The Impact of Nutrition and Statins on Cardiovascular Diseases

By Ioannis Zabetakis, Ronan Lordan and Alexandros Tsoupras

The Impact of Nutrition and Statins on Cardiovascular Diseases presents a summary of the background information and published research on the role of food in inhibiting the development of cardiovascular diseases. Written from a food science, food chemistry, and food biochemistry perspective, the book provides insights on the origin of cardiovascular diseases, an analysis of statin therapy, their side effects, and the role of dietary intervention as an alternative solution to preventing cardiovascular diseases. It focuses on the efficacy of nutrition and statins to address inflammation and inhibit the onset of disease, while also providing nutrition information and suggested dietary interventions.

• Includes a bioscience approach that focuses on inflammation and revisits the lipid hypothesis
• Presents the view that nutritional interventions have considerable value, not only for reducing cardiovascular risk for CVDs patients, but also acting as the best precaution for otherwise healthy people
• Advocates that nutritional habits that are formed at a young age are the best way to tackle the global epidemic that is CVDs

• Language: English
• Publisher: Academic Press
• Release date: Jan 15, 2019
• ISBN: 9780128137932

Ioannis Zabetakis

Ioannis Zabetakis has studied and worked in Greece, United Kingdom and Ireland. Originally a chemist, he fell in love with food science (sensory and functional properties of food). After an academic career at the Universities of Leeds and Athens spanning 15 years, where he developed a strong interest in lipids and cardiovascular diseases, Ioannis joined the Department of Biological Sciences at the University of Limerick (UL) in Ireland. In UL, the ongoing focus of his work is on the cardioprotective properties of food lipids with a particular emphasis on dairy and marine foods. With >75 papers and two patents, his quest is toward a healthier diet and lifestyle that will render us less dependent on medicines. http://scieng.ul.ie/departments/life-sciences/people/dr-ioannis-zabetakis Twitter Handle: @yanzabet

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Chapter 1

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

Abstract

Diseases are complex multifactorial processes that occur due to several external factors and/or various underlying internal biochemical and cellular processes. In this chapter, the fine balance between health and disease is discussed with a particular focus on cardiovascular diseases (CVD). CVD are the leading cause of death in developed and Westernized developing countries. A number of environmental, genetic, nutritional, and lifestyle factors have been linked to our health, especially in relation to CVD. These modifiable risk factors may cause or prevent premature mortality. Over the last few decades, with the advancement of industry and technology toward the improvement of food and drug production, medicine, and other anthropogenic activities, amenities have become more available to developed and developing societies. This often leads toward advancement, but does so sometimes to the detriment of human health. With worldwide human advancement, unforeseen challenges that can affect our health have arisen, such as ambient air pollution and contamination of ecosystems, water resources, and food chains. Consequently, sustainable development has been highlighted as a means to moderate the impact of environmental pollution on human health. However, other challenges such as nutrition and lifestyle can be key modifiable factors with a crucial role in health outcomes, especially in CVD. In this chapter, such factors are deliberated at length in relation to existing and emerging public hazards with reference to chronic diseases such as CVD.

Keywords

Lifestyle factor; Hazards; Chronic disease; Pollution; Human health; Atherosclerosis

Chapter Outline

1.1Introduction

1.2Causes of Chronic Diseases Such as CVD

1.3Unresolved and Emerging Public Health Hazards due to Genetic, Dietary, Environmental, and Lifestyle Factors

1.3.1Genetics

1.3.2Nutrition, Diet, and Lifestyle

1.3.3The Environment and Anthropogenic Activity

1.4Concluding Remarks

References

Further Reading

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.

Fig. 1.1 Dynamic balance between Health and Disease.

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 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 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. 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; Bolós et al., 2017; Haarhaus et al., 2017; Lordan et al., 2018a). In addition, dyslipidaemia and hypercholesterolemia are associated with myeloid 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).

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!

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.

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.

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

Fig. 1.3 Factors affecting disease susceptibility.

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 Hümpel, 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 (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 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 (PREvención con DIeta MEDiterránea), 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 (Martínez-González 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.,