Intensive lifestyle changes have been shown to regress atherosclerosis, improve cardiovascular risk profiles, and decrease angina pectoris and cardiac events. We evaluated the influence of the Multisite Cardiac Lifestyle Intervention Program, an ongoing health insurance-covered lifestyle intervention conducted at our site, on endothelial function and inflammatory markers of atherosclerosis in this pilot study. Twenty-seven participants with coronary artery disease (CAD) and/or risk factors for CAD (nonsmokers, 14 men; mean age 56 years) were enrolled in the experimental group and asked to make changes in diet (10% calories from fat, plant based), engage in moderate exercise (3 hours/week), and practice stress management (1 hour/day). Twenty historically (age, gender, CAD, and CAD risk factors) matched participants were enrolled in the control group with usual standard of care. At baseline endothelium-dependent brachial artery flow-mediated dilatation (FMD) was performed in the 2 groups. Serum markers of inflammation, endothelial dysfunction, and angiogenesis were performed only in the experimental group. After 12 weeks, FMD had improved in the experimental group from a baseline of 4.23 ± 0.13 to 4.65 ± 0.15 mm, whereas in the control group it decreased from 4.62 ± 0.16 to 4.48 ± 0.17 mm. Changes were significantly different in favor of the experimental group (p <0.0001). Also, significant decreases occurred in C-reactive protein (from 2.07 ± 0.57 to 1.6 ± 0.43 mg/L, p = 0.03) and interleukin-6 (from 2.52 ± 0.62 to 1.23 ± 0.3 pg/ml, p = 0.02) after 12 weeks. Significant improvement in FMD, C-reactive protein, and interleukin-6 with intensive lifestyle changes in the experimental group suggests ≥1 potential mechanism underlying the clinical benefits seen in previous trials.
Endothelial dysfunction is the earliest and most important factor in the pathogenesis of atherosclerosis. Inflammation has been shown to contribute to endothelial dysfunction. Intensive lifestyle changes have been shown to regress atherosclerosis, improve cardiovascular risk profiles, and decrease angina pectoris and cardiac events. We evaluated the influence of intensive lifestyle changes on endothelial function and inflammatory markers of atherosclerosis in this pilot study.
Methods
The study group consisted of participants with stable coronary artery disease (CAD) and/or risk factors for CAD. Forty-seven nonsmoking participants were enrolled, 27 in the experimental group who followed Multisite Cardiac Lifestyle Intervention Program as per standard protocol, and the remaining 20 historically (age, gender, CAD and CAD risk factors) matched participants were in the control group with usual standard of care. The Multisite Cardiac Lifestyle Intervention Program is an ongoing comprehensive lifestyle change program for primary and secondary prevention of CAD administered by insurance companies. This program is an integrated approach to prevent or reverse CAD, which includes nutrition (10% fat, whole foods, vegetarian diet), aerobic exercise, stress management, smoking cessation, and group psychosocial support. All patients with CAD had angiographic documentation of severity of stenosis. At least 70% stenosis was considered significant stenosis, 50% to 69% as moderate, and 20% to 49% as mild stenosis. All participants were on stable medications for >4 months. Characteristics of the experimental and control groups at baseline are listed in Table 1 . The research protocol was approved by our institutional review board and written informed consent was obtained from participants before entering the study.
| Experimental | Control | p Value | |
|---|---|---|---|
| (n = 27) | (n = 20) | ||
| Age (years) | 56.0 | 56.6 | 0.98 |
| Caucasian | 27 (100%) | 20 (100%) | |
| Men/women | 14/13 | 11/9 | 0.83 |
| Body mass index (kg/m 2 ) | 33.3 | 32.28 | 0.9 |
| Hypertension ⁎ | 23 | 16 | 0.64 |
| Coronary artery disease severity † | 12 | 10 | 0.70 |
| Mild | 2 | 1 | |
| Moderate | 1 | 1 | |
| Severe | 9 | 8 | |
| Diabetes mellitus | 7 | 6 | 0.75 |
| Previous smoker | 4 | 4 | 0.98 |
| Dyslipidemia ‡ | 22 | 15 | 0.59 |
| ACEI/ARB | 17 | 14 | 0.61 |
| Statins | 12 | 14 | 0.10 |
| β blocker | 13 | 13 | 0.42 |
| Metformin | 2 | 5 | 0.09 |
| Aspirin | 15 | 15 | 0.17 |
| Clopidogrel | 5 | 8 | 0.10 |
⁎ Mean systolic blood pressure ≥140 mm Hg, mean diastolic blood pressure ≥90 mm Hg, or current treatment for hypertension with prescription medication.
† Mild 20% to 49%, moderate 50% to 70%, severe >70% stenosis.
‡ Documented history of hyperlipidemia (e.g., total cholesterol level >5.2 mmol/L).
Inclusion criteria were (1) age >18 years, (2) mentally competent and able to provide consent, and (3) stable medication and physical health for >4 months. Exclusion criteria were (1) patients unable to finish intensive life style changes and (2) change in dose or new medication started during the study.
The primary end point of this study was change in flow-mediated dilatation (FMD) after 3 months in the 2 groups. The secondary end point was change in the inflammatory, endothelial, and angiogenesis markers after 3 months assessed in the experimental group.
At the beginning of the study and after 3 months FMD in the brachial artery was assessed in the experimental and control groups according to standard guidelines. Inflammatory, endothelial dysfunction, and angiogenesis serum markers were measured in the experimental group at baseline and after 3 months.
The recommended diet focused on percent calories from fat (goal 10%). A registered dietitian instructed participants on how to complete 3-day food diaries and verified dietary data entry, as a measurement of quality assurance. Data were analyzed using nationally recognized software (Food Processor, ESHA Research, Inc., Salem, Oregon). Exercise was measured as hours per week (goal 3 hours/week). Stress management was measured as hours per week of yoga/meditation (goal 1 hour/day). Attendance of intervention groups was measured as the number of sessions attended divided by the number of sessions offered.
The control group was enrolled from outpatient clinics and received usual care; advice on diet and lifestyle was based on American Heart Association recommendations. All adherence measurements were made at baseline and 12 weeks. In addition, a lifestyle index, based on a formula validated in previous research, measured overall adherence to intervention guidelines and was calculated as mean percent adherence to each lifestyle behavior. Zero equaled no compliance and 1 equaled 100% compliance.
FMD measurement using brachial artery reactivity testing was performed by 2-dimensional gray-scale and color flow Doppler vascular imaging by a Philips Sonos 7500 ultrasound machine (HP, Andover, Massachusetts) with a 11-MHz vascular ultrasound probe at baseline and after 3 months. Participants fasted ≥6 hours, and all medications were held on the day of study. After resting in the supine position for 10 minutes in a quiet, air-conditioned room, the right-arm brachial artery was used for measurements. The brachial artery was scanned longitudinally 2 to 5 cm above the antecubital crease. This location was marked on the skin and all subsequent measurements were performed at the same location. To calculate FMD, percent diameter changes were determined as follows: (diameter after reactive hyperemia − baseline diameter)/baseline diameter × 100. To avoid confounding effects of arterial compliance and its cyclic changes in dimension, all measurements were obtained at the peak of the R-wave of the electrocardiogram. The mean diameter of the brachial artery was determined at baseline, then continuously up to 3 minutes after reactive hyperemia. These images were then stored on a digitized system (Camtronics Medical Systems, Hartland, Wisconsin) that has a caliper with 0.1-mm resolution. Average diameters (intima to intima) of 3 cardiac cycles were thus obtained. Brachial artery diameter measurements were done in random order and the investigator was blinded to the experimental condition. Shear rate was calculated according to standard protocol blood flow velocity divided by vessel diameter. Intraobserver variation assessment for brachial artery measurements were performed in the 43 study participants using a correlation coefficient, and the variation was found to be small (r = 0.97).
Serum samples were stored at −70°C before analysis of inflammatory endothelial dysfunction markers that were quantified by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota) according to the manufacture’s protocols. The following colorimetric Quantikine assays were used: human high-sensitivity C-reactive protein (CRP), human interleukin-6 (IL-6), human E-selectin/CD62E, human intercellular adhesion molecule-1/CD54, human vascular cell adhesion molecule, and human vascular endothelial growth factor. Tumor necrosis factor-α (TNF-α) quantitation was performed using chemiluminescent QuantiGlo human TNF-α/TNFSF1A assay (R&D Systems, Minneapolis, Minnesota). All assays were performed in duplicate. Plates were read in a Fluostar Optima plate reader (BMG Labtech, Offenburg, Germany), and levels of biomarkers were calculated from standard curves. Based on estimates from multiple identical sample replicates, the coefficient of variation for the assays was <5%.
Baseline characteristics for the 2 groups were compared using Student’s t and chi-square tests as appropriate. Significance of changes from baseline to 3 months was assessed separately for the experimental and control groups using matched-pair t tests. Comparisons of the magnitude and direction of changes between groups was assessed by an analysis of variance appropriate to the repeated measures nature of the experimental design. In particular, the group by period interaction term was used to determine if the changes in 1 group were significantly different from the changes in the other. Associations between changes in inflammatory markers and risk factors with changes in FMD were evaluated by Spearman rank correlation analyses. Significance levels (alpha = 0.05) were used for all comparisons. No adjustment for multiple testing was employed at any point in the analysis.
Results
Of the 47 participants in the study, 27 were in the experimental group and 20 in the control group. Four participants in the experimental group dropped out of the study (1 underwent coronary artery bypass surgery, 1 could not follow the exercise program, 1 moved out of town, and 1 could not adhere to the dietary regime). Of the 23 participants in the experimental group, 12 were men, and of 20 in the control group, 11 were men. Baseline vessel diameter in men was significantly larger than in women (4.5 ± 0.13 vs 3.8 ± 0.08 mm, p <0.0001). FMD percent change was significantly different in favor of the experimental group by repeated measures analysis of variance (p <0.0001; Figure 1 ). Similarly, normalized FMD (FMD/shear rate) significantly increased ( Figure 2 ). Results are presented in Table 2 .
| Variables | Experimental | Control | p Value | ||
|---|---|---|---|---|---|
| Baseline | 3 Months | Baseline | 3 Months | ||
| Flow-mediated dilation | 4.23 ± 0.13 | 4.65 ± 0.15 | 4.62 ± 0.16 | 4.48 ± 0.17 | <0.0001 |
| Flow-mediated dilation/shear rate | 0.02 ± 0.00 | 0.07 ± 0.01 | 0.04 ± 0.00 | 0.03 ± 0.00 | <0.0001 |
| Flow-mediated dilation percent change | 6.7 ± 0.88 | 19.6 ± 1.5 | 12.9 ± 1.6 | 10.7 ± 1.3 | <0.0001 |
| Average peak velocity (cm/s) | 145.7 ± 8.3 | 165.3 ± 7.9 | 126.5 ± 9.0 | 133.2 ± 10.2 | 0.32 |
| Weight (lbs.) | 212 ± 8.3 | 200 ± 8.0 | 200.0 ± 7.8 | 200.1 ± 7.6 | <0.0001 |
| Blood pressure (mm Hg) | |||||
| Systolic | 125.7 ± 3.8 | 118 ± 3.2 | 129.1 ± 3.4 | 121.5 ± 3.7 | 0.98 |
| Diastolic | 74.4 ± 2.1 | 72.6 ± 1.8 | 76.9 ± 1.3 | 75.3 ± 1.7 | 0.94 |
| Heart rate | 67.5 ± 2.4 | 68 ± 2.4 | 64.9 ± 1.7 | 65.7 ± 1.7 | 0.92 |
| Lifestyle index | 0.17 ± 0.04 | 0.89 ± 0.04 | 0.19 ± 0.06 | 0.18 ± 0.06 | <0.0001 |
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