The prevalence of hypertension increases with age . Elderly hypertensive patients also characteristically exhibit increased blood pressure variability . Traditionally, cardiovascular (CV) complications related to hypertension have been distinguished by pressure-dependent (stroke, renal failure, etc.) and atherosclerotic-dependent complications (coronary heart disease, aneurysms, congestive heart failure, etc.). This view has been supported and reinforced by results of early outcome clinical trials showing a significant reduction in fatal stroke (-45%; p < .001), but not in fatal coronary heart disease (-11%; NS) . In fact, these findings were partly attributed to the fact that antihypertensive drugs are not equal in terms of adverse effects on other traditional CV risk factors (lipids, glucose, etc.). Thus, the term “substitution of CV risk” was proposed to indicate that the benefit of drug- related blood pressure lowering was counteracted by an increase in lipids or glucose levels exerted by the same drug . We suggest that arterial aging represents the most prominent link between hypertension and cardiovascular complication, including cognitive decline and dementia .
In Westernized countries, there has been a rapid increase in life expectancy. In the year 2000, there were 600 million people aged 60 and over; there will be 1.2 billion by 2025 and 2 billion by 2050. Additionally, the very old (age 80+) is the fastest growing population group. Aging is a privilege and a medical and societal achievement, but it is also a challenge for the public health system and for society as a whole. In fact, a relevant proportion of older people, about 20%, experiences significant difficulties in independently performing activities associated with daily life (disability).
Better available medical care and treatment together with a longer life expectancy led to a new emerging problem: vascular related cognitive decline. Loss of cognitive function is a common condition in the elderly population and has a significant impact on loss of personal independence. The prevalence of dementia increases with advancing age, affecting around 7% of subjects over age 65 and 30% of those over age 80 [6,7]. In the United States in 1998, the annual cost for the care of patients with dementia was approximately $40,000 per patient. Thus, identification of factors associated with progression from cognitive impairment to dementia would result in significant savings for the health care system.
Vascular factors certainly play a significant role in cognitive decline with aging. Since 1955, the dominant paradigm has suggested that dementia (and severe cognitive decline) should be classified into two major entities: vascular dementia, caused by vascular lesions (historically, stroke and multi-infarct lesions), and Alzheimer’s dementia, caused by a neurodegenerative process . This concept has been challenged by recognition of the increasing prevalence of microvascular subcortical disease [9-11], by observations that traditional cardiovascular risk factors (hypertension, smoking, dyslipidemia, diabetes) represent additional potent risk factors for Alzheimer type dementia [12-14], and that in a considerable portion of the population, vascular and Alzheimer disorders appear together . In addition, a recent hypothesis suggests that Alzheimer’s disease may also have a vascular etiology .
Hypertension has been generally thought to be the most common risk factor not only for stroke, but also for microvascular brain damage [17,18]. Microvascular brain damage may primarily affect the cortical region or cerebral white matter. The most common cortical lesion is represented by lacunar infarcts, small deep infarcts caused by the obstruction of small penetrating arteries , accounting for 15% to 20% of all cerebral infarcts in Western countries and usually associated with low early-case fatality and recurrent stroke rates [20-23]. Confluent deep white matter lesions have been reported as the result of chronic white matter ischemia resulting from injury to the long penetrating arteries [24,25] and have been found to be an independent predictor for subsequent development of dementia.
AGING, HYPERTENSION, AND BRAIN DAMAGE: CLINICAL OBSERVATIONS
Effective management of hypertension with the additional goal of preventing or delaying cognitive decline requires better comprehension of the interactions between hypertension, aging and the brain .
In our opinion, the key factor for disentangling the “dangerous connection” of aging-hypertension-brain damage is to focus on large arteries. Large arteries can no longer be regarded as a passive conduit tube linking the heart to peripheral vessels/tissues. Large arteries, i.e., the aorta and its major branches, have a cushioning function directed at converting the cardiac pulsatile flow into a steady flow at peripheral vessels/tissues: the stiffer the vessel, the more compromized the arterial cushioning function and the higher the pulsatility of blood flow.
The vascular system is affected by the aging process. Stiffening of large arteries is one of the prominent and typical features of aging. It is more noticeable in proximal elastic arteries than in the peripheral muscular arteries [27,28]. Stiffening of the large arteries and the consequent early return of wave reflection result in an increase in systolic pressure (SBP) and a decrease in aortic pressure throughout diastole (DBP), thus widening pulse pressure (PP= SBP-DBP) [5,27,28]. It is widely accepted and well known that higher SBP due to arterial stiffening increases left ventricular load and predisposes to left ventricular hypertrophy (and thus, to an increase in left ventricular oxygen requirements) with increased risk of developing heart failure [29,30]. Age-related stiffening of large arteries is likely the prominent reason for increased prevalence of systolic hypertension in older people  (Figure 1). However, the effects of arterial stiffening on the brain are less investigated and known.
||Figure 1. Different effects of aging on pressure wave contour at radial (left) and ascending aorta (right) levels. With aging, for similar levels of blood pressure at the level of peripheral artery, the aorta faces increased systolic pressure peak (A), increased afterload for left ventricle (B), and reduced coronary perfusion (C). A+B favor onset and progression of left ventricular hypertrophy. Left ventricular hypertrophy + C increase the risk of myocardial ischemia.
Recent data have emphasized the observation that a high pulse pressure, a clinical indicator of arterial stiffness, is associated with an increased risk of dementia . Therefore, it could be postulated that functional changes of the arterial system are involved in the pathogenesis of dementia. Two cross-sectional studies have shown a positive correlation between arterial stiffness and cognitive impairment in subjects with nonvascular  or vascular  dementia. In a recent cross-sectional analysis, we demonstrated that arterial stiffness measured noninvasively as pulse wave velocity (PWV), was associated with lower cognitive performance independently of traditional cardiovascular risk factors and independently of neuordegenerative or microvascular damage on neuroimaging (computed tomography [CT] scan) in older subjects without prior stroke and free of atrial fibrillation . The relationship between arterial stiffness and cognitive impairment was confirmed in another study in France . We extended the reported cross- sectional observations with a longitudinal study. In 102 older subjects, the average per year decline in Mini Mental State Examination (MMSE) (the most widely used screening test for cognitive function in the clinical setting) was 2.9 points after a median follow-up of 12 months; PWV not only predicted cognitive decline independently of age, sex, education, and traditional CV risk factors, it was also was the single strongest predictor of cognitive decline .
FROM PATHOPHYSIOLOGY TO THE MANAGEMENT OF THE OLDER HYPERTENSIVE SUBJECT AT RISK OF COGNITIVE DECLINE
To better understand pathways linking arterial stiffness to brain damage, it should be kept in mind that: a) increased arterial stiffness implies that flow pulsations created by left ventricular contraction cannot be adequately cushioned in the arterial system, and b) the brain has a high resting flow. The high resting cerebral blood flow implies that vessels are more dilated than in other vascular beds; therefore pulsations may extend more deeply towards the smallest vessels [27,38]. Since increased arterial stiffness is responsible for a disproportionate increase in SBP and a relative decrease in DBP, the consequently higher pulse pressure at any given value of mean blood pressure is likely to cause not only cerebral damage secondary to increased risk of stroke  but also microvascular brain damage . Consistent with this hypothesis, prior animal studies showed that locally induced isolated alterations in pressure pulsatility have major effects on cerebral microvascular structure and function . In humans, increased pulsatile load has been found to be associated with the prevalence and severity of cerebral white matter lesions . It is also true that microcirculation damage and rarefaction may lead to proximalization of reflection of incident pulse wave and thus, to an increase in arterial stiffness . According to this latter observation, it would be difficult to distinguish to what extent the increased arterial stiffness is a cause of the (cerebral) microcirculation damage and to which extent it is a consequence of it (Figure 2).
||Figure 2. Age-related large arterial stiffness and microcirculation damage in the genesis and progression of cognitive decline. Large artery stiffening and microcirculation damage may have different and distinct onsets. However, especially at advanced ages, their interplay will result in the potentiation of vascular damage and will trigger a vicious circle exacerbating and amplifying microvascular brain damage.
The abovementioned pathophysiological pathways have great impact on the management of older hypertensive subjects at risk of cognitive decline. Briefly:
- Pulse pressure can be regarded as a good clinical marker of arterial stiffness: the higher the pulse pressure, the stiffer the arterial system.
- Stiffer arteries also means increased blood pressure variability. Increased blood pressure variability which is also related to large artery stiffening, is associated with cognitive impairment [42-44].
Increased blood pressure variability in older hypertensive subjects is in part due to decreases in cardiac baroreceptor sensitivity [45-47]. Additionally, since a stiffer arterial system implies reduced arterial cushioning function, any hemodynamic changes will result in an exaggerated change in blood pressure levels. It is fundamental to recall that high blood pressure levels are as dangerous as low blood pressure levels in older hypertensive subjects especially as far as the risk of cognitive decline is concerned. Indeed, high blood pressure may accelerate cerebral white matter lesions [48,49], but white matter lesions have also been found to be facilitated by excessive fall in blood pressure (BP), [50-53], including orthostatic dysregulation  and postprandial hypotension .
- Cerebral autoregulation is altered in older hypertensive subjects. Cerebral autoregulation refers to the inherent ability of cerebral blood vessels to keep cerebral blood flow constant over a wide range of perfusion pressures [56,57]. Physiologically, cerebral autoregulation allows maintenance of constant cerebral blood flow over a wide range of blood pressure (approximately 80 to 200 mmHg). With aging, there is a progressive reshaping of cerebral autoregulation from a sigmoid curve to a straight line. This implies that any abrupt change in blood pressure, elicited by environmental physiological stressors or by drugs, will result in a rapid and significant change in cerebral blood flow.
- Preserving microcirculation. Since microcirculation damage and rarefaction may lead to proximalization of reflection of incident pulse wave and thus, to an increase in arterial stiffness, the choice of an antihypertensive agent protecting the microcirculation would also result in preventing accelerated arterial stiffening over time.
The critical points in the therapeutic approach to the older hypertensive subject at risk of cognitive decline are briefly summarized below.
Need for treating hypertension
Although clinical trials have extensively demonstrated that lowering the blood pressure level is the principal factor for reduction of cardiovascular risk , a substantial proportion of hypertensive patients are not diagnosed and this considerable degree of under-recognition results in a lack of treatment. Data from the Third National Health and Nutrition Examination Survey (NHANES III) indicate that only 53.6% of hypertensives were treated and only 27.4% were controlled to target levels of <140 mmHg systolic and <90 mmHg diastolic. . The situation is no better in a more recent survey in the primary care setting , nor is it better in other countries .
Risk of undertreatment
Older people carry a high burden of illness for which medications are indicated, along with increased risk of adverse drug reactions. The risk of adverse drug reactions often induced physicians to undertreat older subjects by either not prescribing medications or using low dosages that are not effective .
The risk of cognitive decline associated with hypertension is reversible in older subjects
As described by three outcome trials in the elderly, the cardiovascular risk conferred by hypertension, including systolic hypertension, is reversible by antihypertensive drug treatment [63-65]. Some but not all clinical trials showed that antihypertensive treatment was also able to reduce the incidence of cognitive impairment and dementia .
Treatment goal: systolic pressure or diastolic pressure control? Not widening pulse pressure
In the elderly, the aim of treatment is to preserve diastolic blood pressure  because lowering it contributes to maintaining an elevated pulse pressure. The widening of pulse pressure has deleterious consequences to the coronary circulation that potentially can result in myocardial ischemia and/or recurrent transient episodes of cerebral regional hypoperfusion.
Very recently it has also been shown that higher pulse pressure is associated with a significantly increased risk of developing atrial fibrillation, a known risk factor for microvascular brain damage, independently of left ventricular structure and function .
To reach this goal, the treatment of hypertension in the elderly should focus on changes in the structure and function of conduit arteries rather than the arterioles. This goal is not easy to attain in clinical practice but a clear example is offered by the study of nitrates, which selectively reduce brachial and, to a greater extent, aortic systolic and pulse pressures without altering diastolic and mean blood pressures. In fact, the nitrate-induced decrease of pulse pressure is achieved in the elderly not only acutely  but also in the long-term .
A novel approach is to modify or prevent arterial thickening or to change the composition of the arterial wall, or a combination of both (i.e., modifying arterial stiffness independently of blood pressure changes) in order to restore a normal composition of the vessel wall over time. Converting-enzyme inhibitors or angiotensin type 1- (AT1) receptor blockers, alone or in combination with diuretics, potentially may be active agents, particularly in a specific genetic context. On the other hand, new molecules, such as those acting on collagen cross-linking , need to be tested on the wall of large arteries to develop novel treatment strategies. Experimental studies suggest that angiotensin converting enzyme (ACE) inhibitors and AT1 blockers can act as potent inhibitors of advanced glycation end product (AGE) formation [72-75]. Therefore, a recent manuscript raised the issue that the effects of alagebrium (ALT 711) may be redundant rather than synergistic with ACE inhibitors . A novel perspective may be the search for antihypertensive therapy capable not only of preventing microvascular brain damage but perhaps of ensuring direct “neuroprotection”. Indeed, evidence is mounting with regard to the role of the renin-angiotensin system in learning and memory . There is also increasing evidence that the distribution of angiotensin receptor subtypes differs in most brain regions , and that converting enzyme inhibitors do not cross the blood-brain barrier .
Increased blood pressure in adulthood is associated with large reductions in life expectancy and more years lived with the burden of cardiovascular disease . This effect is greater than previously estimated and affects both sexes similarly. Thus, it is relevant to underline the tremendous importance of preventing high blood pressure and its consequences which result in the disability of older subjects.
Larger longitudinal studies are necessary to clarify the optimal blood pressure level for prevention of the development of microvascular brain damage and which drugs are effective in slowing arterial aging .
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