White Matter Hyperintensity Increase in Chronic Heart Failure and Its Association with Proteomic Markers: A Longitudinal Cohort Study

Background White matter hyperintensity (WMH) is a common cerebral finding in older adults and is associated with an increased risk of neurological diseases, including stroke and dementia. Chronic heart failure (CHF) leads to hypoperfusion of multiple organs, including the brain, and alters neurohumoral factors such as the renin-angiotensin-aldosterone system and inflammatory cytokines. However, the relationship between CHF and WMH progression remains unclear. Purpose This study aimed to determine whether WMH differs between patients with and without CHF and to explore its association with neurohumoral factors. Methods Longitudinal data from 3D-T2 structural brain MRI and plasma samples were analyzed in 32 patients with Stage B CHF (mean age 63.3 ± 10.5 years; 21.5% women) and 23 patients with Stage C CHF (mean age 67.3 ± 7.1 years; 30.4% women) over a mean follow-up period of 3.1 years. WMH volumes were delineated from T2 images using MRI-based image analysis. The segmented WMH volumes were normalized to the Montreal Neurological Institute standard space, a commonly used brain template that allows for anatomical comparisons across individuals. Voxel-wise analysis, adjusted for age, sex, and intracranial volume, was conducted to identify regions with significant WMH changes between Stage B and C patients. Proteomic analysis using Somascan v4.1 (targeting over 7,000 proteins) was performed to identify proteins associated with both Stage C CHF and WMH changes, adjusting for age and sex. Mendelian randomization (MR) analysis was applied to assess potential causal associations between identified proteins and both Stage C CHF and WMH changes. Statistical significance was set at P<0.05, with voxel-wise analyses corrected for multiple comparisons using the family-wise error method. Results Baseline characteristics, including WMH volumes, did not significantly differ between Stage B and C patients (Stage B vs. C: 7,151 ± 9,387 mm³ vs. 10,113 ± 13,646 mm³; P>0.05). However, global WMH volumes increased significantly in Stage C compared to Stage B patients (2,116 ± 3,134 mm³ vs. 4,717 ± 5,334 mm³; P=0.027) (Figure A). Changes in WMH volumes were mapped (Figure B: Stage B; Figure C: Stage C), with voxel-wise analysis revealing increased WMH in the anterior corpus callosum (corrected P<0.05; Figure D [green regions]). Proteomic analysis identified 44 proteins associated with both Stage C CHF and WMH changes (P<0.05; Figure D). MR analysis indicated that inosine triphosphate pyrophosphatase (ITPA) showed causal associations with both WMH changes and Stage C CHF (P<0.05), with a trend toward significance for the association from ITPA to WMH change (P=0.092; Figure E). Conclusions These findings suggest that CHF may contribute to WMH progression, potentially mediated by ITPA. Humoral mediators such as ITPA could represent novel therapeutic targets in the brain-heart axis, potentially aiding in the prevention of stroke and dementia in patients with CHF.