A novel pharmacological strategy by PTEN inhibition for improving metabolic resuscitation and survival after mouse cardiac arrest

Sudden cardiac arrest (SCA) is a leading cause of death in the United States. Despite return of spontaneous circulation, patients die due to post-SCA syndrome that includes myocardial dysfunction, brain injury, impaired metabolism, and inflammation. No medications improve SCA survival. Our prior work suggests that optimal Akt activation is critical for cooling protection and SCA recovery. Here, we investigate a small inhibitor of PTEN, an Akt-related phosphatase present in heart and brain, as a potential therapy in improving cardiac and neurological recovery after SCA. Anesthetized adult female wild-type C57BL/6 mice were randomized to pretreatment of VO-OHpic (VO) 30 min before SCA or vehicle control. Mice underwent 8 min of KCl-induced asystolic arrest followed by CPR. Resuscitated animals were hemodynamically monitored for 2 h and observed for 72 h. Outcomes included heart pressure-volume loops, energetics (phosphocreatine and ATP from 31P NMR), protein phosphorylation of Akt, GSK3β, pyruvate dehydrogenase (PDH) and phospholamban, circulating inflammatory cytokines, plasma lactate, and glucose as measures of systemic metabolic recovery. VO reduced deterioration of left ventricular maximum pressure, maximum rate of change in the left ventricular pressure, and Petco2 and improved 72 h neurological intact survival (50% vs. 10%; P < 0.05). It reduced plasma lactate, glucose, IL-1β, and Pre-B cell colony enhancing factor, while increasing IL-10. VO increased phosphorylation of Akt and GSK3β in both heart and brain, and cardiac phospholamban phosphorylation while reducing p-PDH. Moreover, VO improved cardiac bioenergetic recovery. We concluded that pharmacologic PTEN inhibition enhances Akt activation, improving metabolic, cardiovascular, and neurologic recovery with increased survival after SCA. PTEN inhibitors may be a novel pharmacologic strategy for treating SCA.

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Abstract 87: Cyclosporin A does not Prevent Myocardial Dysfunction after Resuscitation from Cardiac Arrest in Rats

Circulation ◽

10.1161/circ.116.suppl_16.ii_941-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Iyad M Ayoub ◽

Jeejabai Radhakrishnan ◽

Raúl J Gazmuri

Keyword(s):

Cardiac Arrest ◽

Cyclosporin A ◽

Chest Compression ◽

Rat Model ◽

Mitochondrial Permeability Transition ◽

Myocardial Dysfunction ◽

Left Ventricular ◽

List Type ◽

Ischemia And Reperfusion ◽

Biphasic Waveform

Objective: We have previously reported in a rat model of VF and closed-chest resuscitation that cytochrome c is released into the bloodstream after resuscitation from cardiac arrest attaining plasma levels inversely proportional to survival. Recent evidence indicates that release of cytochrome c during ischemia and reperfusion may be a manifestation of prolonged opening of the mitochondrial permeability transition pore (mPTP). In this study, we investigated whether cyclosporin A (CsA, an inhibitor of mPTP opening) can prevent post-resuscitation (PR) myocardial dysfunction and improve survival. Methods: VF was electrically induced and left untreated for 10 mins. Resuscitation was attempted by 8 mins of chest compression followed by biphasic waveform defibrillation. Rats were randomized to received a bolus CsA (10 mg/kg) five minutes before inducing VF (n=6), immediately before starting chest compression (n=6), or to receive vehicle control before inducing VF (n=3) or before starting chest compression (n=3). CsA-treated (n=12) and vehicle-treated (n=6) rats were pooled for this analysis after noticing no differences between subgroups. Resuscitated rats were monitored for up to 6 hours. Results: All rats were successfully resuscitated. Treatment with CsA did not improve PR myocardial function (Table ). Survival time was comparable between CsA-treated (321±67 mins) and vehicle-treated (331±67 mins) rats. Conclusions: In our rat model of VF and resuscitation, CsA failed to prevent PR myocardial dysfunction and improve survival. These data contrast with numerous studies demonstrating a protective effect in isolated heart models of ischemia and reperfusion. Two possible explanations are the mPTP does not open in this unique setting of cardiac arrest and resuscitation, and the optimal in vivo dose of CsA needs to be determined as the protective effects of CsA are dose dependent. Hemodynamic and Left Ventricular Function

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Post–Cardiac Arrest Syndrome

AACN Advanced Critical Care ◽

10.4037/aacnacc2020535 ◽

2020 ◽

Vol 31 (4) ◽

pp. 383-393

Author(s):

Linda Dalessio

Keyword(s):

Cardiac Arrest ◽

Myocardial Dysfunction ◽

The United States ◽

Spontaneous Circulation ◽

Clinical State ◽

Precipitating Factors ◽

Patient Health ◽

Global Brain ◽

The Brain ◽

Post Cardiac Arrest Syndrome

More than 356 000 out-of-hospital cardiac arrests occur in the United States annually. Complications involving post–cardiac arrest syndrome occur because of ischemic-reperfusion injury to the brain, lungs, heart, and kidneys. Post–cardiac arrest syndrome is a clinical state that involves global brain injury, myocardial dysfunction, macrocirculatory dysfunction, increased vulnerability to infection, and persistent precipitating pathology (ie, the cause of the arrest). The severity of outcomes varies and depends on precipitating factors, patient health before cardiac arrest, duration of time to return of spontaneous circulation, and underlying comorbidities. In this article, the pathophysiology and treatment of post–cardiac arrest syndrome are reviewed and potential novel therapies are described.

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Severe Myocardial Dysfunction after Non-Ischemic Cardiac Arrest: Effectiveness of Percutaneous Assist Devices

Journal of Clinical Medicine ◽

10.3390/jcm10163623 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3623

Author(s):

Stéphane Manzo-Silberman ◽

Christoph Nix ◽

Andreas Goetzenich ◽

Pierre Demondion ◽

Chantal Kang ◽

...

Keyword(s):

Cardiac Arrest ◽

Myocardial Dysfunction ◽

Left Ventricular ◽

Ventricular Assist Devices ◽

Left Ventricular Ejection ◽

Ventricular Assist ◽

Ventricular Ejection Fraction ◽

Assist Devices ◽

Significant Difference ◽

Left Ventricular Assist

Introduction: Despite the improvements in standardized cardiopulmonary resuscitation, survival remains low, mainly due to initial myocardial dysfunction and hemodynamic instability. Our goal was to compare the efficacy of two left ventricular assist devices on resuscitation and hemodynamic supply in a porcine model of ventricular fibrillation (VF) cardiac arrest. Methods: Seventeen anaesthetized pigs had 12 min of untreated VF followed by 6 min of chest compression and boluses of epinephrine. Next, a first defibrillation was attempted and pigs were randomized to any of the three groups: control (n = 5), implantation of an percutaneous left ventricular assist device (Impella, n = 5) or extracorporeal membrane oxygenation (ECMO, n = 7). Hemodynamic and myocardial functions were evaluated invasively at baseline, at return of spontaneous circulation (ROSC), after 10–30–60–120–240 min post-resuscitation. The primary endpoint was the rate of ROSC. Results: Only one of 5 pigs in the control group, 5 of 5 pigs in the Impella group, and 5 of 7 pigs in the ECMO group had ROSC (p < 0.05). Left ventricular ejection fraction at 240 min post-resuscitation was 37.5 ± 6.2% in the ECMO group vs. 23 ± 3% in the Impella group (p = 0.06). No significant difference in hemodynamic parameters was observed between the two ventricular assist devices. Conclusion: Early mechanical circulatory support appeared to improve resuscitation rates in a shockable rhythm model of cardiac arrest. This approach appears promising and should be further evaluated.

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Successful Use of Therapeutic Hypothermia in a Pregnant Patient

Texas Heart Institute Journal ◽

10.14503/thij-14-4331 ◽

2015 ◽

Vol 42 (4) ◽

pp. 367-371 ◽

Cited By ~ 5

Author(s):

Kevin N. Oguayo ◽

Ola O. Oyetayo ◽

David Stewart ◽

Steven M. Costa ◽

Richard O. Jones

Keyword(s):

Cardiac Arrest ◽

Therapeutic Hypothermia ◽

Multidisciplinary Approach ◽

Short Term Memory ◽

Memory Loss ◽

Pregnant Patient ◽

The United States ◽

Successful Outcome ◽

Neurologic Recovery ◽

Hospital Cardiac Arrest

Out-of-hospital cardiac arrest is a leading cause of death in the United States. Pregnant women are not immune to cardiac arrest, and the treatment of such patients can be difficult. Pregnancy is a relative contraindication to the use of therapeutic hypothermia after cardiac arrest. A 20-year-old woman who was 18 weeks pregnant had an out-of-hospital cardiac arrest. Upon her arrival at the emergency department, she was resuscitated and her circulation returned spontaneously, but her score on the Glasgow Coma Scale was 3. After adequate family discussion of the risks and benefits of therapeutic hypothermia, a decision was made to initiate therapeutic hypothermia per established protocol for 24 hours. The patient was successfully cooled and rewarmed. By the time she was discharged, she had experienced complete neurologic recovery, apart from some short-term memory loss. Subsequently, at 40 weeks, she delivered vaginally a 7-lb 3-oz girl whose Apgar scores were 8 and 9, at 1 and 5 minutes respectively. To our knowledge, this is only the 3rd reported case of a successful outcome following the initiation of therapeutic hypothermia for out-of-hospital cardiac arrest in a pregnant woman. On the basis of this and previous reports of successful outcomes, we recommend that therapeutic hypothermia be considered an option in the management of out-of-hospital cardiac arrest in the pregnant population. To facilitate a successful outcome, a multidisciplinary approach involving cardiology, emergency medicine, obstetrics, and neurology should be used.

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Post-cardiac arrest syndrome in adult hospitalized patients

Colombian Journal of Anesthesiology ◽

10.5554/22562087.e972 ◽

2021 ◽

Author(s):

Estivalis G. Acosta-Gutiérrez ◽

Andrés M. Alba-Amaya ◽

Santiago Roncancio-Rodríguez ◽

José Ricardo Navarro-Vargas

Keyword(s):

Cardiac Arrest ◽

Latin American ◽

Myocardial Dysfunction ◽

Spontaneous Circulation ◽

Neurologic Recovery ◽

One Year ◽

Meta Analyses ◽

Post Cardiac Arrest Syndrome ◽

Hospital Cardiac Arrest

Adult In-hospital Cardiac Arrest (IHCA) is defined as the loss of circulation of an in-patient. Following high-quality cardiopulmonary resuscitation (CPR), if the return of spontaneous circulation (ROSC) is achieved, the post-cardiac arrest syndrome develops (PCAS). This review is intended to discuss the current diagnosis and treatment of PCAS. To approach this topic, a bibliography search was conducted through direct digital access to the scientific literature published in English and Spanish between 2014 and 2020, in MedLine, SciELO, Embase and Cochrane. This search resulted in 248 articles from which original articles, systematic reviews, meta-analyses and clinical practice guidelines were selected for a total of 56 documents. The etiologies may be divided into 56% of in-hospital cardiac, and 44% of non-cardiac arrests. The incidence of this physiological collapse is up to 1.6 cases/1,000 patients admitted, and its frequency is higher in the intensive care units (ICU), with an overall survival rate of 13% at one year. The primary components of PCAS are brain injury, myocardial dysfunction and the persistence of the precipitating pathology. The mainstays for managing PCAS are the prevention of cardiac arrest, ventilation support, control of peri-cardiac arrest arrythmias, and interventions to optimize neurologic recovery. A knowledgeable healthcare staff in PCAS results in improved patient survival and future quality of life. Finally, there is clear need to do further research in the Latin American Population.

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Myocardial Dysfunction and Shock after Cardiac Arrest

BioMed Research International ◽

10.1155/2015/314796 ◽

2015 ◽

Vol 2015 ◽

pp. 1-14 ◽

Cited By ~ 60

Author(s):

Jacob C. Jentzer ◽

Meshe D. Chonde ◽

Cameron Dezfulian

Keyword(s):

Cardiac Arrest ◽

Ischemia Reperfusion Injury ◽

Systolic Function ◽

Myocardial Dysfunction ◽

Ischemia Reperfusion ◽

Left Ventricular Systolic Function ◽

Left Ventricular ◽

Contributing Factors ◽

Vasopressor Support ◽

Cytokine Activation

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies.

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Cardiopulmonary resuscitation in a rat model of chronic myocardial ischemia

Journal of Applied Physiology ◽

10.1152/japplphysiol.01487.2005 ◽

2006 ◽

Vol 101 (4) ◽

pp. 1091-1096 ◽

Cited By ~ 15

Author(s):

Xiangshao Fang ◽

Wanchun Tang ◽

Shijie Sun ◽

Lei Huang ◽

Yun-Te Chang ◽

...

Keyword(s):

Cardiac Arrest ◽

Coronary Artery ◽

Cardiopulmonary Resuscitation ◽

Myocardial Ischemia ◽

Rat Model ◽

Myocardial Dysfunction ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Control Group ◽

Chronic Myocardial Ischemia

Our group has developed a rat model of cardiac arrest and cardiopulmonary resuscitation (CPR). However, the current rat model uses healthy adult animals. In an effort to more closely reproduce the event of cardiac arrest and CPR in humans with chronic coronary disease, a rat model of coronary artery constriction was investigated during cardiac arrest and CPR. Left coronary artery constriction was induced surgically in anesthetized, mechanically ventilated Sprague-Dawley rats. Echocardiography was used to measure global cardiac performance before surgery and 4 wk postsurgery. Coronary constriction provoked significant decreases in ejection fraction, increases in left ventricular end-diastolic volume, and increases left ventricular end-systolic volume at 4 wk postintervention, just before induction of ventricular fibrillation (VF). After 6 min of untreated VF, CPR was initiated on three groups: 1) coronary artery constriction group, 2) sham-operated group, and 3) control group (without preceding surgery). Defibrillation was attempted after 6 min of CPR. All the animals were resuscitated. Postresuscitation myocardial function as measured by rate of left ventricular pressure increase at 40 mmHg and the rate of left ventricular pressure decline was more significantly impaired and left ventricular end-diastolic pressure was greater in the coronary artery constriction group compared with the sham-operated group and the control group. There were no differences in the total shock energy required for successful resuscitation and duration of survival among the groups. In summary, this rat model of chronic myocardial ischemia was associated with ventricular remodeling and left ventricular myocardial dysfunction 4 wk postintervention and subsequently with severe postresuscitation myocardial dysfunction. This model would suggest further clinically relevant investigation on cardiac arrest and CPR.

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Clinical Predictive Models of Sudden Cardiac Arrest: A Survey of the Current Science and Analysis of Model Performances

Journal of the American Heart Association ◽

10.1161/jaha.119.017625 ◽

2020 ◽

Vol 9 (16) ◽

Author(s):

Richard T. Carrick ◽

Jinny G. Park ◽

Hannah L. McGinnes ◽

Christine Lundquist ◽

Kristen D. Brown ◽

...

Keyword(s):

Cardiac Arrest ◽

Predictive Models ◽

Validation Studies ◽

Predictive Analytics ◽

External Validation ◽

Sudden Cardiac Arrest ◽

The United States ◽

Median Percentage ◽

Neurologic Recovery ◽

C Statistic

Background More than 500 000 sudden cardiac arrests (SCAs) occur annually in the United States. Clinical predictive models (CPMs) may be helpful tools to differentiate between patients who are likely to survive or have good neurologic recovery and those who are not. However, which CPMs are most reliable for discriminating between outcomes in SCA is not known. Methods and Results We performed a systematic review of the literature using the Tufts PACE (Predictive Analytics and Comparative Effectiveness) CPM Registry through February 1, 2020, and identified 81 unique CPMs of SCA and 62 subsequent external validation studies. Initial cardiac rhythm, age, and duration of cardiopulmonary resuscitation were the 3 most commonly used predictive variables. Only 33 of the 81 novel SCA CPMs (41%) were validated at least once. Of 81 novel SCA CPMs, 56 (69%) and 61 of 62 validation studies (98%) reported discrimination, with median c‐statistics of 0.84 and 0.81, respectively. Calibration was reported in only 29 of 62 validation studies (41.9%). For those novel models that both reported discrimination and were validated (26 models), the median percentage change in discrimination was −1.6%. We identified 3 CPMs that had undergone at least 3 external validation studies: the out‐of‐hospital cardiac arrest score (9 validations; median c‐statistic, 0.79), the cardiac arrest hospital prognosis score (6 validations; median c‐statistic, 0.83), and the good outcome following attempted resuscitation score (6 validations; median c‐statistic, 0.76). Conclusions Although only a small number of SCA CPMs have been rigorously validated, the ones that have been demonstrate good discrimination.

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Sodium-Hydrogen Exchanger Isoform-1 Inhibition: A Promising Pharmacological Intervention for Resuscitation from Cardiac Arrest

Molecules ◽

10.3390/molecules24091765 ◽

2019 ◽

Vol 24 (9) ◽

pp. 1765 ◽

Cited By ~ 4

Author(s):

Raúl J. Gazmuri ◽

Jeejabai Radhakrishnan ◽

Iyad M. Ayoub

Keyword(s):

Cardiac Arrest ◽

Animal Models ◽

Myocardial Dysfunction ◽

Sudden Cardiac Arrest ◽

Cardiac Activity ◽

Public Health Problem ◽

Left Ventricular ◽

Pharmacological Intervention ◽

Major Public Health Problem ◽

Electrical Stability

Out-of-hospital sudden cardiac arrest is a major public health problem with an overall survival of less than 5%. Upon cardiac arrest, cessation of coronary blood flow rapidly leads to intense myocardial ischemia and activation of the sarcolemmal Na+-H+ exchanger isoform-1 (NHE-1). NHE-1 activation drives Na+ into cardiomyocytes in exchange for H+ with its exchange rate intensified upon reperfusion during the resuscitation effort. Na+ accumulates in the cytosol driving Ca2+ entry through the Na+-Ca2+ exchanger, eventually causing cytosolic and mitochondrial Ca2+ overload and worsening myocardial injury by compromising mitochondrial bioenergetic function. We have reported clinically relevant myocardial effects elicited by NHE-1 inhibitors given during resuscitation in animal models of ventricular fibrillation (VF). These effects include: (a) preservation of left ventricular distensibility enabling hemodynamically more effective chest compressions, (b) return of cardiac activity with greater electrical stability reducing post-resuscitation episodes of VF, (c) less post-resuscitation myocardial dysfunction, and (d) attenuation of adverse myocardial effects of epinephrine; all contributing to improved survival in animal models. Mechanistically, NHE-1 inhibition reduces adverse effects stemming from Na+–driven cytosolic and mitochondrial Ca2+ overload. We believe the preclinical work herein discussed provides a persuasive rationale for examining the potential role of NHE-1 inhibitors for cardiac resuscitation in humans.

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