The effects of resolvin D1 on myocardial dysfunction after cardiopulmonary resuscitation in swine and its potential mechanisms

Objective To establish a porcine model of cardiopulmonary resuscitation to explore the effectiveness of resolvin D1 in improving post-resuscitation myocardial dysfunction and its potential mechanisms. Methods Twenty-eight male domestic pigs weighing 36±3 kg were utilized. The pig model was established by 8 mins of untreated ventricular fibrillation and then 5 mins of cardiopulmonary resuscitation. The animals were randomly divided into 4 groups (n=7 each): sham operation group (group S), cardiopulmonary resuscitation group (group CPR), low-dose resolvin D1 group (group LRD), and high-dose resolvin D1 group (group HRD). The animals in group S only got the general preparation without the procedure of cardiac arrest and resuscitation. At 5 min after resuscitation, the doses of resolvin D1 0.3 μg/kg and 0.6 μg/kg were respectively injected via the femoral vein of pigs in LRD and HRD groups, and meanwhile the equal volume of vehicle was given into the animals in the other two groups. At 3 h, 6 h and 24 h after resuscitation, the changes of stroke volume (SV) and global ejection fraction (GEF) were evaluated by a PiCCO monitor, and meanwhile the concentration of cardiac troponin I (cTNI) in serum was measured. At 24 h after resuscitation, the pigs were sacrificed, and myocardial tissue was obtained for the determination of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), and superoxide dismutase (SOD) activity. Results Compared with group S, significantly decreased SV and GEF and markedly increased concentration of serum cTNI were observed in the other three groups with post-resuscitation myocardial dysfunction (all P<0.05). Compared with group CPR, the values of SV and GEF were significantly increased while the concentration of serum cTNI was significantly decreased in LRD and HRD groups[SV(ml): 28±5, 31±5 vs. 23±4 at 3 hrs, 32±3, 36±6 vs. 27±6 at 6 hrs, 35±5, 41±5 vs. 29±5 at 24 hrs; GEF(%): 17±2, 19±2 vs. 14±1 at 3 hrs, 20±2, 23±3 vs. 16±3 at 6 hrs, 23±2, 26±3 vs. 20±2 at 24 hrs; cTNI (pg/ml): 247±34, 230±26 vs. 324±56 at 3 hrs, 553±37, 501±34 vs. 611±44 at 6 hrs, 436±23, 371±29 vs. 553±47 at 24 hrs, all P<0.05]. Compared with group LRD, myocardial function and serum markers were further significantly improved in group HRD (all P<0.05). The inflammation and oxidative stress in myocardial tissue were observed in all the animals experiencing cardiac arrest and resuscitation, which were indicated by increased levels of TNF-α, IL-6 and MDA and decreased SOD activity. Compared with group CPR, the levels of TNF-α, IL-6 and MDA were significantly decreased while SOD activity was significantly increased in LRD and HRD groups[TNF-α(pg/ml): 442±87, 218±55 vs. 653±112; IL-6(pg/ml): 563±68, 403±61 vs. 824±117; MDA(nmol/mg): 3.95±0.96, 2.54±1.21 vs. 6.37±1.26; SOD(U/mg): 2.27±0.93, 3.36±0.74 vs. 0.89±0.31, all P<0.05]. The morbidity of myocardial inflammation and oxidative stress were further significantly ameliorated in group HRD evidenced by the figure of biomarkers compared with group LRD (all P<0.05). Conclusions Resolvin D1 can improve post-resuscitation myocardial dysfunction in a dose-dependent manner in swine, and the mechanism is related to the inhibition of inflammation and oxidative stress. Key words: Cardiac arrest; Cardiopulmonary resuscitation; Myocardial dysfunction; Cardiac injury; Resolvin D1; Inflammation; Oxidative stress; Swine