Role of inflammation and extracellular matrix remodelling in dogs with cardiac and systemic diseases

Cardiac diseases are common in dogs and are associated with ventricular dilatation or hypertrophy as well as cardiac dysfunction. In cardiac diseases, activation of the neurohormonal and inflammatory systems contribute to cardiac remodelling through degradation or increased deposition (fibrosis) of the extracellular matrix (ECM). Important factors in this process are cytokines as mediators of inflammation, matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of metalloproteinases; TIMP) as regulators of the myocardial ECM composition. Recently, there was evidence that also leptin plays a role in human cardiac diseases. However, the precise mechanisms that cause pathological cardiac remodelling in both humans and other mammalian species are incompletely understood. Furthermore, functional impairment of the heart and cardiomyocyte damage are observed in human and canine patients with systemic diseases, again without current knowledge on the underlying process. The aim of the present studies was to investigate cardiac remodelling in canine patients with cardiac and systemic diseases. For this purpose, a quantitative assessment of the transcription of cytokines (IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, IFN-γ, TGF-β1, TGF-β2, TGF-β3), MMP (MMP-1, -2, -3, -9, -13), TIMP (TIMP-1, -2, 3, -4) and leptin in the blood of healthy dogs and dogs with cardiac diseases and in the myocardium of dogs with cardiac diseases, dogs with systemic diseases not involving the heart as well as healthy control dogs was obtained. In comparison to healthy dogs, which constitutively transcribed most markers in blood, dogs with cardiac diseases exhibited a selective increase (IL-1, IL-2, MMP-1, 3, TIMP-3) or reduction (TNF-α, TGF-β1, -β3, TIMP-1, -2) of inflammatory and ECM remodelling markers and an increase of leptin. In contrast, in the myocardium of dogs with cardiac and systemic diseases, the transcription of all markers was significantly higher than in hearts of healthy control dogs. This suggests myocardial inflammation and remodelling not only in association with cardiac diseases, but also with systemic diseases that do not involve the heart. The results also indicate a localised myocardial inflammation and remodelling in dogs with cardiac diseases, not secondary to a systemic inflammatory response. Interestingly, transcription levels of most markers exhibited regional differences in diseased dogs in general, with significantly higher mRNA levels in atria than in ventricles. This indicates differences in the remodelling processes depending on localisation, which was reflected by more severe histological changes in the atria of dogs with cardiac diseases. In conclusion, the results of the thesis provide evidence of myocardial inflammation and remodelling with regional quantitative differences in dogs with cardiac and systemic diseases and suggest a role for leptin in canine cardiac disease. The results provide further insights into the complex process of cardiac remodelling, which might influence clinical management and the assessment of prognoses in future.