Clinical diagnosis of AC is made using International Task Force criteria, including structural, histological, electrocardiographic, arrhythmic and genetic features. The sensitivity of endomyocardial biopsies from the right ventricular septum in AC is low, according to our findings this might also be the case in PLN mutation associated cardiomyopathies. The method of fibrosis quantification presented here can be used for several applications. First, determination of the fibrosis pa ern in the heart could provide an important link for genotypephenotype relationships in genetic cardiomyopathies. Previous studies have proposed morphometric evaluation of either fibrosis or adipocytes in different tissues. In our analysis fibrosis and fibrofa y replacement can be assessed simultaneously in layer specific detail. We defined different regions of interest to divide the heart in an Tubuloside-A epicardial, compact and trabeculated layer. In addition, the pa ern of fibrosis can be studied in the different regions of both ventricles. By studying the exact fibrosis pa ern throughout the heart, pa erns of disease might be discovered thereby elucidating mechanisms of pathophysiology. Numerous disease-causing genes for different cardiomyopathies have been identified during the past two decades and the challenge for the future is to link these genetic mutations to specific pa erns of disease in the heart. In future, AC with different underlying causal mutations could be compared to the PLN p.Arg14del mutation carriers with AC. The second application could be validation of cardiac imaging techniques. The Artemisinic-acid reference noninvasive standard for fibrosis detection is late gadolinium enhancement on MRI. Adequate correlation to the gold standard of histology is important. Thus 
far, correlation studies are mostly done with small endomyocardial biopsies that only represent a fraction of the total myocardium or with triphenyl tetrazolium chloride stained heart slices. Recently, several novel techniques for fibrosis detection have been proposed, including T1-mapping, that also require adequate correlation to histology. Cardiac MRI images obtained before autopsy or heart transplantation, indicating fibrosis could be divided in similar segments to produce a bull��s eye plot for comparison with histopathological quantification. However, some heart failure patients are ineligible for MRI because of implanted devices, such as implantable cardioverter-defibrillator, cardiac resynchronization therapy and left ventricular assist devices. A third potential application could be systematic fibrosis quantification in animal models, for example in models of ischemic or nonischemic cardiomyopathy. Effects of novel therapies on myocardial fibrosis can be examined in randomized preclinical trials, by systematically comparing the amount of fibrosis on histology. A standardized preclinical model with induced myocardial infarction can be used to study new therapeutics, such as cell therapy, as a strategy to a enuate cardiac fibrosis and stop progression towards heart failure. In conclusion, in PLN p.Arg14del mutation associated cardiomyopathy myocardial fibrosis is predominantly present in the left posterolateral wall, whereas fa y changes are more pronounced in the wall of the right ventricle.