Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort.

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid ß-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

Very short sleep duration reveals a proteomic fingerprint that is selectively associated with incident diabetes mellitus but not with incident coronary heart disease: a cohort study.

BACKGROUND: The molecular pathways linking short and long sleep duration with incident diabetes mellitus (iDM) and incident coronary heart disease (iCHD) are not known. We aimed to identify circulating protein patterns associated with sleep duration and test their impact on incident cardiometabolic disease. METHODS: We assessed sleep duration and measured 78 plasma proteins among 3336 participants aged 46-68 years, free from DM and CHD at baseline, and identified cases of iDM and iCHD using national registers. Incident events occurring in the first 3 years of follow-up were excluded from analyses. Tenfold cross-fit partialing-out lasso logistic regression adjusted for age and sex was used to identify proteins that significantly predicted sleep duration quintiles when compared with the referent quintile 3 (Q3). Predictive proteins were weighted and combined into proteomic scores (PS) for sleep duration Q1, Q2, Q4, and Q5. Combinations of PS were included in a linear regression model to identify the best predictors of habitual sleep duration. Cox proportional hazards regression models with sleep duration quintiles and sleep-predictive PS as the main exposures were related to iDM and iCHD after adjustment for known covariates. RESULTS: Sixteen unique proteomic markers, predominantly reflecting inflammation and apoptosis, predicted sleep duration quintiles. The combination of PSQ1 and PSQ5 best predicted sleep duration. Mean follow-up times for iDM (n = 522) and iCHD (n = 411) were 21.8 and 22.4 years, respectively. Compared with sleep duration Q3, all sleep duration quintiles were positively and significantly associated with iDM. Only sleep duration Q1 was positively and significantly associated with iCHD. Inclusion of PSQ1 and PSQ5 abrogated the association between sleep duration Q1 and iDM. Moreover, PSQ1 was significantly associated with iDM (HR = 1.27, 95% CI: 1.06-1.53). PSQ1 and PSQ5 were not associated with iCHD and did not markedly attenuate the association between sleep duration Q1 with iCHD. CONCLUSIONS: We here identify plasma proteomic fingerprints of sleep duration and suggest that PSQ1 could explain the association between very short sleep duration and incident DM.

Diagnostic reliability of monitoring for premature atrial and ventricular complexes.

AIMS: Short-term ambulatory electrocardiogram (ECG) monitoring is often used to assess premature atrial complex (PAC) and premature ventricular complex (PVC) frequency, but the diagnostic reliability is unknown. The objective of this study was to study the day-to-day variability of PAC and PVC frequency. METHODS AND RESULTS: We used 14-day full-disclosure mobile cardiac telemetry recordings without atrial fibrillation in 8245 US patients aged 17-103 years to calculate the diagnostic reliability of shorter ambulatory ECG recordings compared with 14-day averages. Over 14 days, 1853 patients had ≥500 PACs/day, 410 patients had ≥5000 PACs/day, and 197 patients had ≥10 000 PACs/day; 1640 patients had ≥500 PVCs/day, 354 patients had ≥5000 PVCs/day, and 175 patients had ≥10 000 PVCs/day. After 3 days, the estimated daily PAC frequency differed by ≥50% from the 14-day mean in 25% of patients; for PVCs, the corresponding duration was 7 days. Ten days of monitoring were needed to estimate PAC and PVC frequency within ±20% of the overall 14-day frequency in 80% of patients. For daily PAC and PVC frequencies ≥10 000, single-day estimation had a specificity of 99.3% [95% confidence interval (CI) 99.1-99.5] at a sensitivity of 76.6 (95% CI 70.1-80.4%) for PACs and a 99.6% (95% CI 99.4-99.7%) specificity at 79.4 (95% CI 72.7-85.2) sensitivity for PVCs. After 7 days, the sensitivity increased to 88.8% (95% CI 83.6-92.9) for PACs and 86.9% (95% CI 80.9-91.5%) for PVCs. CONCLUSION: While there is substantial daily variability across most PAC and PVC levels, findings of ≥10 000 PACs or PVCs are highly specific and do not need to be confirmed with longer recordings.

Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Dietary amino acids and risk of stroke subtypes: a prospective analysis of 356,000 participants in seven European countries.

PURPOSE: Previously reported associations of protein-rich foods with stroke subtypes have prompted interest in the assessment of individual amino acids. We examined the associations of dietary amino acids with risks of ischaemic and haemorrhagic stroke in the EPIC study. METHODS: We analysed data from 356,142 participants from seven European countries. Dietary intakes of 19 individual amino acids were assessed using validated country-specific dietary questionnaires, calibrated using additional 24-h dietary recalls. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of ischaemic and haemorrhagic stroke in relation to the intake of each amino acid. The role of blood pressure as a potential mechanism was assessed in 267,642 (75%) participants. RESULTS: After a median follow-up of 12.9 years, 4295 participants had an ischaemic stroke and 1375 participants had a haemorrhagic stroke. After correction for multiple testing, a higher intake of proline (as a percent of total protein) was associated with a 12% lower risk of ischaemic stroke (HR per 1 SD higher intake 0.88; 95% CI 0.82, 0.94). The association persisted after mutual adjustment for all other amino acids, systolic and diastolic blood pressure. The inverse associations of isoleucine, leucine, valine, phenylalanine, threonine, tryptophan, glutamic acid, serine and tyrosine with ischaemic stroke were each attenuated with adjustment for proline intake. For haemorrhagic stroke, no statistically significant associations were observed in the continuous analyses after correcting for multiple testing. CONCLUSION: Higher proline intake may be associated with a lower risk of ischaemic stroke, independent of other dietary amino acids and blood pressure.

Kidney function, uric acid, and risk of atrial fibrillation: experience from the AMORIS cohort.

BACKGROUND: Uric acid closely relates to both kidney disease and atrial fibrillation (AF), yet the extent to which it influences the kidney-AF association remains uncertain. We examined the relationship between kidney function and risk of AF, accounting for uric acid levels. METHODS: A total of 308,509 individuals in the Swedish Apolipoprotein-Related Mortality Risk (AMORIS) cohort were included and their serum creatinine and uric acid were measured during 1985-1996. Ten-year incident AF was identified via linkage with the national registers. Glomerular filtration rate (eGFR) (ml/min/1.73 m2) was calculated with the 2009 Chronic Kidney Disease Epidemiology Collaboration equation. Hyperuricemia was defined as > 420 µmol/L for men and > 360 µmol/L for women. RESULTS: Over a mean follow-up of 9.4 years, 10,007 (3.2%) incident AF cases occurred. After adjusting for age, sex, cardiovascular diseases, total cholesterol, triglycerides, and glucose, individuals with low eGFR (< 30 and 30-59 ml/min/1.73 m2 ) had a higher risk of AF compared to those with normal eGFR (60-89) (hazard ratio (HR) = 1.72, 95% confidence interval (CI):1.29-2.30; HR = 1.10, 95% CI: 1.03-1.18, respectively). After further adjusting for uric acid levels, the association disappeared (HR = 0.97, 95% CI: 0.72-1.30; HR = 0.93, 95% CI: 0.86-1.00, respectively). When stratifying by hyperuricemia yes/no, eGFR < 30 ml/min/1.73 m2 was associated with higher AF risk in a small group of individuals without hyperuricemia (HR = 2.58, 95% CI: 1.64-4.07). CONCLUSION: Uric acid largely accounted for the relationship between eGFR and AF in this study. However, in individuals without hyperuricemia, eGFR in the lowest range (< 30 ml/min/1.73 m2) was still associated with increased risk of AF.

Associations between physical activity and ankle-brachial index: the Swedish CArdioPulmonary bioImage Study (SCAPIS).

BACKGROUND: The ankle-brachial index (ABI) is the ratio of the ankle and brachial systolic blood pressures. In the clinical setting, low ABI (< 0.9) is an indicator of peripheral atherosclerosis, while high ABI (> 1.4) is a sign of arterial stiffness and calcification. The purpose of the current study was to investigate the association between ABI and physical activity levels, measured by accelerometer. METHODS: The Swedish CArdioPulmonary bioImage Study (SCAPIS) is a Swedish nationwide population-based cross-sectional cohort for the study of cardiovascular and pulmonary diseases, in which individuals aged 50-64 years were randomly invited from the general population. The study population with data on ABI, physical activity, and sedentary time based on accelerometry was 27,737. Differences between ABI categories and associations to sedentary behavior, moderate to vigorous physical activity (MVPA), and other metabolic characteristics were compared. ABI was categorized as low, ABI ≤ 0.9, borderline, ABI 0.91-0.99, normal, ABI 1.0-1.39, and high, ABI ≥ 1.4. RESULTS: Prevalence of low ABI was higher in the most sedentary quartiles compared to the least sedentary (0.6% vs. 0.1%, p < 0.001). The most sedentary individuals also exhibited higher BMI, higher prevalence of diabetes and hypertension. The proportion of wake time spent in MVPA was lowest in those with low ABI (0.033 ± 0.004; p < 0.001) and highest in those with ABI > 1.4 (0.069 ± 0.001; p < 0.001) compared to those with normal ABI. Compared to normal ABI, the proportion of sedentary time was highest in those with low ABI (0.597 ± 0.012; p < 0.001) and lowest in those with ABI > 1.4 (0.534 ± 0.002; p = 0.004). CONCLUSION: This population-based study shows that middle-aged individuals with ABI > 1.4 have the highest level of physical activity, while individuals with a lower ABI, especially those with ABI < 0.9, are less active and spend more time sedentary. Future studies are needed to understand the relationships between ABI, physical activity, and the risk of peripheral arterial and cardiovascular disease in the general population.

Low-level exposure to lead and atherosclerosis in the carotid arteries: Results from the Swedish population-based cohort SCAPIS.

BACKGROUND: Lead exposure is associated with cardiovascular disease. Atherosclerosis has been hypothesized to be one of the underlying mechanisms behind this association. AIM: To investigate whether lead exposure is associated with an increased risk of atherosclerosis in the carotid arteries in a large Swedish population-based cohort. METHODS: We performed a cross-sectional study using data from the population-based Swedish CardioPulmonary bioImage Study (SCAPIS), including 5622 middle-aged men and women, enrolled 2013-2018. Blood lead (B-Pb), measured by inductively coupled plasma mass spectrometry, was used as exposure biomarker. The presence of atherosclerotic plaque in the carotid arteries (yes/no), total plaque area (mm2) and the presence of large plaques (>25 mm2) were determined by ultrasonography. Associations between B-Pb and the different outcomes were analysed using Poisson and linear regression models, adjusted for potential confounders. RESULTS: Atherosclerotic plaque was present in 57% of the individuals, for whom the median total plaque area was 16 mm2 (range: 0.2-222). The median B-Pb concentration was 14 µg/L (range: 0.75-203). After adjusting for potential confounders, individuals in the fourth quartile of B-Pb (Q4) had a prevalence ratio (PR) for plaque of 1.08 (95% CI: 1.01, 1.16) when compared with the first quartile (Q1). A 10 µg/L increase in B-Pb concentrations was associated with an increase of 0.92 mm2 (95% CI: 0.14, 1.71) in total plaque area. The PR for large plaque was 1.09 (95% CI: 0.84, 1.42 for Q4 vs Q1). CONCLUSIONS: This study shows an association between B-Pb and atherosclerosis in the carotid arteries providing some support for the hypothesis that atherosclerosis is one of the mechanisms underlying the association between lead exposure and cardiovascular disease.

Periodontitis is associated with airflow obstruction in the Malmö Offspring Dental Study.

AIM: To investigate the association between periodontitis and lung function in the Malmö Offspring Dental Study. MATERIALS AND METHODS: In all 1001 individuals (49.9% female, mean age: 44.6) from Malmö Offspring Dental Study were included. Periodontitis was assessed by a full-mouth examination protocol including bleeding on probing and classified according to the American Academy of Periodontology/Center for Disease Control definitions. Forced expiratory volume in 1 s (FEV1 ) and forced vital capacity (FVC) were expressed as absolute values and %predicted according to Global Lung Function Initiative reference values. FEV1 , FVC and FEV1 /FVC were analysed in relation to periodontal status using linear regression. RESULTS: Severe periodontitis was found in 7% of the population. Adjusted regression models showed significant associations between lung function and severe periodontitis with 2.1 unit lower FEV1 /FVC ratio (95% CI: -3.91, -0.23) and odds ratio (adjusted) of 2.56 (95% CI: 1.40, 4.75, p = .003) for airflow obstruction (FEV1 /FVC less than the lower limit of normal) if having severe periodontitis. Lower values of %predicted FEV1 and %predicted FVC, but not FEV1 /FVC, were found in individuals with >25% bleeding on probing. CONCLUSIONS: Severe periodontitis was associated with lower FEV1 /FVC ratio and airflow obstruction in the present cohort. More large-scale prospective studies and intervention studies are required for a comprehensive evaluation.

Elevated circulating follistatin associates with increased risk of mortality and cardiometabolic disorders.

BACKGROUND AND AIMS: Previous study showed that elevated circulating hepatokine follistatin (FST) associates with an increased risk of type 2 diabetes by inducing adipose tissue insulin resistance. Here we explore further the relationships between plasma FST levels with mortality and health outcomes. METHODS AND RESULTS: The population-based Malmö Diet Cancer cardiovascular cohort (n = 4733, age 45-68 years) was used to study plasma FST in relation to incidence of health outcomes, by linkage with national patient registers. Cox regression analysis was used to assess the associations of plasma FST and outcomes, with adjustments for multiple potential confounding factors. During the mean follow-up time of 22.64 ± 5.84 years in 4,733 individuals, 526 had incident stroke, 432 had ischemic stroke, 530 had incident coronary events (CE), 339 had incident heart failure (HF), 320 had incident chronic kidney disease (CKD) and 1,843 individuals died. Hazard ratio (HR) per standard deviation increase in FST levels adjusted for multiple risk factors was 1.05 (95%CI: 1.00-1.11, p = 0.036) for mortality; 1.10 (95%CI: 1.00-1.20, p = 0.042) for stroke; 1.13 (95%CI: 1.03-1.25, p = 0.014) for ischemic stroke; 1.16 (95%CI: 1.03-1.30, p = 0.015) for HF; and 1.38 (95%CI: 1.12-1.70, p = 0.003) for a diagnosis of CKD. In MDC-CC individuals without prevalent or incident diabetes, the association between FST and stroke, CE and CKD remained significant; but not with mortality or HF. CONCLUSIONS: Elevated circulating FST associates with an increased risk of mortality and HF, which partly may be mediated by diabetes. FST also associated with stroke, ischemic stroke, CE and CKD, independently of established risk factors including diabetes.

Association between changed self-rated health and the risk of venous thromboembolism in Malmö Preventive Program: a cohort study.

Poor self-rated health (SRH) is associated with incident arterial cardiovascular disease in both sexes. Studies on the association between SRH and incident venous thromboembolism (VTE) show divergent results in women and no association in men. This study focuses on the association between change in SRH and incident VTE in a cohort of 11,558 men and 6682 women who underwent a baseline examination and assessment of SRH between 1974 and 1992 and a re-examination in 2002-2006. To investigate if changes in SRH over time affect the risk of incident VTE in men and women. During a follow-up time from the re-examination of more than 16 years, there was a lower risk for incident VTE among women if SRH changed from poor at baseline to very good/excellent (HR 0.46, 95% CI 0.28; 0.74) at the re-examination. Stable good SRH (good to very good/excellent at the re-examination, HR 0.60, 95% CI 0.42; 0.89), or change from good SRH at baseline into poor/fair at the re-examination (HR 0.68, 95% CI 0.51; 0.90) were all significantly associated with a reduced risk for VTE. All comparisons were done with the group with stable poor SRH. This pattern was not found among men. Regardless of a decreased or increased SRH during life, having an SRH of very good/excellent at any time point seems to be associated with a decreased risk of VTE among women.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.

BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Genetic Susceptibility to Mood Disorders and Risk of Stroke: A Polygenic Risk Score and Mendelian Randomization Study.

BACKGROUND: Mood disorders and strokes are often comorbid, and their health toll worldwide is huge. This study characterizes prognostic and causal roles of mood disorders in stroke. METHODS: We tested if genetic susceptibilities for mood disorders were associated with all strokes, ischemic strokes in the Malmö Diet and Cancer cohort (24 631 individuals with a median follow-up of 21.3 (interquartile range: 16.6-23.2) years. We further examined the causal effects for mood disorders on all strokes and ischemic strokes using summary statistics from large genome-wide association studies of mood disorders (up to 609 424 individuals, Psychiatric Genomics Consortium), all strokes and ischemic strokes (up to 446 696 individuals, MEGASTROKE Consortium). RESULTS: Among 24 366 stroke-free participants at baseline, 2632 individuals developed strokes, 2172 of them ischemic, during follow-up. After properly adjusting for well-known risk factors, participants in the highest quintile of polygenic risk scores for mood disorders had 1.45× (95% CI, 1.21-1.74) higher risk of strokes and 1.44× (95% CI, 1.18-1.76) higher risk of ischemic strokes compared with the lowest quintile in women. Mendelian randomization analyses suggested that mood disorders had a causal effect on strokes (odds ratio, 1.07 [95% CI, 1.03-1.11]) and ischemic strokes (odds ratio, 1.09 [95% CI, 1.04-1.13]). CONCLUSIONS: Our results suggest a causal role of mood disorders in the risk of stroke. High-risk women could be identified early in life using polygenic risk scores to ultimately prevent mood disorders and strokes.

Prevalence of atherosclerosis in individuals with prediabetes and diabetes compared to normoglycaemic individuals-a Swedish population-based study.

BACKGROUND: Patients with type 2 diabetes have an increased risk of death and cardiovascular events and people with diabetes or prediabetes have been found to have increased atherosclerotic burden in the coronary and carotid arteries. This study will estimate the cross-sectional prevalence of atherosclerosis in the coronary and carotid arteries in individuals with prediabetes and diabetes, compared with normoglycaemic individuals in a large population-based cohort. METHODS: The 30,154 study participants, 50-64 years, were categorized according to their fasting glycaemic status or self-reported data as normoglycaemic, prediabetes, and previously undetected or known diabetes. Prevalence of affected coronary artery segments, severity of stenosis and coronary artery calcium score (CACS) were determined by coronary computed tomography angiography. Total atherosclerotic burden was assessed in the 11 clinically most relevant segments using the Segment Involvement Score and as the presence of any coronary atherosclerosis. The presence of atherosclerotic plaque in the carotid arteries was determined by ultrasound examination. RESULTS: Study participants with prediabetes (n = 4804, 16.0%) or diabetes (n = 2282, 7.6%) had greater coronary artery plaque burden, more coronary stenosis and higher CACS than normoglycaemic participants (all, p < 0.01). Among male participants with diabetes 35.3% had CACS ≥ 100 compared to 16.1% among normoglycaemic participants. For women, the corresponding figures were 8.9% vs 6.1%. The prevalence of atherosclerosis in the coronary arteries was higher in participants with previously undetected diabetes than prediabetes, but lower than in patients with known diabetes. The prevalence of any plaque in the carotid arteries was higher in participants with prediabetes or diabetes than in normoglycaemic participants. CONCLUSIONS: In this large population-based cohort of currently asymptomatic people, the atherosclerotic burden in the coronary and carotid arteries increased with increasing degree of dysglycaemia. The finding that the atherosclerotic burden in the coronary arteries in the undetected diabetes category was midway between the prediabetes category and patients with known diabetes may have implications for screening strategies and tailored prevention interventions for people with dysglycaemia in the future.

Arterial stiffness and subclinical atherosclerosis in the coronary arteries at different stages of dysglycaemia.

AIM: Our aim was to investigate in a large population-based cohort study whether increased arterial stiffness and subclinical atherosclerosis in the coronary arteries differ at different stages of dysglycaemia. METHODS: Data were obtained from SCAPIS, a population-based cohort of participants 50-64 years. The study population of 9379 participants was categorised according to glycaemic status: normoglycaemic, pre-diabetes (fasting glucose: 6.1-6.9 mmol/L and/or HbA1c 6%-6.4%) and diabetes. Pulse wave velocity (PWV) was measured by the SphygmoCor XCEL system and arterial stiffness was defined by PWV ≥10 m/s. Coronary artery calcium score (CACS) was assessed by coronary computed tomography and coronary artery calcification was defined by CACS ≥100. RESULTS: We identified 1964 (21%) participants with dysglycaemia, out of which 742 (7.9%) had diabetes mellitus. PWV ≥10 m/s was present in 808 (11%), 191 (16%), 200 (27%) and CACS ≥100 in 801 (11%), 190 (16%), 191 (28%) participants with normoglycaemia, pre-diabetes and diabetes, respectively, all, p < 0.001. The overlap between PWV ≥10 m/s and CACS ≥100 within each glycaemic category was 188 (2.5%), 44 (3.6%) and 77 (10) respectively. There was an association between glycaemic status and increased PWV in the fully adjusted models, but not for glycaemic status and CACS ≥100, where there was no difference for pre-diabetes compared to normoglycaemia, OR 1.2 (95% CI 0.98-1.4). In the total study population, there was an association between HbA1c and PWV after adjustment, p < 0.001. CONCLUSIONS: Our results show that increased arterial stiffness and subclinical coronary artery atherosclerosis are present in the early stages of dysglycaemia, but the overlap between markers of major subclinical vascular damage was small in all glycaemic categories. This could be explained by different pathways in the pathogenesis of arterial stiffness or atherosclerosis in the coronary arteries.

Milk intake, lactase persistence genotype, plasma proteins and risks of cardiovascular events in the Swedish general population.

To investigate the associations of milk intake (non-fermented and fermented milk), lactase persistence (LCT-13910 C/T) genotype (a proxy for long-term non-fermented milk intake), and gene-milk interaction with risks of cardiovascular disease (CVD) and CVD mortality. Also, to identify the CVD-related plasma proteins and lipoprotein subfractions associated with milk intake and LCT-13910 C/T genotype. The prospective cohort study included 20,499 participants who were followed up for a mean of 21 years. Dietary intake was assessed using a modified diet history method. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After adjusting for sociodemographic and lifestyle factors, higher non-fermented milk intake was significantly associated with higher risks of coronary heart disease (CHD) and CVD mortality, whereas higher fermented milk intake was significantly associated with lower risks of CVD and CVD mortality. The genotype associated with higher milk (mainly non-fermented) intake was positively associated with CHD (CT/TT vs. CC HR = 1.27; 95% CI: 1.03, 1.55) and CVD (HR = 1.22; 95% CI: 1.05, 1.42). The association between rs4988235 genotype and CVD mortality was stronger in participants with higher milk intake than among participants with lower intake (P for interaction < 0.05). Furthermore, leptin, HDL, and large HDL were associated with non-fermented milk intake, while no plasma proteins or lipoprotein subfractions associated with fermented milk intake and LCT-13910 C/T genotype were identified. In conclusion, non-fermented milk intake was associated with higher risks of CHD and CVD mortality, as well as leptin and HDL, whereas fermented milk intake was associated with lower risks of CVD and CVD mortality.

Orthostatic blood pressure adaptations, aortic stiffness, and central hemodynamics in the general population: insights from the Malmö Offspring Study (MOS).

PURPOSE: Arterial stiffness is independently associated with orthostatic hypotension in older individuals. The relationship between orthostatic blood pressure adaptation and aortic stiffness has not been thoroughly examined in a younger population. We investigated the relationship between orthostatic blood pressure adaptations, central aortic hemodynamics, and aortic stiffness in a cohort of predominantly younger and middle-aged adults. METHODS: We analyzed an observational, population-based study of 5259 individuals living in Malmö, Sweden. We related aortic stiffness and central hemodynamics assessed by carotid-femoral pulse wave velocity and pulse wave analysis at the arteria radialis using Sphygmocor to orthostatic blood pressure adaptation after 3 min standing. RESULTS: The mean age of the population was 41.9 ± 14.5 years, and 52.1% were women. We observed the highest aortic stiffness and central aortic blood pressure measurements in the lowest and highest quartiles of orthostatic systolic blood pressure differences (p < 0.001). Aortic stiffness and central aortic blood pressure gradually decreased across increasing quartiles of orthostatic diastolic blood pressure difference (p < 0.001). After full adjustment, orthostatic diastolic blood pressure remained significantly associated with aortic stiffness (p = 0.001) and central aortic blood pressure (p < 0.001), whereas orthostatic systolic blood pressure was significantly associated only with central aortic systolic blood pressure (p = 0.009). No significant associations were found between subclinical orthostatic hypotension, aortic stiffness, and central hemodynamics. CONCLUSIONS: Our findings demonstrate that altered blood pressure responses to orthostatic challenges, both blood pressure reductions and blood pressure increases, are independently and inversely associated with markers of aortic stiffness (vascular aging) in a predominantly young to middle-aged population.

Associations between physical activity and autonomic function during deep breathing test: the Swedish CArdioPulmonary bioImage Study (SCAPIS).

PURPOSE: The deep breathing test (DBT) is a sensitive test of cardiovagal function. The aim of this study was to explore associations between physical activity and sedentary time, measured by accelerometer, and autonomic function, using DBT. METHODS: In the Swedish Cardio-Pulmonary bioImage Study, men and women aged 50-64 were randomly invited from the general population. A total of 4325 subjects who underwent DBT and assessment of physical activity and sedentary time by accelerometery were included. ECG files from 1-min DBT were used to calculate measures of respiratory sinus arrhythmia [RSA; expiration-inspiration (E-I) difference and E/I ratio], heart rate variability [HRV; root mean square of successive differences (RMSSD), standard deviation of heart rates and mean circular resultant]. Low RSA and HRV was defined as the lowest 10% in the population. RESULTS: For accelerometer-assessed physical activity, there were significant associations between high percentage of sedentary time and low E/I (p < 0.01), and low RMSSD (p < 0.01) in an age- and sex-adjusted model, and between percentage of sedentary time and low RMSSD (p = 0.04) in a risk factor-adjusted model. Low RMSSD was less common in those with a high percentage of moderate to vigorous physical activity (p = 0.04, after risk-factor adjustment). These associations became non-significant when further adjusting for heart rate. CONCLUSION: We report associations between degree of physical activity and indices of autonomic dysfunction in a large population. The relationships were no longer significant after adjustments for heart rate, indicating that the relationship between physical activity and cardiovagal function partly is accounted for by reduced heart rate.