Although the PPP1R15A deficiency/irradiation model is a novel model of heart failure, it is typified by endoplasmic reticulum stress, mitochondrial dysfunction, and inflammation, which, beyond inflammatory cardiomyopathies, are common features of human heart failure (of both ischemic and non-ischemic origin), as extensively reviewed previously52,53 The high GDF15 production and occurrence of cardiac cachexia within a relatively short timeline are most likely due to the severity of our model in terms of ER stress and mitochondrial dysfunction. Here, GDF15 is linked to heart failure.