In individuals with heterozygous familial hypercholesterolemia (HeFH), it is uncertain whether and to what extent the reduction in low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy is dependent on the residual functional activity of the LDLR gene carrying the pathogenic variant. To evaluate the reduction in LDL-C achieved with PCSK9 inhibition according to FH genotype in a large cohort of patients with HeFH. This nonrandomized clinical trial reports on a predefined, pooled subanalysis of participants with HeFH requiring additional lipid-lowering therapy in the open-label worldwide phase 3 study of the PSCK9 inhibitor lerodalcibep. This study included participants randomized to 5 phase 3 studies with the plasma PSCK9 inhibitor lerodalcibep and who participated in the open-label extension study from December 2020 to May 2025. Data were analyzed from March 2025 to February 2026. All participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks. The co-primary efficacy end points were LDL-C reduction at weeks 48 and 72. Secondary and exploratory end points included LDL-C response according to FH genotype and the achievement of currently recommended LDL-C goals. Among 703 included participants (mean [range] age, 53.8 [18-80] years; 372 male [52.9%]), 86 (12.2%) were Black, South Asian, or multiracial and 617 (87.8%) were White; 217 participants (72.3%) had atherosclerotic cardiovascular disease (ASCVD) or were at very high risk for ASCVD and 195 participants (27.7%) were at high risk for ASCVD. Despite most participants receiving treatment with statins or ezetimibe, the mean (SD) baseline LDL-C was 144.9 (61.9) mg/dL. Mean (SD) reductions in LDL-C associated with lerodalcibep were 50.3% (28.9%) and 50.3% (28.7%) (mean [SD] absolute change, -72.6 [50.5] mg/dL and -71.8 [48.0] mg/dL) at weeks 48 and 72, respectively. Of 740 participants (92.5%) who underwent genetic testing, monogenic FH-causing variants were found in 455 participants (61.5%), including 432 participants (95.7%) with the LDLR pathogenic variant. LDL-C reduction with lerodalcibep was independent of LDLR variant functional activity. More than 70% of participants achieved both a reduction in LDL-C of at least 50% and their ASCVD risk-based LDL-C goal. These findings suggest that lerodalcibep was associated with significantly and consistently reduced LDL-C in patients with HeFH, with response found to be independent of LDLR function of the pathogenic variant. These findings support that LDL-C reductions in patients with HeFH with PCSK9 inhibition are predominantly mediated by upregulation of the unaffected wild-type LDLR. ClinicalTrials.gov Identifier: NCT04798430.

This article commemorates the life and achievements of Eugene Braunwald (1929-2026).

Adverse myocardial remodeling and fibrosis contribute to heart failure progression and are thought to be driven by activated fibroblasts. Noninvasive assessment of myocardial fibroblast activation may improve phenotyping and risk stratification in heart failure. To evaluate myocardial fibroblast activation in patients with heart failure with reduced ejection fraction using gallium 68-labeled fibroblast activation protein inhibitor 46 ([68Ga]FAPI-46) positron emission tomography (PET) and magnetic resonance imaging (MRI). This was a prospective case-control study including patients with heart failure with reduced ejection fraction, patients with prior myocardial infarction without heart failure, and healthy volunteers. A subset of patients with heart failure underwent repeat imaging after more than 6 months. Data analysis was conducted from January 2024 to January 2025. All participants underwent [68Ga]FAPI-46 PET/MRI. Myocardial fibroblast activation quantified using maximum standardized uptake values (SUVmax) of [68Ga]FAPI-46. A total of 81 participants were included (mean [SD] age, 66.2 [9.7] years; 22 [27%] female): 42 with heart failure (21 with heart failure due to ischemic cardiomyopathy from a previous myocardial infarction and 21 with a nonischemic etiology; mean [SD] left ventricular ejection fraction, 41% [9%]), 20 with a prior myocardial infarction but preserved left ventricular systolic function, and 19 healthy volunteers. No myocardial fibroblast activation was observed in healthy volunteers. All patients with heart failure demonstrated increased myocardial [68Ga]FAPI-46 uptake compared with healthy volunteers (mean [SD] SUVmax, 2.7 [1.5] vs 1.5 [0.3]; P < .001). Uptake was highest in patients with ischemic cardiomyopathy, localizing to regions of established myocardial infarction (mean [SD] SUVmax, 3.2 [1.1]). Patients with nonischemic cardiomyopathy exhibited a different pattern of diffuse, lower-intensity uptake (mean [SD] SUVmax, 2.3 [0.5]), with the highest signal in the basal septum irrespective of late gadolinium enhancement. Patients with ischemic cardiomyopathy had higher uptake than patients with prior myocardial infarction without heart failure (n = 20) despite no major difference in infarct size (mean [SD] SUVmax, 3.2 [1.1] vs 2.5 [0.3]; P = .03). Among patients with heart failure who underwent repeat imaging, higher baseline [68Ga]FAPI-46 uptake was associated with less improvement in ejection fraction with optimal medical therapy over time (r = -0.52; P = .02). In this case-control study, patients with heart failure demonstrated persistent myocardial fibroblast activation with distinct spatial patterns according to cardiomyopathy etiology. Noninvasive imaging of fibroblast activation may provide mechanistic insights, aid risk stratification, and support the development of targeted antifibrotic therapies in heart failure.

Low-quality dietary intake is associated with adverse heart failure (HF) outcomes, yet evidence evaluating food-as-medicine interventions that supply high-quality dietary content is limited. To determine the feasibility of providing food supplementation with medically tailored meals or fresh produce and explore the association of food supplementation vs usual care with clinical outcomes in patients recently hospitalized with HF and whether it differs by conditioning food supplementation to health care engagement. This open-label factorial randomized clinical trial was conducted between April 2024 and October 2025 at 2 hospitals in Dallas, Texas. The study included patients who were hospitalized for HF and enrolled within 14 days of discharge, excluding those with prior heart transplant, a left ventricular assist device, or inotropic support at discharge; current enrollment in meal delivery programs; and inability to receive home deliveries. Participants were followed up with for 12 weeks. Of 150 participants enrolled, 2 were withdrawn due to clinical deterioration, 1 died, and 6 were lost to follow-up; all were included in the intention-to-treat analysis. Participants were randomized 1:1:1 to medically tailored meals, fresh produce, or usual care. Those receiving food supplementation underwent secondary 1:1 randomization to conditional (linked to clinic attendance and medication fills) vs unconditional delivery. Implementation outcomes included delivery completion, adherence, and acceptability and exploratory clinical outcomes. The primary clinical outcome was defined as readmission for HF or emergency department (ED) visits for HF over 90-day follow-up. Secondary clinical outcomes included a win-ratio-based hierarchical composite (all-cause death, total HF hospitalizations or ED visits, and ≥10-point Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score [KCCQ-CSS] improvement). Among 150 participants (median [IQR] age, 59.5 [52.0-66.0] years; 91 [60.7%] male), the baseline median (IQR) left ventricular ejection fraction was 35% (25.0-54.0), the baseline median (IQR) KCCQ-CSS was 56.6 (36.8-72.9), and 79 (52.7%) had food insecurity. Food delivery completion was 93.6% with a mean (SD) reported consumption adherence of 4.7 (2.4) days per week (medically tailored meals) and 5.5 (2.3) days per week (fresh produce), with high retention (96.0%). Fresh produce demonstrated superior acceptability compared with medically tailored meals (Net Promoter Score: 8.6 vs 7.3; P = .02). There was no significant difference in the primary clinical outcome (HF readmission or ED visit) between food supplementation (23 events among 100 participants) vs usual care (9 events among 50 participants) (adjusted rate ratio, 1.09; 95% CI, 0.49-2.43; P = .83). The hierarchical composite favored food supplementation vs usual care (win ratio, 1.21; 95% CI, 1.14-1.29; P < .001). Among participants receiving food supplementation, conditional delivery (vs unconditional) was not associated with risk of HF events. In this randomized clinical trial, 90-day food supplementation was feasible and well accepted in individuals with recent HF. Food supplementation was not associated with an improvement in the primary clinical outcome and there was no difference when conditioning food supplementation on health care engagement. ClinicalTrials.gov Identifier: NCT06115369.

Mounting evidence suggests that renin-independent aldosteronism is common and often underrecognized. Yet, whether aldosteronism across this broader spectrum is associated with incident cardiovascular disease (CVD) has not, to the authors' knowledge, been comprehensively evaluated. To determine whether aldosterone measures are associated with incident CVD events in community-dwelling older adults. This prospective cohort analysis included participants from the Atherosclerosis Risk in Communities (ARIC) study with serum aldosterone and renin levels measured in 2011 to 2013. Longitudinal analyses were conducted in March to September 2025 using Cox regression to assess associations between aldosterone parameters and incident CVD among participants free of heart failure (HF), myocardial infarction (MI), stroke, and potassium-sparing diuretic use at ARIC visit 5 (2011-2013). Serum aldosterone level and aldosterone-renin ratio (ARR). Incident HF hospitalization, atrial fibrillation (AF), ischemic stroke, MI, and a composite of these events plus all-cause death. Among 3477 individuals free of baseline CVD (mean [SD] age, 74.8 [4.9] years; 2139 female [61.5%]), the median (IQR) aldosterone level was 5.1 (3.0-8.3) ng/dL (to convert to picomoles per liter, multiply by 27.74), renin activity was 0.78 (0.41-1.90) ng/mL per hour, and ARR was 5.9 (2.2-12.3) ng/dL per ng/mL/h. Over 9 years of follow-up, higher ARR was associated with the composite outcome (adjusted hazard ratio [aHR], 1.04; 95% CI, 1.01-1.08 per doubling), stroke (aHR, 1.13; 95% CI, 1.02-1.26), and AF (aHR, 1.10; 95% CI, 1.05-1.15) but not with incident HF hospitalization (aHR, 1.02; 95% CI, 0.96-1.07) or MI (aHR, 1.01; 95% CI, 0.92-1.12). The findings of this cohort study underscore a spectrum of primary aldosteronism, in which higher ARR was independently associated with increased risks of AF and ischemic stroke among older adults, supporting the aldosterone pathway as a potential target for CVD prevention.

Cardiovascular disease (CVD) is the leading cause of death among women worldwide. Pregnancy serves as a natural cardiovascular stress test and universal clinical encounter, yet few approaches leverage its insights to inform long-term cardiovascular risk. To determine whether clinical measures and biomarkers obtained during pregnancy may identify women at risk of long-term CVD. This was a registry-linked, population-based cohort study of all pregnancies reaching at least 22 weeks between June 2010 and October 2013 in Southern Denmark. Primary analyses were performed in a nested prospective subcohort of Odense Child Cohort participants with available pregnancy biomarker data. Women with preexisting CVD were excluded (n = 114). Follow-up was done through December 31, 2023. Among 38 455 eligible women, 2056 had biomarker data at week 12 or week 29. Analytic subsets with complete data were used for prognostic modeling at week 12 (n = 1379) and week 29 (n = 1389). Clinical characteristics, obstetric outcomes, and pregnancy biomarkers including soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor, high-sensitivity cardiac troponin I (hs-cTnI), and N-terminal pro-B-type natriuretic peptide. Incident maternal CVD, evaluated using Cox proportional hazards models. In the biomarker cohort (median [IQR] age, 30.4 [27.4-33.8] years), 28 women (1.4%) developed CVD during a median (IQR) follow-up of 11.9 (11.2-12.5) years. Maternal age, hypertensive disorders of pregnancy (HDPs), and third-trimester concentrations of hs-cTnI and sFlt-1 were each independently associated with higher long-term CVD risk. A combined model including age and sFlt-1 measured at week 29 improved discrimination for CVD compared with a base model of age alone (ΔAUC, 0.16; 95% CI, 0.02-0.30), whereas a clinical model consisting of age, systolic blood pressure, and non-high-density lipoprotein cholesterol did not. Results were consistent in women without prior hypertension or HDPs and in nulliparous women. CVD incidence and the predictive value of the base model were comparable between the biomarker and the contemporaneous background cohorts (n = 36 274). These findings support pregnancy as an opportunistic window for sex-specific cardiovascular risk assessment and prevention throughout a woman's life course. Further studies are warranted to validate these findings.