Hiroko Kobayashi

Nocturnal Fall of Blood Pressure and Silent Cerebrovascular Damage in Elderly Hypertensive Patients: Advanced Silent Cerebrovascular Damage in Extreme Dippers

To study the relation between diurnal blood pressure variations and silent cerebrovascular damage, we performed both 24-hour ambulatory blood pressure monitoring and brain magnetic resonance imaging in 131 elderly asymptomatic hypertensive patients. Silent cerebrovascular damage was identified by the magnetic resonance imaging findings of lacunae (low intensity in T1-weighted images and high intensity in T2-weighted images) and advanced periventricular hyperintense lesions (on T2-weighted images). The frequency of silent cerebrovascular damage in the 100 patients with sustained hypertension was greater than that in the 31 patients with white coat hypertension. We further classified the former group into nondippers (nocturnal reduction of systolic pressure by < 10% of awake systolic pressure; n = 46), dippers (reduction by > or = 10% to < 20%; n = 38), and extreme dippers (reduction by > or = 20%; n = 16). The extent of silent cerebrovascular damage was least severe in the dipper group (P < .05). This J-shaped relation was not found either with the cardiac hypertrophy detected by electrocardiography or with the renal damage assessed by urinary albumin excretion. More than half of the extreme dippers were patients with isolated systolic hypertension, and this prevalence was significantly greater than that in dippers or in nondippers (21% and 30%, respectively). Extreme dippers also had greater variability of pressure (standard deviation of awake systolic pressure) than dippers. Our results indicate that in addition to nondipping, extreme dipping (marked nocturnal fall of blood pressure) should be considered a type of abnormal diurnal blood pressure variation in elderly patients with hypertension who are likely to have advanced silent cerebrovascular damage.

Earthquake-Induced Potentiation of Acute Risk Factors in Hypertensive Elderly Patients: Possible Triggering of Cardiovascular Events After a Major Earthquake

OBJECTIVES We sought to investigate the potentiation of acute risk factors after the Hanshin-Awaji earthquake (7.2 on the Richter scale). BACKGROUND The frequency of cardiovascular events increases just after a major earthquake, but the causative factors have not been fully investigated. METHODS We studied the changes in cardiovascular risk factors in 42 elderly outpatients with well-controlled hypertension living near the epicenter (Awaji-Hokudan districts) 7 to 14 days after the earthquake when the major felt-aftershocks persisted. They all experienced the highest stress grading of 6 (catastrophic stress) according to the DSM-III-R. To study the hemostatic profile and endothelial cell state, we measured the blood pressure (BP), hematocrit and lipid profiles as well as fibrinogen, a marker of fibrin turnover (D-dimer), fibrinolytic factors (plasmin-alpha2-plasmin inhibitor complex [PIC], tissue-type plasminogen activator [t-PA] antigen and t-PA inhibitor [PAI] activity) and an endothelial cell-derived marker (von Willebrand factor [vWF]). RESULTS Systolic and diastolic blood pressures and other variables increased after the earthquake. Before and after the earthquake, the median (25th to 75th percentiles) systolic BP was 152 (range 142 to 164) and 170 mm Hg (range 161 to 178), respectively (p < 0.0001), and the diastolic BP was 83 (range 79 to 88) and 91 mm Hg (range 84 to 96), respectively (p < 0.0001). Of blood viscosity determinants, hematocrit was 38.1% (range 40.7% to 35.9%) and 39.7% (range 42.9% to 38.3%), respectively (p < 0.001), and fibrinogen 316 (range 272 to 360) and 335 mg/dl (range 307 to 391), respectively (p < 0.05). Von Willebrand factor was 128% (range 74% to 148%) and 148% (range 100% to 178%), respectively (p < 0.01); D-dimer was 410 (range 285 to 633) and 560 ng/ml (range 391 to 888), respectively (p < 0.0001); and PIC was 0.74 (range 0.58 to 0.91) and 0.75 microg/ml (range 0.58 to 1.1), respectively (p < 0.05). In contrast, lipid profiles did not change after the quake. When the patients were classified into the high stress and moderate stress groups according to the degrees of damage to their house and injury to family members, the levels of fibrinogen, vWF, PIC and t-PA antigen were increased only in the former group, whereas BP, hematocrit and D-dimer levels were increased in both groups. These abnormalities of acute risk factors, except for vWF, were transient and decreased to prequake levels by 4 to 6 months after the quake. CONCLUSIONS Earthquake-induced stress seems to induce transient increases in BP, blood viscosity determinants and fibrin turnover and to prolong endothelial cell stimulation. The potentiation of these acute risk factors might contribute to the occurrence of cardiovascular events just after a major earthquake in elderly subjects with hypertension.

Activation of Tissue Factor–Induced Coagulation and Endothelial Cell Dysfunction in Non–Insulin-Dependent Diabetic Patients With Microalbuminuria

We studied the relationships between albuminuria, tissue factor-induced coagulation, and endothelial cell dysfunction in 67 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were divided into three groups on the basis of their urinary albumin excretion rate (AER). To assess the early phase of tissue factor-induced coagulation, activated factor VII (FVIIa) levels in plasma were measured by a direct fluorogenic assay. As markers of endothelial cell dysfunction, levels of von Willebrand factor (vWF), tissue-type plasminogen activator-plasminogen activator inhibitor-1 (TPA-PAI-1) complex, PAI-1, and tissue factor pathway inhibitor (TFPI) were measured. FVIIa levels were increased in normoalbuminuric NIDDM patients (AER < 15 micrograms/min) when compared with normal control subjects. This FVIIa increase was accompanied by an increase in thrombin-antithrombin III complex (TAT) levels, indicating increased activation of coagulation even in normoalbuminuric patients. In NIDDM patients with microalbuminuria (AER = 15-200 micrograms/min), the FVIIa level, the FVIIa-FVII antigen (Ag) ratio (an indicator of activation of FVII zymogen to FVIIa), and the TAT level were further increased. This group also had higher levels of endothelial cell-derived factors (vWF, TPA-PAI-1 complex, and PAI-1) than the control group. The levels of endothelial cell-derived factors (including TFPI) were highest in the NIDDM patients with overt albuminuria (AER > 200 micrograms/min). In all 67 diabetic patients, AER showed a strong positive correlation with FVIIa (r = .574, P < .0001) and a weakly but still significant correlation with FVIIa-FVII:Ag (r = .365, P = .01), vWF (r = .315, P < .01), and TAT (r = .323, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Factor VII Hyperactivity and Endothelial Cell Damage Are Found in Elderly Hypertensives Only When Concomitant With Microalbuminuria

We studied the relationship among albuminuria, factor VII (FVII) hyperactivity, and endothelial cell damage in 6 elderly hypertensive subjects. The plasma levels of activated FVII (FVIIa), FVII coagulant activity, FVII antigen (FVIIag), von Willebrand factor (vWF), and thrombomodulin were measured to assess FVII hyperactivity and endothelial cell damage, and urinary albumin excretion rate (UAE) was calculated using 12-hour nighttime (7 pm to 7 am) urine collection (mean for 2 consecutive nights). We performed 24-hour ambulatory blood pressure monitoring in all 61 hypertensive patients and classified them into a white-coat hypertension group (n=12) and a sustained hypertension group (n=49). For the levels of FVII, vWF, and thrombomodulin, there were no differences between the white-coat hypertension group and normotensive control subjects (n=25). In the sustained hypertensive group, only the microalbuminuric subgroup (UAE, 15 to 300 microgram/min: n=30) showed significant elevation compared with the normotensive group for the level of FVIIa (mean [95% confidence interval]: 4.0 [3.6 to 4.4] versus 3.0 [2.6 to 3.3] ng/mL, P<.001), the FVIIa/FVIIag ratio (an indicator of activation of FVII zymogen to FVIIa) (1.33 [1.19 to 1.50] versus 1.04 [0.92 to 1.19], P<.01), the level of vWF (188 [165 to 214] % versus 144 [129 to 160] %, P<.01), and thrombomodulin (11.7 [10.3 to 13.3] versus 9.3 [8.5 to 10.3] ng/mL, P<.01). In contrast, none of these levels in the normoalbuminuric hypertensive group (UAE <15 microgram/min, n=19) differed from that in the normotensive control group. These results suggest that among elderly hypertensives, only those with microalbuminuria show enhancement of FVII activation and endothelial cell damage, while patients with white-coat hypertension and normoalbuminuric hypertensives do not show these accompanying abnormalities. Thus, increased levels of FVII activity and markers of endothelial cell damage might account for the higher risk of cardiovascular events in essential hypertension with microalbuminuria.

Antibody to Thrombin Receptor Inhibits Neointimal Smooth Muscle Cell Accumulation Without Causing Inhibition of Platelet Aggregation or Altering Hemostatic Parameters After Angioplasty in Rat

An antibody was raised in rabbits against SFFLRNPSEDTFEQF peptide, which is an NH2-terminal peptide of the thrombin-cleaved rat thrombin receptor. In vitro, the antibody inhibited rat smooth muscle cell proliferation but had no effect on rat platelet aggregation or clotting time. These data indicate that the antibody is a specific blocker of the thrombin receptor-signaling pathway in rat smooth muscle cells but does not work as a blocker in rat platelets, suggesting the existence of a second thrombin receptor in the platelets. Using an in vivo balloon catheter-induced injury model in rats, we examined the effect of the anti-rat thrombin receptor IgG on intimal smooth muscle cell accumulation 2 weeks after angioplasty. Analysis of the ratio of intimal to medial cross-sectional areas showed that injection of immune IgG resulted in 43.7% and 53.1% reduction (P<0.01) of neointimal smooth muscle cell accumulation compared with saline and nonimmune IgG treatment, respectively. Moreover, the injection of immune IgG caused a significant decrease of thrombin receptor mRNA expression and also 40.5% and 43.0% decreases (P<0.01) of the proliferating cell nuclear antigen (PCNA) index in the intima compared with the PCNA index after saline and nonimmune IgG treatment, respectively. The suppression of the PCNA index was also observed in the immune IgG-treated group at an early stage after angioplasty. These results suggest that thrombin receptor activation is involved in the proliferation and accumulation of neointimal smooth muscle cells induced by balloon injury.

Hyperinsulinemia and hemostatic abnormalities are associated with silent lacunar cerebral infarcts in elderly hypertensive subjects

OBJECTIVES We sought to study the association of the silent cerebral infarct (SCI), a predisposing condition of stroke, with hyperinsulinemia and hemostatic abnormalities in older hypertensive subjects. BACKGROUND Hypertension is a powerful risk factor for stroke. However, the role of other risk factors for stroke in hypertensive subjects remains incompletely understood. METHODS We performed brain magnetic resonance imaging and measured cardiovascular risk factors, by administering the 75-g oral glucose tolerance test and measuring plasma insulin and hemostatic variables, in 123 asymptomatic hypertensive subjects (mean age 69 years). RESULTS At least one SCI was detected in 80 subjects (65%), and multiple SCIs were found in 48 subjects (39%). The presence of SCIs was associated with older age, higher levels of 24-h systolic blood pressure, 2-h insulin, thrombin-generation markers (prothrombin fragment 1+2 and thrombin-antithrombin complexes), plasminogen activator inhibitor-1 (PAI-1), D-dimer and von Willebrand factor (vWF), but not with plasmin-alpha2-plasmin complex (PIC) levels. The 2-h insulin area under the curve (AUC) was positively correlated with PAI-1 and vWF levels (p < 0.01), and the PAI-1 level was negatively correlated with the PIC level (p < 0.02). Multiple logistic regression analysis revealed that age and the 2-h insulin AUC were significantly associated with SCIs, particularly those located in the subcortical white matter, and hemostatic abnormalities were significantly associated with the presence of multiple SCIs, particularly those located in the basal ganglia. CONCLUSIONS In older asymptomatic hypertensive subjects, hyperinsulinemia appears to be associated with lacunar-type SCIs, particularly those located in the subcortical white matter, and hemostatic abnormalities show an association with the presence of multiple SCIs, particularly those located in the basal ganglia.

Which factors affect high D-dimer levels in the elderly?

To study the age-related changes in plasma D-dimer levels and the effect of atherosclerotic disease and long-term immobilization on haemostasis the elderly, we measured plasma D-dimer levels in 148 subjects aged from 60 to 94 years using an ELISA. We also measured plasma fibrinogen, serum uric acid, total cholesterol, triglycerides, HDL cholesterol, beta-lipoprotein fractions, and apolipoproteins (A-I, A-II, B, E). Plasma D-dimer levels (326 +/- 148 ng/ml) were significantly higher in the healthy elderly subjects than in younger controls (180 +/- 58 ng/ml, p less than 0.01) and increased further with age (r = 0.344, p less than 0.01). D-dimer levels were significantly higher in elderly women than in elderly men (p less than 0.05). The D-dimer level correlated significantly with both the fibrinogen antigen level (r = 0.286, p less than 0.001) and the clotting activity (r = 0.275, p less than 0.01), and also correlated with apolipoprotein E levels. There were no correlations with the other parameters assessed. The D-dimer levels were significantly higher in the elderly subjects with atherosclerotic disease (516 +/- 285 ng/ml) than in healthy elderly subjects (p less than 0.001). Moreover, the levels were even higher in elderly subjects with long-term immobilization (866 +/- 408 ng/ml) than in subjects with atherosclerosis, even after age, sex and underlying diseases were taken into consideration. These results indicate that coagulation and fibrinolysis activity are increased in the elderly, especially those with atherosclerotic disease and that moreover long-term immobilization further accelerates their haemostatic hyperactivity.

Endothelial cell damage and angiotensin-converting enzyme insertion/deletion genotype in elderly hypertensive patients

OBJECTIVES The purpose of this study was to investigate the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotype and endothelial cell dysfunction or hypercoagulable state in elderly hypertensive patients. BACKGROUND Angiotensin-converting enzyme (ACE) insertion/ deletion (I/D) polymorphism was recently reported to be associated with various cardiovascular diseases. However, the precise mechanism of this association remains unknown, and some confounding factors might also affect the association. Endothelial cell dysfunction and coagulation activation play important roles in both the atherosclerotic process and the onset of cardiovascular events. METHODS We identified the ACE I/D genotype and measured the plasma levels of markers of endothelial cell damage (von Willebrand factor [vWF] and thrombomodulin) and of coagulation activation (prothrombin fragment F1 + 2 [F1 + 2]) in 318 asymptomatic elderly patients with hypertension, aged 59-93 years. RESULTS The vWF level was significantly higher in those with the DD genotype (n = 54) than in those with the II genotype (n = 131, p < 0.0001) or with the ID genotype (n = 133, p < 0.0001). The TM levels were also higher in patients with the ID genotype (p < 0.005) and the DD genotype (p < 0.01) than in those with the II genotype. There were no differences in F1 + 2 level among the groups. Positive correlations of systolic blood pressure with levels of both vWF and thrombomodulin were found predominantly in patients with the II genotype (both p < 0.001), but no correlation was noted in those with the DD genotype. CONCLUSIONS Considering the increased plasma levels of both endothelial cell-derived markers in the hypertensive patients with ACE DD genotype, we speculate that the ACE D allele is a risk factor for the development of hypertensive cardiovascular disease associated with endothelial cell damage.

Frequency of Anti-Heparin-PF4 Complex Antibodies (HIT Antibodies) in Uremic Patients on Chronic Intermittent Hemodialysis

The aim of this study was to determine the frequency of heparin/platelet factor (PF) 4 complex antibodies in 305 uremic patients treated with chronic intermittent hemodialysis using unfractionated heparin or low-molecular-weight heparin for 3 months. Heparin-induced thrombocytopenia (HIT) antibodies were detected by ELISA in 7 patients (2.3%) who had no history of HIT. Two patients abruptly developed HIT associated with the formation of clots in the extracorporeal circuit after they were found to be carrying HIT antibodies. These patients were suspected to have a similar trigger: an increased dose of recombinant human erythropoietin (rHuEPO). The drug might induce parallel changes in hematocrit (Ht) levels and platelet counts until the onset of HIT. After the onset of HIT, a parallel phenomenon between Ht and platelet counts was not found because of the thrombocytopenia due to HIT. Although HIT onset has been reported during the initial phase of dialysis sessions, there have been few reports on the onset of HIT in uremic patients on dialysis with long-term heparin anticoagulation. In this study, HIT was observed in 2 uremic patients on chronic dialysis with intermittent use of heparin. In some patients on chronic intermittent dialysis carrying HIT antibodies, HIT may occur following rHuEPO treatment. The presence of HIT should be borne in mind in chronic dialysis patients carrying HIT antibodies for 3 months or more.

Heparin cofactor II deficiency in the elderly : comparison with antithrombin III

We investigated heparin cofactor II (HC II) levels and their relationship to other haemostatic factors in the elderly in comparison with antithrombin III (AT III). We measured plasma HC II activity levels in 166 subjects aged from 61 to 99 years using a chromogenic method. HC II levels (94.4 +/- 18.5%) in the healthy elderly subjects were significantly (p less than 0.001) lower than in 40 healthy adult controls under 60 years of age (mean age: 51.5 years; 111.6 +/- 21.2%). HC II levels in the elderly subjects decreased further with age (r = 0.308, p less than 0.001) and the extent of the decrease was more marked than that for AT III (r = 0.179, p less than 0.05). There was no significant sex difference in HC II levels in the elderly. HC II levels correlated significantly with AT III levels and with acute phase reactants including sialic acid, fibrinogen, and PAI-1. HC II levels also correlated with factor VII, plasminogen, alpha 2-plasmin inhibitor, serum lipid, pseudocholinesterase, and albumin levels. These correlations were also found for AT III except active PAI-1 and tPA-PAI-1 complexes, but the correlations with acute phase reactants were stronger for HC II than AT III. We divided 154 elderly subjects into 4 groups by their pseudocholinesterase and albumin levels to estimate the effect of nutritional status on antithrombin activity in the elderly. HC II levels were normal in the elderly subjects with a good nutritional state (103 +/- 18%), but were significantly decreased in those with malnutrition (85 +/- 15%, p less than 0.001). AT III levels also showed the same tendency. These results indicate a decrease in the reserve capacity to inhibit thrombin generation at sites of atherosclerosis in response to trigger events. The deficiency of two major antithrombin factors in the elderly may indicate a tendency to thrombosis, especially in individuals with malnutrition. When considering the clinical significance of HC II, several other parameters, including age, nutritional status, hepatic synthetic ability, and the presence or absence of acute phase reaction should also be assessed.