Abstract Body (Do not enter title and authors here): Introduction:
Exercise testing has been proven to improve phenotypic resolution and risk stratification in patients with heart failure with preserved ejection fraction (HFpEF). We hypothesized that exercise pulmonary artery pulse pressure (PA PP) has the potential to differentiate HFpEF disease states and predict outcomes.

Methods:
In a single-center cohort of patients referred for invasive cardiopulmonary exercise testing, we identified patients with hemodynamically confirmed HFpEF (resting pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg or PCWP/cardiac output (CO) slope > 2 mmHg/L/min, and left ventricular ejection fraction > 50%). Patients with respiratory exchange ratio < 1 indicating submaximal exercise and < 2 years of follow-up were excluded. We measured PA PP at 3 time points: rest, end of unloaded exercise, and peak exercise. Patients were categorized as having a low versus high PA PP at each time point based on the median value of our cohort, as no cutoff values for PA PP have been defined in the literature thus far. We identified four distinct phenotypes based on PA PP at each time point: Low-Low-Low (Trajectory 1, n=71); Low-Low-High (Trajectory 2, n=29); Low-High-High (Trajectory 3, n=43); and High-High-High (Trajectory 4, n=85) (Figure Panel A). Survival was assessed by Kaplan-Meier analysis and Cox proportional hazards analysis adjusted for age, sex, body mass index, peak oxygen consumption, and ventilation/carbon dioxide production slope.

Results:
Baseline characteristics were similar across PA PP trajectories. Rest and exercise hemodynamics are shown in Panel B. We found that higher PA PP trajectory was associated with worse survival (log rank p=0.0025, Panel C). Specifically, survival in patients who had a rise in PA PP at the end of unloaded exercise (Trajectory 3) was similar to patients with high PA PP throughout (Trajectory 4). In a multivariate Cox proportional hazards model, PA PP trajectory remained a significant predictor of survival (HR 1.58, 95% CI [1.12-2.25], p=0.009).

Conclusion:
We identified four clinically distinct phenotypes of HFpEF based on PA PP trajectory during exercise. In our single-center cohort, exercise PA PP trajectory predicted all-cause mortality in hemodynamically defined HFpEF and may be an early indicator of abnormal pulmonary vasculature. Future studies are needed to correlate PA PP with known measures of ventricular-vascular coupling.