基于心脏停搏动物模型探讨心脏停搏后综合征及其发生机制（英文）

Mechanism of post cardiac arrest syndrome based on animal models of cardiac arrest

摘要

心脏停搏(cardiac arrest，CA)是心血管领域的一种危急重症。从CA中复苏成功的患者病死率一直居高不下，这归因于心脏停搏后综合征(post cardiac arrest syndrome，PCAS)。然而，PCAS引起的损伤及其病理生理机制仍不明确。实验动物模型的价值在于能够通过模型探究CA及PCAS的病因、发病机制及潜在的干预措施。目前主要的CA动物模型包括电诱导的心室颤动(ventricular fibrillation，VF)、心肌梗死、高钾血症、窒息及出血性休克。这些模型与临床实践仍存在一定差异，但是其揭示的CA发生、发展的潜在机制仍具有重要参考价值，例如心脏停搏后脑损伤(post-CA brain injury，PCABI)、心脏停搏后心肌功能不全(post-CA myocardial dysfunction，PAMD)、系统性缺血/再灌注损伤(ischemia/reperfusion injury，IRI)及持续存在的诱发病理因素等。总结CA的建模方法、建模过程中存在的问题及PCAS的发生机制，可为确立规范的CA模型建立流程提供依据。

Abstract

Cardiac arrest (CA) is a critical condition in the field of cardiovascular medicine. Despite successful resuscitation, patients continue to have a high mortality rate, largely due to post CA syndrome (PCAS). However, the injury and pathophysiological mechanisms underlying PCAS remain unclear. Experimental animal models are valuable tools for exploring the etiology, pathogenesis, and potential interventions for CA and PCAS. Current CA animal models include electrical induction of ventricular fibrillation (VF), myocardial infarction, high potassium, asphyxia, and hemorrhagic shock. Although these models do not fully replicate the complexity of clinical CA, the mechanistic insights they provide remain highly relevant, including post-CA brain injury (PCABI), post-CA myocardial dysfunction (PAMD), systemic ischaemia/reperfusion injury (IRI), and the persistent precipitating pathology. Summarizing the methods of establishing CA models, the challenges encountered in the modeling process, and the mechanisms of PCAS can provide a foundation for developing standardized CA modeling protocols.

Graphical abstract

关键词

心脏停搏 / 动物模型 / 心脏停搏后综合征 / 病理生理学 / 建模方法 / cardiac arrest / animal model / post cardiac arrest syndrome / pathophysiology / modeling method

Key words

cardiac arrest / animal model / post cardiac arrest syndrome / pathophysiology / modeling method

Cardiac arrest (CA) is an important public health issue^[1]. The management of CA has benefited from recent advances in cardiopulmonary resuscitation techniques. However, despite these improvements, the incidence of sudden cardiac death remains high^[2]. Post cardiac arrest syndrome (PCAS) is a major determinant of early mortality after CA. To date, interventions targeting this potential therapeutic approach have failed to reduce mortality^[3]. PCAS is a complex condition characterized by systemic ischemia-reperfusion injury. Understanding its pathophysiology and developing effective treatment strategies are essential to improving outcomes^[4]. Animal models are necessary to investigate how CA-induced pathophysiological processes can be modified to achieve this goal.

Animal models of CA constitute a cornerstone in resuscitation research as an instrument to address the poor outcomes following CA^[5]. Unlike animal models of CA, human studies cannot impose strict experimental controls or allow invasive, continuous monitoring. By elucidating potential pathophysiological mechanisms and evaluating new therapies, these models provide unique opportunities for promoting scientific development.

Despite their translational intent, contemporary animal models of CA remain heterogeneous in definition and reporting, as systematic reviews^[6-11] highlight. This makes comparisons between studies difficult and limits the application of various protective strategies in clinical practice.

A concise methodological standard for CA animal models is essential. This review aims to provide a detailed overview of contemporary animal models of CA.

1 Animal models of CA

According to the different intervention measures, the methods for inducing CA are generally divided into electrical induction of ventricular fibrillation (VF), myocardial infarction, high potassium, asphyxia, and hemorrhagic shock (Table 1 and Table 2).

1.1 CA induction via electrically induced VF

Electrical induction of VF is a widely used approach for establishing animal models of CA. Several electrical stimulation protocols have been developed to elicit VF. Depending on the location of the electrode implant, VF can be induced via the right ventricle, extracorporeal transcutaneous electrical stimulation, transesophageal-chest wall electrical stimulation, and open-chest fibrillation.

1.1.1 VF induction via electrical stimulation of right ventricle

VF is induced by inserting one electrode through the right jugular vein into the right ventricle and placing the other electrode at the point where the apical beats are most pronounced, then releasing an electric current to stimulate the endocardium^[12-13]. The depth of electrode placement varies depending on the experimental animal. It is generally around 5 cm for rats (neonatal pacing catheter)^[14-19] and 18 to 22 cm for swines^[20].

To determine whether the electrode has reached the endocardium of the right ventricle, the criteria are: The regular fluctuation of the electrode guidewire in response to the heartbeat; a sudden change of electrocardiogram in the direction of the main QRS wave in the opposite direction; or the presence of arrhythmias such as ventricular pre-phase contraction or ventricular tachycardia accompanied by corresponding changes in blood pressure waveforms.

At the start of current stimulation, VF is induced by 12 mA and 50 Hz alternating current (AC) for 2 min in rats, 4 mA AC for 2 min in rabbits^[21], and 3 mA AC for 3 s in swine^[22-23]. Research^[24] suggests that swines are very susceptible to VF.

The success of model establishment is confirmed based on the assessment criteria outlined in Table 1. Transcatheter right VF achieves higher success and efficiency. This method is closer to clinical practice than other methods of fibrillation and has a similar pathophysiological process to common clinical CA. Depending on the different requirements of experiments, observation is allowed for a few minutes to over 10 min without any other treatment, which is followed by initiation of the cardiopulmonary resuscitation (CPR) process.

1.1.2 VF induction via transcutaneous electrical stimulation

Transcutaneous electrical stimulation is one of the most widely used modeling methods. It essentially uses 2 puncture needles to pierce the chest wall^[25-26] and create an electrical circuit to stimulate the heart or epicardium, thereby inducing VF.

The puncture needles commonly used in this modeling methods are lumbar puncture needles and acupuncture needles^[27]. The lumbar puncture needles come in sizes 22 to 29. The 22 gauge lumbar puncture needles (9.0 to 12.5 cm long) are often used during modeling, with a caliber of 0.4 to 8.0 mm, and are fitted with a core. Lumbar puncture needles are generally made of steel and are relatively hard. They are suitable for use in large animal modeling where the skin is tough.

Acupuncture needles are commonly seen in Traditional Chinese Medicine treatment and the needles are 7 to 100 mm long with a caliber of 0.25 to 0.35 mm. They are generally made of stainless steel, which has good electrical conductivity. Acupuncture needles are generally soft and have varying compliance when they are touched by different tissues. It is recommended to select appropriate puncture needles based on the animal’s size, weight, and skin thickness.

In rats^[28-30], the electrode insertions need to be placed near the sternum and superior margin of the rib when choosing the puncture site. The left electrode is angled at about 75°, oriented horizontally, and directed toward the midline. The right electrode is angled at 45° to 75°, oriented horizontally, and directed towards the left conductive electrode. The insertion depth is approximately 10 mm. Direct electrical stimulation is applied to the chest wall, with a crude current, continuous single stimulation, a delay of 100 ms, a wave width of 1 ms, a frequency of 50 Hz, an initial intensity of 1 mA, and a stimulation duration of 3 min.

In rabbits^[31], VF is triggered by applying an external transthoracic AC through the needles. The procedure begins with a 10 s delivery of 6 V/50 Hz AC. If VF naturally reverts to a normal sinus rhythm, the stimulation is carried out once more.

In swine^[32-34], one electrode is inserted into the fourth intercostal near the right side of the sternum about 3 cm in depth at an angle of 30° to 60° between the chest and the electrode. The depth is adjusted until the electrode handle vibrates with the heartbeat and no premature ventricular contractions appear on the electrocardiogram. The second electrode is inserted into the subcutaneous tissues of the left armpit about 3 cm deep without damaging important organs. VF is induced with 3 s, 60 Hz, and 100 mA transthoracic AC^[35].

Transcutaneous electrical stimulation induces VF with a clear positioning of the electrode placement and a high success rate of operation. However, the method is susceptible to factors such as the thickness of the chest wall, imprecise localization of the puncture site and depth, and variable current requirements that necessitate stepwise escalation. Higher currents are likely to cause complications such as skin burns and myocardial damage, and have a significant impact on other organs and hemodynamics throughout the body^[36]. Therefore, the stability and reproducibility of this method are not high.

1.1.3 VF induction via transesophageal-chest wall electrical stimulation

Transoesophageal-chest wall electrical stimulation induces VF by placing one electrode into the esophagus near the heart and another electrode into the pericardial region where the heartbeat is most pronounced, followed by electrical stimulation^[37]. The placement of the oesophageal electrodes differs based on the animal chosen for the experiment.

In rats^[38], a pacing catheter (5 F) with 2 end ring electrodes (0.5 cm apart) is inserted into the esophagus to a depth of 6.0 to 6.5 cm and connected to a current generator. This ensures that the current is applied close to the heart without generating irreversible respiratory muscle paralysis. Two-phase electrical stimulation using AC consists of 24 V/50 Hz AC (phase 1), followed by 18 V/50 Hz AC (phase 2) to generate the least thermal injury to the oesophagus. Ventilation is stopped during the CA period.

Rabbits are subjected to subcutaneous electrode insertion in the pericardial region where the apical pulse is strongest, and esophageal pacing electrodes are inserted in the esophagus. The distance from the location of the metal ring of the electrodes to the incisor is 16 cm. VF is induced with 35 mA constant current at a frequency of 50 Hz^[39-42].

Although this model is low-cost and less damaging to the experimental animal heart (due to indirectly electric shock), the method requires a high degree of accuracy in the placement of the oesophageal electrodes^[43]. Because the electric shock does not directly touch the endocardium or epicardium, the requirements for voltage and time to induce fibrillation are higher than those for transcatheter right ventricular and percutaneous fibrillation.

1.1.4 VF induction under open chest direct vision

Inducing VF under direct visual inspection of the chest involves exposing the heart and placing electrodes directly^[44-45].

In rabbits^[46], the thoracic cavity is cut from the middle of the sternum, with an incision about 6 to 8 cm long. The apical and right atria are fully exposed, and electrodes are placed in the right atrium and the left ventricle. AC subepicardial defibrillation is used (current of about 20 mA).

An extracorporeal study^[47] of a resuscitated porcine model uses 9 V current stimulation of the right atrium and left ventricle to induce VF under direct visualization of the open chest.

The method of fibrillation under open chest direct vision is closer to clinical reality because it requires less current and has less effect on the heart and other organs. The fibrillation effect is accurate, the resuscitation success rate is high, and the model is more stable and reproducible. However, due to the significant damage caused by open chest operations and the associated risks of secondary infections and hemorrhages^[48], the application of this method is more limited than other methods.

1.2 CA induction via the acute myocardial infarction method

CA induction via acute myocardial infarction involves provoking VF through coronary artery ligation or embolization, replicating ischemic myocardial injury. Traditional coronary ligation typically requires open thoracotomy, which is highly invasive and associated with low procedural success rates and poor animal survival.

At present, this model is often prepared by extruding the heart in rats. The specific operation is as follows: Making a 1 cm longitudinal incision on the left side of the sternum of the rat at an oblique angle of 20° to 30° between the third and fourth intercostal space, bluntly separating the pectoral muscles layer by layer, using the ophthalmic forceps to open up and fix the widest part of the third and fourth rib gaps, extruding the heart, and rapidly ligating the proximal left anterior descending branch with a No. 6-0 wire on the inferior edge of the left auricle^[49].

In rabbits, the left anterior descending (LAD) branch is not visible, often leading to unsuccessful creation of an acute myocardial infarction model. A new approach^[50] is developed to achieve good reproducibility and a high success rate for use as a rabbit acute myocardial infarction model. In this approach, the obtuse marginal (OM) branch of the left circumflex coronary artery is coagulated with an electric knife using a left parasternal approach.

The structure, size, and coronary circulation of the swine heart are similar to those of the human heart^[51]. Coronary artery occlusion in swine induces myocardial infarction that is very similar to acute myocardial infarction in humans, based on pathological changes. The LAD branch is one of the 3 trunks of the coronary artery that support a large area involving the important “passing through” conduction bundle. LAD branch occlusion could lead to malignant ventricular arrhythmia and cause CA^[52]. In one study^[53], the swine LAD branch is blocked using an over-the-wire coronary balloon catheter to establish the acute myocardial infarction reperfusion-VF-CA model.

Although this method is consistent with the clinical reality of CA due to ischaemic heart disease, its application has been limited to some extent. This is due to the complexity of the modeling process, the large number of equipment and devices required, the need for action angiography to confirm the validity of the blockage, and the frequent occurrence of concomitant vascular accidents^[54].

1.3 CA induction via high potassium

High potassium-induced CA mainly utilizes the intravenous rapid injection of high-concentration potassium chloride to inhibit myocardial electrical activity, causing changes in cardiac rhythm and leading to CA^[55]. The amount of potassium chloride injected is determined by the experimental animals. The experimental methods employed vary slightly from one study to the next.

In one study^[56], 50 mL of 10% potassium chloride solution was injected into the ear vein in a short amount of time to establish a swine CA model. In the potassium chloride-induced CA mouse model, CA was induced by administration of potassium chloride (0.08 mg/g body weight) through the femoral venous catheter^[57].

The model has been refined in recent years. For example, potassium chloride is delivered directly into the left ventricular cavity under ultrasound guidance in intubated mice, resulting in immediate asystole. This ultrasound-guided direct injection of potassium chloride allows for rapid and reliable CA in mouse that mirrors human pathology without the need for intra-venous access^[58].

Although it is easy to induce CA with high potassium, high potassium is not a common cause of CA in clinical practice and lead to electrolyte disorders. In addition, there may be other complications during resuscitation, such as pulmonary edema due to over-hydration.

1.4 CA induction via asphyxia

Disconnecting the mechanical ventilator and clamping the tracheal tube is a common method for causing asphyxia CA, with or without vecuronium. Vecuronium is a neuromuscular blocking agent administered to induce apnea without adverse cardiovascular effects. Its application in this model prevents experimental animals from struggling during the modeling process, which could affect the experimental results^[59].

Operationalized CA duration differs between investigators: 1) Using suffocation time as the judgment criterion. This is defined as lasting from the start of disconnecting the mechanical ventilator to clamping the tracheal tube. When using rabbits as experimental subjects, there are currently 2 common methods^[60-61] of suffocation (7 min or 8 min). 2) Using CA duration as the judgment criterion. This is defined as the no-flow period. When rabbits are used as experimental subjects, the commonly seen CA durations are 3 min^[62], 4 min^[63], and 5 min^[64].

In rats^[65], the asphyxia process is separated into 3 stages: 1) The tracheal tube is clamped and apnea is created, usually lasting for 15 s with vecuronium. 2)Hypoxic perfusion occurs, where apnea occurs with some perfusion, usually lasting for 3 min. 3) The last phase is a no-flow phase, with the duration depending on the experimental design.

Various criteria can be used to determine CA caused by asphyxia when using swine as experimental animals. In one study^[66], researchers induced a CA model that is asphyxiated with fentanyl overdose, followed by 9 min of untreated asphyxia. In another study^[67], asphyxia CA is induced by clamping of the endotracheal tube, while the infusion of anesthetic drugs is stopped, and the piglets are left untreated until heart rate is less than 60 beat per minute or mean arterial pressure is below 15 mmHg (1 mmHg= 0.133 KPa).

Unlike electrical stimulation defibrillation method, this method does not require electrical current stimulation, has little damage to myocardial tissues, and requires simple equipment. Therefore, it is highly operable and reproducible. This method can be used to simulate the neurological, cardiac, renal, and other major organ injuries caused by prolonged hypoxia-induced CA in the clinical setting. However, because prolonged hypoxia can lead to severe hypercapnia and respiratory acidosis, it may conceal some pathophysiological mechanisms of CA and is not suitable for the study of CA mechanisms caused by respiratory and metabolic diseases^[68]. In addition, this method lacks uniform criteria for determining CA, resulting in a higher degree of heterogeneity in study results. It is noteworthy that VF-induced CA (electric shock-induced CA) produces worse cardiovascular dysfunction, while asphyxia-induced CA produces worse neurologic injury associated with greater oxidative stress^[69].

1.5 CA induction via hemorrhagic shock

Traumatic CA (TCA) exhibits distinct pathophysiology compared to medical CA, necessitating specialized modeling approaches. Blood loss and electrical stimulation are commonly used.

Researchers^[70] established a hemorrhagic shock-induced CA model in rabbits. They combined arterial and venous bloodletting and maintained CA for 15 min after successful modeling. In a TCA model^[71], swine underwent controlled hemorrhage (40% total blood volume, estimated at 70 mL/kg) via the right femoral artery over 20 min, followed by immediate induction of VF-CA using 1 mA AC.

Alternative models incorporate traumatic injuries prior to CA induction, including continuous ballistic trauma to the thigh^[72] or dissections of the liver lobes with lacerated re-sections^[73]. Following these traumatic manipulations, the process typically involves bloodletting from the femoral artery at a constant rate until the blood loss reaches 30% to 40% of the total blood volume, with simultaneous rehydration of fluids during this period to maintain the mean arterial pressure at 40 to 45 mmHg. After 1 h of compensated shock, progressive exsanguination is performed to induce CA.

2 Discrepancies of CA animal models from clinical practice

Despite the ultimate objective of animal experiments being to reflect clinical scenarios, there are some problems with the current animal models of CA.

Baseline fasting is a crucial factor that cannot be neglected in research. The literature^[74] shows that metabolic, cellular, and circadian mechanisms of fasting periods have direct and indirect influences on the brain, including improvements of cognitive function and the prevention or progression of brain-related disorders. Similarly, fasting induces several molecular and cellular adaptations in neurons, which collectively enhance cellular stress resistance, synaptic plasticity, and neurogenesis^[75]. Different modalities of fasting have been shown to improve the cardiometabolic risk profile of human adults^[76]. The question of whether to fast the experimental animals is often overlooked or not mentioned in some animal experiments related to CA.

Anesthesia can reduce the animal’s stress response and ease surgical procedures such as endotracheal intubation and intraperitoneal administration. Anesthesia is also the first step in establishing a standardized CA animal model, which includes induction, maintenance, and withdrawal. Anesthetic choice has been shown to have an impact on O₂ saturation, heart rate, and blood pressure in several studies^[77-78]. A systematic review^[79] reveals that more than 70% of the studies omit details on whether anaesthesia was discontinued during CA and resuscitation.

Current CA animal models often fail to capture the severity and complexity observed clinically. Moreover, most models use healthy males, whereas women who suffer out-of-hospital CA are typically older and burdened with greater comorbidity^[80]. The prevalence of different presenting rhythms differs between genders. Women present with more non-shockable rhythms than men^[81]. Although women have higher resuscitation rates than men, survival to discharge is comparable^[82]. Even when men and women received equivalent treatment with targeted temperature management (TTM) and exhibited comparable physiological responses, women still exhibit worse neurological outcomes as evaluated by the modified Rankin scales^[83]. The use of medications to treat heart disease has more side effects in women than in men^[84]. These findings underscore the need for further research on sex- and gender-specific therapies so that post-return of spontaneous circulation (ROSC) patients can receive optimal intensive care.

A large number of different methods are used to induce CA, with VF induced by electric shock/pacing and asphyxia as the most common^[85]. Remarkably, only 2% of the studies use myocardial infarction as the induction method^[86], although myocardial infarction is a frequent cause of out-of-hospital CA^[87]. In pediatric models where asphyxia-induced arrest is the leading cause of CA^[88], it may be the preferred method. The modeling process needs to consider the causes of CA and the complexity of its condition for animal models to better reflect clinical reality.

It is encouraging that 52% of the included studies are performed in swine, as swine are very comparable to humans regarding size, physiology, and anatomy^[89]. A significant number of studies involve advanced monitoring that assesses both invasive pressures and arterial blood gas analysis. In animal models of CA, new interventions such as extracorporeal membrane oxygenation (ECMO), ultrasound, and TTM have been widely used. As the survival rate of patients with CA gradually improves, more research focus has shifted towards protecting the nervous system after CA.

3 Mechanisms of PCAS from CA animal models

With an overall survival of only 15% to 22%^[90-92], CA remains a major public-health burden, and the most deaths result from PCAS. The mechanisms of PCAS are made up of 4 main components: Post-CA brain injury (PCABI), post-CA myocardial dysfunction (PAMD), systemic ischemia/reperfusion injury (IRI), and the persistent precipitating pathology (Figure 1).

3.1 PCABI

Neurological damage following CA remains a significant burden for modern resuscitation medicine (Figure 2). PCABI is caused by initial ischemia and subsequent reperfusion of the brain following resuscitation. PCABI manifests as coma in those admitted to the intensive care unit after CA and is the primary reason for mortality and long-term disability^[93].

CA results in the cessation of both cardiac output and oxygen delivery to all vital organs, leading to the near-complete collapse of cerebral blood flow. Severe ischemia results in the synthesis and release of various cytokines and complement anaphylatoxins. Once a CA occurs, there is a no-flow phase that lasts until partial reperfusion is established by CPR^[94]. When CPR is done correctly, cardiac output can be restored to between 25% and 40% of pre-arrest values, with the brain receiving 30% of this amount^[95].

Reperfusion activates coagulation, generating micro-emboli, and promoting neutrophil-platelet accumulation in microvessels. Reactive oxygen species (ROS) generated upon reperfusion markedly intensify endothelial injury, amplifying exchange-vessel permeability and driving pathological microvascular filtration^[96].

There is an intense increase in the levels of inflammation-related cells and various inflammatory factors^[97]. Immediately after ROSC, a temporary increase in catecholamine concentrations results in normal or elevated blood pressure, which requires high-pressure periods to overcome the potential no-reflow phenomenon. An increase in several cytokines is accompanied by tissue damage caused by neutrophil infiltration,which directly inhibit adrenal cortisol synthesis and increase the risk of early refractory shock^[98]. During the early phase after ROSC, the concentration of various inflammatory factors in the blood reaches its peak, indicating the occurrence of systemic inflammatory response syndrome in the early stage after CA.

After ROSC, the conditions encourage the opening of the mitochondrial permeability transition pore (MPTP). The inner mitochondrial membrane becomes non-specifically permeable, causing the mitochondria to swell dramatically and then the outer membrane to break, particularly in reperfused tissues^[99]. The intracellular Ca²⁺ increase caused by the primary injury leads to the release of glutamate, an excitatory neurotransmitter that binds to the cell membrane causing a further intracellular Ca²⁺ influx and cytoplasmic accumulation from the endoplasmic reticulum. Neuronal damage is exacerbated by the activation of Ca²⁺-dependent lattice enzymes. Mitochondrial dysfunction reliant on Ca²⁺ triggers cell energy depletion, the liberation of pro-apoptotic proteins, the generation of ROS, and subsequent neuronal injury.

3.2 PAMD

PAMD is defined as the emergence of low cardiac output or ventricular systolic or diastolic impairment following CA (Figure 3). Approximately two-thirds of patients who undergo successful resuscitation after CA exhibit compromised left ventricular systolic function. The reversible decline in cardiac function subsequent to CA stems from a complex interplay of multiple processes. These processes collectively result in acute cardiac dysfunction that is superimposed on any pre-existing structural heart disease^[100], including energy depletion/ionic dyshomeostasis vicious cycle, systemic inflammatory response syndrome (SIRS), and release of catecholamines^[101].

Ischaemia induced by CA shifts metabolism to anaerobic glycolysis, resulting in cellular energy depletion and lactic acidosis. The depletion of cellular energy impairs the function of the membrane Na⁺/K⁺-transporting ATPase pump. This leads to an excessive accumulation of sodium within the cell and subsequent cell edema. The situation is further exacerbated by an influx of sodium through the membrane Na⁺/H⁺ exchanger (NHE), which is triggered by intracellular acidosis^[102-103]. Intracellular sodium accumulation induces calcium influx through the Na⁺/Ca²⁺ exchanger, leading to myocardial cellular calcium overload, which is exacerbated by the failure of the Ca²⁺ ATPase due to energy depletion^[102-103]. The negative effects of intracellular calcium overload include downstream activation of calcineurin and cellular apoptosis by opening the MPTP, as well as impaired diastolic relaxation^[104]. After transient ischemia returns to normal, too much toxic ROS production sets off a second round of cellular injury.

Following the ROSC, inflammatory cytokines are released, thereby giving rise to SIRS that shares similarities with sepsis^[105-107]. The inflammatory response is characterized by polymorphonuclear leukocyte activation, adhesion molecule expression, ROS production by inducible nitric oxide synthase (iNOS), and release of cytokines like interleukin (IL)-6 and tumor necrosis factor (TNF)-α^[108-109]. Endothelial damage results in abnormal vascular permeability, coagulation cascade activation, tissue edema, and microvascular occlusion, which worsen tissue perfusion^[110].

Cardiotoxicity mediated by catecholamines serves as another significant contributor to PAMD. Elevated concentrations of catecholamines, notably epinephrine, have the potential to induce cardiac dysfunction, encompassing stress-triggered cardiomyopathy^[111]. Excessive catecholamines lead to myocardial injury and dysfunction via calcium overload, excessive generation of ROS, as well as the down-regulation and desensitization of β-receptors^[112].

3.3 Systemic IRI

Systemic IRI is an important mechanism connecting CA to PAMD, shock, and multiple organ dysfunction syndrome. Microcirculation dysfunction, increased vascular permeability, activation of white blood cells/platelets, and further release of inflammatory factors/soluble receptors are some of the manifestations that occur. PCAS is triggered by the inflammatory response, and endothelial damage is closely linked to organ dysfunction^[113].

3.4 Persistent precipitating pathology

In addition to the aforementioned pathological mechanisms, if the primary cause or trigger of CA is not treated and corrected promptly, it will continue to affect the pathological and physiological processes of patients after ROSC and make the pathological and physiological mechanisms of PCAS more complex. Such primary causes include acute coronary syndrome (ACS), pulmonary embolism, chronic obstructive pulmonary disease, traumatic bleeding, sepsis, and various toxins that continue to worsen the patient’s condition.

4 Conclusion

CA is a major public health issue, and the animal models are indispensable for elucidating its pathophysiology. Simulating clinical scenarios is the ultimate goal of animal research to ensure the successful transfer of research findings to clinical practice. To enable translation, models must faithfully simulate clinical scenarios and be transparent, standardized, and reproducible.

Despite recent advancements in the field of CA and resuscitation, the mechanisms of PCAS remain unclear. Moreover, the incidence rate of PCABI is the highest in PCAS, which is an important factor affecting patient survival rate and neurological prognosis. A complex cascade of molecular events is involved in the pathophysiology of PCABI, many of which are still unknown. Related studies have shown that this type of injury may be related to endothelial damage, microthrombosis formation, inflammatory response, and mitochondrial damage. To understand the mechanisms of PCABI, it is necessary to conduct many more rigorous animal experiments related to CA.

Contribution: Halidan ABUDU Literature collection and analysis, article design and drafting; WANG Yiping, HE Kang, XU Guowu, LIU Yangqing, MENG Xiangyan, CAI Jingxia, and LI Yongmao Literature collection and analysis; LIU Ziquan, GUO Liqiong, DONG Jinrui, and Ailijiang KADEER Critical revision of the article for important intellectual content; FAN Haojun Article design and critical revision of the article for important intellectual content. The final version of the manuscript has been approved and read by all authors.

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基金资助

the National Key Research and Development Program(2021YFC3002205)

the Postgraduate Research and Innovation Program of Tianjin Municipal Education Commission(2022BKY113)

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