Blood Oxidant Ties: The Evolving Concepts in Myocardial Injury and Cardiovascular Disease

The generation of certain species of biomolecules described as reactive oxidant species (ROS e.g., superoxide, O2 -; hydrogen peroxide, H2O2; hydroxyl radicals (OH.)) and reactive nitrogen species (RNS e.g., peroxynitrite, OONO-; nitric oxide, •NO) is a critical step in health and disease . These species play critical roles in cell defences in both animals, and plants. They also perform an important function in the regulation of key cellular signalling pathways such as cell differentiation, proliferation, migration, and apoptosis (commonly described as redox signalling pathways). The imbalance between the levels of ROS and RNS generated to that of antioxidant species may lead to oxidative stress and biomolecular damage, especially in situations where the latter are depleted. Redox biology and oxidative stress are particularly important in ischaemia-reperfusion associated diseases in particular the pathogenesis of cardiovascular disease (CVD). CVD is a major cause of mortality on a global scale, although the exact mechanisms underlying the pathological process are not fully understood. It is believed that ROS play a pivotal role in the progression of CVD. In particular, recent evidence suggests that the development of atherosclerosis is modulated by ROS and influenced by other factors such as inflammatory responses, disturbed blood flow, and arterial wall remodelling. This chapter provides an overview of the pathways of oxidative stress and redox-regulated signalling underlying the genesis and progression of cardiovascular disease.

Oxidative stress is a major contributor to ischaemia reperfusion injurymediated myocardial infarction. Coronary ischemia deprives the heart muscles of nutrients and oxygen in the areas away from the site of arterial blockage, rendering cardiomyocytes unable to utilise aerobic metabolism to support their energy requirements. Homeostatic intracellular signalling systems, such as the hypoxiainducible factor (HIF) transcription factor cascade, sense the low oxygen environment. This in turn stimulates the upregulation of numerous compensatory mechanisms which are ultimately involved in elevating anaerobic glycolysis and promoting angiogenesis and vascularization. The increased anaerobic metabolism increases the production of lactic acid hence metabolic acidosis. This leads to myocyte death and the expansion of the size of the original area of the infarct. Under normal aerobic conditions, the myocardium generally metabolises relatively high levels of adenosine triphosphates (ATP). In contrast, during ischemia, the shift in energy production to glycolysis results in the inefficient production of ATP and constitutes a pathological feature, and if not reversed early, it may lead to complications such as heart failure and ischemia-induced atrial or ventricular fibrillation. Despite the widespread use of fibrinolytic agents and new types of angioplasty procedures for the treatment of myocardial infarction, often new sets of complications persist. These include the occurrence of extensive tissue injury caused by myocardial reperfusion through the reintroduction of oxygen to the previous ischemic tissues because of the excessive generation of reactive oxygen species (ROSs) and depletion of antioxidants. Widespread production of ROS damages the plasma membrane and stimulates the release of various proinflammatory agents. Several proteins become denatured for example receptors, ionic channels, transporters, or components of transduction pathways through oxidation by ROS. Altered protein structure inhibits their functions leading to the disruption of vital cellular processes. The onset of reperfusion injury is further exacerbated by the activation and infiltration of the infarcted area by polymorphonuclear leukocytes (PMNs). Several studies have identified the release of different leukocyte intracellular factors during PMN activation such as selectins and b2-integrins to be related to the magnitude of tissue damage. Some studies have shown that antagonists for leukocytes intracellular factors such as selectins abrogate PMN activation and reduce the infarct size.

More recent publications have shown that PMN activation is closely linked to the activation of other cells involved in the inflammatory response. For example, during myocardial ischemia–reperfusion injury, it has been shown that the activity of neutrophils is also modulated by lymphocytes and macrophages. This chapter summarises the interaction between oxidative stress, activation of different leukocytes and the release of factors involved in the generation of reperfusion injury.

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality worldwide with altered lipid metabolism as an important risk factor. In the current chapter we discuss processes involved in lipid metabolism, the past and emerging roles of various lipoprotein cholesterol molecules in this process, free fatty-acid metabolism and the various mechanisms of lipid oxidation and their impact on vascular physiology in health and disease. We further describe the role of reverse cholesterol transport (RCT) in the elimination of lipids as bile acids, and finally discuss current clinical interventions based on emerging technologies against dyslipidemia, hypertriglyceridemia, and CVD

The risk of chronic diseases such as cardiovascular diseases (CVD) during postnatal life is not only determined by environmental factors in adulthood but also by intra-uterine and early life environment according to the Developmental Origins of Health and Disease (DOHaD) concept. Environmental insults including poor nutrition, oxygen availability, maternal stress, alcohol, smoking and drugs, can compromise the maternal uterine and lactational environment leading to short- and long-term adaptations in offspring physiology or programming. While short-term predictive adaptive responses may offer immediate survival value, they can lead to irreversible changes in embryonic/fetal tissues and organs mediated through changes in cellular signalling and metabolic pathways, as well as endocrine axes governing whole-body function. The capacity for developmental adaptation may also be determined by both genetic susceptibility and epigenetic mechanisms, as well as environmentally induced changes in maternal microbiome structure and composition. Basic mechanisms involved in the development of CVD have been described in previous chapters. Here we will focus on how mechanisms involved in developmental programming may contribute to CVD in adulthood.

Cardiovascular disease (CVD) has become one of the leading causes of poor lifelong health and well-being. Meanwhile, the microbiome has emerged as one of the key determinants of human cardiometabolic homeostasis and the risk of CVD. While the clustering of the microbiome into phylum ratios or enterotypes has been correlated to specific disease phenotypes and population characteristics, the composition of a typical ‘healthy human microbiome’ is yet to be defined. Several population-based studies have shown an association between certain microbial species with CVD, although the inconsistencies have made the interpretation of such associations very difficult as it is not possible to pinpoint microbial populations associated with CVD. However, here we discuss current evidence on the role of the microbiome and its metabolites on the risk of CVD. We further explore current clinical studies investigating prebiotics and probiotics as potential therapeutic targets to modulate the microbiome for the benefit of the host to prevent cardiometabolic diseases. We highlight that further work to understand the role of specific species/sub-species, strains and polymorphisms within those strains, as well as microbial gene expression profiles and their respective metabolites is required. Coupled with high-resolution metagenomics and metabolomics as well as a unified approach in characterising common gut microbial communities based on global population observations, this would provide better indicators of disease phenotype and a better framework for a divergence to dysbiosis. The challenges that will need to be overcome in order to define a healthy microbiome and advance the clinical use of prebiotics and probiotics as well as faecal microbiota transplantation will also be discussed.

Oxidative stress and inflammation are parallel self-perpetuating mechanisms that when triggered, appear to be strongly linked with several complications of cardiovascular disease (CVD). Unchecked production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are largely the responsible factors that operate via the activation of several transcriptional messengers and a series of inflammatory pathways. Such messengers include Nuclear Factor-KappaB, known to contribute to a plethora of pathological complications such as endothelial dysfunction, the initiation and progression of atherosclerosis, irreversible ischemic reperfusion injury, and arrhythmias, particularly atrial fibrillation. Although much is known about the link between oxidative stress and CVD, the development of direct therapeutic interventions has remained elusive. In experimental animal models, the use of antioxidants in the form of dietary supplements has been shown to quench ROS/RNS or catalyse the break-up of free radical chains and has resulted in some measure of success. However, these findings have not been able to be replicated in human clinical trials for several different well-known agents, such as vitamin E and beta-carotene. Many potent naturally occurring antioxidants have been exploited by nature such as the oxygenated carotenoids (xanthophylls) and researchers have tested several of them in their natural form in clinical trials but sadly many of them have not translated into useful therapeutic tools. Questions, therefore, remain as to whether the reasons may be solely the inability to find the “right” compound(s) or delivery strategy, or the exact mechanisms of action of existing compounds have unknown targets or whether correct dosages are used. This chapter reviews existing evidence on the thesis that antioxidant/anti-inflammatory compounds may present an opportunity for the development of future therapeutic agents for both cardiovascular oxidative stress and inflammation. 

It has been recognized that oxidative stress plays a key role in the development of cardiac alterations derived from events of ischemia followed by reperfusion, such as in the clinical setting of acute myocardial infarction of patients subjected to coronary angioplasty. During ischemia, due to the occlusion of a coronary branch, biochemical events responsible for anaerobic metabolism, ATP availability and impairment of cell ionic homeostasis are the major deleterious effects. Following the onset of reperfusión, a burst of reactive oxygen species occurs, thus accounting for increased tissue damage due to the endovascular intervention. This iatrogenic damage has not been adequately treated to date. Among the many pharmacological attempts, cardioprotection with antioxidants should be mentioned; however, the experimental studies have not been translated into successful clinical trials aimed to prevent this enhancement of cardiac damage, despite some beneficial effects have been reported in the clinical outcome of the patients. This chapter aimed to present the hypothesis that the combination of antioxidant effects should improve the cardioprotection of the patients subjected to coronary angioplasty following acute myocardial infarction. Therefore, we present an update of previous attempts at cardioprotection with an antioxidant alone and give the basis for the expected improved protection by using two or more antioxidant compounds exerting different mechanisms that could enhance the beneficial protective effect.

In the search for an effective treatment against myocardial damage caused by oxidative stress, it has become necessary to generate new therapies that overcome the difficulties and failures observed in conventional therapies. Therefore, nanotechnology and nanoparticle development may open new horizons for the control and therapy of oxidative stress and associated myocardial damage. The term nanomaterials describe materials with nanoscale dimensions (< 100 nm). In this chapter, different nanoparticle drug delivery systems, along with their targeting strategies, and how they can help to improve therapeutic failure in oxidative stress using nanoparticles in the control of myocardial infarction and oxidative stress will be discussed. Achieving an inhibition of oxidative stress producers or improving the endogenous antioxidant capacity through drug delivery by nanoparticles increases the drug’s aqueous solubility, protects its degradation, allows prolonged release, and improves the bioavailability, determining a targeted delivery, and decreases the toxic side effects. It leads to new therapeutic opportunities for both monotherapies and combined therapies, benefiting from nanoparticles' particularities associated with increased solubility, bioavailability, and specificity.