*4.2. Large Mammals*

Although rodent animal models are commonly used in cardiovascular research and may display some of the characteristics of human cardiac disease, they typically do not recapitulate all aspects of DCM found in humans [124,125]. Preclinical validation of therapeutic approaches can be advanced in large animal models due to their proximity to human cardiac physiology and structure [126]. Canines, swine, sheep, and non-human primates have been the most frequently used large animal models for cardiovascular research [104]. Taking into account the similarities in coronary anatomy, organ size, immunology, and physiology compared to humans, swine are considered the most attractive model for pre-clinical studies [105]. DCM can be induced in large animals by myocardial infarction, coronary micro-embolization, pacing-induced tachycardia, and toxic injury. Infarction models, including both re-perfused and non-re-perfused approaches in dogs [106], pigs [107], and sheep [108], are used to evaluate the pathophysiological mechanisms of post-infarction remodeling as well as DCM development, progression, and therapeutic response.

The availability of large animal models of DMD has been instrumental in gaining insights into the cardiomyopathy and progression to heart failure associated with DMD. The golden retriever muscular dystrophy (GRMD) canine model of DMD has been indispensable, not only for the development of therapeutic approaches, but also for the study of the pathobiology of dystrophin deficiency in the heart [68,109,110]. Muscular dystrophy in GRMD animals closely recapitulates the timing and severity of disease progression observed in DMD patients. In addition to the severe skeletal muscle pathology, GRMD animals have prominent cardiac lesions present as early as 6 months of age [127], with ECG abnormalities present at 1 year [128] and profound myocardial contractile abnormalities by 20 months [129].
