26-A-12924-ACC TRANSCRIPTOMIC PROFILING OF PLASMA MICRORNA REVEALS DISTINCT MOLECULAR SUBTYPES OF HYPERTROPHIC CARDIOMYOPATHY WITH DIFFERENT RISKS OF MAJOR ADVERSE CARDIOVASCULAR EVENTS

Journal of the American College of Cardiology · 2026-03-27

Precision Diagnosis in <i>APOL1</i> Kidney Disease With the p.N264K M1 Protective Variant

JAMA Network Open · 2026-03-11

Importance: The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual's M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored. Objective: To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD. Design, Setting, and Participants: Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls. Exposures: Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry. Main outcome and measure: The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non-kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs). Results: A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10-3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS. Conclusions and relevance: In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.

Atherosclerosis Profiling Reveals BHLHE40 as a Candidate Modulator of VSMC

Circulation Research · 2026-05-13

BACKGROUND: Vascular smooth muscle cells (VSMCs) play a central role in atherosclerosis by undergoing phenotypic modulation from a quiescent, contractile state to a range of synthetic phenotypes, including fibroblast-like, macrophage-like, and lipid-laden foam cell–like states. However, a comprehensive multimodal characterization and understanding of the transcriptional programs driving these transitions remain incomplete. METHODS: To comprehensively define the phenotypic diversity of VSMCs during atherosclerosis progression, we performed in-depth profiling using cellular indexing of transcriptomes and epitopes by sequencing and bulk RNA sequencing in a VSMC-lineage–tracing atherosclerotic mouse model. Insights from these data sets guided the design of targeted in vitro experiments to investigate candidate regulatory mechanisms. RESULTS: Single-cell multiomics revealed extensive cellular heterogeneity within atherosclerotic plaques, including a rare population of VSMC-derived macrophage-like cells, whose presence was confirmed by histological analysis. These studies also identified a large population of VSMC-derived foam cells that exhibited activation of gene programs associated with lipid metabolism, proliferation, and tumor-like features. The transcription factor BHLHE40 emerged as a candidate regulator of this phenotypic transition, with elevated expression and activity in VSMC-derived foam cells during disease progression and expression in modulated VSMC in human carotid atherosclerosis. Functional knockdown of Bhlhe40 reprogrammed immune, cell cycle, and lipid homeostasis genes in cultured VSMC and suppressed VSMC phenotypic switching and foam cell characteristics, consistent with a potential regulatory role in VSMC modulation. CONCLUSIONS: These findings advance our understanding of VSMC phenotypic modulation in atherosclerosis and implicate BHLHE40 as a candidate transcriptional regulator of this process. Elucidating mechanisms governing VSMC plasticity may offer new therapeutic opportunities to reduce cardiovascular risk by targeting disease-driving cellular transitions.

Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy

Nature Cardiovascular Research · 2026-01-06

The heart uses a muscle-specific ribosome in cardiomyocytes, where the ribosomal protein RPL3 is replaced by its paralog RPL3L. Rare biallelic RPL3L mutations cause fatal neonatal dilated cardiomyopathy, yet the mechanisms that link genotype to heart failure are unclear. Despite the recessive inheritance pattern in humans, Rpl3l knockout mice show no overt cardiac phenotype, probably because of compensatory RPL3 upregulation through unknown mechanisms. Here we report four additional cases and propose a unifying pathogenetic model by integrating human genetics, patient tissues and isogenic cell models. Affected individuals typically carry one of two recurrent hotspot missense variants paired with a private allele. Whereas non-hotspot variants phenocopy knockout and allow RPL3 compensation, hotspot variants induce nucleolar protein aggregation, disrupt rRNA processing and block compensation by preserving the role of RPL3L in repressing RPL3 via unproductive splicing. These findings establish combined loss-of-function and gain-of-function mechanisms for RPL3L-associated cardiomyopathy and inform genetic screening, diagnosis and therapeutic development. Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

Perk Is Dispensable for Smooth Muscle Cell Phenotype Switching in Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology · 2026-05-14

BACKGROUND: Smooth muscle cell (SMC) derived cells form the bulk of cells in atherosclerotic lesions and modulate lesion stability and cardiovascular disease outcomes. Unfolded protein response (UPR) markers, thin fibrous caps, and inflammation correlate with human lesion instability and rupture. In mice, UPR drives macrophage and endothelial apoptosis and inflammation, but its impact on lesion stability through SMC modulation is debated. The UPR protein Perk (protein kinase RNA-like ER kinase) was recently shown to drive SMC modulation in vivo, suggesting that depletion of SMC Perk may regulate lesion stability. METHODS: hypercholesterolemic mice. Lesions were scored for features of lesion stability and analyzed for differential expression at the single-cell level. Perk knockdown in primary murine SMCs was used to study Perk's effect on SMC modulation in vitro. UPR marker expression in human carotid lesions was assessed for UPR markers through scRNA-seq, bulk RNA-seq, and Xenium spatial transcriptomics. RESULTS: SMC Perk deletion in adult atherogenic mice did not affect weight gain or serum cholesterol levels. Lesions from Perk knockout mice resembled Perk WT counterparts with similar progression, lesion stability features, and cell populations. Scoring of UPR activity and differential expression analysis found little UPR activity in SMC and smooth muscle-derived cell populations. Perk was not required for in vitro SMC modulation in atherogenic conditions. No correlation was found between UPR markers and lesion stability or symptomatic clinical presentation in human carotid lesions, and UPR markers were expressed primarily in infiltrating leukocytes rather than in SMCs and stromal cells. CONCLUSIONS: SMC Perk UPR does not play a significant role in atherosclerotic SMC modulation, disease progression, or features of lesion stability in mice. Similarly, expression of markers of the Perk UPR pathway in humans does not correlate with human carotid lesion stability or clinical presentation.

Polygenic risk and rare variants in endotypes of idiopathic pulmonary fibrosis: a genetic analysis of population-based and case–control cohorts

The Lancet Respiratory Medicine · 2026-01-27 · 1 citations

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and telomere length are both strongly linked to rare and common genetic variants. Shortened telomere length might itself be causal for IPF. We aimed to evaluate whether rare and common variants compete or cooperate to confer genetic risk of IPF uniformly. METHODS: In this genetic analysis, we used whole-genome sequencing (WGS) data from a discovery case-control cohort sequenced at Columbia University and validated findings using WGS data from Trans-Omics for Precision Medicine (TOPMed) and UK Biobank. In all cohorts, we identified rare damaging variants in disease-associated genes and computed control-normalised non-overlapping polygenic risk scores (PRS) for IPF and telomere length. We assessed the MUC5B rs35705950 single-nucleotide polymorphism (SNP), an IPF common risk variant with a large effect, independently from the polygenic scores. Telomere length in blood leukocytes was measured using a quantitative PCR assay for the discovery cohort and UK Biobank validation cohort. We conducted logistic regression (adjusting for age, sex, and principal components of ancestry) to evaluate the association between IPF risk and the MUC5B SNP, the IPF PRS excluding MUC5B (IPF-PRS-noMUC5B), and the PRS for telomere length in the overall cohort and analysed their effects in patient subgroups for IPF endotypes (carriers and non-carriers of rare variants stratified by telomere length cutoffs). To assess disease prediction, we calculated cross-validated area under the receiver operating receiver operating curve (AUC). We also compared the liability of IPF explained by genetic variables. FINDINGS: The discovery cohort was recruited between April 23, 2003 and June 19, 2019 and included 777 patients with IPF and 2905 controls. We replicated the analyses in the TOPMed (1148 patients with IPF and 5202 controls) and UK Biobank (2739 patients with IPF and 395 331 controls) cohorts. 23-43% of patients with IPF had damaging rare variants or telomeres shorter than the tenth percentile. Analysis of the association of genetic variables with IPF diagnosis yielded odds ratios of 1·63 (95% CI 1·47-1·81) for telomere length PRS and 1·60 (1·44-1·77) for IPF-PRS-noMUC5B in the discovery cohort, with similar effect sizes for the two variables in the replication cohorts (1·47, 1·36-1·59 vs 1·37, 1·25-1·50 in TOPMed; 1·24, 1·19-1·29 vs 1·25, 1·21-1·30 in UK Biobank). The telomere length PRS had the greatest effect on disease risk in patients with IPF not harbouring rare variants and with telomere length shorter than the tenth percentile in the discovery cohort (2·02, 1·76-2·33) and UK Biobank replication cohort (1·70, 1·56-1·85). Accounting for clinical variables and all genetic variables (rare variants, MUC5B SNP, IPF PRS, and telomere length PRS) led to the best disease prediction in the discovery cohort (combined AUC 0·89), TOPMed cohort (0·89), and UK Biobank cohort (0·77). Rare and common variants contributed jointly to the genetic liability of IPF. The telomere length PRS accounted for 13% of the explained genetic liability of IPF in the discovery cohort and 8% and 13% in the TOPMed and UK Biobank cohorts, respectively. INTERPRETATION: Common and rare genetic variation confer context-specific genetic risk in patients with IPF both competitively and cooperatively. In contrast to known IPF common risk variants, the telomere length PRS, which includes more than 180 genetic loci not previously associated with IPF, is associated with increased risk of disease in patients with specific IPF endotypes. Polygenic risk from telomere-associated common variants is a key feature of genetic heterogeneity in IPF. FUNDING: US National Institutes of Health, UK Medical Research Council, and UK National Institute for Health and Care Research.

IgG Propels Atherosclerosis by Noncanonically Activating Macrophages

bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-17

Despite being a central component of adaptive immunity and a highly abundant serum protein, the contribution of IgG to the milieu of atherosclerosis remains unappreciated. Here, we identify a pro-atherogenic role for IgG as it activates an innate immune cascade, independent of its classical antigen-neutralizing function. Analyses of human coronary artery plaques reveal a positive correlation between IgG and cardiovascular and cerebrovascular disease severity. Integrated single-cell plaque analyses localize IgG, coinciding with its recycling receptor FcRn, to pro-inflammatory and foamy macrophages. Genetic ablation of FcRn in myeloid cells prevents IgG from accumulating in mouse atherosclerotic lesions, diminishing plaque size and inflammation. Mechanistically, IgG acts as an endogenous ligand for TLR4, triggering NF-κB-NLRP3 inflammasome signaling without requiring its antigen-binding domain. Additionally, IgG accelerates macrophage foam cell formation through upregulation of downstream effector LCN2. Our work uncovers a role for previously overlooked adaptive immune molecules in the pathogenesis of atherosclerosis through a noncanonical mechanism linked with innate immunity.

Implementation and early outcomes of a team science consultation service: Addressing key challenges in translational research collaborations

Journal of Clinical and Translational Science · 2026-01-01

Background/objective: Team science, defined as scientific collaboration across disciplines and knowledge domains, has become essential for translational research, yet teams face recurrent challenges that can impede progress and are often difficult to overcome without additional support. We describe the implementation and initial outcomes of our Team Advice and Consultation Service (TACS), a program designed to address team science challenges at a research-intensive academic medical center engaged in translational science across a broad range of disciplines. Methods: Grounded in Knowledge-to-Action framework and Transdisciplinary Innovation theory, TACS provides tailored, case-specific support across the team lifecycle. Results: Through thematic analysis of consultations with seven teams (2023-2024), we identified five recurrent challenge domains: organization/structural complexity, team leadership and management, team dynamics and communication, authorship and credit allocation, and conflict resolution. Conclusion: Findings underscore the value of structured support for team science and provide insights and potential strategies for institutions seeking to implement similar services.

Author Correction: The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis

Nature · 2026-05-14

Single-Cell Multimodal Profiling Reveals a Novel CD26 ⁺ Fibroblast Subpopulation in Atherosclerosis

bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-28

Abstract Background Atherosclerosis involves complex interactions between lipids, immune cells, vascular smooth muscle cells (VSMCs), and fibroblasts within the arterial wall. While significant advances in single-cell technologies have shed light on the roles of immune cells and VSMCs in plaque development, fibroblasts remain underexplored, leaving critical gaps in understanding their contributions to disease progression and plaque stability. Comprehensive characterization of fibroblast phenotypes in atherosclerosis is essential to unravel their diverse functions and to distinguish between subsets that may play protective versus pathogenic roles in the disease process. Methods Here, we utilized CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) to comprehensively profile fibroblast diversity in a mouse model of atherosclerosis. Mice were fed an atherogenic diet for 0, 8, 19, and 26 weeks, representing distinct stages of disease progression, enabling a detailed phenotypic characterization of fibroblasts throughout the course of atherosclerosis development. Results We identified four distinct fibroblast subpopulations, including a myofibroblast population closely resembling VSMC-derived chondromyocytes. The proportions of these fibroblast subsets exhibited a modest decline as atherosclerosis progressed. Through multimodal analysis, we identified CD26 as a highly expressed and specific marker for one of these fibroblast subpopulations, distinguishing it from other subsets. Using a combination of flow cytometry and immunohistochemistry, we demonstrated that CD26 + fibroblasts predominantly reside in the adventitia of healthy arteries. During atherosclerosis progression, these cells expand into the intima and primarily localize within the fibrous cap of the lesion. Conclusions Our multi-omic analysis highlights the phenotypic diversity and dynamic changes of fibroblasts during atherosclerosis progression. Among these, CD26+ fibroblasts emerge as a distinct subpopulation that expands within atherosclerotic lesions and may play a critical role in promoting plaque stability through their migration into the fibrous cap.