Sleep-Related Hypoxia, RV Dysfunction, and Survival in PAH
- Increased sleep-related hypoxia was associated with worse right-sided cardiac structural, hemodynamic, and electrophysiological measures in PAH, suggesting that hypoxia specific to sleep contributes to the pathogenesis of this condition.
- The apnea-hypopnea index (AHI) was also associated with some specific measures of RV dysfunction, such as RV ejection fraction, but overall findings were less consistent than with sleep-related hypoxia.
- Increasing sleep-related hypoxia severity (10% increments of T90), but not AHI, was associated with a 17% increased risk of transplant/death.
What is the association of sleep apnea-hypopnea index (AHI) and sleep-related hypoxia with right ventricular (RV) function and survival?
Patients enrolled in the Pulmonary Vascular Disease Phenomics (PVDOMICS) clinical research network—a National Institutes of Health/National Heart, Lung, and Blood Institute funded, prospective, longitudinal cohort study that aims to improve understanding on pulmonary vascular disease through phenomics—were analyzed for this study. Three groups were involved in this study: 1) pulmonary arterial hypertension (PAH) or group 1 PH patients, 2) a comparator group with pulmonary artery pressures (PAPs) <25 mm Hg and PAH risk factors or exercise-induced PH, and 3) a healthy control with normal cardiopulmonary findings and without end-organ disease.
Participants underwent a comprehensive clinical phenotyping protocol including transthoracic echocardiogram (ECHO), cardiac magnetic resonance imaging (CMR), right heart catheterization (RHC), and 12-lead electrocardiograms (ECG). Overnight sleep monitoring was performed during enrollment with the NOX0T3 (Carefusion) portable home sleep study system. Sleep studies, apneas, and hypopneas were scored according to the American Academy of Sleep Medicine Guidelines.
The primary predictors of right heart measures were sleep-related hypoxia and obstructive sleep apnea (OSA) defined by T90 (percentage of time with SpO2 <90% during the sleep study) and AHI, respectively. The primary cardiac measure outcomes in each structural and physiologic domain were: RV systolic pressure (RVSP) (ECHO), RV ejection fraction (RVEF) (CMR), mean PAP (mPAP) (RHC), and RV hypertrophy (ECG).
One hundred eighty-six PAH patients, 32 comparators, and 78 healthy controls were included in this analysis. Ninety-two PAH participants (49.7%), 31 controls (39.7%), and 17 comparators (54.8%) had OSA (AHI ≥5), whereas 41 (22.2%) PAH participants had an AHI ≥15, similar to comparators and more than healthy controls. Central respiratory events were infrequent.
Of the primary RV structural and physiologic measures assessed in PAH, only RVEF (CMR) was associated with increasing AHI. Contrary to AHI, T90 in the PAH group was significantly associated with all primary structural, hemodynamic, and electrophysiological right heart measures. Specifically, for every 10% increment of T90, RVSP assessed by ECHO increased by 2.49 mm Hg (95% confidence interval [CI], 1.58 to 3.40; p < 0.001), RVEF assessed by CMR decreased by 0.94% (95% CI, -1.47 to -0.40; p < 0.001), mPAP from RHC increased by 1.86 mm Hg (95% CI, 1.29 to 2.42; p < 0.001), and the odds of RV hypertrophy assessed by ECG was 26% higher (odds ratio, 1.26; 95% CI, 1.11 to 1.44; p < 0.001).
There were 34 deaths and nine transplants during a median follow-up of 48.3 months. Sleep-related hypoxia, but not AHI, was associated with transplant-free survival. For each 10% increment in T90, the risk of transplant or death increased by 12% (hazard ratio [HR], 1.12; 95% CI, 1.04 to 1.22; p = 0.005) in unadjusted models and 17% (HR, 1.17; 95% CI, 1.07 to 1.28; p < 0.001) when adjusted for multiple variables.
Sleep-related hypoxia was more strongly associated than AHI with measures of RV dysfunction, death, or transplant in PAH patients.
In this prospective study of well phenotyped PAH patients with OSA, Lowery and colleagues show compelling evidence supporting the hypothesis that nocturnal hypoxia, but not airway obstruction, has clinically important pathophysiologic effects on the pulmonary vasculature and RV function.
OSA is characterized by both airway obstruction and sleep-related hypoxia. Airway obstruction can lead to cyclical increases in intrathoracic pressure due to repetitive forced inspiration against a closed airway, leading to repeated increases in pulmonary arterial and right atrial pressure. Hypoxia, a known pulmonary vasoconstrictor, can promptly increase pulmonary arterial pressures, a phenomenon which can be fully reversible with re-oxygenation. This hypoxic pulmonary vasoconstriction can also limit exercise capacity via increase in RV afterload. Moreover, profound hypoxia can also result in dysregulation of metabolic pathways in the RV, leading to greater RV hypertrophy or fibrosis and pulmonary vascular remodeling. Despite these known mechanistic associations, there has been a paucity of evidence on the contribution of airway obstruction and intermittent hypoxia to evolution and impact on mortality in patients with PAH.
In this study, sleep-related hypoxia (T90) was more strongly associated than AHI with measures of RV dysfunction, death, or transplant in PAH patients. Although the association of sleep-related hypoxia and several measures of RV dysfunction was more consistent than with AHI, AHI was significantly associated with a greater reduction in RVEF and CMR RV peak global longitudinal strain, and may also play a significant role in RV function in PAH patients.
Current guidelines recommend screening for OSA in PH patients. An overnight oximetry or polysomnography is proposed, although no emphasis on one specific test is made. The results of this study, particularly that greater duration of hypoxia portended worse transplant-free survival, may suggest the potential utility of routine screening of sleep-related hypoxia to inform risk stratification. Sleep-related hypoxia may represent a new therapeutic target for the management of PAH patients, although further studies are needed to understand the impact of nocturnal hypoxia correction in this population.
Keywords: Pulmonary Arterial Hypertension, Sleep Apnea, Obstructive, Ventricular Dysfunction, Right
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