European Journal of Preventive Cardiology

BackgroundSex hormone alterations, such as estrogen deficiency or testosterone excess, substantially increase cardiovascular disease (CVD) risk in females. Dietary fibre and its microbial by-products, short-chain fatty acids (SCFAs), have cardioprotective effects, but it remains unclear whether these benefits extend to females with an altered sex hormone profile. In this study, we aim to investigate whether dietary fibre intake, measured via plasma acetate--the most abundant SCFA--is associated with improved cardiovascular outcomes in females with altered sex hormone profiles. MethodsThis cohort study included 116,235 female participants from the UK Biobank and Biobank Japan with up to 10 years of follow-up. We analysed early menopause (as a surrogate for estrogen insufficiency) and plasma free testosterone (in a subset). The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were blood pressure. Proteomics analyses explored potential mechanisms. ResultsAcetate levels were associated with lower 10-year MACE incidence (-0.618/1000 woman-year, HR=0.900, p=0.002) and systolic blood pressure (-0.231 mmHg per 1 SD, p<0.001) in the UK Biobank. High acetate levels attenuated the increased MACE risk associated with early menopause (HR=1.158, p=0.057) compared with low acetate (HR=1.425, p<0.001), with similar patterns replicated in Biobank Japan (high: HR=1.322, p=0.090; low: HR=1.385, p=0.042). Proteomics analyses suggested a mechanism involving pro-inflammatory proteins. Moreover, high acetate levels attenuated the increased MACE associated with elevated free testosterone in the UK Biobank (high: HR=1.238, p=0.024; low: HR=1.056, p=0.666). A significant interaction between acetate and free testosterone on systolic blood pressure indicated that the effect of rising testosterone on blunting acetates effect ({beta}=0.167, 95% CI: [5.212x10-2-2.818x10-1], p=0.004) was partially mediated by central obesity (waist-to-hip ratio). ConclusionsHigher plasma acetate levels were associated with lower cardiovascular risk, particularly in females with early menopause or elevated free testosterone, potentially via inflammatory pathways. These findings underscore the importance of hormonal context in shaping cardiometabolic resilience and support personalised CVD prevention strategies for females with altered sex hormone profiles, including increasing dietary fibre intake.

BackgroundTestosterone deficiency in men has historically been associated with an increased risk of cardiovascular disease (CVD), including myocardial infarction, heart failure, and mortality. The potential benefits of testosterone replacement therapy (TRT) on cardiovascular outcomes remain controversial. This systematic review and meta-analysis aimed to investigate if there could be potential benefits of TRT on cardiovascular disease risk and, if so, uncover the underlying mechanisms. MethodsA comprehensive literature search for Level A evidence in multiple databases (PubMed, Embase, Cochrane Library) was conducted, including randomized controlled trials (RCTs), systematic reviews, meta-analyses, cohort studies, review articles and experimental studies published between 1999 and 2024 that investigated the association between TRT and cardiovascular outcomes in men. The primary outcome was the risk of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality. Secondary outcomes included changes in ejection fraction, lipid profiles, side effects, and other cardiovascular risk factors. ResultsFrom 3,727 records identified using the selected criteria, a total of 51 studies were selected for the meta-analysis, comprising 4 RCTs, 9 cohort studies, 6 experimental studies, 23 review articles, 4 systematic reviews, and 5 meta-analyses, with a combined sample size of approximately 3,134,054 men. The findings from the meta-analysis suggests an 18% reduction in the risk of cardiovascular events among men receiving TRT compared to those receiving a placebo. TRT was found to be associated with significant improvements in ejection fraction, lipid profiles (reduction in total cholesterol and low-density lipoprotein cholesterol), and other cardiovascular risk factors, including insulin resistance and inflammatory markers. Potential mechanisms underlying the cardioprotective effects of TRT include improvements in endothelial function, vasodilation, and myocardial remodeling. Subgroup analyses revealed that the beneficial effects of TRT were more pronounced in men with established cardiovascular disease or risk factors, such as diabetes or metabolic syndrome. ConclusionThis systematic review and meta-analysis of high-quality evidence suggest that testosterone deficiency is associated with an increased risk of cardiovascular disease. Conversely, TRT is associated with a reduced risk of cardiovascular events, particularly in men with pre-existing cardiovascular disease or risk factors. TRT was linked to a reduced risk of MACE, improved ejection fraction, and favorable changes in lipid profiles and other cardiovascular risk factors. Despite the relatively large sample size, further long-term studies are needed to confirm these findings and establish optimal dosing and monitoring strategies for TRT in cardiovascular disease prevention.

Background and AimSedentary lifestyle and obesity are considered to be significant risk factors that create a pathway for the appearance of the sedentary cardiac phenotype consisting of cardiac atrophy, myocardial stiffening, and altered haemodynamics. Although exercise training has the potential to reverse this detrimental process, the literature data on the magnitude of improvements and the certainty of evidence are inconsistent. This systematic review and meta-analysis aimed to evaluate the effects of exercise interventions on cardiac morphology, systolic/diastolic function, and haemodynamics in sedentary and obesity-prone individuals. MethodIn accordance with the PRISMA guidelines, the study was conducted by searching the PubMed, Web of Science, and Scopus databases from 1990 to 2025 without applying any filters, using Covidence software. As a result of this comprehensive search, 15 randomised controlled trials (RCTs; N=559) comparing exercise training with a control group in sedentary individuals were included in the analysis. Data were pooled using the Standardised Mean Difference (SMD) and a random-effects model. Publication bias and methodological robustness of the results were tested using the Egger regression test, the Trim-and-Fill method, and Leave-One-Out sensitivity analysis. The certainty of the evidence was graded using the GRADE system. ResultsExercise training was associated with a significant reduction in resting HRs and SBPs, which was a strong improvement in the haemodynamic profile. The improvements in SV and LVEF, although on the statistical threshold in the primary analysis, were statistically significant and methodologically stable in the Leave-One-Out sensitivity analysis, which excluded confounding studies. The exercise training was associated with a marked improvement in the E/A ratio and S wave, and the triggering of a physiological athletes heart-like eccentric hypertrophy, defined by improvements in LVMass and LVEDV. The exercise training was associated with diastolic adaptation and mass increase, with HIIT being the most superior method for diastolic adaptation and mass increase, and aerobic exercise being the most effective method for blood pressure reduction. Importantly, the meta-regression analyses revealed two important findings: first, the improvement in blood pressure and diastolic function was independent of weight loss; second, the improvement in structure and function was linearly related to improvements in body composition. ConclusionExercise acts as a cardiac polypill reversing the sedentary phenotype by improving hemodynamics and diastolic function independently of weight loss, while linking structural remodeling to BMI optimization; our data prioritize HIIT for structural/diastolic gains and Aerobic training for blood pressure control.

BACKGROUNDObesity and metabolic abnormalities were associated with increased risk of cardiovascular diseases (CVD). However, much remains unknown about which metabolic weight phenotypes and how relate to CVD, especially in postmenopausal women. METHODS AND RESULTSWe included 15,575 postmenopausal women aged 35 to 75 years (median age, 60.6 [IQR: 55.0-65.7]) free of CVD at baseline from a subcohort of the China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project between 1 January 2016 and 31 December 2020 in Guangdong Province at 8 sites. Cox regression models were used to investigate the associations of metabolic and overweight/obese status with the risk of developing CVD. Over a median follow-up period of 3.32 years, a total of 1354 CVD events occurred. Overall, 30.3% were metabolically heathy among the 9404 overweight/obese participants, while 49.2% were metabolically unhealthy among the 6171 normal weight subjects. Compared with the metabolically healthy normal weight group, the remaining three groups of participants were all at higher risk of combined CVD, with multivariate-adjusted hazard ratios and 95% confidence intervals of 1.41 (1.16-1.71) for metabolically unhealthy normal weight, 1.42 (1.16-1.73) for metabolically healthy overweight/obesity, and 1.75 (1.47-2.07) for metabolically unhealthy overweight/obesity. When subdividing overweight/obesity separately into overweight and obesity, combined CVD risk was only greater in metabolically unhealthy individuals across different weight categories. CONCLUSIONSPostmenopausal women with metabolically healthy overweight/obesity and metabolically unhealthy normal weight had a higher risk of cardiovascular disease than those with metabolically healthy normal weight, and the association of metabolically unhealthy overweight/obesity was greatest among four categories, suggesting that metabolic abnormalities and overweight/obesity should be monitored and controlled. CLINICAL PERSPECTIVEWhat Is New? O_LIPostmenopausal women with metabolic abnormalities combined with overweight/obesity and even normal weight had a higher risk of cardiovascular disease (CVD) than those with metabolically healthy normal weight. C_LIO_LIMetabolically healthy overweight/obesity were associated with greater risk of CVD, indicating that overweight/obesity alone may contribute to CVD risk in postmenopausal women. C_LI What Are the Clinical Implications? O_LIIndividuals who are metabolically unhealthy and overweight/obese warrant close clinical supervision, while those of normal weight should not be ignored. C_LI

IntroductionVisceral adiposity is emerging as a key driver of cardio-metabolic risk factors and cardiovascular disease (CVD), but its relationship with cardiac structure and function is not well characterized across sexes. Using the Canadian Alliance for Healthy Heart and Minds (CAHHM), a large population-based cohort study, we sought to determine the association of visceral adipose tissue (VAT) on subclinical left ventricular (LV) remodeling in males and females. MethodsAs part of the CAHHM study, 6522 participants free of clinical CVD (mean age: 57.4 [8.8 SD] years; 3,671 females, 56%) underwent magnetic resonance imaging (MRI) in which LV parameters and VAT volume were measured. Information about demographic factors, CV risk factors, and anthropometric measurements were obtained. Subclinical cardiac remodelling was defined as altered LV concentricity, represented by increased LV mass-to-volume ratio (LVMV). ResultsMales had a higher VAT volume (80.8 mL; 95% CI: 74.6 t 86.9) compared to females (64.7 mL; 95% CI: 58.5 to 70.8), adjusted for age and height. Among both males and females, VAT was significantly associated with subclinical cardiac remodeling (increased LVMV), independent of other CV risk factors. In multiple regression models adjusted for cardiovascular risk factors, age, and height, every 1 sex-specific standard deviation increase in VAT corresponded to an increase of 0.037 g/mL in LVMV (95% CI: 0.032 to 0.041; p<0.001), which was consistent across both sexes. Notably, a 1 standard deviation increase in VAT is associated with a LVMV that is 20 times higher than what is observed with natural aging alone (0.0020 g/mL rise in LVMV (95% CI 0.0016 to 0.0025), and 1.5 times higher than the impact of an integrated measure of CV risk factors (0.024 g/mL; 95% CI: 0.020 to 0.028). ConclusionVAT significantly influences subclinical cardiac remodeling in both males and females, independent of other cardiovascular risk factors and age. Further research to understand the pathways by which VAT contributes to accelerated cardiac aging is needed.

BackgroundAngiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are commonly prescribed alongside exercise to manage hypertension in individuals with metabolic syndrome (MetS). However, their potential to interfere with exercise-induced physiological adaptations remains unclear. MethodsIn this prospective, parallel-group study, 62 sedentary obese adults with MetS completed a 16-week supervised high-intensity interval training (HIIT) program. Participants were either chronically medicated with ACEi or ARBs (antihypertensive medication group, AHM, n=27) or a non-medicated control group (CONTROL, n=35). Primary outcomes included changes in resting and graded exercise blood pressure, MetS components, and cardiorespiratory fitness (CRF). ResultsBoth groups exhibited significant comparable improvements (all p time x group > 0.05) in cardiometabolic health (MetS Z-score; AHM -0.22{+/-}0.42; CONTROL - 0.30{+/-}0.33; p time < 0.001) and CRF (VO2MAX: AHM 3.9{+/-}2.1; CONTROL 5.0{+/-}3.1 mL{middle dot}kg-{superscript 1}{middle dot}min-{superscript 1}; p time = 0.003). Resting blood pressure decreased similarly in both groups (Mean Arterial Pressure: AHM -4.2{+/-}8.7; CONTROL -6.5{+/-}6.3 mmHg; both p time = 0.005; p time x group > 0.05). Additionally, antihypertensive medication did not interfere with the maximal (MAP; p time = 0.008) and submaximal (DBP; p time = 0.047) blood pressure exercise responses following training with no significant time x group interaction (both p > 0.05) ConclusionsChronic treatment with angiotensin antagonist medication to treat hypertension does not restrain the effects of supervised HIIT program on improving cardiovascular function, cardiorespiratory fitness, or reducing the components of MetS. Our findings support aerobic exercise training as an effective nonpharmacological co-therapy for hypertensive patients treated with angiotensin antagonists.

Background/AimThe possible association between serum monounsaturated fatty acids (MUFAs) and the risk of cardiovascular diseases (CVDs) has been examined in observational studies, which indicate controversial findings. In the current study, we used the Mendelian randomization (MR) analysis to determine the causal relationship of genetically determined serum MUFAs with the risk of various CVD outcomes, including angina, atherosclerotic, ischemic heart disease (IHD), myocardial infarction (MI), and high blood pressure (BP). MethodThe summary statistics dataset on the genetic variants related to serum MUFAs was used from the published GWAS of European descent in UK Biobank participants (N=114,999). Genetic variants underlying angina, atherosclerotic, IHD, MI, and BP events were ascertained using a GWAS dataset of 461,880 (case= 14,828, control= 447,052), 463,010 (case= 12,171, control= 450,839), 361,194 (case= 20,857, control= 340,337), 462,933 (case= 10,616, control= 452,317), and 461,880 (case= 124,227, control= 337,653) European descent participants from the UK Biobank, respectively. ResultsOur results showed that MUFAs were associated with angina [ORIVW= 1.005, 95% CI: 1.003- 1.007, p = <0.001; Cochrans Q=23.89, p=0.717, I2=0.0%; Egger intercept= -0.0003, p=0.289], atherosclerotic [ORIVW= 1.005, 95% CI: 1.003-1.007, p = <0.001; Cochrans Q=42.71, p=0.078, I2=27.4%; Egger intercept= -0.0004, p=0.146], IHD [ORIVW= 1.004, 95% CI: 1.001-1.007, p = 0.005; Cochrans Q=42.75, p=0.172, I2=18.1%; Egger intercept= -0.0001, p=0.827], MI [ORIVW= 1.001, 95% CI: 0.999- 1.003, p = 0.199; Cochrans Q= 23.03, p=0.631, I2=0.0%; Egger intercept= -0.0003, p=0.196], and BP [ORWM= 1.008, 95% CI: 1.001-1.015, p = 0.022; Cochrans Q= 52.87, p=0.015, I2= 37.6%; Egger intercept= 0.0002, p=0.779]. These results remained consistent using different Mendelian randomization methods and sensitivity analyses. ConclusionIn the present MR analysis, serum MUFA levels were associated with the risk of angina, atherosclerotic, IHD, MI, and BP. These findings prompt significant questions about the function of MUFAs in the progression of CVD events. Further research is required to elucidate the connections between MUFAs and CVD to contribute to health policy decisions in reducing CVD risk.

BackgroundBlood biomarkers can characterize the atrial substrate, helping to elucidate mechanisms of atrial fibrillation (AF) development. Understanding whether sedentary behavior affects AF-related biomarkers is key for future prevention strategies. MethodsWe studied 252 participants in PREDIMED-Plus, a multicenter randomized trial in Spain for the primary prevention of cardiovascular disease. A wrist-worn accelerometer was used to measure physical activity (PA) in a week at baseline and at least once during follow-up at years 3 and 5. Blood samples were collected at each time point to measure selected cardiovascular biomarkers: propeptide of procollagen type I, high-sensitivity (hs) troponin T (hsTnT), hs C-reactive protein, 3-nitrotyrosine, and N-terminal propeptide of B-type natriuretic peptide (NT-proBNP). Sedentary time was assessed as inactive time (< 1.5 METs in waking time). Using isotemporal substitution, we analyzed the impact of replacing 30-min sedentary time per day with low-intensity PA (LPA, 1.5-3 METs), moderate to vigorous PA (MVPA, > 3 METs) and time in bed (time difference between going to bed and getting up) on log-transformed biomarkers cross-sectionally and longitudinally, using linear regression and mixed models. ResultsAt baseline, 252 eligible participants averaged 65 years of age (SD 4.9), and BMI 32.2 kg/m{superscript 2} (SD 3.3), and 40% were female. Cross-sectionally, replacing 30-min sedentary time with LPA, MVPA, or time in bed had no significant association with biomarkers. After 5 years, replacing baseline 30-min of sedentary time per day with LPA or MVPA was associated with lower hs-TnT concentrations compared to baseline (-4%, 95% CI - 8%, -1%; -2%, 95% CI -7%, 4%, respectively). Substituting 30-min sedentary time with LPA or MVPA showed nonsignificant reductions in NT-proBNP (-3%, 95% CI -11%, 5%; - 8%, 95% CI -20%, 5%, respectively), but not a consistent association with other biomarkers. ConclusionIn overweight/obese individuals, prolonged sedentary time, when compared to engaging in PA, was associated with unfavorable changes of hs-TnT over 5 years, but no significant impact on other AF-related biomarkers.

AimsElevated body mass index (BMI) is a known risk factor for heart failure (HF), however, the underlying mechanisms are incompletely understood. The aim of this study was to investigate the role of common HF risk factors as potential mediators. Methods and ResultsElectronic health record data from primary care, hospital admissions and death registrations in England were used to perform an observational analysis. Data for 1.5 million individuals aged 18 years or older, with BMI measurements and free from heart failure at baseline, were included between 1998 and 2016. Cox models were used to estimate the association between BMI and HF with and without adjustment for atrial fibrillation (AF), diabetes mellitus (DM), coronary heart disease (CHD), and hypertension (HTN). Univariable and multivariable two-sample Mendelian randomisation was performed to estimate causal effects. Among non-underweight individuals, BMI was positively associated with HF with a 1-SD ([~] 4.8kg/m2) higher BMI associated with a hazard ratio (HR) of 1.31 (95% confidence interval [CI] 1.30, 1.32). Genetically predicted BMI yielded a causal odds ratio (OR) of 1.64 per 4.8 kg/m2 BMI (95% CI 1.58, 1.70) which attenuated by 41% (to OR of 1.38 (95% CI 1.31 - 1.45), when simultaneously accounting for AF, DM, CHD and SBP. ConclusionAbout 40% of the excess risk of HF due to adiposity is driven by SBP, AF, DM and CHD. These findings highlight the importance of the prevention and treatment of excess adiposity and downstream HF risk factors to prevent HF, even in people in whom the above risk factors are well managed. One-sentence summaryThis study of the role of excess adiposity as a risk factor for HF, including an observational analysis of measured BMI 1.5 million individuals and multivariable MR analysis of genetically elevated BMI, provides evidence that adiposity is causally associated with HF, with approximately 40% of the effect being mediated by conventional risk pathways. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/20200360v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@4f7eborg.highwire.dtl.DTLVardef@306863org.highwire.dtl.DTLVardef@15544corg.highwire.dtl.DTLVardef@51675e_HPS_FORMAT_FIGEXP M_FIG C_FIG

ObjectivesStatins appear to have pleiotropic effects. We examined whether specifically statins, of the major lipid modifiers, operate on ischemic heart disease (IHD) via testosterone. As a validation, we assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. DesignA sex-specific univariable and multivariable Mendelian randomization study SettingA large, population-based cohort study recruited in the UK from 2006-10, the UK Biobank Participants179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases Main Outcome measuresTestosterone and IHD ResultsOf the three lipid modulations considered, statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe, only genetically predicted statin use in men affected testosterone (-0.15 effect size testosterone per effect size lower (of low-density lipoprotein cholesterol), 95% confidence interval (CI) -0.23 to -0.06). The genetically predicted effect of statin use on IHD in specifically men was partially mediated by testosterone (odds ratio (OR) 0.55 per effect size lower (low-density lipoprotein cholesterol), 95% CI 0.38 to 0.79, compared to OR 0.73, 95% CI 0.46 to 1.11 after allowing for testosterone). The estimate for the effect of genetically predicted statin use, independent of testosterone, was very similar in women, giving overall meta-analyzed OR 0.72, 95% CI 0.57 to 0.90 per effect size lower of low-density lipoprotein cholesterol. The genetically predicted effect of anakinra use also affected testosterone (0.022 per effect size (of IL-1Ra), 95% CI 0.01 to 0.04), and increased IHD in men. ConclusionsStatins may partially operate via testosterone in men, which may contribute to sex-specific pleiotropic effects. Anakinra operating by testosterone may also explain its unexpected effects. Our findings could facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific investigations and possibly treatments. Section 1: What is already known on this topicStatins appear to have pleiotropic effects on cardiovascular disease. Whether such effects exist and why they should occur is unclear, but could be highly relevant to the prevention and treatment of the leading cause of death. Section 2: What this study addsOur study shows that statins have similar protective effects on ischemic heart disease via low-density lipoprotein cholesterol in men and women, but unlike other major lipid modifiers statins have an additional effect specific to men via testosterone, while any harms of anakinra in men may operate by a similar mechanism. Our findings highlighting the possibility of sex-specific causes of cardiovascular disease and the need for sex-specific investigations, prevention and treatment.

BackgroundIllicit use of anabolic androgenic steroids (AAS) is common among recreational athletes, yet comprehensive studies on adverse cardiovascular outcomes, especially in female AAS users, are lacking. MethodsA cross-sectional study of recreational athletes of women and men was conducted, involving active and previous AAS users and non-users aged [&ge;]18 years. Previous use was defined as discontinuation of AAS at least three months prior to study. Primary outcomes included atherosclerosis (carotid, femoral, and coronary artery plaques) and cardiac function, assessed using vascular ultrasound, coronary computed tomography angiography and echocardiography. ResultsMedian age was 36 years for active users (n=80, 19 women), 35 years for previous users (n=26, 8 women), and 40 years for non-users (n=58, 16 women) (p=NS). Median AAS usage period was 2.2 years for both active and previous users; the latter group had discontinued intake 2.5 years before study (range: 3 months to 29 years). There was no group differences when comparing the number of femoral/carotid artery plaques, the coronary artery calcium (CAC) score or the number of non-calcified plaques. However, confounder-adjusted logistic regression showed associations between cumulative AAS use and a positive CAC score (OR: 1.23, 95% CI: 1.09-1.39, p=0.001) and the presence of non-calcified plaque (OR: 1.17, 95% CI: 1.05-1.30, p=0.004), respectively, when comparing previous and ongoing users vs. non-users. These associations were also present in men, but not women. Moreover, >5 years of AAS use increased the fraction of athletes with increased severity of calcifications (p=0.043). Echocardiography showed that active AAS using males and females had impaired left ventricular global longitudinal strain (LVGLS) and right ventricular global longitudinal strain (RVGLS) compared to sex-matched non-users (p<0.001). Multivariable analysis showed that cumulative AAS use correlated with worsening of LVGLS (p=0.002) and RVGLS (p=0.001). Finally, after 5 years of cumulative AAS use, nearly all athletes had ventricular mass above and left ventricular ejection fraction below the median of normal range. ConclusionIn men, the cumulative lifetime AAS exposure was an independent predictor of coronary atherosclerosis. However, both male and female AAS users share risks of myocardial dysfunction, underscoring significant cardiovascular risks across genders. CLINICAL PERSPECTIVEKey observations from the study: O_LIIn recreational athletes, the accumulated lifetime AAS exposure associates with a higher prevalence of non-calcified plaques and coronary artery calcification in male recreational athletes. C_LIO_LIOur study suggests that more than 5 years of AAS use constitutes a threshold beyond which the development of coronary calcifications significantly increases compared to non-users. C_LIO_LIIn addition to compromised left ventricular systolic and diastolic function, AAS users exhibited significantly reduced right ventricular function, indicating a biventricular cardiac impact of AAS. C_LIO_LIMale and female AAS users showed similar patterns of cardiac deterioration. C_LI These findings highlight the significant cardiovascular risks associated with AAS use in both male and female recreational athletes, underscoring the importance of targeted research, educational programs, information campaigns, and intervention strategies for this population, regardless of gender.

AimsExplore the cardiovascular effects of long-term anabolic-androgenic steroid (AAS)-use in both current and former weightlifting AAS-users, and estimate the occurrence of severe reduced myocardial function and the impact of duration and amount of AAS. MethodsIn this cross-sectional study 101 weightlifting AAS-users with at least one year cumulative AAS-use (mean 11{+/-}7 accumulated years of AAS-use) were compared to 71 non-using weightlifting controls (WLC) using clinical data and echocardiography. ResultsSixty-nine were current, 30 former (> 1 year since quitted), and 2 AAS-users were not available for this classification. AAS-users had higher left ventricular mass index (LVMI) (106{+/-}26 versus 80{+/-}15 g/m2, P<0.001), worse LV ejection fraction (LVEF) (49{+/-}7 versus 59{+/-}5%, P<0.001) and right ventricular global longitudinal strain (RVGLS) (-17.3{+/-}3.5 versus -22.8{+/-}2.0%, P<0.001), and higher systolic blood pressure (SBP) (141{+/-}17 vs. 133{+/-}11 mmHg, p<0.001) compared with WLC. In current users accumulated duration of AAS-use was 12{+/-}7 years, and in former 9{+/-}6 years (quitted 6{+/-}6 years earlier). Compared to WLC, LVMI and LVEF were pathological in current and former users (p<0.05) with equal distribution of severely reduced myocardial function (LVEF [&le;]40%) (11% vs. 10%, NS). In current users estimated life time AAS-dose correlated with reduced LVEF and LVGLS, p<0.05, but not with LVMI, p=0.12. Regression analyses of the total population showed that the strongest determinant of reduced LVEF were not coexisting strength training or hypertension, but history of AAS-use ({beta} -0.53, P<0.001). ConclusionsLong-term AAS-users showed severely biventricular cardiomyopathy. The reduced systolic function was also found upon discountied use.

BackgroundLoss of functional capacity is one of the hallmarks in cardiovascular aging. Cocoa flavanols (CF) exert favorable effects on endothelial function, blood pressure, and inflammation. These cardiovascular health markers worsen with increasing age and limit functional exercise capacity. AimTo investigate the effect of CF on cardiorespiratory-fitness in healthy elderly. MethodsIn a randomized, double-masked, placebo-controlled, parallel-group dietary intervention trial, 68 healthy elderly (55-79 years, 28 female) received either 500 mg of CF or a nutrient-matched control capsule twice a day for 30 days. Primary endpoint was defined as peak oxygen consumption (VO2) in a cardiopulmonary exercise test (CPET). Secondary endpoints were oxygen pulse (VO2/heart rate (HR)), resting blood pressure (BP), and resting vascular function. ResultsAfter 30 days of CF intake peakVO2 increased by 190 ml/min (95% CI 1-371 ml/min) and peakVO2/kg by 2.5 ml/(min*kg) (95% CI 0.30-4.2 ml/(min*kg)). O2-pulse increased by 1.7 ml (95% CI 0.29-3.2 ml) and max exercise capacity by 9.6 W (95% CI 2.1-17.7 W). CF decreased resting systolic and diastolic BP by 5.4 mmHg (95% CI -10.7 - -0.1 mmHg) and 2.9 mmHg (95% CI (-) 5.5-(-) 0.4 mmHg), respectively. Flow-mediated vasodilation (FMD) increased by an absolute 1.3% (95% CI 0.76-1.79 %) in the CF group. Indexes of pulmonary function were not affected. No changes for primary and secondary endpoints were detected in control. ConclusionCF substantially improve markers of cardiorespiratory fitness in healthy elderly humans highlighting their potential to preserve cardiovascular health with increasing age.

Evidence supports associations of lifestyle-including diet and physical activity--and weight with cognitive functioning, but the pathways responsible for these associations have not been fully elucidated. Because healthier lifestyles have been associated with better left atrial structure and function, which in turn is associated with better cognitive functioning, we tested the hypothesis that left atrial structure and function is a potential mediator of the association between lifestyles and cognition. We included 476 participants with overweight or obesity and metabolic syndrome from three centers in Spain who underwent lifestyle assessment and transthoracic echocardiography at baseline and had repeated measurements of the Trail Making A test, a measure of executive function, at baseline and at the two-year follow-up. We conducted mediation analyses to test if measures of left atrial structure and function mediated associations between adherence to the Mediterranean diet scores, physical activity, or weight at baseline, and two-year change in Trail Making A scores. The analysis did not find an effect between these factors and Trail Making A scores, and no indirect effects mediated through the echocardiographic measurements. The modest sample size in this analysis is a limitation, and larger studies should be conducted to determine potential cardiovascular factors mediating the association between lifestyle and cognition.

AbstractO_ST_ABSBackgroundC_ST_ABSThe association between omega-3 fatty acids and cardiovascular disease has been examined in populations with established disease. However, the definitive role of omega-3 fatty acids in cardiovascular risk remains inconclusive, and evidence from general populations is still limited. This study aims to examine the causal relationship between omega-3 and cardiovascular disease using large-scale genetic data. MethodsWe employed five well-established mendelian randomization (MR) methods to investigate the causal association between omega-3 and cardiovascular events. Two large independent omega-3 GWAS (>110,000 participants each) from general populations were analyzed across 14 cardiovascular and metabolic phenotypes (>50,000 participants each). To understand the direct effect of omega-3 on coronary artery disease (CAD), multivariable MR (MVMR) model and mediation analysis were conducted. Summary-data-based MR (SMR) was applied to identify circulating proteins associated with omega-3 levels. ResultsGenetically elevated omega-3 levels were found associated with increased cardiovascular risk across all MR methods, particularly for CAD (Pmedian = 2.65E-04), myocardial infarction (Pmedian = 1.03E-07) and heart failure (Pmedian = 4.84E-03). Higher genetically predicted omega-3 were linked to elevated LDL-C (Pmedian = 2.50E-33) and its key component apolipoprotein B (Pmedian = 5.60E-08), while reducing triglyceride levels (Pmedian = 4.16E-03). Notably, after adjusting for the genetic effect of LDL-C, omega-3 demonstrated a protective effect on CAD ({beta}combined = -0.025, Pcombined = 0.022), which was strengthened by adjusting for both LDL-C and triglycerides. Mediation analysis suggests that omega-3 is likely to increase CAD risk through elevating LDL-C (P median = 2.40E-12), highlighting the need for effective LDL-C management to maximize the cardiovascular benefits of omega-3. Circulating proteins, such as ANGPTL3 (Psmr = 1.22E-27) and PCSK9 (Psmr = 1.15E-21), were also found positively associated with omega-3 levels. A reanalysis of clinical trial data confirmed that the cardiovascular benefits of omega-3 were closely related to the intensity of LDL-C lowering therapy. ConclusionsOur results suggest that the cardiovascular benefits of omega-3 fatty acids may depend on effective lipid management, particularly LDL-C control. Combining omega-3 supplementation with advanced lipid-lowering therapy may be critical for maximizing their protective impact on cardiovascular health.

BackgroundObstructive sleep apnea (OSA) is an independent risk factor for cardiovascular (CV) morbidity and mortality, but the benefit of continuous positive airway pressure (CPAP) therapy is uncertain. However, most randomized-controlled trials have focused on the role of CPAP in secondary prevention although there is growing evidence of a potential benefit on early CV disease. Weight loss in combination with CPAP may be superior but is difficult to achieve and maintain with conventional measures alone. The aim of this study was to gain insights into the effect of CPAP on early atherosclerotic processes and to compare it to a glucagon-like-peptide (GLP)-1-mediated weight loss regimen in OSA. MethodsWe performed a randomized proof-of-concept study (clinicaltrials.gov: NCT04186494) comparing CPAP, a liraglutide-based weight loss regimen (Lir) alone or both in combination for 24 weeks in 30 non-diabetic patients with moderate to severe OSA (50{+/-}7 years, 80% males, apnea-hypopnea index [AHI] 50{+/-}19/hr, body mass index [BMI] 35.0 {+/-}3 kg/m2). Baseline characteristics were similar between groups. Beside extensive evaluation for CV risk factors and endothelial function at baseline and end of study, subjects underwent 18F-fluorodeoxyglucose (FDG)-PET-CT for measurement of aortic wall inflammation (target-to-background ratio [TBR]) and coronary CT angiography (CCTA) for semi- automated coronary plaque analysis. ResultsCPAP alone and combination resulted in greater reduction in AHI than Lir alone at 24 weeks (mean difference -45/hr and -43/hr, respectively, vs -12/hr, p<0.05). Both Lir and combination led to significant weight loss of 6{+/-}3% and 4{+/-}4%, respectively. Despite CPAP resulting in small weight gain, only the CPAP alone group demonstrated a significant decrease in vascular inflammation (aortic wall TBR from 2.03{+/-}0.34 to 1.84{+/-}0.43, p 0.010) associated with improvement in endothelial function and decrease in C-reactive protein. Low-attenuation coronary artery plaque volume as marker of unstable plaque also decreased with CPAP (from 571{+/-}490 to 334{+/-}185mm3) and with combination therapy (from 401{+/-}145 to 278{+/-}126mm3) but not with Lir. ConclusionThese data suggest that CPAP therapy, but not GLP-1 mediated weight loss, improves vascular inflammation and reduces low-attenuation coronary artery plaque volume in OSA patients. These novel findings support the benefit of CPAP therapy in modifying early CV disease. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSThis is the first study comparing standard CPAP therapy to a GLP-1 mediated weight loss regimen in obstructive sleep apnea (OSA). The study utilized 18F-FDG PET CT and artificial intelligence-enabled coronary CT quantification of coronary artery plaque subtypes to determine treatment effects on early atherosclerotic disease processes. What are the clinical implications?CPAP in contrast to GLP-1-mediated weight loss may improve early atherosclerotic and potentially modifiable disease processes in obstructive sleep apnea (OSA). These data support the benefit of CPAP in the primary prevention of cardiovascular diseases in OSA.

BackgroundIntensive lifestyle intervention(ILI) in type 2 diabetes(T2D) improves cardiometabolic risk factors. Sex differences in these responses may be driven by the sex hormones testosterone(T), estradiol(E2), and sex hormone binding globulin(SHBG). We evaluated whether baseline sex hormone levels modify ILI effects on cardiometabolic risk factors ie, heterogeneity of treatment effect(HTE), and whether these modifications differ by sex. MethodsStudy included 2,260 Look AHEAD participants(1,093 postmenopausal females; 1,167 males, mean age 60 years) randomized to ILI or diabetes support and education with sex hormone measurements. We used linear mixed-effects models, stratified by sex and adjusted for age, race, study site, medications and baseline weight, to examine the association between baseline T, E2, and SHBG with change in lipids, hemoglobin A1c(HbA1c), systolic and diastolic blood pressure(BP), weight, and waist circumference(WC) over an 8-year follow-up. HTE was assessed using a three way interaction term between baseline hormone levels, time and randomization arm. Permutation tests controlled for multiple comparisons. ResultsIn males, lower baseline E2 and total T significantly augmented ILI-induced triglyceride reductions(p=0.019 and 0.008, respectively) throughout follow up. Higher SHBG enhanced LDL-C lowering in females(p=0.018) and HDL-C increases in males(p=0.043). Higher baseline total T predicted greater long-term weight(p=0.013 females; 0.003 males) and WC loss(p=0.061 females; 0.035 males), while fewer hormone interactions were observed for BP and HbA1c. ConclusionsMales with greater endogenous total T achieved larger reductions in triglycerides, weight, and WC, whereas females with higher total T had greater HDL-C improvements and those with higher SHBG experienced more BP lowering. Hormone profiling may guide personalized lifestyle prescriptions to improve long term cardiometabolic benefits. Clinical PerspectiveO_LIWhat Is New? Baseline sex hormone levels especially estradiol in males and testosterone/SHBG in females, sex-specifically modify the cardiometabolic benefits of intensive lifestyle intervention in type 2 diabetes. C_LIO_LIWhat Are the Clinical Implications? Endogenous hormone profiles may help clinicians personalize diet and exercise programs and guide adjunctive therapies to maximize lipid, blood pressure, and adiposity outcomes in females and males with T2D. C_LI

Background and AimsFamilial hypercholesterolemia (FH) is an autosomal dominant monogenic disease characterized by high low-density lipoprotein cholesterol (LDL-C) levels. Although carrying causative FH variants is associated with coronary heart disease (CHD), it remains unclear whether disclosing its associated cardiovascular risk affects outcomes in patients with FH. Here, we evaluated the efficacy of providing future cardiovascular risk based on genetic testing in addition to a standard FH education program. MethodsWe conducted a randomized, wait-list controlled, open-label, single-center trial. In the intervention group, we reported a future cardiovascular risk based on the genetic testing adding to standard FH education at week 0. In the wait-list control group, we only disseminated standard FH education according to the guidelines at week 0; they later received a genetic testing-based cardiovascular risk assessment at week 24. The primary endpoint of this study was the plasma LDL-C level at week 24. ResultsFifty eligible patients with clinically diagnosed FH, without a history of CHD, were allocated to the intervention group (n=24) or the wait-list control group (n=26). At week 24, the intervention group had a significantly greater reduction in LDL-C levels than the wait-list control group (mean changes, -13.1 mg/dL vs. 6.6 mg/dL; difference, -19.7 mg/dL; 95% confidence interval, -34 to -5.6; p=0.009). This interventional effect was consistent with FH causative variant carriers but not with non-carriers. ConclusionsIn addition to standard FH care, providing future cardiovascular risk based on genetic testing can further reduce plasma LDL-C levels, particularly among FH causal variant carriers. RegistrationJapan Registry of Clinical Trials (jRCTs04218002). URL: https://jrct.niph.go.jp/latest-detail/jRCTs042180027

Owing to the often prohibitively high costs of medical examinations, or an absence of infrastructure for linkage of study members to morbidity registries, much aetiological research in the field of cardiovascular research relies on death records. Because they are regarded as being more distal to risk factor assessment than morbidity endpoints, mortality data are generally maligned in this context for seemingly providing less clear insights into aetiology. The relative utility of mortality versus morbidity registries is, however, untested. In a pooling of data from three large cohort studies whose participants had been linked to both death and morbidity registries for coronary heart disease, we related a range of established and emerging risk factors to these two methods of ascertainment. A mean duration of study member surveillance of 10.1 years (mortality) and 9.9 years (morbidity) for a maximum of 20,956 study members (11,868 women) in the analytical sample yielded 289 deaths from coronary heart disease and 770 hospitalisations for this condition. The direction of the age- and sex-adjusted association was the same for 21 of the 24 risk factor- morbidity/mortality combinations. The only marked discordance in effect estimates, such that different conclusions about the association could be drawn, was for social support, total cholesterol, and fruit/vegetable consumption whereby null effects were evident for selected outcomes. In conclusion, variation in disease definition typically did not have an impact on the direction of the association of an array of risk factors for coronary heart disease.

BackgroundInflammation plays a key role in atrial fibrillation (AF) pathogenesis. The empirical dietary inflammatory potential (EDIP) score predicts circulating inflammatory biomarkers and adverse cardiac outcomes, but its association with incident AF is unclear. This study aimed to examine the relationship between EDIP score and AF risk. MethodsParticipants from the Atherosclerosis Risk in Communities (ARIC) free of baseline AF who completed a validated food frequency questionnaire were included. Correlation of EDIP with inflammatory biomarkers (factor VIII, fibrinogen, von Willebrand factor, and C-reactive protein) was examined at baseline. Incident AF was ascertained using electrocardiograms, hospital records, and death certificates. Cox proportional hazards models estimated hazard ratios of AF across EDIP quantiles and per SD increase, adjusting for sociodemographic and cardiovascular risk factors. ResultsAmong 8,277 participants (54.1 years old, 51.3% women, 80% white), higher EDIP score correlated with circulating inflammatory biomarkers at baseline. Over a median 24.2 years of follow-up, 1,453 had incident AF (incident rate 8.6 per 1,000 person-years). Compared with the most anti-inflammatory diet (EDIP Q1), the most pro-inflammatory diet (EDIP Q5) was associated with increased AF risk (HR 1.21; 95% CI 1.03-1.43). Sex-stratified analyses showed a stronger association in men (HR 1.43; 95% CI 1.14-1.79), while no significant association was observed in women. ConclusionsPro-inflammatory dietary patterns are independently associated with higher AF risk in a middle-aged cohort. These findings would support incorporating dietary inflammatory load into AF risk stratification. Clinical Perspective What Is New?O_LIHigher Empirical Dietary Inflammatory Potential (EDIP) scores, indicating a more pro inflammatory diet, were associated with an increased long-term risk of atrial fibrillation (AF) in a large, biracial, community-based cohort followed for over two decades. C_LIO_LISex stratified analyses revealed a significant sex difference: higher EDIP scores were consistently associated with increased AF risk in men, whereas no significant association was observed in women, suggesting sex-specific susceptibility to EDIP. C_LIO_LIObesity modified the association between EDIP and AF, with the strongest risk observed among individuals with BMI [&ge;]30, while an inverse or attenuated association was seen among normal weight participants. C_LI What Are the Clinical Implications?O_LIDietary inflammatory load may serve as a meaningful and modifiable upstream AF risk factor, complementing conventional cardiovascular risk assessment, particularly in men and individuals with obesity. C_LIO_LIIncorporating dietary pattern assessment into routine AF risk stratification may help identify individuals who could benefit most from targeted lifestyle interventions. C_LIO_LIPublic health and clinical prevention strategies promoting anti-inflammatory dietary patterns (e.g., increased intake of fruits, vegetables, and whole grains; reduced intake of processed meats and refined carbohydrates) could meaningfully reduce AF incidence. C_LIO_LIRecognition of sex specific differences in AF pathways reinforces the need for personalized preventive strategies, as diet inflammation mechanisms appear to influence AF development more prominently in men. C_LI