吡那地尔介导超极化心脏停搏液对心肌的保护作用

目的：为了提高心脏停搏液的心肌保护作用，探讨含吡那地尔（pinacidil)超极化心脏停搏液对心肌的保护作用。方法：32只新西兰兔根据体外循环中使用不同的心脏停搏液分为对照组和实验组，对照组用St Thomas Ⅱ号心脏停搏液，实验组用含吡那地尔（50μmol/L）的心脏停搏液。两组又根据主动脉阻断后是否再灌注，分别分为两组（对照组A、对照组B、实验组A、实验组B），每组8只兔。对照组A和实验组A在主动脉阻断60分钟后结束实验；对照组B和实验组B于主动脉阻断60分钟、复滞30分钟结束实验。记录心脏电机械停搏时间，复跳时的心律失常情况，测定实验结束时各组心肌三磷酸腺苷（ATP）、总腺苷酸（TAN）、Ca^2 、丙二醛（MDA）含量，对照组B和实验组B血清心肌酶含量，并观察心肌超微结构变化。结果：4组心脏均迅速发生电机械停搏，对照组B、实验组B复跳时均发生心律失常3例，未发生严重心律失常；实验组A和实验组B的ATP、TAN分别高于对照组A和对照组B（P＜0．01），而Ca^2 和MDA分别显著低于对照组A和对照组B（P＜0．05），实验组B心肌酶的漏出量显著低于对照组B（P＜0．01）。实验组B超微结构损伤轻，优于对照组B。结论：含吡那地尔的心脏停搏液对心肌保护的作用优于高K^ 心脏停搏液。     

Limitations of heart preservation by cold storage.

Clinical heart preservation is currently limited to only 4-6 hr, while the kidney, liver, and pancreas can tolerate 24-48 hr of cold ischemia. A fundamental difference between these organs is that the heart is contractile, containing large quantities of actin and myosin, and is susceptible to contracture-induced injury caused by energy deprivation. We have quantified and correlated the onset of contracture with levels of ATP and glycogen during cold storage in rabbit hearts flushed with UW solution, with and without 1 mM calcium (Ca), or 3 mM iodoacetate (IAA). A fluid-filled left ventricular balloon was used to generate pressure-volume curves (compliance) at 1, 6, 12, 18, and 24 hr of cold storage. Onset of contracture occurred in UW stored hearts at 18 hr, contracture in hearts exposed to Ca occurred between 6 and 12 hr. Compliance was significantly less in hearts exposed to Ca at 12, 18, and 24 hr (P less than .01) than in hearts without Ca. ATP levels were well maintained for up to 18 hr in the hearts preserved in UW solution (78%), but fell more rapidly in the presence of Ca at 12 hr (P less than .005), 18 hr (P less than .005), and 24 hr (P less than .05). In comparison, the ATP supply of the liver and kidney was exhausted by only 4 hr of cold storage. Onset of myocardial contracture correlated with a decrease in ATP to less than 80% of control, and contracture accelerated ATP decline 3-6-fold. IAA caused nearly complete myocardial contracture and ATP depletion within 2 hr. Isolated heart function was 77% and 73% at 6 and 12 hr of storage, but fell to 54% and 42% at 18 and 24 hr, respectively, coinciding with development of contracture. We conclude that ischemic contracture in this model is a major cause of myocardial damage during cold storage, and is accelerated by the presence of Ca. Other organs can be successfully stored despite exhaustion of ATP reserves. Thus successful cold-storage of the heart is highly ATP-dependent. Since cold storage inevitably leads to ATP depletion, extension of myocardial ischemic tolerance will depend on either reversible inhibition of ATP hydrolysis during storage, reversible uncoupling of contracture development from ATP depletion, or maintaining ATP production by continuous hypothermic perfusion.     

Cardioprotective effects of FK409, a nitric oxide donor, after isolated rat heart preservation for 16 hours

BACKGROUND: We examined the cardioprotective effects of FK409, a nitric oxide donor, after isolated rat heart preservation. METHODS: FK409 was administered to the hearts in pretreatment (FK409-1 group), during ischemia (FK409-2), or during reperfusion (FK409-3). The combined nitrate and nitrite level, coronary flow, cardiac function, coronary vasodilatory response, creatine kinase (CK), and myocardial water content were evaluated after the hearts had been preserved in University of Wisconsin solution at 0 degrees C for 16 hours. RESULTS: The release of nitrate and nitrite increased in reperfusion between the 20-to-40-second measurement and the measurement at 40 minutes, and the recovery of cardiac function was significantly improved in the FK409 groups. The coronary vasodilatory response to acetylcholine chloride was enhanced in the FK409-1 and FK409-2 groups. CK release decreased in FK409 groups after 15 minutes in reperfusion. CONCLUSIONS: This study suggests that FK409 has the best protective effect on cardiac function and coronary endothelial function when it is administered in the ischemic period, a less protective effect when administered during pretreatment, and the least protective effect when FK409 is given during reperfusion after heart preservation for 16 hours.     

Cerebral effects of cold reperfusion after hypothermic circulatory arrest

OBJECTIVES: This study was undertaken to explore whether an interval of cold reperfusion can improve cerebral outcome after prolonged hypothermic circulatory arrest. METHODS: Sixteen pigs (27-30 kg) underwent 90 minutes of circulatory arrest at a brain temperature of 20 degrees C. Eight animals were rewarmed immediately after hypothermic circulatory arrest (controls), and 8 were reperfused for 20 minutes at 20 degrees C and then rewarmed (cold reperfusion). Electrophysiologic recordings, fluorescent microsphere determinations of cerebral blood flow, calculations of cerebral oxygen consumption, and direct measurements of intracranial pressure (millimeters of mercury) were obtained at baseline (37 degrees C), before hypothermic circulatory arrest, after discontinuing circulatory arrest at 37 degrees C deep brain temperature, and at 2, 4, and 6 hours thereafter. Histopathologic features and percent brain water were determined after the animals were sacrificed. RESULTS: Cerebral blood flow and oxygen consumption decreased during cooling: cerebral oxygen consumption returned to baseline levels after 4 hours, but cerebral blood flow remained depressed until 6 hours in both groups. Cold reperfusion failed to improve electrophysiologic recovery or to reduce brain weight, but median intracranial pressure increased significantly less after cold reperfusion than in controls (P =.02). Although no significant difference in the incidence of histopathologic abnormalities between groups was found, all 3 animals with an intracranial pressure of more than 15 mm Hg after immediate rewarming had histopathologic lesions, and high intracranial pressure was more prevalent among all animals with subsequent histopathologic lesions (P =.03). CONCLUSIONS: Cold reperfusion significantly inhibited the rise in intracranial pressure seen in control pigs after 90 minutes of circulatory arrest at 20 degrees C, suggesting that cold reperfusion may decrease cerebral edema and thereby improve outcome after prolonged hypothermic circulatory arrest.     

Kinetics of heat shock protein 70 synthesis in the human heart after cold cardioplegic arrest.

OBJECTIVE: Protection of the myocardium against ischemia/reperfusion injury is a major challenge in cardiac surgery and cardiology. A cardioprotective role of heat shock proteins (Hsp), in particular Hsp 70, against ischemia has been demonstrated. A prerequisite for clinical exploitation of high Hsp 70 levels in the heart during ischemia is the determination of the efficacy and the kinetics of cardiac Hsp synthesis in vivo. METHODS: We examined Hsp 70 and other immediate early genes, that are induced by cardioplegia and reperfusion, in right atrial biopsies taken from 15 patients during coronary artery bypass grafting. Specimens were obtained before cardioplegia and after ending of reperfusion and subsequently studied by immunohistochemistry and Western blot analyses. RESULTS: Overall Hsp 70 increased 2.0+/-1.1-fold (P<0.01) in the nucleus as well as in the cytosol of myocytes and endothelial cells during open-heart surgery. As determined by comparison to a dilution series of recombinant protein, Hsp 70 levels amounted up to 6 per thousand of total cellular protein. The increase of Hsp 70 correlated well with the duration of cardioplegia and reperfusion (P<0.005) showing a markedly accelerated increase at periods longer than 2 h. Further, the immediate early gene c-Fos also increased 2.4+/-2.2-fold during open-heart surgery (P<0.05), whereas other members of the Hsp family, like Hsp 27 and Hsp 90, showed no significant changes in protein levels during cardioplegia and reperfusion. CONCLUSIONS: These findings demonstrate that protein levels of Hsp 70 in the myocardium increase to significant amounts within few hours after induction. The optimum time point for induction of Hsp 70 appears to be at least 2 h before open-heart surgery.     

超极化心脏保存液对离体大鼠心脏低温保存的保护作用

目的　探讨含K 通道开放剂的心脏保存液(HCS液)对大鼠离体心脏的保存作用。方法　将24只SD大鼠随机平均分为 3 组,分别用 HCS液、UW液、K H液对心脏进行保存。采用Langendorff心脏灌注和工作模型装置进行心脏功能测定,比较 24h后心功能恢复率以及细胞酶学、心肌含水量、pH值变化和能量变化,观察心肌超微结构改变。结果　心脏保存24 h后, K H组左心室功能损伤严重,UW组及HCS组左心室功能损伤较轻。HCS组冠状动脉流量(CF)恢复率较 K H组、UW组好;HCS组冠脉回流液中乳酸脱氢酶(LDH)、磷酸肌酸激酶(CPK)含量及心肌含水量与UW组比较,差异无统计学意义;HCS组 pH值变化最小, ATP含量最高;HCS组心脏复跳时间与UW组基本相同; HCS组心肌保存良好。结论　HCS保存液对大鼠心脏的保存在 24 h内有明显的保护作用,心脏功能恢复率能达到UW液的水平,在能量保护、改善酸中毒方面则优于UW液。     

Enhanced myocardial preservation by nicotinic acid, an antilipolytic compound. Improved cardiac performance after hypothermic cardioplegic arrest

The effect of nicotinic acid, an antilipolytic drug, on myocardial preservation was studied on the basis of cardiac performance after 2 hours of cardioplegic arrest. Isolated in situ pig hearts were subjected to 120 minutes of hypothermic potassium (35 mEq) crystalloid cardioplegic arrest followed by 60 minutes of reperfusion. The experimental group received nicotinic acid 0.08 mmol/L 15 minutes before cardioplegic arrest, whereas the control group received 15 minutes of unmodified perfusion. There was a marked decline in myocardial creatine phosphate levels during cardioplegic arrest in both groups that returned to the baseline level during reperfusion without a significant intergroup difference, and adenosine triphosphate levels remained stable throughout the experiment in both groups. Myocardial oxygen consumption during reperfusion was significantly higher in hearts treated with nicotinic acid, which was consistent with a significantly greater cardiac contractile force as evaluated by isovolumetric left ventricular pressure measurements. There appeared to be less cardiac membrane damage as measured by creatine kinase release during reperfusion, which was significantly inhibited by treatment with nicotinic acid. The present study supports the conclusion that nicotinic acid improves cardiac performance after hypothermic cardioplegic arrest.     

Intranasal cooling with or without intravenous cold fluids during and after cardiac arrest in pigs

Background: Intranasal balloon catheters circulated with cold saline have previously been used for the induction and maintenance of selective brain cooling in pigs with normal circulation. In the present study, we investigated the feasibility of therapeutic hypothermia initiation, maintenance and rewarming using such intranasal balloon catheters with or without addition of intravenous ice‐cold fluids during and after cardiac arrest treatment in pigs. Material and methods: Cardiac arrest was induced in 20 anaesthetised pigs. Following 8 min of cardiac arrest and 1 min of cardiopulmonary resuscitation (CPR), cooling was initiated after randomisation with either intranasal cooling (N) or combined with intravenous ice‐cold fluids (N+S). Hypothermia was maintained for 180 min, followed by 180 min of rewarming. Brain and oesophageal temperatures, haemodynamic variables and intracranial pressure (ICP) were recorded. Results: Brain temperatures reductions after cooling did not differ (3.8 ± 0.7 °C in the N group and 4.3 ± 1.5 °C in the N+S group; P=0.47). The corresponding body temperature reductions were 3.6 ± 1.2 °C and 4.6 ± 1.5 °C (P=0.1). The resuscitation outcome was similar in both groups. Mixed venous oxygen saturation was lower in the N group after cooling and rewarming (P=0.024 and 0.002, respectively) as compared with the N+S group. ICP was higher after rewarming in the N group (25.2 ± 2.9 mmHg; P=0.01) than in the N+S group (15.7 ± 3.3 mmHg). Conclusions: Intranasal balloon catheters can be used for therapeutic hypothermia initiation, maintenance and rewarming during CPR and after successful resuscitation in pigs.     

NOS substrate during cardioplegic arrest and cold storage decreases stunning after heart transplantation in a rat model.

BACKGROUND: In this study, we evaluated how adding L-arginine to Centre de Résonance Magnétique Biologique et Médicale (CRMBM) solution affected myocardial performance during post-ischemic in vivo reperfusion. METHODS: Experiments were conducted using a modified Lewis-Lewis heterotopic heart transplantation model, with a total ischemic time of 3 hours followed by 1 or 24 hours of blood reperfusion. Heart grafts were arrested using intra-aortic injection of CRMBM solution, either supplemented or not supplemented with 2 mmol/liter L-arginine (n = 12 in each group). We measured systolic indexes and simultaneously performed phosphorus magnetic resonance spectroscopy ((31)P MRS). We quantified total endothelial nitric oxide synthase (eNOS) protein using the Western blot test of freeze-clamped hearts. RESULTS: Contractility during early reperfusion was significantly better in grafts arrested with CRMBM solution enriched with L-arginine: mean rate pressure product, 11249 +/- 1548 vs 5637 +/- 1118 mm Hg/min (p = 0.05), and maximal first derivative of the pressure signal (dP/dt(max)), 1721 +/- 177 vs 1214 +/- 321 mm Hg/sec (p = 0.013). Conversely, during late reperfusion, contractility did not relate to the nature of the preservation solution. The presence of L-arginine in the CRMBM solution did not alter time-related variations of high-energy phosphate ratios measured using in vivo (31)P MRS. The eNOS protein level decreased significantly during early compared with late reperfusion, with no effect caused by L-arginine. CONCLUSIONS: During early reperfusion, the limited myocardial stunning observed with CRMBM solution containing L-arginine does not relate to energy metabolism but to better preservation of the NO pathway.     

Hepatic rupture after cardiac arrest

Key words  cardiac massage - hepatic rupture - pulmonary embolism     

Post-resuscitation syndrome. Role of inflammation after cardiac arrest

Cardiac arrest with subsequent cardiopulmonary resuscitation causes an ischemic reperfusion syndrome of the whole body resulting in localized damage of particularly sensitive organs, such as the brain and heart, together with systemic sequelae. The main factor is a generalized activation of inflammatory reactions resulting in symptoms similar in many aspects to those of sepsis. Systemic inflammation strengthens organ damage due to disorders in the macrocirculation and microcirculation due to metabolic imbalance as well as the effects of direct leukocyte transmitted tissue destruction. The current article gives an overview on the role of inflammation following cardiac arrest and presents in detail the underlying mechanisms, the clinical symptoms and possible therapeutic approaches.