Toshio Ozawa

Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells

Previous studies showed that homocysteine, a thrombo-atherogenic and atherogenic agent, inhibits an endothelial thrombomodulin-protein C anticoagulant pathway. We examined whether homocysteine might affect another endothelial anticoagulant mechanism; i.e., heparin-like glycosaminoglycan-antithrombin III interactions. Incubations of porcine aortic endothelial cell cultures with homocysteine reduced the amount of antithrombin III bound to the cell surface in a dose- and time-dependent fashion. The inhibitory effect was observed at a homocysteine concentration as low as 0.1 mM, and the maximal suppression occurred at 1 mM of homocysteine after 24 h. In contrast with a marked reduction in the maximal antithrombin III binding capacity (approximately 30% of control), the radioactivity of [35S]sulfate incorporated into heparan sulfate on the cell surface was minimally (< 15%) reduced. The cells remained viable after homocysteine treatment. Although neither net negative charge nor proportion in total glycosaminoglycans of cell surface heparan sulfate was altered by homocysteine treatment, a substantial reduction in antithrombin III binding capacity of heparan sulfate isolated from homocysteine-treated endothelial cells was found using both affinity chromatography and dot blot assay techniques. The antithrombin III binding activity of endothelial cells decreased after preincubation with 1 mM homocysteine, cysteine, or 2-mercaptoethanol; no reduction in binding activity was observed after preincubation with the same concentration of methionine, alanine, or valine. This sulfhydryl effect may be caused by generation of hydrogen peroxide, as incubation of catalase, but not superoxide dismutase, with homocysteine-treated endothelial cells prevented this reduction, whereas copper augmented the inhibitory effects of the metabolite. Thus, our data suggest that the inhibited expression of anticoagulant heparan sulfate may contribute to the thrombogenic property resulting from the homocysteine-induced endothelial cell perturbation, mediated by generation of hydrogen peroxide through alteration of the redox potential.

Accuracy of a continuous blood pressure monitor based on arterial tonometry.

A validation study of the continuous noninvasive tonometric blood pressure monitor called JENTOW was performed in 20 normotensive subjects and 10 hypertensive patients. Tonometric and intra-arterial blood pressures were simultaneously recorded at supine rest and during a Valsalva maneuver and tilting test. The results of the strict evaluation of the instruments capacity for reproducing intra-arterial blood pressure were as follows: 1) The overall frequency response of the transcutaneous blood pressure-monitoring system based on arterial tonometry was flat, with negligible delay to intra-arterial blood pressure in the range of 0-5 Hz. 2) The largest discrepancy between intra-arterial and tonometric pressure waveforms was found at the early systolic phase; except for this phase, the tonometric waveform was almost equal to the intra-arterial waveform. 3) The beat-to-beat variability of tonometric pressure corresponded to that of intra-arterial pressure almost perfectly in the physiologically significant frequency range of 0-0.5 Hz. 4) During resting conditions, the averages of the systolic and diastolic values measured tonometrically corresponded well to those measured intra-arterially. 5) The changes in the between-method discrepancy of blood pressure values during the Valsalva maneuver were statistically significant but small (< 5 mm Hg). 6) No significant effect of postural tilting was found on the between-method discrepancy. We conclude that this method is clinically acceptable and reliable except for its limited capacity for recording the higher frequency intra-arterial waveform and for responding to the relatively rapid and large transient changes in blood pressure.

Postural Dysregulation in Systolic Blood Pressure Is Associated With Worsened Scoring on Neurobehavioral Function Tests and Leukoaraiosis in the Older Elderly Living in a Community

BACKGROUND AND PURPOSEnPostural hypotension, which occurs frequently in community-living, apparently healthy elderly adults, is usually asymptomatic. However, the relation between postural changes in blood pressure and quantitative higher cerebral function or silent brain lesions remains unclear. We examined the association of exaggerated postural changes in systolic blood pressure with cognitive and quantitative neurobehavioral functions and with brain lesions on MRI in the community-dwelling older elderly.nnnMETHODSnThe study population consisted of 334 community-dwelling elderly adults, aged 75 years or older (mean age, 80 years). Postural changes in systolic blood pressure (SBP) were assessed using an autosphygmomanometer (BP-203 I). By the difference between the mean of two measurements of SBP at standing and at supine position (dSBP = SBP at upright-SBP at supine position), we divided the subjects into three groups: (1) 20 subjects with postural hypotension (d-SBP < or = -20 mm Hg), (2) 29 subjects with postural hypertension (dSBP > or = 20 mm Hg), and (3) 285 subjects with postural normotension (20 < dSBP < 20 mm Hg). We defined the former two groups as the postural dysregulation group. Scores in four neurobehavioral function tests (Mini-Mental State Exam. Hasegawa Dementia Scale Revised, computer-assisted visuospatial cognitive performance score, and the Up and Go Test) and activities of daily living were compared among the three groups. Brain lesions on MRI, including number of lacunes and periventricular hyperintense lesions, were compared among 15 age- and sex-matched control subjects with postural hypotension, 15 with postural hypertension, and 30 with postural normotension.nnnRESULTSnTwenty subjects (6.0%) exhibited postural hypotension and 29 (8.7%) postural hypertension. Scores in neurobehavioral functions and activities of daily living were significantly lower in the postural dysregulation group (both postural hypotension and hypertension groups) than in the postural normotension group. The postural dysregulation group exhibited significantly more advanced periventricular hyperintensities than the normotension group.nnnCONCLUSIONSnAsymptomatic community dwelling elderly individuals with postural hypotension as well as those with postural hypertension had poorer scores on neurobehavioral function tests and more advanced leukoaraiosis demonstrated on MRI than those without exaggerated postural changes in SBP.

Age-related changes of baroreflex function, plasma norepinephrine, and blood pressure.

Interrelationships between age, baroreflex sensitivity, plasma norepinephrine levels, and systolic blood pressure were assessed in a group of 54 normal subjects ranging in age from 14 to 77 years. Baroreflex sensitivity was measured by the change in R-R intervals per unit change in systolic blood pressure during phase 4 of the Valsalva maneuver. All correlations among these four variables were statistically significant (p less than 0.05 or 0.01). To investigate possible causal relationships between age-related changes of baroreflex sensitivity, plasma norepinephrine levels, and blood pressure, partial correlative analysis was then performed. After the effect of age was eliminated, plasma norepinephrine levels were found to be related positively to blood pressure (r = 0.29, p less than 0.05) and negatively to baroreflex sensitivity (r = -0.34, p less than 0.05). The increase in plasma norepinephrine levels could be causally related to the elevation of blood pressure, as plasma norepinephrine levels could provide an index of sympathetic activity. Furthermore, baroreflex sensitivity was found to be negatively related to age (r = -0.44, p less than 0.01) independent of plasma norepinephrine levels, whereas plasma norepinephrine levels were no longer related to age (r = 0.10) after adjusting for the effect of baroreflex sensitivity. This finding suggests that an increase in plasma norepinephrine levels with age could be mediated by the age-related change of baroreflex sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Exercise on Neurobehavioral Function in Community‐Dwelling Older People More Than 75 Years of Age

OBJECTIVE: We evaluated the effects of exercise on neurobehavioral function in healthy older people more than 75 years of age.

THE TIMED “UP & GO” TEST IS A USEFUL PREDICTOR OF FALLS IN COMMUNITY-DWELLING OLDER PEOPLE

ratio.3 Fihn et al. concluded that “age did not appear to be an important determinant of risk for bleeding in patients receiving warfarin, with the possible exception of age 80 years or older.” These investigators reported that life-threatening or fatal bleeding complications occurred more often among the oldest patients; the incidence of these events was 0.75 per 100 patient-years in patients younger than SO years of age and 3.38 in patients 80 years of age and older (relative risk 4.50; 95% confidence interval, 1.315.6).4 We agree with Dr. Portnoi that the decision-making process regarding the use of warfarin therapy in the management of older patients with atrial fibrillation should engage patients and, when appropriate, their families. In addition, therapeutic management with regard to warfarin therapy does not end with the initiation of treatment. Continued reevaluation of treatment appropriateness, adequate patient surveillance, and maintenance of the patient in the appropriate therapeutic range are essential. In our study, more than one-quarter of the physicians surveyed responded that they preferred a target therapeutic range with a lower INR limit less than 2 for their older patients with atrial fibrillation who are residents in nursing homes.’ More widespread use of specialized clinics to manage warfarin therapy in the long-term care setting may provide a mechanism to address some of these important issues.

Arterial stiffness independently predicts cardiovascular events in an elderly community : Longitudinal Investigation for the Longevity and Aging in Hokkaido County (LILAC) study

We investigated the predictive value of arterial stiffness to assess cardiovascular risk in elderly community-dwelling people by means of a multivariate Cox model. In 298 people older than 75 years (120 men and 178 women, average age: 79.6 years), brachial-ankle pulse wave velocity (baPWV) was measured between the right arm and ankle in a supine position. The LILAC study started on July 25, 2000, consultation was repeated yearly, and the last follow-up ended on November 30, 2004. During this follow-up span of 1227 days, there were nine cardiovascular deaths, the cause of death being myocardial infarction for two men and three women or stroke for two men and two women. In Cox proportional hazard models, baPWV as well as age, Mini-Mental State Examination (MMSE), Hasegawa Dementia Scale Revised (HDSR) and the low-frequency/high-frequency (LF/HF) ratio showed a statistically significant association with the occurrence of cardiovascular death. A two-point increase in MMSE and HDSR score significantly protected against cardiovascular death, the relative risk (RR) being 0.776 (P = 0.0369) and 0.753 (P = 0.0029), respectively. The LF/HF ratio also was significant (P = 0.025), but the other indices of HRV were not. After adjustment for age and HDSR, a 200 cm/s increase in baPWV was associated with a 30.2% increase in risk (RR = 1.302, 95% CI: 1.110-1.525), and a 500 cm/s increase in baPWV with a 93.3% increase in risk (RR = 1.933, 95% CI: 1.300-2.874, P = 0.0011), whereas the LF/HF ratio was no longer associated with a statistically significant increase in cardiovascular mortality. In elderly community-dwelling people, arterial stiffness measured by means of baPWV predicted the occurrence of cardiovascular death beyond the prediction provided by age, gender, blood pressure and cognitive functions. baPWV should be added to the cardiovascular assessment in various clinical settings, including field medical surveys and preventive screening. The early detection of risk by chronomics allows the timely institution of prophylactic measures, thereby shifting the focus from rehabilitation to prehabilitation medicine, as a public service to several Japanese towns.

A U-shaped association between home systolic blood pressure and four-year mortality in community-dwelling older men.

BACKGROUND: Several studies in older people have found a U‐shaped or J‐shaped association of blood pressure with mortality. The increased mortality associated with the lowest levels of blood pressure in older people have been explained by concurrent illnesses and frailty, but previous studies used blood pressure measured on a single occasion. Such a casual value is different from the long‐term average of blood pressure. We investigated the relation between the average level of 5‐day consecutive home blood pressure and mortality in older people while adjusting for potential confounding factors including morbidity and frailty at baseline.

Thrombin generation as an acute effect of cigarette smoking

The effects of acute smoking on hemostatic functions were investigated in healthy young volunteers. Immediately after the volunteers smoked, a significant increase in blood pressure and heart rate was accompanied by a rise in plasma epinephrine. Fibrinopeptide A and thrombin-antithrombin III complex as markers of thrombin generation in vivo were significantly increased after smoking. The increase in thrombin-antithrombin III complex was significantly correlated with that of plasma epinephrine. Both antigen and activity of tissue plasminogen activator and plasmin-inhibitor complex as markers of fibrinolytic activity in vivo were markedly increased after smoking, whereas D-dimer, plasminogen activator inhibitor antigen, fibrinogen, and both beta-thromboglobulin and platelet factor 4 as markers of platelet activation in vivo were not changed. No effects were observed after sham smoking under exactly identical conditions in the same subjects. Thus thrombin generation was observed as acute hemostatic effects of smoking. Enhanced fibrinolytic response may counteract an increased procoagulant activity. Patients with vascular disease might be more susceptible to a state of disequilibrium in favor of coagulation, which may partly explain a mechanism by which cigarette smoking leads to cardiovascular morbidity and mortality.

Prognostic value of thallium-201 perfusion defects in idiopathic dilated cardiomyopathy

To assess the prognostic significance of thallium-201 perfusion defects in patients with idiopathic dilated cardiomyopathy (IDC), 43 patients underwent thallium scintigraphy in addition to clinical, echocardiographic, angiographic and hemodynamic evaluation. Eleven patients had no significant thallium perfusion abnormality, 19 had multiple small defects and 13 had a large defect. During 3.2 +/- 2.2 years, 14 patients had disease-related mortality. The patients who died had a higher incidence of ventricular tachycardia (71 vs 31%; p less than 0.02), increased cardiothoracic ratio (60 +/- 6 vs 54 +/- 6; p = 0.005), decreased fractional shortening (11 +/- 6 vs 15 +/- 5; p less than 0.05), increased pulmonary wedge pressure (15 +/- 7 vs 10 +/- 6 mm Hg; p = 0.05), increased left ventricular end-diastolic pressure (21 +/- 8 vs 14 +/- 6 mm Hg; p = 0.02) and abnormal thallium perfusion defects (13 of 14 vs 16 of 26; p less than 0.05) compared with survivors. Age, gender, left ventricular end-systolic and end-diastolic dimensions, cardiac index and ejection fraction were not statistically different in the survivors versus the patients who died. Kaplan-Meier survival estimates at 1, 3 and 5 years were 100% in patients without significant perfusion abnormality; 89, 77 and 64%, respectively, in patients with multiple small defects; and 84, 76 and 30%, respectively, in patients with a large defect (p less than 0.025 by log rank test).(ABSTRACT TRUNCATED AT 250 WORDS)