Xinshuitong Capsule extract attenuates doxorubicin-induced myocardial edema via regulation of cardiac aquaporins in the chronic heart failure rats.

Doxorubicin (Dox), an effective antineoplastic drug, was limited use for cardiotoxicity. Xinshuitong Capsule (XST), a patented herbal formula, showed desirable beneficial effects in the treatment of chronic heart failure (CHF) patients. However, the drug on Dox-induced cardiotoxicity remains unclear. Ninety male Sprague-Dawley rats were randomized into two groups: 15 rats were selected as the normal group and 75 rats were injected intraperitoneally with Dox to establish CHF rat models, the success ones were randomly divided into five groups: low XST (LXST), medium XST (MXST) or high XST (HXST) (4.9, 9.8, or 19.6 g/kg d) administrated intragastrically twice a day for 4 weeks, with the captopril-treated group and the model group as comparison. The model group showed the cardiac functions generally impaired, and CHF mortality rate higher (47%) than those in the XST-treated groups (averaged 24%, P < 0.05). Compared with XST-treated groups, myocardial remodeling, inflammation and desarcomerization, and higher water content more severe in the cardiac tissue in the model group (P < 0.05), which was associated with higher expressions of mRNA or protein levels of AQP1, 4 and 7. Dox-impaired cardiac functions, cardiac remodeling and myocardial edema could be dose-dependently reverted by XST treatment. XST could inhibit AQP1, 4 and 7 at mRNA levels or at protein levels, which was associated with the attenuation of myocardial edema and cardiac remodeling, decreasing the ventricular stiffness and improving the cardiac functions and rats' survival. AQPs is involved in cardiac edema composed one of the mechanisms of Dox-induced cardiotoxicity, XSTvia inhibition of AQPs relieved the Dox-induced side effects.

The effect of rutin on cisplatin-induced oxidative cardiac damage in rats.

OBJECTIVE: Cisplatin is an anticancer drug used for treating childhood solid tumors. Symptoms related to cisplatin-induced cardiovascular adverse effects may be mild or severe. Rutin (vitamin P1) has many properties, including as antioxidant, anticancer, antidiabetic, antimicrobial, antiulcer, and tissue renewal properties. Therefore, we aimed to biochemically, histopathologically, and immunohistochemically demonstrate the effect of rutin on cisplatin-induced cardiotoxicity in rats. METHODS: The rats included in our study were divided into four groups: Healthy group (HE), 5-mg/kg cisplatin group (CP), 50 mg/kg rutin+5-mg/kg cisplatin (CR-50), 100-mg/kg rutin+5-mg/kg cisplatin (CR-100) group. RESULTS: CP group administered cisplatin had significantly increased blood, serum, and cardiac tissue malondialdehyde (MDA), interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), troponin I, creatine kinase (CK), and CK-MB levels compared to the HE group, whereas there was a significant decrease in the total glutathione (tGSH) levels. Rutin was observed to prevent the increase in MDA, IL-1ß, TNF-α, troponin I, CK, and CK-MB levels as well as prevent the decrease in tGSH levels more significantly when administered at a 100-mg/kg dose than at a 50-mg/kg dose. Histopathologically, cardiac necrosis, dilated/congested blood vessels, hemorrhage, polymorphonuclear leukocyte, edema, and cells with pyknotic nuclei were observed in the CP group. Rutin was shown to prevent cisplatin-induced cardiac damage more effectively when used at a100-mg/kg dose than at a 50-mg/kg dose. CONCLUSION: These results suggest that rutin is useful for preventing cisplatin-related cardiovascular damage.

Steroids Limit Myocardial Edema During Ex Vivo Perfusion of Hearts Donated After Circulatory Death.

BACKGROUND: Normothermic ex vivo heart perfusion (EVHP) has been shown to improve the preservation of hearts donated after circulatory arrest and to facilitate clinical successful transplantation. Steroids are added to the perfusate solution in current clinical EVHP protocols; however, the impact of this approach on donor heart preservation has not been previously investigated. We sought to determine the impact of steroids on the inflammatory response and development of myocardial edema during EVHP. METHODS: Thirteen pigs were anesthetized, mechanical ventilation was discontinued, and a hypoxemic cardiac arrest ensued. A 15-minute warm-ischemic standoff period was observed, and then hearts were resuscitated with a cardioplegic solution. Donor hearts were then perfused ex vivo in a normothermic beating state for 6 hours with 500 mg of methylprednisolone (steroid: n = 5) or without (control: n = 8). RESULTS: The addition of steroids to the perfusate solution reduced the generation of proinflammatory cytokines (interleukin-6, -8, -1ß, and tumor necrosis factor-α) and the development of myocardial edema during EVHP (percentage of weight gain: control = 26% ± 7% versus steroid = 16% ± 10%, p = 0.049). Electron microscopy suggested less endothelial cell edema in the steroid group (injury score: control = 1.8 ± 0.2 versus steroid = 1.2 ± 0.2, p = 0.06), whereas perfusate troponin-I (control = 11.9 ± 1.9 ng/mL versus steroid = 9.5 ± 2.4 ng/mL, p = 0.448) and myocardial function were comparable between the groups. CONCLUSIONS: The addition of methylprednisolone to the perfusion solution minimizes the generation of proinflammatory cytokines and development of myocardial edema during normothermic ex vivo perfusion of hearts donated after circulatory arrest.

Measuring Water Distribution in the Heart: Preventing Edema Reduces Ischemia-Reperfusion Injury.

BACKGROUND: Edema is present in many heart diseases, and differentiation between intracellular (ICW) and extracellular (ECW) myocardial water compartments would be clinically relevant. In this work we developed a magnetic resonance imaging-based method to differentiate ICW and ECW and applied it to analyze ischemia-reperfusion-induced edema. METHODS AND RESULTS: Isolated rat hearts were perfused with gadolinium chelates as a marker of extracellular space. Total water content was measured by desiccation. Gadolinium quantification provided ECW, and ICW was calculated by subtraction of ECW from total water content. In separate experiments, T1, T2, diffusion-weighted imaging and proton-density parameters were measured in isolated saline-perfused hearts. In in-situ rat hearts, ECW and ICW were 79±10 mL and 257±8 mL of water per 100 g of dry tissue, respectively. After perfusion for 40 minutes, ECW increased by 92.4±3% without modifying ICW (-1±3%). Hyposmotic buffer (248 mOsm/L) increased ICW by 16.7±2%, while hyperosmotic perfusion (409 mOsm/L) reduced ICW by 26.5±3%. Preclinical imaging showed good correlation between T2 and diffusion-weighted imaging with ECW, and proton-density correlated with total water content. Ischemia-reperfusion resulted in marked myocardial edema at the expense of ECW, because of cellular membrane rupture. When cell death was prevented by blebbistatin, water content and distribution were similar to normoxic perfused hearts. Furthermore, attenuation of intracellular edema with hyperosmotic buffer reduced cell death. CONCLUSIONS: We devised a method to determine edema and tissue water distribution. This method allowed us to demonstrate a role of edema in reperfusion-induced cell death and could serve as a basis for the study of myocardial water distribution using magnetic resonance imaging.

Effects of tolvaptan in the early postoperative stage after heart valve surgery: results of the STAR (Study of Tolvaptan for fluid retention AfteR valve surgery) trial.

PURPOSE: The purpose of this study was to assess the efficacy of tolvaptan, a vasopressin V2 receptor antagonist, for the management of postoperative surgical fluid retention after heart valve surgery. METHODS: This was a prospective observational study of 64 patients with heart valve disease who underwent valve surgery between 2013 and 2014. Those in the tolvaptan group received tolvaptan in addition to conventional diuretic therapy. The results were compared to the results of 55 patients who underwent heart valve surgery between 2007 and 2010 and received conventional postoperative diuretics alone. RESULTS: The time to return to the preoperative BW was significantly shorter in the patients who received tolvaptan (6.1 ± 3.8 vs. 8.7 ± 6.7 days, p < 0.05), while the level of sodium was significantly decreased in the patients who received conventional diuretics. The degree of increase in the creatinine level tended to be smaller in the tolvaptan group. The response to tolvaptan was related to the postoperative degree of BW increase and the preoperative creatinine level. CONCLUSIONS: Tolvaptan was effective in treating fluid retention during the early postoperative stage in cardiac surgery patients, without increased renal failure or abnormal electrolyte levels. This new type of diuretic therapy may be a suitable option for postoperative fluid management in patients undergoing cardiac surgery.

The involvement of AQP1 in heart oedema induced by global myocardial ischemia.

Aquaporin-1 (AQP1) is a member of aquaporin family that was previously proven to be involved in myocardial dysfunction; however, the role of AQP1 in myocardial stunning is less clear. To determine the change of AQP1 expression level in the heart and its effect on oedema after global myocardial ischemia, 40 adult goats underwent cardiopulmonary bypass (CPB) with an aortic cross-clamp time of 2 h and total bypass time of 6, 12, 24, 48 and 72 h followed by subsequent reperfusion. AQP1 function of eight goats was inhibited by HgCl(2) during the 24 h on CPB. All groups were compared with eight sham bypass control goats. Myocardial water content was measured, and the APQ1 mRNA and protein levels were detected by RT-PCR and immunoblotting, respectively. The results showed that the degree of myocardial oedema increased significantly at 6, 12, 24 and 48 h of reperfusion after CPB as compared with the control and recovered at 72 h of subsequent reperfusion. Expression levels of AQP1 mRNA and protein began to increase at 12 h and peaked at 24 h of CPB following reperfusion. Furthermore, myocardial oedema was reduced in the HgCl(2) group compared with the time-matched CPB and control groups. These data suggested that AQP1 expression increases in CPB and AQP1 plays an important role in myocardial oedema during CPB.

Deleterious effect of hypothermia in myocardial protection against cold ischemia: a comparative study in isolated rat hearts.

BACKGROUND: There is a growing need to improve heart preservation benefit the performance of cardiac operations, decrease morbidity, and more important, increase the donor pool. Therefore, the objective of this study was to evaluate the cardioprotective effects of Krebs-Henseleit buffer (KHB), Bretschneider-HTK (HTK), St. Thomas No. 1 (STH-1), and Celsior (CEL) solutions infused at 10°C and 20°C. METHODS: Hearts isolated from male albino Wistar rats and prepared according to Langendorff were randomly divided equally into 8 groups according to the temperature of infusion (10°C or 20°C) and cardioprotective solutions (KHB, HTK, STH-1, and CEL). After stabilization with KHB at 37°C, baseline values were collected (control) for heart rate (HR), left ventricle systolic pressure (LVSP), coronary flow (CF), maximum rate of rise of left ventricular pressure during ventricular contraction (+dP/dt) and maximum rate of fall of left ventricular pressure during left ventricular relaxation (-dP/dt). The hearts were then perfused with cardioprotective solutions for 5 minutes and kept for 2 hours in static ischemia at 20°C. Data evaluation used analysis of variance (ANOVA) in all together randomized 2-way ANOVA and Tukey's test for multiple comparisons. The level of significance chosen was P < .05. RESULTS: We observed that all 4 solutions were able to recover HR, independent of temperature. Interestingly, STH-1 solution at 20°C showed HR above baseline throughout the experiment. An evaluation of the corresponding hemodynamic values (LVSP, +dP/dt, and -dP/dt) indicated that treatment with CEL solution was superior at both temperatures compared with the other solutions, and had better performance at 20°C. When analyzing performance on CF maintenance, we observed that it was temperature dependent. However, when applying both HTK and CEL, at 10°C and 20°C respectively, indicated better protection against development of tissue edema. Multiple comparisons between treatments and hemodynamic variable outcomes showed that using CEL solution resulted in significant improvement compared with the other solutions at both temperatures. CONCLUSION: The solutions investigated were not able to fully suppress the deleterious effects of ischemia and reperfusion of the heart. However, these results allow us to conclude that temperature and the cardioprotective solution are interdependent as far as myocardial protection. Although CEL solution is the best for in myocardial protection, more studies are needed to understand the interaction between temperature and perfusion solution used. This will lead to development of better and more efficient cardioprotective methods.

Importance of organ preservation solution composition in reducing myocardial edema during machine perfusion for heart transplantation.

OBJECTIVE: Machine perfusion preservation has been used experimentally to extend the storage interval of donor hearts. We previously demonstrated that machine perfusion with glucose-supplemented Celsior preservation solution led to superior reperfusion function but resulted in increased myocardial edema compared with conventional static preservation. We hypothesized that other solutions that contain an oncotic agent, such as University of Wisconsin Machine Perfusion Solution (UWMPS), might reduce graft edema development while maintaining myocardial oxidative metabolism during long-term storage. METHODS: Canine hearts were stored and perfused in a perfusion preservation device (LifeCradle; Organ Transport Systems) after cardioplegic arrest and donor cardiectomy. Hearts were perfused either with glucose-supplemented Celsior (which lacks an oncotic agent) or UWMPS (which contains hydroxyethyl starch) at 5 degrees C in the perfusion device over 10 hours. Oxygen consumption (MVO(2)), lactate accumulation, regional flow distribution, and myocardial water content were measured. RESULTS: Hearts in both groups continued to extract oxygen over the entire perfusion interval. Lactate accumulation was minimal in both groups. Both solutions delivered perfusate evenly to all regions of myocardium. Heart weight increase (Celsior 31.3 +/- 4.3%, UWMPS -3.3 +/- 1.9%) and final myocardial water content (Celsior 80.2 +/- 1.3%, UWMPS 75.9 +/- 0.3%) were higher in the Celsior group (P < .005). CONCLUSIONS: Donor hearts can be supported by a perfusion device over relatively extended storage intervals. These organs continue to undergo oxidative metabolism with little lactate accumulation. An oncotic agent appears to be important in limiting increases in myocardial water content. UWMPS appears to be superior for perfusion preservation of myocardium by reducing edema development during storage.

Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass.

Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). Pyruvate reportedly suppresses degradation of the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). This study tested the hypothesis that pyruvate-enriched cardioplegia evoked EPO expression and mobilized EPO signaling mechanisms in myocardium. Hearts of pigs maintained on CPB were arrested for 60 min with 4:1 blood-crystalloid cardioplegia. The crystalloid component contained 188 mM glucose + or - 24 mM pyruvate. After 30-min cardiac reperfusion with cardioplegia-free blood, the pigs were weaned from CPB. Left ventricular myocardium was sampled 4 h after CPB for immunoblot assessment of HIF-1alpha, EPO and its receptor, the signaling kinases Akt and ERK, and endothelial nitric oxide synthase (eNOS), an effector of EPO signaling. Pyruvate-fortified cardioplegia stabilized arterial pressure post-CPB, induced myocardial EPO mRNA expression, and increased HIF-1alpha, EPO, and EPO-R protein contents by 60, 58, and 123%, respectively, vs. control cardioplegia (P < 0.05). Pyruvate cardioplegia also increased ERK phosphorylation by 61 and 118%, respectively, vs. control cardioplegia-treated and non-CPB sham myocardium (P < 0.01), but did not alter Akt phosphorylation. Nitric oxide synthase (NOS) activity and eNOS content fell 32% following control CPB vs. sham, but pyruvate cardioplegia prevented these declines, yielding 49 and 80% greater NOS activity and eNOS content vs. respective control values (P < 0.01). Pyruvate-fortified cardioplegia induced myocardial EPO expression and mobilized the EPO-ERK-eNOS mechanism. By stabilizing HIF-1alpha, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.

Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion.

AIMS: Antithrombin is an important inhibitor of the coagulation system, additionally exerting specific anti-inflammatory effects on endothelial cells. Healthy vascular endothelium is coated by the endothelial glycocalyx, diminution of which increases capillary permeability, e.g. after ischaemia. Antithrombin is known to infiltrate the glycocalyx, binding to glycosaminoglycans, and to preserve the glycocalyx after application tumour necrosis factor-alpha. We investigated the influence of antithrombin on glycocalyx subjected to ischaemia/reperfusion. METHODS AND RESULTS: Isolated guinea pig hearts were perfused with Krebs-Henseleit buffer (KHB). Antithrombin was applied to achieve physiological levels (1 U/mL) before inducing 20 min of ischaemia (37 degrees C). Hearts were reperfused for 20 min at constant flow (baseline perfusion pressure 70 cmH(2)O) with KHB or KHB plus 2 g% hydroxyethyl starch (130 kDa). Coronary net fluid filtration was assessed directly by measuring transudate formation on the epicardial surface. Post-ischaemic coronary release of syndecan-1 and heparan sulfate was quantified by ELISA. Hearts were perfusion-fixed to visualize the glycocalyx by electron microscopy. Ischaemia/reperfusion caused degradation of the glycocalyx, enhanced coronary perfusion pressure, and increased vascular permeability. Antithrombin significantly reduced post-ischaemic glycocalyx shedding, coronary perfusion pressure, coronary leak, and tissue oedema formation compared to untreated hearts. Additional application of colloid augmented these actions of antithrombin. Electron microscopy revealed a mostly intact glycocalyx after antithrombin treatment. CONCLUSION: Antithrombin preserves the endothelial glycocalyx, sustaining the vascular barrier function and reducing interstitial oedema. The potentiated effect of colloid in these hearts suggests that the prevention of shedding should be of functional benefit also in vivo.

Lidocaine-magnesium blood cardioplegia was equivalent to potassium blood cardioplegia in left ventricular function of canine heart.

This study evaluated the effects of lidocaine-magnesium blood cardioplegia on left ventricular function compared with potassium blood cardioplegia. Crystalloid cardioplegia which contains lidocaine has been reported but blood cardioplegia is rare. Thirteen dogs received 60 min of global ischemia under hypothermic cardioplumonary bypass (30 degrees C). Potassium blood cardioplegia was administered every 20 min in group A (n=6), and lidocaine-magnesium blood cardioplegia in group B (n=7). We compared the ratio of Emax obtained during IVC occlusion at pre- and post-global ischemia (%Emax) and LVSW (%LVSV). Cardiac function was evaluated prior to CPB and 60 min after reperfusion. There was no difference in time required for cardiac arrest between the two groups (group A: 78+/-3 s, group B: 89+/-9 s). Percentage maximal elastance was significantly better in group B (group A: 63+/-3%, group B: 76+/-4%, P<0.05). Percentage tissue water content of the myocardium after CPB was significantly lower in group B (group A: 82.3+/-4%, group B: 75.5+/-2%, P<0.05). Lidocaine-magnesium blood cardioplegia was equivalent to potassium blood cardioplegia in systolic left ventricular function and reduced myocardial edema in canine heart.

5-HT2 receptor blocker sarpogrelate prevents downregulation of antiapoptotic protein Bcl-2 and protects the heart against ischemia-reperfusion injury.

Even though reperfusion is the treatment of choice in patients admitted with acute myocardial infarction, reperfusion itself has been demonstrated to activate various pathological factors especially following procedures of cardiac revascularization. 5-hydroxytryptamine (5HT) is one such factor activated during reperfusion and is known to trigger the post ischemic contractile dysfunction and pathological apoptosis. Here we demonstrate the potential effects of the 5-HT(2)A antagonist sarpogrelate in protecting the myocardium against reperfusion injury of heart. Male Wistar rats weighing between 220 and 240 g were subjected to 30 min left coronary artery (LCA) occlusion and 120 min reperfusion. Sarpogrelate (4 mg/kg) was infused intravenously for 30 min either before LCA occlusion or at reperfusion. Following reperfusion the samples were collected for infarction area, immunohistochemistry, western blotting and myocardial metabolite analysis. Sarpogrelate infusion before ischemia resulted in (a) significant recovery of post ischemic cardiac functions (LVDP, EDP), (b) significant reduction in the infarct size among the risk area after triphenyl tetrazolium chloride staining (p<0.001), (c) decreased tissue water content (p<0.05), (d) well preserved myocardial ATP (p<0.05), (e) reduction in Bcl-2 downregulation and caspase 3 activation and (g) less prevalence of apoptotic cells (3.1+/-0.4% to 15.2+/-0.6%, drug versus control). Treating the rats with sarpogrelate during reperfusion also showed similar results. This study thus demonstrates the protective effects of sarpogrelate and supports the role for 5-HT2A inhibition in preventing the reperfusion injury of the heart.

Passive infusion: a simple delivery method for retrograde cardioplegia.

Some damage to the capillaries and increase in myocardial edema have been shown when retrograde cardioplegia perfusion pressure exceeds 40-50 mmHg, or possibly when it falls within this pressure interval. To avoid these complications, we designed a very simple delivery method for retrograde cardioplegia: passive continuous infusion by gravitational force alone. From August 2002 through April 2003, 147 patients undergoing elective coronary artery bypass surgery were randomly allocated into 2 groups. In both groups, isothermic blood cardioplegic solution was infused continuously in a retrograde fashion, after antegrade cardioplegic arrest. Group 1 (n=76) received retrograde infusion passively by gravitational force, while Group 2 (n=71) received retrograde infusion from a manually controlled pressure bag, with the pressure maintained at about 40 mmHg. Myocardial biopsy specimens were taken just before the aorta was declamped, and myocardial edema was scored upon histopathologic examination. Postoperative myocardial damage was evaluated with periodic measurements of CK-MB isoenzyme and cardiac troponin T levels. We recorded cardioplegic infusion pressures and rates, and the total amount of potassium administered. The mean cardioplegic infusion pressures and rates, total potassium levels, and cardioplegic solution amounts were significantly lower in Group 1 than Group 2. Histologic observations revealed significantly less myocardial edema in Group 1. There were no differences between groups in CK-MB isoenzyme or cardiac troponin T levels, mortality, or morbidity. Retrograde continuous infusion of isothermic blood cardioplegic solution by gravitational force alone appears to provide satisfactory myocardial protection and to eliminate the harmful effects of higher pressures upon the myocardium.

Increasing the colloid osmotic pressure of cardiopulmonary bypass prime and normothermic blood cardioplegia minimizes myocardial oedema and prevents cardiac dysfunction.

UNLABELLED: Our recent work demonstrated that normothermic continuous antegrade blood cardioplegia results in cardiac dysfunction related to myocardial oedema. This oedema was partially due to increased myocardial microvascular fluid filtration induced by crystalloid hemodilution. We hypothesized that increasing the colloid osmotic pressure of blood cardioplegia would stop fluid filtration into the cardiac interstitium, thus preventing myocardial oedema and cardiac dysfunction. METHODS: We determined myocardial water content in six dogs by microgravimetry and myocardial lymph flow from the major prenodal cardiac lymphatic. Preload recruitable stroke work was derived from sonomicrometry and micromanometry. The dogs were subjected to normothermic cardiopulmonary bypass primed with 6% hetastarch and 1 h of normothermic continuous antegrade blood cardioplegia (4:1 blood:6% hetastarch colloid osmotic pressure 21 +/- 2 mmHg) delivered at 50 mmHg perfusion pressure. RESULTS: We found that despite increased colloid osmotic pressure, a small but significant increase in myocardial water content still occurred during blood cardioplegia. As myocardial lymph flow virtually ceased during cardioplegia, myocardial microvascular filtration must have been present. However, increased myocardial lymph flow following cardioplegia resulted in complete oedema resolution associated with normal left ventricular performance post-cardiopulmonary bypass. CONCLUSIONS: Our data show that the plegic myocardium is prone to oedema formation because of both relatively enhanced fluid filtration and lymph flow cessation. We conclude that increasing the colloid osmotic pressure of normothermic blood cardioplegia minimizes myocardial oedema, thus preventing post-cardiopulmonary bypass cardiac dysfunction.

Beta-blockade as an alternative to cardioplegic arrest during cardiopulmonary bypass.

BACKGROUND: As an alternative to cardioplegic arrest, cardiac surgical conditions have been produced using beta-blocker-induced minimal myocardial contraction (MMC) during cardiopulmonary bypass. The technique of MMC involves the use of high-dose intravenous esmolol to suppress myocardial chronotropy and inotropy sufficiently to produce cardiac surgical conditions. The purpose of this study was to compare conventional crystalloid cardioplegic arrest with MMC in terms of ischemia avoidance, myocardial edema formation, and cardiac function. METHODS: Twelve dogs were placed on cardiopulmonary bypass. Six dogs were subjected to crystalloid cardioplegic arrest for 2 hours. Surgical conditions were produced in the other 6 dogs for 2 hours using intravenous esmolol without aortic clamping or cardioplegia. Arterial and coronary sinus lactate concentrations were determined as a gauge of myocardial ischemia. Myocardial water content was determined using microgravimetry and preload recruitable stroke work was determined using sonomicrometry and micromanometry. RESULTS: Significant lactate washout was demonstrated after cardioplegic arrest but not after MMC. Myocardial water content was significantly less during and after MMC compared with cardioplegic arrest (p < 0.05). Preload recruitable stroke work was decreased compared with baseline values in both groups (p < 0.05). CONCLUSIONS: In contrast to a previous study that involved 1 hour of MMC, in this study, ventricular function was decreased to the same extent as with cardioplegic arrest after 2 hours of MMC. This was attributed to the accumulation of ASL-8123, the primary metabolite of esmolol, which possesses beta-antagonist properties. Although postbypass ventricular function is similar in both groups, MMC appears to be superior in terms of ischemia avoidance and myocardial edema formation.

Experimental study of cardiac lymph dynamics and edema formation in ischemia/reperfusion injury--with reference to the effect of hyaluronidase.

This study is designed to evaluate the effect of hyaluronidase on the canine myocardial edema derived from ischemia/reperfusion injury. The mongrel dog's heart received 90 minutes of ischemia under cardiopulmonary bypass consisting of 30 minutes of normothermia alone and 60 minutes of hypothermia with cardioplegic arrest. Reperfusion for 60 minutes was added thereafter. Two kinds of cardioplegic solution, 4 degrees C St. Thomas' Hospital solution with or without 3000 units/L of hyaluronidase, were prepared. The solution was given antegradely every 30 minutes during cardioplegic arrest. Cardiac lymph was collected continuously from the afferent duct of the cardiac lymph node by cannulation. Hyaluronidase in the cardioplegic solution increased cardiac lymph volume significantly and improved postischemic recovery of cardiac function. A high level of adenosine triphosphate was maintained at that time. The myocardial water content at the end of reperfusion revealed a minimum increase with hyaluronidase use. Active drainage of cardiac lymph by hyaluronidase alleviates the myocardial edema formation, thereby preserving cardiac function.

Sodium/hydrogen exchanger inhibition reduces myocardial reperfusion edema after normothermic cardioplegia.

OBJECTIVE: The hypothesis was that Na+/H+ exchange occurring during normothermic cardioplegia contributes to the development of myocardial edema during subsequent reperfusion and impairs functional recovery. METHODS: Rat hearts were perfused in a Langendorff apparatus and submitted to 60 minutes of normothermic cardioplegia and 90 minutes of reperfusion. Hearts were allocated to one of four groups (n = 8): inhibition of Na+/H+ exchanger with HOE642 throughout the whole experiment (HOE group), only during cardioplegia (HOE-C) or during reperfusion (HOE-R), and a control group. RESULTS: In HOE and HOE-C groups, myocardial water content at the end of reperfusion was lower than in the HOE-R and control groups (526 +/- 19 and 533 +/- 18 ml/100 gm dry tissue vs 632 +/- 25 and 634 +/- 17 ml/100 gm dry tissue, respectively, p = 0.001), left ventricular end-diastolic pressure increased less after reperfusion (46.6 +/- 9.7 and 63.2 +/- 10.0 mm Hg vs 75.1 +/- 4.3 mm Hg and 85.7 +/- 8.9 mm Hg, respectively, p = 0.006), and recovery of left ventricular developed pressure was better (46.7% and 45.8% vs 4.5% and 9.8%, p = 0.048). Relative to the control group, total lactate dehydrogenase release during reperfusion was reduced by 80.2%, 69.3% and 36% in HOE, HOE-C, and HOE-R groups, respectively. CONCLUSION: Inhibition of the Na+/H+ exchange during normothermic cardioplegia reduces myocardial edema and necrosis during subsequent reperfusion, improving functional recovery. Inhibition of Na+/H+ exchange during reperfusion only has a much smaller effect.

Improved myocardial protection using continuous coronary perfusion with normothermic blood and beta-blockade with esmolol.

Continuous coronary perfusion with warm beta-blocker-enriched blood has been suggested as an alternative to cardioplegic arrest for myocardial protection during coronary artery surgery. The purpose of the present work was 1.) to experimentally investigate this technique using an animal model, and 2.) to clinically apply this alternative myocardial protection technique and compare it to standard crystalloid cardioplegia in a controlled study. We placed 6 dogs on CPB and 6 dogs on a biventricular assist device and created "beta-blocker-induced cardiac surgical conditions" by suppressing myocardial chronotropy and inotropy with systemic infusion of the ultra-short acting beta-blocker esmolol. For the clinical study we randomized 60 coronary artery surgery patients to receive either crystalloid cardioplegia (Bretschneider HTK) or selective continuous coronary perfusion via the aortic root with warm esmolol-enriched CPB blood. In the experimental study we found that continuous coronary perfusion with warm esmolol-enriched blood avoided myocardial ischemia and minimized myocardial edema, thus completely preserving cardiac performance. Our clinical data showed the alternative technique to be superior to standard crystalloid cardioplegia in terms of both functional and structural myocardial protection. The concept of beta-blocker-induced cardiac surgical conditions is a useful alternative for myocardial protection during coronary artery surgery and may be particularly beneficial for severely compromised hearts.