The Correlation Between Cigarette Smoking and Other Risk Factors With Coronary Stenosis Composition

Contemporary clinical cardiology continues to focus on the identification and treatment of coronary stenoses that significantly reduce luminal dimension and impact fractional flow reserve. The concept underlying this approach is that anatomically “significant” lesions are the substrate for angina pectoris, and when they limit the necessary increase in coronary blood flow to supply myocardial oxygen requirements, produce ischemia. When imaging by angiography and other techniques in symptomatic patients demonstrate a severe obstruction to flow, these symptoms can be relieved highly effectively with revascularization. 

The problem with this paradigm is that it has been known for over 30 years that acute coronary syndromes and myocardial infarction (MI) are most often produced by less severe plaques that acutely rupture with thrombus formation. For this reason, treatment of anatomically significant stenoses does not prevent MI or sudden death. The plaques at risk for this behavior have been termed “vulnerable,” and are characterized by their composition: high lipid content, necrotic core, and a thin fibrous cap. Part of the reason for this emphasis is that the techniques available to identify such plaques with the potential to progress rapidly have poor diagnostic discrimination: coronary computed tomography (CT) is promising, but does not yet have the resolution, and intravascular ultrasound (IVUS) can detect the basic anatomic features but cannot distinguish the propensity to rupture with high assurance.¹ The potential to identify which intermediate-severity plaques have the capability to rapidly transform into a thrombotic milieu is truly game changing; if there was a high degree of confidence in predicting the near and intermediate term, treatments targeting these blockages could be developed, rather than the obvious, severe blockages, which may never be a concern for the patient. Such a change in the target of therapy would accelerate the development of pharmacologic strategies aimed at inducing compositional change and regression, rather than the simplistic “plumbing” treatments of bypass and stenting, which target individual blockages rather than the systemic vascular illness, which is the genuine etiology. 

The role of traditional risk factors in the production of coronary artery disease (CAD) is well recognized, but only recently have attempts been made to correlate how hypertension, hyperlipidemia, smoking, and diabetes impact stenosis composition and plaque dynamics. The clinical factors that cause coronary atherosclerosis have characteristic disease patterns predicated on their mechanism. By examining the composition of the plaque, we might better appraise its likely behavior and response to various therapies.

Age and Gender

Men have a higher incidence of CAD compared to women, and it occurs at an earlier age; women tend to develop CAD at an older age than men, and present less often with acute coronary syndromes and MI. There is an association between negative remodeling, calcification, and age >80 years, suggesting that the elderly are less prone to acute coronary syndromes.² Studies have shown a difference in plaque composition between men and women. IVUS studies have demonstrated more non-calcified plaque in women.³ The potential mechanism of these gender-related and age-related differences is thought to be related to endogenous hormonal factors. Women also have less mixed calcified atherosclerotic plaque, a favorable factor, as this plaque composition is most prone to rupture, especially at interfaces of different stiffness, which typically is at the “shoulder” of the plaque. Women also have a higher tendency for plaque erosion compared with men, who exhibit an equal incidence of erosion and rupture. This may be a reason that women have a lower incidence of acute coronary syndromes and also a higher likelihood of an atypical presentation. The gender gap in coronary calcification narrows with increasing age; this is likely related to menopause. The necrotic core volume also increases with age in both genders; however, men have higher total necrotic cores compared with women, especially in comparison with premenopausal women.⁴ 

Smoking

Smoking is a powerful risk factor for CAD and MI. The study by Bolorunduro et al⁵ in this month’s issue of the Journal of Invasive Cardiology describes the relationship between cigarette smoking and the development of vulnerable coronary artery plaque using virtual histology (VH) IVUS. Cigarette smoking was associated with a higher burden of necrotic core in coronary atherosclerotic plaques (20.7% vs 17.2%; P=.04) and was independently associated with a 4.54% increase in the burden of necrotic core (P=.01). Since the burden of necrotic atherosclerotic plaque predicts vulnerability, and the likelihood for plaque rupture, this compositional difference may partially explain the clinical sequelae of smoking. 

Smoking a single cigarette has a subtle impact on coronary blood flow and endothelial function, but in the aggregate, chronic smoking has substantial deleterious effects on coronary flow reserve.⁶ Smoking increases coronary resistance at the site of a coronary stenosis, limiting the coronary flow response proportionally to the size of the affected vascular bed.⁷ Cigarette smoking inhibits an increase in coronary blood flow that should occur with increased myocardial oxygen demands, and alters thromboxane and prostacyclin production, causing vasoconstriction and platelet aggregation. Components of cigarette smoke that gain access to the circulation will come in contact with blood and with the vascular endothelial cells that form a monolayer lining the vessels. Endothelial injury is produced by the constituents of cigarettes/smoking (eg, nicotine, carbon monoxide). Additionally, cigarette smoke is a rich source of free radicals, and there is a strong association between lipid peroxidation and endothelial cell injury. Smoking accelerates plaque progression.⁸ Studies in both carotid arteries⁹ and coronary arteries show a strong association between smoking and complex plaque morphology, including ulcerations. Smoking is strongly associated with acute thrombosis, superimposed on either plaque rupture or erosion, and sudden death.¹⁰ Exposure to cigarette smoke induces multiple pathological effects in the endothelium, several of which are the result of oxidative stress initiated by reactive oxygen species, reactive nitrogen species, and other oxidant constituents of cigarette smoke. The reactive oxygen species in cigarette smoke contribute to oxidative stress, up-regulation of inflammatory cytokines, and endothelial dysfunction by reducing the bioavailability of nitric oxide. Plaque formation and the development of vulnerable plaques also result from exposure to cigarette smoke via the enhancement of inflammatory processes and the activation of matrix metalloproteinases. Moreover, exposure to cigarette smoke results in platelet activation, stimulation of the coagulation cascade, and impairment of fibrinolysis. Endothelial dysfunction, including an increase in permeability and decreased nitric oxide production, along with increased expression of adhesion molecules and adherence of leukocytes to the vessel wall, are also enhanced by other cardiovascular risk factors such as hypertension, hyperlipidemia, and hyperglycemia.¹¹ 

Hyperlipidemia and Statin Therapy

Hyperlipidemia is an independent predictor of percent necrotic core volume. Hypercholesterolemic patients have a higher percentage of necrotic core volume in the culprit lesion. Lipid lowering with high-intensity statin therapy led to a significantly larger increase in plaque hyperechogenicity, which reflects an increase in fibrous tissue and a decrease in lipid content. IVUS studies have demonstrated significant reduction in plaque volume even after short periods of statin therapy,¹² a finding confirmed with CT coronary angiography. There is no concomitant change in observed lumen size, indicating a regression of plaque volume despite the presence of positive remodeling, which is known to have a higher proportion of vulnerable plaque. Besides reduction in plaque size, a shift of the remodeling pattern toward negative remodeling may be considered a sign of plaque stabilization. Nicholls et al¹³ showed that calcified atheroma were resistant to progression. Conversely, the more vulnerable a plaque is, with a higher necrotic core and a thin cap fibroatheroma, the quicker it responds to statin therapy with a decrease in lipid content and increase in thickness of the cap of the atheroma. Studies assessing changes in high-density lipoprotein levels with plaque composition have not been favorable.  

Diabetes, Hypertension, and Chronic Kidney Disease

Uncontrolled diabetics have more necrotic cores and dense calcium than patients with well-controlled diabetes or non-diabetic patients. Although lesion length is longer in well-controlled diabetics compared to non-diabetics, the volume of necrotic core and calcium content was similar.^14,15 Serial IVUS studies done to assess the effect of antihypertensive drugs showed regression of the plaque with amlodipine compared with enalapril or placebo.¹⁶ Chronic kidney disease patients have longer lesions that encroach on the luminal area and have a higher plaque burden. Their composition demonstrates greater necrotic core and dense calcium with less fibrous tissue.¹⁷ Higher amounts of calcium can be attributed to strong association between renal insufficiency and increased coronary calcification, possibly from secondary hyperparathyroidism.¹⁸ The degradation of the fibrous cap of an atheroma in chronic kidney disease is thought to be secondary to the elevated levels of matrix metalloproteinases,¹⁹ rendering the plaque more vulnerable and prone to rupture. 

Optimal Methods of Intracoronary Plaque Assessment

More recently, optical coherence tomography (OCT) has been used to define vulnerable plaques. It provides excellent resolution (10 µm) and is very useful for identifying the pathology in acute coronary syndromes, helping with stent sizing and determining adequacy of stent expansion. However, this modality is accurate primarily for superficial structures (2-3 mm, ie, assessing the thickness of the atheroma cap); VH-IVUS is optimal for evaluating a wider area of the vessel or deeper structures, including the composition of the plaque. This technique also has limitations, including its resolution (200 µm), inability to image through stent struts and calcium, and difficulty in visualizing neovascularization. Near-infrared spectroscopy (NIRS) provides data on lipid content of plaque, which has been shown to be predictive of periprocedural MI, coronary no-reflow, and distal embolization. Studies are underway to determine whether treatment of vulnerable plaques with plaque burden ≤70% by intervening on them will provide any benefit over guideline-directed medical therapy alone. 

There is no single biochemical marker or imaging modality that has been shown to have a high positive predictive value to identify a plaque that is vulnerable to rupture.²⁰ All attempts to appraise the composition of plaque using inflammatory markers have not yielded much success. The ideal imaging technique should be a combination of high-resolution technology enabling measurement of the atheroma cap, assessment of the entire thickness of the vessel, and compositional study of the core. At this time, the most promising technique is NIRS. Future clinical studies and technological advancements are required before we can predict which vulnerable plaques will rupture in the near future and may benefit from preventive therapies. We need to better comprehend the vascular biology of atherosclerosis before we can ascertain which details are required about plaque composition and the timeline of its predicted behavior. Only then can we can develop specific therapies applied at the appropriate time point to prevent a vulnerable plaque from rupturing.²¹

References

1. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364:226-235.
2. Klein LW. Atherosclerosis regression, vascular remodeling, and plaque stabilization. J Am Coll Cardiol. 2007;49:271-273. 
3. Nasir K, Gopal A, Blankstein R, et al. Noninvasive assessment of gender differences in coronary plaque composition with multidetector computed tomographic angiography. Am J Cardiol. 2010;105:453-458.
4. Qian J, Maehara A, Mintz GS, et al. Impact of gender and age on in vivo virtual histology-intravascular ultrasound imaging plaque characterization. Am J Cardiol. 2009;103:1210-1214.
5. Klein LW, Pichard AD, Holt J, et al. Effects of chronic tobacco smoking on the coronary circulation. J Am Coll Cardiol. 1983;1:421-426.
6. Bolorunduro O, Cushman C, Kapoor D, et al. Comparison of coronary atherosclerotic plaque burden and composition of culprit lesions between cigarette smokers and non-smokers by in vivo virtual histology intravascular ultrasound. J Invasive Cardiol. 2015;27:354-358 2015 May 15 (Epub ahead of print).
7. Klein LW, Ambrose J, Pichard A, et al. Acute coronary hemodynamic response to cigarette smoking in patients with coronary artery disease. J Am Coll Cardiol. 1984;3:879-886.
8. Waters D, Lespérance J, Gladstone P, et al. Effects of cigarette smoking on the angiographic evolution of coronary atherosclerosis. Circulation. 1996;94:614-621.
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10. Burke AP, Farb A, Malcolm GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276-1282.
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12. Kawasaki M, Sano K, Okubo M, et al. Volumetric quantitative analysis of tissue characteristics of coronary plaques after statin therapy using three-dimensional integrated back-scatter intravascular ultrasound. J Am Coll Cardiol. 2007;49:1149-1156.
13. Nicholls SJ, Tuzcu EM, Wolski K, et al. Coronary artery calcification and changes in atheroma burden in response to established medical therapies. J Am Coll Cardiol. 2007;49:263-270.
14. Nasu K, Tsuchikane E, Katoh O, et al. Plaque characterization by virtual histology intravascular ultrasound analysis in patients with type II diabetes. Heart. 2008;4:429-433.
15. Yang DY, Lee MS, Kim WH, et al. The impact of glucose control on coronary plaque composition in patients with diabetes mellitus. J Invasive Cardiol. 2013;3:137-141.
16. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure. JAMA. 2004;292:2217-2225.
17. Baber U, Stone GW, Weisz G, et al. Coronary plaque composition, morphology and outcomes in patients with and without chronic kidney disease presenting with acute coronary syndromes. JACC Cardiovasc Imaging. 2012;5:S53-S61.
18. Kramer H, Toto R, Peshock R, et al. Association between chronic kidney disease and coronary artery calcification: the Dallas Heart Study. J Am Soc Nephrol. 2005; 16: 507-513.
19. Perco P, Pleban C, Kainz A, et al. Protein biomarkers associated with acute renal failure and chronic kidney disease. Eur J Clin Invest. 2006;36:753-763.
20. Gopalakrishnan M, Silva-Palacios F, Taytawat P, et al. Role of inflammatory mediators in the pathogenesis of plaque rupture. J Invasive Cardiol. 2014;26:484-492.
21. Klein LW. Clinical implications and mechanisms of plaque rupture in the acute coronary syndromes. Am Heart Hosp J. 2005;3:249-255.

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From Advocate Illinois Masonic Medical Center and Rush Medical College, Chicago,  Illinois.

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

Address for correspondence: Lloyd W. Klein MD, 3000 North Halsted Avenue, Suite #625, Chicago, IL 60657. Email: lloydklein@comcast.net