Comprehensive cardiac rehabilitation (CR) is an

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1 Circulation Journal doi: /circj.CJ ORIGINAL ARTICLE Cardiac Rehabilitation Impact of Physical Activity on Coronary Plaque Volume and Components in Acute Coronary Syndrome Patients After Early Phase II Cardiac Rehabilitation Miho Nishitani-Yokoyama, MD; Katsumi Miyauchi, MD; Kazunori Shimada, MD; Takayuki Yokoyama, MD, PhD; Shohei Ouchi, MD, PhD; Tatsuro Aikawa, MD, PhD; Mitsuhiro Kunimoto, MD; Miki Yamada, PhD; Akio Honzawa, BSc; Shinya Okazaki, MD; Hiroyuki Daida, MD Background: Cardiac rehabilitation (CR) is an established multidisciplinary secondary preventive program. We investigated the effects of CR involving intensive physical activity (PA) on coronary plaque volume and components in patients with acute coronary syndrome (ACS). Methods and Results: We enrolled 32 consecutive patients with ACS in early phase II CR and randomly assigned them to an intensive CR group (n=18; CR participation twice/week, daily PA 9,000 steps) or a standard CR group (n=14; CR participation once/2weeks, daily PA 6,000 steps). Serial integrated backscatter intravascular ultrasound was performed for non-culprit lesions at baseline and after 8 months. Baseline clinical data were identical between the 2 groups. Unexpectedly, CR participation and PA did not differ significantly between the 2 groups, and there was no significant difference in plaque volume (PV) or components between the 2 groups. Subsequently, we classified the patients into 2 groups according to median PA (7,000 steps). There were significant differences in percent change of PV and of lipid volume between these 2 groups. In addition, these changes were negatively and independently correlated with PA. Conclusions: No significant difference was observed in PV or components between the intensive CR and the standard CR groups. Intensive PA, however, may retard coronary PV and ameliorate lipid component in patients with ACS participating in late phase II CR. Key Words: Acute coronary syndrome; Cardiac rehabilitation; Coronary plaque stabilization; Integrated backscatter intravascular ultrasound; Physical activity Comprehensive cardiac rehabilitation (CR) is an established multidisciplinary secondary prevention program in patients with acute coronary syndrome (ACS), those receiving coronary artery bypass grafting (CABG), and those with heart failure. 1 CR is effective in modulating risk factors and reducing the incidence of future cardiovascular events. 2 According to the guidelines of the Japanese Circulation Society and the American Association of Cardiovascular and Pulmonary Rehabilitation, it is recommended to perform aerobic exercises, such as walking, running, and cycling, for 30 min each time, 3 4 times per week, based on exercise tolerance test. 3 Comprehensive CR and/or multifactorial intervention has been shown to inhibit angiographic minimal lumen stenosis. 4,5 We recently showed that coronary plaque changes in patients with ACS were significantly and negatively correlated with physical activity (PA). 6 Therefore, CR with intensive PA may have beneficial effects on coronary plaque regression in patients with ACS. Recently, advances in coronary plaque imaging, such as serial integrated backscatter intravascular ultrasound (IB- IVUS), have enabled physicians to observe the morphology of the plaque and accurately measure plaque volume (PV). Indeed, recent studies on statins using IB-IVUS have demonstrated significant plaque regression and stabilization. 7,8 Currently, however, there are no studies on the effect of CR involving intensive PA on PV and components using IB-IVUS. The aim of this study was therefore to investigate the effects of CR involving intensive PA on coronary PV and components in patients with ACS. Received June 26, 2018; revised manuscript received September 12, 2018; accepted September 26, 2018; J-STAGE Advance Publication released online November 8, 2018 Time for primary review: 26 days Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Tokyo (M.N.-Y., K.M., K.S., T.Y., S. Ouchi, T.A., M.K., S. Okazaki, H.D.); Cardiovascular Rehabilitation and Fitness, Juntendo University Hospital, Tokyo (M.N.-Y., K.S., M.Y., A.H.), Japan Mailing address: Hiroyuki Daida, MD, Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine, Hongo, Bunkyo-ku, Tokyo , Japan. daida@juntendo.ac.jp ISSN All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 2 NISHITANI-YOKOYAMA M et al. Figure 1. Subject selection. ACS, acute coronary syndrome; CAG, coronary angiography; CR, cardiac rehabilitation; IVUS, intravascular ultrasound; PCI, percutaneous coronary intervention. Methods Study Protocol and Subjects This study was a prospective, randomized, open-label, single-center trial to assess the effects of CR involving intensive PA on coronary PV and components in patients with ACS using serial volumetric IVUS and IB-IVUS analysis. All patients underwent emergency coronary stenting. At baseline and 8 months after percutaneous coronary intervention (PCI), serial volumetric IVUS and IB-IVUS were performed to assess changes in coronary plaque and components in non-culprit lesions (non-pci sites of the culprit vessel). Based on eligibility criteria, 51 consecutive patients with ACS admitted to Juntendo University Hospital between February 2013 and January 2016 were enrolled. ACS was defined as high-risk unstable angina, non-st-elevated myocardial infarction (MI), or ST-elevated MI. MI was diagnosed on a 2-fold increase in serum creatine phosphokinase and positivity for troponin T. 9 Exclusion criteria included failed PCI, diseased bypass graft, recommended CABG, cardiogenic shock, hepatic or renal dysfunction (creatinine 2.0 mg/dl, alanine aminotransferase and aspartate aminotransferase 2-fold the upper limits of normal), inflammatory disease, or known malignant disease. Patients were randomly assigned to an intensive CR group (late phase II CR participation, twice per week and step count, 9,000/day) or a standard CR group (late phase II CR participation, once/2 weeks and step count, 6,000/day) 72 h following PCI. Randomization was stratified according to age, ejection fraction, and presence or absence of diabetes. Following the procedure, all patients participated in early-phase II CR. We recommended all patients to participate in late-phase II CR after discharge and to perform walking in accordance with their exercise protocol. Follow-up visits were scheduled every 4 weeks following PCI. According to randomization, exercise content and daily PA were checked during each visit. Baseline measurements included IVUS and biochemistry data on admission and cardiopulmonary exercise test (CPX) on discharge. Follow-up IVUS data, biochemistry data, and CPX were repeated after 8 months. This study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board of the ethics committee of Juntendo University Hospital. All subjects provided written informed consent prior to participating in the study. This study was registered with the University Hospital Medical Information Network (UMIN ). IVUS and IB-IVUS All IVUS was performed using the same equipment. Briefly, a 40-MHz, 2.5-Fr IVUS catheter (ViewIT TM, Terumo, Tokyo, Japan) was advanced into the culprit vessel meeting specific inclusion criteria and positioned as distally as patient safety permitted following 0.2 mg i.c. nitroglycerin. Pullback was automatically performed at 0.5 mm/s. All measurements were performed at the end of the study. Grayscale IVUS and IB-IVUS were performed by 2 experienced independent observers blinded to the clinical and angiographic information using VISIATRAS TM (Terumo). We had previously performed several IVUS trials, including ESTABLISH, JAPAN-ACS, and ALPS-J Following the methods of these studies, the target segment was determined at a non-pci site (5 mm proximal or distal to the PCI site) of the culprit vessel with a reproducible index, usually a branch site, on the PCI vessel. Baseline and follow-up IVUS were reviewed side by side on a display, and the target segment was selected. Local landmarks, such as side branches and calcium deposits, as well as the topology of the lumen were used to ensure comparable frames. Grayscale IVUS analysis included vessel volume, lumen volume, and PV. PV was calculated as vessel volume lumen volume. Percent change in PV was defined as the change in PV (follow-up baseline PV)/baseline PV. Lesions meeting any of the following criteria were not investigated: calcification, kinking, chronic complete occlusion, bypass graft site, site of coronary atherectomy prior to PCI, located at the left main trunk, small vessel (<2.0 mm), or location of distal protection device. IB-IVUS analysis was performed as previously reported. 7,8 Briefly, integrated backscatter values for each tissue

3 Physical Activity and Coronary Plaque in ACS 3 Table 1. Baseline Patient Characteristics Intensive CR group (n=18) Standard CR group (n=14) P-value Age (years) 58.0± ± Male 17 (94) 13 (93) 0.85 Hypertension 10 (56) 10 (71) 0.35 Diabetes mellitus 6 (33) 5 (35) 0.88 Dyslipidemia 17 (94) 13 (93) 0.85 Current smoking 12 (66) 5 (36) 0.05 Family history 9 (50) 3 (21) 0.10 Prior CAD 1 (6) 1 (7) 0.85 ACS classification ST-elevated MI 9 (50) 3 (21) Non-ST-elevated MI 6 (33) 11 (79) 0.15 Unstable angina 3 (17) 0 (0) Diseased vessels Single 13 (72) 9 (64) Double 4 (22) 5 (36) 0.50 Triple 1 (6) 0 (0) Culprit vessel RCA 3 (17) 6 (43) LAD 14 (78) 7 (50) 0.23 LCX 1 (5) 1 (7) Maximum CK (IU/L) 2,208±2,590 2,174±1, EF (%) 52.7± ± Medication at admission RAS-I 7 (39) 6 (43) 0.41 β-blockers 7 (39) 4 (29) 0.54 CCB 2 (11) 5 (36) 0.09 Statin 10 (56) 4 (29) 0.12 EPA 1 (6) 1 (7) 0.85 α-gi 0 1 (7) 0.73 DPP-4 inhibitors 0 1 (7) 0.73 Insulin 0 (0) 1 (7) 0.73 Medication at discharge DAPT 18 (100) 14 (100) 0.36 RAS-I 16 (89) 14 (100) 0.24 β-blockers 14 (78) 13 (93) 0.24 CCB 2 (11) 1 (7) 0.71 Statin 18 (100) 14 (100) 0.36 Ezetimibe 3 (17) 2 (14) 0.85 EPA 1 (6) 1 (7) 0.85 α-gi 1 (6) 1 (7) 0.85 DPP-4 inhibitors 2 (11) 1 (7) 0.28 Insulin 0 (0) 3 (21) 0.04 Data given as mean ± SD or n (%). α-gi, α-glucosidase inhibitors; ACS, acute coronary syndrome; CAD, coronary artery disease; CCB, calcium-channel blockers; CK, creatine kinase; CR, cardiac rehabilitation; DAPT, dual antiplatelet therapy; DPP-4, dipeptidyl peptidase 4; EF, ejection fraction; EPA, eicosapentaenoic acid; LAD, left anterior descending artery; LCX, left circumflex artery; MI, myocardial infarction; RAS-I, renin-angiotensin-aldosterone system inhibitors; RCA, right coronary artery. component were calculated as an average power using a fast Fourier transform of the frequency component of the backscattered signal (measured in decibels) from a small volume of tissue. IB values for each plaque component (calcified, fibrous, dense fibrous, and lipid) were determined. The percentages of calcification (calcified area/plaque area), fibrous area (fibrous area/plaque area), dense fibrous area (dense fibrous area/plaque area), and lipid area (lipid area/ plaque area) were automatically calculated using the IB-IVUS system at 0.1-mm intervals. Three-dimensional analysis of grayscale IVUS and IB-IVUS was conducted to obtain the PV of each IB-IVUS component. Subsequently, the percentages of calcified volume, fibrous volume (FV), dense FV, and lipid volume (LV) were also calculated.

4 4 NISHITANI-YOKOYAMA M et al. Table 2. Comparison of Anthropometric Parameters, Exercise Tolerance, Physical Activity and Lipid Profiles Between the Intensive and Standard Groups Intensive CR group (n=18) Standard CR group (n=14) Baseline After Baseline After Anthropometry BMI (kg/m 2 ) 24.8± ± ± ±3.7 WC (cm) 90.6± ±6.6*,# 85.2± ±9.6* HC (cm) 94.4± ± ± ±5.1* Fat weight (kg) 18.4± ± ± ±5.6 Lean body weight (kg) 51.2± ± ± ±6.2 Exercise tolerance Peak V O2 (ml/kg/min) 17.2± ±4.3* 15.8± ±3.5* Late phase II CR 12±10 8±6 Daily PA (steps/day) 6,857±2,046 7,789±2,249 6,249±2,477 7,760±2,616* Lipid profile and glucose metabolism LDL-C (mg/dl) 141±47 79±19* 119±39 67±18* HDL-C (mg/dl) 42±9 42±10 40±10 40±11 LH ratio 3.5± ±0.7* 3.1± ±0.6* TG (mg/dl) 183± ±57 152±65 134±46 FBS (mg/dl) 110±40 97±15 132±50 101±16* HbA1c (%) 5.9± ±0.4 # 6.4± ±0.7 Data given as mean ± SD. *P<0.05 vs. baseline, **vs. standard group at baseline, # vs. standard group after 8 months. BMI, body mass index; CR, cardiac rehabilitation; FBS, fasting blood sugar; HbA1c, hemoglobin A1c; HC, hip circumference; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LH, LDL-C/HDL-C; PA, physical activity; TG, triglyceride; V O2, oxygen consumption; WC, waist circumference. Early Phase II CR The CR program, consisting of warm-up stretching, aerobic exercise, and cool down, was scheduled once daily in the hospital, as described previously. 12,13 Aerobic exercise consisted of a cycle ergometer, treadmill, and walking (in-room track). The total time for aerobic exercise was approximately 20 min. Exercise intensity was individually prescribed at the anaerobic threshold (AT) as measured on ergometer test using expiratory gas analysis or a rating of on the standard Borg s perceived exertion scale. At the beginning of CR, all subjects were instructed to follow the phase II diet recommended by the American Heart Association. Moreover, at baseline, an educational program was provided by physicians, nurses, and dietitians to each subject regarding coronary artery disease (CAD) and its risk factors. Measurements Body composition and exercise tolerance were assessed at the beginning and at 8-month follow-up. Anthropometric parameters were assessed using body mass index and waist size. The percentages of body fat and lean body weight were measured using the Tanita MC-780A Body Composition Analyzer (Tanita, Tokyo, Japan), based on bioelectrical impedance analysis. The derivation of body volume, coupled with the measurement of body mass, permits the calculation of body density and the subsequent estimation of percent fat and fat-free mass. Patients underwent ergometer testing (Strength Ergo8, Nihon Kohden, Tokyo, Japan) using an expiratory gas analysis machine (AE-310s, Minato Medical Science, Osaka, Japan) to measure peak oxygen consumption (peak V O2) and oxygen uptake at AT. Following a period of resting, warm-up was performed for a few minutes at 0 W, followed by ramp loading (10 W/min) until subjective exhaustion, progressive angina, ST-segment depression ( 2 mm), or sustained tachyarrhythmia. The point of AT was determined using the V-slope method. Daily PA was evaluated using a pedometer (Lifecoder, Suzuken, Nagoya, Japan) recording mean step count and calculating the mean energy of PA for up to 60 days. Statistical Analysis Results are expressed as mean ± SD and were analyzed using JMP version 12 for Windows (SAS Institute, Cary, NC, USA.). Comparisons between the active and inactive groups were performed using Student s t-test. Correlation coefficients were determined using linear regression analysis. Stepwise multiple regression analysis was used to determine independent predictors of change in plaque and lipid PV. Statistical significance of correlation coefficients was determined using the method of Fisher and Yates. P<0.05 denoted statistical significance. Results Subjects A total of 51 patients were enrolled between February 2013 and January 2016 and randomly assigned to an intensive CR (n=25) or a standard CR (n=26) group. Of the 51 patients, 19 (intensive group; n=7, standard group; n=12) were excluded because of poor IVUS quality. Finally, 32 patients (intensive group; n=18, standard group; n=14) were clinically assessed, including IVUS measurements at baseline and follow-up, and were included in the intentionto-treat analysis reported here (Figure 1). Clinical Characteristics Subject clinical characteristics are listed in Table 1. No significant differences in age, sex, coronary risk factors, number of diseased vessels, or exercise tolerance at baseline were observed between the 2 groups. In addition, the length of hospital stay was not significantly different between the

5 Physical Activity and Coronary Plaque in ACS 5 Table 3. Comparison of IVUS Data Between the Intensive and Standard Groups Intensive CR group (n=18) Standard CR group (n=14) Before After P-value Before After P-value IVUS profile Length (mm) 12.1± ± ± ±5.9 Vessel volume (mm 3 ) 198.5± ±125.1 < ± ±99.8 <0.01 Lumen volume (mm 3 ) 111.3± ± ± ± PV (mm 3 ) 87.2± ±54.5 < ± ± Percent change of PV 8.9± ±5.5 IB-IVUS profile LV (mm 3 ) 27.4± ± ± ± FV (mm 3 ) 30.4± ± ± ± DFV (mm 3 ) 3.2± ± ± ± CV (mm 3 ) 0.58± ± ± ± Percent of LV (%) 38.4± ± ± ± Percent of FV (%) 54.2± ± ± ± Percent of DFV (%) 6.1± ± ± ± Percent of CV (%) 1.1± ± ± ± Percent change of LV 8.0± ±24.3 Data given as mean ± SD. CR, cardiac rehabilitation; CV, calcified volume; DFV, dense fibrous volume; FV, fibrous volume; IB-IVUS, integrated backscatter intravascular ultrasound; IVUS, intravascular ultrasound; LV, lipid volume; PV, plaque volume. Figure 2. Physical activity for each patient during late phase II cardiac rehabilitation. standard and intensive groups (12.2±3.4 vs. 11.7±4.3 days, P=0.76). The number of late phase II CR sessions was not significantly different between the 2 groups. Furthermore, there were no significant difference in clinical characteristics between the 2 groups, which was analyzed in all entry patients (data not shown). Serum Lipid Profiles and Glucose Parameters Serum lipid profiles and glucose parameters at baseline and after 8 months are listed in Table 2. At baseline, there were no significant differences between the 2 groups. At 8 months, low-density lipoprotein cholesterol (LDL-C) was significantly lower than at baseline in both groups (both P<0.01). In the standard group, serum fasting glucose significantly decreased after 8 months compared with baseline (from 132±50 to 101±16 mg/dl, P<0.05). After 8 months, hemo- globin A1c (HbA1c) was significantly lower in the intensive group than in the standard group (5.8%±0.4% vs. 6.2%± 0.7%, P<0.05). Anthropometry, Exercise Tolerance, and Daily PA Anthropometric parameters, exercise tolerance, and PA at baseline and after 8 months in each group are listed in Table 2. Anthropometry at baseline was not significantly different between the 2 groups. After 8 months, waist circumference (WC) was significantly lower than at baseline in both groups (both P<0.05). At baseline, peak V O2 was not different between the 2 groups. At 8-month follow-up, both groups showed significant improvements in exercise tolerance (both P<0.05). Participation in late phase II CR and PA did not differ significantly between the 2 groups.

6 6 NISHITANI-YOKOYAMA M et al. Table 4. Comparison of IVUS Data Between the Active and Inactive Groups Active group (n=12) Inactive group (n=20) Before After P-value Before After P-value IVUS profile Length (mm) 12.1± ± ± ±5.6 Vessel volume (mm 3 ) 183.0± ±100.2 < ± ±125.6 <0.01 Lumen volume (mm 3 ) 101.2± ± ± ± PV (mm 3 ) 81.8± ±39.9 < ± ± Percent change of PV 12.5±9.4* 3.6±11.3 IB-IVUS profile LV (mm 3 ) 21.4± ± ± ± FV (mm 3 ) 32.2± ± ± ± DFV (mm 3 ) 3.5± ± ± ± CV (mm 3 ) 0.5± ± ± ± Percent of LV (%) 35.4± ± ± ± Percent of FV (%) 52.7± ± ± ± Percent of DFV (%) 6.2± ± ± ± Percent of CV (%) 1.0± ± ± ± Percent change of LV 17.5±19.1** 7.7±25.6 Data given as mean ± SD. *P<0.05 vs. inactive group after intervention; **P<0.01 vs. inactive group after intervention. Abbreviations as in Tables 2,3. Figure 3. Percent change in (A,C) plaque volume (PV) and (B,D) lipid volume (LV) according to (A,B) level of daily physical activity and (C,D) steps/day in acute coronary syndrome patients undergoing cardiac rehabilitation. IVUS Parameter Volumetry Volumetric IVUS parameter analysis is given in Table 3. At baseline, there were no significant differences in vessel volume, lumen volume, or PV between the 2 groups. At 8-month follow-up, PV was reduced in both groups (both P<0.05). The percent change in PV, however, did not significantly differ between the intensive and standard groups ( 8.9±14.2% vs. 4.5±5.5%, P=0.28).

7 Physical Activity and Coronary Plaque in ACS 7 Table 5. Significant Indicators of Percent Change of PV and of LV Univariate analysis Multivariate analysis β P-value β P-value A. Percent change of PV Age Sex Classification of ACS Diabetes (absent-present) Ejection fraction Delta waist circumference Delta fasting glucose Physical activity <0.01 Delta peak V O <0.01 Delta LDL-C 0.56 < <0.01 Delta HDL-C Plaque volume at baseline Lipid volume at baseline B. Percent change of LV Age Sex Classification of ACS Diabetes (absent-present) Ejection fraction Delta waist circumference Delta fasting glucose Physical activity 0.45 < Delta peak V O Delta LDL-C Delta HDL-C PV at baseline LV at baseline β, standardized partial regression coefficient. Other abbreviations as in Tables 1 3. IB-IVUS Parameters At baseline, the volume of each component did not significantly differ between the 2 groups (Table 3). At follow-up, absolute LV and FV were significantly decreased in the intensive CR group (from 27.4±29.7 to 24.1±26.1 mm 3, P=0.01 and from 30.4±21.0 to 26.3±18.5 mm 3, P=0.03, respectively), whereas these did not differ significantly in the standard group. Percent change in LV was not significantly different between the intensive and standard groups ( 8.0%±24.9% vs. 6.4%±24.3%, P=0.12). Active vs. Inactive Groups Figure 2 shows PA for a period of 60 days after discharge for each patient. According to the PA records, 58% of patients did not achieve the target exercise level in the intensive CR group and 40% of patients exceeded the target exercise level in the standard CR group. Therefore, the subjects were classified into the following 2 groups according to median PA (i.e., 7,000 steps): active group (n=12), daily PA 7,000 steps; and inactive group (n=20), daily PA <7,000 steps. At baseline, there were no significant differences in clinical characteristics between the 2 groups, except ejection fraction (Table S1). At 8 months, LDL-C was significantly lower than at baseline in both groups (both P<0.01). In the active group, fasting glucose significantly decreased after 8 months compared with baseline (from 128±54 to 97±15 mg/dl, P<0.05). After 8 months, high-density lipoprotein cholesterol (HDL-C) was significantly higher in the active group than in the inactive group (45±10 vs. 38±8 mg/dl, P<0.05). At 8 months, WC was significantly lower than at baseline in both groups (both P<0.05). In the active group, hip circumference (from 96.0±7.1 to 92.0±6.0 cm, P<0.01) and fat weight (from 18.5±6.2 to 14.6±5.8 kg, P<0.01) were significantly decreased compared with baseline. At baseline, peak V O2 was not significantly different between the 2 groups. At 8-month follow-up, both groups had significant improvements in exercise tolerance. In the active group, exercise tolerance was significantly higher than in the inactive group (22.9±4.6 vs. 19.4±2.8 ml/kg/min, P=0.01; Table S2). Volumetric analysis of the IVUS parameters is given in Table 4. At baseline, there was no significant difference in vessel volume, lumen volume, or PV between the 2 groups. At 8-month follow-up, PV was reduced in both groups (both P<0.05). Percent change in PV was significantly different between the active and inactive groups ( 12.5%± 9.4% vs. 3.6%±11.3%, P=0.02; Figure 3A). At baseline, the volume of each component was not significantly different between the 2 groups (Table 4). The absolute change in LV was significantly decreased in the active group (21.4±17.8 to 17.5±14.2 mm 3, P=0.01), unlike in the inactive group (24.1±8.7 to 23.1±25.0 mm 3, P=0.39). Percent change in LV

8 8 NISHITANI-YOKOYAMA M et al. was also significantly different between the active and inactive groups ( 17.5%±19.1% vs. 7.7%±25.6%, P<0.01; Figure 3B). Plaque Change and PA Percent change in PV and in LV with regard to PA is shown in Figure 3C,D, respectively. Percent change in PV (r= 0.43, P=0.01) and in LV (r= 0.45, P<0.01) was significantly negatively correlated with PA. Exercise tolerance was highly and positively correlated with PA. Therefore, we performed multivariable linear regression analyses. On multivariate analysis including age, sex, classification of ACS, presence or absence of diabetes, ejection fraction, change in WC, change in fasting glucose, PA, change in LDL-C, change in HDL-C, PV at baseline and LV at baseline, PA (β= 0.41, P<0.01) and change in LDL-C (β=0.47, P<0.01) were significantly associated with the change in percent PV (Table 5). On multivariate analysis, including the same parameters, only PA was significantly associated with the change in percent LV (β= 0.42, P=0.01; Table 5). Discussion In the present study, there was no significant difference in the change of plaque regression or of components between the intensive and standard CR groups. HbA1c, however, was significantly lower in the intensive group than in the standard group at 8 months; absolute PV was significantly reduced in both groups, whereas absolute FV and LV were significantly reduced in the intensive group at 8 months; intensive PA significantly retarded coronary PV and ameliorated lipid component; and percent change in PV and in the lipid component was significantly and independently correlated with PA. This is the first study investigating the impact of PA on coronary PV and components using IB- IVUS in patients with ACS participating in late phase II CR. A possible explanation for the absence of significant difference in coronary PV and components between the intensive and standard groups may be the difference in training intensity during the study period. In the present study, 58% of patients assigned to the intensive CR group unexpectedly had lower PA intensity than prescribed, whereas 49% of those assigned to the standard CR group had higher PA intensity than prescribed. Achieving >9,000 steps may be difficult in an ordinary CR program. 14 In addition, participation in late phase II CR was not significantly different between the 2 groups. HbA1c and LV, however, were significantly reduced in the intensive group. Therefore, more aggressive participation in late phase II CR may affect PV and components. There are several mechanisms via which the percent change in PV and LV significantly decreased in the active group. Hambrecht et al reported that regression of coronary atherosclerotic lesions was observed in patients with CAD expending an average of 2,200kcal/week during regular physical exercise. 15 In this study, the calculated mean energy expenditure during PA in the active and inactive groups was 297±66 kcal/day (almost 2,000 kcal/week) and 146±45 kcal/day (almost 1,000 kcal/week), respectively. In the Nakanojo study, moderate intensity daily activity was associated with arteriosclerosis, osteoporosis, and sarcopenia. 16 We prescribed an intensity of exercise of approximately 3.5 metabolic equivalents measured using CPX at discharge. Thus, the present PA regimen may be sufficient to reduce PV and change plaque components. At 8-month follow-up, exercise tolerance significantly increased in the active group compared with the inactive group. Yoshikawa et al reported that high exercise tolerance is an independent predictor of coronary plaque composition and fibrous cap thickness in non-culprit lesions in patients with angina pectoris assessed on IB-IVUS and optical coherence tomography. 17 LDL-C, LDL-C/HDL-C ratio, and exercise tolerance at 8 months significantly improved in both groups. In patients with ACS, we previously reported using IVUS that early aggressive lipid-lowering therapy using atorvastatin for 6 months significantly reduced PV. 9 Therefore, changes in these lipid profiles and coronary plaque may be partly induced by statins. At 8 months, HDL-C was significantly higher in the active group than in the inactive group in the present study. Regular exercise increases HDL-C, which is associated with reverse cholesterol transport, LDL antioxidation, endothelial protection, antiplatelet activity, and anticoagulation. 18 Moreover, increased cytokines, such as interleukin (IL)-6 and monocyte chemoattractant protein-1, have been reported in patients with ACS. 19 Walther et al reported that regular physical exercise is associated with a reduction of inflammatory markers and ischemic events in patients with CAD. 20,21 We reported that 6-month CR ameliorated metabolic parameters, exercise capacity, muscle strength, and the inflammatory state in patients with metabolic syndrome following CABG. 13 Furthermore, animal studies reported that exercise improves endothelial dysfunction and the formation of atherosclerotic lesions through anti-inflammatory effects. 22 At 8-month follow-up, IL-6 was low in the active group compared with the inactive group and was significantly and inversely correlated with exercise tolerance and PA (data not shown). This suggests that improvement in lipid profile and reduction of pro-inflammatory cytokines ameliorate plaque progression and plaque components. Step count was done using a pedometer. This device is easy to use and is, thus, appropriate for self-monitoring and quantifying PA. Furthermore, the pedometer step count reflects exercise tolerance, correlates with several vascular or metabolic markers, and enhances PA as a motivational tool. 23 Therefore, CR involving intensive PA monitoring using a pedometer may serve as an additional strategy for residual cardiovascular risk in patients with ACS. Study Limitations The present study is characterized by a number of limitations. First, this was a single-center study with a small sample size. To the best of our knowledge, this is the first study to investigate the effect of CR on coronary plaque regression and stabilization using IB-IVUS. Therefore, it is difficult to calculate the appropriate sample size for an exploratory study. We had previously demonstrated that coronary plaque changes were significantly and negatively correlated with PA using grayscale IVUS in 46 patients with ACS. 6 Therefore, we decided that the required sample size was >50 patients in this study. Studies with a larger sample size are warranted to confirm these findings. Second, a pedometer is unable to provide information regarding non-walking-related activities. Therefore, the evaluation of daily activity may have been underestimated. Third, we enrolled patients receiving CR following ACS. Therefore, the present results may not be representative of all patients with CAD.

9 Physical Activity and Coronary Plaque in ACS 9 Conclusions No significant difference was observed in PV or components between the intensive CR and the standard CR groups. Intensive PA, however, may retard coronary PV and ameliorate the lipid component in patients with ACS participating in late- phase II CR. Late phase II CR, including a program that encourages increased PA, may exert beneficial effects on both the regression and stabilization of coronary plaque in patients with ACS. Acknowledgments This work was supported by JSPS KAKENHI Grant Number JP15K The authors thank Megumi Matsumoto and Yumi Nozawa for their assistance in this study. We greatly acknowledge the contributions made by Nao Naito to IVUS core laboratory management and IVUS planimetry. Disclosure The authors declare no conflicts of interest. References 1. O Connor GT, Buring JE, Yusuf S, Goldhaber SZ, Olmstead EM, Paffenbarger RS Jr, et al. 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Comparison of anthropometric parameters, exercise tolerance, physical activity and lipid profiles between the active and inactive groups Please find supplementary file(s);