Cardiology - Papers

This Nature study reports that engineered heart muscle allografts can be implanted to remuscularize failing myocardium, demonstrated across primates and humans. The work advances a translational path for cell-based myocardial repair.

In 14,606 ambulatory ECG recordings, an ensemble AI (DeepRhythmAI) achieved markedly higher sensitivity for critical arrhythmias than certified technicians (98.6% vs 80.3%), reducing false negatives by ~14-fold per patient compared to human review. Although AI increased false positives modestly, its strong negative predictive value supports direct-to-physician reporting.

This meta-analysis of genome/exome sequencing across 52,416 AF cases and 277,762 controls identifies new rare coding genes (e.g., MYBPC3, LMNA, PKP2, FAM189A2, KDM5B) and structural variants (CTNNA3 deletions, GATA4 duplications) associated with AF. Findings were broadly replicated, and CRISPR knockout of KDM5B in atrial cardiomyocytes shortened action potential duration, linking rare variants to atrial electrophysiology.

Using mouse models and human endothelial cells, the study shows that maternal Western-type diet imprints an AP-1/p300–H3K27ac epigenetic program in aortic endothelium, creating inflammatory memory that accelerates offspring atherogenesis. 27-hydroxycholesterol contributes to memory establishment and acts as a secondary amplifier; blocking AP-1–chromatin binding dampens endothelial inflammation and reduces atherosclerosis.

In a randomized comparison in AF, monthly abelacimab reduced free factor XI by ~97–99% and cut major/CRNM bleeding by 62–69% versus rivaroxaban, leading to early trial termination. Adverse event profiles were similar across arms.

IGFBP6 acts as an endothelial homeostatic mediator that dampens inflammatory signaling and monocyte adhesion via an MVP–JNK/NF-κB pathway. Human, cellular, and mouse data converge to show that loss of IGFBP6 predisposes to atherosclerosis, whereas endothelial overexpression is protective, nominating IGFBP6 as a potential therapeutic target.

In 11,555 CHD probands, burden testing across 248 genes identified 60 dominant genes explaining 10.1% of cases, with similar contributions from de novo and transmitted variants and incomplete penetrance. Tissue- and subtype-specific patterns emerged, including NOTCH1 EGF-like domain cysteine-altering missense variants enriched in tetralogy of Fallot/conotruncal defects and brain-expressed genes linked to neurodevelopmental delay.

This study identifies S-nitrosylated PKM2 as a fibroblast-specific driver of cardiac fibrosis via gelsolin-dependent promotion of mitochondrial fission. Pharmacologic activation of PKM2 (TEPP-46 and the FDA-approved mitapivat) reversed mitochondrial fission and attenuated fibrosis across preclinical models, suggesting repurposing potential for antifibrotic therapy.

Using single-cell and spatial transcriptomics across human and mouse infarcted hearts, the authors identify a CD248hi fibroblast subset that coordinates immune-fibroblast crosstalk. Fibroblast-specific Cd248 deletion reduces fibrosis and dysfunction; mechanistically, CD248 stabilizes TGFβRI and induces ACKR3, retaining T cells that fuel fibroblast activation. Disrupting this axis with an antibody or engineered T cells lowers T-cell infiltration and scar expansion.

Using UK Biobank for development and All of Us for external validation, the authors built a 10-year incident CAD risk model that integrates genetic and clinical data into 15 meta-features and achieved AUC 0.84 (external 0.81). The framework also estimates individualized benefits of standard interventions, enabling tailored prevention strategies based on genetic and phenotypic profiles.

In patients with type 2 diabetes and chronic kidney disease, sotagliflozin reduced total MACE versus placebo (HR 0.77) and independently reduced myocardial infarction (HR 0.68) and stroke (HR 0.66). Benefits were consistent across subgroups, highlighting a potential ischemic risk reduction unique to dual SGLT1/2 inhibition.

In patients with CAD, serum deoxycholic acid was reduced and Bacteroides vulgatus was underrepresented, implicating disrupted bile acid metabolism. Using TGR5 inhibitors and knockout mice, the authors show DCA suppresses agonist-induced platelet activation and thrombosis via platelet TGR5. Oral DCA, B. vulgatus, and healthy donor stool reduced platelet hyperreactivity and thrombosis in atherosclerotic ApoE-deficient mice.

Using modified mRNA targeting desmocollin‑2 deficiency, the authors restored desmosomal function and improved cardiac performance in mouse models of ARVC, bridged by human genetic discovery. This provides first-in-class preclinical evidence that mRNA replacement can treat inherited cardiomyopathy by correcting structural protein deficits.

Using genome-wide CAD variants with endothelial functional effects, the authors built a 35-SNP EC-specific polygenic risk score that was associated with incident CAD in UK Biobank and identified individuals who derive greater benefit from aggressive LDL-C lowering in JUPITER (statin) and FOURIER (PCSK9 inhibitor). This enables endothelial biology–informed precision prevention.

A cross-ancestry GWAS of coronary dominance in >60,000 angiograms identified 10 loci, with the strongest signal near CXCL12. CXCL12 is expressed in human fetal hearts when dominance is set, and reducing Cxcl12 in mice shifts dominance and septal artery trajectories, establishing a developmental mechanism for coronary anatomy.

Using Mendelian randomization across >420,000 participants, the authors identified 70 HFrEF and 10 HFpEF causal targets, largely non-overlapping, highlighting the need for subtype-specific therapies. Druggable candidates include IL6R, ADM, and EDNRA for HFrEF and LPA for both subtypes; findings were replicated in >175,000 multi-ancestry participants.

Using AI-derived CMR measurements across >50,000 individuals, the authors show that age-, sex-, and BSA-adjusted LVH thresholds (10–17 mm) substantially reduce misclassification and sex/body-size bias compared with the fixed 15-mm rule. Personalized z-scores improved HCM ascertainment, especially in women who often have lower absolute MWT but higher standardized burden.

A high-throughput screen identified EF-1, a small-molecule ERBB4 activator that reduces cardiomyocyte injury and cardiac fibrosis via ERBB4-dependent mechanisms. EF-1 conferred protection in angiotensin II, doxorubicin, and myocardial infarction models (sex- and context-dependent), establishing feasibility for a new therapeutic class.

Using iPSC-cardiomyocytes and a stress-augmented mouse model, the authors show that osimertinib triggers reversible sarcomeric dysfunction via GATA4 dephosphorylation, MYLK3 suppression, and reduced MYL2 phosphorylation. Pharmacologic activation of myosin with omecamtiv prevented dysfunction, suggesting a targeted mitigation strategy for TKI cardiotoxicity.

Piezo2 is upregulated in cardiac ganglionated plexi in AF and with higher left atrial pressure; targeted knockdown of Piezo2 in GP reduces neural activity and AF susceptibility in a large-animal model. Transcriptomics implicated Notch pathway downregulation, supporting a mechanistic link between mechanosensation and autonomic modulation in AF.

Using human samples and complementary mouse models, the authors show that cardiometabolic HFpEF is characterized by elevated circulating hematopoietic stem cells, niche remodeling, and maladaptive myeloid fatty acid metabolism that fuels systemic inflammation and diastolic dysfunction. Multi-omics and isotope tracing support a cell-intrinsic macrophage metabolic program as a causal driver.

The authors solved the crystal structure of the troponin complex carrying the TNNT2 K210del mutation, revealing S69 distortion in TnC and calcium discoordination. Structure-guided repurposing identified risedronate, which restored the mutant structure, normalized force in K210del patient iPSC-cardiomyocytes, improved calcium sensitivity in skinned muscle, and normalized LVEF in K210del mice.

The authors introduce LogiRx, a mechanistic AI approach that predicts drug-induced signaling pathways. They demonstrate that escitalopram attenuates cardiomyocyte hypertrophy via an off-target serotonin receptor/PI3Kγ pathway, validating predictions in neonatal cardiomyocytes, adult mice, and human databases.

This mechanistic study identifies a previously unreported NAA10 p.(Arg4Ser) variant that segregates with QT prolongation, cardiomyopathy, and developmental delay in a large kindred, implicating dysregulated N-terminal acetylation as a disease mechanism. The findings link protein acetylation biology to human cardiac electrophysiology and structure, highlighting a new pathogenic pathway.