Rat Model Of Cardiac Arrest Research Articles

Effects of canagliflozin preconditioning on post-resuscitation myocardial function in a diabetic rat model of cardiac arrest and cardiopulmonary resuscitation.

Canagliflozin can reduce the risk of cardiovascular disease in patients except for its targeted antidiabetic effects. However, it remains unknown whether canagliflozin alleviates the post-resuscitation myocardial dysfunction (PRMD) in type 2 diabetes mellitus. To explore the effects and potential mechanisms of canagliflozin on myocardial function after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) in a type 2 diabetic rat model. Twenty-four type 2 diabetic rats were randomized into four groups: (1) sham+canagliflozin, (2) sham+placebo, (3) CPR+placebo, and (4) CPR+canagliflozin. Except for the sham+canagliflozin and placebo groups, both the CPR+placebo and canagliflozin groups underwent 8min of CPR after the induction of ventricular fibrillation for 6min. Myocardial function and hemodynamics were assessed at baseline and within 6h after autonomous circulation (ROSC) return. Left ventricular tissues were sampled to determine the expressions of relevant proteins in the NLRP3 inflammasome pathway. The results demonstrated that the mean arterial pressure (MAP) was significantly improved in the CPR+canagliflozin group after ROSC compared with the CPR+placebo group (p<0.05). Meanwhile, both ejection fraction (EF) and fraction shortening (FS) were dramatically increased in the CPR+canagliflozin group when compared with the CPR+placebo group at 2h, 4h, and 6h after ROSC (p<0.05). In addition, the levels of NT-proBNP, cTn-I, and NLRP3 inflammatory inflammasome-associated proteins were significantly decreased in the CPR+canagliflozin group compared with the CPR+placebo group. In type 2 diabetic rats, pretreatment of canagliflozin alleviates PRMD. The potential mechanisms may include inhibition of the NLRP3/caspase-1 signaling pathway.

A new method to predict return of spontaneous circulation by peripheral intravenous analysis during cardiopulmonary resuscitation: a rat model pilot study

BackgroundEnhancing venous return during cardiopulmonary resuscitation (CPR) can lead to better hemodynamics and improved outcome after cardiac arrest (CA). Peripheral Intravenous Analysis (PIVA) provides feedback on venous flow changes and may indicate an increase in venous return and cardiac output during CPR. We hypothesize PIVA can serve as an early indicator of increased venous return, preceding end-tidal CO2 (etCO2) increase, before the return of spontaneous circulation (ROSC) in a rat model of CA and CPR.ResultsEight male Wistar rats were intubated and ventilated, and etCO2 was measured. Vessels were cannulated in the tail vein, femoral vein, femoral artery, and central venous and connected to pressure transducers. Ventilation was discontinued to achieve asphyxial CA. After 8 min, CPR began with ventilation, epinephrine, and automated chest compressions 200 times per minute until mean arterial pressure increased to 120 mmHg. Waveforms were recorded and analyzed. PIVA was calculated using a Fourier transformation of venous waveforms. Data are mean ± SE. Maximum PIVA values occurred in the tail vein 34.7 ± 2.9 s before ROSC, with subsequent PIVA peaks in femoral vein and centrally at 30.9 ± 5.4 and 25.1 ± 5.0 s, respectively. All PIVA peaks preceded etCO2 increase (21.5 ± 3.2 s before ROSC).ConclusionPIVA consistently detected venous pressure changes prior to changes in etCO2. This suggests that PIVA has the potential to serve as an important indicator of venous return and cardiac output during CPR, and also as a predictor of ROSC.

The Effect of Therapeutic Hypothermia on Ischemic Brain Injury in a Rat Model of Cardiac Arrest: An Assessment Using 18F-FDG PET.

Therapeutic hypothermia (TH) is widely acknowledged as one of the interventions for preventing hypoxic ischemic brain injury in comatose patients following cardiac arrest (CA). Despite its recognized efficacy, recent debates have questioned its effectiveness. This preclinical study evaluated the impact of TH on brain glucose metabolism, utilizing fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in a rat model of CA. Asphyxia CA was induced in Sprague-Dawley rats using vecuronium. Brain PET images using 18F-FDG were obtained from 21 CA rats, who were randomized to receive either TH or no intervention. Of these, 9 rats in the TH group received hypothermia under general anesthesia and mechanical ventilation for eight hours, while the remaining 12 rats in the non-TH group were observed without intervention. We conducted regional and voxel-based analyses of standardized uptake values relative to the pons (SUVRpons) to compare the two groups. Survival rates were identical in both the TH and non-TH groups (67%). There was no discernible difference in the SUVRpons across the brain cortical regions between the groups. However, in a subgroup analysis of the rats that did not survive (n = 7), those in the TH group (n = 3) displayed significantly higher SUVRpons values across most cortical regions compared to those in the non-TH group (n = 4), with statistical significance after false-discovery rate correction (p < 0.05). The enhancement in SUVRpons due to TH intervention was only observed in the cortical regions of rats with severe encephalopathy that subsequently died. These findings suggest that the beneficial effects of TH on brain glucose metabolism in this asphyxia CA model may be confined to cases of severe ischemic encephalopathy.

Cold inducible RNA binding protein-regulated mitochondria associated endoplasmic reticulum membranes-mediated Ca2+ transport play a critical role in hypothermia cerebral resuscitation

Cardiac arrest is a global health issue causing more deaths than many other diseases. Hypothermia therapy is commonly used to treat secondary brain injury resulting from cardiac arrest. Previous studies have shown that CIRP is induced in specific brain regions during hypothermia and inhibits mitochondrial apoptotic factors. However, the specific mechanisms by which hypothermia-induced CIRP exerts its anti-apoptotic effect are still unknown. This study aims to investigate the role of Cold-inducible RNA-binding protein (CIRP) in mitochondrial-associated endoplasmic reticulum membrane (MAM)-mediated Ca2+ transport during hypothermic brain resuscitation.We constructed a rat model of cardiac arrest and resuscitation and hippocampal neuron oxygen-glucose deprivation/reoxygenation model. We utilized shRNA transfection to interfere the expression of CIRP and observe the effect of CIRP on the structure and function of MAM.Hypothermia induced CIRP can reduce the apoptosis of hippocampal neurons, and improve the survival rate of rats. Hypothermia induced CIRP can reduce the expressions of calcium transporters IP3R and VDAC1 in MAM, reduce the concentration of calcium in mitochondria, decrease the expression of ROS, and stabilize the mitochondrial membrane potential. Immunofluorescence and immunocoprecipitation showed that CIRP could directly interact with IP3R-VDAC1 complex, thereby changing the structure of MAM, inhibiting calcium transportation and improving mitochondrial function in vivo and vitro.Both in vivo and in vitro experiments have confirmed that hypothermia induced CIRP can act on the calcium channel IP3R-VDAC1 in MAM, reduce the calcium overload in mitochondria, improve the energy metabolism of mitochondria, and thus play a role in neuron resuscitation. This study contributes to understanding hypothermia therapy and identifies potential targets for brain injury treatment.

Neuroprotective effect of autologous mitochondrial transplantation against global ischemia/reperfusion injury in a rat model of cardiac arrest

BackgroundMitochondria have emerged as a promising target for ischemic disease. A previous study reported the application of mitochondrial transplantation in focal cerebral ischemia/reperfusion injury, but it is unclear whether exogenous mitochondrial transplantation could be a therapeutic strategy for global ischemia/reperfusion injury induced by cardiac arrest. MethodsWe hypothesized that transplantation of autologous mitochondria would rescue hippocampal cells and alleviate neurological impairment after cardiac arrest. In this study, we employed a rat cardiac arrest-global cerebral ischemia injury model (CA-GCII) and transplanted isolated mitochondria intravenously. Behavior test was applied to assess neurological deficit. Apoptosis and mitochondria permeability transition pore opening in hippocampus was determined using immunoblotting and swelling assay, respectively. ResultsTransplanted mitochondria distributed throughout hippocampal cells and reduced oxidative stress. An improved neurological outcome was observed in rats receiving autologous mitochondria. In the hippocampus, mitophagy was enhanced while cell apoptosis was induced by ischemia/reperfusion insult was downregulated by mitochondrial transplantation. Mitochondrial permeability transition pore (MPTP) opening in surviving hippocampal cells was also suppressed. ConclusionsThese results indicated that transplantation of autologous mitochondria rescued hippocampal cells from ischemia/reperfusion injury and ameliorated neurological impairment caused by cardiac arrest.

Ischemic Post-Conditioning in a Rat Model of Asphyxial Cardiac Arrest.

Ischemic post-conditioning (IPoC) has been shown to improve outcomes in limited pre-clinical models. As down-time is often unknown, this technique needs to be investigated over a range of scenarios. As this tool limits reperfusion injury, there may be limited benefit or even harm after short arrest and limited ischemia-reperfusion injury. Eighteen male Wistar rats underwent 7 min of asphyxial arrest. Animals randomized to IPoC received a 20 s pause followed by 20 s of compressions, repeated four times, initiated 40 s into cardiopulmonary resuscitation. If return of spontaneous circulation (ROSC) was achieved, epinephrine was titrated to mean arterial pressure (MAP) of 70 mmHg. Data were analyzed using t-test or Mann-Whitney test. Significance set at p ≤ 0.05. The rate of ROSC was equivalent in both groups, 88%. There was no statistically significant difference in time to ROSC, epinephrine required post ROSC, carotid flow, or peak lactate at any timepoint. There was a significantly elevated MAP with IPoC, 90.7 mmHg (SD 13.9), as compared to standard CPR, 76.7 mmHg (8.5), 2 h after ROSC, p = 0.03. IPoC demonstrated no harm in a model of short arrest using a new arrest etiology for CPR based IPoC intervention in a rat model.

Hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect neurons from cardiac arrest-induced pyroptosis.

JOURNAL/nrgr/04.03/01300535-202504000-00027/figure1/v/2024-07-06T104127Z/r/image-tiff Cardiac arrest can lead to severe neurological impairment as a result of inflammation, mitochondrial dysfunction, and post-cardiopulmonary resuscitation neurological damage. Hypoxic preconditioning has been shown to improve migration and survival of bone marrow-derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest, but the specific mechanisms by which hypoxia-preconditioned bone marrow-derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown. To this end, we established an in vitro co-culture model of bone marrow-derived mesenchymal stem cells and oxygen-glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis, possibly through inhibition of the MAPK and nuclear factor κB pathways. Subsequently, we transplanted hypoxia-preconditioned bone marrow-derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia. The results showed that hypoxia-preconditioned bone marrow-derived mesenchymal stem cells significantly reduced cardiac arrest-induced neuronal pyroptosis, oxidative stress, and mitochondrial damage, whereas knockdown of the liver isoform of phosphofructokinase in bone marrow-derived mesenchymal stem cells inhibited these effects. To conclude, hypoxia-preconditioned bone marrow-derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest, and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.

Ruthenium red alleviates post-resuscitation myocardial dysfunction by upregulating mitophagy through inhibition of USP33 in a cardiac arrest rat model

Cardiac arrest (CA) remains a leading cause of death, with suboptimal survival rates despite efforts involving cardiopulmonary resuscitation and advanced life-support technology. Post-resuscitation myocardial dysfunction (PRMD) is an important determinant of patient outcomes. Myocardial ischemia/reperfusion injury underlies this dysfunction. Previous reports have shown that ruthenium red (RR) has a protective effect against cardiac ischemia-reperfusion injury; however, its precise mechanism of action in PRMD remains unclear. This study investigated the effects of RR on PRMD and analyzed its underlying mechanisms. Ventricular fibrillation was induced in rats, which were then subjected to cardiopulmonary resuscitation to establish an experimental CA model. At the onset of return of spontaneous circulation, RR (2.5 mg/kg) was administered intraperitoneally. Our study showed that RR improved myocardial function and reduced the production of oxidative stress markers such as malondialdehyde (MDA), glutathione peroxidase (GSSG), and reactive oxygen species (ROS) production. RR also helped maintain mitochondrial structure and increased ATP and GTP levels. Additionally, RR effectively attenuated myocardial apoptosis. Furthermore, we observed downregulation of proteins closely related to mitophagy, including ubiquitin-specific protease 33 (USP33) and P62, whereas LC3B (microtubule-associated protein light chain 3B) was upregulated. The upregulation of mitophagy may play a critical role in reducing myocardial injury. These results demonstrate that RR may attenuate PRMD by promoting mitophagy through the inhibition of USP33. These effects are likely mediated through diverse mechanisms, including antioxidant activity, apoptosis suppression, and preservation of mitochondrial integrity and energy metabolism. Consequently, RR has emerged as a promising therapeutic approach for addressing post-resuscitation myocardial dysfunction.

Neuronal and myocardial damage in a rat model of ventricular fibrillation cardiac arrest with extracorporeal cardiopulmonary resuscitation

Neuronal and myocardial damage in a rat model of ventricular fibrillation cardiac arrest with extracorporeal cardiopulmonary resuscitation

Post-cardiac arrest temporal evolution of left ventricular function in a rat model: speckle-tracking echocardiography and cardiac circulating biomarkers.

There is little information from experimental studies regarding the evolution of post-resuscitation cardiac arrest [post-return of spontaneous circulation (post-ROSC)] myocardial dysfunction during mid-term follow-up. For this purpose, we assessed left ventricular (LV) function and circulating cardiac biomarkers at different time points in a rat model of cardiac arrest (CA). Rats were divided into two groups: control and post-ROSC rats. Eight minutes of untreated ventricular fibrillation were followed by 8 min of cardiopulmonary resuscitation. Conventional and speckle-tracking echocardiographic (STE) parameters and cardiac circulating biomarkers concentrations were assessed, at 3, 4, 72, and 96 h post-ROSC. At 3 and 4 h post-ROSC, LV systolic function was severely impaired, and high-sensitivity cardiac troponin T and N-terminal pro-atrial natriuretic peptide (NT-proANP) plasma concentrations were significantly increased, compared with control rats (P < 0.0001 for all). At 72 and 96 h post-ROSC, LV ejection fraction (LVEF) normalized. At 96 h, the following variables were significantly different from control rats: early trans-mitral peak velocity, 56.8 ± 3.1 vs. 87.8 ± 3.8 cm/s, P < 0.0001; late trans-mitral peak velocity, 50.6 ± 4.7 vs. 73.7 ± 4.2 cm/s, P < 0.0001; mean s' wave velocity, 4.6 ± 0.3 vs. 5.9 ± 0.3 cm/s, P < 0.0001, global longitudinal strain (GLS) -7.5 ± 0.5 and vs. -11 ± 1.2%, P < 0.01; GLS rate (GLSR) -0.9 ± 0.4 and -2.3 ± 0.2 1/s, P < 0.01; and NT-proANP concentration, 2.5 (0.2; 6.0) vs. 0.4 (0.01; 1.0) nmol/L, P < 0.01. s' velocity, GLS, and GLSR indicated that LV systolic function was still impaired 96 h post-ROSC. These findings agree with NT-proANP concentrations, which continue to be high. Normalization of LVEF supports the use of STE for its greater sensitivity for monitoring post-CA cardiac function. Further investigations are needed to provide evidence of the post-ROSC LV diastolic function pattern.

Discussion on the relationship between the disposal time of hypobaric oxygen chamber and the establishment of rat cardiac arrest model at high altitude

To establish the rat cardiac arrest model in high-altitude hypobaric hypoxia environment, and to explore the effect of the treatment time in the hypobaric oxygen chamber on the reproduction of high-altitude rat cardiac arrest model. SPF grade healthy male Sprague-Dawley (SD) rats were used as observation subjects. The experiment was conducted in two different altitude areas. The rats from the Plateau Branch of Institute of Cardiopulmonary and Cerebral Resuscitation of Sun Yat-sen University (Xining, Qinghai) were weighed and numbered, and they were placed in a hypobaric oxygen chamber (simulated altitude of 3 000 meters, speed of ascent and descent of 15 m/min, temperature of 20 centigrade, cabin pressure of 69.5 kPa, cabin oxygen pressure of 14.5 kPa). After 30 days of feeding, the rats were obtained according to random number table method, and the cardiac arrest model was established by asphyxia method as the 30-day hypobaric hypoxia group. After 60 days of feeding, rats were randomly selected again, and the cardiac arrest model was established as the 60-day hypobaric hypoxia group. Thirty rats were randomly selected from the Institute of Cardiopulmonary Cerebral Resuscitation at Sun Yat-sen University (Guangzhou, Guangdong) by the same method, and the cardiac arrest model was established as the plain control group. The differences in the body weight of rat modeling precursors and the induction time of asphyxia during the modeling process among different groups were compared. Finally, cardiac arrest model was established in 16 rats in the 30-day hypobaric hypoxia group and in 22 rats in the 60-day hypobaric hypoxia group. There was no significant difference in the body weight of rats before modeling among the plain control group, 30-day hypobaric hypoxia group and 60-day hypobaric hypoxia group [g: 429.00 (389.25, 440.75), 440.00 (415.50, 486.25), 440.00 (400.00, 452.50), all P > 0.05]. The asphyxia induction time of rats in the 60-day hypobaric hypoxia group was significantly longer than that in the 30-day hypobaric hypoxia group (s: 294.59±75.39 vs. 234.31±93.86, P < 0.01), even about 1.4 times of the plain control group (s: 294.59±75.39 vs. 208.73±30.88, P < 0.01). There was no significant difference in the asphyxia induction time between the 30-day hypobaric hypoxia group and the plain control group (P > 0.05). Rats treated in a hypobaric oxygen chamber for 60 days are more suitable for the preparation of high-altitude cardiac arrest model, and are also consistent with the oxygen reserve and hypoxia tolerance of high-altitude rats.

Endogenous orexin and hyperacute autonomic responses after resuscitation in a preclinical model of cardiac arrest.

The study of autonomic responses to cardiac arrest (CA) resuscitation deserves attention due to the impact of autonomic function on survival and arousal. Orexins are known to modulate autonomic function, but the role of endogenous orexin in hyperacute recovery of autonomic function post-resuscitation is not well understood. We hypothesized that endogenous orexin facilitates hyperacute cardiovascular sympathetic activity post-resuscitation, and this response could be attenuated by suvorexant, a dual orexin receptor antagonist. A well-established 7-min asphyxial CA rat model was studied. Heart rate (HR) and blood pressure were monitored from baseline to 90-min post-resuscitation. Autonomic function was evaluated by spectral analysis of HR variability, whereby the ratio of low- and high-frequency components (LF/HF ratio) represents the balance between sympathetic/parasympathetic activities. Plasma orexin-A levels and orexin receptors immunoreactivity in the rostral ventrolateral medulla (RVLM), the key central region for regulating sympathetic output, were measured post-resuscitation. Neurological outcome was assessed via neurologic-deficit score at 4-h post-resuscitation. A significant increase in HR was found over 25-40 min post-resuscitation (p < 0.01 vs. baseline), which was attenuated by suvorexant significantly (p < 0.05). Increased HR (from 15-to 25-min post-resuscitation) was correlated with better neurological outcomes (rs = 0.827, p = 0.005). There was no evident increase in mean arterial pressure over 25-40 min post-resuscitation, while systolic pressure was reduced greatly by suvorexant (p < 0.05). The LF/HF ratio was higher in animals with favorable outcomes than in animals injected with suvorexant over 30-40 min post-resuscitation (p < 0.05). Plasma orexin-A levels elevated at 15-min and peaked at 30-min post-resuscitation (p < 0.01 vs. baseline). Activated orexin receptors-immunoreactive neurons were found co-stained with tyrosine hydroxylase-immunopositive cells in the RVLM at 2-h post-resuscitation. Together, increased HR and elevated LF/HF ratio indicative of sympathetic arousal during a critical window (25-40 min) post-resuscitation are observed in animals with favorable outcomes. The orexin system appears to facilitate this hyperacute autonomic response post-CA.

COMPARISON BETWEEN ACTIVE ABDOMINAL COMPRESSION-DECOMPRESSION CARDIOPULMONARY RESUSCITATION AND STANDARD CARDIOPULMONARY RESUSCITATION IN ASPHYCTIC CARDIAC ARREST RATS WITH MULTIPLE RIB FRACTURES.

Background: Active abdominal compression-decompression cardiopulmonary resuscitation (AACD-CPR) is potentially more effective for cardiac arrest (CA) with multiple rib fractures. However, its effect on survival rates and neurological outcomes remains unknown. This study aimed to assess if AACD-CPR improves survival rates and neurological outcomes in a rat model of asphyctic CA with multiple rib fractures. Methods: Adult male Sprague-Dawley rats were randomized into three groups-AACD group (n = 15), standard cardiopulmonary resuscitation (STD-CPR) group (n = 15), and sham group (n = 10)-after bilateral rib fractures were surgically created and endotracheal intubation was performed. AACD-CPR and STD-CPR groups underwent 8 min of asphyxia followed by different CPR techniques. The sham group had venous catheterization only. Physiological variables and arterial blood gases were recorded at baseline and during a 4-h monitoring period. Neurological deficit scores (NDSs) and cumulative survival rates were assessed at 24, 48, and 72 h. NDS, serum biomarkers, and hippocampal neuron analysis were used to evaluate neurological outcomes. Results: No statistical differences were observed in the return of spontaneous circulation (ROSC), 24-, 48-, and 72-h survival rates between the AACD-CPR and STD-CPR groups. AACD-CPR rats had lower serum levels of neuron-specific enolase and S100B at 72 h post-ROSC, and higher NDS at 72 h post-ROSC compared with STD-CPR animals. Cellular morphology analysis, hematoxylin and eosin staining, and TUNEL/DAPI assays showed more viable neurons and fewer apoptotic neurons in the AACD-CPR group than in the STD-CPR group. Conclusions: AACD-CPR can achieve similar survival rates and better neurological outcome after asphyxial CA in rats with multiple rib fractures when compared with STD-CPR.

Protective effect of canagliflozin on post-resuscitation myocardial function in a rat model of cardiac arrest

BackgroundCurrently, most patients with cardiac arrest (CA) show reversible myocardial dysfunction, hemodynamic instability, systemic inflammation and other pathophysiological state in early stage of resuscitation, some patients may eventually progress to multiple organ failure. There is evidence that heart failure is the terminal stage in the development of various cardiovascular diseases. Although the cardio-protective effect of canagliflozin (CANA) has been confirmed in large clinical studies and recommended in domestic and international heart failure-related guidelines, the effectiveness of CANA after resuscitation remains unclear. In this study, we constructed a modified CA/CPR rat model to investigate whether CANA administered on post-resuscitation improves myocardial function.MethodsTwenty-fourth healthy male Sprague–Dawley rats were randomized into four groups: (1) Sham + placebo group, (2) Sham + CANA group, (3) CPR + placebo group, and (4) CPR + CANA group. Ventricular fibrillation was induced by transcutaneous electrical stimulation on epicardium. After 6 min untreated ventricular fibrillation, chest compressions was initiated. The rats were received an injection of placebo or canagliflozin (3 ug/kg) randomly 15 min after restore of spontaneous circulation (ROSC). Electrocardiogram (ECG) and blood pressure were continuously detected in each group throughout the experiment. The rats were killed 6 h after ROSC to collected the arterial serum and myocardial tissue. Myocardial injury was estimated with concentrations of inflammatory factors, oxidative stress indexes and, apoptosis index, myocardial injury markers, echocardiography and myocardial pathological slices.ResultsAfter resuscitation, mean arterial pressure (MAP) were significantly increased after cardiopulmonary resuscitation in CANA group rats when compared with placebo group. Heart rate, body lactate returned and left ventricular ejection fraction (LVEF) to normal levels in a shorter time and the myocardial injury was obviously attenuated in CPR + CANA group. Inflammatory factors (IL-6, TNF-α) and oxidative stress indexes (MAD, SOD, CAT) were dramatically decreased with the administration of CANA. The expression of apoptosis index (BAX, caspase-3) were higher in CPR + placebo group and the expression of anti-apoptosis index (Bcl-2) was lower (P < 0.05).ConclusionsThe administration of CANA effectively reduces myocardial ischaemia/reperfusion (I/R) injury after cardiac arrest and cardiopulmonary resuscitation (CPR), and the underlying mechanism may be related to anti-inflammation, oxidative stress and apoptosis.

Abstract 13281: The Combined Effect of Omecamtiv Mecarbil and Low-Dose Dobutamine for Post-Arrest Myocardial Dysfunction in a Rat Model of Cardiac Arrest

Introduction: Post-arrest myocardial dysfunction attributes unstable hemodynamic and mortality in successfully resuscitated cardiac arrest victims. Studies demonstrated that low-dose dobutamine (LDb) and Omecamtiv Mecarbil (OM) improved post-arrest myocardial dysfunction and neurological recovery, respectively. Hypothesis: Whether the combination of LDb and OM synergistically improves post-arrest myocardial dysfunction? Methods: Asphyxial cardiac arrest was induced in adult male wistar rats and left untreated for 9.5 minutes followed by cardiopulmonary resuscitation. Successfully resuscitated animal were randomized into control group (without medication), OM group(0.25 mg/kg/h), LDb group (5 micrograms/Kg/min), and OM+LDb group, in which drugs or normal saline were continuously intravenously infused for 4 hours. Hemodynamic were monitored for 4 h after return of spontaneous circulation. Survival status and neurological recovery were observed for 72 h. The difference of biomarkers, histological examinations and mitochondrial function of myocardium between groups were evaluated. Results: As compared with the control group, the OM, LDb, and OM+LDb groups all demonstrated improved left ventricular systolic function (dp/dt40), better cardiac output, lower Troponin-I, higher 72-h survival, and more favorable neurological recovery. The LDb group showed a higher dp/dt40 and cardiac output than the OM group, whereas OM+LDb group did not demonstrated significant benefit when compared to OM and LDb, respectively. The OM, LDb, and OM+LDb mitigated post-arrest myocardial damage and cardiac mitochondrial injury, and ameliorated myocardial and hippocampus apoptosis. However, the OM+LDb group showed no superiority to the OM group or LDb group. Conclusions: Both OM and LDb improved post-arrest myocardial dysfunction, cardiac mitochondrial injury, survival, neurological recovery following cardiac arrest. However, OM+LDb group did not exert synergistic effect in ameliorate post-arrest myocardial dysfunction.

Abstract 166: Novel Mechanism of Docosahexaenoic Acid Reducing Tissue Injury by Targeting Immune Cells and HMGB1 Release

Introduction: Dysregulated immune blood cell response has been implicated in contributing to brain injury following cardiac arrest (CA). Specifically, increased plasma HMGB1 has emerged as a critical mediator of brain damage. However, the underlying mechanisms of the dysregulated immune response and increased HMGB1 after CA remains unclear. Moreover, limited efforts have been made to develop therapeutic interventions targeting this dysregulated immune response. Objective: To elucidate the pathologic immune response during early phase of post-resuscitation and explore this as a targeted therapeutic potential using LPC(22:6), a previously shown neuroprotective compound. Methods and Results: We examined changes in lymphocytes, neutrophils, and monocytes in blood samples obtained from human CA patients. Subsequently, we conducted a time course study in rat CA model to examine changes in these cell populations and investigate the mechanisms underlying the increased HMGB1 levels in post-CA blood with/without plasma supplementation of LPC(22:6). We observed an increase in lymphocytes and neutrophils within one-hour post-resuscitation in human patients and rats. In rats, the increased levels of lymphocytes and neutrophils were followed by an increase in plasma HMGB1 level and monocytes. We further, identified that HMGB1 was significantly upregulated in CD4-positive cells, indicating that T cell-released HMGB1 is the primary source for its elevation. Intriguingly, supplementation of LPC(22:6) prevented the overexpression of HMGB1 in CD4-positive cells, the increase in plasma HMGB1 levels, and the number of monocytes. These findings support the sequential events of dysregulated blood immune response initiated by lymphocyte activation, leading to increased HMGB1 levels and subsequent monocyte activation during early phase of resuscitation after CA. Thus, our results demonstrate the efficacy of LPC(22:6) in inhibiting the expression of HMGB1 in CD4-positive T cells, thereby mitigating this inflammatory cascade. Conclusion: These findings provide novel insights into the mechanisms underlying the dysregulated immune response after CA and highlight the therapeutic potential of targeting this immune response to improve brain function.

A ventricular fibrillation cardiac arrest model with extracorporeal cardiopulmonary resuscitation in rats: 8 minutes arrest time leads to increased myocardial damage but does not increase neuronal damage compared to 6 minutes.

Extracorporeal cardiopulmonary resuscitation (ECPR) is an emerging strategy in highly selected patients with refractory cardiac arrest (CA). Animal models can help to identify new therapeutic strategies to improve neurological outcome and cardiac function after global ischemia in CA. Aim of the study was to establish a reproducible ECPR rat model of ventricular fibrillation CA (VFCA) that leads to consistent neuronal damage with acceptable long-term survival rates, which can be used for future research. Male Sprague Dawley rats were resuscitated with ECPR from 6 min (n = 15) and 8 min (n = 16) VFCA. Animals surviving for 14 days after return of spontaneous resuscitation (ROSC) were compared with sham operated animals (n = 10); neurological outcome was assessed daily until day 14. In the hippocampal cornu ammonis 1 region viable neurons were counted. Microglia and astrocyte reaction was assessed by Iba1 and GFAP immunohistochemistry, and collagen fibers in the myocardium were detected in Azan staining. QuPath was applied for quantification. Of the 15 rats included in the 6 min CA group, all achieved ROSC (100%) and 10 (67%) survived to 14 days; in the 8 min CA group, 15 (94%) achieved ROSC and 5 (31%) reached the endpoint. All sham animals (n = 10) survived 2 weeks. The quantity of viable neurons was significantly decreased, while the area displaying Iba1 and GFAP positive pixels was significantly increased in the hippocampus across both groups that experienced CA. Interestingly, there was no difference between the two CA groups regarding these changes. The myocardium in the 8 min CA group exhibited significantly more collagen fibers compared to the sham animals, without differences between 6- and 8-min CA groups. However, this significant increase was not observed in the 6 min CA group. Our findings indicate a uniform occurrence of neuronal damage in the hippocampus across both CA groups. However, there was a decrease in survival following an 8-min CA. Consequently, a 6-min duration of CA resulted in predictable neurological damage without significant cardiac damage and ensured adequate survival rates up to 14 days. This appears to offer a reliable model for investigating neuroprotective therapies.

13 Therapeutic administration of risperidone attenuates renal oxidative stress following whole-body ischemia and reperfusion injury in a rat model of cardiac arrest

13 Therapeutic administration of risperidone attenuates renal oxidative stress following whole-body ischemia and reperfusion injury in a rat model of cardiac arrest

309 Argon attenuates myocardial injury by modulation of mitochondrial quality control processes in a rat model of cardiac arrest

309 Argon attenuates myocardial injury by modulation of mitochondrial quality control processes in a rat model of cardiac arrest

Alterations of the gut microbial community structure modulates the Th17 cells response in a rat model of asphyxial cardiac arrest

Th17 cells triggered inflammation is a critical element in cerebral ischemic injury, and the gut microbiota intricately impacts T lymphocytes. Nevertheless, it remains unclear whether the gut microbiota involves in cardiac arrest/cardiopulmonary resuscitation (CA/CPR) induced-brain injury through Th17 cells. The present study investigated the interaction between gut microbiota and Th17 cells in a rat model. We observed that CA/CPR induced the alterations of the gut microbial community structure, and elevated the level of IL-17 in the serum, and a slight infiltration of Th17 cells into the brain. The Th17 cells were increased significantly in the peripheral blood, 28.33 ± 6.18% of these Th17 cells were derived from the Peyer’s patches of small intestine. Furthermore, fecal microbiota transplantation (FMT) from rats with CA/CPR induced Th17 cell response, promoting hippocampal cell apoptosis and declining learning ability and memory in recipient rats. Taken together, CA/CPR-induced alterations of the gut microbial community structure stimulated Th17 cell response which aggravated brain injury.