Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation on Alleviating Major Depressive Disorder in Patients With Acute Coronary Syndrome After Percutaneous Coronary Intervention:A Prospective, Double-Blind,Randomized Controlled Study
Phase: NA
Conditions: Depressive Disorder (Per DSM-V Criteria, Mild-to-moderate), Acute Coronary Syndrome (ACS), Percutaneous Coronary Intervention (PCI), Depressive Disorder, Postoperative Psychological Distress, Heart Rate Variability (HRV), Inflammatory Factors, Randomized Controlled Trial (RCT)
Sponsor: Jing Han

Official Title: Efficacy of Transcutaneous Auricular 
Vagus Nerve Stimulation on Alleviating Major 
Depressive Disorder in Patients With Acute 
Coronary Syndrome After Percutaneous Coronary 
Intervention:A Prospective, Double-
Blind,Randomized Controlled Study 
 
NCT Number: 
Date: April 30, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1. Introduction 
Acute Coronary Syndrome (ACS) is a clinical syndrome spectrum pathologically 
based on atherosclerotic plaque rupture or erosion, with subsequent complete or 
incomplete occlusive thrombus formation. It includes unstable angina and acute ST-
segment elevation or non-ST-segment elevation myocardial infarction, representing a 
severe manifestation of coronary artery disease (CAD) and a leading cause of annual 
cardiovascular morbidity and mortality[1]. The incidence and mortality rates of ACS are 
substantial, with nearly half of CAD-related deaths occurring post-ACS, posing a 
severe threat to patients' quality of life[2]. 
Percutaneous coronary intervention (PCI) is a primary treatment for ACS. 
However, as an invasive procedure, PCI carries inherent procedural risks. Coupled with 
patients' lack of understanding, excessive concerns about postoperative complications, 
stent longevity, drug side effects, and treatment costs, patients diagnosed with ACS 
face a series of negative physical and mental health risks following PCI. A meta-
analysis on anxiety and depression in post-PCI patients indicated[3] that varying degrees 
of anxiety and depression are prevalent, with rates ranging from 20% to 82%. 
Furthermore, these mental health issues, prone to occur after PCI, have been confirmed 
to significantly impact treatment adherence and prognosis[4]. Depression is estimated to 
be the second leading cause of global disability[5], and the mortality risk is substantially 
increased in patients with depression following an ACS event[6]. The onset, progression, 
and outcomes of cardiovascular disease are closely linked to psychological factors, 
characterizing it as a psychosomatic condition. Ample evidence indicates that 
psychological factors can promote the development of cardiovascular disease, while 
anti-anxiety and antidepressant treatments can significantly improve the prognosis of 
patients with cardiovascular disease[7]. 
The incidence of anxiety post-PCI ranges from 25% to 37%[8], and the prevalence 
of depression is as high as 20% to 40%. While PCI rapidly and effectively achieves 
vascular recanalization and reperfusion, the requirement for lifelong medication post-
procedure imposes a substantial psychological and economic burden on patients and 

society. Gu et al.[9] conducted Hospital Anxiety and Depression Scale (HADS) 
questionnaires on 170 patients one day before and one day after PCI. They found that 
on the day before PCI, 34.7% experienced anxiety and 23.5% experienced depression; 
whereas on the day after PCI, 54.7% experienced anxiety and 44.7% experienced 
depression. Concerns regarding surgical complications, quality of care, postoperative 
decline in cardiac function, and procedural failure contributed to a marked increase in 
anxiety and depression prevalence post-PCI. Most clinicians focus solely on resolving 
coronary obstruction, often overlooking patients' emotional disorders. However, 
patients with anxiety and depression frequently exhibit unhealthy lifestyles and poor 
medication adherence, leading to unfavorable prognoses. Kala et al.[10] analyzed the 
one-year rehospitalization rate and its influencing factors in 145 post-PCI patients, 
finding that the rate was associated with the presence of depressive symptoms. Li et 
al.[8] followed 303 PCI patients for one year to observe the incidence of major adverse 
cardiovascular events (MACE, e.g., new non-fatal myocardial infarction, stent 
restenosis, heart failure, arrhythmia, death). They found that the risk of MACE in 
anxious patients was 3.742 times that of non-anxious patients, and in depressed patients 
was 3.087 times that of non-depressed patients. Moreover, the risk for patients with 
both anxiety and depression was 7.303 times that of patients without these conditions, 
indicating that anxiety and depression are predictors of poor prognosis in CAD patients 
after stent implantation. Therefore, routine assessment of anxiety and depression in PCI 
patients and active measures to improve negative emotions are warranted in clinical 
practice to enhance patient outcomes. 
Antidepressant medications are considered first-line treatment for depression. 
However, studies have found that one-third to one-half of patients do not respond to 
multiple antidepressants[11]. A response typically requires at least 4 weeks, and side 
effects such as nausea, cardiovascular issues, sexual dysfunction, and headaches are 
common, leading to low medication adherence[12]. Cognitive Behavioral Therapy (CBT) 
is a major psychotherapy, but its complexity and cost hinder accessibility for low-
income patients with depression[13]. Thus, despite urgent need, current treatments for 
major depression remain far from satisfactory. 

Vagus Nerve Stimulation (VNS) is an FDA-approved somatic therapy for 
treatment-resistant depression (TRD) that produces clinically significant antidepressant 
effects[14]. However, despite its efficacy, surgical risks, high procedural costs ($30,000 
- $50,000), and potential side effects limit its appeal and result in low clinical 
utilization[15]. To overcome these barriers associated with invasive VNS (iVNS), a non-
invasive transcutaneous auricular VNS (taVNS) method has been developed and is 
garnering increasing attention. Anatomical studies indicate that the ear is the only 
location on the human body surface with afferent vagus nerve distribution[16]. 
According to the "bottom-up" mechanism of the central nervous system, electrical 
stimulation propagation may follow a reverse pathway from peripheral nerves to the 
brainstem and central structures[17]. Therefore, direct stimulation of afferent nerve 
fibers on the ear should produce effects similar to classical VNS in alleviating 
depressive symptoms, without the burden of surgical intervention[18]. The first study on 
taVNS for depression was conducted in 2009. Since then, a series of clinical studies 
have demonstrated that taVNS can effectively improve depressive symptoms[19-21]. 
However, research on taVNS for treating depression in ACS patients after PCI is 
limited. We will employ a randomized controlled clinical trial to investigate the 
antidepressant effect of taVNS in post-PCI patients with moderate or severe depression. 
 
2. Objectives 
2.1 Study Aims 
Aim 1: To compare the improvement in depression, anxiety, and quality of life 
between patients receiving transcutaneous auricular vagus nerve stimulation or sham 
stimulation using a randomized controlled design. 
Aim 2: To compare the improvement in multiple physiological indicators between 
patients receiving transcutaneous auricular vagus nerve stimulation or sham stimulation 
using a randomized controlled design. 
2.2 Study Endpoints (or Evaluation Metrics) 
2.2.1 Primary Endpoint (or Primary Evaluation Metric) and Definition 

Hamilton Depression Rating Scale (HAMD) score at Week 8: The 17-item 
HAMD is convenient, has clear criteria, is easy to master, and can be used to assess 
depressive symptoms in various conditions including depression, bipolar disorder, and 
neurosis, being particularly suitable for major depressive disorder. 
Scoring criteria: 
 No depressive symptoms: Total score ≤7；Mild depression: Total score ≥8 and 
≤17；Moderate depression: Total score >17 and ≤24 ；Severe depression: Total 
score >24. 
2.2.2 Secondary Endpoints (or Secondary Evaluation Metrics) and Definitions 
1. Hamilton Anxiety Rating Scale (HAMA) score during follow-up: The total 
score effectively reflects the severity of anxiety symptoms and can be used to evaluate 
the severity of anxiety in patients with anxiety and depressive disorders and to assess 
the effects of various drug and psychological interventions. 
According to data from the Chinese Scale Collaboration Group:Total score ≥29: 
Possible severe anxiety;Total score ≥21: Definite significant anxiety;Total score ≥14: 
Definite anxiety;Total score >7: Possible anxiety;Total score ≤7: No anxiety symptoms. 
2. HAMD response rate: Reduction in HAMD-17 score ≥50%. 
3. HAMD remission rate: Post-treatment HAMD-17 score ≤7. 
4. Beck Depression Inventory (BDI) score: A tool specifically designed to assess 
depression severity. The entire questionnaire comprises 21 groups of items, each with 
4 statements preceded by corresponding numbers as grade scores. 
Scoring criteria: 0-4: (Essentially) no depressive symptoms;5-7: Mild 
depression;8-15: Moderate depression;≥16: Severe depression. 
5. Generalized Anxiety Disorder 7-item (GAD-7) score: The GAD-7 consists of 7 
items aiming to understand how often the respondent has been bothered by 7 problems 
including feeling nervous or anxious over the past 2 weeks. 
Scoring rules: Each item scores 0-3, total score 21.0-4: No generalized anxiety;5-
9: Mild generalized anxiety;10-14: Moderate generalized anxiety;15-21: Severe 
generalized anxiety 

6. PTSD Checklist-Civilian Version (PCL-C) score: Developed in 1994 by the 
Behavioral Science Division of the US National Center for PTSD, translated into 
Chinese by Professors Jiang Chao and Zhang Jie in 2003. The scale includes 17 items 
categorized into 3 characteristic symptom clusters: re-experiencing (5 items), 
avoidance (7 items), and hyperarousal (5 items). Each item uses a Likert 5-point scale 
from 1 (not at all) to 5 (extremely). Total score range 17-85, with higher scores 
indicating a higher likelihood of PTSD. 
Test results: 17-37: No significant PTSD symptoms;38-49: Some degree of PTSD 
symptoms; 50-85: Significant PTSD symptoms, possible PTSD diagnosis 
7. Quality of Life Scale (SF-36) score: The 36-Item Short Form Health Survey 
(SF-36) is widely used, covering 8 domains: physical functioning, role-physical, bodily 
pain, general health, vitality, social functioning, role-emotional, and mental health. 
Patients are scored on quality of life to assess changes in physical, energetic, emotional, 
and mental health, using a percentage system. Higher scores indicate better function 
and quality of life. 
8. Heart Rate Variability (HRV): A 10-minute resting ECG is recorded. HRV 
analysis methods mainly include time-domain, frequency-domain, and non-linear 
methods. 
Key time-domain parameters include: 
SDNN (Standard Deviation of all Normal-to-Normal [NN] intervals): Reflects 
overall autonomic nervous system activity, primarily sympathetic tone. Normal value 
(141±39) ms; lower values suggest increased sympathetic activity and reduced 
adaptability. 
⚫ 
SDANN (Standard Deviation of the Averages of NN intervals in all 5-minute 
segments): Evaluates sympathetic nervous system activity. Normal value (127±35) ms. 
⚫ 
rMSSD (Root Mean Square of Successive Differences between adjacent NN 
intervals): Reflects parasympathetic (vagal) activity. Normal value (27±12) ms. 
⚫ 
pNN50 (Percentage of adjacent NN intervals differing by >50 ms): Lower 
values indicate lower parasympathetic activity. 
Frequency-domain indicators include: 

⚫ 
Total Power (TP) (≤0.4 Hz): Reflects overall autonomic nervous system 
activity and regulatory capacity. 
⚫ 
High Frequency (HF) (0.15–0.40 Hz): A good indicator of parasympathetic 
(vagal) function, influenced by respiration depth. 
⚫ 
Low Frequency (LF) (0.04–0.15 Hz): Controlled by both sympathetic and 
parasympathetic systems; some studies consider it influenced by sympathetic activity, 
serving as a reliable indicator of cardiac sympathetic activity, affected by baroreflexes. 
⚫ 
Very Low Frequency (VLF) (0.003–0.040 Hz) 
⚫ 
Ultra-Low Frequency (ULF) (≤0.003 Hz) 
⚫ 
LF/HF ratio: Reflects the balance of sympathetic-parasympathetic tone. 
9. Echocardiography: Includes left 
ventricular 
anterior-posterior diameter 
(diastolic/systolic) and left ventricular ejection fraction (LVEF). 
10. Venous blood biomarkers: Levels of N-terminal pro-B-type natriuretic peptide 
(NT-proBNP), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha 
(TNF-α), high-sensitivity C-reactive protein (hs-CRP). 
11. Incidence of Major Adverse Cardiovascular Events (MACE): Including death, 
myocardial infarction, and target vessel revascularization (definitions based on 
Academic Research Consortium [ARC] criteria). 
 
3. Study Design 
3.1 Overall Study Design 
An investigator-initiated, single-center, prospective, randomized, double-blind, 
parallel-group controlled study. 
 
4. Study Population 
4.1 Inclusion Criteria 
⚫ Age ≥18 years; 
⚫ Meets diagnostic criteria for ACS; 

⚫ 14 days to 12 months post-successful PCI, with stable vital signs; 
⚫ Meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-V) diagnostic criteria for Major Depressive Disorder; 
⚫ HAMD-17 score ≥7 and <24, with HAMA score < HAMD score; 
⚫ After full disclosure of condition, the patient or legal representative refuses 
psychiatric consultation and declines antidepressant medication or psychotherapy; 
⚫ Patient or legal representative voluntarily participates in the study and provides 
written informed consent. 
4.2 Exclusion Criteria 
⚫ Severe heart failure (NYHA class ≥III); 
⚫ Uncontrolled hypertension (≥180/110 mmHg); 
⚫ First-degree atrioventricular block on awake ECG (PR interval ≥0.20s), or 
occurrence of Mobitz type II second-degree or third-degree AV block at any time; 
⚫ 24-hour average heart rate ≤50 beats per minute, RR interval ≥3s, or history of 
syncope unrelated to the current ACS; 
⚫ Patients on dialysis; 
⚫ History of renal denervation or vagal ganglion ablation therapy; 
⚫ Life expectancy less than 4 months; 
⚫ Pre-existing clinical diagnosis of other severe psychiatric disorders prior to PCI, 
including schizophrenia, severe intellectual disability, substance abuse; 
⚫ Patient currently taking antipsychotic medications; 
⚫ High suicide risk; 
⚫ Pregnant or lactating women; 
⚫ Left ear disease, acute exacerbation of asthma or chronic obstructive pulmonary 
disease, or other conditions precluding taVNS treatment; 
⚫ Presence of cardiac pacemaker, implantable cardioverter-defibrillator (ICD), or 
other implantable stimulators (e.g., VNS or deep brain stimulators). 
4.3 Withdrawal Criteria 

Desire to pursue other treatments or voluntary withdrawal from the trial without 
specific reason. 
 
5. Study Treatment Groups 
• Group A (Active Stimulation Group): Patients receive standard ACS treatment 
plus active transcutaneous auricular vagus nerve stimulation (taVNS), twice daily for 
20 minutes each session. 
• Group B (Sham Stimulation Group): Patients receive standard ACS treatment 
plus sham taVNS treatment, twice daily for 20 minutes each session. 
5.1 Randomization 
5.1.1 Method for Generating Random Allocation Sequence 
Stratified block randomization will be used: Eligible patients will be randomly 
assigned to Group A or B in a 1:1 ratio. Using R software, stratification will be based 
on age (two levels: 18-60 years, >60 years) and gender (two levels: male, female), 
resulting in 4 strata. Within each stratum, patients will undergo randomization with 
varying block sizes. The output will determine the stimulation device assigned to each 
patient. 
5.1.2 Allocation Concealment 
1. Personnel generating and safeguarding the random allocation sequence will not 
be involved in the trial. Research personnel will determine subject eligibility. 
2. A central telephone randomization system will be used for allocation 
concealment. Once research personnel confirm a patient is eligible, they will notify the 
central randomization system (holder of the sequence) via telephone. The central 
system will record the subject's name and ID, then inform the researcher of the subject's 
group assignment. 
5.2 Blinding and Unblinding 
This is a double-blind study. Patients, research personnel, and data analysts will 
be blinded. 
 

6. Study Procedures 
6.1 Study Intervention Implementation Steps 
1. For outpatients or inpatients who are 2 weeks to 12 months post-ACS PCI, a 
psychiatrist will conduct assessments using DSM-V, HAMD, and HAMA scales. 
Patients meeting criteria for mild to moderate depression will be advised to receive 
appropriate treatment. If they refuse and meet inclusion/exclusion criteria, they will 
sign informed consent, enroll in the clinical trial, and baseline data will be collected. 
2. Device Usage Method 
Eligible patients will receive transcutaneous auricular non-invasive vagus nerve 
stimulation while awake. The electrode and the patient's left ear target area will first be 
disinfected with 75% alcohol. An abrasive gel will then be applied to the left concha 
cymba and tragus area for gentle abrasion, wiped off, and the area disinfected again 
with alcohol. Conductive gel will be applied to the electrode output points. The 
electrode will be placed on the patient's left ear, ensuring the output points are 
positioned on the left tragus. Pulses will be delivered via the Xidian Keyue brand 
(Product No.: BS-TVNS600) vagus nerve stimulator. The stimulation current will be 
gradually increased to the maximum intensity tolerable by the patient, defined as the 
threshold intensity. 
Active Stimulation Group: Stimulation at threshold intensity, with parameters: 
pulse frequency 20 Hz, pulse width 250 µs, pulse current 0.5-3 mA. Stimulation cycle: 
30 seconds ON, 30 seconds OFF. 
Sham Stimulation Group: Device, parameter adjustment, and placement identical 
to the active group. The stimulator is programmed to deliver stimulation only for the 
first 5 seconds of each session, with no subsequent stimulation. 
Both groups will undergo electrical stimulation twice daily for 20 minutes each 
session, for a total treatment duration of 8 weeks. 
All patients will be trained on how to turn the stimulator on/off, attach the 
electrode to the ear and position it, and increase the intensity. All subsequent operations 
will be performed by the patient at home. Patients can obtain assistance via telephone 

or site visits if they have questions. Each patient will be given a diary card to record 
usage date, duration, adverse reactions, and suggestions. Patients are required to 
complete daily entries, which will be checked during assessment visits. 
Both groups will receive guidance on medication and lifestyle intervention during 
follow-up (including CAD knowledge education, diet/exercise, sleep guidance, 
smoking cessation/alcohol limitation, and weight control). 
6.2 Concomitant Treatment and Follow-up Visits 
All enrolled patients will receive standard post-PCI medication and strict 
secondary prevention for coronary artery disease. 
Follow-up visits will occur at 4, 8, 12, and 16 weeks post-randomization. Follow-
up content includes: HAMA, HAMD, BDI, GAD-7, PCL-C, and SF-36 scale 
assessments; HRV measurement; echocardiography; venous blood tests; assessment of 
smoking/alcohol cessation and lifestyle improvement; record of follow-up visits (time, 
location, results); presence of angina or heart failure-related symptoms; occurrence of 
MACE (time, management, outcome); adverse reactions. 
6.3 Patient Adherence and Withdrawal 
Adherence: A trusting relationship will be established to ultimately improve 
subject adherence. 
Withdrawal: Subjects found during follow-up to have poor treatment adherence, 
including self-discontinuation of device use, heavy smoking, and severely poor 
lifestyle/dietary habits; development of other serious new illnesses post-procedure that 
may affect study endpoints; loss to follow-up. 
 
7. Evaluations 
7.1 Efficacy Evaluation 
HAMA score, HAMD response rate, HAMD remission rate, BDI score, GAD-7 
score, PCL-C score, SF-36 score, heart rate variability parameters, echocardiography 
parameters, venous blood biomarkers, and incidence of MACE. 

7.2 Safety Evaluation 
7.2.1 Baseline Signs and Symptoms 
Heart rate, respiratory rate, blood pressure, body temperature, chest tightness, 
chest pain, shortness of breath, wheezing, dyspnea. 
7.2.2 Auxiliary Examination Safety Assessment 
Myocardial injury markers, NT-proBNP, coagulation panel, complete blood count, 
echocardiography. 
7.2.3 Physical Examination and Vital Signs 
Consciousness, neurological reflexes, breath sounds, heart sounds, skin and 
mucous membrane condition. 
 
8. Adverse Event Reporting 
8.1 Definition of Adverse Events 
8.1.1 Definitions 
• Adverse Event (AE): Any untoward medical occurrence in a subject 
administered an investigational treatment, which may manifest as signs, symptoms, 
disease, or laboratory abnormalities, but does not necessarily have a causal relationship 
with the treatment. 
• Serious Adverse Event (SAE): Any AE occurring in a subject that results in 
death, is life-threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, is a congenital 
anomaly/birth defect, or other medically important events. 
8.1.2 Severity 
• Mild: Tolerable by the subject, does not affect prognosis, does not require 
special treatment, no impact on recovery. 
• Moderate: Causes discomfort to the subject, requires special treatment, has a 
direct impact on recovery. 
• Severe: Life-threatening, causing death or disability, requires immediate 
emergency treatment. 

8.2 Recording and Reporting Pathway for Adverse Events 
Any clinical AEs occurring during treatment will be recorded in detail in the 
source documents, including time of onset, clinical manifestations, management, 
duration, outcome, and relationship to the trial. For abnormal laboratory findings, 
follow-up will continue until results return to normal, baseline levels, or are determined 
unrelated to the investigational treatment. SAEs will be documented on an SAE form 
and reported to the clinical research center within 24 hours. 
8.3 Risk Prevention and Management 
The clinical trial application will be submitted according to regulatory 
requirements, and the trial will commence only after obtaining approval. Scientific rigor 
in trial design and strict adherence to inclusion/exclusion criteria will minimize risks. 
Patient guidance will be strengthened to reduce risks from improper operation. 
Reasonable safety indicators will be established to lower risk occurrence. Each center 
will designate a researcher familiar with taVNS procedures as a quality control 
supervisor responsible for managing risks during treatment. 
 
9. Statistical Analysis 
9.1 Sample Size Determination 
This is a randomized controlled trial. Significance level (α) is set at 0.05, and 
power (1-β) at 0.80. Based on literature, the effect size for taVNS alleviating depression 
is approximately 57%. Using PASS software, the calculated sample size per group is 
n1=n2=56. Considering a 10% dropout/loss-to-follow-up rate and the need for 
stratification by age and gender, the minimum sample size per group is determined to 
be 60, resulting in a total sample size of 120. 
9.2 Analysis Populations 
9.2.1 Full Analysis Set (FAS) 
Based on the Intent-to-Treat (ITT) principle, includes all randomized subjects who 
received at least one treatment session from either the experimental or control group. 

9.2.2 Per Protocol Set (PPS) 
Includes all subjects who completed the treatment regimen as specified in the 
protocol without major protocol violations. The exact definition of major protocol 
violations will be finalized during data review and may include (but is not limited to): 
failure to meet inclusion criteria, receipt of interfering treatments post-enrollment, poor 
adherence, visits outside specified time windows. 
9.3 Efficacy Analysis and Statistical Methods 
9.3.1 Analysis of Primary Endpoint 
Comparison of HAMD scores between groups will be performed using t-tests or 
non-parametric tests. 
9.3.2 Analysis of Secondary Endpoints 
Comparisons of HAMA scores, BDI scores, GAD-7 scores, PCL-C scores, SF-36 
scores, HRV parameters, echocardiography parameters, and blood biomarkers between 
groups will be performed using t-tests or non-parametric tests. Comparison of HAMA 
response rates, remission rates, and MACE incidence between groups will be performed 
using chi-square tests. 
9.4 Safety Analysis and Statistical Methods 
Statistical analysis will be performed using SPSS 26.0 software. Categorical data 
will be presented as counts and percentages. Normally distributed continuous data will 
be presented as mean ± standard deviation; non-normally distributed continuous data 
will be presented as median and interquartile range. Differences between groups for 
normally distributed continuous data and categorical data will be compared using 
independent samples t-tests and chi-square tests, respectively. Non-parametric tests will 
be used for non-normally distributed continuous data. Bayesian analysis will be 
employed to further explore the impact of different stimulation modalities on outcome 
prognosis. All statistical tests will be two-sided, with a P-value <0.05 considered 
statistically significant. 
9.5 Interim Analysis 
This study does not involve interim analysis. 

9.6 Data Monitoring Committee 
Given the low incidence and mild nature of adverse reactions associated with this 
trial, and its high safety profile, a Data Monitoring Committee will not be established. 
 
10. Data Collection and Management 
10.1 Case Report Form / Electronic Data Record 
Table 1: Baseline Characteristics 
Gender(%) 
Male     
Female 
Age ,mean (SD), y 
   
Marriage status(%) 
Single  Married 
BMI （kg/m
2）  
Residential Area(%) 
Urban  Rural 
Living alone(%) 
Yes   No 
Education(%) 
Primary education  
Secondary School 
Technical 
secondary school or 
higher 
Occupation(%) 
Retired  
Unemployed 
Employed 
cigarette(%) 
Yes    No 
Participant 
consumes alcoholic 
beverages(%) 
Yes    No 
Type of health 
insurance(%) 
New rural 
cooperative medical 
scheme  Urban 
Employee Basic 
Medical Insurance 
 Uninsured 
Previous PCI.or 
CABG events(%) 
Yes    No 

Previous cardiac 
events(%) 
Yes    No 
Diagnosticn (%) 
NSTEMI   
UA     
STEMI 
Previous PCI.or 
CABG events(%) 
Yes    No 
Hypertension(%) 
Yes    No 
Diabetes(%) 
Yes    No 
Yes    No 
Yes    No 
hsCRP(mg/L) 
 
Total implanted 
stents mean (SD), 
pc 
 
NYHA_Class(%) 
Ⅰ  Ⅱ 
EF（%） 
 
IL-1
（pg/ml） 
 
IL-6
（pg/ml） 
 
TNF-α（pg/ml） 
 
LVD（d/s） 
 
HAMA 
 
HAMD 
 
BDI 
 
GAD-7 
 
SF-36 
 
PCL-C 
 
HbA1c（%） 
 
HRV（SDNN）
(ms) 
 
HRV（SDANN）(ms) 
 
HRV（RMSSD）(ms) 
 
HRV（TP）
(Hz) 
 
HRV（HF）
(Hz) 
 

HRV（LF）
(Hz) 
 
HRV（VLF）
(Hz) 
 
HRV（ULF）
(Hz) 
 
NT-proBNP（ng/mL） 
 
hsCRP(mg/L) 
 
 
 
 
Note: BMI: Body Mass Index; NSTEMI: Non-ST-Elevation Myocardial Infarction; UA: 
Unstable Angina; STEMI: ST-Elevation Myocardial Infarction; PCI: Percutaneous 
Coronary Intervention; CABG: Coronary Artery Bypass Grafting; LVEF: Left 
Ventricular Ejection Fraction; NT-proBNP: N-terminal pro-B-type Natriuretic Peptide; 
hs-CRP: High-sensitivity C-Reactive Protein; IL-1: Interleukin-1; IL-6: Interleukin-6; 
TNF-α: Tumor Necrosis Factor-alpha; LVD (d/s): Left Ventricular Diameter 
(diastolic/systolic); HAMA: Hamilton Anxiety Rating Scale; HAMD: Hamilton 
Depression Rating Scale; BDI: Beck Depression Inventory; GAD-7: Generalized 
Anxiety Disorder 7-item; SF-36: 36-Item Short Form Health Survey; PCL-C: PTSD 
Checklist-Civilian Version; HRV: Heart Rate Variability; HbA1c: Glycated 
Hemoglobin; SDNN: Standard Deviation of NN intervals; RMSSD: Root Mean Square 
of Successive Differences; TP: Total Power; HF: High Frequency; LF: Low Frequency; 
VLF: Very Low Frequency; ULF: Ultra-Low Frequency.* 
10.2 Data Management 
Data will be entered, saved, and managed using Excel software. Data entry will be 
performed by two individuals simultaneously to enhance accuracy. Data will be subject 
to access control and dual backup to prevent tampering or loss. 
 
11. Research Ethics 
11.1 Ethics Committee Review 

This protocol, written informed consent form, and any materials directly related to 
subjects must be submitted to the Ethics Committee. The study may commence 
formally only after written approval is obtained. The investigator must submit an annual 
progress report (if applicable) to the Ethics Committee at least yearly. The investigator 
must notify the Ethics Committee in writing upon study termination and/or completion. 
The investigator must promptly report all changes to the research work (e.g., protocol 
and/or informed consent form revisions) to the Ethics Committee and must not 
implement these changes prior to obtaining Ethics Committee approval, except for 
changes necessary to eliminate apparent and immediate risks to subjects. In such cases, 
the Ethics Committee will be notified. 
11.2 Informed Consent 
Subjects or their legal guardians will be provided with comprehensible 
information regarding the study's purpose, potential benefits, and risks. They will be 
informed that the study has been approved by the Ethics Committee and provided with 
a photo or copy of the approval letter. Sufficient time will be given for consideration. 
Subjects may not be enrolled until signed written informed consent is obtained. During 
participation, subjects will be provided with all updated versions of the informed 
consent form and written information. Informed consent documents will be retained as 
essential trial documentation. 
 
12. Confidentiality Measures 
The results of this research may be published in medical journals, but patient 
information will be kept confidential in accordance with legal requirements. Patient 
personal information will not be disclosed unless required by relevant laws. 
Government regulatory authorities and the hospital Ethics Committee and its relevant 
personnel may access patient data as stipulated by regulations when necessary. 
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