Mikio Nagata

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.

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.

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 × 10−2–0.19, 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.

Central blood pressure: a powerful predictor of the development of hypertension

We examined whether the central aortic systolic blood pressure, a marker of the function of the systemic arterial tree, might be a more powerful predictor of the development of hypertension than the brachial-ankle pulse wave velocity, a marker of the stiffness of the large- to middle-sized arteries, independent of the conventional risk factors for the development of hypertension. In 1268 Japanese men without hypertension (43±8 years old), the relationships between three variables (the second peak of the radial pressure waveform (SP2), brachial-ankle pulse wave velocity and conventional risk factors measured at the first examination) with the presence of hypertension at the second examination (after 3 years’ follow-up) were examined. Hypertension was detected at the second examination in 154 men. The best cutoff points of the brachial-ankle pulse wave velocity and SP2, for predicting the development of hypertension, were 12.7 m/s and 109 mm Hg, respectively. The results of a logistic regression analysis confirmed that an SP2 of ⩾109 mm Hg (odds ratio=8.493, P<0.001) was a more powerful predictor of the development of hypertension than a brachial-ankle pulse wave velocity of ⩾12.7 m/s, independent of the conventional risk factors. The net reclassification index of SP2 (at the best cutoff point) to brachial-ankle pulse wave velocity was 0.211 (P<0.001), indicating that SP2 is a better predictor of the development of hypertension than brachial-ankle pulse wave velocity. In middle-aged Japanese men without hypertension, SP2 may be a more powerful predictor of the development of hypertension than the assessment of stiffness in large to middle-sized arteries independent of the conventional risk factors.

Effects of aging and persistent prehypertension on arterial stiffening.

An age-related association of blood pressure in the non-hypertensive range (non-hypertensive blood pressure) to the cardiovascular mortality has been demonstrated. This prospective study was conducted to examine the effects of age, persistence of pre-hypertension (preHYP) during the study period, and the interaction between these factors on the rate of progression of arterial stiffening. Among 1563 healthy Japanese subjects without hypertension (age range: 29-95 years), the brachial-ankle pulse wave velocity (baPWV) was measured twice (i.e., at baseline and 5-6 years later). The adjusted (including for blood pressure) value of the annual rate of increase of the baPWV during the study period (delPWV) increased in a linear manner along with the age category (categorized into 29-39 years, 40-59 years, and 60 years or older for this study) and the evolutional category of non-hypertensive blood pressure during the study period (categorized into persistence of normal blood pressure, borderline evolution, and persistence of preHYP), and a significant interaction between the two in relation to the delPWV was also noted (non-standardization coefficient=5.08 [95% confidence interval=3.24-6.92], F-value=29.40, P<0.01). In conclusion, the present study suggests that persistence of preHYP is associated with accelerated structural stiffening of the large- to middle-sized arteries, and that age may exert a synergistic effect on this acceleration of arterial stiffening. Thus, persistence of preHYP also appears, like hypertension, to be associated with progressive vascular damage, and this progression may be more pronounced in middle-aged and elderly subjects.

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.

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.

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/m2]) 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≥25), the estimated annual rate of increase of baPWV (ARbaPWV) in subjects with weight gain (≥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≥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.

Increased arterial stiffness weakens the relationship between wave reflection and the central pressure indexes in men younger than 60 years of age.

BACKGROUND Interactions among age, arterial stiffness, and pressure wave reflection affect the central blood pressure (CBP). We evaluated our hypothesis that the contribution of the wave reflection to the CBP indexes is reduced at higher levels of arterial stiffness, independent of the effect of age. METHODS In 2,691 Japanese men aged <60 years old who are not suffering from cardiovascular disease or receiving medications for cardiovascular risk factors, the brachial-ankle pulse wave velocity (PWV), radial augmentation index (AI), and second peak of the radial pressure waveform (SBP2), a marker of CBP, were measured. RESULTS The increase in the radial AI associated with increase of the brachial-ankle PWV became attenuated at brachial-ankle PWV values of ≥15 m/s. Stepwise multivariate linear regression analysis demonstrated that 33.6% of the total variation in the value of SBP2 and 54.0% of the total variation in the value of the SBP2 minus the diastolic blood pressure, a marker of the central pulse pressure (CPP), were accounted for by the change of the radial AI in the group with brachial-ankle PWV values of <15 m/s, with the corresponding percentages of 16.2 and 38.0% in the group with brachial-ankle PWV values of ≥15 m/s (P < 0.01). CONCLUSIONS In non-elderly Japanese men, the contribution of the wave reflection to the CBP indexes may be reduced in subjects with higher levels of arterial stiffness, independent of the effect of age. Notwithstanding, the wave reflection may still be the major determinant of the CPP at any given level of arterial stiffness.