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.

Arterial stiffness and progression to hypertension in Japanese male subjects with high normal blood pressure.

OBJECTIVES: This observational study was conducted to compare the significance of the relationship between arterial stiffness and progression to higher blood pressure categories among middle-aged Japanese men with high normal blood pressure (HNP), normal blood pressure (NRP) and optimal blood pressure (OPP). METHODS AND RESULTS: During the 3-year observational period, 100 subjects with HNP developed hypertension (n=475; 42 +/- 9 years), and 175 of those with normal NRP (n=581; 41 +/- 8 years) and 249 of those with OPP (n=702; 39 +/- 8 years) showed progression to higher blood pressure categories. A binary logistic regression analysis adjusted for known risk factors revealed that values of the brachial-ankle pulse wave velocity, a surrogate marker of arterial stiffness, in the highest quartile, as compared with those in the lowest quartile, obtained at the start of the study were significantly predictive of the progression to hypertension [adjusted odds ratio = 9.4 (95% confidence interval, 3.0-29.8), P < 0.01]. The predictive value of this parameter for progression to higher blood pressure categories in subjects with HNP was more significant than that in those with NRP or OPP. CONCLUSIONS: Increased arterial stiffness and elevated blood pressure may be mutually causally related, and it appears that the significance of this relationship may increase with increasing blood pressure, even in subjects without hypertension. Assessment of arterial stiffness may be more reliable for predicting the progression to hypertension in cases of HNP than in cases with NRP or OPP.

B-type natriuretic peptide and arterial stiffness in healthy Japanese men.

BACKGROUND: Recent evidence suggests that even a slight increase in the plasma level of B-type natriuretic peptide (BNP) may be a marker of cardiovascular risk; however, the mechanisms underlying the association are currently unclear. Because increased arterial stiffness, as reflected by an increase of the pulse wave velocity (PWV) or pulse pressure (PP), may contribute to increasing plasma BNP levels, in the present study we investigated the relationships between the plasma BNP level and the PWV and PP, all of which are known markers of cardiovascular risk, in a healthy male Japanese cohort. METHODS: This was a cross-sectional study of 725 healthy Japanese men (age, 54 +/- 4 years). The PWV was assessed by the volume-rendering method. Plasma BNP levels were determined with a high-sensitivity noncompetitive immunoradiometric assay. RESULTS: A univariate linear regression analysis demonstrated that the plasma BNP level was significantly correlated with age (r = 0.20, P < .01), PWV (r = 0.12, P < .01), and PP (r = 0.17, P < .01). A stepwise multivariate linear regression analysis demonstrated that both the PWV and PP were significantly associated with the plasma BNP level, independent of age. CONCLUSION: In healthy Japanese men, stiffening of large arteries, as evidenced by an increase of the PWV or PP, may account at least in part for elevated plasma BNP levels, even within the so-called normal range.

Elevated serum levels of alanine aminotransferase and gamma glutamyltransferase are markers of inflammation and oxidative stress independent of the metabolic syndrome.

The present study attempted to establish whether elevated serum levels of alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) are independent (of each other) markers of systemic inflammation and oxidative stress as assessed by the plasma levels of C-reactive protein (CRP) and lipid peroxides (lipOX), regardless of the presence of underlying metabolic syndrome (as defined by the modified Adult Treatment Panel III (ATPIII) criteria). The plasma levels of CRP and lipOX were determined in 1483 middle-age Japanese men (42+/-9 years). A general linear model analysis indicated that elevated serum ALT and/or serum GGT (levels in the respective highest quartiles) were significantly related to the logarithms of the plasma levels of CRP (Beta=0.08 (0.05-0.11) and 0.08 (0.05-0.11), respectively) and the logarithm of the plasma levels of lipOX (Beta=0.03 (0.01-0.05) and 0.03 (0.01-0.05), respectively), regardless of the presence of underlying metabolic syndrome (MetS) (p<0.01). In addition, the presence of MetS and elevated serum levels of both of these liver enzymes additively increased the plasma levels of CRP and lipOX. Thus, it is proposed that elevated serum ALT and elevated serum GGT are independent markers of the activation of systemic inflammation and increased oxidative stress, independent of their relationship to MetS, and that the presence of MetS and elevations of both of these liver enzymes may additively worsen the atherogenic state.

Menopause is an independent factor augmenting the age-related increase in arterial stiffness in the early postmenopausal phase.

The present study examined whether the menopause augments the age-related increase in brachial-ankle pulse-wave velocity (PWV). In total, 3149 women (ranging in age from 21 to 94 years) undergoing an annual health screening examination were enrolled in a cross-sectional study. Conventional atherosclerotic risk factors were examined, and the brachial-ankle PWV of each subject was determined. The relationship between age and the brachial-ankle PWV assumed the form of a quadratic curve, and the slope of the curve was relatively steeper after the menopause (brachial-ankle PWV = 0.17 x age2 - 0.58 x age + 812) than before (brachial-ankle PWV = 0.23 x age2 - 8.92 x age + 1058). A logistic regression analysis conducted for subjects between the ages of 45 and 56 years (mean age of menopause +/- 2 standard deviations) demonstrated that women who had experienced the menopause at least 6 years previously demonstrated a significant risk of belonging to the highest PWV tertile {adjusted odds ratio: 2.08 (95% confidential interval: 1.04-4.17)}, independent of age and other atherosclerotic risk factors (hypertension, hypercholesterolemia, diabetes mellitus, obesity, and smoking). Thus, this study suggested that the menopause augments the age-related increase in arterial stiffness during the early postmenopausal phase and that this augmentation is probably related, at least in part, to estrogen deficiency. The contribution of this menopause-related increase in arterial stiffness to the risk of cardiovascular disease in postmenopausal women should be further evaluated.

The effects of changes in the metabolic syndrome detection status on arterial stiffening: a prospective study.

We conducted a prospective study to examine the effects of alterations of the metabolic syndrome detection status on the rate of progression of arterial stiffness, which is recognized as a marker of arterial damage and an indicator of cardiovascular risk. Brachial-ankle pulse wave velocity as an index of arterial stiffening was recorded twice over a 3-year period in 2080 Japanese men (age, 42 +/- 9 years). At the start of the prospective study, pulse wave velocity was higher in the subjects with metabolic syndrome (n=125) than in those without metabolic syndrome (n=1,955) even after adjusting for mean blood pressure. The annual rate of increase of the pulse wave velocity was higher in the group with persistent metabolic syndrome (27 +/- 51 cm/s/year, n=71) than in the group with regression of metabolic syndrome (6 +/- 39 cm/s/year, n=54) or the group in which metabolic syndrome was absent (13 +/- 37 cm/s/year, n=1843; p < 0.05) after adjustment for changes in blood pressure. In conclusion, the changes in the metabolic syndrome detection status of the subjects during the study period affected the annual rate of progression of arterial stiffening, and persistent metabolic syndrome during the study period was associated with acceleration of arterial stiffening in middle-aged Japanese men. On the other hand, resolution of metabolic syndrome may be associated with attenuation of the progression of arterial damage. Therefore, the increased cardiovascular risk associated with the presence of metabolic syndrome may be at least partly mediated by acceleration of the progression of arterial stiffening.

Brachial -- ankle pulse wave velocity is a simple and independent predictor of prognosis in patients with acute coronary syndrome.

BACKGROUND: Although a very simple method of measuring brachial -- ankle pulse wave velocity (baPWV) has become available in a clinical setting, whether baPWV can predict future cardiovascular events remains uncertain. We examined whether baPWV is a predictor of cardiovascular events in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: baPWV measurement was performed in 215 consecutive patients with ACS. During the follow-up period (26+/-10 months), 46 patients experienced post-hospitalization cardiovascular events (18 patients experienced a major event (eg, stroke, re-admission for heart failure or cardiac death), and 28 patients experienced coronary re-intervention). A receiver operating characteristic curve demonstrated that the best cut-off point of a baPWV for predicting a post-hospitalization cardiovascular event was 17.00 m/s and that for predicting a major cardiovascular event was 18.00 m/s. After the adjustment for the conventional risk factors influencing the prognosis, a multivariate Cox proportional hazards model demonstrated that both cut-off points of baPWV had a significant hazard ratio for a post-hospitalization event: 5.47 (2.69-11.09) and for a major cardiovascular event: 9.22 (2.78-30.56). CONCLUSIONS: baPWV is a simple predictor of the prognosis of patients with ACS that is independent of conventional risk factors for ACS.

Elevated C-reactive protein augments increased arterial stiffness in subjects with the metabolic syndrome.

We examined whether the presence of an increasing number of metabolic syndrome "disorders" was associated with an increasing pulse wave velocity, which is recognized as a marker of cardiovascular risk, and evaluated whether an elevated plasma C-reactive protein level augments this increasing pulse wave velocity. Using a cross-sectional study design, C-reactive protein, metabolic syndrome-related anthropometric parameters, and pulse wave velocity were measured in 5752 middle-aged Japanese men (44+/-10 years old). In linear regression analyses, all of the metabolic "disorders" and the logarithm of the C-reactive protein significantly correlated with pulse wave velocity. Multiple linear regression analysis demonstrated that triglycerides, HDL cholesterol, mean blood pressure, fasting glucose, and the logarithm of the C-reactive protein were significant independent positive predictors of pulse wave velocity (R-square=0.38). The presence of an increasing number of metabolic "disorders" in the subjects was associated with an increasing pulse wave velocity (no disorders 1228+/-139 cm/s > or =3 disorders 1437+/-250 cm/s; P<0.01). Among subjects with the metabolic syndrome, pulse wave velocity was higher in cases with (1508+/-278 cm/s) than in those without an elevated C-reactive protein (1427+/-243 cm/s; P<0.01). In conclusion, an increase in arterial stiffness may constitute a pathophysiological basis for the increased risk of cardiovascular disease in patients with the metabolic syndrome and that an elevated C-reactive protein level may aggravate this cardiovascular risk.

Insulin sensitivity and endothelial function in hypertension: a comparison of temocapril and candesartan.

BACKGROUND: Recent studies have suggested that angiotensin-converting enzyme inhibitors (ACEi) have a more pronounced effect on endothelial function (END) than angiotensin II receptor blocker (ARB); however, whether this pronounced effect is more beneficial to patients with insulin sensitivity (IS) remains uncertain. The present study compared the effects of ACEi and ARB on END and IS in patients with hypertension. METHODS: A total of 23 patients with hypertension were given either ACEi or ARB alternatively in a cross-over manner for 8-week intervals. Both END and IS were examined after each treatment period; END was assessed by the response of forearm blood flow to reactive hyperemia and IS by an insulin tolerance test. The plasma levels of bradykinin (BK), NOx, tumor necrosis factor (TNF-alpha), and adiponectin (Adi) were also measured after each treatment. RESULTS: We found that END, BK, and NOx were higher after the ACEi treatment than after the ARB treatment. Although the IS and the Adi levels were similar after both treatments, the TNF-alpha level was lower after the ARB treatment than after the ACEi. CONCLUSIONS: We conclude that ACEi and ARB may have similar effects on insulin sensitivity, irrespective of the more pronounced effects of ACEi on endothelial function. The BK-NO pathway might contribute, at least in part, to the pronounced effect of ACEi. On the other hand, the underlying mechanisms affecting insulin sensitivity might differ for both treatments. These results suggest that endothelial function is not a major determinant of insulin sensitivity under physiologic conditions.

The age-related increase in arterial stiffness is augmented in phases according to the severity of hypertension.

Although blood pressure and age are major determinants of arterial stiffness, it is still unclear whether age-related changes in arterial stiffness are similar among subjects with different degrees of severity of hypertension. The present study examined the association between age and pulse wave velocity in subjects with different degrees of hypertension stratified according to the JNC-7 classification (Normal, Prehypertensive, and Stage I or II Hypertensive subjects). A number of 5,312 subjects (age range, 30-79 years) with no atherosclerotic risk factors other than high blood pressure were selected from two cohorts who regularly underwent annual health checkups, including the measurement of brachial-ankle pulse wave velocity (baPWV). baPWV was increased according to the severity of hypertension in all age groups. The association between age and baPWV formed a quadratic curve in each stage in both genders. The steepness of the slope of the quadratic curve increased according to the severity of hypertension. In each stage of hypertension, age and the baPWV were divided into tertiles. After adjustment for systolic and diastolic blood pressure, the odds ratio of having an increased baPWV in the 3rd age tertile (the highest-age group) was found to increase according to the severity of hypertension. In conclusion, the age-related increase of baPWV was shown to be augmented in phases according to the severity of hypertension, and this augmentation occurred even between the Normal and Prehypertensive stages. These results support the JNC-7 recommendations for a strict control of blood pressure even in the elderly.

[Effects of acute administration of beraprost sodium on parameters related to atherosclerotic vascular damage in coronary artery disease].

OBJECTIVES: The present study was conducted to examine the effects of acute administration of prostacyclin derivatives on plasma levels of adhesion molecules, endothelial function, and pulse wave velocity in patients with coronary heart disease. METHODS: In 20 patients with coronary heart disease, plasma levels of vascular cell adhesion molecule-1, P-selectin, and beta-thromboglobulin, endothelial function, and pulse wave velocity were assessed before and after the cold pressor test. These assessments were performed again 2 hr after the oral administration of prostacyclin derivatives (beraprost sodium 40 micrograms) or placebo. Endothelial function was assessed by changes in forearm blood flow before and after reactive hyperemia. Pulse wave velocity was determined by the volume rendering method. RESULTS: Prostacyclin derivatives significantly improved endothelial function and decreased plasma beta-thromboglobulin level, but did not affect blood pressure and pulse wave velocity. Prostacyclin derivatives did not prevent the elevations of blood pressure and pulse wave velocity induced by the cold pressor test, but did prevent the elevations of P-selectin and beta-thromboglobulin induced by the cold pressor test. CONCLUSIONS: Prostacyclin derivatives improved endothelial function and prevented platelet activation induced by the cold pressor test. Prostacyclin apparently has an anti-atherogenic effect.