European Journal of Preventive Cardiology

Background Sedentary behavior (SB) has been associated with cardiovascular disease risk, independent of physical activity (PA) and sleep. However, the effect of replacing SB with PA or sleep on atrial fibrillation (AF) risk remains unclear. Methods We studied 86,096 participants from the United Kingdom Biobank (UKB) and 5,777 from the United States (US) REasons for Geographic And Racial Differences in Stroke (REGARDS) prospective cohort studies who were free of AF at baseline and had valid accelerometry data. The two cohorts were included to evaluate the consistency of associations across distinct populations in the UK and the US, two regions with a high burden of AF. Daily time spent in light PA (LPA), moderate to vigorous PA (MVPA), and SB were derived from accelerometer recordings; sleep was accelerometer-derived in UKB and self-reported in REGARDS. Incident AF was identified using ICD-10 codes (I48.x) listed as either a primary diagnosis, secondary diagnosis, or cause of death through hospital and death registry data linkage in UKB and in a follow-up visit through electrocardiogram and self-reported medical history in REGARDS. Isotemporal substitution models were used to examine replacing 30 minutes of SB with LPA or MVPA in both cohorts and with sleep in UKB on the outcome of incident AF. Results Among the UKB participants [57% female, mean age 56.0 (SD 7.8) years, 98% White race], 4,035 AF cases were identified during a median of 7.9 years of follow-up. Replacing 30 minutes of SB with PA was associated with a slightly lower risk of AF in the minimally adjusted models but the associations were attenuated after full adjustment (LPA: HR 0.99, 95% CI 0.95-1.02; MVPA: HR 1.00, 95% CI 0.99-1.02). The REGARDS participants had an average age of 63 (SD 8.3) years, 55% female, 31% Black and 69% White adults, with 486 AF cases identified. Fully adjusted substitution of 30 minutes of SB with MVPA was associated with lower AF odds (OR 0.80, 95% CI 0.63-1.01), whereas LPA showed no association. In UKB, replacing SB with sleep was not associated with AF risk. The magnitude of the association of MVPA substitution with AF appeared stronger among REGARDS participants aged [&ge;]65 years and those reporting <7 hours/day of sleep. Conclusion Replacing SB with moderate or higher intensity PA may decrease AF risk. In REGARDS, these substitutions appeared to benefit older individuals and those reporting shorter sleep duration. These findings highlight the potential benefit of reducing sedentarism to lower AF burden, warranting validation in future studies.

Background The consequences of prolonged exposure to obesity on biomarkers of myocardial stress and injury remain unclear. We examined associations of duration and cumulative severity of obesity from childhood to later adulthood with concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I (hs-cTnI), and growth differentiation factor-15 (GDF-15) at age 62 years. Methods The sample comprised 4,901 participants in the 1958 National Child Development Study who had measurements of NT-proBNP, hs-cTnI, or GDF-15 at age 62 years and at least four BMI assessments between 7 and 62 years of age. Individual BMI trajectories were modelled, from which total duration of obesity and mean excess BMI (area between the trajectory and the age-specific obesity threshold divided by duration) were derived. Associations of ever versus never having been obese, obesity duration, and mean excess BMI with biomarker concentrations were examined using general linear regression models with progressive adjustment for early-life characteristics; contemporaneous cardiometabolic factors; and health behaviours, socioeconomic position, and psychosocial factors. Nonlinear associations of obesity duration were estimated using restricted cubic splines and subsequently approximated using linear splines. Results Overall, 26.3% of participants had ever experienced obesity. There was no evidence of an association between ever versus never having been obese and NT-proBNP. Among men, ever having been obese was associated with 11.00% (95% CI, 4.62-17.37) higher hs-cTnI in the fully adjusted model, whereas there was no evidence of an association among women. Ever having been obese was associated with higher GDF-15, although the association attenuated substantially after adjustment for contemporaneous cardiometabolic factors. Longer obesity duration was associated with higher concentrations of all three biomarkers in fully adjusted models, but the pattern differed by biomarker: hs-cTnI increased approximately linearly with duration, whereas NT-proBNP and GDF-15 remained relatively stable up to approximately 25 years of obesity before increasing with longer duration. In fully adjusted models, each additional year of obesity beyond 25 years was associated with 1.80% (95% CI, 0.54-3.06) higher NT-proBNP and 0.81% (95% CI, 0.25-1.36) higher GDF-15, while each additional year across the full range of obesity duration was associated with 0.41% (95% CI, 0.07-0.76) higher hs-cTnI. Among participants who had ever experienced obesity, each 1 kg/m2 higher mean excess BMI was associated with 4.02% (95% CI, 1.79-6.24) higher NT-proBNP and 2.00% (95% CI, 0.49-3.51) higher hs-cTnI in fully adjusted models; there was no evidence of an association with GDF-15. Conclusions Longer duration of obesity was associated with higher concentrations of biomarkers reflecting myocardial stress, injury, and cellular stress at age 62 years, with associations particularly evident after approximately 25 years of obesity for NT-proBNP and GDF-15. These findings suggest that duration of obesity may provide clinically relevant information beyond current obesity status, supporting its consideration as an additional dimension of cumulative obesity burden in cardiovascular risk assessment.

Background. Information is lacking about everyday psychological states of individuals with a recent myocardial infarction (MI) and whether they influence outcomes. We investigated real world psychological experiences and their association with subsequent cardiovascular events in survivors of an MI. Methods. We studied 287 individuals [&le;] 60 years of age within 8 months from an MI. At the baseline visit, we assessed sociodemographic and clinical factors, and administered a battery of psychological scales of depression, anxiety, anger, perceived stress and social support. Participants underwent a 7-day home monitoring of mood and stress using ecological momentary assessments, and a momentary negative affect (MNA) score, integrating daily mean ratings of sadness, anxiety, anger, distress and loneliness, was calculated. Participants were followed for a median time of 28 months. The study endpoint was a composite index of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal MI, stroke or hospitalizations for heart failure. Cox proportional hazards models adjusted for sociodemographic and clinical factors. Results. The mean age of the sample was 51 years, and 43% of participants were women. Each standard deviation increase in MNA was significantly associated with a 60% increased risk of MACE (95% confidence interval (CI), 20% to 100%), irrespective of adjustment for sociodemographic factors and clinical characteristics. The association was similar in women and men. Momentary positive mood and momentary perceived stress were not associated with MACE. The MNA score showed a larger independent contribution to MACE compared to the combined battery of baseline psychological assessments and the association was independent of baseline history of depression. Conclusion. Among individuals after MI, moment-to-moment negative affect during one week of monitoring in daily life is a powerful predictor of subsequent cardiovascular events. A prospective evaluation of negative mood during everyday living could represent a novel strategy to uncover residual risk after MI.

The COVID-19 pandemic led to significant disruptions in cardiovascular care and reductions in physical activity, but little is known about how exercise patterns changed after this period. This study assessed changes in weekly aerobic and strength training activity between 2020 and 2022 amongst adults aged 18 years or older who reported one or more cardiovascular diseases or risk factors. This study used National Health Interview Survey data from 2020 and 2022. Adjusted differences for moderate-to-vigorous physical activity (MVPA) were calculated using a linear regression model and for strength sessions using a Poisson regression, adjusting for sex and age. Changes in these outcomes were then stratified by age and sex subgroups. The weighted study population included 182,783,008 (standard error, +/-3,334,337) adults in 2020 and 185,388,060 (SE, +/-3,285,161) adults in 2022. Between 2020 and 2022, the overall weekly MVPA increased from 244.2 (SE, +/-4.5) minutes to 266.3 (SE, +/-5.7) minutes (adjusted difference, +22.1 [SE, +/-6.92] minutes). There were no statistically significant changes in the number of strength session per week overall or among sex and age subgroups. Across sex and age subgroups, increases in weekly MVPA were entirely concentrated among males and younger adults. The recovery from pandemic era reductions in aerobic and strength exercise training was uneven amongst demographic subgroups, which aligns with concurrent persistent disruptions in cardiovascular care.

Background. Women with premature myocardial infarction (MI) have worse outcomes than similarly aged men despite less severe disease, and stress-related factors have been implicated. We examined sex differences in the association of mental stress-induced myocardial ischemia (MSIMI) with cardiovascular outcomes after premature MI and explored vascular and inflammatory mechanisms. Methods. We studied 602 individuals (mean age 51 years; 46% women) within 8 months of MI who underwent 99mTc-sestamibi myocardial perfusion imaging at rest and after mental stress. MSIMI was defined as a summed difference score [&ge;]3. We measured reactive hyperemia index (RHI) as peripheral microvascular reactivity to stress and interleukin-6 (IL-6) as inflammatory response to stress. The primary endpoint was cardiovascular death or nonfatal MI; the secondary endpoint added heart failure hospitalization. Cox proportional hazards models adjusted for sociodemographic factors, clinical, and psychiatric history. Results. MSIMI was more common in women than men (19.2% vs. 13.2%, p=0.04). Over a median follow-up of 34.2 months, 51 primary and 91 secondary endpoint events occurred. The hazard ratio (HR) of MSIMI for the primary endpoint was 3.2 (95% CI, 1.3, 7.6) in women and 1.9 (95% CI, 0.8, 4.5) in men (p for interaction=0.41), which remained similar after multivariable adjustment. The adjusted population attributable fraction was 27.6% (99% CI, 3.9%, 36.9%) in women and 11.1% (95% CI, ?5.8%, 18.4%) in men. In exploratory analyses, all MSIMI-related primary endpoint events among women occurred in Black women (HR, 4.3; 95% CI, 1.7?11.1). Associations with the secondary endpoint were weaker and attenuated after adjustment. IL-6 and RHI responses did not attenuate associations. Conclusions. Among women, MSIMI was associated with about threefold increased risk and over one quarter attributable fraction for cardiovascular death or nonfatal MI. Black women were at especially high risk. While larger studies are warranted to confirm sex differences and explore mechanisms, these data underscore the impact of emotional factors on morbidity and mortality in post-MI women.

Background: Endometriosis is a chronic gynecologic condition which has been linked with higher cardiovascular disease (CVD) risk. Although systemic inflammation is central to endometriosis and CVD pathophysiology, it remains unclear whether endometriosis is associated specifically with early-onset CVD and whether systemic inflammation modifies this association. Methods: This was a cross-sectional study of 5,345 women aged 20-54 years from the National Health and Nutrition Examination Survey (1999-2006). Endometriosis and early-onset CVD were self-reported. Early-onset CVD was defined as a composite measure of coronary heart disease, angina/angina pectoris, heart attack, congestive heart failure, or stroke. Systemic inflammation was measured using C-reactive protein [CRP; low/moderate ([&le;] 3 mg/L) and high (>3mg/L)] and the systemic immune-inflammation index (SII; tertiles). Survey-weighted logistic regression was used to assess associations and heterogeneity by systemic inflammation, with stabilized inverse probability weighting (IPW) to adjust for confounding. Results: Of the 5,435 women, 370 (6.9%) reported an endometriosis diagnosis and 162 (3.0%) early-onset CVD. After IPW adjustment for age, body mass index, smoking status, education, age at menarche, physical activity and race/ethnicity, endometriosis was associated with higher odds of early-onset CVD (prevalence odds ratio [POR] = 1.91, 95% CI: 1.23-2.97). This association was strongest among women with high CRP (POR= 2.33, 95% CI: 1.49-3.66), but not among those with low/moderate CRP levels (p-interaction= 0.086). Across SII strata, the strongest association was observed among women in the medium SII tertile (POR = 2.92, 95% CI: 1.47-5.78), with no associations in the low or high tertiles (p-interaction = 0.288). Conclusion: Endometriosis was associated with higher odds of early-onset CVD in this nationally representative sample of U.S. women. Although the strength of the association varied across CRP and SII strata, formal tests for interaction were not statistically significant. These findings should be understood as exploratory and require further investigation in prospective studies

Background Cardiovascular prevention is organized around target metrics. Blood pressure, LDL cholesterol, and A1c define treatment targets, quality metrics, and, implicitly, who is considered safe. Yet a value below a cutoff is a correlative measurement, not an outcome. We tested whether social context recorded before the measurement separated subsequent cardiovascular events among people whose numbers already met the cutoff. Methods In this retrospective cohort study, we analyzed All of Us participants without recorded cardiovascular disease and with low comorbidity in three separately indexed cohorts: systolic blood pressure (SBP), LDL cholesterol, and A1c. A preindex score combined household income, education, food security, physical activity, and ZIP-linked deprivation, standardized against a fixed pooled reference of 325,652 eligible people. The outcome was first myocardial infarction, ischemic stroke, or heart failure. A sensitivity analysis indexed participants at only events recorded in inpatient or emergency settings. Results The SBP, LDL, and A1c cohorts included 19,525, 16,578, and 18,539 participants with 144, 129, and 191 events. Each one-SD more favorable score was associated with lower hazard: HR 0.611 (95% CI 0.498-0.749), 0.631 (0.512-0.778), and 0.544 (0.457-0.648), respectively. Below each study cutoff (SBP <140 mmHg, LDL <100 mg/dL, A1c <8%), less favorable context had event rates of 3.39 versus 1.68, 7.16 versus 2.05, and 8.67 versus 2.34 per 1,000 person-years. In a one-year analysis restricted to 2019-2023 index dates, the corresponding adjusted HRs were 0.530, 0.336, and 0.365. In the sensitivity cohorts (54,338, 41,451, and 33,607 participants; 493, 288, and 316 events), HRs were 0.732 (0.657-0.815), 0.660 (0.573-0.761), and 0.631 (0.552-0.722). Conclusions A biomarker below the study cutoff did not identify a uniform, low-risk population. Social context recorded before the measurement separated cardiovascular events after adjustment for the measured value and clinical factors. Risk assessment that stops at the number misses this variation.

Background: Coronary perivascular fat attenuation index score (FAI-Score) on coronary computed tomography angiography (CCTA) quantifies vascular inflammation and predicts cardiac mortality in symptomatic cohorts. However, its prevalence, anatomical distribution, and clinical correlates in asymptomatic primary prevention populations remain uncharacterized. Methods: In an IRB-approved prospective study across two clinical sites, 84 consecutive asymptomatic adults (mean age 53.7 {+/-} 8.6 years; 63.1% men) with no prior coronary artery disease underwent screening CCTA and comprehensive clinical, metabolic, and biomarker profiling. AI-standardized FAI-Score was quantified across three epicardial vessels (LAD, LCx, RCA). High and very high perivascular inflammation were pre-specified as any vessel [&ge;]75th and [&ge;]90th percentiles, respectively. Luminal stenosis and plaque were graded using CAD-RADS 2.0. Results: Elevated FAI-Score ([&ge;]75th percentile) was present in 42.9% of participants (36/84; 95% CI 32.8% - 53.5%), with 17.9% (15/84; 95% CI 11.1% - 27.4%) exhibiting very high inflammation ([&ge;]90th percentile). Multi-vessel inflammation was identified in 17.9% (15/84), with the RCA most frequently involved ([&ge;]90th percentile in 13.1%). Standard circulating biomarkers, including ApoB, non-HDL-C, HbA1c, and PREVENT-ASCVD 10-year risk showed no association with binary inflammation. Systemic hs-CRP (median 0.8 mg/L) exhibited an inverse correlation with maximum vessel FAI-Score (Spearman {rho}=-0.27, p=0.014). Men demonstrated higher rates of elevated FAI-Score than women (52.8% vs. 25.8%, p=0.016; [&ge;]90th percentile: 26.4% vs. 3.2%, p=0.007). Strikingly, 46.2% (30/65) of participants with normal luminal anatomy (CAD-RADS 0) and 47.2% (25/53) with zero plaque burden harbored elevated FAI-Score; all 15 individuals with very high FAI-Score had CAD-RADS 0 (Fisher's exact p=0.018). Body mass index was the sole secondary correlate surviving false discovery rate correction (AUC = 0.71, p=0.001, all-test FDR q=0.028). Regularized multivariable models showed modest out-of-sample discrimination for FAI-Score elevation (cross-validated AUC = 0.71). Conclusions: Coronary perivascular inflammation is common among asymptomatic adults and frequently uncouples from structural plaque and luminal stenosis. Routine circulating biomarkers and clinical risk calculators fail to identify inflamed vessels, highlighting FAI-Score as an independent dimension of primary cardiovascular risk assessment.

Background: Handgrip strength is associated with cardiometabolic abnormalities, but whether it adds information once detailed adiposity and muscle mass are known is unclear. Methods: We studied adults aged 40-59 years from NHANES 2011-2012 (development, n=508) and 2013-2014 (temporal validation, n=616). The outcome was at least two of four non-adiposity abnormalities (elevated blood pressure, fasting glucose or triglycerides, or low HDL cholesterol); waist circumference was not part of the outcome. A prespecified feature ladder added DXA body fat percentage and visceral adipose tissue to age, sex, BMI and waist circumference (M1), then appendicular skeletal muscle index (M2), then absolute (M3A, primary) or weight-normalised (M3B) grip strength. Logistic regression was primary; elastic-net and XGBoost were supportive. Development performance used nested cross-validation; frozen models were scored once in the validation cohort. Paired increments used 2000 stratified bootstrap resamples. Results: The outcome occurred in 249 (49.0%) and 277 (45.0%) participants. Adding adiposity increased the logistic regression AUC by 0.0209 (95% CI 0.0024-0.0402) in development and 0.0209 (0.0032-0.0375) in temporal validation. Adding absolute grip strength to M2 changed the AUC by -0.0046 (-0.0107 to 0.0013) and 0.0045 (-0.0009 to 0.0098), respectively. All 12 grip-strength AUC increments across algorithms, definitions and cohorts had intervals that included zero. Calibration was unchanged and the incremental net benefit was not consistently positive. Model attributions to grip strength varied by algorithm. Conclusions: In middle-aged adults, detailed adiposity, but not grip strength, added reproducible information for concurrent cardiometabolic risk stratification beyond conventional anthropometry and muscle mass.

Background and Objectives: More research is required to determine the associations of high-density lipoprotein (HDL) cholesterol concentration and particle count with mortality. The objectives of this analysis were to investigate whether there were non-linear associations of HDL concentration with all-cause mortality, whether cardiovascular disease (CVD) deaths, cancer deaths or other deaths drove these associations, and whether small, medium, or large HDL particle count was associated with mortality. Methods and Results: The sample included 47,123 men and 97,589 women from the Mexico City Prospective Study. Models were adjusted for confounders and competing risks. There were 11,264 deaths in men and 15,486 in women. There was a J-shaped association of HDL concentration with all-cause mortality in men driven by other deaths. For example, compared with the >40th-60th percentile, the hazard ratio (95% confidence interval) for other mortality was 1.27 (1.11, 1.44) in the >95th-99th percentile and 1.82 (1.45, 2.28) in the >99th-100th percentile. There was a U-shaped association in women driven by CVD deaths at lower concentrations and other deaths at higher concentrations: the hazard ratio for CVD mortality was 1.23 (1.05, 1.43) in the two lowest percentiles groups and the hazard ratio for other mortality was 1.33 (1.18, 1.50) in the two highest percentile groups. Small HDL particle count was associated with reduced risk of all-cause, CVD, and other mortality in men and women. For example, compared with the bottom quartile, the hazard ratio for all-cause mortality was 0.79 (0.73, 0.86) in the top quartile in men and 0.77 (0.72, 0.82) in the top quartile in women. Conclusions: There is a J-shaped association of HDL concentration with mortality in men and a U-shaped association in women. More research is required to confirm the novel finding that small HDL particle count reduces the risk of all-cause, CVD, and other mortality in men and women.

Introduction: The evidence synthesis on literature characterizing changes in body fatness and adiposity distribution with sex steroid measurements in different matrices (blood, tissue, urine and other excreted matrices) is lacking. Methods: PubMed and Web of Science were used to identify eligible studies published until June 2026. Random-effects meta-analyses were conducted, and the strength of evidence was determined based on the Continuous Update Project criteria. Results: Of 16,875 screened references, 140 studies deemed relevant: 96 on circulating blood biomarkers from 39 weight loss intervention (surgical and lifestyle) and 60 observational studies reporting direct measure of adiposity distribution (e.g., DEXA, MRI), 20 studies on biomarkers measured in urine or other excreted matrices (i.e., saliva, urine, breast ductal lavage), and 25 tissue-based studies (e.g., adipose, breast, endometrial, skin). Weight loss was associated with a reduction of total and free testosterone, and an increase in sex hormone binding globulin (SHBG). While no significant associations were found between weight loss and premenopausal estradiol, dehydroepiandrosterone sulfate, and androstenedione. Decrease in total and free estradiol and estrone were observed in postmenopausal women. Findings in observational studies generally supported those results, as well as tissue-based studies on estrogen-related markers despite the heterogeneous tissue types. Studies on biomarker measured in excreted matrices were largely inconclusive. Conclusion: Strong evidence of a probable association was found between body fatness and SHBG, androgens, and postmenopausal estrogens. Limited evidence remained for other sex steroids.

Background Heart rate fragmentation (HRF) has emerged as a novel marker of sinoatrial instability and neuroautonomic dysregulation and is a predictor of incident cardiovascular disease (CVD) events and cardiovascular mortality. Leveraging heart rate fragmentation as a novel measure may help us better understand the prognostic significance of physical activity. Physical activity (PA) patterns are multidimensional and difficult to study holistically, however. We sought to examine for novel PA clusters in a cohort of veteran men and evaluate their prognostic significance based on their associations with neuroautonomic dysregulation. Methods In this cross-sectional study, we examined 602 male veterans from the Vietnam Era Twins Study of Electrophysiology in Posttraumatic Stress Disorder (VETS-EP) who were enrolled between 2022 and 2026. Accelerometry data were used to derive physical activity parameters across 6 domains: volume, sedentary behavior, intensity, diurnal pattern, fragmentation, and variability. Heart rate fragmentation was assessed using percentage of inflection points (PIP), inverse average length of segments (IALS), percentage of short segments (PSS), and percentage of alternating segments (PAS). Gaussian mixture models were used to derive digital phenotypes of physical activity, and associations with heart rate fragmentation were assessed using linear mixed models. Results Participants had a mean age of 73.8 {+/-} 2.9 years and 93.2% reported White race. Two overlapping phenotypes of physical activity patterns were identified: a compact-early phenotype, characterized by earlier activity timing and slightly greater overall activity, and a diffuse-late phenotype, characterized by later activity timing and greater heterogeneity in activity volume. In fully adjusted models, the diffuse-late phenotype was associated with higher PIP, the primary outcome ({beta}: 1.199, 95% CI: 0.034 to 2.363, p-value: 0.044), and higher IALS ({beta}: 0.01210, 95% CI: 0.00048 to 0.02373, p-value: 0.041), but not PSS or PAS, compared with the compact-early phenotype. Conclusions In older male veterans, Gaussian mixture model phenotyping identified two overlapping physical activity phenotypes, differing mainly in diurnal timing and in the dispersion of overall activity, that were associated with modest differences in heart rate fragmentation. These phenotypes provide a framework for capturing complex physical activity patterns. Future prospective studies representing diverse populations are needed to validate such phenotypes.

Background: Cardiovascular (CV) screening is critical for personnel deploying to Antarctica, where geographic isolation and limited medical care make the management of acute cardiovascular events challenging. The utility of contemporary risk prediction tools such as the AHA PREVENT equations in this unique population remains uncertain. Methods: We retrospectively analyzed 154 individuals referred for enhanced CV evaluation before deployment to the U.S. Antarctic Program (USAP). Participants were evaluated across three temporal cohorts (2018-2020, 2021-2023, and 2024-2026). Demographics, CV risk factors, cardiac testing, and deployment clearance outcomes were collected. Risk was estimated using the Framingham Risk Score (FRS), AHA/ACC Pooled Cohort Equations (PCE), and AHA PREVENT risk models. Results: The cohort was predominantly male (79.9%; mean age 44.6 {+/-} 14.6 years), and abnormal ECG was the most common referral trigger (70.8%). Median 10-year risk was low by PREVENT and FRS and borderline elevated by PCE (PREVENT 2.7% [IQR 1.1-6.6], FRS 2.3% [IQR 0.5-7.1], and PCE 6.1% [IQR 2.4-9.2]). Among 72 participants with all scores, 51% were classified discordantly; PREVENT ASCVD agreed closely with FRS (=0.77) but poorly with PCE (=0.24-0.35), which consistently estimated higher risk. PCE was calculable in 52.6% versus 70.8% for PREVENT. Overall, 132 participants (85.7%) were cleared for deployment, while 8 (5.2%) were not physically qualified (NPQ); 6 of these NPQs were due to cardiovascular causes. Of 22 cardiac medical evacuations during the study period, 21 involved individuals without prior advanced cardiovascular screening. One screened individual was evacuated for symptoms subsequently found to have no cardiac cause. Conclusions: Risk calculators disagree substantially in the fitness-selected population. We recommend PREVENT as the primary risk-stratification tool as it is the most contemporary derivation, incorporates renal function, is race-agnostic, extends to heart failure, applies from age 30, and agrees closely with FRS, easing transition. Targeted imaging, including coronary artery calcium scoring, may supplement intermediate-risk candidates.

IntroductionCirculating proteins may augment prognostic scores and provide mechanistic insights for cardiovascular disease. Their role for adding precision to predicting response to therapeutic exercise training is less certain. Older adults with HF frequently experience geriatric syndromes, which may influence response to a rehabilitation intervention (RI). We sought to determine if the functional benefits of a 12-week tailored, structured, and progressive multidomain physical RI program in older adults, following a HF admission, could be estimated by pre-intervention levels of proteins. MethodsHospitalized adults age [&ge;] 60 years with HF were randomized to 12-week multidimensional (aerobic, strength, balance, flexibility) physical therapist-led RI versus attention control (AC). Outcomes included change in the short physical performance battery (SPPB) and 6-minute walk distance (6MWD). At pre-intervention and 12-weeks, 92 circulating proteins associated with CVD and inflammation were measured. Using linear regression, LASSO and ensemble tree-based approaches for flexible feature selection, proteins were selected for stratification of treatment response. Decision trees were developed to incorporate a multi-protein approach to optimize stratification of treatment response (effect measure modifiers [EMM]) for both functional outcomes. Differences in 12-week temporal changes based on RI vs AC and mediation analysis were used to assess possible causal roles for these proteins. ResultsBaseline proteomic data was available in 243/349 participants (69.6%). For SPPB, 2 proteins (GP6, ST2), and for 6MWD, 3 proteins (ALCAM, Gal-4, PECAM-1) were selected as EMMs. For SPPB, a decision tree with ST2 followed by GP6 level identified a differential 12-week improvement in score for RI vs AC from -0.8 (95%CI -1.9, 0.2) to 2.1 (95%CI 1.5, 2.7). For 6MWD, the optimized decision tree was based only on ALCAM with a differential 12-week improvement in score for RI vs AC from 10m (95%CI -17m, 36m) to 85m (95%CI 56m, 113m). However, none of the EMM proteins were mediators of change for the functional outcomes. ConclusionsCirculating proteins related to CVD and inflammation (GP6, ST2, ALCAM) stratify a successful functional response to the REHAB-HF rehabilitation program in older adults following HF hospitalization. Further investigation is needed to identify proteins associated with a causal role for rehabilitation benefits.

Objectives: To compare high-sensitivity C-reactive protein (hsCRP) profiles in Korean and US adults with low-density lipoprotein cholesterol (LDL-C) below 100 mg/dL and examine differences after adiposity adjustment. Study design: Cross-sectional analysis of national health examination surveys. Methods: We analysed the Korea National Health and Nutrition Examination Survey 2022-2024 (n=5,785) and US National Health and Nutrition Examination Survey August 2021-August 2023 (n=1,056). Eligible adults had Sampson-calculated LDL-C below 100 mg/dL and hsCRP of 10 mg/L or less; elevated hsCRP was defined as 2-10 mg/L. We estimated survey-weighted prevalence differences and adjusted prevalence ratios (PRs). Results: LDL-C distributions closely overlapped (weighted medians, 79.7 vs 80.1 mg/dL), whereas median hsCRP was 0.50 vs 1.34 mg/L. Elevated-hsCRP prevalence was 12.2% in Korea and 35.7% in the United States (difference, 23.5 percentage points; 95% CI, 19.4-27.7); the age-sex-standardised difference was 23.4 percentage points. Among 6,235 common complete cases, the age-sex-adjusted US-versus-Korea PR was 2.86 (95% CI, 2.48-3.30), decreasing to 1.66 (1.40-1.98) after waist circumference adjustment and 1.92 (1.62-2.26) after body mass index adjustment. Conclusions: Similar LDL-C distributions coexisted with markedly different hsCRP profiles. Waist adjustment attenuated the between-country contrast more than BMI adjustment, supporting joint consideration of inflammatory, lipid and anthropometric measures in population surveillance.

Abstract Routine blood tests can be used to calculate several inflammation-related ratios, including the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR). These indices are widely reported as markers of cardiovascular risk, but it is unclear whether they provide comparable information or whether SII, which is derived from platelet count and NLR, adds anything beyond NLR. We analyzed two independent samples from the National Health and Nutrition Examination Survey (NHANES): 15,141 adults from 2005-2010 (development cohort) and 15,392 adults from 2011-2016 (validation cohort), each with complete blood count data and linked mortality follow-up. Survey-weighted Cox models, restricted cubic splines, multiple imputation, and model comparison were used, and the development model was applied to the validation cohort. During a median follow-up of 11.4 years, 795 cardiovascular deaths occurred in the development cohort; the validation cohort recorded 364 cardiovascular deaths over 5.75 years. In the development cohort, hazard ratios per 1-SD increase were 1.32 (95% CI 1.21-1.44) for NLR, 1.21 (1.12-1.32) for SII, and 1.13 (1.04-1.22) for PLR. When NLR and SII were entered together, only NLR remained associated (HR 1.49, 1.23-1.81). The validation cohort showed the same pattern: NLR was strongest (HR 1.35, 1.22-1.49), and neither SII nor PLR remained significant after mutual adjustment. The frozen model showed good discrimination (C-index 0.8991 to 0.9023) and calibration (slope 0.96). Adding NLR produced only a small improvement in discrimination, and reclassification results were inconsistent between cohorts.

Leisure time physical activity (LTPA) in mid-life may have beneficial effects on risk factors for hip fracture in later life. Conversely, physical activity may increase fracture risk through risk of injury, and the optimal amount of physical activity for reducing hip fracture risk remains unclear. We explored the associations between volume and intensity of LTPA in mid-life, and subsequent risk of hip fracture ascertained from linked health data. This prospective observational study used middle aged adults aged 40- 65 years from UK Biobank. LTPA volume (LTPAv) was derived from self-reported walking, moderate and vigorous activity at baseline (2006- 2010). Cox proportional hazard and Fine-Gray sub-distribution models were used to estimate the association between activity and hip fracture, which was sex-stratified. From 324,284 participants with complete data 53% were female and mean age at baseline was 54.5 (SD 7.3). Across 16 years of follow-up there were 2,674 hip fractures. In terms of LTPA volume, the lowest risk of hip fracture occurred in quintile 3 for women (HR 0.78, 95% CI 0.67-0.91), and men (HR 0.74, 95% CI 0.60- 0.90), relating to approximately one hour/day of leisure time physical activity. When activity intensities were examined separately, the lowest estimated hazards were observed for vigorous activity, at quintile 4 in women (HR 0.65, 95% CI 0.55 - 0.76) and quintile 3 in men (HR 0.64, 95% CI 0.52- 0.79), corresponding to approximately 60- 90 minutes of vigorous activity per week. In conclusion, moderately high volumes of mid-life physical activity, particularly vigorous activity, were related to lower risk of subsequent hip fracture, but these relationships appear to attenuate at higher volumes.

Background: Mitral valve prolapse (MVP) causes mitral regurgitation (MR), leading to volume overload and maladaptive left ventricular (LV) remodelling. Objective: To comprehensively characterize markers of maladaptive LV remodelling across MR severity grades in MVP using cardiovascular magnetic resonance (CMR), and their association with functional status. Methods: Patients with MVP undergoing 1.5T CMR (2016-2025) were stratified by MR fraction: mild<20%, moderate 20-39%, and severe [&ge;]40%. Exclusion criteria were significant coronary artery disease, rheumatic valve disease, mitral stenosis, previous mitral valve procedures, endocarditis or signs of primary cardiomyopathy. Global native T1, T2, extracellular volume (ECV), indexed ECV (iECV), indexed intracellular volume (iICV), and late gadolinium enhancement (LGE) were quantified. Indexed LV end-diastolic volume (EDVI) and the EDV-to-LV mass ratio (EDV/LVM-ratio) were also calculated as indices of LV remodelling and adaptive hypertrophy. Functional status was assessed by NYHA class. Results: Among 112 MVP patients (23 mild, 48 moderate, 41 severe MR) and 20 controls, LGE prevalence (17% vs. 46% vs. 51% vs. 0%) and the proportion with LV dilatation (46% vs. 67% vs. 88% vs 15%) rose progressively with MR severity. Increased EDVI, prevalence of LGE, higher EDV/LVM-ratio, global native T1 and iECV showed the strongest associations with more severe MR, whereas EDV/LVM-ratio, iECV and global native T1 were independently related to NYHA class[&ge;]II. Conclusions: CMR markers of maladaptive LV remodelling were abnormal across all MR grades and increased markedly with MR severity. Global native T1, iECV and EDV/LVM-ratio correlated most strongly with symptom burden, rather than MR severity per se.

Observational studies suggest an association between COVID-19 and acute myocardial infarction (AMI), however, whether this relationship is causal remains unclear. We conducted a multi-ancestry Mendelian randomization (MR) study across European, East Asian, South Asian, and African populations, evaluating three COVID-19 phenotypes: very severe COVID-19, hospitalized COVID-19, and general infection association with AMI. GWAS summary statistics were obtained from the COVID-19 Host Genetics Initiative Round 7 and UK Biobank/Biobank Japan for AMI. Inverse-variance weighted (IVW) MR was the primary method, with fixed- or random-effects models selected according to heterogeneity test. MR-Egger, weighted median and weighted mode were conducted as sensitivity analyses. In European ancestry, genetic liability to very severe COVID-19 and hospitalized COVID-19 was slightly inversely associated with AMI risk, but without statistical significances across sensitivity analyses. Hospitalized COVID-19 showed a suggestive but non-significant inverse association in South Asian ancestry. No significant associations were identified in East Asian or African ancestries. Our findings did not support a robust causal association between COVID-19 susceptibility or severity and AMI risk across ancestries, suggesting that the observed cardiovascular burden may be driven more by acute pathophysiological mechanisms than shared genetic architecture.

Background and Aims: Quantifying arterial inflammation can augment risk stratification and drug development in atherosclerosis. While perivascular adipose tissue (PVAT) density, captured as fat attenuation index (FAI) on CT angiography (CTA), is an emerging biomarker of coronary inflammation, it remains unclear whether this concept extends to carotid atherosclerosis. Methods: Using routine CTA data from hospital-based stroke cohorts, we developed a pipeline to quantify attenuation metrics of PVAT surrounding the distal common and proximal internal carotid arteries. We compared PVAT metrics between culprit and contralateral non-culprit plaques in patients with symptomatic carotid atherosclerosis and between culprit plaques and control carotid segments from patients without symptomatic atherosclerosis. In patients undergoing carotid endarterectomy, we assessed associations of CTA-derived PVAT metrics with histological and proteomic markers of plaque inflammation and stability. Results: Across 107 patients with symptomatic carotid atherosclerosis (75.5{+/-}8.7 years; 63% men), PVAT attenuation metrics did not show significant differences between culprit and contralateral non-culprit lesions (all p>0.2). We also found no evidence for higher PVAT attenuation in culprit lesions, when compared to arteries of patients without symptomatic atherosclerosis. In 82 patients undergoing endarterectomy, pre-operative CTA-derived metrics of PVAT attenuation showed no significant correlations with CD68+ macrophage areas in excised plaques (r -0.11 to 0.07, all p>0.3). Similarly, no PVAT attenuation metrics were associated with thinner fibrous cap or higher plaque levels of pro-inflammatory cytokines (IL-6, TNF). Conclusions: In contrast to coronary atherosclerosis, carotid PVAT attenuation was not associated with symptomatic culprit lesions or histological and molecular markers of plaque inflammation and vulnerability.