Evolution of Hypoxic Burden and Sympathetic/Parasympathetic Balance in Patients With Pulmonary Hypertension

Evolution of Hypoxic Burden and Sympathetic/Parasympathetic Balance in Patients With Pulmonary Hypertension

Background and Rationale:

Sleep-disordered breathing and nocturnal hypoxemia are highly prevalent in patients with precapillary pulmonary hypertension (PH), and current guidelines recommend systematic sleep assessment in this population. In obstructive sleep apnea, nocturnal hypoxic burden-defined as the area under the SpO₂ desaturation curve associated with respiratory events (%.min/h)-has demonstrated strong prognostic value for cardiovascular morbidity and mortality. However, its role in precapillary PH has not yet been investigated. Evaluating hypoxic burden in this population may refine indications and therapeutic targets for nocturnal oxygen therapy.

In addition, pulmonary hypertension is characterized by autonomic nervous system (ANS) dysfunction, including increased sympathetic tone, reduced heart rate variability (HRV), and a higher incidence of cardiac arrhythmias, all associated with worse prognosis. The reduction in HRV is particularly deleterious when occurring during restorative slow-wave sleep (N3), a phase marked by predominant parasympathetic activity essential for cardiovascular recovery and homeostasis. A better understanding of the interaction between nocturnal hypoxemia and ANS modulation may provide new prognostic markers and potential therapeutic targets in PH.

Objectives:

1. To describe the evolution of nocturnal hypoxic burden over time in patients with precapillary pulmonary hypertension (at baseline, 12 months, and 24 months).
2. To describe the longitudinal evolution of HRV parameters (RMSSD, LF/HF ratio, HF) at baseline, 12 months, and 24 months.
3. To evaluate cross-sectional correlations (at baseline, M12, and M24) between HRV parameters, hypoxic burden, oxygen desaturation, apnea-hypopnea index (AHI), and clinical status.
4. To evaluate longitudinal correlations between changes in HRV parameters, hypoxic burden, desaturation, AHI, and clinical status between baseline and M12, and between baseline and M24.
5. To assess the 2-year prognostic value of HRV parameters and hypoxic burden for adverse clinical outcomes.

Study Design and Population:

This is a prospective, single-center observational cohort study conducted at the Pulmonary Hypertension Referral Center of Rouen University Hospital. The cohort design allows longitudinal assessment of HRV, hypoxic burden, and clinical status, enabling both cross-sectional and longitudinal correlation analyses, as well as prognostic evaluation. A total of 60 adult patients (≥18 years) with precapillary pulmonary hypertension confirmed by right heart catheterization and requiring pulmonary arterial vasodilator therapy will be included.

Participants will undergo full overnight polysomnography (PSG) at:

• Baseline (inclusion)
• 12 months (M12)
• 24 months (M24) For incident cases, baseline PSG will be performed prior to initiation of vasodilator therapy. All patients will continue to receive standard-of-care management according to current European guidelines for pulmonary hypertension.

Descriptive analyses and cross-sectional correlations will pool repeated measures (excluding incident baseline values for generalization to prevalent cases). Intra-subject correlation will be accounted for using bootstrap methods. Longitudinal analyses will assess changes over time and prognostic associations. The prognostic value of HRV and hypoxic burden will be evaluated over a 2-year follow-up period. This study explores an original dimension of precapillary pulmonary hypertension pathophysiology by investigating the interaction between nocturnal oxygenation, autonomic dysfunction, and clinical evolution. Identification of hypoxic burden and HRV as prognostic markers may contribute to improved risk astratification and therapeutic optimization in this high-risk population.

Inclusion Criteria:

• Patients over 18 years of age
• With precapillary pulmonary hypertension confirmed by pulmonary artery catheterization
• With an indication for pulmonary artery vasodilator treatment
• Affiliation with a social security system
• Women of childbearing age using effective/highly effective contraception (see CTFG) (estrogen-progestogen or intrauterine device or tubal ligation) for 6 months and a negative urine pregnancy test at inclusion, for the duration of the study.
• Postmenopausal women: confirmed diagnosis (non-medically induced amenorrhea for at least 12 months prior to the inclusion visit)
• Individuals who have read and understood the information letter and signed the consent form

Non-Inclusion Criteria:

• Treatment with non-invasive ventilation
• Eisenmenger syndrome
• Systemic scleroderma
• Neurodegenerative disease other than isolated peripheral neuropathies.
• Untreated and/or uncontrolled cardiac rhythm or conduction disorders, including permanent AF
• Untreated coronary artery disease or diagnosis of myocardial infarction within the last six months
• Pacemaker wearer
• Pregnant or breastfeeding women, or women who are not using reliable contraception
• Persons deprived of their liberty by administrative or judicial decision or persons under judicial protection/guardianship or curatorship
• History of psychological or sensory illness or abnormality that may prevent the subject from fully understanding the conditions required for participation in the protocol or prevent them from giving their informed consent