Taylor, Jennifer

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

We tested the hypothesis that the carotid body chemoreceptors (CB) contribute to ventilatory control during steady‐state exercise. Six men completed two randomized bouts of cycling exercise at 65% VO 2 max for up to 2 hours during an IV infusion of dopamine (D; 2 µg/kg/min) to acutely inactivate the CB, or a saline infusion (S). Expired gases were analyzed at baseline, resting‐infusion, and during exercise (25%, 50%, 75% and 100% of total exercise time). A hypoxic ventilatory response (HVR) test was performed after exercise during the infusion condition. Subjects were classified as responders (RS; n=3) if their HVR was lower during D vs. S (1.03 ± 0.6 vs. 2.14 ± 0.4 L/min/%SaO 2 ). In RS, partial pressure of end‐tidal CO 2 had a greater delta from baseline at 75% (2.9 ± 2.1 vs. 1.1 ± 1.9 mmHg) and 100% (0.9 ± 3.4 vs. ‐0.3 ±3.3 mmHg) during D than S, and the increase in oxygen uptake at 100% was greater during D vs. S (34.7 ± 2.6 vs. 33.0 ± 2.6 mL/min/kg). In RS, there were no differences in the changes from baseline for ventilation (VE), VE/VCO 2 , respiratory rate, tidal volume, and respiratory exchange ratio between conditions. In the non‐responders group, there were no differences between D and S in any variables. When the data was pooled, HVR accounted for 37% of the variance in VE at 100%. Despite evidence that CB chemosensitivity was blunted, the CB appear to play a minor role in controlling ventilation during steady state exercise. Grant Funding Source : NIH R01DK090541