- Email: [email protected]
Effect of Intensive Lifestyle Changes on Endothelial Function and on Inflammatory Markers of Atherosclerosis
Effect of Intensive Lifestyle Changes on Endothelial Function and on Inflammatory Markers of Atherosclerosis Harvinder S. Dod, MDa,*, Ravindra Bhardwaj, MBBSa, Venu Sajja, MDa, Gerdi Weidner, PhDe,f, Gerald R. Hobbs, PhDb, Gregory W. Konat, PhDc, Shanthi Manivannan, MDd, Wissam Gharib, MDa, Bradford E. Warden, MDa, Navin C. Nanda, MDg, Robert J. Beto, MDa, Dean Ornish, MDf, and Abnash C. Jain, MDa 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 ⴞ 0.13 to 4.65 ⴞ 0.15 mm, whereas in the control group it decreased from 4.62 ⴞ 0.16 to 4.48 ⴞ 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 ⴞ 0.57 to 1.6 ⴞ 0.43 mg/L, p ⴝ 0.03) and interleukin-6 (from 2.52 ⴞ 0.62 to 1.23 ⴞ 0.3 pg/ml, p ⴝ 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. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:362–367) Endothelial dysfunction is the earliest and most important factor in the pathogenesis of atherosclerosis. Inflammation has been shown to contribute to endothelial dysfunction.1 Intensive lifestyle changes have been shown to regress atherosclerosis, improve cardiovascular risk profiles, and decrease angina pectoris and cardiac events.2– 4 We evaluated the influence of intensive lifestyle changes on endothelial function and inflammatory markers of atherosclerosis in this pilot study.
a
Section of Cardiology, Department of Medicine, and Departments of Community Medicine, cNeurobiology and Anatomy, and dMedicine, West Virginia University, Morgantown, West Virginia; eDepartment of Biology, San Francisco State University, San Francisco, and fPreventive Medicine Research Institute, Sausalito, California; and gDivision of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama. Manuscript received July 16, 2009; revised manuscript received and accepted September 9, 2009. This study was supported by West Virginia University Section of Cardiology Foundation Funds, West Virginia University, Morgantown, West Virginia; by Grant W81XWH-06-2-0565 from the Department of the Army, Fort Detrick, Maryland; and Grant MA 155/75-1 from the German Research Foundation (DFG), Bonn, Germany. *Corresponding author: Tel: 304-293-4096; fax: 304-293-7828. E-mail address: [email protected] (H.S. Dod). b
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.09.038
Methods The study group consisted of participants with stable coronary artery disease (CAD) and/or risk factors for CAD.5 Forty-seven nonsmoking participants were enrolled, 27 in the experimental group who followed Multisite Cardiac Lifestyle Intervention Program as per standard protocol,4,5 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.5–7 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 www.AJConline.org
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Table 1 Baseline characteristics
Age (years) Caucasian Men/women Body mass index (kg/m2) Hypertension* Coronary artery disease severity† Mild Moderate Severe Diabetes mellitus Previous smoker Dyslipidemia‡ ACEI/ARB Statins  blocker Metformin Aspirin Clopidogrel
Experimental (n ⫽ 27)
Control (n ⫽ 20)
p Value
56.0 27 (100%) 14/13 33.3 23 12
56.6 20 (100%) 11/9 32.28 16 10
0.98
2 1 9 7 4 22 17 12 13 2 15 5
1 1 8 6 4 15 14 14 13 5 15 8
0.83 0.9 0.64 0.70
0.75 0.98 0.59 0.61 0.10 0.42 0.09 0.17 0.10
Figure 1. FMD percent change comparison between the experimental and control groups at baseline and after 3 months shows significant improvement in FMD in the experimental group but a downward trend in the control group (p ⬍0.0001).
* Mean systolic blood pressure ⱖ140 mm Hg, mean diastolic blood pressure ⱖ90 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). ACEI/ARBs ⫽ angiotensin converting-enzyme inhibitor/angiotensin II receptor blocker.
and written informed consent was obtained from participants before entering the study. 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.8,9 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.
Figure 2. Comparison between FMD normalized with shear rate at baseline and after 3 months in the experimental (dashed line) and control (solid line) groups. There was significant improvement in normalized FMD in the experimental group (p ⬍0.0001).
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,5,6 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 ⱖ6 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 reac-
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Table 2 Endothelial function, clinical characteristics, and lifestyle index Variables
Flow-mediated dilation Flow-mediated dilation/shear rate Flow-mediated dilation percent change Average peak velocity (cm/s) Weight (lbs.) Blood pressure (mm Hg) Systolic Diastolic Heart rate Lifestyle index
Experimental
Control
p Value
Baseline
3 Months
Baseline
3 Months
4.23 ⫾ 0.13 0.02 ⫾ 0.00 6.7 ⫾ 0.88 145.7 ⫾ 8.3 212 ⫾ 8.3
4.65 ⫾ 0.15 0.07 ⫾ 0.01 19.6 ⫾ 1.5 165.3 ⫾ 7.9 200 ⫾ 8.0
4.62 ⫾ 0.16 0.04 ⫾ 0.00 12.9 ⫾ 1.6 126.5 ⫾ 9.0 200.0 ⫾ 7.8
4.48 ⫾ 0.17 0.03 ⫾ 0.00 10.7 ⫾ 1.3 133.2 ⫾ 10.2 200.1 ⫾ 7.6
⬍0.0001 ⬍0.0001 ⬍0.0001 0.32 ⬍0.0001
125.7 ⫾ 3.8 74.4 ⫾ 2.1 67.5 ⫾ 2.4 0.17 ⫾ 0.04
118 ⫾ 3.2 72.6 ⫾ 1.8 68 ⫾ 2.4 0.89 ⫾ 0.04
129.1 ⫾ 3.4 76.9 ⫾ 1.3 64.9 ⫾ 1.7 0.19 ⫾ 0.06
121.5 ⫾ 3.7 75.3 ⫾ 1.7 65.7 ⫾ 1.7 0.18 ⫾ 0.06
0.98 0.94 0.92 ⬍0.0001
Values are means ⫾ SEMs.
tive 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.8,9 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-␣ (TNF-␣) quantitation was performed using chemiluminescent QuantiGlo human TNF-␣/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. Multivariate Spearman correlation analysis was performed between changes in FMD and changes in other variables (weight, systolic and diastolic blood pressures, and heart rate), and there was no significant relation seen in the 2 groups. Similarly, there was no significant relation between changes in FMD and changes in inflammatory markers, lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides), and exercise capacity, which were assessed only in the experimental group. In the subgroup analysis of participants with CAD, there was significant improvement in FMD percent change (5.6 ⫾ 1.1 vs 17.2 ⫾ 1.3) in favor of the experimental group compared to the control group (11.3 ⫾ 2.7 vs 9.7 ⫾ 1.4, p ⬍0.0001) after 3 months. There was significant change in normalized FMD in favor of the experimental group (0.02 ⫾ 0.003 vs 0.07 ⫾ 0.008) compared to the control group (0.04 ⫾ 0.012 vs 0.03 ⫾ 0.004, p ⬍0.0001).
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Table 3 Experimental group blood analyses
CRP (mg/L) IL-6 (pg/ml) TNF (pg/ml) VEGF (mg/L) ICAM (mg/L) VCAM (mg/L) E-selectin (ng/ml) Lipid profile (mg/dl) Total cholesterol Low-density lipoprotein High-density lipoprotein Triglyceride
Baseline
3 Months
p Value (2-tailed)
2.07 ⫾ 0.57 2.53 ⫾ 0.62 5.58 ⫾ 2.42 0.22 ⫾ 0.02 0.28 ⫾ 0.04 1.11 ⫾ 0.09 34.84 ⫾ 3.86
1.6 ⫾ 0.43 1.24 ⫾ 0.3 2.40 ⫾ 0.25 0.21 ⫾ 0.03 0.27 ⫾ 0.03 1.10 ⫾ 0.09 32.68 ⫾ 3.51
0.03 0.02 0.2 0.8 0.4 0.5 0.4
161.3 ⫾ 7.3 95.9 ⫾ 7.3 40.1 ⫾ 1.9 125.9 ⫾ 10.9
150.2 ⫾ 7.5 86.3 ⫾ 7.1 35.4 ⫾ 1.58 142.5 ⫾ 14.3
0.08 0.12 0.001 0.15
Values are means ⫾ SEMs. ICAM ⫽ intercellular adhesion molecule; VCAM ⫽ vascular cell adhesion molecule; VEGF ⫽ vascular endothelial growth factor.
Figure 3. Serum markers levels at baseline and after 3 months in the experimental group. There were significant decreases in levels of CRP and IL-6. TNF-␣ showed a downward trend but did not reach significance.
Multivariate analysis was performed in this subgroup with CAD and showed a positive correlation between changes in FMD and changes (decrease) in weight after 3 months in the experimental group (r2 ⫽ 0.32, p ⫽ 0.04). Otherwise there was no significant association of changes in FMD to changes in other variables in the 2 groups. Adherence to lifestyle change program: Significant improvements in diet, exercise, and stress management were noted after 3 months in the experimental group (Table 2). In the control group adherence to diet, exercise, and stress management remained unchanged after 3 months. Dietary adherence (goal 10% calories from fat) significantly improved in the experimental group after 3 months (0.13 ⫾
Figure 4. Correlation between change (delta) in intercellular cell adhesion molecule (ICAM) serum marker of endothelial dysfunction and change in high-sensitivity CRP marker of inflammation after 3 months in the experimental group. Spearman rank correlation coefficient analyses were conducted to assess the association of change between variables. There was a significant positive relation seen (p ⫽ 0.01).
0.07 vs 0.52 ⫾ 0.10) compared to the control group (0.0 vs 0.0, p ⫽ 0.0004). All control participants consumed ⬎10% of calories from fat at baseline and after 3 months. Exercise adherence (goal 3 hours/week) significantly improved in the experimental group after 3 months (0.37 ⫾ 0.11 vs 1.28 ⫾ 0.07) compared to the control group (0.55 ⫾ 0.06 vs 0.54 ⫾ 0.06, p ⬍0.0001). Stress management (goal 1 hour/day yoga/meditation) significantly improved in the experimental group after 3 months (0.01 ⫾ 0.11 vs 0.86 ⫾ 0.07) compared to the control group (0.0 vs 0.0, p ⬍0.0001). None of the control participants were performing stress management at baseline and after 3 months. Serum markers of endothelial dysfunction, inflammation, angiogenesis, and lipid profile were performed only in the experimental group at baseline and after 3 months. Results are presented in Table 3. There were significant decreases in high-sensitivity CRP and IL-6 after 3 months; a downward trend was also observed in TNF-␣ but did not reach statistical significance (Figure 3). No significant changes were observed in markers of endothelial dysfunction (E-selectin, intercellular cell adhesion molecule, vascular cell adhesion molecule) and angiogenesis (vascular endothelial growth factor). On lipid profile analyses, total cholesterol and lowdensity lipoprotein cholesterol were lower at 3 months but did not reach the conventional level of statistical significance, but high-density lipoprotein was significantly decreased after 3 months. Level of triglycerides remained unchanged. Multivariate Spearman correlation analysis was performed between markers of endothelial dysfunction, inflammation, and angiogenesis. There was a significant correlation between changes in intercellular cell adhesion molecule and changes in high-sensitivity CRP (Figure 4). A correlation was also seen between intercellular cell adhesion molecule and IL-6 but did not reach statistical significance (p ⫽ 0.09). No other correlation was noted between these variables. In the subgroup analyses of participants with CAD,
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there was a significant decrease in high-sensitivity CRP (0.83 ⫾ 0.22 vs 0.59 ⫾ 0.23 mg/L, p ⫽ 0.01) and IL-6 (2.19 ⫾ 0.95 vs 0.77 ⫾ 0.29 pg/ml, p ⫽ 0.05). TNF-␣ was also decreased in participants with CAD close to significance (4.5 ⫾ 1.8 vs 2.0 ⫾ 0.3 pg/ml, p ⫽ 0.07), whereas the other markers of endothelial dysfunction and angiogenesis (E-selectin, intercellular cell adhesion molecule, vascular cell adhesion molecule, and vascular endothelial growth factor) remained unchanged. Discussion In this pilot study of participants with stable CAD and/or risk factors for CAD, we found that intensive lifestyle changes significantly increase endothelial function compared to a matched control group that received usual care. The experimental group also showed significant decrease in inflammatory biomarkers of atherosclerosis. In the past, intensive lifestyle changes were shown to improve modifiable cardiac risk factors, functional status, angina symptoms, myocardial perfusion, and left ventricular ejection fraction and to slow the progression of coronary atherosclerosis.2– 4,7,10,11 The underlying mechanisms of these improvements have not been elucidated with this intensive lifestyle changes program. This program is an integrated approach to prevent or reverse CAD, which includes nutrition (10% fat, vegetarian diet), aerobic exercise, stress management, smoking cessation, and group psychosocial support. Endothelium plays a very important role in maintaining vascular homeostasis, by balancing between endothelium derived relaxing and contracting factors. Endothelium dysfunction predisposes blood vessels to vasoconstriction, leukocyte adherence, platelet activation, pro-oxidation, proliferation, impaired coagulation, inflammation, thrombosis, and atherosclerosis. Endothelial dysfunction is the earliest and most important factor in the pathogenesis of atherosclerosis.1 Endothelial dysfunction and markers of systemic inflammation are independent predictors of cardiovascular diseases.12,13 Persistent endothelial dysfunction despite therapies to decrease atherosclerotic risk factors was an independent predictor of future cardiovascular events in patients with CAD.14 In our study significant increase in FMD and decrease in CRP and IL-6 with intensive lifestyle changes in the experimental group suggest ⱖ1 potential mechanism of benefits seen in previous trials.2– 4,7,10,11 We found no significant correlation between increase in FMD and changes in serum biomarkers of inflammation, endothelial function, and angiogenesis after 3 months in the experimental group. There was a significant positive correlation between changes in the serum marker of endothelial dysfunction/adhesion molecule (intercellular cell adhesion molecule) and changes in the inflammatory marker (CRP) in the experimental group after 3 months. These findings were similar to previous studies15,16 that had shown a positive correlation of CRP with adhesion molecules. Lowering CRP levels may have beneficial effects on the evolution of atherosclerosis and may decrease complications not only by decreasing inflammatory response but also by decreasing the expression of adhesion molecules. Interestingly, a significant positive correlation was seen between weight de-
crease and improvement in FMD in the experimental group with CAD, which emphasizes the benefit of weight decrease in patients with CAD. This correlation was not seen in a previous study where patients with CAD had undergone short-term weight decrease with sibutramine therapy.17 In previous studies a high–saturated-fat diet adversely affected FMD, whereas a low-fat diet had a beneficial effect.18,19 Similarly exercise and stress management have been shown to have a beneficial effect on FMD.20,21 This study suggests that the various components of the Multisite Cardiac Lifestyle Intervention Program (low-fat diet, exercise, and stress management) contributed to the improvement in endothelial function and were associated with a decrease in inflammatory markers, which may in turn decrease cardiovascular events in patients with CAD and/or risk factors for CAD. This study was not randomized, and the sample was small. Markers of inflammation, angiogenesis, and endothelial dysfunction were not assessed in the control group. Endothelium-independent vasodilatation was not assessed in the 2 groups. All participants were predominantly white, and our findings may not apply to other ethnic/racial groups. Acknowledgment: We sincerely thank Deborah Hammel, RN, and Daniel Fil, MS, for their help in this study. 1. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42:1149 – 1160. 2. Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports TA, McLanahan SM, Kirkeeide RL, Brand RJ, Gould KL. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 1990;336:129 –133. 3. Gould KL, Ornish D, Scherwitz L, Brown S, Edens RP, Hess MJ, Mullani N, Bolomey L, Dobbs F, Armstrong WT, Meritt T, Ports T, Sparler S, Billings J. Changes in myocardial perfusion abnormalities by positron emission tomography after long-term, intense risk factor modification. JAMA 1995;274:894 – 899. 4. Frattaroli J, Weidner G, Merritt-Worden TA, Frenda S, Ornish D. Angina pectoris and atherosclerotic risk factors in the multisite cardiac lifestyle intervention program. Am J Cardiol 2008;101:911–918. 5. Pischke CR, Frenda S, Ornish D, Weidner G. Lifestyle changes are related to reductions in depression in persons with elevated coronary risk factors. Psychol Health; in press. 6. Daubenmier JJ, Weidner G, Sumner MD, Mendell N, Merritt-Worden T, Studley J, Ornish D. The contribution of changes in diet, exercise, and stress management to changes in coronary risk in women and men in the Multisite Cardiac Lifestyle Intervention Program. Ann Behav Med 2007;33:57– 68. 7. Govil S, Weidner G, Merritt-Worden T, Ornish D. Improvements in lifestyle, coronary risk factors, and quality of life by socioeconomic status in the Multi-site Cardiac Lifestyle Intervention Program. Am J Public Health 2009;99:1263–1270. 8. Pyke KE, Tschakovsky ME. The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol 2005;568:357–369. 9. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257–265. 10. Ornish D, Scherwitz LW, Billings JH, Brown SE, Gould KL, Merritt TA, Sparler S, Armstrong WT, Ports TA, Kirkeeide RL, Hogeboom C, Brand RJ. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998;280:2001–2007. 11. Pischke CR, Weidner G, Elliott-Eller M, Scherwitz L, Merritt-Worden TA, Marlin R, Lipsenthal L, Finkel R, Saunders D, McCormac P,
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Scheer JM, Collins RE, Guarneri EM, Ornish D. Comparison of coronary risk factors and quality of life in coronary artery disease patients with versus without diabetes mellitus. Am J Cardiol 2006;97:1267–1273. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836 – 843. Halcox JP, Donald AE, Ellins E, Witte DR, Shipley MJ, Brunner EJ, Marmot MG, Deanfield JE. Endothelial function predicts progression of carotid intima-media thickness. Circulation 2009;119:1005–1012. Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D, Saito Y, Kawabata K, Sano K, Kobayashi T, Yano T, Nakamura K, Kugiyama K. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol 2009;53:323–330. Cottone S, Mulè G, Nardi E, Vadalà A, Guarneri M, Briolotta C, Arsena R, Palermo A, Riccobene R, Cerasola G. Relation of C-reactive protein to oxidative stress and to endothelial activation in essential hypertension. Am J Hypertens 2006;19:313–318. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000;102:2165–2168.
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17. Shechter M, Beigel R, Freimark D, Matetzky S, Feinberg MS. Shortterm sibutramine therapy is associated with weight loss and improved endothelial function in obese patients with coronary artery disease. Am J Cardiol 2006;97:1650 –1653. 18. Miller M, Beach V, Sorkin JD, Mangano C, Dobmeier C, Novacic D, Rhyne J, Vogel RA. Comparative effects of three popular diets on lipids, endothelial function, and C-reactive protein during weight maintenance. J Am Diet Assoc 2009;109:713–717. 19. Vogel RA, Corretti MC, Plotnick GD. The postprandial effect of components of the Mediterranean diet on endothelial function. J Am Coll Cardiol 2000;36:1455–1460. 20. Sivasankaran S, Pollard-Quintner S, Sachdeva R, Pugeda J, Hoq SM, Zarich SW. The effect of a six-week program of yoga and meditation on brachial artery reactivity: do psychosocial interventions affect vascular tone? Clin Cardiol 2006;29:393–398. 21. Blumenthal JA, Sherwood A, Babyak MA, Watkins LL, Waugh R, Georgiades A, Bacon SL, Hayano J, Coleman RE, Hinderliter A. Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial. JAMA 2005;293:1626 –1634.
a
Section of Cardiology, Department of Medicine, and Departments of Community Medicine, cNeurobiology and Anatomy, and dMedicine, West Virginia University, Morgantown, West Virginia; eDepartment of Biology, San Francisco State University, San Francisco, and fPreventive Medicine Research Institute, Sausalito, California; and gDivision of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama. Manuscript received July 16, 2009; revised manuscript received and accepted September 9, 2009. This study was supported by West Virginia University Section of Cardiology Foundation Funds, West Virginia University, Morgantown, West Virginia; by Grant W81XWH-06-2-0565 from the Department of the Army, Fort Detrick, Maryland; and Grant MA 155/75-1 from the German Research Foundation (DFG), Bonn, Germany. *Corresponding author: Tel: 304-293-4096; fax: 304-293-7828. E-mail address: [email protected] (H.S. Dod). b
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.09.038
Methods The study group consisted of participants with stable coronary artery disease (CAD) and/or risk factors for CAD.5 Forty-seven nonsmoking participants were enrolled, 27 in the experimental group who followed Multisite Cardiac Lifestyle Intervention Program as per standard protocol,4,5 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.5–7 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 www.AJConline.org
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Table 1 Baseline characteristics
Age (years) Caucasian Men/women Body mass index (kg/m2) Hypertension* Coronary artery disease severity† Mild Moderate Severe Diabetes mellitus Previous smoker Dyslipidemia‡ ACEI/ARB Statins  blocker Metformin Aspirin Clopidogrel
Experimental (n ⫽ 27)
Control (n ⫽ 20)
p Value
56.0 27 (100%) 14/13 33.3 23 12
56.6 20 (100%) 11/9 32.28 16 10
0.98
2 1 9 7 4 22 17 12 13 2 15 5
1 1 8 6 4 15 14 14 13 5 15 8
0.83 0.9 0.64 0.70
0.75 0.98 0.59 0.61 0.10 0.42 0.09 0.17 0.10
Figure 1. FMD percent change comparison between the experimental and control groups at baseline and after 3 months shows significant improvement in FMD in the experimental group but a downward trend in the control group (p ⬍0.0001).
* Mean systolic blood pressure ⱖ140 mm Hg, mean diastolic blood pressure ⱖ90 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). ACEI/ARBs ⫽ angiotensin converting-enzyme inhibitor/angiotensin II receptor blocker.
and written informed consent was obtained from participants before entering the study. 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.8,9 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.
Figure 2. Comparison between FMD normalized with shear rate at baseline and after 3 months in the experimental (dashed line) and control (solid line) groups. There was significant improvement in normalized FMD in the experimental group (p ⬍0.0001).
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,5,6 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 ⱖ6 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 reac-
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Table 2 Endothelial function, clinical characteristics, and lifestyle index Variables
Flow-mediated dilation Flow-mediated dilation/shear rate Flow-mediated dilation percent change Average peak velocity (cm/s) Weight (lbs.) Blood pressure (mm Hg) Systolic Diastolic Heart rate Lifestyle index
Experimental
Control
p Value
Baseline
3 Months
Baseline
3 Months
4.23 ⫾ 0.13 0.02 ⫾ 0.00 6.7 ⫾ 0.88 145.7 ⫾ 8.3 212 ⫾ 8.3
4.65 ⫾ 0.15 0.07 ⫾ 0.01 19.6 ⫾ 1.5 165.3 ⫾ 7.9 200 ⫾ 8.0
4.62 ⫾ 0.16 0.04 ⫾ 0.00 12.9 ⫾ 1.6 126.5 ⫾ 9.0 200.0 ⫾ 7.8
4.48 ⫾ 0.17 0.03 ⫾ 0.00 10.7 ⫾ 1.3 133.2 ⫾ 10.2 200.1 ⫾ 7.6
⬍0.0001 ⬍0.0001 ⬍0.0001 0.32 ⬍0.0001
125.7 ⫾ 3.8 74.4 ⫾ 2.1 67.5 ⫾ 2.4 0.17 ⫾ 0.04
118 ⫾ 3.2 72.6 ⫾ 1.8 68 ⫾ 2.4 0.89 ⫾ 0.04
129.1 ⫾ 3.4 76.9 ⫾ 1.3 64.9 ⫾ 1.7 0.19 ⫾ 0.06
121.5 ⫾ 3.7 75.3 ⫾ 1.7 65.7 ⫾ 1.7 0.18 ⫾ 0.06
0.98 0.94 0.92 ⬍0.0001
Values are means ⫾ SEMs.
tive 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.8,9 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-␣ (TNF-␣) quantitation was performed using chemiluminescent QuantiGlo human TNF-␣/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. Multivariate Spearman correlation analysis was performed between changes in FMD and changes in other variables (weight, systolic and diastolic blood pressures, and heart rate), and there was no significant relation seen in the 2 groups. Similarly, there was no significant relation between changes in FMD and changes in inflammatory markers, lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides), and exercise capacity, which were assessed only in the experimental group. In the subgroup analysis of participants with CAD, there was significant improvement in FMD percent change (5.6 ⫾ 1.1 vs 17.2 ⫾ 1.3) in favor of the experimental group compared to the control group (11.3 ⫾ 2.7 vs 9.7 ⫾ 1.4, p ⬍0.0001) after 3 months. There was significant change in normalized FMD in favor of the experimental group (0.02 ⫾ 0.003 vs 0.07 ⫾ 0.008) compared to the control group (0.04 ⫾ 0.012 vs 0.03 ⫾ 0.004, p ⬍0.0001).
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Table 3 Experimental group blood analyses
CRP (mg/L) IL-6 (pg/ml) TNF (pg/ml) VEGF (mg/L) ICAM (mg/L) VCAM (mg/L) E-selectin (ng/ml) Lipid profile (mg/dl) Total cholesterol Low-density lipoprotein High-density lipoprotein Triglyceride
Baseline
3 Months
p Value (2-tailed)
2.07 ⫾ 0.57 2.53 ⫾ 0.62 5.58 ⫾ 2.42 0.22 ⫾ 0.02 0.28 ⫾ 0.04 1.11 ⫾ 0.09 34.84 ⫾ 3.86
1.6 ⫾ 0.43 1.24 ⫾ 0.3 2.40 ⫾ 0.25 0.21 ⫾ 0.03 0.27 ⫾ 0.03 1.10 ⫾ 0.09 32.68 ⫾ 3.51
0.03 0.02 0.2 0.8 0.4 0.5 0.4
161.3 ⫾ 7.3 95.9 ⫾ 7.3 40.1 ⫾ 1.9 125.9 ⫾ 10.9
150.2 ⫾ 7.5 86.3 ⫾ 7.1 35.4 ⫾ 1.58 142.5 ⫾ 14.3
0.08 0.12 0.001 0.15
Values are means ⫾ SEMs. ICAM ⫽ intercellular adhesion molecule; VCAM ⫽ vascular cell adhesion molecule; VEGF ⫽ vascular endothelial growth factor.
Figure 3. Serum markers levels at baseline and after 3 months in the experimental group. There were significant decreases in levels of CRP and IL-6. TNF-␣ showed a downward trend but did not reach significance.
Multivariate analysis was performed in this subgroup with CAD and showed a positive correlation between changes in FMD and changes (decrease) in weight after 3 months in the experimental group (r2 ⫽ 0.32, p ⫽ 0.04). Otherwise there was no significant association of changes in FMD to changes in other variables in the 2 groups. Adherence to lifestyle change program: Significant improvements in diet, exercise, and stress management were noted after 3 months in the experimental group (Table 2). In the control group adherence to diet, exercise, and stress management remained unchanged after 3 months. Dietary adherence (goal 10% calories from fat) significantly improved in the experimental group after 3 months (0.13 ⫾
Figure 4. Correlation between change (delta) in intercellular cell adhesion molecule (ICAM) serum marker of endothelial dysfunction and change in high-sensitivity CRP marker of inflammation after 3 months in the experimental group. Spearman rank correlation coefficient analyses were conducted to assess the association of change between variables. There was a significant positive relation seen (p ⫽ 0.01).
0.07 vs 0.52 ⫾ 0.10) compared to the control group (0.0 vs 0.0, p ⫽ 0.0004). All control participants consumed ⬎10% of calories from fat at baseline and after 3 months. Exercise adherence (goal 3 hours/week) significantly improved in the experimental group after 3 months (0.37 ⫾ 0.11 vs 1.28 ⫾ 0.07) compared to the control group (0.55 ⫾ 0.06 vs 0.54 ⫾ 0.06, p ⬍0.0001). Stress management (goal 1 hour/day yoga/meditation) significantly improved in the experimental group after 3 months (0.01 ⫾ 0.11 vs 0.86 ⫾ 0.07) compared to the control group (0.0 vs 0.0, p ⬍0.0001). None of the control participants were performing stress management at baseline and after 3 months. Serum markers of endothelial dysfunction, inflammation, angiogenesis, and lipid profile were performed only in the experimental group at baseline and after 3 months. Results are presented in Table 3. There were significant decreases in high-sensitivity CRP and IL-6 after 3 months; a downward trend was also observed in TNF-␣ but did not reach statistical significance (Figure 3). No significant changes were observed in markers of endothelial dysfunction (E-selectin, intercellular cell adhesion molecule, vascular cell adhesion molecule) and angiogenesis (vascular endothelial growth factor). On lipid profile analyses, total cholesterol and lowdensity lipoprotein cholesterol were lower at 3 months but did not reach the conventional level of statistical significance, but high-density lipoprotein was significantly decreased after 3 months. Level of triglycerides remained unchanged. Multivariate Spearman correlation analysis was performed between markers of endothelial dysfunction, inflammation, and angiogenesis. There was a significant correlation between changes in intercellular cell adhesion molecule and changes in high-sensitivity CRP (Figure 4). A correlation was also seen between intercellular cell adhesion molecule and IL-6 but did not reach statistical significance (p ⫽ 0.09). No other correlation was noted between these variables. In the subgroup analyses of participants with CAD,
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there was a significant decrease in high-sensitivity CRP (0.83 ⫾ 0.22 vs 0.59 ⫾ 0.23 mg/L, p ⫽ 0.01) and IL-6 (2.19 ⫾ 0.95 vs 0.77 ⫾ 0.29 pg/ml, p ⫽ 0.05). TNF-␣ was also decreased in participants with CAD close to significance (4.5 ⫾ 1.8 vs 2.0 ⫾ 0.3 pg/ml, p ⫽ 0.07), whereas the other markers of endothelial dysfunction and angiogenesis (E-selectin, intercellular cell adhesion molecule, vascular cell adhesion molecule, and vascular endothelial growth factor) remained unchanged. Discussion In this pilot study of participants with stable CAD and/or risk factors for CAD, we found that intensive lifestyle changes significantly increase endothelial function compared to a matched control group that received usual care. The experimental group also showed significant decrease in inflammatory biomarkers of atherosclerosis. In the past, intensive lifestyle changes were shown to improve modifiable cardiac risk factors, functional status, angina symptoms, myocardial perfusion, and left ventricular ejection fraction and to slow the progression of coronary atherosclerosis.2– 4,7,10,11 The underlying mechanisms of these improvements have not been elucidated with this intensive lifestyle changes program. This program is an integrated approach to prevent or reverse CAD, which includes nutrition (10% fat, vegetarian diet), aerobic exercise, stress management, smoking cessation, and group psychosocial support. Endothelium plays a very important role in maintaining vascular homeostasis, by balancing between endothelium derived relaxing and contracting factors. Endothelium dysfunction predisposes blood vessels to vasoconstriction, leukocyte adherence, platelet activation, pro-oxidation, proliferation, impaired coagulation, inflammation, thrombosis, and atherosclerosis. Endothelial dysfunction is the earliest and most important factor in the pathogenesis of atherosclerosis.1 Endothelial dysfunction and markers of systemic inflammation are independent predictors of cardiovascular diseases.12,13 Persistent endothelial dysfunction despite therapies to decrease atherosclerotic risk factors was an independent predictor of future cardiovascular events in patients with CAD.14 In our study significant increase in FMD and decrease in CRP and IL-6 with intensive lifestyle changes in the experimental group suggest ⱖ1 potential mechanism of benefits seen in previous trials.2– 4,7,10,11 We found no significant correlation between increase in FMD and changes in serum biomarkers of inflammation, endothelial function, and angiogenesis after 3 months in the experimental group. There was a significant positive correlation between changes in the serum marker of endothelial dysfunction/adhesion molecule (intercellular cell adhesion molecule) and changes in the inflammatory marker (CRP) in the experimental group after 3 months. These findings were similar to previous studies15,16 that had shown a positive correlation of CRP with adhesion molecules. Lowering CRP levels may have beneficial effects on the evolution of atherosclerosis and may decrease complications not only by decreasing inflammatory response but also by decreasing the expression of adhesion molecules. Interestingly, a significant positive correlation was seen between weight de-
crease and improvement in FMD in the experimental group with CAD, which emphasizes the benefit of weight decrease in patients with CAD. This correlation was not seen in a previous study where patients with CAD had undergone short-term weight decrease with sibutramine therapy.17 In previous studies a high–saturated-fat diet adversely affected FMD, whereas a low-fat diet had a beneficial effect.18,19 Similarly exercise and stress management have been shown to have a beneficial effect on FMD.20,21 This study suggests that the various components of the Multisite Cardiac Lifestyle Intervention Program (low-fat diet, exercise, and stress management) contributed to the improvement in endothelial function and were associated with a decrease in inflammatory markers, which may in turn decrease cardiovascular events in patients with CAD and/or risk factors for CAD. This study was not randomized, and the sample was small. Markers of inflammation, angiogenesis, and endothelial dysfunction were not assessed in the control group. Endothelium-independent vasodilatation was not assessed in the 2 groups. All participants were predominantly white, and our findings may not apply to other ethnic/racial groups. Acknowledgment: We sincerely thank Deborah Hammel, RN, and Daniel Fil, MS, for their help in this study. 1. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42:1149 – 1160. 2. Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports TA, McLanahan SM, Kirkeeide RL, Brand RJ, Gould KL. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 1990;336:129 –133. 3. Gould KL, Ornish D, Scherwitz L, Brown S, Edens RP, Hess MJ, Mullani N, Bolomey L, Dobbs F, Armstrong WT, Meritt T, Ports T, Sparler S, Billings J. Changes in myocardial perfusion abnormalities by positron emission tomography after long-term, intense risk factor modification. JAMA 1995;274:894 – 899. 4. Frattaroli J, Weidner G, Merritt-Worden TA, Frenda S, Ornish D. Angina pectoris and atherosclerotic risk factors in the multisite cardiac lifestyle intervention program. Am J Cardiol 2008;101:911–918. 5. Pischke CR, Frenda S, Ornish D, Weidner G. Lifestyle changes are related to reductions in depression in persons with elevated coronary risk factors. Psychol Health; in press. 6. Daubenmier JJ, Weidner G, Sumner MD, Mendell N, Merritt-Worden T, Studley J, Ornish D. The contribution of changes in diet, exercise, and stress management to changes in coronary risk in women and men in the Multisite Cardiac Lifestyle Intervention Program. Ann Behav Med 2007;33:57– 68. 7. Govil S, Weidner G, Merritt-Worden T, Ornish D. Improvements in lifestyle, coronary risk factors, and quality of life by socioeconomic status in the Multi-site Cardiac Lifestyle Intervention Program. Am J Public Health 2009;99:1263–1270. 8. Pyke KE, Tschakovsky ME. The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol 2005;568:357–369. 9. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39:257–265. 10. Ornish D, Scherwitz LW, Billings JH, Brown SE, Gould KL, Merritt TA, Sparler S, Armstrong WT, Ports TA, Kirkeeide RL, Hogeboom C, Brand RJ. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998;280:2001–2007. 11. Pischke CR, Weidner G, Elliott-Eller M, Scherwitz L, Merritt-Worden TA, Marlin R, Lipsenthal L, Finkel R, Saunders D, McCormac P,
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17. Shechter M, Beigel R, Freimark D, Matetzky S, Feinberg MS. Shortterm sibutramine therapy is associated with weight loss and improved endothelial function in obese patients with coronary artery disease. Am J Cardiol 2006;97:1650 –1653. 18. Miller M, Beach V, Sorkin JD, Mangano C, Dobmeier C, Novacic D, Rhyne J, Vogel RA. Comparative effects of three popular diets on lipids, endothelial function, and C-reactive protein during weight maintenance. J Am Diet Assoc 2009;109:713–717. 19. Vogel RA, Corretti MC, Plotnick GD. The postprandial effect of components of the Mediterranean diet on endothelial function. J Am Coll Cardiol 2000;36:1455–1460. 20. Sivasankaran S, Pollard-Quintner S, Sachdeva R, Pugeda J, Hoq SM, Zarich SW. The effect of a six-week program of yoga and meditation on brachial artery reactivity: do psychosocial interventions affect vascular tone? Clin Cardiol 2006;29:393–398. 21. Blumenthal JA, Sherwood A, Babyak MA, Watkins LL, Waugh R, Georgiades A, Bacon SL, Hayano J, Coleman RE, Hinderliter A. Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial. JAMA 2005;293:1626 –1634.