Teruo Omae

Plasma levels of adrenomedullin, a newly identified hypotensive peptide, in patients with hypertension and renal failure.

Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet cAMP. We measured plasma concentration of adrenomedullin in patients with essential hypertension and chronic renal failure. As compared with normal subjects, plasma adrenomedullin was increased by 26% (P < 0.05) in hypertensives without organ damage and by 45% (P < 0.005) in those with organ damage. The increase in plasma adrenomedullin was more prominent in renal failure than in hypertension. Renal failure patients with plasma creatinine of 1.5-3, 3-6, and > 6 mg/dl had higher plasma adrenomedullin levels than healthy subjects by 78% (P < 0.05), 131% (P < 0.001), and 214% (P < 0.001), respectively. Moreover, adrenomedullin showed intimate correlations with norepinephrine, atrial natriuretic peptide, and cAMP in plasma (r = 0.625, P < 0.001; r = 0.656, P < 0.001; and r = 0.462, P < 0.001; respectively). Thus, plasma adrenomedullin is supposed to increase in association with changes in sympathetic nervous activity and body fluid volume in hypertension and renal failure. Considering its potent vasodilator effect, adrenomedullin may be involved in the defense mechanism preserving the integrity of the cardiovascular system in these disorders.

Relationship Between Left Ventricular Geometry and Natriuretic Peptide Levels in Essential Hypertension

Previous studies have shown that plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are increased in essential hypertension. However, whether left ventricular geometry affects plasma ANP and BNP levels remains unknown. To investigate the effect of left ventricular geometry on plasma ANP and BNP levels in essential hypertension, we measured plasma ANP and BNP levels in 90 patients with essential hypertension. All patients were hospitalized, and fasting blood samples were obtained in the early morning after 30 minutes of bed rest. Plasma ANP and BNP levels were measured by immunoradiometric assay. Hypertensive patients were classified into four groups according to echocardiographic findings that showed normal geometry, concentric remodeling, eccentric hypertrophy, or concentric hypertrophy. Mean plasma ANP and BNP levels in all essential hypertensive patients were higher than those in age-matched normotensive control subjects. Plasma ANP levels in hypertensive patients with concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were higher than in normotensive control subjects, although there were no differences between normotensive subjects and hypertensive patients with normal geometry. Plasma BNP levels tended to be higher in hypertensive patients with normal geometry, concentric remodeling, and eccentric hypertrophy than in normotensive control subjects; however, the differences were not significant. Plasma BNP levels and BNP/ANP ratio were specifically higher in concentric hypertrophy. There were significant correlations between ANP and left ventricular mass index, relative wall thickness, interventricular septal thickness, posterior wall thickness, and mean arterial pressure. Plasma BNP levels significantly correlated with relative wall thickness, interventricular septal thickness, posterior wall thickness, and left ventricular mass index but not with mean arterial pressure. In addition, plasma BNP levels were well correlated with ANP levels, and the slope for the linear regression model was steeper in concentric hypertrophy than in the other four groups. These results show that plasma ANP and BNP levels are increased in essential hypertensive patients with left ventricular hypertrophy. Furthermore, BNP secretion is augmented to a greater extent in concentric hypertrophy. Thus, measurement of plasma ANP and BNP levels may be useful for the detection of concentric left ventricular hypertrophy in patients with essential hypertension.

Surgical management of infective endocarditis associated with cerebral complications : multi-center retrospective study in Japan

To establish guidelines for the surgical treatment of patients with infective endocarditis who have cerebrovascular complications, we conducted a detailed retrospective study of 181 of 244 patients with cerebral complications among 2523 surgical cases of infective endocarditis of the Japanese Association of Thoracic Surgery. The results showed that 9.7% of all patients with infective endocarditis had associated cerebral complications: 108 (44.3%) had active native valve endocarditis, 96 (39.3%) had healed native valve endocarditis, and 40 (16.4%) had prosthetic valve endocarditis. The hospital mortality of the patients with cerebral complications was 11.0% in the group as a whole: 13.9% in active native valve endocarditis, 3.1% in healed native valve endocarditis, and 37.5% in prosthetic valve endocarditis. Diseased valves included the following aortic valve in 55.5%, mitral valve 49.8%, tricuspid valve in 1.3%, and pulmonary valve in 1.3%. In 181 patients with cerebral complications, organisms were detected as follows: gram-positive cocci in 133 (73.5% [Streptococcus in 85, Staphylococcus in 32]), gram-negative in 18 (9.9%), fungus in 11 (6.1%), and unknown in 64.6%, cerebral bleeding in 31.5%, cerebral abscess in 2.8%, and meningitis in 1.1%. Hospital mortality rate and an exacerbation rate of cerebral complications, including related death, according to the interval from onset of cerebral infarction to cardiac surgery, were as follows: 66.3% and 45.5% within 24 hours, 31.3% and 43.8% between 2 and 7 days, 16.7% and 16.7% between 8 and 14 days, 10.0% and 10.0% between 15 and 21 days, 26.3% and 10.5% between 22 and 28 days, and 7.0% and 2.3% over 4 weeks later, respectively. A significant correlation existed between the interval and the exacerbation of cerebral complications (tied p = 0.008). Preoperative risk factors affecting exacerbation of cerebral complications were as follows: (1) severity of cerebral complications (p = 0.006), (2) intervals (p = 0.012), and (3) uncontrolled congestive heart failure as indications for cardiac surgery (p = 0.014). One patient underwent a cardiac operation within 24 hours of the onset of cerebral hemorrhage and died of cerebral damage. No exacerbations occurred in 10 patients who underwent their operation between 2 and 28 days. Nevertheless, exacerbations occurred in 19.0% of patients whose operation was done more than 4 weeks later. These data suggest that cardiac operations can be done safely 4 weeks after cerebral infarction, and if the delay is more than 2 weeks, the exacerbation rate will be around 10%. The risk of progression of cerebral damage is still significant 15 days and even 4 weeks after cerebral hemorrhage.

Clinical studies on the sites of production and clearance of circulating adrenomedullin in human subjects.

Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67 +/- 10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42 +/- 14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery.(ABSTRACT TRUNCATED AT 250 WORDS)

'Spectacular shrinking deficit' Rapid recovery from a major hemispheric syndrome by migration of an embolus

We studied the clinical features of a major hemispheric stroke syndrome with rapid recovery (“spectacular shrinking deficit” [SSD]) compared with stroke patients with the same major initial manifestations but without rapid recovery (non-SSD). There were 118 patients with an initial major hemispheric syndrome; 14 patients (12%) had SSD. All but one SSD patient met criteria for cardiogenic brain embolism. Angiographic examination within 24 hours after stroke onset demonstrated that the occlusion sites in SSD differed from those in non-SSD and suggested that rapid embolus migration had occurred in all SSD patients but in only five of 39 non-SSD. Infarcts in SSD were smaller and often scattered over the cortices and deeper structures. Hemorrhagic transformation was less frequent in SSD. In patients with a potential cardiac source of emboli, SSD was more likely to occur in nondiabetic men less than 60 years of age.

Effects of Magnesium Supplementation in Hypertensive Patients Assessment by Office, Home, and Ambulatory Blood Pressures

An increase in magnesium intake has been suggested to lower blood pressure (BP). However, the results of clinical studies are inconsistent. We studied the effects of magnesium supplementation on office, home, and ambulatory BPs in patients with essential hypertension. Sixty untreated or treated patients (34 men and 26 women, aged 33 to 74 years) with office BP >140/90 mm Hg were assigned to an 8-week magnesium supplementation period or an 8-week control period in a randomized crossover design. The subjects were given 20 mmol/d magnesium in the form of magnesium oxide during the intervention period. In the control period, office, home, and average 24-hour BPs (mean+/-SE) were 148.6+/-1.6/90.0+/-0.9, 136.4+/-1.3/86.8+/-0.9, and 133.7+/-1.3/81.0+/-0.8 mmHg, respectively. All of these BPs were significantly lower in the magnesium supplementation period than in the control period, although the differences were small (office, 3.7+/-1.3/1.7+/-0.7 mmHg; home, 2.0+/-0.8/1.4+/-0.6 mmHg; 24-hour, 2.5+/-1.0/1.4+/-0.6 mm Hg). Serum concentration and urinary excretion of magnesium increased significantly with magnesium supplementation. Changes in 24-hour systolic and diastolic BPs were correlated negatively with baseline BP or changes in serum magnesium concentration. These results indicate that magnesium supplementation lowers BP in hypertensive subjects and this effect is greater in subjects with higher BP. Our study supports the usefulness of increasing magnesium intake as a lifestyle modification in the management of hypertension, although its antihypertensive effect may be small.

Role of systolic blood pressure in determining prognosis of hemodialyzed patients

The role of blood pressure in determining the prognosis of hemodialyzed patients was examined in 195 patients who were introduced to hemodialysis. The relationship between blood pressure and survival or death was analyzed. In 46 patients who died within 3 years after the introduction of hemodialysis (nonsurvivors), the age was higher (61 +/- 2 years v 50 +/- 1 years), the occurrence of diabetic nephropathy was higher, and the systolic pressure was higher in both the introduction (178 +/- 4 mm Hg v 167 +/- 2 mm Hg) and maintenance (165 +/- 4 mm Hg v 147 +/- 2 mm Hg) phases than in 132 patients who survived more than 3 years (survivors). On the other hand, there were no significant differences in diastolic pressure during either phase between the two groups of patients. When diabetic nephropathy was excluded, only systolic pressure during the maintenance phase was higher in the nonsurvivors than in the survivors. Therefore, based on systolic pressure during the maintenance phase, patients were divided into two groups, the HT group (> or = 160 mm Hg) and the NT group (< 160 mm Hg), and cumulative survival rates were compared. Whether all patients, only those patients with diabetic nephropathy, or only those patients without diabetic nephropathy were examined, the survival rate was higher in the NT group than in the HT group.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute depressor effect of alcohol in patients with essential hypertension.

To investigate the time course of the effects of alcohol on blood pressure, we studied the response of ambulatory blood pressure, neurohumoral variables, and hemodynamics to a single moderate dose of alcohol in hypertensive patients. Sixteen Japanese men (22-70 years old) with essential hypertension who were habitual drinkers were examined under standardized conditions. On the alcohol intake day, they ingested 1 ml/kg ethanol (vodka) at dinner, and on the control day they consumed a nonalcoholic beverage. The order of the two periods was randomized. Mean ambulatory blood pressure was lower in the alcohol intake period than in the control period (125 +/- 3/74 +/- 2 versus 132 +/- 4/78 +/- 2 mm Hg, p less than 0.05), and the significant depressor effect of alcohol lasted for up to 8 hours after drinking. Blood pressure on the next day did not differ with or without alcohol intake. The acute hypotensive effect of alcohol was associated with an increase in heart rate and cardiac output and with a decrease in systemic vascular resistance as determined by echocardiography. Plasma catecholamine levels and renin activity rose significantly at 2 hours after dinner, whereas vasopressin and potassium levels fell on the alcohol day. Blood glucose and serum insulin levels were comparable between the two periods. Three patients with marked alcohol-induced flush had greater hypotensive and tachycardiac responses than those who did not show an alcohol-induced flush. The change in mean blood pressure induced by alcohol was negatively correlated with age, the baseline blood pressure, and the change in plasma norepinephrine. These results indicate that the major effect of acute alcohol intake is to lower blood pressure through systemic vasodilatation in hypertensive subjects. Ambulatory blood pressure monitoring may be useful for assessing blood pressure in habitual drinkers.

Biphasic effects of repeated alcohol intake on 24-hour blood pressure in hypertensive patients.

BACKGROUND The association between alcohol and blood pressure (BP) may be related to the temporal sequencing of alcohol use and BP measurement. We investigated the effects of single and repeated intakes of alcohol on 24-hour BP. METHODS AND RESULTS Fourteen male habitual drinkers with essential hypertension were placed sequentially on a 4-day control phase: a nonalcoholic drink with the same calories as alcohol was given at dinner (5 PM to 6 PM) and a 7-day drinking phase: alcohol (ethanol, 1 mL/kg) was given at dinner under standardized conditions. Ambulatory BP measurements were performed on day 3 of the control phase and on days 1 and 7 of the alcohol phase. The average 24-hour systolic and diastolic BPs on day 1 were significantly lower than those in the control phase and on day 7. Between 6 PM and midnight, both systolic and diastolic BPs on days 1 and 7 (121 +/- 2/73 +/- 1 and 126 +/- 4/75 +/- 2 mm Hg, respectively) were significantly lower than those in the control phase (139 +/- 4/83 +/- 2 mm Hg). Between midnight and 8 AM (6 to 14 hours after the last drink), both systolic and diastolic BPs on day 7 (138 +/- 4/83 +/- 2 mm Hg) were significantly higher than those in the control phase (131 +/- 4/79 +/- 2 mm Hg) and day 1 (129 +/- 3/77 +/- 1 mm Hg). Between 8 AM and 3 PM, BPs showed no difference among the three phases. CONCLUSIONS A single intake of alcohol has a depressor effect on BP that lasts for several hours after drinking, while repeated intakes for 7 days have both depressor and pressor effects according to the differences in time intervals after the last drink. This study suggests that the chronic effects of alcohol on BP might be overestimated when based on casual BP measurements alone.

Accuracy of diagnosis on death certificates for underlying causes of death in a long-term autopsy-based population study in Hisayama, Japan; with special reference to cardiovascular diseases.

Major categorical diagnosis by International Classification of Diseases and type-specific diagnosis for cardiovascular diseases in death certificates were compared to the diagnosis made at autopsy in 864 consecutive autopsy cases aged 20 or over, among the Japanese residents in Hisayama town. Cerebral stroke was correctly diagnosed in 84%, malignant neoplasms in 78% and cardiac disease in 66%. Cerebral stroke and cardiac disease tended to be overdiagnosed, while malignant neoplasms were underdiagnosed. The validation of certified diagnosis was less reliable in the aged population, and in type-specific diagnosis of cardiovascular diseases. Cerebral hemorrhage with false negative or false positive diagnoses was usually classified into type unspecified stroke or different categories of cerebral stroke, while those misdiagnosed as cases of cerebral infarction frequently had no significant lesions in the autopsied brain. Finally, the relationship between the validation of diagnosis on the death certificates and the secular trend in cardiovascular disease in the Japanese vital statistics was discussed.