Echocardiogram of the pulmonary valve was obtained in 31 normal subjects to examine the effects of atrial contraction on the valve motion.In normal echograms, the mid to late diastolic slope was 5.7 mm/sec (range: 0-18), the depth of 'a' wave 3.5 mm (2-6), opening slope 297 mm/sec (190-460), and right-sided pre-ejection period (RPEP) 92 msec (70-120). The RPEP was not influenced by the heart rate. The 'a' wave width showed good correlation (r=0.81) with the PQ interval, though the latter was longer than the former. There was no statistically significant difference in the width and amplitude of the 'a' wave between aortic and pulmonary valve echoes during expiratory apnea. Typical respiratory change of the normal pulmonary valve echo was such that, during inspiration, the 'a' wave became exaggerated and caused a presystolic opening, although the degree of the change in individual cases was variable. It was concluded: 1) the pulmonary valve echogram had the remarkable variation from presystolic opening to shallow 'a' wave with respiration, 2) pulmonary 'a' wave seemed to be produced mainly by the motion due to the ventricular filling or pressure change during atrial systole superimposed on the entire cardiac motion, especially during inspiration. The 'a' wave appeared to reflect the diastolic hemodynamics of right heart, 3) the pulmonary valve echogram recorded during expiratory phase should be adopted for the assessment of right cardiac dynamics.
It was preliminarily reported that presystolic opening of the pulmonary valve was observed also in constrictive pericarditis.

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It was found from our previous studies that patients suffering from ischemic heart disease with angina, showed either one of the patterns of the left ventricular systolic time intervals on isometric handgrip exercise.
Patients in class I or II NYHA showed a shortened pre-ejection period corrected for heart rate (PEPI), and a prolonged ejection period corrected for heart rate (LVETI) together with a decrease of the PEP/ LVET ratio. This response is normal, because it has also been found in normal subjects.
The patients in class III or IV NYHA showed a prolongation of PEPI, shortening of LVETI and an increase of the PEP/LVET ratio. This response is abnormal, because it occurs in patients with impaired cardiac performance and in ischemic ones with widespread asynergic areas.
Our aim here is to study the response of these 2 groups of patients treated for a 4-week period with perhexiline maleate. This new drug is chiefly used as anti-anginal drug, though it also has anti-arrhythmic properties.
The results show that the response of the left ventricle to isometric handgrip exercise in class I or II patients following perhexiline maleate treatment, is almost normal, thus confirming that the drug has no side effects on the cardiodynamics checked by the left ventricular systolic time intervals.
The responses of class III or IV patients after perhexiline maleate become normal. This shows that the drug acts by removing the contractile dysfunction. It can reasonably be assumed that this takes place following the elimination of the ischemia induced dyssynergic areas.
The effect of this drug has also been evaluated from a clinical point of view. A marked decrease in the frequency of anginal crises and the consequential reduction in the consumption of trinitroglycerin pills during perhexiline maleate treatment could thus be observed.

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Serial precordial mapping was done in 30 patients with acute anterior myocardial infarction, 27 transmural and 3 subendocardial. The sum of ST elevations in the 48 lead map was designated as Σ ST.
Normal Σ ST was calculated as 27.1±3.1 in males and 14.3±2.8 in females. In infarction it was 100.4±58.2 in males and 84.8±50.9 in females on the 1st day of admission.
Σ ST was elevated on day 1 and tended to fall gradually. In 6 patients it was normal by day 7 and in 7 it was still abnormal by day 21. This fall roughly co-related with fall in SGOT and CPK levels.
Significant elevation of Σ ST occurred in 14 of 27 cases after day 1. In 10 of 27 cases significant re-elevation occurred on day 4 or after i.e. when the patient was outside the ICCU. In 10 of the 14 re-elevations there was pain or worsening of clinical picture and in 12 there was reelevation of SGOT. This elevation presumably implied infarct extension.
There was a tendency to more arrhythmias in the patients with higher Σ ST and of the 4 deaths in the series 3 had very high Σ ST and high levels of SGOT. The patient with the highest Σ ST 295 died in cardiogenic shock.
The number of risk factors was found to be higher in the high Σ ST group.

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The prevalence and relative frequency of congenital heart disease in high school and college students were investigated during the period April 1970-March 1976. Forty congenital lesions were found among 13, 127 subjects which shows a rate of 3 per thousand. The ratio of congenital lesion to rheumatic heart disease was 4/1.
Ventricular septal defect was the most common defect, found in 30% of all lesions followed by atrial septal defect (20%) and patent ductus arteriosus (17.5%). The prevalence and relative frequency in those investigated differed only slightly from the results obtained among children.
The possibility of spontaneous closure of ventricular septal defect during adulthood strongly suggested itself when compared with our previous data on post middle age subjects.

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Computer simulation of the ventricular activation sequence of the WPW syndrome was attempted by producing fusion beats in which localized ventricular myocardium was activated earlier than the "normal excitation". It suggested that the site of pre-excitation was; i) at the posterior or the lateral free wall of the left ventricle adjacent to the A-V groove in type A, ii) at the antero-lateral base of the right ventricle in type B, and iii) at the posterior paraseptal region of the right ventricle in type C. A mild degree of pre-excitation at the left ventricular posterolateral region will result in type-B QRS complexes.

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Lysosomal fraction of high renin activity, obtained from renal cortex of normal rats by step-wise centrifugation method, phenylephrine and angiotensin II were injected into bilaterally nephrectomized rats. Blood pressure was raised 20mmHg for 60 min by the pressor agents. Ferritin was used to trace pathways of plasma protein insudation in the arterial wall. Animals infused with saline served as a control. Arterioles in the intestinal submucosa was observed by light and electron microscope. The arterial endothelium and the interendothelial cell junctions appeared to be intact in all the experimental animals. Ferritin was present in pinocytotic vesicles in the endothelial cells and in the subendothelial spaces, but never in the intercellular junctions in each of the experimental groups. Ferritin concentration in the subendothelial spaces, however, was the highest in lysosomal fraction group. Morphometric analysis concerning the vesicular transport, which appeared to be the main pathway of ferritin insudation, was performed in the arterial endothelium. Frequencies of the pinocytotic vesicles in the experimental groups resembled each other. Percentage of the pinocytotic vesicles labeled with ferritin, however, was significantly higher in lysosomal fraction group than that in the other groups. The results suggested that substance(s) contained in lysosomal fraction may exert direct action on the arterial endothelium and accelerate the labeling rate of pinocytotic vesicles with macromolecules, resulting in insudation of the plasma protein into subendothelial spaces of the arterioles.

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A mini-computer system for PCG interpretation has been functioning since 1971. The system can analyze as many as 100 PCG's in 3 hours. Based on our 5 years' experience, computer interpretation of PCG's has proved itself valuable for the rapid mass-screening of cardiovascular disease. It also provides more objective and quantitative information than human auscultation, though it is still at a developmental stage because of the present technical limitations. The solution of these shortcomings should achieve an automated PCG analysis of high accuracy.

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Alterations in the renin-angiotensin system are caused by changes in the vascular perfusing pressures in the renal outer cortex. The renal peripheral resistance to the perfusing pressures in the renal outer cortex is to some extent controlled by the plasma sodium load, sympathetic, and vasoconstrictor stimuli. Logically, therefore, the renin-angiotensin system can be excluded from any primary involvement in the genesis of essential hypertension. Because high plasma renin hypertension inevitably progresses to organic vascular involvement, it is clear that angiotensin-ii plays an important vasoconstrictor role at some later stage. Experiments, involving Goldblatt techniques, which alter the renal perfusion pressure and hence activate the renin-angiotensin system, skip over a preliminary period during which, under natural conditions, unknown factors are slowly inducing an increase in the total peripheral resistance. It is argued that the dominant natural factor during this preliminary period is an excess general vasotonic influence exerted by vasopressin.
It is argued that essential hypertension develops in those individuals who, for some reason, over a long period of time intermittently release excessive amounts of vasopressin and who also possess a particularly hyper-reactive renal-adrenal feed-back system. Built into this system is the capability of activating a catecholamine overdrive postulated by several authors as an important, though secondary factor, in the development of essential hypertension.

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Beta-blocker (propranolol 10mg/Kg body weight, daily) in modest dose lowers the level of blood pressure, decreases the weight of the heart after 10 weeks' administration since 6 weeks age in male Spontaneously Hypertensive Rats. The lowered level of blood pressure in SHR with high-salt diet and β-blocker is similar to the level of SHR with common diet. The β-blocker dilates the sapstic artery in the eye-ground of SHR with high-salt diet and increase the ratio of the caliber of artery/vein.

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Effects of rearing in a different constant temperature on stroke and blood pressure were not clearly observed in WK. For SHRSP, a difference in rearing temperature did not influence blood pressure so greatly as salt loading.

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The diet containing white fish meal, euphausia, euphausia/white fish meal, yolk/egg white, chlorella/white fish meal, hydrocarbon yeast/white fish meal, sweet smelt or dried beef meal/meat bone meal as a protein source could markedly depress the elevation of blood pressure, prevent the incidence of stroke and elongate the life-span in SHRSP. We observed marked or slight enlargements of the kidney (1.6-2.0 times as heavy as the control) and the liver (1.1-1.2 times) in SHRSP fed with the 50% white fish meal diet or the 50% casein diet over a long time, but did not observe it in feeding with the diet containing under about 30% crude protein. Therefore, the 35% euphausia or 25% euphausia/10% white fish meal diet seems to be most effective in preventing stroke in SHRSP.
The incidence of stroke in SHRSP was prevented by providing these diets from an early age-the earlier the better.
The 50% dried beef meal diet was effective, but 25% dried beef meal/25% meat bone meal diet was more effective in males. It seems that not only protein but minerals play a role in the prevention of stroke.

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1. The blood pressure of SHRSP fed with defatted white fish meal or sweet smelt diet was lower than the control, and showed tendencies similar to the nondefatted white fish meal or sweet smelt diet.
2. Ca added 50% casein diet depressed the elevation of blood pressure more effectively in comparison with the 50% casein diet. Stroke lesions were not observed in SHRSP fed with it.
3. Peptide substances from casein, euphausia, white fish meal, soy bean cake and meat bone meal had a tendency to depressing blood pressure when injected intravenously, and especially that from euphausia was more effective than the others.

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The effect of high fat cholesterol diet (HFC diet) on cerebrovascular circulation was significant. I.e., at least at an early stage this diet lowered systemic blood pressure, thus leading to a reduced incidence of "arterionecro-thrombogenic" stroke by maintaining rCBF in normal range. Such result occurs despite clear ring-like fat deposition in the cerebrovascular system (Yamori et al: Stroke 7: 120, 1976), even though chemical cerebrovascular reactivity is reduced. This reduction of chemical cerebrovascular reactivity clearly indicates that fat deposits in cerebral arteries accelerate organic changes of cerebral arteries, i.e., cerebral arterio- or atherosclerosis.
The above-mentioned HFC diet showed little significance in relation to the heart, either electrocardiographically and/or vectorcardiographically. This coincides with our previous report that the degree of myocardial fibrosis was not so remarkable as compared with the control groups. However, problems involving contents of the HFC diet, strain differences in SHR, and duration of feeding remained to be solved in the near future.

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Histological findings of the thyroid gland in SHR-control showed that the process from synthesis of thyroglobulin to pinocytosis of iodinated thyroglobulin was actively metabolized under the increased stimulation of TSH. Therefore, it was suggested that a decreased secretion rate of thyroxine was mainly resulted from an impairment of hydrolysis of iodinated thyroglobulin or that of following metabolic process.
By administration of thyroxine, the thyroid gland of SHR showed less atrophic changes. From the morphological finding of TSH secreting cells of the anterior pituitary gland in SHR, this result would be due to less suppressed TSH secretion.

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Chronic rCBF reduction under severe hypertensive state preceded the development of vascular damages in SHRSP, and by controlling blood pressure under 200mmHg rCBF was maintained well within normal range so that no stroke was observed. Noradrenaline fluorescence was reduced in cerebral lesions which developed spontaneously in SHRSP. When rCBF was reduced in young SHRSP acutely after the bilateral ligation of carotid arteries, depletion of noradrenaline and dopamine was noted. From this observation catecholamines seem to be released when nerve terminals are exposed to hypoxia. It may be possible that released catecholamines accelerate the vasoconstriction of cerebral arteries and further decrease the blood supply to the areas, thus to increase vascular permeability which results in arterionecrosis and/or thrombus formation. Thus, catecholamines might be involved in the vicious circle for inducing cerebrovascular lesions.

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Age-matched SHRSP and RHR produced experimentally from Wistar-Kyoto rats showed similar decreases in rCBF when they developed severe hypertension over 200mmHg 60 days after birth or 2 weeks after the operation, respectively. It is noteworthy that there was a regional difference in rCBF reduction, i.e., the reduction in the frontal cortex fed by recurrent branches was greater than that in the temporal cortex fed by current branches from the main cerebral arteries. The incidence of stroke was higher in the former than in the latter.
On the other hand, model experiments proved that the flow ratio in recurrent branches was lower than that in current branches. These results seemed to support the importance of recurrent branching of the main cerebral arteries, i.e., the significance of hemodynamics as one of the local factors for stroke. Reduction of rCBF, caused by severe hypertension, especially in the region fed by recurrent branches, probably results in long-termed moderate anemic hypoxia followed by initiation of cerebrovascular damage.

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Denervated groups clearly showed low susceptibility to fat deposition in the cerebrovascular system, as compared with the control group. However no significan differences were noted in blood pressure, gain in body weight and serum cholesterol levels. These results suggested the important role of innervation on fat deposition.
On the other hand, our fluorescence microscopic study with concentrated glyoxylic acid immersion revealed that appearance of innervation in the basilar artery seemed to be spiral or ring-like, just as the fatty deposition produced by Yamori's preparation I, II, and III was detected as clear ring-like form.
Further investigation into the relationship between innervation and ring-like sudanophylic rings in the cerebrovascular system should be required. However, the results reported here support and substantiate our previous assumption about the initiation mechanism of arterio- or atherosclerosis based on our experiments. I.e., the vicious circle of repeated vasodilatation and vasoconstriction-probably under the influence of nervous control-might be the basis for fatty degeneration resulting in cerebral arterio- or atherosclerosis.

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Close observation of signs and symptoms in SHRSP enabled us to analyze to some extent the pathology and topography of cerebrovascular lesions. The present study raised the importance of symptomatology in SHRSP, and also reassured that SHRSP is a good animal model for stroke from a symptomatological view point.

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In SHRSP at the terminal stage, brain shift and herniation were confirmed to develop further cerebral damage. Cerebellar herniation is the major cause of brainstem dysfunction which results in brain death. These are also the cause of acceleration of brain swelling and the establishment of massive infarction. Generally, the lethal course of stroke in SHRSP corresponds well to that of patients with severe cerebrovascular lesions.

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The incidence of stroke was clearly decreased in SHRSP fed on high-fat diet or high-protein diet, and it also tended to be decreased in the groups given additional amino acids (lysine and/or proline). However, no remarkable differences in the incidence were noted between vitamin E-deficient and sufficient diet-fed groups. In the high-fat-cholesterol diet-fed and high fish protein diet-fed groups, the prophylactic effect on stroke was accompanied by the attenuation of severe hypertension. However, this was not so in the high soy bean protein diet group, as reported previously by Yamori et al (in "Spontaneous Hypertension", p 198, DHEW Publication No. (NIH) 77-1179, 1977. These data have reassured the importance of environmental factors, especially diet, in the pathogenesis of stroke, clearly indicating that stroke is preventable by the modification of dietary customs.

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In the cerebral arteries in SHR there were findings that indicate an increased cellular activities of the endothelial cells such as an increased number of villi, pits and enlargement of the cells and also regressive findings such as balloon-like protrusion and crater-like cave-ins.

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The retina of SHRSP mainly over the age of 5 months showed moderate to marked arteriolar changes: intimal and medial thickening, luminal occlusion, and necrosis of arteriolar walls. These arteriolar lesions resulted in marked retinopathy with edema and breakdown of retinal structure. These findings well corresponded to the retinopathy in severe hypertensive state.

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In SHRSP, marked hypertensive arteriolar changes were noted ophthalmoscopically and histologically, and retinal or vitreous hemorrhage was observed in some SHRSP with severe hypertension. Quantitative analyses of arteriolar and venular calibers revealed that the narrowing of arteriolar calibers was more marked in SHRSP than SHRSR. Edematous changes of retina or optic disc were often observed in SHRSP at the terminal stage. Ophthalmoscopic findings on optic fundi, also confirmed histologically in this study, are regarded as good indices showing the process of hypertensive vascular changes. Such findings may be utilized to estimate the grade of cerebrovascular lesions.

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Even in younger age, the aortic walls of SHRSP, especially in males, were shown to be brittle or fragile in comparison with those of WK. In spite of their thickening, they showed poor extension. In order to clarify whether or not this fragility is due to the qualitative or quantitative difference in vascular components, and to clarify whether such difference is detected in small cerebral arteries where hypertensive vascular lesions are induced, further study is necessary. Even if such difference is noted only in the aorta, the absorbing function of greater pulse pressure may be less in the aortas of SHRSP because of reduction in elasticity. Such an impairment of aortic function may be involved in the stroke-proneness of SHRSP, where cerebral vessels might be possibly exposed to greater pulsatile changes in blood pressure.

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Arterionecrosis is noted in the brain and kidney but rarely in the heart. Ringlike fat deposits acutely induced by hypertension were frequently noted in the mesenteric and cerebrobasal arteries but rarely in the coronary. Ring-like fat deposits were noted at the sites of vascoconstriction and dilatation, especially at vasodilatation as reported previously by Yamori et al (Jap Circulat J 39: 593, 1975). These hypertensive vascular lesions are induced by high regional perfusion pressure and might also be related to the grade of innervation. Immunity of coronary arteries from hypertensive lesions is due to the fact that they are perfused mainly with diastolic pressure.

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As described above, the proportion of elastin in aorta was high in young rats and decreased with age. And its amino acid composition showed that the content of polar amino acids increased with age. Moreover, the SHRSP showed a high proportion of elastin and a high content of polar amino acids in amino acid compositions after 3 months old, as compared with the Wistar-Kyoto rats. These results indicate that the aging process in the aorta of SHRSP proceeds earlier than in the Wistar-Kyoto rats, but the effects of hypertension upon the arterial wall must be considered.
On the other hand, for the SHRSP fed with white fish meal or casein diet, the proportion of elastin in aorta was higher than in the SHRSP fed with a stock chow diet. This became more remarkable with age. It should be expected that there is some relationship between these results and the inhibition of blood pressure elevation and the decrease in incidence of stroke in SHRSP fed with these experimental diets.

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In SHR, hydroxylysine contents as well as the relative ratios of hydroxylysine to the total of lysine and hydroxylysine were increased in the mesenteric arteries. Concomitantly, uronic acid and hexose content were also increased in the wall of the aorta of SHR. The higher content of hydroxylysine in the collageneous protein may be closely related to the increased carbohydrate content, since most collagen disaccharide or monosaccharide components are generally o-glucosidicallybound to hydroxylysine. Therefore, these findings suggested that alteration of chemical constitutes related to both the hydroxylation of lysine and the glycosylation of hydroxylysine residue influence the formation of intra- and intermolecular cross-links. Thus such alteration would change the physico-chemical characteristics of the arterial walls in SHR and possibly also in SHRSP.

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Compared with WK, ADP-induced platelet aggregation was weaker in SHRSR, SHRSP, and especially in SHRSP with some symptoms of stroke (Apo-SHRSP). Bovine collagen-mediated platelet aggregation was also less in Apo-SHRSP. When collagens from the aortas of WK, SHRSR, SHRSP, and Apo-SHRSP were added to PRP from SHRSR, the aggregation in response to that from Apo-SHRSP was not so markedly changed. These findings might be partly related to the high incidence of stroke in SHRSP, either primarily or secondarily.

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