Kazutaka Kimura

Arterial stiffness/central hemodynamics, renal function, and development of hypertension over the short term.

Objectives: We examined the following: whether the estimated glomerular filtration rate calculated from the serum cystatin C levels (eGFRcys) and the brachial–ankle pulse wave velocity (baPWV) might be independent predictors of the development of hypertension over the short term, without any interaction; whether the baPWV may be directly associated with the development of hypertension without the mediation of the arterial stiffness-related acceleration of renal functional decline; whether the second peak of the radial pressure waveform (SP2) might also be a significant independent predictor of the development of hypertension. Methods: In 1229 middle-aged normotensive Japanese men with preserved renal function, the baPWV, SP2 and eGFRcys were measured at the baseline and at the end of the 3-year study period. Results: Hypertension was detected at the end of the 3-year study period in 127 men. The logistic regression analysis with adjustments demonstrated significant independent odds ratios of the baPWV and eGFRcys for the presence of hypertension at the end of the 3-year study period, without any interaction. When entered simultaneously in this model, the SP2 also showed a significant odds ratio. General linear model analysis revealed that none of the baPWV or SP2 measured at the baseline was related to the renal function assessed at the end of the 3-year study period. Conclusions: The mechanisms underlying the association between arterial stiffness/central hemodynamics and the short-term development of hypertension appear to differ from those underlying the association between kidney function and the short-term development of hypertension.

The contribution of inflammation to the development of hypertension mediated by increased arterial stiffness

Background The mechanisms underlying the possible contribution of chronic inflammation to the development of hypertension remain unclear. We examined the longitudinal association of inflammation with the progression of vascular and/or renal abnormalities in the development of hypertension. Methods and Results In 3274 middle‐aged Japanese men without hypertension at the study baseline, brachial‐ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum CRP (C reactive protein) levels were measured annually during a 9‐year period. During this study period, 474 participants (14.5%) developed hypertension. Analysis of the repeated‐measures data revealed that sustained elevation of serum CRP levels was associated with a longitudinal increase of the brachial‐ankle pulse wave velocity. A linear mixed model analysis revealed that higher log‐transformed serum CRP values (log CRP) at each measurement were associated with a higher annual increase of the brachial‐ankle pulse wave velocity (estimate=32.553±11.635 cm/s per log CRP, P=0.018), and that higher values of the brachial‐ankle pulse wave velocity at each measurement were associated with a higher annual elevation of blood pressure (estimate=0.025±0.002 mm Hg per log CRP, P<0.001). Conclusions In middle‐aged Japanese men without hypertension at study baseline, long‐term active inflammation appears to be associated with a longitudinal increase of arterial stiffness. In turn, this longitudinal increase of arterial stiffness appears to be associated with longitudinal elevation of blood pressure to the hypertensive range. Thus, systemic inflammation may play a role in the pathogenesis of hypertension by the progression of arterial stiffness.

Comparison of the clinical significance of single cuff-based arterial stiffness parameters with that of the commonly used parameters

BACKGROUND We examined the following: (1) whether the new simple markers related to the arterial stiffness/central hemodynamics [i.e. arterial pressure-volume index (API) and arterial velocity pulse index (AVI)] are clinically interchangeable with the commonly used markers [brachial-ankle pulse wave velocity (baPWV) and radial augmentation index (rAI)]; (2) whether the new simple markers reflect vascular damage as reliably as the commonly used markers; (3) which cardiovascular risk factors are reflected by these new simple markers. METHODS API, AVI, baPWV, and rAI were measured simultaneously in consecutive patients admitted for the management of cardiovascular disease and/or cardiovascular risk factors (n=322). RESULTS The API was correlated with the baPWV (R=0.492, p<0.001) and the AVI correlated with the rAI (R=0.462, p<0.001). The API, AVI, baPWV, and rAI were higher in the patients admitted for coronary angiography (CAG group: n=152) than in those admitted for reasons other than coronary angiography (nonCAG group: n=170). After adjustments for confounding factors, only the AVI was found to be higher in the CAG group than in the nonCAG group. Multivariate linear regression analysis revealed that age and the systolic blood pressure were independently associated with the API and AVI after adjustments. CONCLUSION In patients with cardiovascular diseases or cardiovascular risk factors, the new simple markers and the commonly used markers are not interchangeable for assessing vascular damage and/or cardiovascular risk. Further study is proposed to examine whether AVI is higher in subjects with cardiovascular disease than in those without a history of cardiovascular disease. Similar to the case for the commonly used markers, age and the blood pressure significantly influenced both the new markers; therefore, age and the blood pressure need to be taken into account while interpreting the changes in these new simple markers.

Correlations of arterial stiffness/central hemodynamics with serum cardiac troponin T and natriuretic peptide levels in a middle-aged male worksite cohort

BACKGROUND Elevated serum levels of cardiac troponin T (cTnT) and N-terminal fragment of B-type natriuretic peptide (NT-proBNP), and also increased arterial stiffness/abnormal central hemodynamics, are well-known risk factors for future cardiovascular events. The present study was conducted to clarify which of the two - the serum level of cTnT or that of NT-proBNP - might be more closely associated with the arterial stiffness/central hemodynamics. METHODS In 2374 male employees of a company (46±9 years), the following parameters were measured: second peak of the radial systolic pressure waveform (SP2), radial augmentation index (rAI), PP2 (SP2 minus the diastolic blood pressure), brachial-ankle pulse wave velocity (baPWV), and serum levels of cTnT and NT-pro BNP. RESULTS After adjustments for confounding variables, binary logistic regression analyses demonstrated that baPWV was associated with a significant odds ratio for serum NT-proBNP ≥125pg/mL (1.690; 95% confidence interval=1.136-2.514, p=0.002) and rAI was associated with a significant odds ratio for serum NT-proBNP ≥55pg/mL (1.205; 95% confidence interval=1.012-1.435, p=0.036). The baPWV, rAI, SP2, and PP2 were not associated with significant odds ratios for elevated serum cTnT levels (≥0.014ng/mL and ≥0.010ng/mL). CONCLUSIONS In the middle-aged male worksite cohort studied, increased arterial stiffness/abnormal central hemodynamics appeared to be associated with elevated serum NT-proBNP levels, rather than with minimally elevated serum cTnT levels. This difference may be one of the plausible explanations for the independency of the predictive values of the two serum markers for future cardiovascular events.

Longitudinal changes in late systolic cardiac load and serum NT-proBNP levels in healthy middle-aged Japanese men.

BACKGROUND We determined whether any significant association exists between change in late systolic cardiac load with time, estimated by radial pressure waveform analysis, and development of cardiac hemodynamic stress in individuals with preserved cardiac function. METHODS Brachial-ankle pulse wave velocity, radial augmentation index (rAI), first peak of the radial pressure waveform (SP1), systolic and pulse pressure at the second peak of the radial pressure waveform (SP2 and PP2), and serum levels of N-terminal fragment B-type natriuretic peptide (NT-proBNP) were measured at the start (first examination) and at the end (second examination) of this 3-year study in healthy Japanese men (n = 1,851). RESULTS A stepwise multivariate linear regression analysis demonstrated that among the parameters of radial pressure waveform analysis and markers of arterial stiffness analyzed, only PP2 was significantly associated with serum NT-proBNP levels in study participants at both the first and second examinations. Furthermore, among the parameters analyzed, only change in PP2 was significantly correlated with the change in serum NT-proBNP levels during the study period (beta = 0.131, P < 0.001). CONCLUSIONS Sustained late systolic cardiac load might be a more significant determinant of the development of cardiac hemodynamic stress than sustained early systolic cardiac load or arterial stiffening in individuals with preserved cardiac function.

Effect of Wave Reflection and Arterial Stiffness on the Risk of Development of Hypertension in Japanese Men

Background We conducted analyses of repeated‐measures data to examine whether pressure wave reflection acts additively or synergistically with arterial stiffness in the pathogenesis of hypertension. Methods and Results In 3172 middle‐aged (42±9 years) healthy Japanese men without hypertension at the study baseline, systolic and diastolic blood pressures, brachial–ankle pulse wave velocity, and radial augmentation index were measured annually during a 9‐year study period. Of these, 474 participants (15%) developed hypertension by the end of the study period. Binary logistic regression analysis demonstrated significant individual odds ratios for both baseline brachial–ankle pulse wave velocity and radial augmentation index for the development of hypertension. The rate of onset of hypertension during the study period was highest in the participant group with high values for both brachial–ankle pulse wave velocity and radial augmentation index at study baseline (262 of 965 participants: 27%). The generalized estimating equation analysis revealed that both radial augmentation index (estimate=0.06, SE=0.03, P=0.05) and brachial–ankle pulse wave velocity (estimate=0.07×10−1, SE=0.02×10−1, P<0.01) showed significant longitudinal association with new onset of hypertension, with no significant interaction. Conclusions In Japanese men, abnormal wave reflection and increased arterial stiffness may be additively associated with the risk of new onset of hypertension. Abnormal wave reflection and elevated central blood pressure may be longitudinally associated with increase in arterial stiffness, and this longitudinal association may be a mechanism underlying the additive effect of these 2 variables on the risk of new onset of hypertension.

Liver stiffness and arterial stiffness/abnormal central hemodynamics in the early stage of heart failure

Background It remains to be clarified whether liver stiffness is a direct risk factor for heart failure (HF) or whether its association with HF is mediated by vascular damage. We conducted cross-sectional and prospective longitudinal studies to examine whether fibrosis 4 score (FIB-4 score) is directly associated with the serum NT-pro-BNP levels or the association is mediated by arterial stiffness and/or abnormal central hemodynamics. Methods and results In 3040 health Japanese subjects with serum NT-pro-BNP levels < 125 pg/ml, the FIB-4 score was calculated, and the serum NT-pro-BNP levels, brachial-ankle pulse wave (baPWV) velocity and radial augmentation index (rAI) were measured. These parameters were measured again after a 3-year interval in 2135 subjects. Multivariate linear regression analysis demonstrated a significant cross-sectional association of the FIB-4 scores with the log-transformed the serum NT-pro-BNP levels (beta = 0.08, p < 0.01), but not with the baPWV or rAI. The change of serum NT-pro BNP levels during the study period was significantly higher in subjects with increase of the FIB-4 score during the study period (8.2 ± 22.5 pg/ml) than that in those with decrease/no change (5.4 ± 22.3 pg/ml) (p < 0.05). Conclusion Liver stiffness may have a significant direct association with the development of HF from the early stage, without the mediation of arterial stiffness and/or abnormal central hemodynamics. Therefore, the FIB-4 score appears to serve as a direct risk factor for HF from the early stage, and its association with HF may not be mediated by vascular damages.

8A.01: INTERRELATIONSHIPS BETWEEN THE DEVELOPMENT OF HYPERTENSION AND LONGITUDINAL CHANGES OF ARTERIAL STIFFNESS/RENAL FUNCTION, AND PROPER BODY WEIGHT MAINTENANCE.

Objective: The mechanisms of the development of hypertension have not been fully clarified, as conflicting results have been reported on the long term relationships among blood pressure (BP), arterial stiffness, and renal dysfunction. Currently, repeated measure model is regarded as a powerful model for longitudinal data. This prospective study was conducted to examine either the progression of arterial stiffening or renal dysfunction has more close association with the development of hypertension, and to examine interrelationships among BP, arterial stiffness, and renal function, using repeated measure model. We also examined whether proper body weight maintenance affects their interrelationships. Design and method: Middle aged non-hypertensive Japanese men who underwent annual health screening check were prospectively followed up to 11 years from 2002. Arterial stiffness and renal function were measured as brachial-ankle pulse wave velocity (baPWV) and eGFR. A total 3,241 subjects (mean age; 41 ± 9 years) were enrolled in this study. We performed linear mixed models adjusted for conventional risk factors for hypertension to examine longitudinal relationships among baPWV, BP, and eGFR. Subgroup analysis stratified by proper body weight maintenance (keeping BMI <25.0 kg/m2) was also performed. Results: The mean change of baPWV, systolic BP, and eGFR during follow up were, 67 ± 131 cm/sec, 2 ± 12 mmHg, and -10 ± 11 ml/min/1.73 m2, respectively. The results from linear mixed model revealed that baPWV was a significant estimate for annual change of systolic BP independent of eGFR, and systolic BP was a significant estimate for annual change of baPWV as well (both p < 0.05). On contrary, eGFR was not associated with annual changes of either baPWV or BP. These associations were not modified regardless of proper body weight maintenance. Conclusions: In middle-aged Japanese non-hypertensive men, our resuts suggested; 1. The progression of arterial stiffening, rather than that of renal dysfunction, may be a key player for the development of hypertension; 2. The development of hypertension and the progression of arterial stiffening mat have vicious cycle apart from progression of renal dysfunction; 3. The proper body weight maintenance may not be associated with breaking off this vicious cycle.

2A.01: BALANCED OPTIMAL MEDICAL THERAPY IS ESSENTIAL IN MANAGEMENT OF PATIENTS WITH CORONARY ARTERY DISEASE: PULSE WAVE VELOCITY LONG-TERM FOLLOW UP STUDY.

Objective: Global cardiovascular risk stratification is essential in high-risk hypertensive patients. However, it is uncertain how often the strategy is executed in real clinical practice. We sought to evaluate the management of cardiovascular risk in hypertensive patients with coronary artery disease (CAD) using brachial-ankle pulse wave velocity (baPWV). Figure. No caption available. Design and method: A total of 851 hypertensive patients with CAD (age 65 ± 11) were enrolled and baPWV were measured every year (mean follow up periods 4.5 years). All subjects were devided into two groups: optimal medical therapy group (systolic blood pressure<130mmHg, LDL-cho<100 mg/dl and HbA1c<7.0%) and sub-optimal therapy group. Results: In optimal medical therapy group, change of baPWV/year were significantly lower than in sub-optimal therapy group (p < 0.05) (figure). Conclusions: These results suggest that combination of optimal medical therapy is essential in management of high-risk hypertensive patients, and it might also reduce cardiovascular risk.

Differences in effects of age and blood pressure on augmentation index.

BACKGROUND The effect of age on the augmentation index (AI) differs between young adults and the elderly, and the AI reaches a plateau after the age of 60 years. We examined whether the effects of age and an elevation in blood pressure on the AI differ between young adults and the elderly, between subjects with and without high blood pressure, or between subjects with and without a high AI. METHODS The radial AI was measured in 10,190 subjects who were either healthy or had hypertension (n = 5,477 men and 4,743 women). RESULTS In both sexes, a phased increase in the radial AI with age could only be confirmed up to an age of 60 years. A phased increase in the radial AI with the systolic blood pressure (SBP) could be confirmed up to an SBP of >170 mm Hg. Among subjects categorized within the highest age tertile, the highest SBP tertile, or the highest radial AI tertile, stepwise multivariable analyses demonstrated that SBP, but not age, was a significant independent factor influencing the radial AI. CONCLUSIONS The effect of age and blood pressure on AI differ not only between young adults and the elderly but also between those with and those without high blood pressure or between those with and those without a high AI. The effect of an elevation in blood pressure, but not aging, on the AI is significant in the elderly, in subjects with high blood pressure, or in those with a high AI.