The Origin of Chronic Diseases With Respect to Cardiovascular Disease

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The Origin of Chronic Diseases With Respect to Cardiovascular Disease Ronan Lordan, Alexandros Tsoupras, Ioannis Zabetakis Department of Biological Sciences, University of Limerick, Limerick, Ireland

Chapter Outline 1.1 Introduction 1 1.2 Causes of Chronic Diseases Such as CVD 3 1.3 Unresolved and Emerging Public Health Hazards due to Genetic, Dietary, Environmental, and Lifestyle Factors 6 1.3.1 Genetics 7 1.3.2 Nutrition, Diet, and Lifestyle 9 1.3.3 The Environment and Anthropogenic Activity 13

1.4 Concluding Remarks 15 References 16 Further Reading 21

1.1 Introduction One might wonder why, within a group of people that follow similar patterns of diet and has analogous exposure to various external factors (such as environmental factors), some suffer ill health while others do not. What are the underlying causes of diseases? Is there any information in our DNA (i.e., nature) that protects us from falling ill or is it an effect of exposure to disease-promoting factors (i.e., nurture)? It would be useful to visualize a dynamic balance between health and disease (Fig. 1.1). Usually, the balance shifts toward the “health” state; however, under the influence of various risk factors, the balance could be redirected toward the “disease” state. In this chapter, we are going to examine documented traditional factors but also emerging factors that can influence this balance with reference to CVD. In our approach, diseases are complex biological processes that are triggered by external factors and/or various underlying biochemical and cellular processes. These processes can The Impact of Nutrition and Statins on Cardiovascular Diseases. https://doi.org/10.1016/B978-0-12-813792-5.00001-X # 2019 Elsevier Inc. All rights reserved.

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Disease

Fig. 1.1 Dynamic balance between “Health” and “Disease.”

be induced either endogenously or exogenously, and either alone or in different combinations, which may result in cellular dysfunction, damage, or cell death at a cellular level. In the case of prolonged cellular dysfunction, tissues and organs may be affected, resulting in an array of symptoms depending on the specific type of cellular, tissue, or organ dysfunction that occurs (Ardies, 2014). The major difference between this approach to disease and other approaches as presented in a variety of books on prevention medicine (Fauci et al., 2009; Leutholtz and Ripoll, 2011) is that when reaching the disease state, such dysfunctions coexist at both the cellular level and clinical diagnosis. However, when patients present with clinical symptoms of a chronic disease such as CVD, underlying disorders at the cellular or even tissue level (e.g., endothelial dysfunction and formation of atherosclerotic plaques) are sometimes not clinically observed until many years after the initial pathological processes have been triggered and the progress gone undetected. Physicians generally view symptoms as an end result for diagnostic purposes. However, should the symptoms materialize due to a process initiated many years before clinical observation, then the diseased individual was unaware of their developing condition and thus unable to prevent its manifestation. In some cases, individuals who are free of lifestyles or risk factors associated with a disease can often develop a disease due to genetic and/or environmental factors of which they are unaware. Globally, the number of people diagnosed with CVD follows a rising trend. The World Health Organization (WHO) has estimated that one in three global deaths is because of CVD-related events such as myocardial infarction (MI) and stroke. In 2015, there were
17.7 million global deaths due to CVD-related events (World Health Organization, 2017). According to Ireland’s Health Service Executive (HSE),
10,000 Irish people die each year due to CVD, including coronary heart disease (CHD), stroke, and other circulatory diseases. CVD account for 36% of all adult deaths, surpassing cancer, and respiratory diseases as Ireland’s leading cause of death. Of those who die from CVD, 22% are premature deaths (under 65 years old), with the majority of these deaths being related to CHD (5000) (HSE, 2017). In the United Kingdom, CVD cause more than a quarter (27%) of all deaths, or around 155,000 deaths each year—an average of 425 people each day or one every three minutes (Townsend et al., 2015). According to the American Heart Association, a similar worldwide trend exists. CVD globally account for >17.3 million deaths per year, a number that is expected to rise to >23.6 million by 2030. In the United States, 92.1 million American adults are living with some form of cardiovascular disorder or the aftereffects of a stroke, costing more than $316 billion for both direct and indirect costs (Benjamin et al., 2017). As developing countries adopt a more Westernized lifestyle and the incidences of diabetes and obesity continue to increase worldwide, the estimated number of CVD-related deaths is

The Origin of Chronic Diseases With Respect to Cardiovascular Disease 3 expected to globally rise to 23.3 million by 2030 (WHO, 2015). Clearly, the development of CVD is a major global concern, and for several reasons, the aforementioned balance has been tipped toward the disease state for an increasing number of people. Taking into account that CVD are a significant challenge for the healthcare systems around the world and thus a major economic burden, there is a greater need to discover new targets and to develop potential therapies for CVD. Prevention is key in reducing global mortality due to chronic diseases such as CVD. Therefore, it is important to separate the underlying causes and processes of disease from the symptoms of disease. With a focus on atherosclerosis and the corresponding onset of CVD, it is significant that the underlying cause of the disease and the formation, progression, and expansion of plaque in the walls of coronary arteries occur over a period of several decades before clinical symptoms appear. People with subclinical atherosclerosis are free of symptoms throughout the majority of their life. However, we often forget that to have a disease, you do not necessarily have to exhibit the symptoms. In Westernized and developing societies, where the global burden of CVD is most prevalent, people seem to be diagnosed with CVD in their 50s, unaware of the biochemical time bomb within. The underlying biological occurrences that cause chronic inflammatory processes at the endothelium, which in turn leads to atherosclerosis and the eventual onset of CVD symptoms, are initiated at a very young age and continue for several decades before any clinical symptoms appear. In fact, asymptomatic lesions can be formed in early childhood without leading to the onset of CVD (Ross, 1999). Given that the transformation of asymptomatic signals to symptoms is a continual process, preventing CVD should be considered as a continuous process that initiates long before the appearance of the symptoms. It is widely quoted that “the best form of defence is attack,” hence tackling the underlying cause of fatty lesion formation is imperative in order to start the process of disease prevention. Thus, a proactive collaborative approach is required to protect our cardiovascular health, for example starting with the education of youths. In our view, diet and lifestyle are valuable preventive tools against chronic diseases and need to be considered as a lifelong target and not just a middle-aged response to a debilitating disease. Our commitment to following a healthy diet and lifestyle in combination with moderate exercise is integral in minimizing our risk of developing CVD. We believe that nutrition should be regarded as a lifestyle issue and a powerful and important biochemical tool for the prevention of chronic diseases such as CVD.

1.2 Causes of Chronic Diseases Such as CVD Diseases can be regarded as a plethora of biological processes that cause cellular dysfunctions, usually resulting in tissue and/or organ disorders that in turn may lead to symptoms. Thus, we need to readjust our focus on the underlying causes and mechanisms of the diseases at the molecular and cellular levels. The focus of possible preventive measures would need to address inhibiting or minimizing these mechanisms for beneficial outcomes in the long term.

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Additional focus should also be given to the interrelation of several risk factors (such as an unhealthy lifestyle and diet, smoking, stress, low income and education, obesity, genetic causes, etc.) with the triggering and long-term progression of such molecular and cellular mechanisms underlying inflammation-related chronic diseases such as CVD. It is now evident that one of these underlying mechanisms at the molecular and cellular level, which is related to a common mechanistic pathway of the initiation and progression of several chronic diseases (such as CVD, ischemic and renal disorders, cancer, diabetes, etc.), is the manifestation of chronic inflammation, and especially that affecting the endothelium (Lordan et al., 2018a; Tsoupras et al., 2009). Inflammation represents a physiological reaction of the innate immune system in order to maintain and protect a constant internal milieu while being exposed to continuously changing environmental pressures, irrespective of whether the initial causes originate from microbial infection, traumatic injury, or metabolic dysfunction. The inflammatory response aims to reduce the agent that causes tissue injury (and/or minimize these effects) to induce appropriate wound healing and repair programs while restoring tissue homeostasis. Inflammatory responses are initiated by innate sensing mechanisms that detect the presence of microbial infection, stressed or dying cells, loss of cellular integrity, barrier breach, etc. A cascade of inflammatory pathways and mechanistic effects is supposedly well orchestrated by the immune system in order to eradicate the causative agent. Provided that the immune response succeeds in eliminating the infectious agent or repairing the initial tissue injury, the inflammatory process will be timely terminated and thus only transiently affect tissue function. However, in cases where the inflammation fails to resolve, for example due to the persistence of a pathogen and/or not succeeding in repairing the initiating injury and tissue dysfunction, a sustained underlying inflammatory process develops, leading to tissue dysfunctions and detrimental consequences for the established chronic inflammatory conditions. With reference to CVD, chronic and unresolved inflammatory manifestations in the walls of medium and large arteries trigger the initiation and progression of atherosclerosis, a chronic progressive vascular disease that may lead to a subsequent major cardiovascular event (Demopoulos et al., 2003; Tsoupras et al., 2018b). Atherosclerosis is the primary cause of CVD-related events leading to morbidity and mortality. As the pathological basis of CVD, atherosclerosis is featured as a chronic inflammatory condition. In the development of atherosclerosis, molecules that are produced by activated inflammatory cells play an integral role. These molecules can be cellular signaling molecules or reactive molecules and they are involved in a wide variety of diseases such as cancer, type II diabetes mellitus, osteoporosis, Parkinson’s, and Alzheimer’s disease (Coussens and Werb, 2002; Aggarwal et al., 2006; Tsoupras et al., 2009; De Virgilio et al., 2016; Ghodsi et al., 2016; Bolo´s et al., 2017; Haarhaus et al., 2017; Lordan et al., 2018a). In addition, dyslipidaemia and hypercholesterolemia are associated with myeloid

The Origin of Chronic Diseases With Respect to Cardiovascular Disease 5 cell expansion, which stimulates innate and adaptive immune responses, strengthens inflammation, and accelerates atherosclerosis progression (Ma and Feng, 2016). More specifically, atherosclerosis is initiated by inflammation-induced endothelial cell (EC) dysfunction/activation that is often triggered by the accumulation of low-density lipoprotein (LDL) and other apolipoprotein (Apo)B-containing lipoproteins in the walls of large and medium arteries. Specifically oxidized (oxLDL) by reactive oxygen species (ROS) and lipid oxidation induce an inflammatory response in the ECs neighboring the LDL accumulation and vice versa. As a response, the activated ECs begin to further release inflammatory mediators into the bloodstream as well as to express cell adhesion molecules on their surface in order to recruit circulating monocytes and other immune cells to the site of oxLDL build-up. Once the monocytes migrate into the walls of the arteries, they differentiate into macrophages, which are able to uptake oxLDL and form foam cells. Atherosclerotic plaques develop due to the continuous and uncontrollable recruitment of macrophages and build-up of foam cells at the site of oxLDL accumulation and the defective clearance of apoptotic cells/debris that leads to a chronic inflammatory response. As the plaque continues to develop, it can become unstable and rupture, leading to thrombosis, stroke, or myocardial infarction (MI) depending on the location of the rupture (Moss and Ramji, 2016). Thus, inflammation plays a key role in all stages of the formation of vascular lesions maintained and exacerbated by risk factors. The consequence of chronic inflammation is endothelial dysfunction, and we can define it as an integrated marker of the damage to arterial walls by classic risk factors. Atherosclerosis, which develops among these patients, is the main cause for cardiovascular mortality and uncontrolled chronic biological inflammation, which quickly favors endothelial dysfunction (Castellon and Bogdanova, 2016). Therefore, the development of CVD is linked to inflammation and herein identifies the first point of attack for many chronic diseases. An active area of research is the discovery and characterization of inflammatory biomarkers associated with CVD risk. Current therapies for atherosclerosis mainly modulate lipid homeostasis. While successful at reducing the risk of a CVD-related death, they are associated with considerable residual risk and various side effects. There is, therefore, a need for alternative therapies aimed at regulating inflammation in order to reduce atherogenesis. In order to inhibit the development of CVD and other chronic diseases, targeting inflammation may be the key to inhibiting or at least reducing the initial processes that lead to chronic disease development. On the other hand, inflammation is an omnipresent process that is directly related to diet and lifestyle choices. Either poor diet that is associated with the consumption of insufficient amounts of specific essential nutrients or the overconsumption of food (especially food with low nutritional value such as refined carbohydrates or alcohol) can lead to nutritional imbalances. While linking nutritional and dietary choices to cell function and disease development, we need to take into consideration one of the fundamental causes of obesity and metabolic syndrome, which is excessive calorie intake combined with a lack of physical activity (Miglani and Bains, 2017; Tune et al., 2017).

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Fig. 1.2 Lifestyle choices and CVD Modified from Ardies, C.M., 2014. Diet, Exercise and Chronic Disease: The Biological Basis of Prevention, CRC Press, Boca Raton, FL.

Metabolic syndrome is not always regarded as a disease per se; however, it is a cluster of conditions including abdominal obesity, hypertension, insulin resistance, and dyslipidaemia. Therefore, it is linked to factors associated with atherosclerosis, type 2 diabetes, and stroke (Fig. 1.2). Metabolic syndrome and obesity are also associated with cancer (Belloum et al., 2017), neurological diseases (Luchsinger et al., 2007; Gonzalez-Bulnes et al., 2016), and osteoporosis (Da Silva et al., 2017). Interestingly, it has also been suggested that a lack of physical activity on its own (i.e., when not studied in relation to other risk factors) may be associated with the development of chronic diseases (Strong et al., 2005), whereas for some researchers (Booth et al., 2012; Durstine et al., 2013) inactivity is a disease on its own! It is of great scientific importance to clarify the interrelationship between each or a combination of the aforementioned risk factors at a molecular level. It is imperative to discern the mechanisms that trigger and establish such underlying inflammatory manifestations in systemic disorders such as those found in CVD in order to implement long-term appropriate preventive measures.

1.3 Unresolved and Emerging Public Health Hazards due to Genetic, Dietary, Environmental, and Lifestyle Factors When addressing the various clusters of factors that influence the development of chronic diseases and, in particular, CVD, it is worth keeping in mind that these factors can be assembled into three main groups: 1. Genetics and epigenetics factors. 2. Nutrition, dietary, and lifestyle factors. 3. Environmental factors.

The Origin of Chronic Diseases With Respect to Cardiovascular Disease 7

Fig. 1.3 Factors affecting disease susceptibility.

In reality, these groups of risk factors are not completely isolated or unconnected, but seem to be interrelated and sometimes coexisting (Fig. 1.3).

1.3.1 Genetics Until recently, human disease susceptibility was linked to inheritable information that was carried on the primary sequence of our DNA. We are all endowed with different genotypes that dictate our response to endogenous (e.g., hormones) and exogenous factors (e.g., nutrition, physical activity, smoking, stress, pollution, etc.). Epigenetic processes control central genetic functions over the course of one’s lifetime (Walter and H€umpel, 2017), and it is these responses that form the basis of an individual’s genetic variability to disease susceptibility. Abnormal changes in the sequences of linear DNA may result in the occurrence of gene anomalies (mutations, deletions, duplications, or gene amplifications) that in turn cause gene expression to become dysregulated. These processes can lead to the development of genetic diseases or make an individual more susceptible to other diseases later in life. Epigenetic disruption of gene expression can also play an equally important role in disease development, a process that is more susceptible than the former to modulation from environmental factors (Tang and Ho, 2007). Increasingly, it is accepted that epigenetic marks provide a mechanistic link between the environment, nutrition, and disease (Anderson et al., 2012). Atherosclerosis and associated CVD are multifaceted disorders, influenced by environmental and heritable genetic risk factors. Numerous gene variants that are associated with a greater or lesser risk of the different types of CVD and of intermediate phenotypes

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(i.e., hypercholesterolemia, hypertension, diabetes) have been successfully identified. Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in processes underlying CVD, including atherosclerosis, inflammation, hypertension, and diabetes (Muka et al., 2016). Because of the strong predicted genetic components of both CVD and inflammatory biomarkers, there is an interest in identifying genetic determinants of inflammatory markers and characterizing their role in CVD. Recent developments in the methodological approaches of genetic epidemiology, especially genome-wide association studies and Mendelian randomization studies, have been effective in identifying novel gene associations and determining the causality of these genes with CVD (Raman et al., 2013). In addition, the epigenetic regulation of the inflammatory pathways in relation to atherosclerosis with a specific attention to monocyte- and macrophage-related processes is a new approach in the field (Neele et al., 2015). Of considerable importance are the gene-diet interactions as a new field of examining the interrelation of these two risk factors on CVD. Fetal reprogramming is a process that refers to the role of developmental plasticity in response to environmental and nutritional signals during gestation and early life and its potential adverse consequences in later life. It is believed to be responsible for the “fetal origins” hypothesis, which links the development of diseases, including CVD, to fetal undernutrition in late gestation. Further studies support the evidence that maternal undernutrition before and during pregnancy plays a key role in fetal development and reprogramming (Wu et al., 2004; Anderson et al., 2012). An increasing number of studies have indicated that various exogenous and endogenous factors that influence epigenetic processes during developmental reprogramming are of critical importance later in life. The relationship between maternal dietary factors and fetal development is an important source of study in order to understand the role of different factors of disease development and CVD (Gicquel et al., 2008). Other chronic conditions such as an impaired glucose metabolism leading to an increased risk of developing type II diabetes mellitus later in life have also been suggested due to maternal undernutrition (Mi et al., 2000; Newsome et al., 2003). For instance, studies on the maternal dietary ω6/ω3 fatty acid ratio during pregnancy also indicate an inverse relationship to child neurodevelopment during fetal life (Bernard et al., 2013). Other exogenous factors such as smoking and alcohol can also have profound effects on prenatal development, including abortion, sudden infant death, and fetal alcohol syndrome (DiFranza and Lew, 1995; Roozen et al., 2017). Interestingly, studies are now examining the role of paternal nutrition before conception as a risk factor for certain conditions (Lambrot et al., 2013). In the future, many dietary factors (such as dietary methyl donors, cofactors, fat, glucose intake, catechins, and flavonoids) will play an important role in our understanding of gene function and our susceptibility to disease. The connection between gene function and disease is intricately linked to environmental factors such as heavy metals, xenochemicals, and endocrine disruptors, which are also of major

The Origin of Chronic Diseases With Respect to Cardiovascular Disease 9 concern for the progressive burden of global disease (Tang and Ho, 2007). Future results from genome-wide studies coupled with results from functional studies and investigation on gene-environment interactions will allow the improvement of cardiovascular risk assessment and the discovery of new targets for therapy and prevention (Gianfagna et al., 2012).

1.3.2 Nutrition, Diet, and Lifestyle The most famous quote linking food to disease is the following: “Let food be thy medicine and medicine be thy food” by Hippocrates of Kos (460–377 BC), who is universally recognized as the father of modern medicine. Hippocrates’ work was based on observation of clinical signs and rational conclusions that did not rely on religious or magical beliefs (Yapijakis, 2009). In modern medicine, many epidemiological studies focus on the links between diet, nutrition, and disease, with the most notable one being the Seven Countries Study (see Chapter 4). In this study, it was found that certain populations and cultures have notably lower incidences of CVD than others do, due to their diet. Many studies have been carried out since, including PREDIMED (PREvencio´n con DIeta MEDiterra´nea), a multicenter, randomized primary prevention trial that was established to assess the long-term effects of the Mediterranean diet on the incidences of clinical cardiovascular events (Martı´nez-Gonza´lez et al., 2015). A common feature of the diet among populations in the Mediterranean is a relatively high dietary intake of vegetables, fruits, legumes, whole grains, monounsaturated fats, and nuts followed by moderate consumption of fish, dairy products (mainly cheese and yogurt), alcohol, and low consumption of red and processed meat (Tektonidis et al., 2015). Furthermore, there is substantial evidence to support the benefits of fish consumption, particularly oily fish such as salmon, trout, sardines, mackerel, and herring, to inhibit the onset of CVD (Megson et al., 2016). The majority of clinical trials and epidemiological studies have mainly investigated the role of a small group of fish-derived lipids (such as the omega-3 and omega-6 fatty acids of marine origin) as a preventive nutrient against CVD (Bowen et al., 2016; Lands, 2016; Watanabe and Tatsuno, 2017). Nutraceuticals containing such fish lipids have already been on the market and coadministered in several CVD situations (Bowen et al., 2016). On the other hand, emerging studies have reported that the more polar fish lipids (such as phospholipids and glycolipids of marine origin) also play a beneficial preventive role against atherosclerosis and CVD, both in the short and long term, mainly by downregulating the inflammatory status in these disorders (Nasopoulou et al., 2011; Tsoupras et al., 2018a; Lordan et al., 2017). However, further research is required in order to investigate the potential use of polar lipids of marine origin as a new class of marine-derived nutraceuticals. In addition, since the Seven Countries Study, fats have been demonized by scientists, nutritional guidelines, and government policies. Recent research trends have shown that dairy products may possess many health benefits due to their content of anti-inflammatory lipids, contrary

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to the negative perception they earned due to their high levels of SFA (Lordan and Zabetakis, 2017a,b; Lordan et al., 2018b,c; Megalemou et al., 2017). Thus, researchers, the medical community, and nutritional guidelines were focused on reducing the SFA content of food products, including dairy products. Researchers generally agree that the effects of reducing SFA in foods are dependent on what replaces them in the diet. Reduced CVD risk has been associated with the replacement of SFA with either cis-polyunsaturated fatty acids or cis-monounsaturated fatty acids. However, replacement of SFA with carbohydrates is associated with no reduction or even an increased CVD risk (Givens, 2017). Government policy and nutritional guidelines have supported diets based on the reduction of SFA for the prevention of CVD, but it is becoming increasingly apparent that these guidelines have little significant benefits on cardiovascular disease, diabetes mellitus, or insulin resistance (Howard et al., 2006; Tinker et al., 2008; Micha and Mozaffarian, 2010; Estruch et al., 2013; Chowdhury et al., 2014). However, these findings are still contentious and not always supported among researchers (Hooper et al., 2011; Dawczynski et al., 2015). Government policy has been involved in national nutritional guidance in many countries with some negative and some positive effects. Education and concurrent government policy can play crucial roles in encouraging appropriate lifestyle and nutritional changes in populations as preventive measures. For example, countries such as the United Kingdom and Ireland have drafted legislation to introduce a sugar tax on sugar-sweetened beverages by 2018. These beverages contain sugars such as sucrose and high fructose corn syrup that have long been a matter of much scientific and public concern due to their adverse associations with obesity, type II diabetes mellitus, and CVD (Malik and Hu, 2015). In 2014, the Mexican government implemented a 10% excise tax (1 peso per liter) on sugar-sweetened beverages levied on manufacturers (Sa´nchez-Romero et al., 2016). This was to great effect as market research has demonstrated that there was a 12% decrease of sugar-sweetened beverage purchases by Mexican households by December 2014 (Colchero et al., 2016). Meta-analysis by Cabrera Escobar et al. (2013) has shown that a tax on sugar-sweetened beverages does, in fact, reduce their consumption and that this reduction increases with higher tax rates. The study also revealed that these reduced consumption rates resulted in modest reductions of population weight. Therefore, a sugar tax may be a worthwhile preventative measure for obesity and other chronic diseases. Further evidence to support the role of nutrition and diet in the development and prevention of cardiovascular disease will be explored throughout the book. An individual’s lifestyle is an equally important factor in determining susceptibility to disease, and as previously mentioned, people with a healthy balanced diet and regular exercise reduce their risk of developing chronic diseases such as CVD. However, other lifestyle choices can have a profound impact on our health, regardless of diet or regular exercise. One such lifestyle choice is smoking. Mounting research (epidemiological, clinical, behavioral, and biological) has identified cigarette smoking as a major external parameter that triggers cancer as well as cardiovascular and pulmonary diseases. Of all these diseases,

The Origin of Chronic Diseases With Respect to Cardiovascular Disease 11 smoking is responsible for 90% of all lung cancers (Pesch et al., 2012). In 2000, tobacco use was related to >5 million deaths per year globally and this figure is estimated to rise to 8 million by 2030. Passive smoking or second-hand smoke has also emerged as a major health concern with evidence that children and nonsmokers have been victim to premature death and disease through exposure to smoke in public places and the workplace. Smoking and passive smoking are well-established risk factors for CVD. It is hypothesized that toxic exposure to chemical constituents of tobacco smoke causes persistent inflammatory changes in endothelial cells (Ambrose and Barua, 2004). Cigarette smoke is a mixture of thousands of chemicals generated from the burning of tobacco. These chemicals have cytotoxic, mutagenic, and carcinogenic effects while others are addictive compounds. Some of the compounds responsible for acute cardiovascular toxicity have been identified, including carbon monoxide, nicotine (Astrup and Kjeldsen, 1979), and heavy metals such as cadmium (Hecht et al., 2013), but many still remain elusive. Interestingly, studies have shown that whole smoke induces far greater toxicity in contrast to carbon monoxide or nicotine alone (Michael Pittilo, 2000). Therefore, further research is warranted to discover what other compounds induce cytotoxic effects. Smoking has a number of immunomodulatory effects. Cigarette smoke reduces leukocyte chemotaxis, reduces the production of immunoglobulins, modulates antigen presentation, promotes autoimmunity, and causes a stronger inflammatory reaction by increasing the release of tissue-destructive compounds (e.g., reactive oxygen species and proinflammatory cytokines) (Lee et al., 2012a; Johannsen et al., 2014). Globally, efforts have been made to stem the impact of cigarette smoke on the health of our society through the implementation of advertising campaigns and smoking bans. Smoking bans have proved to be successful in reducing the incidences of CVD ( Juster et al., 2007; Richiardi et al., 2009; Abe et al., 2017) and pulmonary diseases (Gala´n et al., 2017) in smokers and passive smokers, as evidenced by the 2004 success of the Irish national smoking ban in workplaces and enclosed public spaces (Mulcahy et al., 2005; Stallings-Smith et al., 2013). Smoking bans have been supplemented with advertising campaigns that have become commonplace in developed nations with the intention of reducing tobacco consumption. Many countries have introduced restrictions on the advertising and promotion of cigarettes with written warnings and images placed on cigarette cartons warning of the health implications of smoking. Economic interventions have also proved to be very beneficial through the increased taxation of cigarettes in many countries (Blecher, 2008). Other approaches include nicotine replacement therapy, which takes the form of absorbing nicotine via tablets, chewing gum, nasal sprays, patches, lozenges, or electronic cigarettes (e-cigarettes) in order to reduce withdrawal symptoms associated with the cessation of smoking by replacing nicotine in the bloodstream. Although the speed of absorption is different between the methods, there is no evidence that one treatment is superior to another. The chances of discontinuing smoking increase by 50%–70% through nicotine replacement therapy (Silagy et al., 2004). A review by Kaisar et al. (2016) has highlighted a number of uncertainties in relation to

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e-cigarette use, and dispels the myth that e-cigarettes merely emit water vapor upon use. Research is growing to support the theory that e-cigarettes emit potentially toxic substances due to the by-products and constituents of the flavoring additives, including traces of heavy metals as well as carcinogenic and teratogenic agents (Goniewicz et al., 2014). Schober et al. (2014) have shown that e-cigarettes are not emission free and their pollutants can impair air quality. Thus, there is a risk of “second-hand vaping.” The use of e-cigarettes may be of major concern for future public health as there is no data available in relation to their use and the risk of chronic disease development. As the trend of e-cigarette use grows, it is clear that the scientific and toxicological evidence to support their usage lags (Rahman et al., 2014). Further research is required in order to either exonerate or reject e-cigarettes as a viable nicotine replacement method and to develop informed manufacturing regulations to safeguard our health. Of all the literate lifestyle factors, inactivity and sedentary lifestyle patterns are detrimental to human health. Low to zero physical exercise and long-term inactivity when combined with an unhealthy diet are directly associated with obesity, metabolic syndrome, and the onset of many adverse health conditions, including major noncommunicable chronic diseases such as CHD, type II diabetes mellitus, and certain cancers, all of which shorten life expectancy. Because much of the world’s population in developed and developing countries is mainly inactive (Lee et al., 2012b), obesity is currently characterized as a disease. An abnormal accumulation of body fat, typically 20% above the normal ideal body weight, may result in adverse effects on health (Agha and Agha, 2017). The causes of obesity are multifactorial and not entirely understood. However, one of the main causes is an energy imbalance between calorie intake and expenditure. Excess calorie intake and associated weight gain are caused by the interaction between the environment, genetics, economics, individual behaviors, nutrition, and even our own microbiota (Le Chatelier et al., 2013; Smith and Smith, 2016). The common metric to characterize an individual’s weight is body mass index (BMI), where a BMI of 25–29.9 indicates an overweight individual. An obese individual is defined as a BMI > 30. It also needs to be taken into consideration that the use of BMI is often criticized. This is because, since the development of the BMI metric, there are more accurate measurements of body mass available such as bioelectrical impedance and body compositional studies (Rothman, 2008). Globally, >2.1 billion people are either overweight or obese. In the United States, almost 35% of adults are classified as obese and one-third of children and adolescents are either overweight or obese. Obesity is the fifth-leading cause of mortality in the world, accounting for 3.4 million deaths annually (Smith and Smith, 2016). Inactivity has long been associated with an increased risk of obesity and CVD. A recent metaanalysis has shown that a modest shift from inactivity to a small amount of physical activity may lower your risk factors for developing CVD (Wahid et al., 2016). These results are supported by the recent prospective cohort study in Rotterdam, where it was found that CVD risk was higher for those that were inactive

The Origin of Chronic Diseases With Respect to Cardiovascular Disease 13 and overweight or obese (Koolhaas et al., 2017). Therefore, it is clear that lifestyle factors such as diet, smoking, and levels of physical activity are modifiable risk factors for disease prevention and should be adopted as part of a healthy lifestyle.

1.3.3 The Environment and Anthropogenic Activity It is now evident that the risk of developing chronic noncommunicable diseases such as CVD in adulthood is influenced not only by the aforementioned factors (e.g., genetics and epigenetics) but also by several environmental factors. Environmental processes occurring during the periconceptual, fetal, and infant phases of life may influence the propensity of disease occurring in adulthood (Gluckman and Hanson, 2004). Currently, 73% of the European population live in urbanized areas in contrast to 54% of the world’s population. These figures are expected to rise with 66% of the world’s population projected to live in urban areas by 2050 (United Nations, 2014). Increased urbanization leads to increased anthropogenic activities, industrialization, and inevitably exposure to rising environmental factors such as ambient air pollution. The list of the environmental factors that affect the onset of diseases is constantly growing. The continuous development of novel products for our use makes life easier (in a way), but not without the risk of novel hazards and challenges. Environmental exposure is an important but underappreciated risk factor contributing to the development and severity of CVD (Cosselman et al., 2015; Oikonomou et al., 2016; Bhatnagar, 2017). Heart and vascular systems are highly vulnerable to a number of environmental agents such as ambient air pollution (either indoor or outdoor), heavy metals, and/or persistent organic pollutants (POPs). For example, polychlorinated biphenyls, dioxins, and pesticides (especially via the food chain) are widespread and the most extensively studied (Lind and Lind, 2012; Cosselman et al., 2015; Kaufman et al., 2016; Oikonomou et al., 2016; Bhatnagar, 2017). Like traditional risk factors (e.g., smoking and diabetes mellitus), these exposures induce chronic diseases via augmentation and/or initiation of pathophysiological processes associated with CVD, including genetic, hemodynamic, metabolic, oxidative, and inflammation parameters related to blood-pressure control, carbohydrate and lipid metabolism, vascular function, and atherogenesis. For example, exposure to several air pollutants [such as nitrogen oxides (NOx), ozone, particulate matter (PM2.5 < 2.5 μm/PM10 < 10 μm), ultrafine particulate matter (PM0.1, < 0.1 μm), carbon monoxide (CO), carbon dioxide (CO2), sulfur oxides (SOx), and volatile organic carbons (VOCs)], is linked to pulmonary and cardiovascular disease development (Mannucci, 2017; M€ unzel et al., 2017). Endothelial dysfunction, atherosclerosis, procoagulation, and alterations to the autonomic nervous system balance and blood pressure are several coinciding pathways that are hypothesized to occur in the development of CVD due to air pollution (Kelly and Fussell, 2017). Particularly, PM has been associated with CVD mortality and the development of chronic conditions such as hypertension, ischemic heart disease, and acute

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events such as myocardial infarction (Brook et al., 2010). The mechanisms responsible for PM-induced health effects are a result of inflammation and oxidative stress in the lungs, heart, and vascular tissue (Donaldson et al., 2001; Lodovici and Bigagli, 2011). In addition, persistent organic pollutants such as glyphosate residues, which are one of the main constituents and active ingredients of several pesticides that have the potential to disrupt homeostasis, have been found in the main foods of the Western diet, including sugar, corn, soy, and wheat (Samsel and Seneff, 2013). Furthermore, the levels of heavy metals that have been found crosscontaminating the food chain are following a rising trend at an alarming rate. Exposure to heavy metals can occur through wastewater irrigation, solid waste disposal, sludge, and vehicular exhaust fumes. High levels of industrial activity are the major sources of heavy metal contamination in soil, leading to an increased risk of heavy metal uptake by food crops grown in soil or supplied with water that is contaminated (Khan et al., 2008). Heavy metals transferred through food pose a dangerous risk for CVD and to human health in general. In addition, intolerable levels of heavy metals leeching from cooking utensils may pose a danger to human health upon consumption, whereas proper manufacture of utensils prevents the leeching of toxic levels of heavy metals during food preparation. Alarmingly, toxic elements have been analyzed in infant formula and infant foods (Ljung et al., 2011). Further research on the intake of heavy metals through milk consumption has shown that Cu and Pb may pose serious health risks (Ismail et al., 2015). Our research team has been focusing on food chain cross-contamination with Ni and Cr. We have found that these two metals are present in irrigation water in the Asopos and Messapia region of Greece, and have contaminated food tubers produced for human consumption (Kirkillis et al., 2012; Stasinos and Zabetakis, 2013). Despite the fact that the European Commission has already set maximum levels for Cr and Ni in water for human consumption (Council Directive 98/83/EC, 1998), the corresponding EU legislation for food (Commission Regulation (EC) No 1881/2006, 2006) has legal limits only for four heavy metals (Sn, Pb, Hg, and Cd). Thus, it is evident that there is a clear legal gap not accounting for other heavy metals that may cause negative effects on human health if they cross-contaminate the food chain. Evidence-based clinical and public health strategies aimed at reducing environmental exposures from current levels could substantially lower the burden of CVD-related death and disability worldwide. Furthermore, concern from consumers and politicians due to the overuse of pesticides has driven an increase in the uptake of organic farming and the purchase of organic produce over the last four decades. Organic farming aims at creating a sustainable agroecological system that accounts for proper management of land and good animal welfare practices (Lund and Algers, 2003) while prohibiting the use of synthetic fertilizers, pesticides, or genetically modified organisms (GMOs). Food labeled organic must meet certified organic standards for production, handling, processing, and marketing. Organic food carries the perception that it is more environmentally friendly and healthier upon consumption due to its strict regulations and practices. A recent review by Brantsæter et al. (2017) identified that organic foods tend to carry fewer pesticide residues, but they concluded that it is unclear whether this had any ramifications

The Origin of Chronic Diseases With Respect to Cardiovascular Disease 15 for human health. A similar review showed that organic foods tend to contain higher antioxidant levels coupled with lower pesticide and cadmium contamination, and that organic meat and dairy products contain superior levels of omega-3 fatty acid (Baranski et al., 2017). Studies have shown that organic produce may possess greater health benefits. In a study by De Lorenzo et al. (2010), they found that consumption of an organic Mediterranean diet is superior to a conventional Mediterranean diet in terms of reducing the risk factors associated with CVD. However, published data in relation to long-term cohort studies focusing on chronic diseases is limited and there are no controlled human dietary intervention studies addressing the differences between organic and conventional diets. Therefore, more research is required to measure what extent organic food consumption may affect human health.

1.4 Concluding Remarks As technology, industry, and agriculture evolve, humanity benefits greatly. However, unforeseen and often unintentional challenges arise that may be a threat to human health. A number of key interlinking factors play a pivotal role in determining the outcome of the balance between health and disease. Environmental, genetic, nutritional, and lifestyle factors are modifiable risk factors that, as discussed, can promote or prevent disease onset and development. For the purpose of this book, some of the key examples of each factor have been described with reference to CVD. More specifically, in this chapter, we summarized which are the main causes and risk factors that can trigger and propagate chronic diseases such as CVD. Traditional and/or emerging risk factors induce underlying molecular and cellular manifestations that result in chronic inflammatory responses in the long term, leading to loss of tissue homoeostasis and dysfunction. These chronic underlying disorders generally develop over a number of years before cellular disturbances manifest into tissue disorders that then become the recognizable symptomatic disease. This leads to a challenging landscape for medical treatment and disease prevention. Consequently, in order to obtain meaningful disease prevention, healthcare professionals with governmental support need to endorse scientifically verified methods. A healthy lifestyle in combination with preventive nutritional and medical approaches is required to hinder and resolve the processes that lead to symptomatic chronic diseases such as CVD. Preventing disease development can also be accomplished through a number of measures, including advertisements and educational programs. Even at the primary level, education is also key in tackling chronic diseases such as CVD and thus it must begin earlier in life and progress throughout school. This can be achieved by developing educational programs for children and adolescents that encourage the adoption of healthy diets and exercise while identifying the risk factors that increase our chances of developing chronic diseases later in life (e.g., smoking or sedentary lifestyles). Educating children would have a beneficial reciprocal effect in adults. As the saying goes: “Let the Children teach us.”

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Further Reading World Health Organization, International Agency for Research on Cancer, 2004. Tobacco Smoke and Involuntary Smoking. World Health Organization.