Association between Sedentary Behaviors, Tobacco Smoke, Epigenetics, and Cardiovascular Disease

The association between sedentary behavior or physical inactivity and risk for developing vascular aging, Cardiovascular (CVD) or Coronary Artery Disease (CAD) as well as developing risk factors for the disease is high. The health benefits of increasing physical activity and reducing sedentary behavior using various recommended intervention strategies are a field that warrants further research. While genetic risk factors for CVD have been well documented, emerging evidence has linked epigenetic mechanisms (i.e., heritable changes to gene expression that are not from differences in the genetic code) with many CVDs. Epigenetic mechanisms are regulated by many factors including physical activity, tobacco smoke and diet. Recent evidence provides support for the theory of epigenetic inheritance in which epigenetic alteration in gametes are transferable from parents to offspring. We must not only understand accelerated vascular aging and CVD risk factors and their regulatory role in prevention, management and diagnosis of CVDs but also practice protective measures that include lifestyle (i.e., physical activity, diet, abstinence of tobacco smoke) and epigenetic influence would play a significant role on cardiovascular health. This review examines the interplaying role of sedentary behavior or physical inactivity, tobacco smoke, and epigenetics in CVD risk. Specifically, we report the association between epigenetics and cardiovascular diseases as well as the interplay of epigenetic mechanisms in cardiovascular diseases and maternal smoking and secondhand smoke that have adverse effects on health of newborns, childhood obesity and off-spring developing smoking habits, asthma, and arterial stiffness.

The purpose of his review is to examine the interplaying role of sedentary behavior or physical inactivity, tobacco smoke, and epigenetics in Cardiovascular Disease (CVD) risk. Specifically, we define physical activity and sedentary behavior by providing physiological characteristics of cardiorespiratory fitness via regular physical activity or exercise; introduce strategies for reducing sedentary behavior time to replace physical activity time; and report the association between epigenetics and CVDs as well as interplay of epigenetic mechanisms in CVDs that include DNA methylation, histone modification, and microRNA alterations, how ancestral high-sugar diet exposure induces transgenerational changes in sweet sensitivity and feeding behavior may contribute to the current obesity and type-2 diabetes problem, as well as maternal smoking and secondhand smoke that have adverse effects on health of newborns such as early-onset metabolic disease and childhood obesity and off-spring developing smoking habits, asthma and arterial stiffness.

Sedentary behavior is defined as any behavioral task that involves less than 1.5 Metabolic Equivalent of Task (MET) energy expenditure [1-3]. This amount of energy expenditure would involve time spent in a seated position while performing desk work, using a desk-top computer, viewing television, driving a motor vehicle, sitting in a bus, train or airplane, using a mobile phone or in a sitting position watching a movie [2]. Furthermore, sedentary behavior is not inclusive to complete rest, rather it includes light-intensity activities ranging from 1.1 to 2.9 METs [2,3]. One MET represents the rate of energy expenditure while at rest and is equivalent to Resting Metabolic Rate (RER) or an oxygen consumption (VO2) of 3.5 ml O2/kg/min [2,3]. It should be noted that light activities of daily living are equivalent to 1.5 to 3.0 METs, moderate to vigorous physical activities are equivalent to 3 or more than 6 METs [3,4].

Physical activity is defined as any bodily movement that results in a substantial increase in energy expenditure over Resting Energy Expenditure (RER) [3]. However, exercise is a mode of physical activity with a structured type of activity to perform and a specific type of location to execute [3]. For instance, playing tennis, walking, and dancing are examples of exercise modalities. “Light” physical activity is defined as requiring < 3 METs of energy expenditure, “moderate” physical activity as between 3 and < 6 METs, and “vigorous” physical activity as equal to or greater than 6 METs [3,5].

Optimal or minimal physical activity level as recommended by the American College of Sports Medicine (ACSM) and U.S. Centers for Disease Control and Prevention (CDC) is that all adults engage in regular physical activity of “moderate intensity” 30 minutes a day on 5 or more days a week (i.e., equal to or > 150 minutes a week of moderate-intensity aerobic activity), preferably all days of the week’s [5]. This description highlights the importance of the amount and intensity of physical activity required for attaining health benefits and lowering susceptibility to chronic disease and decreasing premature mortality. The recommendations also call for all adults engaging in regular “vigorous-intensity” physical activity, 20 minutes a day on 3 or more days a week (i.e., 75 minutes a week of vigorous-intensity aerobic activity [5].

Sedentary behavior

Sedentary behavior can be described according to the studies of the Canadian Sedentary Behavior Guidelines, Canadian Society for Exercise Physiology [6] and the Australia’s Physical Activity and Sedentary Behavior Guidelines [7]. As recommended by the Canadian Sedentary Behavior Guidelines, people should avoid screen time for more than 2 hours per day, avoid motorized transport, or extended sitting and time spent indoor throughout the day [6]. The Australian Sedentary Behavior Guidelines recommended that people should avoid the amount of time spent in sitting and should take frequent breaks when in prolonged periods of sitting [7]. It has been reported that more than 50% of an average person’s waking day involves activities associated with prolonged sitting [5]. Furthermore, sedentary behavior is associated with deleterious health consequences, independent of physical activity levels. [5]. Evidence to support the inverse relationship between regular physical activity and/or exercise and premature mortality, cardiovascular/coronary artery disease, hypertension, stroke, osteoporosis, type-2 diabetes mellitus, metabolic syndrome, obesity, some cancers, depression, functional health, falls, and cognitive function continues to accumulate [5,8,9].

Cardiorespiratory fitness

It has been reported that individuals who have acquired a high level of Cardiorespiratory Fitness (CRF) are often associated with low risk for developing coronary heart disease [10]. One of the key components CRF is aerobic capacity which is a physiological characteristic for quantifying the ability of the body to transport oxygen from the lungs via the cardiovascular system to supply circulating oxygen to and be utilized by the working muscles [3,11]. This physiological function of CRF is associated with maximal stroke volume and heart rate, referred to as the central mechanism, as well as maximal arterial and venous oxygen difference, referred to as the peripheral mechanism [3,11]. It should be noted that regularly engaging in aerobic exercise can enhance cardiovascular and respiratory efficiency, increase muscular oxidative capacity, and lower sympathetic nervous reactivity in response to physical and/or psychological stress [3,11]. It is well known that exercise stress and psychological stress act synergistically to intensify cardiovascular responses which may contribute to the increased risk of developing Cardiovascular Disease (CVD) [12-14]. In addition, there are studies reporting the association between aerobic capacity and CVD morbidity and mortality in adults [3,13,15-18].

Effect of sedentary behavior on cardiovascular and associated non-communicable diseases

Analysis of disease burden and life expectancy revealed that sedentary behavior causes a worldwide average of 6% of the burden of disease from coronary heart disease [19]. Of the associated non-communicable diseases, sedentary behavior causes a worldwide average of 7% of type-2 diabetes, 10% of breast cancer, 10% of colon cancer, and 9% of premature mortality. It was estimated that if the worldwide prevalence of sedentary behavior is lowered by 25%, more than 1.3 million deaths per year could have been prevented [19].

Sedentary behavior and cardiovascular disease risk factors

There are reports showing that there is high association between sedentary behavior and CVD risk factors which includes diabetes, dyslipidemia (i.e., high low density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and triglycerides), insulin resistance, and development of the metabolic syndromes [20]. Banach and colleagues reported that inactivity and walking minimal steps per day increase the risk of cardiovascular disease and general poor health [21]. There is a nonlinear dose-response association between step count and all-cause and cardiovascular mortality (p < 0.001 for both) and a progressively lower risk of mortality with an increased daily step count over 3867 steps per day for all-cause mortality and 2337 steps per day for cardiovascular mortality [21].

Strategies for reducing sedentary behavior time to replace physical activity time

With economic development and modernization of society, change of diet patterns, and the acceleration of population aging, Type 2 Diabetes Mellitus (T2DM), metabolic syndrome, cardiovascular disease risks are alarmingly increasing in both developed and underdeveloped countries. For example, T2DM accounting for the highest prevalence globally and reaching 116.4 million in 2019, results in different macro vascular and micro vascular complications [22]. Specifically, Wang and colleagues found that sitting time negatively affects estimated Glomerular Filtration Rate (eGFR) among T2DM patients and provides new evidence that physical activity could attenuate the association between sitting time and eGFR [22]. The researchers recommended intervention strategies focusing on reduced sitting time and increased physical activity time should be the focus of primary attention [22]. In addition, greater significant improvement in Body Mass Index (BMI) and waist circumference can be achieved with more active stepping time in place of standing time [22]. For example, replacing 2 hours of sitting time per day with standing can improve biomarkers of glucose and lipid metabolism [23]. Also, reducing sedentary behavior can be accomplished by reducing sedentary time with physical activity time by commuting to work, parking your car away from your office, taking the stairs instead of the elevator and taking one walking break every 2 hours from the office desk [1,3]. Note that American adults spent 50% of his or her waking hours in sedentary behavior [24].

Association between epigenetics and cardiovascular disease

The word epigenetic refers to “on top of or in addition to genetics” [25]. Unlike genetics, which refers to the nucleotide triplet base sequence of the DNA code that translates genetic information into a particular peptide chain or protein, epigenetic are chemical tags that regulate the expression pattern of genes. In other words, epigenetics induces a change in phenotype without changes in genotype. Thus, epigenome can modify the genome outcome through several processes that include DNA methylation, histone modification and non-coding RNA (ncRNA) mechanisms that have been correlated with various disorders and diseases including CVDs [26].

DNA methylation involves the addition of a methyl group (CH3) to cytosine converting it into 5’methylcytosine through the action DNA Methyltransferase (DNMT). It occurs predominately (i.e., 90%) in the CpG rich areas where cytosine is linked to guanine by phosphate [26]. Note that CpG rich areas are generally found in promoter sites where transcription is initiated, and methylation of cytosine inhibits transcription silencing gene expression [26]. Histone modifications are post-translational changes that could involve acetylation of lysine, methylation of lysine and arginines, and phosphorylation of serine and threonine [27]. Histone acetylation and deacetylation are epigenetic mechanisms that involve the addition or removal of an acetyl group (CH3CO) on lysines in the N-terminal tail through a group of Histone Acetyl Transferases (HAT) and Histone Deacetylases (HDACs) enzymes. Acetylation results in euchromatin, where chromatin structure is relaxed keeping DNA accessible for transcription. Whereas deacetylation condensing chromatin in heterochromatin prevents transcription due to inaccessibility of DNA [27]. Epigenetic related ncRNA such as micro RNAs (miRNA), small interfering RNAs (siRNA), and Piwiinteracting RNA (piRNA) function to regulate gene expression at the transcriptional and post-transcriptional level. For example, miRNA can bind to complementary sequences in the 3’untranslated region of specifically targeted mRNA resulting in their degradation and inhibition of protein expression [28].

Epigenetic mechanisms and interplay in cardiovascular disease

Epigenetic studies in CVD have identified numerous epigenetic modifications that affect the development and progression of various CVDs including arrhythmias [29-31], cardiac hypertrophy [32], heart failure [33-36], and vascular diseases [34,36,37]. For example, Su Z, et al. [37] reported that endothelial dysfunction not only is the initial factor or promoter of atherosclerosis but also is critical in the transition from a stable to an unstable disease state. Currently, Ash21 (Ash21, Absent, small, or homeotic-like 2) and its mediated H3K4 (histone H3 lysine 4) methylation are reported in tumor-related research [37]. Epigenetic mechanisms are affected by lifestyle factors such as physical activity and diet [38]. For example, monozygotic twins are epigenetically indistinguishable during their early years of life, however, epigenetic differences across different tissue types arise in older homozygous twins with different lifestyle behaviors [39]. Note that acute physical exercise has been found to decrease global and gene-specific promoter methylation in human skeletal muscle following a dose-dependent response [40]. Studies reported by Nitert MD, et al. [41] and Ronn T, et al. [42] that six months of aerobic exercise in healthy sedentary men decreased blood pressure, heart rate, waist circumference, and increased High-Density Lipoprotein (HDL), all of which are considered protective mechanisms of CVD. Further, there is evidence that supports the theory of epigenetic inheritance, where epigenetic germline inheritance of diet-induced obesity and insulin resistance are transferable from parents to offspring’s [43]. In animal studies, researchers used In Vitro Fertilization (IVF) to produce various pairings of egg and sperm cells from parent mice that were fed either a high-fat, low-fat, or a normal diet. Embryos were implanted into healthy surrogate females, eliminating parental external influence beyond the contribution of gametes [43]. The study reported that when 10-week-old offspring were placed on high-fat diet, the offspring from two parents on high-fat diets were heavier than offspring with both parents on normal diet [43,46,47].

Cardiovascular Disease (CVD), a multifactorial disorder, is a leading cause of mortality worldwide and is associated with multiple genetic and environmental risk factors [41,44]. Currently, only a small portion of the variability in CVD risk can be explained by known environmental and genetic influence. In preventive cardiology, scientists and clinicians have made significant advances in the prevention and management of cardiovascular disease, by lowering CVD risk factors (such as tobacco smoke and sedentary behavior), developing pharmacological agents to lower the risk and disease manifestation, and advanced biomedical technology to treat and manage the disease.

However, to develop more efficacious and cost-effective therapy and prevention strategy we need to thoroughly understand factors that contributed to CVD. For example, epigenomes emerged as one of the most promising areas for understanding the interaction between nature and nurture in the development of CVD. Studies have shown several CVD risk factors that have been linked to modification of epigenetic markers [45]. Thus, understanding the epigenetic mechanisms can advance our understanding of how cells respond to environmental changes which include DNA methylation, histone modification, and microRNA alterations. For instance, in a study conducted by Huypens and colleagues who showed that parental high-fat diet renders offspring are more susceptible to developing obesity and diabetes, can serve as a possible explanation for the current obesity and diabetes pandemic [43]. In 2023 Yang and colleagues showed that ancestral high-sugar diet exposure suppressed sweet sensitivity and feeding behavior in the offspring in Drosophila [47]. These behavioral deficits were transmitted through the maternal germline and accompanied by the enhancement of H3K27me3 modifications [47]. In other words, exposure to high-sugar diet induces transgenerational changes in sweet sensitivity and feeding behavior via H3K27me3 reprogramming [47]. This epigenetic inheritance of acquired metabolic disorders may contribute to the current obesity and type-2 diabetes problem worldwide.

Maternal smoking and secondhand smoke have adverse effects on offspring health that includes pre-term delivery, stillbirth, and low birth weight [48,49], and exposes the developing fetus to harmful chemicals in tobacco that negatively impact the health of newborns, resulting in early-onset metabolic diseases and childhood obesity [50-53]. Note that maternal smoking during pregnancy and prenatal exposure have been identified as significant contributors to an elevated risk of the offspring developing smoking habits [54] and asthma [55], both recognized precursors to a sedentary lifestyle [56-58]. Research has consistently highlighted the inverse correlation between smoking status and engagement in physical activity [57,59]. Additionally, heightened nicotine dependence is associated with an increased likelihood of adopting a sedentary lifestyle [57,59], exacerbating Cardiovascular Disease (CVD) risk factor profiles. Studies have shown that active tobacco smoking was associated with increased Left Ventricular (LV) mass and volume and was an independent risk factor for incident heart failure [60-62]. Deng and colleagues employing a cord blood epigenetic score of maternal smoking and tested this score for association with smoking status and secondhand smoke exposure during pregnancy, and health outcomes in offspring measured after birth [48]. The cord blood epigenetic score was consistently associated with smaller birth size (p = 1.19 x 10-6) and lower birth weight (p = 8.79 x 10-7). In addition, Murray R and colleagues employing cord blood DNAm (DNA-methylation) score that integrates all maternal smoking-associated methylation changes that allows the researchers to quantify the impact of maternal smoking and secondhand smoke exposure on newborns [50]. This cord blood DNAm score identified lower birth weight, smaller birth size, and arterial stiffness in the offspring of newborns and highlights the impact of maternal smoking and secondhand smoke on public health related childhood obesity, arterial stiffness, and metabolic disease [50-53,63].

In a recent study Gurven and colleagues reported on aging and arterial elasticity of an indigenous community in the Bolivian Amazon, named Tsimané tribe. This tribe members’ daily heavy physical activity includes hunting, fishing and farming for food and building shelters to raise their family. The Tsimané’s arteries are less rigid than those in various urban and sedentary populations that have been studied previously [64]. The elasticity of large and small arteries of Tsimané individuals, with an average age 55.3 years was 57%-86% higher than those observed in adult men and women in the United States [64]. Their average Carotid-Femoral Pulse Wave Velocity (CFPWV), a direct indicator of arterial stiffness, obtained from 89 Tsimané individuals with an average age of 53.1 years was 6.34 m/s [64]. This value is approximately 25% lower than the average for a healthy Brazilian population, aged 35-74 years [64]. Note that a high level of CFPWV indicated a higher risk of 5-year mortality on atherosclerotic cardiovascular disease with and without standard modifiable risk factors for CVD [65]. It should be noted that after reaching age 70 years, the Tsimané arteries also start to harden, and their arteries cannot indefinitely or forever delay arterial aging [64]. The delayed increase in arterial stiffness associated with age could have contributed to the very low observed levels of coronary atherosclerosis in the Tsimané [64]. The finding suggests the impact of epigenetics on atherosclerosis and delayed vascular aging due to elevated levels of daily physical activity and native diet [66]. This study points to the fact that in preventive cardiology we must not only understand accelerated vascular aging but also practice protective measures that include physically active lifestyle, diet and epigenetic influence would play a significant role on cardiovascular health.

Studies demonstrating the association between sedentary behavior and with risk of CVDs and that genetic risk factors for CVD have been well documented. Emerging evidence has linked epigenetic mechanisms with numerous CVD risk factors including obesity, tobacco smoke and sedentary behaviors. It should be noted that epigenetic mechanisms are regulated by many factors including diet, tobacco smoke, and physical activity. The new dimension of epigenetic inheritance risk factors for CVD susceptibility and its interaction with other factors such as diet, tobacco smoke and physical activity is emerging and underscores the complexity of CVD risk factors and their regulatory role in prevention, management, and diagnosis of CVDs.

Authors declare that they have no conflict of interest.

Michael T.C. Liang and Moustafa Moustafa-Bayoumi equally contributed to the article and drafted the first version of the manuscript. MTCL, MMB, AA and JRR contributed to the overall study design. AA and JRR conducted a literature search and review. All authors read and approved the final version of the manuscript.

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