The importance of LV fibrosis on cardiac function during hyperthyroidism is not well characterized. Using trichrome staining, we were able to confirm in our study that prolonged hyperthyroidism was associated with increased LV fibrosis when compared with age matched control hamsters. The majority of fibrotic deposits were found within the perivascular space and cardiac interstitium without evidence of myocyte necrosis and replacement fibrosis. Moreover, we observed severe relaxation impairment and ultimately systolic dysfunction in hyperthyroid hearts. Our findings further support the notion that LV fibrosis inversely affects LV function in the setting of hyperthyroidism. While increased collagen deposition certainly can impair global cardiac function, it may not similarly affect intrinsic cardiomyocyte mechanics. Accordingly, we also examined the influence of chronic hyperthyroidism on the mechanical function of individual myocytes. We hypothesized that mechanical impairment at the level of individual ventricular myocytes would strongly correlate with the decline observed in global cardiac function. Contrary to our hypothesis, we found that isolated ventricular myocytes from hyperthyroid hamsters had enhanced mechanical function when compared to age matched control hamsters, despite the aforementioned adverse chamber remodeling and diminished global cardiac function. Given the close proximity of fibrillar collagen to myocytes and the finding that fibrillar collagen is a relatively stiff material with a tensile strength greater than steel, it is likely that even a small increase in collagen can impair cardiomyocyte function. Indeed, this notion is supported by reports that small changes in collagen concentration can have a profound impact on passive mechanical properties of cardiac tissue. In agreement, our findings suggest that relatively modest but significant increases in myocardial collagen deposition can impede myocyte contractile ability even when individual myocyte function is enhanced. Consistent with our previous report, we did not observe noticeable areas of fibronecrosis. This suggests that the depressed global cardiac function observed during chronic hyperthyroidism is at least in part the product of inhibited myocyte function caused by increased perivascular and interstitial fibrotic deposition and does not appear to be a product of extensive myocyte loss. Our study has BAY-60-7550 several limitations. While a standard experimental protocol was closely followed to replicate the same experimental conditions for each animal, it is possible that myocytes selected for functional assessment do not represent the total myocyte population within the intact heart. It is also important to note that isolated myocytes in the current study were not tested under loading conditions. Loading conditions can influence muscle function and altered loading theoretically could impact isolated myocyte shortening and tension development. Unfortunately, the technical difficulty of myocyte loading experiments limits its utility and widespread implementation. Unloaded isolated myocyte assessment still is an important tool for evaluating shortening velocity/cross bridge turnover rate and comparisons between treatment groups can be made under similar experimental conditions without influence of potential confounders. Finally, we acknowledge that comprehensive isolated myocyte morphometric analysis would have complemented the echocardiographic and isolated myocyte functional data presente.