Reclassifying 1-year early vulnerability in intermediate-risk HFpEF: utility of a combined thyroid–endothelial biomarker profile
J Yang, Z Y H ZhangAbstract
Background
Management of intermediate-risk HFpEF remains a “grey zone” where standard markers often fail to identify early vulnerability. Despite similar natriuretic peptide and renal profiles, these patients experience disproportionately high 1-year event rates. We evaluated whether integrating thyroid and endothelial biomarkers could refine 1-year risk reclassification beyond clinical assessment.
Aims
To derive an unsupervised thyroid–endothelial phenotype using three biomarkers and quantify its incremental value for 1-year triage and reclassification within the intermediate-risk stratum.
Methods
We analysed three subsets from a retrospective HFpEF cohort (phenotyping n=1754; survival n=1594; clinical utility n=905). Phenotypes were identified via Ward’s hierarchical clustering of TSH, FT3, and Big endothelin-1. Prognostic independence was assessed using multivariable Cox models adjusted for age, sex, LVEF, BMI, NT-proBNP (per 1000 pg/mL), and eGFR (CKD-EPI). Schoenfeld residuals suggested non-proportionality for the phenotype; a prespecified piecewise time-varying analysis compared 0–365 days versus >365 days. Clinical utility was evaluated using decision curve analysis (DCA) with **predicted 1-year risk** thresholds 0.10–0.30 and 3×3 reclassification against a comprehensive clinical baseline model (demographics, comorbidities, therapies), using strata cutpoints derived from the baseline model and applied consistently to both models.
Results
A rare phenotype (Phenotype 2) comprised 7.9% (138/1754) and exhibited a low-FT3/high–Big endothelin-1 signature. In the survival subset, Phenotype 2 had a higher event rate than Phenotype 1 (46.0% vs 32.6%; P<0.001). After full adjustment including eGFR, Phenotype 2 remained independently associated with adverse outcomes (HR 1.659; 95% CI 1.242–2.217; P<0.001). Excess risk was concentrated in the first year (0–365 days HR 1.901; 95% CI 1.308–2.763; P<0.001) and attenuated thereafter (>365 days HR 1.261; P=0.268). In the clinical utility subset, adding phenotype provided higher net benefit within 0.10–0.30 **1-year** thresholds and reclassified 37 intermediate-risk patients to high risk; all belonged to Phenotype 2 and showed a 48.6% event rate (18/37).
Conclusions
Within the intermediate-risk grey zone of HFpEF, a parsimonious three-biomarker thyroid–endothelial profile identifies a small but clinically vulnerable subgroup with a concentrated excess risk during the first year. By reclassifying early vulnerability beyond comprehensive clinical assessment, this approach highlights a time-sensitive window in which patients conventionally considered moderate risk may warrant closer follow-up and earlier optimisation of guideline-directed care. These findings support a shift from static risk categorisation toward biologically informed, time-dependent risk assessment in HFpEF. External validation is required before clinical implementation.Fig 1:KM survival by biomarker phenotypeFig 2:1-year DCA in the grey zone