Cardiology Research Analysis
August’s cardiology literature highlighted mechanistic cardio-oncology toxicity, non-sarcomeric genetic mechanisms in hypertrophic cardiomyopathy, and blood-based epigenetic risk stratification. A Circulation preclinical study mapped ponatinib’s TNFR2-driven endothelial and thromboinflammatory activation and contrasted it with asciminib’s neutral profile. Independent genetic/epigenetic studies broadened disease frameworks and enabled higher-fidelity prognostics in cardiometabolic care. AI-enable
Summary
August’s cardiology literature highlighted mechanistic cardio-oncology toxicity, non-sarcomeric genetic mechanisms in hypertrophic cardiomyopathy, and blood-based epigenetic risk stratification. A Circulation preclinical study mapped ponatinib’s TNFR2-driven endothelial and thromboinflammatory activation and contrasted it with asciminib’s neutral profile. Independent genetic/epigenetic studies broadened disease frameworks and enabled higher-fidelity prognostics in cardiometabolic care. AI-enabled imaging and ECG modeling, along with in silico device-planning frameworks, continued to shape diagnostic and interventional workflows.
Selected Articles
1. Ponatinib, But Not the New Abl-Kinase Inhibitor Asciminib, Activates Platelets, Leukocytes, and Endothelial Cell TNF Signaling to Induce Atherosclerotic Plaque Inflammation, Myocardial Infarction, and Stroke.
Preclinical models show ponatinib uniquely drives endothelial TNFR upregulation, leukocyte/platelet activation, plaque inflammation, and ischemic deaths, while asciminib lacks these effects; TNFR pharmacologic blockade or TNFR2 knockdown abrogates toxicity.
Impact: Clarifies a targetable TNFR2-driven mechanism underlying ponatinib’s arterial events and directly informs safer drug selection and cardioprotective co-therapy development.
Clinical Implications: Prefer Abl inhibitors without TNFR2-mediated vascular activation (e.g., asciminib) in high-risk patients; enhance CV surveillance for ponatinib users and evaluate TNF/TNFR modulation in trials.
Key Findings
- Ponatinib rapidly increases endothelial TNFR expression and adhesion molecules.
- In vivo, it augments leukocyte rolling/adhesion, platelet activation, and plaque inflammation, accelerating MI and stroke.
- TNFR inhibition or TNFR2 knockdown prevents endothelial activation and ischemic events; asciminib lacks these effects.
2. Tubulin tyrosine ligase variant perturbs microtubule tyrosination, causing hypertrophy in patient-specific and CRISPR gene-edited iPSC-cardiomyocytes.
Patient-derived and CRISPR-edited iPSC cardiomyocytes link a pathogenic TTL p.G219S variant to reduced tubulin tyrosination, detyrosinated tubulin accumulation, disrupted redox signaling, and cardiomyocyte hypertrophy, nominating a non-sarcomeric HCM mechanism.
Impact: Expands HCM genetics beyond sarcomeric mutations and identifies the tubulin tyrosination cycle as a potentially druggable pathway.
Clinical Implications: Supports expanding genetic testing panels and motivates precision therapies that restore tubulin tyrosination or redox homeostasis.
Key Findings
- A pathogenic TTL p.G219S variant identified in HCM.
- TTL activity reduction leads to detyrosinated tubulin accumulation.
- Perturbed redox signaling induces hypertrophy in patient-specific and edited iPSC-CMs.
3. Epigenetic biomarkers predict macrovascular events in individuals with type 2 diabetes.
An 87‑CpG methylation risk score predicted incident macrovascular events with high discrimination and reclassification in T2D, outperforming established clinical and polygenic risk tools and validating across external cohorts.
Impact: Demonstrates a scalable, blood-based epigenetic test that materially improves cardiovascular risk stratification in T2D.
Clinical Implications: Could guide intensity of lipid-lowering, blood pressure control, antithrombotic therapy, and surveillance pending implementation and cost-effectiveness studies.
Key Findings
- An 87‑CpG methylation score achieved AUC ~0.81–0.84 with clinical factors.
- Outperformed SCORE2‑Diabetes, UKPDS, Framingham, and polygenic scores; high NPV and large NRI gains.
- Validated in independent cohorts and supported by differential methylation in atherosclerotic tissue.