Arterial-cardiac destiffening following long-term antihypertensive treatment.

BACKGROUND: We examined whether in addition to producing a greater degree of improvement of the arterial stiffness, long-term angiotensin II receptor blocker (ARB) treatment might also have a more beneficial effect on the cardiac diastolic dysfunction than long-term calcium-channel blocker (CCB) treatment; we also evaluated the association between the improvements of the two variables brought about by ARB treatment in subjects with stage I or II hypertension. METHODS: One hundred and thirteen patients were randomly allocated to treatment with an ARB (candesartan) or a CCB (amlodipine). Echocardiography and measurement of the brachial-ankle pulse wave velocity (PWV) were conducted in both groups at the start of the treatment and at the end of 2-3-years' treatment. RESULTS: After adjustments for covariates, the extent of reduction of the brachial-ankle PWV (-200 ± 18 cm/s vs. -141 ± 18 cm/s, P = 0.03) and that of the increase of the E/A ratio (0.08 ± 0.03 vs. 0.01 ± 0.03, P = 0.04) were significantly greater in the candesartan group than in the amlodipine group. A significant relationship was identified between the delta changes of the brachial-ankle PWV and delta changes of the E/A ratio observed following long-term candesartan treatment. CONCLUSION: Long-term candesartan treatment may have a more beneficial effect on the stiffness of the large- to- middle-sized arteries than long-term amlodipine treatment, and this treatment may also concomitantly improve the cardiac diastolic dysfunction; a significant association appeared to exist between the improvements of the two variables observed following long-term candesartan treatment.

Relationships among the serum omega fatty acid levels, serum C-reactive protein levels and arterial stiffness/wave reflection in Japanese men.

OBJECTIVE: We examined the relationship among the serum omega-3 and omega-6 fatty acid (O3FA and O6FA) levels, serum C-reactive protein (CRP) levels, and arterial stiffness/wave reflection (AS/WR) in healthy Japanese men. METHODS: In 2206 Japanese healthy men, parameters related to the AS/WR (i.e., brachial-ankle pulse wave velocity and radial arterial pulse wave analysis) were measured. RESULTS: No significant inverse relationships were observed between the serum O3FA levels and the AS/WR-related parameters. Adjusted values of the AS/WR-related parameters and serum CRP levels were higher in the subjects with serum O6FA levels in the highest tertile than in those with serum O6FA levels in the lowest tertile. CONCLUSIONS: In healthy Japanese men with known high dietary intakes of O3FAs, the serum O3FA levels may not reflect the pathophysiological abnormalities related to AS/WR. Increased serum O6FA levels appeared to be independently associated with the unfavorable conditions related to AS/WR and inflammation.

Effects of Moderate-to-Severe Impairment of the Estimated Glomerular Filtration Rate and of Proteinuria on the Central Hemodynamics and Arterial Stiffness in Middle-Aged Healthy Japanese Men.

We evaluated the effects of moderate-to-severe impairment of the estimated glomerular filtration rate (eGFR: 15 to 59 mL/min per 1.73 m(2)) and of proteinuria on the central hemodynamics and the pulse wave velocity (PWV) in 2244 middle-aged healthy Japanese men who were not receiving any medications for cardiovascular diseases or cardiovascular risk factors. The adjusted value of the radial augmentation index was higher in the subjects with proteinuria than in those without proteinuria. On the other hand, this value was similar between the subjects with and without moderate-to-severe impairment of the eGFR. Not only proteinuria but also moderate-to-severe impairment of the eGFR was associated with increase in the adjusted value of the brachial-ankle PWV. Thus, proteinuria was found to be an independent risk factor for abnormal central hemodynamics and increased stiffness of the large- to middle-sized arteries, while moderate-to-severe impairment of the eGFR was associated with an increase of the arterial stiffness, but not with abnormality of the central hemodynamics.

Arterial stiffness and declines in individuals with normal renal function/early chronic kidney disease.

OBJECTIVE: We evaluated the temporal association between arterial stiffening and the early stage of renal functional decline. METHODS: In 2053 Japanese employees with an estimated glomerular filtration rate (GFR) of > or = 60 ml/min/1.73 m(2) plus no proteinuria (40+/-8 years old) at the start, brachial-ankle pulse wave velocity (baPWV) and serum C-reactive protein (CRP) were measured before and after a 5-6-year follow-up period. RESULTS: After adjusting for confounding variables including serum CRP levels, higher baseline baPWV was associated with lower follow-up GFR (value expressed as per doubling: -16; 95% confidence interval: -24 to -9; P<0.01) and with higher annual rate of decline in GFR (value expressed as per doubling: -3; 95% confidence interval: -4 to -2; P<0.01). Every m/s higher baPWV was associated with a 36% increased odds (95% CI 1.09-1.70; P<0.01) for a development of a GFR <60 ml/min/1.73 m(2) at follow-up. In contrast, baseline GFR was not associated with follow-up baPWV (P=0.08) or the annual rate of change in baPWV (P=0.11). CONCLUSION: In a Japanese occupational cohort with normal renal function/early chronic kidney disease, elevated arterial stiffness was an independent risk factor for the decline in renal function. CRP did not appear to exert any significant influence on this association.

Continuous smoking and progression of arterial stiffening: a prospective study.

OBJECTIVES: We prospectively and longitudinally determined the effects of smoking on the progression of arterial stiffening as well as the involvement of inflammation in this process. BACKGROUND: Smoking is an important avoidable risk factor for cardiovascular disease, and arterial stiffness might be involved in the pathophysiology. No prospective study has examined the effect of continuous smoking on the age-associated progression of arterial stiffening. METHODS: In 2,054 Japanese subjects (40 +/- 8 years of age), brachial-ankle pulse wave velocity (baPWV) and serum C-reactive protein (CRP) levels were measured at the baseline and the end of a 5- to 6-year follow-up period. RESULTS: The annual rate of change of the baPWV during the study period was significantly greater in the continuous heavy smokers (11.0 +/- 1.9 cm/s/year, n = 181) than in the never-smokers (5.5 +/- 0.6 cm/s/year, n = 1,018). This difference remained significant even after adjustments for covariates, including age (p < 0.05). In continuous smokers (n = 493), the mean number of cigarettes smoked/day during the study period showed a significant relationship with the changes in baPWV. No significant relationship was found between the change in baPWV and serum CRP levels. CONCLUSIONS: Continuous smoking might accelerate the age-associated progression of structural stiffening of the large- to middle-size arteries. We also found a dose-response relationship between cigarette consumption and accelerated arterial stiffening. However, we failed to confirm any significant association between the rate of arterial stiffening and the serum CRP levels in the smokers.

Association of serum cystatin C with pulse wave velocity, but not pressure wave reflection, in subjects with normal renal function or mild chronic kidney disease.

BACKGROUND: This prospective cross-sectional study was conducted to clarify whether serum cystatin C levels might be associated with not only arterial stiffness, but also the pressure wave reflection, in middle-aged Japanese subjects with normal renal function or mild chronic kidney disease (CKD) (stage 1 or 2 CKD) (i.e., creatinine-based estimate of the glomerular filtration rate (eGFRcr) > or =60 ml/min/1.73 m(2) plus a result of the urine dipstick test for proteinuria of <1+). METHODS: In 2,904 Japanese subjects (45 +/- 9 years old), the brachial-ankle pulse wave velocity (baPWV), radial augmentation index adjusted to a heart rate of 75 beats/min (rAI75), and serum cystatin C levels were measured. RESULTS: Multivariate linear regression analysis demonstrated that the serum cystatin C levels were significantly correlated with the baPWV (standardized coefficient = 0.04, P < 0.01) even after adjustments for confounding variables, but not with the AI75 (standardized coefficient = 0.01, P = 0.71). adjusted values of the baPWV, but not those of rAI75, were higher in subjects with serum cystatin C levels in the highest tertile than in those with serum cystatin levels in the intermediate or lowest tertile. CONCLUSION: In middle-aged Japanese subjects with normal renal function or mild CKD (stage 1 or 2 CKD) (eGFRcr >60 ml/min/1.73 m(2) plus a result of the urine dipstick test for proteinuria of <1+), the serum cystatin C levels may reflect facet of cardiovascular risk associated with arterial stiffness, but not that associated with the pressure wave reflection.

Relationship of insulin resistance to macro- and microvasculature reactivity in hypertension.

BACKGROUND: Although insulin resistance (IR) is thought to be related to vascular dysfunction, the difference in the relationship of IR to microvasculature and macrovasculature reactivity has not yet been clarified. The present study was conducted to clarify whether the IR is more closely related to the macrovasculature reactivity (flow-mediated vasodilatation of the brachial artery induced by reactive hyperemia: FMD) or microvasculature reactivity (skin reactive hyperemia as assessed by laser Doppler flowmetry: SRH) in patients with hypertension. METHODS: In 75 consecutive hypertensive patients (61 +/- 11 years of age) without obvious cardiovascular (CV) disease and/or risk factors for CV disease other than hypertension, FMD, SRH, and homeostasis model assessment index of IR (HOMA(IR)) were measured. RESULTS: No significant relationship was observed between FMD with the parameters of SRH. In the univariate linear regression analysis, HOMA(IR) showed a significant correlation with the FMD (R(2) = 0.05, P < 0.05), but not with the parameters of SRH. Multivariate linear regression analysis demonstrated a significant association between HOMA(IR) and FMD, even after adjustments for covariates, including the use of medication for hypertension. (R(2) = 0.32, beta = -0.29, P = 0.02). CONCLUSIONS: The complication of IR in hypertensive patients without obvious CV disease/risk factors may be related to impaired macrovasculature rather than microvasculature reactivity, apart from the influence of antihypertensive medication on the reactivity of the vasculature and insulin sensitivity.

Synergistic relationship between changes in the pulse wave velocity and changes in the heart rate in middle-aged Japanese adults: a prospective study.

OBJECTIVES: Temporal associations between rates of increases in pulse wave velocity (PWV), a marker of arterial stiffness, and heart rate (HR) indices (baseline HR and changes in HR) as well as inflammatory markers were examined. METHODS: In 1795 apparently healthy Japanese individuals (mean age 39 +/- 8 years old), brachial-ankle PWV (baPWV) and serum C-reactive protein (CRP) levels were measured at the baseline and at the end of a 5-6-year follow-up period. RESULTS: Heart rate at the baseline examination and changes in HR during the follow-up period were significantly associated with the corresponding changes in baPWV during the study period (nonstandardized co-efficient = 0.14, 95% confidential interval = 8.14 x 10-0.19, P < 0.01) even after the adjustment for atherogenic risk factors. When individuals were divided into four groups categorized by baseline HR (higher or lower than median HR) and increase/decrease in HR during the study period, serum CRP levels and atherogenic risk factors were significantly worse in the individuals with high baseline HR accompanied by increased HR during the study period. There was no significant relationship between the changes in the baPWV and the changes in the serum CRP levels. Even after the adjustment for confounding factors, changes in baPWV were significantly higher in this group than the other three groups (P < 0.01). CONCLUSIONS: The study results suggest a synergistic role of high baseline HR and increase in HR during the study period in accelerating age-associated increases in PWV. Inflammation might not be a major factor for this relationship.

Predictors of progression from prehypertension to hypertension in Japanese men.

BACKGROUND: This 3-year prospective study in middle-aged Japanese men with prehypertension examined the usefulness of the plasma levels of C-reactive protein (CRP) and the brachial-ankle pulse wave velocity (baPWV) as predictors of the development to hypertension as compared with other previously proposed markers, such as the age, initial blood pressure, heart rate, obesity, smoking, and alcohol intake. METHODS AND RESULTS: Among 777 men with prehypertension (42 +/- 8 years old), hypertension developed in 58 men during the observation period. Significant elevation of blood pressure during this 3-year follow-up was not observed in some, but not all, subjects. Univariate linear regression analysis demonstrated that baPWV, body mass index (BMI), age, and alcohol intake, but not plasma levels of CRP, heart rate, and smoking, on the first examination were significant variables related to the changes in systolic blood pressure from the first examination to the second examination. Multivariate linear regression analysis confirmed that baPWV and BMI were weak but significant independent variables related to the changes in systolic blood pressure (R(2) = 0.03). The logistic regression analysis demonstrated that baPWV >13.5 m/s (adjusted odds ratio = 3.32 (1.79-6.15)) and BMI >25.0 (adjusted odds ratio = 2.27 (1.25 - 4.13)) were significant predictors of future hypertension independent of blood pressure on the first examination. CONCLUSION: This 3-year prospective study suggested that the baPWV and BMI, but not plasma CRP levels, are not powerful but significant independent markers to identify middle-aged Japanese men with prehypertension at high risk for hypertension.

Association of blood pressure levels with the effects of alcohol intake on the vasculature in Japanese men.

The association of blood pressure levels with the effects of alcohol intake on the vasculature has not been clarified. We evaluated the differential effects of alcohol intake on the vasculature of subjects with optimal or normal blood pressure (ONbp) and those with high normal blood pressure or higher (HNHbp) in a 6-year follow-up study. The pulse wave velocity (PWV) was measured on three occasions at an interval of 3 years in 1185 middle-aged Japanese men (age 41+/-8 years). In subjects with ONbp (n=677), a U-shaped relationship between alcohol intake (non-drinker, and light-to-moderate and heavy alcohol intake groups) and the increase in the adjusted value of PWV was observed at the end of 6 years' observation. On the other hand, in subjects with HNHbp (n=508), a U-shaped relationship was not observed. At the end of 6 years' observation, the increase in PWV was significantly more in the heavy intake group than in the light-to-moderate intake group or the non-drinker group, even after adjustment for changes in blood pressure and prescribed medication (P<0.01). In conclusion, blood pressure levels may modulate the effects of alcohol intake on the vasculature in middle-aged Japanese subjects. In subjects with ONbp, light-to-moderate alcohol intake appeared to have a possible vasculoprotective effect; on the other hand, in subjects with NHNbp, heavy alcohol intake seemed to exert a detrimental effect on the vasculature.

Concomitant existence and interaction of cardiovascular abnormalities in obstructive sleep apnea subjects with normal clinic blood pressure.

This study was conducted to examine the existence of increased arterial stiffness of the central to middle-sized arteries and left ventricular (LV) structural/functional abnormalities in subjects with obstructive sleep apnea (OSA) who had normal clinic blood pressure. Brachial-ankle pulse wave velocity (baPWV) measurement and echocardiography were conducted in 164 consecutive subjects with normal clinic blood pressure evaluated for sleep disorders. Multivariate linear regression analysis showed that the apnea-hypopnea index (AHI) was an independently associated variable, even after adjustments for age, gender and risk factors for cardiovascular disease, with baPWV (R(2)=0.39, beta=0.19, P<0.01) and the E/A ratio (R(2)=0.51, beta=-0.27, P<0.01). The baPWV and LV relative wall thickness at diastole (RWTd) were significantly higher (P<0.05), and the E/A ratio was significantly lower (P<0.05), in subjects with severe OSA (AHI> or =30 episodes per hour) than in non-OSA subjects (AHI<5 episodes per hour). The analysis also showed that the baPWV bore a significant independent relationship to the RWTd (beta=0.19, P=0.02) and E/A ratio (beta=-0.12, P=0.04) adjusted for the risk factors for cardiovascular disease, the presence of metabolic syndrome and the severity of OSA. Thus, in this study, we showed the existence of increased arterial stiffness of the central to middle-sized arteries and LV structural/functional abnormalities in severe OSA patients, even in subjects with normal clinic blood pressure, suggesting the possible existence of a direct association between OSA and cardiovascular abnormalities.

The relationships of cardiovascular disease risk factors to flow-mediated dilatation in Japanese subjects free of cardiovascular disease.

We examined the relationship of several cardiovascular disease (CVD) risk factors to flow-mediated vasodilatation of the brachial artery (FMD) and the clustering effect of risk factors on FMD in Japanese subjects free of CVD. In 819 Japanese subjects free of CVD (age 45+/-10 years, 611 men and 208 women), FMD correlated significantly with the Framingham risk points score (FRS) (r=-0.27, p<0.01). FMD was higher in subjects in the 1st tertile of the FRS range than in patients in either the 2nd or 3rd tertiles of the FRS range, but it was similar between the subjects in the 2nd and 3rd tertiles. FMD was found to have a significant independent negative correlation with age (beta=-0.19, p<0.01), gender (beta=-0.024, p<0.01) and smoking habit (beta=-0.08, p=0.02). In subjects >or=50 years of age, the FMD in men with one CVD risk factor, excluding smoking, was similar to that in men with no CVD risk factors. CVD risk factors did not attenuate FMD in women. Thus, in Japanese subjects free of CVD, FMD may be a useful marker of CVD risk, but it may not be a robust marker for endothelial damage related to clusters of CVD risk factors. Age, gender and smoking were independent variables related to the impairment of FMD, which therefore appears to be less applicable in subjects aged 50 or more, and especially in women. (Hypertens Res 2008; 31: 2019-2025).

Overweight body mass index classification modifies arterial stiffening associated with weight gain in healthy middle-aged Japanese men.

The present study was conducted to clarify whether body mass index (BMI [kg/m(2)]) classifications (i.e., without excess weight, overweight, and obese) modify the rate of progression of arterial stiffening, a cardiovascular risk factor associated with weight gain. A 3-year observational study was conducted in 2,080 healthy middle-aged Japanese men (aged 42+/-10 years). Brachial-ankle pulse wave velocity (baPWV) was measured at the beginning and end of the study period. In overweight subjects (30>BMI>or=25), the estimated annual rate of increase of baPWV (ARbaPWV) in subjects with weight gain (>or=5% weight gain; ARbaPWV, 21.8+/-4.4 cm/s/year) was significantly higher than in those without weight gain (<5% weight gain; ARbaPWV, 12.5+/-1.6 cm/s/year), after adjustments for changes in blood pressure and other variables (p<0.05). This change was not observed in subjects without excess weight (BMI<25) or in obese subjects (BMI>or=30). The increase in the ARbaPWV associated with weight gain in the overweight group was also higher than that in the without excess body weight or obese groups. Our study revealed that the BMI classifications modified the annual rate of increase in arterial stiffening associated with weight gain. Weight gain seemed to accelerate arterial stiffening in overweight subjects, but not in subjects without excess weight. The weight gain in overweight subjects seemed to worsen the cardiovascular risk related to arterial stiffness in middle-aged healthy Japanese men. Thus, the prevention of weight gain should be emphasized in overweight subjects.

Effects of azelnidipine on the autonomic functions and its influence on arterial stiffness and endothelial functions.

BACKGROUND: The present study was conducted to clarify whether azelnidipine might have beneficial effects on autonomic functions, and whether such beneficial effects might affect the vascular functions (i.e., arterial stiffness and endothelial function). METHODS AND RESULTS: This study with a cross-over design was conducted in 21 hypertensive patients (65 +/- 9 years old) being treated with calcium channel blockers (CCBs) other than azelnidipine or benidipine (i.e., during the study period, the CCB was switched to either azelnidipine 16 mg/day or benidipine 4 mg/day, administered alternately for 8 weeks each). Blood examinations were conducted and the heart rate variability, baro-receptor sensitivity (BRS), brachial-ankle pulse wave velocity (baPWV) and flow-mediated vasodilatation (FMD) in the brachial artery were measured after treatment with each of the two drugs. While the blood pressure levels decreased to a similar degree after both treatments, the BRS (8.8 +/- 5.5 ms/mmHg vs. 6.4 +/- 2.9 ms/mmHg, p < 0.01) and high-frequency power component (HF: 139 +/- 152 ms2/Hz vs. 88 +/- 97 ms2/Hz) were higher after treatment with azelnidipine than after treatment with benidipine (p < 0.05). However, the baPWV, FMD and plasma levels of malonyldialdehyde low-density lipoprotein cholesterol and nitric oxides were similar after treatment with both drugs. CONCLUSION: Azelnidipine has greater beneficial effects on the autonomic functions than benidipine although the degree of reduction of blood pressure induced by the two drugs was similar. However, this greater beneficial effect of azelnidipine on the autonomic functions did not produce any distinguishable differences in effects of azelnidipine and benidipine on the arterial stiffness and endothelial functions.

Brachial-ankle pulse wave velocity as a marker of subclinical organ damage in middle-aged patients with hypertension.

OBJECTIVE: This study was conducted to clarify whether the brachial-ankle pulse wave velocity (baPWV) might serve as a marker of target organ damage in middle-aged hypertensive subjects. METHODS AND RESULTS: Multivariate linear regression analysis demonstrated that while the baPWV showed a significant relationship to the intima-media thickness of the carotid artery (IMT), no such relationship was observed between the baPWV and the left ventricular mass index as assessed by echocardiography or the estimated glomerular filtration rate in either the 162 hypertensive patients who had never previously received antihypertensive medication or the 269 hypertensive patients who were under antihypertensive medication for at least 1 year. Receiver-operator characteristic (ROC) curve analysis suggested that a baPWV=18m/s was the best cutoff value to identify increased IMT in hypertensive patients who had never previously received antihypertensive medication (area under curve=0.77). Binary logistic regression analysis demonstrated that the odds ratio (OR) of a baPWV of ≥18m/s for identifying increased IMT {OR=7.38 (1.94-28.05)} was significant, even after adjustments. In hypertensive patients who had been under antihypertensive medication for at least 1 year, however, the area under the curve and OR were only modest. CONCLUSION: The baPWV may be a marker of carotid atherosclerosis, rather than of left ventricular hypertrophy or renal insufficiency, especially in middle-aged hypertensive subjects (subjects in their 30s to 60s), not only in those who have never previously received antihypertensive medication, but also in those who are under antihypertensive medication.

Effect of telmisartan on forearm postischemic hyperemia and serum asymmetric dimethylarginine levels.

BACKGROUND: Although telmisartan may be more beneficial for glucose metabolism than other angiotensin II receptor blockers (ARBs), it has not been determined whether telmisartan exerts more favorable effects on biological and functional parameters related to endothelial function than other ARBs. METHODS: A study with a crossover design was conducted in 40 hypertensive patients (61 +/- 10 years old, mean +/- SD) who had previously been treated with ARBs other than telmisartan or valsartan (ie, ARBs were switched to either telmisartan 40 mg/day or valsartan 80 mg/day, administered alternately for 12 weeks each). Blood examinations were conducted, and the mean reactive hyperemia ratio (mRHR) was measured by plethysmography for each treatment regimen. RESULTS: There were no significant differences in either blood pressure or plasma levels of monocyte chemoattractant protein-1, C-reactive protein, 3-nitrotyrosine, or vascular cell adhesion molecule-1 between the two treatment regimens. The mRHR (2.7 +/- 1.0 v 2.4 +/- 1.0, mean +/- SD) was larger (P < .05), and the plasma levels of asymmetric dimethylarginine (ADMA) (0.45 +/- 0.08 v 0.50 +/- 0.17 micromol/L, mean +/- SD) and the homeostasis model assessment index of insulin resistance (HOMA-IR) (2.3 +/- 1.6 v 2.8 +/- 2.1, mean +/- SD) were lower (P < .05) in telmisartan-treated patients than in valsartan treated patients. The percent change in ADMA, but not in HOMA-IR, correlated significantly with that in the mRHR (beta = -0.33, t value = -2.00, P = .04). CONCLUSIONS: At doses producing equivalent hypotensive effects, telmisartan apparently had a more favorable effect on functional parameters related to endothelial function than did valsartan. The reduction in plasma ADMA levels may contribute to this more favorable effect of telmisartan.

Relationships among renal function loss within the normal to mildly impaired range, arterial stiffness, inflammation, and oxidative stress.

BACKGROUND AND OBJECTIVES: This study was conducted to clarify whether individuals with mildly impaired renal function show increased arterial stiffness, microinflammation, and oxidative stress as compared with those with normal renal function and also to examine the association of these parameters with the degree of GFR loss in middle-aged Japanese men with a low cardiovascular risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The brachial-ankle pulse wave velocity and plasma levels of C-reactive protein and lipid peroxides were measured in 1873 men (42 +/- 9 yr of age). RESULTS: The brachial-ankle pulse wave velocity but not the plasma C-reactive protein or lipid peroxides, was increased in individuals with mildly impaired renal function. The GFR was significantly correlated with the brachial-ankle pulse wave velocity but not with the log-transformed values of C-reactive protein or lipid peroxides. Multivariate linear regression analysis demonstrated a significant relationship between the brachial-ankle pulse wave velocity and the GFR, independent of the conventional atherosclerotic risk factors. This relationship was significant even in individuals with GFR values within the "normal renal function" range. Thus, GFR loss seems to be more closely associated with arterial stiffness than with microinflammation and/or oxidative stress. CONCLUSIONS: A weak but significant relationship was observed between the degree of GFR loss and arterial stiffness, even in individuals with GFR values within the normal renal function range. Therefore, increased arterial stiffness may underlie, at least in part, the elevated cardiovascular risk in individuals with mildly impaired renal function.

Heart rate elevation precedes the development of metabolic syndrome in Japanese men: a prospective study.

This observational study of Japanese men without metabolic syndrome (MetS) (age: 41+/-8 years) was conducted to clarify whether or not heart rate elevation precedes the development of full-blown MetS. MetS was defined based on two modifications of the criteria of the Japanese Expert Committee on the Diagnosis and Classification of Metabolic Syndrome. Premetabolic syndrome subjects were defined as those having one component of MetS with increased body mass index (BMI). Among the subjects without MetS (n=1,859 when the BMI criterion was >or=25 and n=2,020 when the BMI criterion was >or=27.5), the incidence of progression to full-blown MetS by the time of the second examination at the end of the 3-year study period was higher in the subjects with premetabolic syndrome than in those without it. The receiver-operator characteristic curve analysis and binary logistic regression analysis revealed that the odds ratio (OR) of a heart rate >or=69 beats/min at the first examination for progression to full-blown MetS by the time of the second examination was significant in subjects with premetabolic syndrome (BMI>or=25: OR=3.64 [1.22-10.88]; BMI>or=27.5: OR=3.67 [1.28-10.55]; p<0.05). Thus, heart rate elevation appears to precede the development of full-blown MetS in subjects with premetabolic syndrome. Heart rate seems to be a simple and useful marker for predicting the progression to full-blown MetS of middle-aged Japanese men with premetabolic syndrome.

Relationship between arterial stiffness and the risk of coronary artery disease in subjects with and without metabolic syndrome.

We examined the influence of metabolic syndrome (MetS) on the relationship between arterial stiffness and the risk of coronary artery disease (CAD). In 396 subjects (age, 63+/-11 years) who underwent coronary angiography, multiple linear regression analysis demonstrated that the brachial-ankle pulse wave velocity (PWV), but not the presence of MetS, was a significant determinant of the number of diseased coronary arteries (beta=0.10, p<0.05), even though both the brachial-ankle PWV and the number of diseased coronary arteries were higher in subjects with MetS (n=100) than in those without MetS (n=296). However, in subjects with MetS, multiple linear regression analysis demonstrated that the brachial-ankle PWV was not a significant determinant of the number of diseased coronary arteries. The brachial-ankle PWV values were classified into tertile ranges in subjects with and without MetS. The number of diseased coronary arteries increased significantly with an increase in the tertile number of the brachial-ankle PWV in the subjects without MetS (tertile 1=1.00+/-0.86, tertile 2=1.29+/-1.01, and tertile 3=1.45+/-1.05), but not in those with MetS. In conclusion, the results of this study suggest that arterial stiffness is a marker of the risk of CAD in subjects without MetS, whereas in subjects with MetS, the syndrome may directly produce clinically significant atherosclerotic stenosis of the coronary arteries independent of its significant promotion of the development of coronary atherosclerosis via an increase of arterial stiffness.

Discrepancy between improvement of insulin sensitivity and that of arterial endothelial function in patients receiving antihypertensive medication.

OBJECTIVES: We evaluated whether the changes in the insulin sensitivity observed in hypertensive patients following treatment with an angiotensin II receptor blocker (candesartan) or calcium-channel antagonist (amlodipine) might be related to improvement of the endothelial function (END) and/or plasma level of high-sensitive C-reactive protein (CRP) following such treatment. METHODS AND RESULTS: Seventy-one hypertensive patients (age: 58 +/- 10 years) without obvious target organ damage were allocated randomly to treatment with either candesartan at the dose of 8 mg/day or amlodipine at the dose of 5 mg/day. At the start and end of the 8-month treatment period, the homeostasis model assessment index of insulin resistance (HOMA-IR index), plasma CRP and END, as assessed by changes in the forearm blood flow in reactive hyperemia, were determined. While significant improvement of END was observed in patients receiving either drug, only candesartan, but not amlodipine, also reduced the plasma CRP and HOMA-IR index (2.13 +/- 1.92 --> 1.53 +/- 1.47, P < 0.05). In the patients receiving treatment with candesartan, stepwise multivariate linear regression analysis revealed that the percent change in the HOMA-IR index was significantly and independently correlated with that in the plasma CRP (beta = 0.38, P < 0.05), but not with that in END: CONCLUSION: Improvement of the END alone by the antihypertensive medication might not entirely explain the improvement of the insulin sensitivity observed in these patients. Additional mechanisms may be involved, and the anti-inflammatory effects of the medication observed in patients treated with candesartan may also be related, at least in part, to the observed improvement of insulin sensitivity.