk of CHD, while diabetes and unmarried status showed increased risk of CHD, but not of AAA (all P values for equal association

Background Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive heart rate increase on standing and orthostatic intolerance. Previous data indicate autoimmune involvement. We studied serum activity against G protein–coupled receptors in relation to symptoms in patients with POTS and controls using a commercial cell‐based assay. Methods and Results Forty‐eight patients with POTS (aged 28.6±10.5 years; 44 women) and 25 healthy individuals (aged 30.7±8.6 years; 21 women) were included. The 10‐item Orthostatic Hypotension Questionnaire (OHQ) was completed by 33 patients with POTS and all controls. Human embryonic kidney 293 cells overexpressing one G protein–coupled receptor: adrenergic α 1 receptor, adrenergic β 2 receptor, cholinergic muscarinic type 2 receptor, and opioid receptor‐like 1 were treated with sera from all patients. Receptor response was analyzed using a β‐arrestin–linked transcription factor driving transgenic β‐lactamase transcription by fluorescence resonance energy transfer method. Receiver operating characteristic curves were constructed. G protein–coupled receptor activation was related to OHQ indices in linear regression models. Sera from patients with POTS activated all 4 receptors to a higher degree compared with controls ( P P 1 receptor activation associated with OHQ composite score (β=0.77 OHQ points per SD of activity, P =0.009) and with reduced tolerability for prolonged standing ( P =0.037) and walking for short ( P =0.042) or long ( P =0.001) periods. All 4 receptors were associated with vision problems ( P Conclusions Our results indicate the presence of circulating proteins activating adrenergic, muscarinic, and nociceptin receptors in patients with POTS. Serum‐mediated activation of these receptors has high predictive value for POTS. Activation of adrenergic α 1 receptor is associated with orthostatic symptoms severity in patients with POTS.

The aim of the study was to present the methodology, cohort demographics, and initial results of the Swedish SPinal Cord Injury Study on Cardiopulmonary and Autonomic Impairment (SPICA).The SPICA is based on the Swedish CArdioPulmonary BioImage Study, a study on cardiopulmonary diseases in a cohort of 30,000 people. The assessments in the SPICA cover the structure and function of the cardiopulmonary and autonomic systems using bioimaging and functional analyses, together with a study-specific questionnaire and generic and spinal cord injury-specific assessment tools. The inclusion criteria were as follows: age 50-65 yrs, traumatic spinal cord injury of 5 yrs or more, and injury levels C1-T6, American Spinal Injury Association Impairment Scale A-C.Of 38 potential participants, 25 comprised the final sample (20% women, mean age 58 yrs, mean time since injury 28 yrs). Eight percent had sustained a cardiovascular event, and 72% were classified as a high risk for cardiovascular disease. Asthma was previously diagnosed in only 8%, and none had chronic obstructive pulmonary disease.The risk for cardiovascular disease in people with severe high-level spinal cord injury is a major clinical concern. Forthcoming studies in the SPICA will provide new knowledge of cardiopulmonary health in this cohort, which can guide future research and be used to develop long-term management.

Aims/hypothesis Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. Methods GIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer–Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. Results In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10−5) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD. Conclusions/interpretation In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5–9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.

OBJECTIVE While existing evidence supports beneficial cardiovascular effects of glucagon-like peptide 1 (GLP-1), emerging studies suggest that glucose-dependent insulinotropic peptide (GIP) and/or signaling via the GIP receptor may have untoward cardiovascular effects. Indeed, recent studies show that fasting physiological GIP levels are associated with total mortality and cardiovascular mortality, and it was suggested that GIP plays a role in pathogenesis of coronary artery disease. We investigated the associations between fasting and postchallenge GIP and GLP-1 concentrations and subclinical atherosclerosis as measured by mean intima-media thickness in the common carotid artery (IMTmeanCCA) and maximal intima-media thickness in the carotid bifurcation (IMTmaxBulb). RESEARCH DESIGN AND METHODS Participants at reexamination within the Malmö Diet and Cancer–Cardiovascular Cohort study (n = 3,734, mean age 72.5 years, 59.3% women, 10.8% subjects with diabetes, fasting GIP available for 3,342 subjects, fasting GLP-1 available for 3,299 subjects) underwent oral glucose tolerance testing and carotid ultrasound. RESULTS In linear regression analyses, each 1-SD increment of fasting GIP was associated with increased (per mm) IMTmeanCCA (β = 0.010, P = 0.010) and IMTmaxBulb (β = 0.014; P = 0.040) in models adjusted for known risk factors and glucose metabolism. In contrast, each 1-SD increment of fasting GLP-1 was associated with decreased IMTmaxBulb (per mm, β = −0.016, P = 0.014). These associations remained significant when subjects with diabetes were excluded from analyses. CONCLUSIONS In a Swedish elderly population, physiologically elevated levels of fasting GIP are associated with increased IMTmeanCCA, while GLP-1 is associated with decreased IMTmaxBulb, further emphasizing diverging cardiovascular effects of these two incretin hormones.

Type 2 diabetes mellitus is associated with an elevated risk of cardiovascular disease, but the mechanism through which diabetes contributes to cardiovascular disease development remains incompletely understood. In this study, we compared the association of circulating regulatory T cells, naïve T cells, effector memory T cells or central memory T cells with cardiovascular disease in patients with and without type 2 diabetes mellitus. Percentage of circulating T cell subsets was analysed by flow cytometry in type 2 diabetes mellitus subjects with and without prevalent cardiovascular disease as well as in non-diabetic subjects with and without prevalent cardiovascular disease from the Malmö SUMMIT cohort. Subjects with type 2 diabetes mellitus had elevated percentages of effector memory T cells (CD4+CD45RO+CD62L–; 21.8% ± 11.2% vs 17.0% ± 9.2% in non-type 2 diabetes mellitus, p < 0.01) and central memory T cells (CD4+CD45RO+CD62L+; 38.0% ± 10.7% vs 36.0% ± 9.5% in non-type 2 diabetes mellitus, p < 0.01). In contrast, the frequency of naïve T cells was reduced (CD4+CD45RO–CD62L+, 35.0% ± 16.5% vs 42.9% ± 14.4% in non-type 2 diabetes mellitus, p < 0.001). The proportion of effector memory T cells was increased in type 2 diabetes mellitus subjects with cardiovascular disease as compared to those without (26.4% ± 11.5% vs 18.4% ± 10.2%, p < 0.05), while no difference in regulatory T cells was observed between these two patient groups. This study identifies effector memory T cells as a potential cellular biomarker for cardiovascular disease among subjects with type 2 diabetes mellitus, suggesting a state of exacerbated immune activation in type 2 diabetes mellitus patients with cardiovascular disease.

Objective Because elevated copeptin, a marker of vasopressin, is linked to low water intake and high diabetes risk, we tested the effect of water supplementation on copeptin and fasting glucose. Design, Setting, and Participants Thirty-one healthy adults with high copeptin (>10.7 pmol · L−1 in men and >6.1 pmol·L−1 in women) identified in a population-based survey from 2013 to 2015 and with a current 24-hour urine osmolality of >600 mOsm · kg−1 were included. Intervention Addition of 1.5 L water daily on top of habitual fluid intake for 6 weeks. Main outcome measure Pre- and postintervention fasting plasma copeptin concentrations. Results Reported mean water intake increased from 0.43 to 1.35 L · d−1 (P < 0.001), with no other observed changes in diet. Median (interquartile range) urine osmolality was reduced from 879 (705, 996) to 384 (319, 502) mOsm · kg−1 (P < 0.001); urine volume increased from 1.06 (0.90, 1.20) to 2.27 (1.52, 2.67) L · d−1 (P < 0.001); and baseline copeptin decreased from 12.9 (7.4, 21.9) pmol · L−1 to 7.8 (4.6;11.3) pmol · L−1 (P < 0.001). Water supplementation reduced fasting plasma glucose from a mean (SD) of 5.94 (0.44) to 5.74 (0.51) (P = 0.04). The water-associated reduction of both fasting copeptin and glucose concentration in plasma was most pronounced in participants in the top tertile of baseline copeptin. Conclusions Water supplementation in persons with habitually low water consumption and high copeptin levels is effective in lowering copeptin. It appears a safe and promising intervention with the potential of lowering fasting plasma glucose and thus reducing diabetes risk. Further investigations are warranted to support these findings., In individuals with high plasma concentration of the vasopressin marker copeptin, increased water intake of 1.5 L daily during 6 weeks significantly reduced copeptin and fasting glucose.

BACKGROUND: Red cell distribution width (RDW) reflects heterogeneity of the erythrocyte volumes. High RDW is a novel risk marker, which has been associated with mortality and morbidity both from cardiovascular and respiratory diseases, but the association between RDW and measures of lung function in the general population remains unclear.METHODS: The associations of RDW with spirometry, diffusing capacity (DLCO) and impulse oscillometry (IOS) were investigated among 5767, 5496 and 5598 subjects (aged 50-64 years), respectively, from the Swedish CArdioPulmonary bioImage Study (SCAPIS). Multiple linear regression and general linear models were performed to examine the relationships of lung function measures and RDW, with adjustment for potential confounding factors.RESULTS: Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC were significantly and inversely associated with RDW after multivariate adjustments. For 1- standard deviation (SD) increase in RDW, FEV1 decreased with 0.034 L (95%CI: -0.046 to -0.022 L), p < 0.001; FVC with 0.031 L (95%CI: -0.045 to -0.017 L), p < 0.001; and FEV1/FVC with 0.003 (95%CI: -0.004 to -0.001), p = 0.002. Significant associations of RDW and DLCO were only found among smokers. For IOS, pulmonary reactance rather than resistance was significantly associated with RDW: X5 decreased 0.002 kPa/(L/s) (95%CI: -0.003 to -0.0002 kPa/(L/s)), p = 0.025, per 1-SD higher RDW.CONCLUSIONS: We found significant negative associations between RDW and measures of lung function. However, the effect sizes are small and RDW is not likely to be a sensitive marker of impaired lung function in middle-aged individuals from the general population. (Less)

Purpose High plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon. Methods Thirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water. Results After acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34–45) (p

Background and Purpose— ECP (eosinophil cationic protein) is a marker of eosinophil activity and degranulation, which has been linked to atherosclerosis and cardiovascular disease. We examined the relationship between ECP, carotid plaque, and incidence of stroke in a prospective population-based cohort. Methods— The subjects participated in the Malmö Diet and Cancer Study between 1991 and 1994. A total of 4706 subjects with no history of stroke were included (40% men; mean age, 57.5 years). Carotid plaque was determined by B-mode ultrasound of the right carotid artery. Incidence of stroke was followed up during a mean period of 16.5 years in relation to plasma ECP levels. Results— Subjects in the third tertile (versus first tertile) of ECP tended to have higher prevalence of carotid plaque (odds ratio: 1.18; 95% confidence interval: 1.003–1.39; P =0.044 after multivariate adjustments). A total of 258 subjects were diagnosed with ischemic stroke (IS) during follow-up. ECP was associated with increased incidence of IS after risk factor adjustment (hazard ratio, 1.57; 95% confidence interval: 1.13–2.18; for third versus first tertile; P =0.007). High ECP was associated with increased risk of IS in subjects with carotid plaque. The risk factor–adjusted hazard ratio for IS was 1.86 (95% confidence interval: 1.32–2.63) in subjects with carotid plaque and ECP in the top tertile, compared with those without plaque and ECP in the first or second tertiles. Conclusions— High ECP is associated with increased incidence of IS. The association between ECP and IS was also present in the subgroup with carotid plaque.

OBJECTIVE Diabetes is known to be associated with increased arterial stiffness. However, the temporal association between increased carotid-femoral pulse wave velocity (c-f PWV) and diabetes is unclear. The aim of this study is to explore the relationship between arterial stiffness, as determined by c-f PWV, and incidence of diabetes. RESEARCH DESIGN AND METHODS The study population included participants from the Malmö Diet and Cancer cardiovascular cohort, using measurements from the 2007–2012 reexamination as baseline. Arterial stiffness was evaluated by measuring c-f PWV (SphygmoCor). After excluding participants with prevalent diabetes (according to measurements of fasting glucose, oral glucose tolerance tests, and physician’s diagnoses), the final study population consisted of 2,450 individuals (mean age = 71.9 ± 5.6 years). Incidence of diabetes was followed by linkage to local and national diabetes registers. Cox proportional hazards regression was used to assess the incidence of diabetes in relation to the tertiles of c-f PWV, adjusted for potential confounders. RESULTS During a mean follow-up of 4.43 ± 1.40 years, 68 (2.8%) participants developed diabetes. Crude incidence of diabetes (per 1,000 person-years) was 3.5, 5.7, and 9.5, respectively, for subjects in the first, second, and third tertiles of c-f PWV. After adjustment for potential confounders, the hazard ratio of diabetes was 1.00 (reference), 1.83 (95% CI 0.88–3.8), and 3.24 (95% CI 1.51–6.97), respectively, for the tertiles of c-f PWV (P for trend = 0.002). CONCLUSIONS Increased c-f PWV is associated with increased incidence of diabetes, independent of other risk factors. These results suggest that increased arterial stiffness is an early risk marker for developing diabetes.

Background and aims Diet and smoking expose the general population to cadmium (Cd), which is a toxic metal that accumulates in the arterial wall. In experimental studies, Cd causes reductions in proliferation of smooth muscle cells and cellular synthesis of procollagen. The aim of this study was to examine whether blood Cd levels, a valid measure of Cd exposure, are associated with increased risk of abdominal aortic aneurysm (AAA). Methods All middle-aged men and women enrolled in the Malmo Diet and Cancer study (n = 30 447) were followed from the baseline examination in 1991–1996 through 2009. A total of 297 cases with AAA and two randomly selected control subjects for each case, matched for age and sex, were included. Blood Cd was analysed by inductively coupled plasma mass spectrometry. Diagnoses of AAA, thoracic aortic aneurysm and aortic dissection were obtained from registers. Results Increased blood Cd was associated with increased risk of incident AAA after adjustment for smoking and other established risk factors for AAA. The highest tertile of blood Cd concentrations had a rate ratio of 2.5 (95% confidence interval 1.3, 5.0) for incident AAA. Concentration of blood Cd (log transformed) was not associated with AAA in never-smokers (n = 24). Conclusions Blood Cd levels corresponding to the upper tertile of the distribution in the age- and sex-matched control group were associated with a 2.5-fold increase in rate ratio for incident AAA. This relationship was not found in the small group of never-smokers.

Background Growth hormone (GH) has been linked to cardiovascular disease but the exact mechanism of this association is still unclear. We here test if the fasting levels of GH are cross-sectionally associated with carotid intima media thickness (IMT) and whether treatment with fluvastatin affects the fasting level of GH. Methods We examined the association between GH and IMT in 4425 individuals (aged 46–68 years) included in the baseline examination (1991–1994) of the Malmö Diet and Cancer cardiovascular cohort (MDC-CC). From that cohort we then studied 472 individuals (aged 50-70 years) who also participated (1994–1999) in the β-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS), a randomized, double blind, placebo-controlled, single-center clinical trial. Using multivariate linear regression models we related the change in GH-levels at 12 months compared with baseline to treatment with 40 mg fluvastatin once daily. Results In MDC-CC fasting values of GH exhibited a positive cross-sectional relation to the IMT at the carotid bulb independent of traditional cardiovascular risk factors (p = 0.002). In a gender-stratified analysis the correlation were significant for males (p = 0.005), but not for females (p = 0.09). Treatment with fluvastatin was associated with a minor reduction in the fasting levels of hs-GH in males (p = 0.05) and a minor rise in the same levels among females (p = 0.05). Conclusions We here demonstrate that higher fasting levels of GH are associated with thicker IMT in the carotid bulb in males. Treatment with fluvastatin for 12 months only had a minor, and probably not clinically relevant, effect on the fasting levels of hs-GH. Electronic supplementary material The online version of this article (doi:10.1186/s12872-017-0563-9) contains supplementary material, which is available to authorized users.

BackgroundDiet and smoking are the main sources of cadmium exposure in the general population. Cadmium increases the risk of cardiovascular diseases, and experimental studies show that it induces inflammation. Blood cadmium levels are associated with macrophages in human atherosclerotic plaques. Soluble urokinase-type plasminogen activator receptor (suPAR) is an emerging biomarker for cardiovascular events related to inflammation and atherosclerotic plaques. The aim was to examine whether blood cadmium levels are associated with circulating suPAR and other markers of inflammation.MethodsA population sample of 4648 Swedish middle-aged women and men was examined cross-sectionally in 1991–1994. Plasma suPAR was assessed by ELISA, leukocytes were measured by standard methods, and blood cadmium was analysed by inductively coupled plasma mass spectrometry. Prevalent cardiovascular disease, ultrasound-assessed carotid plaque occurrence, and several possible confounding factors were recorded.ResultsAfter full adjustment for risk factors and confounding variables, a 3-fold increase in blood cadmium was associated with an 10.9% increase in suPAR concentration (p

Background: Advanced glycation end product is an established risk marker in diabetic vascular disease, but its possible associations with atherosclerosis in a general population are yet to be investigated. We studied the degree of carotid atherosclerosis and its association with skin autofluorescence in an elderly population. Methods: Carotid ultrasound and skin autofluorescence measurements were performed in a subpopulation within the ‘Malmö Diet and Cancer Cardiovascular Cohort’ re-examination study ( n = 523). Total plaque area including all prevalent plaques in the right carotid artery was calculated. Complete data on all variables were available for 496 subjects (mean age 72 years). Results: Each 1 standard deviation increment of skin autofluorescence was associated with increased risk of prevalent large plaques (odds ratio, 1.32; 95% confidence interval, 1.05–1.66; p = 0.018) independently of diabetes and cardiovascular risk factors. The top versus bottom tertile of the skin autofluorescence was associated with an approximately twofold risk of being in the population with the highest plaque burden [top quartile with total plaque area ⩾ 35 mm2 (odds ratio, 1.88; 95% confidence interval, 1.05–3.39; p for trend = 0.027)] in fully adjusted analysis. Conclusion: In an elderly population, skin autofluorescence was associated with increasing degree of carotid atherosclerosis measured as total plaque area, independently of diabetes and cardiovascular risk factors.

Long follow up is needed in prospective cohort study evaluation of plasma biomarkers for incident peripheral arterial disease (PAD) Middle-aged PAD-free individuals from the cardiovascular cohort of the Malmö Diet and Cancer study (n = 5550; 1991–94) were followed prospectively for a median time of 23.4 years. The plasma biomarkers lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass, proneurotensin, and CRP, were studied in relation to incidence of PAD until December 31st, 2016. The diagnosis of PAD could be validated and confirmed in 98%. Cox regression was used to calculate hazard ratios (HR) per 1 standard deviation increment of each respective log transformed plasma biomarker. Cumulative incidence of PAD was 4.4% (men 5.9%, women 3.3%). Adjusting for age, gender, smoking, body mass index, hypertension, diabetes mellitus, Lp-PLA2 activity (HR 1.33; 95% CI 1.17–1.52), Lp-PLA2 mass (HR 1.20; 95% CI 1.05–1.37) and CRP (HR 1.55; 95% CI 1.36–1.76) remained independently associated with incident PAD. The plasma biomarkers Lp-PLA2 activity and mass, and CRP were markers of PAD risk, implying that they might be useful biomarkers for subclinical atherosclerosis and atherosclerotic disease.

Produced as a tissue defence response to hypoxia and inflammation, growth differentiation factor-15 (GDF-15) is elevated in people receiving metformin treatment. To gain insight into the relationship of GDF-15 with metformin and major cardiovascular risk factors, we analysed the data from the SUMMIT cohort (n = 1438), a four-centre, nested, case-control study aimed at verifying whether biomarkers of atherosclerosis differ according to the presence of type 2 diabetes and cardiovascular disease. While in univariate analysis, major cardiovascular risk factors, with the exception of gender and cholesterol, increased similarly and linearly across GDF-15 quartiles, the independent variables associated with GDF-15, both in participants with and without diabetes, were age, plasma creatinine, N-terminal pro-brain natriuretic peptide, diuretic use, smoking exposure and glycated haemoglobin. In participants with diabetes, metformin treatment was associated with a 40% rise in GDF-15 level, which was independent of the other major factors, and largely explained their elevated GDF-15 levels. The relatively high GDF-15 bioavailability might partly explain the protective cardiovascular effects of metformin.

Background and Purpose— Orosomucoid (α-1-acid glycoprotein) is an acute-phase protein that has been implicated in anti-inflammatory, immunomodulating, and angiogenic pathways. Orosomucoid has also been associated with coronary disease and stroke. The relationship between orosomucoid, carotid plaque, and stroke incidence were explored in this study. Methods— Plasma levels of orosomucoid were assessed in 4285 subjects (39.8% men; mean age 57.5±5.9 years) without cardiovascular disease, who participated in the Malmö Diet and Cancer Study, between 1991 and 1994. The right carotid artery was examined for plaque using B-mode ultrasound examination. Incidence of stroke was followed up during a median follow-up time of 17.7 years. Results— Carotid plaque was present in 43.5% at baseline. Orosomucoid was significantly higher in subjects with carotid plaque (mean±SD: 0.72±0.22 versus 0.69±0.20 g/L; P Conclusions— Elevated levels of orosomucoid are associated with increased occurrence of carotid plaque and increased incidence of ischemic stroke. The combination of high orosomucoid and carotid plaque substantially increase the risk of stroke.

Context We have previously shown that high levels of atrial natriuretic peptides (ANP) are associated with decreased risk of future diabetes development; however, the mechanism behind this relationship is not fully understood.

The purpose of the study was to investigate the long-term associations between smoking habits, environmental tobacco smoke exposure (ETS), carotid intima-media thickness (IMT) progression rate, and rate of lumen diameter reduction in the carotid artery during a 16-year follow-up. Another objective was to investigate if an effect of smoking on progression rate could be explained by increased low grade inflammation.The study population included 2992 middle-aged men and women in the 1991-1994 (baseline) and the 2007-2012 (re-examination) investigation of the Malmö Diet and Cancer Study cardiovascular cohort. Associations between smoking, progression of carotid IMT and lumen diameter reduction due to plaque protrusion were assessed by linear regression.IMT progression rates and rate of lumen diameter reduction increased from never smokers with no ETS through former, moderate and heavy smokers, even after adjustment for traditional risk factors (e.g., differences in yearly progression rates (mm/year) of maximal IMT in the carotid bifurcation compared to never smokers; former smokers 0.0074 (95% CI: 0.0018-0.0129), moderate smokers 0.0106 (95% CI: 0.0038-0.0175), and heavy smokers 0.0146 (95% CI: 0.0061-0.0230)). Former smokers showed distinct lowering of progression rates after more than five years since smoking cessation. Smoking and former smoking was associated with increased low grade inflammation, however, the effect of smoking on atherosclerotic progression rate remained fairly unchanged after such adjustment.The effect of smoking and former smoking on carotid IMT progression rates and change in lumen reduction due to plaque protrusion could not be explained by differences in traditional risk factors or low grade inflammation.

Impaired glucose metabolism and diabetes mellitus has been linked to a decreased risk for abdominal aortic aneurysm development in men. We evaluated potential relationships between blood glucose levels in 1722 men with mean age 34 years and their aortic diameter measured by ultrasound at age 65 years.Prospective cohort study.Mean follow-up between baseline glucose investigation and aortic ultrasound was 32.8 ± 1.8 years. There was no correlation between baseline blood glucose and later aortic diameter (r = 0.035, p = 0.146), whereas a weak correlation between body mass index (BMI) and aortic diameter was observed (r = 0.097 p 0.001). In a partial correlation between aortic diameter and glucose levels adjusted for BMI, the correlation did not change (r = 0.011, p = 0.66). Neither were there any significant differences in mean aortic diameter between men belonging to different quartiles of baseline blood glucose levels (19.5, 19.1, 19.6 and 19.7 mm, p = 0.18).Fasting blood glucose in 33-year-old men was not associated with their aortic diameter at age 65 years. Potential pathophysiological processes linking disturbed glucose metabolism to a decreased risk for development of abdominal aortic aneurysm in men are therefore probably not relevant until later in life.

Background Chronic low-grade inflammation and associated insulin resistance and metabolic abnormalities have been proposed as ‘common soil’ for diabetes mellitus (DM) and cardiovascular disease (CVD). This paper aimed to investigate the inflammatory profiles of DM and CVD and to distinguish their shared and specific markers. Methods Based on the Malmö Diet and Cancer cohort, total and differential leukocyte counts were measured in 25,969 participants without previous DM or CVD and were studied in relation to incident DM (mean follow-up 17.4 ± 5.58 years) and incident CVD (i.e., coronary events, including fatal and nonfatal myocardial infarction, or stroke); mean follow-up 17.7 ± 5.46 years, using multivariable Cox regression models. Furthermore, plasma concentrations of another seven inflammatory markers were examined in relation to incident DM and incident CVD in a sub-cohort of 4658 participants. The associations of each inflammatory marker with incident DM versus incident CVD were compared using the Lunn–McNeil competing risks approach. In sensitivity analyses, those who developed both DM and CVD during follow-up were excluded. Results After adjustment for conventional risk factors, total and differential leukocyte counts, orosomucoid, and C-reactive protein were associated with an increased risk of both DM and CVD. Neutrophil to lymphocyte ratio, ceruloplasmin, alpha1-antitrypsin and soluble urokinase plasminogen activator receptor predicted increased risk of CVD but not DM, while haptoglobin and complement C3 showed the opposite pattern. In competing risks analyses, lymphocyte count and complement C3 had stronger associations with risk of DM than with risk of CVD (p for equal associations = 0.020 and 0.006). The reverse was true for neutrophil to lymphocyte ratio (p for equal associations = 0.025). Results were consistent in sensitivity analyses. Conclusions The results indicated substantial similarities in the inflammatory profiles associated with DM and CVD. However, there are also significant differences. These findings may help discriminate between individuals at elevated risk of DM and those at elevated risk of CVD, which is a prerequisite for targeted therapies. Electronic supplementary material The online version of this article (10.1186/s12933-018-0733-9) contains supplementary material, which is available to authorized users.

Aims: Maintainance of glucagon response to hypoglycaemia is important as a safeguard against hypoglycaemia during glucose-lowering therapy in type 2 diabetes. During recent years, DPP-4 (dipeptidyl peptidase-4) inhibition has become more commonly used in elderly patients. However, whether DPP-4 inhibition affects the glucagon response to hypoglycaemia in the elderly is not known and was the aim of this study. Methods: In a single-centre, double-blind, randomized, placebo-controlled crossover study, 28 subjects with metformin-treated type 2 diabetes (17 male, 11 female; mean age, 74years [range 65-86]; mean HbA1c, 51.5mmol/mol [6.9%]) received sitagliptin (100mg once daily) as add-on therapy or placebo for 4weeks with a 4-week washout period in between. After each treatment period, the subjects underwent a standard breakfast test, followed by a 2-step hyperinsulinaemic hypoglycaemic clamp (target 3.5 and 3.0mmol/L), followed by lunch. Results: Glucagon levels after breakfast and lunch, and the glucagon response at 3.5mmol/L, were lower after sitagliptin than after placebo. However, the glucagon response to hypoglycaemia at 3.1mmol/L did not differ significantly between the two. Similarly, the noradrenaline, adrenaline and cortisol responses were lower with sitagliptin than with placebo at 3.5mmol/L, but not at 3.1mmol/L glucose. Responses in pancreatic polypeptide did not differ between the two. Conclusions: Elderly subjects with metformin-treated type 2 diabetes have lower glucagon levels at 3.5mmol/L glucose, but maintain the glucagon response to hypoglycaemia at 3.1mmol/L during DPP-4 inhibition, which safeguards against hypoglycaemia and may contribute to decreasing the risk of hypoglycaemia by DPP-4 inhibition in this age group. (Less)

Aims: Previous studies have shown that dipeptidyl peptidase (DPP)-4 inhibition lowers glucagon levels whereas sodium-glucose co-transporter 2 (SGLT-2) inhibition increases them. This study evaluated the extent of these opposite effects in a direct comparative head-to-head study. Methods: In a single-centre, randomized study with a cross-over design, 28 metformin-treated patients with type 2 diabetes (T2D) (mean age, 63 years; baseline HbA1c, 6.8%) were treated with vildagliptin (50 mg twice daily) or dapagliflozin (10 mg once daily) for 2 weeks, with a 4-week wash-out period between the two separate treatments. After each treatment period, a meal test was undertaken, with measurements of islet and incretin hormones and 4-hour area under the curve (AUC) levels were estimated. Results: Fasting glucagon (35.6 ± 2.5 vs 39.4 ± 3.4 pmoL/L; P = .032) and postprandial glucagon (4-hour AUCglucagon, 32.1 ± 2.3 vs 37.5 ± 2.7 nmoL/L min; P = .001) were ~15% lower after vildagliptin compared to dapagliflozin treatment. This was associated with stronger early (15 minute) C-peptide response and higher 4-hour AUCC-peptide (P < .010), higher 4-hour AUC of the intact form of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) (P < .001) and lower 4-hour AUC of total GIP and GLP-1 (P < .001). Conclusion: Treatment with DPP-4 inhibition with vildagliptin results in 15% lower fasting and postprandial glucagon levels compared to SGLT-2 inhibition with dapagliflozin. DPP-4 inhibition also induces more rapid insulin secretion and higher levels of intact incretin hormones, resulting in stronger feedback inhibition of incretin hormone secretion than SGLT-2 inhibition. (Less)

OBJECTIVE Cardiovascular disease (CVD) risk prediction represents an increasing clinical challenge in the treatment of diabetes. We used a panel of vascular imaging, functional assessments, and biomarkers reflecting different disease mechanisms to identify clinically useful markers of risk for cardiovascular (CV) events in subjects with type 2 diabetes (T2D) with or without manifest CVD. RESEARCH DESIGN AND METHODS The study cohort consisted of 936 subjects with T2D recruited at four European centers. Carotid intima-media thickness and plaque area, ankle-brachial pressure index, arterial stiffness, endothelial function, and circulating biomarkers were analyzed at baseline, and CV events were monitored during a 3-year follow-up period. RESULTS The CV event rate in subjects with T2D was higher in those with (n = 440) than in those without (n = 496) manifest CVD at baseline (5.53 vs. 2.15/100 life-years, P < 0.0001). New CV events in subjects with T2D with manifest CVD were associated with higher baseline levels of inflammatory biomarkers (interleukin 6, chemokine ligand 3, pentraxin 3, and hs-CRP) and endothelial mitogens (hepatocyte growth factor and vascular endothelial growth factor A), whereas CV events in subjects with T2D without manifest CVD were associated with more severe baseline atherosclerosis (median carotid plaque area 30.4 mm2 [16.1–92.2] vs. 19.5 mm2 [9.5–40.5], P = 0.01). Conventional risk factors, as well as measurements of arterial stiffness and endothelial reactivity, were not associated with CV events. CONCLUSIONS Our observations demonstrate that markers of inflammation and endothelial stress reflect CV risk in subjects with T2D with manifest CVD, whereas the risk for CV events in subjects with T2D without manifest CVD is primarily related to the severity of atherosclerosis.

OBJECTIVE Counterregulatory responses are critical to prevent hypoglycemia in subjects with type 2 diabetes. This is particularly important in insulin-treated patients. This study explored the effect of the glucagon-like peptide 1 receptor agonist lixisenatide on the hormonal counterregulatory responses to insulin-induced hypoglycemia when added to basal insulin therapy in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS The study was a single-center, double-blind, randomized, placebo-controlled crossover study involving 18 subjects with type 2 diabetes (11 males) with a mean age of 55 years, diabetes duration of 12 years, HbA1c level of 7.7%, fasting blood glucose (FBG) concentration of 9.7 mmol/L, and a BMI of 33 kg/m2, who were treated with basal insulin (mean duration 7 years, daily dose 39 units/day) and metformin (mean daily dose 2.1 g). Subjects received treatment with lixisenatide or placebo for 6 weeks in random order, with a 4-week washout period in between. After 6 weeks of treatment, subjects underwent a two-step hyperinsulinemic hypoglycemic clamp at 3.5 and 2.8 mmol/L. RESULTS After 6 weeks of treatment, HbA1c and FBG levels were lower after lixisenatide therapy than after placebo therapy. At the hypoglycemic level of 3.5 mmol/L, glucagon and epinephrine levels were significantly lower during lixisenatide treatment than during placebo treatment, whereas at 2.8 mmol/L glucagon and epinephrine levels did not differ between the subjects. Cortisol, pancreatic polypeptide, and norepinephrine levels did not differ significantly between the treatments. CONCLUSIONS Glucagon and epinephrine levels are reduced by lixisenatide at a concentration of 3.5 mmol/L, but their counterregulatory responses to deep hypoglycemia at a concentration of 2.8 mmol/L are sustained during treatment with lixisenatide in combination with basal insulin.

Objective : To examine if overall diet quality is associated with cellular and soluble biomarkers of systemic inflammation in middle-aged individuals. Methods : A group of 667 individuals, aged 63–68 years, selected from the cardiovascular arm of the Malmo Diet and Cancer cohort, participated in this study. Baseline examinations consisted of an extensive socio-demographic questionnaire, anthropometric measurements, blood sampling and detailed dietary data. Mononuclear leukocytes frozen at baseline were thawed and analysed with flow cytometry to quantify monocyte subsets based on CD14 and CD16 expression. Plasma cytokines were measured using multiplexed immune assays. A diet quality index consisting of six components (saturated fatty acids, polyunsaturated fatty acids, fish and shellfish, dietary fibre, fruit and vegetables, and sucrose) was constructed to measure adherence to the Swedish Nutrition Recommendations/Dietary Guidelines. General linear models were used to investigate associations between index scores and several biomarkers of inflammation. Results : A higher percentage of women reported adherence to the nutritional recommendations and had better overall diet quality than men. Participants with higher diet quality were more likely to have a healthier lifestyle. The levels of high-sensitive CRP, S100A8/A9, TNF-α, white blood cells, neutrophils, lymphocytes and CD14 + CD16 ++ were lower in participants with higher index scores. The associations remained significant after adjustment for potential confounders. Conclusion : In this cross-sectional study, we found that a high diet quality is associated with lower systemic inflammation. As the incidence of cardiovascular disease and cancer is directly correlated with the levels of inflammation, our findings might indicate a protective role of high-quality diet.

Background: Arterial stiffness plays a fundamental role in the development of hypertension and is a risk factor for both cardiovascular disease and mortality. The stiffening that occurs with increasing age has, in numerous cross-sectional studies, been shown to be associated with several cardiovascular risk factors. This observational study aims to characterize the predictive and cross-sectional markers focusing on the non-hemodynamic component of arterial stiffness. Method: In all, 2679 men and women from Malmö, Sweden, were examined at baseline during 1991–1994, and again at follow-up during 2007–2012 (mean age 72 years, 38% men). Follow-up examination included measurement of arterial stiffness by carotid–femoral pulse wave velocity (c-fPWV), after a mean period of 17 years. The associations between c-fPWV and risk markers were calculated with multiple linear regression. Results: The results indicated that for both sexes, waist circumference (β = 0.17, P

Background Exposure to cadmium has been associated with carotid plaques, inflammation in carotid plaques, and increased risk of ischemic stroke. This study examined the separate and interacting effects of blood cadmium levels and carotid plaques on the risk of incident ischemic stroke. Methods and Results Cadmium levels were measured in 4156 subjects (39.2% men; mean± SD age 57.3±5.9 years) without history of stroke, from the Malmö Diet and Cancer cohort. The right carotid artery was examined using B‐mode ultrasound examination at baseline. Incidence of ischemic stroke was monitored over a mean follow‐up of 16.7 years. Carotid plaque was present in 34.5% of participants. Cadmium was significantly higher in subjects with plaque (mean± SD : 0.53±0.58 μg/L versus 0.42±0.49 μg/L; P P =0.009) and cadmium (hazard ratio for quartile [Q] 4 versus Q1–3: 1.95, confidence interval, 1.33–2.85, P =0.001), after adjustment for risk factors. There was a significant interaction between cadmium and plaque with respect to risk of ischemic stroke ( P =0.011). Adjusted for risk factors, subjects with plaque and cadmium in Q4 had a hazard ratio of 2.88 (confidence interval, 1.79–4.63) for ischemic stroke, compared with those without plaque and cadmium in Q1 to Q3. Conclusions Cadmium was associated with incidence of ischemic stroke, both independently and in synergistic interaction with carotid plaques. This supports the hypothesis that cadmium promotes vulnerability of carotid plaques, thereby increasing the risk of rupture and ischemic stroke.

Background Higher fasting Growth Hormone (GH) has been associated with increased cardiovascular morbidity and mortality. Our objective was to find genetic determinants of fasting GH in order to facilitate future efforts of analyzing the association between fasting growth hormone and cardiovascular disease. A genome-wide association study (GWAS) was performed in a discovery cohort of 4134 persons (58% females; age 46–68 yrs), linking SNPs to fasting hs-GH. Fifteen SNPs were replicated in an independent cohort of 5262 persons (28.9% females; age 56–85 yrs). The best performing SNP was analyzed vs GH-related variables in a third independent cohort (n = 24,047; 61% females; age 44–73 yrs). A candidate gene approach searched for significant SNPs in the genes GH1 and GHR in the discovery cohort and was replicated as previously described. Results In the GWAS, the minor allele of rs7208736 was associated with lower GH in the discovery cohort (p = 5.15*10^-6) and the replication cohort (p = 0.005). The GH reducing allele was associated with lower BMI (P = 0.026) and waist (P = 0.021) in males only. In the candidate gene approach rs13153388 in the GHR-gene was associated with elevated GH-levels (P = 0.003) in the discovery cohort only and reduced height (P = 0.003). Conclusion In the first GWAS ever for GH, we identify a novel locus on chromosome 17 associated with fasting GH levels, suggesting novel biological mechanisms behind GH secretion and GH-related traits. The candidate gene approach identified a genetic variant in the GHR, which was associated with an elevation of fasting hs-GH and lower height suggesting reduced GHR ligand sensitivity. Our findings need further replication. Electronic supplementary material The online version of this article (10.1186/s12864-017-4219-z) contains supplementary material, which is available to authorized users.

The pathogenesis of abdominal aortic aneurysm (AAA) shares several common pathways with atherosclerosis. Prospective clinical plasma biomarker studies in AAA have been hampered by the need for very large cohorts and long follow-up time.We analyzed a prospective longitudinal cohort of middle-aged individuals from the cardiovascular cohort of the Malmö Diet and Cancer study (n = 5551; 1991-94). The plasma biomarkers lipoprotein-associated phospholipase A2 (Lp-PLACumulative incidence of AAA was 1.5% (men 2.9%, women 0.5%) during a median follow-up period of 20.7 years. Overall, 84 individuals had an incident AAA, of whom 22 (26.2%) were operated on and 16 (19.0%) had ruptured. Mean age of individuals with incident AAA was 59.7 years at study entry and AAA was diagnosed on average 14 years later. When adjusting for age, gender, smoking, body mass index, hypertension, and diabetes mellitus, Lp-PLAThe plasma biomarkers Lp-PLA

Objective— Aortic stenosis (AS) shares risk factors with atherosclerotic vascular disease. Carotid intima-media thickness (IMT) and plaque may reflect the cumulative damage from exposure to different atherosclerotic risk factors. We examined the relationship of carotid IMT and plaque with incident AS in a prospective population-based study. Approach and Results— A random sample of participants (age, 45–68 years) in the population-based Malmö Diet and Cancer Study underwent B-mode ultrasound with measurements of IMT and the presence of plaque in the common carotid artery (n=5079). Potential risk factors for incident AS were studied in age- and sex-adjusted and expanded multivariable-adjusted Cox regression models. A total of 69 (1.4%) participants developed AS during up to 20 years of follow-up. Significant risk factors for AS in age- and sex-adjusted analyses were ( P P >0.05). After adjustments, IMT, plaque, age, smoking, C-reactive protein, low-density lipoprotein cholesterol, and diabetes mellitus remained significantly associated with incident AS. IMT was no longer significantly associated with AS after adjustments for plaque and systolic blood pressure, but plaque remained significantly associated with incident AS. Conclusions— Traditional cardiovascular risk factors were individually associated with incident AS, and in multivariable models low-density lipoprotein cholesterol, smoking, age, presence of plaque, C-reactive protein, and diabetes mellitus remained significant predictors of incident AS. AS represents a vascular disorder related to carotid plaque, with potential implications for the pathophysiology and prevention of this disease.

Background Both pathological excess and deficiency of growth hormone (GH) are associated with cardiovascular mortality. Objectives The goal of this study was to test whether fasting levels of growth hormone measured with a high-sensitivity assay (hs-GH) predict cardiovascular morbidity and mortality at the population level. Methods We studied 4,323 participants (age 46 to 68 years; mean age 58 years; 59% women) of the Swedish, population-based Malmö Diet and Cancer study examined in 1991 to 1994. Using multivariate-adjusted Cox proportional hazards models, we related baseline levels of fasting hs-GH to incidence of coronary artery disease, stroke, congestive heart failure, all-cause mortality, and cardiovascular mortality. Results During a median follow-up of 16.2 years, hs-GH (hazard ratio [HR]/SD increment of natural logarithm of fasting hs-GH) was independently associated with increased risk of coronary artery disease (397 events; HR: 1.11; 95% confidence interval [CI]: 1.01 to 1.23; p = 0.04), stroke (251 events; HR: 1.18; 95% CI: 1.04 to 1.34; p = 0.01), congestive heart failure (107 events; HR: 1.25; 95% CI: 1.03 to 1.52; p = 0.02), all-cause mortality (645 events; HR: 1.17; 95% CI: 1.08 to 1.26; p < 0.001) and cardiovascular mortality (186 events; HR: 1.43; 95% CI: 1.24 to 1.66; p < 0.001). The addition of hs-GH to a model with conventional cardiovascular risk factors significantly reclassified risk, with a category-free net reclassification improvement (>0) of 0.542 (95% CI: 0.205 to 0.840) in cardiovascular mortality. Conclusions Higher values of hs-GH were associated with an increased risk of cardiovascular morbidity and mortality.

Creatinine- and cystatin C-based estimates of renal function are considered to be cardiovascular disease (CVD) risk factors, but the clinical utility in middle-aged subjects without a history of CVD is controversial.We related plasma cystatin C and creatinine-based glomerular filtration rate (GFR) [MDRD, CKD-EPI-2009, and CKD-EPI-comb (a combination of creatinine and cystatin C)] to incident CVD, CVD mortality, all-cause mortality, and heart failure in 4650 middle-aged subjects without CVD.The hazard ratio (HR) per standard deviation increment (95% CI) of cystatin C predicted incident CVD (1.22, 1.11-1.33; P0.0001), CVD mortality (1.44, 1.24-1.66; P0.0001), all-cause mortality (1.15, 1.05-1.26; P = 0.002), and heart failure (1.27, 1.05-1.55; P = 0.02), whereas MDRD and CKD-EPI-2009 only predicted CVD mortality (0.79, 0.66-0.93; P = 0.006 and 0.78, 0.66-0.92; P = 0.003, respectively). Cystatin C led to a significant increase in the net reclassification improvement for all endpoints, except heart failure. Only within the quartile with the worst renal function were all measures related to all-cause and CVD mortality. The top 25% of cystatin C in the population significantly predicted risk of incident CVD and CVD mortality, whereas MDRD and CKD-EPI-2009 were predictors of CVD mortality only at a GFR60 mL/min/1.73 m(2) (11-13% of the population) and of incident CVD only at a GFR45 mL/min/1.73 m(2) (1% of the population).Cystatin C is a better risk marker for CVD morbidity and mortality than creatinine-based GFR. Whether this is explained by cystatin C being a better marker for true GFR or through other effects of cystatin C remains to be shown.

Background Activation of the renin-angiotensin-aldosterone-system (RAAS) has been proposed to contribute to development of vascular complications in type 2 diabetes (T2D). The aim of the present study was to determine if plasma renin levels are associated with the severity of vascular changes in subjects with and without T2D. Methods Renin was analyzed by the Proximity Extension Assay in subjects with (n = 985) and without (n = 515) T2D participating in the SUMMIT (SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools) study and in 205 carotid endarterectomy patients. Vascular changes were assessed by determining ankle-brachial pressure index (ABPI), carotid intima-media thickness (IMT), carotid plaque area, pulse wave velocity (PWV) and the reactivity hyperemia index (RHI). Results Plasma renin was elevated in subjects with T2D and demonstrated risk factor-independent association with prevalent cardiovascular disease both in subjects with and without T2D. Renin levels increased with age, body mass index, HbA1c and correlated inversely with HDL. Subjects with T2D had more severe carotid disease, increased arterial stiffness, and impaired endothelial function. Risk factor-independent associations between renin and APBI, bulb IMT, carotid plaque area were observed in both T2D and non-T2D subjects. These associations were independent of treatment with RAAS inhibitors. Only weak associations existed between plasma renin and the expression of pro-inflammatory and fibrous components in plaques from 205 endarterectomy patients. Conclusions Our findings provide clinical evidence for associations between systemic RAAS activation and atherosclerotic burden and suggest that this association is of particular importance in T2D.

Context: Large epidemiological studies often collect non-fasting samples, although the reliability of biomarkers may be uncertain.Objective: To explore the reliability and reproducibility of a single measurement of selected biomarkers in a sub-sample of the Malmo Diet and Cancer cohort.Methods: We estimated single- and average-measures intraclass correlation coefficients (ICC) for oxidized (ox)-LDL, interleukin (IL)-1β, IL-6, IL-8 and TNF-α.Results: Single-measures ICC in non-fasting samples of ox-LDL, IL-1β, IL-6, IL-8 and TNF-α were the following: 0.85, 0.71, 0.61, 0.78 and 0.66 for men, and 0.67, 0.81, 0.87, 0.69 and 0.81 for women. Biomarkers at non-fasting and fasting samples were highly correlated (all r > 0.80).Conclusions: The observed ICC suggest that most of the examined biomarkers (non-fasting blood) would allow meaningful analysis in epidemiological studies.

A high diet quality according to the Swedish nutrition recommendations is associated with a reduced risk of cardiovascular disease in the population-based Malmö Diet and Cancer cohort. To further clarify this protective association, we examined the association between high diet quality and change in triglycerides, high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) after 16 years of follow-up in 3152 individuals (61% women; 46–68 years at baseline). In addition, we examined if genetic risk scores composed of 80 lipid-associated genetic variants modify these associations. A diet quality index based on intakes of saturated fat, polyunsaturated fat, sucrose, fiber, fruit and vegetables, and fish was constructed. A high diet quality was associated with lower risk of developing high triglycerides (p = 0.02) and high LDL-C (p = 0.03) during follow-up compared with a low diet quality. We found an association between diet quality and long-term change in HDL-C only among those with lower genetic risk for low HDL-C as opposed to those with higher genetic risk (p-interaction = 0.04). Among those with lower genetic risk for low HDL-C, low diet quality was associated with decreased HDL-C during follow-up (p = 0.05). In conclusion, individuals with high adherence to the Swedish nutrition recommendation had lower risk of developing high triglycerides and LDL-C during 16 years of follow-up.

Background: Our aim was to test if plasma copeptin, a stable surrogate marker of arginine vasopressin, predicts decline of glomerular filtration rate (GFR) and risk of chronic kidney disease (CKD). Methods: We measured copeptin and renal function at the Malmö Diet and Cancer Cardiovascular Cohort baseline exam and reassessed renal function after a follow-up time of 16.6 ± 1.5 years (n = 3,186). Furthermore, we defined CKD based on an estimated GFR (eGFR) calculated by the Modification of Diet in Renal Disease (MDRD) MDRD), MDRD) and MDRD) ml/min/1.73 m2. Results: After multivariate adjustment (gender, age, baseline eGFR, smoking status, systolic blood pressure, antihypertensive treatment and follow-up time), copeptin (beta-coefficient per 1 SD increment of copeptin) was independently associated with significantly greater annual decline of eGFR (ml/min/1.73 m2) according to the MDRD formula (OR 0.057, 95% CI 0.022-0.093; p = 0.001) as well as according to the CKD Epidemiology Collaboration (CKD-EPI) formula (OR 0.050, 95% CI 0.022-0.077; p < 0.001). Each SD increment of copeptin independently predicted incident CKD_60MDRD (OR 1.19, 95% CI 1.04-1.36; p = 0.010), CKD_45MDRD (OR 1.33, 95% CI 1.04-1.71; p = 0.026) and CKD_30MDRD (OR 3.69, 95% CI 1.41-9.66; p = 0.008). The relationship between copeptin and CKD defined by CKD-EPI gave similar results. Conclusion: Our data suggest that increased levels of copeptin independently predict decline in eGFR and greater risk of new-onset CKD.