
==== Front
BMJ Open
BMJ Open
bmjopen
bmjopen
BMJ Open
2044-6055
BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR

39182936
10.1136/bmjopen-2024-086901
bmjopen-2024-086901
Protocol
Cardiovascular Medicine
1683
1506
Effect of enhanced external counterpulsation on coronary microcirculation dysfunction (CMD) in patients with coronary artery disease (EECP-CMD II): study protocol of a single-centre, open-label, parallel group, randomised controlled trial
http://orcid.org/0009-0009-7568-4594
Cao Fan caofan91@126.com
1
http://orcid.org/0009-0009-9361-5621
Liu Yuxin liuyx358@163.com
2
http://orcid.org/0009-0001-6085-4345
Wei Wenbin weiwb8@126.com
2
http://orcid.org/0000-0001-8110-9216
Liang Jianwen liangjw39@mail.sysu.edu.cn
34
1 The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong Province, China
2 The Eighth Affiliated Hospital of Sun Yat-Sen University Cardiology Department, Shenzhen, China
3 Cardiology, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, Guangdong Province, China
4 Guangdong Innovative Engineering and Technology Research Center for Assisted Circulation, Shenzhen, Guangdong Province, China
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

None declared.

Dr; liangjw39@mail.sysu.edu.cn
2024
24 8 2024
14 8 e08690126 3 2024
07 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Introduction

Coronary microcirculation dysfunction (CMD) is prevalent in patients with coronary artery disease (CAD). Current therapies for CMD are focused on pharmacotherapy, non-pharmacological treatments such as enhanced external counterpulsation (EECP) have shown favourable results in patients with CAD. However, whether EECP can improve CMD remains unknown. This study is designed to evaluate the effectiveness of EECP on CMD in patients with CAD, and to assess the feasibility of conducting a multicentre randomised controlled trial.

Methods and analysis

This study is a single-centre, outcome-assessor-blinded, parallel randomised controlled trial. A total of 110 participants with CAD will be included and randomly assigned to either the intervention group (EECP plus optimal medical therapy (OMT)) or the control group (OMT alone). EECP will be administered by operators for 60 min, 5 times per week for 7 weeks (35 times in total). Outcomes include patients’ retention rates, the primary outcome and secondary outcomes. The primary outcome is the change in Myocardial Perfusion Reserve Index with cardiac MRI from baseline to the end of follow-up. The planned study duration is from 2024 to 2026.

Ethics and dissemination

Ethical approval was obtained from the Ethics Committee of the Eighth Affiliated Hospital, Sun Yat-sen University (ID: 2023-045-03). The findings will be disseminated in peer-reviewed publications.

Trial registration number

ChiCTR2300076231.

CARDIOLOGY
Coronary heart disease
Randomized Controlled Trial
Protocols & guidelines
Clinical Research Program PY-2023-02 http://dx.doi.org/10.13039/501100019341 Shenzhen Scientific and Technological Foundation JCYJ20220530144601003 Scientific Research Foundation of Futian District FTWS2021080 FTWS2022003 FTWS2022054 National Nature Science Foundation of China 82170427 Shenzhen Key Medical Discipline Construction Fund ZDXKJF-002
==== Body
pmcStrengths and limitations of this study

This is a single-centre, open-label, randomised control trial aiming to include 110 participants.

The Myocardial Perfusion Reserve Index as assessed through cardiac MRI (used in the present study) represents a non-invasive, highly precise and reproducible approach for the comprehensive assessment of coronary microcirculation.

The main limitation of this research lies in its open-label design, as attaining full double-blinding is difficult due to the distinctive characteristics of the enhanced external counterpulsation intervention.

Introduction

Coronary microcirculation dysfunction (CMD), a mismatch of myocardial blood supply and oxygen consumption due to a dysfunction of the coronary microcirculation with a diameter <500 µm,1 is common in patients with coronary artery disease (CAD), moreover, CMD is associated with worse outcomes in CAD.2 3 Although clinical guidelines emphasised that secondary prevention measures can reduce mortality by 50% of CAD, there are residual symptoms that affect the prognosis related to CMD.4 5 Until now there is still a lack of effective non-invasive therapeutic recommendations for CMD.6

Evidence has accrued over the past 30 years indicating that CMD can be responsible for the impairment of myocardial perfusion and ischaemia.1 7 8 The underlying mechanisms of CMD are diverse such as structural changes, vascular dysfunction, microvascular obstruction, etc. According to invasive coronary microvascular assessment, CMD can be classified into structural and functional CMD. Structural CMD presents as abnormally elevated microvascular resistance when the demand for blood flow increases or vasodilation is required, leading to reduced flow under congestion. Functional CMD is characterised by abnormal endothelium-dependent or endothelium-independent vasodilation or constriction, with increased resting blood flow and normal minimal microvascular resistance, but reduced coronary flow reserve (CFR) under stress.9 In clinical practice, these mechanisms often act simultaneously, especially in patients with diabetes and after percutaneous coronary intervention (PCI). In patients with diabetes, early coronary microvascular dysfunction is mainly due to functional CMD caused by endothelial dysfunction and as the disease progresses, structural CMD may also occur.10 The mechanisms of post-PCI CMD may include endothelial dysfunction, smooth muscle cell dysfunction, vascular remodelling, reperfusion-related microvascular injury, etc. Due to microvascular injury caused by PCI, there may be impaired microvascular perfusion in both culprit and non-culprit vessel territories, affecting overall myocardial microcirculatory perfusion.11 For complex types of CMD, it may be influenced by many factors and we need to further understand its pathogenesis in order to better comprehend and intervene.12 The latest European Society of Cardiology guideline has recommended the use of statins, β-blockers and calcium channel blockers, which may alleviate CMD, however, there is still a lack of high-quality trials for stronger recommendation of the medications.13 14 On the other side, non-pharmacological treatments such as enhanced external counterpulsation (EECP) have shown favourable results in patients with CAD. EECP has been shown to increase coronary blood flow, decrease endothelin levels and inhibit intimal hyperplasia.1517 Moreover, EECP can promote collaterals, coronary vasodilation and decrease vascular disease progression.18 19 However, whether EECP can improve CMD remains largely unknown.

The index of microcirculatory resistance (IMR) has the advantage of being immediately measurable in the catheterisation laboratory and well correlated with the true microvascular resistance, which is the hallmark of CMD.20 21 The normal range of IMR<25 is based on studies reporting the IMR value in healthy populations.2224 Our previous study (EECP-CMD) showed that IMR was elevated in patients with CAD and decreased significantly after EECP therapy.25 However, IMR has inevitable disadvantages. First, it is an invasive examination technique, which limits the compliance for repeated performance. Second, measuring IMR requires achieving a stable maximum congestion state, otherwise, maximum reduction of microvascular resistance cannot be achieved, which may lead to an overestimation of IMR value. Third, the position of the pressure guide wire placed in the blood vessel will affect the measured hTmn and IMR values. Finally, with the advancement of scientific technology, other haemodynamic assessment methods derived from IMR are also gradually being applied and explored in clinical practice. For example, coronary angiography-based index of microcirculatory resistance (AMR), coronary slow flow. Studies have shown that microvascular resistance may not always differ between the slow flow patterns associated with perfusion defects or normal slow flow patterns. Angiographic coronary slow flow is not strongly correlated with IMR and CFR.26 Therefore, we believe that methods based on haemodynamic calculations still have certain limitations, as they may not always fully and accurately reflect the overall myocardial perfusion status.8 The non-invasive evaluation of coronary microvascular function includes transthoracic Doppler echocardiography, single-photon emission computed tomography (SPECT), positron emission tomography (PET) and combined medication record (CMR). Among them, PET is considered the gold standard for non-invasive diagnosis of myocardial ischaemia. However, its application is limited due to the time-consuming nature of the examination, high cost, limited spatial resolution and the presence of radiation.

Myocardial perfusion MRI shows advantages in non-invasive, reliable and repeatable diagnosis of coronary microvascular dysfunction. With the development of MRI technology, CMR can complete the detection of cardiac morphology, wall motion, myocardial perfusion and myocardial activity in one go, which is non-invasive, economical, practical and non-ionising radiation-free. The advantage of obtaining high-resolution images has gradually become the gold standard for non-invasive evaluation of cardiac structure and function. CMR evaluates coronary microvascular perfusion through load state and resting state myocardial perfusion: myocardial blood flow (MBF), myocardial perfusion reserve (MPR) and Myocardial Perfusion Reserve Index (MPRI). The threshold obtained from clinical studies is as follows: MPR>2.2, MBF>2.25 mL×g–1×min–1, MPRI>2.0 in the normal population. MPRI<2.0 is considered that there is insufficient perfusion. However, there is currently a lack of clinical trials using CMR to evaluate interventions for myocardial microcirculation disorders in coronary heart disease.

Based on the issue, we will perform a randomised controlled trial comparing the efficacy of EECP versus optimal medical therapy (OMT) on CMD in patients with CAD. The results of the study may provide evidence to determine whether EECP is a potential option for CMD.

Methods and analysis

Study design

This study will be a single-centre, outcome-assessor-blinded parallel randomised controlled trial consisting of a complete EECP session followed by a 6-month follow-up phase. A complete EECP treatment is defined as: 35 EECP treatments in a single treatment session, 5 times a week, 60 min each time. The trial flow chart is shown in figure 1 and the procedure and schedule are shown in table 1.

Figure 1 Flow chart. CMD, coronary microcirculation dysfunction; CMR, cardiac magnetic resonance; CTFFR, fractional flow reserve based on coronary CT angiography; EECP, enhanced external counterpulsation; FFR, fractional flow reserve; INOCA, ischaemia with non-obstructive coronary artery; IOCA, ischaemia with obstructive coronary artery; MPRI, Myocardial Perfusion Reserve Index.

Table 1 Schedule of enrolment, interventions and assessments: Standard Protocol Items: Recommendations for Interventional Trials figure

Time point	Screening	Allocation	Baseline	Treatment	Follow-up	
Enrolment	Week 0	Week 0	After baseline	6 months	
Enrolment:						
Eligibility screening	×					
Coronary angiography	×					
Informed consent	×					
Randomisation		×				
Interventions:						
EECP treatment				×		
EECP treatment record				×		
OMT (both groups)				×		
Assessments:						
Demographic characteristics	×		×	×	×	
History and treatment of CAD	×		×	×	×	
CMR (MBF, MPR, MPRI)	×				×	
Echocardiography			×		×	
Carotid ultrasound			×		×	
CPET			×		×	
FMD			×		×	
Ba PWV			×		×	
ABI			×		×	
Urea			×		×	
Liver function tests			×		×	
Renal function tests			×		×	
BP	×	×	×	×	×	
BG	×		×		×	
BL	×		×		×	
AE			×	×	×	
BMR	×		×		×	
CMR	×		×		×	
TRE			×	×	×	
.×, items requiredABI, Ankle-Brachial Index; AE, adverse event records; BGblood glucoseBL, blood lipid; BMR, basic medication records; BP, blood pressure; CADcoronary artery diseaseCMR, combined medication records; CPET, cardiopulmonary exercise test; EECP, enhanced external counterpulsation; FMD, flow-mediated vasodilation; IMR, index of microvascular resistance; MBFmyocardial blood flow MPRmyocardial perfusion reserveMPRIMyocardial Perfusion Reserve Index OMT, optimal medical therapy secondary prevention medication for coronary heart disease; PWV, brachial-ankle pulse wave velocity; TRE, termination of trial evaluation

Participants and recruitment

This trial will be conducted at the Eighth Affiliated Hospital of Sun Yat-sen University in Shenzhen, Guangdong province, China. Patients will be recruited through advertising posters from the inpatient and outpatient department of cardiology. Research assistants will introduce and discuss the trial to potential subjects using Mandarin or the local language. All potential subjects will be given a consent form (online supplemental material 1) and separate information sheets including information on the main aspects of the trial. The potential harms such as muscular soreness would be confirmed before they signed informed consent. Then patients will be able to have an informed discussion with their family and participating consultant. Research assistants will obtain the signed consent form from patients willing to participate in the trial. There will be 10 patients who will be enrolled since 1 May 2024 and we estimate that the enrolment of 110 patients would be ended in June 2026.

Participant eligibility

Inclusion criteria

The inclusion criteria are: (1) Aged 25–70 years old; (2) coronary angiography shows that the stenosis of the main branches of the left and right coronary arteries is less than 50%, or the fractional flow reserve (FFR) of 50–90% of the lesions measured is ≥0.8, without the need for intervention treatment; (3) for post-PCI cases, the distal blood flow after PCI was thrombolysis in myocardial infarction (TIMI3), and the FFR≥0.8 was required for stenosis in the stent, so no interventional treatment was required; (4) there was no history of cardiac muscle disease, and cardiac ultrasound showed no significant thickening (interventricular septal thickness at diastol (IVSD) and left ventricular posterior wall thickness at diastole (LVPWd)≤12 mm) or thinning (IVSD and LVPWd≤8 mm); (5) can accept and cooperate with more than half a year of follow-up; (6) informed consent form approved by the ethics committee.

Exclusion criteria

The exclusion criteria are: (1) coronary angiography with or without coronary stent showed coronary stenosis ≥90%, or coronary stenosis <90% and FFR<0.8; (2) acute coronary syndrome or cardiac insufficiency (New York Heart Association (NYHA) class III-IV); (3) the subject was complicated with myocardial disease; (4) unable to tolerate CMR; (5) subject is allergic to ATP or adenosine; (6) significant aortic regurgitation, aortic aneurysm and dissection aneurysm; (7) coronary artery spasm or severe coronary aneurysm; (8) symptomatic congestive heart failure; (9) heart valve disease, congenital heart disease, cardiomyopathy; (10) cerebral haemorrhage within half a year, haemorrhagic disease or clear bleeding tendency; (11) lower extremity infection, phlebitis, severe varicose veins, deep vein thrombosis; (12) progressive malignancy or serious disease with poor prognosis; (13) systolic blood pressure ≥180 mm Hg, or diastolic blood pressure ≥110 mm Hg when randomly grouped; (14) severe arrhythmia affecting EECP therapy.

Randomisation and allocation concealment

Participants will be randomly allocated to an intervention group (EECP plus OMT) or control group (OMT alone) at a ratio of 1:1. In this study, a completely randomised design method was used and the Interactive Web Response System based on the network was used to set the stratification and corresponding total enrolment according to the requirements of the scheme. Block randomisation will be used to ensure equal numbers of participants are allocated to the two groups. Participants will be advised not to reveal their group allocation to the outcome assessors and statisticians at any time during the trial.

Blinding

Due to the difficulty of blinding participants and cardiologists in trials with EECP, this study was designed as an open-label trial. Independent outcome assessors and statisticians will be blinded to group allocation throughout the entire trial.

Interventions

The investigator will measure the MBF, MPR and MPRI with CMR in patients after coronary angiography. After measurement, participants in both groups will receive OMT and those allocated to the intervention group will also receive EECP treatments. To avoid interference with the trial results, OMT should exclude nitrates and potassium ion channel openers. Subjects who have taken these medications require a drug washout period of 2 weeks before they can begin enrolment.

Standard measurement technique of CMR

CMR examination is performed using a 3.0 T scanner (Prisma, Siemens Healthcare, Germany). The scanning protocol includes cine imaging of the long-axis slices and the short-axis stack covering the left ventricle, the stress and rest first-pass perfusion, as well as the late-gadolinium enhancement. The stress state is induced by 3–5 min intravenous administration of ATP at 140 µg/kg/min, which will be increased to a maximum 210 µg/kg/min if the patient has no symptoms or the heat rate does not increase over 10 beats per minutes, or the systolic blood pressure does not drop over 10 mm Hg within 3 min.27 Both the stress and rest perfusion are acquired at three short-axis slices every heartbeat for a total of 60 beats using the T1-weighted saturation recovery fast gradient-echo sequence. The myocardial blood flow and myocardial perfusion reserve of each segment based on the American Heart Association (AHA) 17-segment model are provided.

EECP add-on treatment in the intervention group

A total of 35 times for EECP treatments, 5 times a week, 60 min each time, will be performed for a period of 7 weeks. The operators who deliver the treatments are qualified practitioners with at least 1 year of EECP experience.

EECP therapy (PSK P-EECP/TI, Chongqing, China) consisted of a treatment bed attached to an air compressor unit that was attached to a computerised control console. The therapy is administered through three pairs of external inflatable cuffs that are applied around the lower legs, upper legs and buttocks. These cuffs continuously inflate and deflate between the resting period of the heartbeat and increase blood returned to the heart. The pressure applied to the cuffs was set at 0.035–0.040 mPa/cm2. Diastolic-to-systolic ratio of 1.2 with the use of the plethysmographic technique is recognised as effective management.

Thediastolic pressure wave (D) to systolic wave (S), (D/S) ratio is susceptible to fluctuations induced by body shaking during EECP. In order to minimise the impact, we will ensure the accuracy and reliability of the measurement by the following procedures: (1) ensure that the skin at the electrode site is smooth and flat, and remove chest hair if necessary; (2) avoid pulling or twisting the lead wires forcefully; (3) instruct the patient to remain quietly at rest during the procedure and avoid significant changes in body position.

Follow-ups

Participants in both groups will receive OMT after the first measurement of IMR until half a year of follow-up. The investigator will record participants’ relevant test results after the first measurement of IMR. To minimise the influence of daily activities on both the intervention and control groups, researchers will monitor and document the participants’ daily activities. This will involve creating WeChat group chats with the subjects and documenting their daily step counts on the WeChat exercise page.

At the end of the follow-up phase, participants will attend the trial clinic for a final assessment, then participants’ involvement in the trial will cease.

Primary outcome

The primary outcome of the study is the change in MPRI measured from baseline to the end of follow-up. MBF, MPR and MPRI will be measured and recorded at baseline (week 0) and end of follow-up (6 months). The threshold obtained from clinical studies is as follows: MPR>2.2, MBF>2.25 mL×g–1×min–1, MPRI>2.0 in the normal population. MPRI<2.0 is considered as coronary microcirculation dysfunction.

Secondary outcomes

The secondary outcomes are to measure the: Biochemical variables and cardiovascular function. Standard biochemical outcomes will be assessed by venous blood sampling. These will include fasting glucose and lipid profile (fasting triglycerides, high-density lipoprotein (HDL), low-density lipoprotein and total cholesterol). Cardiovascular function includes ultrasonography, cardiopulmonary exercise test (CPET).

Statistical analysis plan

Sample size calculation

The primary outcome of the study is to compare the differences in MPRI changes between the two groups. We have done a pretest of invasive IMR with 10 patients, and the results show that EECP can improve CMD in patients with CAD. We conducted this current study (the pretest was not published). Sample size estimation for the study is based on the results of our pretest. The assumption is that adding EECP to OMT is more effective than OMT alone. Accordingly, the EECP group and the OMT group would show a decrease of 4.9 and 0.54 in IMR, respectively, with the SD of 2.5 and 1.05 in each group. Sample size was estimated using software power analysis and sample size V.11.0 (NCSS, LLC, USA), with an alpha error (α=0.05) of a two independent-sample superiority test and 90% power to detect a difference between the two groups. The superiority limit is 1.0. A total sample size of 110 will be required, allowing for equal allocation to the two groups and 10% loss-to-follow-up.

Data collection and management

All data will be collected at the baseline and follow-up assessment by an independent outcome assessor. Participant’s demographic characteristics, medical history and treatment of CAD will be collected at the baseline. CMR test (MBF, MPR, MPRI), echocardiography, carotid ultrasound, biochemical variables, blood pressure, CPET, flow-mediated vasodilation, brachial-ankle pulse wave velocity and Ankle-Brachial Index will be collected at the baseline and end of follow-up (table 1).

The case report form (CRF) including EECP treatment records will be paper-based. All corrections made to the CRFs must be personally signed and dated by the person responsible. Patient identifying information will be replaced with a unique participant ID. All data is linked by the unique participant ID. All data will then be entered into a web-based electronic data capture (ResMan) by an independent investigator who is blinded to group allocation. All data will be double-checked by another researcher. Only the principal researcher and statistician will have access to the final trial data set.

Statistical analysis

Due to the differing pathophysiological mechanisms underlying different types of CMD, there are differences in coronary haemodynamics.12 14 This may affect MPR. Therefore, before data analysis, we excluded CMD related to myocardial disease and iatrogenic CMD and divided the enrolled patients into ischaemia with non-obstructive coronary artery group and ischaemia with obstructive coronary artery group for intergroup comparison.11 28

Demographic, medical history and other baseline characteristics will be analysed for each group. Continuous variables will be expressed as mean±SD if data are normally distributed, otherwise, data will be expressed as the median and IQR (25th and 75th percentile). Categorical variables will be presented using frequencies and percentages.

To compare the changes in primary and secondary outcomes (MPRI, MBF, MPR, CPET, biochemical variables, ultrasonography) between groups from baseline to follow-up. Continuous variables will be compared using the parametric Student’s t-test or the non-parametric Mann-Whitney U test. Categorical variables will be characterised by numbers with percentages and will be compared using the χ2 test or Fisher’s exact test. Superiority will be assumed, if the 95% CI for the difference between the means excludes zero or p values are statistically significantly different at an a priori alpha error of less than 0.05. All analyses will be performed on the intention-to-treat population of participants who have at least one treatment. Missing data will be replaced by multiple imputations or another appropriate approach.

Patient and public involvement

Patient satisfaction and feasibility (in terms of accessibility, compliance, training load and safety) of the EECP programme have been evaluated. Patients were satisfied with the programme, scoring it 95 out of 100; therefore, we did not change the content of the programme and no serious adverse events occurred during the EECP in the pretest. The intensity was defined as a diastolic-to-systolic ratio of 1.2 with the use of the plethysmographic technique. Furthermore, our outcomes are, among others, based on the reasons why patients recommended the programme to other patients, with or without CAD. For example, patients reported that their self-efficacy and physical capacity were improved, so we increased echocardiograph and CPET tests. In this way, the results were taken into account in the further development of the EECP programme and the protocol of this study. The results of this trial will be distributed through various information channels (eg, websites of cardiac patient organisations, social media). Two times a year, we provide a letter about the progress, and the results of the study would be sent to patients who are interested in the end.

Ethics and dissemination

The findings of this study will be disseminated through presentations at local, national and international scientific meetings and in a peer-reviewed journal. The study has received approval from the Ethics Committee of the Eighth Affiliated Hospital, Sun Yat-sen University (ID:2023-045-03) (online supplemental material 2). On completion of the trial and after publication of the primary article, data will be made available in ResMan. Privacy is assured by removing patient identifiers, including names and specific addresses.

Trial status

Protocol V.3.0; 25 January 2024. Recruitment began in 1 May 2024 and is expected to continue until June 2026.

supplementary material

10.1136/bmjopen-2024-086901 online supplemental file 1

10.1136/bmjopen-2024-086901 online supplemental file 2

Review Process File
24 8 2024

Funding: This work was supported by the National Nature Science Foundation of China (82170427), Shenzhen Scientific and Technological Foundation (JCYJ20220530144601003), Shenzhen Key Medical Discipline Construction Fund (ZDXKJF-002), Scientific Research Foundation of Futian District (FTWS2021080, FTWS2022003, FTWS2022054) and Sun Yat-Sen Eighth Affiliated Hospital Clinical Research Program (PY-2023-02). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Prepub: Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-086901).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Patient and public involvement: Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
==== Refs
References

1 Camici PG d’Amati G Rimoldi O Coronary microvascular dysfunction: mechanisms and functional assessment Nat Rev Cardiol 2015 12 48 62 10.1038/nrcardio.2014.160 25311229
2 Corcoran D Young R Adlam D et al Coronary microvascular dysfunction in patients with stable coronary artery disease: the CE-MARC 2 coronary physiology sub-study Int J Cardiol 2018 266 7 14 10.1016/j.ijcard.2018.04.061 29716756
3 Seiler C Stoller M Pitt B et al The human coronary collateral circulation: development and clinical importance Eur Heart J 2013 34 2674 82 10.1093/eurheartj/eht195 23739241
4 Smith SC Jr Benjamin EJ Bonow RO et al AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association J Am Coll Cardiol 2011 58 2432 46 10.1016/j.jacc.2011.10.824 22055990
5 Fuster V Kelly BB Institute of medicine (US) committee on preventing the global epidemic of cardiovascular disease: meeting the challenges in developing countries Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health Washington (DC) National Academies Press (US) 2010
6 Ong P Athanasiadis A Sechtem U Pharmacotherapy for coronary microvascular dysfunction Eur Heart J Cardiovasc Pharmacother 2015 1 65 71 10.1093/ehjcvp/pvu020 27533969
7 Murthy VL Naya M Taqueti VR et al Effects of sex on coronary microvascular dysfunction and cardiac outcomes Circulation 2014 129 2518 27 10.1161/CIRCULATIONAHA.113.008507 24787469
8 Cevik E Tas A Demirtakan ZG et al Intracoronary electrocardiogram detects coronary microvascular dysfunction and ischemia in patients with no obstructive coronary arteries disease Am Heart J 2024 270 62 74 10.1016/j.ahj.2024.01.003 38278503
9 Rahman H Demir OM Khan F et al Physiological stratification of patients with angina due to coronary microvascular dysfunction J Am Coll Cardiol 2020 75 2538 49 10.1016/j.jacc.2020.03.051 32439003
10 Sezer M Kocaaga M Aslanger E et al Bimodal pattern of coronary microvascular involvement in diabetes mellitus J Am Heart Assoc 2016 5 e003995 10.1161/JAHA.116.003995 27930353
11 Sezer M Tas A Demirtakan ZG et al Coronary microcirculation in nonculprit vessel territory in reperfused acute myocardial infarction Microvasc Res 2023 147 104495 10.1016/j.mvr.2023.104495 36739961
12 Hasdemir H Taş A Cevik E et al Primary versus iatrogenic (post-PCI) coronary microvascular dysfunction: a wire-based multimodal comparison Open Heart 2023 10 e002437 10.1136/openhrt-2023-002437 38011991
13 Mihalj M, K Kibel A Stupin A et al Coronary microcirculatory dysfunction in human cardiomyopathies: a pathologic and pathophysiologic review Cardiol Rev 2017 25 165 78 10.1097/CRD.0000000000000140 28574936
14 Crea F Camici PG Bairey Merz CN Coronary microvascular dysfunction: an update Eur Heart J 2014 35 1101 11 10.1093/eurheartj/eht513 24366916
15 Michaels AD Accad M Ports TA et al Left ventricular systolic unloading and augmentation of intracoronary pressure and doppler flow during enhanced external counterpulsation Circulation 2002 106 1237 42 10.1161/01.cir.0000028336.95629.b0 12208799
16 Zhang Y He X Chen X et al Enhanced external counterpulsation inhibits intimal hyperplasia by modifying shear stress–responsive gene expression in hypercholesterolemic pigs Circulation 2007 116 526 34 10.1161/CIRCULATIONAHA.106.647248 17620513
17 Braith RW Conti CR Nichols WW et al Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study Circulation 2010 122 1612 20 10.1161/CIRCULATIONAHA.109.923482 20921442
18 Zhang Y He X Chen X et al Enhanced external counterpulsation inhibits intimal hyperplasia by modifying shear stress responsive gene expression in hypercholesterolemic pigs Circulation 2007 116 526 34 10.1161/CIRCULATIONAHA.106.647248 17620513
19 Kronhaus KD Lawson WE Enhanced external counterpulsation is an effective treatment for syndrome X Int J Cardiol 2009 135 256 7 10.1016/j.ijcard.2008.03.022 18590931
20 Ndrepepa G Tiroch K Fusaro M et al 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction J Am Coll Cardiol 2010 55 2383 9 10.1016/j.jacc.2009.12.054 20488311
21 Fearon F Kobayashi Y Invasive assessment of the coronary microvasculature: the index of microcirculatory resistance Circ Cardiovasc Interv 2017 10 e005361 10.1161/CIRCINTERVENTIONS.117.005361 29222132
22 Melikian N Vercauteren S Fearon WF et al Quantitative assessment of coronary microvascular function in patients with and without epicardial atherosclerosis EuroIntervention 2010 5 939 45 EIJV5I8A158 20542779
23 Luo C Long M Hu X et al Thermodilution-derived coronary microvascular resistance and flow reserve in patients with cardiac syndrome X Circ Cardiovasc Interv 2014 7 43 8 10.1161/CIRCINTERVENTIONS.113.000953 24399243
24 Solberg OG Ragnarsson A Kvarsnes A et al Reference interval for the index of coronary microvascular resistance EuroIntervention 2014 9 1069 75 EIJV9I9A181 10.4244/EIJV9I9A181 24457279
25 Pagonas N Gross CM Li M et al Influence of epicardial stenosis severity and central venous pressure on the index of microcirculatory resistance in a follow-up study EuroIntervention 2014 9 1063 8 EIJV9I9A180 10.4244/EIJV9I9A180 24457278
26 Mayer M Allan T Harkin KL et al Angiographic coronary slow flow is not a valid surrogate for invasively diagnosed coronary microvascular dysfunction JACC: Cardiovascular Interventions 2024 17 920 9 10.1016/j.jcin.2024.02.025 38599696
27 Castañeda-Amado Z Calixto-Aguilar L Loza Munarriz C et al Medical compliance to evidence-based clinical guidelines on secondary prevention of coronary heart disease in a hospital from Lima, Peru: a retrospective study Medwave 2017 17 e6989 10.5867/medwave.2017.05.6989 28665919
28 Chen W Ni M Huang H et al Chinese expert consensus on the diagnosis and treatment of coronary microvascular diseases (2023 Edition) Med Comm 2023 4 e438 10.1002/mco2.438
