and humans. It will be important to define the subset of blood or urine biomarkers that are heart derived and thus potentially useful in cardiac interventional studies. Animal Models for DMD The mouse model has served as an important if imperfect model for DMD. A de novo premature stop codon in exon 23 of the dystrophin gene VR23 leads to the histopathological features seen in DMD muscle.61 62 The mouse has a significant 20% reduction in life span and displays progressive fibrosis and fatty infiltration in most skeletal muscles.63 64 The respiratory muscles especially the diaphragm muscle are significantly affected by DMD pathology and very closely mimic what occurs in the human muscle. At the equivalent age for human cardiomyopathy the mouse displays only mild features of cardiomyopathy. Markedly decreased baseline cardiac function measured by conventional echocardiography is evident only in the aged mouse.64-66 The reason for this relatively preserved function in younger mice under baseline conditions is not known. The shorter life span of mice an VR23 improved regenerative capacity smaller muscles and VR23 heart and limited physical exertion of caged mice have all been suggested as reasons for the milder baseline cardiac phenotype in mice. Importantly cardiomyopathy and acute heart pump failure can be readily unmasked in mice by pharmacological or mechanical cardiac stress testing.67 68 Other genetic murine models with notable cardiomyopathy at baseline also are useful for preclinical studies focused on the rescue of the cardiac phenotype. These models include (but are not limited to) the (utrophin) double-null model and the heterozygous mouse model.69 The double-null mouse has profound kyphoscoliosis respiratory compromise and cardiomyopathy. 70 The short life span of double-null mice is useful when survival is an end point. The heterozygous model is easier to breed and therefore more available for study. The cardiomyopathy in this model can be more readily detected by imaging approaches and therefore may be more useful experimentally. However the model is not a genetic match to the DMD human heart. Mice lacking dystrophin-associated proteins including β- γ- and δ-sarcoglycan have also been used for preclinical studies of muscular dystrophy.71 These models display a more advanced cardiac phenotype at baseline conditions than age-matched mice and are useful for testing drugs and genetic pathways that alter the cardiac outcome. These models share a pathological pathway in that they also have a disrupted dystrophin complex in striated muscle. However like the models they are not genetically identical to DMD. As noted studies using glucocorticoid steroids in these murine models showed adverse cardiac consequences of steroids. It is not known what accounts for the discrepancy between human and murine hearts in this regard but secondary effects of glucocorticoids on systemic blood pressure and other pathways could account for these differences. Large animal models of DMD have been used to study gene- cell- and chemical-based experimental therapies on VR23 cardiac and respiratory outcomes.72-74 The Golden Retriever Muscular Dystrophy model has been studied extensively for gene therapy including cardiac gene therapy for DMD. The canine model may more faithfully replicate key aspects of the cardiac phenotype in DMD. However its scarce supply the need for canine-specific reagents and the high cost of conducting trials argue for judicious and collaborative use of the Golden Retriever Muscular Dystrophy model. Additionally the canine heart has a more developed collateral coronary circulation that differs from what is seen in the human heart and this Rabbit polyclonal to PABPC3. difference in anatomy may alter the manifestation of cardiomyopathy.75 VR23 Recent de novo and engineered mutations in dystrophin in the porcine model could emerge as a new large animal model of dystrophic cardiomyopathy.76 77 The pig model for example could be highly valuable to help advance screening for cardiac arrhythmias in DMD. For all animal models it was recommended that the assessment of cardiac phenotype be updated and in some cases established..