Sex differences in coronary angiographic findings in patients with stable chest pain: analysis of data from the KoRean wOmen’S chest pain rEgistry (KoROSE)

Background: Focused evaluations on potential sex differences in the angiographic findings of the coronary arter‐ ies are scarce. This study was performed to compare the angiographic extent and localization of coronary stenosis between men and women. Methods: A total of 2348 patients (mean age 62.5 years and 60% women) with stable chest pain undergoing inva‐ sive coronary angiography (CAG) were recruited from the database of the nation‐wide chest pain registry. Obstructive coronary artery disease (CAD) was defined as ≥ 50% stenosis of the left main coronary artery and/or ≥ 70% stenosis of any other epicardial coronary arteries. Results: Although women were older than men (64.4 ± 10.3 vs. 59.5 ± 11.4 years, P < 0.001), men had worse risk profiles including high blood pressure, more frequent smoking and elevated triglyceride and C‐reactive protein. The prevalence of obstructive CAD was significantly higher in men than in women (37.0% vs. 28.4%, P < 0.001). Men had a higher prevalence of LM disease (10.3% vs. 3.5%, P < 0.001) and three‐vessel disease (16.1% vs. 9.5%, P = 0.007) compared to women. In multiple binary logistic regression analysis, the risk of men having LM disease or three‐vessel disease was 7.4 (95% confidence interval 3.48–15.97; P < 0.001) and 2.7 (95% confidence interval 1.57–4.64; P < 0.001) times that of women, respectively, even after controlling for potential confounders. Conclusions: In patients with chest pain undergoing invasive CAG, men had higher obstructive CAD prevalence and more high‐risk angiographic findings such as LM disease or three‐vessel disease.


Introduction
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. With improvement in diagnostic and therapeutic tools, the prognosis of patients with CAD has been much improved. However, the prevalence of CAD is still high, and the complications associated with CAD are the number one cause of human death [1][2][3] Therefore, in order to improve patients' prognosis and reduce the enormous medical cost, it is important to find CAD patients earlier and perform customized treatment. For rapid CAD diagnosis and effective treatment, understanding pathophysiology underlying in CAD development should be the basis. Human efforts to understand sex differences in the cardiovascular field, and to apply them in clinical practice have continued [4][5][6]. In CAD, sex differences in several points such as clinical presentation and prognosis are relatively well evaluated. However, little is known regarding potential sex differences in the angiographic findings of coronary arteries. Since invasive coronary angiography (CAG) is the reference standard for CAD diagnosis, understanding sex difference in invasive CAG findings is valuable for the management of patients with CAD. Therefore, this study was performed to compare the extent and localization of coronary stenosis on invasive CAG between men and women.

Study patients
We analyzed data from the nation-wide prospective registry database, the KoRean wOmen'S chest pain rEgistry (KoROSE), which was constructed to investigate clinical characteristics and outcomes of Korean women with suspected CAD in a stable state. For comparison, men were also registered in the registry. Many research articles using this registry data have already been published [7][8][9]. Collection of this registry data began in February 2011, and patient registration is still ongoing. Currently, 22 cardiovascular centers in Korea are participating in this registry. The patients enrolled were Korean adult men and women over the age of 20 years who complained of chest pain and underwent invasive CAG because of suspected CAD. Because study enrollment was based on relatively stable patients who visited the outpatient clinic, patients with acute coronary syndrome were excluded. In most cases, tests such as treadmill exercise test, coronary computed tomography angiography, single-photon emission computed tomography, and dobutamine stress echocardiography were performed according to the patient's renal function and functional capacity. Invasive CAG was performed according to these results of non-invasive tests. After invasive CAG, attending physician explained the study protocol and enrolled patients who agreed to participate in the registry. The Institutional Review Board of Boramae Medical Center (Seoul, South Korea) approved registry registration, and the use of the registered data for research purposes. All patients were given written consent for registry registration.

Data collection
Clinical data were obtained at the time of admission for invasive CAG. Body mass index was the body weight (kg) divided by the height squared (m 2 ). Body mass index ≥ 25 kg/m 2 was considered obese [10]. Waist circumference was measured with a tape measure. A tape measure was placed in the middle of the lowest position of the ribs and the highest position of the pelvis during expiration. Systolic/diastolic blood pressure and heart rate were measured by a trained nurse using an automatic oscillometric device. Hypertension was defined on the basis of (1) previous diagnosis of hypertension by a physician; (2) current anti-hypertensive medications, or (3) systolic/ diastolic blood pressure ≥ 140/90 mmHg in repeated measurements. Diabetes mellitus was defined on the basis of (1) previous diagnosis of diabetes mellitus by a physician; (2) current anti-diabetic medications, or (3) fasting blood glucose level ≥ 126 mg/dL in repeated tests. Dyslipidemia was defined on the basis of (1) previous diagnosis of dyslipidemia by a physician; (2) current antidyslipidemic medications, or (3) low-density lipoprotein cholesterol ≥ 160 mg/dL. A person who smoked regularly within the last 12 months was defined as a smoker. After overnight fasting, blood levels of the following laboratory parameters were obtained: white blood cell count, hemoglobin, creatinine, glucose, glycated hemoglobin, total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol (HDL-C), triglyceride, and C-reactive protein. Estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease (MDRD) Study equation. Information on concomitant cardiovascular medications including antiplatelets, calcium channel blocker, beta-blocker, reninangiotensin system blocker, and statin was also obtained.

Invasive CAG
Invasive CAG was performed using a radial or femoral artery in accordance with current guidelines [11,12]. All management strategies for CAD, including coronary revascularization, were chosen at the discretion of the attending physician. An obstructive CAD was defined as any ≥ 50% stenosis of the left main coronary artery, ≥ 70% stenosis of any other epicardial coronary arteries, or both. The extent of CAD was classified as one-, two-, or threevessel disease. Significant left main stenosis (≥ 50%) was considered as two-vessel diseases. The coronary artery was divided into 17 segments, and we obtained information on the maximum stenosis of each segment [13,14]. Left main disease or three-vessel disease were considered as a high-risk finding.

Statistical analysis
Continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as n (%). Student's t test was used to compare continuous variables and the Chi-square test was used to compare categorical variables between two groups. Binary logistic regression analyses were performed to investigate independent associations between sex and angiographic findings. During multivariable analyses the following potential confounders were controlled: age, body mass index, hypertension, diabetes mellitus, dyslipidemia, smoking and renal function. A P value of < 0.05 was considered statistically significant. All statistical analyses were conducted using SPSS version 21.0 (IBM Crop., Armonk, NY, USA).

Clinical characteristics of the study patients
Nine hundred and forty-one men and 1407 women (59.9%) were analyzed in this study. Comparisons of clinical characteristics between men and women are demonstrated in Table 1. Women were older than men (64.4 ± 10.3 vs. 59.5 ± 11.4 years, P < 0.001). Mean body mass index was similar between men and women, but waist circumference was greater in men than in women. Both systolic and diastolic blood pressures were higher in men than in women. Among traditional cardiovascular risk factors, the proportions of smokers and obesity were higher in men than in women. In laboratory findings, women had lower blood hemoglobin, triglycerides and C-reactive protein levels as well as higher total cholesterol and high-density lipoprotein cholesterol levels than men. Among cardiovascular medications, beta-blockers and statin were more frequently prescribed in women than in men.
About one-third of patients (31.8%) had obstructive CAD. Comparisons of clinical characteristics between patients with and without obstructive CAD in men and women are shown in Table 2. Patients with obstructive CAD were older in both men (62.6 ± 10.2 vs. 57.0 ± 11.6 years, P < 0.001) and women (68.1 ± 9.1 vs. 62.4 ± 10.3 years, P < 0.001). Patients with obstructive CAD had more cardiovascular risk factors such as hypertension, diabetes and smoking than those without in both sexes. Laboratory findings also showed worse profiles including higher levels of white blood cell count, fasting glucose and lowdensity lipoprotein cholesterol as well as lower levels of hemoglobin, glomerular filtration rate, and high-density lipoprotein cholesterol in patients with obstructive CAD than in those without in both men and women. Antiplatelets, beta-blocker, renin-angiotensin system blocker and statin were more frequently prescribed to patients with obstructive CAD than those without in both sexes.

Sex differences in angiographic findings
Angiographic findings of men and women in the total study population are demonstrated in Table 3. The prevalence of obstructive CAD was significantly higher in men than in women (37.0% vs. 28.4%, P < 0.001) (Fig. 1). Twoor three-vessel disease or LM disease was more prevalent in men than in women (16.0% vs. 11.2%, P ≤ 0.001). In addition to the three major epicardial coronary arteries, significant stenosis of the branch arteries was also prevalent in men, compared to women. LM disease with proximal LAD significant stenosis or LM with proximal significant stenosis of at least one of three major epicardial coronary arteries were more frequently observed in men than in women. Even when we considered only patients with obstructive CAD, men had more threevessel disease or LM disease than in women (P < 0.05 for each) (Fig. 2). Significant stenosis of the RCA and branched coronary arteries were more prevalent in men than in women (  (Table 5). Besides male sex, old age was associated with LM disease, and old age, hypertension and diabetes mellitus were associated with three-vessel disease even after controlling for potential confounders (Additional file 1: Table S1).

Discussion
Using a nation-wide registry database, we attempted to find out the sex differences of invasive CAG findings in patients who had chest pain in a stable state. Our results showed several important findings: (1) despite younger age, men more frequently had risk factors for cardiovascular disease than women, which resulted in a higher obstructive CAD prevalence in men; (2) men more frequently had LM disease or three-vessel disease than women, and (3) these sex differences persisted even after controlling for important clinical covariates.

Previous similar studies
The summary of previous studies investigating sex differences in CAG findings is demonstrated in Table 6. Numerous studies have reported that angiographically documented CAD is more severe in men than in women [15][16][17][18][19][20][21][22]. These findings are concordant with ours showing that compared to women, men had more burden of obstructive CAD. However, our study has several differences and strengths compared to the previous studies. Most of the existing studies were conducted in the Western countries. If we consider ethnic differences in cardiovascular disease [23], our study of Koreans is valuable. Our study provides an additional result that in Asians like Westerners, men more frequently have CAD than women. Considering very low proportion of women in previous studies, higher proportion of women was another strength of this study. In addition, the primary research goal in most studies was to determine if there were sex differences in subsequent management and clinical outcomes following CAG. Therefore, only sex differences in CAG findings were demonstrated briefly, and more specific analysis on lesion location were not shown in most studies. Only one study focused primarily on sex differences in angiographic findings, and showed specific CAD locations [15]. Moreover, only a few studies have performed multivariable analysis to demonstrate whether sex is an independent factor associated with CAD severity [18,22]. In our study, the primary aim was to determine the differences in CAG findings between men and women. In addition, we analyzed the detailed lesion location of CAD, and also performed multivariable analysis to evaluate the effect of sex on CAD severity after adjustment for confounding factors. Although not the majority opinion, some other studies have shown that there is no sex difference in the extent and localization of coronary angiographic lesions [24][25][26][27]. Further studies are needed to reach a firmer conclusion on sex difference in the severity and extent of angiographic CAD.

Underlying mechanisms
In our study, higher blood pressure, greater proportions of smokers and obese patients, and worse lipid profiles could explain more significant and extensive CAD in men than in women. Although women were older than men, they less frequently had cardiovascular risk factors than men. Indeed, in addition to old age and male   sex, traditional cardiovascular risk factors including hypertension and diabetes mellitus were significantly associated with the presence of three-vessel disease in our multivariable analysis. However, old age and male sex were only factors associated with LM disease, and the risk of male sex itself was higher than age. It can be assumed that male sex itself had a great influence on LM disease, and cardiovascular risk factors, which have a high prevalence in men, contributed to the development of three-vessel disease. Cardiovascular system protection by female sex hormone may be a commonly proposed reason for lower risk profiles in women [28]. In our study, women had higher HDL-C than men, and those with CAD had significantly lower HDL-C than those without CAD. This result suggests that HDL-C probably played an important role in CAD development and progression [29], and induced sex differences.

Clinical implications
Our results of Asian patients did not differ significantly from the main finding of the existing Western studies indicating that men had a more severe angiographically documented CAD than women. We should always be aware of the high risk of male sex itself when treating patients. In other words, since women generally develop less coronary artery pathology compared to men at the same age, women with CAD represent a vulnerable subgroup and need special attention. In addition, given that men have more severe and extensive CAD, one can expect that women have less symptoms and better prognosis; however, previous studies have shown opposite findings [30]. As ischemia and ischemia-like symptoms are not solely related to the severity of atherosclerosis, we should not overlook the fact that coronary microvascular dysfunction or coronary spasm are a more common cause of stable ischemic heart disease in women [5,6,26].

Study limitations
We acknowledge several limitations of the present study. First, coronary stenosis was visually evaluated in our study. If we had performed quantitative coronary analysis, more accurate data could have been obtained. Second, in our study, no intravascular evaluation or computed tomographic examination was performed, so we could not analyze differences between men and women in coronary plaque properties [4,5,31]. Third, the hemodynamical significance of CAD was not evaluated in our study. Lastly, since all subjects of our study were Koreans and patients with stable chest pain, it would be difficult to apply our results directly to other ethnic groups or patients with acute coronary syndrome.

Perspectives and significance
Among Korean patients with chest pain in a stable state, men had more extensive and severe angiographic CAD compared to women even at younger ages. More critical CAD including LM disease and three-vessel disease were also more prevalent in men. We need to understand this observed sex differences, which could apply in the clinical evaluation and management of patients with suspected CAD. Specifically, since men are more likely to have severe CAD, it is desirable to recommend more active tests and intensified management to men with suspected CAD.