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Background: Although physical activity is associated with cardiovascular health benefits and reduced all-cause mortality, vigorous exertion is also recognized as a trigger for sudden cardiac death (SCD). This study investigated vigorous exertion as a trigger for SCD resulting from myocardial infarction (MI) and the potential modifying effect of habitual vigorous exercise training among Swedish men who subsequently experienced SCD due to MI.

Methods: This prospective nested case-crossover study was performed within the Västerbotten Intervention Programme cohort from 1985 to 2006 and included male participants who later experienced SCD caused by MI. The risk of SCD during and within 30 min of vigorous exertion was compared with the risk during periods of non-exertion. Participants were categorized into three groups according to baseline frequency of habitual vigorous exercise training to assess effect modification.

Results: We included 192 men with SCD caused by MI, with a mean time from screening to event of 6.5 years. A majority of cases reported physical inactivity, with 161 cases reporting no exercise or <1 exercise event per week. 24 men suffered SCD in relation to vigorous exertion, yielding a relative risk of 43.6 (95% CI: 27.1-70.3) compared to non-exertion. The highest relative risk (107.7 [95% CI: 63.4-182.9]) was found among physically inactive men and was mitigated by a higher frequency of habitual exercise training at baseline.

Conclusion: Among Swedish men who experienced SCD caused by MI, vigorous exertion was associated with a transiently increased risk, which was mitigated by higher levels of habitual vigorous exercise training.

Background: Dyslipidaemia in patients with diabetes contributes to the risk of atherosclerotic cardiovascular disease. We aimed to identify a dyslipidemic profile associated with both dysglycemia and subclinical coronary atherosclerosis.

Methods: Study participants (n = 5050) were classified in three groups: normoglycemia, pre-diabetes, and diabetes. A coronary artery calcium score (CACS) > 0 defined subclinical coronary atherosclerosis. Two independent methods were used to identify, among 225 lipid biomarkers, those that were associated with pre-diabetes and diabetes and were further tested for association by zero inflated Poisson regression with CACS and with CACS burden in study participants with CACS>0. Estimates were adjusted for cardiovascular risk factors with an interaction term for dispensed lipid lowering drugs.

Results: Thirty-two biomarkers associated with prediabetes and diabetes were further investigated for association with CACS. HDL diameter [multi-adjusted OR of 0.85 and 95 %CI (0.78–0.92)] as well as free cholesterol, phospholipids and total lipids in extra large HDL were inversely associated with CACS. There was a borderline significant interaction between small HDL and dispensed lipid lowering drugs on the presence of CACS, with and multi-adjusted OR of 0.53 and 95 %CI (0.36–0.77). None of the 32 glycemic profile-related lipid biomarkers associated with the relative increase of CACS in those with CACS>0. No consistent association was observed between non-HDL lipoproteins and CACS.

Conclusions: Changes in composition and relative concentration of HDL associated with both dysglycemia and subclinical coronary atherosclerosis. Treatment with lipid lowering drugs may contribute to reduce the risk associated with high circulating levels of small HDL.

Aims: To investigate the association between dietary patterns at Ages 40, 50, and 60 and subclinical carotid atherosclerosis at Age 60.

Methods and results: Participants who were 60 years of age at the Swedish VIPVIZA (VisualiZation of asymptomatic Atherosclerotic disease) trial baseline (2013-16) with retrospective VIP (Västerbotten Intervention Programme) dietary data at Ages 40, 50, and 60 (n = 1034) were included. Dietary patterns were assessed using the Mediterranean diet score (MDS) and healthy diet score, while carotid ultrasound was used to measure carotid artery intima-media thickness (CIMT) and carotid plaque (CP). Multivariable regressions and mediation analysis investigated associations, sex differences and potential mediating factors. High [odds ratio (OR): 0.72, 95% confidence interval (CI): 0.52-0.98] or midrange (OR: 0.74, 95% CI: 0.55-0.99) cumulative MDS for Ages 40, 50, and 60, as compared with low, was associated with lower CP presence at Age 60. Initial sex-stratified analysis yielded similar, though non-significant, point estimates. Further analysis revealed that the relationship between plaque and MDS seem driven more by women (OR: 0.41, 95% CI: 0.237-0.703) while a significant association between CIMT and MDS was only present in men (P < 0.05). Healthy diet score during midlife did not show any significant associations with CP or CIMT at Age 60.

Conclusion: Findings underscore associations of midlife Mediterranean-style diet and lower presence of subclinical carotid atherosclerosis at Age 60 and confirm the significance of dietary interventions as potential means for cardiovascular disease prevention. The study enhances understanding of long-term dietary patterns and their link to subclinical atherosclerosis, supporting future interventions and further research.Keywords: Carotid intima media thickness; Carotid plaque; Dietary patterns; Healthy diet score; Mediterranean diet score; Subclinical atherosclerosis.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) within sub-Saharan Africa (SSA) is increasing. Despite the pathophysiology of T2D differing by ethnicity and sex, risk stratification and guidelines for the prevention of T2D are generic, relying on evidence from studies including predominantly Europeans. Accordingly, this study aims to develop ethnic-specific and sex-specific risk prediction models for the early detection of dysglycaemia (impaired glucose tolerance and T2D) to inform clinically feasible, culturally acceptable and cost-effective risk management and prevention strategies using dietary modification in SSA and European populations.

METHODS AND ANALYSIS: This multinational collaboration will include the prospective cohort data from two African cohorts, the Middle-Aged Soweto Cohort from South Africa and the Research on Obesity and Diabetes among African Migrants Prospective cohort from Ghana and migrants living in Europe, and a Swedish cohort, the Pre-Swedish CArdioPulmonary bioImage Study. Targeted proteomics, as well as targeted and untargeted metabolomics, will be performed at baseline to discover known and novel ethnic-specific and sex-specific biomarkers that predict incident dysglycaemia in the different longitudinal cohorts. Dietary patterns that explain maximum variation in the biomarker profiles and that associate with dysglycaemia will be identified in the SSA and European cohorts and used to build the prototypes for dietary interventions to prevent T2D. A comparative cost-effectiveness analysis of the dietary interventions will be estimated in the different populations. Finally, the perceptions of at-risk participants and healthcare providers regarding ethnic-specific and sex-specific dietary recommendations for the prevention of T2D will be assessed using focus group discussions and in-depth interviews in South Africa, Ghana, Germany (Ghanaian migrants) and Sweden.

ETHICS AND DISSEMINATION: Ethical clearance has been obtained from all participating sites. The study results will be disseminated at scientific conferences and in journal publications, and through community engagement events and diabetes organisations in the respective countries.

BACKGROUND: Low lung function has been consistently associated with increased cardiovascular disease (CVD) risk, with emerging evidence suggesting a potential causal relationship. However, underlying biological mechanisms remain unclear. AIM: To investigate relationships between CVD-associated plasma proteins and lung function.

METHODS: We analysed plasma protein profiles in two Swedish population-based cohorts: the Swedish CArdioPulmonary bioImage Study (SCAPIS) (n = 4,982, mean age 57.6 years) as the discovery cohort and the SCAPIS pilot study (n = 1,054, mean age 57.7 years) for replication. Multiple linear regression models were used to assess associations between 92 CVD-associated proteins and z-scores of FEV1, FVC, and FEV1/FVC, adjusting for known confounders. P-values were corrected using the Benjamini-Hochberg method (5% FDR). Significantly associated proteins were validated in the replication cohort. R

ESULTS: A total of 69 proteins were associated with FEV1, 57 with FVC, and 9 with FEV1/FVC. Several inflammatory proteins and adipokines, including leptin, interleukin-6, fatty acid-binding protein (adipocyte), were consistently linked to lower lung function. Leptin had the strongest negative association (FEV1: β = -0.50, 95 % CI: [-0.69, -0.31], p < 0.001; FVC: β = -0.52, 95 % CI: [-0.68, -0.35], p < 0.001 per-SD increase).

CONCLUSIONS: Multiple CVD-associated proteins, mainly reflecting inflammatory and metabolic processes, were associated with reduced FEV1 and FVC, supporting a link between systemic inflammation, adipokine metabolism and impaired lung function. Leptin had the strongest association, suggesting that its effects on lung function may extend beyond adiposity. Further research is needed to clarify the mechanisms driving these associations and to assess whether these proteins could serve as early biomarkers or intervention targets.

Objectives: Here we use skeletal muscle fiber composition to investigate whether defects in amino acid metabolism are involved in the early development of IR in healthy young individuals before the onset of clinical manifestations.

Design: Two groups consisting of healthy young men and women, insulin-sensitive and insulin-resistant, were studied using a cross-sectional design.

Methods: Biopsies were obtained from the vastus lateralis muscle, and an intravenous glucose tolerance test was performed. Plasma and muscle tissue were analyzed by metabolomics. Results Subjects in group 1 (n = 20; age 28 ± 5 years; body mass index 22.3 ± 2.7 kg/m2) had an expression of type I muscle fibers and whole-body insulin sensitivity of 58.8% ± 5.7% and 1.8 ± 0.7 units, respectively. Subjects in group 2 (n = 16; age 25 ± 6 years; body mass index 22.6 ± 3.0 kg/m2) had an expression of type I muscle fibers and whole-body insulin sensitivity, respectively, of 29.8% ± 6.6% and 0.8 ± 0.3 units (P < .001 vs group 1 for both). Anserine and β-alanine contents in muscle were significantly higher and taurine lower in group 2 vs 1, consistent with the differences in muscle fiber composition between groups. Taurine correlated well with insulin sensitivity and expression of type I muscle fibers (r = 0.63; P < .001 for both). In contrast, there were no significant differences in plasma or tissue contents of glutamine, arginine, or branched-chain amino acids between groups.

Conclusions: These data demonstrate that the early development of IR is not a consequence of defects in amino acid metabolism. Rather, defects in amino acid metabolism in diseased states are more likely a consequence of IR.

Background: Genetic studies consistently demonstrate that individuals born with reduced Cholesteryl Ester Transfer Protein (CETP) activity experience lower rates of atherosclerotic vascular disease throughout their lives. In contrast, short-term randomized controlled trials of CETP inhibitors have yielded mixed results, with only one of four trials reporting a reduction in clinical events. Several theories have been proposed to explain this discrepancy, but none fully account for the central mechanism of atherosclerosis: the cumulative lifetime exposure to circulating low-density lipoprotein (LDL) particles in the arterial walls.

Objectives: We aimed to reconcile these conflicting findings by examining the relationship between cumulative LDL exposure and atherosclerosis risk across both genetic studies and clinical trials.

Methods: We analyzed 679 carriers of CETP protein-truncating variants (resulting in reduced or non-functional CETP protein) and 505,837 non-carriers in a population with 95,568 atherosclerosis events. Additionally, we assessed treatment effects relative to cumulative LDL reductions in 34 cardiovascular prevention trials involving 328,036 participants and 53,161 events.

Results: Heterozygous CETP protein-truncating variant carrier status reduced atherosclerotic disease risk (odds ratio, 0.70; 95% confidence interval, 0.57– 0.85; P=5×10-4). In clinical trials, we observed a significant interaction between the magnitude and duration of LDL lowering on treatment effects (hazard ratio, 0.69 per 10– mmol/L×years; 95% confidence interval, 0.52–0.90; P=0.007), supporting that reducing cumulative LDL exposure is key to lowering cardiovascular risk. When comparing genetics with trial outcomes, accounting for differences in timing, duration, and follow-up, we observed consistent effects on atherosclerosis-related events per LDL years across genetic and pharmacological CETP inhibition, as well as with statins, ezetimibe, PCSK9 inhibitors, and familial hypercholesterolemia-associated variants (hazard ratio, 0.74 and 0.69 per 10–mmol/L×years, respectively). This suggests that CETP inhibition reduces cardiovascular risk primarily through LDL. Notably, several trials failed to achieve sufficient cumulative LDL reduction to impact clinical events, and this was not unique to CETP inhibitors.

Conclusion: Our findings indicate that future CETP inhibitor trials achieving substantial and sustained LDL reduction will demonstrate efficacy in preventing cardiovascular events. These results highlight the importance of long-term LDL lowering and support further investigation of CETP inhibition as a strategy for cardiovascular prevention.

Aims: APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidaemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation.

Methods and results: We conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements. Genetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) [odds ratio, 0.57 per s.d. protein (95% CI 0.47-0.70)] and Type 2 diabetes (T2D) [odds ratio, 0.73 per s.d. protein (95% CI 0.57-0.94)]. Genetically lowering circulating APOC3 levels also reduced the odds of CAD [odds ratio, 0.90 per s.d. protein (95% CI 0.82-0.99)]. Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of protein-truncating variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.71 per allele [95%CI, 0.58-0.85]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns.

Conclusion: Human genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D.

Aims: Individuals of African ancestry (AA) present with lower insulin sensitivity compared to their European counterparts (EA). Studies show ethnic differences in skeletal muscle fiber type (lower type I fibers in AA), muscle fat oxidation capacity (lower in AA), whilst no differences in total skeletal muscle lipids. However, skeletal muscle lipid subtypes have not been examined in this context. We hypothesize that lower insulin sensitivity in AA is due to a greater proportion of type II (non-oxidative) muscle fibers, and that this would result in an ancestry-specific association between muscle lipid subtypes and peripheral insulin sensitivity. To test this hypothesis, we examined the association between insulin sensitivity and muscle lipids in AA and EA adults, and in an animal model of insulin resistance with muscle-specific fiber types.

Methods: In this cross-sectional study, muscle biopsies were obtained from individuals with a BMI ranging from normal to overweight with AA (N = 24) and EA (N = 19). Ancestry was assigned via genetic admixture analysis; peripheral insulin sensitivity via hyperinsulinaemic–euglycemic clamp; and myofiber content via myosin heavy chain immunohistochemistry. Further, muscle types with high (soleus) and low (vastus lateralis) type I fiber content were obtained from high-fat diet-induced insulin resistant F1 mice and littermate controls. Insulin sensitivity in mice was assessed via intraperitoneal glucose tolerance test. Mass spectrometry (MS)-based lipidomics was used to measure skeletal muscle lipid.

Results: Compared to EA, AA had lower peripheral insulin sensitivity and lower oxidative type 1 myofiber content, with no differences in total skeletal muscle lipid content. Muscles with lower type I fiber content (AA and vastus from mice) showed lower levels of lipids associated with fat oxidation capacity, i.e., cardiolipins, triacylglycerols with low saturation degree and phospholipids, compared to muscles with a higher type 1 fiber content (EA and soleus from mice). Further, we found that muscle diacylglycerol content was inversely associated with insulin sensitivity in EA, who have more type I fiber, whereas no association was found in AA. Similarly, we found that insulin sensitivity in mice was associated with diacylglycerol content in the soleus (high in type I fiber), not in vastus (low in type I fiber).

Conclusions; Our data suggest that the lipid contribution to altered insulin sensitivity differs by ethnicity due to myofiber composition, and that this needs to be considered to increase our understanding of underlying mechanisms of altered insulin sensitivity in different ethnic populations.