Cigarette Smoking and Cardiovascular Health

Volume 4, Jul 2015

Kushagra Mahansaria, MD, MPH, MBA, Ravi R Kasliwal, MD, DM, Gurgaon, India

J Clin Prev Cardiol 2015;4(3):58-65

Introduction

In their pathogenesis, cardiovascular diseases (CVDs) are among the most complex human diseases. The interplay of genes, lifestyle, and the environment defines the onset, mode of initiation, location and type of cardiovascular outcome. The myriads of risk factors, physiochemical interactions, cell types, and biological processes involved add to the complexity of these diseases (1-4). ). In the 1960s, the US Surgeon General and American Heart Association issued reports warning of the dangers of smoking on fatal coronary artery disease (5-7). Since those early publications, 32 US Surgeon General reports have been released exposing the harmful effects of cigarette smoking on cardiovascular health (8,9). The 1983 Surgeon General's Report (10) was devoted entirely to cardiovascular disease. It concluded that cigarette smoking is one of the three major independent risk factors for heart disease. It also concluded that the magnitude of the risk associated with cigarette smoking is similar to that associated with the other two major heart disease risk factors, hypertension and hypercholesterolemia. CVDs caused by cigarette smoke are mediated through multiple interrelated mechanisms, including increased oxidative stress, endothelial injury and dysfunction, altered blood coagulation, and derangements of lipid composition and metabolism (11); all leading to the principal pathophysiological mechanism of coronary thrombosis and atherosclerosis (12). This article serves to provide a brief summary of the current literature on the mechanisms by which cigarette smoke causes CVDs.


Patho-physiological Effects of Cigarette Smoking

Effects on endothelium

Endothelial cells maintain a delicate balance between (a) vasodilating (NO, prostacyclin [PGI2]) and vasoconstricting (endothelin-1) factors; (b) thrombotic (tissue Factor) and antithrombotic (tissue factor pathway inhibitor-1 [TFPI-1] and thrombin activatable fibrinolysis inhibitor) factors; as well as, (c) fibrinolytic (tissue-plasminogen activator [t-PA]) and antifibrinolytic factors (plasminogen activator inhibitor-1 [PAI-1]) (13-15). Nitric Oxide (NO) and PGI2 have direct antithrombogenic effects because they inhibit platelet activation and aggregation by a cGMP-dependent mechanism (13-15). It has been demonstrated that exposure to cigarette smoke decreases NO by altering the expression and activity of the endothelial NO synthase enzyme (16,17). It is proposed that decreases in endothelial derived NO occur via two mechanisms. First is via decreasing the bioavailability of NO by scavenging activity of free radicals derived from cigarette smoke (18,19). Second, cigarette smoke exposure alters endothelial NO synthase protein and its activity, thereby decreasing NO availability (16,17). Since NO helps regulate inflammation, leukocyte adhesion, platelet activation, and thrombosis; an alteration in NO biosynthesis would cause both primary and secondary effects on the initiation and progression of thrombotic events and contributing to all stages of atherosclerotic plaque formation (13,14).


Proinflammatory effects

Cigarette smoke has been found to be associated with increased levels of multiple inflammatory markers, including peripheral leukocytosis, C-reactive protein, homocysteine, interleukin-6, and tumor necrosis factor-α (20-22). Inflammation is known to constitute an essential element in atherogenesis. Smokers were shown to have significantly elevated white blood cell counts, which was tightly correlated to the formation of carotid atherosclerotic plaques (23). Lavi et al (24) reported increased levels of neutrophils, lymphocytes, and monocytes in smokers when compared with nonsmokers in patients with chest pain and early coronary artery disease. These systemic immunologic alterations were found to correlate with local processes within the atherosclerotic plaque, characterized by inflammation and increased expression of matrix metalloproteinases (25).

Lipid modification

Effects of cigarette smoke on lipids have also been extensively studied. Earlier studies by Craig et al (26) demonstrated that cigarette smoke quantitatively affects lipid profiles by finding a statistically significant correlation between smoking and increased total serum cholesterol, very–low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and triglyceride (TG) serum concentrations. They also found HDL and Apolipoprotein A1 levels to be decreased in smokers, in a dose-dependent manner. Subsequent studies reinforced that smoking modifies serum lipid profiles in a proatherogenic manner (27,28).

Increased oxidative stress

Free radicals and oxidants present in cigarette smoke, combined with endogenously produced oxidants and radicals cause a pro-oxidative environment leading to in vivo oxidative stress (29). This oxidative stress is shown to change lipids qualitatively demonstrated by reported increased presence of lipid peroxidation products in the serum of smokers (30), and by increased levels of circulating autoantibodies against oxidized LDL (31). It is suggested that peroxynitrite (generated by a reaction between NO and superoxide anion) is involved in the impairment of in vivo antioxidant systems leading to the oxidative modification of LDL in smokers’ blood (32-34). Since only oxidatively modified LDLs are taken up by macrophages and transformed into foam cells, it is implicated that in vivo the oxidation of lipids is another way by which smoking induces and accelerates atherosclerosis.

Effects of Cigarette Smoke on Vascular Structure and Function

In view of the diagnostic, prognostic and therapeutic significance of endothelial function and arterial stiffness, a number of non-invasive techniques have been introduced for their assessment. These include flow-mediated dilation (FMD), finger plethysmography (RH-PAT), digital thermal monitoring (DTM), pulse wave analysis (PWA), pulse wave velocity (PWV), pulse contour analysis (PCA) and carotid wall distensibility coefficient (DC), carotid intima-media thickness (cIMT) (35-40) and ankle brachial index (ABI) (41,42). Kasliwal et al demonstrated the role of brachial artery FMD for detecting subclinical atherosclerosis (43) and its association with coronary artery disease (44) in the Indian population. The role of cIMT as a predictor of CAD in Indians has also been well-established (45-47).

The relationship between FMD and IMT has also been studied to some detail, but the results are inconsistent (48). In The Cardiovascular Risk in Young Finns study (49) brachial FMD was inversely associated with cIMT in a multivariate model adjusted for age, sex, brachial vessel size, and several other risk variables. When comparing brachial FMD and cIMT to Framingham Risk Scores (FRS) in African Americans (50), significant inverse relation between FMD and FRS was found, but IMT was not statistically different among the risk groups. However, in a study comparing FMD, CFVR and IMT to the Framingham Risk Score in patients without clinical atherosclerosis, IMT correlated best with the Framingham score (51). Within Indian subsets, similar inverse correlation of cIMT and brachial FMD was found in diabetic patients (52) along with significant correlation between cIMT and brachial-ankle PWV in patients with coronary artery disease but no correlation in individuals without major atherosclerotic vascular disease (53).

Effects of smoking on FMD

A landmark study in 1993 by Celermajer et al (54) showed that continuous smoking impairs brachial FMD in a dose-dependent manner in healthy young adults. FMD was observed in all the control subjects (10 ± 33%; range 4% to 22%) but was impaired or absent in the smokers (4 ± 3.9%; range 0% to 17%; P<0.0001). FMD in the smokers was inversely related to lifetime dose smoked (6.6 ± 4.0% in very light smokers, 4.0 ± 3.1% in light smokers, 3.2 ± 3.2% in moderate smokers, and 2.6 ± 1.2% in heavy smokers; P<0.01).

Zeiher et al (55) showed that long-term cigarette smoking is independently associated with impaired endothelium-dependent coronary vasodilation with a reduced flow-dependent dilator response of epicardial arteries regardless of the presence or absence of coronary atherosclerotic lesions. Since then, numerous studies have evaluated the effect of cigarette smoke FMD with similar results (56-60).

Effects of smoking on cIMT

Two of the earliest population-based studies linking cigarette smoke exposure to decreased cIMT were both published in 1994. The Cardiovascular Health Study (61) found that increased smoking (current smokers>former smokers>never-smokers) led to significantly greater internal and common carotid wall thickening and internal carotid stenosis. Also, a significant dose response relation was seen with pack years of smoking: the prevalence of clinically significant (>50%) internal carotid stenosis increased from 4.4% in never-smokers to 7.3% in former smokers to 9.5% in current smokers. Similar results were published in The Atherosclerosis Risk in Communities Study (62) which confirmed that increase in exposure to cigarette smoke was significantly related to increased IMT. Subsequently, a score of studies evaluated the effects of chronic cigarette smoking on cIMT with comparable results (63-70).

Few studies also looked at acute cigarette smoke exposure. It was found that smoking even 1 cigarette caused similar effects to chronic cigarette exposure by acutely increasing cIMT, heart rate and blood pressure (71) including increased platelet dependent thrombin levels (72) leading to increased vulnerability of plaque rupture. Moreover, smokers had sustained and more intensive unfavorable effects in endothelial function than non-smokers after smoking one cigarette: endothelial dysfunction after smoking (measured by reduction in FMD), remained significant for 1 hour in smokers, but only for 30 min in non-smokers. FMD 1 hour after smoking was significantly higher in non-smokers than in smokers (73).

A recent study revealed that smoking light cigarettes impairs FMD as much as smoking regular cigarettes, arguing against light cigarettes as a less harmful alternative (74). Similarly, consumption of light cigarettes did not reduce the atherogenic effect of smoking on cIMT. No differences were found in cIMT (75) or CFVR (76) between smokers of cigarettes with high or low nicotine, tar, or carbon monoxide content strengthening the case for a dose dependence on the number of pack years smoked rather than the strength of the ingredients of the cigarette.


Effect of cigarette smoke on clinical outcomes

The effects of cigarette smoking on vascular physiology, structure and function translate directly, and correspond to clinical outcomes related to the cardiovascular system (77). Numerous studies have documented that exposure to cigarette smoke increases the risk of developing myocardial infarction multifolds (78-80). It also increases the risk of developing heart failure (81,82), number of admissions due to heart failure (83), and the duration of heart failure related hospital stay.

Cigarette smoke exposure was has also been shown to increase the risk of peripheral artery disease (84,85) including increased odds of developing abdominal aortic aneurysms (86,87). Additionally, cigarette smoking universally increases the risk for stroke in both men and women of multiple ethnicities (88).

Apart from vascular disease, cigarette smoking also increases the risk of developing new arrhythmias in a dose-dependent manner (89-92). Many large observational studies including the Rotterdam Study (93) and the ARIC Study (94) have found that the incidence of atrial fibrillation was almost twice as high in current smokers than never smokers after adjusting for other independent risk factors. The risk of ventricular tachycardia and ventricular fibrillation as assessed by number of shocks delivered by implantable cardioverter-defibrillator was also higher in smokers as compared to non-smokers (95,96). The risk of sudden cardiac death also increased dose-dependently in smokers when compared to ex-smokers or non-smokers (97).

In patients who have undergone revascularization through either PCI or CABG, continued exposure to cigarette smoke is associated with increased incidences of adverse clinical outcomes (98) including stent thrombosis (99-101) or graft occlusion (102,103), new MI and reinfarction (104-106), and increased length of hospital stay (107).


Effects of Passive Smoke

Having established through numerous studies that active cigarette smoking increases the risk of developing cardiovascular diseases multifold, the paradigm shifted to the evaluation of the effect of passive smoking. One of the first reports indicating the detrimental effects of passive smoking was published in 1986 by the US Surgeon General (108,109). Further research has shown that the mechanisms by which passive smoking affects the cardiovascular system is the same as active smoking, which includes endothelial dysfunction, increased oxidative stress, lipid modification, platelet activation and a pro-inflammatory state (110). Individuals are exposed to 2 types of passive smoking: second hand smoke (SHS) and environmental tobacco smoke (ETS). In a review of 10 published epidemiological studies, it was found that ETS affected the cardiovascular system in the same was as active smoking did (111).

SHS has two main components: sidestream and mainstream smoke. Sidestream smoke emerges from the tip of a burning cigarette and accounts for 85% of the total amount of SHS. The remaining 15% is made up of mainstream smoke, which has been inhaled and is exhaled by an active smoker (112,113). The concentration of numerous toxins has been shown to be dramatically (up to 100-fold) elevated in sidestream smoke when compared with mainstream smoke. Additionally, the particles in sidestream smoke are smaller than those in mainstream smoke, allowing them to be deeply inhaled in the lungs and underscoring the potential adverse impact of SHS on health (114).

A large meta-analysis (115) of 18 studies found that nonsmokers exposed to environmental smoke had a relative risk of coronary heart disease of 1.25 (P<0.001) as compared with nonsmokers not exposed to smoke. Passive smoking was consistently associated with an increased relative risk of coronary heart disease in both cohort and case–control studies, irrespective of gender or exposure at home or work. A significant dose–response relation was identified, with respective relative risks of 1.23 and 1.31 for non- smokers who were exposed to the smoke of 1 to 19 cigarettes per day and those who were exposed to the smoke of 20 or more cigarettes per day, as compared with nonsmokers not exposed to smoke.

Many studies also evaluated the effect of exposure to passive smoking in childhood to the risk of cardiovascular diseases in adulthood (116-118). The most notable results were published by West et al in The Cardiovascular Risk in Young Finns Study (119) where during a 26 year follow-up period, it was found that childhood exposure to passive smoking was associated with carotid atherosclerotic plaque in young adults. Again, the risk was dose dependent; children living in households where both parents smoked were at higher risk when compared to households where only one parent smoked.

Benefits of Smoking Cessation

Though cigarette smoke exposure leads to detrimental effects on the human body and especially on the cardiovascular system, it was found that these effects could potentially be reversed through smoking cessation (33,58,110). Improvements in both FMD and cIMT values were found in as little as 1 year post smoking cessation in active smokers (22,41,56,112,118). A meta-analysis of 20 studies showed a 36% reduction in the crude relative risk of mortality for patients with coronary heart disease who quit smoking compared with those who continued smoking. Smoking cessation also leads to an exponential reduction in acute cardiovascular events, particularly in the first year after quitting (120).


A notable effect of smoking cessation was seen on second hand smoke. It was noted in various cities across the globe that public smoking bans resulted in fewer hospitalizations due to cardiovascular events including acute myocardial infarction and stroke (121-123). Some of these results were apparent in as little as 6 months after enforcement of the ban legislature (124). Several meta-analyses have also been conducted to support the relation between decline in acute cardiac events and implementation of smoking ban legislature (125-127). A recent meta-analysis concluded that public smoking bans reduced hospital admissions due to various conditions not only limited to cardiovascular events. These included reduced hospital admissions due to causes like acute coronary events (including acute myocardial infarction, acute coronary syndrome, angina and ischemic heart disease), sudden cardiac death, stroke, transient ischemic attack, chronic obstructive pulmonary disease, asthma, lung infections, and spontaneous pneumothorax (128). The study also concluded that more comprehensive laws were associated with greater reductions in risk.


Conclusion

Smoking kills 6 million humans per year, with ≈10% of these deaths related to secondhand smoking. Smoking is responsible for an alarming but preventable 10% of CVDs (129). New research suggests that the effects of passive smoking are largely underestimated and these effects might be as large as active smoking itself (130). Cigarette smoke consists of more than 4000 different chemicals, most of which have not been identified or investigated. Consequently, the mechanisms by which cigarette smoke affects cardiovascular functions are still poorly understood. Smoking plays a strong role not only in CVD initiation but also significantly contributes to and causes disease progression and fatal cardiovascular outcomes. Therefore, smoking cessation still remains the cornerstone of the strategy to reduce the mortality and morbidity associated with smoking. It has been demonstrated through various studies that cessation of smoking not only benefits the smoker, but also that smoke-free laws are followed by fewer hospitalizations and lower healthcare expenditures for a wide range of diseases and that comprehensive laws ending smoking in workplaces, restaurants, and bars are associated with greater effects. The general public, health professionals, and policy makers should consider these positive associations as they develop smoking cessation programs.


References

1. McBride PE. The health consequences of smoking. Cardiovascular diseases. The Medical Clinics of North America. 1992;76(2):333-353.
2. Health UDo, Services H. The health consequences of using smokeless tobacco: a report of the advisory committee to the Surgeon General. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute. DHHS Publication No.(NIH); 1986.
3. Kannel WB, Doyle JT, Fredrickson DT, Harlan WR, Jr. American Heart Association report of ad hoc committee on cigarette smoking and cardiovascular diseases. Circulation. 1978;57(2):406A-407A.
4. Sharma M, Ganguly NK. Premature Coronary Artery Disease in Indians and its Associated Risk Factors. Vascular Health and Risk Management. 2005;1(3):217-225.
5. Cigarette Smoking and Cardiovascular Diseases: REPORT BY THE AMERICAN HEART ASSOCIATION. Circulation. 1960;22(1):160-166.
6. The health consequences of smoking: A Public Health Service review. Revised US Government Printing Office, Washington, DC (PHS Publication, No 1696). 1968.
7. Smoking and health: report of the Advisory Committee to the Surgeon General of the public health service. 1964.
8. The Health Consequences of Smoking-50 Years of Progress: A Report of the Surgeon General. Atlanta (GA)2014.
9. Alberg AJ, Shopland DR, Cummings KM. The 2014 Surgeon General's Report: Commemorating the 50th Anniversary of the 1964 Report of the Advisory Committee to the US Surgeon General and Updating the Evidence on the Health Consequences of Cigarette Smoking. American Journal of Epidemiology. 2014;179(4):403-412.
10. SERVCES USDOHAH. The Health Consequences of Smoking - Cardiovascular Disease: A Report of the Surgeon General. Rockville, Maryland 1983.
11. Grundy SM. Role of low-density lipoproteins in atherogenesis and development of coronary heart disease. Clin Chem. 1995;41(1):139-146.
12. Barua RS, Ambrose JA. Mechanisms of coronary thrombosis in cigarette smoke exposure. Arteriosclerosis, thrombosis, and vascular biology. 2013;33(7):1460-1467.
13. Napoli C, Ignarro LJ. Nitric oxide and atherosclerosis. Nitric oxide. 2001;5(2):88-97.
14. Loscalzo J. Nitric oxide insufficiency, platelet activation, and arterial thrombosis. Circ Res. 2001;88(8):756-762.
15. Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V,  Ignarro LJ. Nitric oxide and atherosclerosis: an update. Nitric oxide. 2006;15(4):265-279.
16. Barua RS, Ambrose JA, Srivastava S, DeVoe MC, Eales-Reynolds LJ. Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation. 2003;107(18):2342-2347.
17. Barua RS, Ambrose JA, Eales-Reynolds LJ, DeVoe MC, Zervas JG, Saha DC. Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation. Circulation. 2001;104(16):1905-1910.
18. Pryor WA, Stone K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann N Y Acad Sci. 1993;686:12-27; discussion 27-18.
19. Pittilo RM, Mackie IJ, Rowles PM, Machin SJ, Woolf N. Effects of cigarette smoking on the ultrastructure of rat thoracic aorta and its ability to produce prostacyclin. Thromb Haemost. 1982;48(2):173-176
20. Bermudez EA, Rifai N, Buring JE, Manson JE, Ridker PM. Relation between markers of systemic vascular inflammation and smoking in women. The American journal of cardiology. 2002;89(9):1117-1119.
21. Tracy RP, Psaty BM, Macy E, et al. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol. 1997;17(10):2167-2176.
22. McEvoy JW, Nasir K, DeFilippis AP, et al. Relationship of Cigarette Smoking With Inflammation and Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35(4):1002-1010.
23. Ishizaka N, Ishizaka Y, Toda E-i, Hashimoto H, Nagai R, Yamakado M. Association between white blood cell count and carotid arteriosclerosis in Japanese smokers. Atherosclerosis. 2004;175(1):95-100.
24. Lavi S, Prasad A, Yang EH, et al. Smoking is associated with epicardial coronary endothelial dysfunction and elevated white blood cell count in patients with chest pain and early coronary artery disease. Circulation. 2007;115(20):2621-2627.
25. Kangavari S, Matetzky S, Shah PK, et al. Smoking increases inflammation and metalloproteinase expression in human carotid atherosclerotic plaques. J Cardiovasc Pharmacol Ther. 2004;9(4):291-298.
26. Craig WY, Palomaki GE, Haddow JE. Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. BMJ. 1989;298(6676):784-788.
27. Nakamura K, Barzi F, Huxley R, et al. Asia Pacific Cohort Studies Collaboration: Does cigarette smoking exacerbate the effect of total cholesterol and high-density lipoprotein cholesterol on the risk of cardiovascular diseases. Heart. 2009;95:909-916.
28. Freedman DS, Srinivasan SR, Shear CL, et al. Cigarette smoking initiation and longitudinal changes in serum lipids and lipoproteins in early adulthood: the Bogalusa Heart Study. Am J Epidemiol. 1986;124(2):207-219.
29. Garbin U, Fratta Pasini A, Stranieri C, et al. Cigarette smoking blocks the protective expression of Nrf2/ARE pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation. PLoS One. 2009;4(12):e8225.
30. Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers—smoking as a cause of oxidative damage. New England Journal of Medicine. 1995;332(18):1198-1203.
31. Salonen JT, Yla-Herttuala S, Yamamoto R, et al. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992;339(8798):883-887.
32. Yamaguchi Y, Haginaka J, Morimoto S, Fujioka Y, Kunitomo M. Facilitated nitration and oxidation of LDL in cigarette smokers. Eur J Clin Invest. 2005;35(3):186-193.
33. Pilz H, Oguogho A, Chehne F, Lupattelli G, Palumbo B, Sinzinger H. Quitting cigarette smoking results in a fast improvement of in vivo oxidation injury (determined via plasma, serum and urinary isoprostane). Thromb Res. 2000;99(3):209-221.
34. Reilly M, Delanty N, Lawson JA, FitzGerald GA. Modulation of oxidant  stress in vivo in chronic cigarette smokers. Circulation. 1996;94(1):19-25.
35. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of Clinical Cardiovascular Events With Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis. Circulation. 2007;115(4):459-467.
36. Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: The multi-ethnic study of atherosclerosis (mesa). Archives of Internal Medicine. 2008;168(12):1333-1339.
37. O'Leary DH, Bots ML. Imaging of atherosclerosis: carotid intima–media thickness. European Heart Journal. 2010;31(14):1682-1689.
38. Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M. Carotid Intima-Media Thickening Indicates a Higher Vascular Risk Across a Wide Age Range: Prospective Data From the Carotid Atherosclerosis Progression Study (CAPS). Stroke. 2006;37(1):87-92.
39. Stein JH, Korcarz CE, Hurst RT, et al. Use of Carotid Ultrasound to Identify Subclinical Vascular Disease and Evaluate Cardiovascular Disease Risk: A Consensus Statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force Endorsed by the Society for Vascular Medicine. Journal of the American Society of Echocardiography.21(2):93-111.
40. Postley JE, Perez A, Wong ND, Gardin JM. Prevalence and Distribution of Sub-Clinical Atherosclerosis by Screening Vascular Ultrasound in Low and Intermediate Risk Adults: The New York Physicians Study. Journal of the American Society of Echocardiography.22(10):1145-1151.
41. Frolow M, Drozdz A, Kowalewska A, Nizankowski R, Chlopicki S. Comprehensive assessment of vascular health in patients; towards endothelium-guided therapy. Pharmacological Reports. 2015;67(4):786-792.
42. Widlansky ME, Gokce N, Keaney JJF, Vita JA. The clinical implications of endothelial dysfunction. Journal of the American College of Cardiology. 2003;42(7):1149-1160.
43. Kasliwal RR. Brachial artery flow-mediated dilatation for detecting subclinical atherosclerosis. Indian heart journal. 2003;55(3):282-283; author reply 283-285.
44. Tandon S, Bhargava K, Gupta H, Bansal M, Kasliwal RR. Non-invasive assessment of endothelial function by brachial artery flow mediated vasodilatation and its association with coronary artery disease: an Indian perspective. Journal of the Indian Medical Association. 2004;102(5):243-246, 251-242.
45. Kasliwal RR, Bansal M, Desai D, Sharma M. Carotid intima–media thickness: Current evidence, practices, and Indian experience. Indian Journal of Endocrinology and Metabolism. 2014;18(1):13-22.
46. Kasliwal RR, Bansal M, Gupta H, Agrawal S. Association of carotid intima-media thickness with left main coronary artery disease. Indian heart journal. 2007;59(1):50-55.
47. Hansa G, Bhargava K, Bansal M, Tandon S, Kasliwal RR. Carotid Intima-Media Thickness and Coronary Artery Disease: An Indian Perspective. Asian Cardiovascular and Thoracic Annals. 2003;11(3):217-221.
48. Gijsberts CM, Groenewegen KA, Hoefer IE, et al. Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events. PLoS ONE. 2015;10(7):e0132321.
49. Juonala M, Viikari JSA, Laitinen T, et al. Interrelations Between Brachial Endothelial Function and Carotid Intima-Media Thickness in Young Adults: The Cardiovascular Risk in Young Finns Study. Circulation. 2004;110(18):2918-2923.
50. Kwagyan J, Hussein S, Xu S, et al. The Relationship Between Flow-Mediated Dilatation of the Brachial Artery and Intima-Media Thickness of the Carotid Artery to Framingham Risk Scores in Older African Americans. The Journal of Clinical Hypertension. 2009;11(12):713-719.
51. Campuzano R, Moya JL, García-Lledó A, et al. Endothelial dysfunction, intima–media thickness and coronary reserve in relation to risk factors and Framingham score in patients without clinical atherosclerosis. Journal of Hypertension. 2006;24(8):1581-1588.
52. Kasliwal RR, Agrawal S, Bansal M. Carotid Intima-Media Thickness and Brachial Artery Flow-Mediated Dilatation in Patients with and without Metabolic Syndrome. Indian heart journal. 2006;58(1):42-46.
53. Kasliwal RR, Bansal M, Bhargava K, Gupta H, Tandon S, Agrawal V. Carotid intima-media thickness and brachial-ankle pulse wave velocity in patients with and without coronary artery disease. Indian heart journal. 2004;56(2):117-122.
54. Celermajer DS, Sorensen K, Gooch V, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. The Lancet. 1992;340(8828):1111-1115.
55. Zeiher AM, Schachinger V, Minners J. Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation. 1995;92(5):1094-1100.
56. Johnson HM, Gossett LK, Piper ME, et al. Effects of Smoking and Smoking Cessation on Endothelial Function: One-Year Outcomes from a Randomized Clinical Trial. Journal of the American College of Cardiology. 2010;55(18):1988-1995.
57. Neunteufl T, Heher S, Kostner K, et al. Contribution of nicotine to acute endothelial dysfunction in long-term smokers. Journal of the American College of Cardiology. 2002;39(2):251-256.
58. Stadler RW, Ibrahim SF, Lees RS. Measurement of the time course of peripheral vasoactivity: results in cigarette smokers. Atherosclerosis.138(1):197-205.
59. Tanriverdi H, Evrengul H, Kuru O, et al. Cigarette Smoking Induced Oxidative Stress may Impair Endothelial Function and Coronary Blood Flow in Angiographically Normal Coronary Arteries. Circulation Journal. 2006;70(5):593-599.
60. Thomas GN, Chook P, Yip TWC, et al. Smoking without exception adversely affects vascular structure and function in apparently healthy Chinese: Implications in global atherosclerosis prevention. International Journal of Cardiology.128(2):172-177.
61. Tell GS, Polak JF, Ward BJ, Kittner SJ, Savage PJ, Robbins J. Relation of smoking with carotid artery wall thickness and stenosis in older adults. The Cardiovascular Health Study. The Cardiovascular Health Study (CHS) Collaborative Research Group. Circulation. 1994;90(6):2905-2908.
62. Howard G, Burke GL, Szklo M, et al. Active and passive smoking are associated with increased carotid wall thickness: The atherosclerosis risk in communities study. Archives of Internal Medicine. 1994;154(11):1277-1282.
63. Sharrett AR, Ding J, Criqui MH, et al. Smoking, diabetes, and blood cholesterol differ in their associations with subclinical atherosclerosis: The Multiethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2006;186(2):441-447.
64. Fan AZ, Paul-Labrador M, Merz CNB, Iribarren C, Dwyer JH. Smoking status and common carotid artery intima-medial thickness among middle-aged men and women based on ultrasound measurement: a cohort study. BMC Cardiovascular Disorders. 2006;6:42-42.
65. Corrado E, Muratori I, Tantillo R, Contorno F. Relationship between endothelial dysfunction, intima media thickness and cardiovascular risk factors in asymptomatic subjects. International Angiology. 2005;24(1):52.
66. Richey Sharrett A, Coady SA, Folsom AR, Couper DJ, Heiss G. Smoking and diabetes differ in their associations with subclinical atherosclerosis and coronary heart disease—the ARIC Study. Atherosclerosis. 2004;172(1):143-149.
67. Esen AM, Barutcu I, Acar M, et al. Effect of Smoking on Endothelial Function and Wall Thickness of Brachial Artery. Circulation Journal. 2004;68(12):1123-1126.
68. Poredoš P, Orehek M, Tratnik E, Poredoš P. Smoking is Associated with Dose-Related Increase of Intima-Media Thickness and Endothelial Dysfunction. Angiology. 1999;50(3):201-208.
69. Howard G, Wagenknecht LE, Burke GL, et al. Cigarette smoking and progression of atherosclerosis: The atherosclerosis risk in communities (aric) study. JAMA. 1998;279(2):119-124.
70. Belcaro G, Nicolaides AN, Ramaswami G, et al. Carotid and femoral ultrasound morphology screening and cardiovascular events in low risk subjects: a 10-year follow-up study (the CAFES-CAVE study1). Atherosclerosis.156(2):379-387.
71. Kool MJF, Hoeks APG, Struijker Boudier HAJ, Reneman RS, Van Bortel LMAB. Short and long-term effects of smoking on arterial wall properties in habitual smokers. Journal of the American College of Cardiology. 1993;22(7):1881-1886.
72. Hioki H, Aoki N, Kawano K, et al. Acute effects of cigarette smoking on platelet-dependent thrombin generation. European Heart Journal. 2001;22(1):56-61
73. Karatzi K, Papamichael C, Karatzis E, et al. Acute smoke-induced endothelial dysfunction is more prolonged in smokers than in non-smokers. International Journal of Cardiology.120(3):404-406.
74. Amato M, Frigerio B, Castelnuovo S, et al. Effects of smoking regular or light cigarettes on brachial artery flow-mediated dilation. Atherosclerosis.228(1):153-160.
75. Baldassarre D, Castelnuovo S, Frigerio B, et al. Effects of Timing and Extent of Smoking, Type of Cigarettes, and Concomitant Risk Factors on the Association Between Smoking and Subclinical Atherosclerosis. Stroke. 2009;40(6):1991-1998.
76. Gullu H, Caliskan M, Ciftci O, et al. Light cigarette smoking impairs coronary microvascular functions as severely as smoking regular cigarettes. Heart. 2007;93(10):1274-1277.
77. Morris PB, Ference BA, Jahangir E, et al. Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic CigarettesClinical Perspectives From the Prevention of Cardiovascular Disease Section Leadership Council and Early Career Councils of the American College of Cardiology. Journal of the American College of Cardiology. 2015;66(12):1378-1391.
78. Aronow WS, Kaplan MA, Jacob D. Tobacco: a precipitating factor in angina pectoris. Annals of internal medicine. 1968;69(3):529-536.
79. Parish S, Collins R, Peto R, et al. Cigarette smoking, tar yields, and non-fatal myocardial infarction: 14000 cases and 32000 controls in the United Kingdom. BMJ. 1995;311(7003):471-477.
80. Willett WC, Green A, Stampfer MJ, et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. New England Journal of Medicine. 1987;317(21):1303-1309.
81. Gopal DM, Kalogeropoulos AP, Georgiopoulou VV, et al. Cigarette smoking exposure and heart failure risk in older adults: The Health, Aging, and Body Composition Study. American heart journal. 2012;164(2):236-242.
82. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Archives of internal medicine. 2001;161(7):996-1002.
83. Evangelista LS, Doering LV, Dracup K. Usefulness of a history of tobacco and alcohol use in predicting multiple heart failure readmissions among veterans. The American journal of cardiology. 2000;86(12):1339-1342.
84. Lu J, Creager M. The relationship of cigarette smoking to peripheral arterial disease. Reviews in cardiovascular medicine. 2003;5(4):189-193.
85. Willigendael EM, Teijink JA, Bartelink M-L, et al. Influence of smoking on incidence and prevalence of peripheral arterial disease. Journal of vascular surgery. 2004;40(6):1158-1165.
86. Cornuz J, Pinto CS, Tevaearai H, Egger M. Risk factors for asymptomatic abdominal aortic aneurysm. The European Journal of Public Health. 2004;14(4):343-349.
87. Guirguis-Blake JM, Beil TL, Sun X, Senger CA, Whitlock EP. Primary Care Screening for Abdominal Aortic Aneurysm. 2014.
88. Stackelberg O, Björck M, Larsson S, Orsini N, Wolk A. Sex differences in the association between smoking and abdominal aortic aneurysm. British Journal of Surgery. 2014;101(10):1230-1237.
89. Benjamin EJ, Levy D, Vaziri SM, D'Agostino RB, Belanger AJ, Wolf PA. Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. Jama. 1994;271(11):840-844.
90. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. The American journal of medicine. 1995;98(5):476-484.
91. Krishnamoorthy S, Lim SH, Lip GY. Assessment of endothelial (dys) function in atrial fibrillation. Annals of medicine. 2009;41(8):576-590.
92. Li J, Solus J, Chen Q, et al. Role of inflammation and oxidative stress in atrial fibrillation. Heart Rhythm. 2010;7(4):438-444.
93. Heeringa J, Kors JA, Hofman A, van Rooij FJ, Witteman JC. Cigarette smoking and risk of atrial fibrillation: the Rotterdam Study. American heart journal. 2008;156(6):1163-1169.
94. Chamberlain AM, Agarwal SK, Folsom AR, et al. Smoking and incidence of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) study. Heart Rhythm. 2011;8(8):1160-1166.
95. Daubert JP, Zareba W, Cannom DS, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. Journal of the American College of Cardiology. 2008;51(14):1357-1365.
96. Goldenberg I, Moss AJ, McNITT S, et al. Cigarette Smoking and the Risk of Supraventricular and Ventricular Tachyarrhythmias in High Risk Cardiac Patients with Implantable Cardioverter Defibrillators. Journal of cardiovascular electrophysiology. 2006;17(9):931-936.
97. Sandhu RK, Jimenez MC, Chiuve SE, et al. Smoking, Smoking Cessation and Risk of Sudden Cardiac Death in Women. Circulation: Arrhythmia and Electrophysiology. 2012:CIRCEP. 112.975219.
98. Zhang YJ, Iqbal J, van Klaveren D, et al. Smoking is associated with adverse clinical outcomes in patients undergoing revascularization with PCI or CABG: the SYNTAX trial at 5-year follow-up. J Am Coll Cardiol. 2015;65(11):1107-1115.
99. Chen T, Li W, Wang Y, Xu B, Guo J. Smoking status on outcomes after percutaneous coronary intervention. Clinical cardiology. 2012;35(9):570-574.
100. Haddock CK, Poston WS, Taylor JE, Conard M, Spertus J. Smoking and health outcomes after percutaneous coronary intervention. American heart journal. 2003;145(4):652-657.
101. Hasdai D, Garratt KN, Grill DE, Lerman A, Holmes Jr DR. Effect of smoking status on the long-term outcome after successful percutaneous coronary revascularization. New England Journal of Medicine. 1997;336(11):755-761.
102. Iqbal J, Vergouwe Y, Bourantas CV, et al. Predicting 3-year mortality after percutaneous coronary intervention: updated logistic clinical SYNTAX score based on patient-level data from 7 contemporary stent trials. JACC: Cardiovascular Interventions. 2014;7(5):464-470.
103. Zhang Y-J, Iqbal J, van Klaveren D, et al. Smoking Is Associated With Adverse Clinical Outcomes in Patients Undergoing Revascularization With PCI or CABG: The SYNTAX Trial at 5-Year Follow-Up. Journal of the American College of Cardiology. 2015;65(11):1107-1115.
104. D'Ascenzo F, Bollati M, Clementi F, et al. Incidence and predictors of coronary stent thrombosis: evidence from an international collaborative meta-analysis including 30 studies, 221,066 patients, and 4276 thromboses. International journal of cardiology. 2013;167(2):575-584.
105. Grines CL, Topol EJ, O’Neill WW, et al. Effect of cigarette smoking on outcome after thrombolytic therapy for myocardial infarction. Circulation. 1995;91(2):298-303.
106. Stone SG, Serrao GW, Mehran R, et al. Incidence, Predictors, and Implications of Reinfarction After Primary Percutaneous Coronary Intervention in ST-Segment–Elevation Myocardial Infarction The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction Trial. Circulation: Cardiovascular Interventions. 2014;7(4):543-551.
107. Poole L, Kidd T, Leigh E, Ronaldson A, Jahangiri M, Steptoe A. Depression, C-reactive protein and length of post-operative hospital stay in coronary artery bypass graft surgery patients. Brain, behavior, and immunity. 2014;37:115-121.
108. Windom R. The health consequences of involuntary smoking. A report of the Surgeon General. U. S. DEPARTMENT HEALTH AND HUMAN SERVICE. 1986. 1986.
109. Health UDo, Services H. The health consequences of involuntary exposure to tobacco smoke: a report of the Surgeon General. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. 2006;709.
110. Raupach T, Schäfer K, Konstantinides S, Andreas S. Secondhand smoke as an acute threat for the cardiovascular system: a change in paradigm. European Heart Journal. 2006;27(4):386-392.
111. Glantz SA, Parmley WW. Passive smoking and heart disease .Epidemiology, physiology, and biochemistry. Circulation. 1991;83(1):1-12.
112. Hulka B. Environmental tobacco smoke: Measuring exposures and assessing health effects. World Health Statistics Quarterly. 1986;40(1).
113. Consortium A. Tobacco or health in the European Union: past, present and future. European Commission, Directorate General for Health and Consumer Protection; 2004.
114. Kritz H, Schmid P, Sinzinger H. Passive smoking and cardiovascular risk. Archives of internal medicine. 1995;155(18):1942-1948.
115. He J, Vupputuri S, Allen K, Prerost MR, Hughes J, Whelton PK. Passive Smoking and the Risk of Coronary Heart Disease — A Meta-Analysis of Epidemiologic Studies. New England Journal of Medicine. 1999;340(12):920-926.
116. Juonala M, Magnussen CG, Venn A, et al. Parental Smoking in Childhood and Brachial Artery Flow-Mediated Dilatation in Young Adults: The Cardiovascular Risk in Young Finns Study and the Childhood Determinants of Adult Health Study. Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;32(4):1024-1031.
117. Gall S, Huynh QL, Magnussen CG, et al. Exposure to parental smoking in childhood or adolescence is associated with increased carotid intima-media thickness in young adults: evidence from the Cardiovascular Risk in Young Finns study and the Childhood Determinants of Adult Health Study. European Heart Journal. 2014;35(36):2484-2491.
118. Mendelson MM, de Ferranti SD. Childhood Environmental Tobacco Smoke Exposure: A Smoking Gun for Atherosclerosis in Adulthood. Circulation. 2015;131(14):1231-1233.
119. West HW, Juonala M, Gall SL, et al. Exposure to Parental Smoking in Childhood is Associated with Increased Risk of Carotid Atherosclerotic Plaque in Adulthood: The Cardiovascular Risk in Young Finns Study. Circulation. 2015.
120. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review. Jama. 2003;290(1):86-97.
121. Bartecchi C, Alsever RN, Nevin-Woods C, et al. Reduction in the incidence of acute myocardial infarction associated with a citywide smoking ordinance. Circulation. 2006;114(14):1490-1496.
122. Cayla G, Sie P, Silvain J, et al. Short-term effects of the smoke-free legislation on haemostasis and systemic inflammation due to second hand smoke exposure. Thromb Haemost. 2011;105(6):1024-1031.
123. Pell JP, Haw S, Cobbe S, et al. Smoke-free legislation and hospitalizations for acute coronary syndrome. New England Journal of Medicine. 2008;359(5):482-491.
124. Sargent RP, Shepard RM, Glantz SA. Reduced incidence of admissions for myocardial infarction associated with public smoking ban: before and after study. Bmj. 2004;328(7446):977-980.
125. Lightwood JM, Glantz SA. Declines in acute myocardial infarction after smoke-free laws and individual risk attributable to secondhand smoke. Circulation. 2009;120(14):1373-1379.
126. Mackay D, Irfan M, Haw S, Pell J. Meta-analysis of the effect of comprehensive smoke-free legislation on acute coronary events. Heart. 2010:hrt. 2010.199026.
127. Meyers DG, Neuberger JS, He J. Cardiovascular effect of bans on smoking in public places: a systematic review and meta-analysis. Journal of the American College of Cardiology. 2009;54(14):1249-1255.
128. Tan CE, Glantz SA. Association Between Smoke-Free Legislation and Hospitalizations for Cardiac, Cerebrovascular, and Respiratory Diseases: A Meta-Analysis. Circulation. 2012;126(18):2177-2183.
129. Tobacco W. Fact sheet no 339. Geneva: World Health Organization, 2013.
130. Barnoya J, Glantz SA. Cardiovascular Effects of Secondhand Smoke: Nearly as Large as Smoking. Circulation. 2005;111(20):2684-2698.