Autonomic maladaptation is associated with exertional dyspnoea and systemic inflammation in pre-capillary pulmonary hypertension: a hypothesis-generating pilot study

The link between autonomic dysregulation and systemic inflammation has not been systematically investigated across pulmonary hypertension subtypes. Therefore, this hypothesis-generating pilot study investigated whether heart rate (HR) and heart rate variability (HRV) at rest and during exertion are related to exertional dyspnoea, disease severity, and alterations in inflammatory cytokines in patients with pre-capillary pulmonary hypertension (PH). Patients diagnosed with pre-capillary PH (including pulmonary arterial hypertension [PAH] and chronic thromboembolic pulmonary hypertension [CTEPH]) by right heart catheterisation were recruited. Clinical disease severity was assessed, HR and HRV at rest and during inspiratory exercise were recorded, and a variety of inflammatory markers were measured using multiplex enzyme-linked immunosorbent assay kits. 33 patients with pre-capillary PH (age 68 years [IQR = 50–76], 22 female, body mass index [BMI] 26 kg/m 2 [IQR = 23–35]) and 16 age-, sex-, and BMI-matched healthy controls (age 62 years [IQR = 60–63], 7 female, BMI 26 kg/m 2 [IQR = 24–27]) were enrolled. All patients showed a decreased LF/HF ratio at rest and blunted HR response to exercise compared with matched controls ( P < 0.05 for PH vs. controls, P- ANOVA > 0.1 across PH subgroups). A lower LF/HF ratio was associated at the trend level with PH severity ( P -ANOVA = 0.07) and significantly with exertional dyspnoea ( P -ANOVA = 0.02). Alterations in sympathovagal balance were moderately to strongly correlated with levels of inflammatory cytokines (including tumour necrosis factor-alpha, interferon-gamma, interleukin [IL]-1 beta, IL-2, and IL-12p70). Autonomic maladaptation (and, as a hypothesis-generating sub-analysis of the present data, systemic inflammation) are key features and are related to both disease severity and exertional dyspnoea in pre-capillary PH, whether it is PAH or CTEPH. On a speculative, hence hypothesis-generating basis, this might be a potential target for therapeutic approaches. Trial Registration: Clinicaltrials.gov; Unique identifier: NCT05903001; Registration date: 18 May 2023.