A Prospective Analysis of the Association of Smoking with Cardiometabolic Risk

doi:10.21203/rs.3.rs-2876379/v1

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A Prospective Analysis of the Association of Smoking with Cardiometabolic Risk

https://doi.org/10.21203/rs.3.rs-2876379/v1

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Background

This study aimed to explore the possible effects of cigarette smoking on the cardiometabolic risk of apparently healthy Saudi individuals in Jeddah City.

Methods

A blood sample was withdrawn from each participant (100 smokers [60 males and 40 females] and 60 nonsmokers [36 males and 24 females]) for the assessment of their cardiometabolic functions (lipid profile, von Willebrand factor (vWF), Troponin I) and liver function tests using an automated enzymatic method.

Results

Among participant smokers, 80% smoked one pack daily, while 20% smoked more than one pack daily. Smokers had significantly higher vWF functional activity and high-sensitivity cardiac troponin I (p < 0.001 for both), but significantly lower albumin and total bilirubin levels than nonsmokers (p = 0.026, and p < 0.001, respectively). The number of daily cigarettes consumed correlated positively and significantly with plasma levels of LDL-cholesterol (r = 0.225, p = 0.004), non-HDL cholesterol (r = 0.220, p = 0.005), vWF function activity (r = 410, p < 0.001), high-sensitivity cardiac troponin I (r = 0.686, p < 0.001), but negatively correlated with total bilirubin (r=-0.459, p < 0.001). Moreover, heavy smokers had a significantly higher BMI (p = 0.001) and waist-to-hip ratio among male smokers compared to control non- smokers (p = 0.003). Thus,

Conclusions

Cigarette smoking is associated with increased dyslipidemia, body mass index, and central obesity, in addition to higher vWF functional activity. Increased hs-cTnI levels in smokers, indicating a higher susceptibility to heart failure and cardiovascular mortality among smokers.

Smoking

cardiometabolic risk factors

lipid profile

liver function tests

troponin I

Smoking is a leading health concern ¹, with a heavy toll on life directly through active inhalation and indirectly via passive inhalation ². World “No Tobacco Day”, May 31st, is a reminder of its hazards and the importance to quit smoking ³. The tobacco epidemic is globally considered one of the worst public health problems, annually killing more than seven million people, with almost six million deaths among smokers due to direct tobacco use, in addition to approximately one million non-smokers who die as a result of exposure to second-

hand smoke ⁴. Cigarette smoking remains one of the most common forms of addiction and it is a risk factor for several chronic diseases, infections, tumours, and cardiac and respiratory conditions ⁵. In addition to tobacco’s addictive properties, tobacco manufacturers reap the benefits of high-end marketing skills and strategies to aggressively promote their tobacco products, while adults, the elderly, and even children are becoming progressively attracted toward these extremely harmful products ⁴.

Tobacco use remains highly prevalent ⁶, for reasons that are not completely clear and may be attributed to its addictive nature ⁷. Nicotine fulfils the criteria for drug dependency by promoting its compulsive use, psychoactive effects, and reinforcing its own use ⁸. Smoke constituents are either particulate (e.g. tar, poly nuclear hydrocarbons, phenols, cresol, catechol, trace elements, nicotine, indole, carbazole, and 4-aminobiphenyl) or gaseous (e.g. CO, HCN, NH3, CH2O, C2H4O, C3H4O, and oxides of nitrogen) ^9,10. Lighting a cigarette is responsible for several harmful adverse effects on most body organs, including the lungs, heart, and even organs with no direct contact with the smoke. The liver, for example, is a vital organ affected by smoking, thus interfering with its ability to process and expel drugs and toxins ^9,10.

Recently, Heggen et al. (2022) screened subjects with stable coronary artery disease using the troponin test to assess cardiac-specific troponin blood levels to detect heart injury ¹¹. They found reduced concentrations of circulating “high sensitivity cardiac troponin” among cigarette smokers. “cardiometabolic diseases” is a term that is being applied to include common cardiovascular and metabolic diseases. These diseases may result from primary or metabolic drivers ¹². Despite being mostly preventable and treatable, cardiometabolic diseases are the highest cause of worldwide mortality, with 22.4 million deaths, almost half of them were described as “premature deaths”, i.e., before 60 years of age and considerable proportion of years spent with a reduced quality of life ¹³.

Cigarette smoke contains over 4,000 harmful compounds, including more than 200 toxicants, 80 carcinogens, and other compounds which induce oxidative stress ¹⁴. Cigarette smoking has been shown to be a significant risk factor for cardiometabolic diseases and an independent risk factor for diabetes, likely by promoting insulin resistance ¹⁵. It is also associated with hypertension, dyslipidaemia, and low HDL levels ¹⁶.

Smoking also influences the von Willebrand factor (vWF) protein, which facilitates platelet aggregation and adhesion to the subendothelium of injured vessel walls ¹⁷. Fibrinogen is another inflammatory marker elevated in smokers ¹⁸. High fibrinogen levels affect blood viscosity, platelet aggregation, and fibrin formation ¹⁹. Despite great efforts by the Saudi government to fight tobacco smoking, the prevalence of smoking is still growing ²⁰. Between 2013 and 2018, the prevalence of tobacco smoking among the Saudi population substantially increased within five years, from 12.2–21.4% ^21,22. Moreover, several studies have concluded that cigarette smoking and impaired liver function are associated with a lower health-related quality of life ^23,24. Therefore, cardiometabolic profiles of current and former smokers should be actively evaluated and compared with that of non-smokers to lower health and economic burdens of these medical conditions. This research aims to explore the possible effects of cigarette smoking on the cardiometabolic risk (lipid profile, vWF, Troponin I, liver function) of apparently healthy Saudi individuals in Jeddah City.

Subjects and ethical consideration:

The study was approved by the Biomedical Ethics and Research Committee of East Jeddah General Hospital, Jeddah, Saudi Arabia (reference no A0289, 10-02-2022). All potential participants were informed of the objectives of the present study. Informed written consent was obtained from all subjects and/or their legal guardian(s). Those attending the primary healthcare centres at East Jeddah Hospital, Jeddah City, Saudi Arabia for vaccination or with their children at the Well-Baby Clinic were considered as potential participants. Following consecutive sampling, 40 smokers and 40 age- and sex-matched non-smokers were enrolled in the present study. All participants completed a questionnaire on their medical history and smoking patterns. We adapted a study questionnaire from the European risk assessment tool ²⁵. It consists of the following three sections: A) personal characteristics; B) smoking pattern; C) Cardiometabolic risk assessment

Blood Sampling Procedures and Biochemical Assays

Forty fasting smokers and 40 non-smokers had 9 ml of venous blood collected. The samples were split into three different tubes: 4 mL containing lithium heparin, 3 mL containing serum, and 2 mL containing tri-sodium citrate. The samples from the lithium heparin tubes (green top) were analysed for alanine transaminase (ALT), albumin, total bilirubin, lipid profile, and fasting blood glucose levels. In contrast, serum tube samples (red top) and tri-sodium citrate samples (blue top) were used to examine troponin I and vWF, respectively. Using a Heraeus Labofug centrifuge (Thermo Scientific™, PA, USA), all green- and red-capped tubes were spun once at 4400 × g for 5 min at room temperature, whereas blue-capped tubes were centrifuged twice at 2000 × g for 15 min.

After the enzymatic reaction, Alinity c (Abbott, Wiesbaen-Germany) was used to evaluate liver function, lipid profile, and fasting blood glucose levels spectrophotometrically by measuring light absorption. Highly sensitive troponin I was measured using Alinity I (Abbott, Wiesbaden-Germany). This assay is a two-step immunoassay using chemiluminescent microparticle immunoassay (CMIA) technology to measure cardiac troponin in human serum. The concentrations of vWF were assessed using STA R Max3 (Stago, Parsippany-USA), which assesses the clotting time in the presence of cephalin and activator.

Statistical analysis

The Statistical Package for Social Sciences (IBM, SPSS, version 25) was used to describe and compare the demographic, clinical, and laboratory findings of the three compared groups. Data were expressed as frequency and percentage for qualitative variables and arithmetic mean and standard deviation for numerical continuous variables. The Kolmogorov-Smirnov and Shapiro-Wilk tests were applied to explore the normality of quantitative variables. Accordingly, parametric or non-parametric statistical tests of significance were applied. A power of 0.8 (i.e., 80% probability of correctly rejecting the null hypothesis) was chosen within the present study. The effect size (d) was calculated by dividing the estimated difference between two comparison groups by their pooled estimated standard deviation ²⁶.

The minimum sample size for the study groups was determined according to the Raosoft online sample size calculator to be 92 in the study group, with a 0.1 margin of error, 95% confidence level, and a reported 39.8% prevalence of cardiometabolic risk among the Saudi population ²⁷. However, the sample size in the study group was increased to 100 participants, with 2:1 proportion between the study group and the control group. The Chi-square test was used to compare qualitative variables, and the Student t-test was used to compare the arithmetic means of continuous variables between two or more different groups, respectively. The Pearson’s correlation coefficient (r) was done to describe the strength and direction of a linear relationship between the number of cigarettes smoked per day and the participants’ age as well as the results of cardiometabolic tests. By using the independent variable t-test, the results of cardiometabolic tests according to participants’ smoking status and smoking duration were statistically analyzed. Results with p-values of < 0.05 were considered statistically significant.

Participants

Table (1) shows that participants’ age and sex did not differ significantly according to smoking status. However, participants’ body mass index differed significantly according to their smoking status, with significantly more obese smokers than nonsmokers (21% and 8.3%, respectively, p = 0.017).

Our results show that 80% of smokers smoked one pack daily (up to 20 cigarettes per day), while 30% smoked more than one pack daily (more than 20 cigarettes per day).

The effect of smoking on cardiometabolic test

Table (2) shows that smokers had higher lipid profile parameters than non-smokers, with higher serum total cholesterol, LDL-cholesterol, and non-HDL levels but lower serum HDL cholesterol. However, the differences between smokers and non-smokers were not statistically significant. Regarding liver function, smokers had significantly lower serum albumin levels (p = 0.026) but significantly lower total mean serum bilirubin levels (p < 0.001) compared to non-smokers. Regarding haematological findings, smokers had significantly higher vWF functional activity (p < 0.001) than non-smokers. Fasting blood glucose levels did not differ significantly according to the smoking status. High-sensitivity cardiac troponin I was significantly higher among smokers than among non-smokers (p < 0.001). Moreover, smokers had significantly higher systolic and diastolic blood pressures than nonsmokers (p = 0.003 and p = 0.004, respectively). Smokers also had a significantly higher waist-to-hip ratio than non-smokers (p < 0.001 for both males and females).

Table (3) shows that number of cigarettes smoked per day correlated positively and significantly with participants’ plasma LDL cholesterol (r = 0.225, p = 0.004), plasma non-HDL cholesterol (r = 0.220, p = 0.005), vWF functional activity (r = 0410, p < 0.001), cardiac troponin I serum level (r = 0.686, p < 0.001), systolic blood pressure (r = 0.303, p < 0.001), diastolic blood pressure (r = 0.300, p < 0.001), body mass index (r = 0.448, p < 0.001), and waist-to-hip, ratio (r = 0.493, p < 0.001). Moreover, number of cigarettes smoked per day correlated negatively and significantly with HDL-cholesterol (r=-0.177, p = 0.025), and total bilirubin (r=-0.459, p < 0.001). However, other results of cardiometabolic function tests did not correlate significantly with participants’ number of cigarettes smoked per day.

Table (4) shows that the highest smoking intensity (> 1 pack/day) was greatest among older smokers aged > 40 years than among younger smokers aged < 30 years or 30–40 years (41.7%, 12.5, and 30%, respectively). However, the difference in smoking intensity according to participants’ age was not statistically significant. Prevalence of high smoking intensity (> 1 pack/day) was significantly higher among male smokers than female smokers (31.7% and 12.5%, respectively, p = 0.028). Moreover, the prevalence of high smoking intensity (> 1 pack/day) was significantly higher among obese than normal and overweight participants (57.1%, 25.0%, 14.7% and 12.5%, respectively, p < 0.001).

Table (5) shows that smokers who had smoked for > 10 years had significantly higher serum total cholesterol (p = 0.023), LDL (p = 0.011), non-HDL-cholesterol (p = 0.008), and triglycerides (p = 0.031) when compared to those who smoked < 10 years. Regarding liver function and hematological findings, participants who smoked for > 10 years had significantly higher vWF functional activity (p < 0.001) when compared to those who smoked < 10 years. Moreover, those who smoked for more than ten years had significantly higher BMI (p = 0.001), higher systolic blood pressure (p = 0.011), higher diastolic blood pressure (p = 0.011), and a higher waist-to-hip ratio among males (p = 0.003). Other laboratory parameters (triglycerides, LDL cholesterol, non-HDL cholesterol, ALT, total bilirubin, vWF functional activity, or troponin I) did not differ significantly according to the duration of smoking.

As shown in Table (6), smokers who smoked more than one pack/day had higher lipid profile parameters, with significantly higher serum total cholesterol (p = 0.014), LDL cholesterol (p = 0.011), and non-HDL levels (p = 0.017) when compared to other participants. Regarding liver function, participants who smoked > 1 pack/day had significantly lower serum albumin levels (p = 0.021). With hematological findings, participants who smoked > 1 cigarette pack/day had significantly higher vWF functional activity (p < 0.001) when compared to other participants. Fasting blood glucose levels were higher among those who smoked > 1 cigarette pack/day when compared to those who smoked less, but the difference was not significant. High-sensitivity cardiac troponin I levels were higher among those who smoked > 1 pack/day than those who smoked < 1 pack/day. However, the difference in mean troponin I levels was not statistically significant. Systolic and diastolic blood pressures were significantly higher among those who smoked > 1 cigarette pack/day (p = 0.004 for both). Moreover, the waist-to-hip ratio for males was significantly higher among those who smoked > 1 cigarette pack/day (p = 0.020).

The risk factors for the development of cardiometabolic diseases, such as dyslipidaemia and smoking, are modifiable and preventable. However, estimates of the magnitude and distribution of these risk factors are relatively scarce ²⁸. Despite strong and consistent epidemiological evidence linking cigarette smoking with several cardiovascular and liver diseases ²⁹, the exact mechanisms of these links remain inadequately understood. Therefore, this study aimed to explore the possible effects of cigarette smoking on the cardiometabolic risk in apparently healthy Saudi individuals in Jeddah City.

Findings of the present study revealed that changes in laboratory findings were worse among smokers than non-smokers and correlated with the intensity of smoking. Heavy smokers (i.e. those who smoked more than one pack of cigarettes daily) had a higher prevalence of dyslipidaemia than did moderate smokers (< one pack of cigarettes daily) than non-heavy smokers. Smokers had significantly lower total mean serum bilirubin levels in addition to a significantly higher vWF functional activity when compared to non-smokers. Heavy smokers had higher levels of lipid profile parameters when compared to other participants. In addition, high-sensitivity cardiac troponin I was significantly higher among smokers than among non-smokers. Gastaldelli et al. (2010) explained the observed changes related to dyslipidaemia among smokers by showing that increased dyslipidaemia is associated with increased concentrations of triglycerides, LDL, and HDL ¹⁶. These associations were confirmed by the fact that quitting is associated with improved lipid metabolism, with increased HDL and decreased LDL concentrations, which are usually observed after a short period of abstinence. Different components of tobacco smoking are linked to alterations in lipid metabolism. It has been reported that nicotine promotes lipolysis, i.e., increases the release of free fatty acids into the circulation and the production of lipoproteins, especially pro-atherosclerotic LDL. Moreover, carbon monoxide and other oxidant gases produced during smoking are associated with increased oxidative stress and platelet aggregation ¹⁶. A significantly lower mean serum concentration of total bilirubin among smokers was previously reported by Alsalhen and Abdalsalam (2014) ³⁰. Milman et al. (2001) explained these findings by showing that cigarette smoking is positively associated with haemoglobin, which regulates bilirubin concentrations. Hence, differences in bilirubin concentrations between smokers and non-smokers may be secondary to haemoglobin concentrations ³¹. However, Alsahlen and Abdalsalam (2014) reported that the association between total serum bilirubin concentration and smoking was independent of haemoglobin, and that bilirubin levels were consistently lower in smokers than in non-smokers. They explained that low serum bilirubin levels could have been caused by increased levels of free radicals, as direct result of cigarette smoking. Sokolowska et al. (2009) noted that cigarette smoke causes adverse effects on several organs, even those which are not in direct contact with the smoke, such as the liver, because it is involved in toxin processing and elimination from the body ³². Albumin binds to water, cations, fatty acids, bilirubin, thyroxine, hormones, and various drugs metabolised in the liver. Hence, reduced serum albumin levels are a sign of poor health status ³³. Clerici et al. (2014) stressed that since albumin synthesis takes place in the liver, a significant reduction in serum albumin is observed among heavy smokers compared to control subjects ³⁴. Albumin has antioxidant properties that are modified by carbonylation induced by cigarette smoke. Moreover, high levels of free radicals increase proteolytic activity. The albumin excretion rate is approximately 2.8 times higher in smokers than in non-smokers during the development and progression of diabetic renal damage ³⁵. Therefore, the significantly lower serum albumin levels among heavy smokers in the present study may be explained by the fact that most of the proteins are synthesised in the liver and albumin is the most abundant protein in the serum. Therefore, a significantly increased serum albumin level may indicate an early impairment of liver function. Ramamurthy et al. (2012) reported that chemicals in cigarette smoke have both direct and indirect effects on serum protein profiles ³⁶. Non-smokers have normal serum albumin levels, which play a role in the transport of biomolecules. The toxic compounds directly alter the binding properties of albumin, resulting in its degradation in the liver and loss of albumin by the kidney, that is, hypoalbuminuria. Shaktour et al. (2019) noted that smokers had higher blood sugar levels than non-smokers or ex-smokers ³⁷. Moreover, it has been shown that health benefits for diabetics who quit smoking start immediately and continue to increase with increasing duration of smoking cessation. Gastaldelli et al. (2010) reported that cigarette smoking is an independent risk factor for increased insulin resistance and the development of type 2 diabetes, possibly due to overwhelming evidence indicating that smoking promotes insulin resistance ¹⁶.

Wannamethee et al. (2005) argued that the early detection of endothelial damage is a useful step in the diagnosis of atherosclerosis ¹⁹. Therefore, it is important to assess the functional activity of vWF, which is a stable and useful marker of endothelial damage as it is specific to endothelial cells. Skranes et al. (2019) stated that high concentrations of cardiac troponin I indicate subclinical myocardial injury and are a strong predictor of incident heart failure and cardiovascular mortality ³⁸. Moreover, the high levels observed among heavy smokers in the present study may indicate an early injury to the endothelium. Although the mechanism by which smoking influences vWF release is still not clear, it has been suggested that this increase may be due to the cytotoxic effects of lipid peroxidase formed by O2 free radicals and the effects of nicotine and CO2 among others ²⁹. In addition, fibrinogen is another inflammatory marker that has also been reported to be elevated in smokers compared to non-smokers ³⁹. Higher fibrinogen levels among smokers may promote cardiovascular disease by affecting blood viscosity, platelet aggregation, and general fibrin formation ¹⁹.

The present study indicated that high sensitivity cardiac troponin I levels were higher among heavy smokers who smoked > 1 pack/day than among those who smoked < 1 pack/day; however, the difference in mean troponin I levels between the two groups was not significant. Our findings are not in agreement with those of a recent study by Skranes et al. (2022) ⁴⁰, who reported that non-smokers had significantly higher concentrations of high-sensitivity cardiac troponin I than smokers (P < 0.001). They added that an elevated cardiac troponin I concentration is a marker of subclinical myocardial damage. The observed difference between our findings and those of Skranes et al. (2022) regarding concentrations of high-sensitivity cardiac troponin I according to smoking status may be attributed to differences in characteristics of included samples, sampling techniques, or even differences in types of cigarettes smoked by participants ⁴⁰. However, this may mean that more research is needed to determine how smoking affects high-sensitivity cardiac troponin I levels. The present study showed a significant impact of smoking on both body mass index and waist-to-hip ratio. Graff-Iversen et al. (2019) showed a positive association between current smoking and waist-hip ratio, concluding that smoking enhances abdominal obesity as an unhealthy outcome ⁴¹. Also, Morris et al. (2015) used a Mendelian randomization approach to indicate a causal effect of tobacco smoking on abdominal fat accumulation ⁴².

Our study showed that participant smokers had significantly higher systolic and diastolic blood pressures than nonsmokers. Moreover, the number of daily cigarettes correlated positively and significantly with participants' systolic and diastolic blood pressures. Similarly, in the study of Mann et al. (1991), 24-hour ambulatory blood pressure monitoring for participants revealed that smokers maintained a higher mean daytime ambulatory systolic blood pressure than nonsmokers ⁴³. Primatesta et al. (2001) stressed that smoking causes an acute increase in blood pressure and is associated with malignant hypertension. The high blood pressure among smokers could be explained by nicotine acting as an adrenergic agonist, mediating local and systemic catecholamine release and possibly the release of vasopressin. However, several epidemiological studies have found that blood pressure levels among cigarette smokers were the same or lower than nonsmokers ⁴⁴.

The present study has some limitations. First, smoking habits were determined through self-report. Therefore, further studies should include confirmation by objective assessments, such as exhaled carbon monoxide and nicotine testing. Second, the generalisability of the results is limited by the consecutive non-random sampling, limited sample size, and the single-centre geographical study setting. Finally, clinical examinations and anthropometric measurements could not be performed in the present study. Therefore, body mass index and cardiometabolic index could not be assessed.

Based on the findings of the present study, it can be concluded that heavy cigarette smoking is significantly higher among males than females. Heavy smokers and those who smoked for longer durations had significantly worse lipid profiles and higher vWF functional activity when compared to other participants. It was also associated with significantly higher serum total cholesterol, LDL cholesterol, non-HDL cholesterol, and vWF activity, but significantly lower serum albumin levels. The number of cigarettes smoked daily was significantly correlated with serum levels of total cholesterol, LDL, and non-HDL cholesterol, in addition to vWF activity. Troponin I levels are higher among smokers than among non-smokers, indicating a higher susceptibility to heart failure and cardiovascular mortality among smokers.

Therefore, smoking cessation programs should be implemented and comprehensive health promotion programs should be widely applied. Primary healthcare providers can actively participate in reducing smoking-induced consequences related to cardiometabolic diseases by initiating innovative health promotion programs. As the present study followed a cross-sectional design, further prospective studies with larger sample sizes are needed to supplement the results of this study.

ALT Alanine transaminase

FBS Fasting blood sugar

HDL High-density lipoprotein

hs-cTnI High-sensitivity cardiac troponin I

LDL Low density lipoprotein

LFTs Liver functions tests

vWF von Willebrand Factor

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of the Biomedical Ethics and Research Committee of East Jeddah General Hospital, Jeddah, Saudi Arabia (reference no A0289, 10-02-2022). Informed written consent was obtained from all subjects and/or their legal guardian(s).

Consent for publication

Not applicable

Availability of data and materials

The datasets generated and/or analyzed during the current study are all

presented within the manuscript

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable

Authors' contributions

SS and FL design and wrote the main manuscript text and All authors reviewed the manuscript.

Acknowledgements

We would like to thank all the participants in this study.

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