The SI! Program is a long-term, school-based intervention promoting cardiovascular health across multiple age groups. This article presents the design of a new cluster-randomized controlled trial incorporating a reintervention to strengthen sustainability and promoting a school-family approach. A total of 977 children (age 6.2 years, 51.6% girls) from 50 schools in Spain were recruited. Schools were randomized to a reintervention group (intervention in second grade and reintervention in fifth grade) or a single-intervention group (intervention only in fifth grade). The primary endpoint is the change in the SI!-Child score—diet, physical activity, sleep health, and body mass index—between baseline and 5-year follow-up. The secondary endpoints include 5-year changes in SI!-Child subcomponents, sedentarism, adiposity, and the Life’s Essential 8 score and subcomponents. This revised SI! Program builds on insights from earlier trials, emphasizing adherence and long-term behavior change through a reintervention combined with active engagement of the school community and families. (The SI! Program Reintervention for Elementary Schools Trial [PSIR]; NCT06715358)

Background:SGLT2i (sodium-glucose cotransporter-2 inhibitors) improve clinical outcomes in patients with heart failure, but the mechanisms of action are not completely understood. SGLT2i increases circulating levels of ketone bodies, which has been demonstrated to enhance myocardial energetics and induce reverse ventricular remodeling. However, the role of SGLT2i or ketone bodies on myocardial ischemia reperfusion injury remains in the dark. The objective of this study is to investigate the cardioprotective potential of empagliflozin and ketone bodies during acute myocardial infarction (MI). Methods:We used a nondiabetic porcine model of ischemia reperfusion using a percutaneous occlusion of proximal left anterior descending artery for 45 minutes. Animals received 1-week pretreatment with either empagliflozin or placebo prior to MI induction. Additionally, a third group received intravenous infusion of the ketone body BOHB (beta-hydroxybutyrate) during the MI induction. Acute effects of the treatments were assessed 4-hour post-MI by cardiac magnetic resonance and histology (thioflavin for area at risk, triphenyltetrazolium chloride staining for MI size). All animals were euthanized immediately postcardiac magnetic resonance, and heart samples were collected. Results:The area at risk was similar in all groups. Empagliflozin treatment increased BOHB levels. Empagliflozin-treated animals showed significantly higher myocardial salvage, smaller MI size (both by cardiac magnetic resonance and histology), less microvascular obstruction, and improved cardiac function (left ventricle ejection fraction and strain). Furthermore, empagliflozin-treated animals demonstrated reduced biomarkers of cardiomyocyte apoptosis and oxidative stress compared with placebo. The BOHB group showed similar results to the empagliflozin group. Conclusions:One-week pretreatment with empagliflozin ameliorates ischemia reperfusion injury, reduces MI size and microvascular obstruction, increases myocardial salvage, preserves left ventricle systolic function, and lowers apoptosis and oxidative stress. Periprocedural intravenous infusion of BOHB during myocardial ischemia also induces cardioprotection, suggesting a role for BOHB availability as an additional mechanism within the wide spectrum of actions of SGLT2i.

BACKGROUND AND AIMS:Recent trials have challenged the guideline recommendation of beta-blockers for post-myocardial infarction (MI) patients without reduced left ventricular ejection fraction (LVEF). Whether these recent findings apply equally to women and men remains unknown. METHODS:Using data from REBOOT (tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion), the largest randomized trial evaluating the effect of beta-blockers after acute MI with LVEF > 40%, a pre-specified sex-specific subgroup analysis was performed. A total of 8438 out of the 8505 randomized patients comprised the intention-to-treat population. RESULTS:Among 8438 patients, 1627 were women, who were older, had more comorbidities, and received fewer guideline-based therapies than men. Over a median follow-up of 3.7 years, women had overall higher rates of the primary composite outcome (death, MI, or heart failure hospitalization) than men. The incidence rate of the primary endpoint in women was 30.4 and 21.0/1000 patient-years in the beta-blocker group and no beta-blocker group, respectively (hazard ratio 1.45, 95% confidence interval 1.04-2.03). No significant differences were observed in men (hazard ratio .94, 95% confidence interval .79-1.13; P for interaction = .026). The excess risk in women was mainly driven by increased mortality and was most evident among those with preserved LVEF (P for interaction = .030) and those receiving higher beta-blocker doses (P for interaction = .045). CONCLUSIONS:In the REBOOT trial of MI patients managed according to contemporary standards, beta-blocker therapy was associated with evidence of harm in women-particularly those with preserved LVEF and receiving higher doses-an effect not observed in men.

Most forms of heart failure are characterized by a metabolic switch from the use of fatty acids to glucose as the main fuel source for ATP generation in the myocardium. Whether metabolic reprogramming is a therapeutic target remains controversial. In this study, heart failure with reduced ejection fraction (HFrEF) and metabolic switch (i.e., increased myocardial glucose uptake) was induced in pigs by generating viable dysfunctional myocardium secondary to progressive coronary artery stenosis. Pigs (n = 19) were then randomized to a high-fat diet (HFD, chow diet supplemented with 20

AbstractCluster-randomized trials are increasingly relevant to the evaluation of preventive and treatment strategies for chronic disease, especially when interventions are delivered through groups, practices, communities, or health systems rather than individuals. Using cardiovascular prevention as an illustrative example, we review key design, conduct, and analytic issues that determine when cluster randomization is appropriate and how such trials should be designed, analyzed, and interpreted. Particular attention is given to the choice of the unit of randomization, protection of internal validity, implications for statistical efficiency, and alignment of outcomes and analyses with the level and mechanism of intervention delivery. A clear understanding of these principles should strengthen the design, interpretation, and policy relevance of cluster-randomized trials.

Background Diabetes mellitus is associated with dyslipidemia, elevated blood pressure, and increased risk for incident cardiovascular disease (CVD). Objectives This study examined whether diagnosed diabetes before age 40 years is associated with incident CVD risk independent of other measured risk factors. It also evaluated whether cumulative glucose exposure from young adulthood to age 40 years is associated with subsequent CVD risk and explored the relative contribution of diabetes compared with other CVD risk factors. Methods Using CARDIA (Coronary Artery Risk Development in Young Adults) study data, we created a sequential propensity-score-matched sample at age 40 years: Each participant with diabetes was matched to one prediabetes participant and up to 2 without diabetes. Cox proportional hazards regression models were used to assess associations of diabetes and cumulative glucose exposure with incident CVD and its components: coronary heart disease, stroke, and congestive heart failure. Results Of 4,931 individuals, 766 propensity-score-matched participants experienced 103 incident CVD events during a median 22-year follow-up after age 40 years. Diagnosed diabetes was independently associated with incident CVD after adjustment for other known risk factors (HR: 2.13; 95% CI: 1.33-3.41 for diabetes vs nondiabetes, P = 0.002); CVD risk rose as cumulative glucose exposure increased. Among matched participants, the excess CVD rate associated with diabetes was greater than the rate difference associated with other cardiovascular risk factors commonly elevated in diabetes. Conclusions Diabetes by age 40 years was associated with higher subsequent CVD risk beyond established risk factors, with CVD risk increasing as cumulative glucose exposure rose.

BACKGROUND AND AIMS:Healthcare professionals (HCPs) play a central role in preventive care, yet their own cardiovascular health management remains poorly characterised. We evaluated cardiovascular risk profiles, awareness, treatment use, target achievement and subclinical atherosclerosis among HCPs attending the European Society of Cardiology (ESC) Congress. METHODS:HCPs participating in the ESC Congress Cardiovascular Health Check 2025 (n=1366) underwent standardised assessment of cardiovascular risk factors, medication use, treatment targets, and carotid ultrasonography in a subgroup. HCPs without established atherosclerotic cardiovascular disease (ASCVD) were compared with age- and sex-matched individuals from the general population (REACT initiative; n=2732). RESULTS:Among HCPs, excess body weight was the most prevalent modifiable risk factor (46.8%), followed by hypertension (23.2%), and hyperlipidaemia (22.7%). Established ASCVD was present in 11.1% and subclinical atherosclerosis was detected in 21.8% of HCPs without established ASCVD. Compared with matched controls, unrecognised hyperlipidaemia (7.5% vs. 8.4%; P=0.293), hypertension (11.9% vs. 13.9%; P=0.079), and diabetes (0.4% vs. 0.4%; P=0.864) were similarly frequent; awareness was higher only for hyperlipidaemia (62.2% vs. 54.9%; P=0.049). In primary prevention, HCPs were less likely to use recommended antihypertensive (27.6% vs. 46.5%; P<0.001) and glucose-lowering therapy (60.0% vs. 85.0%; P=0.001), but more often achieved LDL-C (57.5% vs. 32.0%; P<0.001) and systolic blood pressure targets (47.5% vs. 24.6%; P=0.003). In secondary prevention, 41.4% of HCPs used lipid-lowering therapy, only 9.2% used antiplatelet therapy, and only 22.2% of those using lipid-lowering therapy achieved the LDL-C target. CONCLUSIONS:HCPs showed important gaps in cardiovascular prevention, particularly regarding the use of guideline-recommended therapy, highlighting the need for systematic implementation strategies among HCPs.Clinical Trial Registration: NCT07613229.

AIMS:Current guidelines recommend beta-blocker therapy after myocardial infarction (MI) regardless of left ventricular ejection fraction (LVEF). However, recent trials question their benefit in patients with preserved LVEF. No study has yet compared beta-blocker effects during the acute coronary syndrome (ACS) phase (≤1 year post-MI) vs. the chronic coronary syndrome (CCS) phase (>1 year). METHODS AND RESULTS:In this pre-specified landmark analysis of the REBOOT trial, we evaluated the effect of beta-blocker therapy on outcomes in two post-MI phases: the ACS period (first year; cohort 1, n = 8438) and the CCS period (>1 year, event-free patients with follow-up; cohort 2, n = 7783). The primary endpoint was all-cause death, nonfatal reinfarction, or heart failure hospitalization; secondary endpoints included individual and additional cardiovascular events. Among 623 primary outcome events, 238 occurred in the first year (28.9/1000 patient-years) and 385 thereafter (19.3/1000 patient-years). Secondary prevention use was generally high, but patients with early events had lower prescription rates than those with late events or no events. Beta-blockers were not associated with lower risk of the primary or component outcomes in either phase. A nonsignificant trend towards benefit of beta-blockers appeared during the first year in patients with mildly reduced LVEF (41-49%), whereas in the CCS phase, higher beta-blocker doses were associated with worse outcomes. CONCLUSION:In invasively treated MI patients with LVEF >40%, beta-blockers did not reduce adverse outcomes in either the ACS or CCS phases. These findings challenge their routine use in this population and support reconsidering current guidelines. Long-term beta-blocker users after MI may be candidates for deprescription.

Background Hypertrophic cardiomyopathy (HCM) and infiltrative cardiomyopathies are important causes of cardiogenic syncope with overlapping clinical and radiologic features. Case Summary A 49-year-old gentleman presented with syncope while walking across the Brooklyn Bridge. Electrocardiogram revealed low-voltage QRS with diffuse T-wave inversions. Echocardiography revealed moderate left ventricular hypertrophy, wall motion abnormalities with left ventricular ejection fraction 35% to 40%, and a dilated, hypokinetic right ventricle. Cardiac magnetic resonance showed biventricular hypertrophy and evidence of late gadolinium enhancement. Positron emission tomography/magnetic resonance (PET/MR) 18F-FDG revealed right ventricle uptake along with matching late gadolinium enhancement and FDG avidity in the hilar and mediastinal lymph nodes. Endomyocardial biopsy showed noncaseating granulomas, confirming sarcoidosis. An implantable cardioverter-defibrillator was inserted. Despite immunosuppression and guideline-directed medical treatment, the patient eventually required cardiac transplantation. Discussion Cardiac sarcoidosis mimicking genetic cardiomyopathy, and vice versa, has often been reported. Combined PET/MR helped distinguish these pathologies in our patient. Take-Home Messages Cardiac sarcoidosis can mimic HCM; multimodal imaging, including PET/MR, guided by clinical suspicion, is important. Biventricular involvement in HCM is infrequent.

BACKGROUND:Excess energy intake upregulates de novo lipogenesis (DNL). Circulating palmitoleic acid (POA) is an objective DNL biomarker associated with higher cardiovascular risk, which has been linked to cerebral hypometabolism. Whether POA also relates to altered cerebral glucose metabolism in midlife remains unknown. OBJECTIVES:This study aimed to examine cross-sectional and longitudinal associations between circulating POA (predictor) and cerebral glucose hypometabolism (outcome), a neuroimaging marker linked to increased risk of subsequent cognitive decline. METHODS:We studied 461 middle-aged [median age, 51 (47-54) y] individuals with subclinical atherosclerosis from the Progression of Early Subclinical Atherosclerosis (PESA) study, a longitudinal observational cohort of asymptomatic individuals (NCT01410318). Red blood cell (RBC) POA was quantified by gas chromatography in blood samples collected at 2 visits of PESA participants who had undergone longitudinal cerebral 18F-fluorodeoxyglucose (FDG) positron emission tomography (4.9 y of follow-up time). Dietary data were derived from a validated food-frequency questionnaire. Associations were assessed using region-of-interest and voxelwise multiple regression models as well as mediation analysis. RESULTS:Cross-sectionally, higher RBC POA was associated with widespread lower FDG uptake across the brain [β = -0.119 (95% confidence interval: -0.206, -0.032), P = 0.007], even after adjusting for cardiovascular risk. Longitudinally, participants with sustained high RBC POA exhibited a 65% greater decline in cerebral FDG uptake compared with those with sustained low POA [β = -0.403 (-0.744, -0.063), P = 0.021], particularly in frontal and parietal regions. RBC POA proportions were higher among individuals adhering to the predefined "Social-Business" dietary pattern and were significantly associated with increased alcohol intake. Furthermore, the association between alcohol intake and subsequent precuneus hypometabolism was partially mediated by RBC POA proportions. CONCLUSIONS:RBC POA, a marker of DNL, is associated with cerebral glucose hypometabolism, supporting that healthy dietary habits in midlife are key to preserving brain health. This trial was registered at clinicaltrials.gov as NCT01410318.

Epidemiological population studies may include cardiac magnetic resonance (CMR)-derived phenotyping and large-scale genotyping, providing unprecedented level of detail to investigate novel gene-lifestyle-disease interactions. The systematic review presents high-level summaries and critically appraises contemporary challenges and biobank opportunities. The authors identified 17 relevant biobanks by searching "CMR," "genome" and "population study" on MEDLINE, EMBASE, and Web of Science 2025. Collectively, studies recruited ∼1 million participants with stored blood samples for extensive genomic analyses, of whom >180,000 have or will undergo CMR. Use of expansive personal data must safeguard participant confidentiality, encourage technological standardization, and champion inclusivity and sustainability. Application of genotypic and imaging-derived phenotypic information will be readily translatable to clinical practice through investigation of, among others, new therapeutic targets and highly sensitive and specific biomarkers. Imaging biobanks are accessible to researchers by application. This systematic review should inspire greater use and cross-collaboration and facilitate powerful discoveries in more heterogeneous population samples.

This review examines the effectiveness of school-based interventions for preventing cardiovascular disease and promoting healthy lifestyles, drawing on evidence from the SI! Program. It addresses two key questions: how such interventions influence health behaviors throughout childhood and adolescence, and which contextual factors shape their effectiveness and sustainability. Evidence from multiple randomized controlled trials conducted over 15 years in diverse school settings shows that multicomponent, multilevel interventions can positively shape cardiovascular health behaviors. Studies involving more than 7,000 students in Colombia, Spain, and the United States highlight adherence and socioeconomic background as key determinants of impact. Intervention effects are strongly influenced by educational stage, adherence, and the school and home environment. Periodic reinterventions appear necessary to sustain benefits over time. Baseline health status and intervention responsiveness are also conditioned by socioeconomic context. Scaling and supporting such programs may foster lasting healthy habits early in life and help reduce global cardiovascular disease burden.

Subclinical atherosclerosis (SA) burden and progression are independently associated with all-cause mortality. However, monitoring SA progression requires reliable and cost-effective biomarkers. While leukocyte telomere length (LTL) attrition has been linked to cardiovascular disease and mortality, it remains uncertain whether changes in LTL over time can predict SA progression. In this study, we conducted a longitudinal study to assess whether accelerated LTL attrition is associated with SA progression over a 6-year period in healthy middle-aged individuals. LTL was measured by high-throughput quantitative fluorescence in-situ hybridization in peripheral-blood leukocyte samples obtained 6 years apart from a sub-cohort of 1068 Progression of Early Subclinical Atherosclerosis (PESA)-study participants. SA was assessed by 3D vascular ultrasound in the carotid and femoral territories. Associations were evaluated using linear and logistic regression models. LTL parameters at baseline and after 6 years showed a positive correlation, but no significant associations were found between changes in LTL and changes in plaque volume over 6 years, either in the total sample or when stratified by sex. Likewise, no significant associations were found between LTL changes and the odds of SA progression over a 6-year period. Similar results were found when considering short telomere load changes. These findings suggest limited utility of LTL dynamics as an early biomarker for SA progression in healthy middle-aged individuals.

BACKGROUND:Atherosclerosis may begin in early adulthood and remain clinically silent for decades before cardiovascular disease manifests. Although silent atherosclerosis is associated with cardiovascular events and death independent of traditional cardiovascular disease risk factors, its age- and sex-specific prevalence, vascular territory distribution, and plaque volume across adult life remain incompletely defined. METHODS:We conducted a prospective cohort study in Denmark and Spain. Adults 18 to 70 years of age without known atherosclerotic cardiovascular disease were enrolled in five prespecified age strata that included balanced numbers of women and men. Silent atherosclerosis was assessed at baseline with three-dimensional vascular ultrasonography of the carotid and femoral arteries and with coronary computed tomographic angiography. RESULTS:A total of 16,808 adults were enrolled in the study. The mean (±SD) age of the participants was 45±12 years, and 51.4% were women. Silent atherosclerosis was present in 57.1% of the participants (95% confidence interval, 56.3 to 58.0). In the youngest age stratum (18 to 29 years), atherosclerosis was present in 8.7% of the men and 6.7% of the women; prevalence increased with age, with a later, steeper midlife rise among women. Among participants in the younger age strata, atherosclerosis was most often peripheral and confined to a single vascular territory; with increasing age, plaque volume increased exponentially and the prevalence of multiarterial involvement became more frequent. Isolated coronary-artery atherosclerosis was uncommon in every age stratum (≤9.3% of men and ≤5.0% of women). CONCLUSIONS:This study of silent atherosclerosis showed that the disease was detectable in early adulthood, with age- and sex-associated increases in prevalence across arterial territories and marked increases in plaque volume. (Funded by the Novo Nordisk Foundation; REACT ClinicalTrials.gov number, NCT06692127.).

BACKGROUND AND AIMS:Hypertension and valvular heart disease, both associated with left ventricular (LV) pressure overload, increase the risk of anthracycline cardiotoxicity. While epidemiologically established, the underlying mechanisms remain unclear, precluding identification of therapeutic targets. METHODS:Two-month-old Yucatan pigs (males and females) underwent aortic banding to induce LV pressure overload or no operation. After 4 months, animals received a low-risk cumulative dose of doxorubicin (5 weekly 1 mg/kg intravenous injections) or vehicle, generating four groups: (i) healthy controls (no LV overload, no doxorubicin), (ii) Dox (doxorubicin, no LV overload), (iii) Banding (B: LV overload, no doxorubicin), and (iv) B + Dox (LV overload plus doxorubicin). Cardiac function, structure, and metabolism were assessed over 8 months by cardiac magnetic resonance, magnetic resonance spectroscopy, and hybrid positron emission tomography/computed tomography. At study end, proteomics and mitochondrial structure and function were analysed. Complementary in vivo and ex vivo studies examined the mechanistic role of energetic imbalance. RESULTS:LV overload increased LV mass (P < .0001) and ejection fraction (P = .0081), with compensatory metabolic changes (drop in phosphocreatine (P = .022)). Low-risk Dox alone altered myocardial metabolism (increased glucose uptake, P = .014) but preserved cardiac function. In pigs with pre-existing LV pressure overload, doxorubicin increased mortality (P < .0001 vs all other groups), reduced left ventricular ejection fraction (LVEF) (P < .0001), increased fibrosis, and impaired mitochondrial respiration (P = .032). In HL-1 cardiomyocytes, reducing energy demand with mavacamten rescued cell viability under combined doxorubicin and hypertrophic stress. CONCLUSIONS:LV pressure overload increases myocardial susceptibility to anthracycline cardiotoxicity by inducing a high-energy-demand state. Anthracycline treatment, even at a low-risk dose, disrupts compensatory mechanisms in the pressure-overloaded heart, rapidly leading to cardiac dysfunction and heart failure. Preventive strategies targeting this metabolic vulnerability are urgently needed for patients with extant LV pressure overload (e.g. hypertension or valvular heart disease) who are undergoing anthracycline therapy.