Heart failure (HF) patients show gray and white matter changes in multiple brain sites, including autonomic and motor coordination areas. It is unclear whether the changes represent acute or chronic tissue pathology, a distinction necessary for understanding pathological processes that can be resolved with diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures. We collected four DTI series from 16 HF (age 55.1±7.8 years, 12 male) and 26 control (49.7±10.8 years, 17 male) subjects with a 3.0-Tesla magnetic resonance imaging scanner. MD maps were realigned, averaged, normalized, and smoothed. Global and regional MD values from autonomic and motor coordination sites were calculated by using normalized MD maps and brain masks; group MD values and whole-brain smoothed MD maps were compared by analysis of covariance (covariates; age and gender). Global brain MD (HF vs. controls, units × 10-6 mm2/sec, 1103.8±76.6 vs. 1035.9±69.4, P=0.038) and regional autonomic and motor control site values (left insula, 1,085.4± 95.7 vs. 975.7±65.4, P=0.001; right insula, 1,050.2± 100.6 vs. 965.7±58.4, P=0.004; left hypothalamus, 1,419.6±165.2 vs. 1,234.9±136.3, P=0.002; right hypothalamus, 1,446.5±178.8 vs. 1,273.3±136.9, P=0.004; left cerebellar cortex, 889.1±81.9 vs. 796.6±46.8, P<0.001; right cerebellar cortex, 797.8±50.8 vs. 750.3± 27.5, P=0.001; cerebellar deep nuclei, 1,236.1±193.8 vs. 1,071.7±107.1, P=0.002) were significantly higher in HF vs. control subjects, indicating chronic tissue changes. Whole-brain comparisons showed increased MD values in HF subjects, including limbic, basal-ganglia, thalamic, solitary tract nucleus, frontal, and cerebellar regions. Brain injury occurs in autonomic and motor control areas, which may contribute to deficient function in HF patients. The chronic tissue changes likely result from processes that develop over a prolonged period.