Cardiac depression and cellular injury in hemorrhagic shock and reinfusion: Role of free radicals

We investigated the effects of hemorrhagic shock and reinfusion on the cardiac function and contractility, plasma CK and CK-MB activity and lactate concentration, oxyradical-producing activity of polymorphonuclear leukocytes (PMNL-CL), cardiac chemiluminescence (LV-CL), antioxidant enzyme activity [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-P_X)] and malondialdehyde (MDA) concentration in anesthetized dogs to determine the role of oxyradicals in cardiac depression and cellular injury in hemorrhagic shock and reinfusion. The dogs were assigned into three groups: I (sham), 4 h duration; II (S + R), 2 h of shock followed by reinfusion for 2 h; III (SOD + S + R), as II but pretreated with PEG-SOD. Hemorrhagic shock was produced by withdrawal of blood to maintain the mean arterial pressure at 50 ± 5 mm Hg. Cardiac function and contractility were depressed during hemorrhagic shock. Plasma CK, CK-MB and lactate increased during shock. Following reinfusion after 2 h of shock hemodynamic parameters and plasma lactate tended to return towards control values. Plasma CK and CK-MB, PMNL-CL and cardiac MDA, total-, Mn- and CuZn-SOD activity increased while LV-CL decreased. In spite of the increase in the antioxidant reserve, there was oxidative damage. Pretreatment with SOD attenuated the deleterious effects of shock and reinfusion on the cardiovascular function, plasma CK, and CK-MB, PMNL-CL, cardiac MDA, SOD, and LV-CL. Protection was incomplete for cardiovascular function and plasma CK and CK-MB. These results suggest that oxyradicals may partly be involved in the deterioration of cardiovascular function and cellular injury during hemorrhagic shock and reinfusion.     

刺激腓深神经对低血压或休克狗心血管活动的影响

实验在麻醉狗中进行。静脉内匀速注射硝普钠时,平均动脉压和左心室收缩压明显降低,左心室dp/dt_(max)、-dp/dt_(max)和心力环面积均明显减小。此时电刺激一侧腓深神经可使动脉血压和左心室收缩压明显升高,dp/dt_(max)和心力环面积也显著增加。停止刺激后,动脉血压和左心室收缩压逐渐回向刺激前的水平。停止注射硝普钠5～15分钟后,上述各项观察指标基本恢复到注药前的水平。在用大肠杆菌内毒素造成休克的狗中,电刺激一侧腓深神经,也能使平均动脉压和左心室收缩压升高,同时dp/dt_(max)、-dp/dt_(max)和肠系膜血管阻力明显增高,但肾血管阻力增加不明显。本实验结果与以往的实验资料一起表明,在用扩血管药造成低血压时,躯体神经刺激引起的升压效应似乎以心肌收缩力增加为主;而在内毒素休克时,躯体神经刺激可通过改善心肌收缩功能和增加内脏血管阻力而引起升压作用。     

Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression

Although studies indicate that 17beta-estradiol administration after trauma-hemorrhage (T-H) improves cardiac and hepatic functions, the underlying mechanisms remain unclear. Because the induction of heat shock proteins (HSPs) can protect cardiac and hepatic functions, we hypothesized that these proteins contribute to the salutary effects of estradiol after T-H. To test this hypothesis, male Sprague-Dawley rats ( approximately 300 g) underwent laparotomy and hemorrhagic shock (35-40 mmHg for approximately 90 min) followed by resuscitation with four times the shed blood volume in the form of Ringer lactate. 17beta-estradiol (1 mg/kg body wt) was administered at the end of the resuscitation. Five hours after T-H and resuscitation there was a significant decrease in cardiac output, positive and negative maximal rate of left ventricular pressure. Liver function as determined by bile production and indocyanine green clearance was also compromised after T-H and resuscitation. This was accompanied by an increase in plasma alanine aminotransferase (ALT) levels and liver perfusate lactic dehydrogenase levels. Furthermore, circulating levels of TNF-alpha, IL-6, and IL-10 were also increased. In addition to decreased cardiac and hepatic function, there was an increase in cardiac HSP32 expression and a reduction in HSP60 expression after T-H. In the liver, HSP32 and HSP70 were increased after T-H. There was no change in heart HSP70 and liver HSP60 after T-H and resuscitation. Estradiol administration at the end of T-H and resuscitation increased heart/liver HSPs expression, ameliorated the impairment of heart/liver functions, and significantly prevented the increase in plasma levels of ALT, TNF-alpha, and IL-6. The ability of estradiol to induce HSPs expression in the heart and the liver suggests that HSPs, in part, mediate the salutary effects of 17beta-estradiol on organ functions after T-H.     

Hemodynamic and therapeutic effects of intravenous dopamine

The effects of intravenous dopamine were evaluated in 10 patients with severe but stable coronary artery disease, 17 consecutive patients with primary cardiogenic shock and 3 with severe congestive heart failure and oliguria. Dopamine infusion at 10 μg/kg·min in the 10 patients increased cardiac output by 35%, left ventricular peak dP/dt by 38%, left ventricular minute work index by 44% and mean systolic ejection rate by 7% (P < 0.01); heart rate, aortic pressure, left ventricular end-diastolic pressure and tension-time index were unchanged. For oxygen, potassium and lactate, arterial and coronary sinus values, coronary arteriovenous oxygen differences and myocardial extraction were unchanged. Hemodynamically 13 of the 17 patients in shock responded favourably to dopamine infusion (0.5 to 15 μg/kg·min), with decrease in heart rate, increase in systolic arterial pressure from 75 to 100 mm Hg (P <0.001), decrease in ventricular filling pressure from 20 to 16 mm Hg (P < 0.01) and increase in urine output from 10 to 100 ml/h (P < 0.01). Eleven of those patients survived the shock episode. A close relation was observed between the hemodynamic response to dopamine, survival from the shock episode and the time between onset of shock and initiation of therapy. Low rates of dopamine infusion induced diuresis in the three patients with severe cardiac failure.Dopamine thus seems to improve the mechanical efficiency of the heart in coronary artery disease. Cardiac output is selectively increased and myocardial ischemia does not appear to be induced; those beneficial effects as well as presumably specific action on renal flow and natriuresis, improve immediate survival from cardiogenic shock and severe heart failure.     

左西孟旦对脓毒症休克患者心肌损伤的保护作用探讨

目的:探讨左西孟旦对脓毒症休克患者心肌损伤的保护作用。方法:选择我院2013年1月至2017年12月收治的149例脓毒症休克患者,根据随机数字表法分为观察组(73例)及对照组(76例),对照组给予常规治疗及静脉注射多巴酚丁胺48 h,观察组在常规治疗基础上给予静脉注射多巴酚丁胺24h后再静脉注射左西孟旦24 h。观察和比较两组的心脏功能参数、血流动力学指数、肌钙蛋白、乳酸、去甲肾上腺素、机械通气例数及ICU病死率。结果:治疗前,两组的左室射血分数、左室舒张期末容积指数及左室收缩期末容积指数对比差异无统计学意义(P0.05);治疗后,观察组的心排血量、每搏量指数、左室每搏作功指数均明显高于对照组,中心静脉压低于对照组(P0.05)。对比治疗前,治疗后观察组的心脏功能参数有明显改善(P0.05),而对照组无明显差别(P0.05)。此外,两组治疗后肌钙蛋白及乳酸水平均低于治疗前,且观察组明显低于对照组(P0.05)。两组的去甲肾上腺素总用量、机械通气例数及ICU病死率对比差异均无统计学意义(P0.05)。结论:左西孟旦对脓毒症休克患者具有心肌保护作用,可以改善患者心脏功能,优化血流动力学,但并不能降低患者ICU病死率。     

Acute cardiovascular failure and its treatment--value of defibrillation in preclinical management]

Ventricular fibrillation is the most common cause of cardiac arrest. The only scientifically proved therapy that guarantees a long time survival is the early electrical defibrillation. As early as 200 years ago electricity was employed in trying to regain circulation in cases of unexpected death. In the field of emergency medicine almost all rescue services are equipped with defibrillators nowadays and the personnel is trained in using them. Since the application of electricity on the myocardium can lead to damage, there are devices with a varied defibrillation pulse available since recently. The advantage of the biphasic defibrillation is a less harmful impact on the myocardium at lower shock intensity. A further novelty which enables the application by groups other than the rescue services, is the automatic external defibrillator (AED). Extending the availability of defibrillators can contribute to an increase in the presently low success rates of resuscitation.     

Heat shock regulates the respiration of cardiac H9c2 cells through upregulation of nitric oxide synthase

Mild and nonlethal heat shock (i.e., hyperthermia) is known to protect the myocardium and cardiomyocytes against ischemic injury. In the present study, we have shown that heat shock regulates the respiration of cultured neonatal cardiomyocytes (cardiac H9c2 cells) through activation of nitric oxide synthase (NOS). The respiration of cultured cardiac H9c2 cells subjected to mild heat shock at 42 degrees C for 1 h was decreased compared with that of control. The O2 concentration at which the rate of O2 consumption is reduced to 50% was increased in heat-shocked cells, indicating a lowering of O2 affinity in the mitochondria. Western blot analyses showed a fourfold increase in the expression of heat shock protein (HSP) 90 and a twofold increase in endothelial NOS (eNOS) expression in the heat-shocked cells. Immunoblots of eNOS, inducible NOS (iNOS), and neuronal NOS (nNOS) in the immunoprecipitate of HSP90 of heat-shocked cells showed that there was a sevenfold increase in eNOS and no changes in iNOS and nNOS. Confocal microscopic analysis of cells stained with the NO-specific fluorescent dye 4,5-diaminofluorescein diacetate showed higher levels of NO production in the heat-shocked cells than in control cells. The results indicate that heat shock-induced HSP90 forms a complex with eNOS and activates it to increase NO concentration in the cardiac H9c2 cells. The generated NO competitively binds to the complexes of the respiratory chain of the mitochondria to downregulate O2 consumption in heat-shocked cells. On the basis of these results, we conclude that myocardial protection by hyperthermia occurs at least partly by the pathway of HSP90-mediated NO production, leading to subsequent attenuation of cellular respiration.     

Role of TNF-alpha in myocardial dysfunction after hemorrhagic shock and lower-torso ischemia

Ruptured abdominal aortic aneurysm (RAAA) repair, a combination of hemorrhagic shock and lower-torso ischemia, is associated with a 50-70% mortality. Myocardial dysfunction may contribute to the high rate of mortality after aneurysm repair. We attempted to determine whether RAAA repair results in cardiac dysfunction mediated by tumor necrosis factor-alpha (TNF-alpha). We modeled aortic rupture and repair in the rat by inducing hemorrhagic shock to a mean blood pressure of 50 mmHg for 1 h, followed by supramesenteric clamping of the aorta for 45 min. After 90 min of reperfusion, cardiac contractile function was assessed with a Langendorff preparation. Myocardial TNF-alpha, ATP and creatine phosphate (CP) levels, and markers of oxidant stress (F(2)-isoprostanes) were measured. Cardiac function in the combined shock and clamp rats was significantly depressed compared with sham-operated control rats but was similar to that noted in animals subjected to shock alone. Myocardial TNF-alpha concentrations increased 10-fold in the combined shock and clamp rats compared with sham rats, although there was no difference in myocardial ATP, CP, or F(2)-isoprostanes. TNF-alpha neutralization improved cardiac function by 50% in the combined shock and clamp rats. Hemorrhagic shock is the primary insult inducing cardiac dysfunction in this model of RAAA repair. An improvement in cardiac contractile function after immunoneutralization of TNF-alpha indicates that TNF-alpha mediates a significant portion of the myocardial dysfunction in this model.     

Pulmonary Embolectomy

Embolectomy was carried out in eight patients with pulmonary emboli. Angiographic diagnosis was obtained in six, and in two cases pulmonary angiography could not be done because of the very critical condition of the patients. In the latter two, diagnosis was made based only on clinical findings. Two patients died in the operating room (25 percent). Six patients were discharged in good condition.It is emphasized that pulmonary embolectomy should be done in cases of pulmonary emboli when a clinical status of shock is present (systolic blood pressure less than 80 mm of mercury and the patient in low cardiac output syndrome) and when there is no response to medical treatment regardless of the degree of obstruction in the pulmonary arterial tree.     

Leukocytosis of exercise: role of cardiac output and catecholamines

The effect of propranolol (5 mg iv) on the leukocytosis of exercise was studied in seven normal young males. Leukocyte counts, plasma norepinephrine (NE), epinephrine (E), and cardiac output were measured at rest and in the steady state of several submaximal work loads when subjects exercised on a cycle ergometer. The results in control experiments were compared with those obtained on a different day with propranolol. Propranolol decreased heart rate at all work loads (P less than 0.001) but had no effect on the increase in cardiac output at increasing work loads. Plasma NE and E levels were similar at rest and in exercise in control and propranolol studies. There was no effect of propranolol on the increase in leukocyte counts with increasing work loads. Although propranolol did not affect the increase in total leukocyte count, the increase in lymphocyte count at higher work loads was less with propranolol. We conclude that the demargination of leukocytes from the pulmonary circulation in exercise is probably a mechanical effect of the increase in cardiac output. However, we have not excluded a contribution from a humoral event that would decrease the adherence of leukocytes to endothelium during exercise. The smaller increase in lymphocytes at higher work loads in the presence of propranolol suggests that catecholamines affect the lymphocyte count over and above their effect on cardiac output.     

Cardiac shock wave therapy: assessment of safety and new insights into mechanisms of tissue regeneration

Although low-energy extracorporeal cardiac shock wave (ECSW) therapy represents an attractive non-invasive treatment option for ischaemic heart disease, the precise mechanisms of its action and influence on the cardiac tissue remain obscure. The goal of this study was to evaluate the effects of SW application on cardiac function and structure. Four-month-old Fisher 344 rats were subjected to ECSW therapy. Echocardiographic measurements of cardiac function were performed at baseline and at 1 and 3 months after treatment. Signs of inflammation, apoptosis and fibrosis were evaluated by immunohistochemistry in the control and treated hearts. ECSW application did not provoke arrhythmia or increase the troponin-I level. At all time points, the left ventricular ejection fraction and fractional shortening remained stable. Histological analysis revealed neither differences in the extracellular matrix collagen content nor the presence of fibrosis; similarly, there were no signs of inflammation. Moreover, a population of cardiac cells that responded eagerly to ECSW application in the adult heart was identified; c-kit-positive, Ki67-positive, orthochromatic cells, corresponding to cardiac primitive cells, were 2.65-fold more numerous in the treated myocardium. In conclusion, non-invasive ECSW therapy is a safe and effective way of activating cardiac stem cells and myocardial regeneration. Because many factors influence cellular turnover in the ischaemic myocardium during the course of ischaemic heart disease, cardiac remodelling, and heart failure progression, studies to identify the optimal treatment time are warranted.     

两种败血症休克模型大鼠心肌细胞一氧化氮合酶活性的改变

目的：观察两种败血症休克模型大鼠的血流动力学及心肌细胞一氧化氮合酶活性变化的异同,探讨一氧化氮合酶参与败血症休克性心肌抑制的机制。方法：采用注射脂多糖（LPS）诱导及盲肠结扎穿孔（CLP）致腹膜炎诱导败血症休克模型,测定血流动力学指标以及心肌细胞胞浆一氧化氮合酶（NOS）活性。结果：①CLP模型大鼠的血流动力学指标随时间呈先上升后下降的趋势,LPS模型直接表现为类似于CLP模型晚期的动力学状态。在使用NOS抑制剂N-硝基-L精氨酸甲酯（L-NAME）后,CLP模型晚期及LPS模型的心室动力学指标均有明显改善。②CLP模型大鼠心肌细胞胞浆NOS活性在败血症中期达到最大。与假手术组相比,LPS模型、CLP模型晚期心肌细胞胞浆NOS活性均有明显增加,但是LPS模型与CLP模型晚期两组之间无明显差异。③使用L-NAME后,CLP晚期组与LPS组亚硝基及硝基化合物生成量均明显降低（P〈0.01）。其中,LPS组与CLP晚期组相比,前者固定表达型NOS生成亚硝基及硝基化合物生成量明显高于后者（P〈0．01）。结论：在LPS与CLP诱导的败血症休克模型中,心肌NOS是引起心室动力学变化的主要因素;在两种模型,心肌NOS亚型的表达不同,在LPS模型中主要为iNOS,而在CLP模型中则可能是cNOS和iNOS共同发挥作用。     

Anti-shock effect of pituitary adenylate cyclase activating polypeptide (PACAP) on experimental endotoxin shock in dogs

Effects of pituitary adenylate cyclase activating polypeptide with 38 amino acid residues (PACAP-38) on both cardiovascular functions and plasma hormone levels during endotoxin shock were studied in anesthesized dogs. When PACAP-38 (a bolus 420 pmol/kg injection or a bolus 420 pmol/kg injection followed by a continuous 30 pmol/kg/min infusion for 60 min) was administered intravenously 5 min after application of endotoxin, both mean arterial pressure and cardiac output were restored at 10 min. The continuous administration of PACAP-38 was more effective in improving the symptoms of shock. Plasma adrenalin and cortisol levels were significantly increased by both regimens. These results clearly indicate that the anti-shock properties of PACAP-38 may be attributed to its abilities to increase plasma cortisol and adrenalin levels and to stimulate cardiac function.     

Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases

Following dexamethasone (DEX), cardiac energy generation is mainly through utilization of fatty acids (FA), with DEX animals demonstrating an increase in coronary lipoprotein lipase (LPL), an enzyme that hydrolyzes lipoproteins to FA. We examined the mechanisms by which DEX augments cardiac LPL. DEX was injected in rats, and hearts were removed, or isolated cardiomyocytes were incubated with DEX (0-8 h), for measurement of LPL activity and Western blotting. Acute DEX induced whole body insulin resistance, likely an outcome of a decrease in insulin signaling in skeletal muscle, but not cardiac tissue. The increase in luminal LPL activity after DEX was preceded by rapid nongenomic alterations, which included phosphorylation of AMPK and p38 MAPK, that led to phosphorylation of heat shock protein (HSP)25 and actin cytoskeleton rearrangement, facilitating LPL translocation to the myocyte cell surface. Unlike its effects in vivo, although DEX activated AMPK and p38 MAPK in cardiomyocytes, there was no phosphorylation of HSP25, nor was there any evidence of F-actin polymerization or an augmentation of LPL activity up to 8 h after DEX. Combining DEX with insulin appreciably enhanced cardiomyocyte LPL activity, which closely mirrored a robust elevation in phosphorylation of HSP25 and F-actin polymerization. Silencing of p38 MAPK, inhibition of PI 3-kinase, or preincubation with cytochalasin D prevented the increases in LPL activity. Our data suggest that, following DEX, it is a novel, rapid, nongenomic phosphorylation of stress kinases that, together with insulin, facilitates LPL translocation to the myocyte cell surface.     

Sub-chronic administration of doxorubicin to Wistar rats results in oxidative stress and unaltered apoptotic signaling in the lung

Despite the vast published data on cardiac toxicity, there is still little work done regarding the toxicity of the antineoplastic agent Doxorubicin (DOX) in the lung. The aim of the present work was to determine if DOX causes alterations in selected apoptotic proteins and oxidative stress in the lung, in a similar manner to what occurs in the heart. For that purpose, lungs from Wistar-Han rats sub-chronically treated with vehicle or DOX for seven weeks were collected and analyzed concerning several proteins involved in mitochondrial permeabilization and apoptotic pathways, including p53, Bax and Bcl-2 and different oxidative stress markers. After sub-chronic DOX treatment, no alterations in lung proteins involved in mitochondrial membrane permeabilization or caspase 3 and 9-like activities were found. Nevertheless, an increase in malondialdehyde levels and a decrease in the lung concentration of vitamin E were detected, despite no alterations in reduced and oxidized glutathione. The results obtained indicate for the first time that lungs from DOX-treated rats appear to be susceptible to increased lipid peroxidation, which can explain some cases of DOX-induced lung toxicity.     

Myocardial accumulation and localization of the inducible 70-kDa heat shock protein, Hsp70, following exercise

Exercise increases the 70-kDa heat shock protein (Hsp70) in the myocardium, and this exercise-induced increase is associated with significantly improved cardiac recovery following insult. However, while heat shock has been shown to elevate Hsp70 primarily in the cardiac vasculature of the myocardium, the localization following exercise is unknown. Male Sprague-Dawley rats performed continuous treadmill running at 30 m/min for 60 min (2% incline) on either 1 or 5 consecutive days. At 30 min and 24 h following exercise, hearts were extirpated, and the left ventricle was isolated, OCT-cork mounted, and sectioned for immunofluorescent analysis. Whereas immunofluorescent analysis revealed little to no Hsp70 in control hearts and 30 min postexercise, the accumulation of Hsp70 24 h after a single exercise bout or 5 days of training was predominantly located in large blood vessels and, in particular, colocalized with a marker of smooth muscle. Furthermore, higher core temperatures attained during exercise led to more abundant accumulation in smaller vessels and the endothelium. It is concluded that the accumulation of myocardial Hsp70 following acute exercise predominantly occurs in a cell type-specific manner, such that changes in the cardiac vasculature account for much of the increase. This accumulation appears first in the smooth muscle of larger vessels and then increases in smaller vessels and the endothelium, as core temperature attained during exercise increases. This finding supports the observations after heat shock and further suggests that the vasculature is a primary target in exercise-induced cardioprotection.     

Low Energy Defibrillation in Human Cardiac Tissue: A Simulation Study

We aim to assess the effectiveness of feedback-controlled resonant drift pacing as a method for low energy defibrillation. Antitachycardia pacing is the only low energy defibrillation approach to have gained clinical significance, but it is still suboptimal. Low energy defibrillation would avoid adverse side effects associated with high voltage shocks and allow the application of implantable cardioverter defibrillator (ICD) therapy, in cases where such therapy is not tolerated today. We present results of computer simulations of a bidomain model of cardiac tissue with human atrial ionic kinetics. Reentry was initiated and low energy shocks were applied with the same period as the reentry, using feedback to maintain resonance. We demonstrate that such stimulation can move the core of reentrant patterns, in the direction that depends on the location of the electrodes and the time delay in the feedback. Termination of reentry is achieved with shock strength one-order-of-magnitude weaker than in conventional single-shock defibrillation. We conclude that resonant drift pacing can terminate reentry at a fraction of the shock strength currently used for defibrillation and can potentially work where antitachycardia pacing fails, due to the feedback mechanisms. Success depends on a number of details that these numerical simulations have uncovered.     

Role of helmet in the mechanics of shock wave propagation under blast loading conditions

The effectiveness of helmets in extenuating the primary shock waves generated by the explosions of improvised explosive devices is not clearly understood. In this work, the role of helmet on the overpressurisation and impulse experienced by the head were examined. The shock wave-head interactions were studied under three different cases: (i) unprotected head, (ii) head with helmet but with varying head-helmet gaps and (iii) head covered with helmet and tightly fitting foam pads. The intensification effect was discussed by examining the shock wave flow pattern and verified with experiments. A helmet with a better protection against shock wave is suggested.