Cerebral hypoperfusion in pulmonary arterial hypertension: Association with right ventricular dysfunction and risk stratification

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Background Pulmonary arterial hypertension (PAH) is a progressive disease that affects the central nervous system. The cardiopulmonary-brain axis hypothesis links right ventricular dysfunction to cerebral hypoperfusion, yet the association between regional cerebral blood flow (CBF) alterations, right heart dysfunction, and the clinical utility of CBF for risk stratification remains poorly understood. Objectives To investigate the association between CBF and right heart dysfunction in patients with PAH, and to evaluate the potential of CBF as a non-invasive biomarker for risk stratification. Design Cross-sectional, retrospective study. Methods Thirty PAH patients and 51 age- and sex-matched healthy controls (HCs) were retrospectively identified. Brain MRI data, including 3D arterial spin labeling (ASL) at 3.0 T for CBF quantification were analyzed. For the PAH cohort, clinical assessment included right heart catheterization (RHC) and transthoracic echocardiography (TTE) to evaluate the structure of the right ventricle (RV) and hemodynamics. Patients were stratified into low and intermediate/high-risk groups according to the 2022 ESC/ERS guidelines. Receiver operating characteristic (ROC) analysis was used to evaluate the discriminatory value of CBF for risk stratification. Generalized Linear Models were applied to analyze associations between CBF, cardiac and hemodynamic parameters, and neuropsychological metrics. Results Compared with HCs, PAH patients exhibited significant regional hypoperfusion, predominantly in the right hippocampus, frontal gyri, and insula. Regional CBF values correlated inversely with RV area (systolic RV area and right caudate: r = -0.569, P = 0.006, systolic RV area and right thalamus: r = -0.587, P = 0.004, diastolic RV area and right caudate: r = -0.513, P = 0.012, diastolic RV area and right thalamus: r = -0.545, P = 0.007) and septal thickness (right superior frontal gyrus: r = -0.528, P = 0.015, left anterior cingulate: r = -0.495, P = 0.024). Notably, intermediate/high-risk patients demonstrated significantly lower CBF compared to low-risk patients, particularly in the parietal and frontal cortices. ROC analysis indicated that regional CBF, in addition to patient sex and age, could distinguish intermediate/high-risk patients from low-risk patients (right superior frontal region: AUC = 0.793, Sensitivity = 71%). Additionally, reduced CBF in the insula was associated with lower Mini-Mental State Examination (MMSE) scores. Conclusion This study demonstrates that cerebral hypoperfusion in PAH is closely associated with right ventricular dysfunction and disease severity. ASL-derived CBF holds promise as a non-invasive biomarker to refine risk stratification, offering novel insights into the cardiopulmonary-brain interaction.

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