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Phenomapping in Heart Failure With Reduced Ejection Fraction to Identify Subpopulations With High Residual Risk: A
Palak Shah1, Yinggan Zheng2, Burkert Pieske3
1Inova Schar Heart and Vascular, Falls Church, VA (P.S., C.R.d.F., C.M.O.).
Circulation. Heart Failure
|October 8, 2025
Summary
Researchers identified three distinct subgroups of heart failure with reduced ejection fraction (HFrEF) patients using multimodality data. These subgroups, differentiated by clinical factors and GDF-15 levels, predict varying risks of cardiovascular events in HFrEF.
Area of Science:
- Cardiology
- Biomarker Discovery
- Clinical Trials
Background:
- Patients with heart failure with reduced ejection fraction (HFrEF) face significant residual risks of hospitalization and cardiovascular death.
- Identifying distinct patient subgroups is crucial for targeted therapies and risk stratification in HFrEF management.
Purpose of the Study:
- To utilize multimodality data to identify unique subgroups within the HFrEF population.
- To characterize these subgroups based on clinical, electrocardiographic, echocardiographic, and proteomic data.
- To assess the differential residual risk of cardiovascular death or heart failure hospitalization among identified HFrEF subgroups.
Main Methods:
- The VICTORIA substudy collected extensive clinical and biomarker data from 564 HFrEF participants.
- Agglomerative hierarchical clustering using 105 variables identified three distinct HFrEF phenogroups.
- Cox regression and multinomial logistic regression analyzed the association between phenogroups and clinical outcomes, with external validation in the BIOSTAT-CHF cohort.
Main Results:
- Three distinct HFrEF phenogroups were identified: Phenogroup 1 (young, well-treated), Phenogroup 2 (atrial fibrillation, Q-waves), and Phenogroup 3 (older, biventricular dysfunction, renal disease).
- A stepwise increase in the composite outcome risk was observed from Phenogroup 1 to 3 (HR 7.0).
- Phenogroup 3 showed similar characteristics and the highest 1-year event rate (41%) in external validation; GDF-15 was the key differentiator.
Conclusions:
- Unique HFrEF subpopulations with distinct biological characteristics and differential residual risk were identified and validated.
- Growth differentiation factor 15 (GDF-15) emerged as the most significant protein marker for distinguishing these HFrEF phenogroups.
- These phenogroups and biomarkers may refine entry criteria for future HFrEF therapeutic trials.
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