Unravelling the genetic basis of heart failure via systems genetics.

Heart failure (HF) is the leading cause of death worldwide. It is a complex disease involving multiple aspects of pathology affected by genetic pre-disposition, the aging process, and environmental stressors. Defining the genetic basis for HF can provide keys to the underlying mechanisms and lead to a better personalized diagnosis and therapy. A systems genetics approach was developed to perform functional characterization of 107 mouse strains from a Hybrid Mouse Diversity Panel (HMDP). Three categories were designated, sensitive, intermediate, and resistant, after β-adrenergic stimulation using isoproterenol (ISO). Extremely resistant and sensitive strains were selected for angiotensin II (AngII) and transverse aortic constriction (TAC) treatment to study the contribution of genetic background on the pathogenesis of HF. ISO, AngII, and TAC share the hypertrophic and fibrotic responses in a strain and stressor specific manner. The contractility phenotype is common for sensitive and resistant strains. Itga1, the alpha subunit of integrin receptors was found to have significant association with left ventricular hypertrophy (LVH). Together, these results suggest that genetic variants significantly contribute to the development of heart failure and the genes implicated in the specific pathological features of heart failure can be revealed via systems genetics. In addition, we have identified a number of cardiac phenotypes implicated in diastolic dysfunction. More extensive studies using highly sensitive and resistant strains from the HMDP have shown differential responses and offer support for investigating HF using this mouse model which is suffering from Heart Failure with preserved Ejection Fraction (HFpEF). These results provide validation for our approach to unraveling the effects of genetic background associated with multiple cardiac phenotypic manifestations to pathological stressors and continue to generate hypotheses and analytical understanding in heart failure