Autonomic Nervous System Dysfunction, Cardiovascular Risk, Heart Rate Variability (HRV), Nocturnal Hypoxemia, Precapillary Pulmonary Hypertension, Pulmonary Arterial Hypertension, Sleep-disordered Breathing
Conditions
Keywords
Precapillary pulmonary hypertension, Pulmonary arterial hypertension, Hypoxic burden, Nocturnal hypoxia, Polysomnography, Sleep-disordered breathing, Heart rate variability (HRV), RMSSD, LF/HF ratio, High frequency, Autonomic nervous system, Sympathetic activation, Parasympathetic tone, Risk stratification, Prognostic markers, Right heart failure, Apnea-Hypopnea Index (AHI)
Brief summary
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.
Interventions
OTHERStandard 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.
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).
Sponsors
University Hospital, Rouen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Prospective, single-center, longitudinal cohort study of adult patients with precapillary pulmonary hypertension confirmed by right heart catheterization. Participants undergo standardized overnight polysomnography (PSG) at baseline, 12 months, and 24 months as part of routine clinical follow-up. The study evaluates longitudinal changes in nocturnal hypoxic burden and heart rate variability parameters and their cross-sectional and longitudinal correlations with clinical status and 2-year prognosis. No experimental intervention is assigned. All patients receive standard-of-care management according to current European guidelines for pulmonary hypertension.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hypoxic Load | Baseline, after 12 months and after 24 months | Assessed by the area under the SpO2 curve during desaturations associated with respiratory events divided by sleep time expressed as % min/h during polysomnographies |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Root mean square of successive differences (RMSSD) | Baseline, after 12 months and after 24 months | 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. |
| Low frequency / high frequency (LF/HF) | Baseline, after 12 months and after 24 months | 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. |
| High frequency (HF) | Baseline, after 12 months and after 24 months | 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. |
| Cross-sectional correlation - HRV RMSSD | Baseline, after 12 months and after 24 months | 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. |
| Cross-sectional correlation - HRV LF/HF | Baseline, after 12 months and after 24 months | 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. |
| Cross-sectional correlation - HRV HF | Baseline, after 12 months and after 24 months | 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. |
| Cross-sectional correlation - HRV Hypoxic load | Baseline, after 12 months and after 24 months | Assessed by the area under the SpO2 curve during desaturations associated with respiratory events divided by sleep time expressed as %.min/h during polysomnography. |
| Cross-sectional correaltion - HRV Desaturation | Baseline, after 12 months and after 24 months | As a percentage of time spent with SpO2 \< 90% |
| Cross-sectional correlation - HRV Apnea-hypopnea index | Baseline, after 12 months and after 24 months | In number per hour of sleep |
| Cross-sectional correlation - HRV Pulmonary hypertension | Baseline, after 12 months and after 24 months | 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 |
| Correlation of evolution - HRV RMSSD | Baseline, after 12 months and after 24 months | 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. |
| Correlation of evolution - HRV LF/HF | Baseline, after 12 months and after 24 months | 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. |
| Correlation of evolution - HRV HL | Baseline, after 12 months and after 24 months | 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. |
| Correlation of evolution - HRV Hypoxic load | Baseline, after 12 months and after 24 months | Assessed by the area under the SpO2 curve during desaturations associated with respiratory events divided by sleep time expressed as %.min/h during polysomnography. |
| Correlation of evolution - HRV Desaturation | Baseline, after 12 months and after 24 months | As a percentage of time spent with SpO2 \< 90% |
| Correlation of evolution - HRV Apnea-hypopnea index | Baseline, after 12 months and after 24 months | In number per hour of sleep. |
| Correlation of evolution - HRV Pulmonary hypertension | Baseline, after 12 months and after 24 months | 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 |
| Analysis of the 2-year prognostic value of hypoxic load and HRV for an unfavorable prognosis defined by a composite event | After 2 years | 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. |
Countries
France
Contacts
CONTACTDRCI
CONTACTMarie-Anne Melone, Dr
Outcome results
None listed