👤 Santiago Rodriguez

Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5-7.5 mg] or 4 once-weekly doses [5-12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was -4.7% to -8.0% across CT-388 doses vs -0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes. Show less

Dysregulation of the melanocortin-4 receptor (MC4R) pathway can lead to severe hyperphagia and early-onset obesity. Symptoms may present before age 6 years, but there is limited clinical data on treatment outcomes in very young children. Setmelanotide, an MC4R agonist, is approved for patients age ≥2 years with rare MC4R pathway disease due to Bardet-Biedl syndrome, pro-opiomelanocortin or proprotein convertase subtilisin/kexin type 1 deficiency or leptin receptor (LEPR) deficiency. This case report describes the use of setmelanotide in a 2-year-old child with hyperphagia and obesity due to LEPR deficiency. The patient presented with early-onset hyperphagia, rapid weight gain, and obesity-associated delays in motor development. Following a medical assessment in May 2021 he was diagnosed with LEPR deficiency. Setmelanotide treatment via subcutaneous injection was initiated in March 2023 (patient age 2 years 4 months) at a dose of 0.5 mg/day, increased to 2.5 mg/day in 0.5 mg increments, and the patient was followed for 23 months. Following treatment initiation, significant clinical improvements were observed, including reductions in hyperphagia, food intake and cravings, and body mass index (BMI). Motor skill function also improved, with the child achieving milestones such as crawling and kneeling. Reported adverse events included skin rash and skin hyperpigmentation. Setmelanotide treatment started in a 2-year-old patient and continued for 23 months led to reductions in hyperphagia and food-seeking behavior, as well as improved motor skill function, BMI, and blood lipids. These findings support the use of setmelanotide in young children with hyperphagia and obesity due to LEPR deficiency. Show less

Extracellular matrix (ECM) remodelling is critical in abdominal aortic aneurysm (AAA), a life-threatening condition lacking effective pharmacotherapy. However, key ECM components regulating vascular integrity and remodelling remain poorly understood. Transcriptome profiling and studies in human AAA and in aneurysms from two models susceptible to angiotensin II (Ang II)-induced AAA-apolipoprotein E knockout mice (ApoE Transcriptome profiling highlighted the relevance of the ECM-mediated pathway and the upregulation of THBS4 in human AAA. In a large cohort of patients and donors and in Ang II-infused ApoE We uncover the early and sustained induction of TSP4 in AAA and its protective role in limiting vascular inflammation and destructive remodelling. Modulation of TSP4-dependent pathways may represent a novel avenue to improve vascular stability in AAA. Show less

Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 (APOEε4), informant-reported race, and African ancestry. This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025. Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status. Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] score), and cognitive function (Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies. The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant. The findings indicate that female sex, APOEε4, and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease. Show less

BackgroundEducation promotes cognitive reserve (CR), potentially buffering Alzheimer's disease pathology (ADP). However, the education-CR relationship may differ by population and genetic background.ObjectiveTo examine education, Show less

Late-onset Alzheimer's disease is a devastating and complex neurodegenerative disorder with a multifactorial etiology. Over the past decade, advances in genetic research have identified novel risk genes, shedding light on the underlying pathogenic mechanisms of late-onset Alzheimer's disease. This review provides a comprehensive overview of several of these crucial genetic factors and their potential mechanisms in the pathogenesis of Alzheimer's disease. Genome-wide association studies, whole-genome sequencing, and multi-omics studies have played a crucial role in identifying key risk genes, particularly those involved in amyloid-β metabolism and clearance, such as CLU and APOE, which influence amyloid-β aggregation. Tau pathology, characterized by neurofibrillary tangles, is another hallmark of Alzheimer's disease, with genes such as BIN1 implicated in tau-mediated neurodegeneration. Additionally, immune regulatory genes, including CR1, MS4A6A, CD33, and TREM2, play crucial roles in microglial activation and neuroinflammation, thereby contributing to disease progression. Synaptic dysfunction is also a critical factor in Alzheimer's disease pathology, with genes such as IQCK, EPHA1, and CD2AP linked to synaptic function and plasticity, highlighting their potential impact on cognitive decline. Understanding these genetic risk factors provides valuable insights into the complex genetic landscape of Alzheimer's disease and its highly heterogeneous pathological mechanisms, including amyloid-β metabolism, tau pathology, immune response and neuroinflammation, and synaptic dysfunction. Future research should focus on elucidating the functional roles of these individual genes and their potential as therapeutic targets for altering the course of Alzheimer's disease. Show less

Single-cell RNA-sequencing has identified that Alzheimer's disease (AD) pathology in humans is associated with activation of disease-associated microglia (DAM). Microglial signatures of human AD have not been consistently identified in AD mouse models. Since the inflammatory response of rats is more like humans, we profiled microglial transcriptomes in aging TgF344-AD rats, which overexpress two human AD risk genes. Classic DAM gene activation ( Show less

Childhood obesity is associated with alterations in lipoprotein metabolism and increased oxidative stress, assessed by lipid peroxidation products, reactive oxygen species (ROS) and nitric oxide (NO) levels, oxidized/reduced glutathione (GSH/GSSG) ratio, and the activities of superoxide dismutase (SOD) and catalase. High-density lipoproteins (HDL) play an antioxidant role, conditioned by cholesteryl ester transfer protein (CETP), paraoxonase (PON) 1, lecithin:cholesterol acyltransferase (LCAT), lipoprotein-associated phospholipase A This study aims to evaluate HDL antioxidant capacity in children and adolescents with obesity and the status of its conditioning factors. Thirty children and adolescents, 15 with obesity and 15 normal-weight controls were studied in a cross-sectional observational study. Lipid profile and high-sensitivity C-reactive protein were assessed using standardized methods. Lipid peroxidation products, ROS, NO, GSH and GSSG levels, and catalase, SOD, CETP, LCAT, PON 1 (PON and arylesterase [ARE]) and Lp-PLA Children with obesity showed lower HDL cholesterol and apo A-I levels (P < .01), reduced CETP (P < .05), ARE (Lp-PLA Children and adolescents with obesity exhibited reduced HDL antioxidant activity, alterations in its conditioning factors, intrinsic oxidative modification of HDL particles, and increased oxidative stress. These alterations may affect long-term cardiovascular risk in children and adolescents with obesity. Show less

Recent advances in molecular pathology have transformed the diagnostic landscape and management of human cancer. Increasingly, integration of genomic and epigenomic data with conventional histopathology has improved tumor classification, refined prognostic assessment, and revealed previously unsuspected therapeutic targets. High-throughput techniques such as next-generation sequencing, gene fusion panels, and methylation arrays have expanded applicability to formalin-fixed tissue and enabled simultaneous evaluation of multiple cancer-defining alterations/genetic drivers. In optic nerve gliomas, MAPK pathway activation through BRAF or FGFR1 alterations, or NF1 inactivation, is a basic biological feature with diagnostic implications, while MEK inhibitors may be of clinical benefit in selected patients. Optic nerve sheath/orbital meningiomas demonstrate divergent molecular landscapes depending on location, with NF2-driven and non-NF2-driven pathways informing recurrence risk and behavior. In the orbit, characteristic genetic drivers facilitate diagnosis of mesenchymal tumors such as solitary fibrous tumor (NAB2::STAT6) and alveolar rhabdomyosarcoma (PAX3/7::FOXO1), while molecular profiling assists in distinguishing challenging peripheral nerve and melanocytic lesions. Similarly, lacrimal gland neoplasms parallel salivary gland counterparts, with recurrent fusions such as PLAG1, HMGA2, and MYB::NFIB of great diagnostic utility. These advances underscore the growing role of molecular diagnostics in improving accuracy, guiding prognostication, and refining the classification of rare ocular tumors. As high-throughput techniques continue to mature, integration with evolving spatial and single-cell-based approaches promises to expand our understanding and further personalize diagnostic and therapeutic strategies. Show less

Lipoprotein(a) (Lp[a]) can refine atherosclerotic cardiovascular disease risk assessment and guide lipid-lowering therapy intensification (LLTI). However, the association between Lp(a) testing and LLTI across large health systems is not well characterized. Using Veterans Affairs electronic health record data, we conducted a retrospective cohort study of veterans undergoing lipid testing from January 1, 2017, to June 30, 2024. We first compared a 1:1 propensity-matched cohort with concurrent low-density lipoprotein cholesterol (LDL-C) and Lp(a) testing with those with LDL-C testing alone. We then compared veterans with elevated versus nonelevated Lp(a) (>50 versus <50 mg/dL). The primary outcome was LLTI within 12 months, defined as therapy initiation, dose escalation, or addition of another lipid-lowering agent. LDL-C goal attainment (<100 mg/dL primary prevention; <70 mg/dL secondary prevention) was assessed within 12 months. Multivariable logistic regression adjusted for sociodemographic and clinical factors. Among 6 941 840 veterans with LDL-C testing, 10 384 (0.1%) underwent Lp(a) testing. The propensity-matched cohort included 20 768 veterans (mean±SD age, 58.4±15.3 years; 12.4% women; 19.2% Black individuals). Elevated Lp(a) (>50 mg/dL) was present in 25% (n=2562). Lp(a) testing was associated with greater LLTI (odds ratio [OR], 2.11 [95% CI, 1.95-2.29]), LDL-C testing (OR, 1.27 [95% CI, 1.19-1.36]), and LDL-C goal attainment (OR, 1.22 [95% CI, 1.12-1.33]). Compared with Lp(a) <50 mg/dL, Lp(a) >50 mg/dL was associated with increased LLTI (OR, 1.73 [95% CI, 1.55-1.94]). Lp(a) >100 mg/dL was associated with lower LDL-C goal attainment (OR, 0.68 [95% CI, 0.56-0.84]). Lp(a) testing was associated with increased LLTI and LDL-C goal attainment. Elevated Lp(a) identified individuals more likely to undergo LLTI, suggesting testing may motivate preventive treatment optimization. Show less

Lipoprotein(a) (Lp[a]) is an independent risk factor for atherosclerotic cardiovascular events and aortic stenosis. In Spain, the prevalence of elevated Lp(a) and its clinical impact remain poorly defined. We conducted a cross-sectional study including two cohorts: patients discharged after a non-fatal acute coronary syndrome (secondary prevention), and asymptomatic patients with subclinical atherosclerosis ("1.5 prevention"). The prevalence of elevated Lp(a) levels was assessed in both groups. Associations with multivessel coronary artery disease (secondary prevention) and with a coronary artery calcium (CAC) score ≥300 AU (1.5 prevention) were analyzed. A total of 1043 patients were included (788 secondary prevention). Median Lp(a) levels were 61 nmol/L in secondary prevention and 29 nmol/L in the 1.5 prevention cohort. In secondary prevention, 36.8%, 33.6%, 29.2%, and 24.5% had Lp(a) ≥125, ≥150, ≥175, and ≥ 200nmol/L, respectively; in the 1.5 prevention cohort the corresponding proportions were 27.5%, 24.3%, 17.6%, and 14.1%. In secondary prevention, Lp(a) ≥175 nmol/L was associated with multivessel disease after multivariable adjustment for age, sex, LDLc, and statin treatment (OR 1.45, 95% CI: 1.04-2.01; Elevated Lp(a) levels are common in both populations and correlate with greater atherosclerotic burden. These findings support the systematic assessment of Lp(a) to guide preventive strategies across both patient populations. Show less

Endothelial lipase (EL) is a key regulator of high-density lipoprotein (HDL) metabolism. Many aspects of EL function remain incompletely understood due to challenges in purifying active EL. This study identifies apolipoprotein J (ApoJ) as a novel chaperone for EL, crucial for its solubility and activity. Using an optimized purification protocol that yields active EL, we discovered that ApoJ consistently co-purifies with EL, maintaining its activity. We further show that knocking down ApoJ decreases the activity of EL. We demonstrate that ApoJ interacts with EL via its hydrophobic lid and tryptophan loop regions, and that mutating these regions abolishes the effect of ApoJ on the solubility and activity of EL. We show that ApoJ, EL, and ApoA1 (the defining lipoprotein of HDL particles) colocalize in HDL particles in mouse plasma. However, we find that ApoJ is not a direct carrier for EL to HDL particles. Instead, our data suggest that ApoJ primarily serves to enhance EL activity through its role as a chaperone, even when incorporated into lipid substrates. Our findings suggest a model in which ApoJ protects EL in plasma and enhances its hydrolysis of lipoprotein substrates. We propose that ApoJ is an accessory protein for EL, analogous to GPIHBP1 for LPL and co-lipase for PL. Further study of the interaction between EL and ApoJ will promote a better understanding of HDL metabolism. Show less

Glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists have recently been shown to play a significant role in the treatment of diabetes and obesity. Better understanding of their signaling and mechanism of action could further improve their therapeutic effects. In the current study, we investigate the impact of biased cyclic AMP (cAMP) signaling of GLP-1R and GIPR, individually, as well as the combined effects of a unimolecular dually biased GLP-1R/GIPR agonist, CT-859, on glucose, food consumption, and body weight regulation. Our data demonstrate that biased agonism of either GLP-1R or GIPR leads to better glycemic regulation, greater food intake suppression, and weight loss. In addition, concerted biased activation of both GLP-1R and GIPR results in substantially higher efficacy. Activation of GLP-1R and GIPR with a combination of individually biased agonists or via a dually biased unimolecular approach with CT-859 may provide significant therapeutic advantages for the treatment of diabetes and obesity. Show less

Apolipoprotein B (apoB) distribution and its implications as an atherosclerotic cardiovascular disease (ASCVD) risk-enhancing factor among individuals of diverse Hispanic or Latino backgrounds have not been described. To describe the distribution of apoB in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort and to characterize associations of baseline sociodemographic and clinical variables with apoB and self-identified Hispanic or Latino background. The HCHS/SOL was a prospective, population-based cohort study of diverse Hispanic or Latino adults living in the US who were recruited and screened between March 2008 and June 2011. Sampling weights were used to generate a population-based sample of Hispanic or Latino participants aged 18 to 74 years who resided in 4 US metropolitan areas (Bronx, New York; Chicago, Illinois; Miami, Florida; and San Diego, California). ApoB concentration was measured in participants from the HCHS/SOL, and apoB tertiles were compared across demographic groups, including self-identified Hispanic or Latino background. Median percentage continental genetic ancestry (West African, Amerindian, and European) was compared across apoB tertiles. ApoB measured in mg/dL from serum or plasma using an immunoturbidimetric assay. ApoB tertiles were determined, and traditional lipids were evaluated across apoB tertiles. ApoB and traditional lipid measurements were assessed across ASCVD risk categories. Additionally, scatterplots were created to observe correlations between apoB and low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. Overall mean (SD) apoB concentration was 99.8 (0.4) mg/dL, with male participants displaying significantly higher mean levels than female participants (102.4 vs 97.4 mg/dL, respectively). Mean (SD) participant age was 41.1 (0.8) years, and 8376 participants (51.9%) were female. ApoB levels were higher among older age groups. There was significant heterogeneity in mean apoB concentrations across self-identified Hispanic or Latino background groups, ranging from 95.1 mg/dL in Dominican individuals to 104.8 mg/dL in Cuban individuals. The prevalence of elevated apoB (≥130 mg/dL) was greater across higher predicted ASCVD risk categories. Among participants with a 10-year predicted ASCVD risk of 7.5% or higher, 26.5% had an elevated apoB. Median West African ancestry was lower across higher tertiles of apoB. In this cohort study among participants from the HCHS/SOL, elevated apoB was present in one-quarter of a diverse cohort study of Hispanic or Latino individuals who were at intermediate or high predicted ASCVD risk. Differences in apoB distribution among Hispanic or Latino individuals may have important implications for apoB's use in ASCVD risk assessment. Show less

The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear. In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1. A total of 363 participants (234 with a CPS of ≥10 and 347 with a CPS of ≥1) were assigned to the pembrolizumab group and 351 (231 with a CPS of ≥10 and 335 with a CPS of ≥1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P = 0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P = 0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P = 0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group. The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.). Show less

The 2025 American Society for Preventive Cardiology meeting highlighted evolving strategies in cardiovascular disease prevention, spanning risk models based on traditional risk factors, emerging biomarkers, novel therapeutics, and digital health innovations. Key discussions addressed lipoprotein(a) [Lp(a)] and inflammation as a causal risk factor, their clinical management, and readiness for targeted therapies; optimal systolic blood pressure targets informed by recent randomized controlled trials; and ongoing debate regarding apolipoprotein B versus low-density lipoprotein cholesterol (LDL-C) as the primary lipid target. Advances in digital health emphasized prevention through artificial intelligence, health equity in technology, and the growing role of wearables. Imaging emerged as a central theme, with sessions highlighting its role in risk assessment, monitoring treatment response, and refining prevention strategies, especially in young adults. Sessions on women's cardiovascular health underscored female-specific risk enhancers and limitations of current risk prediction models. Additional debates addressed the use of polygenic risk scores in young adults and strategies for universal screening with LDL-C, hsCRP, and Lp(a). Heart failure prevention was highlighted as a critical frontier, with emphasis on stage-based risk stratification, early identification of subclinical disease, and targeted interventions to avert progression to symptomatic heart failure. Updates on renal denervation reaffirmed its safety, efficacy, and durability as an adjunctive therapy in resistant hypertension. Collectively, these highlights emphasize the rapid evolution of preventive cardiology, integrating precision risk stratification, digital tools, and novel therapies into routine care. Show less

Lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease. An Lp(a) threshold of ≥125 nmol/L is commonly used to identify individuals at higher risk for events, but there is a paucity of data on individuals of Hispanic/Latino descent. The purpose of this study was to provide a comprehensive evaluation of Lp(a) and its association with 10-year cardiovascular disease risk and mortality among Hispanic/Latino adults in the United States. We evaluated the association between Lp(a) and myocardial infarction (MI), ischemic stroke, and all-cause mortality among 16,117 Hispanic Community Health Study/Study of Latinos individuals. Event rates were compared across Lp(a) quintiles. Multivariable Cox proportional hazards models assessed the relationship between events and Lp(a) across increasing quintiles, log-transformed Lp(a), and ≥125 nmol/L vs <125 nmol/L. Sampling weights and survey methods were used to account for the stratified probability sampling of the cohort. Among the Hispanic Community Health Study/Study of Latinos target population (median age 41.1 years, 52.4% women), the median Lp(a) was 19.7 nmol/L (Q1-Q3: 7.3-60.6 nmol/L), with 11.4% having Lp(a) ≥125 nmol/L, and the highest Lp(a) quintile defined as >77 nmol/L. Over a median follow-up of 9.8 years, 883 events (135 MI, 99 stroke, 649 all-cause mortality) occurred. The age-adjusted incidence rate of the composite events (MI, stroke, and all-cause mortality) was 505.2 per 100,000 person-years. After multivariable adjustment, each 1-SD increase in log-transformed Lp(a) was associated with a higher risk of MI (HR: 1.47; 95% CI: 1.14-1.89). Compared with Lp(a) <125 nmol/L, elevated Lp(a) ≥125 nmol/L conferred an increased risk of MI (HR: 2.29; 95% CI: 1.45-3.63), all-cause mortality (HR: 1.43; 95% CI: 1.05-1.93), and composite events (HR: 1.56; 95% CI: 1.22-2.01), but not stroke. Findings were consistent when comparing the highest Lp(a) quintile to the lower 4 quintiles, but the elevated risk was observed only for MI and composite events. Hispanic/Latino individuals with elevated Lp(a) are at an increased risk of MI and all-cause mortality. Although Lp(a) ≥125 nmol/L is a valid risk threshold, Hispanics/Latinos show a continuous relationship between increasing Lp(a) levels and MI risk. Show less

This review aims to explore the epidemiology of lipoprotein(a) [Lp(a)] by its structural and genetic make-up variation amongst ancestry groups. Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein particle, causally implicated in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Given its genetic basis, studies have shown marked ancestry-related differences in different races and ethnicities. Lp(a) plasma concentrations vary by more than 100-fold among individuals, primarily due to LPA gene polymorphisms and the number of kringle-IV type 2 (KIV2) repeats, which define apolipoprotein(a) [apo(a)] isoform size. Individuals of African descent have the highest median concentrations, followed by South Asians, with Hispanics/Latinos and East Asians having lower levels. Admixed populations display heterogeneity reflecting genetic ancestry. Despite differences in absolute levels, the relative ASCVD risk per unit increase in Lp(a) is consistent across groups, highlighting the universal atherogenicity of elevated Lp(a). Small apo(a) isoforms are associated with higher Lp(a) concentrations and risk, though isoform size is mainly a surrogate for Lp(a) burden. Despite a strong genetic basis and disproportionate burden in some populations, ancestry-specific testing guidelines are limited and testing rates remain low. Therapies targeting LPA transcription are in development, with outcome trials underway. Integrating ancestry-informed perspectives with universal risk principles is essential for equitable prevention and treatment. Routine, one-time Lp(a) testing enables cost-effective early risk stratification as Lp(a)-directed therapies emerge. Show less

Lipoprotein(a) [Lp(a)] is underutilized in short-term atherosclerotic cardiovascular disease (ASCVD) risk prediction. This study investigates Lp(a) contribution to short-term ASCVD event prediction using contemporary real-world data and machine learning (ML). A cohort of 731,983 individuals from a claims database was used to investigate the association of Lp(a) with incident ASCVD and all-cause mortality using Cox proportional hazards models. Novel ML models were developed to predict incident ASCVD events at 1, 2, and 3 years after Lp(a) testing. The models were validated in an independent cohort of 53,930 patients. An increase of 50 nmol/L in Lp(a) was independently associated with incident ASCVD events (HR: 1.072; 95% CI: 1.059-1.084) and all-cause mortality (HR: 1.041; 95% CI: 1.015-1.068) after adjustment for age, sex, and race/ethnicity. Novel ML models featuring Lp(a) predicted incident ASCVD events at 1, 2, and 3 years with robust discrimination (C-statistic: 0.83-0.84) in both the derivation and validation cohorts. Modest underestimation of risk was observed in the validation cohort for the 1-year model (calibration slope 1.25). Lp(a) contributed more to 1-year ASCVD prediction than smoking, diabetes, and other lipid parameters. Inclusion of Lp(a) in the 1-year model led to an integrated discrimination improvement of 0.03 and an optimal net reclassification improvement of 10% at a risk threshold of 26%. Lp(a) is a significant predictor of short-term ASCVD risk. Assessing Lp(a) and imminent ASCVD risk may assist in identifying patients who may benefit from escalation of preventative therapies. Show less

Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States. Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM, with the majority of mutations resulting in haploinsufficiency. To restore cardiac MYBPC3, we use an adeno-associated virus (AAV9) vector and engineer an optimized expression cassette with a minimal promoter and cis-regulatory elements (TN-201) to enhance packaging efficiency and cardiomyocyte expression. Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival. Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct. These findings suggest that TN-201 may offer therapeutic benefits in MYBPC3-associated cardiomyopathy, pending further validation in clinical settings. Show less

Apolipoprotein B (ApoB) and lipoprotein (a) (Lp[a]) are predictors of cardiovascular disease (CVD) risk; therefore, current recommendations for CVD risk assessment and management advocate that patients receive testing for ApoB and Lp(a) in addition to the standard lipid panel. However, US guidelines around ApoB and Lp(a) testing have evolved over time and vary slightly by expert committee. The objective of this analysis was to estimate the number of insured individuals in the USA who received any component of a lipid test, or ApoB and/or Lp(a) testing, during 2019. We conducted a cross-sectional analysis to estimate the prevalence of any component of a lipid test, ApoB, and/or Lp(a) in the USA using four different claim data sources (including Medicaid, Medicare, and commercially insured enrollees). Prevalence estimates were age-, sex-, payor-, and region-standardized to the 2019 US Annual Social and Economic Supplement of the Current Population Survey. We also described the clinical profile of patients who received lipid testing between 2019 and 2021 (cohort analysis) in Optum claims database. Enrollees were grouped into four non-mutually exclusive cohorts based on their completion of any component of the lipid panel, ApoB, Lp(a), or ApoB and Lp(a). In the prevalence cohort, over a third (38 %) of insured adults in the USA underwent testing for any component of a lipid panel in 2019. This proportion was higher for individuals aged ≥65 years compared to younger adults (62% vs 31 %). The proportion of ApoB and Lp(a) testing represented only <1 % of testing for any component of a lipid panel. In the cohort analysis, we found that lipid testing increased with age and comorbidities. These data should be considered by guideline-issuing agencies and organizations to develop education campaigns encouraging more frequent use of tests beyond the standard lipid panel. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations in genes involved in chylomicron metabolism. On the other hand, multifactorial chylomicronemia syndrome (MCS) is a polygenic disorder and the most frequent cause of chylomicronemia, which results from the presence of multiple genetic variants related to chylomicron metabolism, in addition to secondary factors. Indeed, the genetic determinants that predispose to MCS are the presence of a heterozygous rare variant or an accumulation of several SNPs (oligo/polygenic). However, their clinical, paraclinical, and molecular features are not well established in our country. The objective of this study was to describe the development and results of a screening program for severe hypertriglyceridemia in Colombia. A cross-sectional study was performed. All patients aged >18 years with triglyceride levels ≥500 mg/dL from 2010 to 2020 were included. The program was developed in three stages: 1. Review of electronic records and identification of suspected cases based on laboratory findings (triglyceride levels ≥500 mg/dL); 2. Identification of suspected cases based on laboratory findings that also allowed us to exclude secondary factors; 3. Patients with FCS scores <8 were excluded. The remaining patients underwent molecular analysis. In total, we categorized 2415 patients as suspected clinical cases with a mean age of 53 years, of which 68% corresponded to male patients. The mean triglyceride levels were 705.37 mg/dL (standard deviation [SD] 335.9 mg/dL). After applying the FCS score, 2.4% (n = 18) of patients met the probable case definition and underwent a molecular test. Additionally, 7 patients had unique variants in the APOA5 gene (c.694 T > C; p. Ser232Pro) or in the GPIHBP1 gene (c.523G > C; p. Gly175Arg), for an apparent prevalence of familial chylomicronemia in the consulting population of 0.41 per 1.000 patients with severe HTG measurement. No previously reported pathogenic variants were detected. This study describes a screening program for the detection of severe hypertriglyceridemia. Although we identified seven patients as carriers of a variant in the APOA5 gene, we diagnosed only one patient with FCS. We believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder. Show less

Aortic valve calcification (AVC) shares pathological features with atherosclerosis. Lipoprotein components have been detected in aortic valve tissue, including HDL (high-density lipoprotein). HDL measures have inverse associations with cardiovascular disease, but relationships with long-term AVC progression are unclear. We investigated associations of HDL cholesterol, HDL-particle number and size, apoC3-defined HDL subtypes, and, secondarily, CETP (cholesteryl ester transfer protein) mass and activity, with long-term incidence and progression of AVC. We used linear mixed-effects models to evaluate the associations of baseline HDL indices with AVC. AVC was quantified by Agatston scoring of up to 3 serial computed tomography scans over a median of 8.9 (maximum 11.2) years of follow-up in the Multi-Ethnic Study of Atherosclerosis (n=6784). After adjustment, higher concentrations of HDL-C (high-density lipoprotein cholesterol), HDL-P (HDL particles), large HDL-P, and apoC3-lacking HDL-C were significantly associated with lower incidence/progression of AVC. Neither small or medium HDL-P nor apoC3-containing HDL-C was significantly associated with AVC incidence/progression. When included together, a significant association was observed only for HDL-C, but not for HDL-P. Secondary analyses showed an inverse relationship between CETP mass, but not activity, and AVC incidence/progression. In exploratory assessments, inverse associations for HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL with AVC incidence/progression were more pronounced for older, male, and White participants. ApoC3-containing HDL-C only showed a positive association with AVC in these subgroups. In a multiethnic population, HDL-C, HDL-P, large HDL-P, and apoC3-lacking HDL-C were inversely associated with long-term incidence and progression of AVC. Further investigation of HDL composition and mechanisms could be useful in understanding pathways that slow AVC. Show less

Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer. Show less