Inosine Triphosphate Pyrophosphatase as a Candidate Associated with White Matter Abnormalities in Chronic Heart Failure

Background: White matter hyperintensities (WMHs) are common with normal brain aging and frequently observed also in chronic heart failure (CHF). However, the relationship between CHF and white matter abnormalities and the biological factors remain unclear. We investigated WMH and associated white matter microstructural changes, such as fractional anisotropy (FA), in CHF and explored candidate molecular factors. Methods: We conducted a longitudinal prospective observation including brain T2-FLAIR magnetic resonace imaging for 32 asymptomatic Stage B (mean age 63.3{+/-}10.5 years; 25% women) and 23 symptomatic Stage C CHF patients (mean age 67.3{+/-}7.1 years; 30% women). Plasma proteomics and Mendelian randomization (MR) were used to identify candidate proteins associated with both CHF and WMH. The association of candidate proteins was further investigated using complementary analyses in CHF rats, cultured cortical neurons, and community-based genetic data in UK Biobank. Results: Global WMH volume increased more in Stage C than Stage B patients, predominantly near the anterior periventricular white matter, despite comparable cardiac indices (4,717{+/-}5,335 mm3 vs. 2,116{+/-}3,134 mm3, P=0.027). SomaScan-based proteomic analysis of plasma samples from this patient cohort revealed that 44 proteins are significantly associated with both Stage C CHF and WMH progression (P<0.05). Of these 44 proteins, two-step Mendelian randomization analysis identified inosine triphosphate pyrophosphatase (ITPA) as the only candidate protein, further supported by an association between rare variants in ITPA and FA. In CHF rats, the anterior pericallosal cortex showed decreases in myelin basic protein density and FA and an increase in ITPA expression compared to sham rats. In cultured cortical neurons, recombinant ITPA exposure reduced total axonal length. Conclusions: Symptomatic CHF was associated with WMH and impaired white matter integrity. ITPA emerged as a candidate factor across human, animal, and cellular analyses. These findings provide a basis for investgating the biological pathways linking CHF and white matter injury.