Causal Effect of Pulmonary Hypertension on Brain Structure: A Mendelian Randomization Study Combined With Brain Magnetic Resonance Imaging.

BACKGROUND: The causal effect of pulmonary hypertension (PH) on brain structures remains unknown. Our objective is to study the causal association between pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and brain structures using a Mendelian randomization approach combined with brain magnetic resonance imaging (MRI) and to analyze the mechanism by which PH affects the brain. METHODS: We analyzed genome-wide association study results from 1,970 patients and 10,363 controls and from 277 patients and 316,345 controls for genetically predicted CTEPH and PAH, respectively. Brain MRI data from the ENIGMA consortium were included as outcomes. Inverse-variance weighting was used to estimate causal associations among CTEPH, PAH, and brain changes, accounting for heterogeneity and pleiotropy. Furthermore, network mediation estimations were performed to analyze the possible mechanisms underlying the impacts of CTEPH and PAH on brain changes. RESULTS: No heterogeneity or horizontal pleiotropy existed in this Mendelian randomization analysis. CTEPH changed the entorhinal surface (β: 1.13 mm2, p: 0.047) and inferior parietal surface (β: 10.98 mm2, p: 0.022) on brain MRI. CTEPH could accelerate the increase of lateral ventricular volume (β: 22.56 mm3/year, p: 0.039). For PAH, the year-change rate of cerebral white matter volume can be altered (β: -52.72 mm3/year, p: 0.033). Different circulating immune cells mediated the distinct effects of CTEPH and PAH on brain structure. CONCLUSIONS: CTEPH and PAH exhibit causal associations with distinct brain regions and electrical activity, indicating a varied lung-brain axis linked to the different subtypes of PH and seemingly associated with disturbances in circulating immune cells.