Objectives The aim of this study was to translate the Attitudes and Beliefs about Cardiovascular Disease (ABCD) Risk Questionnaire into Norwegian and assess its psychometric properties among individuals with a history of myocardial infarction.Design The study adopted a cross-sectional design. The original questionnaire was translated into Norwegian and adapted for use in the target population. The Norwegian version was pilot tested in a sample of patients and then validated in the target population.Setting Norway, using a web-based solution to collect data.Patients A random sample of Norwegian individuals <85 years old with a history of myocardial infarction and no cardiovascular disease before their first myocardial infarction.Main outcome measures Internal consistency was tested using Cronbach’s α and test–retest reliability using intraclass correlation coefficient (ICC). Difficulty and discrimination indices were determined for the Knowledge scale. Confirmatory factor analysis (CFA) was used to assess structural validity of the Risk scale.Results Data for 746 participants (mean age, SD: 66.4, 10.3 years), of which 26.9% females were analysed. The Norwegian version showed satisfactory internal consistency (Cronbach’s α 0.73–0.79) but modest test–retest reliability (ICC 0.35–0.64). The Knowledge scale showed moderate difficulty (0.39–0.84) and good discrimination power (0.44–0.60). The one-factor model CFA for each scale achieved acceptable fit, and the four-factor model showed moderate fit (root mean square error of approximation=0.05, standardised root mean squared residual=0.07, Comparative Fit Index=0.91, Tucker-Lewis Index=0.88).Conclusions The Norwegian translated ABCD Risk Questionnaire demonstrated satisfactory psychometric properties and can be considered a useful instrument for assessing knowledge and risk perception among individuals with a history of myocardial infarction.

Polygenic scores can improve atrial fibrillation risk prediction. However, limited accuracy and cross-ancestry transferability hinder clinical translation. Here, we explore several ensemble approaches to generate ancestry-optimized polygenic scores, with development in diverse participants from the All of Us Research Program, BioBank Japan, and three additional cohorts. Our ancestry-specific multi-trait approach particularly improves prediction in South-Asian (odds-ratio/standard deviation 1.5-1.8; area under curve 0.60-0.64; relative R² +71%), Admixed-American (1.5; 0.60; +34%) and African ancestry groups (1.4; 0.57; +56%). Nevertheless, performance remains highest in European and East-Asian ancestries (1.8-2.2; 0.65-0.68), where >50% of SNP-heritability is explained. Improved risk stratification is also observed at the extremes, identifying European and East-Asian ancestry individuals with risk comparable to rare TTN variants (e.g., 6-11% with >4-fold odds). Finally, our scores improve incident risk prediction alongside clinical models. Together, we show that our ancestry-tailored multi-trait polygenic scores advance atrial fibrillation risk prediction and stratification, providing an equitable foundation for implementation.

Lipedema is a chronic and painful adipose tissue disorder that primarily affects women and is characterized by abnormal adipose tissue accumulation, mainly in the lower limbs. The condition is associated with substantial physical and psychological morbidity and negatively impacts daily functioning. Effective treatment options remain limited and are largely restricted to conservative approaches such as compression therapy and pain management. The LipidEx study (ClinicalTrials.gov identifier: NCT06558851; first registered 07 October 2024) aims to investigate high-intensity interval training (HIIT) as a novel therapeutic approach for women with lipedema. We will conduct a randomized controlled trial with sequential intervention and control periods to evaluate the effects of 12 weeks of HIIT compared with a control period of usual daily activities. Participants will be randomly assigned to one of two sequences, such that all participants undergo both the intervention and control conditions. The primary outcome is change in pain. Secondary outcomes include changes in quality of life and adipose tissue mass. Trial registration ClinicalTrials.gov identifier: NCT06558851. Date of first registration: 07 October 2024.

Low cardiorespiratory fitness (CRF) is a well-established risk factor for cardiovascular disease (CVD) and all-cause mortality. Since CRF is largely genetically determined, understanding the genetic influences on CRF might reveal the protective mechanisms of high CRF. One gene found to be associated with CRF is COX7A2L. COX7A2L is a mitochondrial supercomplex assembly factor, but its role in cellular metabolism remains a topic of discussion. We hypothesized that COX7A2L could play a role in cellular respiration in cardiomyocytes, affecting cardiac function and CRF. To determine the effect of COX7A2L on cardiomyocyte function, we overexpressed and knocked down COX7A2L in human AC16 cardiomyocytes and performed MTT assays and Seahorse XF Cell Mito Stress Tests to assess cell viability and mitochondrial function. For the mitochondrial function measurements, we stimulated the cells with isoproterenol to investigate if the effect of altering COX7A2L levels would be larger under simulated increased energy demand. Overexpression and knockdown were validated using sandwich ELISA. Our findings showed that altering COX7A2L expression in human AC16 cardiomyocytes did not significantly affect cell viability or mitochondrial function. Further research is necessary to determine whether COX7A2L influences cardiomyocyte function and CRF.

AIMS:Current risk prediction models, such as the Norwegian NORRISK 2, explain only a modest proportion of cardiovascular disease (CVD) incidence. This study aimed to develop improved sex-specific models for predicting the 10-year CVD risk as well as sex- and age-specific thresholds for intervention. METHODS:Data from 31,946 participants (40-79 years) without prior CVD were analyzed. Data were randomly split into a training set (for estimation) and a test set (for model evaluation). An extreme gradient boosting (XGBoost) model was used to identify the most important predictive variables. Next, prediction models were developed on the training set for each sex separately using XGBoost and logistic regression. The models were evaluated on the test set using receiver-operating characteristic (ROC) and precision recall (PR) curves. Finally, age- and sex-specific thresholds for intervention were explored. RESULTS:All traditional risk factors included in NORRISK 2 and the European SCORE2 model were important predictors for males, but not for females. Potential new risk predictors were identified. The XGBoost model improved CVD risk prediction for males: 0.013- and 0.012-unit increase in ROC-AUC compared to NORRISK 2 and SCORE2 respectively, and 12% and 11% increase in PR-AUC respectively. For females, neither the XGBoost nor logistic regression model performed significantly better than NORRISK 2 and SCORE2. Age- and sex-specific thresholds showed an improvement in sensitivity compared with NORRISK 2-suggested thresholds. CONCLUSIONS:By employing statistical learning and incorporating sex-specific risk factors, we propose improved risk prediction models for CVD in males. Introducing sex-specific thresholds for intervention could enhance CVD prevention for both sexes.

Lipedema is a chronic adipose tissue disorder that primarily affects women. The etiology remains unclear and involves abnormal buildup of fat mainly in the lower limbs. It causes physical and psychological morbidity, often with negative impact on daily life. Effective treatment options are still limited, primarily involving conservative treatment such as compression therapy and pain reliever. As endurance training is shown to have beneficial effects on both pain and obesity management in patients suffering of other disorders, LipidEx aims to explore the potential of high-intensity interval training (HIIT) as a novel therapeutic option for women with lipedema. We will perform a cross-over randomized controlled trial (RCT) exploring the effects of 12 weeks of HIIT compared to a control period of usual care. The primary outcome is changes in pain, and secondary outcomes are changes in adipose tissue mass and quality of life. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT06558851 ### Funding Statement The study will be supported by grants from the DAM Foundation Joint Research Committee between St. Olavs hospital and the Faculty of Medicine and Health Sciences, NTNU (FFU). The funders have/had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a protocol paper for Registered Report, and not a full manuscript. The Regional Ethics committee (REK) of Norway have given ethical approval to preform the LipidEx-study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced will be available online.

Background:Cardiorespiratory fitness (CRF) has a strong genetic component and low CRF is a major risk factor for cardiovascular morbidity and mortality. The purpose of this study was to develop and validate a polygenic score (PGS) for CRF (CRFPGS) and assess its associations with cardiovascular disease (CVD) and all-cause mortality. We hypothesized that the CRFPGS would demonstrate similar cardioprotective benefits as the CRF phenotype. Methods:Effect estimates from a genome-wide association study on directly measured CRF in the Trøndelag Health Study (HUNT; n = 4 525) were used in a Bayesian regression framework to develop multiple PGSs in an independent cohort from the UK Biobank (n = 65 165). The top performing score was applied in the HUNT target cohort, excluding the discovery sample (n = 82 109). Results:The PGS-CRF association varied considerably as a function of model fit and phenotypic accuracy. In the target population, we observed a difference in CRF of 1.55 [95% confidence interval: 1.26, 1.84] mL·kg-1·min-1 between the bottom and top decile of the CRFPGS. Moreover, a high CRFPGS demonstrated cardioprotective effects, with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality. We also found that the CRFPGS predisposed to lower risk of heart failure and hypertrophic cardiomyopathy in women. Conclusion:A PGS for CRF derived from gold-standard phenotypes captures small, but potentially clinical meaningful variations in CRF, and is associated with reduced risk of cardiovascular morbidity and mortality. Heterogeneity in CRF phenotyping in large populations remains a challenge to PGS development and refinement.

Cardiorespiratory fitness (CRF) has a strong genetic component and low CRF is a major risk factor for cardiovascular morbidity and mortality. The purpose of this study was to develop and validate a polygenic score (PGS) for CRF (CRFPGS) and assess its associations with cardiovascular disease (CVD) and all-cause mortality. We hypothesized that the CRFPGS would demonstrate similar cardioprotective benefits as the CRF phenotype. Effect estimates from a genome-wide association study on directly measured CRF in the Trøndelag Health Study (HUNT; n = 4525) were used in a Bayesian regression framework to develop multiple PGSs in an independent cohort from the UK Biobank (n = 65,165). The top performing score was applied in the HUNT target cohort, excluding the discovery sample (n = 82,109). The PGS-CRF association varied considerably as a function of model fit and phenotypic accuracy. There was a difference of 1.55 [95% confidence interval: 1.26, 1.84] mL·kg−1·min−1 between the bottom and top decile of the CRFPGS. Moreover, a high CRFPGS demonstrated cardioprotective effects, with reduced risk for CVD, myocardial infarction, hypertension, and all-cause mortality. Additionally, in women, we observed that the CRFPGS predisposed to lower risk of heart failure and hypertrophic cardiomyopathy. We developed the first PGS for CRF using gold standard phenotypes and multiple independent cohorts. Genetic susceptibility to high CRF may have a clinically meaningful impact on the phenotype. The CRFPGS was better to identify individuals with slightly higher lifelong levels of CRF, which appears to protect against cardiovascular morbidity and mortality.

OBJECTIVE:Energy-saving sedentary behaviour may be an evolutionarily selected trait that is no longer advantageous. We investigated the associations between genetic liability to sedentary behaviour and the incidence of the most common cardiovascular disease (CVD). METHODS:We constructed and validated a genome-wide polygenic score for leisure screen time (PGS LST) as a measure of genetic liability to sedentary behaviour. We performed survival analyses between higher PGS LST and register-based CVDs using the FinnGen cohort (N=293 250-333 012). Replication and exploratory analyses were conducted in an independent Norwegian Trøndelag Health Study (HUNT) cohort (N=35 289). RESULTS:In FinnGen, each SD increase in PGS LST was associated with a higher risk of incident CVD (HR: 1.05 (95% CI 1.05 to 1.06)) (168 770 cases over 17 101 133 person-years). The magnitudes of association for the three most common CVDs were 1.09 ((95% CI 1.08 to 1.09), 1.06 ((95% CI 1.05 to 1.07) and 1.05 ((95% CI 1.04 to 1.06) for hypertensive disease, ischaemic heart disease and cerebrovascular disease, respectively. Those in the top decile of PGS LST had 21%, 35%, 26% and 19% higher risk of any CVD, hypertensive disease, ischaemic heart disease and cerebrovascular disease, respectively, than those in the bottom decile. Associations were replicated in HUNT and remained independent of covariates (socioeconomic status, body mass index and smoking) except for cerebrovascular disease. Besides direct effects, reduced physical activity served as a potential mediating pathway for the observed associations. CONCLUSIONS:We found that genetic liability to sedentary behaviour is associated with incident CVD, although effect sizes with current PGS remained small. These findings suggest that genetic liability to sedentary behaviour is an under-recognised driver of common CVDs.

We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO2max), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we created a webtool, OMAx, featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omics framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention.

Cardiorespiratory fitness (CRF) has a strong genetic component estimated to be up to 60%. Further, CRF is a major risk factor for cardiovascular morbidity and mortality. However, the specific genetic architecture of CRF and how this relates to cardiovascular disease (CVD) risk is poorly understood. There is a clinical need for improved risk prediction accuracy as many patients free from traditional risk factors still experience different CVDs. To develop and validate a polygenic score (PGS) for CRF (CRFPGS) and assess its associations with CVD. The Bayesian approach PRS-CS was applied to construct a genome-wide PGS for CRF. Genetic effect estimates from a genome-wide association study on directly measured VO2peak in the Trøndelag Health Study (HUNT; n = 4 525) was used as the base data and an independent cohort from the UK Biobank (n = 65 674) with estimated CRF from a submaximal bicycle test was used as the tuning cohort. The top performing score was identified and applied in the independent target cohort in HUNT (n = 82 109) with estimated CRF (eCRF) from clinical measurements, to test for associations with different CVD outcomes. The correlation between the CRFPGS and the CRF measurements varied between the cohorts and accuracy of the phenotype. There was a clinically meaningful difference of 1.5 mL·kg-1·min-1 in the eCRF between the bottom and top decile of the CRFPGS. Moreover, the CRFPGS demonstrated cardioprotective effects, where a high CRFPGS was associated with reduced risk for all-cause mortality, CVD, myocardial infarction, hypertension, heart failure, and hypertrophic cardiomyopathy (Figure 1). When considering women and men separately, the association between the CRFPGS and risk of heart failure and hypertrophic cardiomyopathy disappeared in men, suggesting sex-specific effects. The CRFPGS appeared to be more suited to identify individuals with a genetic susceptibility to slightly higher lifelong levels of CRF, in part driven by lower BMI, rather than individuals with a potential for supraphysiological levels. We developed the first PGS for CRF using gold standard phenotypes as the base data and independent tuning and validation cohorts. A genetic susceptibility to a high CRF had a clinically meaningful impact on the phenotype and associated disease risk. The CRFPGS was better to identify individuals with slightly higher lifelong levels of CRF which seems to protect against cardiovascular morbidity and mortality. These results suggest that a CRFPRS could be used in clinic to identify individuals with excessive genetic risk for different CVDs in the future.Hazard ratio for CVD outcomes

Abstract Aims Several risk prediction models are available for determining the 10-year risk of cardiovascular disease (CVD), including the Norwegian NORRISK 2 model. However, the existing models explain only a modest proportion of the incidence. Therefore, this study aimed to develop improved models for predicting the 10-year risk of myocardial infarction (MI) for both sexes. Methods Data from 31,946 participants without prior CVD were analyzed. The data set was divided into a training set (for estimation) and a test set (for model evaluation). Prediction models were developed on the training set for each sex using XGBoost and logistic regression, using 96 (men) and 100 (women) variables. The models were evaluated on the test set using Receiver-Operating-Characteristic (ROC) and Precision-Recall (PR) curves. Age and sex-specific thresholds for intervention were explored through cross-validation on the training set. Model performance was compared to the NORRISK 2 model using the test set. Results The XGBoost model improved CVD risk prediction for men across all age groups (AUCROC for XGBoost and NORRISK 2, respectively, 0.72 and 0.65 (age 45-54), 0.63 and 0.62 (age 55-64), 0.69 and 0.62 (age 65-74)). For women, NORRISK2 performed better than XGBoost in ROC curve evaluation. However, XGBoost were superior to NORRISK2 when evaluated by PR-curves in women aged 55-64 (PR-AUC for XGBoost and NORRISK 2, respectively, 0.20 and 0.12 compared to 0.06 for a no-skills model). Potential new risk predictors, such as alkaline phosphatase (ALP) for men and thyroid stimulation hormone (TSH) for women, were identified. The results also indicate that the thresholds for intervention should be sex specific. Conclusion By employing machine learning and incorporating sex-specific risk factors, we propose improved risk prediction models for CVD, particularly in men. Introducing sex-specific thresholds for intervention could enhance CVD prevention for both women and men.

AIMS:Resting heart rate (RHR) is associated with cardiovascular disease (CVD) and mortality. This study aimed to identify genetic loci associated with RHR, develop a genome-wide polygenic risk score (PRS) for RHR, and assess associations between the RHR PRS and CVD outcomes, to better understand the biological mechanisms linking RHR to disease. Sex-specific analyses were conducted to potentially elucidate different pathways between the sexes. METHODS AND RESULTS:We performed a genome-wide meta-analysis of RHR (n = 550 467) using two independent study populations, The Trøndelag Health Study (HUNT) and the UK Biobank (UKB), comprising 69 155 and 481 312 participants, respectively. We also developed a genome-wide PRS for RHR using UKB and tested for association between the PRS and 13 disease outcomes in HUNT. We identified 403, 253, and 167 independent single nucleotide polymorphisms (SNPs) significantly associated with RHR in the total population, women, and men, respectively. The sex-specified analyses indicated differences in the genetic contribution to RHR and revealed loci significantly associated with RHR in only one of the sexes. The SNPs were mapped to genes enriched in heart tissue and cardiac conduction pathways, as well as disease-pathways, including dilated cardiomyopathy. The PRS for RHR was associated with increased risk of hypertension and dilated cardiomyopathy, and decreased risk of atrial fibrillation. CONCLUSION:Our findings provide insight into the pleiotropic effects of the RHR variants, contributing towards an improved understanding of mechanisms linking RHR and disease. In addition, the sex-specific results might contribute to a more refined understanding of RHR as a risk factor for the different diseases.

AbstractBackgroundIt is unclear how the genetics of sedentary behavior are associated with incident cardiovascular disease (CVD). We investigated the associations between genetic liability to sedentary behavior, sedentariness, and four main CVD outcomes: any CVD, hypertensive diseases, ischemic heart diseases, and cerebrovascular diseases.MethodsLeisure screen time was used as a proxy for sedentary behavior. We developed a polygenic score for leisure screen time (PGS LST) based on over 890,000 genetic variants. We tested the validity of this score against self-reported LST in the older Finnish Twin Cohort (FTC, N=2,689, mean age of 60.5±3.7 years, 54.7% women) using linear regression. We examined the associations between PGS LST and register-based records of CVDs using survival models among FinnGen participants (N=293,250–333,012, 67.0±13.0 years at follow-up, 52.3% women). We replicated analyses in an independent cohort (Trøndelag Health Study [HUNT], N=35,289, 64.0±13.1 years, 51.6% women) and explored if the associations persist following adjustments for socioeconomic status, body mass index, and smoking or are mediated via reduced physical activity.ResultsIn the FTC, each standard deviation increase in PGS LST was associated with greater self-reported LST (hours/day) (β = 0.09, 95% CI: 0.05–0.14). In FinnGen, each standard deviation increase in PGS LST was associated with a higher risk of incident CVD (hazard ratio: 1.05, [1.05–1.06]) (168,770 cases over 17,101,133 person-years).The magnitudes of association for three most common CVDs were 1.09 (1.08–1.09), 1.06 (1.05–1.07), and 1.05 (1.04–1.06) for hypertensive diseases, ischemic heart diseases, and cerebrovascular diseases, respectively. Those in the top decile of PGS LST had 21%, 35%, 26%, and 19% higher risk of any CVD, hypertensive diseases, ischemic heart diseases, and cerebrovascular diseases, respectively, than those in the bottom decile. Associations replicated in HUNT and remained independent of covariates except for cerebrovascular diseases. Besides direct effects, reduced physical activity served as a potential mediating pathway for the associations.ConclusionsA higher genetic liability to sedentary behavior is associated with a greater risk of developing CVDs, although effect sizes with current PGS remain small. Our findings suggest that genetic liability to sedentary behavior is an underrecognized driver of common CVDs.Clinical perspectiveWhat is new?It is not known whether a genetic liability to sedentary behavior is a mutual underlying factor for both sedentary behavior and incident cardiovascular disease at the population level.We observed that a higher polygenic score for leisure screen time was associated with more self-reported leisure screen time and a higher risk of common cardiovascular diseases.What are the clinical implications?This study provides novel insights into the relationship between genetic predisposition to sedentary behavior and the development of cardiovascular diseases, shedding light on a previously underexplored aspect of disease etiology.These results may motivate health professionals to encourage sedentary persons to undertake at least some physical activity.

Lipid-rich coronary atherosclerotic plaques often cause myocardial infarction (MI), and circulating biomarkers that reflect lipid content may predict risk of MI. We investigated the association between circulating microRNAs (miRs) are lipid-rich coronary plaques in 47 statin-treated patients (44 males) with stable coronary artery disease undergoing percutaneous coronary intervention. We assessed lipid content in non-culprit coronary artery lesions with near-infrared spectroscopy and selected the 4 mm segment with the highest measured lipid core burden index (maxLCBI 4mm ). Lipid-rich plaques were predefined as a lesion with maxLCBI 4mm ≥ 324.7. We analyzed 177 circulating miRs with quantitative polymerase chain reaction in plasma samples. The associations between miRs and lipid-rich plaques were analyzed with elastic net. miR-133b was the miR most strongly associated with lipid-rich coronary plaques, with an estimated 18% increase in odds of lipid-rich plaques per unit increase in miR-133b. Assessing the uncertainty by bootstrapping, miR-133b was present in 82.6% of the resampled dataset. Inclusion of established cardiovascular risk factors did not attenuate the association. No evidence was found for an association between the other analyzed miRs and lipid-rich coronary plaques. Even though the evidence for an association was modest, miR-133b could be a potential biomarker of vulnerable coronary plaques and risk of future MI. However, the prognostic value and clinical relevance of miR-133b needs to be assessed in larger cohorts.

BACKGROUND:Traditional biomarkers used to measure risk of myocardial infarction (MI) only explain a modest proportion of the incidence. Lipoprotein subfractions have the potential to improve risk prediction of MI.AIM:We aimed to identify lipoprotein subfractions that were associated with imminent MI risk.METHODS:We identified apparently healthy participants with a predicted low 10-year risk of MI from The Trøndelag Health Survey 3 (HUNT3) that developed MI within 5 years after inclusion (cases, n = 50) and 100 matched controls. Lipoprotein subfractions were analyzed in serum by nuclear magnetic resonance spectroscopy at time of inclusion in HUNT3. Lipoprotein subfractions were compared between cases and controls in the full population (N = 150), and in subgroups of males (n = 90) and females (n = 60). In addition, a sub analysis was performed in participants that experienced MI within two years and their matched controls (n = 56).RESULTS:None of the lipoprotein subfractions were significantly associated with future MI when adjusting for multiple testing (p<0.002). At nominal significance level (p<0.05), the concentration of apolipoprotein A1 in the smallest high-density lipoprotein (HDL) subfractions was higher in cases compared to controls. Further, in sub analyses based on sex, male cases had lower lipid concentration within the large HDL subfractions and higher lipid concentration within the small HDL subfractions compared to male controls (p<0.05). No differences were found in lipoprotein subfractions between female cases and controls. In sub analysis of individuals suffering from MI within two years, triglycerides in low-density lipoprotein were higher among cases (p<0.05).CONCLUSION:None of the investigated lipoprotein subfractions were associated with future MI after adjustment for multiple testing. However, our findings suggests that HDL subfractions may be of interest in relation to risk prediction for MI, especially in males. This need to be further investigated in future studies.

Abstract Shared genetic factors may contribute to the associations between higher levels of physical activity (PA) and lower risk for cardiometabolic diseases (CMDs), and may partially explain these associations observed in cohort studies. To explore this, we used novel methodology to calculate PA genotypes (polygenic risk score, PRS) and validated them against measured or reported PA in three independent cohorts. We then investigated the associations between polygenic inheritance of PA and cardiometabolic risk factors and diseases in two large population-based biobank datasets, and examined whether selected associations were independent of self-reported PA. Our study utilized the UK Biobank as a base dataset (N = 400,124) and constructed genomewide PRSs for both self-reported and device-measured PA using single nucleotide polymorphism (SNP)-specific weights and SBayesR methodology. Both PRSs for PA included over one million SNPs. PRSs were constructed in the Finnish Twin cohort (N = 759–11,528), the Northern Finland Birth Cohort 1966 (N = 3,263–4,061), the Trøndelag Health Study cohort (HUNT, N = 47,148), and the FinnGen (N = 218,792). Cardiometabolic risk factors were measured in laboratory conditions, and CMD outcomes were derived from national health registers (ICD codes). We utilized linear, logistic, and cox regression methods for analysis. Our results showed that genotypes predisposing to higher PA were associated with higher levels of PA in independent datasets, but PRSs accounted for only a limited amount of variation (0.13-1.44%). Genotypes supporting higher PA were associated with lower body mass index [B=-0.002 in HUNT and B=-0.025 in FinnGen] and favorable cardiometabolic health in HUNT (waist circumference [B=-0.003] and HDL cholesterol [B = 0.004]). Genotypes supporting higher PA volumes were associated with lower incidence of CMDs in both HUNT and FinnGen. The strongest associations were found in hypertensive diseases and Type 2 Diabetes. In HUNT, the observed associations were not materially changed after accounting for self-reported PA. Higher PRS for PA was also associated with lower risk of mortality in FinnGen. Our findings suggest small pleiotropic effects between PA and CMDs. This means that same genetic variation may explain both physical activity behaviour and risk of diseases. PRSs provide new tools for genetic studies in sport science, but they currently have substantial practical limitations.

Endurance training is associated with increased cardiorespiratory fitness (CRF) and decreased risk of cardiovascular disease (CVD). However, a causal relationship between exercise, CRF, and CVD has not been confirmed. Exercise and CRF have a strong genetic component, estimated to be & SIM;50%. However, few genetic studies have been performed, as the gold-standard method for quantifying CRF is expensive, time-consuming, and requires advanced equipment. Conversely, self-reported information on physical activity (PA) is more easily available, but the uncertainty related to these data can introduce bias. Improved knowledge of genetic variants associated with exercise and CRF could provide causal links between exercise and CVD and contribute to new prevention and treatment strategies for CVD. This review presents the current knowledge of the genetics of exercise and CRF, and potential relationship with CVD, by highlighting the most comprehensive genetic and epigenetic studies on CRF, PA, and exercise response, as well as studies of gene-environment interactions.

Abstract Aims A low resting heart rate (RHR) implies a more efficient heart function and a lower risk of cardiovascular disease. However, observational studies have reported a U-shaped association between RHR and atrial fibrillation (AF). In contrast, Mendelian randomization (MR) studies have found an inverse causal association between RHR and AF. Hence, the causal nature of the relationship is not clear. The aim is to investigate the causal association and its shape between RHR on AF using linear and non-linear MR (NLMR). Methods and results Linear and non-linear MR were performed on individual-level data in the Trøndelag Health Study (HUNT) and UK Biobank (UKB). HUNT consists of 69 155 individuals with 7,062 AF cases, while UKB provides data on 431 852 individuals with 20 452 AF cases. The linear MR found an inverse relationship between RHR and AF with an OR = 0.95 [95% confidence interval (CI): 0.93–0.98] and OR = 0.96 (95% CI: 0.95–0.97) per unit decrease in RHR in HUNT and UKB, respectively. The NLMR was supportive of an inverse linear relationship in both HUNT and UKB for RHR values <90 beats per minute (bpm). Several sensitivity analyses were also consistent. Conclusion In contrast with the current observational knowledge of RHR and AF, an inverse causal association between RHR and AF was demonstrated in both linear and non-linear MR for RHR values up to 90 bpm. Further exploring the underlying mechanisms of the genetic instrument for RHR may shed light on whether pleiotropy is biasing this association.

Lipoprotein subfractions currently represent a new source of cardiovascular disease (CVD) risk markers that may provide more information than conventional lipid measures. We aimed to investigate whether lipoprotein subfractions are associated with coronary atherosclerosis in patients without prior known CVD. Fasting serum samples from 60 patients with suspected coronary artery disease (CAD) were collected before coronary angiography and analyzed by nuclear magnetic resonance (NMR) spectroscopy. The severity of coronary atherosclerosis was quantified by the Gensini score (<20.5 = nonsignificant coronary atherosclerosis, 20.6-30.0 = intermediate coronary atherosclerosis, >30.1 = significant CAD). Differences in lipoprotein subfractions between the three Gensini groups were assessed by two-way ANOVA, adjusted for statin use. Despite no differences in conventional lipid measures between the three Gensini groups, patients with significant CAD had higher apolipoprotein-B/apolipoprotein-A1 ratio, 30% more small and dense low-density lipoprotein 5 (LDL-5) particles, and increased levels of cholesterol, triglycerides, and phospholipids within LDL-5 compared with patients with nonsignificant coronary atherosclerosis and intermediate coronary atherosclerosis (P < 0.001). In addition, the low-density lipoprotein (LDL) cholesterol/highdensity lipoprotein cholesterol ratio, and triglyceride levels of LDL 4 were significantly increased in patients with significant CAD compared with patients with nonsignificant coronary atherosclerosis. In conclusion, small and dense lipoprotein subfractions were associated with coronary atherosclerosis in patients without prior CVD. Additional studies are needed to explore whether lipoprotein subfractions may represent biomarkers offering a clinically meaningful improvement in the risk prediction of CAD.