HTN can influence the endothelium, vascular smooth muscle, extracellular matrix, and connective tissue of the arteries. Alterations of vascular structure that occur during chronic HTN may be referred to as remodeling or hypertrophy.
47 Eutrophic inward remodeling, or “remodeling,” refers to a decrease in lumen diameter without a change in the thickness of the arterial wall or the characteristic of the material within the vessel wall. In contrast, hypertrophic inward remodeling, or “hypertrophy,” is defined as a decrease in lumen diameter associated with an increase in wall thickness and vessel wall material. In either case, narrowing of the vessel lumen is associated with increased vascular resistance.
48 Some of the factors that contribute to the hypertrophy and remodeling processes appear to be different. Mechanisms of hypertrophy may include increased arterial pulse pressure, sympathetic nerve activity, angiotensin II, genetic factors, endothelin-1, nitric oxide, and oxidative stress.
47,
49 Mechanisms of remodeling may include intravascular pressure, angiotensin II, genetic factors, endothelin-1, αβυ3 integrins.
47
Changes in the Vascular Endothelium.
The vascular endothelium is the largest organ in the body.
50 Vascular endothelial cells are extremely active and play a critical role in regulation of blood vessel tone and cellular activity in the vascular wall. Endothelial cells modulate blood vessel tone by secreting a variety of dilator and constrictor substances. In addition to their effect on vascular tone, these substances and other factors produced by the endothelium, may also modify platelet aggregation, thrombogenicity of the blood, vascular inflammation, and oxidative stress and, over the long term, influence cell migration and proliferation with subsequent development and progression of atherosclerosis and its complications.
50
Impaired endothelial vasodilation has been identified in persons with HTN and even in the normotensive children of hypertensive parents.
51,
52 However, it is not yet clear whether endothelial dysfunction is a precursor of HTN or a sequel. Improved understanding of the molecular basis for endothelial dysfunction in HTN may provide a pathway to developing new therapies to reduce the impact of HTN. Other factors that cause endothelial dysfunction include aging, hyperlipidemia, insulin resistance/diabetes, tobacco use, physical inactivity, and hyperhomocysteinemia.
50
Atherosclerosis.
Atherosclerosis is a complex degenerative condition that is characterized by endothelial dysfunction and lipid accumulation in the endothelium and media, followed by wall thickening and outward remodeling, and later by luminal encroachment, thrombosis, and occlusion.
53 Atherosclerosis manifests as coronary heart disease, cerebrovascular, and peripheral arterial disease and is a major worldwide source of morbidity and mortality. Atherosclerotic plaque formation involves the interaction of genetic predisposition and environmental risk factors with diffuse vascular injury. Many of these factors are also involved in the pathogenesis of HTN. HTN promotes or accelerates all phases of the development of atherosclerotic lesions, from plaque formation to rupture.
53
Heart.
Parallel structural and functional changes in the large arteries (stiffness), cardiac mass (hypertrophy), and myocardial relaxation and filling (diastolic dysfunction) occur at an accelerated rate with chronic HTN. The pressure overload associated with HTN promotes left ventricular hypertrophy (LVH) that leads to left ventricular dysfunction and heart failure. HTN also promotes vascular endothelial and renal dysfunction that directly impacts the progression of heart failure, which in turn affects vascular endothelial and renal dysfunction.
54 Hypertensive individuals have a two- to four-fold increased risk of coronary heart disease and heart failure and those individuals with prehypertension have a 1.6- to 2.5-fold increased risk of CVD, both compared with those who are normotensive.
55,
56 Aggressive HTN control can prevent the development of LVH and lead to regression of LVH. However, it remains controversial whether there are differential drug effects on reversing LVH related to HTN.
Kidney.
HTN is both a cause and consequence of chronic kidney disease (CKD). The incidence and prevalence of CKD and end-stage renal disease, presumed to be secondary to primary HTN, have increased considerably over the past two decades and are particularly high among African Americans. HTN causes renal damage through multiple mechanisms.
57 One mechanism is ischemia with glomerular hypoperfusion causing glomerulosclerosis and subsequently tubulointerstitial fibrosis. Other mechanisms of injury, such as endothelial dysfunction, cholesterol oxidation, cigarette smoking, and proteinuria, act in concert with high systemic
and glomerular capillary pressures to accelerate nephrosclerosis. While the presence of macroalbuminuria (proteinuria > 300 mg/day), indicates presence of kidney disease, even lower level microalbuminuria (30 to 300 mg/day) is associated with increased cardiovascular risk.
CKD mandates more aggressive treatment and lower target BP: <130/80 mm Hg in patients with diabetes or CKD and <120/75 mm Hg in patients with proteinuria >1 g/day.
7 Antihypertensive drugs classes differ in ability to lower proteinuria and slow the progression of CKD. Drugs that block the rennin-angiotensin system, that is, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are the most potent antiproteinuric agents and also have been shown to be highly effective in slowing the progression of renal insufficiency.
58
Eye.
HTN has profound effects on the structure and function of the eye. Hypertensive retinopathy refers to a spectrum of microvascular signs in the retina related to HTN.
59 HTN initially causes retinal circulation vasospasm and increased vasomotor tone, which are reflected as the sign of generalized arteriolar narrowing. Persistent HTN leads to arteriosclerotic changes, including intimal thickening, media wall hyperplasia, and hyaline degeneration. This is seen as increasingly severe generalized arteriolar narrowing, arteriolar wall opacification, and focal narrowing. Thickening of the retinal arteriolar wall by these arteriosclerotic processes may compress the venules, resulting in the sign of AV nicking. In the presence of more acute elevations in BP, an exudative stage may occur, manifesting as microaneurysms, hemorrhages, hard exudates, and cotton wool spots. Optic disk swelling and macular edema may occur with severely elevated BP. These processes may not occur in the sequence described above. Numerous studies have confirmed the strong association between the presence of signs of hypertensive retinopathy and elevated BP.
59 The strongest evidence of the usefulness of the evaluation of hypertensive retinopathy for risk stratification is based on its association with stroke as the retinal circulation shares anatomical, physiological, and embryologic features with the cerebral circulation. A simplified classification of hypertensive retinopathy—none, mild, moderate, and malignant —according to the severity of the retinal signs is presented in
Table 35-2.
59
Brain.
HTN has adverse consequences in the brain, including ischemia and hemorrhagic stoke, cognitive impairment/dementia, and encephalopathy. HTN contributes to the development of atherosclerotic plaques in the extracerebral and intracranial vessels as well as the process of microatheroma and hypertensive hyalinosis. Despite the brain’s adaptive mechanisms to maintain cerebral blood flow, loss or reduction of blood flow results in stroke producing pathologic changes related to the duration and degree of ischemia. Research has documented the positive relationships between stroke and HTN as well as the reduction in stroke with HTN control.
5,
60,
61,
62,
63
Cognitive impairment spans the spectrum from mild cognitive impairment to dementia. Cerebrovascular damage leading to cognitive impairment can occur not only from atherothrombosis but also through cerebral hemorrhage, hypoperfusion, and other arteriopathies. Longitudinal studies strongly suggest an adverse effect of elevated BP in middle age on cognitive functioning.
64 There is also an adverse effect of low BP in the older adults for development of dementia; however, studies suggest no deterioration in cognitive performance with antihypertensive therapy in older adults hypertensive individuals who are well. Hypertensive encephalopathy is a consequence of accelerated or malignant HTN. Encephalopathy occurs when the BP levels exceed the upper limit of autoregulation so that the cerebral arteries become dilated, disrupting the blood-brain barrier and leading to the formation of cerebral edema; local changes in ion and cytokine concentrations; and/or alteration in neural function.
65