Comparative phenotypic assessment of cardiac pathology, physiology, and gene expression in C3H/HeJ, C57BL/6J, and B6C3F1/J mice

Human cardiomyopathies often lead to heart failure, a major cause of morbidity and mortality in industrialized nations. Described here is a phenotypic characterization of cardiac function and genome-wide expression from C3H/HeJ, C57BL/6J, and B6C3F1/J male mice. Histopathologic analysis identified a low-grade background cardiomyopathy (murine progressive cardiomyopathy) in eight of nine male C3H/HeJ mice (age nine to ten weeks), but not in male C57BL/6J and in only of ten male B6C3F1/J mice. The C3H/HeJ mouse had an increased heart rate and a shorter RR interval compared to the B6C3F1/J and C57BL/6J mice. Cardiac genomic studies indicated the B6C3F1/J mice exhibited an intermediate gene expression phenotype relative to the 2 parental strains. Disease-centric enrichment analysis indicated a number of cardiomyopathy-associated genes were induced in B6C3F1/J and C3H/HeJ mice, including Myh7, My14, and Lmna and also indicated differential expression of genes associated with metabolic (e.g., Pdk2) and hypoxic stress (e.g. Hif1a). A novel coexpression and integrated pathway network analysis indicated Prkaa2, Pdk2, Rhoj, and Sgcb are likely to play a central role in the pathophysiology of murine progressive cardiomyopathy in C3H/HeJ mice. Our studies indicate that genetically determined baseline differences in cardiac phenotype have the potential to influence the results of cardiotoxicity studies. Ten C3H/HeJ, ten B6C3F1/J, and ten C57BL/6J male mice from The Jackson Laboratories, Bar Harbor, Maine were used for these studies. Surgery to implant a Data Sciences radiotelemetry transmitter in the abdominal cavity was performed on mice anesthetized with tribromoethanol (Avertine) 250 mg/kg IP at seven weeks of age. After collection of phenotype measurements (two to two and a half weeks post-surgery; nine and a half weeks of age),animals were euthanized with CO2; the heart was collected for histopathologic analysis, and a piece of the heart apex was collected for RNA analysis. RNA was extracted from the hearts of five control C3H/HeJ, C57BL/6J, and B6C3F1/J mice.