Myocardial protection: left ventricular ultrastructure after different forms of cardiac arrest

Clinically applied methods of cardioplegia show very different effects on the rapidity of decay of energy-rich phosphates as well as on kind and progression of ultrastructural alterations of the ischemic myocardium. Comparing the methods of cardioplegia according to Kirklin, St. Thomas's Hospital and Bretschneider (solution HTK) with pure ischemia at 25 degrees C (model A) and Kirklin's or St. Thomas's cardioplegia and subsequent 210 min or HTK cardioplegia and 300 min ischemia at 22 degrees C plus 20 min subsequent reperfusion (model B) leads to the following results: Model A: Compared with pure ischemia cardioplegia according to Kirklin and the St. Thomas's Hospital slows down the decay of the left ventricular ATP-concentration by a mean factor of 3 and the progression of structural alterations of the left ventricular subendocardium by a factor of 2. HTK retards the ATP-decay by a factor of 6, the alterations of ultrastructure by a factor of 6.5. St. Thomas's solution, in contrast to all other methods of cardioplegia, at the onset of ischemia already causes a cellular edema of myocytes; the edema increases during ischemia, and at the ATP-concentration of 4 mumol per gram myocardium is more pronounced than with pure ischemia, Kirklin or HTK. After application of Kirklin's solution, in contrast, a cellular edema of capillary endothelia develops during ischemia, which at 4 mumol ATP is more pronounced than with each of the other methods. Model B: After global ischemia until the ATP-concentration of left ventricular myocardium is 4 mumol/g and a subsequent 20 minutes post-ischemic recovery the ultrastructural alterations in principle resemble those occurring during ischemia (model A).(ABSTRACT TRUNCATED AT 250 WORDS)     

Transcardiac release of soluble adhesion molecules during coronary artery bypass grafting: effects of crystalloid and blood cardioplegia

BACKGROUND: Dysfunction of myocardium as a result of ischemia/reperfusion during coronary artery bypass grafting (CABG) is currently one of the biggest problems in cardiovascular surgery. In previous studies, it has been well established that activated leukocytes and coronary vascular endothelial cells play an important role in the development of cardiac tissue damage during ischemia followed by reperfusion. Interactions between both of these cell types require the expression of adhesion molecules on their surface. In certain conditions, on cell activation, the adhesion proteins may be released from activated cells in soluble form into circulation. The purpose of our study was to establish whether the use of blood cardioplegia modifies plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and soluble L-selectin (sL-selectin) in comparison with crystalloid cardioplegia in patients undergoing CABG. METHODS: Patients undergoing CABG were classified into two groups to receive cold crystalloid cardioplegia (St. Thomas' Hospital) or cold blood cardioplegia (method of Buckberg), followed by a "warm-shot" of the solution. Coronary sinus and arterial blood samples were obtained from 50 patients (42 men and 8 women; age range, 34 to 73 years) before aortic cross-clamping, at the beginning of reperfusion, and after 30 min of reperfusion. Plasma levels of soluble adhesion molecules were measured using sensitive enzyme-linked immunosorbent assays. RESULTS: The transcardiac release of sICAM-1 and sVCAM-1 following myocardial ischemia/reperfusion during CABG was evident in both groups of patients. However, the increase of soluble forms of both of these adhesion proteins was more significant in the group of patients receiving crystalloid cardioplegia. Crystalloid cardioplegia resulted in decreased plasma level of sE-selectin in the coronary sinus blood sample after 30 min of reperfusion. No significant changes in plasma levels of sL-selectin in either group were observed. CONCLUSION: Cardioplegia may affect the release of soluble forms of adhesion molecules from ischemic myocardium and modify endothelium activation in patients undergoing CABG.     

Initial reperfusion with magnesium after cardioplegic arrest attenuates myocardial reperfusion injury

BACKGROUND: Magnesium's effect on calcium ion concentrations may attenuate myocardial reperfusion injury. The aim of this study was therefore to investigate the effects on the recovery of myocardial function of initial reperfusion with varying Mg(2+) concentrations following cardioplegic arrest. METHODS: Isolated guinea pig hearts underwent 3.5 hours of cardioplegic arrest in St. Thomas Hospital II solution (STH) or Bretschneider HTK solution (HTK) at 24 degrees C. Control hearts were reperfused with normal Krebs-Henseleit solution (KHS). In the therapy groups, hearts were initially reperfused with 5, 10, or 20 mM Mg(2+) for 15 minutes, followed by 30 minutes of perfusion with KHS. RESULTS: During initial reperfusion, elevated Mg(2+) concentrations markedly reduced rate-pressure product, dP/dt and O 2 demand. Release of LDH and CK was reduced in the therapy groups pretreated with Bretschneider HTK. After Mg(2+) washout, left ventricular function recovery and compliance was improved after HTK but not after STH cardioplegia. Following both STH and HTK cardioplegia, Mg(2+) reperfusion reduced reperfusion arrhythmias. CONCLUSIONS: The combination of HTK cardioplegia with 15 min initial Mg(2+) (5 and 10 mM, but not 20 mM) reperfusion was clearly superior to HTK followed by immediate Krebs-Henseleit reperfusion as well as STH cardioplegia with or without initial Mg(2+) reperfusion. The high Mg(2+) concentrations in the STH solution might mask beneficial effects of Mg(2+) reperfusion.     

Protective Effect of JTV519, A New 1,4-Benzothiazepine Derivative, on Prolonged Myocardial Preservation

A bstract Background: JTV519 is know to protect cardiomyocytes from calcium overloading-induced damage. The aim of this study was to investigate the potential protective effect of JTV519 on myocardium subjected to prolonged ischemia and the underlying mechanism of such protection. The effect of JTV519 was also compared with that of diltiazem, a 1,5-ben-zothiazepine derivative. Methods: Isolated rat hearts were randomly divided into three groups. Control hearts were arrested with histidine-tryptophan-ketoglutarat (HTK) cardio-plegic solution alone. In the JTV519 group of hearts, cardiac arrest was achieved with JTV519 (10^--³ mmol/L) in the HTK solution. Hearts in the diltiazem group were arrested with diltiazem (0.5 mmol/L) in the HTK solution. All the hearts were then subjected to 6-hour storage in HTK solution at 4°C. Results: After a 30-minute reperfusion, the left ventricular developed pressure in the JTV519 and diltiazem groups were improved significantly compared with the control group. There was a significantly lower left ventricular end-diastolic pressure level and higher recovery of coronary flow in the JTV519 group than in the control group. The postischemic intracellular calcium concentration was attenuated by adding JTV519 or diltiazem to HTK cardioplegia. Conclusion: As an adjunct to cardioplegia, JTV519 showed a significant protective effect on myocardium undergoing 6 hours of ischemia. The beneficial protective effects of JTV519 are correlated with its ability to inhibit the postischemic rise in intracellular calcium.     

未成熟兔心缺血再灌注对心肌和冠脉微循环损伤的实验研究

采用离体心做功模型，比较单低温（１０℃～１５℃）与低温加Ｓｔ．ＴｈｏｍａｓⅡ号心停搏液单剂与多剂灌注对未成熟兔全心缺血１２０分钟复灌６０分钟的作用。结果单剂组较单低温和多剂组心肌含水量，心肌线粒体丙二醛及心肌和冠脉流出液内皮素含量减少，冠脉流出液一氧化氮（ＮＯ）含量增加，微血管再开放良好，心肌细胞和内皮细胞超微结构损伤轻，最终心脏功能恢复优于其他二组；多剂组与单低温组差别不明显。提示低温加ＴｈｏｍａｓⅡ号液单剂灌注对未成熟兔心冠脉微循环及心功能保护作用优于单低温，多剂灌注无明显优点。     

Structural protection of the myocardial capillary endothelium by different forms of cardiac arrest and subsequent global ischemia at 5 degrees C.

BACKGROUND: In transplantation surgery sufficient myocardial protection achieved by cardioplegic cardiac arrest and deep hypothermia is a prerequisite for successful resumption of donor heart function. Intraischemic damage of the endothelium combined with capillary compression may lead to the "no-reflow phenomenon" during reperfusion, resulting in insufficient cardiac resuscibility. METHODS: We evaluated the endothelial ultrastructure after various common forms of cardiac arrest and subsequent ischemia in deep hypothermia. Canine hearts were arrested by aortic cross clamping and surface cooling with Tutofusin' (ACC) or by coronary perfusion with Custodiol (histidine tryptophane ketoglutarate, HTK solution), with University of Wisconsin solution (UW), or with St. Thomas' Hospital solution. After extirpation the hearts were incubated at 5 degrees C in the solution used for cardiac arrest. Myocardial samples were taken immediately after cardiac arrest and after 2h, 4h, 6h, and 10 h of global ischemia. The degree of structural damage was evaluated by a scoring system. Endothelial swelling was determined as the mean barrier thickness of the capillary endothelium. RESULTS: At all selected time points our results show that 1) after cardioplegia with St. Thomas' solution, the degree of endothelial cell swelling was higher than after aortic cross clamping; 2) using HTK or UW solution, the endothelial ultrastructure was better preserved than after aortic cross clamping or using St. Thomas' solution, whereby HTK was slightly better than UW; 3) using UW solution, endothelial cell swelling was a little (up to 10%) but significantly less than after HTK perfusion. CONCLUSIONS: With respect to the intraischemic structural preservation of endothelial cells, UW or HTK solution combined with deep hypothermia promises adequate protection, compared with other clinically used methods tested.     

三种心脏停搏液对未成熟猪体外循环中的心肌保护效果

目的比较St．Thomas停搏液（STH液）、氧合血停搏液和组氨酸一色氨酸一酮戊二酸停搏液fhistidine—tryptophan—ketoglutarate,HTK液）对未成熟猪围体外循环（cardiopulmonarybypass,CPB）期的心肌保护效果。方法21只年龄为（15～20）天、体重为（4．5～8．0）kg的中华小型猪随机分为STH液组、氧合血停搏液组和HTK液组,每组7只。分别于CPB前（T1）、升主动脉阻断（aorticcross—clamping,ACC）后10min（T2）、升主动脉开放（cross—clampingremission,CCR）后5min（T3）、CPB后5min（T4）、CPB后60min（T5）、CPB后120min（T6）抽取颈动脉血,实验结束后取少量右房心肌组织。ELISA法测肌酸激酶同工酶（CK—MB）、肌钙蛋白T（cTnT）和肌钙蛋白Ⅰ（cTnI）的含量,电镜下观察心肌超微结构的变化;同时记录每只动物的用血量。结果停跳前各组血浆CK—MB、cTnI、cTnT组间差异均无统计学意义（P〉0．05）;随着体外循环进行,各组血浆心肌生化标志物含量逐渐增加,HTK液组和氧合血停搏液组心肌生化标志物漏出率小于STH液组,差异有统计学意义（P〈0．05）。氧合血停搏液组和HTK液组相比,血浆心肌生化标志物含量无明显差异（P〉0．05）。氧合血停搏液组、HTK液组动物心肌细胞线粒体超微结构Flameng评分低于sTH液组（P〈0．05）。结论氧合血停搏液和HTK液组心肌细胞线粒体的损伤程度小,对未成熟心肌的保护效果均优于STH液组。     

Temporal and spatial development of myocardial infarcts in porcine hearts without significant collateral blood flow

To evaluate the time-dependent beneficial effect of reperfusion on infarct size, we investigated the temporal and spatial development of infarcts in porcine hearts. The left anterior descending coronary artery was occluded in 17 pigs for different periods of time. Ischemia was always followed by 4 hours of reperfusion. After 60 minutes of ischemia, transmural needle biopsies subdivided into subendocardial and subepicardial halves were removed from the ischemic apex to determine the tissue concentrations of adenosine triphosphate and nicotinamide adenine dinucleotide. The myocardium at risk was determined with a fluorescent dye, and the infarcted tissue with nitroblue tetrazolium stain. Infarct size was expressed as the ratio of the infarcted myocardium over the risk region. Ischemic cell death began in the jeopardized left ventricular subendocardial septum after about 30 minutes of ischemia. Further progress involved the right subendocardial septum and the subendocardium of the left anterior free wall. After 75 minutes of ischemia, most of the myocytes were already irreversibly injured. Tissue damage from the infarctions was complete after 90 to 120 minutes of ischemia. These results indicate that in hearts without a significant collateral blood flow, reperfusion can only reduce infarct size if initiated within 60 to 75 minutes of ischemia. As in canine hearts, infarctions in porcine hearts progress from the ischemic subendocardium toward the outer layers.     

Ultrastructural changes of ischemic injury due to coronary artery occlusion in the porcine heart

Using the ultrastructural criteria established by Schaper et al. 1979 [27] for distinguishing between different degrees of ischemic change in dog myocardium, slight ischemic changes are observed in the pig suboendocardium as early as 1 min after occlusion of the LAD artery. Moderate change throughout the thickness of the myocardium is seen after 6 to 12 min of ischemia and continues to be found up until 20 min after commencement of the ischemic period. 20 to 30 min ischemia produces severe ischemic damage and more than 30 min leads to irreversible damage. The changes are uniform at all stages of ischemia and there is no evidence of a transmural gradient of ultrastructural damage. Of particular interest in the early part of the ischemic period is the observation of ultrastructural changes in the subendocardial specialized conducting tissue. In these specialized cells, although morphological features consistent with slight and moderate ischemia are found as early as 1 to 2 min after occlusion, spontaneous recovery occurs and is complete by 15 min. This biphasic time course parallels the electro-physiological changes known to occur in ischemic Purkinje fibres.     

Inhibition of caspase-3 improves contractile recovery of stunned myocardium, independent of apoptosis-inhibitory effects

OBJECTIVES: The aim of this study was to investigate whether the caspase-3 inhibitor Ac-DEVD-CHO functionally improves stunned myocardium. BACKGROUND: Degradation of troponin I contributes to the pathogenesis of myocardial stunning, whereas the role of apoptosis is unknown. Caspase-3 is an essential apoptotic protease that is specifically inhibited by Ac-DEVD-CHO. METHODS: Isolated working hearts of rats were exposed to 30 min of low-flow ischemia, followed by 30 min of reperfusion. Ac-DEVD-CHO (0.1 to 1 micromol/l) was added 15 min before ischemia/reperfusion or 5 min before reperfusion. Cardiac output, external heart power, left ventricular (LV) developing pressure and contractility (dp/dt(max)) were measured. Apoptosis was assessed by TUNEL staining and internucleosomal deoxyribonucleic acid fragmentation. Caspase-3 processing and troponin I cleavage were determined by immunoblotting. Caspase-3 activity was measured using a fluorogenic substrate. RESULTS: The addition of Ac-DEVD-CHO before ischemia/reperfusion or before reperfusion dose-dependently and significantly (p < 0.05) improved post-ischemic recovery of cardiac output, external heart power, LV developing pressure and dp/dt(max), compared with the vehicle (0.01% dimethyl sulfoxide). Ac-DEVD-CHO was similarly effective when given before reperfusion. Ac-DEVD-CHO blocked ischemia/reperfusion-induced caspase-3 activation, but cardiomyocyte apoptosis was unaffected. Troponin I cleavage was not inhibited by Ac-DEVD-CHO. CONCLUSIONS: Caspase-3 is activated in stunned myocardium. Inhibition of caspase-3 by Ac-DEVD-CHO significantly improves post-ischemic contractile recovery of stunned myocardium, even when given after the onset of ischemia. The mechanism(s) of protection by Ac-DEVD-CHO appear to be independent of apoptosis. Inhibition of caspase-3 is a novel therapeutic strategy to improve functional recovery of stunned myocardium.     

吗啡对大鼠离体心脏再灌注损伤的保护作用

目的研究吗啡对大鼠离体心脏缺血再灌注损伤的保护作用及其机制。方法32只雄性wistar大鼠随机分为对照组,吗啡组,吗啡+纳络酮组,吗啡+格列本脲组,建立离体工作心脏模型。4℃St.ThomasⅡ停搏液诱导心脏停搏30min,观察缺血再灌注后吗啡对心排血量(CO)、左心室压力微分(±dp/dtmax)、左心室舒张压(LVDP)恢复率及乳酸脱氢酶(LDH)、肌酸激酶同工酶(CK-MB)、心肌超微结构的影响,并观察纳络酮和格列本脲对吗啡作用的影响。结果吗啡组CO、±dp/dtmax、LVDP的恢复率优于其他各组(P<0.05),LDH漏出明显低于其他组(P<0.05),心肌线粒体等超微结构损伤明显减轻;纳络酮和格列本脲可以完全阻断吗啡的心肌保护作用。结论吗啡可以减轻大鼠心肌的缺血再灌注损伤。吗啡是通过心脏局部的阿片受体及心肌细胞三磷腺苷(ATP)敏感性钾通道(KATP通道)介导产生心肌保护作用。     

Multi-dose crystalloid cardioplegia preserves intracellular sodium homeostasis in myocardium.

The goal of this study was to assess the effect of multi-dose St Thomas' cardioplegia on intracellular sodium homeostasis in a rat heart model. A new magnetic resonance method was applied which enable us to detect intracellular Na changes without chemical shift reagents. Three groups of isolated rat hearts were subjected to 51 min of ischemia and 51 min of reperfusion at 37 degrees C: Group 1-three infusions of St Thomas' cardioplegia every 17 min for 2 min (n=7); Group 2-single-dose infusion of cardioplegia at the beginning of stop-flow ischemia (n=8); and Group 3-clamp ischemia (n=3) without cardioplegia administration. Performance of the heart was assessed by rate-pressure product relative to the pre-ischemic level (RPP). An NMR method was applied which continuously detects the Na(i) concentration in the heart, using the ability of bound sodium to exhibit triple-quantum transitions and the growth of the corresponding signal when sodium ions pass from extracellular to intracellular space. Clamp ischemia without cardioplegia and 50 min of reperfusion left the heart dysfunctional, with Na(i) growth from the pre-ischemic level of 13.9+/-1.2 mM to 34.9+/-1.3 mM and 73. 9+/-1.9 mM at the end of ischemia and reperfusion, respectively. During single-dose cardioplegia the corresponding values for Na(i) were 30.2+/-1 mM and 48.5+/-1.7 mM (RPP=29%). Multiple infusions of cardioplegic solution resulted in a remarkable preservation of the heart's intracellular Na concentration with a non-significant increase in Na(i) during ischemia and only 16.7+/-1 mM, (P=0.01), after subsequent reperfusion (RPP=85%). The time course of Na(i) changes in the rat heart model demonstrates a prominent potential of multi-dose St Thomas' cardioplegia in preserving intracellular sodium homeostasis at 37 degrees C. The growth of Na(i) concentration during ischemia, as an indicator of the viability of the myocytes, can have a prognostic value for the heart's performance during reperfusion.     

Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1

This study examined if thioredoxin, the major redox-regulator in the mammalian system, plays any role in the redox signaling of ischemic myocardium. Isolated working rat hearts were made globally ischemic for 30 min followed by 2 h of reperfusion. Another group of hearts was rendered tolerant to ischemia by four cyclic episodes of 5 min ischemia each followed by another 10 min of reperfusion. Reperfusion of ischemic myocardium resulted in the downregulation of thioredoxin 1 (Trx1) expression, which was upregulated in the adapted myocardium. The increased expression of Trx1 was completely blocked with cis-diammine-dichloroplatinum (CDDP), an inhibitor of Trx1. CDDP also abolished cardioprotection afforded by ischemic adaptation as evidenced by a reduction of post-ischemic ventricular recovery, increase in myocardial infarct size and cardiomyocyte apoptosis. The decreased amount of reactive oxygen species in the adapted heart was increased significantly, when Trx1 was blocked with CDDP. The cardioprotective role of Trx1 was further confirmed with transgenic mouse hearts overexpressing Trx1. The Trx1 mouse hearts displayed significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size as compared to the corresponding wild-type mouse hearts. Taken together, the results of this study implicate a crucial role of Trx1 in redox signaling of the ischemic myocardium.     

Dynamics and pathogenesis of ischemic contracture of the heart

In experiments on 34 dogs, the authors studied myocardial rigidity, ATP levels and Ca2+-accumulating function of the membranes of the sarcoplasmic reticulum (SR) in the external (subepicardial) and internal (subendocardial) layers of the myocardium at 1 and 2 h of total ischemia at 37 degrees C and also 30 min after cardiac reperfusion by heterotopic transplantation. It was revealed that contracture changes in ischemia first affect the internal and then the external layer of the myocardium which corresponds to the initial and completed phases of ischemic contracture (IC) of the heart, correspondingly. IC of the heart is irreversible and in cases of total contracture of all layers of the myocardium (the completed phase) the heart loses contractile function. Changes in the contractility in the external and internal layers of the myocardium show a stronger inverse correlation with the capacity of SR membranes to absorb Ca2+ rather than with ATP levels in the tissues which indicates an essential role of the Ca2+ accumulating function of SR in the pathogenesis of IC.     

Leukocyte-depleted secondary blood cardioplegia attenuates reperfusion injury after myocardial ischemia

BACKGROUND: Activated neutrophils have been implicated in reperfusion injury of the myocardium; leukocyte depletion at the time of reperfusion may contribute to better myocardial protection after cardiac surgery. In the present study, we examined whether leukocyte depletion as an adjunct to terminal blood cardioplegia attenuates reperfusion injury. METHODS: Porcine hearts that had undergone 60 minutes of normothermic ischemia with cardioplegia and 60 minutes of reperfusion under cardiopulmonary bypass were divided into four groups according to the methods of 15 min of controlled initial reperfusion: whole blood reperfusion (n = 6), leukocyte-depleted reperfusion (n = 6), secondary blood cardioplegia (n = 6) and leukocyte-depleted secondary blood cardioplegia (n = 6). At 60 min of reperfusion, hemodynamic recovery, release of malondialdehyde (MDA) as a marker for free oxygen radicals, CK-MB-isoenzyme from the coronary sinus, recovery of adenosine triphosphate, and myocardial water content were evaluated. RESULTS: The group with leukocyte-depleted secondary blood cardioplegia showed the best hemodynamic recovery (Emax and total dp/dt), lowest levels of MDA, CK-MB and myocardial water content, and highest adenosine triphosphate recovery. CONCLUSIONS: These results suggest that controlled reperfusion with leukocyte-depleted secondary blood cardioplegia attenuated severe damage of the myocardium as compared to whole blood reperfusion.     

Normothermic ischemic cardiac arrest in the isolated working rabbit heart: Effects of dl-nebivolol and atenolol

Summary The effect of pretreatment with selective ₁-adrenoceptor blockers (dl-nebivolol or atenolol) on myocardial mechanical activity, mitochondrial function, morphology, and calcium cytochemistry was studied during normothermic ischemic arrest and reperfusion of isolated working rabbit hearts. The hearts subjected to 25 min of ischemia followed by 30 min of post-ischemic reperfusion showed typical signs of severe myocardial ischemic damage. The ultrastructural changes showed a good relation with the changes in mechanical activity and mitochondrial function. To determine whether these changes could be prevented or reduced by ₁-adrenoceptor blockade, dl-nebivolol or atenolol (0.62 mg/liter) was added to the perfusate 30 min before the induction of ischemia. The results showed that dl-nebivolol exerted a protective effect on recovery of mechanical activity, on mitochondrial function during reperfusion as well as on the ultrastructure as examined at the end of the reperfusion period. On the other hand, atenolol failed to protect the myocardium against ischemia-reperfusion damage in the isolated working rabbit heart.     

Temporal and spatial development of infarcts in porcine hearts

Summary We investigated the temporal and spatial development of infarcts in porcine hearts to evaluate the time-dependent beneficial effect of reperfusion on infarct size. The left anterior descending coronary artery (LAD) was occluded in 17 pigs for different periods of time followed by 4 hours of reperfusion. Transmural needle biopsies subdivided into subendocardial and subepicardial halves were taken from the ischemic apex after 60 min of ischemia to determine the tissue concentrations of ATP and NAD. The myocardium-at-risk was assessed with a fluorescent dye injected into the right atrium at the end of the experiments, just after the LAD had been reoccluded. The excised hearts were cut into slices parallel to the heart basis. The ischemic myocardium was measured by planimetry of the nonfluorescent areas whereas the infarcted tissue was determined with the NBT stain and related to the area-at-risk. Ischemic cell death started in the jeopardized left ventricular subendocardial septum after about 30 min of ischemia. The further progress involved the right subendocardial septum and the subendocardium of the left anterior free wall. Already after 75 min of ischemia most of the myocytes-at-risk were irreversibly injured.Infarctions reached their final extent after 90–120 min of ischemia. These results indicate that in hearts without a significant collateral blood flow reperfusion can only reduce infarct size if its initiated within 60–75 min of ischemia. Like in canine hearts infarctions progress from the ischemic subendocardium towards the outer layers.This study was supported by a grant from SFB 89 Kardiologie, Göttingen     

Protection of the myocardium during ischemic arrest: possible toxicity of carnitine in cardioplegic solutions

Carnitine has been suggested as an agent for the protection of the myocardium during regional ischemia and it might therefore be able to reduce tissue injury during surgically induced global ischemia. Using an isolated working rat heart model we have assessed the way in which various concentrations of carnitine infuence the efficacy of the St. Thomas' Hospital Cardioplegic Solution. Carnitine was found to exert a dose-dependent detrimental effect upon the ischemic myocardium, with high concentrations abolishing all the protective properties of the cardioplegic solution. Furthermore, this compound appeared to promote the occurrence of reperfusion dysrhythmias.     

The role of potassium and sodium-calcium exchange currents in the action potential durations of normal Purkinje fibres and Purkinje fibres surviving infarction

Ventricular arrhythmias following myocardial infarction may originate from subendocardial Purkinje fibres in the infarcted area. The role of potassium and sodium-calcium exchange currents on action potential duration was therefore investigated in Purkinje fibres surviving infarction and in normal Purkinje fibres. Barium was used to reduce potassium conductance and replacement of sodium chloride by lithium chloride was used to reduce the sodium-calcium exchange current. Barium (1 x 10(-5) to 3 x 10(-5) M) produced a concentration dependent lengthening of action potential duration in normal Purkinje fibres but these concentrations had no effect in Purkinje fibres surviving infarction. The resting membrane potential, activation voltage, amplitude and Vmax were decreased in Purkinje fibres surviving infarction and in barium treated fibres v normal Purkinje fibres. These results show that action potential characteristics of barium treated normal Purkinje fibres closely resemble those seen in Purkinje fibres surviving infarction. A similar reduction of action potential duration was seen in normal Purkinje fibres, fibres surviving infarction and barium treated fibres when the sodium "window" current was decreased by lignocaine. Without any effect on the Vmax, the replacement of sodium chloride by lithium chloride resulted in a similar effect on the action potential duration in normal Purkinje fibres and fibres surviving infarction. The results show that the longer action potential duration found in Purkinje fibres surviving infarction can be explained by a decrease of the potassium conductance and not by an increase of the sodium "window" current or the sodium-calcium exchange current.     

Polarization and myocardial protection

Heart surgery or transplantation generally involve global ischemia, and techniques have been developed to protect the myocardium from ischemic and reperfusion injury. Hyperkalemic cardioplegia has been the gold standard for myocardial protection for years, but patients undergoing surgery almost invariably have some postoperative dysfunction. One factor may be the depolarizing nature of hyperkalemia, which results in continuing transmembrane fluxes and metabolism, even during hypothermic ischemia. A potentially beneficial alternative to hyperkalemic (depolarizing) cardioplegia is arrest in a "hyperpolarized" or "polarized" state, which maintains the myocardial membrane potential at or near the resting potential. This should minimize transmembrane fluxes and metabolic demand and improve myocardial protection. These alternative concepts have recently been investigated by using adenosine and potassium-channel openers (which are thought to induce hyperpolarized arrest) or the sodium-channel blocker tetrodotoxin (which induces polarized arrest), and results have been beneficial compared with the results of hyperkalemia. Additional studies are needed before experimental promise can become clinical reality.