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Predictors of Beneficial Coronary Plaque Changes after Aerobic Exercise

MADSSEN, ERIK1,2,3; VIDEM, VIBEKE4,5; MOHOLDT, TRINE1,2,6; WISLØFF, ULRIK1,2; HEGBOM, KNUT3; WISETH, RUNE1,3

Medicine & Science in Sports & Exercise: November 2015 - Volume 47 - Issue 11 - p 2251–2256
doi: 10.1249/MSS.0000000000000672
CLINICAL SCIENCES
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Purpose It has been demonstrated that aerobic exercise induces beneficial changes in coronary atherosclerosis via reduced necrotic core and plaque burden. Clinical factors that may be associated with favorable exercise-induced intracoronary effects are unknown.

Methods This study used post hoc analysis of associations between baseline clinical variables and reductions in coronary necrotic core and plaque burden after aerobic exercise intervention. Coronary plaque characteristics were measured with grayscale and radiofrequency intravascular ultrasound in 36 patients (median age, 58.5 yr; seven women) with stable CAD (SCAD) or non-ST elevation acute coronary syndrome (NSTE-ACS). Screening of clinical variables was performed with random forest analysis followed by multivariate linear regression.

Results The only significant clinical variable for necrotic core reduction was clinical presentation of disease (SCAD vs NSTE-ACS, P = 0.011). The changes in necrotic core after exercise were −4.94 mm3 (−10.33; −1.33) in patients with SCAD and 1.03 mm3 (−4.29; 3.71) in patients with NSTE-ACS (P = 0.01). Necrotic core was reduced in 17 patients (94%) with SCAD and eight patients (44%) with NSTE-ACS (P = 0.01). R2 for the model including baseline clinical presentation and baseline necrotic core volume was 0.90. There were no significant explanatory variables for plaque burden reduction.

Conclusions Exercise-induced plaque stabilization via reduced coronary necrotic core may be strongly dependent on clinical presentation of CAD. We hypothesized that an increased proinflammatory load renders patients with NSTE-ACS more resistant to exercise-induced plaque stabilization than patients with SCAD. Furthermore, aerobic exercise may have a particular potential for inducing beneficial effects on coronary atherosclerosis in patients with SCAD compared with patients in the early phase after an acute coronary syndrome.

1Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, NORWAY; 2K. G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, NORWAY; 3Department of Cardiology, St. Olavs Hospital, Trondheim, NORWAY; 4Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, NORWAY; 5Department of Immunology and Transfusion Medicine, St. Olavs Hospital, Trondheim, NORWAY; and 6Women’s Clinic, St. Olavs Hospital, Trondheim, NORWAY

Address for correspondence: Erik Madssen, M.D., Department of Circulation and Medical Imaging, Faculty of Medicine, Norwegian University of Science and Technology, Mailbox 8905, MTFS, N-7491, Trondheim, Norway; E-mail: erik.madssen@ntnu.no.

Submitted for publication January 2015.

Accepted for publication March 2015.

Acute coronary syndromes (ACS) are frequently the first clinical manifestation of atherosclerosis. ACS are most often caused by a rupture of a destabilized lipid-rich atheroma with a thin fibrous cap (31). Necrotic core is a dominant feature of vulnerable coronary plaques (33) and may be assessed by radiofrequency intravascular ultrasound (9). To date, no clinical intervention, such as statin therapy (24), has been able to significantly reduce coronary necrotic core content in serial radiofrequency intravascular ultrasound trials despite improved clinical outcomes (6).

Physical inactivity is an independent risk factor for CAD (4), and exercise-based rehabilitation in patients with CAD is clearly associated with reduced morbidity and mortality (16). However, the mechanisms responsible for improved outcomes are largely unknown. We have recently demonstrated a moderate reduction in coronary necrotic core and plaque burden in patients with CAD on optimal medical treatment undergoing two different aerobic exercise protocols (18), arguing for a direct effect on atherosclerosis from exercise.

Clinical factors that are potentially associated with favorable exercise-induced intracoronary effects are still unknown. In the present study, we therefore assessed the association between clinical factors at baseline and the reduction in necrotic core and plaque burden at follow-up in revascularized patients with CAD undergoing an aerobic exercise intervention.

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METHODS

This study was a post hoc analysis of data from a randomized controlled trial conducted between December 2010 and April 2012 at St. Olavs University Hospital, Trondheim, Norway, including 36 patients (median age, 58.5 yr; seven women) with stable CAD (SCAD) or non-ST elevation ACS (NSTE-ACS). The study protocol was registered at ClinicalTrials.gov (identifier NCT01228201), approved by the Regional Ethics Committee of Central Norway (2010/1112), and performed according to the Helsinki declaration.

The original trial compared effects on coronary plaque geometry and composition from aerobic interval training (four times 4-min intervals at approximately 90% of HRpeak) versus moderate continuous exercise (continuous exercise for 46 min at approximately 70% of HRpeak) after coronary stent implantation. The two exercise protocols were isocaloric (26), and all patients exercised three times a week for 12 wk, giving a total of 36 exercise sessions. The study end points were evaluated by grayscale and radiofrequency intravascular ultrasound.

Study design, patient population, registered variables, and intervention have been described in detail elsewhere (18). Briefly, patients diagnosed with significant CAD requiring percutaneous coronary intervention with stent implantation were screened for participation in the study. All patients received optimal medical treatment according to current guidelines, and a written informed consent was obtained. Patients were randomized after completion of baseline testing, including a treadmill cardiopulmonary exercise test on treadmills (Woodway PPS55, Weil am Rhein, Germany) with measurement of HRpeak and peak oxygen uptake (Oxycon Pro Jaeger, Höchberg, Germany).

The index coronary artery was imaged using the Eagle Eye Platinum intravascular ultrasound 20-MHz probe (Volcano Corporation, Rancho Cordova, CA). A fixed pullback rate of 0.5 mm·s−1 was used (Volcano R100 pullback device), and radiofrequency backscatter data were collected with a dedicated console (Volcano) at every R-peak in the ECG. All patients underwent follow-up intracoronary imaging 2–3 d after completion of the exercise protocols. There were no procedural complications during intracoronary imaging.

Grayscale and radiofrequency intravascular ultrasound data were analyzed using a dedicated software (QIvus software 2.1; Medis Medical Imaging Systems, Leiden, the Netherlands) at an independent Core Laboratory (Krakow Cardiovascular Research Institute, Krakow, Poland) according to current recommendations (10,19). Fiduciary points such as side braches and the implanted stent were used to identify matched segments at baseline and follow-up, and only segments that were visible in both pullbacks were included in the analysis. The stented coronary segment and stent edges (defined as the two 5 mm-long nonstented segments in proximal and distal direction from the stent edge) were excluded from the analysis. In the remaining part of the pullback, separate lesions were identified as any segment with a plaque burden >40% over at least three consecutive frames separated by 5 mm of artery with a plaque burden <40% (10). Plaque burden (defined as plaque plus media area divided by the vessel area) and necrotic core volume (based on procession of backscattered radiofrequency signals) were calculated in every separate lesion (Fig. 1) and consequently reexamined for changes in end points at follow-up.

FIGURE 1

FIGURE 1

Data are given as frequencies and percentages or as medians with 95% confidence intervals in parenthesis. Baseline characteristics were compared using the chi-square test or Mann–Whitney U test. Statistical analysis was performed in two steps. For the first screening step, the outcome variables were dichotomized into “reduction” versus “no change/increase.” Random forest analysis (12,30) (bootstrap n = 2000) was performed using the “party” package in the R statistical environment (version 3.0.2; R Foundation, http://www.r-project.org). The method avoids the risk of overfitting, as seen with univariate variable screening; for example, using linear or logistic regression. Baseline explanatory variables that potentially could be associated with exercise-induced reduction in plaque burden and necrotic core were screened, including sex, age, body mass index, smoking habits, hypertension, previous myocardial infarction, renal failure, diabetes mellitus, clinical presentation at baseline (SCAD or NSTE-ACS), medication and blood biomarkers (as shown in Table 1), endothelial function (estimated as percent flow-mediated vasodilation in the brachial artery), and peak oxygen uptake. In the second step, significant variables from the random forest analysis were further analyzed using multivariate robust linear regression with the outcome variables in the original continuous form (mm3). Model fit was evaluated by residual plotting. The statistical software SPSS (version 20.0; IBM, Chicago, IL), Stata (version 13.0; StataCorp, College Station, TX), and Minitab (version 16.2.1; Minitab, State College, PA) were used.

TABLE 1

TABLE 1

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RESULTS

Baseline clinical characteristics of the study population are given in Table 1. In the random forest analysis, total cholesterol was the only variable associated with plaque burden reduction at follow-up, having a signal slightly stronger than random noise. The relation was not confirmed in linear regression (P = 0.33). Significant variables for necrotic core reduction in random forest analysis were use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonist (weak signal) and clinical presentation (SCAD or NSTE-ACS) at baseline (strong signal). In linear regression, only clinical presentation at baseline remained significantly associated with necrotic core volume at follow-up (P = 0.011), whereas use of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonist was not (P = 0.41). R2 for the model including baseline clinical presentation and baseline necrotic core volume was 0.90.

The median change in necrotic core per patient was significantly larger in patients with SCAD than that in patients with NSTE-ACS (P = 0.01) (Table 2). Mean necrotic core volume at follow-up was 7.19 mm3 (1.87; 13.14) higher in patients with NSTE-ACS compared with that in patients with SCAD. Necrotic core volume was reduced in 17 patients (94%) in the SCAD group compared with that in eight patients (44%) in the NSTE-ACS group (P = 0.01) (Fig. 2). The numerical value for the reduction in plaque burden was larger in the SCAD group than that in the NSTE-ACS group but did not reach statistical significance (Table 2).

TABLE 2

TABLE 2

FIGURE 2

FIGURE 2

When comparing baseline characteristics between patients with SCAD and patients with NSTE-ACS (Table 1), statin use before study inclusion (>6 months) and HDL cholesterol (HDL-C) were higher in patients with SCAD versus those in patients with NSTE-ACS (both P < 0.05). Fourteen of 18 patients in the SCAD group used statins before study enrolment compared with five of 18 patients in the NSTE-ACS group, and HDL-C was 1.4 mM (1.3–1.7) in the SCAD group compared with 1.1 mM (1.0–1.3) in the NSTE-ACS group. In a sensitivity analysis, neither statin use before study enrolment nor HDL-C was significantly associated with the change in necrotic core volume or plaque burden (P > 0.2 for all tests).

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DISCUSSION

We have previously demonstrated that aerobic exercise induces coronary plaque stabilization, measured as reduced necrotic core, and plaque burden reduction (18). In the present study, we assessed potential associations between clinical explanatory variables at baseline and the reduction in necrotic core and plaque burden after aerobic exercise intervention. Our main finding was that the clinical presentation of CAD at baseline, i.e., SCAD or NSTE-ACS, was strongly associated with necrotic core reduction at follow-up in favor of patients with SCAD. In fact, the model including baseline clinical presentation and baseline necrotic core volume explained 90% of the variation in necrotic core volume at follow-up. We found no clinical variables at baseline that were associated with reduction in plaque burden.

Although exercise is associated with improved prognosis in patients with CAD (16,29), there is a paucity of data regarding exercise-induced effects on coronary atherosclerosis. Previous studies, using angiography to assess disease burden, have shown promising results with respect to regression of atherosclerosis after lifestyle intervention, including exercise (20,22,27). Some evidence, although not consistent, also supports the theory that exercise reduces cardiovascular risk factors (1), including chronic inflammation (5). Two randomized trials demonstrated a reduction in markers of inflammation, including C-reactive protein, in patients with SCAD after aerobic exercise intervention (11,32), but this was not confirmed in a third study (2).

To date, only a few studies have used intravascular ultrasound to evaluate coronary atherosclerosis after exercise intervention. In heart transplant recipients, aerobic interval training for 1 yr resulted in attenuated progression of cardiac allograft vasculopathy but did not have an effect on necrotic core (21). In another study, plaque burden was not reduced in patients with SCAD and concomitant diabetes mellitus after exercise (28). We have recently demonstrated a moderate reduction in plaque burden and necrotic core after a 12-wk aerobic exercise intervention (18). These findings strongly support the hypothesis that aerobic exercise has a direct effect on atherosclerosis (15), but this needs to be confirmed in other studies. As we did not demonstrate any differences between patients undergoing aerobic interval training and those undergoing moderate continuous training, exercise protocols inducing the optimal effects on coronary plaques need to be elucidated.

Patients with ACS may present with multiple nonculprit vulnerable lesions (13) characterized by generalized coronary inflammation and a high macrophage density (17). The mechanisms promoting plaque destabilization and acceleration of atherosclerosis after ACS include T lymphocyte imbalance, monocyte recruitment, and macrophage apoptosis (3,7). Patients with SCAD are found to have thicker fibrous caps and smaller areas of thin-cap fibroatheromas as well as less inflammation compared with patients with ACS (8). In the present study, fibrous cap thickness was not measured and necrotic core content in separate lesions did not differ between patients with SCAD and patients with NSTE-ACS at baseline (Table 2). On the basis of our main finding, we hypothesize that an increased proinflammatory load renders patients with recent NSTE-ACS more resistant to exercise-induced plaque stabilization. Thus, exercise-induced effects on coronary atherosclerosis may differ between SCAD and NSTE-ACS patients. As 17 of 18 patients with SCAD demonstrated reduced necrotic core after only 12 wk of aerobic exercise in our study, this nonpharmacological intervention may have an underestimated potential for plaque stabilization in this large patient population.

Statin use before enrolment was more frequent in the SCAD group than in the NSTE-ACS group. This difference in statin use at baseline was neither significantly associated with the change in necrotic core volume (P = 0.70) nor plaque burden (P = 0.27) in our study. This is in contrast to the study of Rodes-Cabau et al. (25) where initiation of statins after ACS was associated with rapid regression of plaque burden. Accordingly, the different statin use at baseline in our study may have resulted in an underestimation of the exercise-induced difference in plaque burden reduction between patients with SCAD and patients with NSTE-ACS. No previous statin trial in patients with SCAD (23) or ACS (24) has demonstrated a reduction in necrotic core. Whether the imbalance in statin use at baseline in our study also led to an underestimation of the exercise-induced difference in necrotic core reduction between patients with SCAD and patients with NSTE-ACS cannot be concluded.

HDL-C levels were slightly higher in the SCAD group than that in the NSTE-ACS group at baseline. One study found higher incidence of attenuated grayscale intravascular ultrasound plaques in patients with very low HDL-C (14), arguing for greater plaque vulnerability in patients with low HDL-C. However, necrotic core content at baseline did not differ between patients with SCAD and patients with NSTE-ACS (Table 2), HDL-C was not associated with change in necrotic core (P = 0.81), and there was no evidence for HDL-C as an explanatory variable for necrotic core reduction in the random forest analysis. It is therefore unlikely that a small group difference in baseline HDL-C levels at baseline can explain our findings.

Our study is limited by its small sample size. Therefore, our results must be interpreted with caution and should be seen as hypothesis generating for future studies. Nevertheless, we demonstrated a strong association between clinical presentation of CAD and necrotic core reduction after aerobic exercise that could be clinically important with respect to exercise-induced effects on coronary atherosclerosis. Our data provide a basis for optimism regarding the beneficial intracoronary effects from exercise in patients with SCAD.

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CONCLUSIONS

Reduction of coronary atheroma necrotic core volume in patients undergoing aerobic exercise may be strongly dependent on clinical presentation and was much more frequent in patients with SCAD than in patients with NSTE-ACS. We hypothesize that an increased proinflammatory load renders patients with recent NSTE-ACS more resistant to exercise-induced plaque stabilization. Our data suggest that aerobic exercise may have a particular potential for inducing beneficial effects on coronary atherosclerosis in patients with SCAD compared with patients in the early phase after an ACS.

We thank Tove Vindsetmo, Ann Mari Myraunet, Anita Størdal, Ingerid Arbo, and Kirsti Krohn Garnæs for their assistance in patient inclusion and follow-up.

This study was funded by the following non-profit organizations: the Liaison Committee for Central Norway Regional Health Authority and the Norwegian University of Science and Technology, the Research Fund at St. Olavs University Hospital, the Norwegian Council on Cardiovascular Disease, and the Norwegian Council for Public Health.

The authors declare that there is no conflict of interest.

The results of the study do not constitute endorsement by the American College of Sports Medicine.

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Keywords:

CORONARY ARTERY DISEASE; ATHEROSCLEROSIS; AEROBIC EXERCISE; PATHOPHYSIOLOGY; INTRAVASCULAR ULTRASOUND

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