High Occurrence of Hypoxemic Sleep Respiratory Disorders in Precapillary Pulmonary Hypertension and Mechanisms

doi:10.1378/chest.11-3124

Chest

Volume 143, Issue 1, January 2013, Pages 47-55

https://doi.org/10.1378/chest.11-3124 Get rights and content

Background

The occurrence and mechanisms of nocturnal hypoxemia in precapillary pulmonary hypertension (PH) are not clearly defined.

Methods

In an observational, prospective, and transversal design, we studied 46 clinically stable patients with PH and a BMI < 35 kg/m², an FEV₁ > 60% predicted, and idiopathic pulmonary arterial hypertension (n = 29) or chronic thromboembolic pulmonary hypertension (n = 17). They underwent nocturnal polysomnography with transcutaneous capnography.

Results

Most patients (69.6%) had New York Heart Association functional class II disease. Mean pulmonary artery pressure was 44 ± 13 mm Hg, and the cardiac index was 3.2 ± 0.6 L/min/m². Duration of sleep time spent with oxygen saturation as measured by pulse oximetry < 90% was 48.9% ± 35.9%, and 38 of 46 patients (82.6%) had nocturnal hypoxemia. Mean apnea-hypopnea index was 24.9 ± 22.1/h, and 41 patients (89%) had sleep apnea. The major mechanism of nocturnal hypoxemia was a ventilation/perfusion mismatch alone or associated with obstructive apneic events. Multivariate logistic regression identified both FEV_25%–75% (OR, 0.9519; 95% CI, 0.9089-0.9968; P = .036) and mean pulmonary artery pressure (OR, 1.1068; 95% CI, 1.0062-1.2175; P = .037) as significant predictors of nocturnal hypoxemia. Clinical symptoms were not predictive of nocturnal hypoxemia.

Conclusions

The occurrence of nocturnal hypoxemia is high in PH and should be screened for systematically. Further studies are needed to determine the impact of nocturnal hypoxemia on the outcome of patients with PH.

Trial registry

ClinicalTrials.gov; No.: NCT01371669; URL: www.clinicaltrials.gov

Section snippets

Materials and Methods

This observational, prospective, and transversal study was proposed to patients being treated for IPAH or CTEPH and who were hospitalized for follow-up in the pulmonary department of Antoine-Béclère Hospital, which is the national referral center for PH in France. PH was defined by right-sided heart catheterization with a mean pulmonary artery pressure (mPAP) of > 25 mm Hg and a mean pulmonary wedge pressure of ≤ 15 mm Hg.¹ In IPAH, there was no identified cause for the disease, but in CTEPH,

Results

The charts of 218 patients admitted to the Antoine-Béclère referral center for PH between June 2010 and July 2011 were examined. The study was proposed to 81 patients fulfilling the inclusion criteria. Final analyses were done on 46 of 50 eligible patients (Fig 1).

Baseline characteristics of the study population are detailed in Table 1. Right-sided heart catheterization confirmed PH with an mPAP of 44 ± 13 mm Hg and cardiac index of 3.2 ± 0.6 L/min/m². The group included 29 patients with IPAH

Discussion

The relevant findings of this study are that nocturnal hypoxemia is common in patients with stable IPAH and CTEPH (observed in > 80% of cases) and that the most frequent mechanism responsible for this hypoxemia is

mismatch, which was present in 76% of desaturator patients, alone or associated with apneic events. We studied a well-defined population with two major causes of PH, namely IPAH and CTEPH, at a steady state for at least 3 months without any confounding factors inducing hypoxemia,

Acknowledgments

Author contributions: Dr Roisman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Jilwan: contributed as the main investigator and as a writer.

Dr Escourrou: contributed as a senior coinvestigator and as a writer.

Dr Garcia: contributed as an assistant writer.

Dr Jaïs: contributed as an assistant writer.

Dr Humbert: contributed as an assistant writer.

Dr Roisman: contributed as a senior coinvestigator and

References (36)

M Humbert et al.
Cellular and molecular pathobiology of pulmonary arterial hypertension
J Am Coll Cardiol
(2004)
AL Rafanan et al.
Nocturnal hypoxemia is common in primary pulmonary hypertension
Chest
(2001)
S Ulrich et al.
Sleep-related breathing disorders in patients with pulmonary hypertension
Chest
(2008)
SM Parker et al.
Evaluation of a transcutaneous carbon dioxide monitor (“TOSCA”) in adult patients in routine respiratory practice
Respir Med
(2007)
D Launay et al.
Clinical characteristics and survival in systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease
Chest
(2011)
OA Minai et al.
Predictors of nocturnal oxygen desaturation in pulmonary arterial hypertension
Chest
(2007)
S Javaheri
Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report
Int J Cardiol
(2006)
NJ Douglas
Control of ventilation during sleep
Clin Chest Med
(1985)
Z Zhai et al.
Differences in ventilatory inefficiency between pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
Chest
(2011)
R Bauer et al.
Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension
Respir Med
(2007)

ZC Jing et al.

Pulmonary function testing in patients with pulmonary arterial hypertension

Respir Med

(2009)

XG Sun et al.

Pulmonary function in primary pulmonary hypertension

J Am Coll Cardiol

(2003)

N Galiè et al.

Guidelines for the diagnosis and treatment of pulmonary hypertension

Eur Respir J

(2009)

DL Prisco et al.

Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing

Sleep Breath

(2011)

R Schulz et al.

Nocturnal periodic breathing in primary pulmonary hypertension

Eur Respir J

(2002)

O Pak et al.

The effects of hypoxia on the cells of the pulmonary vasculature

Eur Respir J

(2007)

GP Pidgeon et al.

Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2

Circulation

(2004)

KR Stenmark et al.

Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms

Circ Res

(2006)

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We retrospectively examined 450 consecutive pre-capillary PH patients undergoing cardiorespiratory polygraphy and right heart catheterization between May 2020 to November 2021 at Fuwai Hospital. The prevalence of OSA was 34.2%, and the presence and severity of OSA in pre-capillary PH patients was associated with increased left heart mass index (P < 0.001), pulmonary arterial wedge pressure (P = 0.06) and H₂FPEF score (P < 0.001). After adjustment for confounding factors, the severity of OSA measured as apnea-hypopnea index (AHI) was an independent risk factor associated with obesity, systemic hypertension, diabetes mellitus and an atypical phenotype (OR: 1.054, P = 0.004) in pre-capillary PH. A dose-response relationship was also identified between sleep parameters (AHI, oxygen desaturation index, the percentage of sleep time with oxygen saturation<80%) and the number of key comorbidities. Patients with ≥3 comorbidities (atypical phenotype) were older, experienced negative alterations in left ventricular structure and function, and were at a higher risk of OSA.
OSA is relatively prevalent in pre-capillary PH patients, independently associated with the presence of a variety of comorbidities and the atypical phenotype of PH. These findings highlight the importance of OSA as a modifiable target for optimal treatment in PH with comorbidities.
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Obstructive sleep apnoea (OSA) occurs frequently in patients with coronary artery disease, with associated intermittent hypoxia a possible stimulus for coronary collateral recruitment through ischaemic preconditioning. We sought to determine whether OSA affects recruitment of coronary collaterals and prognosis of patients presenting with ST elevation myocardial infarction (STEMI).
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Obstructive sleep apnea (OSA) is an under-recognized yet highly prevalent disease that has major implications to cardiovascular health. Pulmonary hypertension (pH) is less common but none the less a fatal condition. The association of OSA and PH is a known but not well understood phenomenon. Furthermore, the relationship appears to be bi-directional with limited understanding of the mechanism(s) driving the processes. PH in OSA has real time consequences as it has been shown to increase mortality. Limited data suggests that treatment with continuous positive pressure therapy may be beneficial and reduce pulmonary pressure. In this review, we discuss current data on prevalence of PH in OSA and vice versa. We also explore the pathophysiology of this relationship and a proposed mechanism for their connection. Finally, we address the treatment of OSA with CPAP and its impact on pulmonary pressures. Gaps in knowledge and future research potential are illustrated and discoursed.

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Funding/support: The sponsor was Assistance Publique-Hôpitaux de Paris (Département de la Recherche Clinique et du Développement).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Chest

Original ResearchSleep DisordersHigh Occurrence of Hypoxemic Sleep Respiratory Disorders in Precapillary Pulmonary Hypertension and Mechanisms

Background

Methods

Results

Conclusions

Trial registry

Section snippets

Materials and Methods

Results

Discussion

Acknowledgments

J Am Coll Cardiol

Chest

Chest

Respir Med

Chest

Chest

Int J Cardiol

Clin Chest Med

Chest

Respir Med

Respir Med

J Am Coll Cardiol

Guidelines for the diagnosis and treatment of pulmonary hypertension

Eur Respir J

Correlation of pulmonary hypertension severity with metrics of comorbid sleep-disordered breathing

Sleep Breath

Nocturnal periodic breathing in primary pulmonary hypertension

Eur Respir J

The effects of hypoxia on the cells of the pulmonary vasculature

Eur Respir J

Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2

Circulation

Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms

Circ Res

Original Research
Sleep Disorders
High Occurrence of Hypoxemic Sleep Respiratory Disorders in Precapillary Pulmonary Hypertension and Mechanisms