Minoru Yambe

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 ≥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.

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.

Synergistic Acceleration of Arterial Stiffening in the Presence of Raised Blood Pressure and Raised Plasma Glucose

Arterial stiffness is recognized as a marker of arterial damage and an indicator of cardiovascular risk. This observational study was conducted to examine the synergistic effect of raised blood pressure (RBP; ≥130/85 mm Hg) and raised plasma glucose (RPG; ≥110 mg/dL) even at levels below those conventionally used to define hypertension and diabetes on the rate of increase of the pulse wave velocity (PWV) over a 3-year period in 2080 Japanese men (age 42±9 years). First, the subjects were classified into 4 groups based on the presence at the first examination of RBP, RPG, both abnormalities, or neither abnormality. The estimated annual rate of increase of the PWV was higher in subjects with both the abnormalities than in those with either abnormality alone or neither of the 2 abnormalities. Second, the subjects were also classified based on the evolutional status of these abnormalities during the study period; persistence of both of the abnormalities synergistically accelerated the rate of increase of the PWV (68.3±7.1 cm/s per year), as compared with the persistence of either abnormality alone (persistence of RBP alone: 18.2±1.6 cm/s per year; persistence of RPG alone: 21.2±7.4 cm/s per year) or persistence of neither abnormality (11.1±0.8 cm/s per year; P<0.01). Thus, blood pressure and fasting plasma glucose levels even below those defining hypertension and diabetes may synergistically lead to progression of arteriosclerotic arterial damage. This synergistic progression may contribute to the additive increases in the risk of cardiovascular events, at least in part.

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 2,080 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=1,843; 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.

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 ≥25 and n=2,020 when the BMI criterion was ≥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 ≥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≥25: OR=3.64 [1.22–10.88]; BMI≥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 (β=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.