Beruflich Dokumente
Kultur Dokumente
Motoki Fukutomi1 Aging is known to be a dominant risk factor in the progression of hypertension. Thus,
andKazuomi Kario2 accompanied by an increasing mean age of the population in developed countries, prevention
and management of hypertension in the elderly is a task of pressing urgency. Age-associated
1
Department of Cardiology, Yamaguchi
Grand Medical Center, 77 Osaki, Hofu, blood pressure elevation is a result of the aging process in organ systems, which play a key role
Yamaguchi 747-8511, Japan in the regulation of blood pressure. In addition, advanced aging of the cardiovascular system
2
Division of Cardiovascular Medicine, contributes to the presence of a varied phenotype in elderly hypertension, such as nocturnal
Department of Medicine, Jichi Medical
University School of Medicine, 3311-1,
hypertension and morning hypertension. Therefore, in order to detect and treat age-associated
Yakushiji, Shimotsuke, hypertension appropriately, it is important to assess ambulatory blood pressure monitoring
Tochigi329-0498, Japan throughout the 24-h period.
intimal wall with aging is composed of increased matrix pro- Recent studies documented that increase of PWV precedes the
teins including collagen, fibronectin, proteoglycans and vas- development of hypertension [5,9] , suggesting that stiffening of
cular smooth muscle cells (VSMCs) [4] . Such age-associated a large artery may play an important role in the initiation of
structural changes in the central artery are accompanied by a age-associated BP elevation. In addition, it was reported that
reduction in compliance of elastic arteries and increased vascular capillary BP in peripheral sites increases throughout human
stiffness. Pulse wave velocity (PWV), a noninvasive index of aging [10] . Such increased peripheral resistance accompanied by
arterial stiffness, has been established as increasing with age[5] . endothelial dysfunction contributes to enhance the magnitude
Furthermore, advancing age is associated with endothelial dys- of the reflection wave and further augments the systolic BP.
function [6,7] , which is caused by a progressive impairment of
the nitric oxide (NO) pathway and increased oxidative stress. Age-associated change of renal function
These age-dependent subclinical changes in vascular structure Elevation in perfusion pressure in the renal artery results in
and function strongly contribute to the development of hyper- an increase in sodium and water excretion by the kidneys, and
tension. Recently, this pathophysiology has been recognized as this pressure-natriuresis mechanism maintains the appropriate
the early vascular aging (EVA) concept, which was proposed level of body fluid volume. More than 40years ago, Guyton
by Nilsson etal. [8] . and colleagues suggested that the kidneys play a central role
In young individuals who have distensible aorta with pre- in BP control, and the shift in the pressurenatriuresis curve
served windkessel function, the arterial pressure wave travels at a higher set point is the dominant mechanism of persistent
at a slow speed and returns from the peripheral reflection site in hypertension[11] . Such a kidney hypothesis is supported by the
diastole of the cardiac cycle. On the other hand, in the stiffened transplant study that demonstrated that a kidney from a nor-
large artery of older people, the arterial pressure wave travels motensive donor cured hypertension in subjects with end-stage
down faster and returns earlier to the heart in late systole and renal disease [12] . With advancing age, the weight and size of a
augments aortic systolic peak pressure with a decrease of dia- kidney progressively declines after the 40s decade of life, and
stolic pressure. These changes in the arterial wave form are the renal regression phenomenon involves a change of histological
pathophysiological mechanism of isolated systolic hyperten- features in the kidney; for example, glomeruli decrease, glo-
sion, which is commonly seen in elderly hypertensives (Figure1) . merulosclerosis, tubular atrophy and arterial intimal fibrosis[13] .
Arterial thickness
VSMCs
Matrix proteins
Endothelial dysfunction
Microvascular remodeling Arterial system Arterial wave-form in elderly subject
in elderly subject
Ejected wave
Reflected wave
Expert Rev. Cardiovasc. Ther. Future Science Group (2010)
These structural changes have a close association with functional suggesting that systemic RAAS activation is a key determinant
decline in the kidney, suggesting that age-associated renal dys- in the development of obesity-related hypertension [28] . However,
function may be one of the most important determinants in BP it is unclear whether this systemic RAAS activation is associated
elevation with aging. with the progression of age-associated hypertension, because it is
In addition, it has been reported that dysregulation of effec- known that systemic RAAS is gradually suppressed throughout
tive sodium excretion by the kidney is largely related to the the aging process [29,30] .
circadian BP abnormality. In healthy subjects, ambulatory BP According to previous findings, angiotensinII (ATII) is known
displays a normal dipping pattern during the night by 1020% to be not only generated in the circulation, but also produced
compared with daytime, and this normal type is called dipper. in systemic organs, including the kidney vessels, heart, adrenal
However, some patients with renal dysfunction tend to show a gland, eye, testis and brain [31] . It was also reported that such
diminished fall of BP during the night (<10%), which is called local RAAS tend to increase with advancing age, indicating that
nondipper[14,15] . This nondipping pattern in patients with renal this age-associated activation of the local hormonal system may
dysfunction is a compensatory phenomenon, which enhances partly affect BP dysregulation with aging. In a rat model study,
pressure natriuresis during the night for diminished natriuresis of it was reported that ATII administered into this rostral ventro-
the daytime [16] . Thus, it has been suggested that elderly hyper- lateral medulla (RVLM), which is known to be in the brainstem
tensives with advanced renal aging tend to show nocturnal BP region regulating the sympathetic tone and baroreceptor reflex,
elevation as well as daytime hypertension. caused a greater increase in sympathetic nerve activity and BP.
In addition, another study revealed that transgenic rats that have
Age-associated changes of the sympathetic a deficiency in brain angiotensin did not show age-associated BP
nervoussystem elevation [32] .
Earlier studies have documented the increase of sympathetic ner- It has also been documented that diffuse intimal media thick-
vous activity in the spontaneously hypertensive rat (SHR)[17,18] ening of aged central arteries exhibits increased ATII immuno
and hypertensive patients [19] . Based upon this evidence, it has staining and an increase of ATII downstream proinflammatory
been suggested that overactivity of the sympathetic nervous signaling molecules, including TGFb1, matrix metalloprotein-
system largely contributes to the development of essential hyper- ases (MMPs) and monocyte chemoattractant protein-1 (MCP1)
tension. It is also well known that this sympathetic nerve acti- in rodents [33] , primates [34] and humans [35] . This age-associated
vation gradually progresses with human aging [2022] . In addi- proinflammatory state promoted by exaggerated local ATII sig-
tion, there is a positive correlation between sympathetic nervous naling may have a key role in progression of arterial remodeling
activity and BP level in older female subjects [23] . These find- and hypertension.
ings indicate the possibility that enhancement of sympathetic Furthermore, in the Trial of Preventing Hypertension
nerve activation with increasing age plays an important role in (TROPHY) study, early pharmacological treatment with ARBs
the pathogenesis of age-associated hypertension, particularly of subjects with highnormal BP prevented or delayed the
in women. development of clinical hypertension [36] . These findings sug-
Furthermore, previous studies demonstrated that sympathetic gest that RAAS activation at the tissue level contributes to
nerve activation affects not only BP level, but also the 24h BP cardiovascular aging, and that inhibition of this system may
profile including day/night BP rhythm. It was documented that induce a significant protective effect on the development of
extreme dippers, who have a marked nocturnal BP reduction age-associatedhypertension.
(>20%), demonstrated an increase of plasma norepinephrine[24] .
In addition, it was reported that greater levels of sympathetic Environmental factors
activity were linked to increased daytime BP variability and It has been well established that there is a positive relationship
greater BP fall at night in a study of young normotensive sub- between sodium intake and BP, as habitual high sodium intake
jects [25,26] . On the other hand, Grassi and colleagues reported accelerates the development of hypertension. However, accord-
that the riser pattern of circadian BP rhythm, which has higher ing to a previous report, Yanomamo Indians in the Brazilian
nocturnal BP than that of the daytime, was associated with a Amazon jungle, who did not use salt in their diet, showed no
greater sympathetic activation compared with dippers, nondip- BP elevation with aging [37] . This finding suggests that daily
pers and extreme dippers [27] . These findings suggest that sym- sodium intake is an important factor in the progression of
pathetic nervous activation may be linked to the two extremes of age-associatedhypertension.
circadian BP abnormality, extreme dippers and risers. Furthermore, a previous longitudinal study demonstrated
that nuns, who live in environments with little psychosocial
Age-associated change of RAAS stress, maintained a normal level of BP during 30 years of
Normal aging is characterized by changes in the activity or follow-up study [38] . In addition, a recent report demonstrated
responsiveness of hormonal systems, including the RAAS. In that chronic but not acute psychosocial stress may be a cause
general, the systemic, circulating RAAS is inappropriately nor- of BP elevation [39] . These findings suggest that psychosocial
mal or elevated in patients with obesity, despite increased sodium stress is also an important factor for BP elevation throughout
intake, sodium/water retention and central blood volume, human life.
www.expert-reviews.com 1533
Review Fukutomi & Kario
Sleep
Morning hypertension
BP (mmHg)
135/85
Morning BP surge
120/75
Surge type
Time
p = 0.003
Urinary albumin excretion rate (mg/g Cr)
p = 0.003
Brain natriuretic peptide (pg/ml)
p < 0.02
75.7
250 80
209.1
200 60
150
33.4
40
100 23.6
39.7 20
50 34.1
0 0
OHYPO ONT OHT OHYPO ONT OHT
Figure3. Relationship betweeen orthostatic blood pressure change and the measurement of target organ damage.
OHT: Orthostatic hypertension; OHYPO: Orthostatic hypotension; ONT: Orthostatic normotension.
Reproduced with permission from [75] .
www.expert-reviews.com 1535
Review Fukutomi & Kario
Aging
relatively younger people may be a sign
Sodium intake
Psychosocial stress of increased cardiovascular risk with
Local RAAS advanced physical aging.
Key issues
Aging is a dominant risk factor of hypertension.
Advanced aging of the arteries, kidneys and the sympathetic nerve system, and local reninangiotensinaldosterone system activation,
contribute to the development of hypertension.
There are several types of age-associated hypertension with abnormal blood pressure variability.
Ambulatory blood pressure monitoring is useful for the detection and management of age-associated hypertension.
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