Characterization of diffuse fibrosis in the failing human heart via diffusion tensor imaging and quantitative histological validation

Non-invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end-stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end-stage heart failure as a result of idiopathic dilated cardiomyopathy (n=14) and from normal donors (n=5). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary (D₁), secondary (D₂) and tertiary (D₃) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D₂ and D₃ increased by 12%, 14% and 24%, respectively (P<0.01). No significant change was detected for D₁ between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearson's correlation coefficients (r) between collagen content and FA, MD, D₂ and D₃ were -0.51, 0.59, 0.56 and 0.62 (P<0.05), respectively. The correlation between D₁ and collagen content was not significant (r=0.46, P=0.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non-invasive assessment of diffuse fibrosis in failing hearts.