The involvement of gap junctions in the delayed phase of the protection induced by cardiac pacing in dogs

The present study has examined the role of GJ (gap junctions) in the delayed anti-arrhythmic effect of cardiac pacing, with particular reference to the time-course changes in Cx43 (connexin43) expression both after pacing (4×5?min, at a rate of 240 beats/min) and 24?h later, when the dogs were subjected to a 25?min occlusion and reperfusion of the LAD (left anterior descending coronary artery). Compared with the SP (sham-paced) controls (n=20), in dogs paced 24?h previously (n=16) there were reductions in arrhythmia severity [e.g. number of VPB (ventricular premature beats) during occlusion 294±78 compared with 63±25; survival from the combined ischaemia/reperfusion insult 20% compared with 78%], and in other ischaemic changes [epicardial ST-segment, TAT (total activation time) and tissue impedance]. Pacing also prevented the ischaemia-induced structural impairment of the intercalated discs, and preserved GJ permeability and Cx43 phosphorylation, without modifying Cx43 protein content. Following cardiac pacing the membrane and total Cx43 protein contents were unchanged up to 6?h, but were significantly reduced 12?h later (preceded by a down-regulation of Cx43 mRNA at 6?h), and returned to normal by 24?h. Interestingly, dogs that were subjected to ischaemia 12?h after cardiac pacing showed increased arrhythmia generation. We conclude that cardiac pacing results in time-dependent changes in Cx43 expression, which may alter GJ function and influence arrhythmia generation during a subsequent ischaemia/reperfusion insult. This effect is manifested in protection 24?h after pacing, but of potential clinical interest is the finding that there is a time interval after pacing during which an ischaemic event may generate severe ventricular arrhythmias.     

Delayed cardioprotective effects of exercise in dogs are aminoguanidine sensitive: possible involvement of nitric oxide

Dogs were subjected to exercise on a treadmill, using a protocol in which the speed and slope were increased every 3 min, and which elevated both heart rate (to a mean of 198+/-14 beats.min(-1)) and mean arterial blood pressure (to 150+/-4 mmHg). Then, 24 or 48 h later, the dogs were anaesthetized with a mixture of alpha-chloralose and urethane and subjected to a 25 min occlusion of the left anterior descending coronary artery. The control dogs (instrumented but not exercised) were subjected to the same procedure. In some dogs the nitric oxide synthase inhibitor aminoguanidine (50 mg.kg(-1); intravenous) was administered 30 min before occlusion. Baroreflex sensitivity (BRS) was determined by the rapid bolus injection of phenylephrine 60 min before, and again 3 min after, the onset of occlusion. Exercise markedly reduced the consequences of coronary artery occlusion 24 h (but not 48 h) later, without modifying myocardial tissue blood flow. In the exercised dogs there were reductions in arrhythmia severity [ventricular fibrillation (VF) during occlusion, 0%; survival from the combined ischaemia/reperfusion insult, 70%] compared with controls (VF during occlusion, 36%; survival, 9%). BRS was preserved during occlusion in the exercised dogs (before occlusion, 1.60+/-0.54 ms.mmHg(-1); 3 min after occlusion, 1.37+/-0.4 ms.mmHg(-1)), but not in controls (before occlusion, 1.28+/-0.29 ms.mmHg(-1); 3 min after occlusion, 0.45+/-0.12 ms.mmHg(-1); P<0.05), and other ischaemic changes (inhomogeneity of electrical activation and changes in the ST-segment, recorded over the ischaemic region) were also less marked in the exercised dogs. Exercise-induced cardioprotection was abolished by aminoguanidine (VF during occlusion, 25%; survival, 0%). The results show that even a single period of exercise affords delayed protection against ischaemia/reperfusion-induced VF and other ischaemic changes. Since this protection is abolished by aminoguanidine, and since (inducible) NO synthase activity was elevated 3-fold in left ventricular samples 24 h after exercise, we suggest that this protection is mediated by nitric oxide.     

Spontaneous gasping produces carotid blood flow during untreated cardiac arrest

We have shown previously that arginine vasopressin (AVP) given during sinus rhythm increases mean arterial blood pressure (MAP) and left anterior descending (LAD) coronary artery cross sectional area. AVP was assumed to result in vasodilatation via activation of the endothelial nitric oxide system. The purpose of the present study was to assess the effects of AVP before and after NO-inhibition. Nine domestic pigs were instrumented for measurement of haemodynamic variables using micromanometer-tipped catheters, and measurement of LAD coronary artery cross sectional area employing intravascular ultrasound (IVUS). Haemodynamic variables, LAD coronary artery cross sectional area and cardiac output were measured at baseline, 90 s and 5, 15, and 30 min after AVP (0.4 U kg (-1) IV) before and after blockade of nitric oxide synthase with N(G)-nitro L-arginine methyl ester (L-NAME). Compared with baseline, AVP significantly increased MAP after 90 s (89+/-4 versus 160+/-5 mm Hg), increased LAD coronary artery cross sectional area (11.3+/-1 versus 11.8+/-1 mm(2)) and decreased cardiac index (138+/-6 versus 53+/-6 mL/min kg(-1)). After blockade of nitric oxide synthase, AVP significantly increased MAP after 90 s (135+/-4 versus 151+/-3 mm Hg), increased LAD coronary artery cross sectional area (8.7+/-1 versus 8.9+/-1 mm(2)), and significantly decreased cardiac index (95+/-6 versus 29+/-4 mL/min kg (-1)). IMPLICATIONS: During sinus rhythm, AVP increased MAP and LAD coronary artery cross sectional area, but decreased cardiac index.     

Reflex Inhibition of Renal Sympathetic Nerve Activity during Myocardial Ischemia Mediated by Left Ventricular Receptors with Vagal Afferents in Dogs

The major goal of this investigation was to determine if activation of cardiac receptors during coronary artery occlusion could inhibit efferent renal sympathetic nerve activity. In nine chloralose anesthetized dogs with only carotid (n = 3) or with sinoaortic (n = 6) baroreceptors operative, anterior descending coronary artery (LAD) occlusion resulted in a small decrease in mean arterial pressure (-9.8+/-5.1 mm Hg, NS) and in a significant (P < 0.05) increase in renal nerve activity (24.0+/-4.1%). In these dogs, circumflex coronary artery (Cx) occlusion resulted in greater hypotension (-18.4+/-4.0 mm Hg), and yet no change (1.1+/-9%) in renal nerve activity was noted. Changes in left atrial pressure during LAD and Cx occlusion were not different. In seven dogs with carotid sinus denervation, coronary occlusions resulted in decreases both in arterial pressure and in renal nerve activity which were consistently greater during Cx occlusion. The responses to coronary occlusion in six dogs after sinoaortic deafferentation were similar to those observed with only carotid sinuses denervated. In all experiments, vagotomy abolished the difference in the blood pressure responses and the decreases in renal sympathetic nerve activity during Cx occlusion. Vagotomy also abolished the decrease in nerve activity during LAD occlusion in dogs with carotid or sinoaortic denervation. These data show that Cx occlusion and, to a lesser degree, LAD occlusion resulted in reflex withdrawal of renal sympathetic nerve activity mediated by left ventricular receptors with vagal afferents. The reflex withdrawal of renal nerve activity during Cx occlusion occurred in spite of hypotension and the presence of functioning sinoaortic baroreceptors.     

Study of the electrophysiological effects of early or subendocardial ischaemia with intracavitary electrodes in the dog

The early electrophysiological patterns of regional subendocardial ischaemia were studied by using the paced endocardial evoked response and simultaneous endocardial monophasic action potential recordings in 16 experiments in open chested dogs. Ischaemia was produced by transient (1-3 min) coronary artery occlusion. Regional subendocardial isochaemia caused asynchronous activation due to differential conduction delay and shortened repolarization as evaluated by the duration of the paced evoked response from 175 +/- (SD) 18.7 ms to 167 +/- 16 ms (P less than 0.001). These changes occurred within 60 s of occlusion and reversed rapidly after release of the occlusion. In simultaneous endocardial monophasic action potentials there was a decrease in plateau amplitude and the duration of repolarization shortened from 180 +/- (SD) 21.2 ms to 167 +/- 20.4 ms (P less than 0.001). The delay in endocardial activation after 2 min ischaemia was 5.5 ms, which is considerably shorter than the conduction delay previously reported in the subepicardial layers. The calcium-channel blocking drug verapamil (infused at 0.4 mg/kg) altered the rate at which shortening of repolarization and asynchronous activation occurred during ischaemia in six experiments. These experiments suggest that intracavitary electrodes could provide earlier and more sensitive detection of regional subendocardial ischaemia and may permit the assessment of therapy on the early electrical changes in the intact heart.     

Effects of proximal ventricular septal pacing on hemodynamics and ventricular activation

Recently the use of alternate site pacing to improve cardiac function in patients with bradyarrhythmias has increased. In the present study, hemodynamics of right ventricular septal pacing were studied in seven dogs. A bipolar screw-in lead and endocardial lead were placed in the proximal right ventricular septum and right ventricular apex, respectively. The right ventricle was paced from each site. A conductance catheter and Millar catheter were inserted into the left ventricle to determine the left ventricular pressure and the pressure-volume loop. Cardiac output was measured using the thermodilution method. In five of the seven dogs, ventricular activation was documented by isochronal epicardial activation mapping during each pacing mode. Mean arterial pressure and cardiac output during septal pacing were significantly higher than during apical pacing (110 +/- 17 mmHg vs 100 +/- 18 mmHg; 1.00 +/- 0.39 L/min vs 0.89 +/- 0.33 L/min). The positive dp/dt during septal pacing was significantly higher than during apical pacing (2137 +/- 535 mmHg/s vs 1911 +/- 404 mmHg/s). End-systolic elastance during septal pacing was significantly higher compared to apical pacing (13.1 +/- 0.3 mmHg/mL vs 8.9 +/- 4.0 mmHg/mL). The ventricular activation time during septal pacing was significantly shorter than during apical pacing. The epicardial maps generated during septal pacing were similar to those from atrial pacing. We conclude that hemodynamics and interventricular conduction are less disturbed by proximal right ventricular septal pacing than apical pacing in dogs with normal hearts.     

Calcitonin gene-related peptide receptor antagonism does not affect the severity of myocardial ischemia during atrial pacing in dogs with coronary artery stenosis

Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide that also has potent vasodilator activity. There are conflicting preclinical reports regarding the effect of CGRP receptor antagonism in the setting of myocardial ischemia. The present study was conducted in a canine model in which regional myocardial ischemia was reproducibly evoked by serial periods of atrial pacing (80 beats per min above baseline rate) in the presence of a 40% stenosis of the left anterior descending (LAD) coronary artery. Ischemia severity was quantitated by changes in unipolar epicardial electrograms (EG) recorded in the area of ischemia. In validation studies, the calcium entry blocker diltiazem reduced ischemia severity (before versus after treatment: DeltaEG, 1.92 +/- 0.23 versus 0.54 +/- 0.24 mV; p < 0.05) and tended to increase LAD flow (7.7 +/- 0.7 versus 9.4 +/- 1.4 ml/min; p = 0.10), whereas the coronary constrictor serotonin increased ischemia severity (before versus after treatment: DeltaEG, 2.11 +/- 0.44 versus 4.90 +/- 1.46 mV; p < 0.05) concomitant with a reduction in LAD flow (9.1 +/- 1.1 versus 5.4 +/- 1.5 ml/min; p < 0.05). A 30 microg/kg/min i.v. infusion test dose of the CGRP receptor antagonist CGRP((8-37)) was validated by demonstrating complete block of the depressor effects of exogenous i.v. 0.03 to 0.3 microg/kg CGRP. This dose of CGRP((8-37)), administered either intravenously or intra-atrially, had no effect on ischemia severity or paced LAD flow, indicating no intrinsic effect of CGRP receptor antagonism on the severity of acute myocardial ischemia. Likewise, the administration of a hemodynamically active dosing regimen of CGRP (0.03 microg/kg/min i.v.) had no effect on paced coronary flow or ischemia severity, suggesting no major role of CGRP in regulating ischemic blood flow.     

Effects of vasopressin on left anterior descending coronary artery blood flow during extremely low cardiac output

Because of the possibility of vasopressin-mediated coronary vasospasm, this study was designed to assess effects of vasopressin compared to saline placebo on left anterior descending (LAD) coronary artery blood flow. Twelve anaesthetized domestic swine were prepared for LAD coronary artery blood flow measurement with ultrasonic flow probes, using cardiopulmonary by-pass adjusted to 10% of the prearrest cardiac output. This 10% value approximates that reported for cardiac output during conventional closed-chest CPR. After 4 min of untreated ventricular fibrillation, and 3 min of cardiopulmonary by-pass blood flow, 12 pigs were randomly assigned to receive intravenously, every 5 min, either vasopressin (0.4, 0.4, and 0.8 U/kg; n = 6) or saline placebo (n = 6). The mean +/- S.D. LAD coronary artery blood flow in the vasopressin and placebo pigs was comparable before cardiac arrest, and during cardiopulmonary by-pass low flow; but increased significantly (P < 0.05) 90 s after each of three vasopressin injections compared to placebo (78 +/- 1 versus 42 +/- 2 ml/min; 62 +/- 2 versus 36 +/- 1 ml/min; and 54 +/- 1 versus 27 +/- 1 ml/min), respectively. Coronary vascular resistance decreased significantly (P < 0.05 ) 90 s after each of three vasopressin and placebo injections. In this model, repeated bolus administration of vasopressin, given during simulated extremely low cardiac output improved LAD coronary artery blood flow to prearrest levels without affecting coronary vascular resistance. Conclusions: during extremely low blood flow using cardiopulmonary by-pass, vasopressin improves LAD coronary artery blood flow without affecting coronary vascular resistance.     

Compensatory responses of left atrial conduit flow to atrial fibrillation with acute myocardial infarction in a canine model.

The aim of this study was to examine the interaction of acute atrial fibrillation (Af) and acute myocardial infarction (AMI) on left atrial (LA) and left ventricular (LV) filling in atrioventricular (A-V) sequential paced, open chest, anesthetized dogs. Left atrial conduit function was determined from pulmonary venous flow (PVF) and detailed analysis of early diastolic flow with the use of micromanometers and transmitral Doppler echocardiography. We studied 8 dogs with regular ventricular rates to avoid the confounding effect of ventricular arrhythmia in Af. In the control stage, Af increased the diastolic PVF volume to the left atrium compared with that during regular A-V pacing (from 0.58 +/- 0.11 mL/beat to 0.70 +/- 0.13 mL/beat, P <.05), as a compensatory response to the impaired systolic PVF volume (from 0.56 +/- 0.12 mL/beat to 0.41 +/- 0.11 mL/beat, P <.05). As a result, cardiac output was maintained. However, in the AMI stage, Af decreased cardiac output (from 0.95 +/- 0.32 L/min to 0.80 +/- 0.23 L/min, P <.05 versus AMI with A-V pacing), and decreased diastolic PVF volume (from 0.46 +/- 0.13 mL/beat to 0.33 +/- 0.14 mL/beat, P <.05 versus AMI with A-V pacing). These changes were associated with a prolonged LV isovolumic pressure decay rate. Our study demonstrates that Af does not affect cardiac output in the setting of normal LV function at a controlled ventricular rate because enhanced LA conduit flow compensates for impaired LA reservoir function. In contrast, in the setting of AMI, the compensatory response to Af is attenuated because of abnormal LV relaxation, resulting in a decrease in cardiac output.     

Moderate normovolaemic haemodilution increases regional myocardial blood flow but has no effect on experimental infarct size

Regional myocardial blood flow was measured with radioactive microspheres before and 1, 3, 6, and 12 h after occlusion of the left anterior descending coronary artery (LAD) in anaesthetized cats. In one group of cats, 1 h after LAD occlusion, moderate normovolaemic haemodilution was started with a dextran 40 solution, which reduced the haematocrit by 20-25% throughout the rest of the experiment. In the other group, the haematocrit was kept at the original level. Infarct size was measured planimetrically 12 h after the coronary ligation, using the tetrazolium staining technique for disclosing the ischaemic myocardium. Haemodilution increased blood flow in the non-ischaemic myocardium and in the so-called 'border zone' comprising both normal, and ischaemic tissue. However, in the severely ischaemic myocardium dependent on collateral blood flow, where there was no admixture of non-ischaemic myocardium, the blood perfusion was not significantly affected by the haemodilution. After 12 h of ischaemia the infarct size in the control group was fully comparable with that in the haemodiluted group: 28 +/- 3 and 27 +/- 4 (percentage of the left ventricle, mean +/- SEM), respectively.     

Myocardial adenine nucleotide depletion within 1 h of acute coronary artery occlusion.

In anaesthetized open-chest casts with occlusion of the left anterior descending coronary artery (LAD), adenine nucleotides and degradation products were studied in small myocardial tissue samples (10-20 mg) with high-pressure liquid chromatography, and tissue blood flow was measured with radioactive microspheres 5, 10, 20, 40, and 60 min after LAD occlusion. There was a rapid and parallel decrease of myocardial ATP and accumulation of adenosine, inosine, hypoxanthine, and xanthine both in epicardial and endocardial half-layers of the ischaemic myocardium within the first 20 min of coronary occlusion. After 40 and 60 min, myocardial ATP content decreased and degradation products accumulated further in the endocardium but stabilized epicardially. Analysis of covariance showed that the slightly higher blood flow in ischaemic epicardial layers, did not explain the transmural difference in ATP content after 40 and 60 min. Adenosine decreased after 40 min of ischaemia in both wall layers reaching negligible amounts after 60 min. It is concluded that breakdown of energy stores is less severe in epicardial than in endocardial wall layers during the first hour after acute coronary occlusion in the cat heart. This transmural difference cannot be explained entirely by less severe epicardial ischaemia. Therefore, transmural heterogeneity in metabolic function during severe ischaemia may also be important.     

Decline of atrial natriuretic peptide release in dogs during sustained rapid cardiac pacing

1. To assess the ability of the atria to maintain elevated plasma concentrations of atrial natriuretic peptide (ANP), the temporal changes in plasma ANP concentrations were studied in seven chloralose-anaesthetized dogs during 4 h of sustained rapid cardiac pacing. 2. Heart rate increased from 124 +/- 26 (mean +/- SEM) to 278 +/- 28 beats/min for the 4 h duration of rapid cardiac pacing. Mean pulmonary wedge pressure increased from 3.6 +/- 1.8 to 17.4 +/- 7.1 mmHg at 30 min (P less than 0.01) and mean right atrial pressure rose from -1.7 +/- 1.9 to 2.0 +/- 2.8 mmHg at 30 min (P less than 0.01). Both remained constant at these elevated pressures for the entire 240 min of rapid pacing. 3. Arterial ANP concentrations increased in all dogs from 87 +/- 11 to a maximum of 1263 +/- 592 pmol/l at 30 min (P less than 0.01), falling to 411 +/- 42 pmol/l after 60 min and to 146 +/- 70 pmol/l after 240 min of rapid continuous pacing (P less than 0.01 compared with 30 min). Coronary sinus ANP concentrations showed a similar pattern, rising from 241 +/- 79 to a maximum of 1837 +/- 203 pmol/l after 30 min (P less than 0.01). These peak values likewise were not sustained, falling to 962 +/- 198 pmol/l after 60 min and 297 +/- 41 pmol/l after 240 min of rapid pacing (P less than 0.01 compared with 30 min). 4. It is concluded that atria are unable to maintain the peak concentrations of ANP reached after 30 min of rapid pacing despite persistently elevated atrial pressures.     

急性缺血再灌注心肌细胞凋亡及凋亡基因与左室局部功能的实验研究

目的 应变率成像观察犬急性缺血再灌注后左心室局部功能，与细胞凋亡及心肌组织中caspase-3 mRNA和蛋白表达的变化。方法 健康杂种犬30只，分对照组（10只），缺血组（10只），再灌注组（10只）。缺血组于第一对角支1cm以下套扎左冠状动脉前降支30min，再灌注组套扎30min后再灌注120min，对照组游离左冠状动脉前降支不结扎。超声心动图左室收缩期应变率测量左室局部收缩功能，TUNEL法检测缺血区心肌细胞凋亡数，RT-PCR法检测caspase-3 mRNA的表达，免疫组化法测caspase-3蛋白的表达。结果 结扎30min后，左室前壁缺血节段收缩期应变率明显降低（P〈0.01）。并出现收缩后压缩（PSC），再灌注120min后缺血节段的应变率有所恢复，但仍低于对照组（P〈0.05）。缺血组缺血区心肌TUNEL阳性细胞数与对照组比较无显著性差异;再灌注组缺血区心肌TUNEL阳性数明显增加（P〈0.05）。缺血组缺血区caspase-3 mRNA与对照组比较表达增高（P〈0.05），再灌注组进一步增高（P〈0.01）。缺血组缺血区心肌细胞caspase-3表达升高，与对照组比差异有显著意义（P〈0.05），再灌注组caspase-3表达进一步增强（P〈0.01）。结论 急性心肌缺血再灌注促凋亡基因capase-3激活，缺血心肌细胞凋亡可能为其早期改变，应变率成像可以评价缺血早期心肌局部收缩功能。     

Functional characterization of left ventricular segmental responses during the initial 24 h and 1 wk after experimental canine myocardial infarction.

Characterization of the temporal evolution of resting segmental function and inotropic reserve after coronary occlusion may be important in evaluating attempts to salvage ischemic but non-necrotic myocardium. Accordingly, we chronically implanted up to six pairs of pulse-transit piezoelectric crystals in the left ventricular myocardium of dogs to measure segmental wall thickness. Segments were separated into groups according to the loss of net systolic thickening (NET) at 5 min postocclusion of the left anterior descending coronary artery in awake, unsedated dogs. Group 1 included segments with NET values of 67--100+ (percent control); group 2 between 67 and 0; and group 3 less than 0 (paradoxical motion). 5 min after coronary occlusion, group 1 NET was 92 +/- 5% (SEM) although significant decreases occurred in NET in group 2 (36 +/- 4%) and group 3 segments (-33 +/- 5%). Between 5 min and 24 h after coronary occlusion, no further significant changes occurred in NET in groups 1, 2, and 3 crystals. Some segments underwent further functional deterioration between 24 h and 1 wk after left anterior descending coronary artery occlusion, although no overall change occurred in segments with mild to moderate ischemic dysfunction. Segments with NET less than 0 at 24 h, on the other hand, exhibited a reduction in aneurysmal bulging between 24 h and 1 wk from -41 +/- 10 to -23 +/- 11% (n = 12, P = 0.02). Inotropic reserve was assessed with postextrasystolic potentiation (PESP) in 14 dogs, and with infusions of dopamine (11 dogs), and isoproterenol (13 dogs). PESP was the most potent intervention and produced a significant augmentation in NET in group 2 crystals at 1, 2, 4, 6,8, and 24 h after coronary occlusion but only at 1 and 2 h in NET in group 3 crystals. Thus, following experimental coronary occlusion, the evolution of ischemic segmental dysfunction is dynamic and variable. A significant degree of inotropic reserve, as assessed by PESP, dopamine, and isoproterenol, exists in segments with moderate ischemic dysfunction for 24 h but for only 2 h after coronary occlusion in those segments with the most severe ischemic dysfunction. In addition, at least some segmental sites with mild to moderate ischemic dysfunction at 24 h deteriorate further between 24 h and 1 wk after experimental coronary occlusion.     

Left atrial tachyarrhythmia in fetal lambs

To evaluate the hemodynamic effect of rapid left atrial pacing on fetal circulation, a fetal supraventricular tachyarrhythmia model was made and the aortic pressure, central venous pressure, and left and right ventricular outputs were measured in ten fetal lambs. Under maternal anesthesia, the uterus was opened, and under local anesthesia, catheters were inserted into thefetal superior vena cava and ascending aorta through a neck incision. Pacing leads were then sutured onto the fetal left atrial appendage via left thoracotomy. Ventricular output was estimated using echocardiography by a transuterine approach. Fetal hemodynamics were observed without pacing (control), and at the pacing rates of 200, 300, 350, and 400/min. The aortic pressure decreased when the left atrium was paced at 300/min or more and the central venous pressure increased when the left atrium was paced at 350/min or more. The left and right ventricular outputs decreased when the left atrium was paced at 350/min or more. The left ventricular output was 215+/-54 mL/kg per minute at control, 205+/-60 mL/kg minute when paced at 200/min, 178+/-58 mL/kg per minute when paced at 300/min, but decreased to 164+/-44 mL/kg per minute when paced at 350/min and to 149+/-57 mL/kg per minute when paced at 400/min. The right ventricular output was 338+/-66 mL/kg per minute at control, 336+/-95 mL/kg per minute when paced at 200/min, 273+/-91 mL/kg per minute when paced at 300/min, but decreased to 256+/-80 mL/kg per minute when paced at 350/min and to 202+/-76 mL/kg per minute when paced at 400/min. Fetal circulatory failure was initially confirmed when the left atrium was paced at 300/min in this left atrial tachyarrhythmia model.     

Myocardial ischaemic preconditioning in the pig has no effect on the ventricular fibrillation and defibrillation thresholds

INTRODUCTION: The effects of myocardial ischaemia preconditioning in pigs on the vulnerability to ventricular fibrillation during subsequent ischaemic events are controversial. This study examined the time course of changes in ventricular fibrillation (VFT) and defibrillation (DFT) thresholds during transient myocardial ischaemia after a 45 min preconditioning period. METHODS AND RESULTS: In five open-chest pigs, VFT was measured after 3 min of regional myocardial ischaemia, at time 0, 2, 15, 30, 60 and 90 min (Control group). In seven other pigs (Test group), VFT was measured before (time 0) and 2, 15, 30, 60 and 90 min after ischaemic preconditioning by three consecutive 5 min periods of regional coronary occlusion, followed by 10 min of reperfusion. DFT was measured by increasing the stored energy systematically until successful defibrillation. Ischaemic preconditioning caused no significant change in the effective refractory period (ERP), VFT or DFT over the 90 min of the experiments. In the Control group, ERP remained stable for 30 min, though was significantly lower at 90 min (178 +/- 28 ms) than at baseline (204 +/- 32 ms, P = 0.007). VFT and DFT remained unchanged throughout the experiments, and no difference was observed in ERP, VFT and DFT between the two groups at any time during the experiment. CONCLUSION: No changes were observed in the refractory duration, ventricular vulnerability or defibrillation energy requirements up to 90 min after ventricular ischaemic preconditioning in the pig.     

The influence of inosine on the size of myocardial ischaemia and myocardial metabolism in the pig*

Summary. In acute experiments on open chest pigs 15 min occlusions of the left anterior descending coronary artery were performed, each occlusion followed by 45 min reperfusion. Myocardial ischaemia was defined by epicardial electrogram recorded from the border of the ischaemic area. Myocardial extraction of lactate and glucose as well as the extraction of FFA were measured before and at the 15th min of occlusion. Inosine (5 mg/kg/min) or 0·9% NaCl infusion was administered i.v. throughout the occlusion period. Inosine significantly diminished the number of ischaemic points and reduced an increase in R-wave voltage induced by coronary occlusion. Myocardial extraction of measured substrates was not significantly influenced by inosine administration. In conclusion, inosine decreases the area of ischaemic injury induced by acute coronary occlusion in the pig.     

Atrial pacing lead location alters the effects of atrioventricular delay on atrial and ventricular hemodynamics

The combined role of atrial pacing lead location and AV timing on cardiovascular performance has not been defined. This study tested the hypothesis that atrial pacing lead location can change the dependence of LA and LV hemodynamics on AV timing in vivo. Dogs anesthetized with isoflurane (n = 8) were instrumented for measurement of hemodynamics including LA pressure, LA volume, and pulmonary venous bloodflow. Data were recorded during normal sinus rhythm, and atrial overdrive pacing from the right atrial appendage (RAA), proximal coronary sinus (CS), and LA lateral wall (LAW). The AV node was then ablated and measurements repeated during synchronous ventricular pacing and during dual chamber pacing from each atrial lead location at various AV delays (20, 60, 120, 180, 240, and 350 ms). Hemodynamics during intrinsic sinus rhythm and overdrive atrial pacing from different sites were similar. In contrast, ventricular or dual chamber pacing caused significant (P < 0.05) changes in cardiac output with different AV timing during RAA (3.5 +/- 0.2 vs 2.9 +/- 0.2 L/min at 120 and 350 ms, respectively) and LAW pacing but not CS pacing. A significant interaction between atrial lead location and AV delay was observed for changes in stroke volume, pulmonary venous blood transport, LA volume, and LV preload. The results indicate that the atrial contribution to cardiac output depends on AV timing and atrial lead location in isoflurane-anesthetized dogs with AV nodal conduction block.     

Hemodynamic effect of rapid atrial pacing in fetal lambs

To determine the threshold at which rapid atrial pacing brings on fetal circulatory failure, we made a fetal supraventricular tachyarrhythmia model and measured the central venous pressure, aortic pressure, and right and left ventricular outputs in five fetal lambs. Under maternal anesthesia, the uterus was opened, and under local anesthesia, polyvinyl catheters were inserted into the fetal superior vena cava and ascending aorta through a neck incision. Pacing leads (Medtronic model 6492) were then sutured onto the fetal right atrial appendage via right thoracotomy. Ventricular output was estimated using a Toshiba SSH-65A echocardiography by a transuterine approach. Fetal hemodynamics were observed without pacing (control), and at the atrial pacing rates of 200, 300, 350, and 400/min. Central venous pressure (CVP) increased and the aortic pressure decreased when the right atrium was paced at 350/min or more. Right ventricular output decreased when the right atrium was paced at 300/min or more. The left ventricular output, however, remained constant. The right ventricular output was 382 +/- 106 mL/kg/min at control, and 391 +/- 117 mL/kg/min when paced at 200/min, but decreased to 210 +/- 138 mL/kg/min when paced at 300/min, to 223 +/- 102 mL/kg/min when paced at 350/min, and to 186 +/- 86 mL/kg/min when paced at 400/min. Fetal circulatory failure occurred when the right atrium was paced at 300/min or more.     

Ischaemia or reperfusion: which is a main trigger for changes in nitric oxide mRNA synthases expression?

OBJECTIVE: To investigate alterations in endothelial nitric oxide synthase and inducible nitric oxide synthase mRNA expressions and nitric oxide release in the myocardium during ischaemia/reperfusion and determine whether these changes are ischaemic and/or reperfusion dependent. MATERIALS AND METHODS: Isolated rat hearts were perfused by a modified Langendorff system. Following 1 h of global cardioplegic ischaemia, left ventricle haemodynamic parameters were recorded at baseline and during 30 min of reperfusion. Levels of endothelial, inducible nitric oxide synthases mRNA expression and nitric oxide release were measured at baseline, after ischaemia and at 30 min of reperfusion. RESULTS: Global cardioplegic ischaemia caused a significant depression of left ventricular function and a decrease of coronary flow. Postischaemic intensities of the endothelial nitric oxide synthase mRNA bands were significantly lower than at baseline (P < 0.01). There were no significant differences in endothelial nitric oxide synthase mRNA band intensities immediately after ischaemia compared to the end of reperfusion, nor between the intensities of inducible nitric oxide synthase mRNA bands at baseline, at end of ischaemia and at end of reperfusion. Nitric oxide in the myocardial effluent was below detectable levels at all measured points. CONCLUSION: Ischaemic injury causes down-regulation of endothelial nitric oxide synthase mRNA expression, which is then associated with reduction of coronary flow during reperfusion, representing one possible mechanism of ischaemia/reperfusion injury. We did not find expected elevations of inducible nitric oxide synthase mRNA expression during ischaemia or reperfusion and we suggest that ischaemia/reperfusion injury is not associated with nitric oxide overproduction.