The prognostic significance of the doughnut pattern of technetium-99m pyrophosphate myocardial uptake was evaluated in 140 patients with acute anterior infarction. There were significantly higher early complications, greater mortality and more severe hemodynamic abnormalities in the doughnut pattern group than in the non-doughnut pattern group. The former had a more depressed left ventricular ejection fraction and larger thallium-201 defect size (27.6±10.4 versus 40.0±13.5%, p<0.001 and 9.9±3.6 versus 5.6±3.3, p<0.001, respectively). There was, however, considerable overlap of the ranges of these variables for both groups. The patency rate of the infarct vessel during the acute phase of infarct in each group was similar (54.8 versus 45.2%). It is concluded that the prognostic value of the doughnut pattern may be limited to some extent by this overlapping and the presence of this pattern does not appear to correlate with the lack of residual blood flow to the infarcted area.

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Myocardial infarct size is definitely related to cardiac function and prognosis. For a critical evaluation of infarct size estimation methods, we weighted infarcted myocardium from 44, autopsy cases (24 men and 20 women, mean age of 76.8 yr.) and compared the weight with the peak value of serum CPK activity (peak-CPK), the peak value of serum CPKMB isoenzyme activity (peak-CPKMB), the total CPK release (ΣCPK), and the QRS scoring system in the standard 12-lead electrocardiogram (ECG) modified by Wagner et al.. The mean infarcted myocardial weight (MI weight) of the 44 cases was 38.4g. The mean value of the peak-CPK, peak-CPKMB, and ΣCPK were 2487, 221, and 4597 IU/ml, respectively, and the mean QRS point score was 7.2. The interval between serial CPK determination and ECG recording or autopsy averaged 130.1 or 52.4 days, respectively. There were significant (p<0.01) correlations between the MI weight and peak-CPK (r=0.63, n=17), peak-CPKMB (r=0.79, n=17), ΣCPK (r=0.72, n=11), and the QRS scoring system (r=0.64, n=39), respectively. Especially in cases of non-transmural myocardial infarction, the QRS scoring system showed a high correlation with MI weight (r=0.82, n=11, p<0.01). We conclude that the peak-CPK, peak-CPKMB, CPK, and the QRS scoring system are useful for the estimation of myocardial infarct size.

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Multiple regression analysis of 16 risk factors, including serum apolipoproteins in angiographically measured coronary stenosis, was carried out in 239 consecutive patients (159 males and 80 females, ranging in age from 30-80 years and mean 56.4 years) who underwent coronary angiography for suspected coronary artery disease during the past five years (1981-1985). The risk factors (independent variables) were age, total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), HDL-C/TC, apolipoprotein (Apo) A-I, A-II, B, C-II, C-III, E, YRSMOK (average number of packs per day x years of smoking), weight index (WI), glucose tolerance (GT), and blood pressure (BP). Severity of coronary atherosclerosis was scored as the extent of disease seen at arteriography (coronary score: CS). The order of importance of risk factors to CS in the five groups of subjects studied were as follows. (1) All patients: YRSMOK>Apo A-I>TC>GT, (2) Male group: Apo A-I>TC>Age>GT, (3) Female group: TC, (4) Young group (age below 54 years): BP>YRSMOK, and (5) Old group (age over 55 years): YRSMOK>TG>TC>GT. The results clearly indicated the importance of Apo A-I but not other apolipoproteins including Apo B in males, and that of blood pressure in the young group of the patients studied.

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We evaluated whether heparin pretreatment accelerates the development of coronary collateral vessels induced by repeated, brief coronary occlusions. Sixteen dogs were instrumented for the measurement of subendocardial segment length in the area perfused by the left circumflex coronary artery (LCCA), LCCA flow and left ventricular pressure. An externally inflatable pneumatic occluder was placed around the LCCA. Two min coronary occlusions (CO) at rest were repeated hourly until there was no reduction in ischemic segment systolic shortening at the end of CO and negligible reactive hyperemia following the release of CO. Eight control dogs developed collaterals sufficient for resting myocardial oxygen requirements in the LCCA region by 129±45 (SD) CO. The remaining 8 dogs given heparin daily developed collaterals by 81±33 CO (p<0.05). Thus, in the presence of severe myocardial ischemia known to promote collateralization, heparin accelerated the development of coronary collaterals.

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Using the histo-and cytochemical technique we assessed the Ca²⁺-transporting function of mitochondria (Mit) and sarcoplasmic reticulum (SR), and the ATP producing function of Mit in the ischemic myocardial cell of a dog's heart. In comparing ultrastructural ischemic changes, cytochrome oxidase (CO) and Ca²⁺-ATPase were cytochemically and histochemically measured when the myocardium was subjected to the ischemia of left anterior descending coronary artery occlusion for 15 min, and 60 min. After 15 min of occlusion the ischemic alterations consisted of a wide I band, decreased glycogen (G) and Mit swelling with a slight reduction of matrix density. Although CO activity was not reduced, Ca²⁺-ATPase had decreased mainly in Mit. sixty min of ischemia resulted in loss of G, intermyofibrillar edema, marked Mit swelling with loss of matrix density and partial disruption of cristae, and dilatation of SR. Ca²⁺-ATPase activity was significantly reduced in Mit, SR and myofibrils. although there was Mit swelling with partial disruption of cristae after 60 min of ischemia, CO activity was found to still exist in the remaining cristae. These findings suggests that intracellular organelle dysfunction progresses in the ischemic myocardial cell at different rates, and that disruption of intracellular Ca²⁺homeostasis may occur early in the ischemic state.

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The degradation of the sarcoplasmic reticulum (SR) in acute myocardial ischemia was studied with references to the regional irreversibility and to the mechanism of ischemic degradation by the measurements of Ca⁺⁺-stimulated ATPase activity and composition of the major ATPase protein of the SR and activity of cathepsin B of the SR and lysosome (Ly) fractions. Ca⁺⁺-stimulated ATPase activity decreased to 66% of that of the non-ischemic portion at 20 min after coronary ligation in the subendocardium (Endo) and to 44% at 30 min in the subepicardium (Epi). composition of the major ATPase protein decreased to 55 % and 73% at 30 min in Endo and Epi, respectively. In both SR and Ly fractions cathepsin B exhibited the maximal activity at 6.0-6.5, and pH dependent. And incubation of the SR at pH 6.0 induced the degradation of the ATPase protein quite similarly to that in vivo ischemia. These results suggest that the degradation of the SR membrane of ischemic myocardial cells begins earlier in Endo 20 to 30 min after the cease of the coronary blood flow, and extends to Epi later. Cathepsin B is strongly conceivable to play an initial role of necrotic process of the ischemic myocardial cells by activation inside of the SR in ischemic acidic state.

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We have investigated the effect of ONO-3144 (2-aminomethyl-4-tert-butyl-6-propionylphenol), which facilitates the conversion of prostaglandin G₂ to H₂ and acts as a scavenger of free radicals, on the reoxygenation injury in the anoxic heart. Rat hearts were perfused retrogradely with Krebs-Henseleit (KH) medium for 30 min (n=8). Group III hearts were similar to those in Group II except that 4 mg ONO-3144/liter was added to both anoxic and reoxygenation media (n=8). coronary effluent was collected for creatine kinase (CK) loss. four rats hearts in each group were fixed for electron microscopic study and the remaining hearts were frozen in liquid nitrogen for measurement of adenosine triphosphate (ATP). A six-fold increase in CK leakage, observed after reoxygenation of anoxic heart, was prevented by ONO-3144. Tissue ATP was reduced from 22.2±0.9μmol/g dry weight (Group I) to 5.5±1.1 μmol/g dry weight (Group II). A significant amount of ATP (9.05±1.22μmol/g dry weight) was preserved in the treated Group III. The number of normal cells obtained by morphometrical analysis increased significantly from 56.77.8% (Group II) to 86.21.0% (Group III) and moderately injured cells were reduced to 3% in Group III as compared to 16% in the untreated Group I. Injury to the severely injured cells was not prevented by the drug treatment. At electron microscopic level, the cellular membranes, mitochondria and glycogen deposits were well preserved in Group III. Thus, ONO-3144 treatment provides a protection against reoxygenation injury in the anoxic myocardium by scavenging. -OH or other closely related species of free radicals. Therefore, free radicals generated through the conversion of prostaglandin G₂ to H₂ might play an important role in the reoxygenation injury of the anoxic myocardium.

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The requirement of heparin in experimental coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was studied in closed-chest dogs with one hour old coronary thrombi and compared with that in urokinase (UK)-induced coronary thrombolysis. Animals were divided into 5 treatment groups as follows: group 1 received intracoronary t-PA along (1, 000 IU/kg/min; n=5), and if thrombolysis was not induced within 40 to 50 min, dogs then received an intravenous injection of heparin (300 U/kg) plus intracoronary t-PA; group 2 received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received intracoronary t-PA (n=5); group 3 also received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received t-PA but intravenously, as compared with the groups administered by the intracoronary route (n=6); group 4 received intracoronary UK alone (1, 000 IU/kg/min; n=6); group 5 received intravenous heparin at first, and if thrombolysis was not induced within 10 min, dogs subsequently received intracoronary UK (n=5). Thrombolysis was confirmed angiographically. In group 1, coronary thrombolysis could not be induced within 444 min by intracoronary t-PA alone, but it occurred in 84 min when administered in combination with heparin in all dogs. Heparin alone failed to elicit reperfusion within 10 min in group 2, 3 and 5. t-PA, however, induced successful reperfusion in 165 min (group 2) and in 236 min (group 3), respectively. Intracoronary urokinase alone elicited thrombolysis in 274 min in group 4, but in group 5, treated in combination with heparin, rapid reperfusion was obtained in 125 min (p<0.001).

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A patient was presented with severe congestive heart failure due to myocardial sarcoidosis diagnosed at autopsy. We found that the diagnosis of myocardial sarcoidosis is difficult when there is no other organ involvement.

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Actions of prostaglandin I₂ (PGI₂) and thromboxane A₂ (TXA₂) on vascular smooth muscles were investigated in relation to the function of the endothelium. In intact vascular smooth muscle tissues of the thoracic aorta, PGI₂-Na, used as a substitute substrate of PGI₂, relaxed the precontracted tissue, in a dose dependent manner, in tact tissues and also after mechanical ablation of the endothelium. Acetylcholine (ACh) relaxed the tissue precontracted by noradrenaline, in the presence or absence of indomethacin; however, the relaxation required the presence of an intact endothelium. On the other hand, increased amounts of PGI₂ with the application of acetylcholine, as estimated from the amount of 6-keto-PGF_1α, were markedly attenuated by indomenthacin. In smooth muscles of this tissue without the endothelium, ACh synthesized lesser amounts of PGI₂, while PGI₂-Na increased the amount of cyclic AMP. Thus, PGI₂ was synthesized in both the endothelium and smooth muscles. The former produces a larger amount of PGI₂ than the latter, but the PGI₂ synthesized in smooth muscles may act more potently on the smooth muscle than does that synthesized in the endothelium. In the canine coronary artery, mechanical responses induced by TXA₂, as estimated from action of 9, 11, , -epithio-11, 12-methanothromboxane A₂ (STA₂) were enhanced after ablation of the endothelium. The minimum concentration of STA₂ required to produce the contraction was above 1 nM and the maximum amplitude was evoked with 30 nM. the amplitude of the STA₂-induced contraction was reduced in Ca-free solution or with the application of nifedipine. However, prazosin, propranolol or atropine had no effect on the STA₂-induced contraction. STA₂ enhanced the influx of Ca through the nifedipine sensitive voltage dependent Ca channel and also the release of Ca following augmentations of synthesis of inositol 1, 4, 5-trisphosphate (InsP₃). Thus, the action sites of PGI₂ and TXA₂, as related to regulation of the muscle tone, may differ.

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Thromboxane (TX) A₂ is involved in platelet aggregation, which initiates thrombus formation. The platelet thrombi in microcirculation, however, are not homogeneous in nature. Two types of platelet thrombi, formed in an arteriole of the hamster cheek pouch, could be differentiated in sensitivity to indomethacin and PGI₂. The "stable thrombus" was sensitive to indomethacin, and was not inhibited by PGI₂, when applied after the formation, whereas the "ADP-induced thrombus" was sensitive to PGI₂, but insensitive to indomethacin. These characteristics were reflected by two types of aggregation of composed platelets. Leukotriene B₄ induced adhesion of the leukocytes on the venular wall in very low concentrations, when perfused over the microvasculature of hamster cheek pouch. The leukocyte adhesion on the venular wall was followed by migration into interstitial space. This adhesion was attributed to a change of ieukocytes, rather than of the endothelial cell surface, as ascertained by selective microinjection of LTB₄ with a glass capillary. LTB₄ was also accumulated in the ischemic cardiac tissue after ligation of the rat coronary artery, followed by a peak in the accumulation of leukocytes. Inhibition of the LTB₄ generation by a 5-lipoxygenase inhibitor not only suppressed the leukocyte count by 40%, but also the infarct size by 34.4%.

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To observe platelet TXA₂ synthesizing activities in acute myocardial infarction (AMI, 38 cases) and effort angina (EA, 23 cases), radioimmunoassay was used to measure the amount of synthesized TXB₂3 at 5 min after an addition of arachidonic acid or thrombin to the platelet suspension. The amount of TXB₂ in AMI patients did not show a significant difference from that of 13 healthy controls. However, there were significant changes during thee time course of AMI. It increased in the super acute phase within the first 12 hrs from the onset of AMI. The activity decreased in 4 days, increased again in 10 days and then gradually recovered to the normal value. Platelet aggregation was elevated immediately after the onset of AMI and recovered during the time course. A significant negative correlation was observed between aggregation and TXA₂ production in AMI, but not in the healthy controls, suggesting that platelets with hyper TXA₂ synthesizing activity are consumed selectively in AMI. In EA, activity increased after treadmill exercise. Under ticlopidine-treatment, activity was depressed, and these patients were able to tolerate a longer exercise time than before ticlopidine. Since the pressure rate products did not change under treatment, changes in microcirculation such as the appearance of platelet aggregates may be important in the occurrence of anginal attacks.

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Effects of prostanoids on coronary circulation were studied in anesthetized open chest dogs with intact coronary arteries or in closed chest Gottingen miniature pigs with denuded vessels. In the latter model, coronary artery spasm was repeatedly provoked at the previously denuded area by histamine i.c. after pretreatment with cimetidine i.v. H₂-blocker. In the canine model, prostacyclin (PGI₂) dilated to a greater extent the diameter of the large epicardial coronary artery than did PGE₂, and both equally reduced the total coronary resistance. Vasoconstrictive effects of carbocyclic thromboxane A₂, a stable analogue of thromboxane A₂ (TxA₂) on the epicardial coronary artery was augmented from 1.1±0.3 to 6.5±1.3% (p<0.01) after pretreatment with cyclooxygenase inhibitors. In case of Gottingen miniature pigs 3 months after endothelial denudation and cholesterol freeding, neither PGI₂ nor indomethacin prevented histamine-induced coronary artery spasm. Thiothromboxane A₂, a stable analogue of TxA₂, did not provoke coronary artery spasm in the animals. Therefore, prostanoids may not be crucial to the provocation or prevention of coronary artery spasm from which myocardial ischemia ensues.

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Human serum or plasma contains two factors which regulate PGI₂ metabolism. The one is "PGI₂-synthesis stimulating factor" which stimulates PGI₂ synthesis in the vessel wall. The other is "#PGI₂-stabilizing factor" which stabilizes PGI₂ in the blood. In the very early phase of acute myocardial infarction, the serum levels of these two factors were significantly reduced, which may be related to the thrombus formation in the coronary artery in acute myocardial infarction.

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We compared amounts of lipoxygenase products with the extent of leukocyte infiltration in the ischemic myocardium with an occlusion-reperfusion model of open-chest dog. Changes in peripheral leukocyte count and leukocyte function estimated by neutrophil aggregation induced by calcium inophore A23187 were also examined. The ischemic tissue (120±40 ng/g, mean±SEM) showed a marked increase in 12-hydroxyeicosatetraenoic acid (HETE) production compared with the normal tissue (13±1 ng/g, p<0.01). The production of 5-HETE in the ischemic tissue was also augmented as well. When we examined the correlation between production of either 12-HETE or 5-HETE and leukocyte infiltration in the ischemic tissue, the former was augmented markedly in proportion to the extent of the latter. Leukocyte count in peripheral circulation was gradually increased after reperfusion. Similarly, neutrophil aggregation was significantly augmented during reperfusion. These results indicate that production of lipoxygenase metabolites associated with leukocyte infiltration in the reperfused ischemic tissue was increased during the course of myocardial infarction, which was accompanied by activation of leukocyte in peripheral circulation. Further studies should be done to clarify the importance of lipoxygenase metabolites in the evolution of reperfusion-induced myocardial injury.

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Effects of dietary supplementation with highly purified EPA (1.8-2.7 g/day) for 16 weeks on platelet and red blood cell function and serum lipids concentration were investigated in patients with various thrombotic diseases. Decreases in platelet aggregation, thromboxane formation in platelets, platelet retention and whole blood viscosity, increased red blood cell deformation and prolongation of bleeding time were observed in the present study. In addition a reduction in serum cholesterol and triglyceride concentrations was noted in patients with hyperlipidemia after EPA ingestion. Some clinical improvements such as improvement of diabetic gangrene or peripheral vascular occlusive disease were observed. These results indicate that dietary supplementation of purified EPA may be beneficial for prevention and treatment of cerebro- and cardiovascular diseases.

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