This chapter deals with diseases of the heart with the following chapter focusing on diseases of the blood vessels.
The Biology of Oxygen Radicals: Threats and Defenses
Normal cardiac structure and function are summarized here, and pathophysiologic mechanisms for commonly encountered cardiac problems are then discussed, with emphasis on arrhythmias, heart failure, valvular heart disease, coronary artery disease, and pericardial disease. The heart is a complex organ whose primary function is to pump blood through the pulmonary and systemic circulations. Peripheral venous return from the inferior and superior venae cavae fills the right atrium and ventricle through the open tricuspid valve Figure 10—1B. With atrial contraction, additional blood flows through the tricuspid valve and completes the filling of the right ventricle.
Unoxygenated blood is then pumped to the pulmonary artery and lung by the right ventricle through the pulmonary valve Figure 10—1C.
The Biology of Oxygen Radicals: Threats and Defenses | SpringerLink
Oxygenated blood returns from the lung to the left atrium via four pulmonary veins Figure 10—1D. Sequential left atrial and ventricular contraction pumps blood back to the peripheral tissues. The mitral valve separates the left atrium and ventricle, and the aortic valve separates the left ventricle from the aorta Figures 10—1D and 10—1E. Anatomy of the heart. A: Anterior view of the heart. B: View of the right heart with the right atrial wall reflected to show the right atrium. C: Anterior view of the heart with the anterior wall removed to show the right ventricular cavity.
D: View of the left heart with the left ventricular wall turned back to show the mitral valve. E: View of the left heart from the left side with the left ventricular free wall and mitral valve cut away to reveal the aortic valve. Redrawn, with permission, from Cheitlin MD et al, eds. Clinical Cardiology, 6th ed.
The heart lies free in the pericardial sac, attached to mediastinal structures only at the great vessels. During embryologic development, the heart invaginates into the pericardial sac like a fist pushing into a partially inflated balloon.
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Clinical Sports Medicine Collection. This property also dictates that full reduction of oxygen to water as a terminal event in the electron transport chain requires 4 electrons. Donation of a second electron yields peroxide, which then undergoes protonation to yield hydrogen peroxide H 2 O 2. Finally, donation of a fourth electron yields water. ROS formation in the heart can be induced by the action of cytokines and growth factors as well. This NAD P H-dependent pathway is best described in vascular smooth muscle cells but has also been documented in other cell types, including cardiomyocytes 16 — A number of additional ligands have been associated with the induction of ROS, including several with particular relevance to the cardiovascular system reviewed by Thannickal et al.
There are several cellular mechanisms that counterbalance the production of ROS, including enzymatic and nonenzymatic pathways Thioredoxin and thioredoxin reductase together form an additional enzymatic antioxidant and redox regulatory system that has been implicated in a wide variety of ROS-related processes Thioredoxin and thioredoxin reductase can catalyze the regeneration of many antioxidant molecules, including ubiquinone Q10 , lipoic acid, and ascorbic acid, and as such constitute an important antioxidant defense against ROS.
Deletion of thioredoxin reductase results in developmental heart abnormalities and in cardiac death secondary to a severe dilated cardiomyopathy They also include glutathione, which acts as a reducing substrate for the enzymatic activity of glutathione peroxidase. ROS have an important role in several important biological processes, including the oxidative burst reaction essential to phagocytes Thus ROS can play an important role in modulating inflammation. Perhaps the most widely recognized biological effects of ROS, however, are those that occur when cellular antioxidant defenses are overwhelmed and ROS react directly with cellular lipids, proteins, and DNA, causing cell damage and death 4 , 27 , 35 , Lipid peroxidation, for example, is a well-characterized effect of ROS that results in damage to the cell membrane as well as to the membranes of cellular organelles 37 , ROS can contribute to mutagenesis of DNA by inducing strand breaks, purine oxidation, and protein-DNA cross-linking, and other ROS-mediated alterations in chromatin structure may significantly affect gene expression 39 , Modification of proteins by ROS can cause inactivation of critical enzymes and can induce denaturation that renders proteins nonfunctional 41 , General aging and age-related alteration in the cardiovascular system have been attributed to the long-term cumulative effects of ROS, although the relative contribution of ROS to the aging process remains the subject of debate 43 , Figure 2 depicts several pathways by which ROS can mediate biological effects germane to the cardiovascular system.
Mechanisms by which ROS can alter the structure and function of cardiac muscle. MAPK activation can lead to cardiac hypertrophy or to apoptosis. The ROS that is generated can also signal through ASK-1 to induce cardiac hypertrophy, apoptosis, or phosphorylate troponin T, an event that reduces myofilament sensitivity and cardiac contractility. ONOO —— can cause lipid peroxidation, an event that can alter ion channel and ion pump function.
Catalase and glutathione reductase GPx are shown as enzymatic pathways to produce water and oxygen from H 2 O 2. A significant number of in vitro and animal studies have demonstrated ROS activation in the cardiovascular system in response to various stressors and in the failing heart 6 , 14 , 20 , 36 , 45 — Further, although the results are somewhat inconsistent, animal studies have also delineated that antioxidants and ROS defense pathways can ameliorate ROS-mediated cardiac abnormalities 26 , 48 — Many ROS-mediated biological processes that are germane to the heart and to the genesis of heart failure have been described.
Given that coronary artery disease CAD with consequent myocardial ischemia and necrosis is a leading cause of heart failure worldwide, it is important to note that ROS may play an important role in the genesis and progression of CAD 51 , ROS activity in the vessel wall, for example, is thought to contribute to the formation of oxidized LDL, a major contributor to the pathogenesis of atherosclerosis ROS-associated activation of MMPs may play an important role in vessel plaque rupture, initiating coronary thrombosis and occlusion In the setting of acute myocardial infarction MI , ROS are purported to play a significant role in tissue necrosis and reperfusion injury 55 , Transgenic overexpression of SOD has been shown to reduce infarct size in mice, which supports the contention that ROS are important mediators of myocardial damage in MI ROS also play a significant role in the pathogenesis of myocardial stunning, which can complicate acute ischemic syndromes Interestingly, administration of the XO inhibitor allopurinol in the setting of acute MI attenuates stunning and ameliorates the excitation-contraction uncoupling that occurs in stunned myocardium 58 , The manner in which the ventricle heals and remodels after MI is a major determinant of eventual cardiac function and the progression to heart failure ROS may contribute to the remodeling processes in a number of ways, including activating MMPs that participate in reconfiguration of the extracellular matrix; acting as signaling molecules in the development of compensatory hypertrophy; and contributing to myocyte loss via apoptosis or other cell death mechanisms 20 , 61 , Recently it was shown that inhibition of XO with allopurinol after experimental MI in dogs diminished ROS production in the myocardium and attenuated maladaptive LV remodeling, leading to improved post-MI cardiac function While this does not prove that ROS are a major clinical target for decreasing the progression to failure after MI, these findings are part of a growing list of data suggesting a major contribution of ROS to this process.
Cardiac hypertrophy can be either compensatory and adaptive or a maladaptive precursor to cardiac failure.
Mounting evidence has strongly implicated ROS signaling in the genesis of cardiac hypertrophy 64 — Many extracellular factors are capable of inducing hypertrophy of cardiomyocytes, and many of the various downstream signaling pathways that mediate the hypertrophic growth response to these factors can be activated directly or indirectly by ROS.
In vitro and in vivo data suggest that the small G-protein Rho may be involved in this link.
Inhibition of Rho with a dominant-negative construct in neonatal rat cardiomyocytes prevents ATII-mediated intracellular oxidation events, and inhibition of Rho activation by the HMG-CoA reductase inhibitor simva-statin blocked ATII-mediated increases in protein synthesis in these cells, leading to smaller cell sizes 20 , 73 , Simva-statin administration in vivo also prevented cardiac hypertrophy in response to either ATII administration or pressure overload induced by aortic banding, which establishes that the effects of ROS on hypertrophy are not an artifactual in vitro finding Another mechanism by which ROS can induce cardiac hypertrophy is via transcription factor—mediated alterations in gene expression.
AP-1 activity is also purportedly regulated by ROS and is involved in the transcriptional expression of several genes involved in cardiac hypertrophy. In addition, it is possible that regulation of transcription by ROS may be far more widespread than anticipated and that ROS-mediated alterations in gene structure and function contribute significantly to the pathogenesis of disease in many organ systems, including the heart. Recently the roles of ROS in chromatin remodeling and in DNA damage have become more established, and consideration of the potential involvement of these effects in the failing heart is warranted.
Overexpression of ASK-1 induces apoptosis in cardiomyocytes, and ASK-1—null mice demonstrate attenuated ventricular remodeling in response to pressure overload, a finding attributed in part to a reduction in cardiac apoptosis Cardiomyocyte apoptosis occurs in hypertrophied, ischemic, and failing hearts and may contribute to the development and progression of cardiac dysfunction and heart failure 47 , Experimental evidence suggests that ROS can mediate apoptosis by a variety of mechanisms, including direct mediation of genotoxicity 62 , 68 , Interestingly, whether or not apoptosis is induced in cardiomyocytes by oxidative stress appears to be dependent upon the level of ROS produced Another clinically relevant potential link between heart failure and ROS involves adrenergic signaling 14 , Ion flux is critical to normal cardiac function, and there is significant evidence that ROS alter ion channel flux and membrane ion pump function in a biologically important manner in heart muscle General membrane damage secondary to ROS-mediated lipid peroxidation is one mechanism by which this can occur; however, more specific ROS-mediated effects also contribute.
In another ROS-mediated pathway that may lead to reduced contractility, ROS can decrease the calcium sensitivity of the myofilaments. Recently it was shown that the ROS-related kinase ASK-1 associates with and phosphorylates troponin T in vitro and in vivo and that this event diminishes contractility and alters calcium handling in cardiomyocytes Whether this pathway contributes to human heart failure remains unknown.
It has been postulated, however, that via mechanisms such as this ROS-mediated abnormality in excitation-contraction coupling, chronic exposure to ROS contributes to the progression of failure. Myocardial lipotoxicity refers to the accumulation of intramyocardial lipids concomitant with contractile dysfunction, often associated with myocyte death 87 , Recently it was shown that lipid accumulation is a significant feature of clinical heart failure NO, by virtue of its unpaired outer shell electron, is a reactive molecule.
Mitochondrial function as a therapeutic target in heart failure
In addition to the expansive array of crucially important biological processes in which it plays a role, NO is also a determinant of cardiac contractility. Initially NO was characterized as a contractility depressant, although the role of NO, and the NO-generating NO synthases, is now understood to be much more complex with regard to effects on cardiac contractility 90 , Although its general biology will not be reviewed here, NO does react and interact with ROS, and this crosstalk can also have significant effects on cardiac function NO can mediate the S -nitrosylation of proteins at specific cysteine residues This process also occurs in the heart and has significant functional implications, especially with regard to calcium flux and excitation-contraction coupling 94 , A compelling argument has been made that the effectiveness of this therapy is due in part to restoration of nitroso-redox balance.
Several clinical observations support the hypothesis that ROS play a role in human heart failure, although to date the clinical data has been conflicting and less than compelling 98 , In a handful of defined cardiomyopathies, the contribution of ROS is well established, including alcohol-mediated and anthrocycline-induced cardiomyopathies In other forms of human heart failure, the role of ROS has not been definitively established.
One problem is that it has been difficult to determine ROS activity in vivo, and clinical studies have relied on indirect measures, using biochemical markers of ROS activity, including indices of lipid peroxidation. Further, the patients included in these studies often had confounding comorbidities that could induce alterations in these biochemical markers, independent of cardiac-specific ROS activity Finally, the presence of ROS in the heart concomitant with heart failure does not prove a causal relationship, and clinical trials using antioxidant therapy have yielded mixed and often disappointing results.
This may, however, reflect the difficulty in altering ROS-associated processes in vivo rather than an absence of their involvement in human cardiac failure or may indicate that the relationship between ROS and heart failure is too complex to be addressable by a single intervention Representative examples of the conflicting clinical data follow.
Treatment of heart failure patients with statins decreased rac-1 activity in myocardium from these patients, possibly via statin effects on ROS activity. Treatment with the XO inhibitor allopurinol improved cardiac contractility and restored normal vasomotor reactivity , Treatment with vitamin C inhibited endothelial cell apoptosis Conversely, large clinical trials of the antioxidant vitamins or precursors have not shown benefit in preventing cardiac morbidity or mortality — A larger clinical trial of a XO inhibitor to follow up on the earlier positive clinical results is planned, but at this time, the jury remains out regarding the therapeutic utility of antioxidant therapy for heart failure Myocardial oxygen consumption and availability must be matched to ensure normal cardiac function and viability.