Differences and Interactions between Risk Factors for Coronary Spasm and Atherosclerosis Smoking, Aging, Inflammation, and Blood Pressure

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1 ORIGINAL ARTICLE Differences and Interactions between Risk Factors for Coronary Spasm and Atherosclerosis Smoking, Aging, Inflammation, and Blood Pressure Sumio Morita 1,2, Yuji Mizuno 1, Eisaku Harada 1, Hitoshi Nakagawa 3, Yoshinobu Morikawa 3, Yoshihiko Saito 3,DaisukeKatoh 4, Yusuke Kashiwagi 4, Michihiro Yoshimura 4, Toyoaki Murohara 2 and Hirofumi Yasue 1 Abstract Objective Coronary spasm as well as atherosclerosis plays an important role in the pathogenesis of coronary heart disease. However, the relationship between coronary spasm and atherosclerosis is not well known. The purpose of the present study was to examine the differences and interactions between risk factors for coronary spasm and atherosclerosis and thereby explore the pathogenesis of coronary spasm. Methods The study subjects consisted of 938 patients with chest discomfort (522 men and 416 women, mean age 65.2±11.0) who underwent intracoronary-acetylcholine provocation tests for coronary spasm. Coronary risk factors, including age, gender, body mass index, blood pressure, high-sensitivity C-reactive protein (hscrp), white blood cells, glucose, lipid profiles, and other laboratory chemistries were examined. Results Four hundred and ninety-six patients (315 men and 181 women, mean age: 65.1±11.4) were diagnosed with coronary spastic angina (CSA), while the remaining 442 patients (207 men and 235 women, mean age: 65.3±10.7) were diagnosed with non-csa. A multiple logistic regression analysis revealed men, smoking, hscrp, and low diastolic blood pressure (DBP) to be predictors (p=0.001, p=0.009, p=0.034, and p=0.041, respectively) for CSA, while age, diabetes mellitus, low high-density lipoprotein-cholesterol, systolic blood pressure (SBP), uric acid and male gender were found to be predictors (p<0.001, p<0.001, p< 0.001, p=0.002, p=0.006 and p=0.029, respectively) for atherosclerosis. Conclusion Predictors for coronary spasm were smoking, hscrp and low DBP, whereas those for atherosclerosis were age, diabetes mellitus, high SBP, and uric acid in that order. These findings suggest that the pathogenesis of coronary spasm differs from that of atherosclerosis. Key words: aging, chronic inflammation, coronary spastic angina, blood pressure, smoking () () Introduction Coronary spasm as well as coronary atherosclerosis plays an important role in the pathogenesis of coronary heart disease (CHD) (1-3). However, the relationship between coronary spasm and coronary atherosclerosis is not well known. We have shown that the endothelial nitric oxide (NO) activity is deficient, oxidative stress is increased, and the endothelial function is impaired in the coronary arteries of patients with coronary spastic angina (CSA) or angina pectoris caused by coronary spasm (1, 4). Impairment of the endothelial function also plays a central role in the initiation and progression of coronary atherosclerosis (5). Division of Cardiovascular Medicine, Kumamoto Kinoh Hospital, Kumamoto Aging Research Institute, Japan, Department of Cardiology, Nagoya University Graduate School of Medicine, Japan, First Department of Internal Medicine, Nara Medical University, Japan and Division of Cardiology, Department of Internal Medicine, The Jikei University School of Medicine, Japan Received for publication February 15, 2014; Accepted for publication April 29, 2014 Correspondence to Dr. Hirofumi Yasue, yasue@juryo.or.jp 2663

2 Previous studies have shown that smoking alone is a significant risk factor for coronary spasm among conventional coronary risk factors (1, 4, 6-8). However, these studies were performed decades ago, when the smoking rate was very high and the population was relatively young and sensitive markers for inflammation such as high sensitivity C- creative protein (hscrp) were not yet clinically available in Japan (6-8). The smoking rate has markedly decreased in association with life style changes, and the population has rapidly aged in recent years. Furthermore, sensitive markers for inflammation such as hscrp are now routinely used in clinical practice. Accordingly, risk factors for coronary spasm may also have changed and/or remain to be newly detected at the present time. There is increasing evidence that aging involves a chronic low-grade inflammation (9-11). In the present study, we examined the differences and interactions between risk factors for coronary spasm and atherosclerosis and thereby sought to elucidate the pathogenesis of CSA. Study subjects Materials and Methods The study subjects consisted of 938 consecutive Japanese patients (522 men and 416 women, mean age: 65.2±11.0) who were admitted to our institution under suspicion of CSA due to episodes of chest discomfort occurring mostly at rest between November 2002 and May 2013 and in whom coronary angiography and intracoronary injection of acetylcholine were performed. Patients with acute myocardial infarction, atherosclerotic stenosis of 90%, left main trunk lesions, uncontrolled arrhythmias, heart failure, resting hypertension of >180/110 mmhg, acute inflammatory disease, malignant tumors, hepatic or renal insufficiency and other severe conditions were excluded from the study. In addition, patients with an elevated white blood cell (WBC) count (>9,000/μL) and/or hscrp level (>10 mg/l) were excluded to avoid the possible confounding effects of occult infection or other systemic inflammatory diseases (12). Vasoactive drugs, including Ca-antagonists, nitrates, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers and statins, were withdrawn for at least five days before the study, except sublingual nitroglycerin, which was withdrawn within eight hours of the study. None of the patients was on hormonal replacement therapy. The assessed risk factors included hypertension, history of smoking, plasma levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride, high-density lipoprotein (HDL)-cholesterol, glucose, uric acid, diabetes mellitus, body mass index and previous history of cardiovascular disease. The patients were divided into current smokers (within the last 6 months) or nonsmokers. Nonsmokers included both previous smokers and never-smokers. Blood pressure was measured in the supine position after more than five minutes of rest. Hypertension was defined as a systolic blood pressure (SBP) of >140 mmhg, diastolic blood pressure (DBP) of >90 mmhg or the use of antihypertensive medications. The study was approved by the ethics committee of our institution and written informed consent was obtained from each patient. Angiographic documentation of coronary spasm Coronary spasm was defined as a transient total, or subtotal occlusion and/or severe diffuse constriction of an epicardial coronary artery concomitant with ischemic changes (ST segment elevation >2 mm or depression >1 mm and/or negative U waves on more than two contiguous leads) on electrocardiogram (ECG) and chest discomfort. Angina pectoris induced by coronary spasm was defined as CSA. Coronary spasm was induced by the intracoronary injection of acetylcholine (ACh) (Daiichi-Sankyo Co., Tokyo, Japan) following diagnostic catheterization in the morning. ACh dilates human coronary arteries by stimulating endothelial nitric oxide, but it constricts those with endothelial dysfunction (13, 14). The details of this method have been previously reported (13). Briefly, ACh was infused in incremental doses of 20, 50 and 100 μg into the left coronary artery followed by 20 and 50 μg into the right coronary artery under the continuous monitoring of ECG and blood pressure. The coronary spasm induced by this method usually disappeared spontaneously within 1-2 minutes, and both the right and left coronary arteries were examined separately unless severe spasm occurred in the left coronary artery. At the end of the test, nitroglycerin (0.1 mg) was injected into the coronary artery and angiography was again performed. Significant atherosclerotic coronary stenosis was defined as a luminal diameter of >50% and atherosclerotic coronary artery disease was divided into one-vessel, two-vessel and threevessel disease. Blood chemistry measurements Blood samples were obtained via venipuncture with the subject in the fasting state 1-2 days before coronary angiography. The serum hscrp level was measured in duplicate using an automated immunoturbidimetric assay with the Synchron LX20 Prosystem (Beckman Coulter, Miami, USA) (15). The lower limit of this assay was 0.2 mg/l with intra- and inter-assay coefficients of variation of <5.0% at 0.25 mg/l of CRP. The total and differential WBC counts were assessed according to the Coulter principle using the Beckman Coulter UniCel DxH800 and Coulter LH 750 (Beckman Coulter). Other biochemical analyses were performed using standard laboratory procedures. Statistical analysis Data were expressed as mean ± SD or median (25th, 75th percentile) for continuous variables and differences within the group were evaluated using the unpaired t test or Mann- Whitney rank sum test. For discrete variables, the data were expressed as counts and percentages and analyzed with the Chi square test. The correlation between the variables was 2664

3 Table 1. Comparison of Clinical Characteristics between CSA and Non-CSA Patients CSA (n=496) Non-CSA (n=442) p Normal range Age, years 65.1± ± Men, n (%) 315 (63.5) 207 (46.8) <0.001 Body Mass Index, kg/m (22.3, 26.2) 24.1 (22.3, 26.2) Hypertension, n (%) 290 (58.5) 267 (60.4) Systolic hypertension, n (%) 259 (54.6) 228 (54.3) Diastolic hypertension, n (%) 74 (15.6) 87 (20.7) SBP 140 (118, 149) 140 (120, 150) <140 DBP 76 (64, 84) 78 (67, 86) <90 PP 58 (48, 70) 59 (46, 70) Diabetes mellitus, n (%) 143 (28.8) 111 (25.1) Smoker, n (%) 160 (32.3) 85 (19.2) <0.001 Total WBC, 10 9 /L 6.0 (4.9, 7.1) 5.7 (4.8, 6.7) Basocy 33 (24, 44) 31 (23, 44) Eosinocyte, / L 147 (97, 235) 135 (81, 225) Neutrophil, / 3,375 (2,651, 4,287) 3,204 (2,509, 4,003) Lymphocyte, 1,801 (1,442, 2,286) 1,740 (1,401, 2,143) Monocyte, / L 447 (360, 547) 421 (331, 519) hscrp, mg/l 0.9 (0.3, 2.6) 0.7 (0.3, 1.8) Total protein, g/l 67 (64, 71) 67 (64, 71) Albumin, g/l 40 (37, 41) 40 (37, 42) A/G 1.43± ± Total cholesterol, mmol/l 5.1 (4.6, 5.7) 5.1 (4.5, 5.7) HDL-cholesterol, mmol/l 1.4 (1.2, 1.7) 1.5 (1.2, 1.8) LDL-cholesterol, mmol/l 2.9 (2.4, 3.4) 2.9 (2.4, 3.4) Triglyceride, mmol/l 1.4 (1.0, 2.0) 1.3 (0.9, 1.8) Fast plasma glucose, mmol/l 5.3 (5.1, 5.7) 5.3 (5.1, 5.6) Uric acid, mol/l 315 (262, 381) 309 (256, 363) egfr, ml/min/1.73m (57.1, 79.4) 69.5 (57.3, 78.3) Atherosclerotic stenosis, n (%) 161 (32.5) 81 (18.3) <0.001 Values are n (%), median (25%, 75%), and mean ± SD. A/G: albumin globulin ratio, CSA: coronary spastic angina, DBP: diastolic blood pressure, egfr: estimated glomerular filtration rate, HDL-cholesterol: high density lipoprotein cholesterol, hscrp: high sensitivity C-reactive protein, LDL-cholesterol: low density lipoprotein cholesterol, PP: pulse pressure, SBP: systolic blood pressure, WBC: white blood cell assessed using the Spearman rank correlation coefficient. Variables that were not statistically significant (p>0.05) were excluded from further analyses. A multiple logistic regression analysis was performed to determine predictors of CSA and coronary atherosclerotic stenosis. Predictor variables were included based on theoretical grounds, clinical implications, collinearity, and the results of a bivariate analysis. A two-tailed p value of <0.05 was considered to be statistically significant. The analyses were carried our using the SPSS software package (IBM SPSS Statistics for Windows, Version 19.0., IBM Corp., Armonk, USA). Results The clinical characteristics of the CSA patients in comparison with those of the non-csa patients are shown in Table 1. The values for gender (male), smoking, total WBC count, plasma levels of hscrp, triglyceride and uric acid, and prevalence of coronary atherosclerotic stenosis were higher (p<0.001, p<0.001, p=0.002, p=0.006, p=0.009, p= 0.012, p<0.001, respectively), while those for and plasma levels of HDL-cholesterol, DBP and prevalence of diastolic hypertension were lower (p=0.002, p=0.043, p=0.048, respectively) in the CSA group than in the non-csa group. Relationship between CSA and age, inflammatory markers, and smoking status The number of CSA patients and levels of monocyte and hscrp increased, whereas total WBC and lymphocyte counts and the number of smokers decreased with age in men (Fig. 1A). The number of CSA patients increased, hscrp level and monocyte count tended to increase, and lymphocyte count tended to decrease with age, and the number of smokers remained lower throughout all age in women (Fig. 1B). The prevalence of CSA patient rose with age until the 7th decade of life and tended to decline thereafter in both men and women (Fig. 1). The changes with age in the levels of hscrp, total WBC, monocyte and lymphocyte counts, however, occurred almost within the normal ranges. Multiple logistic regression analyses The multiple logistic regression analyses for predictors of coronary spasm and atherosclerotic stenosis were performed. The results revealed that gender (male), smoking and hscrp level were positive predictors (p=0.001, p=0.010 and p= 0.040, respectively) and DBP was a negative predictor (p= 2665

4 Figure 1. Number and prevalence of CSA patients and smokers and the levels of inflammatory markers in relation to age. The prevalence of CSA patients, hscrp levels, and monocyte counts increased, while lymphocyte and total leukocyte counts, and prevalence of smokers decreased, with age in men (A). The prevalence of CSA patients, hscrp levels, and monocyte counts increased, while lymphocyte counts decreased with age, whereas the total WBC counts and the frequency of smoking remained stable and low with age in women (B). The prevalence of CSA rose until years of age and tended to decline thereafter in both men and women. CSA: coronary spastic angina, hscrp: high sensitivity C-reactive protein, WBC: white blood cell 0.035) for coronary spasm. On the other hands, age, diabetes mellitus, SBP, uric acid level and gender (male) were positive predictors (p<0.001, p<0.001, p=0.002, p=0.006 and p=0.029, respectively) and HDL-cholesterol level was a negative (p<0.001) predictor for atherosclerotic stenosis (Table 2). Current smoking failed to reach a significant level (p=0.077) as a predictor for atherosclerotic stenosis. This is likely due to the fact that age was the most powerful predictor of atherosclerotic stenosis and the proportion of current smokers declined with age as shown in Fig. 1. It is therefore probable that age negatively affected smoking as an independent variable in the multivariable regression analysis in this study. The predictors of coronary spasm were thus distinct from those of atherosclerotic stenosis. When atherosclerotic stenosis was added as a predictor of coronary spasm in the analysis, atherosclerotic stenosis was found to be the most significant predictor of CSA, followed by gender (male), smoking, and hscrp level (p=0.001, p=0.002, p= 0.017, p=0.043, respectively). We therefore stratified the study patients into the atherosclerotic stenosis and nonatherosclerotic stenosis groups and analyzed the predictors of CSA in each subgroup. Interestingly, the results revealed that only DBP was a significant predictor (p=0.009) of CSA in the atherosclerotic stenosis group, whereas male gender and smoking were significant predictors (p=0.017 and p= 0.024, respectively) of CSA in the non-atherosclerotic stenosis group. We further stratified the study patients according to age ( 65 or >65 years of age), gender, and smoking status and analyzed the predictors of CSA in each subgroup. Smoking, age, gender (male) and WBC count were significant predictors (p=0.011, p=0.030, p=0.032, and p=0.037, respectively) of CSA in the group 65 years of age, whereas gender (male) and hscrp level were positive predictors (p= 0.007, p=0.038, respectively) and DBP was a negative predictor for CSA (p=0.003) in the group >65 years of age. Accordingly, the predictors of CSA differed depending on the age group. Smoking was a significant predictor (positive) (p=0.030) for CSA in men, whereas DBP was a significant predictor (negative) (p=0.043) of CSA in women. DBP was not a significant predictor for CSA in the smoker group, whereas gender (male) was a positive (p=0.004) and DBP a negative predictor (p=0.035) for CSA in the non- 2666

5 Table 2. Multiple Logistic Regression Analysis for Coronary Spasm and Atherosclerotic Stenosis Coronary Spasm Atherosclerotic Stenosis Coef. Wald Significant Exp(B) 95% Conf.interval Coef. Wald Significant Exp(B) 95% Conf.interval Age < Men SBP DBP Diabetes mellitus < Smoker Total WBC hscrp A/G HDL-cholesterol < LDL-cholesterol Triglyceride Uric acid _cons < A/G: albumin globulin ratio, CSA: coronary spastic angina, DBP: diastolic blood pressure, HDL-cholesterol: high density lipoprotein cholesterol, hscrp: high sensitivity C-reactive protein, LDL-cholesterol: low density lipoprotein cholesterol, SBP: systolic blood pressure, WBC: white blood cell Figure 2. Comparison of diastolic blood pressure values between the patients with CSA and those without in the subgroups determined according to atherosclerotic stenosis, age, gender and smoking. The diastolic blood pressure values were higher or tended to be higher in the patients with CSA than in those without. CSA: coronary spastic angina smoker group. Accordingly, the predictors of CSA differed depending on the subgroup according to atherosclerotic stenosis, age, gender and smoking status. Each of these predictors was associated with each other (data not shown). Because DBP was found to be a significant negative predictor for CSA for the first time in this study, we presented Fig. 2 comparing DBP values between the CSA and non-csa patients in each subgroup of the study patients. DBP values were found to be significantly lower or tended to be lower in the patients with CSA than those without except in the subgroup 65 years of age. Comparison of clinical characteristics between the CSA patients with atherosclerotic stenosis and those without Table 3 compares the clinical characteristics of the CSA 2667

6 Table 3. Comparison of Clinical Characteristics between CSA Patients with Atherosclerotic Stenosis and Those without Atherosclerotic stenosis (n=161) No Atherosclerotic stenosis (n=335) p Normal range Age, years 67.3± ± Men, n (%) 119 (73.9) 196 (58.5) Body Mass Index, kg/m (22.1, 25.9) 24.1 (22.3, 26.4 ) Hypertension, n (%) 112 (69.6) 178 (53.1) Systolic hypertension, n (%) 102 (67.1) 157 (48.8) <0.001 Diastolic hypertension, n (%) 23 (15.1) 51 (15.8) SBP 142 (120, 150) 138 (116, 148) <140 DBP 76 (64, 84) 77 (64, 83) <90 PP 61 (51, 72) 57 (46, 69) Current smoker, n (%) 59 (36.6) 101 (30.1) Total WBC, 10 9 /L 6.2 (5.1,7.3 ) 5.9 (4.9,7.0 ) Basocyte, 35 (24, 47) 32 (23, 44) Eosinocyte, / L 168 (111, 285) 138 (88, 223) Neutrophil, 3,435 (2,767, 4,410) 3,355 (2,581, 4,242) Lymphocyte, / 1,765 (1,429, 2,253) 1,818 (1,448, 2,291) Monocyte, / L 456 (387, 564) 432 (346, 544) hscrp, mg/l 1.3 (0.4, 3.0) 0.8 (0.3, 2.3) Total protein, g/l 67 (63,71 ) 67 (64,70 ) Albumin, g/l 40 (37, 41) 40 (37, 42) A/G 1.41± ± Total cholesterol, mmol/l 5.0 (4.5, 5.6) 5.1 (4.6, 5.7) HDL-C, mmol/l 1.3 (1.1, 1.6) 1.4 (1.2, 1.7) LDL-C, mmol/l 2.9 (2.5, 3.5) 2.9 (2.4, 3.4) Triglyceride, mmol/l 1.4 (1.1, 1.9) 1.4 (1.0, 2.0) Fast plasma glucose, mmol/l 5.3 (5.1, 5.8) 5.3 (5.1, 5.6) Uric acid, mol/l 333 (271, 399) 309 (256, 369) egfr, ml/minutes/1.73m (52.5, 74.0) 71.5 (60.0, 81.1) <0.001 Values are n (%), median (25%, 75%), and mean ± SD. A/G: albumin globulin ratio, CSA: coronary spastic angina, DBP: diastolic blood pressure, egfr: estimated glomerular filtration rate, HDL-cholesterol: high density lipoprotein cholesterol, hscrp: high sensitivity C-reactive protein, PP: pulse pressure, SBP: systolic blood pressure, LDL-cholesterol: low density lipoprotein cholesterol, WBC: white blood cell patients with and without atherosclerotic stenosis. The CSA patients with atherosclerotic stenosis were older and exhibited a higher prevalence of hypertension and dyslipidemia, and higher levels of hscrp and uric acid, and lower estimated glomerular filtration rates than those without. Therefore, the CSA patients with atherosclerotic stenosis had more age-related risk factors for atherosclerosis than those without. Discussion Coronary spasm plays an important role in the pathogenesis of CHD and is prevalent among Japanese (1-3). However, the precise mechanisms by which coronary spasm develops remain to be elucidated (1-3, 16). Previous studies have shown that smoking alone is a significant risk factor for CSA among conventional coronary risk factors (1, 4, 6-8). However, these studies were performed decades ago, when the rate of smoking was very high, the population was relatively young, and sensitive markers for inflammation were not clinically available (6-8). The current study showed that gender (male), smoking, DBP, and hscrp were the significant predictors for CSA, whereas age, diabetes mellitus, low HDL-cholesterol, high SBP, uric acid, and gender (male) were the significant predictors for atherosclerotic coronary stenosis in that order. Therefore, the predictors and/or risk factors for coronary spasm and their orders of significance are distinct from those of coronary atherosclerotic stenosis, suggesting that the underlying mechanisms for coronary spasm may also be distinct from those of coronary atherosclerosis. The present study further showed that smoking and age were significant predictors in the age group of 65 years of age, whereas these factors were no longer significant, while instead hscrp and low DBP were the significant predictors in the age group of >65 years of years. This observation is likely due to the fact that the rate of smoking declined, whereas the levels of hscrp rose with aging. The WBC (particularly monocyte) counts and hscrp levels were higher in the CSA patients than non-csa patients, although these levels were almost within the normal ranges in both groups. These findings therefore indicate that CSA is a manifestation of chronic low-grade inflammation with a predominant innate immunity activity (7, 17, 18). The precise mechanisms by which CSA is associated with smoking remain to be elucidated. Smokers exhibit low-grade inflammation, as shown in this and previous studies (19, 20). Smoking impairs the vascular endothelium, induces inflammation (19-21), and enhances the contractile response of vascular smooth muscle cells (SMCs) via Rho-kinase activa- 2668

7 tion (22, 23). Hence, the presence of SMCs with a contractile phenotype and enhanced Rho-kinase activity may make the spasm segments distinct (24) from those of atherosclerosis, where SMCs are switched to a synthetic phenotype associated with lipid deposition or apoptosis (5, 25). Interestingly, DBP was found to be a negative predictor for CSA, whereas SBP was found to be a positive predictor for coronary atherosclerotic stenosis. This is the first study to demonstrate an association between CSA and DBP. The underlying mechanisms of this finding remain to be elucidated. There are reports that smokers have lower blood pressure values than non-smokers (20, 26). Furthermore, in the present study, the DBP values were lower in the smokers than non-smokers after adjusting for age, gender and WBC count. Smoking may thus account for the lower DBP values observed in the CSA patients. However, DBP remained a significant negative predictor for CSA, even in the nonsmokers. DBP reflects the function of systemic resistance arteries and arterioles (27). It is therefore probable that the function of small resistance arteries and arterioles including the coronary microvasculature may be preserved despite the presence of dysfunctional epicardial conduit arteries in the CSA patients. Indeed, we and others have reported that both CSA patients and smokers display endothelial dysfunction in the epicardial arteries and yet exhibit a preserved coronary microvascular function (20, 28, 29). Large epicardial arteries have a greater dependency on NO-mediated, endotheliumdependent mechanisms for the maintenance of tone, while small resistance arteries and arterioles depend on metabolic and myogenic mechanisms (30, 31). Coronary spasm is closely associated with atherosclerotic stenosis as shown in this study. However, the causal relationship between these two diseases remains to be clarified. In the present study, age and the prevalence of age-related risk factors were higher in the CSA patients with atherosclerotic stenosis than in those without. This finding suggests that coronary spasm may precede and contribute to the progression of atherosclerotic stenosis. On the other hand, the prevalence of coronary spasm declined, whereas that of atherosclerotic stenosis increased with age in the older group. Coronary atherosclerotic stenosis may therefore rather restrain coronary spasm, although the two conditions often coexist. We previously demonstrated that the sites of coronary spasm differ from those of atherosclerotic stenosis (32). Clinical implications Ca-channel blockers are the mainstay of treatment for CSA at present (1, 3). However, CSA often recurs upon withdrawal of these drugs and a substantial number of CSA patient exhibit attacks that are resistant to even high doses of Ca-channel blockers and other drugs (1, 3). The results of the study thus may shed new light on the pathogenesis of CSA and suggest that therapeutic interventions targeting chronic low-grade inflammation and endothelial dysfunction may prove to be a novel treatment approach for CSA. Such treatments would include lifestyle modification including physical exercise (33, 34) and smoking cessation (17-19), and pharmacological interventions such as the use of 3- hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which suppress inflammation (35, 36). Limitations The patients in the present study consisted of subjects suspected of having CSA who underwent CSA provocation test in addition to coronary angiography. Therefore, the results of this study may not necessarily be applicable to other populations. There are also racial differences in the prevalence of CSA (37), and the results may therefore not be applicable to the ethnic groups than other the Japanese. However, a recent study showed that CSA was also prevalent in Western countries (38). In addition, this was a crosssectional study, and the causal relationships between CSA and smoking, inflammation, and coronary atherosclerosis could not be established. Furthermore, the study did not address genetic risk factors, which may play an important role in the pathogenesis of CSA (1, 3, 16, 39-41). Conclusions Predictors for coronary spasm include smoking, low DBP and systemic low-grade inflammation. These predictors differ from those for coronary atherosclerotic stenosis, which comprise age, diabetes mellitus, low HDL-cholesterol, hypertension or high SBP and uric acid. These findings suggest that the pathogenesis of coronary spasm may also differ from that of atherosclerosis. The authors state that they have no Conflict of Interest (COI). 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