Accepted Manuscript Randomized controlled trial of heart rate variability biofeedback in cardiac autonomic and hostility among patients with coronary artery disease I-Mei Lin, Sheng-Yu Fan, Hsueh-Chen Lu, Tsung-Hsien Lin, Chih-Sheng Chu, HsuanFu Kuo, Chee-Siong Lee, Ye-Hsu Lu PII:

S0005-7967(15)00076-5

DOI:

10.1016/j.brat.2015.05.001

Reference:

BRT 2855

To appear in:

Behaviour Research and Therapy

Received Date: 16 February 2015 Revised Date:

20 April 2015

Accepted Date: 4 May 2015

Please cite this article as: Lin, I.-M., Fan, S.-Y., Lu, H.-C., Lin, T.-H., Chu, C.-S., Kuo, H.-F., Lee, C.S., Lu, Y.-H., Randomized controlled trial of heart rate variability biofeedback in cardiac autonomic and hostility among patients with coronary artery disease, Behaviour Research and Therapy (2015), doi: 10.1016/j.brat.2015.05.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Randomized controlled trial of heart rate variability biofeedback in cardiac autonomic and hostility among patients with coronary artery disease

Chuc, Hsuan-Fu Kuod, Chee-Siong Leec, Ye-Hsu Luc

RI PT

I-Mei Lina,*, Sheng-Yu Fanb, Hsueh-Chen Lua, Tsung-Hsien Linc, Chih-Sheng

Department of Psychology, Kaohsiung Medical University, Taiwan

b

Institute of Gerontology, National Cheng Kung University, Taiwan

c

Division of Cardiology, Kaohsiung Medical University Hospital, Taiwan

d

Division of Cardiology, Kaohsiung Municipal Ta-Tung Hospital, Taiwan

M AN U

SC

a

TE D

* Corresponding author: I-Mei Lin

Address: No 100, Shiquan 1 st Rd., Kaohsiung City, 807, Taiwan.

EP

E-mail: [email protected], [email protected]

AC C

Tel.: +886-73215422 ext. 837 Fax: +886-73233716

ACCEPTED MANUSCRIPT Abstract Hostility is a psychosocial risk factor that may decrease heart rate variability

RI PT

(HRV) in coronary artery disease (CAD) through cardiac autonomic imbalance. Heart rate variability biofeedback (HRV-BF) increases HRV indices and baroreflex gain. This study examines the effectiveness of HRV-BF in restoring cardiac autonomic

SC

balance and decreasing hostility among patients with CAD. One hundred and

M AN U

fifty-four patients with CAD were assigned randomly to receive 6 weeks of HRV-BF, in addition to the standard medical care received by the wait-list control (WLC) group. A 5-min electrocardiogram, blood pressure, and hostility were assessed pre-intervention, post-intervention, and at 1-month follow-up. The standard deviation

TE D

of normal-to-normal intervals (SDNN), low frequency (LF), and log LF at post-intervention was significantly higher than that at pre-intervention in the HRV-BF

EP

group. Baseline log LF was significantly higher post-intervention and at follow-up

AC C

after HRV-BF training than at pre-intervention. The treatment curve of log LF pre-session increased significantly after session 2, which was maintained to post-intervention. Expressive hostility, suppressive hostility, and hostility total score at post-intervention and one-month follow-up after HRV-BF were significantly lower than at pre-intervention. This study showed increased HRV and decreased expressive and suppressive hostility behavior in patients with CAD following HRV-BF. 2

ACCEPTED MANUSCRIPT Keywords: heart rate variability biofeedback, hostility, cardiac autonomic, coronary

AC C

EP

TE D

M AN U

SC

RI PT

artery disease

3

ACCEPTED MANUSCRIPT

Introduction1 Cardiac autonomic imbalance—sympathetic neuron system (SNS) hyperactivity

RI PT

and parasympathetic neuron system (PNS) withdrawal—is related to low heart rate variability (HRV), which is a pathogenic mechanism linking psychosocial risk factors and coronary artery disease (CAD) (Kop, 2003; Sloan et al., 2010; Smith, 2006).

SC

Heart rate variability biofeedback (HRV-BF) is a behavioral neurocardiac

M AN U

intervention that applies diaphragmatic breathing at approximately 6 times per minute to stimulate efferent vagal activity to the sinoatrial node, modulate heart rate and blood pressure, increase HRV indices and respiratory sinus arrhythmia (RSA) amplitude, and achieve a power spectral distribution of low frequency (LF) at 0.1 Hz

TE D

(Del Pozo, Gevirtz, Scher, & Guarneri, 2004; Lehrer & Gevirtz, 2014; Reyes del Paso, Langewitz, Robles, & Pérez, 1996; Vaschillo, Lehrer, Rishe, & Konstantinov, 2002;

EP

Wheat & Larkin, 2010). HRV-BF, also called RSA biofeedback, is a natural

AC C

oscillation between the breathing cycle and heart rate. Inhalation temporarily suppresses vagal activity, causing a decrease in the inter-beat interval and an increase in heart rate; exhalation activates vagal activity, causing an increase in the inter-beat SNS = sympathetic nervous system; PNS = parasympathetic nervous system; HRV = heart rate variability; CAD = coronary artery disease; HRV-BF = heart rate variability biofeedback; RSA = respiratory sinus arrhythmia; LF = low frequency; SDNN = standard deviation of normal-to-normal intervals; HF = high frequency; WLC = wait list control; SBP = systolic blood pressure; DBP = diastolic blood pressure; ECG = electrocardiogram; CHI-SF = Chinese Hostility Inventory-Short Form; ANOVA = analysis of variance. 4

ACCEPTED MANUSCRIPT interval and a decrease in heart rate (del Paso, Godoy, & Vila, 1992; Lehrer & Gevirtz, 2014; Lehrer, Vaschillo, & Vaschillo, 2000; Shaffer, McCraty, & Zerr, 2014). RSA is

RI PT

related to cardiac vagal control, while maximizing RSA magnitude can increase resonance frequency, regulate synchronizing respiratory and cardiovascular processes (Grossman & Taylor, 2007; Lehrer et al., 2000), increase baroreflex sensitivity

SC

(Lehrer & Gevirtz, 2014), and decrease heart rate and blood pressure (Palomba et al.,

M AN U

2011; Wang et al., 2010).

Lehrer et al. (2000) set up a 10-session HRV-BF protocol to increase LF power, including: (1) diaphragmatic breaths to increase resonant frequency at 0.1 Hz; (2) RSA biofeedback using diaphragmatic breathing, pursed-lips breathing, and paced

TE D

breathing; and (3) a home training biofeedback unit. Several studies have utilized Lehrer’s HRV-BF protocol and confirmed the treatment effectiveness on increasing

EP

standard deviation of normal-to-normal intervals (SDNN) and LF of HRV in asthma

AC C

(Lehrer et al., 2004), sudden cardiac arrest survivors (Cowan, Kogan, Burr, Hendershot, & Buchanan, 1990; Cowan, Pike, & Budzynski, 2001), CAD (Cowan et al., 2001; Del Pozo et al., 2004; Mikosch et al., 2010; Nolan et al., 2005), heart failure (Swanson et al., 2009), major depression disorder (Karavidas et al., 2007), prehypertension (Wang et al., 2010), and fibromyalgia (Hassett et al., 2007). Regarding the treatment effectiveness of HRV-BF in cardiovascular disease, 5

ACCEPTED MANUSCRIPT Cowan and colleagues (1990) first applied a five-week HRV-BF intervention in cardiovascular disorders and found significant increases in high frequency (HF) and

RI PT

inter-beat interval, and a decrease in LF. However, this study involved only six participants and no control group. Cowan and colleagues (2001) then increased the

sample size to 133 patients with CAD in the HRV-BF group and used a control group.

SC

Their 11 sessions of HRV-BF for patients with CAD involved three components: (1)

M AN U

HRV-BF combining diaphragmatic breathing, progressive muscle relaxation, and autogenic training; (2) Beck’s cognitive-behavior therapy and Lazarus’ stress appraisal and coping theory, which are used in depression, anxiety, and anger management; and (3) psychosocial education for the risk factors for cardiovascular

TE D

disorder. This result showed there were no significant group differences in HRV indices after HRV-BF, as well as no within-session effect on HRV-indices in HRV-BF

EP

group. However, after 2 years follow-up there was a significant reduction (86%) in

AC C

cardiovascular death risk in the HRV-BF group compared with that in the control group. Del Pozo et al. (2004) and Swanson et al. (2009) found that SDNN, which reflects total HRV, increased significantly after HRV-BF in patients with CAD and heart failure. Nolan and colleagues (2005) combined HRV-BF with cognitive-behavior therapy and paced breathing, and the intervention increased HF and decreased subjective perceived stress and depressive mood in patients with CAD. 6

ACCEPTED MANUSCRIPT Therefore, HRV-BF has been verified to increase PNS activation and total HRV, as well as increase vagal tone and baroreflex gain while slowing down the breathing rate

RI PT

to about 6 breaths per minute (Del Pozo et al., 2004; Hassett et al., 2007; Karavidas et al., 2007; Lehrer et al., 2003, 2004, 2006), and decreasing subjective perceived stress and depressive moods (Mikosch et al., 2010; Nolan et al., 2005).

SC

A recent meta-analysis indicated that hostility is related to heart disease in both

M AN U

healthy and patient populations (Chida & Steptoe, 2009). Sloan et al. (1994, 2001) found that high hostility individuals had higher SNS activity (heart rate and blood pressure) than those with low hostility when they encountered an anger or harassment task. This confirms the psychophysiological reactivity model that hostility is an

TE D

important psychosocial risk factor for CAD morbidity and mortality through cardiac autonomic imbalance (Smith, 1992, 2006; Chida & Hamer, 2008; Chida & Steptoe,

EP

2009). Hostility is a multidimensional personality trait that includes hostility

AC C

cognition, hostility affect, expressive hostility behavior, and suppressive hostility behavior (Lin & Weng, 2002). The research found that expressive hostility behavior and suppressive hostility behavior were related to cardiac autonomic imbalance (Lin, Weng, Lin, & Lin, in press). With respect to hostility intervention and restoring cardiac autonomic balance, Sloan and colleagues (2010) applied cognitive-behavior therapy to a healthy population with the hostility trait, and found a significant 7

ACCEPTED MANUSCRIPT decrease in hostility and heart rate, but no increase in HRV indices. The treatment effectiveness of HRV-BF on hostility related to cardiac autonomic imbalance was

RI PT

unknown. Limited research has explored the treatment effectiveness of HRV-BF on

increasing HRV indices and decreasing the hostility trait in patients with CAD.

SC

Previous studies examined the treatment effectiveness between pre-intervention,

M AN U

post-intervention, and follow-up (Cowan et al., 2001; Del Pozo et al., 2004); however, the treatment curve of HRV-BF has not been elucidated to clarify how many sessions it takes for the HRV indices to undergo significant improvement. The aims of this study were: (1) to examine the treatment effectiveness of HRV-BF on HRV indices,

TE D

blood pressure, and hostility among patients with CAD; and (2) to examine the treatment curve of HRV-BF from pre-intervention, across the six sessions, to

AC C

Method

EP

post-intervention.

Participants

Patients with CAD were referred by cardiologists from Kaohsiung Medical

University Hospital and Kaohsiung Municipal Ta-Tung Hospital. The inclusion criteria were patients aged 35–75 years with one of the following: (1) a blockage of >50% in the left main artery, or >70% in the left anterior descending, left circumflex, 8

ACCEPTED MANUSCRIPT and right coronary arteries identified by coronary angiography; (2) a history of coronary intervention such as percutaneous transluminal coronary angioplasty, stent,

RI PT

or laser; (3) a history of coronary artery bypass surgery; (4) a reversible perfusion defect on chemical stress testing such as Cardiolite, positron emission tomography, or thallium; or (5) abnormality on a stress echocardiogram. Participants with class III

SC

and IV congestive heart failure, atrial fibrillation, unstable angina, arrhythmia, other

M AN U

severe physical illness or mental disorder, or a pacemaker were excluded. Institutional Review Board approval was obtained from the ethics committee of Kaohsiung Medical University Hospital, and informed consent was obtained from each participant. All participants received a NT$300 (about USD$ 11) and a

TE D

relaxation CD for participating.

Research design and HRV-BF protocol

EP

A randomized controlled trial design was adopted so that participants were

AC C

randomly assigned to either the HRV-BF group or the wait-list control (WLC) group at pre-intervention. The HRV-BF group received standard medical care and one 60-min session of HRV-BF weekly for six weeks, and then participated in a post-intervention and one-month follow-up measurement. The WLC group received standard medical care and participated in a post-intervention measurement. The participants in the WLC group were invited to receive HRV-BF intervention after 9

ACCEPTED MANUSCRIPT post-intervention if they were willing to participate; these data were coupled with that of the HRV-BF group as a combined group to examine treatment effectiveness of

RI PT

HRV-BF (Figure 1). Psychophysiological measurement

Electrocardiogram (ECG) raw signals and blood pressure were measured for

SC

5-min baseline and hostility inventory was administered at pre-intervention,

M AN U

post-intervention, and a 1-month follow-up. In addition, 5-min ECG raw signals both at pre-session and at post-session of each six sessions were measured for the combined group. The measurements included the following:

(1) HRV: The lead II ECG raw signals were collected by the ProComp Infiniti™

TE D

(Thought Technology, Quebec, Canada) with a sampling rate of 2048/s. The fast Fourier transform was set to acquire real-time inter-beat intervals (IBI) from ECG and

EP

transferred to the frequency domain of HRV indices: LF power (0.04–0.15 Hz), high

AC C

frequency (HF) power (0.15–0.4 Hz), and the LF/HF ratio, as well as SDNN, the time domain of the HRV index (Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology, 1996). (2) Blood pressure: The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected from the GE Marquette SmartPac Tram transport display (Absolute Medical Equipment, NY) at 2-min intervals. 10

ACCEPTED MANUSCRIPT (3) Chinese Hostility Inventory-Short Form (CHI-SF): The CHI-SF is a 20-item, 5-point Likert scale (1 = strongly disagree; 5 = strongly agree) with good

RI PT

psychometric properties (Weng et al., 2008). The CHI-SF includes four dimensions of hostility: (a) hostility cognition: 6 items, suspicious belief and cynical belief; (b)

hostile affect: 4 items, emotional tendencies for annoyance, disgust, and anger; (c)

SC

expressive hostility behavior: 5 items, verbal or physical aggression behaviors; and (d)

M AN U

suppressive hostility behavior: 5 items, holding anger internally.

Experimental procedure and HRV-BF protocol: All participants were instructed to take medications as usual, refrain from caffeine or alcoholic beverages, and not exercise excessively or smoke 3 h prior to measurement. The psychophysiological

TE D

measurement was arranged between 9 AM and 5 PM. The participants sat in a sound-attenuated and temperature-controlled room. After finishing the hostility

EP

questionnaire and a 10-min rest, resting ECG and blood pressure were measured for

AC C

5-min at pre-intervention, post-intervention, and 1-month follow-up. In addition, resting ECG was measured for 5-min at pre-session and at post-session of each session of HRV-BF.

The HRV-BF protocol was modified from the protocols of Lehrer et al. (2000), Del Pozo et al. (2004), and Swanson et al., (2009) which included diaphragmatic breathing, paced breathing, pursed-lips breathing, and RSA biofeedback; we added 11

ACCEPTED MANUSCRIPT self-guided muscle relaxation to session 1 and hostility psychoeducation to sessions 5 and 6 in this study. We followed the Lehrer’s protocol to set up the paced stimulus for

RI PT

determining individual resonance frequency in the first session. The breathing frequency was gradually stepped down based on the breathing rate of the previous session to reach the target of participants’ resonance frequency. The standardized

SC

principal was to decrease the breathing rate by 20 % for each time. The HRV-BF

M AN U

protocol was assisted by the ProComp Infiniti™ software; HRV-BF training screens are presented in Figure 2. The goals of HRV-BF were to increase LF power at 0.1 Hz, increase RSA and heart rate amplitude, and restore cardiac vagal control; as well as decrease hostility. In addition, we followed the Lehrer et al. (2000) protocol and

TE D

assigned 10-min homework of self-guided muscle relaxation after the first session, diaphragmatic breathing after sessions 2 and 3, provided biofeedback equipment

EP

(StressEraser) for home training after sessions 4 and 5, and encouraged participants to

AC C

practice diaphragmatic breathing every day (Table 1). Data reduction and statistics The CardioPro Infiniti HRV analysis module (Thought Technology, Quebec,

Canada) was used to detect and analyze the ECG signals. We used the automatic filter to exclude the IBI that differed by more than 20% from the previous IBI. If the frequency of ECG artifacts, detected by visual inspection in a 5-s window, was more 12

ACCEPTED MANUSCRIPT than 5% in the period then data were deleted. The data were modified by adding, splitting, and averaging pairs of consecutive IBIs (Task Force of the European Society

RI PT

of Cardiology the North American Society of Pacing Electrophysiology, 1996). The frequency domains of the HRV indices were analyzed by fast Fourier transform; the

absolute power and log transformation of LF and HF are shown in Tables 2 to 4. The

SC

time domain of the HRV index was calculated from the inter-beat intervals of the

M AN U

ECG signals. SBP and DBP were averaged at 2-min intervals at baseline. Treatment effectiveness was examined as follows: (1) Two-way repeated-measures analysis of variance (ANOVA) was used to examine the group differences in HRV indices, blood pressure, and hostility at pre-intervention and at post-intervention between the

TE D

HRV-BF group and the WLC group. (2) One-way repeated-measures ANOVA was used to examine the between-session effects in HRV indices, blood pressure, and

EP

hostility at pre-intervention, at post-intervention, and at 1-month follow-up in the

AC C

combined group. Mauchly sphericity test with Greenhouse-Geisser adjustment was applied in one-way repeated-measures ANOVA. (3) One-way repeated-measures ANOVA was used to compare the between-session effects in HRV indices from pre-intervention, each pre-session measurement, and post-intervention in the combined group. (4) The HRV treatment curves (SDNN, log LF, and log HF) at the baseline of pre-intervention, pre-session and post-session of six sessions, and 13

ACCEPTED MANUSCRIPT post-intervention were presented to describe the within-session effects in the combined group.

RI PT

The effect size of partial eta squared (ηp2) was calculated. A ηp2 of lower than 0.05 represents a small effect size, 0.06–0.14 reflects a medium effect size, and higher than 0.15 is a large effect (Stevens, 2002). All analyses were performed using SPSS

SC

predictive analytics software version 20.0 (SPSS Inc., Chicago, IL).

M AN U

Results

One hundred and fifty-four patients with CAD were randomly assigned to either the HRV-BF group or the WLC group. Seven participants in the HRV-BF group refused the HRV-BF after pre-intervention for reasons of employment conflict or

TE D

distance. Seven participants dropped out during the HRV-BF intervention for reasons of employment conflict or departure from the city during the Chinese New Year

EP

holiday (dropout rate was 10% [7/70]); three participants were excluded from data

AC C

analysis for reasons of ECG artifacts more than 5% in 5-min. In the end, 60 participants finished the HRV-BF intervention and post-intervention measurement. In the WLC group, ten participants refused the post-intervention measurement (dropout rate was 12.99% [10/77]. A total of 67 participants finished the post-intervention measurement (Figure 1). The mean age of participants in the HRV-BF group was 61.01 years (SD = 8.41; 14

ACCEPTED MANUSCRIPT range from 39 to 75 years), with 6 female and 71 male. The mean age of participants in the WLC group was 60.61 years old (SD = 8.03; range from 37 to 75 years), with

RI PT

11 female and 66 male. There were no significant differences between the HRV-BF group and the WLC group at pre-intervention in age, gender, blood sample, blood

pressure and heart rate, the number of vessel stenosis, maximum percentage of vessel

SC

narrowing, left ventricular ejection fraction (LVEF), hostility scores, medications used,

M AN U

or HRV indices (Table 2). In addition, 48 participants in the HRV-BF group completed the 1-month follow-up measurement, and 53 participants in the WLC group received HRV-BF post-intervention, of which 35 participants completed 1-month follow-up. Data from these 83 participants (48 in HRV-BF group and 35 in WLC group) who

TE D

completed all measurements were combined as a combined group (Figure 1). Treatment effectiveness for HRV indices, blood pressure, and hostility scores

EP

With respect to the differences in HRV indices between the HRV-BF group and

AC C

the WLC group, there was a significant group × time interaction effect in SDNN, LF, and log LF (F = 5.70, p < 0.05, with medium effect size [ηp2 = 0.08]; F = 14.76, p < 0.001, with large effect size [ηp2 = 0.18]; and F = 12.90, p < 0.01, with large effect size [ηp2 = 0.16], respectively). SDNN, LF, and log LF increased from pre-intervention to post-intervention in the HRV-BF group; however, these HRV indices decreased from pre-intervention to post-intervention in the WLC group (Table 15

ACCEPTED MANUSCRIPT 3). There was no significant interaction effect for HF and log HF; as well as SPB, DBP, and heart rate (Table 3).

RI PT

With respect to the changes in HRV and blood pressure after HRV-BF intervention, there was a significant increase in SDNN, LF, and log LF

post-intervention and at follow-up compared to that at pre-intervention in the

SC

combined group (F = 6.40, p < 0.01, with medium effect size [ηp2 = 0.14]; F = 9.66, p

M AN U

< 0.01, with large effect size [ηp2 = 0.20]; and F = 30.26, p < 0.001, with large effect size [ηp2 = 0.44], respectively). Moreover, there were significant decreases in SDB and DBP at follow-up than that at pre-intervention in combined group (F = 5.91, p < 0.01, with medium effect size [ηp2 = 0.08]; F = 5.31, p < 0.01, with medium effect

TE D

size [ηp2 = 0.07] in the combined group (Table 4). With respect to the differences in hostility scores between the HRV-BF group and

EP

the WLC group, there were significant time × group interaction effects in expressive

AC C

hostility, suppressive hostility, and hostility total score (F = 7.54, p < 0.01, with medium effect size [ηp2 = 0.06]; F = 5.65, p < 0.05, with small effect size [ηp2 = 0.04]; and F = 5.25, p < 0.05, with small effect size [ηp2 = 0.04], respectively). We used the mixed design of analysis of variance to examine the simple main effects in expressive hostility and hostility total score. The results showed a significant decrease in expressive hostility in the HRV-BF group (F = 16.77, p < 0.001) but not in the WLC 16

ACCEPTED MANUSCRIPT group (F = 0.11, p > 0.05), as well as a significant decrease in hostility total score in the HRV-BF group (F = 12.22, p < 0.001) but not in the WLC group (F = 0.09, p >

RI PT

0.05). After HRV-BF in the combined group, there were significant decreases in

expressive hostility, suppressive hostility, and hostility total score post-intervention

SC

and at follow-up compared with that at pre-intervention (F = 14.94, p < 0.001; F =

M AN U

13.56, p < 0.001; and F = 10.05, p < 0.001, respectively; with medium to large effect size (ηp2 = 0.13 to 0.17), and a significant decrease in hostility affect at follow-up compared with that at pre-intervention (F = 4.77, p < 0.05, with medium effect size

TE D

[ηp2 = 0.06]) (Table 4).

Treatment curve of HRV indices at pre-intervention, at the six sessions, and at post-intervention for the combined group

EP

There were significant differences in log LF at the baseline of pre-intervention, at

AC C

the pre-session of six sessions, and at the baseline of post-intervention (F = 15.02, p < 0.0001, with large effect size [ηp2 = 0.27]). The post hoc comparison found a significantly higher log LF under the resting at session 2, 3, 4, 5, 6, and post-intervention than that at pre-intervention (Figure 3). In order to avoid Type I error caused from repeated use of paired t tests, we only analyzed the treatment trends in SDNN, log LF, and log HF at pre-intervention, each HRV-BF session, and 17

ACCEPTED MANUSCRIPT post-intervention, which are shown in Figure 4.

Discussion

RI PT

This study examined the effects of HRV-BF on HRV indices, BP, and hostility in patients with CAD. The results found an increase in SDNN, LF, and log LF from

pre-intervention to post-intervention in the HRV-BF group compared with that in the

SC

WLC group. After HRV-BF intervention, SDNN, LF, and log LF increased

M AN U

significantly from pre-intervention to post-intervention and one-month follow-up in the combined group. Expressive hostility, suppressive hostility, and hostility total score decreased significantly in this period. With respect to the treatment curve during the six sessions of HRV-BF intervention, log LF increased significantly after session 2,

TE D

and this increase was maintained to post-intervention. The trend in the HRV indices of log LF was a gradual increase from pre-session to post-session of each session.

EP

These results indicate that baroreflex gain and total HRV increased progressively

AC C

from session 2 to the end of the HRV-BF intervention. These results are consistent with prior studies that applied HRV-BF in asthmatic and healthy adults (Lehrer et al., 2006; Lehrer et al., 2003; Lehrer et al., 2004) and patients with cardiovascular disease (Cowan et al., 1990; Del Pozo et al., 2004; Nolan et al., 2005). Increasing log LF indicated that efferent vagal activity stimulation of the sinoatrial node by diaphragmatic breathing could restore cardiac vagal control, modulate heart rate and 18

ACCEPTED MANUSCRIPT blood pressure, and increase HRV indices (Lehrer & Gevirtz, 2014; Lehrer et al., 2000; Reyes del Paso et al., 1996; Shaffer et al., 2014).

RI PT

Lehrer and colleagues (Lehrer et al., 2006; Lehrer et al., 2003) only analyzed sessions 1, 4, 7, and 10 and did not compare HRV parameters at pre-session and at post-session of each session. Because the treatment curve increases gradually,

SC

participants were motivated to continue the HRV-BF intervention and home practices,

M AN U

and received positive reward and treatment effects. There was a slight decrease in log LF after sessions 5 and 6; however, there was still higher log LF at the post-intervention compared with that at pre-intervention. The possible explanation for the log LF decrease in session 5 was the difficulty underlying RSA training. In session

TE D

5, participants were guided to follow their heart rate while breathing to maximize their HRV—this may be difficult to achieve due to old age and heart function.

EP

The clinical mechanisms and interpretations for increasing LF after HRV-BF

AC C

remain unclear. Recent reviews indicate that LF is an index of baroreflex control, which modulates heart rate and blood pressure through changes in vagal efferent activity (Lehrer & Gevirtz, 2014; Reyes del Paso et al., 1996, 2013; Shaffer et al., 2014). Vagal activity regulates the sinoatrial node to influence heart rate, blood pressure, and cardiac output, and leads to increased LF. When vagal activity was withdrawn, HRV indices decreased (Lehrer & Gevirtz, 2014; Reyes del Paso et al., 19

ACCEPTED MANUSCRIPT 2013; Shaffer et al., 2014). Therefore, HRV-BF intervention activates the efferent vagal activity that increases log LF and regulates baroreflex gain (Lehrer, 2003;

RI PT

Lehrer, Vaschillo, Trost, & France, 2009). The present study observed increased LF and RSA amplitude by HRV-BF intervention, supporting the previous arguments that LF is influenced by the baroreflex modulation of autonomic outflow and vasomotor

SC

tone (Billman, 2013; Lehrer et al., 2003; Reyes del Paso, Langewitz, Mulder, Roon,

M AN U

& Duschek, 2013).

SBP decreased in both groups from pre-intervention to post-intervention, and a significant decrease in SBP and DBP was seen at the follow-up compared with that at pre-intervention in the combined group. These results were consistent with Palomba

TE D

et al. (2011) and Wang et al. (2010), who found a significant decrease in SBP and DBP though HRV-BF for pre-hypertension. The possible explanations for the

EP

non-significant result for DBP and heart rate are as follows: (1) our CAD participants

AC C

were taking medications that might have influenced blood pressure, such as β-blockers; and (2) baseline blood pressure was in the normal range (125.69/72.40 mmHg for the HRV-BF group and 124.16/71.81 mmHg for the WLC group). Therefore, the floor effect may cause no significant decrease in blood pressure and heart rate after HRV-BF post-intervention. With respect to treatment effectiveness for hostility, this study found decreased 20

ACCEPTED MANUSCRIPT expressive and suppressive hostility behavior though HRV-BF among patients with CAD. Treatment effectiveness may be related to the hostility psychoeducation in

RI PT

sessions 5 and 6. During the hostility intervention, the researcher illustrated the cardiac autonomic imbalance related to expressive and suppressive hostility behavior based on the results of Sloan et al. (1994, 2001) and Lin et al. (in press), and asked

SC

participants to use diaphragmatic breathing for dealing with anger situations. This had

M AN U

a similar effect to prior studies, which reduced hostility by cognitive behavioral therapy, stress management, or psychological intervention programs in healthy adults (Sloan et al., 2010) and in patients with CAD (Daubenmier et al., 2007; Davidson, Gidron, Mostofsky, & Trudeau, 2007; Gidron, Davidson, & Bata, 1999; Linden,

TE D

Phillips, & Leclerc, 2007). According to the neurovisceral integration model, the potential mechanisms of HRV-BF may be through direct and indirect pathways to the

EP

amygdale to modulate emotion (Lehrer & Gevirtz, 2014; Shaffer et al., 2014; Thayer

AC C

& Lane, 2000). The central autonomic network modulates the sinoatrial node and increase HRV directly. The indirect pathway is that the central autonomic network modulates the prefrontal cortex to decrease hostility, and then increases HRV (Thayer & Lane, 2007). This study is the first study to apply HRV-BF to decrease hostility, and this study found that expressive hostility behavior and suppressive hostility behavior decreased after HRV-BF intervention. 21

ACCEPTED MANUSCRIPT Study limitations Some limitations of this study should be acknowledged. First, the Hawthorne

RI PT

effect, in which the hostility inventory was measured repeatedly by the same researcher and experimenter, may lead to decreased hostility scores in both the

HRV-BF group and the WLC group, which may reflect social desirability. Second,

SC

repeated ECG and blood pressure measurements may cause habituation of

M AN U

physiological response. Third, the treatment trend is presented in Figure 4 without statistical analyses, because a high number of paired t-tests to compare pre-session and post-session values may increase Type I error. Finally, there was no sham control group in this study; therefore, the high intensity and duration of HRV-BF, and

TE D

participants’ treatment expectation may cause the differences between the HRV-BF group and the WLC group.

EP

In future studies, experimenter effect should be addressed by separating the

AC C

therapists who execute the HRV-BF and the researchers who execute standardized experimental measurement. A longitudinal study design should be applied to calculate the rate of cardiac events, hospitalizations, and cardiac deaths during follow-up to examine the effects of HRV-BF. In conclusion, HRV-BF combined with slow breathing about 6 times per minute was successful in increasing efferent vagal activity to moderate the sinoatrial node, 22

ACCEPTED MANUSCRIPT increase baroreflex gain and total HRV, and decrease expressive and suppressive hostility behavior in this study with a randomized, controlled, design across multiple

RI PT

medical centers. HRV-BF is an effective invasive psychological intervention in cardiac rehabilitation.

SC

Acknowledgements

M AN U

This study was supported by Ministry of Science and Technology, Taiwan, and grand number: 100-2410-H-037-002 and 102-2410-H-037-003. Thanks for student assistants Mr. Te-Lun Hu and Miss Lin-Yuan Tai for data collection. Thanks for

Disclosures

TE D

Didier Combatalade of Thought Technology for HRV analysis consultations.

AC C

EP

All authors have no conflicts of interest to disclose.

23

ACCEPTED MANUSCRIPT References Billman, G.E. (2013). The effect of heart rate of the heart rate variability response to autonomic interventions. Frontiers in Physiology, 4(222), 1-9. Chida, Y., & Hamer, M. (2008). Chronic psychosocial factors and acute physiological responses to laboratory-induced stress in healthy populations: A quantitative review of 30 years of investigations. Psychological Bulletin, 134(6), 829-885.

RI PT

Chida, Y., & Steptoe, A. (2009). The association of anger and hostility with future coronary heart disease: A meta-analytic review of prospective evidence. Journal of the American College of Cardiology, 53(11), 936-946. Cowan, M. J., Kogan, H., Burr, R., Hendershot, S., & Buchanan, L. (1990). Power

M AN U

SC

spectral analysis of heart rate variability after biofeedback training. Journal of Electrocardiology, 23(Supplement 1), 85-94. Cowan, M. J., Pike, K. C., & Budzynski, H. K. (2001). Psychosocial nursing therapy following sudden cardiac arrest: Impact on two-year survival. Nursing Research, 50(2), 68-76. Daubenmier, J., Weidner, G., Sumner, M., Mendell, N., Merritt-Worden, T., Studley, J., . . .Ornish, D. (2007). The contribution of changes in diet, exercise, and

TE D

stress management to changes in coronary risk in women and men in the Multisite Cardiac Lifestyle Intervention Program. Annals of Behavioral Medicine, 33(1), 57-68. Davidson, K. W., Gidron, Y., Mostofsky, E., & Trudeau, K. J. (2007). Hospitalization

EP

cost offset of a hostility intervention for coronary heart disease patients. Journal of Consulting and Clinical Psychology, 75(4), 657-662. del Paso, G. A. R., Godoy, J., & Vila, J. (1992). Self-regulation of respiratory sinus arrhythmia. Applied Psychophysiology and Biofeedback, 17(4), 261-275.

AC C

Del Pozo, J. M., Gevirtz, R. N., Scher, B., & Guarneri, E. (2004). Biofeedback treatment increases heart rate variability in patients with known coronary artery disease. American Heart Journal, 147(3), 545-545. Grossman, P., & Taylor, E. W. (2007). Toward understanding respiratory sinus arrhythmia: Relations to cardiac vagal tone, evolution and biobehavioral functions. Biological Psychology, 74(2), 263-285. Hassett, A. L., Radvanski, D. C., Vaschillo, E., Vaschillo, B., Sigal, L. H., Karavidas, M. K., . . . Lehrer, P. (2007). A pilot study of the efficacy of heart rate variability (HRV) biofeedback in patients with fibromyalgia. Applied Psychophysiology and Biofeedback, 32(1), 1-10. Karavidas, M. K., Lehrer, P., Vaschillo, E., Vaschillo, B., Marin, H., Buyske, S., . . . Hassett, A. (2007). Preliminary results of an open label study of heart rate variability biofeedback for the treatment of major depression. Applied 24

ACCEPTED MANUSCRIPT Psychophysiology and Biofeedback, 32(1), 19-30. Kop, W. J. (2003). The integration of cardiovascular behavioral medicine and psychoneuroimmunology: New developments based on converging research fields. Brain, Behavior, and Immunity, 17(4), 233-237. Lehrer, P., & Gevirtz, R. (2014). Heart rate variability biofeedback: How and why does it work? Frontiers in Psychology, 5(756), 1-9.

RI PT

Lehrer, P., Vaschillo, E., Lu, S. E., Eckberg, D., Vaschillo, B., Scardella, A., & Habib, R. (2006). Heart rate variability biofeedback: Effects of age on heart rate variability, baroreflex gain, and asthma. Chest, 129(2), 278-284. Lehrer, P., Vaschillo, E., Trost, Z., & France, C. R. (2009). Effects of rhythmical

M AN U

SC

muscle tension at 0.1Hz on cardiovascular resonance and the baroreflex. Biological Psychology, 81(1), 24-30. Lehrer, P., Vaschillo, E., & Vaschillo, B. (2000). Resonant frequency biofeedback training to increase cardiac variability: Rationale and manual for training.

Applied Psychophysiology and Biofeedback, 25(3), 177-191. Lehrer, P., Vaschillo, E., Vaschillo, B., Lu, S. E., Eckberg, D. L., Edelberg, R., . . . Hamer, R. M. (2003). Heart rate variability biofeedback increases baroreflex

TE D

gain and peak expiratory flow. Psychosomatic Medicine, 65(5), 796-805. Lehrer, P., Vaschillo, E., Vaschillo, B., Lu, S. E., Scardella, A., Siddique, M., . . . Habib, R. H. (2004). Biofeedback treatment for asthma. Chest, 126(2), 352-361.

EP

Lin, I. M., & Weng, C. Y. (2002). Relationship between hostility pattern and psychophysiological disorders: Cases of coronary artery disease and headache. Chinese Journal of Psychology, 44(2), 211-226. Lin, I. M., Weng, C. Y., Lin, T. K., & Lin, C. L. (in press). The relationship between

AC C

expressive/ suppressive hostility behavior and autonomic nervous activations in coronary artery disease patients. Acta Cardiologica Sinica. Linden, W., Phillips, M. J., & Leclerc, J. (2007). Psychological treatment of cardiac patients: A meta-analysis. Eruropean Heart Journal, 28, 2972-2984. Mikosch, P., Hadrawa, T., Laubreiter, K., Brandl, J., Jurgen., P., Stettner, H., & Grimm, G. (2010). Effectiveness of respiratory-sinus-arrhythmia biofeedback on state-anxiety in patients undergoing coronary angiography. Journal of Advanced Nursing, 66(5), 1101-1110.

Moak, J. P., Goldstein, D. S., Eldadah, B. A., Saleem, A., Holmes, C., Pechnik, S., . . . Sharabi, Y. (2009). Supine low-frequency power of heart rate variability reflects baroreflex function, not cardiac sympathetic innervation. Cleveland Clinic Journal Medicine, 76(2), 51-59. Nolan, R. P., Kamath, M. V., Floras, J. S., Stanley, J., Pang, C., Picton, P., . . . Young, 25

ACCEPTED MANUSCRIPT Q. R. (2005). Heart rate variability biofeedback as a behavioral neurocardiac intervention to enhance vagal heart rate control. American Heart Journal, 149(6), 1137-1137. Palomba, D., Ghisi, M., Scozzari, S., Sarlo, M., Bonso, E., Dorigatti, F., & Palatini, P. (2011). Biofeedback-assisted cardiovascular control in hypertensives exposed to emotional stress: A pilot study. Applied Psychophysiology and Biofeedback,

RI PT

36(3), 185-192. Reyes del Paso, G. A., Langewitz, W., Mulder, L. J. M., Roon, A., & Duschek, S. (2013). The utility of low frequency heart rate variability as an index of sympathetic cardiac tone: A review with emphasis on a reanalysis of previous

M AN U

SC

studies. Psychophysiology, 50, 477-487. Reyes del Paso, G. A., Langewitz, W., Robles, H., & Pérez, N. (1996). A between-subjects comparison of respiratory sinus arrhythmia and baroreceptor cardiac reflex sensitivity as non-invasive measures of tonic parasympathetic cardiac control. International Journal of Psychophysiology, 22(3), 163-171. Shaffer, F., McCraty, R., & Zerr, C. L. (2014). A healthy heart is not a metronome: An integrative review of the heart's anatomy and heart rate variability.

TE D

Frontiers in Psychology, 5, 1-19. Sloan, R. P., Bagiella, E., Shapiro, P. A., Kuhl, J. P., Chernikhova, D., Berg, J., . . . Myers, M. M. (2001). Hostility, gender, and cardiac autonomic control. Psychosomatic Medicine, 63(3), 434-440.

EP

Sloan, R. P., Shapiro, P. A., Bigger, J. T., Bagiella, E., Steinman, R. C., & Gorman, J. M. (1994). Cardiac autonomic control and hostility in healthy subjects. American Journal of Cardiology, 74(3), 298-300. Sloan, R. P., Shapiro, P. A., Gorenstein, E. E., Tager, F. A., Monk, C. E., McKinley, P.

AC C

S., . . . Bigger, J. T. (2010). Cardiac autonomic control and treatment of hostility: A randomized controlled trial. Psychosomatic Medicine, 72(1), 1-8. Smith, T. W. (1992). Hostility and health: Current status of a psychosomatic hypothesis. Health Psychology, 11(3), 139-150. Smith, T. W. (2006). Personality as risk and resilience in physical health. Current Directions in Psychological Science, 15(5), 227-231. Stevens, J. C. (2002). Applied multivariate statistics for the social sciences. NJ: Lawrence Erlbaum Associates. Swanson, K., Gevirtz, R., Brown, M., Spira, J., Guarneri, E., & Stoletniy, L. (2009). The effect of biofeedback on function in patients with heart failure. Applied Psychophysiology and Biofeedback, 34(2), 71-91. Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology. (1996). Heart rate variability: Standards of 26

ACCEPTED MANUSCRIPT measurement, physiological interpretation, and clinical use. Circulation, 93(5), 1043-1065. Thayer, J. F., & Lane, R. D. (2007). The role of vagal function in the risk for cardiovascular disease and mortality. Biological Psychology, 74(2), 224-242. Vaschillo, E., Lehrer, P., Rishe, N., & Konstantinov, M. (2002). Heart rate variability biofeedback as a method for assessing baroreflex function: A preliminary

RI PT

study of resonance in the cardiovascular system. Applied Psychophysiology and Biofeedback, 27(1), 1-27. Wang, S. Z., Li, S., Xu, X. Y., Lin, G. P., Shao, L., Zhao, Y., & Wang, T. H. (2010). Effect of slow abdominal breathing combined with biofeedback on blood

M AN U

SC

pressure and heart rate variability in prehypertension. The Journal of Alternative and Complementary Medicine, 16(10), 1039-1045. Weng, C. Y., Lin, I. M., Lue, B. H., Chen, H. J., Wu, Y. C., & Cheng, Y. R. (2008). Development and psychometric properties of the Chinese Hostility Inventory -short form. Psychological Testing, 55(3), 463-486. Wheat, A., & Larkin, K. (2010). Biofeedback of heart rate variability and related physiology: A critical review. Applied Psychophysiology and Biofeedback,

AC C

EP

TE D

35(3), 229-242. Tzeng, Y. C., Sin, P. Y. W., Lucas, S. J. E., & Ainslie, P. N. (2009). Respiratory modulation of cardiovagal baroreflex sensitivity. Journal of Applied Physiology, 107(3), 718-724.

27

ACCEPTED MANUSCRIPT

Table 1

Session S1

RI PT

Heart rate variability biofeedback protocol for each session.

HRV-BF protocol

(1) Interpret the results of psychological questionnaires and autonomic nervous system response at pre-intervention

SC

(2) Set up the paced stimulus to determine the individual resonance frequency

(3) Introduce HRV-BF: Guide and interpret the biofeedback equipment and signals

M AN U

(4) Provide breathing training with slow, regular, stable, and smooth breathing; do not breathe too hard or too slow to prevent hyperventilation and dizziness (5) Teach self-guided muscle relaxation

(6) Homework: Practice self-guided muscle relaxation for 10 min daily

(1) HRV-BF: Introduce and guide diaphragmatic breathing with HRV-BF

TE D

S2

(2) Use paced breathing and gradually stepped down the breathing frequency based on the breathing rate at pre-intervention to reach the target of individual resonance frequency (decrease the rate by 20% for each time)

EP

(3) Observe the breathing rate, breathing pattern, and LF power (0.1 Hz) (4) Homework: Practice diaphragmatic breathing for 10 min daily (1) HRV-BF: Combine pursed-lip breathing and diaphragmatic breathing with HRV-BF

AC C

S3

(2) Use paced breathing and gradually stepped down the breathing frequency based on the breathing rate at S2 to reach the target of individual resonance frequency (decrease the rate by 20% for each time) (3) Observe the breathing rate, breathing pattern, and LF power (0.1 Hz)

ACCEPTED MANUSCRIPT

(4) Homework: Practice pursed-lip breathing and diaphragmatic breathing for 10 min daily (1) HRV-BF: RSA training

RI PT

S4

(2) Use paced breathing and gradually stepped down the breathing frequency based on the breathing rate at S3 to reach the target of individual resonance frequency (decrease the rate by 20% for each time)

SC

(3) Observe the RSA and increase LF at 0.1 Hz (4) Transfer the diaphragmatic breathing to daily life

M AN U

(5) Teach how to use the biofeedback equipment for home training: StressEraser (6) Homework: Practice with the StressEraser for 10 min daily S5

(1) HRV-BF: RSA training to increase RSA amplitude

(2) Hostility psychoeducation: Introduce the relationship between expressive hostility, suppressive hostility, and cardiac autonomic

TE D

imbalance (3) Transfer the diaphragmatic breathing to daily life

(4) Homework: Practice with the StressEraser for 10 min daily (1) HRV-BF: RSA training to increase RSA amplitude

EP

S6

(2) Hostility psychoeducation: Discuss coping strategies when they encounter the anger situation

AC C

(3) Review the treatment effectiveness of HRV-BF

Note: HRV-BF = heart rate variability biofeedback; LF = low frequency; RSA = respiratory sinus arrhythmia.

ACCEPTED MANUSCRIPT

The social demographic characteristics and research variables of participants.

(n = 77)

Range

61.01(8.41)

39-75

6

Male

71

Blood

Total cholesterol

161.31(31.29)

Sample

Low density lipoprotein

90.80(23.25)

High density lipoprotein

41.64(11.28)

M AN U

Female

SC

Age Gender

WLC group

HRV-BF group

Variables

RI PT

Table 2

(n = 77)

Range

60.61(8.03)

37-75

t /χ2 t = -0.30

11 χ2 = 1.65

66

84-236

158.03(24.56)

111-217

t = -0.65

17.90-135.70

89.04(23.42)

33-140.80

t = -0.42

22.80-78.20

44.10(10.43)

26.60-72.80

t = 1.18

34-439

120.03(60.35)

33-324

t = -1.20

135.56(81.57)

Fasting sugar

118.57(35.55)

85-264

116.81(34.37)

82-265

t = -0.27

6.61(1.06)

5.30-10.20

6.66(1.28)

5.70-11.60

t = 0.19

Systolic blood pressure (SBP, mmHg)

126.48(12.99)

103-159.33

125.46(14.31)

90-160.67

t = -0.46

Diastolic blood pressure (DBP, mmHg)

72.40(10.71)

54-102.33

73.00(10.60)

37-96.67

t = 0.35

Heart rate (HR, bpm)

77.00(15.24)

48.67-109

75.27(15.58)

46.33-117.33

t = -0.70

2.03(0.91)

1-4

2.25(0.88)

1-4

t = 1.28

Maximum percentage of vessel narrowing

93.63(8.74)

70-100

93.04(8.58)

75-100

t =-0.33

Left ventricular ejection fraction (LVEF)

64.27(13.23)

23-85.40

63.32(17.59)

20-97.60

t=-0.27

AC C

Number of vessel stenosis

EP

Glycated hemoglobin (HbA1c)

TE D

Triglyceride

ACCEPTED MANUSCRIPT

6-30

14.07(4.93)

6-24

t = 0.26

7.77(3.49)

4-16

8.33(3.69)

4-18

t = 0.95

Expressive hostility

13.03(4.65)

5-23

12.70(4.34)

5-22

t = -0.45

Suppressive hostility

13.95(5.07)

5-25

14.00(5.01)

5-25

t = 0.06

Hostility total score

48.65(13.49)

21-79

48.93(12.41)

26-73

t = 0.13

Hostility affect

66

χ2 = 0.12

12

χ2 = 0.29

51

χ2 = 0.67

48

χ2 = 0.75

55

χ2 = 0.27

22

χ2 = 0.01

12

10

χ2 = 0.15

5

11

χ2 = 2.74

67

α-blocker

10

β-blocker

48

Anti-lipid

54

ACE inhibitors

54

Nitroglycerin (NTG)

22

SDNN (ms)

indices

LF (ms2) log LF (ms2) HF (ms2) log HF (ms2) LF/HF ratio

27.91(14.79)

7.77-83.03

30.41(20.02)

9.42-116.09

t = 0.65

64.43(143.99)

1.02-892.60

99.63(232.45)

3.21-1452.89

t = 0.83

3.22(1.36)

0.02-6.79

3.50(1.34)

1.17-7.28

t =0.96

65.83(131.56)

2.53-820.73

82.75(206.53)

1.21-1069.97

t = 0.45

3.34(1.30)

0.93-6.71

3.32(1.37)

0.19-6.98

t = -0.09

1.53(2.14)

0.15-11.26

2.04(2.95)

0.15-16.17

t = 0.90

EP

HRV

AC C

Calcium channel blocker

TE D

Medications Antiplate

Diuretic

RI PT

13.85(4.96)

SC

Hostility cognition

M AN U

Hostility

Note: ACE inhibitors = Angiotensin converting enzyme inhibitors; HbA1c = glycated hemoglobin.

ACCEPTED MANUSCRIPT

HRV indices, blood pressure, and hostility for the HRV-BF group and the WLC group. HRV-BF group

WLC group

(n = 77)

(n = 77)

Pre- intervention Post- intervention

Pre-intervention

Post- intervention

27.16(15.12)

26.08(12.66)

2.37

3.03

5.70*

0.08

14.76***

0.18

Group Time

Group*Time

35.39(19.94)

LF (ms )

73.28(157.36)

217.36(274.11) 72.86(129.63)

53.45(72.90)

5.32*

8.58**

log LF (ms2)

3.27(1.47)

4.36(1.67)

3.34(1.29)

3.34(1.13)

2.52

13.26** 12.90**

0.16

HF (ms2)

69.05(142.92)

94.72(319.09)

70.93(177.97)

38.34(37.28)

0.58

0.01

0.92

0.01

log HF (ms2)

3.35(1.31)

2.99(1.56)

3.26(1.35)

3.21(1.01)

0.07

1.36

0.82

0.01

SBP (mmHg)

125.69(13.16)

120.96(15.41)

124.16(13.85)

121.37(14.11)

006

10.84** 0.73

0.01

DBP (mmHg)

72.40(10.81)

70.45(10.38)

71.81(10.44)

71.41(11.14)

0.01

2.99

1.31

0.01

Heart rate (bmp)

73.89(15.17)

72.63(13.36)

75.44(14.93)

73.37(15.45)

0.20

5.66*

0.34

0.00

Hostility cognition

13.55(4.95)

12.67(5.16)

13.79(5.06)

13.54(5.32)

0.45

1.58

0.50

0.00

Hostility affect

7.93(3.62)

7.24(3.55)

8.76(3.69)

8.25(3.76)

2.49

3.50

0.08

0.00

Expressive hostility

13.05(4.79)

11.08(4.38)

12.61(4.21)

12.45(3.97)

0.43

10.27** 7.54**

0.06

Suppressive hostility

13.92(5.06)

12.14(4.84)

13.86(4.95)

13.92(4.67)

1.23

4.93*

5.65*

0.04

Hostility total score

48.47(13.58)

43.03(14.54)

48.64(12.55)

48.18(13.38)

1.43

7.37**

5.25*

0.04

* p < 0.05 **p < 0.01

***p < 0.001

EP

TE D

M AN U

28.52(15.54)

2

AC C

SDNN (ms)

ηp2

F

SC

Variables

RI PT

Table 3

ACCEPTED MANUSCRIPT

Table 4

Time

Pre-intervention (1)

F

Post- intervention

Follow-up

(2)

(3)

29.16(16.45)

36.00(18.47)

38.57(22.85)

LF (ms2)

73.84(148.52)

239.37(246.55)

log LF (ms2)

3.36(1.42)

HF (ms2)

ηp2

Post hoc comparison

6.40**

0.14

2>1, 3>1

334.66(536.41)

9.66**

0.20

2>1, 3>1

4.69(1.56)

4.84(1.61)

30.26***

0.44

2>1, 3>1

65.92(133.58)

88.97(295.32)

81.69(244.09)

0.22

0.01

log HF (ms2)

3.34(1.27)

2.96(1.55)

2.85(1.59)

2.27

0.06

SBP (mmHg)

124.28(13.28)

121.16(15.98)

119.35(13.79)

5.91**

0.08

3