Cardiomics in canine acquired heart diseases: Histopathological, proteomic, and transcriptomic analyses

Myxomatous mitral valve disease (MMVD) and dilated cardiomyopathy (DCM) are two of the most common cardiac diseases in dogs. The mechanisms underlying MMVD and DCM remain incompletely understood. This thesis aimed to systematically explore and compare pathological and molecular changes associated with MMVD and DCM in dogs by evaluating cardiac tissue using complementary histopathological, proteomic, and transcriptomic approaches.
Dogs with MMVD (n = 42), DCM (n = 16), and cardiac-healthy controls (n = 32) were enrolled in this thesis. Histopathological features were evaluated in multiple, region-matched cardiac tissue samples using quantitative and qualitative histopathological methods. Samples from the left ventricular (LV) lateral wall and posterior papillary muscle (PPM) were analyzed using proteomics, whereas PPM samples from 24 Cavalier King Charles Spaniels were analyzed using transcriptomics.
Dogs with MMVD had a higher degree of fibrosis and fatty infiltration, predominantly in left-sided cardiac regions, than controls. Dogs with DCM had a higher degree of atrial fibrosis than controls, with more extensive fibrosis in dogs with atrial fibrillation (AF) than in those without AF. Neither arterial lumen-to-area ratio nor the presence of attenuated wavy fibers differed among the groups in any cardiac region. The LV protein expression profiles of dogs with MMVD reflected a shift in energy metabolism towards increased reliance on fatty acid and branchedchain amino acid, whereas those of dogs with DCM primarily reflected alterations in muscle cell homeostasis and glucose metabolism. Gene expression changes in dogs with MMVD-associated left-sided cardiac enlargement primarily involved polymeric cytoskeletal fiber components.
In conclusion, histopathological changes in dogs with MMVD predominantly involved the left-sided heart, whereas in dogs with DCM, they involved both sides of the heart. Proteomic analysis suggested distinct metabolic processes associated with the two diseases, while transcriptomic analysis indicated that structural remodeling of the LV PPM may contribute to the pathophysiology of MMVD.