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Background: It has been proposed that vascular progenitor cells play an important role in vascular repair, but their possible clinical importance in cardiovascular disease has not been fully characterized. Vascular endothelial growth factor A, placental growth factor and stem cell factor (SCF) are three growth factors that are important in recruiting vascular progenitor cells. In this study, we investigated the association between the plasma levels of these growth factors and incident coronary events (CEs). Methods: Levels of the three growth factors were measured using the proximity extension assay technique in baseline plasma samples from 384 subjects with a first CE (mean follow-up 14.0 ± 4.3 years) and 409 event-free control subjects matched by sex and age, as well as in homogenates from 201 endarterectomy specimens. Results: After controlling for known cardiovascular disease risk factors in a Cox regression model, subjects in the lowest SCF tertile had a hazard ratio of 1.70 (95% confidence interval 1.14-2.54) compared with subjects in the highest SCF tertile. Lower SCF levels were also associated with more severe carotid disease, less fibrous atherosclerotic plaques and an increased incidence of heart failure. Expression of the SCF receptor c-kit was demonstrated in the subendothelial layer and fibrous cap of human atherosclerotic plaques. Smokers and subjects with diabetes had decreased levels of SCF compared with control subjects. Conclusion: To our knowledge, this is the first clinical study to provide evidence to support a key role for SCF and progenitor cells in vascular repair. We suggest that the SCF-c-kit pathway may be a promising biomarker and therapeutic target in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started. [ABSTRACT FROM AUTHOR]

Objectives Red blood cell distribution width ( RDW), a measure of variation in erythrocyte volume, has been associated with several cardiovascular disorders, but the relationship with atrial fibrillation ( AF) remains unclear. We investigated the association between RDW and incidence of first hospitalization due to AF in a population-based cohort. Design Red blood cell distribution width was measured in 27 124 subjects from the general population (age 45-73 years, 62% women) with no history of AF, heart failure, myocardial infarction or stroke. The association between baseline RDW and incidence of AF identified from the Swedish Hospital Discharge Register was evaluated. Results During a mean follow-up of 13.6 years, 1894 subjects (53% men) were hospitalized with a diagnosis of AF. After adjustment for potential confounding factors, including cardiovascular disease risk factors, nutrient intake (iron, vitamin B12 and folate) and several haematological parameters (haemoglobin concentration, mean corpuscular volume and corpuscular haemoglobin content), the hazard ratio ( HR) for incidence of AF was 1.33 [95% confidence interval ( CI) 1.16-1.53] for the fourth versus first quartile of RDW ( P for trend <0.001). The results were essentially unchanged when subjects with incident myocardial infarction or hospitalizations because of heart failure were censored from the analysis ( HR 1.30, 95% CI 1.13-1.51; P for trend = 0.001). Conclusion Red blood cell distribution width was associated with incidence of AF independently of several cardiovascular, nutritional and haematological factors in this study of middle-aged subjects from the general population. [ABSTRACT FROM AUTHOR]

. Hlebowicz J, Persson M, Gullberg B, Sonestedt E, Wallström P, Drake I, Nilsson J, Hedblad B, Wirfält E (Lund University, Skåne University Hospital, Malmö, Sweden). Food patterns, inflammation markers and incidence of cardiovascular disease: the Malmö Diet and Cancer study. J Intern Med 2011; 270: 365-376. Objectives. To examine the associations between food patterns constructed using cluster analysis and markers of systemic and vascular inflammation, and incident cardiovascular disease (CVD) after 13 years of follow-up. Design. Population-based, prospective cohort study. Setting and subjects. Cluster analysis identified six food patterns from 43 food group variables among 4999 subjects, aged 45-68 years, who participated in the Malmö Diet and Cancer cardiovascular programme between 1991 and 1994. Lipoprotein-associated phospholipase A2 (Lp-PLA2), C-reactive protein concentration and white blood cell (WBC) count were measured using blood samples at baseline. Incidence of CVD (coronary events and ischaemic stroke) was monitored over 13 years of follow-up. Results. The fibre-rich bread pattern was associated with favourable effects on WBC count in women, and the low-fat and high-fibre pattern with favourable effects on Lp-PLA2 mass in women, and on Lp-PLA2 activity in men. However, the milk fat and sweets and cakes patterns were both associated with adverse effects; the former on WBC count in women and on Lp-PLA2 mass in men, and the latter on WBC count and Lp-PLA2 mass in women. The milk fat and sweets and cakes patterns were associated with increased CVD risk in women. Conclusions. The results of this study support the present Nordic dietary recommendations indicating that diets rich in high-fibre, low-fat and low-sugar foods are favourably associated with markers of inflammation and, potentially, with CVD risk. [ABSTRACT FROM AUTHOR]

Background To determine if the common Pro12Ala polymorphism (rs1801282) of the peroxisome proliferator-activated receptor ( PPARG) gene is associated with the metabolic syndrome (MetS) or with its individual components in middle-aged Swedish individuals. Methods MetS was defined according to the National Cholesterol Education Program/Adult Panel III (NCEP/ATP III), the International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance (EGIR) criteria in a population-based sample of nearly 5000 subjects participating in the Malmö Diet and Cancer-cardiovascular arm. Results Of the subjects included in the analysis, 21.8, 29.4 and 20.4% had MetS according to the NCEP/ATP III, IDF and EGIR (only in subjects without diabetes) definitions, respectively. The Pro12Ala was not associated with MetS or with its individual components. These results were similar when patients with diabetes were excluded. Hypertensive and obese ala-carriers had lower fasting glucose and hypertensive ala-carriers also had lower level triglycerides ( P < 0.05). Conclusions Our data do not support a major role for the Pro12Ala variant of the PPARG gene in MetS and its individual components. The modest difference in triglyceride and glucose levels, restricted to hypertensive and obese subjects in our cohort, suggests that the polymorphism has a minor effect on glucose and lipid metabolism, particularly in individuals at risk for gluco-metabolic disturbances. [ABSTRACT FROM AUTHOR]

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Objective. Moderately reduced lung function in apparently healthy subjects has been associated with incidence of coronary events. However, whether lung function is related to the fatality of the future events is unknown. This study explored whether reduced forced vital capacity ( FVC) and forced expiratory volume in 1 s ( FEV1) in initially healthy men is related to the fatality of the future coronary events. Design. Prospective cohort study. Setting. Population-based study from Malmö, Sweden. Subjects. A total of 5452 healthy men, 28–61 years of age. Main outcome measures. Incidence of first coronary events was monitored over a mean follow-up of 19 years. The fatality of the future events was studied in relation to FEV and FVC. Results. A total of 589 men suffered a coronary event during follow-up, 165 of them were fatal during the first day. After risk factors adjustment, low FEV or FVC were associated with incidence of coronary events (fatal or nonfatal) and this relationship was most pronounced for the fatal events. Amongst men who subsequently had a coronary event, the case-fatality rates were higher in men with low FEV or FVC. Adjusted for risk factors, the odds ratio for death during the first day was 1.00 (reference), 1.63 (95% CI: 0.9–3.1), 1.86 (1.0–3.5) and 2.06 (1.1–3.9), respectively, for men with FVC in the 4th, 3rd, 2nd, and lowest quartiles (trend: P < 0.05). FEV showed similar relationships with the fatality rates. Conclusion. Apparently healthy men with moderately reduced lung function have higher fatality in future coronary events, with a higher proportion of coronary heart disease deaths and less nonfatal myocardial infarction. [ABSTRACT FROM AUTHOR]

Objective. To study to what extent geographical differences of the mortality from ischaemic heart disease (IHD) can be accounted for by the 28-day case fatality rate (CFR) following first hospital admittance for acute myocardial infarction (MI) and whether the geographical pattern of survival has any relationship with socio-economic circumstances. Design. Register-based surveillance study. Setting. Seventeen residential areas in Malmö, Sweden. Subjects. All 5533 patients were admitted during 1986–1995 for a first acute MI at Malmö University Hospital. Main outcome measures. CFR is based on record linkage with national registers. Area-specific cardiovascular and socio-economic scores (SES) are based on previous cross-sectional studies. Results. In patients below 75 years of age, differences of the 28-day CFR accounted for 20–30% of the geographical variance in mortality from IHD. No corresponding association was found in older age groups. Patients from areas with low SES had the highest CFR, 23.8%. The odds ratios of fatal outcome for patients from areas with median and low SES (versus high SES) were 1.23 (95% CI: 1.01–1.50) and 1.25 (95% CI: 1.03–1.52), respectively ( P for trend: 0.060). The strongest correlation was observed in men below 75 years of age ( P for trend: 0.007). During the study period there was an improvement of the survival rate for patients from high and medium SES areas but no corresponding change for patients coming from areas having a low SES. Conclusions. In patients below 75 years, geographical differences of the mortality from IHD were related to differences of the 28-day CFR following hospital admittance for a first MI. Rates of survival were inversely related to socio-economic circumstances in the patient's residential area. [ABSTRACT FROM AUTHOR]

Objective: To study effects on non-cancer mortality of observational weight loss in middle-aged men stratified for body mass index (BMI), taking a wide range of possible confounders into account.Design: Prospective, population based study.Setting: Male population of Malmö, Sweden.Participants: In all 5722 men were screened twice with a mean time interval of 6 years in Malmö, southern Sweden. They were classified according to BMI category at baseline (<21, 22-25, overweight: 26-30, and obesity: 30+ kg m(-2)) and weight change category until second screening (weight stable men defined as having a baseline BMI +/- 0.1 kg m(-2) year-1 at follow-up re-screening).Main Outcome Measures: Non-cancer mortality calculated from national registers during 16 years of follow-up after the second screening. Data from the first year of follow-up were excluded to avoid bias by mortality caused by subclinical disease at re-screening.Results: The relative risk (RR; 95% CI) for non-cancer mortality during follow-up was higher in men with decreasing BMI in all subgroups: RR 2.64 (1.46-4.71, baseline BMI <21 kg m(-2)), 1.39 (0.98-1.95, baseline BMI 22-25 kg m(-2)), and 1.71 (1.18-2.47, baseline BMI 26+ kg m(-2)), using BMI-stable men as reference group. Correspondingly, the non-cancer mortality was also higher in men with increasing BMI, but only in the obese group (baseline BMI 26+ kg m(-2)) with RR 1.86 (1.31-2.65). In a subanalysis, nonsmoking obese (30+ kg m(-2)) men with decreased BMI had an increased non-cancer mortality compared with BMI-stable obese men (Fischer's test: P=0.001). The mortality risk for nonsmoking overweight men who increased their BMI compared with BMI-stable men was also significant (P=0.006), but not in corresponding obese men (P=0.094). CONCLUSIONS. Weight loss in self-reported healthy but overweight middle-aged men, without serious disease, is associated with an increased non-cancer mortality, which seems even more pronounced in obese, nonsmoking men, as compared with corresponding but weight-stable men. The explanation for these observational findings is still enigmatic but could hypothetically be because of premature ageing effects causing so-called weight loss of involution. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to estimate retrospectively the costs of health care resources used in the Malmö Preventive Project, Sweden and estimate the costs of in-patient care that were avoided because of early intervention.Setting and Subjects: A large-scale community intervention programme was conducted from 1974 to 1992 in Malmö, Sweden with the aim of reducing morbidity and mortality of cardiovascular diseases (CVD), alcohol related illnesses, and breast cancer. Between 1974 and 1992, 33 336 male and female subjects were screened for hypertension, hyperlipidaemia, type-2 diabetes and alcohol abuse. Intervention programmes that included life-style modifications, follow-up visits with physicians and nurses and drug therapy were offered to about 25% of screened subjects.Methods: Recruitment costs were generated through out the screening period. Intervention costs were estimated for 5 years after screening. Excess in-patient care costs were estimated by subtracting hospital consumption for an unscreened, matched cohort from that of the screened cohort over follow-up periods of 13-19 years. Intervention and excess in-patient care costs were estimated until 1996.Results: The net expenditures for recruitment and intervention was SEK253 million and saved costs for in-patient care of SEK143 millions (1998 prices). Considering the opportunity cost of the resources used in the study, the net cost rises to about SEK200 millions.Conclusions: The results suggest that only part of the intervention costs were offset by reduction in future morbidity health care costs. This is in line with results from prospective analyses of other primary prevention programmes. [ABSTRACT FROM AUTHOR]

Objective: This study of myocardial infarction (MI) amongst urban women has sought to assess whether there are differences in fatal outcome, in-hospital respectively out-of-hospital, between residential areas defined in terms of socio-economic circumstances.Design: Register-based surveillance study 1986-95.Setting: Seventeen residential areas in the city of Malmö, Sweden.Subjects: Women 20-74 years of age.Main Outcome Measures: Differences in fatal outcome, in-hospital respectively out-of-hospital, between residential areas were expressed in terms of age-adjusted odds ratios (ORs), calculated by means of logistic regression. Socio-economic circumstances in the areas were expressed in terms of a composite score.Results: Between residential areas there were marked and statistically significant differences in incidence (range 124-328/10(5), P < 0.001, d.f.=16) and mortality (range 38-132/10(5), P < 0.005, d.f.=16). Area rates of mortality covaried with incidence (r=0.85, P < 0.001) and with odds ratios of fatal outcome out-of-hospital (r=0.52, P=0.031) but not in-hospital. The odds ratios of fatal outcome out-of-hospital decreased in a statistically significant stepwise fashion from areas in the lowest socio-economic quintile (reference) to areas in the highest socio-economic quintile (OR: 0.67, 95% CI: 0.48-0.94). There was no corresponding association with the odds ratios of fatal outcome in-hospital.Conclusions: The high rate of mortality from MI amongst women in areas with deprived socio-economic circumstances was related to deaths occurring out-of-hospital. In order to assess the preventive potential there is a need for further studies that may clarify to what extent the association with socio-economic circumstances can be explained by other factors and conditions known to influence the probability of survival. [ABSTRACT FROM AUTHOR]

Objective: New treatments have improved the prognosis for patients with acute myocardial infarction. However, studies on long-term survival are not unequivocally in favour of an improved long-term prognosis. This study aimed to analyse trends in 3-year survival in relation to sex, age and socioeconomic level of residential area.Setting: The Malmö myocardial infarction register, Sweden.Participants: All men and women in the city who, between 1978 and 1995, were admitted for a first acute myocardial infarction (n = 11 226).Main Outcome Measures: Age-standardized 3-year survival rates.Results: Both 28-day and 3-year survival rates improved markedly during the study period. Age-standardized 3-year survival (per 100 patients) amongst men and women who survived 28 days increased, between 1978-81 and 1991-95, from 64 to 78 in men and from 66 to 77 in women, an annual increase of 1.4% (95% CI = 1.1-1.7) and 1.2% (0.8-1.5), respectively. There were marked differences in survival between residential areas with different socioeconomic circumstances. The 3-year survival rates amongst men correlated significantly with the socioeconomic circumstances in the areas expressed in terms of a socioeconomic score (men: r = 0.60, n = 17, P = 0.01; women: r = 0.37, P = 0.15). Trends tended to be less favourable in deprived areas.Conclusion: Three-year survival after first myocardial infarction has continuously improved for men and women in all age groups. Prognosis was worse and trends tended to be less favourable for patients from deprived areas. [ABSTRACT FROM AUTHOR]

Objective: Age adjusted incidence of myocardial infarction has been found to vary substantially between the residential areas of the city of Malmö. The objective of this study was to assess the extent to which major biological risk factors and socio-economic circumstances account for the differences in incidence of and mortality from myocardial infarction.Design: Ecological study of risk factor prevalence and incidence and mortality from myocardial infarction.Setting: Seventeen administrative areas in Malmö, Sweden.Subjects: Assessment of risk factor prevalence was based on 28 466 men and women, ranging from 45 to 73 years old, who were recruited as participants in the Malmö Diet and Cancer study. Information on serum lipids was available in a random subsample of 5362 subjects. Information about socio-economic level of the residential area was based on statistics from the Malmö City Council and Statistics Sweden.Main Outcome Measures: Weighted least square regressions between prevalence of risk factors (i.e. smoking, hypertension, obesity, diabetes, hypercholesterolemia and hypertriglyceridemia), a myocardial infarction risk score, a socio-economic score and incidence and mortality from myocardial infarction.Results: The risk factor prevalence and myocardial infarction incidence was highest in areas with low socio-economic level. Prevalence of smoking, obesity and hypertension was significantly associated with myocardial infarction incidence and mortality rates amongst men (all r > 0.60). Prevalence of smoking was significantly associated with incidence and mortality from myocardial infarction amongst women (r = 0.66 and r = 0.61, respectively). A myocardial infarction risk score based on four biological risk factors explained 40-60% of the intra-urban geographical variation in myocardial infarction incidence and mortality. The socio-economic score added a further 2-16% to the explained variance.Conclusion: In an urban population with similar access to medical care, well-known biological cardiovascular risk factors account for a substantial proportion of the intra-urban geographical variation of incidence of and mortality from myocardial infarction. The socio-economic circumstances further contribute to the intra-urban variation in disease. [ABSTRACT FROM AUTHOR]

Abstract: Background:: The carotid intima-media thickness (IMT) has been associated with incidence of stroke. Whether this association is independent of carotid plaque is controversial. Methods and results:: The associations among B-mode ultrasound determined common carotid IMT, carotid plaque (focal IMT>1.2mm) and incident stroke, were investigated in 5163 Swedish middle-aged men and women over a median follow-up of 7 years. Age and sex-adjusted carotid IMT, and carotid plaque were significantly (p &#60;0.05) related to future stroke. Adjustment for cardiovascular risk factors generally reduced the hazard rate ratios, however more prominently so with regard to the carotid measure of plaque than with IMT. The associations between carotid IMT and stroke remained after adjustment for presence of carotid plaque, and graded associations between carotid IMT and stroke was found both among those with and without carotid plaque. Conclusions:: In this population-based study, common carotid IMT was associated with incidence of stroke. This relation was independent of presence of carotid plaque. [Copyright &y& Elsevier]

Background: Low 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., Objective: To study the association between low heart rate at 24hECG, PACs and incident AF in a prospective population-based cohort., Methods: In 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., Results: There 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)., Conclusion: Low 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., Competing Interests: Competing interests: SJ-M is a previous medical director of Cardiome Inc., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lead exposure has been associated with increased incidence of adverse clinical cardiovascular outcomes. Atherosclerosis has been suggested as one of the underlying mechanisms, and findings from experimental studies support this, but human data are scarce., Objectives: Our objective was to determine the association between environmental lead exposure based on blood lead (B-Pb) concentrations and the prevalence of atherosclerotic plaque in the carotid artery., Methods: We used cross-sectional data from the Malmö Diet and Cancer Study cardiovascular cohort (MDCS-CC; recruitment in 1991-1994) covering 4,172 middle-aged men and women. B-Pb at baseline, measured by inductively coupled plasma mass spectrometry, was used as the exposure biomarker. The presence of atherosclerotic plaque in the carotid artery was determined by B-mode ultrasonography. We used logistic regression to estimate odds ratios (ORs) for prevalence of plaque in the carotid artery according to B-Pb quartiles., Results: The median B-Pb was 25 μ g / L (range: 1.5-258), and 36% of the cohort had any atherosclerotic plaque. After controlling for confounders and known cardiovascular risk factors, the OR for prevalence of plaque in the highest quartile (Q4) of B-Pb compared with the lowest quartile (Q1) was 1.35 (95% CI: 1.09, 1.66) in the total group, 1.58 (95% CI: 1.20, 2.08) among women, and 1.18 (95% CI: 0.83, 1.69) among men. Among women, associations were limited to those who were postmenopausal [OR for Q4 vs. Q 1 = 1.72 (95% CI: 1.26, 2.34) vs. OR = 0.96 (95% CI: 0.49, 1.89 in premenopausal women)]. Associations were weak and nonsignificant in never-smokers [OR for Q4 vs. Q 1 = 1.14 (95% CI: 0.81, 1.61)]., Discussion: Our study shows an association between B-Pb concentrations and occurrence of atherosclerotic plaque in the carotid artery, adding evidence for an underlying pro-atherogenic role of lead in cardiovascular disease. Associations appeared to be limited to postmenopausal (vs. premenopausal) women. https://doi.org/10.1289/EHP5057.

Background: Smoking is a strong risk factor for cardiovascular disease (CVD) and causes exposure to cadmium, which is a pro-atherosclerotic metal. Cadmium exposure has also been shown to increase the risk of CVD, even after adjustment for smoking. Our hypothesis was that part of the risk of CVD in smokers may be mediated by cadmium exposure from tobacco smoke. We examined this hypothesis in a mediation analysis, trying to assess how much of the smoking-induced CVD risk could be explained via cadmium., Methods: We used prospective data on CVD (incidence and mortality) in a Swedish population-based cohort of 4304 middle-aged men and women (the Malmö Diet and Cancer Study). Blood cadmium was analyzed in base-line samples from 1991, and clinical events were followed up for 16-19 years based on registry data. Mediation analysis was conducted to evaluate the indirect effect (via cadmium) of smoking on CVD. Survival was analyzed by the accelerated failure time (AFT) model and the Aalen additive hazard model., Results: The mean blood cadmium level in the study population was 0.43 μg/L (median 0.24 μg/L) and increased with recent and current smoking. As expected, shorter survival time (AFT model) and higher incidence rate (Aalen model) were found in current smokers for all CVD outcomes and this effect seemed to be partly mediated by cadmium. For the sum of acute myocardial infarction, bypass grafts and percutaneous coronary intervention, and death in ischemic heart disease, about half of the increased risk of such events in current smokers was mediated via cadmium, with similar results for the AFT and Aalen models., Conclusions: Cadmium plays an important role in smoking-induced CVDs. This provides evidence for mechanisms and is of importance for both individuals and policy makers.

Background/objectives: Studies on the health effects of whole grains typically use self-reported intakes which are prone to large measurement errors. Dietary biomarkers that can provide an objective measure of intake are needed. New alkylresorcinol (AR) metabolites (3,5-dihydroxycinnamic acid (DHCA), 2-(3,5-dihydroxybenzamido)acetic acid (DHBA-glycine) and 5-(3,5-dihydroxyphenyl) pentanoic acid (DHPPTA)) in 24 h urine samples have been suggested as biomarkers for whole grain (WG) wheat and rye intake but remain to be evaluated in spot urine samples., Subjects/methods: The reproducibility of the new AR metabolites (DHCA, DHBA-glycine and DHPPTA) was investigated in 4 repeated samples over a period of 2 wk in spot urine from 40 Swedish men and women enroled in the SCAPIS-study, after adjustment of creatinine. Metabolite concentrations were correlated with total whole grain intake estimated during the same period., Results: The medium-term reproducibility determined for DHCA, DHPPTA and DHBA-glycine varied from moderate to excellent (intra-class correlation coefficient = 0.35-0.67). Moreover, DHCA and DHBA-glycine were independently associated with self-reported total WG intake (β = 0.18, P = 0.08 and β = 0.18, P = 0.02, respectively) and all metabolites except for DHPPA were higher among women., Conclusions: This study supports the idea of using AR metabolites in one or several spot urine samples as biomarkers of whole grain intake. These findings need to be confirmed in different populations.

Background: Environmental lead exposure has been associated with decreased kidney function, but evidence from large prospective cohort studies examining low exposure levels is scarce. We assessed the association of low levels of lead exposure with kidney function and kidney disease., Study Design: Prospective population-based cohort., Setting & Participants: 4,341 individuals aged 46 to 67 years enrolled into the Malmö Diet and Cancer Study-Cardiovascular Cohort (1991-1994) and 2,567 individuals subsequently followed up (2007-2012)., Predictor: Blood lead concentrations in quartiles (Q1-Q4) at baseline., Outcomes: Change in estimated glomerular filtration rate (eGFR) between the baseline and follow-up visit based on serum creatinine level alone or in combination with cystatin C level. Chronic kidney disease (CKD) incidence (185 cases) through 2013 detected using a national registry., Measurements: Multivariable-adjusted linear regression models to assess associations between lead levels and eGFRs at baseline and follow-up and change in eGFRs over time. Cox regression was used to examine associations between lead levels and CKD incidence. Validation of 100 randomly selected CKD cases showed very good agreement between registry data and medical records and laboratory data., Results: At baseline, 60% of study participants were women, mean age was 57 years, and median lead level was 25 (range, 1.5-258) μg/L. After a mean of 16 years of follow-up, eGFR decreased on average by 6mL/min/1.73m 2 (based on creatinine) and 24mL/min/1.73m 2 (based on a combined creatinine and cystatin C equation). eGFR change was higher in Q3 and Q4 of blood lead levels compared with Q1 (P for trend = 0.001). The HR for incident CKD in Q4 was 1.49 (95% CI, 1.07-2.08) compared with Q1 to Q3 combined., Limitations: Lead level measured only at baseline, moderate number of CKD cases, potential unmeasured confounding., Conclusions: Low-level lead exposure was associated with decreased kidney function and incident CKD. Our findings suggest lead nephrotoxicity even at low levels of exposure., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Exposure to cadmium confers increased cardiovascular risk. Tobacco smoke contains cadmium, which, hypothetically, may mediate parts of the tobacco-associated risk of developing atherosclerotic plaques. Baseline data from the Swedish Malmö Diet and Cancer cohort (1991-1996) were used to test this hypothesis. Mediation analysis was used to examine associations between smoking and blood cadmium levels and the prevalence of ultrasound-assessed carotid atherosclerotic plaques. The total association with smoking status (never smokers, 2 categories of former smokers, and current smokers) was split into direct and indirect association, and the proportion mediated was estimated. The adjusted estimated plaque prevalence was approximately 27% among never smokers. We identified both a direct and an indirect pathway between smoking and carotid plaques; the indirect association, through cadmium, was observed among current smokers and former smokers who had quit smoking less than 15 years before. For current smokers, the prevalence ratio for plaque was 1.5, with 60%-65% of the association with smoking being mediated through cadmium. Recent former smokers had a prevalence ratio of 1.3, and 40%-45% was mediated through cadmium. Long-time former smokers had a prevalence ratio of 1.2, but none of the association was mediated through cadmium. In conclusion, about two-thirds of the proatherosclerotic association with smoking was mediated by cadmium.

Aims: ST-depression at 24hECG has not been studied in relation to atrial fibrillation (AF) risk. We aimed to determine whether ST-depression at 24hECG was associated with incident AF in two Swedish population-based cohorts - a sub-cohort of the Malmö Diet and Cancer study (MDCS), and the cohort 'Men born in 1914', and to determine whether 24hECG could be used to predict AF development., Methods and Results: There were 378 acceptable 24hECG recordings in the MDCS (mean age 64.5 years, 43% men) and 394 acceptable recordings in 'Men born in 1914' (mean age 68.8 years). Incidence of AF was monitored using national registers of hospitalizations and outpatient visits in Sweden. Mean follow-up ± SD (cumulative incidence) was 10.4 ± 2 years (11.3%) in MDCS, and 10.9 ± 4 years (7.3%) in 'Men born in 1914'. ST-depressions were independently associated with incident AF; hazard ratio (HR) (95% CI) 2.41 (1.29-4.50, P = 0.006) and 2.28 (1.05-4.95, P = 0.038) after adjustment [age, sex, height, weight, systolic blood pressure, smoking, anti-hypertensive drugs, LDL/total cholesterol, and HOMA-IR (in MDCS)]. AF incidence was substantially lower in individuals who had neither ST-depressions or high supraventricular activity (SVA, negative predictive value 0.97 and 0.94, in MDCS and 'Men born in 1914', respectively), and similar in men and women., Conclusion: ST-depression at 24h-ECG is independently associated with incident AF, and incidence is substantially lower in individuals with neither ST-depression or high SVA. 24hECG can be used not only to diagnose AF but also to identify individuals at high and low AF risk., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study explored whether complement factor 3 (C3) in plasma is associated with incidence of diabetes in a population-based cohort. We also identified genetic variants related to C3 and explored whether C3 and diabetes share common genetic determinants., Methods: C3 was analyzed in plasma from 4368 nondiabetic subjects, 46 to 68 years old, from the Malmö Diet and Cancer Study. Incidence of diabetes was studied in relationship to C3 levels during 17.7± 4.4 years of follow-up. Genotypes associated with C3 were identified in a genome-wide association study. Diabetes Genetics Replication and Meta-Analysis and the European Genetic Database were used for in silico look-up., Results: In all, 538 (12.3%) subjects developed diabetes during 18 years of follow-up. High C3 was significantly associated with incidence of diabetes after risk factor adjustments (hazard ratio comparing 4th vs 1st quartile, 1.54 (95% confidence interval, 1.13 to 2.09; P = 0.005). C3 was associated with polymorphisms at the complement factor H locus (P < 10-8). However, no relationship with diabetes was observed for this locus. Another eight loci were associated with C3 with P < 10-5. One of them, the glucose kinase regulatory protein (GCKR) locus, has been previously associated with diabetes. The relationship between C3 levels and the GCKR locus was replicated in the European Genetic Database cohort., Conclusions: Plasma concentration of C3 is a risk marker for incidence of diabetes. The results suggest that this association could, in part, be explained by pleiotropic effects related to the GCKR gene., (Copyright © 2017 Endocrine Society)

Background: High parity has been suggested to increase risk of maternal cardiovascular disease independent of body mass index measured after childbearing. Pregnancy is, however, associated with persistent weight gain and metabolic changes that, independent of parity, increase the risk of cardiovascular disease. It could therefore be questioned if high parity independently increases the risk of cardiovascular disease or if this association may be confounded, mediated, or modified by other parity-related factors., Objective: We sought to investigate the association between parity and risk of cardiovascular disease, and secondary outcomes in terms of myocardial infarction and cerebral infarction, with particular focus on potential mediation by anthropometric measures and effect modification by lactation., Study Design: We used data from 16,515 female participants (age 44.5-73.6 years) of the population-based Malmö Diet and Cancer Study with baseline examination from 1991 through 1996. The Malmö Diet and Cancer Study was followed up throughout 2010, with a median follow-up of 15.8 years. We used Cox proportional hazards model to examine the association between parity and cardiovascular disease., Results: Adjusted for age and other potential confounders, grand multiparous women (≥5 children) had an increased risk of cardiovascular disease (hazard ratio, 1.60; 95% confidence interval, 1.20-2.14), myocardial infarction (hazard ratio, 1.68; 95% confidence interval, 1.15-2.45), and cerebral infarction (hazard ratio, 1.74; 95% confidence interval, 1.18-2.58) compared to women with 2 children. Additional adjustment for baseline body mass index and weight change since age 20 years attenuated the risk, but the increased risk for cardiovascular disease (hazard ratio, 1.38; 95% confidence interval, 1.02-1.87) and myocardial infarction (hazard ratio, 1.53; 95% confidence interval, 1.04-2.26) in grand multiparous women remained significant. Models stratified by lactation time showed that risk was only raised in grand multiparous women who had a mean lactation time of <4 mo/child. In sensitivity analyses excluding women with a history of diabetes at baseline, risk estimates for grand multiparous women became nonsignificant in the full model., Conclusion: Part of the increased risk of cardiovascular disease and myocardial infarction in grand multiparous women seems to be mediated by weight gain and potentially by higher likelihood of type 2 diabetes mellitus. Lactation may modify the increased risk of grand multiparity in that longer duration might offset the cardiovascular disease risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Previous smaller studies have indicated inverse associations between autoantibodies to oxidized low-density lipoprotein epitopes, and cardiovascular disease. The present study investigated associations between autoantibodies against the apolipoprotein B-100 peptides p45 and p210, respectively, and risk of incident cardiovascular disease in a large population-based cohort., Approach and Results: Apolipoprotein B-100 autoantibodies were analyzed by ELISA in a prospective study, including 5393 individuals (aged 46-68 years) belonging to the cardiovascular arm of the Malmö Diet and Cancer study with a follow-up time of >15 years. Subjects that suffered an acute coronary event during follow-up (n=382) had lower levels at baseline of IgM autoantibodies recognizing the native and malondialdehyde-modified apolipoprotein B-100 peptides p45 and p210 and also lower IgG levels recognizing native p210, whereas no association was found with risk for stroke (n=317). Subjects in the highest compared with lowest tertile of IgM-p45MDA (hazard ratio [95% confidence interval]: 0.72 [0.55, 0.94]; P=0.017) and IgG-p210native (hazard ratio [95% confidence interval]: 0.73 [0.56, 0.97]; P=0.029) had lower risk for incident coronary events after adjustment for cardiovascular risk factors in Cox proportional hazard regression models. Moreover, subjects with high levels of IgG-p210native were less likely to have carotid plaques as assessed by ultrasonography at baseline (odds ratio=0.81, 95% confidence interval 0.70-0.95, P=0.008 after adjustment for risk factors)., Conclusions: This large prospective study demonstrates that subjects with high levels of apolipoprotein B-100 autoantibodies have a lower risk of coronary events supporting a protective role of these autoantibodies in cardiovascular disease., (© 2016 American Heart Association, Inc.)

Objective: High concentrations of leukocytes in blood have been associated with diabetes mellitus. This prospective study aimed to explore whether total and differential leukocyte counts are associated with incidence of diabetes. A missense variant R262W in the SH2B3 (SH2B adaptor protein 3) gene, coding for a protein that negatively regulates hematopoietic cell proliferation, was also studied in relation to incidence of diabetes., Methods and Results: Leukocyte count and its subtypes (neutrophils, lymphocytes and mixed cells) were analyzed in 26,667 men and women, 45-73 years old, from the population-based Malmö Diet and Cancer study. Information about the R262W polymorphism (rs3184504) in SH2B3 was genotyped in 24,489 subjects. Incidence of diabetes was studied during a mean follow-up of 14 years. Cox proportional hazards regression was used to examine incidence of diabetes by total and differential leukocyte counts. Mendelian randomization analysis using R262W as an instrumental variable was performed with two-stage least squares regression. A total of 2,946 subjects developed diabetes during the follow-up period. After taking several possible confounders into account, concentrations of total leukocyte count, neutrophils and lymphocytes were all significantly associated with incidence of diabetes. The adjusted hazard ratios (95% confidence interval; quartile 4 vs quartile 1) were 1.37 (1.22-1.53) for total leukocytes, 1.33 (1.19-1.49) for neutrophils and 1.29 (1.15-1.44) for lymphocytes. The R262W polymorphism was strongly associated with leukocytes (0.11x109 cells/l per T allele, p = 1.14 x10-12), lymphocytes (p = 4.3 x10-16), neutrophils (p = 8.0 x10-6) and mixed cells (p = 3.0 x10-6). However, there was no significant association between R262W and fasting glucose, HbA1c or incidence of diabetes., Conclusions: Concentrations of total leukocytes, neutrophils and lymphocytes are associated with incidence of diabetes. However, the lack of association with the R262W polymorphism suggests that the associations may not be causal, although limitations in statistical power and balancing pleiotropic effects cannot be excluded.

Objective: Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM., Design: Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1996., Methods: Four tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort)., Results: In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (β-coefficient ± s.e.m.; 0.30 ± 0.14, P=0.03) and waist (0.78 ± 0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21 ± 0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00-1.20), P=0.04)., Conclusions: Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation., (© 2016 The authors.)

Background: Obesity is the major modifiable risk factor for diabetes. This study investigated the incidence of diabetes in relation to multiple anthropometric measures., Methods: Body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), waist-hip ratio (WHR) and body fat percentage (BF %) were measured among 26,604 subjects (aged 45-73 years) without history of diabetes from the Malmö Diet and Cancer cohort., Results: During 14 years of follow-up, 2935 subjects (1519 men, 1416 women) were diagnosed with diabetes. In men, incidence of diabetes was 24.1 and 4.0 per 1000 person-years comparing the fourth vs. first quartile of WHtR. The multivariate adjusted hazard ratios (HR; fourth vs first quartile) were 6.00 [95% confidence interval (CI): 5.02-7.16) for WHtR, 5.95 (CI: 4.96-7.14) for WC, 5.19 (CI: 4.38-6.15) for BMI, 4.71 (CI: 3.96-5.60) for WHR and 3.21 (CI: 2.75-3.76] for BF%. For women, incidence of diabetes was 15.1 and 1.4 per 1000 person-years for fourth vs first quartile of WHtR (HR: 10.19, CI: 8.10-12.82). HR was 9.16 (CI: 7.40-11.33) for WC, 6.42 (CI: 5.27-7.81) for BMI, 6.75 (CI: 5.52-8.25) for WHR and 5.39 (CI: 4.42-6.57) for BF%. Model discrimination was marginally increased when WC, WHtR or WHR was used in combination with BMI., Conclusion: All measures of obesity were associated with substantially increased incidence of diabetes. Abdominal obesity was associated with higher incidence rates in men than in women, but in terms of relative risks the relationships were stronger in women. The combination of BMI and abdominal obesity measures had stronger association with diabetes than BMI alone., (© The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: Atrial fibrillation (AF) episodes are thought to be started by an electrical trigger reaching susceptible atria. Such a trigger could be present long before the occurrence of sustained symptomatic arrhythmia., Objective: We sought to determine whether supraventricular extrasystoles (SVESs) and supraventricular tachycardias (SVTs) measured at 24-hour Holter electrocardiogram were associated with an increased incidence of AF., Methods: In 1998-2000, 389 individuals (44% men; mean age 65 years) were examined using 24-hour Holter electrocardiogram. Six individuals with known prevalent AF were excluded. After a mean follow-up of 10.3 years, there were 45 cases of incident AF. Hazard ratios (HRs) were computed using multivariable Cox regression adjusting for age, sex, systolic blood pressure, height, weight, smoking, and homeostatic model assessment of insulin resistance., Results: Frequency of SVESs as well as SVT episodes per hour were independent predictors of incident AF (HR per log unit 1.38; 95% confidence interval 1.14-1.68; P = .001 and HR 1.95; 95% confidence interval 1.21-3.13; P = .006, respectively). Further adjustment for education level, alcohol use, use of medication, and physical activity did not substantially alter the results, nor did analysis using competing risks regression accounting for a competing risk of death. The maximum duration of SVT or the heart rate at SVT was not significantly associated with the incidence of AF., Conclusion: SVESs and SVTs independently predict AF. The prognostic significance was similar for SVESs, SVTs, and a combination of the two. Repeated efforts to detect AF could be of merit in individuals with frequent supraventricular activity., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other 'traditional risk factors', also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS P=0.003) with similar trends in all three samples: LSR (1.050 (0.967-1.140); P=0.25), MDC (1.168 (1.060-1.288); P=0.002) and SAHLSIS (1.124 (0.997-1.267); P=0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension.

Objectives: Cadmium is a non-essential toxic metal with multiple adverse health effects. Cadmium has been shown to be associated with cardiovascular diseases, but few studies have investigated heart failure (HF) and none of them reported atrial fibrillation (AF). We examined whether cadmium exposure is associated with incidence of HF or AF., Design: A prospective, observational cohort study with a 17-year follow-up., Setting: The city of Malmö, Sweden., Participants: Blood cadmium levels were measured in 4378 participants without a history of HF or AF (aged 46-67 years, 60% women), who participated in the Malmö Diet and Cancer (MDC) study during 1992-1994., Primary and Secondary Outcome Measures: Incidence of HF and AF were identified from the Swedish hospital discharge register., Results: 143 participants (53% men) were diagnosed with new-onset HF and 385 individuals (52% men) were diagnosed with new-onset AF during follow-up for 17 years. Blood cadmium in the sex-specific 4th quartile of the distribution was significantly associated with incidence of HF. The (HR, 4th vs 1st quartile) was 2.64 (95% CI 1.60 to 4.36), adjusted for age, and 1.95 (1.02 to 3.71) after adjustment also for conventional risk factors and biomarkers. The blood cadmium level was not significantly associated with risk of incident AF., Conclusions: Blood cadmium levels in the 4th quartile were associated with increased incidence of HF in this cohort with comparatively low exposure to cadmium. Incidence of AF was not associated with cadmium., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Increased red cell distribution width (RDW) has been related to poor prognosis in patients with cardiovascular disease, and is a predictor of cardiovascular mortality in the general population. The purpose of the present study was to investigate if RDW is associated with increased incidence of stroke and its subtypes in individuals from the general population., Methods: Red cell distribution width was measured in 26,879 participants (16,561 women and 10,318 men aged 45-73 years) without history of coronary events or stroke, from the population-based Malmö Diet and Cancer Study. Incidences of total stroke and stroke subtypes over a mean follow-up of 15.2 years were calculated in relation to sex-specific quartiles of RDW. The presence of carotid plaque and intima-media thickness, as assessed by ultrasound, was studied in relation to RDW in a randomly selected subcohort (n = 5,309)., Results: Incidences of total stroke (n = 1,869) and cerebral infarction (n = 1,544) were both increased in individuals with high RDW. Hazard ratios (HRs) in the highest compared to the lowest quartile were 1.31 for total stroke (95% confidence interval [CI]: 1.11-1.54, p for trend = 0.004) and 1.32 for cerebral infarction (95% CI: 1.10-1.58, p for trend = 0.004) after adjustment for stroke risk factors and hematological parameters. The adjusted HR for intracerebral hemorrhage (n = 230) was 1.44 (95% CI: 0.90-2.30) and the HR for subarachnoid hemorrhage (n = 75) was 0.94 (95% CI: 0.43-2.07), in the highest compared to the lowest quartile of RDW. Red cell distribution width was positively associated with intima-media thickness of the common carotid artery (p for trend = 0.011)., Conclusions: Red cell distribution width in the highest quartile was associated with increased incidence of total stroke and cerebral infarction. There was no significant association between RDW and incidence of intracerebral or subarachnoid hemorrhage.

Background: We previously discovered that high copeptin is associated with incidence of diabetes mellitus (diabetes), abdominal obesity, and albuminuria. Furthermore, copeptin predicts cardiovascular events after myocardial infarction in diabetic patients, but whether it is associated with heart disease and death in individuals without diabetes and prevalent cardiovascular disease is unknown. In this study, we aim to test whether plasma copeptin (copeptin), the C-terminal fragment of arginine vasopressin prohormone, predicts heart disease and death differentially in diabetic and nondiabetic individuals., Methods: We related plasma copeptin to a combined end point composed of coronary artery disease (CAD), heart failure (HF), and death in diabetes (n = 895) and nondiabetes (n = 4187) individuals of the Malmö Diet and Cancer Study-Cardiovascular cohort., Results: Copeptin significantly interacted with diabetes regarding the combined end point (P = .006). In diabetic individuals, copeptin predicted the combined end point (hazard ratio [HR] 1.32 per SD, 95% CI 1.10-1.58, P = .003) after adjustment for conventional risk factors, prevalent HF and CAD, and remained significant after additional adjustment for either fasting glucose (P = .02) or hemoglobin A1c (P = .02). Furthermore, in diabetic individuals, copeptin predicted CAD (HR 1.33 per SD, 95% CI 1.04-1.69, P = .02), HF (HR 1.62 per SD, 95% CI 1.09-2.41, P = .02), and death (HR 1.32 per SD, 95% CI 1.04-1.68, P = .02). Interestingly, among nondiabetic individuals, copeptin was not associated with any of the end points., Conclusions: Copeptin predicted heart disease and death, specifically in diabetes patients, suggesting copeptin and the vasopressin system as a prognostic marker and therapeutic target for diabetic heart disease and death., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Community screening to guide preventive interventions for acute aortic disease has been recommended in high-risk individuals. We sought to prospectively assess risk factors in the general population for aortic dissection (AD) and severe aneurysmal disease in the thoracic and abdominal aorta., Methods and Results: We studied the incidence of AD and ruptured or surgically treated aneurysms in the abdominal (AAA) or thoracic aorta (TAA) in 30 412 individuals without diagnosis of aortic disease at baseline from a contemporary, prospective cohort of middle-aged individuals, the Malmö Diet and Cancer study. During up to 20 years of follow-up (median 16 years), the incidence rate per 100 000 patient-years at risk was 15 (95% CI 11.7 to 18.9) for AD, 27 (95% CI 22.5 to 32.1) for AAA, and 9 (95% CI 6.8 to 12.6) for TAA. The acute and in-hospital mortality was 39% for AD, 34% for ruptured AAA, and 41% for ruptured TAA. Hypertension was present in 86% of individuals who subsequently developed AD, was strongly associated with incident AD (hazard ratio [HR] 2.64, 95% CI 1.33 to 5.25), and conferred a population-attributable risk of 54%. Hypertension was also a risk factor for AAA with a smaller effect. Smoking (HR 5.07, 95% CI 3.52 to 7.29) and high apolipoprotein B/A1 ratio (HR 2.48, 95% CI 1.73 to 3.54) were strongly associated with AAA and conferred a population-attributable risk of 47% and 25%, respectively. Smoking was also a risk factor for AD and TAA with smaller effects., Conclusions: This large prospective study identified distinct risk factor profiles for different aortic diseases in the general population. Hypertension accounted for more than half of the population risk for AD, and smoking for half of the population risk of AAA., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: Rupture of atherosclerotic plaques is the major cause of acute coronary events (CEs). Plaque destabilization is the consequence of an imbalance between inflammatory-driven degradation of fibrous tissue and smooth muscle cell-dependent tissue repair. Proinflammatory factors have been documented extensively as biomarkers of cardiovascular risk but factors that contribute to stabilization of atherosclerotic plaques have received less attention. The present study aimed to investigate whether plasma levels of the smooth muscle cell growth factor epidermal growth factor (EGF), heparin-binding-EGF (HB-EGF), and platelet-derived growth factor correlate with plaque phenotype and incidence of CEs., Approach and Results: HB-EGF, EGF and platelet-derived growth factor were measured in plasma from 202 patients undergoing carotid endarterectomy and in 384 incident CE cases and 409 matched controls recruited from the Malmö Diet and Cancer cohort. Significant positive associations were found between the plasma levels of all 3 growth factors and the collagen and elastin contents of the removed plaques. CE cases in the Malmö Diet and Cancer cohort had lower levels of HB-EGF in plasma, whereas no significant differences were found for EGF and platelet-derived growth factor. After adjusting for cardiovascular risk factors in a Cox proportional hazard model, the hazard ratio for the highest HB-EGF tertile was 0.61 (95% confidence interval, 0.47-0.82; P<0.001)., Conclusions: The associations between high levels of smooth muscle cell growth factors in plasma and a more fibrous plaque phenotype as well as the association between low levels of HB-EGF and incident CEs point to a potential clinically important role for factors that contribute to plaque stabilization by stimulating smooth muscle cells., (© 2014 American Heart Association, Inc.)

Background: Epidemiological studies indicate that cadmium exposure through diet and smoking is associated with increased risk of cardiovascular disease. There are few data on the relationship between cadmium and plaques, the hallmark of underlying atherosclerotic disease., Objectives: To examine the association between exposure to cadmium and the prevalence and size of atherosclerotic plaques in the carotid artery., Methods: A population sample of 4639 Swedish middle-aged women and men was examined in 1991-1994. Carotid plaque was determined by B-mode ultrasound. Cadmium in blood was analyzed by inductively coupled plasma mass spectrometry., Results: Comparing quartile 4 with quartile 1 of blood cadmium, the odds ratio (OR) for prevalence of any plaque was 1.9 (95% confidence interval 1.6-2.2) after adjustment for sex and, age; 1.4 (1.1-1.8) after additional adjustment for smoking status; 1.4 (1.1-1.7) after the addition of education level and life style factors; 1.3 (1.03-1.8) after additional adjustment for risk factors and predictors of cardiovascular disease. No effect modification by sex was found in the cadmium-related prevalence of plaques. Similarly, ORs for the prevalence of small and large plaques were after full adjustment 1.4 (1.0-2.1) and 1.4 (0.9-2.0), respectively. The subgroup of never smokers showed no association between cadmium and atherosclerotic plaques., Conclusions: These results extend previous studies on cadmium exposure and clinical cardiovascular events by adding data on the association between cadmium and underlying atherosclerosis in humans. The role of smoking remains unclear. It may both cause residual confounding and be a source of pro-atherogenic cadmium exposure., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: A recently published genome wide association study identified 29 single nucleotide polymorphisms (SNPs) influencing blood pressure (BP). Case-control studies suggest that a genetic risk score (GRS) based on these 29 SNPs affect the risk of cardiovascular disease (CVD), but its role for CVD at population level is unknown. Here, we prospectively evaluate the impact of this polygenetic BP component on CVD morbidity and mortality in a large urban-based middle-aged population., Method: The 29 previously BP associated SNPs were genotyped in the Swedish Malmö Diet and Cancer Study; (n = 27,003 with at least 24 valid SNPs). The number of BP elevating alleles of each SNPs, weighted by their effect size in the discovery studies, was summed into a BP-GRS., Results: Using regression models, we found significant associations of the BP-GRS, cross-sectionally, with BP and hypertension prevalence, prospectively, with incident cardiovascular morbidity and mortality during 14.2 ± 3.2 years of follow-up. After adjustment for traditional cardiovascular risk factors (TRF), including hypertension, the BP-GRS remained significantly associated only with CVDs [in terms of strokes and coronary artery disease; hazard ratio 1.15; 95% confidence interval (CI) 1.06-1.24 comparing the third vs. first tertile; P = 0.003]. Calibration, discrimination and reclassification analyses did not show a meaningful increment in prediction using the BP-GRS in addition to the model encompassing only the TRF., Conclusion: The polygenetic component of BP influences risk of cardiovascular morbidity and mortality. However, the effect size is small and unlikely to be useful for prediction at the population level.

Background: Snus is a moist smokeless tobacco product with high nicotine content. Its use has a short-term effect on the cardiovascular system, but the relationship between snus use and stroke is unclear., Objective: The aim of this study was to assess the associations between use of snus and incidence of and survival after stroke, both overall and according to subtypes., Methods: Pooled analyses of eight Swedish prospective cohort studies were conducted, including 130 485 men who never smoked. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of incidence and death after diagnosis using Cox proportional hazard regression models and case fatality and survival using logistic regression and Kaplan-Meier methods, respectively., Results: No associations were observed between the use of snus and the risk of overall stroke (HR 1.04, 95% CI 0.92-1.17) or of any of the stroke subtypes. The odds ratio (OR) of 28-day case fatality was 1.42 (95% CI 0.99-2.04) amongst users of snus who had experienced a stroke, and the HR of death during the follow-up period was 1.32 (95% CI 1.08-1.61)., Conclusion: Use of snus was not associated with the risk of stroke. Hence, nicotine is unlikely to contribute importantly to the pathophysiology of stroke. However, case fatality was increased in snus users, compared with nonusers, but further studies are needed to determine any possible causal mechanisms., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Background: It is unclear which anthropometric measure is most useful for assessment of the cardiovascular risk. We investigated the association between different anthropometric measures and risk of heart failure (HF) hospitalization., Methods: BMI, waist-hip ratio (WHR), waist circumference (WC), body fat percentage (BF%), weight and height were measured among 26,653 subjects (aged 45-73 years) without history of myocardial infarction (MI), stroke or HF from the Malmö Diet and Cancer cohort at baseline in 1991-96. Incidence of HF hospitalizations was monitored during a mean follow-up of 15 years., Results: Seven hundred and twenty-seven subjects were hospitalized with HF as primary diagnosis, of whom 157 had an MI before or concurrent with the HF. After adjustment for potential confounding factors, the hazard ratios of HF hospitalization (fourth vs. first sex-specific quartile) were 1.80 (95% CI: 1.45-2.24) for BMI, 1.87 (1.50-2.34) for WC, 1.77 (1.43-2.19) for WHR, 1.35 (1.09-1.68) for BF%, 1.93 (1.57-2.39) for weight and 1.18 (0.96-1.44) for height. Significant interactions between BMI and WC and WHR, respectively, were observed, and the joint exposure of high BMI and high WC or high WHR further increased the risk. The results were similar in secondary analyses, i.e., excluding incident HF with previous MI during the follow-up., Conclusion: Our results support the view that raised BMI, WC, WHR or BF% increases the risk of HF hospitalization. The joint exposure of high BMI and high WHR or high WC further increased the risk in an additive way.

Background: We have recently shown that low plasma levels of mid-regional atrial natriuretic peptide (MR-ANP) predict development of diabetes and glucose progression over time, independently of known risk factors for diabetes development. However, since MR-ANP levels might be influenced by unknown factors causing diabetes, we cannot rule out that such relationship might be confounded. Previous studies have shown an association of a single nucleotide polymorphism rs5068 on the natriuretic peptide precursor A (NPPA) locus gene with higher levels of circulating ANP. Since gene variants are inherited randomly and not subject to confounding, we aimed to investigate whether the variant rs5068 within the NPPA locus is associated with incident type 2 diabetes., Methods: We genotyped the variant rs5068 within the NPPA locus in 27,307 individuals without known diabetes from the Malmö Diet Cancer Study. Incident diabetes was retrieved through national and regional registers (median follow-up time of 14 years, 2,823 incident diabetes cases)., Results: In Cox regression analysis adjusted for age, sex and BMI, we found that the carriers of at least one copy of the G allele of rs5068 had lower likelihood of incident diabetes within 14 years (HR = 0.88, 95% CI 0.78-0.99, p = 0.037)., Conclusion: Our results indicate a role of the ANP system in the etiology of type 2 diabetes and might help provide insight in the metabolic actions of natriuretic peptides and the pathophysiology of type 2 diabetes.

Objectives: Inflammatory diseases and inflammatory markers secreted by the liver, including C-reactive protein (CRP) and ceruloplasmin, have been associated with incident atrial fibrillation (AF). Genetic studies have not supported a causal relationship between CRP and AF, but the relationship between ceruloplasmin and AF has not been studied. The purpose of this Mendelian randomization study was to explore whether genetic polymorphisms in the gene encoding ceruloplasmin are associated with elevated ceruloplasmin levels, and whether such genetic polymorphisms are also associated with the incidence of AF., Design: Genetic polymorphisms in the ceruloplasmin gene (CP) were genotyped in a population-based cohort study of men from southern Sweden (Malmö Preventive Project; n = 3900). Genetic polymorphisms associated with plasma ceruloplasmin concentration were also investigated for association with incident AF (n = 520) during a mean follow-up of 29 years in the same cohort. Findings were replicated in an independent case-control sample (The Malmö AF cohort; n = 2247 cases, 2208 controls)., Results: A single nucleotide polymorphism (rs11708215, minor allele frequency 0.12) located in the CP gene promoter was strongly associated with increased levels of plasma ceruloplasmin (P = 9 × 10(-10) ) and with AF in both the discovery cohort [hazard ratio 1.24 per risk allele, 95% confidence interval (CI) 1.06-1.44, P = 0.006] and the replication cohort (odds ratio 1.13, 95% CI 1.02-1.26, P = 0.02)., Conclusions: Our findings indicate a causal role of ceruloplasmin in AF pathophysiology and suggest that ceruloplasmin might be a mediator in a specific inflammatory pathway that causally links inflammatory diseases and incidence of AF., (© 2013 The Association for the Publication of the Journal of Internal Medicine.)

Aims: Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors., Methods and Results: A total of 24,944 middle-aged subjects (62% females) from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309), ischemic stroke (N = 1253) and CVD-mortality (N = 1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035) and CVD-mortality (P = 0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N = 9642) for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001) and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000) for both CAD (HR = 1.05; 95%CI 0.95-1.16; P = 0.326) and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574., Conclusion: Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.

Objective: The S100 alarmins A8, A9, and A8/A9, secreted by activated neutrophils and monocytes/macrophages, are involved in the pathogenesis of various inflammatory diseases. S100A8/A9 has previously been linked to atherogenesis and cardiovascular (CV) disease. We investigated whether S100A8, A9, and A8/A9 correlate with carotid artery disease and CV risk in apparently healthy individuals., Approach and Results: We measured baseline S100A8, A9, and A8/A9 in 664 individuals aged 63 to 68 years, with no previous history of CV disease, randomly selected from the Malmö Diet and Cancer population cohort. We examined the correlations between S100 proteins and circulating cell populations, plasma cytokines, carotid artery disease, and incidence of CV events during a median follow-up period of 16.2 years. We found that plasma S100A8/A9 concentration is positively influenced by circulating neutrophil numbers, smoking, body mass index, glycosylated hemoglobin A1c, and low-density lipoprotein. High-density lipoprotein was negatively associated with S100A8/A9. S100A8/A9 and the neutrophil counts were positively correlated with intima-media area in the common carotid artery, independently of age, sex, and CV risk factors. S100A8/A9 and circulating neutrophils presented similar associations with the incidence of coronary events (hazard ratio [95% confidence interval] per 1 SD: 1.28 [1.03-1.59] and 1.26 [1.04-1.53], respectively) and CV death (1.34 [1.06-1.71] and 1.59 [1.33-1.90], respectively). These relationships were mainly supported by strong associations in women, which were independent of traditional risk factors. There were no independent relationships between S100A8 and S100A9, and CV disease., Conclusions: Our study supports the value of S100A8/A9 as a potentially important link between neutrophils, traditional CV risk factors, and CV disease.

Aims: Atrial fibrillation (AF) is a frequent co-morbidity in heart failure (HF) associated with increased mortality, but little is known about the mechanisms underlying AF onset in HF patients. We evaluated the association of cardiovascular and genetic risk factors with AF in HF patients., Methods and Results: Individuals hospitalized for HF (n = 1040; 500 with AF) were identified from a large, population-based cohort study (n = 30 447; 2339 with AF). Genetic polymorphisms in the chromosomal regions 4q25 (rs2200733) and 16q22 (rs2106261) associated with AF in genome-wide association studies were genotyped. Association of cardiovascular risk factors and polymorphisms with AF was tested in HF patients and the entire cohort using both prospective and non-time-dependent models. Cardiovascular risk factors-hypertension, body mass index, sex, smoking, diabetes, and myocardial infarction-were associated with AF in the entire cohort but not in HF patients. In contrast, polymorphisms on chromosomes 16q22 and 4q25 were associated with AF both in the entire cohort and in HF patients, conferring 75% [95% confidence interval (CI) 35-126, P = 2 × 10(-5)] and 57% (95% CI 18-109, P = 0.002) increased risk of AF per copy in HF patients, respectively. In the entire cohort, AF risk in the presence of HF was multiplicatively magnified by genotype for 16q22 (P for interaction = 7 × 10(-4)) but not 4q25 (P = 0.83). In prospective analyses excluding patients with AF diagnosis prior to or simultaneously with HF diagnosis, 16q22 but not 4q25 remained robustly associated with AF (hazard ratio 1.96, 95% CI 1.40-2.73, P = 8 × 10(-5)). The proportion of AF diagnoses in HF patients attributable to polymorphisms was 19% and 12%, respectively., Conclusions: A polymorphism in the ZFHX3 gene, encoding a cardiac transcription factor, was associated with increased AF risk in HF patients, and the genetic association with AF was more pronounced in HF patients than in the general population.

Objective: To examine how different scoring models for a diet quality index influence associations with mortality outcomes., Design: A study within the Malmö Diet and Cancer cohort. Food and nutrient intakes were estimated using a diet history method. The index included six components: SFA, PUFA, fish and shellfish, fibre, fruit and vegetables, and sucrose. Component scores were assigned using predefined (based on dietary recommendations) and population-based cut-offs (based on median or quintile intakes). Multivariate Cox regression was used to model associations between index scores (low, medium, high) and all-cause and cause-specific mortality by sex., Setting: Malmö, the third largest city in Sweden., Subjects: Men (n 6940) and women (n 10,186) aged 44-73 years. During a mean follow-up of 14.2 years, 2450 deaths occurred, 1221 from cancer and 709 from CVD., Results: The predictive capability of the index for mortality outcomes varied with type of scoring model and by sex. Stronger associations were seen among men using predefined cut-offs. In contrast, the quintile-based scoring model showed greater predictability for mortality outcomes among women. The scoring model using median-based cut-offs showed low predictability for mortality among both men and women., Conclusions: The scoring model used for dietary indices may have a significant impact on observed associations with disease outcomes. The rationale for selection of scoring model should be included in studies investigating the association between dietary indices and disease. Adherence to the current dietary recommendations was in the present study associated with decreased risk of all-cause and cause-specific mortality, particularly among men.

Recent Genome-Wide Association Studies (GWAS) have pinpointed different single nucleotide polymorphisms consistently associated with blood pressure (BP) and hypertension prevalence. However, little data exist regarding single nucleotide polymorphisms predicting BP variation over time and hypertension incidence. The aim of this study was to confirm the association of a genetic risk score (GRS), based on 29 independent single nucleotide polymorphisms, with cross-sectional BP and hypertension prevalence and to challenge its prediction of BP change over time and hypertension incidence in >17 000 middle-aged Swedes participating in a prospective study, the Malmö Preventive Project, investigated at baseline and over a 23-year average period of follow-up. The GRS was associated with higher systolic and diastolic BP values both at baseline (β ± SEM, 0.968 ± 0.102 mm Hg and 0.585 ± 0.064 mm Hg; P<1E-19 for both) and at reinvestigation (β ± SEM, 1.333 ± 0.161 mm Hg and 0.724 ± 0.086 mm Hg; P<1E-15 for both) and with increased hypertension prevalence (odds ratio [95% CI], 1.192 [1.140-1.245] and 1.144 [1.107-1.183]; P<1E-15 for both). The GRS was positively associated with change (Δ) in BP (β ± SEM, 0.033 ± 0.008 mm Hg/y and 0.023 ± 0.004 mm Hg/y; P<1E-04 for both) and hypertension incidence (odds ratio [95% CI], 1.110 [1.065-1.156]; P=6.7 E-07), independently from traditional risk factors. The relative weight of the GRS was lower in magnitude than obesity or prehypertension, but comparable with diabetes mellitus or a positive family history of hypertension. A C-statistics analysis does not show any improvement in the prediction of incident hypertension on top of traditional risk factors. Our data from a large cohort study show that a GRS is independently associated with BP increase and incidence of hypertension.

Background and Aims: Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of red-ox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events., Methods and Results: The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmö Diet and Cancer" (MDC-CVA) study and successively in 17874 participants of the "Malmö Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP. Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females. However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in the MDC-CVA was not significantly different in carriers of different genotypes., Conclusions: Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Context: Neurotensin regulates both satiety and breast cancer growth in the experimental setting, but little is known about its role in the development of breast cancer or cardiometabolic disease in humans., Objective: To test if fasting plasma concentration of a stable 117-amino acid fragment from the neurotensin precursor hormone proneurotensin is associated with development of diabetes mellitus, cardiovascular disease, breast cancer, and mortality., Design, Setting, and Participants: Proneurotensin was measured in plasma from 4632 fasting participants of the population-based Malmö Diet and Cancer Study baseline examination 1991-1994. Multivariate Cox proportional hazards models were used to relate baseline proneurotensin to first events and death during long-term follow-up until January 2009, with median follow-up ranging from 13.2 to 15.7 years depending on the disease., Main Outcome Measures: Incident diabetes mellitus, cardiovascular disease, breast cancer, and mortality., Results: Overall, proneurotensin (hazard ratio [HR] per SD increment of log-transformed proneurotensin) was related to risk of incident diabetes (142 events; HR, 1.28; 95% CI, 1.09-1.50; P = .003), cardiovascular disease (519 events; HR, 1.17; 95% CI, 1.07-1.27; P < .001), and cardiovascular mortality (174 events; HR, 1.29; 95% CI, 1.12-1.49; P = .001) with a significant interaction between proneurotensin and sex (P < .001) on risk of cardiovascular disease. Exclusively in women, proneurotensin was related to incident diabetes (74 events; HR, 1.41; 95% CI, 1.12-1.77; P = .003), cardiovascular disease (224 events; HR, 1.33; 95% CI, 1.17-1.51; P < .001), breast cancer (123 events; HR, 1.44; 95% CI, 1.21-1.71; P < .001), total mortality (285 events; HR, 1.13; 95% CI, 1.01-1.27; P = .03), and cardiovascular mortality (75 events; HR, 1.50; 95% CI, 1.20-1.87; P < .001)., Conclusion: Fasting proneurotensin was significantly associated with the development of diabetes, cardiovascular disease, breast cancer, and with total and cardiovascular mortality.

The use of snus (also referred to as Scandinavian or Swedish moist smokeless tobacco), which is common in Sweden and increasing elsewhere, is receiving increasing attention since considered a tobacco smoke "potential reduction exposure product". Snus delivers a high dose of nicotine with possible hemodynamic effects, but its impact on cardiovascular morbidity and mortality is uncertain. The aim of this study was to investigate whether snus use is associated with risk of and survival after acute myocardial infarction (AMI). Data from eight prospective cohort studies set in Sweden was pooled and reanalysed. The relative risk of first time AMI and 28-day case-fatality was calculated for 130,361 men who never smoked. During 2,262,333 person-years of follow-up, 3,390 incident events of AMI were identified. Current snus use was not associated with risk of AMI (pooled multivariable hazard ratio 1.04, 95 % confidence interval 0.93 to 1.17). The short-term case fatality rate appeared increased in snus users (odds ratio 1.28, 95 % confidence interval 0.99 to 1.68). This study does not support any association between use of snus and development of AMI. Hence, toxic components other than nicotine appear implicated in the pathophysiology of smoking related ischemic heart disease. Case fatality after AMI is seemingly increased among snus users, but this relationship may be due to confounding by socioeconomic or life style factors.

Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmö Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants <55 years of age, as well as the TOAST subgroups large vessel disease, small vessel disease and cardioembolism, were also assessed. Univariate odds ratios (ORs) and ORs controlling for hypertension, diabetes and current smoking were calculated. We additionally performed a meta-analysis including 10,500 patients and 10,102 control subjects from 17 publications (including the present study). When assessing pooled data from LSR, MDC and SAHLSIS we obtained no association between IS and rs12188950 for all participants (OR=0.93; 95% confidence interval (CI): 0.83-1.05). Significant associations were not found for hypertensive participants or participants with age <55, or when separately evaluating patients from the three different TOAST subgroups. The meta-analysis showed no significant overall estimate (OR=0.96; 95% CI: 0.89-1.04) with significant heterogeneity for random effect (P=0.042). No effect from rs12188950 on IS was found from either our pooled multi-centre data or the performed meta-analysis. We did not find any association between the examined subgroups and rs12188950 either.