Development of structural changes in the heart and in the systemic vasculature is the end result of established hypertension regardless of the initiating mechanism(s).84 The heart, the arterial vessels, the brain, the kidney and the retinal vasculature are the major target organs adversely affected by high blood pressure, responsible for subsequent clinical events. The assessment of alterations in the function and structure of these organs is therefore an important part of the evaluation of hypertensive patients before the onset of clinical symptoms. This is because it has been shown that some of these target organ alterations predictive of subsequent cardiovascular events, 99 can be
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regressed and /or even normalized by antihypertensive treatment,100 and that regression is associated with a reduction of cardiovascular clinical events.101
2.2.1 Atherosclerosis in hypertension
The association between arterial hypertension and target organ damage (TOD) identifies a high-risk clinical condition for developing future cardiovascular events independently of blood pressure (BP) and other coexistent risk factors.102-105 In this respect the structural changes observed in the carotid artery by ultrasonographic means (e.g. intima-media thickening and plaques) are particularly important because they are very common even in patients with mild-moderate hypertension.106, 107
There is a graded increase in the risk of atherosclerosis with increasing severity of hypertension. As the risk for atherosclerosis increases, that of IMT growth increases as well. Those individuals with severe hypertension have consequently been found to experience the greatest IMT growth.108, 109 Numerous studies have identified the interaction between several related events as being central to the development of the atherosclerotic process.
Such events include oxidative stress, inflammation and endothelial dysfunction. 110,111
Hypertension, oxidative stress and inflammation form a self-propagating cycle of interplay where it is not clear as to which process precedes and causes the other and such can lead to tissue injury as in atherosclerosis.112, 113
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Oxidative stress is a state of excessive production of Reactive oxygen species (ROS) that overwhelms the defense capacity of the body’s antioxidant systems.
Besides an enhanced production of ROS, oxidative stress may result exclusively from an impaired antioxidant system or a co-existence of both a down-regulated antioxidant defense and an increased production of ROS.113 Levels of anti-oxidant molecules have been found to be lower in some hypertensives.114 The endothelium of the vasculature acts as the primary sensor to mechanical factors emanating from blood flow.115 In hypertension, an increase in blood pressure stimulates endothelial mechano-receptors to activate transcription factors such as Nuclear factor kappa B (NF-kappaB) which in turn activates mechano-sensitive genes. This activation includes that of mechano-sensitive genes that will cause Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase to produce heightened levels of ROS and thereby lead to an onset of a state of oxidative stress.114 NADPH oxidases are groups of enzymes that are major sources of ROS in the vasculature.113
Activation of the renin-angiotensin-aldosterone system (RAAS) which occurs in hypertension is also implicated in the onset of hypertension associated oxidative stress. Angiotensin II (AII) is one of the central mediators of the system with strong associations with both oxidative stress and inflammatory processes.116 It promotes oxidative stress also through stimulating NADPH oxidase to produce more ROS cytokines. 117
Besides the close association between oxidative stress and hypertension as discussed above, there also exists a relationship between oxidative stress, inflammation and atherosclerosis. Both oxidative stress and inflammation are regarded as the link between hypertension and atherosclerosis.113 Oxidative stress through a number of pathways promotes an inflammatory response
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while the same can also be induced directly by the same factors that were involved in the onset of oxidative stress. Atherosclerosis is believed to be an inflammatory condition with a strong oxidative stress link or component.117 One of the important pro-atherogenic stages to occur in oxidative stress is the oxidative modification of low density lipoprotein (LDL). Through hydrogen peroxide action on tyrosine kinases, oxidative stress alters the endothelium permeability making it more permeable to lipids.117 The lipids that had moved into the sub-endothelial space due to altered permeability of the endothelium get trapped by fibers produced by the vascular wall cells and eventually get oxidized.113 Oxidized lipids in the sub-endothelial space are a powerful stimulant of an inflammatory response causing expression of leukocyte adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, endothelial-leukocyte adhesion molecule-1. 118,119 Circulating monocytes are as a result bound at the arterial endothelial surface from where they migrate into the sub-endothelial space to become macrophages. These macrophages then engulf large amounts of oxidized LDL and transform into foam cells causing atherosclerotic changes to the vascular wall.
Over time smooth muscles join in and start to proliferate and produce extracellular matrix.114 Oxidative stress may also cause inflammation/atherosclerosis through activation of redox sensitive transcription factors such as activator protein 1 (AP-1) and NF-κB which enhances the production of pro-inflammatory cytokines and chemokines such as adhesion molecules Vascular Cellular Adhesion Molecule 1 (VCAM-1).
Proinflammatory cytokines and chemokines will cause inflammation and consequently atherosclerosis by among others activating leukocytes and
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macrophages.115, 117 It is believed that oxidative stress activates NK-κβ by degrading the inhibitory proteins bound to it and once it is activated, NK-κβ moves to the nucleus where it will activate inflammatory genes leading to production of cytokines and chemokines mentioned above.114
IL-6 is another inflammatory marker that is found elevated in individuals with atherosclerosis. It has been detected in atherosclerotic lesions as well and is involved in causing endothelial dysfunction, recruitment of inflammatory cells and stimulation of adhesion to the endothelial layer by the monocytes, all of which are important steps in the development of atherosclerosis.120 These studies demonstrate that inflammatory markers are indeed useful indicators of inflammation that can be used in clinical settings and research.
One of the changes to occur in the vasculature during hypertension related oxidative stress is endothelial dysfunction believed to be induced by excessive production of free oxidative radicals. This is another pathway through which oxidative stress contributes to the thickening of the vascular wall. Endothelial dysfunction is one of the events to occur in the early stages of atherosclerosis.
Increased levels of ROS lead to them reacting with and inactivating Nitric Oxide (NO), thereby reducing NO bioavailability.113, 117,121 A healthy endothelium synthesizes and releases a number of vaso-active substances such as NO, prostaglandins, AII and endothelin. Among the vasodilators, NO is the most potent, the under-expression of which increases the risk to endothelial dysfunction and development of atherosclerosis.
Besides its vasodilatory function, NO also prevents platelet activation, smooth muscle cell proliferation, production of chemokines and cytokines, leukocyte recruitment and adhesion to the endothelium and their subsequent migration
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into the vessel wall. These are important prevention steps in the development of the atherosclerotic process122-124
Endothelial dysfunction therefore abolishes the endothelium’s anti-atherogenic properties. Indeed, the key features of endothelial dysfunction have been found to include platelet adhesion/aggregation, increased vascular permeability and leukocyte-endothelial interactions.116 An increase in arterial pressure does not only cause altered vascular wall thickness through inducing oxidative stress and its downstream effects as demonstrated above but can do so through VSMC hypertrophic remodeling as well.115, 125 Hypertrophic remodeling occurs when the vascular wall due to hyperplasia of VSMC and altered production of extracellular matrix, as some of the factors, encroaches into the luminal space; eventually, the cross section of the vascular wall increases and luminal diameter decreases.115