Alterations in cardiac function and gene expression during autoimmune myocarditis in mice

Although myocarditis has been implicated in the pathogenesis of heart failu re, a definitive relationship between myocardial inflammation, cardiac dysf unction, and changes in myocyte gene expression has not been established. I n this study, we examined the hypothesis that myo cardial inflammation and replacement fibrosis following an autoimmune response can progress to cardi ac dysfunction and may result in progression to the heart failure phenotype . SWXJ mice were immunized with cardiac myosin on day 0 and day 7, in order to induce an autoimmune response to the myosin protein. Cardiac catheteriz ation via the right carotid artery was performed on days 14, 21, 28, 35, an d 42, using a 1.4F Millar transducer-tipped catheter. Hearts were weighed, and cross-sections were cut and stained with either haematoxylin and eosin or Masson's trichrome, in order to identify areas of inflammation and/or fi brosis. Myocardial gene expression was determined by Northern blot analysis . In mice with histological evidence of myocarditis, the heart weight/body weight ratio increased beginning on day 14, and cardiac function decreased beginning on day 21. Myocardial inflammation was accompanied by significant fibrosis beginning pn day 21, Quantitation of mRNA showed expression of ve ntricular atrial naturietic factor, as well as a decrease in myosin heavy c hain alpha, beginning on day 21. These data demonstrate that autoimmune inf lammation of the heart results in significant cardiac dysfunction, leading to phenotypic alterations similar to those demonstrated in human heart fail ure and animal models of heart failure. (C) 2000 Academic Press.