Littérature scientifique sur le sujet « Cardiac hypoxia reoxygenation »

An adequate supply of oxygen is important for the survival of all tissues, but it is especially critical for tissues with high-energy demands, such as the heart. Insufficient tissue oxygenation occurs under a variety of conditions, including high altitude, embryonic and fetal development, inflammation, and thrombotic diseases, often affecting multiple organ systems. Responses and adaptations of the heart to hypoxia are of particular relevance in human cardiovascular and pulmonary diseases, in which the effects of hypoxic exposure can range in severity from transient to long-lasting. This study uses the genetic model system Drosophila to investigate cardiac responses to acute (30 min), sustained (18 h), and chronic (3 wk) hypoxia with reoxygenation. Whereas hearts from wild-type flies recovered quickly after acute hypoxia, exposure to sustained or chronic hypoxia significantly compromised heart function upon reoxygenation. Hearts from flies with mutations in sima, the Drosophila homolog of the hypoxia-inducible factor alpha subunit (HIF-α), exhibited exaggerated reductions in cardiac output in response to hypoxia. Heart function in hypoxia-selected flies, selected over many generations for survival in a low-oxygen environment, revealed reduced cardiac output in terms of decreased heart rate and fractional shortening compared with their normoxia controls. Hypoxia-selected flies also had smaller hearts, myofibrillar disorganization, and increased extracellular collagen deposition, consistent with the observed reductions in contractility. This study indicates that longer-duration hypoxic insults exert deleterious effects on heart function that are mediated, in part, by sima and advances Drosophila models for the genetic analysis of cardiac-specific responses to hypoxia and reoxygenation.

There is a sudden release of intracellular constituents upon reoxygenation of isolated perfused hypoxic heart tissue (O2 paradox) or on perfusion with calcium-free medium after a period of hypoxia. Rat hearts were perfused by the method of Langendorff (Pfluegers Arch. 61: 291-332, 1895) with Krebs-Henseleit medium containing 10 mM glucose. Hearts were equilibrated for 30 min, followed by 90 min of hypoxia or 60 min of hypoxia and 30 min of reoxygenation. The massive enzyme release observed upon reoxygenation after 60 min of hypoxia was prevented by infusing 0.5 or 5 mM cyanide 5 min before reoxygenation. Lactate dehydrogenase (LDH) release commenced immediately upon withdrawal of cyanide. Hearts perfused with calcium-free medium throughout hypoxia did not release increased amounts of LDH at reoxygenation. Perfusing heart tissue with medium containing 0 or 25 microM calcium, but not 0.25 or 2.5 mM, after 50 min of hypoxia initiated a release of cardiac LDH, which was not further enhanced by reoxygenation. Enzyme release was significantly inhibited when the calcium-free perfusion medium included 10 mM 2-deoxyglucose (replacing glucose), 0.5 mM dinitrophenol, or 2.5 mM cyanide. Histologically, hearts perfused with calcium-free medium after 50 min of hypoxia showed areas of severe necrosis and contracture without any evidence of the contraction bands that were seen in hearts reoxygenated in the presence of calcium. Cardiac ATP and creatine phosphate (PCr) levels were significantly decreased after 50-60 min of hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Background. Nitric oxide can successfully compete with oxygen for sites of electron-transport chain in conditions of myocardial hypoxia. These features may prevent excessive oxidative stress occurring in cardiomyocytes during sudden hypoxia-reoxygenation.Aim. To study the action of the potent stable NO donor dinitrosyl iron complex with glutathione (Oxacom®) on the recovery of myocardial contractile function and Ca2+transients in cardiomyocytes during hypoxia-reoxygenation.Results. The isolated rat hearts were subjected to 30 min hypoxia followed by 30 min reoxygenation. The presence of 30 nM Oxacom in hypoxic perfusate reduced myocardial contracture and improved recovery of left ventricular developed pressure partly due to elimination of cardiac arrhythmias. The same Oxacom concentration limited reactive oxygen species generation in hypoxic cardiomyocytes and increased the viability of isolated cardiomyocytes during hypoxia from 12 to 52% and after reoxygenation from 0 to 40%. Oxacom prevented hypoxia-induced elevation of diastolic Ca2+level and eliminated Ca2+transport alterations manifested by slow Ca2+removal from the sarcoplasm and delay in cardiomyocyte relaxation.Conclusion. The potent stable NO donor preserved cardiomyocyte integrity and improved functional recovery at hypoxia-reoxygenation both in the isolated heart and in cardiomyocytes mainly due to preservation of Ca2+transport. Oxacom demonstrates potential for cardioprotection during hypoxia-reoxygenation.

The NAD(P)+-hydrolyzing enzyme CD38 is activated in the heart during the process of ischemia and reperfusion, triggering NAD(P)(H) depletion. However, the presence and role of CD38 in the major cell types of the heart are unknown. Therefore, we characterize the presence and function of CD38 in cardiac myocytes, endothelial cells, and fibroblasts. To comprehensively evaluate CD38 in these cells, we measured gene transcription via mRNA, as well as protein expression and enzymatic activity. Endothelial cells strongly expressed CD38, while only low expression was present in cardiac myocytes with intermediate levels in fibroblasts. In view of this high level expression in endothelial cells and the proposed role of CD38 in the pathogenesis of endothelial dysfunction, endothelial cells were subjected to hypoxia-reoxygenation to characterize the effect of this stress on CD38 expression and activity. An activity-based CD38 imaging method and CD38 activity assays were used to characterize CD38 activity in normoxic and hypoxic-reoxygenated endothelial cells, with marked CD38 activation seen following hypoxia-reoxygenation. To test the impact of hypoxia-reoxygenation-induced CD38 activation on endothelial cells, NAD(P)(H) levels and endothelial nitric oxide synthase (eNOS)-derived NO production were measured. Marked NADP(H) depletion with loss of NO and increase in superoxide production occurred following hypoxia-reoxygenation that was prevented by CD38 inhibition or knockdown. Thus, endothelial cells have high expression of CD38 which is activated by hypoxia-reoxygenation triggering CD38-mediated NADP(H) depletion with loss of eNOS-mediated NO generation and increased eNOS uncoupling. This demonstrates the importance of CD38 in the endothelium and explains the basis by which CD38 triggers post-ischemic endothelial dysfunction.

Hypothermia before and/or during no-flow ischemia promotes cardiac functional recovery and maintains mRNA expression for stress proteins and mitochondrial membrane proteins (MMP) during reperfusion. Adaptation and protection may occur through cold-induced change in anaerobic metabolism. Accordingly, the principal objective of this study was to test the hypothesis that hypothermia preserves myocardial function during hypoxia and reoxygenation. Hypoxic conditions in these experiments were created by reducing O2 concentration in perfusate, thereby maintaining or elevating coronary flow (CF). Isolated Langendorff-perfused rabbit hearts were subjected to perfusate (Po2 = 38 mmHg) with glucose (11.5 mM) and perfusion pressure (90 mmHg). The control (C) group was at 37°C for 30 min before and 45 min during hypoxia, whereas the hypothermia (H) group was at 29.5°C for 30 min before and 45 min during hypoxia. Reoxygenation occurred at 37°C for 45 min for both groups. CF increased during hypoxia. The H group markedly improved functional recovery during reoxygenation, including left ventricular developed pressure (DP), the product of DP and heart rate, dP/d tmax, and O2 consumption (MVo2) ( P < 0.05 vs. control). MVo2 decreased during hypothermia. Lactate and CO2 gradients across the coronary bed were the same in C and H groups during hypoxia, implying similar anaerobic metabolic rates. Hypothermia preserved MMP βF1-ATPase mRNA levels but did not alter adenine nucleotide translocator-1 or heat shock protein-70 mRNA levels. In conclusion, hypothermia preserves cardiac function after hypoxia in the hypoxic high-CF model. Thus hypothermic protection does not occur exclusively through cold-induced alterations in anaerobic metabolism.

We tested the hypothesis that the renin-angiotensin system (RAS) protects the contractile function of the myocardium against the damaging effect of hypoxia-reoxygenation. For this purpose, the contractility of isolated papillary muscles from wild-type (WT) rats and from rats expressing human renin and angiotensinogen as transgenes (TGR) was compared. After 15 min of hypoxia, peak force (PF) was decreased to 24 ± 5% of the normoxic values in TGR ( n = 10) and to 18 ± 1% in WT rats ( n = 12). PF and relaxation rates recovered completely in TGR but not in WT rats during 45 min of reoxygenation. Improved contractility of the papillary muscles from TGR during hypoxia-reoxygenation correlated with increased glutathione peroxidase activities and creatine kinase (CK)-MB and CK-BB isoenzyme levels. On the other hand, inhibition of the RAS with ramipril (1 mg/kg body wt for 3 wk) in WT animals resulted in deterioration of the contractile function of the papillary muscles during reoxygenation compared with untreated rats. These findings suggest that activation of the RAS protects contractile function of the cardiac muscle against hypoxia-reoxygenation, possibly through changes in CK isoenzymes and enhanced antioxidant capacity.

In cardiovascular surgery ischemia-reperfusion injury is a challenging problem, which needs medical intervention. We investigated the effects of curcumin on cardiac, myocardial, and mitochondrial parameters in perfused isolated working Guinea pig hearts. After preliminary experiments to establish the model, normoxia was set at 30 minutes, hypoxia was set at 60, and subsequent reoxygenation was set at 30 minutes. Curcumin was applied in the perfusion buffer at 0.25 and 0.5 μM concentrations. Cardiac parameters measured were afterload, coronary and aortic flows, and systolic and diastolic pressure. In the myocardium histopathology and AST in the perfusate indicated cell damage after hypoxia and malondialdehyde (MDA) levels increased to 232.5% of controls during reoxygenation. Curcumin protected partially against reoxygenation injury without statistically significant differences between the two dosages. Mitochondrial MDA was also increased in reoxygenation (165% of controls), whereas glutathione was diminished (35.2%) as well as glutathione reductase (29.3%), which was significantly increased again to 62.0% by 0.05 μM curcumin. Glutathione peroxidase (GPx) was strongly increased in hypoxia and even more in reoxygenation (255% of controls). Curcumin partly counteracted this increase and attenuated GPx activity independently in hypoxia and in reoxygenation, 0.25 μM concentration to 150% and 0.5 μM concentration to 200% of normoxic activity.

Cardiac tissue from female rainbow trout demonstrates a sex-specific preference for exogenous glucose and glycolysis, impaired Ca2+ handling, and a greater tolerance for hypoxia and reoxygenation than cardiac tissue from male rainbow trout. We tested the hypothesis that dichloroacetate (DCA), an activator of pyruvate dehydrogenase, enhances cardiac energy metabolism and Ca2+ handling in female preparations and provide cardioprotection for hypoxic male tissue. Ventricle strips from sexually immature fish with very low (male) and nondetectable (female) plasma sex steroids were electrically paced in oxygenated or hypoxic Ringer solution with or without 1 mM DCA. In the presence of 5 mM glucose, aerobic tissue from male trout could be paced at a higher frequency (1.79 vs. 1.36 Hz) with lower resting tension and less contractile dysfunction than female tissue. At 0.5 Hz, DCA selectively reduced resting tension below baseline values and lactate efflux by 75% in aerobic female ventricle strips. DCA improved the functional recovery of developed twitch force, reduced lactate efflux by 50%, and doubled citrate in male preparations after hypoxia-reoxygenation. Independent of female sex steroids, reduced myocardial pyruvate dehydrogenase activity and impaired carbohydrate oxidation might explain the higher lactate efflux, compromised function of the sarcoplasmic reticulum, and reduced mechanical performance of aerobic female tissue. Elevated oxidative metabolism and reduced glycolysis might also underlie the beneficial effects of DCA on the mechanical recovery of male cardiac tissue after hypoxia-reoxygenation. These results support the use of rainbow trout as an experimental model of sex differences of cardiovascular energetics and function, with the potential for modifying metabolic phenotypes and cardioprotection independent of sex steroids.

An intracellular mechanism that senses decreases in tissue oxygen level and stimulates hypoxia-related gene expression has been reported in various cell types including the cardiac cell. The mechanism can also be activated by Co2+ in normoxia. Thus we investigated the effects of prior chronic oral CoCl2 on mechanical functions of isolated, perfused rat hearts in hypoxia-reoxygenation. In normoxic rats, 43 days of Co2+ administration increased hematocrit from 45 ± 0.3% (control, n = 18) to 51 ± 0.6% ( n = 19). In hypoxia and reoxygenation, Co2+-pretreated hearts exhibited a significantly higher rate-pressure product (267 and 163%, respectively) and coronary flow (127 and 118%, respectively) and lower end-diastolic pressure (72 and 60%, respectively) compared with the control hearts. Although the oral Co2+ administration significantly raised myocardial Co2+ concentration, it did not affect mitochondrial respiration, tissue glycogen concentration, or myocardial tissue histology. The levels of vascular endothelial growth factor, aldolase-A, and glucose transporter-1 mRNA were significantly elevated in the Co2+-treated myocardium. We conclude that cardiac contractile functions would gain hypoxic tolerance when the endogenous cellular oxygen-sensing mechanism is activated.

L'ischemia miocardica determina una drastica riduzione della produzione di ATP, con conseguente squilibrio ionico e morte cellulare. La fornitura di substrati metabolici durante la riperfusione è in grado di aumentare significativamente la tolleranza cardiaca al danno ischemico migliorando le funzioni mitocondriali. In condizioni di normossia, il glutammato può contribuire all'equilibrio energetico del miocardio agendo come substrato per le reazioni anaplerotiche. In questo contesto, lo scambiatore Na+/Ca2+ (NCX1) svolge un ruolo fondamentale come supporto funzionale, favorendo sia l’ingresso di glutammato all’interno della cellula sia il suo conseguente utilizzo per la sintesi di ATP. A tal proposito, nel presente studio è stato valutato il ruolo svolto da NCX nel miglioramento del metabolismo energetico e della sopravvivenza cellulare indotto da glutammato in modelli cardiaci sottoposti ad uno specifico protocollo di ipossia/riossigenazione (I/R). In particolare è stato osservato in cellule H9c2-NCX1 che, i livelli di ATP, le funzioni mitocondriali e la sopravvivenza cellulare risultano significativamente compromessi in seguito al danno da I/R. La somministrazione di glutammato all'inizio della fase di riossigenazione incrementava, in modo significativo, la vitalità, migliorava le funzioni mitocondriali e normalizzava l'aumento dell'attività “inversa” di NCX1 indotto dal protocollo di I/R. Gli effetti benefici del glutammato non venivano osservati sono sorprendentemente in cellule H9c2-WT (caratterizzate da una mancata espressione di NCX1), e in cellule H9c2-NCX1 e cardiomiociti di ratto trattati con inibitori dello scambiatore e con bloccanti dei trasportatori degli amminoacidi eccitatori (EAAT), suggerendo che un'interazione funzionale tra questi due trasportatori è necessaria per ottenere la protezione indotta da glutammato. Collettivamente, i risultati ottenuti hanno rivelato per la prima volta il ruolo chiave di NCX1 nell’effetto protettivo del glutammato contro il danno cellulare da I/R.
Myocardial ischemia culminates in ATP production impairment, ionic derangement and cell death. The provision of metabolic substrates during reperfusion significantly increases heart tolerance to ischemia by improving mitochondrial performance. Under normoxia, glutamate contributes to myocardial energy balance as substrate for anaplerotic reactions, and we demonstrated that the Na+/Ca2+ exchanger1 (NCX1) provides functional support for both glutamate uptake and use for ATP synthesis. Here the role of NCX1 was studied in the potential of glutamate to improve energy metabolism and survival of cardiac cells subjected to hypoxia/reoxygenation (H/R). Specifically, in H9c2-NCX1 myoblasts, ATP levels, mitochondrial activities and cell survival were significantly compromised after H/R challenge. Glutamate supplementation at the onset of the reoxygenation phase significantly promoted viability, improved mitochondrial functions and normalized the H/R-induced increase of NCX1 reverse-mode activity. The benefits of glutamate were strikingly lost in H9c2-WT (lacking NCX1 expression), or in H9c2-NCX1 and rat cardiomyocytes treated with either NCX or Excitatory Amino Acid Transporters (EAATs) blockers, suggesting that a functional interplay between these transporters is critically required for glutamate-induced protection. Collectively, these results revealed for the first time the key role of NCX1 for the beneficial effects of glutamate against H/R-induced cell injury.

Dong Yingying.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 99-125).
Abstracts in English and Chinese.
Declaration --- p.i
Acknowledgement --- p.ii
Publication list --- p.iii
Abstract (English) --- p.ix
Abstract (Chinese) --- p.xii
Abbreviations --- p.xiv
List of figures / tables --- p.xvi
Chapter Chapter 1. --- General Introduction
Chapter 1.1 --- The role of endothelium in regulating vascular tone --- p.1
Chapter 1.1.1 --- Nitric oxide (NO) --- p.2
Chapter 1.1.2 --- Endothelium-derived hyperpolarizing factor (EDHF) --- p.7
Chapter 1.1.3 --- Prostacyclin (PGI2) --- p.20
Chapter 1.2 --- EDHF-mediated endothelial function in coronary circulation --- p.22
Chapter 1.2.1 --- Role of EDHF in coronary microarteries --- p.23
Chapter 1.2.2 --- Role of EDHF in cardiac veins --- p.24
Chapter 1.3 --- Effect of ischemia-reperfusion on endothelial function in coronary circulation --- p.25
Chapter 1.3.1 --- Ischemia-reperfusion injury --- p.26
Chapter 1.3.2 --- Effect of ischemia-reperfusion on endothelial function in coronary microarteries --- p.28
Chapter 1.3.3 --- Effect of ischemia-reperfusion on endothelial function in cardiac veins --- p.29
Chapter 1.4 --- Alteration of endothelial function during cardiac surgery
Chapter 1.4.1 --- Cardioplegia and organ preservation solutions --- p.31
Chapter 1.4.2 --- Combined effects of hypoxia-reoxygenation and ST solution on endothelial function in coronary microarteries/cardiac veins --- p.34
Chapter 1.4.3 --- Effect of nicorandil on endothelial function --- p.34
Chapter Chapter 2. --- Materials and Methods --- p.37
Chapter 2.1 --- Isometric force study in micro arteries/veins --- p.37
Chapter 2.1.1 --- Preparation of vessels --- p.37
Chapter 2.1.1.1 --- Preparation of porcine coronary microarteries --- p.37
Chapter 2.1.1.2 --- Preparation of porcine cardiac veins --- p.37
Chapter 2.1.2 --- Technique of setting up --- p.39
Chapter 2.1.2.1 --- Mounting of microvessels --- p.39
Chapter 2.1.2.2 --- Normalization procedure for microvessels --- p.39
Chapter 2.1.3 --- EDHF-mediated vasorelaxation --- p.40
Chapter 2.1.3.1 --- Precontraction and stimuli of EDHF --- p.40
Chapter 2.1.3.2. --- “Truéحresponse of EDHF --- p.40
Chapter 2.1.4 --- Data acquisition and analysis --- p.41
Chapter 2.2 --- Hypoxia and reoxygenation --- p.41
Chapter 2.2.1 --- Calibration of 02-special electrode --- p.41
Chapter 2.2.2 --- Measurement of --- p.02
Chapter 2.3 --- Statistical analysis --- p.42
Chapter 2.4 --- Chemicals --- p.43
Chapter Chapter 3. --- Hypoxia-Reoxygenation in Coronary Microarteries: Combined Effect with St Thomas Cardioplegia and Temperature on the Endothelium- derived Hyperpolarizing Factor and Protective Effect of Nicorandil --- p.44
Chapter 3.1 --- Abstract --- p.44
Chapter 3.2 --- Introduction --- p.45
Chapter 3.3 --- Experimental design and analysis --- p.47
Chapter 3.3.1 --- Vessel Preparation --- p.47
Chapter 3.3.2 --- Normalization --- p.48
Chapter 3.3.3 --- Hypoxia --- p.48
Chapter 3.3.4 --- Effect of H-R on EDHF-mediated relaxation in coronary microarteries --- p.49
Chapter 3.3.5 --- Combined effects ofH-R and ST solution on EDHF-mediated relaxation in coronary microarteries --- p.49
Chapter 3.3.6 --- Effect of addition of nicorandil Krebs or ST solution under H-R on EDHF-mediated relaxation in coronary microarteries --- p.49
Chapter 3.3.7 --- Data analysis --- p.50
Chapter 3.4 --- Results --- p.51
Chapter 3.4.1 --- Resting force --- p.51
Chapter 3.4.2 --- U46619-induced contraction force --- p.51
Chapter 3.4.3 --- Partial pressure of oxygen in hypoxia --- p.51
Chapter 3.4.4 --- EDHF-mediated relaxation in coronary microarteries --- p.51
Chapter 3.4.4.1 --- Effect of H-R --- p.51
Chapter 3.4.4.2 --- Combined effects ofH-R and ST solution on EDHF-mediated relaxation --- p.52
Chapter 3.4.4.3 --- Effects of addition of nicorandil to Krebs or ST solution under H-R on EDHF-mediated relaxation --- p.52
Chapter 3.5 --- Discussion --- p.53
Chapter 3.5.1 --- EDHF-mediated relaxation after exposure to H-R --- p.53
Chapter 3.5.2 --- EDHF-mediated relaxation after H-R in ST solution at different temperature --- p.54
Chapter 3.5.3 --- Effect of addition of nicorandil to Krebs or ST solution during H-R on EDHF-mediated relaxation --- p.55
Chapter 3.5.4 --- Clinical implications --- p.56
Chapter Chapter 4. --- Hypoxia-Reoxygenation in Cardiac Microveins: Combined Effect with Cardioplegia and Temperature on the Endothelial Function --- p.68
Chapter 4.1 --- Abstract --- p.68
Chapter 4.2 --- Introduction --- p.69
Chapter 4.3 --- Experimental design and analysis --- p.73
Chapter 4.3.1 --- Vessel Preparation --- p.73
Chapter 4.3.2 --- Normalization --- p.73
Chapter 4.3.3 --- Hypoxia --- p.73
Chapter 4.3.4 --- Effect of H-R on EDHF-mediated relaxation in cardiac micro veins --- p.74
Chapter 4.3.5 --- Combined effects of H-R and ST solution on EDHF-mediated relaxation in cardiac microveins --- p.74
Chapter 4.3.6 --- Data analysis --- p.75
Chapter 4.4 --- Results --- p.75
Chapter 4.4.1 --- Resting force --- p.75
Chapter 4.4.2 --- U46619-induced contraction force --- p.76
Chapter 4.4.3 --- Partial pressure of oxygen in hypoxia --- p.76
Chapter 4.4.4 --- EDHF-mediated relaxation after H-R in Krebs solution at 37°C --- p.76
Chapter 4.4.5 --- EDHF-mediated relaxation after exposure to H-R in ST solution at different temperatures --- p.77
Chapter 4.5 --- Discussion --- p.78
Chapter 4.5.1 --- Effect of H-R on EDHF-mediated relaxation --- p.78
Chapter 4.5.2 --- Combined effects of H-R with ST solution on EDHF-mediated relaxation --- p.80
Chapter 4.5.3 --- Clinical implications
Chapter Chapter 5. --- General Discussion --- p.89
Chapter 5.1 --- EDHF-mediated endothelial function in porcine coronary circulation --- p.89
Chapter 5.1.1 --- EDHF in porcine coronary microarteries --- p.92
Chapter 5.1.2 --- EDHF in porcine cardiac veins --- p.90
Chapter 5.2 --- Alteration of EDHF-mediated function after exposure to H-R --- p.91
Chapter 5.2.1 --- In coronary microarteries --- p.91
Chapter 5.2.2 --- In cardiac veins --- p.92
Chapter 5.3 --- Alteration of EDHF-mediated function after exposure to ST solution under H-R --- p.92
Chapter 5.3.1 --- In coronary microarteries --- p.93
Chapter 5.3.2 --- In cardiac veins --- p.93
Chapter 5.4 --- EDHF-mediated function in nicorandil-supplemented ST solution under H-R in coronary microarteries --- p.93
Chapter 5.5 --- Clinical implications
Chapter 5.5.1 --- H-R injury --- p.94
Chapter 5.5.2 --- H-R injury and cardioplegic solution --- p.95
Chapter 5.5.2 --- Nicorandil-supplementation in cardioplegic solution --- p.95
Chapter 5.6 --- Limitation of the study --- p.96
Chapter 5.7 --- Future investigations --- p.96
Chapter 5.8 --- Conclusions --- p.97
References --- p.99

碩士
國立交通大學
應用化學系碩博士班
104
Cardiac arrest (CA) remains a critical challenge of public health. Almost 50% of all cardiovascular deaths is contributed by CA, which is mainly caused by and myocardial ischemia as a result of coronary stenosis or occlusion. Among the victims who are successfully rescued from CA to returning of spontaneous circulation (ROSC), only 5 to 10% of them would survive mainly because of complex pathophysiological processes that occur during ischemia and the subsequent reperfusion after ROSC (generally termed post cardiac arrest syndrome). A variety of animals have been developed as a model of cardiac arrest and these model systems have provided a useful platform for translational research and development of therapeutic intervention. However, they still suffer from limitations such as unsatisfactory reproducibility or complicated procedures of surgery. Recently, the zebrafish has become a popular model for cardiac research because of its high reproductive rate, high degree of genetic and functional conservation relative to human beings, and translucent body at larvae stage that facilitates dynamic observation of cardiac morphology and function in vivo. In this research, we report a novel zebrafish model of CA using hypoxia treatment to induce CA, and reoxygenation treatment to mimic the effect of CPR. By using pseudodynamic three-dimensional imaging, we particularly determined the cardiac function of zebrafish at varied phases post reoxygenation. We discovered that zebrafish larvae at 8 days post fertilization is suitable to model hypoxia induced cardiac arrest and ROSC after reoxygenation. More importantly, our observations conformed to some essential features of post cardiac arrest syndrome in higher animals, including an increased oxidative stress in the zebrafish heart, an increased myocardial cell death, and the dynamic change of cardiac function (dysfunction and resumption) after the onset of reoxygenation. We expect that our approach will benefit not only the fundamental research on diseases related to CA but also the investigation of new therapeutic strategies targeting these diseases.

Pre-clinical studies of new molecules which can be developed as possible therapeutic effectors: in particular, the study of the protective effects of the hormone relaxin, as well as scavenger molecules of oxygen reactive species on cardiac hypoxia/reoxygenation.