Daily Cardiology Research Analysis
Three impactful cardiology papers advance therapy, mechanism, and risk prediction. A prespecified analysis of the FINEARTS-HF trial shows finerenone benefits patients with heart failure and improved ejection fraction. Mechanistic work reveals that EPA inhibits platelet COX-1 to reduce arterial thrombosis, while a multi-ancestry polygenic score robustly stratifies risk for peripheral artery disease and major adverse limb events.
Summary
Three impactful cardiology papers advance therapy, mechanism, and risk prediction. A prespecified analysis of the FINEARTS-HF trial shows finerenone benefits patients with heart failure and improved ejection fraction. Mechanistic work reveals that EPA inhibits platelet COX-1 to reduce arterial thrombosis, while a multi-ancestry polygenic score robustly stratifies risk for peripheral artery disease and major adverse limb events.
Research Themes
- MRA antagonism for HF with improved EF
- EPA–COX-1 mechanism in platelet inhibition and thrombosis
- Genomic polygenic risk stratification for peripheral artery disease
Selected Articles
1. Finerenone in Heart Failure With Improved Ejection Fraction: The FINEARTS-HF Randomized Clinical Trial.
In a prespecified analysis of 6001 patients with HF and EF ≥40%, 273 with prior EF <40% (HFimpEF) had higher crude event rates, but after adjustment risk was similar to those without prior HFrEF. Finerenone reduced the composite of CV death and total worsening HF events consistently across HFimpEF and non-HFimpEF (no interaction), yielding a greater absolute risk reduction in HFimpEF. Hypotension occurred more often in HFimpEF, but overall safety was similar.
Impact: This prespecified RCT analysis extends the therapeutic benefit of finerenone to HFimpEF, a growing and high-risk phenotype often overlooked after EF recovery. The consistency of effect supports continued neurohormonal modulation despite EF improvement.
Clinical Implications: For HFimpEF, continuing/initiating finerenone can reduce CV death and HF events; clinicians should monitor blood pressure given increased hypotension. These data support guideline convergence between HFpEF and HFimpEF management.
Key Findings
- Among 6001 patients with EF ≥40%, 273 (5%) had prior EF <40% (HFimpEF).
- Unadjusted primary composite rates were higher in HFimpEF (21.4 vs 16.0 per 100 patient-years), but adjusted rate ratio was not significant (1.13; 95% CI, 0.85–1.49).
- Finerenone’s treatment effect was consistent in HFimpEF and non-HFimpEF (P for interaction=0.36), with greater absolute risk reduction in HFimpEF (9.2 vs 2.5 per 100 patient-years).
- Hypotension was more frequent with finerenone in HFimpEF; other safety outcomes were similar.
Methodological Strengths
- Prespecified subgroup analysis within a large, contemporary randomized clinical trial
- Adjudicated composite endpoint with recurrent event analysis over a median 2.6-year follow-up
Limitations
- HFimpEF subgroup was small (n=273), limiting power for interaction and safety signals
- Subgroup findings may not fully generalize to all HFimpEF phenotypes or dosing contexts
Future Directions: Head-to-head comparisons across EF strata and pragmatic trials to test finerenone continuation after EF improvement; refine risk–benefit in hypotension-prone subgroups.
2. Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1-induced platelet reactivity.
EPA dose-dependently inhibited platelet adhesion, degranulation, and aggregation, and oral EPA reduced arterial thrombosis in mice. Photoaffinity labeling and docking supported a direct, competitive interaction of EPA with COX-1, and platelet-specific COX-1 deficiency abrogated EPA’s antithrombotic effect. In patients, switching from high-dose EPA (2 g BID) to a DHA-containing 1 g daily product blunted platelet inhibition.
Impact: This study provides a mechanistic bridge explaining divergent omega-3 trial results by identifying COX-1 as a direct EPA target, linking formulation/dose to platelet biology and arterial thrombosis.
Clinical Implications: Findings support preferential use of pure/high-dose EPA (icosapent ethyl) for antithrombotic benefit and caution against extrapolating effects from mixed EPA/DHA products; COX-1 interaction suggests synergy with aspirin and implications for bleeding risk assessment.
Key Findings
- EPA dose-dependently inhibits platelet adhesion, degranulation, and aggregation in vitro.
- Oral EPA reduces arterial thrombosis in wild-type mice; effect is lost in platelet-specific COX-1–deficient mice.
- Photoaffinity labeling and in silico docking demonstrate direct, competitive binding of EPA to COX-1.
- In patients, switching from EPA 2 g BID to a once-daily DHA-containing product abrogated platelet inhibition.
Methodological Strengths
- Multisystem translational approach (in vitro human platelets, rodent in vivo thrombosis, and patient formulation-switch study)
- Mechanistic validation using photoaffinity labeling, docking, and genetic (COX-1–deficient) models
Limitations
- Clinical sample sizes for the formulation switch were limited; no clinical outcomes trial within this study
- Generalizability across different omega-3 formulations and dosing regimens requires further testing
Future Directions: Prospective randomized studies comparing pure EPA versus mixed EPA/DHA on platelet function and clinical thrombotic outcomes; exploration of EPA-aspirin interactions and bleeding profiles.
3. Polygenic Prediction of Peripheral Artery Disease and Major Adverse Limb Events.
Across UK Biobank (n≈400k), All of Us (n≈218k), and MGBB (n≈33k), PRS-PAD predicted PAD (OR per SD 1.63) and improved discrimination (C≈0.76), similar to diabetes and smoking. Among prevalent PAD, high PRS-PAD predicted incident major adverse limb events in all cohorts (HR ~1.56–1.75). Notably, 30% of PAD cases without diabetes, smoking, or CKD fell in the top 20% PRS.
Impact: This study delivers a validated, multi-ancestry polygenic score that stratifies PAD risk and future limb events across three large healthcare-linked cohorts, enabling precision screening beyond traditional risk factors.
Clinical Implications: PRS-PAD can identify high-risk individuals—including those without classic risk factors—for earlier PAD screening, surveillance, and preventive therapies; integration with clinical scores and equitable deployment across ancestries are key.
Key Findings
- In UK Biobank validation, OR per SD for PAD was 1.63 (95% CI, 1.60–1.68). Top 20% PRS had adjusted OR 1.68 vs others.
- PRS-PAD improved incident PAD discrimination (C≈0.761), comparable to diabetes and smoking.
- Among prevalent PAD, high PRS predicted incident major adverse limb events across three cohorts (HR ~1.56–1.75).
- 30.1% of PAD cases without diabetes, smoking, or CKD had high PRS (top 20%).
Methodological Strengths
- Large, multi-ancestry cohorts with external validation across three biobanks
- EHR linkage with consistent phenotype definitions and time-to-event analyses
Limitations
- Observational design limits causal inference and clinical utility assessment
- Heterogeneity in recruitment and follow-up across cohorts; need for prospective implementation trials
Future Directions: Prospective trials to test PRS-guided screening/treatment pathways, calibration across ancestries, and cost-effectiveness; integration with imaging (ABI/CAC) and wearable data.