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.

Silent and clinically overt stroke in older Japanese subjects with white-coat and sustained hypertension.

OBJECTIVES: We investigated whether white-coat hypertension is a risk factor for stroke in relation to silent cerebral infarct (SCI) in an older Japanese population. BACKGROUND: It remains uncertain whether white-coat hypertension in older subjects is a benign condition or is associated with an increased risk of stroke. METHODS: We studied the prognosis for stroke in 958 older Japanese subjects (147 normotensives [NT], 236 white-coat hypertensives [WCHT] and 575 sustained hypertensives [SHT]) in whom ambulatory blood pressure monitoring was performed in the absence of antihypertensive treatment. In 585 subjects (61%), we also assessed SCI using brain magnetic resonance imaging. RESULTS: Silent cerebral infarcts were found in 36% of NT (n = 70), 42% of WCHT (n = 154), and 53% of SHT (n = 361); multiple SCIs (the presence of > or =2 SCIs) were found in 24% of NT, 25% of WCHT and 39% of SHT. During a mean 42-month follow-up period, clinically overt strokes occurred in 62 subjects (NT: three [2.0%]; WCHT: five [2.1%]; SHT: 54 [9.4%]), with 14 fatal cases (NT: one [0.7%]; WCHT: 0 [0%]; SHT: 13 [2.3%]). A Cox regression analysis showed that age (p = 0.0001) and SHT (relative risk, [RR] [95% confidence interval, CI]: 4.3 [1.3-14.2], p = 0.018) were independent stroke predictors, whereas WCHT was not significant. When we added presence/absence of SCI at baseline into this model, the RR (95% CI) for SCI was 4.6 (2.0-10.5) (p = 0.003) and that of SHT was 5.5 (1.8-18.9) versus WCHT (p = 0.004) and 3.8 (0.88-16.7) versus NT (p = 0.07). CONCLUSIONS: In older subjects the incidence of stroke in WCHT is similar to that of NT and one-fourth the risk in SHT. Although SCI is a strong predictor of stroke, the difference in stroke prognosis between SHT and WCHT was independent of SCI. It is clinically important to distinguish WCHT from SHT even after assessment of target organ damage in the elderly.

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.

Malignant hyperthermia induced by general anesthesia for bone marrow harvesting.

We present a case of a bone marrow donor who developed rhabdomyolysis, acute renal failure and pulmonary edema following an apparently uneventful general anesthesia for bone marrow harvesting. Because malignant hyperthermia (MH) was suspected, he was treated with dantrolene, fluid loading, and continuous hemodiafiltration along with symptomatic supportive care. He made a full recovery and was discharged 3 weeks after harvest. Although the incidence of MH is low, marrow donation involves the risks of anesthesia as is seen in this case. Close monitoring is required to prevent life-threatening complications associated with the bone marrow harvesting procedure.

Different patterns of silent cerebral infarct in patients with coronary artery disease or hypertension.

The aim of the present study was to clarify the differences in the progression and the characteristics of silent cerebral infarcts (SCI) between patients with coronary artery disease (CAD) and hypertensive patients. Silent cerebral infarcts, a powerful prognostic indicator for stroke, are frequently found in patients with CAD and in hypertensives. However, the differences in the characteristics of SCI and related risk factors between CAD and hypertensive patients have not been thoroughly investigated. We evaluated the number of SCI and their distribution using brain magnetic resonance imaging (T1- and T2-weighted images) in 107 patients with CAD (validated by coronary angiography) and 101 hypertensive patients without history of clinical stroke. The prevalence of multiple SCI (three or more infarcts per person) in patients with CAD and with hypertension was significantly higher than in hypertensives without CAD (46% v 21%; P = .001), whereas that of patients with CAD without hypertension was intermediate (31%). The patients with multi- (two- or three-vessel) vessel diseases (VD) had a significantly higher prevalence of multiple SCI than the hypertensives and the no-stenosis or 1-VD group (68.1% in the 3-VD group, 52.0% in the 2-VD group, 26.8% in the 1-VD group, and 21.0% in the no-stenosis group). Multiple logistic regression analysis revealed that in the CAD group, the number of involved coronary arteries was an independent determinant of SCI (P < .005), whereas in the hypertensive group, age was an independent determinant of SCI (P < .005). When we investigated the distribution of SCI, in the CAD group, SCI in the deep perforator territory (the basal ganglia and the thalamus) were independently associated with the number of involved coronary arteries (P < .005), whereas SCI in the white matter were independently associated with age only (P < .005). In conclusion, SCI were more advanced in the patients with multivessel CAD than in the hypertensive patients, and were more common in patients with CAD and hypertension than in those without hypertension. Coronary atherosclerosis was independently and specifically associated with SCI located in the deep perferator territory but not of SCI located in the white matter. The CAD-atherosclerosis and hypertension may be independently involved in the pathologic process of SCI.

Silent cerebral infarcts in basal ganglia are advanced in congenital protein C-deficient heterozygotes with hypertension.

Congenital protein C deficiency is now widely recognized as a genetic risk for venous thrombosis. However, it remains uncertain whether this condition also confers risk for arterial thrombosis. We evaluated the association of congenital protein C deficiency with hypertension and silent cerebrovascular disease using brain magnetic resonance imaging (MRI) (T1- and T2-weighted and proton density images) in a large family pedigree of protein C deficiency diagnosed by gene analysis, compared with 46 non-pedigree related control subjects with normal protein C levels (> or = 75%) who were selected from among 55 asymptomatic hypertensive subjects matched for age and cardiovascular risk factors. Of the 58 living subjects in this pedigree, we measured plasma protein C levels in 45 subjects, and found 2 cerebral infarctions in the 24 heterozygotic subjects, whereas there was no stroke in the 21 normal homozygotic subjects. We performed brain MRI in 14 asymptomatic hypertensive subjects without any cardiovascular disease and in two patients with cerebral infarction, and found 28 cerebral infarcts (two corresponded to the patients' neurologic deficits and 26 were silent). All were lacunar infarcts < 10 cm in size. A total of 25 silent lacunar infarcts were found in nine heterozygotic subjects, whereas only one was found in the seven normal homozygotic subjects (2.8 v 0.14 lacunes per person, P = .002). No advanced white matter hyperintense lesions in T2-weighted images were found in either group. The prevalence of silent lacunar infarcts in the heterozygotic subjects was also significantly higher than that in normal control subjects (1.0 per person, P = .01). Concerning the distribution of silent infarcts, the number of lacunes located in the basal ganglia was higher in the heterozygotic subjects (2.3 per person, P < .001) than in the seven normal homozygotic subjects (0.14 per person) or in the control group (0.28 per person), whereas the number of lacunes in the white matter was not different among the groups. In conclusion, congenital protein C deficiency may accelerate the progression of silent cerebral infarct formation in hypertension, particularly in the basal ganglia, and may be a potential risk for stroke or vascularly induced dementia.

Is there any difference between intermediate-acting and long-acting calcium antagonists in diurnal blood pressure and autonomic nervous activity in hypertensive coronary artery disease patients?

Recently, there have been some reports indicating that calcium antagonists induce a reflex increase in sympathetic activity, triggering cardiac events, especially in coronary artery disease (CAD) patients. In this study, we assessed heart rate (HR) variability (HRV) using power spectral analysis of the 24-h RR interval in 25 hypertensive outpatients with CAD treated with nifedipine. We compared blood pressure (BP), HR, and HRV variation in the same patients substituting benidipine (long-acting) for nifedipine (intermediate-acting). There were no significant differences in 24-h, daytime, nighttime, and morning BP between the nifedipine phase and the benidipine phase. HRV parameters (LF: low frequency power, HF: high frequency power, LF/HF ratio) also showed no significant differences in 24-h, daytime, nighttime, and morning LF, HF, and LF/HF ratio between the nifedipine phase and the benidipine phase. Blood pressure, HR, and HRV parameters, except the LF component from 2 to 4 h after nifedipine administration (the most effective duration), showed no differences compared to before administration. The LF component after the nifedipine administration was lower than before administration. In conclusion, in hypertensive patients with CAD, whose BP levels were well-controlled by twice-daily use of intermediate-acting nifedipine, switching from nifedipine to a long-acting calcium antagonist, benidipine, maintained well-controlled BP levels to a similar degree, but it may not have additional benefit in sympatho-vagal balance.

Angiotensinogen and angiotensin-converting enzyme genotypes, and day and night blood pressures in elderly Japanese hypertensives.

There are inconsistent reports that the angiotensinogen (ATG) variant Met235-->Thr (T235) allele and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) variants are associated with hypertension and related target organ damage. Both high blood pressure (BP) and abnormal diurnal BP variation patterns are related to target organ damage, but it is not known whether the above genetic variants of the renin-angiotensin system are related to 24 h BP and the diurnal BP pattern in Japanese. We studied the association of the ATG T235 allele and ACE D allele with 24 h BP and diurnal BP variation in 235 of 262 consecutive untreated (or off medication) elderly Japanese hypertensives who underwent 24 h ambulatory BP monitoring. There was no significant association between the T235 or ACE D allele with office BP, but the T235 allele was significantly associated with 24 h BP and day BP, and the D allele was significantly associated with increased 24 h BP, day BP, and night BP. There were no effects of the T235 or D alleles on any BP parameters. Those with white-coat hypertension had a significantly lower T235 allele frequency (0.68) than those with sustained hypertension (0.79, p=0.010), but the difference in D allele frequency was marginal (0.30 vs. 0.38, p=0.057). In conclusion, in elderly Japanese hypertensive individuals, both the ATG T 235 and ACE D alleles are associated with increased 24 h BP and day BP, while only the ACE D allele is associated with increased night BP.

Species specificity of anticoagulant activity of activated human protein C: involvement of factor V as well as protein S.

Activated protein C (APC) possesses species specificity in its anticoagulant activity. Human APC exerts only weak activity in rat plasma compared with that in human plasma. The present study was undertaken to estimate the difference in interaction of human and rat factors with human APC and to assess the cause of the species specificity. Human or rat protein S (PS), factor V, or factor VIII was used to supplement human plasma depleted of each respective factor, and the anticoagulant activity of human APC was measured in term of the elongation of activated partial thromboplastin time (APTT). The activity of human APC in rat PS- or factor V-supplemented plasma was weaker than that in the human PS- or factor V-supplemented plasma. Furthermore, using purified human and rat factor V, human APC showed weaker inactivation of rat factor V than human factor V. Equal anticoagulant activity was observed in human or rat factor VIII-supplemented plasma. And there was a little difference in the interaction of APC with its inhibitors in human or rat plasma during a few minutes of incubation as judged by measurement of residual activity by an enzyme capture assay. From these results factor V as well as PS seems to play a major role in the species specificity of APC.

Lipid-lowering therapy corrects endothelial cell dysfunction in a short time but does not affect hypercoagulable state even after long-term use in hyperlipidemic patients.

Lipid-lowering therapy reduces cardiac events to an extent that is disproportionate to the small degree of regression of coronary atherosclerosis observed among hyperlipidemic patients. We prospectively investigated the effects of lipid reduction using simvastatin on the endothelial dysfunction and hypercoagulability found in hyperlipidemic patients. We measured levels of coagulation factors [factor VII (FVII) coagulant activity (FVIIc), FVII antigen (FVIIAg), activated FVII (FVIIa), and fibrinogen], and markers of coagulation activation [prothrombin fragment 1 + 2 (F1 + 2)] and endothelial cell dysfunction [von Willebrand factor (vWF)] in 20 hyperlipidemic patients, 20 hypertensive patients, and 20 normotensive normolipidemic controls. The levels of FVIIa, FVIIc, FVIIAg, F1 + 2, and vWF were all higher in hyperlipidemic patients, but only FVIIa, F1 + 2, and vWF levels were higher in hypertensive patients than in controls. We measured the above parameters in 13 hyperlipidemic patients before and after 1, 3, 6, 12 and 24 months of simvastatin therapy and compared these values with those in 15 hypertensive patients at baseline and after 12 and 24 months. The median (25th-75th percentile) level of total cholesterol was decreased from 259 (255-278) to 206 (176-220) mg/dl after 1 month of simvastatin therapy and this reduction persisted for 2 years. The plasma level of vWF [136% (113-158%)] was not changed after 1 month of administration of simvastatin [132% (115-153%)], but was decreased after 3 months of treatment [114% (96-128%), P<0.01]. This decrease also persisted for 2 years during simvastatin therapy and both of these reductions were significant, compared with levels in hypertensive patients. In contrast, levels of fibrinogen, FVIIc, FVIIAg, FVIIa, and F1 + 2 did not change throughout the 2 years of simvastatin therapy. We conclude that lipid reduction using simvastatin corrects endothelial cell dysfunction but not hypercoagulability in hyperlipidemic patients. The improvement in endothelial cell function brought about by lipid-lowering therapy might contribute to the reduction in cardiac events within a relatively short time period in hyperlipidemic patients.

Early morning surge in blood pressure.

Early-morning blood pressure is generally viewed as an important therapeutic target, for two reasons. First, for antihypertensive agents taken once daily in the morning, the timing of the trough plasma drug level, and thereby the lowest pharmacodynamic effect, often coincides with the early morning rise in blood pressure and heart rate. Evidence has been accumulated to suggest that blood pressure control throughout the 24 h period may be necessary to gain complete benefit from antihypertensive medication. In fact, in a longitudinal study, the regression of cardiac hypertrophy in patients with hypertension was more accurately predicted by treatment-induced changes in average 24 h ambulatory blood pressure than by clinic or home-monitored blood pressure readings. The other reason for the importance of morning blood pressure is that cardiovascular risk is heightened at this time of day. A morning surge in sympathetic activity alters haemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. At the same time as this risk of plaque rupture is greatest, circadian variations in haemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting the formation of intraluminal thrombi. We recently showed that, in older hypertensives, a greater morning blood pressure surge, mediated at least in part by an exaggerated alpha-sympathetic activity, is associated with more advanced silent cerebrovascular disease as well as a higher future incidence of stroke. The early morning surge in blood pressure could become a new therapeutic target for preventing target-organ damage and subsequent cardiovascular events in hypertension. Of greatest interest is the potential benefit of a chronotherapeutic approach, involving, for example, long-acting chronoformulations, which has not yet been extensively studied.

PK/PD and safety of a single dose of TMX-67 (febuxostat) in subjects with mild and moderate renal impairment.

A single oral dose of 20 mg febuxostat was administered to subjects with normal, mild or moderate impairment in renal function. There was less than a 2-fold difference in AUC of plasma unchanged febuxostat among the renal function groups, and changes in plasma urate levels from pre-dose levels were not significant. A total of five adverse events were reported with all mild in severity. The results indicate that renal impairment will have little clinical impact on the pharmacokinetics (PK), pharmacodynamics (PD) and safety of the study drug.

Pharmacokinetics and pharmacodynamics of febuxostat (TMX-67), a non-purine selective inhibitor of xanthine oxidase/xanthine dehydrogenase (NPSIXO) in patients with gout and/or hyperuricemia.

The diurnal change of sUA and the effect of febuxostat on this change were investigated in 10 patients with gout and/or hyperuricemia. The diurnal sUA change after the last dose during the 4-week treatment phase (20 mg, QD) was almost the same as the pre-treatment value. Considering the dose, the AUC(obs) and Cmax of unchanged drug in patients with gout and/or hyperuricemia were estimated to be similar to those of healthy male adults. The results show that a 6-week treatment with febuxostat is safe and well-tolerated in the target patient population for this drug.

[Determinants of endothelial cell damage in the elderly hypertension: assessment by plasma von Willebrand factor].

To investigate the determinants of endothelial cell damage in hypertensive elderly patients, we measured the plasma von Willebrand factor (vWF) levels by a recently developed enzyme-linked immunosorbent assay using monoclonal antibody for the functional epitope. Plasma vWF level was markedly increased in the elderly normotensive subjects (n = 42) than in younger normotensive subjects (n = 39) (127 vs 88%, p < .0001), and was further increased in elderly hypertensive subjects (n = 68) (148%, p < .05 vs elderly normotensives). The vWF level was positively correlated with body mass index in younger normotensive subjects (r = 0.41, p < .01), with systolic blood pressure (BP) in elderly normotensive subjects (r = 0.41, p < .01), and with age (r = 0.44, p < .001) and fibrinogen level (r = 0.37, p < .01) in elderly hypertensive subjects. In elderly hypertensive subjects (n = 150), vWF level had a stronger positive correlation with 24-hr systolic BP measured (r = 0.41, p < .0001) by ambulatory BP monitoring than with clinic systolic BP (r = 0.33, p < .0001). In conclusion, in hypertensive elderly patients, endothelial cell damage increases with systolic BP and fibrinogen levels, indicating a prethrombotic condition.

How many clinic BP readings are needed to predict cardiovascular events as accurately as ambulatory BP monitoring?

We tested the hypothesis that multiple clinic blood pressure (BP) readings over an extended baseline period would be as predictive as ambulatory BP (ABP) for cardiovascular disease (CVD). Clinic and ABP monitoring were performed in 457 hypertensive patients at baseline. Clinic BP was measured monthly and the means of the first 3, 5 and 10 clinic BP readings were taken as the multiple clinic BP readings. The subjects were followed up, and stroke, HARD CVD, and ALL CVD events were determined as outcomes. In multivariate Cox regression analyses, ambulatory systolic BP (SBP) best predicted three outcomes independently of baseline and multiple clinic SBP readings. The mean of 10 clinic SBP readings predicted stroke (hazards ratio (HR)=1.39, 95% confidence interval (CI)=1.02-1.90, P=0.04) and ALL CVD (HR=1.41, 95% CI=1.13-1.74, P=0.002) independently of baseline clinic SBP. Clinic SBPs by three and five readings were not associated with any CVD events, except that clinic SBP by three readings was associated with ALL CVD (P=0.015). Besides ABP values, the mean of the first 10 clinic SBP values was a significant predictor of stroke and ALL CVD events. It is important to take more than several clinic BP readings early after the baseline period for the risk stratification of future CVD events.