Fátima Sánchez-Cabo

Mavacamten is a targeted treatment for hypertrophic cardiomyopathy, a disease caused by genetic variants affecting mainly sarcomeric myosin and its regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here we generate knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which unlike carriers of cMyBP-C truncations, develop pathogenic myocardial remodeling with preserved cMyBP-C levels and localization. Mechanistically, R502W reduces cMyBP-C–myosin affinity and generates sarcomere hypercontractility due to increased Ca²⁺ sensitivity and a favored ON structural state of myosin. Even though these pathomechanisms do not overlap with those triggered by truncating MYBPC3 variants, mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient hearts, correlating with the drug’s ability to restore OFF myosin in R502W sarcomeres. In R502W human engineered heart tissues, mavacamten also opposes hypercontractility. Hence, our results indicate that mavacamten is effective in treating hypertrophic cardiomyopathy caused by both truncating and missense MYBPC3 variants regardless of their primary pathomechanisms.

Large Language Models (LLMs) are transforming clinical practice and research, but their adoption requires rigorous evaluation. While human assessment is ideal, its cost has driven the widespread use of LLMs as evaluators. We introduce an open-source reciprocal framework comparing 71 human experts against six LLMs. AI evaluators show a strong self-preference bias, yet neither group reliably identified whether a response was human- or AI-generated. AI scores correlated with surface features such as length and lexical diversity, whereas human scores did not. By probing the evaluator’s hidden states and applying targeted steering, we show that verbosity is a major causal driver of the bias. Moreover, shuffling question–response pairings shows that long responses keep high scores even when they no longer answer the question, whereas short ones do not, demonstrating that AI judges reward verbosity largely independently of content alignment. Finally, API-based and batch inference inflate stochasticity, underscoring the need for controlled deployment.

Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes¹, which control pathways including redox and calcium homeostasis^2,3. Recent studies have also reported direct mitochondria–nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling^4,5. Here we identify direct interactions between mitochondria and nuclear pores. Using two unbiased proteomic screens, GST pulldown and BioID, we found that VDAC1 was the top mitochondrial candidate that interacts with the filamentous nuclear pore protein RANBP2. In vitro RANBP2 CRISPR knockout, RANBP2 truncation or site-directed mutagenesis of RANBP2–VDAC1 interacting amino acids resulted in reduced mitochondria–nucleus proximity and decreased nuclear ATP and phosphocreatine levels. This was accompanied by a decline in the levels of the nuclear phosphoproteome and downregulation of pathways involved in histone modification, cellular differentiation and transcriptional regulation in vitro. Moreover, deletion of the RANBP2 C-terminal domain in vivo in mice resulted in embryonic lethality due to cardiac and neural crest differentiation defects. Collectively, these results describe a mechanism by which mitochondria directly interact with the nuclear pore complex, a phenomenon critical for regulation of nuclear energetics and cellular differentiation. Undoubtedly, additional roles of this interaction remain to be revealed.

BACKGROUND: Global Vhl knockout results in vascular defects and early lethality, limiting our knowledge of von Hippel–Lindau/HIF (hypoxia-inducible factor) signaling in coronary vessel formation and homeostasis. The hypoxia pathway has been implicated in cardiovascular diseases characterized by inflammation and vascular remodeling, such as atherosclerosis, but its involvement in Kawasaki disease (KD) remains unknown. Coronary artery dilation and vessel rupture are the most serious complications of KD. However, the molecular mechanisms underlying these cardiac events are not fully understood. We investigated the role of the von Hippel–Lindau/HIF pathway in cardiovascular pathology and its relevance to KD. METHODS: We generated a novel mouse model with genetic hyperactivation of the hypoxia pathway in progenitors contributing to coronary vessels and cardiac fibroblasts. We characterized the model using echocardiography, magnetic resonance imaging, histology, and molecular profiling. In parallel, we examined cardiac tissues from patients with KD with fatal coronary aneurysms for evidence of HIF signaling and inflammation using immunohistochemistry. RESULTS: Mice with conditional deletion of Vhl in Wt1 (Wilms tumor 1)–expressing cells developed normally but exhibited cardiomegaly, vascular abnormalities, progressive coronary artery dilation, pericardial hemorrhage, and systemic inflammation shortly after birth. Histologic analysis revealed coronary arteritis, elastin breaks, vascular remodeling, smooth muscle cell loss, perivascular fibrosis, and frequent intracoronary thrombus formation. In addition, vascular calcification, severe cardiac inflammation, and interstitial hemorrhages were observed, culminating in sudden death between 15 and 20 weeks of age, likely due to vessel rupture. Cardiac transcriptomic profiling identified dysregulated expression of genes involved in extracellular matrix organization, epithelial–mesenchymal transition, angiogenesis, inflammation, coagulation, and calcification, indicating compromised vascular stability and increased remodeling in Vhl conditional knockout mice. Simultaneous deletion of Hif2a rescued both the cardiovascular abnormalities and transcriptomic profile observed in Vhl conditional knockout mice, implicating Hif2 (hypoxia-inducible factor 2) as a key mediator. Human KD cardiac samples showed expression of HIF2 in coronary lesions and surrounding inflammatory infiltrates, confirming hypoxia pathway activation in severe KD. CONCLUSIONS: Our findings establish HIF2 as a central driver of coronary inflammation, vascular remodeling, and thrombotic complications resembling those observed in severe KD. The Vhl /Wt1 conditional knockout mouse model recapitulates key cardiovascular features of KD and offers a valuable platform for mechanistic studies and therapeutic exploration.

Tissue-resident macrophages receive signals from their microenvironment that coordinate the activity of transcription factors (TFs) to establish distinct transcriptional profiles and identities. However, the molecular mechanisms whereby interactions with other cells of the niche imprint a distinct macrophage identity remain poorly understood. Here, we report that retinoid X receptors (RXRs) determine the differentiation and identity of alveolar macrophages (AM) by regulating chromatin accessibility and transcriptional activity of AM-core and function genes, enabling PPARγ-dependent programs. AM differentiation and maintenance in vivo require RXR upregulation in response to tissue-derived δ-like canonical Notch ligand 4 (DLL4), GM-CSF, and TGF β (TGFβ). Interplay among these signals leads to cooperation between RXRα, RBPJ, STAT5, and SMAD4 for the transcriptional and epigenetic regulation of key AM-core genes. These results underscore the role of RXRs as key TFs that cooperate with other regulatory elements to establish the AM population and determine AM identity.

In alignment with the European Health Data Space (EHDS), Spain’s IMPaCT - Precision Medicine Infrastructure associated with Science and Technology - aims to establish a trusted research environment (TRE) for secure and FAIR data sharing and analysis. It is structured into three pillars: Predictive Medicine (IMPaCT-Cohort), Genomic Medicine (IMPaCT-Genomics), and Data Science (IMPaCT-Data). IMPaCT-Data leads the development of the IMPaCT Digital Platform (IDP), integrating clinical, genomic, and imaging data to support the national IMPaCT-Cohort and Personalised Medicine Projects (IMPaCT-PMPs). Its Reference Implementation defines the architecture across a federated model.

BACKGROUND: Excessive trabeculations and myocardial crypts are recurrent features across cardiomyopathies, yet their developmental origins and clinical significance remain poorly defined. To reveal the link between cardiac morphogenesis and disease, we generated humanized mouse models carrying patient-derived MYBPC3 frameshift mutations associated with overlapping hypertrophic cardiomyopathy (HCM) and left ventricular non-compaction (LVNC). METHODS: We applied CRISPR-Cas9 to introduce distinct MYBPC3 frameshift alleles into the mouse genome and performed comprehensive phenotypic and transcriptomic profiling from fetal life through adulthood. RESULTS: Adult homozygous Mybpc3 frameshift mutant mice like humans displayed hallmark HCM; however, without LVNC. Fetal and neonatal mutant hearts exhibited markedly enlarged ventricular trabeculae and crypts that progressed postnatally into the observed adult hypertrophy. Transcriptomic analysis revealed stage-specific dysregulation of oxidative metabolism, nonsense-mediated decay (NMD), and cell cycle pathways, peaking at postnatal days 1 and 7, indicating that these stages represent critical time points in disease onset. The persistent NMD signature, also observed in phenotype-negative heterozygotes, suggests a compensatory stress response. Enlarged trabeculae exhibited 2-fold increased trabecular cardiomyocyte proliferation, reversing the normal compact–trabecular proliferative gradient and leading to impaired ventricular compaction in neonates. Hey2 ^CreERT2 lineage tracing demonstrated invasion of Hey2 ⁺ compact cardiomyocytes into the trabeculae and ectopic trabecular expression of the Prdm16 transcription factor, indicating defective ventricular wall patterning and maturation. Postnatally, Hey2 ⁺ -derived cardiomyocytes became restricted to the outer/compact myocardium in mutants, while the inner/trabecular myocardium underwent accelerated hypertrophy concurrent with Prdm16 downregulation. Mice with a Mybpc3 missense variant also exhibited Hey2 ⁺ myocardial lineage expansion into trabeculae but no increased proliferation, implicating additional mechanisms beyond Hey2 regulation. Postnatal Prdm16 restoration, via transgenic expression in Mybpc3-null mice effectively attenuated hypertrophy, establishing a causal link between Mybpc3 loss, Prdm16 decline, and pathological remodeling. CONCLUSIONS: Mybpc3 governs ventricular wall maturation by regulating cardiomyocyte proliferation, patterning, and maturation, partly via Prdm16. Disruption of these developmental programs precedes and drives adult HCM, highlighting a developmental role for sarcomeric proteins, and revealing postnatal Prdm16 modulation as an antihypertrophic therapeutic strategy.

BACKGROUND: Nonmyocytes may contribute to regional adaptive changes during persistent atrial fibrillation (PsAF), favoring its perpetuation. We aimed to investigate the differential features of fibroblast and macrophage populations within individual-specific atrial regions associated with PsAF maintenance. METHODS: The study was conducted in 2 pig models of PsAF with and without infarct-related substrate (N=27 and N=27, respectively) and further validated in humans with PsAF (N=20). Sham-operated pigs (N=9), healthy animals (N=4), and patients in sinus rhythm (N=7) were used as comparative controls. In pigs, in vivo high-density instantaneous frequency modulation maps were used to identify atrial regions associated with PsAF maintenance (drivers). Regional cellular composition and phenotypic states of fibroblast and myeloid lineages were determined using flow cytometry, single-cell RNA sequencing, immunohistochemistry, and proteomic analyses. The functional relevance of driver regions was further studied in patients with symptomatic PsAF undergoing ablation. Flow cytometry and single-cell RNA sequencing analyses were performed in tissue samples of the left atrial appendage in a complementary cohort of patients with PsAF undergoing thoracoscopic-guided ablation. RESULTS: PsAF terminated acutely in 12 of 14 pigs undergoing mapping and ablation of driver regions. In humans, driver ablation was associated with 90% AF-freedom (on/off antiarrhythmic drugs) after 2 years of follow-up. Samples from nonablated pigs revealed a phenotypic shift towards ACTA2 (actin alpha 2)-fibroblasts and PTX3 (pentraxin 3)-fibroblasts during PsAF. Although ACTA2-fibroblasts were highly preserved in human samples, paired comparisons in pig samples showed that PTX3-fibroblasts were enriched only in driver regions. PsAF also showed changes in myeloid cells towards inflammatory profiles. However, regional analysis revealed that, in both humans and pigs with PsAF, driver regions were enriched in cardiac resident macrophages with transcriptomic and proteomic profiles favoring cardiomyocyte homeostasis and cell survival. CONCLUSIONS: PsAF shows differential regional changes in fibroblast and myeloid populations with distinctive gene signatures in areas that drive the overall arrhythmia.