60 Original research
Impact of cigarette smoking on coronary plaque composition Soichiro Kumagaia, Tetsuya Amanoa, Hiroaki Takashimaa, Katsuhisa Wasedaa, Akiyoshi Kuritaa, Hirohiko Andoa, Kazuyuki Maedaa, Yoshitaka Itoa, Hideki Ishiib, Mutsuharu Hayashib, Daiji Yoshikawab, Susumu Suzukib, Akihito Tanakab, Tatsuaki Matsubarac and Toyoaki Muroharab Objectives Cigarette smoking is associated with atherosclerosis and is an important risk factor for cardiovascular disease. We evaluated the impact of cigarette smoking on coronary plaque composition using integrated backscatter intravascular ultrasound (IB-IVUS).
showed that the current smoking state (odds ratio 3.51, 95% confidence interval 1.02–12.10, P = 0.04) was independently associated with the presence of lipid-rich plaques, which was defined as the upper 75th percentile of the study population.
Methods A total of 143 consecutive patients undergoing percutaneous coronary intervention were enrolled. A history of illness, as well as smoking habits, was obtained by interview. Participants were asked to report whether they were current smokers, had quit smoking, or had never smoked. According to interview results, patients were divided into the following three groups: current, former, and never smokers. Conventional and IB-IVUS tissue characterization analyses were carried out. Threedimensional analyses were carried out to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcified).
Conclusion Smoking is independently associated with lipid-rich plaques, contributing to the increasing risk for plaque vulnerability. Coron Artery Dis 26:60–65 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Results IB-IVUS analysis indicated that the patients in the current smoker group had significantly increased percent lipid volume and significantly decreased percent fibrous volume (P = 0.01 and 0.03). Logistic regression analysis
Introduction Cigarette smoking is associated with atherosclerosis and is an important risk factor for cardiovascular disease. Strong smoke-free laws would lead to a reduction in acute myocardial infarction (AMI) cases [1,2]. Several such laws in North America and Europe have been studied as natural experiments to estimate the reduction in community AMI risk, with reductions from 11 to 40% [3, 4]. With a focus on secondary prevention, the mortality after an AMI was significantly reduced in patients who stopped smoking compared with those who continued to smoke [5], and it is highly likely that smoking was strongly associated with cardiac events. Cigarette smoking in patients with an increased incidence of cardiac events might not be responsible for only plaque growth. In such situations, plaque vulnerability might be induced by cigarette smoking and might be related to major adverse cardiac events. Thus, it is important to evaluate the status of coronary plaque components or plaque vulnerability in patients who smoke cigarettes. 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Coronary Artery Disease 2015, 26:60–65 Keywords: cigarette smoking, coronary plaque tissue components, integrated backscatter intravascular ultrasound, lipid profiles, percutaneous coronary intervention a
Department of Cardiology, Aichi Medical University, Nagakute, Aichi, Department of Cardiology, Nagoya University Graduate School of Medicine and Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan
b c
Correspondence to Soichiro Kumagai, MD, PhD, Department of Cardiology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi 480-1195, Japan Tel: + 81 561 62 3311; fax: + 81 561 63 8482; e-mail: [email protected] Received 9 June 2014 Revised 1 August 2014 Accepted 4 August 2014
Recently, studies have reported that integrated backscatter intravascular ultrasound (IB-IVUS) can detect coronary plaque tissue components [6,7]. Lipid-rich plaques detected using IB-IVUS may predict future cardiac events [8]. Recent studies have suggested that lipidrich plaques are more frequently seen in patients with cardiovascular risks [9–12]. However, reports on the relationships between cigarette smoking and tissue characteristics of a coronary plaque are limited. Accordingly, in the present study, we evaluated the impact of cigarette smoking on coronary plaque composition using IB-IVUS.
Methods Patients and study design
This observational study consisted of 202 consecutive patients who had underdone elective percutaneous coronary intervention (PCI) with IVUS guidance for stable angina pectoris between May 2009 and July 2012 at Nagoya University Hospital. All patients had angina pectoris or documented myocardial ischemia. Thirty-three DOI: 10.1097/MCA.0000000000000168
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Impact of smoking on coronary plaque Kumagai et al. 61
patients with severe coronary lesions or chronic total occlusion that could not be crossed by the IVUS catheter and needed balloon angioplasty before evaluation by IBIVUS, and 16 patients with lesions with severe calcification in which the plaque area could not be evaluated were excluded. Eight patients who needed multivessel stenting in a single procedure were excluded. Two patients who had obvious thrombus formation detected by coronary angiography and needed thrombus aspiration were excluded, because thrombus aspiration is routinely performed before IB-IVUS for these patients in our institution and because thrombus formation, which is often detected in patients with acute coronary syndrome, was not color coded and analyzed by IB-IVUS. After exclusion of 59 patients, data from 143 patients with 143 target lesions were evaluated. Information on previous illness, including heart disease and stroke, and smoking habits was obtained by interview. Participants were asked to report whether they were current smokers, had quit smoking, or had never smoked. Smokers were asked about the number of cigarettes smoked per day and the duration of smoking in years. The lifetime consumption of cigarettes was expressed as the Brinkman index (number of cigarettes per day × years of smoking). According to the interview results, patients were divided into the following three groups: current smokers, former smokers, and patients who never smoked (never smokers). The patients who, at the time of the interview, smoked either every day or some days were defined as ‘current smokers’. The patients who, at the time of the interview, did not smoke at all were defined as ‘former smokers’. The patients who reported never having smoked 100 cigarettes were defined as ‘never smokers’. Those found eligible comprised a total of 143 patients, all of whom had received dual antiplatelet therapy with aspirin (100–162 mg/day) and thienopyridine before PCI. In addition, a statin had been administered for at least 1 month. Various biomarkers were measured using commercial radioimmunoassay kits and specific immunoradiometric assays. For this purpose, blood samples were collected from patients 10–12 h after overnight fasting before PCI. This study was approved by the ethics committee of Nagoya University Hospital. Written informed consent was obtained from all patients before the procedure. Diabetes mellitus was defined as a history of diabetes mellitus, a fasting plasma glucose concentration of 126 mg/dl or higher, a randomized plasma glucose concentration of 200 mg/dl or higher, and/or treatment with antihyperglycemic agents. Hypertension was defined as a history or presence of hypertension, with a systolic blood pressure of 140 mmHg or higher and/or a diastolic blood
pressure of 90 mmHg or higher, and treatment with antihypertensive agents. Quantitative coronary angiography analysis and intravascular ultrasound procedure
Before coronary angiography and PCI, patients were administered an intracoronary injection of 0.5 mg isosorbide dinitrate to prevent coronary spasm. Online quantitative coronary angiography analysis was carried out, and the reference diameter and the percentage diameter of stenosis were measured with a validated automated edge-detection program (CMS; MEDIS Medical Imaging System, Leiden, the Netherlands). Conventional IVUS and IB-IVUS parameters were measured in the target lesion at locations with the worst plaque (plaque burden > 40% in at least three consecutive frames) within the target vessel at the time of the PCI procedure. The entire vessel pullback from the IVUS dataset was analyzed frame by frame in each patient and the minimal lumen area frame was selected. Continuous ultrasound imaging was performed during withdrawal of the catheter through the segment of the artery at a constant rate of 0.5 mm/s. A personal computer equipped with a commercially available custom software (VISIATLAS; YD, Nara, Japan) was connected to the IVUS imaging system (VISIWAVE; Terumo, Tokyo, Japan) to obtain radiofrequency and signal-trigger outputs. Ultrasound backscattered signals were acquired using a 40 MHz (motorized pullback 0.5 mm/s) mechanically rotating IVUS catheter, digitized, and subjected to spectral analysis. IB data for each tissue component were calculated as average power levels, measured in decibels, of the frequency component of backscattered signals from a small volume of tissue using a fast Fourier transform. In the conventional IVUS analysis, two-dimensional images were quantified for lumen cross-sectional area (LCSA), external elastic membrane (EEM) crosssectional area (CSA), and plaque (P) + media (M) CSA (P + M CSA = EEM CSA − LCSA) using the IVUS system software. Three-dimensional analysis of conventional IVUS images was carried out to compute vessel volume, lumen volume, and plaque volume (sum of EEM CSA, LCSA, and P + M CSA 1-mm axial intervals for the analysis segments). IB-IVUS has recently been utilized for the analysis of coronary plaque tissue components in vivo [6,13,14]. IB-IVUS analysis was carried out as reported previously [9–12]. The segmentation of each tissue component was entirely automated, and the excellent correlation of IB-IVUS with histology has been reported in validation studies [14]. The percentages of lipid, fibrous, and calcified areas were automatically calculated by the IB-IVUS system. Three-dimensional analysis of IB-IVUS images was carried out for each component volume (sum of each component area in each CSA at 1-mm axis intervals of the IB-IVUS images per
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62 Coronary Artery Disease 2015, Vol 26 No 1
patient, respectively). Thereafter, the percentages of lipid, fibrous, and calcified volumes were calculated. Statistical analysis
Statistical analyses were carried out using SPSS (SPSS Inc., Chicago, Illinois, USA). Continuous and categorical variables were expressed as median (interquartile range). The χ2-test and Fisher’s exact test were applied when appropriate for categorical variables. The relationship of the three groups with each variable was evaluated using the Kruskal–Wallis test. Logistic regression analysis was applied to study the predictors of lipid-rich plaques, defined as the upper 75th percentile of the study population, adjusted for confounding factors (age and sex) and predefined variables (P < 0.20 on univariate analysis). P less than 0.05 was considered as statistically significant.
Results Clinical baseline characteristics of patients in each group are given in Table 1. There were significant differences in sex and the Brinkman index between groups; however, between the former smoker group and the current smoker group, there was no difference in the Brinkman index (P = 0.55 by the Mann–Whitney test for each pair of groups, and the P-value was adjusted using the Bonferroni method). Table 1
Table 2 shows the findings of quantitative coronary angiography and IVUS. There were no significant differences in the reference diameter and the diameter of the stenosis between the groups. On conventional IVUS analysis, the patients in the current smoker group were found to have significantly increased vessel volume (P = 0.01) and plaque volume (P = 0.02). With regard to plaque components, IB-IVUS analysis indicated that the patients in the current smoker group had significantly increased percent lipid volume (P = 0.01) and significantly decreased percent fibrous volume (P = 0.03). Figure 1 shows the percent lipid volume in the target lesions distributed by the patients’ smoking status. Univariate and multivariate logistic regression analyses showed that the current smoking state (odds ratio 3.51, 95% confidence interval 1.02–12.10, P = 0.04) was independently associated with the presence of lipid-rich plaques, which was defined as the upper 75th percentile of the study population (Table 3). Representative images of conventional IVUS and IB-IVUS for each smoking status are shown in Fig. 2.
Discussion In the present study, smoking was an independent predictor of lipid-rich plaques. The lipid volume of coronary plaques in former smokers was higher than in never smokers; however, this was insignificant.
Baseline characteristics
Variables Male [n (%)] Age (years) BMI (kg/m2) Ejection fraction (%) Clinical history [n(%)] Hypertension Diabetes mellitus CKD Old myocardial infarction Previous PCI Previous CABG Blood lipid levels (mg/dl) Triglycerides HDL cholesterol LDL cholesterol hsCRP EPA/AA HbA1c (%) Medication ACE-I [n (%)] ARB [n (%)] Calcium-channel blockers [n (%)] β-Blockers [n (%)] Statins [n (%)] Lesion location [n (%)] Left main trunk Left anterior descending artery Right coronary artery Left circumflex artery Brinkman index
Never smoker (n = 49) 35 73 23.7 63.4 36 23 29 8 19 6 128.5 44.0 97.0 0.14 0.39 6.2
(71.4) (65–78) (21.2–26.0) (49.4–68.5) (73.4) (53.1) (59.1) (16.3) (38.8) (12.2) (102.3–166.5) (37.3–54.3) (82.0–121.5) (0.07–0.41) (0.28–0.70) (5.8–6.4)
Former smoker (n = 56) 52 70 24.4 65.6 44 26 20 10 25 6 127.0 43.0 97.0 0.16 0.37 5.9
6 26 26 15 34
(12.2) (53.1) (53.1) (30.6) (69.4)
4 25 26 16 39
0 18 14 17 0
(0.0) (36.7) (28.6) (34.7) (0–0)
0 20 18 18 870
(94.5) (63–76) (22.3–26.6) (55.2–69.0) (78.6) (46.4) (35.7) (17.8) (44.6) (10.7) (96.3–153.8) (37.0–50,0) (85.0–121.0) (0.05–0.22) (0.27–0.69) (5.7–6.3) (7.2) (44.6) (46.4) (28.6) (69.6) (0.0) (35.7) (32.1) (32.1) (500.0–1200)
Current smoker (n = 38) 37 69 22.7 61.7 30 22 19 1 10 1 114.0 44.0 99.0 0.14 0.37 6.4 1 19 15 11 26 1 15 15 7 800
(97.4) (63–72) (21.0–24.6) (53.9–67.4)
P-value < 0.05 0.14 0.08 0.51
(78.9) (57.9) (50.0) (2.6) (26.3) (2.6)
0.71 0.59 0.08 0.07 0.17 0.25
(96.0–183.0) (38.8–49.5) (75.0–118.0) (0.06–0.75) (0.26–0.51) (6.1–6.6)
0.95 0.66 0.86 0.70 0.85 0.44
(2.6) (50.0) (39.5) (28.9) (68.4)
0.25 0.74 0.45 0.94 0.88 0.67
(2.6%) (39.5) (39.5) (18.4) (420–1120)
< 0.05
Data are presented as median (interquartile range) for continuous variables or number (%) for categorical variables. ACE-I, angiotensin converting enzyme inhibitors; ARB, angiotensin II type 1 receptor antagonists; CABG, coronary artery bypass graft; CKD, chronic kidney disease; EPA/AA, eicosapentaenoic acid/arachidonic acid ratio; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, lowdensity lipoprotein; PCI, percutaneous coronary intervention.
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Impact of smoking on coronary plaque Kumagai et al. 63
Table 2
Quantitative coronary angiography and intravascular ultrasound measurements
Variables QCA analysis Reference diameter (mm) Diameter stenosis (%) Conventional IVUS analysis Vessel area (mm2) Lumen area (mm2) Plaque area (mm2) Lesion length (mm) Vessel volume (mm3) Lumen volume (mm3) Plaque volume (mm3) IB-IVUS analysis % fibrous volume % lipid volume % calcified volume
Never smoker (n = 49)
Former smoker (n = 56)
2.8 (2.5–3.2) 71.7 (59.7–80.2)
2.8 (2.6–3.2) 72.8 (63.7–81.3)
8.3 1.8 6.6 13.5 123.0 46.0 78.2
(6.4–11.1) (1.4–2.2) (5.1–9.1) (11.0–17.8) (91.2–182.9) (36.1–61.3) (55.1–137.5)
49.6 (39.1–57.4) 38.7 (30.0–53.0) 3.7 (1.9–5.6)
9.9 1.7 8.3 13.0 166.0 42.4 108.9
Current smoker (n = 38)
P-value
2.8 (2.6–3.1) 72.0 (62.7–78.0)
(8.1–14.2) (1.3–2.0) (6.4–12.0) (9.0–17.3) (85.4–227.4) (26.8–82.9) (57.0–153.1)
12.2 1.8 10.1 15.0 171.0 59.4 116.3
44.6 (38.3–53.9) 46.3 (34.5–54.7) 2.0 (0.9–3.7)
0.81 0.78
(8.9–15.7) (1.4–2.3) (6.7–12.1) (10.0–20.0) (135.3–280.5) (43.8–81.0) (90.6–199.4)
0.01 0.55 0.01 0.40 0.01 0.06 0.02
42.0 (31.8–48.6) 50.2 (38.8–61.0 2.2 (1.1–3.5)
0.03 0.01 0.01
Data are presented as median (interquartile range) for continuous variables. IB-IVUS, integrated backscatter intravascular ultrasound; QCA, quantitative coronary angiography.
Predictive value for lipid-rich plaques determined using logistic regression analysis
Fig. 1
Table 3
% lipid volume of coronary plaques
70
Univariate
P = 0.01
Variables
60
50
40
30 Never smokers
Former smokers
Current smokers
The percent lipid volume of coronary plaques in patients according to smoking status. The percent lipid volume was significantly associated with smoking status (P = 0.01).
The impact of cigarette smoking on atherosclerosis was affected by many factors. Previous reports have shown that smoking induced insulin resistance or hyperinsulinemia and was independently associated with high plasma insulin levels in nondiabetic men [15,16]. We reported previously that increased insulin resistance and metabolic syndrome were associated with lipid-rich plaques [9,10]. The hyperinsulinemia induced by smoking contributes to increased lipid volume in coronary plaques. Furthermore, nicotine, a major component of cigarette smoke, alters the function of the vascular endothelium, initiates the adhesion cascade, and stimulates the vascular inflammatory events to induce atherosclerosis and hypertension [17,18]. Moreover, it has been demonstrated that nicotine causes macrophage activation and upregulates proinflammatory cytokine production through the
Smoking status Former smoker/ never smoker Current smoker/ never smoker BMI > 25 Hypertension Diabetes mellitus CKD Old myocardial infarction Triglycerides HDL < 40 LDL >100 hsCRP EPA/AA
Multivariate
OR (95% CI)
P-value
OR (95% CI)
P-value
1.29 (0.48–3.50)
0.61
1.95 (0.61–6.27)
0.26
2.37 (0.86–6.54)
0.09
3.51 (1.02–12.10)
0.04
1.74 0.89 2.15 1.17 0.61
(0.74–4.11) (0.36–2.23) (0.95–4.87) (0.53–2.55) (0.16–2.24)
0.20 0.81 0.07 0.70 0.45
2.30 (0.92–5.74)
0.09
2.29 (0.92–5.74)
0.08
1.00 0.55 1.24 0.46 0.36
(0.99–1.01) (0.24–1.30) (0.57–2.71) (0.04–5.02) (0.05–2.86)
0.97 0.18 0.59 0.53 0.34
0.42 (0.15–1.16)
0.09
After adjustment for confounding variables (age and sex). CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; EPA/AA, eicosapentaenoic acid/arachidonic acid ratio; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; OR, odds ratio.
activation of nuclear factor-κB to promote atherogenesis [19]. Inflammation might make coronary plaques more lipid rich. With regard to the impact of cigarette smoking on the prognosis of patients with ischemic heart disease, smoking cessation rapidly reduces the risk for AMI in the short term [20]. In the present study, the lipid volume of coronary plaques in former smokers was lower than in current smokers. Thus, it follows that smoking cessation stabilizes and reduces the lipid volume of coronary plaques. Interestingly, the relationship between smoking cessation and coronary events has varied over the ages. In the 1980s and 1990s, some articles reported that there was no statistical significance of smoking cessation, and a metaanalysis showed a 29% reduction in the relative risk of
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64 Coronary Artery Disease 2015, Vol 26 No 1
Fig. 2
(a)
A
(b)
A A
A
B
B
C E
B
CD E
D
B
C
C
D
D
E
E
A
(c) ABC D E
B
C
D
E
Representative images of conventional and integrated backscatter (IB) color-coded maps of coronary artery plaques in each group of patients according to smoking status. The lipid and fibrous volumes were (a) 38 and 59% in never smokers, (b) 47 and 51% in former smokers, and (c) 66 and 32% in current smokers, respectively. Blue, lipid plaques; green–yellow, fibrous plaques; red, calcified plaques.
mortality for patients with coronary heart disease who quit smoking compared with those who continued to smoke [21]. Other studies reported similar findings [22,23]. Recently, Clair et al. [24] reported that recently reformed smokers had a hazard ratio of 0.47 (53% risk reduction) for cardiovascular disease compared with current smokers. In addition, in a recently published report, the risk reduction rate reported for smoking cessation was greater than 50% [25]. This difference is attributed to a reduction in mortality among patients who stopped smoking, and the improvement was caused by the introduction of medication for plaque stabilization, such as statin. Hiro et al. [26] reported that the regression of coronary plaques induced by statin therapy was weaker in patients with diabetes. Insulin resistance and inflammation caused by smoking, like diabetes mellitus, make current smokers low responders. Smoking cessation might improve the response to optimal medical treatment and stabilize coronary plaques. This response is an
explanation for our results and the reason why smoking cessation reduces the risk for coronary events.
Study limitation
Several limitations of the study should be discussed. The present study was conducted at a single center and included a relatively small sample. The definition of smokers and others only depended on interview. There are no objective data that confirm current smoking habits, such as the higher CO content in expiration or enhanced biomarkers for oxidative stress. These limitations need to be considered with respect to our study.
Conclusion
Smoking is independently associated with lipid-rich plaques, contributing to the increasing risk for plaque vulnerability.
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Impact of smoking on coronary plaque Kumagai et al. 65
Acknowledgements
13
Conflicts of interest
There are no conflicts of interest. 14
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Impact of cigarette smoking on coronary plaque composition Soichiro Kumagaia, Tetsuya Amanoa, Hiroaki Takashimaa, Katsuhisa Wasedaa, Akiyoshi Kuritaa, Hirohiko Andoa, Kazuyuki Maedaa, Yoshitaka Itoa, Hideki Ishiib, Mutsuharu Hayashib, Daiji Yoshikawab, Susumu Suzukib, Akihito Tanakab, Tatsuaki Matsubarac and Toyoaki Muroharab Objectives Cigarette smoking is associated with atherosclerosis and is an important risk factor for cardiovascular disease. We evaluated the impact of cigarette smoking on coronary plaque composition using integrated backscatter intravascular ultrasound (IB-IVUS).
showed that the current smoking state (odds ratio 3.51, 95% confidence interval 1.02–12.10, P = 0.04) was independently associated with the presence of lipid-rich plaques, which was defined as the upper 75th percentile of the study population.
Methods A total of 143 consecutive patients undergoing percutaneous coronary intervention were enrolled. A history of illness, as well as smoking habits, was obtained by interview. Participants were asked to report whether they were current smokers, had quit smoking, or had never smoked. According to interview results, patients were divided into the following three groups: current, former, and never smokers. Conventional and IB-IVUS tissue characterization analyses were carried out. Threedimensional analyses were carried out to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcified).
Conclusion Smoking is independently associated with lipid-rich plaques, contributing to the increasing risk for plaque vulnerability. Coron Artery Dis 26:60–65 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Results IB-IVUS analysis indicated that the patients in the current smoker group had significantly increased percent lipid volume and significantly decreased percent fibrous volume (P = 0.01 and 0.03). Logistic regression analysis
Introduction Cigarette smoking is associated with atherosclerosis and is an important risk factor for cardiovascular disease. Strong smoke-free laws would lead to a reduction in acute myocardial infarction (AMI) cases [1,2]. Several such laws in North America and Europe have been studied as natural experiments to estimate the reduction in community AMI risk, with reductions from 11 to 40% [3, 4]. With a focus on secondary prevention, the mortality after an AMI was significantly reduced in patients who stopped smoking compared with those who continued to smoke [5], and it is highly likely that smoking was strongly associated with cardiac events. Cigarette smoking in patients with an increased incidence of cardiac events might not be responsible for only plaque growth. In such situations, plaque vulnerability might be induced by cigarette smoking and might be related to major adverse cardiac events. Thus, it is important to evaluate the status of coronary plaque components or plaque vulnerability in patients who smoke cigarettes. 0954-6928 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Coronary Artery Disease 2015, 26:60–65 Keywords: cigarette smoking, coronary plaque tissue components, integrated backscatter intravascular ultrasound, lipid profiles, percutaneous coronary intervention a
Department of Cardiology, Aichi Medical University, Nagakute, Aichi, Department of Cardiology, Nagoya University Graduate School of Medicine and Department of Internal Medicine, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan
b c
Correspondence to Soichiro Kumagai, MD, PhD, Department of Cardiology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi 480-1195, Japan Tel: + 81 561 62 3311; fax: + 81 561 63 8482; e-mail: [email protected] Received 9 June 2014 Revised 1 August 2014 Accepted 4 August 2014
Recently, studies have reported that integrated backscatter intravascular ultrasound (IB-IVUS) can detect coronary plaque tissue components [6,7]. Lipid-rich plaques detected using IB-IVUS may predict future cardiac events [8]. Recent studies have suggested that lipidrich plaques are more frequently seen in patients with cardiovascular risks [9–12]. However, reports on the relationships between cigarette smoking and tissue characteristics of a coronary plaque are limited. Accordingly, in the present study, we evaluated the impact of cigarette smoking on coronary plaque composition using IB-IVUS.
Methods Patients and study design
This observational study consisted of 202 consecutive patients who had underdone elective percutaneous coronary intervention (PCI) with IVUS guidance for stable angina pectoris between May 2009 and July 2012 at Nagoya University Hospital. All patients had angina pectoris or documented myocardial ischemia. Thirty-three DOI: 10.1097/MCA.0000000000000168
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Impact of smoking on coronary plaque Kumagai et al. 61
patients with severe coronary lesions or chronic total occlusion that could not be crossed by the IVUS catheter and needed balloon angioplasty before evaluation by IBIVUS, and 16 patients with lesions with severe calcification in which the plaque area could not be evaluated were excluded. Eight patients who needed multivessel stenting in a single procedure were excluded. Two patients who had obvious thrombus formation detected by coronary angiography and needed thrombus aspiration were excluded, because thrombus aspiration is routinely performed before IB-IVUS for these patients in our institution and because thrombus formation, which is often detected in patients with acute coronary syndrome, was not color coded and analyzed by IB-IVUS. After exclusion of 59 patients, data from 143 patients with 143 target lesions were evaluated. Information on previous illness, including heart disease and stroke, and smoking habits was obtained by interview. Participants were asked to report whether they were current smokers, had quit smoking, or had never smoked. Smokers were asked about the number of cigarettes smoked per day and the duration of smoking in years. The lifetime consumption of cigarettes was expressed as the Brinkman index (number of cigarettes per day × years of smoking). According to the interview results, patients were divided into the following three groups: current smokers, former smokers, and patients who never smoked (never smokers). The patients who, at the time of the interview, smoked either every day or some days were defined as ‘current smokers’. The patients who, at the time of the interview, did not smoke at all were defined as ‘former smokers’. The patients who reported never having smoked 100 cigarettes were defined as ‘never smokers’. Those found eligible comprised a total of 143 patients, all of whom had received dual antiplatelet therapy with aspirin (100–162 mg/day) and thienopyridine before PCI. In addition, a statin had been administered for at least 1 month. Various biomarkers were measured using commercial radioimmunoassay kits and specific immunoradiometric assays. For this purpose, blood samples were collected from patients 10–12 h after overnight fasting before PCI. This study was approved by the ethics committee of Nagoya University Hospital. Written informed consent was obtained from all patients before the procedure. Diabetes mellitus was defined as a history of diabetes mellitus, a fasting plasma glucose concentration of 126 mg/dl or higher, a randomized plasma glucose concentration of 200 mg/dl or higher, and/or treatment with antihyperglycemic agents. Hypertension was defined as a history or presence of hypertension, with a systolic blood pressure of 140 mmHg or higher and/or a diastolic blood
pressure of 90 mmHg or higher, and treatment with antihypertensive agents. Quantitative coronary angiography analysis and intravascular ultrasound procedure
Before coronary angiography and PCI, patients were administered an intracoronary injection of 0.5 mg isosorbide dinitrate to prevent coronary spasm. Online quantitative coronary angiography analysis was carried out, and the reference diameter and the percentage diameter of stenosis were measured with a validated automated edge-detection program (CMS; MEDIS Medical Imaging System, Leiden, the Netherlands). Conventional IVUS and IB-IVUS parameters were measured in the target lesion at locations with the worst plaque (plaque burden > 40% in at least three consecutive frames) within the target vessel at the time of the PCI procedure. The entire vessel pullback from the IVUS dataset was analyzed frame by frame in each patient and the minimal lumen area frame was selected. Continuous ultrasound imaging was performed during withdrawal of the catheter through the segment of the artery at a constant rate of 0.5 mm/s. A personal computer equipped with a commercially available custom software (VISIATLAS; YD, Nara, Japan) was connected to the IVUS imaging system (VISIWAVE; Terumo, Tokyo, Japan) to obtain radiofrequency and signal-trigger outputs. Ultrasound backscattered signals were acquired using a 40 MHz (motorized pullback 0.5 mm/s) mechanically rotating IVUS catheter, digitized, and subjected to spectral analysis. IB data for each tissue component were calculated as average power levels, measured in decibels, of the frequency component of backscattered signals from a small volume of tissue using a fast Fourier transform. In the conventional IVUS analysis, two-dimensional images were quantified for lumen cross-sectional area (LCSA), external elastic membrane (EEM) crosssectional area (CSA), and plaque (P) + media (M) CSA (P + M CSA = EEM CSA − LCSA) using the IVUS system software. Three-dimensional analysis of conventional IVUS images was carried out to compute vessel volume, lumen volume, and plaque volume (sum of EEM CSA, LCSA, and P + M CSA 1-mm axial intervals for the analysis segments). IB-IVUS has recently been utilized for the analysis of coronary plaque tissue components in vivo [6,13,14]. IB-IVUS analysis was carried out as reported previously [9–12]. The segmentation of each tissue component was entirely automated, and the excellent correlation of IB-IVUS with histology has been reported in validation studies [14]. The percentages of lipid, fibrous, and calcified areas were automatically calculated by the IB-IVUS system. Three-dimensional analysis of IB-IVUS images was carried out for each component volume (sum of each component area in each CSA at 1-mm axis intervals of the IB-IVUS images per
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62 Coronary Artery Disease 2015, Vol 26 No 1
patient, respectively). Thereafter, the percentages of lipid, fibrous, and calcified volumes were calculated. Statistical analysis
Statistical analyses were carried out using SPSS (SPSS Inc., Chicago, Illinois, USA). Continuous and categorical variables were expressed as median (interquartile range). The χ2-test and Fisher’s exact test were applied when appropriate for categorical variables. The relationship of the three groups with each variable was evaluated using the Kruskal–Wallis test. Logistic regression analysis was applied to study the predictors of lipid-rich plaques, defined as the upper 75th percentile of the study population, adjusted for confounding factors (age and sex) and predefined variables (P < 0.20 on univariate analysis). P less than 0.05 was considered as statistically significant.
Results Clinical baseline characteristics of patients in each group are given in Table 1. There were significant differences in sex and the Brinkman index between groups; however, between the former smoker group and the current smoker group, there was no difference in the Brinkman index (P = 0.55 by the Mann–Whitney test for each pair of groups, and the P-value was adjusted using the Bonferroni method). Table 1
Table 2 shows the findings of quantitative coronary angiography and IVUS. There were no significant differences in the reference diameter and the diameter of the stenosis between the groups. On conventional IVUS analysis, the patients in the current smoker group were found to have significantly increased vessel volume (P = 0.01) and plaque volume (P = 0.02). With regard to plaque components, IB-IVUS analysis indicated that the patients in the current smoker group had significantly increased percent lipid volume (P = 0.01) and significantly decreased percent fibrous volume (P = 0.03). Figure 1 shows the percent lipid volume in the target lesions distributed by the patients’ smoking status. Univariate and multivariate logistic regression analyses showed that the current smoking state (odds ratio 3.51, 95% confidence interval 1.02–12.10, P = 0.04) was independently associated with the presence of lipid-rich plaques, which was defined as the upper 75th percentile of the study population (Table 3). Representative images of conventional IVUS and IB-IVUS for each smoking status are shown in Fig. 2.
Discussion In the present study, smoking was an independent predictor of lipid-rich plaques. The lipid volume of coronary plaques in former smokers was higher than in never smokers; however, this was insignificant.
Baseline characteristics
Variables Male [n (%)] Age (years) BMI (kg/m2) Ejection fraction (%) Clinical history [n(%)] Hypertension Diabetes mellitus CKD Old myocardial infarction Previous PCI Previous CABG Blood lipid levels (mg/dl) Triglycerides HDL cholesterol LDL cholesterol hsCRP EPA/AA HbA1c (%) Medication ACE-I [n (%)] ARB [n (%)] Calcium-channel blockers [n (%)] β-Blockers [n (%)] Statins [n (%)] Lesion location [n (%)] Left main trunk Left anterior descending artery Right coronary artery Left circumflex artery Brinkman index
Never smoker (n = 49) 35 73 23.7 63.4 36 23 29 8 19 6 128.5 44.0 97.0 0.14 0.39 6.2
(71.4) (65–78) (21.2–26.0) (49.4–68.5) (73.4) (53.1) (59.1) (16.3) (38.8) (12.2) (102.3–166.5) (37.3–54.3) (82.0–121.5) (0.07–0.41) (0.28–0.70) (5.8–6.4)
Former smoker (n = 56) 52 70 24.4 65.6 44 26 20 10 25 6 127.0 43.0 97.0 0.16 0.37 5.9
6 26 26 15 34
(12.2) (53.1) (53.1) (30.6) (69.4)
4 25 26 16 39
0 18 14 17 0
(0.0) (36.7) (28.6) (34.7) (0–0)
0 20 18 18 870
(94.5) (63–76) (22.3–26.6) (55.2–69.0) (78.6) (46.4) (35.7) (17.8) (44.6) (10.7) (96.3–153.8) (37.0–50,0) (85.0–121.0) (0.05–0.22) (0.27–0.69) (5.7–6.3) (7.2) (44.6) (46.4) (28.6) (69.6) (0.0) (35.7) (32.1) (32.1) (500.0–1200)
Current smoker (n = 38) 37 69 22.7 61.7 30 22 19 1 10 1 114.0 44.0 99.0 0.14 0.37 6.4 1 19 15 11 26 1 15 15 7 800
(97.4) (63–72) (21.0–24.6) (53.9–67.4)
P-value < 0.05 0.14 0.08 0.51
(78.9) (57.9) (50.0) (2.6) (26.3) (2.6)
0.71 0.59 0.08 0.07 0.17 0.25
(96.0–183.0) (38.8–49.5) (75.0–118.0) (0.06–0.75) (0.26–0.51) (6.1–6.6)
0.95 0.66 0.86 0.70 0.85 0.44
(2.6) (50.0) (39.5) (28.9) (68.4)
0.25 0.74 0.45 0.94 0.88 0.67
(2.6%) (39.5) (39.5) (18.4) (420–1120)
< 0.05
Data are presented as median (interquartile range) for continuous variables or number (%) for categorical variables. ACE-I, angiotensin converting enzyme inhibitors; ARB, angiotensin II type 1 receptor antagonists; CABG, coronary artery bypass graft; CKD, chronic kidney disease; EPA/AA, eicosapentaenoic acid/arachidonic acid ratio; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, lowdensity lipoprotein; PCI, percutaneous coronary intervention.
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Impact of smoking on coronary plaque Kumagai et al. 63
Table 2
Quantitative coronary angiography and intravascular ultrasound measurements
Variables QCA analysis Reference diameter (mm) Diameter stenosis (%) Conventional IVUS analysis Vessel area (mm2) Lumen area (mm2) Plaque area (mm2) Lesion length (mm) Vessel volume (mm3) Lumen volume (mm3) Plaque volume (mm3) IB-IVUS analysis % fibrous volume % lipid volume % calcified volume
Never smoker (n = 49)
Former smoker (n = 56)
2.8 (2.5–3.2) 71.7 (59.7–80.2)
2.8 (2.6–3.2) 72.8 (63.7–81.3)
8.3 1.8 6.6 13.5 123.0 46.0 78.2
(6.4–11.1) (1.4–2.2) (5.1–9.1) (11.0–17.8) (91.2–182.9) (36.1–61.3) (55.1–137.5)
49.6 (39.1–57.4) 38.7 (30.0–53.0) 3.7 (1.9–5.6)
9.9 1.7 8.3 13.0 166.0 42.4 108.9
Current smoker (n = 38)
P-value
2.8 (2.6–3.1) 72.0 (62.7–78.0)
(8.1–14.2) (1.3–2.0) (6.4–12.0) (9.0–17.3) (85.4–227.4) (26.8–82.9) (57.0–153.1)
12.2 1.8 10.1 15.0 171.0 59.4 116.3
44.6 (38.3–53.9) 46.3 (34.5–54.7) 2.0 (0.9–3.7)
0.81 0.78
(8.9–15.7) (1.4–2.3) (6.7–12.1) (10.0–20.0) (135.3–280.5) (43.8–81.0) (90.6–199.4)
0.01 0.55 0.01 0.40 0.01 0.06 0.02
42.0 (31.8–48.6) 50.2 (38.8–61.0 2.2 (1.1–3.5)
0.03 0.01 0.01
Data are presented as median (interquartile range) for continuous variables. IB-IVUS, integrated backscatter intravascular ultrasound; QCA, quantitative coronary angiography.
Predictive value for lipid-rich plaques determined using logistic regression analysis
Fig. 1
Table 3
% lipid volume of coronary plaques
70
Univariate
P = 0.01
Variables
60
50
40
30 Never smokers
Former smokers
Current smokers
The percent lipid volume of coronary plaques in patients according to smoking status. The percent lipid volume was significantly associated with smoking status (P = 0.01).
The impact of cigarette smoking on atherosclerosis was affected by many factors. Previous reports have shown that smoking induced insulin resistance or hyperinsulinemia and was independently associated with high plasma insulin levels in nondiabetic men [15,16]. We reported previously that increased insulin resistance and metabolic syndrome were associated with lipid-rich plaques [9,10]. The hyperinsulinemia induced by smoking contributes to increased lipid volume in coronary plaques. Furthermore, nicotine, a major component of cigarette smoke, alters the function of the vascular endothelium, initiates the adhesion cascade, and stimulates the vascular inflammatory events to induce atherosclerosis and hypertension [17,18]. Moreover, it has been demonstrated that nicotine causes macrophage activation and upregulates proinflammatory cytokine production through the
Smoking status Former smoker/ never smoker Current smoker/ never smoker BMI > 25 Hypertension Diabetes mellitus CKD Old myocardial infarction Triglycerides HDL < 40 LDL >100 hsCRP EPA/AA
Multivariate
OR (95% CI)
P-value
OR (95% CI)
P-value
1.29 (0.48–3.50)
0.61
1.95 (0.61–6.27)
0.26
2.37 (0.86–6.54)
0.09
3.51 (1.02–12.10)
0.04
1.74 0.89 2.15 1.17 0.61
(0.74–4.11) (0.36–2.23) (0.95–4.87) (0.53–2.55) (0.16–2.24)
0.20 0.81 0.07 0.70 0.45
2.30 (0.92–5.74)
0.09
2.29 (0.92–5.74)
0.08
1.00 0.55 1.24 0.46 0.36
(0.99–1.01) (0.24–1.30) (0.57–2.71) (0.04–5.02) (0.05–2.86)
0.97 0.18 0.59 0.53 0.34
0.42 (0.15–1.16)
0.09
After adjustment for confounding variables (age and sex). CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; EPA/AA, eicosapentaenoic acid/arachidonic acid ratio; HDL, high-density lipoprotein; hsCRP, high-sensitivity C-reactive protein; LDL, low-density lipoprotein; OR, odds ratio.
activation of nuclear factor-κB to promote atherogenesis [19]. Inflammation might make coronary plaques more lipid rich. With regard to the impact of cigarette smoking on the prognosis of patients with ischemic heart disease, smoking cessation rapidly reduces the risk for AMI in the short term [20]. In the present study, the lipid volume of coronary plaques in former smokers was lower than in current smokers. Thus, it follows that smoking cessation stabilizes and reduces the lipid volume of coronary plaques. Interestingly, the relationship between smoking cessation and coronary events has varied over the ages. In the 1980s and 1990s, some articles reported that there was no statistical significance of smoking cessation, and a metaanalysis showed a 29% reduction in the relative risk of
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64 Coronary Artery Disease 2015, Vol 26 No 1
Fig. 2
(a)
A
(b)
A A
A
B
B
C E
B
CD E
D
B
C
C
D
D
E
E
A
(c) ABC D E
B
C
D
E
Representative images of conventional and integrated backscatter (IB) color-coded maps of coronary artery plaques in each group of patients according to smoking status. The lipid and fibrous volumes were (a) 38 and 59% in never smokers, (b) 47 and 51% in former smokers, and (c) 66 and 32% in current smokers, respectively. Blue, lipid plaques; green–yellow, fibrous plaques; red, calcified plaques.
mortality for patients with coronary heart disease who quit smoking compared with those who continued to smoke [21]. Other studies reported similar findings [22,23]. Recently, Clair et al. [24] reported that recently reformed smokers had a hazard ratio of 0.47 (53% risk reduction) for cardiovascular disease compared with current smokers. In addition, in a recently published report, the risk reduction rate reported for smoking cessation was greater than 50% [25]. This difference is attributed to a reduction in mortality among patients who stopped smoking, and the improvement was caused by the introduction of medication for plaque stabilization, such as statin. Hiro et al. [26] reported that the regression of coronary plaques induced by statin therapy was weaker in patients with diabetes. Insulin resistance and inflammation caused by smoking, like diabetes mellitus, make current smokers low responders. Smoking cessation might improve the response to optimal medical treatment and stabilize coronary plaques. This response is an
explanation for our results and the reason why smoking cessation reduces the risk for coronary events.
Study limitation
Several limitations of the study should be discussed. The present study was conducted at a single center and included a relatively small sample. The definition of smokers and others only depended on interview. There are no objective data that confirm current smoking habits, such as the higher CO content in expiration or enhanced biomarkers for oxidative stress. These limitations need to be considered with respect to our study.
Conclusion
Smoking is independently associated with lipid-rich plaques, contributing to the increasing risk for plaque vulnerability.
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Impact of smoking on coronary plaque Kumagai et al. 65
Acknowledgements
13
Conflicts of interest
There are no conflicts of interest. 14
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