Abstract 3854: Correction of Diastolic Dysfunction by Cardiac Troponin Modifications in Restrictive Cardiomyopathic Mice
Restrictive cardiomyopathy (RCM) is associated with cardiac troponin mutations in human patients. We have created transgenic mice (cTnI193His mice) that express human RCM R192H (R193H in mouse sequence). The phenotype of the RCM animal model is characterized by restrictive ventricles, biatrial enlargement and an increased risk of sudden cardiac death (SCD), which are similar to those observed in RCM patients carrying the same cTnI mutations (Du, et al, 2006; 2008). The cellular studies indicate that an alteration in myofibril sensitivity for Ca2+ is a key mechanism that causes diastolic dysfunction in RCM. In this study, we have modified cTnI molecules in the heart by crossing cTnI193His mice with cTnI-ND transgenic mice, the latter contains 100% N-terminal deleted cTnI in the heat characterized by an accelerated cardiac muscle relaxation and an enhanced ventricular diastolic function. The protein analyses data indicate that wild type cTnI is replaced by cTnI-ND in double transgenic mice while the RCM cTnI R193H levels are very similar in the hearts between cTnI193His mice and the double transgenic mice (about 25% of the total cTnI). The mortality rate is significantly reduced in double transgenic mice (10%) compared to that in RCM cTnI193His mice (30%). The cardiac function and performance are significantly improved in double transgenic mice measured by echocardiograph. Cell based studies indicate that the delayed sarcomere relaxation time observed in RCM cTnI193His myocardial cells is significantly shortened in myocardial cells incorporated with cTnI-ND from double transgenic hearts. The left-shift of Ca2+-dependent myofibril ATPase activities observed in skinned myofibrils from RCM cTnI193His mouse hearts is also corrected in myofibrils incorporated with cTnI-ND from double transgenic hearts. The results have demonstrated that Ca2+ desensitization caused by cTnI-ND molecules in myocardial cells can correct diastolic dysfunction and rescue RCM transgenic mice, suggesting that Ca2+ desensitization in myofibrils is a therapeutic option for treatment of diastolic dysfunction and cardiomyopathies (supported by grants from NIH HL-078773 and GM-073621).
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).