Effects of high arterial oxygen tension on function, blood flow distribution, and metabolism in ischemic myocardium.

BACKGROUND. Although oxygen inhalation therapy has long been used in the treatment of acute myocardial ischemia, experimental evidence that increased arterial PO2 has any beneficial effect in the absence of hypoxemia is equivocal. In this study, we used a swine model of subendocardial myocardial ischemia to determine the effects of arterial hyperoxia on regional myocardial contractile function (sonomicrometry), myocardial blood flow distribution (microspheres), and regional myocardial glycolytic metabolism (carbon isotope-labeled substrates). METHODS AND RESULTS. In 10 domestic swine, the left anterior descending coronary artery was cannulated and flow to this artery was strictly controlled via a roller pump in the perfusion circuit. Arterial PO2 was controlled by manipulating inspired oxygen concentration (FIO2). Low-flow myocardial ischemia was induced by reducing pump flow to 50% of the control value, which diminished regional endocardial systolic shortening to 30-50% of normal. After a 15-minute period of flow stability, each animal was exposed in randomized order to two additional 15-minute experimental periods: coronary normoxia (PO2 = 90-110 mm Hg) and coronary hyperoxia (PO2 greater than 400 mm Hg). At each level of oxygenation, we measured regional myocardial function, regional myocardial blood flow and metabolism, and hemodynamic indexes of myocardial oxygen demand. Myocardial ischemia during normoxia reduced systolic shortening to 10.9 +/- 5.3% in the ischemic zone. Hyperoxia increased ischemic zone systolic shortening substantially to 15.2 +/- 4.6%. During myocardial ischemia, endocardial blood flow was decreased to 0.26 +/- 0.06 ml.g-1.min-1 in the ischemic zone. During hyperoxia, endocardial blood flow rose to 0.34 +/- 0.10 ml.g-1.m-1. The endocardial: epicardial flow ratio was 0.45 +/- 0.18 in the initial ischemia period and rose to 0.61 +/- 0.23 in the hyperoxic period. Myocardial ischemia increased regional uptake of glucose, conversion of glucose to released lactate, and net myocardial lactate release. In the ischemic myocardium, coronary hyperoxia decreased both chemically measured lactate production and isotopically measured lactate release and decreased glucose extraction and the conversion of glucose to lactate. CONCLUSIONS. These data demonstrate for the first time that increasing arterial PO2 to high levels during acute low-flow myocardial ischemia improves both function and flow distribution in the ischemic myocardium and decreases glycolytic metabolism in the ischemic zone. The degree of improvement in contractile function (5% absolute increase in systolic shortening or 25% change normalized to preischemic values) is consistent with the observed increase in subendocardial blood flow.     

Effects induced on blood platelets in ischemic and nonischemic myocardium

The function of blood platelets sampled from the coronary sinus and the superior vena cava was studied in 50 men with coronary artery disease at rest and during pacing-induced angina. At rest, a lower platelet aggregation and retention response was found in coronary sinus compared with vena caval blood. This may be due to refractoriness after previous platelet stimulation or to release of platelet inhibitors in the coronary circulation. During pacing-induced angina, lactate levels indicated that blood was sampled from ischemic myocardium in only 27 of the patients. Pacing-induced angina influenced platelet function differently in blood from ischemic and nonischemic regions. Adenosine diphosphate- and collagen-induced aggregation, platelet retention and plasma beta-thromboglobulin levels remained unchanged in blood from ischemic myocardium during pacing, but increased in blood from nonischemic regions. Thus, factors other than ischemia activated platelets in the coronary circulation during tachycardia-induced stress.     

Effects of perhexiline maleate on coronary flow distribution in the ischemic canine myocardium.

Intravenous perhexiline maleate in a canine preparation with fixed coronary flow increases coronary diastolic pressure. It also redistributes coronary flow so as to preserve endocardial flow. Myocardial oxygen consumption was reduced and lactate uptake enhanced by the drug. It had no effect upon the threshold for ischemic-induced left ventricular failure.     

Effects of nifedipine on collateral blood flow at the lateral border of the acutely ischemic myocardium

Summary In open-chest dogs (n=5) the effects of nifedipine (25 g/kg infused over a period of 15 min) on the collateral blood flow after left anterior descending coronary artery (LAD) ligation were separated from those on heterogeneous blood supply, i.e. flow of collateral origin plus flow in nonischemic myocardium projecting into the ischemic area. This separation was possible using a technique based on microspheres, allowing analysis of perfusion via the left anterior descending coronary artery (LAD). Secondary effects on the ischemic heart induced by the hypotensive effect of nifedipine per se were minimized by counterbalancing the blood pressure change with an intra-aortic balloon. Nifedipine increased non-ischemic myocardial blood flow in the subendocardium from 1.11±0.10 to 2.71±0.17 (p<0.001) and in the subepicardium from 1.12±0.08 to 3.95±0.49 (p<0.001) (ml/min/g, mean ±SE). Collateral blood flow in the centre of the ischemic area was not affected by nifedipine. In the subendocardium, it was 0.12±0.05 before and 0.09±0.09 after nifedipine, and in the subepicardium, the corresponding values were 0.21±0.10 and 0.29±0.04, respectively. At the lateral ischemic border, the nifedipine-induced increase in myocardial blood flow was only directed to the admixed normal tissue. When the blood flow was corrected for this overlapping non-ischemic tissue, no significant effect of nifedipine was measurable in the subendocardial blood flow, which was 0.12±0.03 before and 0.18±0.04 ml/min/g after drug administration. However, in the subepicardium, the collateral blood flow was significantly reduced from 0.33±0.09 to 0.15±0.05 (p<0.05). It is concluded that nifedipine was able to decrease collateral blood flow at the lateral border, while leaving the blood flow unaffected in the centre of the ischemic are.     

The relationship between regional blood flow and contractile function in normal, ischemic, and reperfused myocardium

During normoperfusion, both myocardial blood flow and contractile function are heterogeneously distributed throughout the left ventricle, in that midwall segment shortening is higher at the apex than at the base of the left ventricle, and greater in the anterior than in the posterior wall. Also, transmural heterogeneity of myocardial deformation exists with greater segment shortening and wall thickening occurring in inner than in outer myocardial layers. A transmural heterogeneity of myocardial blood flow – with greater inner as compared to outer wall perfusion – exists which is not simply related to temporal fluctuations since the heterogeneous flow pattern is stable over at least a few minutes. While an increase in myocardial contractile function will lead to a metabolically mediated increase in regional coronary perfusion within or above the autoregulatory range does not increase regional myocardial contractile function. During hypoperfusion, the reduction in subendocardial blood flow is more pronounced than that in subepicardial blood flow, and contractile function in the inner myocardial layers ceases more rapidly than in the outer myocardial layers. The reduced regional myocardial contractile function is closely matched to the reduced regional myocardial blood flow; however, such a coupling between reduced flow and function is lost when ischemia is prolonged for several hours in that function for a given flow is further reduced. During reperfusion, regional myocardial contractile function remains depressed for a prolonged period of time, depending on the severity, duration, and location of the preceding ischemic episode, while regional myocardial blood flow is restored to almost normal. Recovery of contractile function in the outer myocardial layers is faster than in the inner myocardial layers. Received: 30 April 1998, Accepted: 28 May 1998     

The relationship between regional blood flow and contractile function in normal,ischemic, and reperfused myocardium

Summary The prevailing paradigm of coronary physiology and pathophysiology is that a balance between blood flow (i.e., supply) and function (i.e., demand) exists under normal conditions and that an imbalance between supply and demand occurs during ischemia. However, this paradigm is derived largely from studies relating changes in total coronary inflow to global ventricular function. The present article examines the relationship between myocardial blood flow and function on a regional level and proposes that a change may be needed in the current paradigm of coronary pathophysiology. In normal myocardium, considerable heterogeneity of regional blood flow exists, indicating either similar heterogeneity of metabolic demand and function or questioning the precision of metabolic coupling between flow and function. After the onset of ischemia, a transient imbalance between the reduced blood flow and function may exist. However, myocardial function rapidly declines and during early steady-state ischemia regional myocardial blood flow and function are once again evenly matched. Such supply-demand balance may persist over prolonged periods of ischemia enabling the myocardium to remain viable through reduction of energy expenditure for contractile function, i.e., to hibernate. Whereas in hibernating ischemic myocardium, regional myocardial blood flow and function are both reduced but appropriately matched to one another, flow and function appear to be largely uncoupled in reperfused stunned myocardium. The clinical identification of viable but ischemic (hibernating) and postischemic (stunned) myocardium is of utmost importance in patients undergoing reperfusion procedures. A new paradigm of coronary and myocardial pathophysiology, encompassing a regional as well as a global view of perfusion and function, will have to include explanations for phenomena such as myocardial hibernation and myocardial stunning.     

Increased injury of hypertrophied myocardium with ischemic arrest: Preservation with hypothermia and cardioplegia

Many patients undergoing cardiac surgery have some degree of myocardial hypertrophy. To assess the response of hypertrophied myocardium to simulated cardiac surgery, left ventricular hypertrophy was induced in rats by aortic banding, and ventricular function was measured by means of the isolated, isovolumic heart perfusion technique. The hypertrophied hearts had a greater susceptibility to ischemic injury than nonhypertrophied control hearts, as manifested by a greater degree of diastolic contracture during the recovery period after 30 minutes of ischemic arrest at 37 degrees C. Hypothermia without cardioplegia during a 2-hour arrest did not completely preserve diastolic function in the hypertrophied hearts, but cardioplegia combined with hypothermia completely protected the hypertrophied hearts against 2 hours of ischemia. The results suggest a need for both hypothermic and cardioplegic preservation techniques in patients with myocardial hypertrophy who have cardiac surgical procedures requiring a significant period of myocardial ischemia.     

Effects of anesthesia and K+ ATP channel blockade on interstitial adenosine accumulation in ischemic rabbit myocardium

Glibenclamide, a K⁺ _ATP channel antagonist, blocks the anti-infarct effect of ischemic preconditioning in rabbits, but only when the latter are anesthetized with ketamine-xylazine. Furthermore, the protection triggered by pinacidil, a K⁺ _ATP channel opener, can be aborted by treatment with the adenosine antagonist 8-(P-sulfo-phenyl) theophylline. This study tests whether either the anesthetic regimen or glibenclamide affects infarct size by modulating interstitial adenosine levels. Interstitial adenosine and total purine concentrations were assessed in open-chest rabbits by the microdialysis technique. Dialysis fibers were inserted into myocardium served by a coronary artery branch surrounded by a snare. All animals sustained a 30-min coronary occlusion and then 120-min reperfusion. Rabbits were anesthetized with either sodium pentobarbital or a ketamine-xylazine mixture. Half of the latter animals also received glibenclamide. The control levels of adenosine in the dialysate were comparable in the three groups, as were those of total purines, and the infusion of glibenclamide caused no change. Ischemia led to 10- to 20-fold increases in interstitial adenosine and 10-to-40-fold rises in total purine concentrations. These increase were equivalent in all groups. Furthermore, infarct size as a percentage of the myocardium at risk was also comparable in the three groups. Neither the anesthetic agent nor glibenclamide appears to modulate interstitial adenosine release from ischemic tissue.This work was supported in part by grants from the National Institutes of Healt, Heart, Lung, and Blood Institute, HL-20468, HL-46027, and HL-50688 and Bristol Myers Squibb, and was performed during the tenure of an Established Investigator Award from the American Heart Association (DGLVW).     

Comparative effects of cardioselective versus noncardioselective beta blockade on subendocardial blood flow and contractile function in ischemic myocardium.

The comparative effects of three beta adrenergic antagonists, bevantolol (CI-775, a new cardioselective agent), practolol and propranolol, on regional myocardial blood flow and contractile function distal to a severe flow-limiting stenosis of the left circumflex coronary artery were studied in the anesthetized dog. Equivalent beta₁ receptor blocking doses of each agent were administered 30 minutes after production of a stenosis sufficient to reduce resting coronary blood flow and contractile force approximately 40 percent. Regional myocardial blood flow and contractile force were measured with radioactive labeled microspheres and Brodie-Walton strain gauge arches, respectively. After treatment with propranolol (0.3 mg/kg), subepicardial flow in the ischemic area decreased significantly whereas subendocardial flow was maintained, resulting in an increased endocardial/epicardial blood flow ratio (0.59 ± 0.05 to 0.93 ± 0.09) (mean ± standard error of the mean). No significant change was observed in contractile performance of the ischemic area. Practolol (1.0 mg/kg) also produced a significant increase in endocardial/epicardial ratio (0.59 ± 0.05 to 0.69 ± 0.10) in the ischemic myocardium. Contractile performance remained unchanged. In contrast, after treatment with bevantolol (1.0 mg/kg), subendocardial flow (0.64 ± 0.13 to 0.77 ± 0.13 ml/min per g) and contractile function increased significantly (36.0 ± 11.0 percent) in ischemic myocardium. A marked increase in endocardial/ epicardial ratio (0.59 ± 0.05 to 0.93 ± 0.09) was also observed.These results suggest that a redistribution of blood flow within an ischemic region of the myocardium occurs with either beta₁ or a simultaneous beta₁ and beta₂ receptor blockade. Furthermore, these data indicate a possible advantage of a new cardioselective beta adrenergic antagonist, bevantolol, in improving ischemic subendocardial blood flow and contractile function.     

The effect of noradrenaline on blood flow and oxygen consumption in normal and ischemic areas of myocardium

The effects of infusions of noradrenaline (1.0 μg/Kg./min.) were studied in dogs 2 to 3 hr. after acute ligation of the anterior descending branch of the left coronary artery. The model allowed blood flow to be simultaneously measured in the ischemic (infarcting) region and in the normal myocardium. Sampling blood from a local vein (draining the ischemic region) and from the coronary sinus (draining the normal myocardium) allowed comparisons to be made of oxygen consumption by the two regions.Coronary artery ligation resulted in a marked decrease in cardiac output and external cardiac work and an increase in left ventricular end-diastolic pressure with an unchanged LV $\text{dP}\text{dt}$. This is indicative of reduced myocardial contractility. Blood flow in the area supplied by the ligated vessel fell to a mean of 17.6 ± 2.7 ml./100 Gm./min., which is about 20 per cent of the normal flow in this region.Infusing noradrenaline 2 to 3 hr. after ligation increased systemic arterial pressure, LV $\text{dP}\text{dt}$ max, external cardiac work, and blood flow and oxygen consumption in normal areas of the myocardium. There was some evidence that pulmonary shunting was increased by the drug.Noradrenaline also markedly increased peripheral coronary pressure and blood flow in the ischemic region, as assessed by ¹³³Xenon clearance and by retrograde flow from the ligated vessel. Oxygen consumption in the ischemic region was also increased by noradrenaline. It is suggested that part of the increase in flow occurs in the endocardial region since the effective subendocardial perfusion pressure is increased by noradrenaline. This increase in flow would account for the reduction in infarct size which has been observed by other workers when the systemic arterial pressure is raised.     

Cardiotrophin-1 protects the human myocardium from ischemic injury. Comparison with the first and second window of protection by ischemic preconditioning

BACKGROUND: There are reports suggesting that cardiotrophin 1 (CT-1) is cytoprotective. We investigated the cardioprotective effects of CT-1 on the human myocardium and compared this benefit with the early and delayed protection afforded by ischemic preconditioning (PC). METHODS: Right atrium specimens were prepared and incubated in buffer solution at 37 degrees C for 30 min stabilisation, before entering one of the three following studies. In study 1, muscles (n=6/group) were allocated to one of four groups: (i) aerobic control - incubated in oxygenated media for 210 min, (ii) ischemia alone - 90 min ischemia followed by 120 min reoxygenation, (iii) PC by 5 min ischemia-5 min reoxygenation before 90 min ischemia-120 min reoxygenation and (iv) CT-1 (1 nM) - 90 min ischemia-120 min reoxygenation with exposure to CT-1 throughout the protocol. In study 2, muscles (n=6/group) were allocated to one of four protocols as in study 1with the exception that were incubated for 24 h followed by 30 or 90 min ischemia-120 min reoxygenation on day 2. In study 3, the same groups were employed as in study 2 with the exception that only a 30-min period of ischemia was used and that CT-1 antibody (5 microg/ml) was added to all groups throughout the experimental protocol. Creatine kinase (CK, U/g wet wt.) leakage into the medium and MTT reduction (OD/mg wet wt.), an index of cell viability, were assessed at the end of the experiment. RESULTS: In study 1, a first window of cardioprotection was observed with PC (CK=4.39+/-0.34; MTT=0.58+/-0.03 vs. CK=7.11+/-0.4;MTT=0.32+/-0.02 in the ischemic alone group; P<0.001) but not with CT-1(CK=6.65+/-0. 67; MTT=0.31+/-0.03, P=NS vs. ischemia alone). In study 2, PC applied on day 1 was protective against 30-min ischemia (CK=3.28+/-0. 43; MTT=0.68+/-0.046, P<0.001 vs. ischemia alone) but not against 90-min ischemia (CK=7.13+/-0.66; MTT=0.24+/-0.03, P=NS vs. ischemia alone) induced on day 2 (second window). However, when the tissue was exposed to CT-1 for 24 h, protection was similar to that of PC when subjected to 30 min of ischemia (CK=2.95+/-0.71; MTT=0.77+/-0. 05, P=NS vs. PC) and greater than PC when subjected to 90 min of ischemia (CK=4.56+/-0.51; MTT=0.39+/-0.03, P=0.002 vs. PC). In study 3, the CT-1 antibody did not affect the protection induced by PC (CK=3.36+/-0.6; MTT=0.69+/-0.06) but it abolished the protection obtained with CT-1(CK=5.15+/-0.81; MTT=0.42+/-0.06, P=NS vs. ischemia alone group). CONCLUSIONS: CT-1 exhibits a significant protection of the human myocardium against ischemic injury when tissue is exposed to this factor for a long period (e.g. 24 h) but not when exposed for a short period (e.g. 2 h). In addition, the protection afforded by long exposure to CT-1 is as potent or even greater than the one obtained by the second window of PC. The protection induced by CT-1 but not that induced by PC can be abolished by CT-1 antibody suggesting that their beneficial action is attained by different mechanisms.     

Relation between regional distribution of thallium-201 and myocardial blood flow in normal,acutely ischemic,and infarcted myocardium

Myocardial localization of thallium-201 was compared with direct measurements of myocardial perfusion in normal, acutely ischemic, and recently infarcted myocardium. Studies were performed in 6 chronically instrumented dogs that were subjected to myocardial infarction by occlusion of the proximal left circumflex coronary artery. Four days after myocardial infarction, thallium-201 and 9 ± 1 μm niobium-95-labelled microspheres were injected simultaneously after acute left anterior descending coronary arterial occlusion; the animals were killed 5 minutes later and the entire left ventricle was sectioned into 1 to 2 g samples. Regression analyses between thallium-201 activity and regional myocardial blood flow using all myocardial samples demonstrated a very close linear relation in each dog; r values were 0.98 or greater, indicating that the initial localization of thallium-201 in acutely ischemic and recently infarcted myocardium as a function of regional blood flow was essentially identical. Consequently, in each dog the regional distribution of thallium-201 closely approximated myocardial perfusion over a wide range of blood flow and potentially different local metabolic conditions that may be encountered in the clinical use of the isotope.     

The effect of molsidomine on intramyocardial pressure and regional myocardial blood flow in the canine ischemic myocardium

Molsidomine was administered intraduodenally to anesthetized dogs which were instrumented for measurements of aortic and left ventricular (LV) pressures, coronary perfusion pressure, intramyocardial pressure in the subendocardium, and subendocardial and subepicardial myocardial blood flow in the ischemic and non-ischemic regions. The dogs were divided into two groups: group M (n = 9) was administered molsidomine (0.2 mg/kg), group S (n = 10), saline only. Maximum LV systolic pressure decline was 20% in group M and 3% in group S (p less than 0.05). Maximum LV end-diastolic pressure decline was 63% and 35% in groups M and S, respectively (p less than 0.05). There was no difference between mean aortic pressure and coronary perfusion pressure between the two groups. The subepicardial blood flow in the ischemic region was decreased (-23% in group M vs 5% in group S; p less than 0.05), but subendocardial blood flow in the ischemic region increased only slightly in group M. The ratio of subendocardial to subepicardial blood flow increased at 15 and 30 min after administration of molsidomine in the ischemic area (67% in group M vs -10% in group S; p less than 0.05), but did not show any change in the non-ischemic region. Intramyocardial pressure at systole did not show any change but it decreased at end-diastole, (-32% in group M vs -7% in group S; p less than 0.05). Thus molsidomine redistributed the myocardial blood flow from the subepicardium to the subendocardium and from the non-ischemic to the ischemic region. This redistribution was associated with a reduction in both LV end-diastolic pressure and intramyocardial pressure at end-diastole.     

Alpha 1-adrenoceptor activity regulates release of adenosine from the ischemic myocardium in dogs

The goal of this study was to test the hypothesis that alpha 1-adrenoceptor activity plays a key role in the release of adenosine from the ischemic myocardium. In 51 open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery, and adenosine release into the local coronary vein was measured by the radioimmunoassay technique following the reduction of perfusion pressure for 20 minutes under alpha 1-, alpha 2-, and beta-adrenoceptor attenuations. Adenosine and lactate concentrations in the coronary arterial and venous blood sampled from the perfused area were determined, as well as fractional shortening. In the untreated condition, adenosine release was significantly (p less than 0.01) increased from 1.7 +/- 0.8 (SEM) to 8.8 +/- 1.3 nmol/100 g/min, 20 minutes after the onset of hypoperfusion (coronary blood flow: 28 +/- 2 ml/100 g/min) following the initial overshoot release. Neither beta- nor alpha 2-adrenoceptor attenuation affected the increase in adenosine release during hypoperfusion except for the slight attenuation of the overshoot release by beta-attenuation. In contrast, intracoronary infusions of prazosin and phentolamine during coronary hypoperfusion markedly attenuated (p less than 0.01) release of adenosine (1.8 +/- 0.7 nmol/100 g/min at 20 minutes). The extents of decreases in fractional shortening and lactate production were comparable between the untreated and alpha 1-adrenoceptor attenuation.(ABSTRACT TRUNCATED AT 250 WORDS)     

曲美他嗪对心肌缺血时细胞骨架损伤的作用

目的　探讨心肌缺血时细胞骨架改变并观察曲美他嗪对心肌缺血时细胞骨架损伤的影响 ,为临床应用提供理论依据。方法　将大白鼠随机分为对照组和用药组并制成缺血模型 ,分别于缺血 30 m in、6 0 min、12 0 min时取心肌组织用免疫组化的方法观察肌动蛋白、波形蛋白、肌球蛋白、结蛋白等心肌细胞骨架蛋白的改变 ,并用计算机图象模拟分析系统计算骨架蛋白量的变化。结果　心肌缺血 30 min即有肌动蛋白、肌球蛋白损伤 ,12 0 min时有结蛋白损伤 (P<0 .0 5 )。曲美他嗪干预后 ,心肌缺血 6 0 min、12 0 min时肌动蛋白、肌球蛋白损伤明显减少 (P<0 .0 5 )。结论　心肌缺血时可以导致细胞骨架损伤 ,曲美他嗪对心肌缺血时细胞骨架损伤有保护作用     

Increased oxidant production by peripheral blood granulocytes in patients with idiopathic pulmonary fibrosis

Oxidant production by peripheral granulocytes stimulated with phorbol myristate acetate (PMA) was investigated in 11 patients with idiopathic pulmonary fibrosis (IPF), 6 with interstitial pneumonia associated with collagen vascular disease (IP-CVD), 8 with sarcoidosis and 12 healthy subjects. Oxidant production was examined by flow cytometry using dichlorofluorescein diacetate. The reactivity of granulocytes to PMA was assessed according to the ratio between mean fluorescent intensity of granulocytes stimulated maximally with PMA and that without PMA, (stimulation index: S.I.). The concentration of PMA that induced half maximal fluorescent intensity of granulocytes (PC 1/2 max) was used as the index of sensitivity. The S.I. was 7.2 +/- 0.45 in IPF, 6.3 +/- 0.6 in IP-CVD, 6.0 +/- 0.71 in sarcoidosis, and 5.8 +/- 0.2 in healthy subjects. However differences between groups were not significant. PC 1/2 max was 7.3 +/- 2.1 ng/ml in IPF, 9.1 +/- 3.0 ng/ml in IP-CVD, 12 +/- 6.9 ng/ml in sarcoidosis and 16.1 +/- 5.8 ng/ml in healthy subjects. There was significant difference between IPF and healthy subjects (p less than 0.05) indicating that peripheral granulocytes in patients with IPF are more highly sensitive to PMA than healthy subjects.