To evaluate the reservoir function of the pulmonary vascular bed for the left ventricle, the compliance of the pulmonary "venous" system (Cp'v') (consisting of the pulmonary veins and the left atrium) and that of the pulmonary arterial system (Cpa) were sequentially estimated in each of 31 subjects by using Hirakawa's and Engelberg's methods, respectively. In control cases (n=6), Cpa was 6.68 ± 3.52 (mean ± SD) ml/mmHg and Cp'v' was 15.81 ± 6.85 ml/mmHg. In patients with mitral stenosis (MS) of Class I (previous classification of NYHA) (n=7), Cpa was 4.05 ±2.71 ml/mmHg and Cp'v' was 13.15 ± 4.51 ml/mmHg. In patients with MS of Class II (n=13), Cpa was 2.81 ± 1.05 ml/mmHg and Cp'v' was 8.40 ± 2.95 ml/mmHg. In MS of Class III (n=5), Cpa was 1.54 ± 0.80 ml/mmHg and Cp'v' was 7.10 ± 1.91 ml/mmHg. These results indicate that both systems become less compliant as the cardiac functional capacity deteriorates. The ratio of Cp'v' to Cpa (Cp'v'/Cpa) was 2.7 ± 1.1 in control cases, 3.9 ± 1.4 in MS of Class I, 3.4 ± 1.6 in MS of Class II and 5.3 ± 2.1 in MS of Class III. When one compares these results with the compliance in the systemic circulation, i.e., 118 ml/mmHg in the veins and 2.5 ml/mmHg in the arteries, giving the ratio of 118/2.5 ≒ 50, it is obvious that the compliance of the pulmonary arterial system shares a sizable portion of the total compliance in the pulmonary vascular bed. The relationship between Cp'v' and the internal pressure, namely the mean pulmonary artery wedge ((PAW)^^^-) pressure, was expressed with a regression equation of, Cp'v' = 1/(0.003 (PAW)^^^- + 0.080), indicating that Cp'v' is inversely related to the internal pressure. In 12 of patients with MS, sublingual nitroglycerin shifted the Cp'v' - (PAW)^^^- pressure plots upwards and to the left, roughly along the Cp'v' - (PAW)^^^- regression curve for the entire groups of MS.

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The relationship between hypertension and cardiovascular damage was assessed in three groups of spontaneously hypertensive rats (SHR): 1. stroke prone SHR (SHR-SP) treated orally with an angiotensin I converting enzyme inhibitor (captopril) (100-400 mg/L in the drinking water) from 6 to 35 weeks of age, 2. SHR-SP maintained on tap water until 30 weeks of age, 3. stroke resistant SHR (SHR-SR) maintained on tap water. The controls were Wister Kyoto rats (WKY) maintained on tap water. Captopril-treated SHR-SP showed blood pressure lower than that of untreated SHR-SP, similar to SHR-SR. The ratio of heart weight to body weight was 0.55% in SHR-SP, 0.39% in captopril-treated SHR-SP, 0.46% in SHR-SR, and 0.39% in WKY. The kidneys of SHR-SP showed glomerular sclerosis, glomerular fibrosis, tubular casts, interstitial cell infiltration and vascular wall thickening or hyperplasia of the small arteries and arterioles. The severe glomerular sclerosis was mostly distributed in the inner and middle portions of cortex. Immunohistological study showed IgG, C3 and fibrinogen in the glomeruli and arterioles in SHR-SP. In captopril-treated SHR-SP, similar to SHR-SR, only minor histological changes were seen and there was no deposition of IgG, C3 or fibrinogen. No changes were seen in WKY. Thus, it was concluded that nephrosclerosis and cardiac hypertrophy in SHR-SP are prevented by captopril. The role of the renin-angiotensin and kallikrein-kinin systems in organ pathogenesis in SHR-SP is discussed.

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In order to investigate how a change in the size of a ischemic region is reflected in ST-segment mapping studies, we produced two different sizes of ischemic regions by occluding proximal or distal portions of the left circumflex artery for five minutes, using ten isolated canine heart preparations. We examined the relationship between the geometry of the ischemic region and ST-segment potential distribution on the epicardial surface and that in the "precordium", in which the heart was suspended. The extent of the ischemic region was reflected differently on epicardial and "precordial" sites, in that the magnitude of epicardial ST-segment elevation decreased (p < 0.001) while the "precordial", one increased (p < 0.01). In the epicardium the degree of ST-segment elevation was almost uniform over the ischemic region, whereas in the "precordium" it was maximal at sites overlying the center of the ischemic region and progressively decreased approaching the periphery. However, frequent occurrence of intraventricular conduction disturbance was observed near the center of the ischemic region. As a result, the magnitude of epicardial ST-segment elevation near the center became larger than in the periphery. These results suggest that the classical solid angle theory provides a useful approximation of the ST-segment deflection in very acute ischemic phase, until development of the intraventricular conduction delay.

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IN order to discuss the mechanism of onset in myocardial infarction (MI), clinical cases were reviewed and various clinical findings were analyzed according to the premise that the onset of MI requires both a predisposition and a trigger. The majority of subjects did present conditions that constituted predispositions for MI, including a history of angina pectoris (especially unstable angina), poor therapeutic results for angina pectoris, organic stenosis of the coronary artery, life changes and overwork. Patients with multiple factors tended to develop MI without a definite trigger, i.e., onset during sleep or rest whereas, in patients with fewer predisposing factors, it was obvious effort, excitation or stress that triggered MI. However, not a few of the patients presented with no organic stenosis of the coronary artery or no history of angina pectoris. There were patients without ST segment elevation at onset of MI, and patients in whom ST elevation was recorded after onset. These findings suggest the existence of mechanisms other than coronary occlusion in onset of MI. Occlusion of the coronary artery distributed to the infarct region occurred frequently among patients with delayed CPK efflux as well as prolonged chest pain and ST segment elevation. These lines of evidence suggest extension of infarction due to secondary coronary occlusion.

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To examine the vasospastic cause of myocardial infarction (MI) we studied 1) the incidence of rest angina before MI, 2) clinical features of postinfarction angina and 3) the occurrence of MI in variant angina. 1) Of 178 patients with MI, 60 (34%) experienced rest angina for 1 day to 10 years before the onset of MI. The incidence of rest angina was significantly higher in patients having milder coronary stenosis of 75% or less (15/30, 50%) than in others having severe stenosis of 90% or more (45/148, 30%), p < 0.05. 2) Postinfarction angina with ST elevation was observed in 16 patients (9%) and ST elevation developed in leads with pathological Q waves in all patients. The incidence of postinfarction angina was significantly higher in those having milder coronary stenosis than in others having severe stenosis, (27% versus 5%, p < 0.005). Patients with postinfarction angina experienced rest angina before MI more frequently (81%) than others (29%, p < 0.005). Sublingual nitroglycerin was effective in relieving postinfarction angina attacks and oral calcium antagonist prevented attacks in all patients. 3) MI developed in 9 of 97 patients with variant angina. Six patients had transmural and 3, non-transmural MI. Pathological Q waves and/or coronary T waves appeared in leads where ST elevation was observed during anginal attack. In 7 patients MI developed when antispastic agents were not used and in 2, when angina persisted even under treatment with calcium antagonist. These data strongly suggest that the coronary spasm can be a cause of MI in some patients.

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We examined platelet aggregation and plasma levels of thromboxane B₂, a stable metabolite of thromboxane A₂, in patients with unstable angina and correlated these platelet indices with the response to antianginal conventional therapy such as isosorbide dinitrate and calcium channel blocker. Eight of 36 patients exhibited anginal attacks more than 5 times/week in spite of the therapy, designated refractory unstable angina, associated with augmented platelet aggregation induced by arachidonate (0.3 mM, 71 ± 3%, mean ± SEM) and collagen (2 μg/ml, 72 ± 5%), and elevated plasma levels of thromboxane B₂ (350 ± 19 pg/ml). In the remainder of the patients whose anginal attacks were effectively subsided by the therapy, platelet aggregation was much lower (arachidonate: 34 ± 9%, collagen: 31 ± 8%, p < 0.01) and plasma levels of thromboxane B₂ were also lower (295 ± 12 pg/ml, p < 0.05). To evaluate the effect of selective thromboxane A₂ blockade on clinical findings and platelet reactivity in refractory unstable angina, OKY-046 (600 mg/day, p.o.) was administered to another 14 patients with refractory unstable angina in addition to the conventional therapy. We found that platelet aggregation induced by arachidonate (71 ± 4%) and collagen (65 ± 8%) was markedly reduced (44 ± 7% and 24 ± 3%, respectively, p < 0.01) and plasma levels of thromboxane B₂ (358 ± 31 pg/ml) and thromboxane B₂ production in serum (29 ± 5 ng/ml) were also significantly reduced after OKY-046 treatment (262 ± 21 pg/ml, p < 0.05, and 1.4 ± 0.2 ng/ml, p < 0.001). In accordance with these findings, frequency of anginal attacks (8.4 ± 1.1 times/week) was markedly decreased to less than one half (3.6 ± 1.1 times/week, p < 0.01). Under these conditions, during the first month of admission occurrence of myocardial infarction in refractory unstable angina treated with OKY-046 was effectively decreased (7%) compared with that in controls (50%, p < 0.05). These results suggest that augmented platelet reactivity and thromboxane A₂ production by platelets play a key role in the pathogenesis of refractory unstable angina.

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In order to investigate the role of coronary thrombosis as a precipitating factor of acute myocardial infarction (AMI), we examined coronary angiographic findings in 89 patients with AMI taken within 24 hours of the onset and in 42 patients with prolonged angina attack of impending myocardial infarction (impending MI) taken within 50 hours of the last angina attack. Furthermore, in the patients with impending MI, the effects of intracoronary and intravenous thrombolytic therapy and anticoagulant therapy used to prevent impending MI from developing into AMI, were also studied. (1) In 73 of 89 patients (81%) with AMI, coronary thrombi were detected angiographically. The thrombi were detected most frequently (88%) in angiographs taken within 3 hours of onset. (2) In 23 of 42 patients with impending MI, coronary thrombi were detected angiographically. In 6 patients with coronary thrombi who underwent intracoronary thrombolysis during angina attack, occlusive coronary thrombi in ischemia-related vessels were the observed, and recanalization by thrombolysis with intracoronary urokinase infusion relieved chest pain and improved ECG changes. (3) The incidence of AMI in 42 patients with impending MI who were treated with intracoronary and intravenous thrombolytic therapy and anticoagulant therapy was significantly less than in the conventional therapy group (80 patients) (11.9% vs. 27.5%; p < 0.05). In 4 of 5 patients with developing AMI, coronary thrombi were detected angiographically in the acute phase of impending MI. These results indicate that coronary thrombosis plays an important role not only n the precipitation of impending MI but also in the development of impending MI to AMI.

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Autopsy studies of hearts from 140 patients who had suffered acute myocardial infarction (AMI) and 26 cases of sudden coronary death revealed two distinct types of myocardial cell death: "kinetic cell death" (KD) and "static cell death" (SD). In KD, the predominant type of cell death in AMI-myofibrils disintegrated through alternating overextension. KD was found not only in patients having died after some time had elapsed from the onset of AMI, but also in cases of sudden coronary death. Muscle fibers in SD, which by contrast began to appear at least seven hours after the onset of AMI, characteristically preserved cross striations, while their nuclei were pyknotic or had already disappeared. Such fibers were observed only in territories peripheral to occlusive coronary thrombus, a secondary rather than a primary event that takes place during the course of AMI. As a result of the above observations, we were able to produce a new experimental model of AMI using mongrel dogs. As a preparatory procedure we first injected them intravenously with 2% calcium chloride at a constant rate for 90 or 120 minutes, and then with a sudden injection of caffeine, calcium chloride and catecholamine in order to induce KD. In contrast, ligation of the intraventricular coronary artery near its origin caused SD of myocardial fibers in the dependent territories. Overall results led us to conclude that AMI is initiated by instantaneous overcontraction of myocardial fibers, resulting in their KD, a phenomenon that could be called "myocardial self-destruction."

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