European Journal of Preventive Cardiology

Aims: Sex differences in cardiac electrophysiology and cardiovascular (CV) risk are well established, but the extent to which circulating hormonal markers contribute to electrocardiogram (ECG) morphology remains unclear. We investigated whether hormone-related ECG components are associated with incident CV events and whether these associations differ by sex and menopausal status. Methods: In a prospective cohort (N=8,056 UK Biobank participants; median follow-up: 12.8 years), we first evaluated direct associations between sex hormones and incident CV disease. Based on initial risk signals, two-stage analyses focused on premenopausal females and males. Linear regressions evaluated associations between standardized hormonal markers and residualized lead-I ECG parameters after confounders adjustment. Cox proportional hazards models then tested whether the hormone-predicted ECG components were associated with incident CVD events. Results: In premenopausal females (N=980), higher free androgen index (FAI) was positively associated with QRS amplitude ({beta}=19.17V, p-value=0.038) and the FAI-predicted QRS amplitude component was associated with incident CVD (Hazard Ratio [HR]=1.41, p-value=0.02). In males (N=3,997), FAI was inversely associated with QTc duration ({beta}=-0.95ms, p-value=0.005), and its predicted component with increased CVD risk (HR=1.32, p-value<0.001). Conversely, higher sex hormone-binding globulin (SHBG) prolonged QTc, with its predicted component also conferring risk (HR=1.15, p-value=0.004). Additionally, FAI directly associated with ST segment deviation ({beta}=19.17V), whose predicted component was protective (HR=0.76, p-value<0.001). Conclusions: This study shows that SHBG and FAI subtly modulate specific depolarization and repolarization ECG parameters. Relative androgen excess in premenopausal females and lower androgenic status in males appear to be associated with subclinical electrophysiological variations linked to long-term CV risk.

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.

Introduction: Psychological distress is associated with metabolic alterations that contribute to adverse cardiometabolic outcomes across diverse populations. We previously developed a metabolite-based distress score (MDS) in predominantly White women. Because men and Black individuals suffer high rates of cardiometabolic disease, we evaluated whether the MDS is similarly associated with depression in these populations, and derived a multi-ethnic MDS (MDS-ME) among Black individuals with replications in independent samples. Methods: Data were from three U.S. cohorts, the Multi-Ethnic Study of Atherosclerosis (MESA), Women's Health Initiative (WHI), and Nurses' Health Study (NHS), evaluated in 4 stages. Stages 1-3 included 2,477 White and 1,625 Black MESA participants with depression status data and plasma metabolomics assessed at baseline. Stage 1: We calculated the MDS and examined its association with depression status. Stage 2: We conducted an agnostic analysis among a 70% random subset of Black participants to identify additional relevant metabolites. Stage 3: We derived an MDS-ME in Black participants. Stage 4: We evaluated the MDS-ME using independent samples from all three cohorts. Results: The previously validated 20-metabolite MDS showed stronger associations with prevalent depression in White (OR: 1.93, 95% CI: 1.71, 2.19) versus Black (OR: 1.13, 95% CI: 0.97, 1.33) MESA participants. Associations were generally similar in men and women. The MDS-ME comprised 33 metabolites, and relative to the MDS was more strongly associated with depression in Black participants (OR: 1.45; 95% CI: 1.04, 2.03), with associations also evident in White participants (OR: 1.81; 95% CI: 1.60, 2.04). The MDS-ME was similarly associated with depression in Black women in WHI and NHS. Conclusion: Results suggest that incorporating metabolites identified in Black participants enhances the utility and generalizability of the MDS across more diverse populations.

Aims: Religiosity and spirituality (R/S) are generally associated with a more favourable cardiovascular risk profile, but longitudinal evidence is limited. We examined whether multidimensional R/S predicts its future behavioural and biological components. Methods: This prospective cohort study analysed 6,844 adults aged [&ge;]50 (56% women; mean R/S score 2.1; 20% weekly attenders; 81% Christian) from waves 4-7 of the English Longitudinal Study of Ageing (ELSA). Behavioural outcomes included smoking, exercise, alcohol intake, and fruit and vegetable consumption; biological outcomes included blood pressure (BP), haemoglobin A1c (HbA1c), and the inflammatory risk markers C-reactive protein (CRP) and fibrinogen. R/S was assessed with four items from the Santa Clara Strength of Religious Faith Questionnaire. Hierarchical linear and logistic regressions adjusted for age, sex, wealth, education and ethnicity; biomarker models also adjusted for health behaviours and body mass index. Results: Greater spirituality (B=-0.019; 95%CI[-0.036,-0.003]), daily prayer/meditation (B=-0.017; 95%CI[-0.032,-0.002]), participation in organized religion (B=-0.017; 95%CI[-0.032,-0.002]), and importance of religious faith (B=-0.017; 95%CI[-0.033,-0.002]) were independently associated with lower fibrinogen levels. Daily prayer/meditation also independently predicted higher fruit and vegetable intake (B=0.004; 95%CI[0.000,0.008]). However, frequent attendance (OR=0.846; 95%CI[0.730,0.982]), the significance of faith (OR=0.935; 95%CI[0.879,0.994]), and religious purpose (OR=0.939; 95%CI[0.884,0.997]) independently reduced the odds of meeting exercise recommendations. Similarly, frequent attendance was associated with higher HbA1c (B=0.002; 95%CI[0.000,0.005]). There were no independent associations with CRP or blood pressure. Conclusion: R/S showed mixed prospective associations with the cardiovascular risk profile: favourable for fibrinogen and fruit and vegetable intake, unfavourable for physical activity and HbA1c.

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.

Abstract Background: Coronary artery calcium (CAC) imaging directly assesses subclinical calcified coronary atherosclerosis, but population-wide imaging is not recommended. Simple pre-screening may help identify individuals most likely to benefit from CAC imaging. We previously developed a self-report-based model to estimate the probability of CAC [&ge;]100. This study prospectively evaluated a strategy based on this model to select individuals for CAC imaging. We assessed agreement between model-predicted probability and observed prevalence of CAC [&ge;]100 among participants undergoing computed tomography (CT) imaging and examined patterns of preventive lipid-lowering therapy. Methods: The PRedict and Identify cOronary atherosclerosis-Now (PRIO-Now) study applied a prospective, two-step, population-based screening approach. Individuals aged 59-60 years were invited to complete a self-report questionnaire. Eligible respondents without previous ischemic heart disease whose model-predicted probability of CAC [&ge;]100 exceeded the predefined threshold were invited to clinical assessment and non-contrast coronary CT imaging. The primary analysis assessed agreement between model-predicted probabilities and the observed prevalence of CAC [&ge;]100 among CT completers. Results: Of 8,000 invited individuals, 2,588 (32%) completed the questionnaire. Of 2,375 eligible respondents, 814 were classified as high risk and 563 underwent CT imaging. Among CT completers, the mean predicted probability of CAC [&ge;]100 was 28.3% (95% CI 27.2-29.3), compared with an observed prevalence of 28.4% (95% CI 24.8-32.4), corresponding to an expected/observed ratio of 0.99 and a Brier score of 0.19. Among participants with CAC [&ge;]100, 64% were not receiving lipid-lowering therapy and 11% had LDL-C [&ge;]1.8 mmol/L. Conclusions: A self-report-guided strategy enabled targeted CAC imaging in a model-selected cohort. Among participants completing CT imaging, the observed prevalence of CAC [&ge;]100 was comparable with the mean model-predicted probability. These findings suggest that self-report data may support pre-selection for CAC imaging and help identify opportunities for preventive treatment among individuals with elevated CAC.

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: Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTCA) has emerged as a novel non-invasive biomarker of coronary inflammation and cardiovascular risk. The degree to which PCAT reflects local or systemic inflammation remains uncertain. We hypothesized that the presence, location and extent of PCAT would be associated with transcoronary or transcardiac cytokine gradient. Methods: This prospective cohort study involved 31 adults with stable coronary artery disease who underwent clinically indicated CTCA within 90 days of invasive coronary angiography. Patients with acute coronary syndromes or unstable angina were excluded. Blood samples were obtained from peripheral vein, coronary sinus, aortic root, and right coronary artery at time of cardiac catheterization. Plasma interleukin-6 (IL-6) and interleukin-1{beta} (IL-1{beta}) concentrations from each site were used to calculate transcardiac and transcoronary cytokine gradients. PCAT attenuation was measured using semi-automatic software by readers blinded to clinical and biochemical endpoints. Results: Participants were predominantly male (76%), aged 66.6 {+/-} 9.4 years, with a high prevalence of hypercholesterolemia (76%), hypertension (73%), and diabetes (36%). Mean PCAT attenuation was -74.8 HU (RCA), -70.3 HU (LCx), and -73.6 HU (LAD). Regression analyses showed no significant associations between PCAT attenuation and IL-6 gradients across any coronary territory (all p >0.40; R2 {approx} 0), including in plaque-free subgroup analyses. IL-1{beta} was below the assay detection limit in 81% of participants; analyses using non-parametric testing and logistic no association with PCAT attenuation. RCA (OR 0.96, 95% CI 0.88-1.06, p=0.46), LCx (OR 1.00, 95% CI 0.91-1.09, p=0.94), LAD (OR 0.99, 95% CI 0.90-1.08, p=0.81). Conclusion: In a cohort with predominantly stable coronary disease, PCAT attenuation was not associated with intracardiac or intracoronary IL-6 or IL-1{beta} gradients, including in plaque-free vessels. These findings suggest that PCAT attenuation may not reflect active cytokine-mediated coronary inflammation in stable disease.

Background and Aims: Steps are increasingly used to prescribe physical activity, but their impact on quality of life (QoL) remains unclear. We examined the dose-response association between step metrics and QoL, and whether cardiovascular disease (CVD) status moderates this association. Methods: Individual-level data of five studies were pooled. Physical activity was measured with thigh-worn accelerometry. We assessed steps/day, daily minutes of fast stepping ([&ge;]100 steps/min), peak 1- and 30-min cadence. We investigated the association of step metrics and QoL (questionnaire-based; standardized) with multivariable (non-)linear regression, and the interaction with CVD status. Results: We included 9,371 participants (62 [54-68] years; 47% female), comprising 1,977 individuals with and 7,394 without CVD. Significant, curvilinear dose-response associations between step metrics and QoL were found. The optimal step volume was 6,561 steps/day which associated with a 0.35 SD (95%CI: 0.28-0.42) higher QoL compared to the referent 4,000 steps/day. The optimal doses for peak 1-min and peak 30-min cadence were 107 steps/minute (+0.34 SD; 95%CI: 0.28-0.41) and 74 steps/minute (+0.29 SD; 95%CI: 0.24-0.34) respectively, compared to references of 90 and 60 steps/minute. Only fast stepping interacted with CVD status, with a lower optimum in those with versus without CVD (4 minutes/day, +0.20 SD, 95%CI: 0.12-0.28 versus 9 minutes/day, +0.19 SD, 95%CI: 0.12-0.25), compared to the referent 2 minutes/day. Conclusions: Step metrics were curvilinearly associated with QoL with optimal benefits at ~6,500 steps/day. Optimal QoL benefits can be reached at feasible stepping targets, and at slightly fewer daily minutes of fast stepping in CVD versus non-CVD.

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.

Abstract Background Premature, or early-onset, coronary artery disease (CAD) carries lifelong consequences. Ethnic inequalities in CAD are established in the UK, but risk estimates mostly derive from events after middle age, while ethnicity is aggregated for South Asian and Black populations. Disaggregated, sex-specific risk estimates would permit better recognition and more targeted prevention. Methods We used Clinical Practice Research Datalink (CPRD) Aurum, an English primary care database linked to hospital, mortality, and deprivation data. We included adults aged 18-45 of White European, South Asian (Indian, Pakistani, Bangladeshi), or Black (African, Caribbean) ethnicity, followed for up to 20 years. Incident premature CAD (onset [&le;]45) was a first myocardial infarction or coronary revascularisation. We estimated age-adjusted and fully adjusted incidence rate ratios (IRRs) versus White Europeans by Poisson regression, testing an ethnicity-sex interaction. Findings Among 14.8 million adults contributing 80.9 million person-years, 16,001 premature CAD events occurred (77.6% in men). In men, the combined South Asian age-adjusted IRR was 1.87 [95% CI 1.77, 1.99], ranging from 1.39 [1.28, 1.50] in Indian to 2.79 [2.52, 3.07] in Bangladeshi men, persisting after full adjustment and already evident at ages 18-26. The combined Black IRR was 0.64 [0.57, 0.71], lowest in African (0.57[0.50, 0.65]) and highest in Caribbean men (0.82 [0.68, 0.98]). In women, the combined South Asian IRR showed no overall excess (1.10 [0.95, 1.26]), concealing a clear excess in Pakistani women (1.56 [1.29, 1.89]). The ethnicity-sex interaction was significant (p<0.001); the male-to-female ratio was highest in Bangladeshi individuals (8.4:1 versus 3.3:1 in White Europeans). Interpretation Aggregated ethnic categories conceal sex-specific subgroups at high risk of premature CAD, a risk already present in early adulthood. Current screening and health check programmes beginning at age 40, start too late to reach these higher-risk, underserved groups. Funding: Kusuma Trust and NIHR UCLH BRC.

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 Atrial fibrillation (AF) is associated with declines in physical function. While physical activity is linked to better physical function in the general population, its long-term impact in people with AF remains unclear. Investigating this relationship could provide insights and inform interventions for this population. Methods 624 participants with AF from the Atherosclerosis Risk in Communities (ARIC) cohort assessed in 2011-2013 were studied. Physical activity was assessed using the modified Baecke Physical Activity Questionnaire. Physical function was measured using the Short Physical Performance Battery (SPPB), grip strength, and 4-meter walk time up to 3 times over an 8-year period, with 4-meter walk speed as a secondary outcome evaluated in supplemental analyses. Confounder-adjusted linear mixed models were used to assess associations between physical activity and change in physical function trajectories over time. Results Participants had a mean age of 78.5 {+/-} 5.4 years, with 52.6% males and 13.8% Black. Median follow-up was 6.6 years. At baseline, greater sport-related leisure time, non-sport leisure time, and total moderate-to-vigorous physical activity (MVPA) were cross-sectionally associated with better physical function. However, physical activity measures were not significantly associated with temporal trajectories in physical function over time. Conclusions In participants with AF, greater habitual physical activity was significantly associated with better baseline physical function but not with future trajectories. Randomized trials are needed to examine whether interventions that improve habitual physical activity or MVPA can improve physical functioning in individuals with AF.

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: The INTERHEART-Middle East study identified the Middle East and North Africa (MENA) region as having the youngest age at first acute myocardial infarction (AMI) globally, with a population-attributable risk of 97.5% across nine modifiable risk factors. The population-level trajectories of cardiometabolic risk factors that precede this premature MI signature in young MENA adults remain incompletely characterized. Methods: NCD Risk Factor Collaboration (NCD-RisC) modeled prevalence estimates were analyzed across 16 MENA countries (Bahrain, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunisia, United Arab Emirates, Yemen) in adults aged 20-29 and 30-39 years, stratified by sex: obesity and diabetes prevalence through 2022, hypertension prevalence through 2019 (ages 30-39 only, by data availability), and non-HDL cholesterol through 2018. Five-year age bands were aggregated into 20-29 and 30-39 groups by equal-weighted mean (with UN World Population Prospects 2024 population-weighted aggregation tested as a sensitivity analysis). Each country x sex x age-band x risk-factor series was analyzed using (1) joinpoint regression for the average annual percent change (AAPC); (2) posterior probability of true 1990-to-endpoint change derived from published credible intervals; and (3) a mixed-effects model with a year x region (MENA vs. rest-of-world [ROW]) interaction and country-level random slopes. Sensitivity analyses excluded conflict-affected states and Iran. Results: MENA diverged significantly from ROW in 6 of 14 sex x age-band comparisons, with a sex-asymmetric direction. In men, MENA worsened faster than ROW: obesity, ages 20-29 (AAPC +3.49%/year; p=0.009); obesity, ages 30-39 (AAPC +2.65%/year; p=0.043); and diabetes, ages 30-39 (AAPC +1.90%/year; p=0.014). In women, MENA improved faster than ROW: hypertension, ages 30-39 (AAPC -0.58%/year; p=0.001); non-HDL cholesterol, ages 20-29 (p=0.017); and non-HDL cholesterol, ages 30-39 (p=0.017). Country-level posteriors confirmed near-universal regional patterns: 60 of 64 obesity cells showed a very probable increase since 1990, and 52 of 64 (81%) non-HDL cholesterol cells showed a probable or very probable decrease. Five of the six divergent findings survived correction for multiple testing. Conclusion: Cardiometabolic risk in young MENA adults is diverging from global patterns in a sex-asymmetric way: obesity and diabetes are accelerating in young men, while hypertension and lipid profiles are improving in young women. This pattern maps directly onto the young-male AMI signature reported by INTERHEART-Middle East and identifies obesity and diabetes in young men as the most urgent targets for regional primary prevention.

Objective: To investigate the association between usual moderate-to-vigorous leisure-time physical activity (MVLTPA) and longitudinal trajectories of BMI and waist-to-height ratio (WHtR), as well as the incidence of obesity (BMI >=30 kg/m2) and central adiposity (WHtR >=0.6), in older adults at high cardiovascular risk. Methods: In PREDIMED participants aged 60-80 years (61% women; n=5,273 for BMI, n=4,940 for WHtR), MVLTPA was assessed using the Minnesota questionnaire (MET-min/day, cumulative mean). Mixed-effects models with cubic splines were used to estimate BMI and WHtR trajectories according to MVLTPA levels (>=100 [adequate] vs <100 [insufficient]). Incident obesity outcomes were assessed with Cox models. Results: Participants reporting >=100 MET-min/day showed lower BMI and WHtR values compared with less active individuals (differences ranging from -1.27 to -1.48 kg/m2 and -0.021 to -0.026, respectively), and slower declines in BMI. Adequate MVLTPA was associated with a 34% lower risk of central adiposity (HR 0.66 [0.56; 0.77]) and a 24% lower risk of obesity only in women (HR 0.76 [0.57; 1.00], p-interaction = 0.084). Nonlinear analyses suggested that central adiposity risk decreased up to 400 MET-min/day and plateaued thereafter. Conclusions: Higher MVLTPA is associated with favourable adiposity trajectories and lower central adiposity risk in older adults at high cardiovascular risk.

Background: Electrocardiographic markers of atrial cardiomyopathy (AtCM) are associated with adverse cardiovascular outcomes. Whether AtCM further refines cardiovascular disease (CVD) mortality risk across increasing cardiometabolic risk factor (CMRF) burden is unclear. Methods: We analyzed 7,083 adults free of baseline CVD. AtCM was defined by the presence of [&ge;]1 ECG marker: prolonged P-wave duration [&ge;]120 ms in lead II, abnormal P-wave axis outside 0-75, or deep terminal negativity of the P wave in V1 <-100 V. CMRF burden was defined as the presence of 0, 1, or [&ge;]2 of hypertension, diabetes, and obesity. CVD mortality was ascertained through December 31, 2006. Results: Among 7,083 participants (mean age 58 years and 48% men), CVD mortality rates increased progressively across the six combined exposure groups. In a multivariable adjusted Cox proportional hazard analysis, AtCM identified higher-risk subgroups within each CMRF burden category, with risk increasing progressively across combined exposure groups and highest among participants with [&ge;]2 risk factors and AtCM (HR 2.25, 95% CI 1.75-2.87). In secondary analyses, a similar pattern was observed for individual CMRFs, with the combination of AtCM and hypertension, diabetes, or obesity conferring the highest risk compared with participants with neither condition (HR (95% CI): 1.58 (1.31-1.89); 2.08 (1.62-2.68); and 1.47 (1.19-1.82), respectively). Conclusions: ECG-defined AtCM refined CVD mortality risk across increasing CMRF burden. Individuals with both AtCM and multiple CMRFs had the highest risk. These findings support the potential role of ECG-based AtCM assessment as a scalable approach to improve cardiovascular risk stratification among individuals with CMRFs.

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.