UCSF

Congenital heart disease (CHD), a structural malformation of the heart or great vessels, is associated with brain abnormalities and an elevated risk of neurodevelopmental deficits. The mechanisms underlying these abnormalities remain incompletely characterized. The glymphatic system, the primary waste clearance system for the central nervous system, is driven by arterial pulsatility and dependent on systemic venous pressure. The glymphatic system may be impaired in CHD due to altered vascular pulsatility and systemic venous pressure resulting from abnormal cardiac physiology and surgical palliations. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is an MRI-based non-invasive metric that is used to evaluate glymphatic function and has not been previously applied to adolescents with CHD. This study includes 34 adolescents with critical CHD (Transposition of great arteries (TGA): n = 17, Single-ventricle physiology (SVP): n = 9, Other CHD: n = 8) and 99 healthy adolescent controls. DTI-ALPS indices were calculated using a publicly available diffusion MRI processing pipeline (alps.sh). The expected results of this study included lower DTI-ALPS indices in subjects with CHD compared to controls, with subjects with SVP expected to have significantly lower ALPS indices compared to those with TGA. Statistical analysis included Bland-Altman analysis, group comparisons using two-tailed t-tests, and multivariable linear regression adjusting for age. DTI-ALPS mean indices were significantly lower in the CHD group compared to controls (1.348 vs. 1.499; β = -0.152, 95% CI: -0.216 - -0.089, p < 0.001), and this difference remained significant after adjusting for age (β = -0.083, 95% CI: -0.118 - -0.049, p < 0.001). Additionally, each CHD sub-type demonstrated significant reduction in DTI-ALPS mean indices compared against healthy controls. No significant difference was found between TGA and SVP subgroups (p = 0.671). No significant relationship was found between DTI-ALPS index and age or sex within either CHD or control group. Overall, these findings represent preliminary evidence of potential glymphatic dysfunction in CHD patients, with DTI-ALPS being a novel non-invasive biomarker for brain health and potential future neuroprotective interventions. Further research with larger cohorts and neurodevelopmental outcomes is needed to determine the clinical implications of these findings.