Chapter 3 / Mechanisms of Hypertension
3
23
Aging, Arterial Stiffness,
and Systolic Hypertension
Joseph L. Izzo, Jr., MD
CONTENTS
INTRODUCTION
POPULATION STUDIES
PATHOPHYSIOLOGY
NONINVASIVE MEASUREMENT OF ARTERIAL STIFFNESS
REFERENCES
INTRODUCTION
Within the past few years, the paradigm in hypertension has shifted
from an emphasis on diastolic blood pressure (DBP) to one that emphasizes the importance of systolic blood pressure (SBP), especially in individuals over age 50 years (1–4). The rationale for this shift is based on a
large body of observational and clinical trial data demonstrating that
SBP is a better risk predictor, and that SBP control markedly reduces
cardiovascular morbidity and mortality. At the same time, there has been
relatively little information available to practitioners about the many
new concepts that underlie this new approach to cardiovascular pathophysiology. Most important is the notion that age-related changes in
vascular stiffness are at the center of future efforts to provide important
new diagnostic and therapeutic advances in hypertension care.
From: Clinical Hypertension and Vascular Diseases: Hypertension in the Elderly
Edited by: L. M. Prisant © Humana Press Inc., Totowa, NJ
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Hypertension in the Elderly
Fig. 1. Mean systolic and diastolic blood pressures (BPs) by age and race/
ethnicity for men and women, US population 18 years old. (From ref. 5.)
POPULATION STUDIES
Age, Blood Pressure, and Cardiovascular Risk
Cross-sectional population studies showed that SBP increases
throughout life, whereas DBP increases until about age 50 years and then
declines in men and women and in all racial groups (5) (Fig. 1). Of
interest, the relationship of age and SBP is only found in complex industrialized societies; primitive peoples and cloistered groups such as nuns
or institutionalized people do not experience this effect. By age 60 years,
about two-thirds of those with hypertension have isolated systolic hypertension (ISH); by age 75 years, almost all hypertensives have systolic
hypertension, and about three-fourths of hypertensives have ISH (3).
It is now widely recognized that the risk of cardiovascular diseases
(CVDs) in individuals beyond 50 years of age is best predicted by SBP
(1-4,6). In fact, some studies in individuals 50 to 79 years of age suggested that the risk of coronary artery disease is inversely related to DBP
at any given level of SBP. Wide pulse pressure (PP; PP = SBP – DBP)
has been found to be an independent predictor of CVD risk in people over
60 years of age, even after adjusting for previous clinical CVD, age,
gender, and other cardinal risk factors (7). PP is a stronger predictor of
CVD risk in those with dyslipidemia, left ventricular hypertrophy (LVH),
albuminuria, chronic kidney disease, or prior cardiovascular events
(myocardial infarction, ventricular dysfunction, or heart failure) (8–10).
Chapter 3 / Mechanisms of Hypertension
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Yet, there are important limitations to using PP as a reliable risk
indicator. In middle-aged, healthy populations or older individuals with
both systolic and diastolic hypertension, any blood pressure (BP) component (systolic, diastolic, or mean arterial pressure [MAP]) may be
equal or superior to PP as a risk predictor (6).
Impact on Classification of Hypertension
There are important implications of aging effects on the value of SBP
and DBP as diagnostic indices in hypertension. After age 50 years, SBP
becomes more reliable in the classification of hypertension and in risk
stratification, as was shown in the Framingham Heart Study (11). By
convention, when both SBP and DBP are considered, the higher value
determines the correct stage of hypertension. For example, using the
current classification system, a person with a BP of 162/90 mmHg would
be classified as having stage 2 hypertension because the 162 mmHg
exceeds the threshold for stage 2 hypertension (>160 mmHg) and thus
“upstages” the diastolic value (which would by itself be considered stage
1). When used as the sole classifier of the stage of hypertension, SBP is
accurate more than 90% of the time, whereas the diastolic value accurately predicts the stage of hypertension only about 60% (11).
Benefits of SBP Control
The best study conducted in systolic hypertension is the Systolic
Hypertension in the Elderly Program, a 4-year intervention that included
4694 individuals over age 60 with pretreatment SBP over 160 and DBP
under 90 mmHg. Compared to placebo, individuals treated with
chlorthalidone (with or without β-blocker) achieved favorable benefits
in the primary end point of stroke (–36%), as well as reductions in heart
failure events (–54%), myocardial infarctions (–27%), and overall CVD
events (–32%) (12). Using a similar design and sample size, the Systolic
Hypertension in Europe trial compared a regimen based on nitrendipine
(a dihydropyridine calcium antagonist) to a placebo-based regimen and
found a significant benefit on stroke (–41%) as well as overall CVD
events (–31%) (13). A meta-analysis of eight placebo-controlled trials in
15,693 elderly patients followed for 4 years found that active antihypertensive treatment reduced coronary events (23%), strokes (30%), cardiovascular deaths (18%), and total deaths (13%), with the benefit
particularly high in those older than 70 years of age (14). Most experts
now feel that the choice of initial agent is less important than the level
of BP reduction achieved (4,15).
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Hypertension in the Elderly
PATHOPHYSIOLOGY
Why is there such a great benefit of treating systolic hypertension?
The answer becomes clearer after a review of basic cardiovascular pathophysiology. Although it is currently fashionable to describe hypertension as a complex metabolic syndrome that involves insulin resistance
and other derangements; in the main, hypertension remains a hemodynamic syndrome with properties that change with age.
Steady-State Hemodynamics
Basic teaching of the hemodynamics of hypertension has historically
ignored the intrinsic pulsatility of the circulation. Typically, a steadystate flow model has been used to approximate circulatory hemodynamics, and MAP has been used as a surrogate for systemic vascular
resistance (SVR) and the integrated pressure burden on the vasculature.
MAP is analogous to voltage in the electrical steady-state model (Ohm’s
law), where Voltage = Current × Resistance. Thus, MAP = Total flow
(Cardiac output) × SVR. In this simplified model, MAP is more closely
related to DBP than SBP. Parallel increases in SBP and DBP up to age
50 years are primarily the result of age-related increases in SVR, but it
is common to find systolic hypertension associated with increased cardiac stroke volume in younger hypertensives (16).
Pulsatility and Blood Flow
To understand the pathophysiological relevance of systolic hypertension, it is necessary to review the physiology of circulatory pulsatility.
In conjunction with cardiac contraction, the arterial system serves two
basic interrelated functions: conveyance of a sufficient quantity of blood
to various tissues (the conduit function) and damping of pulsatile flow
to provide a smoother flow profile in the microcirculation. The pulsatile or dynamic component of blood pressure is the summation of three
major factors: cardiac contractility (stroke volume), aortic impedance
(central arterial stiffness), and late systolic pressure augmentation caused
by pulse wave reflection from the distal circulation (Fig. 2).
Central Arterial Stiffness
Large central arteries, predominantly the thoracic aorta and its proximal branches, fulfill the damping function by expanding during systole,
storing some but not all of each stroke volume, and utilizing elastic recoil
to propel the residual of each stroke volume to the periphery during
diastole. The resulting damping of pulsatility in normal young arteries
creates a relatively narrow PP (Fig. 3). When central arteries are stiffer,
Chapter 3 / Mechanisms of Hypertension
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Fig. 2. Components of blood pressure (BP) and cardiac load. Various parameters are needed to describe pulsatile phenomena. DN, dicrotic notch, the division between systole and diastole. Left-hand panel demonstrates a typical aortic
pulse contour in an individual with hypertension. Pulse pressure (PP) represents
the maximal difference between systolic BP (SBP) and diastolic BP (DBP);
mean arterial pressure (MAP) = DBP + 1/3 PP. Major components of PP include
(a) cardiac stroke volume, (b) aortic impedance to early systolic outflow, and (c)
late systolic augmentation pressure (AP) caused by arterial stiffening and premature return of reflected waves. Total cardiac load, the integral of the systolic
pulse contour, depends mainly on the interactions of three factors proportionally
represented by the bar graph at the right: DBP, coupled effects of ventricular
contraction and aortic impedance, and AP.
two related events occur: (a) SBP increases because more blood is delivered to the periphery during systole, and (b) DBP decreases because
there is less residual stroke volume to be delivered to the periphery
during diastole. Thus, central arterial stiffness causes PP to increase, a
phenomenon that is independent of any change in MAP.
The cellular basis of age-related arterial stiffening is only partly understood. The elastic behavior of arteries depends primarily on the composition and arrangement of collagen, elastin, and vascular smooth muscle
cells in the tunica media of the arterial wall. An elastin matrix attached
to vascular smooth muscle cells acts to damp changes in intraluminal
pressure and tension. There is a functional dependency of arterial wall
tension and stiffness on the distending pressure; increased BP stretches
the load-bearing elastic lamellae, making the arteries functionally stiffer.
Over a lifetime, other structural changes occur, including loss of elastin
and increased collagen deposition. This degenerative process is some-
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Hypertension in the Elderly
Fig. 3. Effect of central arterial stiffness on pulse pressure (PP). Age-related
increases in central arterial stiffness convert a smooth peripheral pressure wave
with a narrow PP to a more pulsatile peripheral pressure wave with increased PP.
Changes in PP are independent of changes in stroke volume or systemic vascular
resistance. The central problem is the loss of aortic elasticity; systolic pressure
is increased and diastolic blood pressure (BP) is decreased because of the loss
of elastic recoil of the aorta. (Adapted from ref. 26.)
times called arteriosclerosis to differentiate it from atherosclerosis, the
occlusive result of endovascular inflammatory disease caused by lipid
oxidation and plaque formation. Hypertension, diabetes, and chronic
renal failure accelerate the aging of central elastic arteries and cause
premature arterial stiffening.
Reflection, Augmentation, and Amplification
A fundamental property of stiff arteries is that they conduct pulse
waves faster than more elastic vessels. Arterial stiffness thus can be
approximated by measuring pulse wave velocity (PWV). Another fundamental property of pulse wave transmission is that pulse waves can be
reflected within arterial walls, leading to both forward and backward
transmission of pulse waves (17) (Fig. 4). Reflected waves have their
origins at points of “impedance mismatch,” where the flow and pressure
waves are not perfectly matched, especially from branch points, constrictions, or areas of turbulence.
Chapter 3 / Mechanisms of Hypertension
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Fig. 4. Components of arterial pulse waves in older and younger subjects.
Because of the property of wave reflection, any pulse wave can be decomposed into a forward-traveling and backward-traveling wave. The velocity of
travel of these pulse waves (PWV) is directly proportional to the stiffness of the
arterial wall. In older people, increased PWV causes early return of the principal
reflected wave, which summates with the incident wave to augment late systolic
pressure. Vertical line is the dicrotic notch that separates systole from diastole.
(Modified from ref. 17.)
Wave reflection can have important effects on cardiac function and
structure. In young people with elastic arteries, the primary reflected
wave returns to the aortic root during early diastole, where it serves to
augment coronary artery filling. In older people with stiffer arteries, the
high PWV causes the primary reflected wave to return to the aortic root
before the end of systole, where it summates with the forward-traveling
pulse wave and augments late SBP (Fig. 4).
Another interesting and poorly understood property of the arterial tree
is PP amplification (18) (Fig. 5). In normal young individuals with highly
elastic arterial walls, PP at distal arterial sites is greater than that measured centrally. This contrasts with MAP, which is relatively constant
throughout the arterial tree. PP amplification is the result of the progressive increase in impedance that occurs in the distal circulation and the
corresponding differences in the summation of incident and reflected
waves along the arterial tree. In normal young people, it is not uncom-
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Hypertension in the Elderly
Fig. 5. Pulse pressure (PP) amplification and wave reflection. In normal young
individuals, PP is amplified as the wave travels downstream because of a progressive increase in impedance, and mean arterial pressure remains constant.
With age and increased central pressure augmentation, the difference between
central and peripheral PP decreases. Thus, peripheral PP is not always equivalent to central PP. (From ref. 27.)
mon to observe a brachial PP that is 20 to 30 mmHg higher than that at
the aortic root. With aging, however, the greater magnitude of the reflected
waves and the increased PWV contribute to a progressive diminution of
the apparent central–peripheral PP differential (Fig. 5). The importance
of this effect is that brachial SBP (or PP) is not always a reliable surrogate
for central SBP (19).
The Integrated Hemodynamic Model
Age-related increases in SBP and widening of PP usually signify that
arterial stiffness has become the dominant hemodynamic lesion. There
remains a role for excessive vasoconstriction in the syndrome of hypertension, however, because systemic vasoconstriction and increased SVR
contribute to both systolic and diastolic hypertension (Fig. 6). Overall,
increased SBP can be the result of increases in stroke volume, arterial
stiffness, or SVR, whereas DBP is decreased when central arterial stiffness increases. DBP thus varies directly with SVR and inversely with
central arterial stiffness.
The ability of increased SVR to cause increases in either SBP or DBP
(depending on the degree of central arterial stiffness) causes otherwise
unexpected differences in the therapeutic responses of SBP and DBP to
Chapter 3 / Mechanisms of Hypertension
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Fig. 6. Integrated hemodynamic model of hypertension. Factors promoting
increased systolic blood pressure (BP) are increased cardiac contractility (stroke
volume), increased central arterial stiffness, and increased arteriolar constriction (systemic vascular resistance). Peripheral arteriolar constriction directly
increases diastolic BP and mean arterial pressure, whereas central artery stiffness lowers diastolic BP.
Fig. 7. Effect of arterial stiffness on BP responses to vasodilation. The net effect
of an arteriolar dilator drug on systolic and diastolic BP can be very different
depending on the stiffness of an individual’s central arteries. For the same
degree of vasodilation, an individual with stiff arteries and isolated systolic
hypertension (ISH) will respond with a marked reduction in systolic BP (-20/
-5 mmHg = -10 mmHg MAP), whereas an individual with isolated diastolic
hypertension will experience a predominant effect on diastolic BP (–6/–12
mmHg = –10 mmHg MAP). (Modified from ref. 20.)
vasodilators (20). In ISH, a vasodilator causes a disproportionate drop
in SBP; the same vasodilator in a person with diastolic hypertension
decreases DBP. If both SBP and DBP are elevated, both will be decreased
by the vasodilator therapy (Fig. 7).
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Hypertension in the Elderly
Fig. 8. Effect of age and central pressure augmentation on cardiac load. Increased
arterial stiffness causes increased pulse wave velocity and promotes late systolic
pressure augmentation. Augmentation index increases with age, but this effect
is accelerated by the presence of hypertension. Increased late systolic pressure
contributes to the overall cardiac load and can be considered “wasted” cardiac
work. Increased cardiac load contributes directly to left ventricular hypertrophy.
Pathological Implications
Systolic hypertension and increased PP are strong surrogate markers
for CVD morbidity and mortality. Increased pulsatile load is the major
factor in increased left ventricular systolic wall stress and LVH, both of
which impair left ventricular relaxation and contribute to diastolic
dysfunction. Increased ventricular mass increases coronary blood flow
requirements and decreases coronary flow reserve. Late systolic pressure augmentation further increases ventricular load; in elderly persons
with ISH, late systolic pressure can be increased by as much as 20 to 40
mmHg as a result of wave reflection. In general, central systolic augmentation is age dependent and contributes to “wasted cardiac output” and
LVH (Fig. 8). Simultaneously, as PP widens, decreases in DBP further
compromise coronary filling. At the same time, greater shear stress on
the central arteries accentuates aortic, carotid, and coronary atherosclerosis and probably contributes to rupture of unstable atherosclerotic
plaques. The distal vasculature is also affected because increased pulsatile stress promotes endothelial dysfunction, thus affecting the balance
in the forces controlling arteriolar constriction and dilation and favoring
arteriolar smooth muscle hypertrophy and arteriolar remodeling.
Chapter 3 / Mechanisms of Hypertension
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NONINVASIVE MEASUREMENT OF ARTERIAL
STIFFNESS
As discussed in this review, information related to the assessment of
SBP, PP, and central arterial stiffness is fundamentally different from
that related to DBP or MAP. Thus, the elastic properties of the arteries
and the impact of arterial stiffness on pulse wave transmission and reflection are of increasing interest to researchers and clinicians. Because brachial PP is only loosely related to central PP and wide PP in general is
a late indicator of CVD risk, many investigators are searching for more
sensitive measures of earlier changes in arterial wall properties.
Changes in central artery stiffness can be quantitated using research
methods that measure PWV, aortic impedance, and analysis of arterial
waveform morphology. Increased PWV has been correlated with increased
CVD mortality (21), and aortic impedance can be affected differently by
different antihypertensive agents (22). In the future, it may be possible
to use these indicators of central artery stiffness to allow targeted primary prevention of CVD or improved therapeutic monitoring of antihypertensive drugs or new compounds that directly reduce arterial stiffness.
At present, all techniques that assess arterial stiffness should be considered primarily research tools not ready for immediate clinical application (23–25).
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