We observed a heterogeneous effect of plna R14del in 2-year-old zebrafish, as some fish appeared completely healthy while others displayed end-stage heart disease characterized by the accumulation of fibroblasts, immune cells and fat in the sub-epicardial region. A similar heterogenous effect of the PLN R14del mutation is seen in patients, with fibrofatty infiltrates that are usually located in the posterolateral region of the left ventricular myocardium, right underneath the epicardium. Cardiac fibrofatty replacement in PLN R14del patients has a likely (sub)epicardial origin, which implicates that the underlying mechanisms of disease might be comparable between zebrafish and man37. The epicardium is a mesothelial cell layer that acts as an important source of trophic signals to maintain continued growth and differentiation of the developing heart. The importance of the epicardium as a driver of morphological changes in the heart is increasingly recognized38. In the adult zebrafish the epicardium responds to injury by inducing embryonic epicardial gene expression (e.g. tbx18) and proliferation27,39. After cardiac injury, the epicardial cells undergo a process called epithelial-to-mesenchymal transformation (EMT). They migrate into the cardiac tissue, where they can give rise to cardiac smooth muscle cells and fibroblasts40. Epicardial cells can also give rise to fat cells via mesenchymal transformation and peroxisome proliferator-activated receptor Î (PPARÎ) activation41. As the remodeled tissue within plna R14del hearts showed a strong expression of tbx18, it suggests that it may have an epicardial origin. This should be studied further by lineage tracing experiments.
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