Evolution of Hypoxic Burden and Sympathetic/Parasympathetic Balance in Patients With Pulmonary Hypertension (HRV&PH)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Arterial Hypertension; Cardiovascular Risk; Sleep-disordered Breathing; Precapillary Pulmonary Hypertension; Nocturnal Hypoxemia; Autonomic Nervous System Dysfunction; Heart Rate Variability (HRV)
• Intervention / Treatment: Other: Standard Clinical and Functional Assessment; Other: Overnight Polysomnography

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marie-Anne Melone, Dr; Email: Marieanne.Melone@chu-rouen.fr
• Study Contact Backup: Name: DRCI; Phone Number: 02 32 88 56 07; Email: secretariat.DRC@chu-rouen.fr

Study Locations

• France
  • Rouen, France, 76031
    • CHU Rouen
    • Principal Investigator: Marie-Anne Melone, Dr
    • Contact: Marie-Anne Melone, Dr; Email: Marieanne.Melone@chu-rouen.fr
    • Sub-Investigator: Julien Maris, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Precapillary Pulmonary Hypertension Cohort; Participants are hospitalized for 5 days (4 nights) at baseline, Month 12 (M12), and Month 24 (M24) in the pulmonology department for routine clinical reassessment. During each hospitalization, patients undergo standard-of-care clinical evaluation including physical examination, NYHA functional class assessment, NT-proBNP measurement, arterial blood gas analysis, 6-minute walk test, transthoracic echocardiography, and pulmonary function testing. At baseline (incident cases only), additional diagnostic procedures may include thoracic CT scan, ventilation/perfusion lung scintigraphy, and right heart catheterization. An overnight polysomnography (PSG) is performed during each hospitalization (baseline, M12, M24). Heart rate variability (HRV) parameters and nocturnal hypoxic burden are derived from PSG recordings. No experimental therapeutic intervention is assigned. All patients receive guideline-based management according to current European recommendations for pulmonary hypertension

Other: Standard Clinical and Functional Assessment; Routine evaluation of pulmonary hypertension during scheduled hospitalizations at baseline, Month 12, and Month 24, including: Physical examination and NYHA functional class assessment; NT-proBNP measurement; Arterial blood gases; 6-minute walk test; Transthoracic echocardiography; Pulmonary function testing For incident cases at diagnostic evaluation only: thoracic CT scan, ventilation/perfusion lung scintigraphy, and right heart catheterization. All procedures are performed as part of standard clinical care.; Other: Overnight Polysomnography; Standard overnight in-hospital polysomnography performed at baseline, Month 12, and Month 24. The recording includes electrocardiogram (ECG), oxygen saturation (SpO₂), respiratory parameters, and sleep staging. Heart rate variability (HRV) is assessed using RMSSD, LF/HF ratio, and HF power derived from ECG during a continuous ≥30-minute NREM sleep period. Nocturnal hypoxic burden is calculated as the area under the SpO₂ desaturation curve associated with respiratory events divided by total sleep time (%.min/h).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypoxic Load	Assessed by the area under the SpO2 curve during desaturations associated with respiratory events divided by sleep time expressed as % min/h during polysomnographies	Baseline, after 12 months and after 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Root mean square of successive differences (RMSSD)	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Low frequency / high frequency (LF/HF)	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep, lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
High frequency (HF)	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep, lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Cross-sectional correlation - HRV RMSSD	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Cross-sectional correlation - HRV LF/HF	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Cross-sectional correlation - HRV HF	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Cross-sectional correlation - HRV Hypoxic load	Assessed by the area under the SpO2 curve during desaturations associated with respiratory events divided by sleep time expressed as %.min/h during polysomnography.	Baseline, after 12 months and after 24 months
Cross-sectional correaltion - HRV Desaturation	As a percentage of time spent with SpO2 < 90%	Baseline, after 12 months and after 24 months
Cross-sectional correlation - HRV Apnea-hypopnea index	In number per hour of sleep	Baseline, after 12 months and after 24 months
Cross-sectional correlation - HRV Pulmonary hypertension	Defined by the 4-strata risk assessment (low, intermediate low, and high risk) based on NYHA functional class, the 6-minute walk test, and NTproBNP	Baseline, after 12 months and after 24 months
Correlation of evolution - HRV RMSSD	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Correlation of evolution - HRV LF/HF	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Correlation of evolution - HRV HL	Obtained by Labchart software from an electrocardiogram during a period of NREM (non-rapid eye movement) sleep lasting at least 30 minutes, the earliest after falling asleep as measured by polysomnography.	Baseline, after 12 months and after 24 months
Correlation of evolution - HRV Hypoxic load	Assessed by the area under the SpO2 curve during desaturations associated with respiratory events divided by sleep time expressed as %.min/h during polysomnography.	Baseline, after 12 months and after 24 months
Correlation of evolution - HRV Desaturation	As a percentage of time spent with SpO2 < 90%	Baseline, after 12 months and after 24 months
Correlation of evolution - HRV Apnea-hypopnea index	In number per hour of sleep.	Baseline, after 12 months and after 24 months
Correlation of evolution - HRV Pulmonary hypertension	Defined by the 4-strata risk assessment (low, intermediate low, and high risk) based on NYHA functional class, the 6-minute walk test, and NTproBNP	Baseline, after 12 months and after 24 months
Analysis of the 2-year prognostic value of hypoxic load and HRV for an unfavorable prognosis defined by a composite event	Based on : The occurrence of right heart failure; The introduction of additional vasodilator therapy; The introduction of non-invasive ventilation therapy; Death; Lung or heart-lung transplantation.	After 2 years

Collaborators and Investigators

• Sponsor: University Hospital, Rouen

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: February 27, 2026
• First Submitted That Met QC Criteria: March 5, 2026
• First Posted (Actual): March 11, 2026

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Prognostic markers; Polysomnography; Risk stratification; Autonomic nervous system; Pulmonary arterial hypertension; Sleep-disordered breathing; Sympathetic activation; Right heart failure; Parasympathetic tone; Apnea-Hypopnea Index (AHI); Heart rate variability (HRV); Hypoxic burden; LF/HF ratio; RMSSD; Precapillary pulmonary hypertension; Nocturnal hypoxia; High frequency
• Additional Relevant MeSH Terms: Nervous System Diseases; Cardiovascular Diseases; Heart Diseases; Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Sleep Wake Disorders; Apnea; Sleep Disorders, Intrinsic; Dyssomnias; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Heart Failure; Sleep Apnea Syndromes
• Other Study ID Numbers: 2023/0292/HP; 2025-A00017-42 (Other Identifier: ANSM)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No