Cardiovasc Toxicol DOI 10.1007/s12012-014-9280-0

Tobacco and Cardiovascular Health Prajeena Mainali • Sadip Pant • Alexis Phillip Rodriguez Abhishek Deshmukh • Jawahar L. Mehta

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Ó Springer Science+Business Media New York 2014

Abstract Tobacco consumption has been inextricably intertwined with society and its evolution. At one time, centuries ago, thought to be a sign of refinement and nobility, fortunately, this perception has been changing worldwide. Currently, this change in perception has been so dramatic that laws are enacted to limit tobacco exposure through second-hand smokers. Countless studies continue to emerge on tobacco’s healthcare toll to the point that we now consider indisputable facts that smokers have a higher incidence of coronary artery disease, peripheral vascular disease, chronic obstructive pulmonary disease, stroke, among many others. However, there are other less wellknown emerging facts that still require close attention such as the effect on the immune and hematopoietic systems. Tobacco smoke is injurious to all major organs in our bodies. With over 30 known carcinogens, it should not be surprising that it affects all aspects of human health. In this chapter, we will focus on the effects of tobacco on cardiovascular health.

P. Mainali Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA S. Pant (&)
A. Deshmukh
J. L. Mehta University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA e-mail: [email protected]; [email protected] A. P. Rodriguez University of Miami-Miller School of Medicine, Miami, FL, USA

Keywords Tobacco
Atherosclerosis
Hypertension
Coronary artery disease
Coronary revascularization
Aortic aneurysm
Peripheral arterial disease

Introduction Almost all societies have consumed tobacco for millennia. Cigarette smoking became widely popular among Americans with the arrival of the Europeans, and over the last century, cigarette smoking was accepted as norm. In the last two decades, there has been a shift in attitude toward cigarette smoking, especially after the realization of the social, economic, and medical burden of this habit. Although cigarette smoking has declined markedly in the last decade, in the USA alone, cigarette smoking claims roughly 440,000 deaths per year and about 5.4 million worldwide, which is likely to continue to increase unless cigarette smoking declines further [1, 2]. Cigarette smoking imposes a heavy economic toll on the society worth about $200 billion annually in health care and loss of productivity [1]. Considering these facts, many states as well as the US federal government have run campaigns aimed to educate consumers regarding the adverse effects of cigarette smoking and to implement clean indoor air and other policies designed to reduce smoking and protect people from secondhand smoke. New initiatives to thwart tobacco consumption include clean indoor air laws mandating smoke free public places and workplaces, age restriction, limiting advertisement, and increase in taxes among many others. These steps have successfully decreased the rate of tobacco sales and consumption; however, smokeless and water pipe tobacco are increasing in popularity. In actuality, these forms of tobacco products are becoming more prevalent in

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adolescents, especially among girls. Smokeless and water pipe tobacco both can be just as toxic as cigarette smoking. In 2010, the Surgeon General addressed the physiology behind tobacco dependence, especially in teenagers who can become readily addicted when exposed to tobacco [1]. Tobacco smoke affects all aspects of human health. Given that tobacco smoke contains thousands of chemicals with over 70 known carcinogens, it should not be surprising that there is no major organ that does not suffer the injurious effects [1, 2]. In this chapter, we will focus on the effects of tobacco on the cardiovascular system. In light of these effects, cigarette smoking remains one of the most important modifiable risk factors in the development and progression of coronary and peripheral vascular diseases [3].

Smoking and Atherosclerosis Scientific evidences linking cigarette smoking with cardiovascular diseases started to appear in mid-1960s. Since then, numerous studies have shown that tobacco exposure increases the risk of coronary, aortic and peripheral atherosclerosis as evidenced by the higher prevalence of acute coronary events, aortic aneurysms, and peripheral vascular disease in smokers [4–6]. There are multiple ways by which cigarette smoking can lead to the development and progression of atherosclerosis. All these pathways essentially lead to heightened inflammatory state, vasomotor dysregulation and oxidative stress [7].While the role of nicotine in atherogenesis has been stressed, there are many other chemically active ingredients in tobacco that are toxic to the vessel wall which are likely more important than nicotine. It is also important to recognize that smoking activates platelets and depresses endothelial function as well as induces a hyper-adrenergic state characterized by increase in heart rate, cardiac output, and blood pressure and thus can provoke acute cardiovascular events [8, 9]. The inflammatory state has been widely studied in smokers. This state encompasses the upregulation of T cells and monocytes as well as increased expression of proinflammatory cytokines, which in turn aid in further recruitment of leukocytes [10–12]. Smokers have been documented to have higher levels of intercellular adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E selectin [13]. There is also an increase in white blood cell counts (WBC) in blood, which some have hypothesized is due to enhanced leukocyte migration out of the bone marrow; other contributing factors might include higher incidence of chronic infections and their acute exacerbations in smokers [14, 15]. Leukocytes adhesion molecules

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such as CD 11 and 18 have been noted to be upregulated, but so are other pro-inflammatory markers such as C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-a) [16]. Another important element in the development of atherosclerosis with tobacco exposure is the vasomotor dysregulation. Impaired microvascular physiology may be one of the initial manifestations of atherosclerosis, which results in an increase in vascular resistance, and concomitant rise in blood pressure; this effect may be especially pronounced in hypertensive patients [8, 17]. These effects seem to be multifactorial and related to reduced activity of constitutive nitric oxide (NO) synthase and increased activation of renin-angiotensin system (RAS). Investigators have shown decreased NO secretion in response to acetylcholine [18]. Activation of RAS results in increased formation of angiotensin II [18], which may have a dual role in exacerbating hypertension as well as enhancing ensuing endothelial damage [19]. Oxidative stress is another element in the formation and growth of the atheromatous plaque. The underlying mechanism involves abnormal lipid profile and excessive generation of reactive oxygen species (ROS) [13]. Abnormal ROS generation is more commonly found in diabetic patients [4–6]. These ROS, formed primarily by activation of NADPH oxidase in vascular tissues, modify low density lipoproteins (LDL), which are phagocytosed by macrophages with ensuing formation of foam cells [20]. ROS are also formed as end-products of cigarette combustion. These oxidant species react with NO to generate reactive nitrogen entities, e.g., peroxynitrites, which directly affect proteins by nitration [21]. Investigators have measured nitrated proteins and oxidized entities in the serum of smokers with lung cancer and found a correlation between oxidative stress and carcinogenesis [22]. As previously mentioned, the effects of nicotine are pivotal to understanding ramifications of cigarette smoke on the cardiovascular system. Studies in humans show increased myocardial oxygen demands in smokers associated with decrease in coronary artery diameter with parallel increase in coronary resistance [23] and decreased splanchnic and renal flow [24]. Some investigators have studied changes in electrocardiograms and echocardiograms in smokers, but have found no significant direct effect of nicotine [25], while others have noted significant changes in cardiac output, heart rate, systemic vascular resistance, and electrographic P wave duration [26]. Echocardiography is also a helpful tool. Smokers have a greater incidence of cor pulmonale as evidenced by ventricular and atrial enlargement, eventual reversal of the septal curvature, and elevated pulmonary artery pressures; however, assessing systolic pulmonary artery pressures may be challenging in patients with tricuspid regurgitation,

Cardiovasc Toxicol

which is also common in smokers, with an incidence of about 24–66 % [27]. Many of the chemicals in modern cigarettes include compounds such as nicotine extracts, glue, fillers, ammonia, heavy metals, N-Nitrosamines, polycyclic aromatic hydrocarbons, humectants, and others [4–6, 28]. The tobacco industry has recently acknowledged that in modern cigarettes, there may be up to 7,000 chemicals, with about 70 of them recognized as carcinogens [1, 29]. Most of these chemicals are responsible for effects other than enhanced smoke flavor, craving, and ultimately addiction [1]. It is crucial to acknowledge that most of the studies have been conducted in animal models that do corroborate epidemiological observation on human studies. However, these animal models represent only an underestimation of what chronic exposure to smoking might do [1].

Smoking and Coronary Artery Disease Smoking is the most important preventable risk factor in the development of coronary artery disease (CAD) and high morbidity and mortality in patients with pre-existing CAD [3]. Up to 30 % of CAD-associated mortality results from tobacco consumption. Smoking itself is a cardiovascular risk factor, but it also enhances the effects of dyslipidemia and insulin resistance [30]. Further, smoking adversely affects the prognosis in patients with acute coronary syndromes [31]. Many investigators have studied at the effects of chronic tobacco use in patients with stable CAD. As mentioned earlier, the risk is multifactorial; smokers have been noted to have abnormal lipid profiles with higher serum LDL and triglycerides, which have also been described in secondhand smokers [32]. Furthermore, chronic cigarette smoking has been noted to influence (lower) HDL levels through oxidative stress [33]. It has been shown that smoking cessation leads to an increase in HDL levels of 4 mg/dL without change in total cholesterol [34]. The mechanism for this increase in HDL with tobacco cessation involves enhanced activity of lecithin cholesterol acyltransferase as well as cholesterol ester transfer protein [35]. The complex biochemical actions of tobacco extend beyond dyslipidemia (Fig. 1) [36]. Active smoking is associated with a decrease in body weight, and tobacco cessation is associated with weight gain. There is not a clear explanation for this phenomenon, but it seems like multifactorial from increased caloric intake, decreased resting heart rates, and improved lipoprotein lipase activity [37]. However, this increase does not correlate with increased coronary events when compared to controls that did not quit but adopted healthier lifestyles [38]. The weight loss associated with continued smoking is most

likely to increased inflammatory and oxidative stress, which increases beta cell dysfunction. These individuals often have insulin resistance and increased central adiposity [1, 3–5, 25, 28, 29, 39]. Smoking oxidizes lipids and oxidized lipids are toxic to many cell types including the endothelium [3–6, 13, 14, 18, 21, 28, 33, 40–42]. In smokers, the plaque contains high levels of triglycerides and LDL, both of which predispose to degradation by matrix metalloproteases, leading to plaque rupture and hemorrhage. These changes in plaque biology renders the arterial surface highly thrombogenic [43]. The thrombogenic properties of the plaque from smokers is further enhanced by the increased expression of tissue factor in the endothelial cells as a result of oxidative stress, which in turn binds to factor VII, which then initiates the coagulation cascade. Smokers also suffer from altered fibrinolytic state, probably secondary to diminished secretion of plasminogen activator from vascular endothelial tissue [44]. Many studies have demonstrated that tobacco users present with ACS at early age, on average 6–13 years earlier than non-smokers [3, 5, 6, 23, 29, 45–47]. Other studies have been inconclusive or have reported what appears to be paradoxical—improved outcome in smokers who present with ACS. For instance, an analysis of pre and thrombolytic era trials reveals that smokers have lower mortality after ACS when compared to non-smokers [48]. The plausible explanation for this paradoxical phenomenon may be related to presentation of ACS in smokers at an early age, and therefore lower likelihood of concurrent comorbidities [49]. A recent meta-analysis looked at this issue in detail. The authors concluded that this result was mostly seen during the 1980–1990s, but not after since the WHO modified the criteria of ACS. This ‘‘paradox’’ is yet to be demonstrated in the PCI era where the only finding seems to be that smokers do benefit from earlier and more aggressive intervention [49].

Smoking and Outcome on Coronary Revascularization Coronary artery revascularization is in itself difficult and confounded by multiple factors, including lesion extent and size, the presence of diabetes, age, and tobacco consumption, among others. However, the accruing evidence is clear regarding smoking, which is simply just detrimental for both surgical and percutaneous intervention. It has been observed that patients with coronary revascularization that have successfully quit have decreased levels of morbidity and mortality following CABG when compared to those that did not [50]. In general, 25–50 % of smokers undergoing CABG will successfully quit prior to the surgery without any intervention; however, up to 75 % of these will

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Cardiovasc Toxicol Fig. 1 Reproduced with permission from Ambrose JA, Barua RS ‘‘The pathophysiology of cigarette smoking and cardiovascular disease: an update’’ [37]. Potential pathways and mechanisms for cigarette smoking-mediated cardiovascular dysfunction. The bold boxes and arrows in the flow diagram represent the probable central mechanisms in the complex pathophysiology of cigarette smoking-mediated athero-thrombotic disease. H2O2 = hydrogen peroxide; METC = mitochondrial electron transport chain; NADPH = nicotinamide adenine dinucleotide phosphate reduced form; NOS = nitric oxide synthase; ONOO- = peroxinitrite; O
2 = superoxide

resume smoking at a later time [51]. The AHA/ACC guidelines recommends aggressive smoking cessation be implemented along with pharmacologic intervention, i.e., nicotine replacement formulation along or in addition to bupropion as needed [50]. In relation to PCI, the PLATO (Platelet inhibition and patient The Outcomes) trial also analyzed the smoker subgroup, finding that they indeed have a higher intra-stent thrombosis [52]. Similarly, an analysis of the PRESTO (Prevention of REStenosis with Tranilast and Its Outcomes) trial revealed that smokers suffered from higher rates of in-stent thrombosis and were associated with worse prognosis [53].As previously explained, smoking increases platelet reactivity; however, it also enhances the activity of the CYP1A2, which catalyzes the conversion of clopidogrel to its active metabolites [54].

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Smoking and Hypertension Many investigators have showed a positive relationship where tobacco predisposes to increase blood pressure readings, even leading to hypertension diagnosis while others found contrasting results [1, 29, 55]. Evidence from bench research has shown that tobacco exposure predisposes to decrease in synthesis of NO with impaired vasodilation from endothelial dysfunction, activation of the renin-angiotensin system, and a surge in catecholamine release with sympathetic system activation. NO is synthesized in the endothelial cells through the action of a synthase that uses L-arginine as substrate, and nicotinamide adenine dinucleotide phosphate (NADPH) and tetrahydrobiopterin (BH4)as cofactors [56]. NO acts through multiple mechanisms to decrease the contractile response [56].

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Another effect of cigarette smoking is the activation of the renin-angiotensin system (RAS) and increased conversion of angiotensin I to II [18, 19]. The effects of nicotine on the RAS have been long known, it is believed that it increases the actions of angiotensin II. Laustiola et al. measured the plasma renin activity of smokers and found it to be higher than in non-smokers, along with concomitant increased aldosterone synthesis likely due to enhanced response to angiotensin II [18, 19, 57]. Garcia et al. similarly found increased aldosterone with correlated blood pressure increases after nicotine inhalation, but did not note any significant changes in plasma renin activity [8]. Finally, cigarette smoking has also been implicated with increased catecholamine release from the adrenals and activation of beta-adrenoceptors [58, 59]. Within days of smoking cessation, in chronic smokers, there is a decline in urinary excretion of both epinephrine and norepinephrine, which further corroborates their enhanced secretion associated with tobacco use [60]. The effects of smoking on hypertension are detrimental especially in those who smoke at least 15 cigarettes daily [61], and it seems to improve with smoking cessation. However, associated vascular stiffening may still persist for years [62]. These effects are more pronounced in those patients with underlying history of hypertension, CAD, or heart failure [1, 3, 5, 29]. Jatoi et al. [62] assessed vascular stiffness through pulse wave velocity, wave reflection, and transit time in patients. Smokers and former smokers had higher pulse wave velocities and wave reflection with an almost linear relationship. Similarly, former smokers showed improvement of arterial stiffness parameters after a decade of smoking cessation.

Smoking and Peripheral Artery Disease Smoking has long been recognized as a predisposing factor for the development of symptomatic peripheral artery disease, in a dose dependent manner, and this correlation is stronger if the individual started at an early age, especially if before 16 [63]. Thus far, research has continued to show that all forms of tobacco, including smokeless tobacco affect the vasculature one way or another, albeit differently. It has also been associated with non-atherosclerotic vascular pathologies such as thromboangiitis obliterans and Raynaud’s phenomenon [64, 65]. In thromboangiitis obliterans (also known as Buerger’s disease), the characteristic findings include non-atherosclerotic, segmental, inflammation of the small, and medium-sized vasculature and associated with occlusive thrombi that spare the blood vessel itself [66]. Although the etiology is not completely known, there is a very strong correlation with tobacco exposure [66]. The treatment requires complete tobacco

cessation to stop the disease progression and prevent limb amputations [66]. Smoking has also been implicated with Raynaud’s phenomenon, especially with increasing the severity and frequency of the exacerbations. There are two modalities of Raynaud’s, primary, or idiopathic, and the secondary or that with a specific etiology. The role of smoking has been a pivotal role in primary Raynaud’s. However, even though the treatment of choice depends on etiology; many patients will not require pharmacological intervention, but everyone should be counseled to avoid smoking [67]. In smokers, ischemic ulcers have also been found to be more reluctant to treatment and less likely to heal [67, 68].

Smoking and Abdominal Aortic Aneurysm Most of abdominal aortic aneurysm (AAA) occur below the renal arteries and above the aortic bifurcation and pose a life-threatening risk to the point that are considered the 14th leading cause of mortality in the USA [69, 70]. Multiple studies have noted the association between tobacco exposure and the development of AAA. Some have even reported that tobacco does indeed represent the strongest predisposing factor, directly dependent on the number of pack-years of exposure [71]. In mice models, tobacco smoke was noted to cause larger aneurysms and associated with substantial vessel damage that included increased elastic fiber degradation [72]. The underlying physiopathology explanation for this phenomenon seems to correlate cigarettes and increased metaoloprotease activity that degrades the medial elastic fibers of the vessels [73]. In turn, in metalloprotease deficient animals, there was a consistently lower incidence and prevalence in the AAA formation [74]. However, other studies have failed to replicate these results, and even found no changes in AAA incidences despite pharmacological metalloprotease inhibition; thus hypothesizing that the enzymatic breakdown of the blood vessel may be more complex than previously considered [75].

Smoking Cessation And Cardiovascular Risk The ‘‘smoking paradox’’ gained attention in 1990s when investigators noticed the fact that smokers enjoyed better outcomes after ACS [48]; however, this theory has been demystified [49]. When adjusted for all other risk factors, former smokers had lower risk of developing CAD, an acute coronary event and thus mortality than patients that continued to smoke [76]. The risk precipitously falls by almost half after a year in those who successfully quit [77]. Similarly, smokers with prior myocardial infarction and

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have successfully quit, show lower rates of re-infarction. In this particular population, of former smokers, morbidity, and mortality may decrease up to 50 % [78]. Conversely, experts agree that it only takes 3–5 years of tobacco abstinence for most of the cardiovascular risk factor it poses to be eradicated [77]. From which, one can safely conclude that smoking cessation, and especially prevention by targeting populations at risk, such as teenagers, is always a cost-effective intervention.

Table 1 Pathophysiological effects of smoking on different aspects of vascular and hemostatic milieu Site

Effects

Pathophysiology

Endothelium

Endothelial cell dysfunction, injury, and death

Smooth Muscle Cells

Smooth muscle cell proliferation Vasomotor dysfunction Vasoconstriction

Matrix

Enhanced oxidative stress Matrix weakening with aneurysm formation in larger arteries

Lipid Profile

Higher LDL levels Lower HDL levels Abnormal triglyceride to HDL ratio Proliferation and enhanced activation Hyperaggregability

Increased oxidative stress through the uncoupling of: mitochondrial electron chain, endothelial nitric oxide synthase, oxidation of lipids Impaired endotheliumdependent vasodilation CYP1A1 and NO intron 4 polymorphisms increases smoke susceptibility to endothelial damage Decreased of nitric oxide generation and bioavailability Activation of the reninangiotensin system Free radical phagocytosis by macrophages with foam cell formation Metalloprotease activation with alteration of the matrix and abnormal deposition of lipids and tissue factor expression Vulnerable plaque generation, and upon disruption, acute atherothrombosis ensues with areas of microhemorrhage and subsequent deposition of platelets and activation of coagulation cascade Insulin resistance Abnormal lipid oxidation Decreased paraoxonase activity Migration of platelets to sites of unstable plaque with generation of a unstable fibrous cap Decreased platelet-derived NO concentrations Higher fibrinogen levels— linearly proportional to tobacco exposure Alterations in tissue factor and decreased tissue factor pathway inhibitor Decreased substance-P stimulated t-PA Alteration of t-PA to PAI1 ratio Activation of inflammatory genes Increased expression of inflammatory cytokines like ICAM, VCAM, and E Selectin Increased CRP and TNF-a Monocytes show enhanced adhesion properties through the increased expression of CD 11 and 18

Passive Smoking and Smokeless Tobacco Besides smoking, there are other forms of consuming tobacco, for instance smokeless tobacco and water pipe. Although the use of smokeless and water pipe modalities is lower than the conventional tobacco use, it still represents an epidemiological problem. These are actually experiencing resurgence throughout the world. In many countries, new laws have actually increased the general population’s smoking awareness; nonetheless, this is partially offset by the increasing number of smokeless tobacco consumers, who in the USA alone accrue to over eight million [28]. Similarly, the use of water pipe has become more popular in younger generations [45]. Second-hand smoking has been extensively reviewed and found to be a predictor for heart disease, as well as increased mortality. These findings have also been validated by the Surgeon General, and as such made publicly available [5]. This report concluded that involuntary tobacco exposure due to passive smoking was associated with increased risk of coronary heart disease, morbidity, and mortality in men and women. ROS generation, intracellular Ca(2?) mishandling, apoptosis, and myocardial fibrosis have been shown to play role in passive smokingrelated cardiac damage [79, 80]. A recent study looked at outcomes after acute coronary events depending on which tobacco modality patients used. It was noted that water pipe smokers had higher mortality rates compared to smokeless tobacco users within 1-month and 1-year followups, but this was not statistically significant. Similarly, these two groups seemed to have worse outcomes when compared to cigarette smokers [45]. Nevertheless, the authors recognize that smokers generally tend to get more aggressive interventions and treatments that are more consistent with evidence-based medicine. Other studies have argued that indeed differences can be seen. For instance, two large prospective studies in the USA looked at men who use snuff or chewing tobacco [81]. It was seen that in men who use smokeless tobacco, cardiovascular disease, and stroke carried a heavier burden of morbidity and mortality. Smoking during pregnancy increases the risk of congenital cardiac defect by odds of 1.09 [82].

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Platelets

Thrombosis

Increased prothrombosis and decrease fibrinolytic factors

Leukocytes

Proliferation and activation of neutrophils, monocytes, and T cells Leukocytosis

Cardiovasc Toxicol

Conclusion In summary, smoking has deleterious effect on cardiovascular health (Table 1). Smoking is a major risk factor for the development of coronary vascular disease, stroke, aortic aneurysm, and peripheral vascular disease. The etiology seems to be likely multifactorial given the enhanced inflammatory state that alters the atherosclerotic plaque, as well as the narrowing of the vessels, and hypertensioninduced changes. Risk also appears to depend on the level of exposure, with chronic and heavier smokers having a higher burden of disease and tobacco-induced comorbid conditions. It has been proven that while cessation may not completely eradicate the risk from prior exposure, it dramatically reduces it. It is crucial to understand that there is no minimal-risk-free level of exposure, and that all smokers are affected in a dosage dependent fashion. Scientific evidence continues to emerge confirming cigarette’s psychosocial, biological, and genetic impact, which seems more pronounced in some patient populations. In this new millennium, one of the major epidemiological concerns should be ending the current tobacco epidemic. Thus, smoking cessation is always the best answer, second only to abstinence. And as such, one fact remains, only by understanding tobacco’s imposed shackles, will society be able to accomplish so.

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Smoking is a major risk factor for the development of coronary vascular disease, stroke, aortic aneurysm, and peripheral vascular disease Risk also appears to depend on the level of exposure; there is no minimal-risk-free level of exposure, and that all smokers are affected in a dosage dependent fashion The pathophysiology includes enhanced inflammatory state that alters the atherosclerotic plaque, the narrowing of the vessels, and hypertension-induced changes Cessation may not completely eradicate the risk from prior exposure, and it dramatically reduces it

Conflict of interest None of the authors have any conflict of interest and have participated, written, and agree this manuscript contents.

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