Abstract 1466: Re-expression of Slow Skeletal Troponin I Prevents Hypertrophic Remodeling during Ischemic Heart Failure
Slow skeletal Troponin I (ssTnI) expressed in the embryonic heart plays a key role in regulating myofilament function under acidic conditions. During postnatal growth, the ssTnI isoform is replaced with the adult cardiac TnI (cTnI) isoform and is not reported to be re-expressed in response to pathologic stress. We have observed that ssTnI is regionally and transiently re-expressed, both mRNA and protein, in the border zone of a myocardial infarct (MI). We hypothesize that re-expression of ssTnI is a compensatory adaptation aimed at preserving myocyte viability in response to an acidic environment surrounding an infarct. To test this, infarcts were created in transgenic mice that express ssTnI in place of cTnI and cardiac function assessed by pressure-volume loop analysis in non-transgenic (NTG) and transgenic (TG) mice at 2 and 10 wk post-MI. No differences in heart rate were noted but mean arterial and end-systolic pressures declined equally in NTG and TG groups post-MI. There was a significant increase in both end-systolic and diastolic volume in the NTG-MI mice that was attenuated in TG-MI mice (ESV, NTG vs. TG control=66±4 vs.66±7, 2wkMI=98±7* vs. 86±7, 10wkMI=102±5* vs. 89±5: EDV, controls=81±5 vs. 91±8, 2wkMI=105±8 vs. 98±6, 10wkMI=112±5* vs. 97±4, ul, p<0.05). Despite relative differences at baseline in a number of systolic and diastolic load-dependent parameters, the decline in function was equivalent between the NTG and TG groups post-MI. Although cardiac dysfunction was comparable, the extent of hypertrophy as measured by heart to body weight differed between the NTG and TG post-MI mice (NTG vs. TG control=5.5±0.2 vs. 5±0.2, 2wkMI=7.2±0.4* vs. 6.5±0.4, 10wkMI=8.9±0.5* vs. 6.8±0.3, mg/g, p<0.05). Examination of gene expression using qRT-PCR showed that both ANF and MMP2 were increased in NTG-MI mice compared to TG-MI, whereas βMHC was similar between the MI groups. These results suggest that re-expression of ssTnI post-MI serves to preserve cardiac myocyte viability and prevents hypertrophic remodeling. We conclude that the mechanisms regulating cardiac remodeling and contractility are distinct and separable events and that the prevention of hypertrophy does not avert the decompensation into heart failure following myocardial infarction.