Insular infarct size but not levosimendan influenced myocardial injury triggered by cerebral ischemia in rats.

Cerebral injuries can trigger stress-related cardiomyopathy. The extent of cerebral injury and the involvement of the insular cortex influence the incidence and extent of myocardial injury (MI), and drugs with proven neuroprotective and cardioprotective properties such as levosimendan might be beneficial. This hypothesis was addressed in a rat model of transient middle cerebral artery occlusion. Transient brain ischemia was induced for 60 min by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats. Treatment with levosimendan (24 µg/kg) was started briefly before reperfusion. Hemodynamic parameters were recorded and cerebral and MI quantified after 24 h. Levosimendan treatment significantly reduced cerebral infarct size in the cortex, but not in the striatal and insular regions. However, its effects on survival (28 vs. 45%), incidence of MI (8 vs. 33%) as indicated by a troponin I (sTnI) threshold of 4.8 µg/L and large insular infarcts of ≥10 mm(3) (23 vs. 50%) failed to reach statistical significance. Blood pressure demonstrated significant differences related to insular infarct size during reperfusion. Levosimendan demonstrated no relevant effects on markers of MI (sTnI = 1.5 ± 2.8 vs. 5.3 ± 7.2 µg/L, P = 0.121). Insular infarct size could be identified as the only predictor of MI (odds ratio = 1.86, P = 0.037). In conclusion, the current investigation confirmed insular infarct size as a predictor of MI and source of hemodynamic compromise, but failed to demonstrate an effect of levosimendan on MI trigged by brain ischemia. A hardly protectable insular region might explain this.

Simplified detection of myocardial ischemia by seismocardiography. Differentiation between causes of altered myocardial function.

Seismocardiography (SCG) is a noninvasive technique for recording cardiac vibrations. Changes in these waves have been correlated with chronic and acute alterations in myocardial function. This analysis is complex and clinical integration limited. The current study aimed to simplify the utilization of SCG by fast Fourier transformation for a reliable discrimination between different intra- and postoperative causes of hypotension (i.e., myocardial ischemia or hypovolemia). We operated on nine pigs and recorded SCG at baseline, at hypovolemia (occlusion of the inferior vena cava), and at ischemia (occlusion of the right coronary artery). In conclusion, SCG enables detection and differentiation of ischemia and hypovolemia as important causes of altered myocardial function during and after surgery. Thus, this simple and noninvasive diagnostic tool may be used intra- and postoperatively to identify patients at risk.

Myocardial effects of local shock wave therapy in a Langendorff model.

OBJECTIVE: Applying shock waves to the heart has been reported to stimulate the heart and alter cardiac function. We hypothesized that shock waves could be used to diagnose regional viability. METHOD: We used a Langendorff model to investigate the acute effects of shock waves at different energy levels and times related to systole, cycle duration and myocardial function. RESULTS: We found only a small time window to use shock waves. Myocardial fibrillation or extrasystolic beats will occur if the shock wave is placed more than 15 ms before or 30 ms after the onset of systole. Increased contractility and augmented relaxation were observed after the second beat, and these effects decreased after prolonging the shock wave delay from 15 ms before to 30 ms after the onset of systole. An energy dependency could be found only after short delays (-15 ms). The involved processes might include post-extrasystolic potentiation and simultaneous pacing. CONCLUSION: In summary, we found that low-energy shock waves can be a useful tool to stimulate the myocardium at a distance and influence function.

Effect of anesthesia and cerebral blood flow on neuronal injury in a rat middle cerebral artery occlusion (MCAO) model.

Middle cerebral artery occlusion (MCAO) models have become well established as the most suitable way to simulate stroke in experimental studies. The high variability in the size of the resulting infarct due to filament composition, rodent strain and vessel anatomy makes the setup of such models very complex. Beside controllable variables of homeostasis, the choice of anesthetics and the grade of ischemia and reperfusion played a major role for extent of neurological injury. Transient MCAO was induced during either isoflurane or ketamine/xylazine (ket/xyl) anesthesia with simultaneously measurement of cerebral blood flow (CBF) in 60 male Wistar rats (380-420 g). Neurological injury was quantified after 24 h. Isoflurane compared with ket/xyl improved mortality 24 h after MCAO (10 vs. 50 %, p = 0.037) and predominantly led to striatal infarcts (78 vs. 18 %, p = 0.009) without involvement of the neocortex and medial caudoputamen. Independent of anesthesia type, cortical infarcts could be predicted with a sensitivity of 67 % and a specificity of 100 % if CBF did not exceed 35 % of the baseline value during ischemia. In all other cases, cortical infarcts developed if the reperfusion values remained below 50 %. Hyperemia during reperfusion significantly increased infarct and edema volumes. The cause of frequent striatal infarcts after isoflurane anesthesia might be attributed to an improved CBF during ischemia (46 ± 15 % vs. 35 ± 19 %, p = 0.04). S-100ß release, edema volume and upregulation of IL-6 and IL-1ß expression were impeded by isoflurane. Thus, anesthetic management as well as the grade of ischemia and reperfusion after transient MCAO demonstrated important effects on neurological injury.

Xenon is not superior to isoflurane on cardiovascular function during experimental acute pulmonary hypertension.

BACKGROUND: Acute right ventricular afterload increase is a known perioperative challenge for the anaesthetic regime especially for patients with a compromised right ventricle. The accused negative inotropic action of volatile anaesthetics, with the exception of xenon, might be crucial for the adaptation of the right ventricle. METHODS: Reversible pulmonary hypertension (mean pressure 40 mmHg) was induced by an infusion of the stable thromboxane A(2) analog U46619 in a porcine model (n = 35). The effects of 70 vol% xenon and 0.9 vol% isoflurane on biventricular function were studied by conductance catheter technique. Inflammation and myocardial injury was quantified using serum probes [tumour necrosis factor α (TNFα), interleukin 6 (IL-6), troponin] and myocardial tissue [B natriuretic peptide (BNP), TNFα, activated caspase 3] by enzyme-linked immunosorbance assays and reverse-transcription polymerase chain reaction. RESULTS: After wash in of xenon global haemodynamic parameters remained stable whereas isoflurane caused a systemic vasodilation. This led to a significant decrease in mean arterial pressure in the isoflurane group whereas cardiac output remained stable. Both substances did not alter the biventricular contractility nor did they induce changes in preload for both ventricles. Xenon led to an additional increase in right ventricular afterload, whereas isoflurane reduced pulmonary vascular resistance. No effects on systemic inflammatory response and myocardial injury were found, whereas higher apoptosis rate and expression of BNP and IL-6 was determined in the right ventricle. CONCLUSIONS: These results do not support the idea that xenon is more beneficial than isoflurane in right ventricular failure during pulmonary hypertension. Isoflurane did not compromise systolic ventricular function during acute PHT it only led to vasodilation in contrast to xenon.

The effects of metoprolol on hypoxia- and isoflurane-induced cardiac late-phase preconditioning.

BACKGROUND: The detrimental effects of metoprolol on early-phase preconditioning (pc) have been proven. The late phase of pc is mediated via gene transcription and cyclooxygenase-2 (COX-2) was identified as one of the key mediators. The effect of metoprolol on this is yet unknown as is its effect on cellular energy metabolism and reactive oxygen species (ROS) creation. METHODS: Cardiomyocytes from neonatal rats were cultured and randomly assigned to four pairs of treatment groups. In each pair, one group received metoprolol at a dose of 0.5 µg/ml medium. One pair served as a control; the others were subjected to 5 h of hypoxia 24 h after either hypoxia-induced, isoflurane-induced or no pc. Cell survival was measured with a redox indicator for cell metabolism. COX-2 transcription, ATP and ROS creation were measured. RESULTS: Whereas both ischemic and isoflurane pc produced mild beneficial effects (48.8±6.0% and 48.2±7.8% of surviving cells, respectively) compared with unpreconditioned controls (35.9±7.9%, P<0.01 for both), adding metoprolol was detrimental for both kinds of pc (hypoxia: 31.5±3.5%; isoflurane: 25.7±3.8%, P<0.001) but not in the unpreconditioned group (39.4±4.9%). mRNA for COX-2 was up to 10-fold elevated in pc cells. This induction was suppressed by metoprolol. Hypoxic and isoflurane-induced pc showed significant differences in ATP balance and ROS generation. CONCLUSION: Metoprolol abolishes the protection of both isoflurane- and hypoxia-induced late-phase pc in our model. This effect is accompanied by the blockade of COX-2 induction. The differences between hypoxic and isoflurane pc in ATP and ROS creation allow to presume distinct pathways on the mitochondrial level.

Accidental renal injury by an external heating device during surgery in rats.

Hypothermia can be caused by anaesthesia and/or surgery and represents a daily challenge in the operating room. Experimental animal surgery settings typically use heating pads or warming blankets to maintain the rodent's body temperature during long-lasting experiments. Warming is crucial in small animal experiments because these animals quickly lose temperature due to their large body surface to body weight ratio. While establishing a left ventricular infarction model in rats, we inserted a rectal temperature probe. The heating pad's set point was 37°C. Although a dual set point control circuit should prevent overheating, we observed a maximum heating pad's surface temperature of 43°C between the animal's back and the surface of the heating pad. At the end of the experiments, which lasted up to 8 h, the animals showed severe haematuria and segmental kidney damage. We hypothesized that overheating of the heating pad and uneven distribution of temperature led to kidney damage. Therefore, the maximal temperature of commonly used heating pads must be tightly controlled to avoid overheating, which may cause kidney or tissue injury, may falsify the experimental data and could influence the study results.

Xenon and isoflurane improved biventricular function during right ventricular ischemia and reperfusion.

BACKGROUND: Although anesthetics have some cardioprotective properties, these benefits are often counterbalanced by their negative inotropic effects. Xenon, on the other hand, does not influence myocardial contractility. Thus, xenon may be a superior treatment for the maintenance of global hemodynamics, especially during right ventricular ischemia, which is generally characterized by a high acute complication rate. METHODS: The effects of 70 vol% xenon and 0.9 vol% isoflurane on biventricular function were assessed in a porcine model (n=36) using the conductance catheter technique, and the expression of the type B natriuretic peptide (BNP) gene was measured. The animals underwent 90 min of right ventricular ischemia followed by 120 min of reperfusion. A barbiturate-anesthetized group was included as a control. RESULTS: Cardiac output was compromised in unprotected animals during ischemia by 33+/-18% and during reperfusion by 53+/-17%. This was mainly due to impaired contractility in the left ventricle (LV) and increased stiffness. Isoflurane attenuated the increase in stiffness and resulted in a higher preload. In contrast, xenon increased the right ventricular afterload, which was compensated by an increase in contractility. Its effects on diastolic function were less pronounced. Upregulation of BNP mRNA expression was impeded in the remote area of the LV by both isoflurane and xenon. CONCLUSIONS: Xenon and isoflurane demonstrated equipotent effects in preventing the hemodynamic compromise that is induced by right ventricular ischemia and reperfusion, although they acted through somewhat differential inotropic and vasodilatory effects.

Anti-ischemic effects of inotropic agents in experimental right ventricular infarction.

BACKGROUND: Right ventricular (RV) function is an important determinant of survival after myocardial infarction. The efficacy of reperfusion therapy might be increased by the cardioprotective action of inotropic agents, which are used for symptomatic therapy in situations with compromised hemodynamics. Therefore, we used a porcine model of RV ischemia and reperfusion (IR) injury to study the influence of milrinone, levosimendan and dobutamine on the extent and degree of myocardial injury. METHODS: IR injury was induced by temporary ligation of the distal right coronary artery for 90 min, followed by 120 min of reperfusion. Treatment was initiated 30 min after coronary artery occlusion. A bolus of milrinone (n=12; 50 microg/kg) and levosimendan (n=10; 24 microg/kg) was applied in different groups, followed by continuous infusion of the drugs at 0.5 and 0.2 microg/kg/min, respectively. The effects on myocardial injury and inflammation were compared with a control (n=12) and a dobutamine group (n=10), where treatment was started with an infusion of 5 microg/kg/min. RESULTS: Milrinone and levosimendan reduced the resulting infarct size with respect to the area at risk (41.7+/-10.2%, 45.7+/-8.1%) when compared with the control group (58.3+/-6.1%). In contrast, dobutamine had no effect (55.8+/-7.7%). All drugs reduced the number of neutrophils infiltrating into the different myocardial regions and the circulating levels of interleukin-6. Increased levels of tumor necrosis factor alpha during reperfusion were only abated by milrinone and levosimendan. CONCLUSIONS: Cardioprotective properties of milrinone and levosimendan were demonstrated for the first time in a clinically relevant model of RV infarction.

Xenon alters right ventricular function.

BACKGROUND: In contrast to other volatile anesthetics, xenon produces less cardiovascular depression with fewer fluctuations of various hemodynamic parameters, but reduces cardiac output (CO) in vivo. Besides an increase in left ventricular afterload and reduction of heart rate, an impairment of the right ventricular function might be an additional pathophysiological mechanism for the reduction of CO. Therefore, we used an animal model to study the effects of xenon as a supplemental anesthetic on right ventricular function, especially right ventricular afterload. METHODS: Right ventricular function was monitored with a volumetric pulmonary artery catheter in 11 pigs during general anesthesia with thiopental. Six animals received additional 70% (volume) xenon (equivalent to 0.55 MAC minimum alveolar concentration). Parameters for systolic function, afterload, and preload were calculated at baseline and during 50 min of xenon application, and in a corresponding control group. Significant differences were detected by multivariate analyses of variance for repeated measures. RESULTS: Xenon reduced CO on average by 30% and increased pulmonary arterial elastance by 60%, which led to a reduction of the right ventricular ejection fraction by 25%. Whereas right ventricular preload remained stable, maximal slope of pulmonary artery pressure and the right ventricular elastance increased. No effect on the ratio of stroke work and end-diastolic volume was found. CONCLUSION: The reduction in CO during xenon anesthesia was partly due to an impairment of the right ventricular function, mainly caused by an increased afterload, without an impairment of systolic ventricular function.

Establishment of a porcine right ventricular infarction model for cardioprotective actions of xenon and isoflurane.

BACKGROUND: Right ventricular (RV) function is an important determinant of post-operative outcome. Consequences of RV infarction might be limited by pre-conditioning with volatile anesthetic drugs. Therefore, we used a porcine model of RV ischemia and reperfusion (IR) injury to study the influence of isoflurane and xenon on the extent and degree of myocardial injury. METHODS: IR injury was induced by a 90-min ligation of the distal right coronary artery and 120-min reperfusion in thiopental anesthetized pigs. A control group (n=12) was compared with two groups, which received either 0.55 minimum alveolar concentration (MAC) isoflurane (n=10) or xenon (n=12) starting 60 min before ischemia. Myocardial injury was described by three criteria: the infarct size related to area at risk (IS/AAR), the infiltration of neutrophils as determined by myeloperoxidase (MPO) activity, and the plasma levels of tumor necrosis factor alpha (TNFalpha), interleukin 6 (IL-6), myoglobin and troponin-T (TnT). RESULTS: IS/AAR was reduced from 58.3+/-6.2% in the control group to 41.8+/-7.8% after isoflurane and 42.7+/-8.5% after xenon pre-treatment, which equals an absolute reduction of 16.5% [95% confidence interval (CI): 10.9-22.1] and 15.5% (95% CI: 10.1-20.9). The maximum increase of TnT could be observed within the xenon group. Both treatment groups were characterized by lower MPO activity, in the infarct and periinfarct region and lower plasma concentrations of TNFalpha and IL-6. CONCLUSIONS: It could be demonstrated for the first time in a model of RV infarction that the continuous application of isoflurane or xenon before, during and after ischemia reduced the extent (size) and severity (inflammation) of myocardial injury.