Abstract P15: Periodic Acceleration (pGz) Preconditioning in Swine Increases Endothelial Derived NO and Phosphorylated eNOS via Akt Pathway

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jose A Adams ◽  
Jaqueline Arias ◽  
Jorge Bassuk ◽  
Heng Wu ◽  
Arkady Uryash ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Myocardial Stunning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Spontaneous Circulation ◽  
Akt Pathway ◽  
Phosphorylated Akt ◽  
Manual Chest Compression ◽  
Periodic Acceleration ◽  
Pulsatile Shear Stress

Periodic acceleration (pGz) is the motion of the supine body using a motorized platform (3Hz & ±0.4G). pGz produces pulsatile shear stress increasing release of endothelial derived NO (eNO) which, also decreases myocardial stunning and improves outcomes from ventricular fibrillation (VF) cardiac arrest. Preconditioning with pGz (PRE-pGz) prior to VF cardiac arrest ameliorates global post resuscitation cardiac dysfunction and reduces arrhythmias. To test whether pGz and PRE-pGz increase eNOS and phosphorylated eNOS (p-eNOS) via the PI3-kinase-Akt pathway, anesthetized, intubated male swine (40 –50lbs) were studied. Five animals had no intervention (BL) and 5 received 1 hr pGz preconditioning (pGz) followed by Western Blot of myocardial tissue. Additional animals (10 per group) received 1 hr pGz (PRE-pGz) or no treatment (CPR-CONT). In the latter groups VF was electrically induced and unsupported for 8 min followed by continuous manual chest compression and defibrillation for 10 min or until return of spontaneous circulation (ROSC). PRE-pGz animals showed less hemodynamically significant arrhythmias after ROSC than CPR-CONT (35 vs 7; p<0.05) and less myocardial stunning. eNOS and phosphorylated-eNOS (p-eNOS) significantly increased after pGz and after CPR but were significantly higher in pGz preconditioned animals along with increased phosphorylated Akt (p-Akt). The graph below shows % changes relative to BL (M±SD). *p < 0.01 PRE-pGz vs CPR-CONT. Conclusion: pGz applied prior to ischemia reperfusion injury increases eNOS and p-eNOS expression and increased p-Akt. Thus, pGz preconditioning protects myocardium during I-R in part by activating eNOS through p-Akt

Abstract 107: Mitochondrial Dysfunction Mediated Myocardial Stunning Following Resuscitation From Cardiac Arrest

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Willard W Sharp ◽  
Lin Piao ◽  
Yong Fang ◽  
David G Beiser ◽  
James K Liao ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Myocardial Stunning ◽  
Mitochondrial Dynamics ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Myocardial Necrosis ◽  
Spontaneous Circulation ◽  
Contractile Dysfunction ◽  
Myocardial Contractile ◽  
Induced Changes

Rationale: Severe myocardial contractile dysfunction following resuscitation from cardiac arrest (CA) is a major contributor to CA mortality. The pathophysiology and etiology of this dysfunction is not known and there are no pharmacological therapies known to improve outcomes. Previously, we demonstrated that Dynamin related protein 1 (Drp1) is activated and recruited to the mitochondria during CA and that the Drp1 inhibitor Mdivi-1 improves post CA survival. Objective: To determine the effects of CA length on myocardial and mitochondrial function. We also sought to determine the effects of Mdivi-1 on post CA outcomes. Methods and Results: Asystolic cardiac arrest (CA) was induced in mice by IV injection of 0.08 mg/g KCL. CPR begun at 4, 8, 12, and 16 minutes post-cardiac arrest had rates of return of spontaneous circulation (ROSC) of 100%(12/12), 93%(14/15), 71%(10/14), and 44% (4/9) and 2-hour survival of 100%(12/12), 67%(10/15), 50%(7/14), and 11%(1/9). Transthoracic echocardiography 15 min post-resuscitation demonstrated percent fractional shortening of 36±4% (Sham,n=6), 30±4% (4 minCA,n=11), 24±5% (8minCA,n=10), 15±2% (12minCA,n=12). In surviving animals, myocardial dysfunction persisted for 2 hours post-resuscitation, but slowly recovered to baseline by 72 hours. No evidence of myocardial necrosis, inflammation, or apoptosis was noted following resuscitation. Progressive increases in mitochondrial derived reactive oxygen species (ROS) during CA was observed by MitoSOX red myocardial tissue staining. Mitochondria isolated from 12 min CA hearts demonstrated decreased substrate coupled and uncoupled respiration. Mdivi-1, a mitochondrial inhibitor of division (fission), improved survival and neurological scores in mice following an 8 min cardiac arrest compared to controls. Conclusions: Severe, time dependent myocardial stunning (contractile dysfunction in the absence of irreversible injury) was observed following asystolic cardiac arrest. This myocardial stunning was associated with mitochondrial injury and improved by an inhibitor of Drp1. Strategies targeting ischemia/reperfusion-induced changes in mitochondrial dynamics hold promise for improving myocardial function and survival following cardiac arrest.

Abstract 296: Adult Swine Model of Ventricular Fibrillation Arrest for Resuscitation with Perfluorocarbon Emulsions

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_4) ◽  
Author(s):  
Travis W Murphy ◽  
Jiepei Zhu ◽  
Travis Parsons ◽  
Bruce D Spiess ◽  
Torben K Becker
Keyword(s):  
Cardiac Arrest ◽  
Ventricular Fibrillation ◽  
Minimally Invasive ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Circulatory Arrest ◽  
Spontaneous Circulation ◽  
Blood Levels ◽  
Swine Model ◽  
Initial Attempt

Background: The purpose of this study was to develop a model of ventricular fibrillation arrest with reliable outcomes and minimally invasive methods to study the use of perfluorocarbon emulsions (PFC) as agents to prevent ischemia-reperfusion injury after cardiac arrest as quantified by known biomarkers. Methods: Female Yorkshire swine underwent anesthesia and minimally invasive instrumentation for monitoring under ultrasound. Cardiac arrest was induced with spinal needle insertion at the apex and right parasternal space. Ventricular fibrillation was reliably obtained in all animals on initial attempts. A three-minute circulatory arrest state was observed. Administration of PFC was concurrent with resuscitation including closed chest compressions, epinephrine, amiodarone, and defibrillation at 1J/kg. Primary endpoint was induction of cardiac arrest and tolerance of PFC with return of spontaneous circulation. Blood levels of glial fibrillary acidic protein (GFAP) and ubiquitin C-Terminal Hydrolase-L1 (UCLH1) were secondary end points for three animals. Results: Six of six animals were induced into ventricular fibrillation on initial attempt and two of three survival experiments were able to obtain spontaneous circulation. PFC with pretreatment was tolerated well and no signs of increased pulmonary pressures. GFAP, UCHL1 were significantly lower in intervention animals compared to controls. Conclusions: The results obtained from this preliminary study and technical refinements via additional donated animals have allowed us to make modifications in the choice of PFC, vascular access, and anticoagulation plan. This model provides a consistent method for inducing ventricular fibrillation with minimally invasive techniques. The PFC tested was well tolerated. More robust evaluation of PFC as resuscitative agents is needed with appropriately powered studies.

scholarly journals Comparing anesthesia with isoflurane and fentanyl/fluanisone/midazolam in a rat model of cardiac arrest

2017 ◽  
Vol 123 (4) ◽  
pp. 867-875 ◽  
Author(s):  
Niels Secher ◽  
Christian Lind Malte ◽  
Else Tønnesen ◽  
Leif Østergaard ◽  
Asger Granfeldt
Keyword(s):  
Cardiac Arrest ◽  
Reperfusion Injury ◽  
Perfusion Pressure ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coronary Perfusion Pressure ◽  
Spontaneous Circulation ◽  
Coronary Perfusion ◽  
Return Of Spontaneous Circulation ◽  
Arterial Blood

Only one in ten patients survives cardiac arrest (CA), underscoring the need to improve CA management. Isoflurane has shown cardio- and neuroprotective effects in animal models of ischemia-reperfusion injury. Therefore, the beneficial effect of isoflurane should be tested in an experimental CA model. We hypothesize that isoflurane anesthesia improves short-term outcome following resuscitation from CA compared with a subcutaneous fentanyl/fluanisone/midazolam anesthesia. Male Sprague-Dawley rats were randomized to anesthesia with isoflurane ( n = 11) or fentanyl/fluanisone/midazolam ( n = 11). After 10 min of asphyxial CA, animals were resuscitated by mechanical chest compressions, ventilations, and epinephrine and observed for 30 min. Hemodynamics, including coronary perfusion pressure, systemic O2 consumption, and arterial blood gases, were recorded throughout the study. Plasma samples for endothelin-1 and cathecolamines were drawn before and after CA. Compared with fentanyl/fluanisone/midazolam anesthesia, isoflurane resulted in a shorter time to return of spontaneous circulation (ROSC), less use of epinephrine, increased coronary perfusion pressure during cardiopulmonary resusitation, higher mean arterial pressure post-ROSC, increased plasma levels of endothelin-1, and decreased levels of epinephrine. The choice of anesthesia did not affect ROSC rate or systemic O2 consumption. Isoflurane reduces time to ROSC, increases coronary perfusion pressure, and improves hemodynamic function, all of which are important parameters in CA models. NEW & NOTEWORTHY The preconditioning effect of volatile anesthetics in studies of ischemia-reperfusion injury has been demonstrated in several studies. This study shows the importance of anesthesia in experimental cardiac arrest studies as isoflurane raised coronary perfusion pressure during resuscitation, reduced time to return of spontaneous circulation, and increased arterial blood pressure in the post-cardiac arrest period. These effects on key outcome measures in cardiac arrest research are important in the interpretation of results from animal studies.

Abstract 16996: Controlled Pauses (“Stutter”) CPR Did Not Improve ROSC or 4-hour Survival in a Porcine Model of VF-induced Cardiac Arrest

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Alexander Esibov ◽  
Tyson G Taylor ◽  
Sharon B Melnick ◽  
Fred W Chapman ◽  
Gregory P Walcott
Keyword(s):  
Cardiac Arrest ◽  
Neurological Outcome ◽  
Porcine Model ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Survival Rates ◽  
Data Gathering ◽  
Aortic Pressure ◽  
Spontaneous Circulation ◽  
Mechanical Cpr

Introduction: Ischemic post-conditioning (IPC) has shown promise in mitigating ischemia-reperfusion injury. Controlled pauses during CPR (CP-CPR) following cardiac arrest (CA) and prolonged downtime may help invoke IPC mechanisms and have been shown to improve neurological outcome in swine. We tested whether CP-CPR would improve return of spontaneous circulation (ROSC) and/or 4-hr survival rates, compared with standard CPR from a mechanical chest compression device (M-CPR), following prolonged downtime in a porcine model of ventricular fibrillation (VF)-induced CA. Methods: Twenty anesthetized and instrumented pigs were block randomized to two protocols. Following 10 min of VF, mechanical CPR was initiated (100 comp/min, 50% duty cycle, 2 inch depth). Over the first 5 minutes of CPR, the M-CPR protocol group received continuous chest compressions, while the CP-CPR protocol included four 20-sec pauses in compressions starting at 40, 100, 160, and 220 sec. All other interventions were the same in the two groups. After 5 minutes, a first shock was delivered during a pause. If the shock failed to convert to a perfusing rhythm for ≥ 30 s with a systolic aortic pressure (sAoP) ≥ 50 mmHg for at least the first three contiguous sAoP values, CPR was continued in 2 min cycles, followed by a shock (if indicated) at the end of each cycle, for up to 10 cycles. As soon as these criteria were met between two CPR cycles, ROSC was documented and a post-resuscitation protocol was initiated. During the post-resuscitation protocol, inotropic agents were provided as needed to maintain sAoP ≥ 50 mmHg. Survival was declared if the sAoP was maintained above threshold for 4 hrs following ROSC. Results: Nineteen animals were successfully instrumented for data gathering (9 CP-CPR, 10 M-CPR). In the CP-CPR and M-CPR groups respectively, 3/9 (33%) vs. 5/10 (50%) achieved ROSC (p = 0.46); when ROSC was achieved, time to ROSC was 7.7±1.2 min vs. 5.8±1.1 min (p = 0.08). All animals that achieved ROSC survived to 4 hours. Conclusions: In a porcine model of CA following prolonged VF, CP-CPR did not improve ROSC or 4-hr survival. The trend towards delayed time to ROSC suggests controlled pauses may impair initial resuscitation, even if they ultimately improve neurological outcome. Further studies are warranted.

scholarly journals Mild Hypothermia Inhibits Systemic and Cerebral Complement Activation in a Swine Model of Cardiac Arrest

2015 ◽  
Vol 35 (8) ◽  
pp. 1289-1295 ◽  
Author(s):  
Ping Gong ◽  
g Zhao ◽  
Rong Hua ◽  
Mingyue Zhang ◽  
Ziren Tang ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Complement Activation ◽  
Ischemia Reperfusion Injury ◽  
Mild Hypothermia ◽  
Ischemia Reperfusion ◽  
Spontaneous Circulation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Swine Model ◽  
Factor Α ◽  
Necrosis Factor

Complement activation has been implicated in ischemia/reperfusion injury. This study aimed to determine whether mild hypothermia (HT) inhibits systemic and cerebral complement activation after resuscitation from cardiac arrest. Sixteen minipigs resuscitated from 8 minutes of untreated ventricular fibrillation were randomized into two groups: HT group ( n = 8), treated with HT (33 °C) for 12 hours; and normothermia group ( n = 8), treated similarly as HT group except for cooling. Blood samples were collected at baseline and 0.5, 6, 12, and 24 hours after return of spontaneous circulation (ROSC). The brain cortex was harvested 24 hours after ROSC. Complement and pro-inflammatory markers were detected using enzyme-linked immunosorbent assay. Neurologic deficit scores were evaluated 24 hours after ROSC. C1q, Bb, mannose-binding lectin (MBL), C3b, C3a, C5a, interleukin-6, and tumor necrosis factor- α levels were significantly increased under normothermia within 24 hours after ROSC. However, these increases were significantly reduced by HT. Hypothermia decreased brain C1q, MBL, C3b, and C5a contents 24 hours after ROSC. Hypothermic pigs had a better neurologic outcome than normothermic pigs. In conclusion, complement is activated through classic, alternative, and MBL pathways after ROSC. Hypothermia inhibits systemic and cerebral complement activation, which may provide an additional mechanism of cerebral protection.

scholarly journals Catalase Predicts In-Hospital Mortality after Out-of-Hospital Cardiac Arrest

2021 ◽  
Vol 10 (17) ◽  
pp. 3906
Author(s):  
Anton Früh ◽  
Andrea Bileck ◽  
Besnik Muqaku ◽  
Raphael Wurm ◽  
Benjamin Neuditschko ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Plasma Levels ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Plasma ◽  
Spontaneous Circulation ◽  
Multiple Organ ◽  
Kaplan Meier ◽  
Median Plasma ◽  
Hospital Cardiac Arrest

The generation of harmful reactive oxygen species (ROS), including hydrogen peroxide, in out-of-hospital cardiac arrest (OHCA) survivors causes systemic ischemia/reperfusion injury that may lead to multiple organ dysfunction and mortality. We hypothesized that the antioxidant enzyme catalase may attenuate these pathophysiological processes after cardiac arrest. Therefore, we aimed to analyze the predictive value of catalase levels for mortality in OHCA survivors. In a prospective, single-center study, catalase levels were determined in OHCA survivors 48 h after the return of spontaneous circulation. Thirty-day mortality was defined as the study end point. A total of 96 OHCA survivors were enrolled, of whom 26% (n = 25) died within the first 30 days after OHCA. The median plasma intensity levels (log2) of catalase were 8.25 (IQR 7.64–8.81). Plasma levels of catalase were found to be associated with mortality, with an adjusted HR of 2.13 (95% CI 1.07–4.23, p = 0.032). A Kaplan–Meier analysis showed a significant increase in 30-day mortality in patients with high catalase plasma levels compared to patients with low catalase levels (p = 0.012). High plasma levels of catalase are a strong and independent predictor for 30-day mortality in OHCA survivors. This indicates that ROS-dependent tissue damage is playing a crucial role in fatal outcomes of post-cardiac syndrome patients.

scholarly journals LncRNA LSINCT5/miR-222 regulates myocardial ischemia‑reperfusion injury through PI3K/AKT pathway

2021 ◽  
Author(s):  
Xueying Tong ◽  
Jiajuan Chen ◽  
Wei Liu ◽  
Hui Liang ◽  
Hezhong Zhu
Keyword(s):  
Myocardial Ischemia ◽  
Cell Viability ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Akt Signaling Pathway ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

AbstractCardiovascular diseases rank the top cause of morbidity and mortality worldwide and are usually associated with blood reperfusion after myocardial ischemia/reperfusion injury (MIRI), which often causes severe pathological damages and cardiomyocyte apoptosis. LSINCT5 expression in the plasma of MI patients (n = 53), healthy controls (n = 42) and hypoxia-reoxygenation (HR)-treated cardiomyocyte AC16 cells was examined using qRT-PCR. The effects of LSINCT5 on cell viability and apoptosis were detected by MTT and flow cytometry, respectively. The expression of apoptosis-related proteins Bcl2, Bax and caspase 3 were tested by Western blot. The interaction between LSINCT5 and miR-222 was predicted by bioinformatic analysis. Moreover, changes in viability and apoptosis of AC16 cells co-transfected with siLSINCT5 and miR-222 inhibitor after HR treatment were examined. At last, the expression of proteins in PI3K/AKT pathway, namely PTEN, PI3K and AKT, was examined to analyze the possible pathway participating in LSINCT5-mediated MI/RI. Our study showed that LSINCT5 expression was upregulated in the plasma of MI patients and HR-treated AC16 cells. LSINCT5 overexpression significantly decreased cell viability and apoptosis. Luciferase reporter gene assay and RNA pulldown assay showed that LSINCT5 was a molecular sponge of miR-222. MiR-222 silencing in AC16 cells simulated the phenotypes of MIRI patients and HR-treated cells, indicating that LSINCT5 functions via miR-222 to regulate proliferation and apoptosis of HR-treated AC16 cells. We also showed that proteins of PI3K/AKT signaling pathway were affected in HR-treated AC16 cells, and LSINTC5 knockdown rescued these effects. LncRNA LSINCT5 was upregulated during MI pathogenesis, and LSINCT5 regulated MIRI possibly via a potential LSINCT5/miR-222 axis and PI3K/AKT signaling pathway. Our findings may provide novel evidence for MIRI prevention.

scholarly journals Overexpression of SP1 restores autophagy to alleviate acute renal injury induced by ischemia-reperfusion through the miR-205/PTEN/Akt pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Chong Huang ◽  
Yan Chen ◽  
Bin Lai ◽  
Yan-Xia Chen ◽  
Cheng-Yun Xu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Akt Pathway ◽  
Acute Renal Injury ◽  
Injury Model ◽  
Renal Ischemia Reperfusion Injury

Abstract Background Acute kidney injury (AKI) is a major kidney disease with poor clinical outcome. SP1, a well-known transcription factor, plays a critical role in AKI and subsequent kidney repair through the regulation of various cell biologic processes. However, the underlying mechanism of SP1 in these pathological processes remain largely unknown. Methods An in vitro HK-2 cells with anoxia-reoxygenation injury model (In vitro simulated ischemic injury disease) and an in vivo rat renal ischemia-reperfusion injury model were used in this study. The expression levels of SP1, miR-205 and PTEN were detected by RT-qPCR, and the protein expression levels of SP1, p62, PTEN, AKT, p-AKT, LC3II, LC3I and Beclin-1 were assayed by western blot. Cell proliferation was assessed by MTT assay, and the cell apoptosis was detected by flow cytometry. The secretions of IL-6 and TNF-α were detected by ELISA. The targeted relationship between miR-205 and PTEN was confirmed by dual luciferase report assay. The expression and positioning of LC-3 were observed by immunofluorescence staining. TUNEL staining was used to detect cell apoptosis and immunohistochemical analysis was used to evaluate the expression of SP1 in renal tissue after ischemia-reperfusion injury in rats. Results The expression of PTEN was upregulated while SP1 and miR-205 were downregulated in renal ischemia-reperfusion injury. Overexpression of SP1 protected renal tubule cell against injury induced by ischemia-reperfusion via miR-205/PTEN/Akt pathway mediated autophagy. Overexpression of SP1 attenuated renal ischemia-reperfusion injury in rats. Conclusions SP1 overexpression restored autophagy to alleviate acute renal injury induced by ischemia-reperfusion through the miR-205/PTEN/Akt pathway.

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