Effects of allopurinol pretreatment on myocardial ultrastructure and arrhythmias following coronary artery occlusion and reperfusion

The effect of the xanthine oxidase inhibitor, allopurinol, on myocardial ultrastructure after left circumflex coronary artery occlusion (40 min) with or without reperfusion (60 min) was examined in rabbits. Pretreatment of rabbits for 7 days with allopurinol (0.1% in the drinking water) resulted in a lower incidence of ventricular fibrillation in both ischemic and reperfusion phases. However, the number of Q waves, ST-segment elevation and premature ventricular contractions were similar in both groups of animals. Examination of hearts from allopurinol-treated animals revealed a distinct decrease in ultrastructural alterations following ischemia and reperfusion. Among the subcellular organelles studied, allopurinol had a preferential protective effect on the mitochondria both during the ischemic and reperfusion phases. In the allopurinol-treated animals, most mitochondria were intact and the cristae network preserved. Our study suggests that the preservation of mitochondrial structural and functional integrity by allopurinol may be an important determinant of its protective actions in myocardial ischemic/reperfusion injury.     

Influence of dietary lipids on arrhythmias and infarction after coronary artery ligation in rats

Coronary artery ligation (CAL) was used to produce an in vivo model of cardiac arrhythmias and myocardial infarction using anaesthetized male Hooded Wistar rats which had been fed for 6-7 or 18-20 months on either a standard reference diet alone or supplemented (12% w/w) with sunflower seed oil (linoleic acid rich) or sheep kidney fat (linoleic acid poor). The number of ventricular extra beats and duration of tachycardia or fibrillation in the 30-min postligation was increased in sheep kidney fat-fed rats. Infarct size 4 h postCAL was reduced in sunflower seed oil-fed rats. Arrhythmias, infarct size, and dietary-induced differences were increased with age. The diets employed produce changes in myocardial membrane phospholipids which could result in altered prostaglandin production. These results show that in the rat (as in man), age and dietary saturated fat are risk factors for sudden cardiac death and myocardial infarction and suggest that the rat is a useful model for the investigation of dietary interventions in heart disease.     

Catecholamine release and ventricular arrhythmias during coronary occlusion and reperfusion in the dog

In anesthetized dogs, 60-min occlusions of either the proximal (n = 14), distal (n = 8) left circumflex (LCX), or left anterior descending (LAD, n = 10) arteries were followed by reperfusion. Coronary sinus and aortic norepinephrine and epinephrine plasma concentrations were measured. The ventricular arrhythmias were ventricular premature depolarizations (VPDs), unsustained ventricular tachycardia (VT) (greater than or equal to 3 and less than 20 VPDs), sustained VT (greater than or equal to 20 VPDs), and ventricular fibrillation (VF). A gradual twofold increase (p less than 0.05) in myocardial norepinephrine overflow followed occlusion in all three groups. The increases in the amounts of norepinephrine released in the coronary sinus blood during reperfusion were significant and proportional to the size of the occluded area: proximal LCX, from 0.236 +/- 0.038 to 1.528 +/- 0.490 ng/mL of plasma (p less than 0.001); LAD, from 0.180 +/- 0.027 to 0.795 +/- 0.286 ng/mL (p less than 0.05); distal LCX, from 0.215 +/- 0.039 to 0.404 +/- 0.110 ng/mL (p less than 0.05). Aortic epinephrine concentrations were significantly increased only by LAD occlusion; at 15 min, the value had increased to 0.187 +/- 0.053 ng/mL from an initial value of 0.069 +/- 0.029 ng/mL (p less than 0.001). Two phases of ventricular arrhythmias followed both occlusion and reperfusion. Phase 1 postocclusion was characterized by VPDs and phase 2 by VPDs and unsustained VT. Sustained VT was seen only in phase 1 postreperfusion, whereas unsustained VT was seen in phase 2. VF was seen in 50, 35, and 25% of the dogs with proximal LCX, LAD, and distal LCX occlusion and reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ventricular arrhythmias following coronary artery occlusion in the streptozotocin diabetic rat

The following investigation was designed to assess whether or not streptozotocin diabetes has an influence on the number and severity of ventricular arrhythmias following coronary artery occlusion in the conscious rat. In addition, electrocardiogram and haemodynamic data were compared between streptozotocin groups and control. Diabetes was induced in male Sprague-Dawley rats with streptozotocin (55 mg/kg iv) and left anterior descending coronary artery ligation was performed either 6 or 9 weeks later. Rats were allowed to recover from preparative surgery for 1 week prior to ligation. Streptozotocin diabetes (untreated or insulin controlled) appeared to have little influence on the variables tested. When exposed to equivalent degrees of ischaemia (the rat is a microangiopathy-resistant species), the streptozotocin diabetic rat heart was not appreciably more prone to arrhythmias of any type compared with control.     

Effects of yohimbine and desipramine on cardiac noradrenaline release and ventricular arrhythmias during acute coronary artery occlusion and reperfusion in anesthetized dogs

Effects of yohimbine (YHMB, an alpha 2-antagonist) and desipramine (DMI, a neuronal uptake inhibitor) were compared on cardiac noradrenaline (NA) release either upon left ansa subclavia nerve stimulation during acute occlusion of the left anterior descending coronary artery (LAD) or upon subsequent LAD reperfusion without stimulation in anesthetized dogs. In control dogs, before LAD occlusion, coronary sinus (CS) NA output increased from 5.4 +/- 1.0 to 26.8 +/- 4.0 ng/min (p less than 0.05) upon stimulation (2 Hz, 30 s). The response to stimulation remained unchanged 25 min after LAD occlusion. During reperfusion 60 min after occlusion, the output of CS-NA and lactate increased from 6.1 +/- 0.8 to 51.3 +/- 19.4 ng/min (p less than 0.05) and from 2.7 +/- 0.5 to 6.7 +/- 1.3 mg/min (p less than 0.05), respectively. In dogs treated with YHMB, the stimulation-induced increase in NA output was potentiated at least fourfold (p less than 0.05) either before or during LAD occlusion, but not during reperfusion. In dogs receiving DMI, stimulation-induced CS-NA output was enhanced to a similar extent (approximately twofold, p less than 0.05) either before or during occlusion, while reperfusion-induced NA output was markedly potentiated by approximately ninefold (p less than 0.05). Maximum dP/dt of left ventricular pressure remained unchanged upon reperfusion in all groups. The total arrhythmic ratio in the drug-treated groups did not significantly differ from the ratio in control dogs upon either stimulation or reperfusion. The data suggest that an abrupt increase in NA output upon reperfusion may result from a washout of NA locally accumulated in the ischemic and (or) peri-ischemic region during the preceding occlusion period, and that NA thus released does not have substantial hemodynamic effects. The results indicate that in the presence of YHMB or DMI, the potentiated increase in NA release in response to either nerve stimulation during LAD occlusion or to reperfusion without stimulation did not aggravate ventricular arrhythmia, most probably owing to the antiarrhythmic properties of these substances.     

Effects of HNS-32, a novel antiarrhythmic drug,on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats

HNS-32 (N¹,N¹-dimethyl-N²-(2-pyridylmethyl)-5-isopropyl-3, 8-dimethylazulene-1-carboxamidine: CAS 186086-10-2) is a newly synthesized compound, and possesses antiarrhythmic properties with vasodilator action in dog hearts. The aim of this study was to investigate the dose-dependent effects of HNS-32 on ischemia- and/or reperfusion-induced ventricular arrhythmias in anesthetized rats in vivo and compared with those of mexiletine. Saline or drugs were administered intravenously 5 min prior to coronary artery occlusion. On the ischemia-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of total number of premature ventricular complexes (PVC) from 2091 ± 225 to 656 ± 116 and 286 ± 69 beats/30 min (p < 0.05), the ventricular tachycardia (VT) duration from 183 ± 33 to 28 ± 9 and 4 ± 2 sec (p < 0.05), the incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), and the incidence of ventricular fibrillation (VF) from 50 to 0 and 0% (p < 0.05) with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 936 ± 159 beats/30 min (p < 0.05), 39 ± 22 sec (p < 0.05), 90% (n.s.) and 10% (n.s.), respectively. HNS-32 completely suppressed the late reperfusion-induced arrhythmias, however mexiletine did not affect them. On the early reperfusion-induced ventricular arrhythmias, HNS-32 showed dose-dependent reduction of VT duration from 126 ± 34 to 37 ± 12 and 3 ± 2 sec (p < 0.05), incidence of VT from 100 to 90 (n.s.) and 40% (p < 0.05), incidence of VF from 100 to 10 and 0% (p < 0.05), and mortality rate from 90 to 0 and 0% (p < 0.05), with 3 and 5 mg/kg, respectively. Mexiletine also reduced these parameters to 16 ± 9 sec (p < 0.05), 80 (n.s.), 50 (p < 0.05), and 10% (p < 0.05), respectively. HNS-32 significantly reduced the heart rate in a dose-dependent manner, from 399 ± 14 to 350 ± 8 and 299 ± 10 beats/min (p < 0.05) with 3 and 5 mg/kg, respectively. The antiarrhythmic effects of HNS-32 were more potent than that of the similar dose of mexiletine against occlusion-induced and reperfusion-induced arrhythmias in in vivo rats.     

Adaptation in properties of skeletal muscle to coronary artery occlusion/reperfusion in rats

The present study was designed to determine if changes in function and metabolism of heart muscle induce alterations in characteristics of skeletal muscle. We investigated the histochemical and biochemical properties of soleus (SOL) and extensor digitorum longus (EDL) muscles in Wistar rats at the chronic phase after coronary artery occlusion/reperfusion. The size of myocardial infarct region was evaluated using a high resolution pinhole single photo emission computed tomography (SPECT) system. 4 wk after left coronary artery occlusion/reperfusion, the SOL and EDL of hindlimb were dissected out and immersed in isopentane cooled with liquid nitrogen for subsequent histochemical and biochemical analysis. From SPECT imaging, the blood circulation was recovered, but the recovery of fatty acid metabolism was not observed in infarct region of heart. Citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activities in infarct region of heart were lower in the myocardial infarction (MI, n = 6) group compared with that of age-matched sham-operated (Sham, n = 6) group. In addition, heart muscle hypertrophy caused by the dysfunction in MI group was observed. In skeletal muscle, the atrophy and transition of fiber type distribution in MI group, reported in previous studies of heart failure, were not observed. However, the succinate dehydrogenase (SDH) activity in the slow twitch oxidative (SO) from SOL of MI group decreased by 9.8% and in the fast twitch oxidative glycolytic fibers (FOG), 8.0% as compared with sham group. Capillary density of the SO fibers from SOL of MI group also reduced by 18.5% and in the FOG fibers, 18.2% as compared with Sham group. Decreased capillary density in this study related significantly to decreased SDH activity of single muscle fibers in chronic phase of perfusion after surgical infarction. Our results make it clear that there is a difference in the reaction of skeletal muscle to coronary artery occlusion/reperfusion compared with chronic heart failure. However, our data would support the notion that there is a linkage between the function of heart and physiological properties of skeletal muscle.     

The role of sphingosine 1 phosphate in coronary artery disease and ischemia reperfusion injury

Coronary artery disease (CAD) is a common cause of morbidity and mortality worldwide. Atherosclerotic plaques, as a hallmark of CAD, cause chronic narrowing of coronary arteries over time and could also result in acute myocardial infarction (AMI). The standard treatments for ameliorating AMI are reperfusion strategies, which paradoxically result in ischemic reperfusion (I/R) injury. Sphingosine 1 phosphate (S1P), as a potent lysophospholipid, plays an important role in various organs, including immune and cardiovascular systems. In addition, high-density lipoprotein, as a negative predictor of atherosclerosis and CAD, is a major carrier of S1P in blood circulation. S1P mediates its effects through binding to specific G protein-coupled receptors, and its signaling contributes to a variety of responses, including cardiac inflammation, dysfunction, and I/R injury protection. In this review, we will focus on the role of S1P in CAD and I/R injury as a potential therapeutic target.     

Release of pro-inflammatory mediators during myocardial ischemia/reperfusion in coronary artery bypass graft surgery

Inflammation has been reported to play an important role in cardiac surgery under cardiopulmonary bypass due to systemic endotoxemia. In order to develop strategies against this injury in future we studied the combined effect of a number of inflammatory mediators in myocardial ischemia/reperfusion. Coronary sinus blood samples of ten patients undergoing coronary artery bypass graft surgery (CABG) were obtained at three time intervals (1) before onset of bypass (2) 30 min after cross clamp, and (3) 10 min after removal of cross clamp. The samples were subjected to evaluate levels of nitric oxide byproducts (nitrite and nitrate and citrulline), inflammatory cytokines (interleukin-2, interferon- and interleukin-6), adhesion molecules, (CD62L and CD54), ratio of cell surface markers (CD4/CD8 and TCR/) cell activation markers (CD69 and HLA DR) and second messengers (protein kinase C, inositol 1,4,5 triphosphate and intracellular calcium levels). Ischemia and further reperfusion resulted in significant rise in nitrite and nitrate levels (p < 0.001), interleukin-6 (p < 0.01), CD62L (p < 0.001), CD69 (p < 0.05), protein kinase C (p < 0.001) and intracellular calcium (p < 0.001). A fall in CD4/CD8 ratio was observed on reperfusion. These changes during CABG show that ischemia/reperfusion leads to a release of an array of pro-inflammatory mediators of tissue injury, which could lead to pathophysiological changes. Hence the study suggests the need of some protective therapies against these inflammatory markers.     

Management of dyslipidemia after coronary artery bypass grafting

The results of serial angiographic studies and intervention trials in patients after coronary artery bypass artery grafting have provided ample evidence that abnormalities of the plasma lipoprotein system are one of the most significant risk factors for a rapid atherosclerotic attrition of saphenous vein grafts. In addition to confirming the well recognized role and contribution of cholesterol-rich LDL or lipoprotein B particles to the progression of atherosclerotic lesions, intervention trials have also provided strong evidence for the atherogenic capacity of some intact and partly delipidized triglyceride-rich very low density lipoprotein and intermediate density lipoprotein (lipoprotein B complex) particles, and the protective effect of some (high density lipoprotein 3) but not all high density lipoprotein particles. Most importantly, those studies have emphasized the need for an early, aggressive treatment of dyslipoproteinemias with pharmacological agents as the most efficient therapeutic approach to delaying, if not preventing, the detrimental effect of atherosclerosis on saphenous vein grafts.     

Haemodynamics in the first seconds after coronary artery occlusion.

The changes in cardiac and in total haemodynamics, occurring during the first seconds of occlusion and the subsequent desocclusion of coronary arteries were studied on 28 dogs. The most intensive changes were observed after the trunk occlusion of the left coronary artery. Simultaneously with decreasing blood inflow into the myocardium its contractility and the systolic pressure in the left ventricle and the outflow from the coronary sinus began to fall rapidly. The systolic pressure in the left ventricle decreased within the first 10 s from 24 to 13-15 kPa (180 to 100-110 mm Hg), which means that the systolic pressure fell about 1 kPa (7-8 mm Hg) per second, or 0.5-0.6 kPa (4-5 mm Hg) per systole. At the same time the end-diastolic pressure in the left ventricle also increased from zero to 3-4 kPa (25-30 mm Hg). After the trunk desocclusion of the left coronary artery the systolic pressure in the left ventricle proceeded to fall by about 2-3 kPa (15-22 mm Hg). Only then, 20-25 s after the desocclusion, blood flow in the left coronary artery began to rise intensively and 4-6 s later the myocardial contractility and the systolic pressure in the left ventricle also increased. After unclamping (50-60 s), there was an overshoot of haemodynamic values above preocclusive values and then followed the compensatory phase. This phase lasted 80-90 s and on its peak the pressure and flow parameters increased by about 50-60% above preocclusive values. During the occlusion of ramus interventricularis anterior or ramus circumflexus for 30-60 s the haemodynamic parameters changed only slightly. The same was observed during trunk occlusion of the right coronary artery (30-60 s), but in that case many extrasystoles occurred.     

Epicardial coronary spasm due to endothelial dysfunction after spontaneous coronary artery dissection

Netherlands Heart Journal -     

Ventricular fibrillation following canine coronary artery reperfusion: different outcomes with pentobarbital and alpha-chloralose

We compared the incidence of ventricular fibrillation after release of a 20 min-proximal left anterior descending coronary artery ligation in dogs anesthetized with either pentobarbital (N = 26) or morphine sulfate plus alpha-chloralose (N = 26). Results were analyzed using the logistic risk regression model. In each group, outcome correlated with the amount of myocardium perfused by the ligated vessel (myocardium "at risk") as measured by postmortem coronary injection of monastral dyes. At any given myocardium at risk, animals anesthetized with alpha-chloralose were less likely to fibrillate after release than those anesthetized with pentobarbital (p less than 0.01). This difference in outcome can be described by the myocardium at risk at which half the animals are expected to fibrillate (MAR50). MAR50 was 20.9 g for the pentobarbital group and 30.7 g for the alpha-chloralose group. Myocardium at risk should be taken into account in intervention studies using this coronary reperfusion arrhythmia model. We chose the logistic risk regression model to correct for this variable because it allowed a good fit of the data and offered a concise standard format for expressing the results. Outcome in reperfusion studies may be influenced by the choice of anesthetic agent.     

Stretch-induced ventricular arrhythmias during acute ischemia and reperfusion.

Mechanical stretch has been demonstrated to have electrophysiological effects on cardiac muscle, including alteration of the probability of excitation, alteration of the action potential waveform, and stretch-induced arrhythmia (SIA). We demonstrate that regional ventricular ischemia due to coronary artery occlusion increases arrhythmogenic effects of transient diastolic stretch, whereas globally ischemic hearts showed no such increase. We tested our hypothesis that, during phase Ia ischemia, regionally ischemic hearts may be more susceptible to triggered arrhythmogenesis due to transient diastolic stretch. During the first 20 min of regional ischemia, the probability of eliciting a ventricular SIA (P(SIA)) by transient diastolic stretch increased significantly. However, after 30 min, P(SIA) decreased to a value comparable with baseline measurements, as expected during phase Ib, where most ventricular arrhythmias are of reentrant mechanisms. We also suggest that mechanoelectrical coupling may contribute to the nonreentrant mechanisms underlying reperfusion-induced arrhythmia. When coronary artery occlusion was relieved after 30 min of ischemia, we observed an increase in P(SIA) and the maintenance of this elevated level throughout 20 min of reperfusion. We conclude that mechanoelectrical coupling may underlie triggered arrhythmogenesis during phase 1a ischemia and reperfusion.     

Effect of statins on coronary blood flow after percutaneous coronary intervention in patients with stable coronary artery disease

Aims

Statins have favourable effects on the vascular system. However, few data are available regarding the effect of these drugs on patients undergoing percutaneous coronary intervention (PCI). We sought to determine the impact of prior statin use on coronary blood flow after PCI in patients with stable coronary artery disease (CAD) by using the corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC).

Methods

A total of 80 consecutive eligible patients (mean age: 60 ± 7 years, 65?% male) with the diagnosis of stable CAD who were hospitalised for elective PCI were retrospectively enrolled in our study. The study population was divided into two groups according to statin use at least 6 months before PCI. Group 1 comprised of 51 patients (67?% male; mean age: 58 ± 4 years) taking statins and group 2 comprised of 29 patients (62?% male; mean age: 60 ± 3 years) not taking statins. PCI was applied to de novo type A lesions. CTFC was calculated for the treated vessels at baseline and after PCI.

Results

The two groups had similar characteristics in terms of age, sex, concomitant medications, lesion characteristics, pre-procedural CTFC, lipid parameters, and risk factors for CAD. Post-PCI CTFC (16 ± 3 vs. 22 ± 5, p = 0.01) and hs-CRP (2.1 ± 0.7 mg/l vs. 6.1 ± 2 mg/l, p = 0.01) in patients receiving statins before PCI were significantly lower than in patients without statin therapy. Multiple logistic regression analysis showed that statin pre-treatment (OR 2.5, 95?% CI 1.2 to 3.8, p < 0.001) and hs-CRP level (OR 1.8, 95?% CI 1.2 to 2.4, p = 0.001) were independent predictors of post-PCI CTFC.

Conclusions

In patients with stable CAD undergoing PCI, receipt of long-term statin therapy was associated with improvement in epicardial perfusion after PCI.

     

Diagnosis of coronary artery restenosis after radiologic endovascular dilatation]

Altogether 40 patients with stable angina of effort were investigated in a long-term period after roentgenovascular dilatation of one or two coronary arteries. Control coronarography was performed in 22 patients with lowered exercise tolerance. A reliable feature in the development of hemodynamically significant restenosis and/or "new" coronary stenosis in 11 patients was a combination of average and low exercise tolerance with its negative dynamics. For patients with I functional class, a sign of restenosis and/or "new" stenosis was the appearance of the ischemic shift of the CT-segment on ECG during bicycle testing. An efficient selection of patients resulted in increased sensitivity and specificity of noninvasive tests.