Weekly Cardiology Research Analysis
This week’s cardiology literature highlights translational advances across mechanisms, diagnostics, and therapeutics. Mechanistic studies nominate novel targets linking microbiota–bile acids (TGR5) and chromatin regulators (SETD2) to thrombosis and HFpEF respectively, while RNA therapeutics show preclinical rescue in inherited cardiomyopathy. Diagnostic and implementation innovations include CT radiomics for opportunistic ATTR-CM detection and AI-enhanced natriuretic peptide algorithms (CoDE-HF)
Summary
This week’s cardiology literature highlights translational advances across mechanisms, diagnostics, and therapeutics. Mechanistic studies nominate novel targets linking microbiota–bile acids (TGR5) and chromatin regulators (SETD2) to thrombosis and HFpEF respectively, while RNA therapeutics show preclinical rescue in inherited cardiomyopathy. Diagnostic and implementation innovations include CT radiomics for opportunistic ATTR-CM detection and AI-enhanced natriuretic peptide algorithms (CoDE-HF); several trials and meta-analyses support earlier SGLT2i initiation in acute heart failure and practical perioperative interventions (NO) to reduce AKI.
Selected Articles
1. The gut microbiota-bile acid-TGR5 axis orchestrates platelet activation and atherothrombosis.
This translational study found reduced serum deoxycholic acid and underrepresentation of Bacteroides vulgatus in patients with coronary artery disease, and demonstrated that deoxycholic acid (DCA) suppresses platelet activation and thrombosis via platelet TGR5. Pharmacologic TGR5 inhibition or genetic knockout abrogated the effect; oral DCA, B. vulgatus, or healthy stool reduced platelet hyperreactivity and thrombosis in atherosclerotic mice, identifying a microbiome–bile acid–platelet axis.
Impact: Provides a mechanistic, multi-model link between the gut microbiome, bile acids and platelet biology, nominating platelet TGR5 as a druggable antithrombotic target and suggesting microbiome- or bile-acid–based adjunct strategies.
Clinical Implications: Although preclinical, the findings justify early-phase translational studies of TGR5 agonism or bile-acid/microbiome modulation in thrombosis-prone CAD patients, with careful safety and interaction assessments alongside standard antiplatelet therapy.
Key Findings
- Serum deoxycholic acid is reduced and Bacteroides vulgatus is underrepresented in CAD patients, implicating altered bile-acid metabolism.
- DCA inhibits agonist-induced platelet activation and thrombosis via platelet TGR5; inhibition or knockout of TGR5 removes protection.
- Oral DCA, B. vulgatus, or healthy-donor fecal transfer reduced platelet hyperreactivity and thrombosis in atherosclerotic ApoE−/− mice.
2. Modified mRNA Treatment Restores Cardiac Function in Desmocollin-2-Deficient Mouse Models of Arrhythmogenic Right Ventricular Cardiomyopathy.
From human genetic discovery of a novel DSC2 variant to mechanistic validation, modified mRNA replacement restored desmosomal protein expression and improved right ventricular structure/function in Dsc2-deficient mouse models of ARVC. The work demonstrates feasibility of mRNA-based structural protein replacement as a disease‑modifying approach for inherited cardiomyopathies.
Impact: First-in-class translational evidence that cardiac-targeted modified mRNA can correct structural protein deficits and rescue phenotype in vivo, expanding therapeutic modalities beyond gene editing or small molecules.
Clinical Implications: Supports clinical development pathways for cardiac mRNA replacement (delivery, dosing, immunogenicity) in ARVC and other desmosomal cardiomyopathies, with emphasis on translational safety and durability studies prior to human trials.
Key Findings
- Identification of a novel pathogenic DSC2 variant linked to ARVC and functional modeling.
- Modified mRNA delivery restored desmosomal protein levels and improved right ventricular function in mouse models.
- Therapeutic mRNA replacement reduced arrhythmogenic substrate and structural dysplasia, demonstrating disease modification potential.
3. The Heart Has Intrinsic Ketogenic Capacity that Mediates NAD+ repletion.
This mechanistic human-and-animal study shows that human myocardium expresses HMGCS2 and can produce ketones; acetylation reduces HMGCS2 activity, while NAD+ repletion deacetylates and restores activity, increasing fatty-acid oxidation and rescuing HFpEF phenotypes. Cardiomyocyte-specific HMGCS2 was necessary for NAD+ therapeutic benefit, linking cardiac ketogenesis mechanistically to HFpEF treatment response.
Impact: Provides first direct evidence of cardiac ketogenesis in humans and mechanistic necessity of HMGCS2 for NAD+-based rescue in HFpEF, reframing metabolic targets and biomarker-guided therapeutic stratification.
Clinical Implications: Motivates biomarker development for cardiac ketogenesis (HMGCS2 activity) and early-phase trials of NAD+ augmentation or deacetylation modulators in HFpEF, with patient stratification by HMGCS2 status.
Key Findings
- Human myocardium has intrinsic HMGCS2-dependent ketogenic capacity; acetylation reduces enzyme activity.
- NAD+ repletion deacetylates and restores HMGCS2, increases fatty-acid oxidation, and rescues HFpEF physiology.
- Cardiomyocyte-specific HMGCS2 knockdown abolishes the therapeutic benefit of NAD+ repletion in HFpEF models.