Tomikazu Fukuoka

Relationship between cardio-ankle vascular index (CAVI) and carotid atherosclerosis in patients with essential hypertension

Aortic stiffness measured by aorta-iliac or carotid-femoral pulse wave velocity (PWV) predicts all-cause and cardiovascular mortality. Brachial-ankle PWV (baPWV) has been developed as a more convenient assessment of arterial stiffness. However, the problem with clinical use of baPWV is that the index itself is closely dependent on blood pressure. Recently, a new method, termed the cardio-ankle vascular index (CAVI), has been proposed in Japan to overcome the disadvantages associated with measuring PWV. However, its clinical usefulness has not yet been fully clarified. In the present study, we compared the usefulness of CAVI with that of ultrasound for evaluating atherosclerosis in patients with essential hypertension. CAVI was measured in 70 hypertensive patients. The intima-media thickness (IMT), cross-sectional distensibility coefficient (CSDC), stiffness parameter β, and mean diastolic (Vd) and systolic (Vs) flow velocities were evaluated by carotid ultrasound. The Vd/Vs ratio, an index of peripheral arterial resistance, was also calculated. CAVI was positively correlated with IMT (r=0.360, p=0.0022) and stiffness β (r=0.270, p=0.0239) and negatively correlated with Vd/Vs (r=−0.471, p<0.0001) and CSDC (r=−0.315, p=0.0079). Stepwise regression analysis revealed that age (r=0.475, p<0.0001) and pulse pressure (r=0.492, r<0.0001) were independent determinants of CAVI. These results suggest that CAVI is a useful clinical marker for evaluating atherosclerosis and arteriolosclerosis in patients with essential hypertension.

Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with essential hypertension.

Chronic inflammation is common in hypertension and acts as an independent determinant of arterial blood pressure. Hypertensive patients are reported to have high circulating levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP). Recently, angiotensin II receptor blockers (ARBs) have been shown to possess benefits in addition to their ability to lower blood pressure, including anti-inflammatory and antioxidative properties within the vasculature. We evaluated the effects of the angiotensin II receptor blocker, valsartan, on these inflammatory cytokines. Thirty-nine patients with essential hypertension participated. These subjects received valsartan, 40 to 80 mg/day. Serum TNF-α, IL-6, CRP, and serum amyloid A (SAA) were measured before and after 3 months of treatment with valsartan. Valsartan significantly decreased systolic and diastolic blood pressure (160 ± 16/92 ± 11 mm Hg to 147 ± 21/84 ± 11 mm Hg, P = 0.001/P = 0.001, respectively). Serum TNF-α (9.1 ± 8.6 pg/mL to 6.1 ± 1.0 pg/mL, P = 0.006) and IL-6 (9.3 ± 1.7 pg/mL to 8.9 ± 1.4 pg/mL, P = 0.005) were significantly reduced after treatment with valsartan. However, C-reactive protein and serum amyloid A did not change. The angiotensin II receptor blocker, valsartan, may inhibit the development of atherosclerosis by lowering serum pro-inflammatory cytokines.

Postprandial Hypotension Is Associated With Asymptomatic Cerebrovascular Damage in Essential Hypertensive Patients

offelucidate the relationship between postprandial hypotension (PPH) and asymptomatic cerebrovascular damage, we evaluated changes in blood pressure after a meal by 24-hour blood pressure monitoring in 70 hospitalized essential hypertensive patients aged >/=50 years. They received a diet containing standard nutritional ingredients with 120 mmol (7 g) NaCl and were free from medication for at least 1 week. PPH was defined as the mean reduction of systolic blood pressure during 2 hours after a meal. Patients were divided into three groups according to mean values of PPH after 3 meals: PPH-1 (n=16, 5 mm Hg</=PPH<10 mm Hg), PPH-2 (n=18, PPH>/=10 mm Hg), and normal (n=36, PPH<5 mm Hg). As asymptomatic cerebrovascular damage, lacunae and leukoaraiosis were evaluated by magnetic resonance imaging. PPH did not correlate with daytime or nighttime blood pressure or the nondipper phenomenon; however, PPH was significantly related to asymptomatic cerebrovascular damage. The prevalence of lacunae in the normal, PPH-1, and PPH-2 groups was 44%, 69%, and 83%, respectively (chi2=8.22, P<0.05). The number of lacunae in the normal, PPH-1, and PPH-2 groups was 1.0+/-1.3, 1.3+/-1.2, and 1. 9+/-1.4, respectively (F[2,67]=3.2, P<0.05). The prevalence of advanced leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 44%, 50%, and 83%, respectively (chi2=7.63, P<0.05). Severity score of leukoaraiosis in the normal, PPH-1, and PPH-2 groups was 1.5+/-0. 7, 1.7+/-0.8, and 2.1+/-0.7, respectively (F[2,67]=4.3, P<0.05). These findings indicate that elderly hypertensive patients with marked PPH should be considered to have advanced cerebrovascular damage even in the absence of abnormal neurological findings.

Relation of left ventricular hypertrophy and geometry to asymptomatic cerebrovascular damage in essential hypertension

Increased left ventricular (LV) mass and abnormal geometry have a powerful prognostic value for cardiovascular morbidity and mortality including stroke. However, there have been no studies on the association between LV hypertrophy and preclinical brain damage in essential hypertensive patients. In the present study, we investigated the relation between LV hypertrophy and asymptomatic cerebrovascular damage identified by magnetic resonance imaging in 150 essential hypertensive patients, with an emphasis on LV geometry. Patients were divided into the following 4 groups according to their LV mass index and relative wall thickness; normal ventricular geometry (n = 50), concentric remodeling (n = 22), eccentric hypertrophy (n = 44), and concentric LV hypertrophy (n = 34). Lacunar lesions and leukoaraiosis were evaluated. The prevalence of lacunae was significantly higher in patients with LV remodeling than in patients with normal LV (chi-square 19.6, p = 0.0002). The number of lacunae was significantly higher in patients with LV hypertrophy than in patients with normal LV or concentric remodeling (F [3,146] = 8.03, p<0.0001). The severity of leukoaraiosis was also significantly greater in patients with LV hypertrophy than in patients with a normal left ventricle (chi-square 14.5, p = 0.02). Stepwise regression analysis confirmed that LV mass index and relative wall thickness, in addition to age and systolic blood pressure, were independent predictors for asymptomatic cerebrovascular damage, even in the absence of neurologic abnormalities. In hypertensive patients, LV hypertrophy, and especially concentric LV hypertrophy, provides important prognostic information on the presence of pre-clinical brain damage.

Osteopontin and carotid atherosclerosis in patients with essential hypertension

OPN (osteopontin), a pro-inflammatory cytokine, has recently emerged as a key factor in both vascular remodelling and the development of atherosclerosis. However, the relationship between OPN and atherosclerosis in patients without symptomatic cardiovascular disease is not clear. Therefore we measured plasma OPN levels and evaluated the correlation between plasma OPN levels and atherosclerosis as target organ damage in patients with EHT (essential hypertension). Plasma OPN levels were measured in 76 patients with EHT using a solid-phase sandwich ELISA. IMT (intima-media thickness), and V(d) and V(s) (mean diastolic and systolic flow velocities respectively) were evaluated by carotid ultrasound. The V(d)/V(s) ratio, an index of peripheral arterial resistance, was also calculated. The patients were divided on the basis of median OPN levels into a high-OPN group and a low-OPN group. The mean IMT and aldosterone levels were higher (P=0.024 and 0.031 respectively) and V(d)/V(s) was lower (P=0.007) in the high-OPN group than in the low-OPN group. Plasma OPN levels were positively correlated with mean IMT (r=0.308, P=0.0068) and negatively with V(d)/V(s) (r=-0.293, P=0.010). Stepwise regression analysis revealed that OPN was an independent determinant of mean IMT (P=0.007) and V(d)/V(s) (P=0.009), and aldosterone was an independent determinant of OPN. These results suggest that OPN plays a role in the development of atherosclerosis and may be a potential clinical marker for the prediction of atherosclerosis in patients with EHT.

Transcriptional Regulation of the Platelet-derived Growth Factor α Receptor Gene via CCAAT/Enhancer-binding Protein-δ in Vascular Smooth Muscle Cells

Inflammatory cytokines stimulate the proliferation of vascular smooth muscle cells (VSMC) and play a pivotal role in the pathogenesis of vascular diseases including atherosclerosis and restenosis. Mitogenic response of interleukin-1β (IL-1β) on VSMC is thought to be mediated by induction of endogenous platelet-derived growth factor (PDGF), especially PDGF-AA. Although the action of PDGF-AA is mediated by its specific receptor, PDGFα-receptor (PDGFαR), very little is known about the regulatory mechanism of PDGFαR gene expression in VSMC. To understand the mechanism, we studied the transcriptional control of the PDGFαR gene in VSMC after treatment with IL-1β. IL-1β (10 ng/ml) drastically increased both PDGFαR and CCAAT/enhancer-binding protein δ (C/EBPδ) mRNA levels in a time dependent manner. A rapid induction of C/EBPδ mRNA within 30 min was followed by slower emergence of PDGFαR mRNA, which reached the maximum level in 12 h, whereas C/EBPδ mRNA was detectable at 30 min and reached the maximum level at 3 h. Electromobility shift and supershift assays revealed that IL-1β markedly increased DNA-protein complex, which was mainly composed of C/EBPβ and/or -δ. Both Western blotting and immunohistochemistry demonstrated that either C/EBPβ or -δ expression was induced by IL-1β exclusively in nuclei of VSMC. On the other hand, overexpression of C/EBPδ specifically transactivated the promoter activity of the PDGFαR gene and significantly enhanced VSMC proliferation in PDGF-treated cells. We conclude that induction of PDGFαR expression is mainly mediated by C/EBPδ expression in VSMC, and a high level of C/EBPδ expression may be involved in the pathogenesis of atherosclerosis and restenosis.

Valsartan reduces serum cystatin C and the renal vascular resistance in patients with essential hypertension.

A high level of albuminuria and increased renal vascular resistance are associated with hypertensive renal damage. In this study, the authors investigated the effect of the angiotensin II receptor blocker, valsartan, on renal function and intrarenal hemodynamics in non-diabetic patients with essential hypertension. A prospective three-month study of the effects of valsartan, 40–80 mg/day, was performed in 30 hypertensive patients. As an assessment of renal function, serum creatinine, urine albumin/creatinine (Alb/Cr) ratio, and serum cystatin C levels were evaluated. Doppler ultrasonography of the kidney was performed for the evaluation of renal hemodynamics. Peak-systolic, end-diastolic, and mean velocities of interlobar arteries were evaluated, and the pulsatility index (PI) and resistive index (RI) were calculated. It was determined that patients with microalbuminuria had higher levels of serum cystatin C, PI, and RI compared to patients without microalbuminuria. Valsartan treatment significantly reduced systolic and diastolic blood pressure and decreased the Alb/Cr ratio. Serum creatinine was not changed, whereas serum cystatin C levels were significantly reduced. Valsartan treatment significantly decreased the PI in all patients and both PI and RI in patients with microalbuminuria. These results suggest that the angiotensin II receptor blocker, valsartan, is able to improve renal function by reducing renal vascular resistance in hypertensive patients, especially in patients with microalbuminuria, and may prevent future renal failure in patients with essential hypertension.

Osteopontin in Rat Renal Fibroblasts: Functional Properties and Transcriptional Regulation by Aldosterone

Osteopontin (OPN), a proinflammatory cytokine, plays an important role in renal fibrosis. We reported that plasma OPN levels were higher in patients with primary aldosteronism than with essential hypertension. However, the regulatory mechanism of OPN by aldosterone remains unclear. Here, we report the transcriptional regulation of OPN expression by aldosterone and the functional effects of aldosterone-mediated OPN transcription in renal fibroblasts. Aldosterone induced OPN expression in a dose-dependent manner with significant responses at 10 nmol/L (1.6±0.2-fold of controls, P<0.05, n=5) and elicited maximal effects at 10 &mgr;mol/L (3.5±0.4-fold of controls, P<0.01, n=5). Aldosterone increased OPN expression in a time-dependent manner with a maximal effect after 48 hours (2.7±0.3-fold of controls, P<0.01, n=5). This effect was abolished by the mineralocorticoid receptor (MR) antagonist spironolactone. Luciferase promoter deletion assays identified a novel cis regulatory element (−2153 to −1758) in the OPN promoter that is responsive to aldosterone. This element contains an activator protein-1 (AP-1) and nuclear factor kappa B (NF&kgr;B) site. Electrophoretic mobility shift assays, supershift assays, and chromatin immunoprecipitation assays identified both AP-1 and NF&kgr;B as the DNA binding proteins induced by aldosterone with spironolactone inhibiting aldosterone-induced AP-1 or NF&kgr;B activity. OPN-siRNA inhibited completely the induction of cell proliferation, type I, III, and IV collagen synthesis by aldosterone. These results indicate that aldosterone induced MR-mediated OPN expression through AP-1 and NF&kgr;B activation and suggest that aldosterone plays an important role in renal fibrosis through the induction of OPN.

Platelet-derived growth factor induces apoptosis in vascular smooth muscle cells: roles of the Bcl-2 family

Apoptosis (programmed cell death) is observed in vascular smooth muscle cells (VSMC) in atherosclerotic lesions and stenotic lesions after injury, and modulates the cellularity of these lesions. It is recognized that cell growth and apoptosis are two linked processes. Platelet-derived growth factor (PDGF) induces VSMC proliferation and migration in vitro. We studied the effect of PDGF on apoptosis in VSMC. Cultured rat VSMC were treated with PDGF-AA or PDGF-BB. PDGF-BB induced cell death in cultured VSMC in a time- and dose-dependent manner, but PDGF-AA did not. Gel electrophoresis of genomic DNA and in situ DNA labeling confirmed that the cell death induced by PDGF-BB is apoptosis. PDGF-BB treatment reduced bcl-2 mRNA and bcl-xl mRNA expression, in contrast, induced bcl-xs mRNA expression, linked with the induction of apoptosis in cultured VSMC.

Autonomic Nervous Function in Essential Hypertension in the Elderly: Evaluation by Power Spectral Analysis of Heart Rate Variability

Autonomic nervous function in elderly essential hypertensive patients was investigated by power spectral analysis of heart rate variability. Fifty-seven essential hypertensive patients participated in this study. They were divided into two groups: the middle-aged group (age < or = 59 years, n = 30) and the elderly group (age > or = 60 years, n = 27). All examinations were performed during hospitalization. Power spectral analysis of R-R interval was performed from Holter electrocardiogram every 10 min by the maximum entropy method to obtain the low frequency band (LFB; 0.04 to 0.15 Hz), which is an index of both sympathetic and parasympathetic nervous activity. Twenty-four-hour blood pressure measurement was performed by the cuffoscillometric method to evaluate the nocturnal decrease in blood pressure. Nondipper patients were defined as those whose nocturnal decrease in systolic blood pressure was < 10% of daytime blood pressure. Both LFB and HFB were significantly lower in elderly hypertensive patients than in middle-aged patients (P < .001 and P < .05, respectively). Elderly nondipper patients had further reduced power spectral densities throughout the day. Both LFB and HFB showed a negative correlation with age. However, the age-related decline of power densities was more prominent in dipper patients and was not statistically significant in nondipper patients. These findings indicate that the nondipper phenomenon is superimposed on age-related attenuation of autonomic nervous function in essential hypertension.