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Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1,2 Takashi Hitsumoto,3 Akira Takahara,4 Kohji Shirai1,5 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Internal Medicine, Nagayama Clinic, Oyama, Tochigi, Japan; 3Hitsumoto Medical Clinic, Shimonoseki, Yamaguchi, Japan; 4Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan; 5Department of Internal Medicine, Seijinkai Mihama Hospital, Chiba, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura, Chiba, 285-8741, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.med.toho-u.ac.jpAbstract: Predictive factors for vascular events have not been established. The vasculature of the atheroma is supplied by penetration of the vasa vasorum through the smooth muscle cell layer from the adventitia. Smooth muscle cell contraction induces compression of the vasa vasorum, resulting in ischemia in intimal atheromatous lesions. Cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. We hypothesized that rapidly increased arterial stiffness evaluated by CAVI may be a predictor of impending cardiovascular events.Keywords: arterial stiffness, stress, plaque rupture, CAVI

Daiji Nagayama,1,2 Kentaro Fujishiro,3 Kenji Suzuki,3 Kohji Shirai4 1Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Chiba, Japan; 3Research and Development Division, Japan Health Promotion Foundation, Tokyo, Japan; 4Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Daiji Nagayama, Nagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi, 323-0032, Japan, Tel +81-285-22-0219, Fax +81-285-22-0219, Email deverlast96071@gmail.comAbstract: Cardio-ankle vascular index (CAVI) was developed to reflect the stiffness of the arterial tree from the aortic origin to the ankle. This arterial stiffness parameter is useful for assessing the severity of cardiovascular disease (CVD) and its risk. However, compared to pulse wave velocity (PWV), the conventional gold standard of arterial stiffness parameter, there has been a concern regarding CAVI that there are fewer longitudinal studies for CVD. Furthermore, the accuracy of CAVI for atherosclerotic diseases compared to other parameters has not been well validated. This review article aims to summarize recent findings to clarify the predictive ability of CAVI in longitudinal studies. First, several large longitudinal studies have found that not only baseline CAVI but also CAVI changes during the observation period predict cardiovascular events. Second, CAVI may have superior discriminatory power for all-cause mortality and major adverse cardiovascular endpoints compared to PWV. Furthermore, one large longitudinal study found CAVI to be a stronger predictor for renal function decline compared to PWV as well as CAVI0, a variant of CAVI that mathematically excludes BP dependence. Additionally, CAVI shows the properties that allow the elucidation of specific hemodynamics in aortic valve disease or hypovolemia. In conclusion, CAVI may be a modifiable arterial stiffness parameter not only for predicting and preventing atherosclerotic diseases but also for elucidating specific hemodynamic pathophysiology.Keywords: cardio-ankle vascular index, pulse wave velocity, CAVI0, longitudinal study, cardiovascular disease, renal function decline

Daiji Nagayama,1,2 Tomonori Sugiura,3 Su-Yeon Choi,4 Kohji Shirai5 1Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Chiba, Japan; 3Department of Cardiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 4Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea; 5Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Daiji Nagayama, Nagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi, 323-0032, Japan, Tel/Fax +81-285-22-0219, Email deverlast96071@gmail.comAbstract: Obesity has been known to relate to various diseases and metabolic disorders. Since the implication of body shape has been mentioned, obesity can be divided into visceral obesity and subcutaneous obesity. The former is considered the upstream pathophysiology of metabolic syndrome (MetS), and has been emphasized worldwide for the prevention of cardiovascular diseases in the last quarter century. However, some prospective studies have shown that cardiovascular mortality and morbidity are not necessarily higher in patients with MetS compared to those without. Recently, cardio-ankle vascular index (CAVI) has been established as an indicator of arteriosclerosis. This parameter is independent of blood pressure at the measuring time, and reflects systemic arterial stiffness from the aortic origin to the ankle. However, since CAVI is not necessarily high in MetS patients, attempts have been made to clarify this unexpected phenomenon. In several studies, CAVI was found to correlate negatively with body mass index (BMI), and also with waist circumference (WC) which is a widely used representative visceral obesity index. On the other hand, a body shape index (ABSI) is also a visceral obesity index designed to be minimally associated with BMI, and is calculated by dividing WC by an allometric regression of weight and height. Replacing high WC with high ABSI in MetS diagnosis promoted the identification of MetS patients with increased CAVI in cross-sectional studies on Japanese and Korean populations. Additionally, the incidence of MetS diagnosed using high ABSI was associated with significant increase in CAVI after 1 year of observation. Enhanced predictive ability for renal function decline by replacing WC with ABSI in MetS diagnosis was also observed in a longitudinal study in Japanese urban residents. These findings suggest that MetS diagnosis using high ABSI instead of high WC as a visceral obesity index needs to be reconsidered. However, further research is desirable on Caucasian, whose body shape differs slightly from that of Asians.Keywords: CAVI, metabolic syndrome, waist circumference, a body shape index, renal function decline

Daiji Nagayama,1,2 Kentaro Fujishiro,3 Keijiro Nakamura,4 Yasuhiro Watanabe,2 Takashi Yamaguchi,2 Kenji Suzuki,3 Kazuhiro Shimizu,5 Atsuhito Saiki,2 Kohji Shirai6 1Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Chiba, Japan; 3Japan Health Promotion Foundation, Tokyo, Japan; 4Division of Cardiovascular Medicine, Toho University, Ohashi Medical Center, Tokyo, Japan; 5Division of Cardiovascular Medicine, Toho University, Sakura Medical Center, Chiba, Japan; 6Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Daiji NagayamaNagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi, 323-0032, Japan, Tel/Fax +81-285-22-0219, Email deverlast96071@gmail.comAim: Physiological tests to assess systemic vascular function are not included in the risk score for atrial fibrillation (AF). We aimed to examine whether cardio-ankle vascular index (CAVI), a systemic arterial stiffness parameter, is associated with the presence of AF in Japanese general population.Methods: A cross-sectional study (N = 47,687) and a cohort study (N = 5418, four consecutive years) in Japanese urban residents who participated in annual health screening were conducted.Results: A total of 164 subjects (0.34%) had AF in the cross-sectional data. After propensity score matching for age and gender, logistic regression analysis revealed that CAVI is independently associated with AF, as are body mass index and estimated glomerular filtration rate. In a 4-year cohort study, 22 subjects (0.41%) with new-appearance of AF showed higher CAVI at baseline than those without. In the receiver-operating-characteristic curve analysis, the area under the curve, which is a measure of predictability, of CAVI for the new-appearance of AF was 0.747, and the cut-off value of CAVI was 8.0. Kaplan–Meier analysis revealed that the cumulative incidence of new-appearance of AF was higher in subjects with CAVI ≥ 8.0 compared to those with CAVI < 8.0. In Cox-proportional hazards analysis, CAVI ≥ 8.0 as well as gender were identified as independent predictors for the new-appearance of AF, whereas age ≥ 65 years was not.Conclusion: Increased CAVI may represent a major modifiable risk factor for the development of AF. Studies are needed to confirm that CAVI is a predictor of AF independent of various AF risk factors and that CAVI-lowering interventions can prevent new-appearance or recurrence of AF.Keywords: atrial fibrillation, cardio-ankle vascular index, CAVI, arterial stiffness, health screening

Kouichi Murakami,1 Emi Inayama,1 Yukiko Itoh,1 Shoji Tuchiya,1 Masashi Iwasaki,2 Nobuko Tamura,1 Toshihiko Suzuki,3 Noriko Iwai,1 Junji Utino,4 Motoyuki Masai,4 Daiji Nagayama,5,6 Kohji Shirai4,6 1Seijinaki Mihama Narita Clinic, Narita City, Chiba, 286-0041, Japan; 2Seijinkai Mihama Katori Clinic, Katori City, Chiba, 287-0041, Japan; 3Seijinkai Mihama Sakura Clinic, Sakura City, Chiba, 285-0841, Japan; 4Seijinkai Mihama Hospital, Chiba City, Chiba, 261-0013, Japan; 5Nagayama Clinic, Oyama City, Tochigi, 323-0032, Japan; 6Sakura Hospital, School of Medicine Toho University, Sakura City, Chiba, 285-8741, JapanCorrespondence: Daiji NagayamaNagayama Clinic, 2-12-22, Tenjin-Cho, Oyama City, Tochigi, 323-0032, JapanTel/Fax +81-285-22-0219Email deverlast96071@gmail.comAim: Mortality rate of maintenance hemodialysis patients is known to be high. Cardio-ankle vascular index (CAVI) is an index reflecting the proper stiffness of the arterial tree from the origin of the aorta to the ankle. We aimed to clarify the utility of CAVI as a predictor of mortality in hemodialysis patients. The roles of age and nutritional conditions on survival were also examined.Methods: We followed 242 patients undergoing hemodialysis for 6 consecutive years. Data from 209 patients (mean age was 60 ± 11 years) excluding those with ankle-brachial index < 0.90 were then analyzed. CAVI and heart to ankle pulse wave velocity (haPWV) were measured using Vasera 1500.Results: Thirty-eight hemodialysis patients who died during the 6-year period had higher age, cardiothoracic ratio (CTR), CAVI, and haPWV, and lower diastolic blood pressure, albumin, phosphate, and calcium phosphate product. The Kaplan–Meier curves for cumulative survival among the tertile groups showed that the mortality rate was higher in the highest tertile (T3) compared to T1/T2 for both CAVI and haPWV. Receiver operating characteristic (ROC) analysis revealed that CAVI had better discriminatory power for all-cause mortality compared to haPWV. In the Cox-proportional hazards analyses, 1 SD increase in both parameters contributed independently to all-cause mortality [CAVI: HR 1.595 (95% CI 1.108– 2.297), haPWV: HR 1.695 (95% CI 1.185– 2.425)], as well as age and CTR. Both parameters above the cut-offs estimated in the ROC analysis (CAVI ≥ 9.2, haPWV ≥ 8.9) also had independent contributions to mortality.Conclusion: Through the 6 consecutive years of follow-up in 209 HD patients, increased CAVI might represent a major modifiable risk factor for all-cause mortality. Further research is needed to examine whether CAVI-lowering interventions contribute to improved prognosis.Keywords: hemodialysis patient, mortality, cardio-ankle vascular index, phosphorus

Koji Takahashi,1 Tomoyuki Yamamoto,1 Kohji Shirai2 1Fukuda Denshi Co., Ltd., Tokyo, Japan; 2Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Tomoyuki Yamamoto, Email tomoyuki.yamamoto@fukuda.co.jp

Daiji Nagayama,1,2 Atsuhito Saiki,2 Kohji Shirai3 1Department of Internal Medicine, Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, Chiba, Japan; 3Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Daiji NagayamaDepartment of Internal Medicine, Nagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi, 323-0032, JapanTel/Fax +81-285-22-0219Email deverlast96071@gmail.comAbstract: The significance of statin treatment for the reduction of cardiovascular (CV) disease has been reported, whereas other reports have also described anti-cancer properties associated with the class effect of statins. However, the differences in anti-cancer effect of various types of statins have rarely been examined. Pitavastatin is a statin with a different chemical structure and pharmacokinetics from other statins, and the mechanism of the specific anti-cancer effect of pitavastatin has been reported in in vivo therapeutic models. We previously revealed that pitavastatin therapy was superior to atorvastatin therapy in the prevention of CV events, despite similar LDL-cholesterol-lowering effect in the TOHO Lipid Intervention Trial Using Pitavastatin (TOHO-LIP). Furthermore, in subgroup analysis of the TOHO-LIP study, cumulative 240-week incidence of new cancer cases tended to be lower in the pitavastatin group compared to the atorvastatin group [0.32% (1/312) vs 1.94% (6/310), log-rank P=0.051]. This finding might reveal the superiority of pitavastatin to prevent carcinogenesis. The molecular mechanism by which pitavastatin suppresses the incidence of any-organ cancer is gradually elucidated, and new combination of cancer treatments with pitavastatin will be developed in the future to further enhance the anti-cancer activity and reduce the side effects.Keywords: pitavastatin, anti-cancer effect, TOHO-LIP

Shuji Sato,1 Kazuhiro Shimizu,1 Takuro Ito,1 Masakazu Tsubono,1 Akihiro Ogawa,2 Takeshi Sasaki,3 Mao Takahashi,1 Mahito Noro,1 Kohji Shirai4 1Department of Cardiology, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Rehabilitation, Toho University Sakura Medical Center, Chiba, Japan; 3Department of Clinical Functional Physiology, Toho University Sakura Medical Center, Chiba, Japan; 4Department of Internal Medicine, Mihama Hospital, Chiba, JapanCorrespondence: Kazuhiro ShimizuDepartment of Cardiology, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura City, Chiba, 285-8741, JapanTel +81-43-462-8811Fax +81-43-462-8820Email k432@sakura.med.toho-u.ac.jpBackground: The role of arterial stiffness in the pathophysiology of chronic thromboembolic pulmonary hypertension (CTEPH) is unclear. The cardio-ankle vascular index (CAVI) is a novel arterial stiffness index reflecting stiffness of the arterial tree from the origin of the aorta to the ankle, independent from blood pressure at the time of measurement. CAVI reflects functional stiffness, due to smooth muscle cell contraction or relaxation, and organic stiffness, due to atherosclerosis. Here, we report the case of a patient with an increased CAVI due to CTEPH and the improvement after riociguat administration and balloon pulmonary angioplasty (BPA).Case Presentation: A 65-year-old man suffered from dyspnea on exertion, and he was diagnosed with distal CTEPH. The mean pulmonary artery pressure (mPAP) was 51 mmHg, and the initial CAVI was 10.0, which is high for patient’s age. In addition to right ventricular dysfunction, left ventricular dysfunction was observed as reduced global longitudinal strain (GLS-LV). After riociguat administration, CAVI decreased to 9.1 and GLS-LV improved from − 10.3% to − 17.3%, although pulmonary hypertension remained (mPAP 41 mmHg). Subsequently, a total of five BPA sessions were performed. Six months after the final BPA, mPAP decreased to 19 mmHg and GLS-LV improved to 19.3%. The patient was symptom free and his 6-minute walk distance improved from 322 m to 510 m. CAVI markedly decreased to 5.8, which is extremely low for his age.Conclusion: These observations suggested that arterial stiffness as measured by CAVI was increased in CTEPH, potentially deteriorating cardiac function because of enhanced afterload. The mechanism of the increase of CAVI in this case of CTEPH was obscure; however, riociguat administration and BPA might improve the pathophysiology of CTEPH partly by decreasing CAVI.Keywords: cardio-ankle vascular index, chronic thromboembolic pulmonary hypertension, arterial stiffness, ventricular afterload

Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1 Masashi Harada,2 Chikao Miyazaki,2 Akira Takahara,3 Kohji Shirai1 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Neurosurgery, Toho University Omori Medical Center, Omori, Tokyo, Japan; 3Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, JapanCorrespondence: Kohji ShiraiDepartment of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura City, Chiba, 285-8741, JapanTel +81-43-462-8811Fax +81-43-462-8820Email kshirai@kb3.so-net.ne.jpAbstract: Cardiovascular diseases have been recognized as the main cause of death all over the world. Recently, the established cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. Considering the vasculature of the atheroma where vasa vasorum penetrates the smooth muscle cell layer and supplies blood to the intimal atheromatous lesion, a rapid rise of CAVI means “choked” atheroma. Thus, we proposed a “smooth muscle cell contraction” hypothesis of plaque rupture.Keywords: arterial stiffness, atherosclerosis, smooth muscle cell contraction, CAVI

Koji Takahashi,1 Tomoyuki Yamamoto,1 Shinichi Tsuda,1 Mitsuya Maruyama,1 Kohji Shirai2 1Fukuda Denshi Co., Ltd., Tokyo, Japan; 2Mihama Hospital, Chiba, JapanCorrespondence: Tomoyuki YamamotoFukuda Denshi Co., Ltd., 35-8 Hongo-2-Chome Bunkyo-Ku, Tokyo 113-8420, JapanTel +81-3-5684-1249Fax +81-3-5684-1322Email tomoyuki.yamamoto@fukuda.co.jpAbstract: Arterial stiffness is a good predictor of cardiovascular events. As a substitute for elastic modulus representing stiffness, pulse wave velocity (PWV) has been used for over a century as it is easy to measure; however, PWV is known to essentially depend on blood pressure at the time of measurement. The cardio-ankle vascular index (CAVI) is a relatively new index of global arterial stiffness of the origin of the aorta to the ankle arteries. The characteristic feature is its independency from blood pressure at the measuring time. Recently, a variant index CAVI0 was proposed, which was claimed to be a more accurate arterial stiffness index than CAVI, considering independency from blood pressure. The purpose of this review is to evaluate the properties of CAVI more precisely by comparing with CAVI0, and to confirm the true meaning of CAVI as an index of arterial stiffness. First, the properties of PWV depending on the blood pressure and the variation of PWV values in the cardiac cycle were analyzed. Then, we attempted to clarify the point at which the PWV, adopted in CAVI or in CAVI0, was measured in cardiac cycle. A comprehensive comparison of the clinical data of CAVI and CAVI0 showed that CAVI is more appropriate than CAVI0. In conclusion, CAVI is reconfirmed to be a reliable and useful index of blood pressure-independent arterial stiffness composed of both organic and functional stiffness.Keywords: CAVI, CAVI0, PWV, Bramwell–Hill’s equation, stiffness parameter β

Daiji Nagayama,1,* Haruki Imamura,2,* Kei Endo,3 Atsuhito Saiki,2 Yuta Sato,2 Takashi Yamaguchi,2 Yasuhiro Watanabe,2 Masahiro Ohira,2 Kohji Shirai,4 Ichiro Tatsuno2 1Nagayama Clinic, Tochigi, Japan; 2Center of Diabetes, Endocrinology and Metabolism, Toho University, Sakura Medical Center, Chiba, Japan; 3Endo Clinic, Chiba, Japan; 4Department of Internal Medicine, Mihama Hospital, Chiba, Japan*These authors contributed equally to this workCorrespondence: Daiji NagayamaNagayama Clinic, 2-12-22, Tenjin-Cho, Oyama-City, Tochigi 323-0032, JapanTel +81-285-22-0219Fax +81-285-22-0219Email deverlast96071@gmail.comIntroduction: The main pathophysiology of sepsis is considered to be circulation crisis with an imbalance of vasodilation and vasoconstriction mechanisms, which contributes to multiple organ failure. However, sepsis-induced hemodynamic changes have not been fully validated by novel arterial stiffness parameter. The aim of this study was to clarify the acute vascular alteration and hemodynamic change in sepsis using cardio-ankle-vascular index (CAVI).Methods: Twenty-one Japanese patients (14 males and 7 females, age 62.8 ± 19.0 years) with sepsis were recruited. CAVI was measured before and 1-week after sepsis treatment.Results: The leading underlying cause of sepsis was pyelonephritis, followed by pneumonia, lung abscess, hepatic abscess and cholecystitis. All subjects recovered from sepsis. Analysis of all subjects showed a significant increase in CAVI after 1-week treatment (7.9 ± 2.4 to 9.6 ± 1.8, P < 0.001), but no significant change in blood pressure (BP) was observed. Significant correlations were observed for all combinations among the change in CAVI, systolic BP and ln[procalcitonin (PCT)], respectively. Additionally, in subjects with PCT at presentation ≥2.0 ng/mL, the increase in CAVI after treatment was significantly greater compared to those with PCT < 2.0 ng/mL (2.4 ± 1.6 vs 1.1 ± 0.9, P = 0.037).Discussion: CAVI may reflect sepsis-induced vascular alteration which is not indicated by BP change, and is associated with sepsis severity. These findings suggest the usefulness of CAVI in the management of circulatory failure in sepsis patients.Keywords: SIRS, circulation crisis, procalcitonin, arterial stiffness

Daiji Nagayama,1,2 Haruki Imamura,2 Yuta Sato,2 Takashi Yamaguchi,2 Noriko Ban,2 Hidetoshi Kawana,2 Masahiro Ohira,2 Atsuhito Saiki,2 Kohji Shirai,3 Ichiro Tatsuno2 1Center of Endocrinology and Metabolism, Shin-Oyama City Hospital, Oyama-City, 2Center of Diabetes, Endocrinology and Metabolism, 3Department of Vascular Function, Sakura Medical Center, Toho University, Sakura-City, Japan Objective: The objective of this study is to investigate the association of body mass index (BMI) with arterial stiffness assessed by cardioankle vascular index (CAVI). Subjects and methods: A retrospective cross-sectional study was conducted in 23,257 healthy Japanese subjects (12,729 men and 10,528 women, aged 47.1 ± 12.5 years, BMI 22.9 ± 3.4 kg/m2) who underwent health screening between 2004 and 2006 in Japan. Exclusion criteria were current medication use and a past history of cardiovascular disease, hypertension, stroke, diabetes, and nephritis. Results: Male subjects showed significantly higher BMI, CAVI, and triglycerides and lower high-density lipoprotein (HDL)-cholesterol compared with female subjects. Next, the subjects were divided into tertiles of BMI: lower, middle, and upper, in a gender-specific manner. After adjusting for confounders including age, systolic blood pressure, and HDL-cholesterol identified by multiple regression analysis, the mean CAVI decreased progressively as BMI tertile increased in both genders. Furthermore, a negative inverse relationship between BMI and adjusted CAVI was observed throughout the BMI distribution. Multivariate logistic regression model for contributors of high CAVI (≥90th percentile) identified obesity (odds ratios (95% confidence interval): 0.804 (0.720–0.899)], older age [15.6 (14.0–17.4)], male gender [2.26 (2.03–2.51)], hypertension [2.28 (2.06–2.54)], impaired fasting glucose [1.17 (1.01–1.37)], and low HDL-cholesterol [0.843 (0.669–1.06)] as independent factors. Conclusion: We demonstrated an inverse relationship between CAVI and BMI in healthy Japanese subjects, suggesting that systemic accumulation of adipose tissue per se may lead to a linear decrease of arterial stiffness in nonobese and obese subjects without metabolic disorders. Keywords: BMI, cardioankle vascular index, arterial stiffness

Kazuhiro Shimizu,1 Tomoyuki Yamamoto,2,3 Kohji Shirai2,4 1Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Vascular Function, Toho University Sakura Medical Center, Chiba, Japan; 3Biological Information Analysis Section, Fukuda Denshi Co., Ltd., Tokyo, Japan; 4Department of Internal Medicine, Mihama Hospital, Chiba, Japan Abstract: The cardio–ankle vascular index (CAVI) is an indicator of arterial stiffness from the heart to the ankles. The CAVI increases as arteriosclerosis progresses, but it can be decreased by appropriate treatment. There are several risk factors for coronary artery disease, however, the degree of stress caused by each separate risk factor to arteries cannot be assessed. CAVI increases with age and according to the severity of atherosclerosis. We found that CAVI also changes in response to the control of risk factors, which may be associated with the functional stiffness of arteries. CAVI can be a useful indicator of risk control for coronary artery disease. We followed a patient aged 71 years who had diabetes mellitus and obstructive sleep apnea (OSA) by measuring CAVI for 8 years from age 63. He underwent coronary artery bypass grafting due to angina pectoris when he was 63 years old. Before coronary artery bypass grafting, CAVI was 11.8 on the right and 11.5 on the left. Three years later he was found to have OSA and received treatment with continuous positive airway pressure. There was a marked improvement in CAVI after continuous positive airway pressure (age 68; right 10.4, left 10.2). However, following a gradual increase in body weight and worsening of diabetes mellitus, CAVI showed an increasing trend. CAVI decreased with biguanides treatment, but increased again with an increase in body weight. In conclusion, CAVI responded to the patient’s conditions including obesity, diabetes mellitus, and OSA. CAVI is not only a marker of arterial stiffness, but can also be a useful indicator of physiological status; it may be effective in total risk control for coronary artery disease. Keywords: obstructive sleep apnea, continuous positive airway pressure, cardio-ankle vascular index, biguanides, obesity

Kazuhiro Shimizu,1 Tomoyuki Yamamoto,2,3 Mao Takahashi,1 Shuji Sato,1 Hirofumi Noike,1 Kohji Shirai2 1Department of Internal Medicine, 2Department of Vascular Function, Toho University Sakura Medical Center, Chiba, 3Biological Information Analysis Section, Fukuda Denshi Co., Ltd, Tokyo, Japan Purpose: The purpose of this study was to clarify the difference between effects of nitroglycerin (NTG) on the functional stiffness in patients with and without coronary artery disease (CAD) using a newly developed stiffness index, cardio-ankle vascular index (CAVI).Subjects and methods: The two subject groups in this study were normal controls (n=31) and CAD patients (n=25). The normal controls had no medical history and were not on regular medications. On the other hand, the CAD patients had received various treatments like antihypertensive drugs, hypoglycemic agents, and statins. This study was conducted in CAD patients under medications. After a single sublingual administration of NTG 0.3 mg, CAVI, blood pressure (BP), and heart rate (HR) were measured every 5 minutes for 20 minutes. Comparisons of each parameter before and after taking NTG were evaluated for statistical significance using analysis of variance and post hoc tests. Tukey–Kramer test was used for post hoc comparisons.Results: In the normal controls, CAVI significantly decreased from baseline after 5, 10, and 15 minutes (from 6.5±0.9 to 5.2±0.9, 5.5±0.9, and 5.7±0.9, respectively). Systolic BP and HR were not significantly changed. Diastolic BP significantly decreased from baseline after 5 and 10 minutes (from 72±8 to 64±9 and 63±9 mmHg, respectively). On the other hand, CAVI, HR, and diastolic BP were not changed significantly in CAD patients. Systolic BP was significantly decreased from baseline after 5, 10, and 15 minutes (from 147±16 to 131±14, 129±12, and 129±13 mmHg, respectively). In the comparison of the two groups, ΔCAVI was not significantly different between the normal controls and CAD patients (–1.4±0.7 vs –1.4±0.9, –1.1±0.7 vs –1.4±1.0, –0.8±0.7 vs –1.2±1.0, and –0.5±0.7 vs –1.1±1.0 at 5, 10, 15, and 20 minutes, respectively). ΔHR was not significantly different between the two groups. ΔSystolic BP in the CAD patients was significantly higher than in the normal controls at 5, 10, 15, and 20 minutes (normal controls vs CAD; –3±7 vs –10±11, –3±5 vs –10±11, –3±6 vs –13±10, and –1±6 vs –11±10 mmHg, respectively). ΔDiastolic BP in the normal controls was significantly higher than in the CAD patients at 5 and 10 minutes (normal controls vs CAD; –8±6 vs –4±4 and –9±4 vs –6±5 mmHg, respectively). Conclusion: After NTG administration, the stiffness of the arteries from the origin of the aorta to the ankle as measured by CAVI decreased in both the normal controls and CAD patients, indicating that the response of arterial smooth muscle cells to nitric oxide is preserved even in CAD patients under medication. Keywords: arterial stiffness, cardio-ankle vascular index, nitroglycerin, nitric oxide, stiffness parameter

Masayo Suzuki,1 Mao Takahashi,1 Takuo Iizuka,1 Hitoshi Terada,2 Hirohumi Noike,1 Kohji Shirai3 1Cardiovascular Center, Internal Medicine, 2Department of Radiology, 3Department of Vascular Function, Sakura Hospital, Medical Center, Toho University, Sakura City, Chiba Prefecture, Japan Background: Familial hypercholesterolemia (FH) is associated with premature coronary arterial disease. We aimed to determine the incidence of coronary artery stenosis (CAS) in asymptomatic FH patients using coronary computed tomography angiography (CCTA). To investigate the association between CAS and atherosclerosis of carotid arteries, we performed ultrasonography to measure the mean intima-media thickness (IMT), maximum IMT, and plaque score. We also aimed to examine the significance of the cardio-ankle vascular index (CAVI) and its association with the incidence of CAS in asymptomatic FH patients. Patients and methods: We enrolled consecutively, 31 FH patients without symptoms of coronary artery disease. Based on the CCTA findings, we divided the patients into two groups, those with and without CAS, and compared various parameters and risk factors of the two groups. Results: Of 31 FH patients, seven patients (22.6%) had CAS. The proportion of male patients and mean low-density lipoprotein-cholesterol level were higher in patients with CAS than in those without CAS (P22.6% of the asymptomatic FH patients. Patients with CAS tended to have enhanced levels of carotid plaque markers, but no increase was noted in CAVI. FH patients should be continuously monitored using CCTA and ultrasonography. Keywords: CAVI, coronary artery stenosis, heterozygous familial hypercholesterolemia, CCTA, ultrasound evaluation of the carotid artery

Takashi Hitsumoto,1 Kohji Shirai2 1Hitsumoto Medical Clinic, Yamaguchi, Japan; 2Department of Vascular Function (donated), Sakura Hospital, Toho University School of Medicine, Chiba, Japan Purpose: The blood concentration of cardiac troponin T (ie, high-sensitivity cardiac troponin T [hs-cTnT]), measured using a highly sensitive assay, represents a useful biomarker for evaluating the pathogenesis of heart failure or predicting cardiovascular events. However, little is known about the clinical significance of hs-cTnT in metabolic syndrome. The aim of this study was to examine the factors affecting hs-cTnT elevation in Japanese metabolic syndrome patients. Patients and methods: We enrolled 258 metabolic syndrome patients who were middle-aged males without a history of cardiovascular events. We examined relationships between hs-cTnT and various clinical parameters, including diagnostic parameters of metabolic syndrome. Results: There were no significant correlations between hs-cTnT and diagnostic parameters of metabolic syndrome. However, hs-cTnT was significantly correlated with age (P

Masahiro Ohira,1 Takashi Yamaguchi,1 Atsuhito Saiki,1 Noriko Ban,1 Hidetoshi Kawana,1 Ayako Nagumo,1 Takeyoshi Murano,2 Kohji Shirai,3 Ichiro Tatsuno1 1Center for Diabetes, Endocrinology and Metabolism, 2Department of Clinical Laboratory Medicine, 3Department of Vascular Function, Sakura Hospital, Toho University Medical Center, Chiba, Japan Background: Type 2 diabetes is known to be associated with elevated cardiovascular mortality. Pioglitazone improves blood pressure (BP) and pulse wave velocity (PWV), which is an arterial stiffness parameter. Arterial stiffness is closely associated with cardiovascular disease. However, PWV is correlated with BP. The cardio-ankle vascular index (CAVI) reflects arterial stiffness independent of BP. Pioglitazone improves PWV but reduces blood pressure. The aim of this study was to re-evaluate the effect of pioglitazone on arterial stiffness with CAVI. Methods: Sixty patients with type 2 diabetes mellitus and already on 500 mg/day of metformin received add-on therapy of pioglitazone 15 mg/day or glimepiride 1 mg/day for 6 months, during which time changes in their metabolic parameters and CAVI were observed. Results: After 6 months of treatment, both pioglitazone (n=30) and glimepiride (n=30) improved fasting blood glucose and glycated hemoglobin. The changes in fasting blood glucose and glycated hemoglobin between the two groups were greater in the pioglitazone group. Systolic and diastolic BP was decreased in both groups, with no significant between-group differences. Only pioglitazone increased serum adiponectin levels, and the change in adiponectin between the pioglitazone and glimepiride groups was significantly different. CAVI was decreased significantly by pioglitazone but remained unchanged after treatment with glimepiride. The change in CAVI between the two groups was significantly different. Conclusion: These results suggest that pioglitazone improves CAVI, a BP-independent arterial stiffness parameter, in patients with type 2 diabetes mellitus treated with metformin. Keywords: biguanide, thiazolidinediones, sulfonylurea, blood pressure, cardiovascular disease, arterial stiffness

James D Cameron,1 Roland Asmar,2 Harry Struijker-Boudier,3 Kohji Shirai,4 Yuriy Sirenko,5 Yulia Kotovskaya,6 Jirar Topouchian71Monash Cardiovascular Research Centre, Clayton, Melbourne, Victoria, Australia; 2Roland Asmar, Foundation Medical Research Institutes, Paris, France; 3Department of Pharmacology, Maastricht University, Maastricht, The Netherlands; 4Department of Vascular Function, Sakura Hospital, Toho University, Tokyo, Japan; 5Institute of Cardiology, Kiev, Ukraine; 6ESH Hypertension Excellence Center of Peoples Friendship University of Russia, Moscow, Russia; 7Department of Diagnosis and Therapeutics, Hôtel-Dieu University Hospital, Paris, FranceAbstract: Central arterial structure and function comprise a primary determinant of vascular health, and are integral to the important concept of ventriculo-vascular coupling or interaction. Central aortic stiffening is a major influence on central blood pressure, and directly relates to coronary perfusion. The joint session of the International Society of Vascular Health (Eastern Region) and the Ukrainian Congress of Cardiology was held in Kiev, Ukraine, on September 23, 2011; it provided an expert forum to discuss arterial evaluations, clinical applications, and progress toward translating arterial protection into cardiovascular benefits. The conclusions of the expert panel were:1. Aortic stiffness is not presently a treatment target but may be useful for substratifying cardiovascular risk in individuals in order to better target the intensity of conventional therapy, and it may be useful in assessing response to treatment.2. Crosstalk between macro- and microcirculation in hypertension has important implications for pharmacological treatment. An antihypertensive regimen should abolish the vicious cycle between the increased resistance in the microcirculation and the increased stiffness of the larger arteries. Such treatment should be based on drugs with multiple actions on the vascular tree, or on drug combinations that target the various segments of the arterial system.3. Several blood pressure-independent mechanisms of large artery stiffness exist. Future considerations for clinical understanding of large artery stiffness should involve new drugs and new evaluation methods – with a focus on vascular health, for the initiation of cardiovascular prevention, for newly designed studies for treatment evaluation, and for new studies of drug combinations.4. Arterial stiffening is a sign of cardiovascular aging and is a major factor affecting the biomechanics of large arteries. Arterial stiffness is an attractive therapeutic target in terms of vascular aging. Healthy lifestyle, physical exercise, and smoking cessation are the most effective ways of preventing and treating early vascular aging. Long-term effects of cardiovascular drugs on arterial stiffness need to be further investigated.5. The emerging clinical data on the cardio ankle vascular index (CAVI) technique of arterial health assessment is presented, showing that the CAVI is elevated in aging, coronary artery diseases, chronic kidney disease, hypertension, diabetes mellitus, smoking, and stress. The CAVI decreased with the administration of statins, angiotensin II receptor blocking agents, and calcium channel blockers. The CAVI is suggested as an important predictor of cardiovascular diseases.Future development of a clinical understanding of large artery stiffness is important and should include consideration of new drugs and new evaluation methods, with a focus on vascular health aimed at cardiovascular prevention.Keywords: arterial stiffness, cardiovascular protection, hypertension, arterial hemodynamic evaluation

Suzuki M, Takahashi M, Iizuka T et al. Frequency of coronary artery stenosis in patients with asymptomatic familial hypercholesterolemia and its association with carotid intimal thickness and cardio-ankle vascular index. Research Reports in Clinical Cardiology. 2016;7:83–90. Read the original article

Objective: This study aimed to use short-form visual analogue scale cochlear implantation questionnaires to evaluate subjective aspects at each out-patient visit. The correlation between subjective hearing tests using the short-form visual analogue scale and objective hearing outcomes was evaluated. Method: This study was conducted in a single centre. Cochlear implant users (n = 199) evaluated their hearing on a scale of 0 to 100 for the right, left and both ears. The Japanese speech perception test (CI-2004) Japanese monosyllable speech perception test (67-S) and cochlear implantation threshold were used for the objective cochlear implantation evaluation. Results: A significant correlation was found between the short-form visual analogue scale questionnaire and objective hearing outcome, for words (r = 0.64) and sentences (r = 0.62) in CI-2004 and 67-S (r = 0.56) tests. No significant correlation was found between the short-form visual analogue scale score and cochlear implantation threshold (r = −0.18). Conclusion: Short-form visual analogue scale cochlear implantation questionnaires mean cochlear implant users spend less time answering subjective visual analogue scale questionnaires, and clinicians estimate a patient's cochlear implantation hearing and abnormality by chronological evaluation. [ABSTRACT FROM AUTHOR]