Cardiovascular Toxicity of Nicotine: Implications for Nicotine Replacement Therapy

This review discusses the known cardiovascular effects of smoking and the effects of nicotine without tobacco smoke and interprets the available data on cardiovascular risk during nicotine replacement therapy (NRT). Nicotine gum and patches are now approved for over the counter sale in the United States. Smokers with cardiovascular disease are advised to seek physician counseling before using nicotine products, but information regarding the safety of these products in such patients is not readily available to most physicians. Nicotine may contribute to cardiovascular disease, presumably by hemodynamic consequences of sympathetic neural stimulation and systemic catecholamine release. However, there are many potential cardiovascular toxins in cigarette smoke other than nicotine. The doses of nicotine obtained by regular cigarette smoking generally exceed those delivered by NRTs, and the cardiovascular effects of nicotine are, in general, more intense when delivered rapidly by cigarette smoking than the slower delivery by transdermal nicotine or nicotine gum. Because the dose–cardiovascular response relation for nicotine is flat, the effects of cigarette smoking in conjunction with NRT are similar to those of cigarette smoking alone. Cigarette smoking increases blood coagulability, a major risk factor for acute cardiovascular events, whereas transdermal nicotine does not appear to do so. Clinical trials of NRT in patients with underlying, stable coronary disease suggest that nicotine does not increase cardiovascular risk. At worst, the risks of NRT are no more than those of cigarette smoking. The risks of NRT for smokers, even for those with underlying cardiovascular disease, are small and are substantially outweighed by the potential benefits of smoking cessation.

(J Am Coll Cardiol 1997;29:1422–31)     

Does extinction of responses to cigarette cues occur during smoking cessation?

Aims This study investigated whether Pavlovian extinction occurs during smoking cessation by determining whether experience abstaining from smoking in the presence of cigarette cues leads to decreased probability of lapsing and whether this effect is mediated by craving. Design Secondary analyses were carried out with data sets from two studies with correlational/observational designs. Setting Data were collected in smokers' natural environments using ecological momentary assessment techniques. Participants Sixty‐one and 207 smokers who were attempting cessation participated. Measurements Multi‐level path models were used to examine effects of prior experience abstaining in the presence of available cigarettes and while others were smoking on subsequent craving intensity and the probability of lapsing. Control variables included current cigarette availability, current exposure to others smoking, number of prior lapses and time in the study. Findings Both currently available cigarettes [odds ratios (OR) = 36.60, 11.59] and the current presence of other smoking (OR = 5.00, 1.52) were powerful predictors of smoking lapse. Repeated exposure to available cigarettes without smoking was associated with a significantly lower probability of lapse in subsequent episodes (OR = 0.44, 0.52). However, exposure to others smoking was not a reliable predictor, being significant only in the smaller study (OR = 0.30). Craving functioned as a mediator between extinction of available cigarettes and lapsing only in the smaller study and was not a mediator for extinction of others smoking in either study. Conclusions This study showed that exposure to available cigarettes is a large risk factor for lapsing, but that this risk can also be reduced over time by repeated exposures without smoking. Smoking cessation interventions should attempt to reduce cigarette exposure (by training cigarette avoidance) but recognize the potential advantage of unreinforced exposure to available cigarettes.     

Why children start smoking cigarettes: predictors of onset

We review findings from 27 prospective studies of the onset of cigarette smoking conducted since 1980. Almost 300 measures of predictors of smoking onset were examined, and 74% of them provided multivariate support for predictors of onset derived from theory and previous empirical findings. Expected relationships were strongly supported for (a) socioeconomic status, with students with compromised status being more likely to try smoking; (b) social bonding variables, particularly peer and school bonding, with less support for family bonding; (c) social learning variables, especially peer smoking and approval, prevalence estimates, and offers/availability, with less consistent support for parent smoking and approval; (d) refusal skills self efficacy; (e) knowledge, attitudes and intentions, with the expected stronger predictions from intentions than from attitudes than from knowledge; and (f) broad indicators of self-esteem. The few investigators who analyzed their data separately by age, gender, or ethnicity found many differences by these factors, though there were too few of them to detect any pattern with confidence. Though the 27 studies are far from perfect, we believe that they confirm the importance of many well-accepted predictors and raise some questions about others. In particular, family smoking, bonding and approval each received unexpectedly low support, ft is not clear whether this lack of support reflects reality as it has always been, is due to a changing reality, reflects developmental changes, either in the age of subjects or the stage of onset, or is due to poor measurement and too few tests. Future prospective studies need to be theory-driven, use measures of known reliability and validity, report analyses of scale properties, and use statistical methods appropriate to the hypotheses or theories under study. Finally, we encourage more investigations of the potentially different predictors of transitions to experimental or regular cigarette smoking. This will require multi-wave studies and careful measurement of changes in smoking behavior.     

Young children's understandings of cigarette smoking

Aims We explore young children's attitudes toward, beliefs about, and life‐style associations with cigarette smoking using direct and indirect measures. Design, setting and participants Second (n = 100) and fifth grade (n = 141) elementary school students (i.e. 7–8 and 10–11‐year‐olds) were excused from class and individually interviewed. Methods Participants selected pictures in response to the questions: who would like to smoke cigarettes the most and who would like to smoke cigarettes the least? Their picture choices were probed using open‐ended prompts designed to elicit the beliefs and life‐style associations underlying their choices. Survey‐based measures of attitudes and beliefs were also collected. Findings Second graders reported life‐style associations with cigarette smoking that were consistent with those of fifth graders. While their associations with smoking are generally negative, children appear to perceive that others feel that smoking makes them look cool and feel cool and also helps them to fit in. By fifth grade, many children believe that smoking can help to reduce stress and alleviate negative mood states. The presence of a smoker in the household does not appear to affect these associations, suggesting that they may be being shaped by external socialization agents. Conclusion Young children appear to be developing understandings of cigarette smoking that go beyond knowing that cigarettes are products that are smoked. As some of their perceptions appear likely to predispose them for future experimentation, young children need to be included in prevention research so that age‐appropriate interventions can be developed.     

Cigarette smoking increases copy number alterations in nonsmall-cell lung cancer

Cigarette smoking has been a well-established risk factor of lung cancer for decades. How smoking contributes to tumorigenesis in the lung remains not fully understood. Here we report the results of a genome-wide study of DNA copy number and smoking pack-years in a large collection of nonsmall-cell lung cancer (NSCLC) tumors. Genome-wide analyses of DNA copy number and pack-years of cigarette smoking were performed on 264 NSCLC tumors, which were divided into discovery and validation sets. The copy number-smoking associations were investigated in three scales: whole-genome, chromosome/arm, and focal regions. We found that heavy cigarette smokers (>60 pack-years) have significantly more copy number gains than non- or light smokers (≤60 pack-years) (P = 2.46 × 10(-4)), especially in 8q and 12q. Copy number losses tend to occur away from genes in non/light smokers (P = 5.15 × 10(-5)) but not in heavy smokers (P = 0.52). Focal copy number analyses showed that there are strong associations of copy number and cigarette smoking pack-years in 12q23 (P = 9.69 × 10(-10)) where IGF1 (insulin-like growth factor 1) is located. All of the above analyses were tested in the discovery set and confirmed in the validation set. DNA double-strand break assays using human bronchial epithelial cell lines treated with cigarette smoke condensate were also performed, and indicated that cigarette smoke condensate leads to genome instability in human bronchial epithelial cells. We conclude that cigarette smoking leads to more copy number alterations, which may be mediated by the genome instability.     

Nicotine, Cigarette Smoking, and Body Weight

A century of studies indicate that cigarette smokers weigh less than comparably aged nonsmokers and that many smokers who give up cigarettes gain weight. Behavioural, psychological, and biological explanations have been offered to account for these relationships but most of these explanations have limited empirical support. A recent series of animal and human studies suggest that changes in specific food consumption contribute to the inverse relationship between nicotine and body weight and between cigarette smoking and body weight. This paper reviews and discusses the smoking/body weight relationship, the possible explanations for this relationship, relevant recent studies, and the implications of the findings regarding nicotine and specific food consumption. It is commonly believed that cigarette smoking keeps body weight down and that cessation of smoking results in excessive weight gains. In fact, some smokers continue to smoke in order to avoid gaining weight [1]. Because an inverse relationship between cigarette smoking and body weight may deter smoking cessation and may even encourage some people (e.g., young women who are concerned about their appearance) to begin smoking, it is important to determine whether the relationship exists and what causes it. This paper first discusses research establishing the inverse relationship between smoking and body weight and then examines possible explanations for the relationship.     

40 years of U.S. cigarette smoking and heart disease and cancer mortality rates

This paper reviews some recent studies of the associations between cigarette smoking and mortality rates. It also reports on time series correlation studies of the relationships between per capita cigarette smoking and mortality rates for heart disease and respiratory cancer for the period 1940-1979 for the United States. Major findings tend to support the view that there is a 20 year lag relationship between smoking (especially number of cigarettes consumed per capita) and respiratory cancer mortality, while there appears to be no lag in the relationship of smoking (especially pounds of tobacco consumed per capita) to heart disease mortality. Smoking is found to explain over 90% of the variance in the relationship between smoking and respiratory cancer mortality, while it explains only 50% of the variance between smoking and heart disease mortality.     

Anal cancer in women

We studied predisposing factors in 56 women with anal cancer, comparing them with 56 matched controls drawn from the population. A detailed pretested questionnaire was administered to each study subject in a structured interview and blood was drawn for detection of herpes simplex virus antibodies by radioimmunoassay. Pathologic material from cases was obtained and evidence of human papilloma virus infection was sought. By univariate analyses we found associations between anal cancer and positive herpes simplex virus 2 titer (p = 0.0017), cigarette smoking (p = 0.0028), previous positive or questionable cervical Papanicolaou smear (p = 0.0124), and increasing number of sexual partners (p = 0.0224). By the multivariate technique of logistic regression there were independent and significant associations with cigarette smoking (p = 0.0126), previous use of hemorrhoid preparations (p = 0.0149), and history of disturbed bowel habits for greater than 1 mo (p = 0.0273). Anal cancer in women is a rare disease associated with cigarette smoking and sexual experience. Its association with previous anorectal disease is unclear and deserving of further study.     

Correlates of regular cigarette smoking in a population-based sample of Australian twins

AIMS: To investigate the role of measured risk factors and the influence of genetic and environmental factors on regular cigarette smoking. Design Members of monozygotic and dizygotic, including unlike-sex twin pairs (n = 6257) from a young adult cohort from the Australian Twin Registry. METHODS: Cox proportional hazards models were used to determine whether putative risk factors were significantly associated with regular cigarette smoking. Risk factors were classified into four tiers: tier 1 (parental history, including parental education, alcoholism and cigarette smoking), tier 2 (early home and family influences), tier 3 (early life events, e.g. trauma) and tier 4 (psychiatric symptoms/disorders with onset prior to 14 years), after controlling for gender, zygosity and their interactions. Genetic models were fitted to examine the heritability of smoking behavior before and after controlling for significant covariates from the four tiers. FINDINGS: Parental history of cigarette smoking and alcoholism, parental closeness and home environment, as well as incidence of childhood sexual abuse or other trauma, a history of early onset panic attacks and conduct problems were associated with regular cigarette smoking. Important age interactions were found, particularly for family background risk factors. Regular cigarette smoking was moderately heritable, even after accounting for significant covariates. CONCLUSIONS: Several measured risk factors are associated with regular smoking. While some of the genetic influences on regular smoking may be shared with these risk factors, a significant proportion of the genetic vulnerability to regular smoking is phenotype-specific.     

Smoking and coronary heart disease in the elderly.

This paper is concerned with the question of whether elderly people (ages 65-84) are more likely to develop coronary heart disease (CHD) if they continue or stop cigarette smoking. Age-standardized CHD rates and mortality ratios have been computed from data available in four major prospective cohort investigations of smoking and health. The data examined gave consistent results. For elderly men, there were no appreciable excess risks of CHD mortality or morbidity among cigarette smokers compared to ex-cigarette smokers and non-cigarette smokers. For elderly women, the CHD rates seemed lower in continuing cigarette smokers than in ex-cigarette smokers. These results obtained from cohort data are concordant with previous analyses of secular data. Among elderly people, the risk of CHD is essentially the same with persistence of cigarette smoking than with its cessation.     

Measuring the Heaviness of Smoking: using self-reported time to the first cigarette of the day and number of cigarettes smoked per day

Two simple self-report measures have been used to assess the heaviness of smoking,‘number of cigarettes per day’(CPD) and‘time to the first cigarette of the day’(TTF). Little attention, however, has been given to the precise method of scoring this information. Using biochemical indicators of heaviness of smoking (alveolar carbon monoxide and cotinine), we explore the optimum data transformations for regression analysis and categorical analysis. We suggest a four category scoring scheme for both time to the first cigarette of the day (5, 6–30, 31–60 and 61 + mm) and average daily consumption of cigarettes (1–10, 11–20, 21–30, 31 + cigarettes) as the most powerful and practical categorical scoring of these variables. Due to possible ceiling effects on biochemical measures, we suggest using logarithmic transformations of CPD or TTF for regression or correlation analyses.     

Variables associated with changes in spirometry in patients with obstructive lung diseases.

One hundred fifty subjects were enrolled in a long-term study of obstructive lung diseases; 84 of these were subjected to five or more spirometric studies over a period of two or more years. Stepdown regression analysis was performed to determine the association between many different variables and the annual rates of change in the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). The following associations were noted to be significant (p less than 0.03); more favorable rates of change of the FVC and FEV1 were associated with a higher alpha1-antitrypsin level and older age. Less favorable changes were associated with more years of cigarette smoking, more airway reactivity and more frequent lower respiratory tract illnesses.     

Cigarette smoking and gastroesophageal reflux disease.

Proposed pathophysiologic mechanisms relating gastroesophageal reflux disease to cigarette smoking are reviewed. Acute experiments have shown that smokers have chronically diminished lower esophageal sphincter (LES) pressure and that periods of smoking are associated with an increased rate of reflux events. Reflux occurred primarily by the 'abdominal strain mechanism' rather than by transient LES relaxation. Smoking also caused chronically diminished salivary function that results in prolonged acid clearance time. Thus, smoking potentially increases esophageal acid exposure, both by increases in the number of reflux events, and a prolongation of the esophageal acid clearance time.     

Lifestyle and cardiovascular disease in middle-aged British men: the effect of adjusting for within-person variation.

AIMS: To examine the effect that within-person variation has on the estimated risk associations between cigarette smoking, physical inactivity, and increased body mass index (BMI) and the development of cardiovascular disease (CVD) in middle-aged British men. METHODS AND RESULTS: In total, 6452 men aged 40-59 with no prior evidence of CVD were followed for major CVD events (fatal/non-fatal myocardial infarction or stroke) and all-cause mortality over 20 years; lifestyle characteristics were ascertained at regular points throughout the study. A major CVD event within the first 20 years was observed in 1194 men (18.5%). Use of baseline assessments of cigarette smoking and physical activity in analyses resulted in underestimation of the associations between average cumulative exposure to these factors and major CVD risk. After correction for within-person variation, major CVD rates were over four times higher for heavy smokers (> or =40 cigarettes/day) compared with never smokers and three times higher for physically inactive men compared with moderately active men. Major CVD risk increased by 6% for each 1 kg/m(2) increase in usual BMI. If all men had experienced the risk levels of the men who had never regularly smoked cigarettes, were moderately active, and had a BMI of < or =25 kg/m(2) (6% of the population), 66% of the observed major CVD events would have been prevented or postponed (63% before adjustment for within-person variation). Adjustment for a range of other risk factors had little effect on the results. Similar results were obtained for all-cause mortality. CONCLUSION: Failure to take account of within-person variation can lead to underestimation of the importance of lifestyle characteristics in determining CVD risk. Primary prevention through lifestyle modification has a great preventive potential.     

Report of the Conference on Low Blood Cholesterol: Mortality Associations.

BACKGROUND. A National Heart, Lung, and Blood Institute (NHLBI) Conference was held October 9-10, 1990, to review and discuss existing data on U-shaped relations found between mortality rates and blood total cholesterol levels (TC) in some but not other studies. Presentations were given from 19 cohort studies from the United States, Europe, Israel, and Japan. A representative of each study presented its findings and also submitted tables of proportional hazards regression coefficients for entry TC levels in regard to death, and these were incorporated into a formal statistical overview adjusted for age, diastolic blood pressure, cigarette smoking, body mass index, and alcohol intake, as available. METHODS AND RESULTS. The U-shape for total mortality in men and the flat relation in women resulted largely from a positive relation of TC with coronary heart disease death and an inverse relation with deaths caused by some cancers (e.g., lung but not colon), respiratory disease, digestive disease, trauma, and residual deaths. Risk for combined noncardiovascular, noncancer causes of death decreased steadily across the range of TC. The conference considered possible explanations for the statistical associations found between low TC levels or active TC lowering and certain causes of death. One is that TC is lowered by some disease conditions themselves, such as wasting in chronic pulmonary disease or reduced production and secretion of cholesterol-bearing lipoproteins with liver disease. In this sort of situation, the TC:mortality association found in observational studies may be due to preexisting disease. This was addressed by excluding early deaths from the analysis, which did not change the results. The conference considered as well the biological function of cholesterol, which, if seriously deranged, might hypothetically cause a wide variety of diseases and dysfunction. The conference also considered the biological functions that might provide plausible mechanisms for the associations found. CONCLUSIONS. Definitive interpretation of the associations observed was not possible, although most participants considered it likely that many of the statistical associations of low or lowered TC level are explainable by confounding in one form or another. The conference focused on the apparent existence and nature of these associations and on the need to understand their source rather than on any pertinence of the findings for public health policy. Further research is recommended to explain the observed associations of low TC levels (and TC lowering) with certain noncardiovascular diseases. This includes studies of the time course of TC change in disease, the relation of TC to morbidity, further studies of possible epidemiological confounding, monitoring of population trends in TC and mortality, further studies of the relations in women, auditing of noncardiovascular events in trials, studies of cell membrane, genetic and molecular links to cholesterol metabolism, TC level and disease, studies of disease manifestations in specific lipid disorders, and further study of the proposed causal mechanisms linking low TC and hemorrhagic stroke.     

What happens to women's self‐reported cigarette consumption and urinary cotinine levels in pregnancy?

Aims To describe the pattern of self‐reported cigarette consumption and nicotine consumption, measured by urinary cotinine concentration, in a cohort of pregnant women who did not stop smoking. Design Cohort study. Setting Randomly selected general practices from the West Midlands, UK. Participants Five hundred and fifty‐nine pregnant women in a clinical trial who were enrolled at booking for maternity care (about 12 weeks of gestation), who were followed up in mid and late pregnancy and 10 days post‐natal and who did not stop smoking during that period. Measurements Retrospectively collected self‐reported cigarette consumption prior to pregnancy and contemporaneously collected self‐reported cigarette consumption and urinary cotinine concentrations at booking for maternity care, 20 weeks of gestation, 30 weeks of gestation and 10 days post‐natal. Findings Women reported smoking a median of 10–19 cigarettes per day prior to pregnancy and a median of 5–9 cigarettes per day at booking for maternity care. At booking, women reported consuming a mean [95% confidence interval (CI)] of 6.3 (5.6–7.0) cigarettes per day. At 20 weeks of pregnancy this had risen to mean (95% CI) 11.5 (10.9–12.2), and remained at 11 cigarettes per day when measured again at 30 weeks of gestation and 10 days post‐natal. Mean (95% CI) urinary cotinine levels at booking were 6.0 (5.4–6.6) µg/mL, and did not change much through pregnancy. There were statistically significant associations between urinary cotinine and reported cigarette consumption at all time points except at booking. Conclusions Women smokers report lower cigarette consumption at booking for maternity care than they do prior to pregnancy or from mid pregnancy onwards, but cotinine data imply that their intake of toxins does not change throughout pregnancy. Reports suggesting many women reduce their smoking in pregnancy have probably been over‐optimistic.     

Cigarette smoke – an aging accelerator?

Cigarette smoking reduces life span by an average of 7 years, and tobacco consumption accounts for a shortening of disease free life by 14 years. The exact mechanisms by which smoking causes disease and death are generally not well understood, but evidence continues to mount that cigarette smoking exhausts cellular defense and repair functions, leading to an accumulation of damage e.g. mutations and malfunctioning proteins. In this review, we make an attempt to ascribe many of the deleterious effects of smoking on human health to a general principle, namely the acceleration of aging processes by cigarette smoke chemicals.     

Tobacco use among Mexicans and their descendants in the United States

OBJECTIVE: To show the information obtained in U.S. surveys and studies on cigarette smoking or other tobacco use in Mexicans residing in the United States. MATERIAL AND METHODS: Different information systems and surveys were used. Those used in the study herein presented include the Youth Risk Behavior Survey, 1991-2001, the National Survey on Drug Use and Health, 1999-2001, the National Health Interview Survey, 1978-2001, the Current Population Survey, 1998-1999, The National Health Vital Statistics, 1999, and the U.S. Census Bureau, 2001. RESULTS: A decreased prevalence of cigarette smoking has been observed in the U.S. both in young persons and adults. A decreased prevalence among subjects reporting Mexican and Mexican-American (combined) ethnicity was also noted. Young adults and adults of Mexican or Mexican-American origin smoke cigarettes less frequently than non-Hispanic whites or American Indians. However, this lower rate among Mexicans and Mexican-Americans is due mainly to the lower use of cigarettes among Mexican-American and Mexican women (combined). Although these women have a lower prevalence of cigarette smoking than non-Hispanic white females, among Mexican-American and Mexican males (combined) cigarette smoking may be as common as in non-Hispanic white males. Moreover, those who identify themselves as Mexican-American have higher cigarette use than those who identify themselves as Mexicans. Finally, Mexican and Mexican-American women (combined) of a lower education level are more prone to smoking during pregnancy than females of the same group with a higher education level. CONCLUSIONS: This report shows differences by age, sex, self-definition of ethnicity (Mexican or Mexican-American), and education level, regarding smoking among Mexicans or persons with a Mexican background living in the United States. It is crucial to understand the demographic changes and trends and patterns among Mexicans and Mexican-Americans in the U.S. so as to design and implement smoking control programs that are efficient, culturally sensitive, and designed specifically for Mexicans and Mexican-Americans. The English version of this paper is available at: http://www.insp.mx/salud/index.html.