Abstract 3573: Protection of Hypothermia-induced Contractile Dysfunction in Mice With Cardiac Specific Expression of Slow Skeletal Troponin I
Rewarming the intact heart from hypothermia is associated with reduced contractile function, decrease in myofilament response to Ca2, and increased cardiac troponin I (cTnI) phosphorylation. To further investigate the functional significance of increased TnI phosphorylation in this setting, we tested the hypothesis that transgenic murine hearts with a complete stoichiometric replacement of cTnI with the isoform slow skeletal TnI (TG-ssTnI) results in improved myocardial function after deep hypothermia followed by rewarming (H/R). This isoform lacks PKA-induced phosphorylation sites and myofilaments show increased Ca2+ sensitivity. A group of non-transgenic littermates (NTG, n=7) were used for controls. Hypothermia (3 h at 22°C) was induced in anesthetized NTG and TG-ssTnI mice (n=7), followed by rewarming to normothermia (37°C). Cardiac function was determined in close chest animals using a 1.4F pressure-volume Millar catheter placed inside the left ventricle (LV) via the right carotid artery. Change in core temperature, measured by esophageal thermocouple, was achieved by surface cooling and rewarming. At baseline, cardiac output (CO) was similar between groups. During deep hypothermia, CO remained significantly reduced in NTG animals compared to TG (3.4±0.9 vs. 4.2±1.2 ml•min−1, p<0.05). After rewarming, significant differences (p<0.05) were found in CO (NTG 6.6±0.7 vs. TG-ssTnI 8.8±0.7 ml·min−1), stroke work (SW) (NTG 796±112 vs. TG-ssTnI 1208±67 mmHg·μl−1), and preload recruitable stroke work (PRSW) (NTG 38.3±4.9 vs. TG-ssTnI 68.8±8.2 mmHg). The isovolumic relaxation constant (Tau) was prolonged in TG-ssTnI both at baseline conditions (NTG=7.0±0.5 and in TG-ssTnI=8.6±0.4, p<0.05). However, after H/R, end diastolic pressure volume relationship remained unaltered in both groups. We conclude that TnI phosphorylation plays a significant role in the systolic dysfunction observed after H/R. Further, the expression of the ssTnI isoform results in functional preservation in hearts subjected to deep hypothermia followed by normothermia.