Genetic Basis of Dilated Cardiomyopathy in Dogs and Its Potential as a Bidirectional Model

SIMPLE SUMMARY: Heart disease is a leading cause of death for both humans and dogs. Inherited heart diseases, including dilated cardiomyopathy (DCM), account for a proportion of these cases. Human and canine patients with DCM suffer from an enlarged heart that can no longer pump efficiently, resulting in heart failure. This causes symptoms or clinical signs like difficulty breathing, irregular heartbeat, and eventually death. The symptoms or clinical signs of this disease vary in age of onset at the beginning of symptoms, sex predisposition, and overall disease progression. Despite the many similarities in DCM in both species, only a few candidate genes so far have been linked to this disease in dogs versus tens of genes identified in human DCM. Additionally, the use of induced pluripotent stem cells, or engineered stem cells, has been widely used in the study of human genetic heart disease but has not yet been fully adapted to study heart disease in dogs. This review describes the current knowledge on the genetics and subtypes of naturally occurring DCM in dogs, and how advances in research might benefit the dog but also the human patient. Additionally, a novel method using canine engineered stem cells to uncover unknown contributions of mistakes in DNA to the progression of DCM will be introduced along with its applications for human DCM disease modeling and treatment. ABSTRACT: Cardiac disease is a leading cause of death for both humans and dogs. Genetic cardiomyopathies, including dilated cardiomyopathy (DCM), account for a proportion of these cases in both species. Patients may suffer from ventricular enlargement and systolic dysfunction resulting in congestive heart failure and ventricular arrhythmias with high risk for sudden cardiac death. Although canine DCM has similar disease progression and subtypes as in humans, only a few candidate genes have been found to be associated with DCM while the genetic background of human DCM has been more thoroughly studied. Additionally, experimental disease models using induced pluripotent stem cells have been widely adopted in the study of human genetic cardiomyopathy but have not yet been fully adapted for the in-depth study of canine genetic cardiomyopathies. The clinical presentation of DCM is extremely heterogeneous for both species with differences occurring based on sex predisposition, age of onset, and the rate of disease progression. Both genetic predisposition and environmental factors play a role in disease development which are identical in dogs and humans in contrast to other experimental animals. Interestingly, different dog breeds have been shown to develop distinct DCM phenotypes, and this presents a unique opportunity for modeling as there are multiple breed-specific models for DCM with less genetic variance than human DCM. A better understanding of DCM in dogs has the potential for improved selection for breeding and could lead to better overall care and treatment for human and canine DCM patients. At the same time, progress in research made for human DCM can have a positive impact on the care given to dogs affected by DCM. Therefore, this review will analyze the feasibility of canines as a naturally occurring bidirectional disease model for DCM in both species. The histopathology of the myocardium in canine DCM will be evaluated in three different breeds compared to control tissue, and the known genetics that contributes to both canine and human DCM will be summarized. Lastly, the prospect of canine iPSCs as a novel method to uncover the contributions of genetic variants to the pathogenesis of canine DCM will be introduced along with the applications for disease modeling and treatment.