successful diet and exercise therapy as evaluated on self

Circulation Journal Vol.77, November 2013

Circulation JournalOfficial Journal of the Japanese Circulation Societyhttp://www.j-circ.or.jp

etabolic syndrome (MetS) is associated with accu-mulation of multiple cardiovascular risk factors and is characterized by the retention of visceral fat

and abdominal obesity.1 It has been linked to increased risk of cardiovascular disease and mortality.1 The traditional cardio-vascular risk factors lead to impaired nitric oxide bioactivity resulting in endothelial dysfunction, and increased visceral fat level also causes endothelial dysfunction even in the absence

of changes in blood pressure and heart rate.2 In previous stud-ies, endothelial dysfunction has been implicated as the key pathogenesis and clinical course of all known cardiovascular diseases, and is associated with future risk of adverse cardio-vascular events.2

Lifestyle intervention with diet and exercise therapy is an important fundamental approach to the prevention of cardio-vascular disease in MetS, but maintenance of patient motiva-

M

Received April 25, 2013; revised manuscript received June 20, 2013; accepted July 25, 2013; released online August 28, 2013 Time for primary review: 31 days

Department of Cardiovascular Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Y.M., S.S., K.S., H. Sumida, H.K., K.F., M.K., E.A., N.N., M.Y., S.I., H.O.); Jinnouchi Hospital, Kumamoto (S.S., H.J.); Division of Cardiology, Yokohama City Univer-sity Medical Center, Yokohama (Y.M., M.K., E.A., H. Suzuki, N.N., K.K.); and Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama (S.U.), Japan

Grant-in-aid for scientific research (No. C22590786 and C25461086 for S. Sugiyama) from the Ministry of Education, Science, and Culture in Japan. Grant from the West Japan Vascular Function Society.

Mailing address: Seigo Sugiyama, MD, PhD, Department of Cardiovascular Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan. E-mail: [email protected]

ISSN-1346-9843 doi: 10.1253/circj.CJ-13-0549All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Successful Diet and Exercise Therapy as Evaluated on Self-Assessment Score Significantly Improves Endothelial

Function in Metabolic Syndrome PatientsYasushi Matsuzawa, MD, PhD; Seigo Sugiyama, MD, PhD; Koichi Sugamura, MD, PhD;

Hitoshi Sumida, MD, PhD; Hirofumi Kurokawa, MD; Koichiro Fujisue, MD; Masaaki Konishi, MD, PhD; Eiichi Akiyama, MD; Hiroyuki Suzuki, MD;

Naoki Nakayama, MD, PhD; Megumi Yamamuro, MD, PhD; Satomi Iwashita; Hideaki Jinnouchi, MD, PhD; Kazuo Kimura, MD, PhD; Satoshi Umemura, MD, PhD; Hisao Ogawa, MD, PhD

Background: Simple office-based counseling for diet and exercise does not appear to positively affect success rates in metabolic syndrome (MetS) patients. The utility of the lifestyle modification self-assessment score (Self-AS) in the improvement of endothelial function by office-based counseling for patients with MetS was investigated.

Methods and Results: Patients with MetS (n=207) and age- and sex-matched individuals without MetS (n=124) were enrolled in this cross-sectional study. Endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry index (RHI). Patients with MetS had significant endothelial dysfunction compared with those with-out MetS (RHI, 0.502±0.178 vs. 0.614±0.229; P<0.001). Seventy MetS patients participating in the prospective in-terventional study received simple office-based lifestyle modification counseling that was accompanied by Self-AS questionnaire after 10 months. RHI was significantly improved following lifestyle modifications (from 0.452±0.136 to 0.547±0.202, P<0.001). Reductions in waist circumference (R2=0.094, P=0.01) and increased high-density lipopro-tein cholesterol (R2=0.227, P<0.001) independently correlated with improved RHI. Self-AS significantly correlated with changes in waist circumference (r=−0.57, P<0.001) and RHI (r=0.30, P=0.02). Patients with a good achievement of lifestyle modifications (higher Self-AS) had significant improvement in endothelial function compared with those with lower scores (% change in RHI, +48.7±61.6 vs. +7.8±35.1, P=0.001).

Conclusions: Good achievement of lifestyle modifications as evaluated on Self-AS significantly improved endothe-lial function with concomitant reductions in waist circumferences in MetS patients. (Circ J 2013; 77: 2807 – 2815)

Key Words: Endothelial function; Lifestyle modification; Metabolic syndrome; Self-assessment

ORIGINAL ARTICLEPreventive Medicine


2808 MATSUZAWA Y et al.

good achievement of lifestyle modification, as reflected by high self-assessment score (Self-AS), could be associated with this improved endothelial function.

MethodsSubjects and ProtocolThe study flowchart is given in Figure 1A. We enrolled 231 stable MetS patients who were under 70 years of age without heart failure; they were referred to the Kumamoto University Hospital with more than 1 conventional coronary risk factor between August 2006 and June 2010. We excluded 24 patients on the basis of active inflammatory disease (n=10); chronic kidney disease on hemodialysis (n=1); cancer (n=4); advanced endocrine disease (n=1); advanced hepatic disease (n=5); leu-kemia (n=1); and cerebrovascular disease with residual hemi-plegia (n=2). Age- and sex-matched individuals (n=124) with-out MetS were also enrolled.

Reactive hyperemic changes in finger pulse volume were monitored on RH-PAT using the Endo-PAT2000 (Itamar Medical, Caesarea, Israel). For all subjects, we performed height, weight, waist circumference, and blood pressure mea-surements and gave them a questionnaire, including smoking habits and family histories. We performed office-based life-style modification counseling with Self-AS survey in the MetS patients.

The present study complied with the Declaration of Helsinki

tion is difficult, and an objective assessment of the cardiovas-cular efficacy of the lifestyle intervention and extent of waist reduction is still undetermined. The simple use of office-based counseling for diet and exercise alone does not appear to be associated with sufficient success rates;3 consequently, an objective strategy that improves patient motivation is desir-able. Previous research has suggested that self-monitoring is a very important factor in all behavioral change strategies.4

The cardiovascular benefits of lifestyle intervention may be accompanied by improved endothelial function.5 A recent study reported that the digital hyperemic response as assessed by re-active hyperemia-peripheral arterial tonometry (RH-PAT) is a non-invasive, automatic, reproducible, and less operator-depen-dent clinical test for evaluating endothelial function.6 In the Framingham Heart Study, cardiovascular risk factors, particu-larly obesity and metabolic abnormalities, were associated with vascular endothelial dysfunction as assessed on RH-PAT.7 We have previously reported that RH-PAT was clinically useful in the identification of high-risk female patients with ischemic heart disease.8 Kitta et al reported that the improvement of vas-cular endothelial function is associated with a future decrease in cardiovascular events.9 Taken together, lifestyle interventions that are accompanied by self-assessment targeting improved endothelial function as assessed using RH-PAT may be an ef-fective treatment strategy in patients with MetS.

We hypothesized that diet and exercise therapy effectively improved endothelial function in patients with MetS, and the

Figure 1. (A) Study flow chart and (B) visual analog scale for dietary and exercise self-assessment score (Self-AS). MetS, meta-bolic syndrome.


2809Lifestyle Modification and Endothelial Function

Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATP III), which proposes 5 criteria.10 We thought it in-appropriate, however, to use the ATP III criterion for abdominal obesity in the present study because body mass in the Japanese population tends to be less than that in Caucasian peoples. Instead, as proposed by the Japanese Society for Obesity, we defined waist circumference ≥90 cm in women and ≥85 cm in men as indicative of abdominal obesity.11

Endothelial Function TestTo evaluate peripheral endothelial function, RH-PAT was mea-sured using an Endo-PAT 2000 in a dark room with constant temperature and humidity. RH-PAT was carried out during the early morning fasting period prior to breakfast and the ingestion of any medication. The principle of the PAT technology has been described previously.12 Briefly, a blood pressure cuff was placed on 1 upper arm (occluded arm), the other arm served as a control (control arm), and the PAT probes were placed on 1 finger of each hand. The PAT signals were recorded electroni-cally and analyzed online in an operator-independent manner (Endo-PAT2000 software, version 3.0.4). RH-PAT measure-

and was approved by the Kumamoto University Institutional Review Board. We conducted this study in accordance with the guidelines of the institution ethics committee. Written in-formed consent was obtained from each patient before par-ticipation.

Coronary Risk FactorsCoronary risk factors were defined as a family history of coro-nary artery disease, current smoking (within 1 year), hyperten-sion (>140/90 mmHg or taking anti-hypertensive medication), dyslipidemia (high-density lipoprotein cholesterol [HDL-C] <40 mg/dl, low-density lipoprotein cholesterol [LDL-C] ≥140 mg/dl, triglycerides ≥150 mg/dl or taking medications for dyslipidemia), and diabetes mellitus (symptoms of diabetes plus casual plasma glucose concentration ≥200 mg/dl, fasting plasma glucose concentration ≥126 mg/dl, and 2-h plasma glucose concentration ≥200 mg/dl following 75 g oral glucose tolerance test or taking hypoglycemia medication).

MetSMetS was defined according to the guidelines of the National

Figure 2. Endothelial function as assessed on RHI. (A) RHI vs. presence of metabolic syndrome (MetS). Data is expressed in mean and standard deviation. (B) Relationship between RHI and number of MetS factors. (C) Improvement of RHI after lifestyle modifications. Data is expressed in mean and standard deviation. RHI, reactive hyperemia-peripheral arterial tonometry index.



Karvonen method or Borg scale (Karvonen method, target heart rate =[(220−age)−resting heart rate]×0.5+resting heart rate; Borg scale, 11–13). At least 30 min of exercise was rec-ommended per day, 4–5 days per week.

Follow-up of MetS Patients: Re-Evaluation of Endothelial Function and Lifestyle Self-AssessmentFollow-up was carried out in 70 patients with MetS. We inves-tigated changes in RHI and cardiovascular risk factors after 10 months. At the end of follow-up, a self-assessment questionnaire was used with a visual analog scale for diet and for exercise modification, respectively (Figure 1B), in which non-achieve-ment was defined as 0 points and complete achievement as 10 points. Diet and exercise Self-AS were added to calculate the total score (maximum of 20). For evaluation of Self-AS, good achievement of lifestyle modifications was originally defined as higher Self-AS, >13 (median) points in the present study.

Statistical AnalysisThe distribution of the continuous variables was tested for normality using the Kolmogorov-Smirnov test. The normally distributed continuous variables are expressed as mean ± SD, while the continuous variables with skewed distributions are expressed as median (interquartile range [IQR]). Continuous variables were analyzed with the paired t-test, unpaired t-test, Mann-Whitney U-test or Wilcoxon’s matched pairs test as appropriate. Categorical variables are represented by numbers (percent), and intergroup comparisons were analyzed with the chi-squared test (and Fisher’s exact test). We categorized pa-tients using the cut-off of Self-AS (median, 13 points) for the good achievement of lifestyle modifications and change in RHI (median, 0.184). We examined linear regression models to determine the correlations of baseline RHI with the clinical data using age- and sex-adjusted models and stepwise multi-variate model (with age and sex included). We investigated

ments were assessed using a computerized, automated algo-rithm (Itamar Medical Ltd, Caesarea, Israel); thus, there was less intra-observer or inter-observer variability. After a 5-min equilibration period, the cuff on the upper arm was inflated to 60 mmHg above the systolic blood pressure or 200 mmHg for 5 min and then deflated to induce RH. The PAT recording con-tinued for 5 min following cuff deflation.

The RH-PAT ratio was calculated as the ratio of the average amplitude of the PAT signal over a 1-min time interval begin-ning 1.5 min after cuff deflation (control arm, A; occluded arm, C) divided by the average amplitude of the PAT signal for the 2.5-min time period before cuff inflation (baseline; control arm, B; occluded arm, D). Because the RH-PAT ratios have skewed distributions (Kolmogorov-Smirnov test, P<0.001), we used the RH-PAT index (RHI) for the present analysis. RHI is derived from the following equation:

RHI=Ln{(C/D)/(A/B)×[0.226×Ln(baseline)−0.2]}.7 Previ-ous studies have shown that the RH-PAT technology has ex-cellent reproducibility.12–14

Lifestyle InstructionsWe gave simple office-based lifestyle modification counseling to all of the MetS patients. We distributed printed educational information and instructed patients on diet and exercise guide-lines according to the Japan Atherosclerosis Society Guidelines for the Prevention of Atherosclerotic Cardiovascular Diseas-es.15 For diet, they were directed by the dietician to limit total energy intake to their ideal body weight×125.6 kilojoules at 1 individual, 30-min session (ideal body weight=height2×22). The recommended nutrient distribution was as follows: 60% carbohydrates, 15–20% proteins, 20–25% lipids, ≤300 mg/day cholesterol, ≥25 g/day dietary fiber, and ≤25 g/day alcohol. In-structions regarding the moderate-intensity physical exercise therapy were given by the attending physician at 1 individu-al, 30-min session. Exercise intensity was determined by the

Table 1. RHI and Cardiovascular Risk Factors (n=331)

VariablesAge- and sex-adjusted model Stepwise model

B (SE) Partial R2 P-value B (SE) Partial R2 P-value

Age –0.011 (0.011) 　0.003 　0.32　　 –0.011 (0.011) 0.003 　0.31　　Male –0.107 (0.025) 　0.057 <0.001 –0.096 (0.024) 0.046 <0.001

Currently smoking –0.005 (0.027) <0.001 　0.85　　 Not selected

BMI –0.048 (0.011) 　0.055 <0.001 Not selected

WC –0.062 (0.011) 　0.091 <0.001 –0.055 (0.011) 0.072 <0.001

SBP –0.012 (0.011) 　0.003 　0.30　　 Not selected

DBP –0.014 (0.011) 　0.005 　0.20　　 Not selected

FBG –0.029 (0.011) 　0.020 　0.009 Not selected

HbA1c –0.040 (0.011) 　0.037 <0.001 –0.024 (0.011) 0.014 　0.03　　HDL-C 0.029 (0.011) 　0.021 　0.008 Not selected

Triglycerides –0.026 (0.011) 　0.016 　0.02　　 Not selected

hs-CRP –0.026 (0.011) 　0.016 　0.02　　 –0.021 (0.011) 0.011 　0.047

Anti-hypertensive drugs –0.056 (0.025) 　0.015 　0.002 Not selected

Anti-diabetes drugs –0.064 (0.028) 　0.015 　0.003 Not selected

HMG CoA-reductase inhibitors –0.047 (0.022) 　0.013 　0.04　　 Not selected

Prior CAD –0.048 (0.023) 　0.013 　0.04　　 Not selected

Model R2 0.163

Age and sex were forced into all models. Not selected, not selected by stepwise algorithm with significance level of 0.10. HbA1c, hemoglobin A1c (Japan Diabetes Society)+0.4. Continuous variables were standardized to mean of 0 and SD of 1, and all categorical variables were coded as 1, presence of factor; or 0, absence of factor.BMI, body mass index; CAD, coronary artery disease; DBP, diastolic blood pressure; FBG, fasting blood glucose; HDL-C, high-density lipoprotein cholesterol; HMG, hydroxymethylglutaryl; hs-CRP, high-sensitivity C-reactive protein; RHI, reactive hyperemia-peripheral arterial tonometry index; SBP, systolic blood pressure; WC, waist circumference.



male sex (partial R2=0.046, P<0.001), higher waist circumfer-ence (partial R2=0.072, P<0.001), higher hemoglobin A1c (par-tial R2=0.014, P=0.03), and higher high-sensitivity C-reactive protein (hs-CRP; partial R2=0.011, P=0.047) were independent factors significantly associated with endothelial dysfunction (Table 1).

Lifestyle Instructions for MetS Patients and Self-AssessmentThe baseline characteristics of the 70 patients from the follow-up study are listed in Table 2. The MetS patients with good improvement of endothelial function (change in RHI >0.184; median) had higher systolic blood pressure, higher HDL-C, and lower triglycerides than those with poor improvement of en-dothelial function (change in RHI ≤0.184; median) at baseline (Table 2). Before follow-up RH-PAT, self-assessment question-naires were completed for diet and exercise, respectively. The mean Self-AS for diet was 6.5±2.3, that for exercise was 6.1±2.6, and total Self-AS was 12.6±4.0. In the stable MetS patients in this interventional study, 34 patients (48.6%) achieved good lifestyle modification. The MetS patients with a good improve-ment of endothelial function had significantly higher Self-AS than those with poor improvement of endothelial function (Self-AS, median, IQR: 14, 12–16 vs. 12, 8–14, P=0.01).

associations between changes in RHI and changes in covari-ates using univariate and multivariate analysis with a back-ward algorithm linear and logistic regression analysis. P<0.05 denoted statistical significance; all of the tests were 2-tailed. Statistical analysis was done using PASW 18 for Windows (SPSS, Tokyo, Japan).

ResultsMetS and RHIThe baseline clinical characteristics for MetS patients and age- and sex- matched patients without MetS are given in Table S1. Endothelial function as assessed using RHI was sig-nificantly impaired in MetS patients compared with the non-MetS group (non-MetS, 0.614±0.229; MetS, 0.502±0.178; P<0.001; Table S1; Figure 2A). As the number of ATP-III metabolic diagnostic criteria increased, RHI, reflecting endo-thelial function, correspondingly decreased (r=−0.33, P<0.001; Figure 2B).

Clinical Correlation of Baseline Characteristics and RHI in 331 PatientsStepwise multivariate linear regression analysis showed that

Table 2. Baseline MetS Clinical Characteristics (n=70)

All patientsn=70

Change in RHI ≤0.184n=35

Change in RHI >0.184n=35

P-value†

Male 56 (80.0) 30 (85.7) 26 (74.3) 　0.37

Age (years) 57.0±8.8　　 57.3±8.4 56.7±9.3 　0.78

BMI (kg/m2) 26.3±3.6　　 26.8±3.0 25.7±4.1 　0.20

Waist (cm)

Male (n=56) 92.8±7.3　　 93.7±6.8 91.8±7.9 　0.35

Female (n=14) 96.4±10.8 99.0±8.1 94.9±12.3 　0.52

Abdominal obesity 64 (91.4) 34 (97.1) 30 (85.7) 　0.20

Hypertension 62 (88.6) 32 (91.4) 30 (85.7) 　0.71

Diabetes mellitus 36 (51.4) 16 (45.7) 20 (57.1) 　0.47

Dyslipidemia 64 (91.4) 34 (97.1) 30 (85.7) 　0.20

Currently smoking 23 (32.9) 14 (40.0) 9 (25.7) 　0.31

SBP (mmHg) 133.3±18.3　　 128.1±12.8 138.4±21.4 　0.02

FBG (mg/dl) 101 (92–128)　　　 99 (92–116)　 106 (91–134)　　　　0.47

HbA1c (%) 6.5±1.2 6.4±1.2 6.6±1.3 　0.52

HOMA-IR 2.2±1.7 2.3±2.0 2.1±1.4 　0.75

Total cholesterol (mg/dl) 190.4±43.4　　 188.2±42.8 192.6±44.6 　0.67

HDL-C (mg/dl) 50.9±16.9 46.4±13.1 55.4±19.1 　0.02

LDL-C (mg/dl) 111.2±33.9　　 111.4±32.8 111.1±35.5 　0.97

Triglycerides (mg/dl) 150 (91–199)　　　 164 (128–219)　 122 (81–187)　　　　0.04

hs-CRP (mg/L) 1.15 (0.50–1.83) 1.30 (0.40–1.80) 1.10 (0.50–2.20) 　0.79

eGFR (ml · min–1 · 1.73 m–2) 76.0±16.4 78.1±13.3 73.6±19.3 　0.31

Aspirin 46 (65.7) 25 (71.4) 21 (60.0) 　0.45

HMG CoA-reductase inhibitors 40 (57.1) 19 (54.3) 21 (60.0) 　0.81

Calcium channel blockers 36 (51.4) 15 (42.9) 21 (60.0) 　0.23

ACEIs or ARBs 36 (51.4) 17 (48.6) 19 (54.3) 　0.81

β-blockers 18 (25.7) 11 (31.4) 7 (20.0) 　0.41

Anti-diabetes drugs 23 (32.9) 9 (25.7) 14 (40)　　　　0.31

Prior CAD 42 (60.0) 21 (60.0) 21 (60.0) >0.99

Data given as mean ± SD, median (IQR) or n (%). †Comparison of RHI groups: unpaired t-test, Mann-Whitney U-test, or Fisher’s exact test. HbA1c, hemoglobin A1c (Japan Diabetes Society)+0.4.ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; HOMA-IR, homeostasis model assessment-insulin resistance; LDL-C, low-density lipoprotein choles-terol; MetS, metabolic syndrome. Other abbreviations as in Table 1.



rithm, identified the reductions in waist circumference as sig-nificantly associated with good improvement of endothelial function (defined as change in RHI >0.184, median; odds ratio [OR] for per 1-cm change in waist circumference, 0.885; 95% confidence interval [95% CI]: 0.791–0.989, P=0.03).

Self-AS Correlated With Changes in Waist Circumference and Endothelial FunctionTotal Self-AS was significantly correlated with reduction in waist circumference (r=−0.57, P<0.001; Figure 3A) and in-crease in RHI (r=0.30, P=0.02; Figure 3C). Endothelial func-tion and waist circumference did not change significantly in patients with poor achievement of lifestyle modifications (lower Self-AS; Table 3); and patients with good achievement of lifestyle modifications (higher Self-AS) had significant re-duction in waist circumference (% change in waist circumfer-ence, −7.0±8.4 vs. +0.5±2.5, P<0.001; Figure 3B) and sub-stantial improvement in endothelial function compared with the lower Self-AS group (% change in RHI, +48.7±61.6 vs. +7.8±35.1, P=0.001; Figure 3D). Multivariate logistic regres-sion analysis in the forced inclusion model with age, gender, and baseline BMI showed that good achievement of lifestyle modifications (higher Self-AS ≥14) was significantly associ-ated with good improvement of endothelial function assessed on RHI (change in RHI >0.184, median; (OR, 5.353; 95% CI: 1.670–17.16, P=0.005).

Lifestyle Modification Improved Metabolic Status in MetS PatientsAnthropometric data, laboratory data, and endothelial function at baseline and follow-up are listed in Table 3. Body mass index (from 26.3±3.6 to 25.9±3.7 kg/m2, P=0.03), waist cir-cumference (93.6±8.2 to 90.2±9.9 cm, P<0.001), systolic blood pressure (133.3±18.3 to 124.6±14.6 mmHg, P=0.001), triglyc-erides (150, 91–199 to 117, 89–155 mg/dl, P<0.001), hs-CRP (1.15, 0.50–1.83 to 0.60, 0.30–1.20 mg/L, P=0.03), and prev-alence of smoking (32.9% to 10.0%, P<0.001) were signifi-cantly decreased at follow-up compared to baseline. Hemoglo-bin A1c (P=0.19) and HDL-C (P=0.17) tended to improve following the lifestyle modifications, but the changes were not significant. As a whole, RHI significantly improved following lifestyle intervention (baseline, 0.452±0.136; follow-up, 0.547±0.202, P<0.001; Table 3; Figure 2C). In the patients with the poor achievement of lifestyle modifications (lower Self-AS), although prevalence of smoking significantly de-creased, endothelial function did not improve (Table 3). We investigated the continuous factors that were associated with change in RHI. Reductions in waist circumference (β=−0.023, SE=0.009, partial R2=0.094, P=0.01) and increased HDL-C (β=0.017, SE=0.004, partial R2=0.227, P<0.001) were signifi-cantly and independently correlated with improved RHI on multivariate linear regression analysis (Table 4). Multivariate logistic regression analysis, which included age, gender, and changes in risk factors during follow-up with backward algo-

Table 3. Follow-up MetS Data (n=70)

MetS (n=70) Self-assessment score ≥14 (n=34)

Baseline Follow-up P-value† Baseline Follow-up P-value†

BMI (kg/m2) 26.3±3.6　　 25.9±3.7　　　0.03　　 26.5±4.0　　 25.6±3.9　　　0.001

WC (cm) 93.6±8.2　　 90.2±9.9　　 <0.001 94.7±8.2　　 87.7±10.7 <0.001

SBP (mmHg) 133.3±18.3　　 124.6±14.6　　　0.001 137.5±20.3　　 123.3±16.2　　 <0.001

FBG (mg/dl) 101 (92–128)　　　 101 (90–119)　　　　0.35　　 108 (91–130)　　　 98 (87–116)　　0.002

HbA1c (%) 6.5±1.2 6.4±1.1 　0.19　　 6.4±1.2 6.2±1.1 　0.20　　HDL-C (mg/dl) 50.9±16.9 53.2±16.4 　0.17　　 52.4±18.9 56.0±19.9 　0.18　　Triglycerides (mg/dl) 150 (91–199)　　　 117 (89–155)　　　 <0.001 136 (82–188)　　　 109 (83–142)　　　 <0.001

hs-CRP (mg/L) 1.15 (0.50–1.83) 0.60 (0.30–1.20) 　0.03　　 0.95 (0.48–1.83) 0.40 (0.30–1.00) 　0.054

Smoking 23 (32.9) 7 (10.0) <0.001 10 (29.4) 2 (5.9) 　0.003

RHI 0.452±0.136 0.547±0.202 <0.001 0.459±0.127 0.644±0.206 <0.001

Self-assessment score ≤13 (n=36)

Baseline Follow-up P-value†

BMI (kg/m2) 26.1±3.3　　 26.2±3.6　　 0.45　　WC (cm) 92.5±8.2　　 92.6±8.5　　 0.78　　SBP (mmHg) 129.9±15.7　　 125.8±13.0　　 0.21　　FBG (mg/dl) 99 (92–128)　 107 (94–124)　　　 0.09　　HbA1c (%) 6.6±1.2 6.5±1.1 0.61　　HDL-C (mg/dl) 49.5±14.9 50.7±12.0 0.59　　Triglycerides (mg/dl) 159 (97–218)　　　 119 (99–186)　　　 0.10　　hs-CRP (mg/L) 1.30 (0.50–1.88) 0.80 (0.40–1.30) 0.31　　Smoking 13 (36.1) 5 (13.9) 0.003

RHI 0.446±0.146 0.455±0.152 0.71　　

Data given as mean ± SD, median (IQR) or n (%). Patients were divided by 13 points (median) of self-assessment score. †Paired t-test and Wilcoxon’s matched-pairs test. HbA1c, hemoglobin A1c (Japan Diabetes Society)+0.4. Categorical data (smoking) were coded as: 1, pres-ence of factors; 0, absence of factors.Abbreviations as in Tables 1,2.



style modifications in the form of caloric restriction and mod-erate-intensity physical exercise in the MetS patients allowed for reductions in waist circumference and increased HDL-C level, which were significantly associated with improvement in endothelial function as shown on the multivariate model.

DiscussionThe present study showed that endothelial function as assessed on RHI was significantly impaired in patients with MetS com-pared with age- and sex-matched patients without MetS. Life-

Table 4. Continuous Factors Associated With Change in RHI

VariablesUnivariate Multivariate

B (SE) Partial R2 P-value B (SE) Partial R2 P-value

Change in BMI –0.094 (0.048) 　0.054 0.06　　 Not selected

Change in WC –0.025 (0.009) 　0.101 0.008 –0.023 (0.009) 0.094 　0.01　　Change in SBP –0.004 (0.003) 　0.028 0.17　　 Not selected

Change in HbA1c 0.040 (0.075) 　0.004 0.60　　 Not selected

Change in triglycerides <0.001 (0.001)　 <0.001 0.96　　 Not selected

Change in HDL-C 0.014 (0.004) 　0.129 0.002 0.017 (0.004) 0.227 <0.001

Change in hs-CRP –0.755 (0.335) 　0.089 0.03　　 Not selected

Model R2 0.306

Not selected, not selected by backward algorithm with significance level of 0.10. HbA1c, Hemoglobin A1c (Japan Diabetes Society)+0.4.Abbreviations as in Table 1.

Figure 3. (A,B) Higher total self-assessment score was associated with greater reduction in waist circumference and (C,D) greater improvement of RHI. (B,D) Data is expressed in mean and standard deviation. RHI, reactive hyperemia-peripheral arte-rial tonometry index.



dilation (FMD) is a common method that can non-invasively assess peripheral endothelial function, the results of which have been correlated with coronary endothelial function.23 Results of FMD, however, vary due to technical issues that frequently occur during measurement, and thus, FMD has not been stan-dardized among institutions.24 RH-PAT is also a non-invasive clinical test to evaluate peripheral endothelial function. Past studies have shown that RHI is well correlated with coronary artery response to acetylcholine.8,25 Furthermore, Rubinshtein et al reported that RHI predicted adverse cardiovascular events in patients without known coronary artery disease.19 In the present study with MetS patients, we assessed endothelial func-tion using RH-PAT, which significantly reflects obesity and cardio-metabolic abnormalities.6,26 Vascular endothelial dys-function has been shown to be reversible, and we have shown that successful lifestyle modification, as assessed on Self-AS, is significantly associated with the improvement of endothelial function as assessed on RH-PAT in the present study. RH-PAT can be performed repeatedly in clinical practice because of its non-invasive, reproducible, and less operator-dependent qual-ity. Thus, it is a potentially useful clinical strategy for both physicians and patients in the treatment of MetS using RHI as a marker of endothelial function, in order to evaluate vascular condition and the efficacy of ongoing treatment.

The present findings are in accordance with past studies, in which significant weight reduction was achieved by dietary and exercise interventions, and reduced waist circumference rather than body mass index reduction strongly correlated with improvement in endothelial function as assessed on FMD.27 It has been reported that visceral fat decreases in the early phase of weight loss due to calorie restriction because lipid metabo-lism-related genes that are associated with calorie restriction are more sensitive in visceral fat than in subcutaneous fat.28 These facts may in part explain the present results, which in-dicated greatly reduced waist circumference despite the small reduction in body weight observed in the present study.

Study LimitationsAlthough it has been reported that Self-AS using a visual ana-log scale is useful,29 this still has not been established. We did not have exact data on diet therapy, such as total calorie intake and dietary composition. This study was limited by the small number of subjects and lack of assessment of the long-term prognostic value of RHI and Self-AS. We included patients who presented with clinically suspected cardiovascular disease, and the MetS patients who were enrolled in the follow-up study were younger, and had higher eGFR and higher prevalence of male gender and statins intake compared to the non-enrolled MetS patients. Thus, there may be a selective bias and the pres-ent results might have limited application for all patients with MetS. Moreover, this was not a randomized study with control group. Larger-scale randomized studies are needed to confirm the present results and to define the utility of Self-AS and RHI in the treatment of MetS.

ConclusionsMetS strongly influenced the deterioration of endothelial func-tion, which was significantly improved by lifestyle modifica-tions that were associated with reduction in waist circumfer-ence in MetS patients. The self-monitoring system with diet and exercise therapy using Self-AS is easy and useful for evaluating the efficacy of lifestyle interventions in achieving improvement in endothelial function, leading to cardiovascu-lar benefits during management of patients with MetS.

Patients with good achievement of lifestyle modifications, as reflected by high Self-AS, had greater improvement in endo-thelial function in association with greater reduction in waist circumference.

Lifestyle intervention with diet and exercise therapy is an important fundamental approach in MetS. Successful lifestyle intervention and the objective assessment of treatment efficacy decrease the occurrence of cardiovascular events, which is the objective of MetS treatment. In this study, patients with high Self-AS had considerable reduction in waist circumference accompanied by improvement in endothelial function. We sug-gest that the daily use of the simple self-monitoring system with Self-AS can increase the treatment efficacy of lifestyle interven-tions in MetS patients, and treatment strategies that are guided by repeated non-invasive evaluation of endothelial function using RH-PAT may potentially be effective in clinical practice.

Patients with MetS have increased risk of cardiovascular events and death compared with healthy people.1 Abdominal obesity plays a pivotal role in MetS, and visceral fat has been recognized to be an important endocrine organ that releases many hormones and inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and others.16,17 Known and unrecognized factors lead to vascular endothelial dysfunction followed by cardiovascular disease events.2,18 The vascular endothelium plays several crucial roles in the regulation of va-somotor tone, thrombosis, and platelet adhesion.2 Patients with advanced endothelial dysfunction are at high risk for the pro-gression of atherosclerosis and future cardiovascular events.9,19 We have here demonstrated a direct association between MetS as defined by ATP-III criteria and endothelial dysfunction as assessed on RH-PAT. More importantly, waist circumference reflecting abdominal obesity was strongly associated with en-dothelial function, and the degree of waist circumference re-duction by lifestyle modifications substantially correlated with improvement in endothelial function. This indicates the clini-cal importance of endothelial dysfunction in the pathogenesis of MetS and the clinical significance of lifestyle modification-induced waist circumference reduction, which correlates with the improvement of endothelial function in the treatment of MetS.

In this study, we used the guideline-based nutrient distribu-tion (60% carbohydrates, 15–20% proteins, and 20–25% lipids). The rationale for this nutrient distribution was that it would help decrease cardiovascular disease risk by maintaining the lowest possible plasma LDL-C concentration. Reaven et al recom-mended the following nutrient distribution for MetS patients: 45% carbohydrates, 15% proteins, 5–10% saturated fats, and 30–35% polyunsaturated and monounsaturated fats.20 It stands to reasons that the diet helps reduce elevated insulin level, lower elevated triglycerides, raise HDL-C, and lower LDL-C. The improvement of endothelial function was correlated with the increase in HDL-C level rather than LDL-C level in the present study. Thus, the nutrient distribution recommended by Reaven et al might be more effective to improve endothelial function and decrease cardiovascular disease risk in MetS.

Because the endothelial function test is important in clinical practice, multiple invasive and non-invasive techniques have been developed.21 Although invasive measurement of coronary vasodilator response by acetylcholine infusion is an established method for assessment of coronary endothelial function,22 re-peat evaluation of endothelial function is required in the clini-cal setting, and thus non-invasive methods to evaluate periph-eral endothelial function have been developed. Although there may be a difference between the coronary artery and forearm artery in endothelial function, brachial artery flow-mediated



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29. Bouchard DR, Langlois MF, Domingue ME, Brown C, LeBrun V, Baillargeon JP. Age differences in expectations and readiness re-garding lifestyle modifications in individuals at high risk of diabetes. Arch Phys Med Rehabil 2012; 93: 1059 – 1064.

Supplementary FilesSupplementary File 1

Table S1. Baseline clinical characteristics (n=331)

Please find supplementary file(s);http://dx.doi.org/10.1253/circj.CJ-13-0549

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successful diet and exercise therapy as evaluated on self

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