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Cardiomyopathies are progressive diseases of heart muscle often caused by mutations in genes encoding sarcomeric, cytoskeletal and nucleoskeletal proteins though in many cases the cause of disease is not identified. Whilst nucleus hypertrophy has been described, it is not known whether nucleus shape changes are a general feature of cardiomyopathy. Due to the rod-shaped nature of cardiomyocytes and their elliptical nuclei we hypothesised that orientation of analysis would be an important determinant of any changes observed between patients exhibiting primarily unexplained cardiomyopathy and control samples from non-failing donors. To investigate this we performed image analysis of cardiomyocyte nuclei in myocardial cryosections from a cohort of cardiomyopathy patients. We discovered that circularity, solidity and aspect ratio were sensitive to orientation of the myocardium and that in the transverse plane only circularity was reduced in cardiomyocyte nuclei of cardiomyopathy patients. These findings show that orientation dependent changes in nucleus shape may be a property of cardiomyopathy and with appropriate follow up studies, may prove to have mechanistic and diagnostic value.