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ORIGINAL RESEARCH
A Randomized, Controlled Pilot Study of the Effects of Acupuncture on Circulating Endothelial Progenitor Cells in Coronary Heart Disease Jeannette Painovich, DAOM, LAc; Anita Phancao, MD; Puja Mehta, MD; Supurna Chowdhury, MS; Shivani Dhawan, MS; Ning Li, PhD; Doris Taylor, PhD; Yi Qiao, LAc; Anna Brantman, DAOM, LAc; Xiuling Ma, PhD, LAc; C. Noel Bairey Merz, MD
Abstract Context: Coronary heart disease (CHD) remains the number one killer of men and women in the United States, and despite traditional secondary prevention, individuals with the disease remain at risk. Endothelial progenitor cells (EPCs) may have beneficial effects on atherosclerosis, angiogenesis, and vascular repair and may contribute systemically to ongoing endogenous repair processes. Traditional acupuncture (TA), a modality used in the practice of Chinese medicine, appears to have beneficial effects in many areas associated with CHD. Objective: The study examined the effects of TA on circulating EPCs in individuals with CHD. Design: The research team performed a randomized, controlled pilot study. Setting: All interventions were performed at the Cedars-Sinai Medical Center in Los Angeles, CA. Participants: The study included 13 participants in 3 groups: (1) TA (n = 5), (2) sham acupuncture (SA, n = 5), or (3) waiting control (WC, n = 3). Intervention: The TA group received acupuncture treatments for 12 wk at CHD-specific sites, while the SA
Jeannette Painovich, DAOM, LAc, is a research acupuncturist; Anita Phancao, MD, is a cardiology fellow; Puja Mehta, MD, is director of the Non-Invasive Vascular Function Research Lab; Supurna Chowdhury, MS, is a research associate III; Shivani Dhawan, MS, is a clinical research associate II; Ning Li, PhD, is a research scientist and assistant professor; Yi Qiao, LAc, is an acupuncturist; Anna Brantman, DAOM, LAc, is an acupuncturist; Xiuling Ma, PhD, LAc, is an acupuncturist; and C. Noel Bairey Merz, MD, is a professor of medicine and the center director. All are located at Barbra Streisand Women’s Heart Center at the Cedars-Sinai Heart Institute of the Cedars-Sinai Medical Center in Los Angeles, California. Doris Taylor, PhD, is the director of regenerative medicine research at the Texas Heart Institute in Houston, Texas. Painovich—Acupuncture and Endothelial Progenitor Cells
IMCJ_13_2.indd 27
group received no-needle pressure at nonacupuncture sites for the same period, and the WC group received no intervention. Outcome Measures: The study measured the number of EPCs circulating in peripheral blood to determine cell surface markers for expressions of cluster of differentiation 34, 133 (CD34+/CD133+) and vascular endothelial growth factor receptor 2 (VEGF-R2+). Results: Eight men and 5 women with a mean age of 59 ± 10.9 y were included. Compared with their measurements at baseline, members of the TA group had a significantly greater change in the level of EPCs expressing CD34+/VEGF-R2+ compared with the SA group (P = .04). No group differences were evident in immature EPCs expressing CD34+/CD133+. Conclusion: The study’s results suggest that TA can alter the number of EPCs circulating in peripheral blood by increasing the mobilization of the VEGF-R2+ EPC subpopulations. Further studies are warranted to evaluate whether TA can beneficially affect CHD via augmentation of EPC regenerative pathways.
Corresponding author: C. Noel Bairey Merz, MD Email address: [email protected]
C
oronary heart disease (CHD) remains the number one killer of men and women in the United States, and despite traditional secondary prevention, individuals with the disease remain at risk.1-2 A majority of individuals with established CHD have recurrent cardiovascular events despite aggressive management of traditional risk factors such as hyperlipidemia, tobacco use, and hypertension, thereby prompting the need for continued exploration of novel therapeutic options.3-4 Endothelial Integrative Medicine • Vol. 13, No. 2 • April 2014
27
3/4/14 11:34 AM
dysfunction, leading to a reduced bioavailability of nitric oxide (NO), with impaired anti-inflammatory and endothelial-cell antiproliferative effects, has been implicated as a key event in the pathogenesis of atherosclerosis.5 As a potential novel therapy, endothelial progenitor cells (EPCs), a population of cells mobilized from bone marrow, may have beneficial effects on atherosclerosis, angiogenesis, and vascular repair.6-9 An inverse correlation has been found between EPCs circulating in the peripheral blood and CHD risk, while a positive correlation exists between plaque accumulation and endothelial impairment.10 EPCs have also been found to migrate to areas of neovascularization when injected into animal models of ischemia11 and to affect postinfarction remodeling processes beneficially in humans.12 These findings suggest that circulating EPCs may provide a reservoir of cells available to repair injured ones or to replace dysfunctional endothelium, while their absence may exacerbate the progression of CHD, although the association regarding causality has not been carefully examined in humans. Traditional acupuncture (TA), a modality used in the practice of Chinese medicine, appears to have beneficial effects in many areas associated with CHD. Several studies have reported a reduction in blood pressure when hypertensive participants received TA.13-16 Mechanistically, researchers have shown that specific TA points, such as neiguan (P-6), can inhibit sympathetically induced increases in blood pressure.14 Most recently, Park et al17 showed that the acute treatment of TA in hypertensive participants improved endothelial dysfunction. The current research team recently conducted a randomized, controlled trial with 151 participants with stable CHD that examined the effects of 12 weeks of TA— compared with sham acupuncture (SA) and waiting control (WC)—on the outcomes of cardiac autonomic function. The study measured heart rate variability (HRV), blood pressure, lipoprotein profile, and insulin resistance as determined by homeostasis model assessment (HOMA) and endothelial function as determined by peripheral arterial tonometry (PAT). In this study, the team showed that 12 weeks of TA had significant effects on HRV under mental stress and resulted in cardiac autonomic remodeling by sympatho-vagal modulation when compared to SA (P. Mehta, D. Polk, N. Li, et al, unpublished data, 2013). Accordingly, the team performed a concordant pilot study within the larger randomized, controlled study of TA versus SA versus WC in individuals with CHD to determine the effect of TA on EPCs circulating in the peripheral blood. The team hypothesized that TA aimed at improving CHD would increase levels of circulating EPC. Methods Participants The parent study and the current pilot were approved by the Cedars-Sinai Institutional Review Board on September 30, 2008, and all interventions were performed 28
Integrative Medicine • Vol. 13, No. 2 • April 2014
IMCJ_13_2.indd 28
at the Cedars-Sinai Medical Center in Los Angeles, CA. During the last 10 months of the parent trial, October 2008 to July 2009, the last 21 of the 151 participants who had given written consent to participate were asked to take part in the current pilot study. Like all participants in the parent study, they were randomly assigned to the TA group (n = 5), the SA group (n = 5), or the WC group (n = 3), and 13 of the 21 who consented to take part in the pilot study completed the parent trial and underwent EPC serum collection at baseline and at the end of the study as part of the pilot. The inclusion criteria for the parent study was as follows: (1) must be > 18 years of age and (2) must have documented CHD as indicated by acute myocardial infarction (MI), coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), or angiographic evidence of > 50% epicardial, coronary artery stenosis in at least 1 coronary artery. Exclusion criteria included having the following: (1) a comorbid disease precluding survival while in the study; (2) recent MI/unstable angina/CABG/PTCA or stroke within 3 months; (3) an HIV infection, chronic or active hepatitis, or other blood-borne illness; (4) cognitive, psychological, or substance-abuse-related impairment; (5) clinically assessed atrial fibrillation, predominant pacemaker rhythm, significant cardiac conduction system disease, or implantable cardioverter defibrillator; (6) significant valvular heart disease; (7) class III or IV heart failure; (8) renal or liver failure; and (9) previous participation in TA. Also excluded were individuals participating in a formal psychosocial stress management program or currently participating in another trial. Randomization to the TA, SA, or WC group was performed via a computerized program with blocking, whereby eligible patients were assigned to age- (
ORIGINAL RESEARCH
A Randomized, Controlled Pilot Study of the Effects of Acupuncture on Circulating Endothelial Progenitor Cells in Coronary Heart Disease Jeannette Painovich, DAOM, LAc; Anita Phancao, MD; Puja Mehta, MD; Supurna Chowdhury, MS; Shivani Dhawan, MS; Ning Li, PhD; Doris Taylor, PhD; Yi Qiao, LAc; Anna Brantman, DAOM, LAc; Xiuling Ma, PhD, LAc; C. Noel Bairey Merz, MD
Abstract Context: Coronary heart disease (CHD) remains the number one killer of men and women in the United States, and despite traditional secondary prevention, individuals with the disease remain at risk. Endothelial progenitor cells (EPCs) may have beneficial effects on atherosclerosis, angiogenesis, and vascular repair and may contribute systemically to ongoing endogenous repair processes. Traditional acupuncture (TA), a modality used in the practice of Chinese medicine, appears to have beneficial effects in many areas associated with CHD. Objective: The study examined the effects of TA on circulating EPCs in individuals with CHD. Design: The research team performed a randomized, controlled pilot study. Setting: All interventions were performed at the Cedars-Sinai Medical Center in Los Angeles, CA. Participants: The study included 13 participants in 3 groups: (1) TA (n = 5), (2) sham acupuncture (SA, n = 5), or (3) waiting control (WC, n = 3). Intervention: The TA group received acupuncture treatments for 12 wk at CHD-specific sites, while the SA
Jeannette Painovich, DAOM, LAc, is a research acupuncturist; Anita Phancao, MD, is a cardiology fellow; Puja Mehta, MD, is director of the Non-Invasive Vascular Function Research Lab; Supurna Chowdhury, MS, is a research associate III; Shivani Dhawan, MS, is a clinical research associate II; Ning Li, PhD, is a research scientist and assistant professor; Yi Qiao, LAc, is an acupuncturist; Anna Brantman, DAOM, LAc, is an acupuncturist; Xiuling Ma, PhD, LAc, is an acupuncturist; and C. Noel Bairey Merz, MD, is a professor of medicine and the center director. All are located at Barbra Streisand Women’s Heart Center at the Cedars-Sinai Heart Institute of the Cedars-Sinai Medical Center in Los Angeles, California. Doris Taylor, PhD, is the director of regenerative medicine research at the Texas Heart Institute in Houston, Texas. Painovich—Acupuncture and Endothelial Progenitor Cells
IMCJ_13_2.indd 27
group received no-needle pressure at nonacupuncture sites for the same period, and the WC group received no intervention. Outcome Measures: The study measured the number of EPCs circulating in peripheral blood to determine cell surface markers for expressions of cluster of differentiation 34, 133 (CD34+/CD133+) and vascular endothelial growth factor receptor 2 (VEGF-R2+). Results: Eight men and 5 women with a mean age of 59 ± 10.9 y were included. Compared with their measurements at baseline, members of the TA group had a significantly greater change in the level of EPCs expressing CD34+/VEGF-R2+ compared with the SA group (P = .04). No group differences were evident in immature EPCs expressing CD34+/CD133+. Conclusion: The study’s results suggest that TA can alter the number of EPCs circulating in peripheral blood by increasing the mobilization of the VEGF-R2+ EPC subpopulations. Further studies are warranted to evaluate whether TA can beneficially affect CHD via augmentation of EPC regenerative pathways.
Corresponding author: C. Noel Bairey Merz, MD Email address: [email protected]
C
oronary heart disease (CHD) remains the number one killer of men and women in the United States, and despite traditional secondary prevention, individuals with the disease remain at risk.1-2 A majority of individuals with established CHD have recurrent cardiovascular events despite aggressive management of traditional risk factors such as hyperlipidemia, tobacco use, and hypertension, thereby prompting the need for continued exploration of novel therapeutic options.3-4 Endothelial Integrative Medicine • Vol. 13, No. 2 • April 2014
27
3/4/14 11:34 AM
dysfunction, leading to a reduced bioavailability of nitric oxide (NO), with impaired anti-inflammatory and endothelial-cell antiproliferative effects, has been implicated as a key event in the pathogenesis of atherosclerosis.5 As a potential novel therapy, endothelial progenitor cells (EPCs), a population of cells mobilized from bone marrow, may have beneficial effects on atherosclerosis, angiogenesis, and vascular repair.6-9 An inverse correlation has been found between EPCs circulating in the peripheral blood and CHD risk, while a positive correlation exists between plaque accumulation and endothelial impairment.10 EPCs have also been found to migrate to areas of neovascularization when injected into animal models of ischemia11 and to affect postinfarction remodeling processes beneficially in humans.12 These findings suggest that circulating EPCs may provide a reservoir of cells available to repair injured ones or to replace dysfunctional endothelium, while their absence may exacerbate the progression of CHD, although the association regarding causality has not been carefully examined in humans. Traditional acupuncture (TA), a modality used in the practice of Chinese medicine, appears to have beneficial effects in many areas associated with CHD. Several studies have reported a reduction in blood pressure when hypertensive participants received TA.13-16 Mechanistically, researchers have shown that specific TA points, such as neiguan (P-6), can inhibit sympathetically induced increases in blood pressure.14 Most recently, Park et al17 showed that the acute treatment of TA in hypertensive participants improved endothelial dysfunction. The current research team recently conducted a randomized, controlled trial with 151 participants with stable CHD that examined the effects of 12 weeks of TA— compared with sham acupuncture (SA) and waiting control (WC)—on the outcomes of cardiac autonomic function. The study measured heart rate variability (HRV), blood pressure, lipoprotein profile, and insulin resistance as determined by homeostasis model assessment (HOMA) and endothelial function as determined by peripheral arterial tonometry (PAT). In this study, the team showed that 12 weeks of TA had significant effects on HRV under mental stress and resulted in cardiac autonomic remodeling by sympatho-vagal modulation when compared to SA (P. Mehta, D. Polk, N. Li, et al, unpublished data, 2013). Accordingly, the team performed a concordant pilot study within the larger randomized, controlled study of TA versus SA versus WC in individuals with CHD to determine the effect of TA on EPCs circulating in the peripheral blood. The team hypothesized that TA aimed at improving CHD would increase levels of circulating EPC. Methods Participants The parent study and the current pilot were approved by the Cedars-Sinai Institutional Review Board on September 30, 2008, and all interventions were performed 28
Integrative Medicine • Vol. 13, No. 2 • April 2014
IMCJ_13_2.indd 28
at the Cedars-Sinai Medical Center in Los Angeles, CA. During the last 10 months of the parent trial, October 2008 to July 2009, the last 21 of the 151 participants who had given written consent to participate were asked to take part in the current pilot study. Like all participants in the parent study, they were randomly assigned to the TA group (n = 5), the SA group (n = 5), or the WC group (n = 3), and 13 of the 21 who consented to take part in the pilot study completed the parent trial and underwent EPC serum collection at baseline and at the end of the study as part of the pilot. The inclusion criteria for the parent study was as follows: (1) must be > 18 years of age and (2) must have documented CHD as indicated by acute myocardial infarction (MI), coronary artery bypass grafting (CABG), percutaneous transluminal coronary angioplasty (PTCA), or angiographic evidence of > 50% epicardial, coronary artery stenosis in at least 1 coronary artery. Exclusion criteria included having the following: (1) a comorbid disease precluding survival while in the study; (2) recent MI/unstable angina/CABG/PTCA or stroke within 3 months; (3) an HIV infection, chronic or active hepatitis, or other blood-borne illness; (4) cognitive, psychological, or substance-abuse-related impairment; (5) clinically assessed atrial fibrillation, predominant pacemaker rhythm, significant cardiac conduction system disease, or implantable cardioverter defibrillator; (6) significant valvular heart disease; (7) class III or IV heart failure; (8) renal or liver failure; and (9) previous participation in TA. Also excluded were individuals participating in a formal psychosocial stress management program or currently participating in another trial. Randomization to the TA, SA, or WC group was performed via a computerized program with blocking, whereby eligible patients were assigned to age- (
