Non-obstructive Coronary Artery Disease in Chinese Patients with Angina Diagnosed by Coronary Angiography: A Retrospective Study : Cardiology Discovery

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Non-obstructive Coronary Artery Disease in Chinese Patients with Angina Diagnosed by Coronary Angiography: A Retrospective Study

Peng, Chengfei1; Nie, Shaoping2; Sun, Yingxian3; Chen, Hui4; Yuan, Zuyi5; Gong, Yanjun6; Wang, Xiaozeng1,∗; Han, Yaling1,∗

Editor(s): Fu, Xiaoxia; Xu, Tianyu

Author Information
Cardiology Discovery 1(4):p 223-227, December 2021. | DOI: 10.1097/CD9.0000000000000039
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Abstract

CLINICAL PERSPECTIVE

WHAT IS NEW?

  • This report provides prevalence of non-obstructive coronary artery disease (CAD) in large percutaneous coronary intervention centers in China.
  • This report provides proportion of angina pectoris symptoms in patients with obstructive and non-obstructive CAD in China.

WHAT ARE THE CLINICAL IMPLICATIONS?

  • The results suggest that we should pay more attention to the treatment of non-obstructive CAD.

Introduction

Myocardial ischemia refers to a pathological state in which blood perfusion of the heart is reduced, resulting in reduced oxygen supply and abnormal energy metabolism in the heart, eventually leading to impaired heart function. Coronary heart disease (CHD) is often caused by a build-up of plaque, a waxy substance, inside the lining of larger coronary arteries, which can partially or completely block blood flow in the large arteries of the heart. Consistent with standard definitions of flow-limiting stenosis, non-obstructive coronary artery disease (CAD) is defined as coronary artery stenosis of 20% or greater but less than 50% in the left main coronary artery.[1] As non-obstructive CAD has a long asymptomatic phase, it can easily be overlooked and left untreated and can culminate in acute clinical coronary events similar to those seen with obstructive CAD.[2–4] Recently, it has been reported that patients with non-obstructive CAD are at increased risk of cardiovascular morbidity and death, thus contrasting with the original idea that it was a benign condition.[5] The 2013 European Society of Cardiology Stable Coronary Artery Disease (ESC-SCAD) guidelines proposed non-obstructive CAD as an independent type of CAD. Therefore, the present study aimed to determine the proportion of non-obstructive CAD in the Chinese population who underwent coronary angiography (CAG). The prevalence of non-obstructive CAD in patients who received CAG due to symptoms of angina was determined through a review of consecutive CAG-based reports from 6 large percutaneous coronary intervention (PCI) centers located in China.

Materials and methods

Study population

The inclusion criteria were as follows: Age ≥18 years; typical or atypical symptoms of angina before CAG according to the 2013 ESC-SCAD guidelines, accompanied by ischemia-like electrocardiogram (ECG) findings (eg, ST-segment deviations, T-wave inversions, and Q-waves); patients underwent CAG between January 1, 2013 and December 31, 2015 from the 6 hospitals (General Hospital of Northern Theater Command, Beijing Anzhen Hospital, The First Hospital of China Medical University, Beijing Friendship Hospital, First Affiliated Hospital of Xi’an Jiaotong University, and Peking University First Hospital). The exclusion criteria were as follows: Patients with a history of PCI or coronary artery bypass surgery; patients with a history of myocardial infarction (MI) as evidenced by an ECG report or hospital discharge records; patients with a history of cardiac transplant or heart-valve surgery; patients with acute MI diagnosed by CAG; CAG showing myocardial bridge and coronary stenosis ≥50% during systole; incomplete or missing data in the CAG report; and patients with other diseases, such as critical congenital heart defects, valvular heart disease, cardiomyopathy, or organic heart disease [Figure 1]. A total of 1713 patients were consecutively screened, 1600 of whom were included in the study. The study was approved by the Ethics Committee of the General Hospital of Northern Theatre Command of the Chinese People's Liberation Army (Shenyang, China; Approval No: K(2016)41). Informed written consents were obtained for all participants.

F1
Figure 1:
Flow chart showing the study design. CABG: Coronary artery bypass graft; CAD: Coronary artery disease; CAG: Coronary angiography; PCI: Percutaneous coronary intervention.

Data collection

The demographic and clinical data of the eligible patients were collected from medical records, prescription records, and laboratory reports of patients with symptoms of angina who underwent CAG. Additionally, the data were imported into an electronic case report form (eCRF) in a complete, accurate, clear, and timely manner. Data reported on the eCRF were consistent with the relevant source documents.

Statistical analysis

Statistical analysis was performed using SAS 9.1.3 software (SAS Institute, Cary, North Carolina, USA). Frequency (n) and percentage (%) were calculated for all categorical variables, including missing data; percentages were rounded to 1 decimal place. Univariate and multivariate logistic regression analyses were undertaken to identify relationships between patients with obstructive CAD confirmed by CAG and different clinical characteristics. The dependent variable was obstructive CAD confirmed by CAG (yes/no). Independent variables were age, gender, location of residence, and typical/atypical symptoms of angina. All independent variables with a P value <0.05 in the univariate logistic regression analysis were considered for multivariate logistic regression analysis. Backward elimination was utilized for feature selection.

Results

Demographic characteristics, coronary stenosis, and symptoms of the patients

In the current study, a total of 1713 patients were screened, 1600 of whom were included in the full analysis set. The demographic characteristics of the patients are presented in Table 1. CAG revealed that 300 (18.8%) patients had non-obstructive CAD and 1300 (81.3%) had obstructive CAD. The mean age was (59.6 ± 10.1) years for patients in the non-obstructive CAD group and (62.0 ± 1.0) years for those in the obstructive CAD group. In the non-obstructive CAD group, 50.3% of patients were between 40 and 60 years of age and 48.0% were >60 years old. In the obstructive CAD group, 39.8% of patients were aged between 40 and 60 years and 58.5% were >60 years old. A few patients in both groups were under 40 years of age. In the non-obstructive CAD group, 51.3% of patients were female and 48.7% were male; in the obstructive CAD group, 39.4% were female and 60.6% male. Thus, there were more women than men in the non-obstructive CAD group, whereas the opposite was observed in the obstructive CAD group. Regarding location of residence, among patients residing in North China, 101 (13.3%) had non-obstructive CAD and 659 (86.7%) had obstructive CAD; of the patients residing in Northeast China, 107 (19.8%) had non-obstructive CAD and 433 (80.2%) had obstructive CAD; for patients in Western China, meanwhile, 92 (30.7%) had non-obstructive CAD and 208 (69.3%) had obstructive CAD [Table 1]. Two hundred and three of the 300 patients in the non-obstructive CAD group displayed mild coronary stenosis (20%–49%), while 91 had a normal coronary status. Among the 300 patients in the non-obstructive CAD group, 148 (49.3%) had typical and 152 (50.7%) had atypical symptoms of angina [Table 1]. Of the 1300 patients with obstructive CAD, 801 (61.6%) and 499 (38.4%) had typical and atypical symptoms of angina, respectively. Of the 1300 patients with obstructive CAD, 1-Vessel, 2-Vessel, and 3-Vessel are 460 (35.4%), 379 (29.2%), and 461 (35.5%), respectively. Among the 300 patients in the non-obstructive CAD group, the numbers of patients with 0% stenosis, 1% to 19% stenosis, and 20% to 49% stenosis were 66 (22%), 25 (8.3%), and 203 (67.7%), respectively. Besides, 5 (0.3%) irregular vessel walls were not evaluated and 1 is not shown in the case.

Table 1 - Demographic characteristics and angina symptoms category of the CAD patients.
Variable Non-obstructive CAD (n = 300) Obstructive CAD (n = 1300)
Age (years), mean ± SD 59.6 ± 10.1 62.0 ± 1.0
Age category (years), n (%)
 <40 5 (1.7) 23 (1.8)
 40–60 151 (50.3) 517 (39.8)
 >60 144 (48.0) 760 (58.5)
Gender, n (%)
 Female 154 (51.3) 512 (39.4)
 Male 146 (48.7) 788 (60.6)
Region, n (%)
 Xi’an 92 (30.7) 208 (69.3)
 Beijing 101 (13.3) 659 (86.7)
 Northeast 107 (19.8) 433 (80.2)
Angina symptom, n (%)
 Typical 148 (49.3) 801 (61.6)
 Atypical 152 (50.7) 499 (38.4)
The percentage was calculated using the total number of patients in each region as the denominator.CAD: Coronary artery disease.

Relationships between demographic and clinical characteristics and the onset of non-obstructive CAD confirmed by CAG

We examined the relationships between patients with obstructive CAD/non-obstructive CAD and demographic and clinical characteristics, including cardiovascular risk factors and symptoms of angina, using univariate and multivariate logistic regression analyses. The results showed that hypertension, diabetes mellitus, and typical symptoms of angina were predictors of obstructive CAD, while female gender could predict non-obstructive CAD [Table 2].

Table 2 - Univariate and multivariate logistic regression analysis of risk factors for obstructive CAD.
Univariate analysis Multivariate analysis


Independent variable Category Regression coefficient P OR (95% CI) Regression coefficient P OR (95% CI)
Gender Male 1.00 1.00
Female −0.4846 0.0002 0.62 (0.48–0.79) −0.6053 <0.0001 0.55 (0.42–0.71)
Region Northeast 1.00 1.00
Beijing 0.4777 0.0017 1.61 (1.20–2.17) 0.5675 0.0003 1.76 (1.30–2.40)
Xi’an −0.5822 0.0004 0.56 (0.40–0.77) −0.6656 0.0001 0.51 (0.37–0.72)
Hypertension No/Unknown 1.00 1.00
Yes 0.5024 0.0001 1.65 (1.28–2.13) 0.4643 0.0007 1.59 (1.22–2.08)
Diabetes mellitus No/Unknown 1.00 1.00
Yes 0.5988 0.0003 1.82 (1.31–2.52) 0.4822 0.0051 1.62 (1.16–2.27)
Angina symptoms Atypical 1.00 1.00
Typical 0.5000 0.0001 1.65 (1.28–2.12) 0.7756 <0.0001 2.17 (1.65–2.85)
The dependent variable was obstructive CAD confirmed by coronary angiography (Yes/No).“–” indicates the data is not available.CAD: Coronary artery disease; CI: Confidence interval; OR: Odds ratio.

Discussion

CAG has been the main method of diagnosing CHD for nearly 60 years and is the “gold standard” for CHD diagnosis. In general, non-obstructive CAD is defined as coronary artery stenosis of 20% or greater but less than 50% in the left main coronary artery.[6] Although non-obstructive CAD is relatively common and occurs in 10% to 25% of patients undergoing CAG,[7] its pathogenesis has remained elusive. It has been proposed to be related to hypertension, aortic stenosis, anemia, type 2 MI, coronary malformations and shunts, drug effects, heart failure or cardiogenic shock, coronary spasm, and myocardial diseases (eg, myocarditis and hypertrophic cardiomyopathy), as well as other factors.[8] Moreover, most patients with non-obstructive CAD have endothelial dysfunction or microcirculation disorders and are at a higher risk of major cardiovascular events than healthy individuals. Importantly, the present study provided data about the proportion of patients with non-obstructive CAD who were admitted to PCI centers in China.

Typical angina is defined as substernal chest pain precipitated by physical exertion or emotional stress and relieved with rest or nitroglycerin. Women and elderly patients are typically more prone to displaying atypical symptoms at rest and during stress, often in the setting of non-obstructive CAD. To our knowledge, typical angina symptoms are more frequent in individuals with obstructive CAD than in those with non-obstructive CAD, explaining why non-obstructive CAD has often been regarded as “insignificant” in the medical literature.[9] Patients with non-obstructive CAD are reportedly associated with a higher risk of cardiovascular events compared with individuals with near-normal coronary arteries.[10] Consequently, further attention should be paid to patients with non-obstructive CAD to better understand the risk factors for major adverse cardiovascular events as well as the potential therapeutic implications.[11] Moreover, a degree of coronary stenosis may not be related to symptoms of angina.

The incidence of non-obstructive CAD is higher in women than in men; additionally, the symptoms of persistent chest pain are more severe and the mortality rate is higher among women.[12–15] The Women's Ischemia Syndrome Evaluation cohort study reported that female patients with chest pain and non-obstructive CAD were at an increased risk of death, and stated that female gender may be a risk factor despite atypical symptoms and non-obstructive disease.[16] In addition, data published by the Women's Health Initiative suggested that women with non-specific chest pain have a 2-fold greater risk than men for non-fatal MI.[17] One possible reason may be that, compared with men, women have a lower degree of interstitial fibrosis, a lower incidence of plaque rupture, and worse physical and mental health status.[4] Consistent with these observations, the results of the current study indicated that female gender may be a significant risk factor for non-obstructive CAD.

Compared with individuals with normal coronary arteries, patients with non-obstructive CAD are at a significantly higher risk of mortality,[18] stressing the importance of early disease detection and treatment. Hence, further multicenter research on the diagnosis and treatment of non-obstructive CAD is warranted to better guide treatment and improve the prognosis of affected patients.

Study limitations

The present study had several limitations. First, selection bias was inevitable owing to the retrospective nature of the study. Secondly, because of limited information on cardiovascular risk factors, only individual risk factors were analyzed. Thirdly, most data pertaining to CTA and ECG were unknown/not acquired in both the obstructive and non-obstructive CAD groups, meaning that no diagnostic consistency could be identified between CAG and CTA or ECG. Finally, the clinical data were limited to the degree of stenosis in coronary arteries and no data relating to lesion characteristics were collected.

Conclusions

The prevalence of non-obstructive CAD was found to be approximately 20% in the Chinese population with CHD. Additionally, our data indicated that typical symptoms of angina, hypertension, and diabetes mellitus could be predictors of obstructive CAD, whereas female gender was noted as a risk factor for non-obstructive CAD.

Acknowledgments

The authors thank David P. Figgitt for providing editorial assistance. The authors thank Dr. Ke Zheng and Dr. Shuangshuang Dong at Chugai Pharma China Co., Ltd for revising the manuscript.

Funding

None.

Conflicts of Interest

None.

Editor note: Yaling Han is the Editor-in-Chief of Cardiology Discovery. Zuyi Yaun is a member of the editorial board of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of these editors and their research groups.

References

[1]. Ouellette ML, Löffler AI, Beller GA, et al. Clinical characteristics, sex differences, and outcomes in patients with normal or near-normal coronary arteries, non-obstructive or obstructive coronary artery disease. J Am Heart Assoc 2018;7(10):e007965. doi: 10.1161/JAHA.117.007965.
[2]. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34(38):2949–3003. doi: 10.1093/eurheartj/eht296.
[3]. Maddox TM, Stanislawski MA, Grunwald GK, et al. Nonobstructive coronary artery disease and risk of myocardial infarction. JAMA 2014;312(17):1754–1763. doi: 10.1001/jama.2014.14681.
[4]. Pepine CJ, Ferdinand KC, Shaw LJ, et al. Emergence of nonobstructive coronary artery disease: a woman's problem and need for change in definition on angiography. J Am Coll Cardiol 2015;66(17):1918–1933. doi: 10.1016/j.jacc.2015.08.876.
[5]. Herscovici R, Sedlak T, Wei J, et al. Ischemia and no obstructive coronary artery disease (INOCA): what is the risk? J Am Heart Assoc 2018;7(17):e008868. doi: 10.1161/JAHA.118.008868.
[6]. Sandhu A, Maddox TM. Is non-obstructive coronary artery disease clinically important? Future Cardiol 2014;10(6):673–675. doi: 10.2217/fca.14.69.
[7]. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med 2010;362(10):886–895. doi: 10.1056/NEJMoa0907272.
[8]. Bairey Merz CN, Pepine CJ, Walsh MN, et al. Ischemia and no obstructive coronary artery disease (INOCA): developing evidence-based therapies and research agenda for the next decade. Circulation 2017;135(11):1075–1092. doi: 10.1161/CIRCULATIONAHA.116.024534.
[9]. Hwang IC, Lee H, Yoon YE, et al. Risk stratification of non-obstructive coronary artery disease for guidance of preventive medical therapy. Atherosclerosis 2019;290:66–73. doi: 10.1016/j.atherosclerosis.2019.09.018.
[10]. Emami H, Takx R, Mayrhofer T, et al. Nonobstructive coronary artery disease by coronary CT angiography improves risk stratification and allocation of statin therapy. JACC Cardiovasc Imaging 2017;10(9):1031–1038. doi: 10.1016/j.jcmg.2016.10.022.
[11]. Gu J, Yin ZF, Pan JA, et al. Visit-to-visit variability in low-density lipoprotein cholesterol is associated with adverse events in non-obstructive coronary artery disease. Anatol J Cardiol 2019;22(3):117–124. doi: 10.14744/AnatolJCardiol.2019.26428.
[12]. Mahajan AM, Dugan KE, Reynolds HR. Letter by Mahajan et al regarding article, “Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries”. Circulation 2015;132(19):e231. doi: 10.1161/CIRCULATIONAHA.115.016773.
[13]. Mommersteeg PM, Arts L, Zijlstra W, et al. Impaired health status, psychological distress, and personality in women and men with nonobstructive coronary artery disease: sex and gender differences: the TWIST (Tweesteden Mild Stenosis) study. Circ Cardiovasc Qual Outcomes 2017;10(2):e003387. doi: 10.1161/CIRCOUTCOMES.116.003387.
[14]. Campisi R, Marengo FD. Coronary microvascular dysfunction in women with nonobstructive ischemic heart disease as assessed by positron emission tomography. Cardiovasc Diagn Ther 2017;7(2):196–205. doi: 10.21037/cdt.2017.04.08.
[15]. Mauricio R, Srichai MB, Axel L, et al. Stress cardiac MRI in women with myocardial infarction and nonobstructive coronary artery disease. Clin Cardiol 2016;39(10):596–602. doi: 10.1002/clc.22571.
[16]. Robinson JG, Wallace R, Limacher M, et al. Cardiovascular risk in women with non-specific chest pain (from the Women's Health Initiative Hormone Trials). Am J Cardiol 2008;102(6):693–699. doi: 10.1016/j.amjcard.2007.12.044.
[17]. Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med 2009;169(9):843–850. doi: 10.1001/archinternmed.2009.50.
[18]. Ford TJ, Rocchiccioli P, Good R, et al. Systemic microvascular dysfunction in microvascular and vasospastic angina. Eur Heart J 2018;39(46):4086–4097. doi: 10.1093/eurheartj/ehy529.
Keywords:

Non-obstructive coronary artery disease; Percutaneous coronary intervention; Coronary angiography; Coronary stenosis

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