Weekly Cardiology Research Analysis
This week’s cardiology literature highlights three high-impact directions: mechanistic cardio-oncology work identifying TNFR2-mediated vascular thromboinflammation from ponatinib with a tractable protective strategy; a validated blood-based 87-CpG methylation risk score that markedly improves macrovascular event prediction in newly diagnosed type 2 diabetes; and randomized-trial meta-analysis evidence that left atrial appendage closure reduces all-cause and cardiovascular mortality versus oral a
Summary
This week’s cardiology literature highlights three high-impact directions: mechanistic cardio-oncology work identifying TNFR2-mediated vascular thromboinflammation from ponatinib with a tractable protective strategy; a validated blood-based 87-CpG methylation risk score that markedly improves macrovascular event prediction in newly diagnosed type 2 diabetes; and randomized-trial meta-analysis evidence that left atrial appendage closure reduces all-cause and cardiovascular mortality versus oral anticoagulation. Together these studies advance precision risk stratification, nominate actionable therapeutic targets in cardio-oncology and myocarditis, and inform durable device- and procedure-based strategies for stroke prevention.
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 mechanistic studies across multiple mouse models and human endothelial cells showed that ponatinib (but not asciminib or imatinib) induces endothelial TNFR2 upregulation, adhesion molecule expression, leukocyte–platelet activation, plaque inflammation and increased MI/stroke deaths; pharmacologic TNFR blockade or TNFR2 knockdown prevented these effects, identifying a modifiable pathway.
Impact: Clarifies the molecular basis for clinically observed arterial events with ponatinib, differentiates a safer Abl inhibitor (asciminib), and identifies TNFR2-mediated endothelial activation as an actionable cardioprotective target in cardio-oncology.
Clinical Implications: Oncologists and cardiologists should preferentially consider asciminib where oncologically appropriate, closely monitor cardiovascular risk in patients on ponatinib, and prioritize clinical evaluation of TNF/TNFR modulators as potential cardioprotective co-therapies.
Key Findings
- Ponatinib uniquely upregulated endothelial TNFR expression and adhesion molecules (P-selectin, ICAM1, VCAM1) and activated TNFR2 signaling.
- In vivo, ponatinib increased leukocyte rolling/adhesion, platelet–leukocyte aggregates, plaque necrotic core and inflammation, accelerating MI and stroke deaths in mice.
- Pharmacologic TNFR inhibition or TNFR2 knockdown prevented endothelial activation, plaque inflammation, and MI/stroke in models; asciminib did not produce these toxicities.
2. Epigenetic biomarkers predict macrovascular events in individuals with type 2 diabetes.
In a prospective cohort of newly diagnosed type 2 diabetes (n=752, 102 events), investigators identified 461 CpG sites associated with incident macrovascular events and built an 87-CpG methylation risk score (MRS) that predicted events with AUC 0.81 (0.84 when combined with clinical factors). The MRS outperformed clinical and polygenic scores, had NPV 95.9%, showed continuous NRI improvement, and was externally validated (AUC 0.80).
Impact: Provides a validated, blood-based epigenetic prognostic tool that substantially improves cardiovascular risk stratification in T2D beyond established clinical and genetic models, with direct translational potential for preventive therapy targeting.
Clinical Implications: If prospectively implemented, the MRS could identify low- and high-risk T2D patients to tailor intensity of lipid-lowering, antihypertensive, and antithrombotic strategies; prospective utility and cost-effectiveness studies are needed before routine use.
Key Findings
- Identified 461 CpG sites associated with incident macrovascular events in 752 newly diagnosed T2D patients (102 events).
- An 87-CpG methylation risk score predicted events with AUC 0.81 alone and AUC 0.84 combined with clinical factors, outperforming SCORE2-Diabetes, UKPDS, Framingham, and polygenic risk scores.
- External validation in EPIC-Potsdam and OPTIMED cohorts (MRS AUC ~0.80) and biological plausibility supported by differentially methylated sites in atherosclerotic aorta.
3. Left atrial appendage closure vs oral anticoagulation for stroke prevention in atrial fibrillation: Long-term outcomes from 4 randomized trials.
A meta-analysis of four randomized trials (n=3,116; follow-up 36–49.6 months) found left atrial appendage closure (LAAC) reduced all-cause death (RR 0.78) and cardiovascular/unexplained death (RR 0.69) versus oral anticoagulation, with lower hemorrhagic stroke and non-procedural clinically relevant bleeding and no increase in ischemic stroke or systemic embolism.
Impact: Synthesizes randomized long-term evidence that LAAC provides mortality and bleeding advantages over anticoagulation in selected AF patients, informing shared decision-making and guideline discussions on device-based stroke prevention.
Clinical Implications: For AF patients with bleeding concerns or contraindications to long-term OAC, LAAC should be discussed as a durable alternative with potential survival and hemorrhagic-bleeding benefits; counseling must include device-related risks and patient goals.
Key Findings
- LAAC reduced all-cause mortality compared with OAC (RR 0.78; 95% CI 0.64–0.95).
- LAAC reduced cardiovascular or unexplained death (RR 0.69; 95% CI 0.51–0.94) and hemorrhagic stroke (RR 0.34).
- No increase in ischemic stroke, systemic embolism, or major bleeding overall; lower non-procedural clinically relevant bleeding with LAAC.