Preload failure and small fiber neuropathy are associated with persistent dyspnea following acute pulmonary embolism: Insights from invasive cardiopulmonary exercise testing

INTRODUCTION: For the majority of patients who experience persistent dyspnea 3 months after an acute pulmonary embolism (PE), the cause of exercise limitation is unknown. We hypothesized that data collected from invasive cardiopulmonary exercise (iCPET) would inform whether pre-load failure (PLF) may be an under-recognized cause of post-PE dyspnea. METHODS: Between 2015 and 2023, we retrospectively identified patients with prior PE and unexplained dyspnea who underwent iCPET testing. Those with chronic thromboembolic pulmonary hypertension (CTEPH) were excluded. RESULTS: Thirty-four patients with PE history and unexplained dyspnea were identified. The mean peak VO2 for the cohort was reduced at 71.0 ± 20.5%. This cardiovascular limit was explained by PLF with a reduced right atrial pressure (RAP) at peak exercise (4.5 [5.0] mmHg). There was no evidence of ventilatory inefficiency (VE/VCO2 slope: 30.8 [10.9]). However, dead space ventilation at peak exercise was increased (0.24 ± 0.10). Owing prior work establishing an association between PLF and small fiber neuropathy (SFN), we evaluated the results of post-PE patients referred for skin biopsies at the providers' discretion (32.4%, n = 11). Of these, 9 patients (82%) had confirmed SFN. CONCLUSION: This is the first case series to utilize iCPET data to investigate novel causes of post-PE dyspnea. We describe PLF, characterized by a central cardiac limit to exercise and low RAP at peak, in post-PE patients with otherwise unexplained symptoms. We additionally describe an association between PLF and SFN and hypothesize a mechanistic link between an inflammatory PE insult, peripheral neuronal injury, and resultant dyspnea.