Comparison of Coronary Atherosclerotic Plaque Burden and Composition of Culprit Lesions Between Cigarette Smokers and Non-Smokers by In Vivo Virtual Histology Intravascular Ultrasound

Abstract: Cigarette smoking is a major risk factor in the progression of atherosclerosis and has been shown to cause endothelial dysfunction, inflammation, and modification of lipid profile. However, its role in the pathogenesis of vulnerable coronary plaque remains unknown. We investigated the relationship between cigarette smoking and the development of vulnerable coronary artery plaque using virtual histology intravascular ultrasound (VH-IVUS). Data from consecutive patients who underwent VH-IVUS assessment of native coronary artery stenosis during clinically indicated cardiac catheterization at our institution over a 2-year period were analyzed. Baseline demographic and study characteristics were collected on all patients. Coronary plaque compositions of the culprit lesion were compared on bivariate and multivariate analysis. We analyzed data on 160 patients with a mean age of 60 ± 11 years. Sixty-nine percent of these patients were admitted for acute coronary syndrome, 31% were smokers, and the mean plaque burden was 66%. On average, 58% of these plaques were fibrous, 19% were fibro-fatty, 18.3% had a necrotic core, and 5.4% were composed of dense calcium. Cigarette smokers had a higher burden of necrotic core (20.7% vs 17.2%; P=.04). On multivariate analysis, cigarette smoking was independently associated with a 4.54% increase in the burden of necrotic core (P=.01).  Older age (>80 years) was also a predictor of higher necrotic core burden (P=.02). In conclusion, cigarette smoking is associated with a higher burden of necrotic core in coronary atherosclerotic plaques. This may represent one of the mechanisms for increased cardiovascular events. 

J INVASIVE CARDIOL 2015;27(8):354-358. Epub 2015 May 15

Key words: acute coronary syndrome, intravascular ultrasound, atherosclerosis, cigarette smoking

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Cigarette smoking is a major risk factor in the progression of atherosclerosis.^1-3 It has been shown to cause endothelial dysfunction, inflammation, and modification of lipid profile.^1,4,5 In recent years, the role of vulnerable plaque in the pathogenesis of acute coronary syndrome has been described.^6,7 Lipid deposition in the intima of the coronary arteries leads to a cascade of events that result in macrophage-mediated inflammatory reaction and the evolution of lipid-laden foam cells.^6,8 Death of these foam cells gives rise to regions within plaques containing necrotic debris. This necrotic product of proteolytic activity within an atherosclerotic plaque is described as the necrotic core and is covered by a fibrous cap.⁸ Erosion and rupture of this fibrous cap lead to occlusion of the coronaries and are believed to be responsible for most cases of acute coronary syndrome.⁹ The burden of the necrotic component in atherosclerotic plaque has been shown to predict vulnerability of a plaque and the likelihood for plaque rupture.⁶ It is unknown if an increased burden of vulnerable plaque is one of the mechanisms that explain the increased risk of acute coronary events among cigarette smokers. The aim of this study was to compare the morphologic characteristics of atherosclerotic plaques in the culprit vessel between cigarette smokers and non-smokers. 

Methods

A retrospective cohort study was conducted using data collected from 160 consecutive patients who underwent virtual histology intravascular ultrasound (VH-IVUS; Volcano Corporation) assessment of native coronary artery stenosis during cardiac catheterization at our institution between 2008 and 2010. The VH-IVUS was performed prior to balloon inflation or coronary intervention. The patients underwent VH-IVUS examination of the de novo native coronary artery stenosis to characterize the coronary plaque in the culprit vessels in angiographically indeterminate lesions prior to coronary intervention. The study patients were a proportion of all the patients undergoing cardiac catheterization in our laboratory. VH-IVUS was performed on the suspected culprit lesion only. The most obstructive lesion in the culprit vessel angiographically was studied. The VH-IVUS findings were obtained before balloon inflation so as not to distort the plaque characteristics prior to obtaining the images. The indications for catheterization included chest pain with abnormal stress test, acute coronary syndromes (defined as unstable angina, non-ST elevation myocardial infarction [NSTEMI] and ST-elevation myocardial infarction [STEMI]), ventricular arrhythmia, and cardiomyopathy. Patients were included in the study if they were over 18 years old and had a clinical indication for coronary angiography. They were excluded if they had a chronic total occlusion of any artery or had target lesions with angiographically determined thrombus. The ethics committee at our institution approved the protocol. 

VH-IVUS is a novel IVUS modality utilizing spectral analysis of the radiofrequency ultrasound backscatter signals, which allows accurate in vivo evaluation of 4 coronary plaque components, namely fibrotic, fibro-fatty, dense calcium, and necrotic core (Figures 1A and 1B).^10-13 Compared with in vitro histopathology tissue sample obtained by directional coronary atherectomy, in vivo VH-IVUS allowed detection of the necrotic core and dense calcium with a predictive accuracy of 88.3% and 96.5%, respectively.¹¹

Cigarette smoking status was defined by patient self-report of smoking a cigarette within the last month. Diabetic patients had a confirmed diagnosis of diabetes mellitus or were using diabetic medications within the last month. The primary outcome variable in this study was the burden of necrotic core in the atherosclerotic plaque. The burden of necrotic core was defined as the proportion of coronary plaque in the culprit lesion composed of necrotic core.

Baseline demographic and study characteristics were collected on all patients (Tables 1 and 2). The proportions of specific morphologic characteristics of the plaques (Figure 2) were compared on bivariate analysis. A multiple linear regression analysis was done to control for the role of known confounding variables in the relationship between smoking and the burden of necrotic core. Controlled variables in our model include age, gender, race, low-density lipoprotein levels, body mass index, and diabetic status. A stratified analysis was performed to explore the role of cigarette smoking on vulnerable plaque in patients with acute coronary syndrome and those without acute coronary syndrome. A sensitivity analysis was also conducted using generalized linear model analysis for a Gaussian distribution, which showed quantitatively similar results. All statistical analysis was performed using STATA IC, version 10.

Results

Data were obtained on 160 patients. Mean age was 60 years, 60% of the population was male, 31% of patients were cigarette smokers, and 36% of patients had diabetes, among whom 38% where insulin-treated diabetics. A total of 74% had hyperlipidemia, of which 93% were treated with medications. The mean body mass index (BMI) was 30.6, with 47% of the population classified as obese. Acute coronary syndrome was the admission diagnosis in 77% of the population; 73% of these patients were admitted for unstable angina/NSTEMI and 4% were admitted for STEMI. The target vessel was the left anterior descending (LAD) artery in 61% of cases. The mean percentage stenosis of the culprit lesion was 66%. The average culprit lesion plaque composition was 58% fibrous, 19% fibro-fatty, 18.3% necrotic core, and 5.4% dense calcium. Cigarette smokers had a higher burden of necrotic core (20.7% vs 17.2%; P=.04). Multivariate analysis after controlling for age, sex, low-density lipoprotein level, high-density lipoprotein level, BMI, and diabetes mellitus showed that cigarette smoking was independently associated with a 4.54% increase in the burden of necrotic core (P=.01). Furthermore, stratified analysis revealed that when restricted to only patients with acute coronary syndrome, cigarette smoking was also associated with increased burden of necrotic core (P=.01) after controlling for other factors (Table 3). In the overall study population, older age (>80 years) was a predictor of higher necrotic core burden (P=.02). Among patients with acute coronary syndrome, age ≥40 years was associated with a greater burden of necrotic core compared with age <40 years after controlling for the other confounders (P<.01). Other covariates were not shown to be significant predictors of necrotic core burden. Notably, diabetes mellitus did not predict a significantly higher burden of necrotic core in this population when compared with non-diabetic patients (19.2% vs 17.8%; P=.44). Also, the proportion of necrotic core in insulin versus non-insulin treated DM was comparable (20.19% vs 17.98%; P=.36). 

Discussion

This study showed that cigarette smoking was associated with an increased burden of necrotic core (P=.01) compared with non-smokers. The burden of necrotic core correlated with exposure to known cardiovascular risk factors – diabetes mellitus and cigarette smoking (Figure 3). Patients with both risk factors present had higher necrotic core burden than those with either or none of these risks. In this study, there was no statistically significant difference in the burden of necrotic core comparing diabetic with non-diabetic patients.

Since necrotic core burden has been consistently shown to predict the presence of vulnerable plaque,^6,9,14 our findings can be translated to mean that cigarette smoking increases the risk of having vulnerable plaque and this risk is greater than the increased risk attributed to diabetes. Recent studies have suggested that the identification of vulnerable plaque in living patients might help reduce the risk of sudden cardiac death.^14,15 These patients with vulnerable plaque may not have angiographically obstructive lesions on coronary angiography, so a thorough understanding of these patients at increased risk for vulnerable plaque is essential to prevent sudden cardiac death in this population.

Cigarette smoking is also known to increase the risk for acute coronary syndrome and sudden cardiac death.^16,17 More than two-thirds of sudden cardiac deaths resulting from acute atherothrombosis occur in smokers.¹⁶ Endothelial dysfunction, thrombosis, lipoprotein oxidation, platelet dysfunction, and vasomotor dysfunction are all mechanisms implicated in the pathogenesis of smoking-induced coronary artery disease.^2,18-20 Our findings are in keeping with prior studies suggesting that cigarette smoking promotes the development of vulnerable plaques and plaque rupture by enhancing inflammation and proteolytic activity.^1,21 Virmani et al showed that in men with coronary artery disease who died suddenly, cigarette smoking was associated with coronary thrombosis regardless of whether erosion or rupture was the mechanism of plaque disruption. Multivariate analysis in this study revealed no difference between plaque rupture or erosion among male smokers (P=.02).¹⁶ In contrast, a subsequent study in women who had sudden coronary death showed that cigarette smoking was associated with plaque erosion leading to acute thrombus.¹⁷ This association was independent of other risk factors in multivariate analysis (P=.03). Plaque erosions are more common in women than in men because of the protective effect of estrogen on plaque rupture.¹⁷ Plaque erosions are most frequently seen in women with sudden death when they are younger than 50 years of age.¹⁷ Our study consisted of a predominantly older population of female smokers, and this may account for the similarity in the necrotic core burden between the male and female patients on multiple linear regression analysis (P=.41). 

This study did not find a significant difference in necrotic core burden comparing diabetics with non-diabetics (19.2% vs 17.8%; P=.44); this was not in keeping with some other studies that reported increased burden in diabetic patients.^15,22,23 We attribute this lack of a difference to the fact that most diabetics in our sample were relatively well controlled. Hemoglobin A1C levels were not available for most study subjects (59%), but 66% of patients with HbA1c tests had values less than 7. In any case, the study by Virmani et al also failed to show any association between diabetes mellitus and acute plaque disruption, suggesting that non-coronary mechanisms may be playing a more prominent role in patients with diabetes mellitus.¹⁶ 

Cigarette smoking is a modifiable risk factor for coronary artery disease, so an important finding from this study was that the burden of necrotic core was higher in cigarette smokers than in relatively well controlled diabetic patients. This suggests a possible major risk reduction in thrombotic events that can be achieved with the control of modifiable risk factor. 

 Study limitation. A limitation of this study was the absence of information about the quantity of cigarettes patients smoked and the duration of smoking. This information would have helped evaluate a smoking threshold at which vulnerable plaque is noted. 

Conclusion

This study showed that cigarette smoking was associated with a higher burden of necrotic core among patients undergoing coronary angiography. We propose that this increase in vulnerable plaque may be one of the mechanisms accounting for increased risk of sudden cardiac death in this population.

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From the ¹Division of Cardiovascular Diseases, University of Tennessee Health Sciences Center, Memphis, Tennessee; and ²Division of Cardiology, Department of Medicine, Georgia Regents University, Augusta, Georgia.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted October 6, 2014, provisional acceptance given November 24, 2014, final version accepted January 12, 2015.

Address for correspondence: Uzoma Ibebuogu, MD, FACC, Division of Cardiovascular Diseases, University of Tennessee Health Science Center, 365 Court Avenue, Suite D334, Memphis, TN 38163. Email: uibebuog@uthsc.edu; ibebuogu@gmail.com