Abstract Background Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disorder marked by pulmonary vascular remodeling, right ventricular dysfunction, and high mortality. Sleep disturbances are often reported among patients with PAH; however, the impacts of sleep disruption on PAH pathogenesis have not been investigated. Moreover, the mechanistic links between sleep disruption and pulmonary vascular disease pathology remain poorly understood. Methods Sleep patterns were continuously monitored in patients with pulmonary hypertension (PH) and age and sex-matched healthy controls using Fitbit devices. Complementary experimental models of sleep disturbance (sleep fragmentation and chronic jet lag) and various preclinical models of PAH were used to evaluate the mechanistic effects of poor disruption on PAH progression. A wide range of molecular techniques, including RNA sequencing, immunostaining, immunoblotting, and cell proliferation assays, were used to unravel the effects of sleep disruption on pulmonary signaling. Finally, electroencephalogram and electromyogram (EEG/EMG) recordings were used to test whether PAH itself disturbs sleep architecture in mice. Results Patients with PH had significantly decreased total sleep durations and sleep quality, including reduced rapid eye movement (REM) and non-rapid eye movement (NREM) sleep durations compared with their healthy counterparts. In experimental models, sleep disruption elevated right ventricular systolic pressure, cardiac dysfunction, and vascular remodeling in PAH mice. Transcriptomic and immunostaining analyses revealed that sleep disruption increased inflammation and perivascular macrophage recruitment in the lung of PAH mice. Further analyses showed that inflammation activated the IL6/STAT3/SMAD2/3 pathway and increased pulmonary artery smooth muscle cell proliferation, contributing to pulmonary vascular remodeling. Importantly, concurrent improvement of sleep with melatonin and reduction of inflammation with clodronate inhibited pulmonary vascular remodeling and mitigated PAH. Conclusion These findings identify a bidirectional relationship between PAH and sleep disturbance in a self-amplifying cycle, in which PAH disrupts sleep architecture, and sleep disruption accelerates pulmonary inflammation and vascular remodeling. This study highlights the therapeutic potential of targeting both sleep quality and inflammation and improving clinical outcomes in patients with PAH. This abstract is funded by: National Institutes of Health grant R01HL160963 to Y.S, American Heart Association Predoctoral Fellowship 25PRE1377423 to S.I., and the WoodNext Foundation to S.Y.C.
Imani et al. (Fri,) studied this question.