Effects of Intralipid on myocardial dysfunction and SAFE pathway signaling following ex vivo global ischemia-reperfusion.

BACKGROUND

Myocardial dysfunction after cardiac arrest (CA) is a major determinant of post-resuscitation mortality and is driven by ischemia-reperfusion injury (IRI). Intralipid has shown cardioprotective effects in preclinical models of IRI and in cardiac surgery. However, the underlying mechanisms remain unclear, particularly the involvement of Signal Transducer and Activator of Transcription 3 (STAT3), a component of the Survivor Activating Factor Enhancement (SAFE) pathway.

METHODS

Isolated rat hearts underwent 20 min of normothermic global ischemia-induced CA followed by 60 min of reperfusion. Intralipid (1%) was given at reperfusion for 5 min, with or without JAK/STAT3 inhibitor AG490. Hemodynamic parameters, including left ventricular developed pressure (LVDP), rate-pressure product (RPP), left ventricular end-diastolic pressure (LVEDP), heart rate (HR), and coronary flow (CF), were monitored. STAT3 activation in cytosolic and nuclear fractions was assessed by western blotting.

RESULTS

Baseline cardiac function was similar across groups. Global ischemia-reperfusion impaired contractility, reduced CF, and elevated LVEDP in all groups. Intralipid improved LVDP recovery (72 ± 5 vs. 54 ± 2 mmHg at 60 min, P < 0.05) and increased RPP (22 ± 1 vs. 15 ± 1 × 103 mmHg·bpm, P < 0.05), while limiting the maximal LVEDP rise (63 ± 7 vs. 83 ± 6 mmHg, P < 0.05). HR and CF showed no differences between controls and Intralipid. AG490 neither affected post-ischemic recovery nor abolished Intralipid-induced cardioprotection. STAT3 phosphorylation (ser727 and Tyr705) remained unchanged across groups.

CONCLUSIONS

Intralipid enhanced myocardial systolic recovery and limited diastolic dysfunction following global ischemia-induced CA. Our findings suggest that cardioprotection occurs through mechanisms other than SAFE pathway activation and support Intralipid as a potential therapy to improve cardiac recovery after CA.