Cardiovascular Diseases: Nutritional and Therapeutic Interventions PDF

Preface

There have been significant clinical advances in the management of cardiovascular diseases in the past few decades. A pertinent example is the effective therapy for acute coronary syndrome caused by coronary artery disease through percutaneous transluminal coronary angioplasty (stenting) and coronary artery bypass surgery. Nevertheless, cardiovascular diseases remain one of the highest causes of morbidity and mortality worldwide. Therefore, there is a need to further understand the molecular basis of this class of diseases, and new therapeutic or preventative interventions are necessary. This book represents an up-to-date collection and analysis of information related to the pathobiology of cardiovascular diseases, with an emphasis on emerging therapeutics and nutritional interventions. The book is divided into four main parts, namely, epidemiological studies, epigenetics, pathobiology, and therapies for cardiovascular diseases. Part I consists of Chapter 1, which details the epidemiology of cardiovascular diseases and highlights the magnitude of the clinical problem.

Part II consists of Chapters 2 through 4, which are related to the genetic and, predominantly, epigenetic modifications associated with cardiovascular diseases. In this context, with the advent of microarray and, more recently, next generation sequencing technologies, our understanding of the genetics of cardiovascular diseases has increased significantly. For example, numerous groups have performed microarray experiments using various models of cardiovascular disease and have identified disease-specific gene expression signatures. In vivo models of cardiac hypertrophy have been relatively well-investigated with the transverse aortic constriction and volume overload– induced models of hypertrophy being the most well-characterized to date. It is anticipated that with the increasing utilization of microarray and sequencing technologies, the molecular basis of cardiovascular diseases will be further unraveled. Most importantly, new targets for potential therapeutic interventions are expected to be identified using these approaches. Identification of receptor targets for noninvasive imaging applications represents a major goal. To date, relatively nonspecific targets of inflammation and various receptors, such as low-density lipoprotein receptor (LDLR) LOX-1 in atherosclerosis, are being investigated for imaging, and defining more specific targets using sequencing approaches is an exciting possibility.

The major consideration of Part II is related to epigenetic modifications. Epigenetics refers to the relatively new science that broadly involves the study of gene expression changes that are not associated with changes in the underlying DNA sequence. The most investigated of these mechanisms is DNA methylation, with the current paradigm suggesting that heavily methylated DNA is associated with transcriptional repression. The importance of DNA methylation status in cardiovascular diseases is an important subject in this book. In particular, the association between cardiovascular diseases and changes in DNA methylation during development is an important topic, representing a unique target for early intervention with simple dietary modifications using methyldonating nutrients.

Posttranslational histone modifications have also been associated with cardiovascular diseases, including atherosclerosis, cardiac hypertrophy, and reperfusion injury. The modifications may include changes in histone methylation status, which has implications for transcriptional regulation. In general, some emerging rules dictate that mono-, di-, or tri-methylation of lysine 4 on histone 3 (H3K4me1, 2, or 3) is associated with active gene transcription. Conversely, methylation of lysine 9 on histone 3 is associated with gene silencing. Numerous other histone methylation events have been associated with cardiovascular diseases; however, the functional significance and therapeutic value of these targets remain largely unexplored.

In contrast, aberrant histone acetylation status associated with cardiovascular diseases represents a potentially useful therapeutic target for which both synthetic and dietary compounds are available. Histone acetylation status is regulated by the opposing actions of histone acetyl transferases (HATs) and histone deacetylase inhibitors (HDACs). HATs are responsible for adding acetyl groups to the core histones, resulting in a more relaxed, transcriptionally permissive chromatin conformation. On the other hand, HDACs catalyze the removal of acetyl groups, resulting in more condensed chromatin conformation and transcriptional repression. The mammalian enzymes are divided into two families-the classical 11 metal-dependent enzymes, representing classes I, II, and IV (HDAC11), and 7 sirtuins (class III HDACs). The HDAC enzymes have been widely investigated in cardiovascular diseases, and it is emerging that different isoforms of the 18 identified mammalian enzymes are important. For example, in cardiac hypertrophy, evidence indicates that class I HDACs (1, 2, 3, and 8) augment cardiac hypertrophy and class II HDACs (4, 5, 6, 9, and 10) are thought to suppress pro-hypertrophic responses. Therefore, class I–specific HDAC inhibitors may be more appropriate for investigation as potential therapeutics for cardiac hypertrophy. Although class- or isoform-specificity appears to be important, classical broad-spectrum HDAC inhibitors, including the prototypical Trichostatin A, have shown beneficial effects in both in vitro and in vivo models of cardiovascular diseases. Furthermore, numerous dietary compounds contain potent HDAC inhibition activity. Potent compounds include diallyl disulfide from garlic and l-sulforaphane from cruciferous vegetables, and these have been investigated in models of cardiovascular disease.

The sirtuin (class III) HDACs represent an interesting group of HDAC enzymes having received much recent attention in the fields of anti-aging effects and longevity. In particular, resveratrol, a component of red wine, is a well-known sirtuin 1 agonist and has been shown to have beneficial effects in numerous conditions, including neurodegenerative conditions and cardiovascular diseases. Similarly, curcumin, a major component of turmeric, possesses epigenetic effects, including HDACmodulating activity, and represents another of extensive series of dietary components that have been shown to have beneficial effects in cardiovascular disease.

Part III relates to the etiology and pathobiology of various cardiovascular diseases and consists of Chapters 5 through 12. Apart from a detailed discussion of lipid regulation (Chapter 5) and genetic and epigenetic effects, including regulation by micro-RNAs (Chapter 9), this part deals with various therapies, including cell-based therapies (Chapters 11 and 12), that are emerging as potentially important new tools for the investigation and management of cardiovascular diseases. Further, this topic deals with potential new receptor targets (Chapter 7), which, as discussed earlier, are important not only from a therapeutic standpoint but also for potential targeted imaging applications. In addition, the link between conventional cancer therapies and cardiovascular diseases is detailed (Chapter 10). The anthracycline, doxorubicin, is a well-known frontline anticancer therapeutic. While it has potent antineoplastic efficacy, it targets proliferating cells, including normal cells. Given their intrinsically low antioxidant capacity, cardiac myocytes are particularly susceptible to the damaging and cytotoxic effects of doxorubicin. Indeed, cardiac toxicity is the limiting toxicity of doxorubicin. Numerous studies have attempted to alleviate the side effects of doxorubicin in cardiac myocytes using dietary antioxidants. In this book, vitamin C (Chapter 10) is discussed as a potential dietary component that can ameliorate the effects of doxorubicin-induced cardiomyopathy. In the context of doxorubicin-induced cardiac hypertrophy, HDAC inhibitors are important. Controversy still exists regarding the potential for clinical use of HDAC inhibitors in cardiac hypertrophy, with numerous studies indicating beneficial effects both in vitro and in vivo. In contrast, studies have shown that classical metal-dependent HDAC enzymes can augment the DNA damaging and cytotoxic effects of doxorubicin in cardiac myocytes. As described earlier, it will be interesting to note if these controversies can be resolved with class- or isoform-specific HDAC inhibitors or with dietary chromatin-modifying compounds, which typically possess more subtle HDAC-inhibiting effects.

Although potential therapies for cardiovascular diseases are discussed throughout this book, Part IV (Chapters 13 through 30) is dedicated to therapeutic, including the well-known Sildenafil (Viagra^®) (Chapter 23), and nutritional interventions for cardiovascular diseases. In continuation from previous sections, this part includes chapters related to stem cell therapies (Chapter 13) and to emerging nanomedicines (Chapter 14), with clinical potential for cardiovascular diseases. Further, it contains a plethora of information related to the potential use of dietary components for the management of a wide range of dietary interventions. These include more general discussions related to the importance of healthy diet (Chapters 15 through 17), fruit and vegetables (Chapters 22, 27, and 28), and botanicals (Chapter 29) to analysis of the beneficial effects of specific compounds including antioxidants (Chapter 19) such as resveratrol (Chapter 21). The discussion of garlic (containing the HDAC inhibitor diallyl disulfide) (Chapter 20), curcumin (HDAC modifier) (Chapter 26), and the red wine polyphenol (Chapter 18), resveratrol (sirtuin agonist) (Chapter 21), also links with chapters in previous sections discussing the potential of chromatin-modifying compounds for the treatment of cardiovascular diseases. Overall, this book contains a comprehensive account of cardiovascular diseases with a strong focus on dietary and lifestyle factors as highlighted by the discussion on the importance of stress (Chapter 8) and meditation (Chapter 30) in the incidence and management of cardiovascular diseases. Given the breadth of topics and detailed discussion of emerging therapeutics and dietary interventions, this book will serve as an important reference for clinicians and scientists with an interest in the pathobiology and management of cardiovascular diseases.