Abstract
Background
Heart rate variability (HRV) is reduced in stable ischemic heart disease (SIHD) patients and is associated with sudden cardiac death (SCD). We evaluated the impact of traditional acupuncture (TA) on cardiac autonomic function measured by HRV in SIHD patients.
Methods
We conducted a randomized controlled study of TA, sham acupuncture (SA), and waiting control (WC) in 151 SIHD subjects. TA group received needle insertion at acupuncture sites, SA group received a sham at non-acupuncture sites, while WC received nothing. TA and SA received 3 treatments/week for 12 wks. 24-hour, mental arithmetic stress, and cold pressor (COP) HRV was collected at entry and exit, along with BP, lipids, insulin resistance, hs-CRP, salivary cortisol, peripheral endothelial function by tonometry(PAT), and psychosocial variables.
Results
Mean age was 63±10; 50% had prior myocardial infarction. Comparison of WC and SA groups demonstrated differences consistent with the unblinded WC status; therefore by design, the control groups were not merged. Exit mental stress HRV was higher in TA vs. SA for markers of parasympathetic tone (p≤0.025), including a 17% higher vagal activity (p=0.008). There were no differences in exit 24-hour or COP HRV, BP, lipids, insulin resistance, hs-CRP, salivary cortisol, PAT, or psychosocial variables.
Conclusions
TA results in intermediate effects on autonomic function in SIHD patients. TA effect on HRV may be clinically relevant and should be explored further. These data document feasibility and provide sample size estimation for a clinical trial of TA in SIHD patients for prevention of SCD.
Keywords: Acupuncture, Autonomic Nervous System, Heart Rate Variability, Coronary Heart Disease
Introduction
Sudden cardiac death (SCD) is a significant problem in patients with stable ischemic heart disease (SIHD), and accounts for 30 to 50% of deaths in this group (~150,000 deaths annually) despite identification and treatment of their disease [1–3]. Risk factors for SCD are similar to those for SIHD, and include cigarette smoking, hypertension, physical inactivity, hyperlipidemia, and diabetes [4, 5]. The mechanism of SCD in SIHD patients is predominantly arrhythmic, and involves the cardiac autonomic nervous system (ANS) [6]. Heart rate variability (HRV), a measure of cardiac ANS function, is reduced in patients with SIHD and predictive of arrhythmic SCD [7]. Cardiac arrhythmias have been implicated both as a risk factor and an etiology for SCD, suggesting that alteration of cardiac ANS tone may provide an opportunity for reducing acute cardiac events and SCD.
Traditional Acupuncture (TA) is a Complementary and Alternative Medicine (CAM) practice with documented beneficial effects on the cardiovascular system. For example, the TA technique has been shown to significantly reduce arrhythmias [8], hypertension in an animal model [9], mental stress in humans [10], and angina pectoris in SIHD patients [11]. These effects are consistent with the hypothesis that the TA technique causes autonomic remodeling , likely by reducing sympathetic and increasing parasympathetic activity.
We undertook a randomized, controlled trial of 12 weeks of TA compared to sham acupuncture (SA) and waiting control (WC) in 151 SIHD patients with the primary outcome of cardiac autonomic function measured by HRV. We also measured the secondary outcomes of blood pressure, lipoprotein profile, and insulin resistance, salivary cortisol, vascular inflammation, endothelial function measured by peripheral arterial tonometry (PAT), and psychosocial variables.
Methods
Patient Population
Inclusion criteria: Women and men aged >18 years, with SIHD documented by prior myocardial infarction, coronary angiography, angioplasty, or coronary bypass surgery. Exclusion criteria: 1. Unstable acute coronary syndrome; 2. Congestive heart failure > than New York Heart Association class III; 3. Renal failure; 4. Acute myocardial infarction in the preceding 3 months; 5. Atrial fibrillation or a predominantly paced rhythm, significant conduction system disease, or automatic internal defibrillator; 6. Prior TA; 7. HIV infection, chronic or active hepatitis or other blood-borne illness that precluded the safe use of needles; 8. Renal or liver failure as clinically assessed; 9. Cognitive, psychological or substance-related impairment, as clinically assessed; 10. Participation in formal psychosocial stress management program or participation in another trial. The Institutional Review Board at Cedars-Sinai Medical Center (CSMC) approved the study; all participants gave written informed consent prior to participation.
Study Design
Patients were recruited from a supervised cardiac exercise and rehabilitation program at CSMC and the surrounding community. The study design was a randomized, single-blind, attention-controlled trial. Randomization to TA, SA or WC for 12 weeks was performed via a computerized program with blocking, whereby eligible patients were grouped according to age > 65 and sex (male vs female), then assigned to treatment group accordingly. The outcome data were collected and analyzed by personnel blinded to patient treatment status. At study entry and exit, following an overnight fast, patients underwent a medical history review including cardiac risk factors, physical activity level, psychosocial assessment, and medication assessment along with PAT (Endo-PAT, Itamar, Israel) and blood sampling. HRV was collected for 24-hour holter monitoring, 2-minute mental arithmetic and 2-min cold pressor (COP) at study entry and exit. Compliance to the TA and SA sessions was assessed by attendance. Participation in the cardiac rehabilitation exercise program was assessed by enrollment. The blood pressure protocol included 5 minutes of sitting quietly followed by three blood pressure measurements at one-minute intervals using a mercury sphygmomanometer, and then averaged for screening, entry and exit visits [12, 13]. Body weight and height were measured to the nearest 0.1 kg and 0.1 cm, and body mass index (BMI) calculated (kg/m2).
TA, SA and WC Interventions
The eight TA point protocol (Table 1, Figure 1) was selected based upon the expertise of our team members, literature review, and the time-honored TA practice that uses multiple points. The SA points were selected by our acupuncturist team to be proximate to the TA site (to enhance the treatment blind), but not in the TA meridian, and not known to be relevant for SIHD outcomes. Figure 1 depicts both the active TA and sham sites. The TA and SA groups underwent three 30-minute sessions weekly while the WC received nothing for 12 weeks. All TA and SA subjects had their eyes covered with eye shades from the beginning of each session, so that they will not be able to view the treatment procedure. Following skin site cleansing with alcohol, disposable acupuncture needles (1–1.5 inch sterilized stainless steel) were inserted up to one inch deep through a plastic needle tube. The tube was then secured with adhesive tape to mimic SA protocol. For the SA group, pressure was initially applied with plastic needle tube to produce a discernible sensation at non-acupuncture sites near TA acupoints but no needle was inserted, and plastic tubes were secured with adhesive tape.
Table 1.
ACUPOINT | ANTICIPATED EFFECT |
---|---|
PC 6 | HRV, PAT, ST Depression, Arrhythmia |
PC 4 | HRV, PAT, ST Depression, Arrhythmia |
HT 7 | HRV, ST Depression, Arrhythmia |
Ren 17 | HRV, ST Depression, Arrhythmia |
Ll 4 | Psychosocial Stress, ST Depression |
LIV 3 | Psychosocial Stress, ST Depression |
ST 36 | HRV |
SP 6 | Vessel Dilation |
PC 6 - Location: 2 cun above of the transverse crease of the wrist, between the tendons of m. palmaris longus and m. flexor carpi radialis. Method: Puncture perpendicularly 0.5 –0.8 inch, even method.
PC 4 - Location: 5 cun above of the transverse crease of the wrist, between the tendons of m. palmaris longus and m. flexor carpi radialis. Method: Puncture perpendicularly 0.5 –1 inch, even method.
HT 7 - Location: At the ulnar end of the transverse crease of the wrist, in the depression on the radial side of the tendon of m. flexor carpi ulnaris. Method: Puncture perpendicularly 0.3 –0.5 inch, even method.
Ren 17 - Location: On the anterior midline, at the level with the fourth intercostal space, midway between the nipples.
Method: puncture subcutaneously 0.3 –0.5 inch, even method.
LI 4 - Location: On the dorsum of the hand, between the 1st and 2nd metacarpal bones, approximately in the middle of the 2nd metacarpal bone on the radial side. Method: Puncture perpendicularly 0.5–1 inch, reducing method.
LIV 3 - Location: On the dorsum of the foot, in the depression distal to the junction of the first and second metatarsal bones. Method: Puncture perpendicularly 0.3 –0.5 inch, reducing method.
ST 36 - Location: 3 cun below St35 (It is at the lower board of the patella, in the depression lateral to the patellar ligament.), one index finger-breadth from the anterior crest of the tibia, in m. tibialis anterior. Method: Puncture perpendicularly 0.5 –1.2 inch, reinforcing method.
SP 6 – Location: 3 cun directly above the tip of the medial malleolus, on the posterior border of the medial aspect of the tibia. Method: Puncture perpendicularly 0.5 –1 inch, reinforcing method.
TA and SA were delivered in a standardized fashion using our Acupuncture Delivery Protocol, which provided guidelines about communications between the acupuncturist and subject. We validated our SA technique using an Acupuncture Delivery Subject Assessment questionnaire, evaluating subjective feelings and the strength of perceived benefit of procedure; in a pilot study among 17 SIHD patients randomized to TA vs SA which demonstrated no differences in ratings between the TA and SA in this subject population.
Autonomic Nervous System Provocative Testing
Patients fasted overnight and withdrew from caffeine, tobacco, and vasoactive medications for 48 hours prior to provocative testing. HRV was obtained during a 24-hour period and during two provocative tests following 15 minutes of rest in a quiet, temperature-controlled room: (1) Mental arithmetic stress test, where subjects were instructed to subtract serial 7s from a four-digit number for 2 minutes. Subjects were mildly harassed during this procedure; (2) COP, where subjects had a 1.5 liter bag filled with 800 ml crushed ice and 200 ml of water (Temp 4°C) placed on their forehead for 2 minutes. The two provocative tests were administered in a counterbalanced order, with a 10-minute recovery period between tasks.
Holter Monitor HRV
Holter monitoring was recorded and analyzed during a 24-hour period and during provocative testing using our previously validated and published methods [13]. A 24-hour recording was considered eligible for this study if it had more than 12 hours of analyzable data, had half of the nighttime and daytime periods analyzable, and if more than 50% of the recording revealed sinus rhythm. The HRV was analyzed using the Marquette® software (Marquette electronics, Milwaukee, WI). To analyze the effect of provocative stimulation on HRV, a 5-minute period of baseline HRV was compared to the 2-minute period during provocative testing, at study entry and exit.
Blood, Saliva and Homeostasis Model Assessment (HOMA) Testing
Total plasma cholesterol, triglyceride, LDL, and HDL were determined as previously published [14]. Serum glucose concentrations and plasma insulin were measured using Elan Glucose reagent [15], and an automated immunoassay instrument and ultra-sensitive insulin kit from Beckman-Coulter [16], respectively. Assays were performed in batches, and in duplicate. The degree of insulin resistance in each subject was estimated by the Homeostasis Model Assessment (HOMA) using the formula: fasting plasma glucose level (mmol/L) times fasting plasma insulin (mU/l) divided by 22.5 according to the method by Matthews [17], where high values indicate high insulin resistance. Prior study has documented the reliability of HOMA by comparison to euglycemic-hyperinsulinemic clamp technique [18, 19]. Salivary cortisol was collected and measured at baseline, at study entry and exit.
Peripheral Arterial Tonometry (PAT)
To specifically test the effect of TA modulation on peripheral endothelial function, we performed PAT 30 minutes after the sympathetic stimulus of mental stress testing at study entry and exit, following an overnight fast and withdrawal of vasoactive medications for 48 hours prior to testing[12, 20]. Subjects were lying down supine comfortably with legs uncrossed, in a quiet, temperature-controlled room. A fitted blood pressure cuff was placed on one arm, and the PAT was performed as previously published and validated [21, 22] [23, 24].
Psychosocial, Angina, and Functional Status Measures
Psychosocial variables obtained at study entry and exit included: 1) perceived environmental stress – assessed by a questionnaire previously demonstrated to be predictive of future adverse cardiac events in patients with SIHD [25]; 2) hostility – assessed by Cook-Medley Hostility Inventory [26, 27]; 3) anxiety – assessed by Spielberger trait anxiety scale [28]; 4) social support- assessed by Duke Support Index[29] ; and 5) quality of life – assessed by Short-Form Health Survey (SF-36) [30]. Duke Activity Status Inventory (DASI) [31] and the Seattle Angina Questionnaire (SAQ) [32] to assess physical functioning and angina were obtained at study entry and exit. The Center for Epidemiological Studies-Depression Scale (CES-D), a self-reported, validated, reliable measure of detecting depressive symptoms during the previous week, [33, 34] was also obtained at study entry and exit.
Statistical Analysis
Data are presented in tables as means ± standard deviations for continuous variables and frequencies and percentages for categorical variables. Comparison of treatment groups at entry and exit was performed using ANOVA for normally-distributed continuous data, Kruskal-Wallis test for non-normal continuous variables, and Chi-square or Fisher’s exact test for categorical data. HRV outcomes are classified into two spectral domains (the time and frequency domains). A MANOVA model was fitted to test overall between-group difference in both domains. Post-hoc analysis used Bonferroni adjustment to adjust the significance level for the two spectral domain HRV outcomes hypothesized to be effected by the intervention. Since data are correlated within each domain, p-values ≤ 0.025 were regarded statistically significant for comparisons of individual HRV variables across the treatment groups. In all other comparisons, a p-value < 0.05 was required for statistical significance. Analyses were performed using SAS 9.2 (Cary, NC). We also conduct repeated measure analysis using SAS procedure Proc Genmod for measures from the time domain (LF, HF, LF/HF, TP) and frequency domain (MeanNN, SDNN, rMSSD, pNN50). For each measurement, we used the values of the difference between exit and entry. We also conducted pairwise comparisons among three groups for the baseline, arithmetic, COP, and 24-hour tests, respectively.
Results
Among the 151 patients enrolled, 131 (87%) subjects completed the study. The primary reason for subject withdrawal was time commitment and inability to take time off from work or unrelated, non-cardiac illness. The Acupuncture Delivery Protocol TA and SA were well-tolerated and there were no adverse side effects. The subject study flow is depicted in Figure 2.
By design, the WC group served as a second control group for the purpose of detecting a potential placebo effect in the SA group. Accordingly, initial analyses of entry and exit variables compared the two control groups (SA and WC), in order to merge the two control groups if no significant differences were found. At baseline, more people in the WC group had prior MI (p=0.05), and total cholesterol was higher in the WC group compared to SA (p=0.05), however no differences in LDL, HDL, or triglycerides. The WC group demonstrated important exit differences in better endothelial function (PAT: WC 2.43 ± 0.61 vs SA 2.08 ± 0.54 vs TA 2.19 ± 0.61, p = 0.03) and a trend toward a greater average number of cardiac rehabilitation exercise sessions (WC 5.9 vs SA 4.3 vs TA 3.9, p=0.06) compared to the SA and TA groups, most consistent with higher health-seeking behavior related to their unblinded, waiting status. By pre-specified study design due to our experience with improved exit behavioral health variables in a prior open label CAM trial [35], we therefore did not merge the control groups.
The entry demographic and clinical characteristics of the three groups are shown in Table 2, and demonstrate a predominantly male, older SIHD population with high rates of hypertension, dyslipidemia and obesity. A minority of patients had diabetes. Medical management of SIHD was near optimal, with high rates of statin, aspirin and anti-hypertensive medication use. The WC group had lower statins use compared to TA (p=0.03) although total and LDL cholesterol were not different (Table 2). Over the intervention period, the number of patients who had changes in their cardiac medications (discontinued, started or dosing changes directed by their treating physician) was similar between the groups (TA= 6.4%, SA= 2%, WC =6%, p= 0.63). More subjects in the SA compared to TA group were actively participating in cardiac rehabilitation during the study (p=0.05) (Table 2).
Table 2.
TA (n = 47) |
SA (n = 52) |
WC (n = 52) |
p- value (TA vs. SA) |
p- value (TA vs. WC) |
p- value (SA vs. WC) |
|
---|---|---|---|---|---|---|
Age (years) (mean ± SD) | 64.9 ± 11 | 63.0 ± 11 | 62.5 ± 11 | 0.41 | 0.27 | 0.79 |
Male (N, %) | 32 (68%) | 37 (71%) | 35 (67%) | 0.74 | 0.93 | 0.67 |
BMI (kg/m2) (mean ± SD) | 28.7 ± 5.3 | 30.5 ± 5.7 | 28.5 ± 6.5 | 0.13 | 0.63 | 0.35 |
History of Hypertension (N, %) | 32 (68%) | 31 (59.6%) | 34 (65.4%) | 0.30 | 0.66 | 0.54 |
History of Diabetes (N, %) | 9 (19%) | 11 (21.2%) | 7 (13.5%) | 0.50 | 0.41 | 0.30 |
Prior Myocardial Infarction (N, %) | 24 (51%) | 20 (38.5%) | 30 (57.7%) | 0.17 | 0.58 | 0.05 |
Prior Angioplasty or Stenting (N, %) | 35 (74.5%) | 38 (73.1%) | 33 (63.5%) | 0.73 | 0.22 | 0.36 |
Current Smoking (N, %) | 2 (4.3%) | 3 (5.8%) | 2 (3.8%) | 0.83 | 0.80 | 0.63 |
Statin use (N, %) | 32 (68.1%) | 30 (57.7%) | 23 (44.2%) | 0.31 | 0.03 | 0.18 |
ACE-Inhibitor use (N, %) | 9 (19.1%) | 15 (28.8%) | 15 (28.8%) | 0.16 | 0.09 | 0.75 |
Calcium Channel Blocker use (N, %) | 13(27.7%) | 8 (15.4%) | 6 (11.5%) | 0.17 | 0.08 | 0.68 |
Beta-Blocker use (N, %) | 24 (51.1%) | 24 (46.2%) | 22 (42.3%) | 0.86 | 0.87 | 1.00 |
DASI Entry (mean ± SD) | 33.7 ± 18.5 | 36.5 ± 17.6 | 36.4 ±18.6 | 0.45 | 0.47 | 0.99 |
Resting Heart Rate (mean ± SD) | 65 ± 12 | 65 ± 10 | 62 ± 7 | 0.97 | 0.25 | 0.19 |
Resting Systolic Blood Pressure (mm Hg) (mean ± SD) | 130 ± 19 | 128 ±18 | 125 ± 26 | 0.63 | 0.28 | 0.47 |
Resting Diastolic Blood Pressure (mm Hg) (mean ± SD) | 74 ± 10 | 73 ± 9 | 70 ± 10 | 0.51 | 0.06 | 0.20 |
Blood Sugar (mean ± SD)* | 103 ± 33 | 106 ± 32 | 101 ± 20 | 0.37 | 0.65 | 0.58 |
HOMA (mean ± SD) | 1.82 ± 1.70 | 2.12 ± 1.45 | 1.93 ± 1.39 | 0.14 | 0.53 | 0.42 |
hs-CRP (mg/L) (mean ± SD)* | 1.98 ± 2.96 | 3.40 ± 4.96 | 2.13 ± 3.2 | 0.13 | 0.83 | 0.26 |
Total Cholesterol (mean ± SD) | 168 ± 39 | 158 ± 36 | 179 ± 55 | 0.20 | 0.31 | 0.05 |
LDL(mean ± SD) | 100 ± 35 | 91 ± 34 | 108 ± 51 | 0.24 | 0.41 | 0.07 |
HDL(mean ± SD) | 49 ± 17 | 47 ± 16 | 53 ± 16 | 0.70 | 0.28 | 0.12 |
Triglycerides (mean ± SD) | 98 ± 49 | 97 ± 55 | 96 ± 65 | 0.79 | 0.48 | 0.55 |
RH-Peripheral Arterial Tonometry (mean ± SD) | 2.37 ± 0.47 | 2.36 ± 0.62 | 2.39 ± 0.54 | 0.92 | 0.87 | 0.38 |
Salivary Cortisol (mean ± SD)* | 0.19 ± 0.11 | 0.26 ± 0.35 | 0.23 ± 0.41 | 0.48 | 0.44 | 0.09 |
Actively participating in Cardiac Rehabilitation (N, %) | 11 (23%) | 18 (35%) | 17 (33%) | 0.22 | 0.31 | 0.84 |
Values expressed as either (mean ± standard deviation) or [frequency (%)]
Wilcoxon t-test for determining differences between the two treatment groups.
ACE=angiotensin converting enzyme, BMI=body mass index, DASI=Duke Activity Status Inventory, TA=traditional acupuncture, SA=sham acupuncture.
Primary Outcome HRV Results
24-Hour HRV
There were no differences in the time or frequency domain 24-hour HRV variables at study entry or exit among the three groups. There were no group differences in entry to exit (delta) HRV. When stratified by prior myocardial infarction, diabetes, or gender there were no significant group differences in entry or exit 24-hour HRV. There was also no difference between daytime (6 AM to 11 PM) and nighttime (11 PM to 6 AM) HRV in both men and women.
Provocative testing HRV
Mental arithmetic stress HRV
There were no differences at entry mental stress HRV between groups, however exit mental arithmetic stress HRV was significantly higher in the TA compared to the SA group, evidenced by differences in high frequency (HF), low frequency (LF)/(HF) ratio, mean NN, rMSDD, and pNN50 (Table 3). Compared to SA, the TA HF (determined by efferent vagal activity) was 17% higher (p = 0.008, Table 3). Both rMSSD and pNN50, measures of rapid change from one heart beat to the next [36], was higher in the TA group compared to SA (Table 3). In contrast, parasympathetic tone was lower in SA vs. WC group, with 11% lower vagal activity (p=0.009). The LF/HF ratio, a measure of sympathovagal balance, was better in TA group [8% lower compared to SA (p=0.015) and 2% lower compared to WC (p=0.38)]. Interestingly, SDNN was lower in the SA vs. WC (p=0.02) consistent with WC group improvement (Table 3). Multivariate analysis for time and frequency domain HRV during mental stress showed no significant treatment effects among the groups (Supplemental Table A).
Table 3.
TA (n = 38) Mean ± SD |
SA (n = 43) Mean ± SD |
WC (n = 50) Mean ± SD |
p-value (TA vs. SA) |
p-value (TA vs. WC) |
p-value (SA vs. WC) |
|
---|---|---|---|---|---|---|
Mental Stress | ||||||
Frequency Domain ln (ms2) | ||||||
LF | 6.09 ±1.44 | 5.63 ± 0.97 | 5.97 ± 0.92 | 0.100 | 0.65 | 0.09 |
HF | 5.25 ± 1.41 | 4.50 ± 1.00 | 5.08 ± 1.06 | 0.008 | 0.54 | 0.009 |
LF/HF | 1.18 ± 0.16 | 1.28 ± 0.24 | 1.2 ± 0.16 | 0.015 | 0.38 | 0.08 |
TP | 7.44 ± 1.24 | 7.00 ±0.93 | 7.5 ± 0.75 | 0.070 | 0.80 | 0.006 |
Time Domain | ||||||
Mean NN (ms) | 1028 ± 166 | 953 ± 115 | 993 ± 127 | 0.021 | 0.27 | 0.13 |
SDNN (ms) | 77.54 ± 43.8 | 59.33 ± 29.7 | 74.1 ± 33.6 | 0.033 | 0.85 | 0.02 |
rMSSD (ms) | 38.30 ± 26.6 | 24.21 ± 11.7 | 32.5 ± 15.0 | 0.019 | 0.43 | 0.02 |
pNN50 (%) | 15.26 ± 18.9 | 5.66 ± 8.5 | 9.2 ± 10.3 | 0.025 | 0.37 | 0.05 |
COP | ||||||
Frequency Domain ln (ms2) | ||||||
LF | 6.04 ± 1.59 | 5.81 ± 0.94 | 6.10 ± 1.00 | 0.43 | 0.81 | 0.15 |
HF | 5.44 ± 1.57 | 5.01 ± 1.01 | 5.36 ± 0.92 | 0.14 | 0.76 | 0.09 |
LF/HF | 1.14 ± 0.24 | 1.19 ± 0.21 | 1.15 ± 0.16 | 0.14 | 0.42 | 0.37 |
TP | 7.70 ± 1.16 | 7.33 ± 0.90 | 7.82 ± 0.81 | 0.12 | 0.58 | 0.008 |
Time Domain | ||||||
Mean NN (ms) | 1038.55 ± 169.82 | 968.19 ± 121.37 | 1016.94 ± 124.56 | 0.03 | 0.49 | 0.06 |
SDNN (ms) | 74.79 ± 39.19 | 63.67 ± 27.15 | 77.84 ± 27.29 | 0.23 | 0.23 | 0.010 |
rMSSD (ms) | 38.76 ± 26.28 | 26.86 ± 12.23 | 32.54 ± 14.99 | 0.05 | 0.64 | 0.06 |
pNN50 (%) | 16.01 ± 18.90 | 7.51 ± 9.15 | 10.43 ±10.97 | 0.04 | 0.40 | 0.11 |
Abbreviations as in the text
When stratified by three frequency domain HRV thresholds previously reported to be associated with adverse cardiac prognosis (SDNN < 50 ms [37], rMSSD <17 ms [38], and pNN50 <4% [39]), lower risk was evident in the TA vs. SA groups at exit for two variables (Figure 3).
COP HRV
Similar to arithmetic mental stress HRV, exit markers of parasympathetic tone with COP were higher with TA compared to SA and WC groups, although they failed to reach statistical significance (rMSSD: p=0.05; pNN50: p= 0.04) (Table 3). Interestingly, COP SDNN was also lower in the SA group compared to WC (p=0.01), again consistent with WC group improvement. Comparison of the 5-minute period of baseline HRV to 2-minute period of COP HRV at study entry and exit, demonstrated no significant differences detected between TA vs. SA groups. Unlike mental arithmetic stress, multivariate analysis for HRV domains for COP did not demonstrate any significant treatment effects in the TA group (Supplemental Table A).
In a multivariate analysis, combined baseline, mental stress, and COP showed a strong trend to improvement in SDNN from entry to exit with TA vs. SA (p= 0.027) (Table 4). Again, stratification by prior myocardial infarction, diabetes, gender, or daytime vs. nighttime 24-hour HRV variables did not demonstrate any group differences in the provocative HRV outcome.
Table 4.
Time Domain HRV Variable |
Pairwise Group Comparison |
Treatment Differences |
Standard Error | p-value |
---|---|---|---|---|
mean NN | TA vs. SA | −2.363 | 18.15 | 0.90 |
TA vs. WC | −13.093 | 18.81 | 0.49 | |
SA vs. WC | −10.730 | 16.89 | 0.53 | |
SDNN | TA vs. SA | 9.578 | 4.34 | 0.027 |
TA vs. WC | 6.626 | 4.36 | 0.129 | |
SA vs. WC | −2.952 | 3.70 | 0.425 | |
rMSSD | TA vs. SA | 3.109 | 2.13 | 0.14 |
TA vs. WC | 1.887 | 1.97 | 0.34 | |
SA vs. WC | −1.221 | 2.12 | 0.57 | |
pNN50 | TA vs. SA | 2.375 | 1.65 | 0.15 |
TA vs. WC | 1.692 | 1.51 | 0.26 | |
SA vs. WC | −0.683 | 1.76 | 0.70 |
Abbreviations as in the text
Secondary Outcome Results
There were no group differences between TA vs. SA for exit resting heart rate, blood pressure, lipid profile, HOMA, hs-CRP, salivary cortisol, PAT, or psychosocial variables.
Discussion
The current study results demonstrate that 12 weeks of TA resulted in significantly higher HRV compared to SA. The physiological effects were accomplished without changes in traditional risk factors or medication changes. Both time and frequency domain components of HRV indicative of parasympathetic activity were significantly higher at exit with TA vs. SA, suggesting the observed effect was reasonably robust. The magnitude of exit SDNN difference between TA vs. SA may be clinically relevant, as prior work has shown that SDNN < 70 ms predicts arrhythmias in patients with low ejection fraction post-myocardial infarction [40]. HRV is a practical, validated approach to study cardiac autonomic function, and an intermediate outcome which predicts an adverse prognosis, including sudden cardiac death [37, 41–43]. To our knowledge, our study is the first sham controlled study to show the beneficial impact of TA in an optimally-treated, stable SIHD population.
We did not find significant group differences between TA vs. SA vs. WC at entry and exit 24 hour HRV or cold pressor HRV. Long term 24 hour HRV recordings can be difficult to interpret because HRV is influenced by many internal as well as external factors, such as temperature changes, activity, sleep patterns and habits, mid-day naps, environmental stimuli, etc, and we did not normalize external environmental conditions for 24 hours in this study. Parasympathetic tone was significantly lower in the SA group compared to WC group at exit for mental arithmetic and COP. We are cautious to draw any conclusions about the negative impact of SA because the WC engaged in higher health-seeking behavior in this trial, similar to our prior experience with an unblinded WC CAM trial [35] .
Acupuncture has been used for thousands of years to treat many cardiovascular illnesses, including angina, arrhythmias, and hypertension [11, 44]. It is known that cardiovascular-specific acupuncture points stimulate group III and IV afferent autonomic nervous system pathways that transmit to regions in the hypothalamus, midbrain, and medulla that regulate the cardiovascular system [8]. Our acupuncture team chose the points based primarily on Chinese literature that had demonstrated reductions in cardiac dysfunction and arrhythmia burden in non-randomized, uncontrolled and unblinded studies[11, 45–52]. Accordingly, using a more rigorous design, our current results suggest that TA causes autonomic remodeling by improving parasympathetic tone.
A recent systematic review by Lee et al[53] of 12 randomized trials conducted in non-SIHD subjects examined the effect of acupuncture vs. sham treatment on HRV, and concluded that the results were inconsistent regarding the impact of acupuncture on HRV and more rigorous research is warranted [53]. The impact of TA on HRV in the setting of mental stress has also been previously studied in two randomized trials in normal healthy subjects[54] [55], and a meta-analysis of these two trials showed no favorable effects of acupuncture on HF, LF, or LF/HF ratio [53]. Our findings expand these prior findings and indicate thatTA may be be beneficial in diseased SIHD subjects. Consistent with our findings, a recent trial on acupuncture in patients with atrial fibrillation demonstrated that acupuncture treatment prevents arrhythmic recurrences and is as effective as amiodarone after cardioversion in patients with persistent atrial fibrillation [56].
We did not find significant TA vs SA group differences in our secondary outcome measures of exit blood pressure, fasting lipid panel, insulin resistance, hs-CRP, or salivary cortisol. We also did not find a group difference in endothelial function measured by PAT despite the established role of the autonomic nervous system in the regulation of arterial vasomotor function[57–60]. Because episodes of mental stress cause transient autonomic nervous system imbalance[61] and endothelial dysfunction[62], we measured PAT following stress testing to improve sensitivity to detect beneficial effects, yet were unable to detect group differences. Our overall resting blood pressures at exit did not differ between TA vs. SA, which could be due to well controlled hypertension with medications, or a lack of a TA effect in SIHD subjects. While some work on smaller trials in medically treated hypertensive patients has suggested a beneficial impact of TA on blood pressure [63, 64], a randomized, sham controlled clinical trial of acupuncture in 141 untreated patients with moderate hypertension[65] failed to show a benefit of active acupuncture over sham acupuncture on blood pressure, hyperlipidemia, glucose, or quality of life, consistent with our results. Finally, we did not observe group differences in the various psychosocial parameters. There are a variety of explanations for not seeing a beneficial effect of TA on the secondary outcomes in our study. Our population was optimally treated with anti-anginal, anti-atherosclerotic medications such that the additive impact of TA on blood pressure, lipid profile, hsCRP, and angina may not have been present or too small to be detectable.
Limitations
Our population may not be representative of the general SIHD population, as it is well documented that rates of optimal medical management achievement in non-selected SIHD populations [66–69] are below that observed in our study subjects. We used a predictor of sudden cardiac death risk (HRV) that is used as an outcome in clinical trials [37, 70]; and while a significant beneficial effect was observed in HRV as hypothesized, this may have been minimized by the involvement in a proportion of our subjects in cardiac rehabilitation and the role exercise conditioning plays in cardiac autonomic nervous system tone [61]. A major limitation of our study is that we did not collect sleep characteristics (sleep habits and sleep quality) which can impact HRV. While our finding of a 17% difference in HF HRV is noteworthy, we acknowledge that HRV measurements can have a range of intra-individual variability that can make it difficult to determine the significance of changes noted with intervention [71]. Our results may also have been minimized by the use of SA, as prior work has shown that SA can have a therapeutic effect over non-sham placebos [72–74]. Due to the improved health behavior in our unblinded WC group, we were unable to test this hypothesis. While we hypothesize that the WC group had increased “health seeking behavior”, it is also possible that the TA and SA groups had worse parameters due to “liberalization” of medication or lifestyle efforts due to belief in the benefits of acupuncture. We cannot fully exclude that our findings are due to chance, despite the Bonferroni correction, although our consistent findings to mental stress in a similar direction argue against this. Our subgroup analyses were underpowered to test specific hypotheses in diabetic subjects, post-CABG, women and the elderly.
Implications
We studied TA in a blinded, randomized fashion, with a practical sham technique. Trials to study alternative and complimentary techniques are difficult due to various problems inherent in the nature of this type of study, however, given the rise in the use of alternative and complimentary techniques such as acupuncture in United States, our work sheds light into the practical and possibly beneficial use of acupuncture in optimally-treated, SIHD patients. Given acupuncture’s beneficial impact on HRV, it should be studied with regard to its ability to reduce sudden cardiac death. Our current results suggest that the next most appropriate outcome for this line of investigation should be actual sudden cardiac death/defibrillator cardioversions in patients with implantable cardiac defibrillators (ICDs). In the landmark Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) [75] trial of 2521 patients with congestive heart failure and a left ventricular ejection fraction of 35% or less, those in the NYHA Class II had a 32% mortality rate in the placebo arm vs. 20% in the ICD arm over 5-years. Based on these prior data and applying the effect size in our current study to test the impact of TA vs. SA in a stable heart failure population, a sample size of 229 subjects per group (total 458) would provide 80% power at the 0.05 significance level to detect a 12% group difference in mortality/ICD shocks at 5 years. Given the magnitude of the problem of sudden cardiac death, further clinical trials evaluating TA as an adjunct or temporary replacement of ICDs in subjects at risk for SCD are warranted and should be conducted.
Conclusions
Our current trial results demonstrate that 12 weeks of TA compared to SA has intermediate effects in cardiac autonomic modulation measured by HRV in SIHD patients. The TA magnitude of benefit on HRV may be clinically relevant and should be explored further. These data document feasibility and provide sample size estimation for a sudden cardiac death outcome clinical trial of sympatho-vagal modulation using TA in subjects at high risk for sudden cardiac death.
Supplementary Material
Highlights.
Compared to sham acupuncture, traditional acupuncture results in intermediate effects on cardiac autonomic nervous system function in stable ischemic heart disease patients.
The effect of traditional acupuncture on cardiac autonomic nervous system function, measured by heart rate variability, may be clinically relevant and should be explored further.
Our data document feasibility and provide sample size estimation for a clinical trial of traditional acupuncture in stable ischemic heart disease patients for prevention of sudden cardiac death.
Acknowledgments
This work was supported by grants from the National Institutes of Health-National Center for Alternative and Complementary Medicine, nos. 5R01AT1482, K23HL105787, GCRC grants MO1-RR00425 from the National Center for Research Resources and UL1RR033176 which is now the National Center for Advancing Translational Sciences, Grant UL1TR000124, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey, the Women’s Guild of Cedars-Sinai Medical Center, the Society for Women’s Health Research (SWHR), Washington, D.C., , the Edythe L. Broad Women’s Heart Research Fellowship, the Barbra Streisand Women’s Cardiovascular Research and Education Program, and the Linda Joy Pollin Women’s Heart Health Program, Cedars-Sinai Medical Center, Los Angeles. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, or the National Institutes of Health.
Glossary
Abbreviations List
- CES-D
Center for Epidemiologic Study Depression Scale
- COP
cold pressor testing
- DASI
Duke Activity Status Index
- HOMA
Homeostasis Model Assessment
- HRV
heart rate variability
- PAT
peripheral arterial tonometry
- SA
sham acupuncture
- SAQ
Seattle Angina Questionnaire
- SIHD
Stable Ischemic Heart Disease
- TA
traditional acupuncture
- WC
waiting control
HRV Abbreviations
- TP
total power
- HF
high frequency
- LF
low frequency
- SDNN
standard deviation of normal RR (NN) intervals
- SDANN
standard deviation of 5-minute mean RR intervals
- aSDNN
average of standard deviations of normal RR intervals in 24 hours
- rMSSD
root-mean square of difference of successive RR intervals
- pNN50
proportion of adjacent RR intervals more than 50 milliseconds different
Footnotes
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