Stuttering reperfusion of ischemic myocardium does not exacerbate myocardial infarction: Evidence against lethal cell reperfusion injury in the rabbit

In the clinical setting of acute myocardial infarction, coronary reperfusion may occur intermittently. Whether this intermittent or stuttering reperfusion exacerbates reperfusion cell injury is not known. To investigate whether stuttering reperfusion affects the development of necrosis, anesthetized male rabbits were randomized to either control or stuttering-reperfusion groups. The control rabbits underwent 40 minutes of continuous left anterior descending (LAD) occlusion followed by 3 hours of continuous reperfusion. The stuttering-reperfusion rabbits were occluded for the same 40 minutes but were reperfused for 1 minute at 37, 39, and 41 minutes into the occlusion period. Each of these brief reperfusion periods was followed by 1 minute of occlusion. After 40 minutes of occlusion (43 minutes after initial occlusion), the stuttering-reperfusion group was continuously reperfused for 3 hours. Regional myocardial blood flow was measured during occlusion and 30 minutes after final reperfusion in both groups. Area at risk (AR, %LV) was delineated by in vivo blue dye injection and the area of necrosis (AN) by in vitro tetrazolium staining.Results There was no difference in AR blood flow between groups, Ischemic blood flow (ml/min/g) was 0.05 ± 0.02 in the control group and 0.09 ± 0.04 in stuttering-reperfusion group. After reperfusion, blood flow in the ischemic area was 1.36 ± 0.13 in control and 1.87 ± 0.40 in stuttering-reperfusion rabbits. The AN expressed as a percentage of the AR was 43 ± 8 in the control rabbits and 36 ± 6 in the stuttering-reperfusion rabbits. Stuttering-reperfusion did not augment the development of necrosis compared with the control group.Conclusion Reperfusing the myocardium in a stuttering fashion had no effect on the amount of necrosis and did not contribute to lethal cell reperfusion injury in this model.     

Improved detection of acute myocardial infarction by magnetic resonance imaging using Gadolinium-DTPA

Summary To assess the value of the paramagnetic contrast agent Gadolinium (Gd)-DTPA in Magnetic Resonance Imaging (MRI) of acute myocardial infarction (AMI), we studied 20 patients with a first AMI by ECG-gated MRI before and after intravenous administration of 0.15mmol/kg Gd-DTPA. The MRI studies were performed after a mean of 98 hours (range 15–241) after the acute onset of AMI. Spin-echo measurements (TE 30 msec) were made using a Philips Gyroscan (0.5 Tesla). After performing the baseline MRI scans, the MRI procedure was repeated every 10 minutes for up to 40 minutes following injection of Gd-DTPA. In 18 (90%) patients contrast enhancement in the infarcted myocardial areas was observed after Gd-DTPA. In these patients intensity versus region curves, derived from 9 to 11 adjacent myocardial regions of interest, showed increased signal intensities in the infarcted areas after administration of Gd-DTPA. The precontrast signal intensity ratio between infarcted and normal myocardium was 1.14±0.15 (mean±SD); the postcontrast ratios at 10 minutes were 1.41±0.21 (P <0.05), at 20 minutes 1.61±0.19 (P <0.01), at 30 minutes 1.43±0.20 (P < 0.05), and at 40 minutes 1.33±0.20 (P=NS). It is concluded that MRI using the contrast agent Gd-DTPA significantly improves the visualization and detection of infarcted myocardial areas in patients with AMI and that optimal contrast enhancement is obtained 20 minutes after administration of Gd-DTPA.     

Prevention of the “no reflow” phenomenon in the canine heart by mioflazine

Summary The effects of oral pretreatment with mioflazine (2.5 mg·kg^–1) on regional myocardial reflow, infarct size reduction and hemodynamic recovery were studied in 24 anesthetized open-chest dogs undergoing 90 minutes of acute left anterior descending coronary artery (LAD) occlusion followed by 150 minutes of reperfusion.Regional myocardial blood flow was measured with tracer microspheres, and infarct size was determined by triphenyl tetrazolium chloride staining. Pretreatment with mioflazine resulted in a reduced diastolic aortic pressure (p<0.05) and an elevated cardiac output and LV dpdt max (p<0.05). These effects persisted throughout the experiment. In control animals (n=12) a hyperemic reflow response was found in the perfusion area of the LAD during the first minutes of reperfusion. After 150 min of reperfusion, however, the viable myocardium of the LAD area became underperfused, and almost no reflow was found in the infarcted zones.In the animals pretreated with mioflazine (n=12) the hyperemic response persisted throughout the reperfusion phase and the no-reflow phenomenon was prevented. Infarct size (expressed as percentage of perfusion area) tended to be smaller in this group: 23.7±12.4% versus 33.7±19.2% (p>0.05).Left atrial pressure increased during LAD occlusion in both groups but normalized completely in the drug-pretreated animals (p<0.05).It is concluded that pretreatment with mioflazine prevents the no-reflow phenomenon after reperfusion of an evolving infarction, tends to reduce infarct size and improves hemodynamic recovery.In part supported by a grant from I.W.O.N.L.     

Evidence for decreased coronary flow reserve in viable postischemic myocardium

To try to unravel the complexity and heterogeneity of the "no-reflow" phenomenon and its underlying mechanisms, we studied tissue perfusion in reperfused heart muscle by using tracer microspheres in an anesthetized dog model of 90-minute coronary occlusion followed by reperfusion for 2 1/2 hours, 24 hours, or 1 week. Regional myocardial blood flow was determined both in basal flow conditions and during reactive hyperemia. The effect of intracoronary adenosine administration was examined, and the ultrastructure of postischemic myocardium was analyzed. In viable reperfused tissue (as delineated by triphenyltetrazolium chloride staining), reflow in basal conditions is unimpaired. Coronary flow reserve (as approximated by peak reactive hyperemic flow) is intact at the start of reperfusion, decreases by more than half after 2 1/2 hours, and recovers completely within 1 week. This impairment of coronary reserve can be relieved by intracoronary adenosine administration. On ultrastructural examination, the capillaries are patent. On the other hand, in irreversibly damaged myocardium, both the basal reflow impairment and the decrease in coronary flow reserve are severe and permanent. Coronary flow reserve is already decreased at the start of reperfusion, and the pharmacological intervention has no beneficial effect. Ultrastructurally, extracellular and intracellular edema invariably are present, whereas the vascular endothelium is damaged and the capillaries are packed with red blood cells. We conclude that the no-reflow phenomenon (i.e., mechanical obstruction to blood flow) is limited to infarcted tissue. In viable myocardium, however, coronary flow reserve is transiently diminished, probably because of washout and subsequent insufficient availability of the chemical mediator adenosine after breakdown and slow recovery of the precursor ATP pool.     

Dissociation of regional adaptations to ischemia and global myolysis in an accelerated Swine model of chronic hibernating myocardium

We tested the hypothesis that an acute critical limitation in coronary flow reserve could rapidly recapitulate the physiological, molecular, and morphological phenotype of hibernating myocardium. Chronically instrumented swine were subjected to a partial occlusion to produce acute stunning, followed by reperfusion through a critical stenosis. Stenosis severity was adjusted serially so that hyperemic flow was severely reduced yet always higher than the preocclusion resting level. After 24 hours, resting left anterior descending coronary artery (LAD) wall thickening had decreased from 36.3+/-4.0% to 25.5+/-3.7% (P<0.05), whereas resting flow had remained normal (67+/-6 versus 67+/-8 mL/min, respectively). Although peak hyperemic flow exceeded the prestenotic value, resting flow (45+/-10 mL/min) and LAD wall thickening (17.0+/-5.0%) progressively decreased after 2 weeks, when physiological features of hibernating myocardium had developed. Regional reductions in sarcoplasmic reticulum proteins were present in hibernating myocardium but absent in stunned myocardium evaluated after 24 hours. Histological analysis showed an increase in connective tissue along with myolysis (myofibrillar loss per myocyte >10%) and increased glycogen typical of hibernating myocardium in the LAD region (33+/-3% of myocytes from animals with hibernating myocardium versus 15+/-4% of myocytes from sham-instrumented animals, P<0.05). Surprisingly, the frequency of myolysis was similar in normally perfused remote regions from animals with hibernating myocardium (32+/-7%). We conclude that the regional physiological and molecular characteristics of hibernating myocardium develop rapidly after a critical limitation in flow reserve. In contrast, the global nature of myolysis and increased glycogen content dissociate them from the intrinsic adaptations to ischemia. These may be related to chronic elevations in preload but appear unlikely to contribute to chronic contractile dysfunction.     

Platelet depletion in experimental myocardial infarction

Summary Accumulation of platelets in the microvasculature after acute myocardial ischemia may exacerbate tissue injury through the formation of microthrombi and by the release of vasoactive substances. To assess the role of platelets in myocardial ischemic injury and infarction, circulating platelets were reduced by 94±2% (mean±S.E.M.) with sheep antiserum to canine platelets. Regional myocardial ischemia was produced by occlusion of the left circumflex coronary artery (LCCA) for 90 min followed by reperfusion for 5 hours. Infarct size did not differ significantly between antiplatelet serum and nonimmune serum groups: 36±8vs. 43±4% of the area at risk, determined by a post-mortem dual staining technique (p>0.05). A second occlusion-reperfusion control group, sacrificed at 24 hours, did not differ from 5 hr reperfused groups with regard to infarct size. Coronary sinus thromboxane B₂ (TXB₂) concentrations were not altered significantly by platelet depletion. Histopathologic examination confirmed the presence of necrosis in the infarcted myocardium and revealed substantial leukocytic infiltration in both groups. The results suggest that circulating platelets are not required for the full expression of myocardial ischemic injury resulting from temporary coronary artery occlusion followed by reperfusion.     

Effect of coronary stenosis on myocardial function, ultrastructure and aortocoronary bypass graft hemodynamics.

The relation between different degrees of stenosis of the left anterior descending coronary artery and total and regional left ventricular function, myocardial ultrastructure, flbrotic content of the myocardium and hemodynamics of graft flow was studied in 70 patients with coronary artery disease. Patients with arteriographically visible collateral supply to the obstructed vessel were excluded. The degree of stenosis (quantitative measurement of luminal obstruction) and total and regional left ventricular function were measured angiographically. Regional contractile reserve was determined from postextrasystolic angiograms. Ultrastructure and fibrotic content of the myocardium (morphometry) were determined from biopsy material taken at the time of bypass surgery from the area perfused by the left anterior descending artery. Graft flow to this artery was measured under basal conditions and after release of a 30 second graft occlusion (hyperemic response). Five groups were formed: I, no stenosis; II, stenosis of 50 to 79 percent; III, of 80 to 89 percent; IV, of 90 to 99 percent; and V, 100 percent occlusion. Patients in group II had normal values for ejection fraction, regional function and reserve, normal ultrastructure, a small degree of fibrosis and no hyperemic response after release of graft occlusion. Patients in group III had similar findings except for a significant hyperemic response. Patients in group IV had moderate depression of ejection fraction, regional function and reserve, moderate ultrastructural alterations, increased myocardial fibrosis and a high hyperemic response. Patients in group V had a severely impaired ejection fraction, absent regional function and reserve, severe cell alterations and extensive scar formation.Thus, a clear sequence of events occurs with progression of coronary stenosis: until 79 percent stenosis no significant reduction of mechanical function and myocardial structure occurs. With 80 to 89 percent stenosis, poststenotic vasodilation fully compensates for the stenosis as documented by normal mechanical function and normal myocardial structure. At 90 to 99 percent stenosis, vasodilatory compensation is inadequate: Regional function decreases, degenerative ultrastructural alterations appear and the fibrotic content of the myocardium increases. With complete occlusion, compensation is ineffective, and severe loss of function and extensive scars develop.     

Changes of Colonic Mucosal Microcirculation and Histology in Two Colitis Models: An Experimental Study Using Intravital Microscopy and a New Histological Scoring System

This study investigated capillary blood flow (CBF) and pathomorphological alterations in the mucosa of different bowel segments at different times after disease onset in rats with colitis induced by either trinitrobenzensulfonic acid (TNBS) or mitomycin-C. CBF was determined by intravital microscopy using fluorescein-labeled erythrocytes. The histological degree of inflammation was assessed by a new scoring system. Severe acute histological changes were found in the distal colon 24 hr after induction of TNBS colitis (score: 8.9 ± 1.0). CBF was increased (2.9 ± 0.05 vs. 2.6 ± 0.04 nl/min in healthy controls). The histological alterations persisted until day 3 (8.5 ± 0.9) when CBF significantly decreased (1.8 ± 0.05 nl/min). After 15 days, moderate acute inflammation was still detectable histologically (5.4 ± 1.3), but CBF had returned to normal values. In mitomycin-C colitis, changes developed mainly in the proximal colon: After three days, there was mild inflammation (2.8 ± 1.2) with normal CBF (2.5 ± 0.1 nl/min). After seven days, the inflammation had increased (4.8 ± 1.1), while CBF had decreased (1.5 ± 0.06 nl/min). These changes persisted for six weeks (5.3 ± 0.7; 1.2 ± 0.05 nl/min). These data suggest that disturbed colonic microcirculation may play an important role in the pathogenesis of inflammatory bowel disease regardless of the histopathomorphological alterations.     

Perfusion delay causes unintentional ischemic preconditioning in isolated heart preparation

This study sought to show that unintentional preconditioning can be induced in the isolated perfused heart during the preparation procedure. The following four groups were compared: hearts were placed in ice cold saline and cooled for 15 s and then mounted to the Langendorff apparatus (n=5; cool immediate group); hearts were cooled for 60 s and mounted (n=5; cool delay group); hearts were mounted directly to the apparatus within 15 s after the isolation without cooling (n=5; noncool immediate group); hearts were mounted without cooling, but the mounting was delayed for 60 s after the isolation (n=5; noncool delay group). All hearts were paced at a fixed rate of 300 bpm, and an occlusion of left coronary (LCA) for 60 min was performed, which was followed by reperfusion for another 60 min. Coronary flow (CBF), left ventricular developed pressure (LVDP), and creatine phosphokinase (CPK) release did not change among the four groups during ischemia. At the end of reperfusion the LVDP values were 70±1 %, 66±2 %, 62 ±3 %, and 73±2 % of preischemic values in cool immediate, cool delay, noncool immediate, and noncool delay groups, respectively. CPK values were 116±4, 121±7, 138±6, and 29±1×10³ U/g myocardium, and percentage necrosis/risk areas were 24±1.0 %, 21±1.7%, 38±2.6 %, and 13±0.5 % in cool immediate, cool delay, noncool immediate, and noncool delay groups, respectively. The noncool delay group demonstrated high LVDP, least amount of CPK release, and smallest size of necrosis. These results indicate that an unintentional preconditioning effect can be induced when the cooling procedure is not applied and perfusion is delayed.     

Nisoldipine Selectively Induces Coronary Vasodilation and Improves Mild Myocardial Ischemia in Dogs: A Potential Role of Cellular Acidosis

We examined whether nisoldipine, a calcium (Ca) channel blocker, increases coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with ischemic and nonischemic hearts, and whether the presence of cellular acidosis in ischemic myocardium contributes to the augmentation of coronary vasodilation due to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that CBF decreased to 60% of the baseline, and CPP was maintained constant thereafter. First, we administered nisoldipine into a systemic vein in the ischemic and nonischemic hearts. Second, nisoldipine was administered into the canine coronary artery of the ischemic myocardium with and without administration of either sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), or amiloride. Nisoldipine (0.25–4.0 mg/kg, IV) increased CBF by 59% in the ischemic myocardium more than the nonischemic myocardium (by 34%) without reducing AoP. The infusion of nisoldipine (40 ng/kg/min, IC) increased CBF markedly by about 55% in the ischemic myocardium with increases in fractional shortening (FS; 11 ± 2% to 21 ± 2%) and lactate extraction ratio (LER; –19 ± 4% to 15 ± 2%). Increases in CBF, FS, and LER were markedly attenuated during administration of nisoldipine with concomitant administration of either NaHCO3 or NaOH. Furthermore, the extent of increases in CBF (54 ± 2 mL/100 g/min), FS (13 ± 2%), and LER (–17 ± 4%) were also markedly attenuated due to the concomitant treatment with amiloride. We conclude that myocardial cellular acidosis plays an important role in mediating coronary vasodilation affected by nisoldipine in the ischemic myocardium. H+ may modulate the property of voltage-dependent Ca channels via Na+–H+ exchange.     

The Effects of a Highly Purified Hyaluronidase Preparation on Experimental Myocardial Infarction in the Rat

Abstract Several substances have been claimed to be effective in reducing the area of necrosis in acute myocardial infarction. The effects of a highly purified hyaluronidase preparation (Hyalas®) on experimental myocardial infarction in the rat have been evaluated in this study. In the first series, one group of rats was treated with hyaluronidase 1 500–2 000 IU/kg injected intravenously 2, 4, 18, 24, 28 and 42 hours after induction of infarction by coronary artery occlusion. Another group was treated with NaCl solution. The infarction size was evaluated by serum lactate dehydrogenase and weight of infarcted myocardium. In a second series, the substances were administered immediately after the occlusion. In this experiment, the infarction size was estimated by planimetry. The percentage of salvaged myocardium in the hyaluronidase-treated groups was within the range of 20%. It seems reasonable to suggest that the use of highly purified hyaluronidase may be of clinical value for reduction of the myocardial infarction size.     

Effect of acute cardiac lymph stasis on metabolic coronary adaptation in the dog

Surgical blockade of cardiac lymph drainage was performed in dogs to examine the effect of acute cardiac lymph stasis on coronary adaptive mechanisms. Coronary blood flow (CBF) was measured using an electromagnetic flow probe on the left anterior descending (LAD) artery. Metabolic autoregulatory capacity was assessed by eliciting reactive hyperemic responses after flow interruptions of 10-60 second duration and by administering submaximal doses (250-500 micrograms) of adenosine, the putative transmitter of reactive hyperemia, into the left heart. The effect of lymph stasis was tested in two experimental groups, one hour and 48 hours after lymph obstruction and the data compared to control dogs. Although cardiac lymph stasis did not notably affect baseline arterial pressure and CBF, both reactive hyperemic response and adenosine-induced coronary vasodilation were reduced significantly (equal to or less than 50% control). On occasion, a complete absence of autoregulation was observed. These findings suggest that cardiac lymph stasis decreases vascular responsiveness to physiologic vasodilator stimuli and/or retards diffusion of biologically unstable substance(s) presumably involved in autoregulation. Persistently impaired coronary autoregulation in the lymphedematous heart may contribute to progressive ischemic damage as for example after myocardial infarction.     

Myocardial infarction following acute occlusion and reperfusion of the septal coronary artery

Summary It has been demonstrated that temporary occlusion of major epicardial arterics of the dogs produces a nontransmural myocardial infarction (MI) whose size is reduced by early reperfusion. This study was undertaken to determine the location and extent of MI following acute occlusion and reperfusion of the septal artery (SA). The SA was occluded for four hours in group I (7 dogs). Occlusion time for group II (6 dogs) was 2 hours and for group III (6 dogs) was 1 hour, followed by 2 and 3 hours of reperfusion, respectively. The hearts were then removed and cut into transverse slices from base to apex. The triphenyl tetrazolium chloride technique identified the areas of infarction, which were quantitated with a microcomputer-based graphics system. To determine the extent of necrosis across the interventricular septum (IVS), the IVS was divided into 5 transverse segments of equal depth and the amount of MI was determined for each. In group I, MI involved 3.42±0.9% (mean±SEM) of the left ventricle (LV) and 13.49±3.4% of the IVS. In group II, 6.11±1.3% of the LV and 25.00±5.5% of the IVS were infarcted. In group III, 5.63±1.3% of the LV and 31.9±14.3 % of the septum were infarcted. MI was larger on the left side of the IVS than on the right in all groups, and the extent of MI did not differ significantly between the three groups. This study showed that early reperfusion of the SA did not reduce MI as reported for other coronary beds.This project was supported in part by Research Grant HL20597 and Medical Student Research Program Grant AM07405 from the National Institutes of Health, Bethesda, MD     

Bucindolol,a beta blocker,decreased ventricular fibrillation and maintained mechanical function in a pig model of acute myocardial ischemia

Summary Bucindolol is a new beta blocker with marked vasodilatory properties and intrinsic sympathomimetic activity. We tested its potential effect against ventricular fibrillation (VF), in a pig model of acute myocardial ischemia. Bucindolol 6 mg/kg IV was administered in two equally divided doses, the first 30 minutes prior to, and the second 10 minutes after, ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Bucindolol decreased the incidence of VF to 1/11 versus 14/16 in the control group (p<0.005). Bucindolol also decreased the duration of ventricular tachycardia, 15±8 seconds versus 104±32 seconds in the control group (p<0.01). Bucindolol maintained LV_maxdP/dt at predrug and pre-CAL values, whereas LV_maxdP/dt was decreased by CAL in the control group. Bucindolol decreased arterial pressure and heart rate. Bucindolol increased blood flow in the peripheral ischemic zone (24.6±1.8% versus 16.2±1.7% (percent of pre-CAL value) in controls, p<0.002), as well as in the nonischemic zones (perlischemic zone: 126.4±6.1% versus 96.7±4.8% in the control group, p<0.0005; remote nonischemic zone: 126.6± 7.1% versus 87.1±4.3% of pre-CAL value in the control group, p<0.0001). Bucindolol had marked antiarrhythmic effects that were associated with beneficial effects on the mechanical function of the left ventricle and on blood flow to the ischemic myocardium.     

Coronary hemodynamics during reperfusion following acute coronary ligation in dogs.

The coronary hemodynamic effects of re-establishing blood flow to ischemic myocardium and the regional distribution of myocardial flow during reperfusion were studied in anesthetized open-chest dogs. A large portion of the left ventricular wall was rendered ischemic by occlusion of the left anterior descending coronary artery for 2 hours. During reperfusion of the LAD, coronary resistance in the reperfused vasculature increased progressively for the first 3 hours, while resistance in the intact LC vasculature was unchanged. Minimal resistances in the reperfused vascular bed, calculated from mean aortic pressure and peak coronary reactive hyperemic blood flow following a 90 sec. LAD occlusion, were elevated significantly during reperfusion. The increased minimal resistance values, which reflect the passive physical component of resistance, indicate structural changes in the reperfused vascular bed which were evident shortly after the initiation of reperfusion and persisted throughout the experimental period. Coronary resistances (RH) in the reperfused (LAD) and intact (LC) vasculatures during the reactive hyperemia following 10 sec. coronary occlusions were evaluated. During reperfusion, RH in the reperfused vasculature increased progressively while RH in the intact bed was unchanged. The marked increase in RH in the LAD indicates that the reactive hyperemic flow response to a consistent period of coronary occlusion progressively diminished, and reflects a gradual reduction in the vasodilatory potential of the reperfused coronary circulation. The regional distribution of myocardial blood flow following 5 minutes, 2 hours, and 4 hours of reperfusion was measured with multiple injections of radioactive microspheres. These measurements demonstrated a progressive reduction of blood flow to the reperfused myocardium with no significant change in flow to the control myocardium. In contrast to the uniform transmural distribution of flow in the normal myocardium, the reperfused region showed a distinctly nonuniform distribution of flow after 2 hours and 4 hours of reperfusion, with more severe reduction of flow to the endocardial layer. These studies would suggest that rechannelling blood flow distal to an acute coronary occlusion in human subjects might not in itself be capable of reversing the myocardial injury. It is hoped that additional therapeutic measures might be applied to salvage the injured myocardium.     

Experimental myocardial infarction in a closed-chest canine model Observations of temporal and spatial evolution over 24 hours

Summary Myocardial infarction was induced in 7 mongrel dogs by transfemoral intraluminal occlusion of the left anterior descending coronary artery. Perfusion area at risk was determined by post-mortem coronarography and infarct size by macrohistological staining with para-nitrophenoltetrazolium. Regional flow was determined by injection of radioactive microspheres 0.2 hours, 12 hours, and 24 hours post occlusion. Infarct size as determined by planimetry of post-mortem angiograms and macrohistological stains at identical magnification revealed 74.5±12.1% infarcted tissue of the perfusion area at risk. The flow of the necrotic tissue was below 13 ml/100 g min without exception, indicating a threshold perfusion for maintenance of myocardial viability. Accordingly, a flow of 10 ml/100 g min identified 93% of the entire infarcted myocardium, resulting in 71±20% as compared to the perfusion area at risk. Based on the good agreement of macrohistological and flow data, the evolution of myocardial injury was determined by flow measurements. The results indicated a different progression of the borders of critical flow in the subendocardial and subepicardial layers, whereas in the subendocardium 85% of the tissue at risk was identified by the critical flow at 0.2 hours and 97% at 12 hours, the subepicardial flow changed at a different pace: only 53% showed subcritical perfusion at 0.2 hours, 61% at 12 hours with a final increase of 39% from 12 to 24 hours.     

Significance of cardiac innervation on spontaneous ventricular arrhythmias elicited by left stellate ganglion stimulation in dogs 4 days after myocardial infarction: Comparison of two experimental models

Summary The effects of cardiac sympathetic overactivity on spontaneous arrhythmias and transmural left ventricular effective refractory period (LVERP) were assessed by left stellate stimulation (LSS) in 16 anesthetized dogs. The experiments were performed 4 days after proximal occlusion of the left anterior descending (LAD) coronary artery produced by either ligation (9 dogs) or embolization with histoacryl (7 dogs). The innervation of left ventricular myocardium was studied by light and electron microscopies. Synaptophysin (SYN)- and neuropeptide Y (NPY)- immunoreactive nerve fibers and terminals were thereby detected. In dogs subjected to ligation, LSS elicited negligible arrhythmias in spite of a decrease in LVERP by 6.9±2.2% (mean±SD, p<0.001). However, dogs with intravascular occlusion were more susceptible to LSS, as indicated by development of sustained ventricular rhythms. In these animals, the LVERP decreased with LSS by 14.6±3.4% (p<0.001). The innervation of the enterior left ventricular wall distal to the place of occlusion revealed a higher reduction of SYN- and NPY-immunoreactive nerves in infarcted myocardium and a more heterogeneous distribution of nerves in undamaged regions after ligation compared to intravascular occlusion. Ultrastructurally, nerve terminals containing small agranular and large dense-core vesicles were found innervating ischemically damaged myocardiocytes. Our findings indicate a higher preservation of nerves in infarcted and noninfarcted myocardium of animals subjected to embolic occlusion of the LAD. Because LSS apparently elicited more arrhythmias in these animals, we suggested a proarrhythmic effect of intact myocardial innervation after infarction.Supported by the Deutsche Forschungsgemeinschaft within the SFB 320 Herzfunktion und ihre Regulation.     

急性心肌梗塞发生中肿瘤坏死因子的作用探讨

本文观察了22例AMI患者及免心便模型血浆中TNF的含量变化，以研究TNF对心肌梗塞坏死面积的影响。结果发现：（1）AMI患者心肌梗塞早期血浆TNFα迅速升高，高峰在胸痛发作后4小时，显著高于正常对照组（P＜0．001），以后逐渐下降，48小时与正常对照组比较无差异（P＞0．05）。（2）在免心梗模型中，用TNF单克隆抗体中和血浆中的TNF后，坏死区占缺血区和坏死区占左心室的体积百分比ATM组显著低于AMI组（P＜0．01）。提示：TNFα在AMI发生中起重要作用，TNFα单克隆抗体可显著减少心肌梗塞范围。     

Ultrastructural evaluation of postischemic cell death (lethal reperfusion injury) in porcine hearts

This study investigated whether reperfusion results in an increase of ultrastructurally determined myocardial injury in pig hearts. The left anterior descending coronary artery (LAD) was distally occluded in 12 pigs for 35–45 minutes and then reperfused for 3 hours. At the end of ischemia, as well as after 3 hours of reperfusion, one transmural biopsy was removed from the center of the risk region and subdivided into four specimens, representing the subendocardial (I), subendo-midmyocardial (II), subepi-midmyocardial (III), and subepicardial layers (IV). The degree of injury was assessed by electronmicroscopy and was scored as reversible (1), an almost equal mixture of reversible and irreversible (2), and totally irreversible (3) damage. In addition, infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic (dye technique) myocardium. Infarct sizes ranged from 29.3% to 93% (mean 61.2%). The scores of injury of the four tissue layers before and after reperfusion did not differ significantly: layer I, 2.4 ± 0.8/2.3 ± 0.9; layer II, 2.2 ± 0.9/2.0 ± 0.9; layer III, 1.8 ± 0.9/2.0 ± 0.9; and layer IV, 1.6 ± 0.9/1.3 ± 0.6. The means of the four layers were almost identical at the end of ischemia (2.1 ± 0.8) and after 3 hours of reperfusion (2.0 ± 0.6). A linear regression analysis with 95% confidence limits of the score values before and after reperfusion indicated that maximally 25% of a mean final infarct size of about 50% may be due to lethal reperfusion injury. This study suggests that cell death in regional ischemia and reperfusion occurs predominantly during ischemia and not during reperfusion.     

抗心肌肌凝蛋白抗体亲大鼠梗塞心肌特性的研究

目的　探讨抗心肌肌凝蛋白单克隆抗体 (antimyosinantibody ,AMA)亲梗塞心肌的特点。方法　心肌梗死大鼠静脉注射放射性锝 99m标记的抗心肌肌凝蛋白单克隆抗体 (99mTc AMA) ,观察注射时间 ,梗死时间和梗塞区对梗塞心肌摄取AMA的影响。结果　注射后 2h梗塞心肌开始摄取AMA ,以后摄取逐渐增加 ,2 4h达到高峰。心肌梗死后 2 0d ,梗塞心肌持续摄取AMA ,期间心肌梗死后 1～ 5d摄取最强 ,梗塞中央区以及梗塞区内层摄取强于其他梗塞区域。结论　急性心肌梗死大鼠梗塞心肌特异性地摄取AMA ,注射AMA后摄取迅速、持久 ,受心肌梗死时间影响较小 ,梗塞中央区内层心肌摄取最强 ,AMA具有亲梗塞心肌的特性。