Consequences of arterial stiffening and increase in central blood pressure in hypertension






Michael F. O’ROURKE, MD, DSc
St. Vincent’s Clinic/University of New South Wales/Victor Chang
Cardiac Research Institute
Darlinghurst, AUSTRALIA

Consequences of arterial stiffening and increase in central blood pressure in hypertension


by M. F. O’Rourke, Australia



The arterial system is beautifully designed for its role of receiving blood in spurts from the heart’s left ventricle, and passing this on in a (near) steady stream through the tiny vessels of organs and tissues in the body. Optimal heart function seen in adolescence is progressively lost with age as a consequence of arterial (especially thoracic aortic) stiffening. Such stiffening with age is attributable to the fatiguing effects of pulsatile stretch on elastic elements in the aorta. The aortic elastin fibers fracture and the wall stretches, with stresses being progressively transferred to collagen fibers. Progressive stiffening depends on extent of stretch, and so occurs earliest and is most marked in the ascending aorta; with age the aorta changes from the body’s most distensible to its least distensible systemic artery! Ill effects of aortic stiffening are caused by stiffening itself, which causes a greater rise in pressure for a given flow pulse into the aorta, and magnified by wave reflection, which leads to waves returning early, boosting systolic pressure in the aorta and left ventricle, and causing relative reduction in coronary perfusion pressure. In consequence of aging and increase in aortic systolic and pulse pressure, the left ventricle hypertrophies, predisposing to cardiac failure. The increase in systolic and fall in diastolic pressures predispose to myocardial ischemia. Increase in pulse pressure in small and large arteries predisposes to early progression of atherosclerosis. Increase in pulsations in central arteries cause the same fatiguing problem as seen in the aorta, but principally at physically weak arterial bifurcations in the brain, where small aneurysms arise, with risk of rupture and bleeding. Hemodynamic changes also predispose to higher endothelial shear, shedding of endothelial cells, and cerebral artery occlusion, leading to cerebral infarction. The aorta is thus progressively altered by fatiguing effects of cyclic stress into an organ utterly unsuited to its task and responsible for cardiac failure and arterial ruptures and occlusions that are the scourge of the elderly.

Medicographia. 2015;37:380-390 (see French abstract on page 390)



Aortic stiffening is the major cause of cardiac disease and of cerebral and renal vascular disease in our aging society,1 and the physiological importance of arterial elasticity has long been known.2 the aim of this article is to describe the pathophysiological principles that form the blueprint for understanding aortic stiffening and for linking together the topics undertaken by other authors in this issue of Medicographia. Almost one century ago, the importance of aortic stiffening was described by Crighton Bramwell and Nobel laureate A. V. Hill3 with respect to left ventricular (LV) work and LV failure.

The amount of energy expended by the heart as measured by its oxygen consumption or CO2 output has been shown to be proportional to the pressure developed; hence the amount of energy which the heart has to expend per beat, other things being equal, varies inversely with the elasticity of the arterial system.
Bramwell and Hill, 19223

Only in the case of young children do we find that the elasticity of arteries is so perfectly adapted to the requirements of the organism as it is in the case of the lower animals.
Roy, 18802

Modern attention was drawn to the subject of arterial stiffening by early Framingham Investigators,4,5 who pointed out the emerging importance of arterial rigidity as well as atherosclerotic disease as a cause of stroke and cardiac failure.the Framingham Investigators were the first to describe pulse waveform analysis as a complement to brachial cuff pressure in a clinical trial.4,5 Pulse wave analysis6,7 actually preceded the introduction of the brachial artery cuff method for measuring systolic and diastolic pressure and acceptance of its predictive capacity in life insurance just over one hundred years ago.8

The earliest radial artery studies were undertaken by Marey in Paris around 18639 and extended into the clinical arena of aging, hypertension, and renal disease by Mahomed in the 1870s.6 these studies were next used by Murrell et al in 187910 to show the effect of nitrates on arterial pulse, and then taken up by Sir James Mackenzie at the turn of the 19th century.7 All the above were more concerned with aortic stiffness than arteriolar resistance—but in Mackenzie’s name, brachial cuff diastolic pressure was taken up as a measure of peripheral resistance, and the “sine qua non” of arterial hypertension—until the importance of cuff systolic pressure was clarified by Framingham Investigators4,5 and then by the Systolic Hypertension in the Elderly Project (SHEP).11

Over the last 50 years, the prime focus of clinicians has been directed toward atherosclerotic disease, and many came to see the arteries in terms of obstructive atherosclerosis, ie, in terms of their conduit function. However, at the turn of the 19th century, Osler in his teachings and undergraduate textbooks,1 and Mackenzie in his,7 were stressing the importance of arterial stiffness. Osler,1 after Councilman at Johns Hopkins, divided arteriosclerosis into nodular arteriosclerosis (now called atherosclerosis), diffuse arteriosclerosis (probably an accompaniment of severe untreated hypertension), and senile arteriosclerosis (which was a consequence of aging). Osler sometimes paradoxically referred to senile arteriosclerosis as “physiological arteriosclerosis”, probably to emphasize that such arterial stiffening was a consequence of aging in apparently normal older subjects without any other sign of disease.1

Physical laws and principles of measurement

Elastic arteries play a major role in the early studies of elasticity, since there were no synthetics, and arteries were readily available from abattoirs together with ligamenta nuchae. the studies of thomas Young, physician and physicist,12 on modulus of elasticity (Table I) utilized such tissues, and with others13 he established the relationships between elastic modulus and pulse wave velocity (PWV) in arteries. the Waterhammer formula describes the relationship between aortic PWV and aortic characteristic impedance (Zc) as numerically almost identical since, when impedance is expressed in terms of velocity, “aortic” PWV multiplied by density equals Zc,13 since the density of blood is almost one (usually 1.05).


Table I
Table I. Measures of elastic properties.

Abbreviations: d,
diastole; h, wall thickness; i, inflection
point; ln, natural logarithm; P, pressure;
s, systole; t, travel time of pulse;
V, volume; z, measuring site.
From reference 13:
Nichols et al.
Mc-Donald’s Blood Flow
in Arteries. 6th ed.
London, UK: Hodder Arnold; 2011.
© 2011, Taylor & Francis Group, LLC.



Measures of arterial stiffness include: aortic PWV, Zc, ratio of diameter change to pressure change in relative terms (distensibility or stiffness; one the inverse of the other) or absolute terms, as compliance (absolute pressure change to absolute diameter or volume change). Other measures indirectly related to aortic stiffness are brachial pressures—brachial systolic pressure (BSP) and brachial pulse pressure (BPP)—and central aortic pressures—central systolic pressure (CSP) and central pulse pressure (CPP). Since the arteries have a mixture of elastin and collagen fibers, with elastin predominantly engaged at diastolic pressure and with collagen fibers progressively engaged as pressure rises, elasticity needs be measured by the tangent of the pressure/diameter curves at around mean pressure.13 Arrangement of elastin and collagen fibers is such that the artery acts as a distensible conduit at physiological pressure, but is prevented from breaking at very high pressure by engagement of collagen fibers.


Figure 1
Figure 1. Changes in manifestation and indices of aortic stiffness with age in adult humans (20-80 years).

Increase in brachial systolic pressure (BSP) from ≈120 to 150 mm Hg represents 25%, and is far lower than the increases in central aortic systolic pressure (ASP, ≈100 to 145 mm Hg, ≈45%), brachial pulse pressure (BPP, ≈80%), central aortic pulse pressure (APP, ≈160%), “aortic” pulse wave velocity (PWV) and characteristic impedance (≈250%), and aortic Young’s modulus (YM, ≈600%), while central augmented pressure rises from zero at age 20 to ≈30 mm Hg at age 80. Data from reference 13.
Abbreviation: AIx, augmentation index.



Other (indirect) measures of arterial elasticity are: augmentation pressure (AP), a measure of the reflected wave and pressure; augmentation index (AIx), a measure of the reflected wave divided by incident plus reflected wave in the ascending aorta; and reflection magnitude,13 calculated as amplitude of the reflected wave divided by amplitude of the incident wave when a particular incident wave is assumed. the above are practical indices of arterial stiffness, but do depend on approximations— ie, nonlinear wall elasticity as described, inhomogeneity of the aortic wall, with measured thickness including non–load-bearing as well as load-bearing components of the media. A further assumption is that AIx is a complete measure of wave reflection (it is not, but depends on pattern of flow from the left ventricle as well as wave reflection).13





Figure 1 shows measures and indices of aortic stiffness and their changes over a lifetime. It is apparent that all increase markedly with age. Changes are much greater than estimated from conventional brachial cuff pressure, and in the average person appear to represent an increase of 4- to 9-fold in elastic (Young’s) modulus, and 2- to 3-fold increase in aortic PWV, Zc, and CPP. AP increases from below zero in children to around 40% of pulse pressure in older persons, especially women. BSP increases by around 30% from adolescence to 80 years of age. Aortic stiffening with age is substantially underestimated by current routine measures of brachial blood pressure (BP) (Figure 2).13

There is normally a gradient in distensibility of the aorta down to muscular peripheral arteries, with the aorta expanding by 15%-20% in youth with each beat of the heart, and the femoral or brachial arteries expanding by just 3%-5%.13 Such is seen in all young mammals we have studied. Humans, however, have a different pattern, so that by the age of around 50, expansion of the proximal aorta is the same as, if not less than, the peripheral arteries. the human life span is so long in comparison to other mammals that degenerative changes with stiffening are ubiquitous in middle-aged humans.13,14 Only older birds, with high BP and fast heart rate,13,14 show anything similar.

Physiology

The function of the arterial system is to distribute blood from the left ventricle to the peripheral organs and tissues, according to need. to do this most efficiently it is necessary to accept pulsatile flow from the intermittently contracting left ventricle at the input then pass this on as a near-continuous, nonpulsatile flow to the peripheral tissues.13 Hence there is another function for the arterial system, which is to “cushion” pulsations so that organ flow in the tiny capillaries is continuous or almost so.13,14

This function of the arterial system, undertaken principally by the proximal thoracic aorta, is similar to that of the medieval fire engines, whereby an inverted air-filled dome cushioned intermittent pumping by firemen to produce a continuous stream through the nozzle of a hose, so that water could be directed at the seat of a fire. This analogy was made by Steven Hales15 and described as “Windkessel” in the German translation of his book. The term has stuck to this simple model of the arterial tree and the aorta’s function. this is a useful primary conceptual model, and is approximated by the arterial function in an elderly person with a very stiff aorta. But the concept loses all value when applied to a young person, an elderly person with aortic PWV reduced by hypotension, or when ejection from the heart is shortened by tachycardia. From a clinical perspective, a model for interpreting cardiovascular function must remain appropriate under extreme conditions, such as those encountered in an intensive care ward, and be able to account for changes in BP, heart rate, heart rhythm, and blood vessel dilation (Figure 3).16


Figure 2
Figure 2. Typical pressure (top) and flow (bottom) waves in the
ascending aorta of a young adult (left) and in an apparently normal
80-year-old elderly person (right).

Ejection from the heart (aortic flow waves) is virtually identical in the young and
old subject, but in the younger person (left), at normal heart rate, the reflected
wave returns from the periphery just as the aortic valve shuts. This means there
is no ill effect on left ventricular (LV) load, but aortic pressure at the coronary
orifices is boosted, which helps maintain flow during cardiac diastole when LV
wall perfusion can occur. In the older subject (right), increased characteristic
impedance generates a higher initial rise in pressure to the early systolic shoulder,
then systolic pressure is augmented—and thus LV load and oxygen requirements
caused by blood expulsion from the heart are augmented too. Additionally, the
boost in coronary pressure during diastole is lost.
From reference 13: Nichols et al. McDonald’s Blood Flow in Arteries. 6th ed.
London, UK: Hodder Arnold; 2011. © 2011, Taylor & Francis Group, LLC.



Figure 3
Figure 3. Pressure waves as might be recorded in the intensive
care ward in a single patient under different conditions, as
recorded in a rabbit and as explained from physical principles.

The central pressure wave (Control) represents the normal aortic pressure
wave, that at top right (Norepinephrine), the effects of elevated blood pressure
from peripheral vasoconstriction, which causes increased pulse wave velocity
and characteristic impedance and early arrival of the reflected wave from peripheral
sites during systole. At bottom left (Pilocarpine) is the pressure wave
seen with hypotension associated with peripheral dilation, as in the rabbit after
hemorrhagic shock treated late by transfusion after compensatory vasoconstriction
had been followed by near terminal vasodilation.
From reference 16: Wetterer. Minn Med. 1954;37:77-86; passim. All rights reserved.



The more appropriate model is a single tube, such as that now used for interpretation of cardiac output, peripheral resistance, and BP (Figure 4, page 384). In this model, the heart ejects in to one end; the other end represents peripheral resistance. For mean pressure, cardiac output, and peripheral resistance, this is appropriate; but for pulsatile lV ejection, this model is incomplete. the appropriate model is an elastic tube activated by the left ventricle at one end and with (near) continuous flow against the peripheral resistance at the other. this model allows for the generation of a pressure wave at one end, with the passage of this wave at a finite wave velocity along the tube, wave reflection at the distal end(s), and travel backwards and some re-reflection at the proximal end. this model better represents the function of the arterial tree, optimal matching of the lV and arterial system, and understanding of how arterial function changes with age in humans.

In Figure 4, the present conceptual model for steady flow, mean pressure and peripheral resistance is shown above (Panel A); the distributed model below (Panel B) is appropriate for pulsatile pressure and flow as well as mean pressure and flow. Panel B is a traditional figure showing mean pressure maintained along the aorta and peripheral arteries almost down to the arterioles, with abrupt fall in the high resistance arterioles. there is pulsation around mean pressure, with pulsation suddenly falling at the origin of the arterioles when pulsatile pressure and flow encounter high resistance arterioles and are reflected backwards towards the heart. Reflection is inevitable at the junction of a high conductance artery and a high resistance arteriole, with flow and pressure downstream being virtually devoid of pulsations. Reflection is strong at the multiple individual peripheral junctions, with some 90% of the pressure wave reflected and just 10% of pulsatile pressure and flow entering the microvessels (arterioles and capillaries) of all but the brain and kidneys at rest.13 In contrast to peripheral arterioles, wave reflection is minor in the major arteries. Indicative of this is the relative constancy of pressure wave forms above and below major branches in the proximal and distal aorta, and the trivial drop in mean pressure from the aorta to tiny peripheral arteries.


Figure 4
Figure 4. A conceptual model (A) and realistic model (B) of the
arterial tree.

A conceptual model (top, A) explaining the relationship between pressure (P),
cardiac output (I), and peripheral resistance (R) on the basis of the hydraulic
equivalent of Ohm’s Law. A more realistic model of the arterial tree (bottom, B),
represented as an elastic tube, which receives spurts of blood from the left
ventricle of the heart and discharges blood as a near-steady stream into the arterioles
and capillaries of the body. Below the tube are shown the systolic and
diastolic pressures (peak and nadir of the pressure wave) at different sites along
the arterial model. Mean pressure (MP) in the arterial model is maintained close
to that in the aorta, until the smallest arterioles and the arterioles are reached,
when MP falls precipitously together with amplitude of the pressure wave. Reflection
at the junction of conduit artery and arteriole is nearly 100%, and accounts
for the reflected wave that travels back to the heart, and increase in amplitude
of this pressure wave close to peripheral reflecting sites; it accounts also for the
near-steady flow and low pressure pulsations in peripheral arterioles.


Pathophysiology

Wave onset in Figure 5, which shows pressure waves recorded sequentially between the aortic arch and iliac arteries in a young human adult (center) and an older adult (right),13 is timed to the electrocardiogram and seen to be delayed between the proximal aorta and the iliac artery. the wave is delayed more in the younger subject than in the older subject indicating that wave velocity is slower (around 5 m/s) in the younger subject than the older subject, where it is usually in the region of 10-15 m/s. the subsequent waves travelling back to the proximal aorta at the same speed are seen to create the diastolic wave in the younger subject and the late systolic wave (earlier echo) in the older subject.

The LV output flow velocity wave and the pressure wave in the young subject are seen at center in Figure 5 and the older subject at right as expected from wave travel and reflection in the arterial tree supplying the trunk and lower limbs (left).13 In Figure 5, the initial wave is generated around the same time, some 100 ms after the beginning of ejection, but its amplitude is greater in the older subject as expected from higher Zc (and PWV). For the same monophasic flow waveform, there are thus two fluctuations in pressure. In the younger subject, the secondary wave—from an appropriately slow return of wave reflection—is seen only in diastole, whereas in the older subject the reflected wave returns earlier, during late systole. the aging change is disadvantageous to the left ventricle, since wave reflection adds to aortic pressure and LV load while reducing pressure maintained during diastole in the aorta, when coronary arteries are perfused after being squeezed shut during systole. the same changes can be explained in the frequency domain from ascending aortic impedance.17,18


Figure 5
Figure 5. Tubular models of the arterial system (left), showing pressure waves recorded sequentially between the aortic arch and iliac arteries in a young human adult (center) and an old subject with aortic stiffening (right).

Increased stiffness of the aortic wall in the old subject causes the initial wave generated by left ventricular ejection to be higher (increased aortic characteristic impedance), then causes the reflected wave to return early (increased aortic pulse wave velocity), boosting late systolic pressure and reducing coronary perfusion pressure.
From reference 13: Nichols et al. McDonald’s Blood Flow in Arteries. 6th ed. London, UK: Hodder Arnold; 2011. © 2011, Taylor & Francis
Group, LLC.



Figure 6
Figure 6. Fatiguing effects of cyclic stress on natural rubber, as shown by the curve representing fracture as predicted by the extent of strain and log of cycle number.

If elastin fibers in the aortic wall behaved in the same way as natural rubber, one would expect to see evidence of fracture in the aorta at 30 years with a heart rate ≈70 beats per minute, given the aorta pulsates by ≈15% over 800 million cycles. Widespread fracture with disorganization of the aortic media would occur by age 80.
From reference 13: Nichols et al.
McDonald’s Blood Flow in Arteries.
6th ed. London, UK: Hodder Arnold;
2011. © 2011, Taylor & Francis
Group, LLC.



Increased aortic stiffness increases amplitude of the primary pressure wave—as a consequence of increased aortic Zc and aortic PWV. Impedance at high frequencies is increased as a consequence of this, as is impedance at lower frequencies. The minimal value of impedance and phase cross over is increased to a higher frequency (from ≈3 to 6 Hz) as a consequence of earlier return of wave reflection. Since most of the energy of the LV ejection wave occurs at the frequency of the first, second, and third harmonics, amplitude of the pressure waves is lower in the younger subject than the older subject, 13,14,17,18 where impedance modulus remains high with a minimal frequency around or above 6 Hz.

Aging and elastic fatigue and fracture

Aorta
Typical changes with aging in the aortic media are well known, and are gross, with fracture and fragmentation of load-bearing elastin fibers, and with disorganization of the aortic wall.13,14 the thoracic aorta dilates and stiffens. Changes can be attributed to fatigue, alterations in the crystalline structure of nonliving elastin fibers so that these become brittle and eventually break. A branch of engineering is devoted to these phenomena in various structural nonliving materials, such as steel (bridges and ships), aluminium (aircraft frames and spars), concrete (buildings), timber (buildings), and natural rubber. Different materials have different resistances to fatigue; these resistances are described as S/N curves (Figure 6), the relationship between extent of strain (S) and the logarithm of number of cycles (N) of such strain to the time when fracture is expected.13 These curves are utilized to determine when aircraft spars need be replaced in scheduled maintenance, ships have reached their safe life span, or components of a bridge need to be replaced.

There is no reason to believe that elastin fibers in arteries are immune to this process, which is illustrated in Figure 6,13 which shows the S/N curve for natural rubber. At cycles of 15% stretch, as seen in the proximal thoracic aorta, one would expect to see fracture at 1 × 10913,14 the gene that controls elastin synthesis is “silenced” in childhood.19 Elastin is not replaced by elastin, but by collagen and mucoid material in the arterial wall. Remodelling of the aorta with age is a degenerative process characterised by chemical and cellular changes. these changes can most rationally be considered as secondary attempts at repair, with the process initiated by physical damage that is a consequence of pulsation and stress in the aorta.

Small arteries, arterioles
A similar physical process affects the small arteries and arterioles and helps explain small vessel damage—microinfarcts and microbleeds—that occurs in the brain and kidneys of older persons, particularly when pulsations are increased by aortic stiffening, and so in long-standing hypertension20 and in acute hypertension.21 Susceptibility of brain and kidney microvasculature to pulsatile stresses can be explained by low vascular resistance, which permits passage of greater pulsations of flow and pressure into dilated distal vessels. Such microvascular lesions are rarely seen in other systemic tissues and organs, one exception being similar lesions in the pulmonary vasculature of children born with left to right shunts,22,23 which develop over years and cause irreversible pulmonary hypertension.

The same physical principles of mechanical fatigue and fracture are at play in the microvasculature as in the aorta, but they affect the microvasculature differently. Instead of the elastin fibers being uniformly affected, manifesting as elastin fracture in the aorta, in the microvasculature the process appears to affect the vessels that supply the most vulnerable organs and at weak spots—ie, the brain and kidney, branching points, and where elastin and connection to muscle is weakened— leading to development of aneurysmal dilatation as described by Charcot and Bouchard.24 these defects are responsible for rupture with microbleeds and frank cerebral hemorrhage. This microvascular disease22 takes the form either of disruption of the wall of small arteries as a consequence of high circumferential tension or thrombosis in the lumen caused by higher pulsatile shear with shedding of endothelial cells, with platelet adherence and arterial occlusion causing small infarcts in the area of supply.25 this is the ultimate endothelial dysfunction. Microvascular disease of this type—quite independent of atherosclerotic disease—is responsible for the initial lesions that, over time, appear to be the cause of Alzheimer’s disease and other cerebral syndromes.25

Consequences of aortic stiffening

LV load is still commonly related only to peripheral resistance, but this should include terms related to the heart’s pulsatile ejection during systole.2,3,25 the load is best characterised as ascending aortic impedance,13,14,18 and should consider Zc, which increases 2- to 3-fold between the ages of 20 and 80 (Figure 1), and also the effects of wave reflection, which typically increase late systolic pressure for LV and aortic systolic pressure in older subjects with aortic stiffening by 20-40 mm Hg over a lifetime. this occurs even if mean pressure and peripheral resistance are unchanged. Such increase in LV afterload has been described by Katz26,27 as the cause of “cardiomyopathy of overload,” which is most common with aging, and in women, and characterised by LV hypertrophy, LV diastolic dysfunction, and LV failure. It can progress in its terminal state to systolic dysfunction, where LV ejection against highly increased aortic impedance is markedly impaired on account of LV weakening.14,26-28

A further depressant of LV function is due to ischemia caused by impaired LV coronary perfusion related to a reduction in coronary perfusion pressure, ie, the pressure in the proximal aorta during diastole when the intramyocardial coronary arteries are freed from the throttling effect of the myocardial contraction around them.29 this impairment is worsened by accompanying lV hypertrophy and diastolic dysfunction that increase ejection duration, shorten the duration available for coronary perfusion,18,30 and eventually cause an increase in LV pressure during diastole. All these changes are extremely common in older humans and predispose individuals to myocardial ischemia even in the absence of coronary atherosclerosis. These changes account for increasing disability, dyspnea, and discomfort,31 especially in women.

Small blood vessels in the brain and kidney

These blood vessels, like those in the lungs, have continuously high blood flow through vasodilated arteries at rest as well as during exercise. As previously described, they are subject to greater pulsatile circumferential tensile stresses and to greater longitudinal shear stresses at the endothelial level.

The former can account for susceptibility to arterial rupture and micro- or macrohemorrhage, which are part and parcel of “pulse wave encephalopathy”32,33 and “pulse wave nephropathy”, as in the presence of acute “malignant” hypertension.14,20,21 In the brain, lesions appear as white matter hyperintensities, lacunar infarcts, and microhemorrhages, even in asymptomatic older persons, and are becoming increasingly common. Lesions are characterized at autopsy by deposition of β-amyloid plaques, tangles, and inflammatory reactions attributable to damage caused by the microhemorrhages, microinfarcts, and cerebral ischemia.25 Studies on brain circulation and renal circulation continue. Attrition of cerebral and renal cells with age has been known for many years, but had not in the past been linked with increase in pulse waveform intensity (pressure and flow), brought about by aortic stiffening.25 Even now, it is difficult for many clinicians to consider that cerebral microvascular damage could be due to aortic stiffening, ie, to have a cause so far distant from the brain.

Principles of prevention

Emphasis on cause of aortic stiffening and small arterial disruption is directed at physical stresses that are a consequence of the heartbeat, epitomized by Stone’s assertion that “the brain is destroyed by the pulse”.25 One cannot avoid the fact that changes associated with aging are virtually all degenerative, and in one way or other contribute to death of most humans between 60 and 100 years of age. the word “remodelling” is a euphuism—a graceful term that is easier for patients to hear. this argument is not new, but is a continuation of that offered by William Osler1 and James Mackenzie7 100 years ago. Osler referred to the quality of elastin that had been inherited, and to the “wear and tear” to which this natural rubber had been subjected. Mackenzie7 referred to physical deterioration and breathlessness in the 4th decade of life as caused by stiffening of the aorta and elastic arteries.

Like Osler and Mackenzie, I agree that arterial stiffening is inevitable and impairs enjoyment of life. These ill effects of aortic stiffening, which can be treated, are not simply due to aortic stiffening, but are magnified by increased PWV and change in the timing of wave reflection. Wave reflection in young adults returns to the heart at the time of aortic valve closure. The wave does not add to LV load, but it does boost aortic pressure throughout diastole, and this aids coronary perfusion. When with aging and aortic stiffening arterial PWV increases, the reflected wave returns early and boosts (augments) the level of pressure against which the heart needs to eject. At the same time, pressure during diastole falls more steeply and coronary perfusion is threatened. The design of the human body evolved to provide optimal ventricular/vascular interaction for 20-30 years, the length of a typical lifetime for our ancestors.

Wave reflection is desirable, and the body is so designed that reflection must occur.13 However, beyond a certain age, at which in generations past there was no survival benefit and at which aortic stiffness develops, wave reflection is no longer beneficial.13 Evolution in humans occurred over eons, during which there was no survival benefit in living into, let alone beyond, the fourth decade. This was identified by James Mackenzie.7

From the fourth decade on (and earlier in women), wave reflection is detrimental and becomes a target for therapy. The amplitude of wave reflection can be reduced by arterial dilating drugs, particularly those which have little or no effect on resistance. Such are epitomized by nitrates.10,13 Other drugs such as calcium channel blockers can have a similar effect, as can angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.13 These drugs can have the effect of “trapping” wave reflection in the peripheral circulation. this effect is apparent on examination of the aortic pressure waveform, and explains the benefits of nitrate in angina pectoris and in acute heart failure in older adults.10,13 Aortic stiffening is little affected by nitrates or other vasodilators, so that PWV and timing of wave reflection is not substantially improved in the aorta, but some drugs do appear to reduce stiffness of muscular arteries, and a number of studies attest to this. In present practice, reduction in aortic stiffness is usually improved modestly by reduction in arterial pressure.


Figure 7
Figure 7. Cardiovascular mortality over 31 years in 27 000 persons aged 18-49 years designated as having normal ideal blood pressure
(BP), high-normal BP, isolated systolic hypertension (ISH) (systolic BP >140 mm Hg, diastolic BP <90 mm Hg), isolated diastolic hypertension (IDH) (diastolic BP >90 mm Hg, systolic BP <140 mm Hg), or systolic/diastolic hypertension (SDH) (systolic BP >140 mm
Hg, diastolic BP >90 mm Hg).

Results show the expected higher mortality of SDH compared to individuals with normal or high-normal BP. Cardiovascular mortality of individuals with ISH was different to that of those with IDH or SDH. In men, there was no significant difference in cardiovascular mortality in individuals with ISH compared those with normal BP over the 20 years following diagnosis.
From reference 41: Yano et al. J Am Coll Cardiol. 2015;65:327-335. © 2015, The American College of Cardiology Foundation.


Treatment

In persons with aortic stiffening, and subject to its ill effects on the heart, brain, and kidney, there is every prospect that improvements in amplitude and timing of wave reflection can be achieved by therapy. We do this now with treatment of isolated systolic hypertension (ISH) in the elderly. Since the major effect is on wave reflection, it may be useful to monitor and identify reflection in the ascending aortic pulse so as to optimize the reduction in systolic pressure and to encourage any increase in aortic pressure during diastole.

ISH in persons over the age of 60 is characterised by a late systolic pressure peak caused by early return of wave reflection. The SHEP study11 showed how active antihypertensive therapy reduced cardiovascular events, while SYSt-EUR (Systolic Hypertension in Europe)34 and SYSt-CHINA (Systolic Hypertension in China)35 showed similar benefit in persons over the age 60, irrespective of diastolic pressure. These trials were interpreted by guideline committees throughout the world as applicable to all adults, irrespective of age. Increasing concern has been directed at evidence (or lack thereof) for treating patients with ISH under the age of 60.36,37 In young adults, especially tall men, elevation of BSP may not be caused by aortic stiffening, but by exaggerated wave reflection in the arm.38 this is characterised by normal aortic systolic pressure, but very high brachial and radial pressure from a highly peaked upper limb systolic peak. Ironically this condition is usually seen in fit, tall, young men with low aortic stiffness.39 While initially considered rare, and described as “spurious systolic hypertension of youth,”38 it appears to be relatively common and to be a factor in the generation of high systolic pressure in the upper limb in many persons under the age of 60. It has been identified in European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines40 as a good reason for measuring aortic pressure from the peripheral radial pulse before labelling a person “hypertensive” and prescribing therapy. In such cases, information available from the arterial pulse waveform will support a clinician’s decision not to treat.

In pursuing this issue, the Chicago Heart Association Detection Project in Industry Study41 has followed a cohort of over 27 000 persons aged 18-49 over 31 years, on the basis of initial BP categorization: normal BP, high-normal BP, ISH, isolated diastolic hypertension (IDH), or systolic/diastolic hypertension (SDH). Cardiovascular mortality at 20 years was low in men with ISH; it was similar to the normal groups, but different to the two groups with IDH and SDH (Figure 7, page 387).41 this supports a view that results of SHEP cannot be extrapolated to younger populations,38 and the views of the ESH/ESC40 that central aortic pressure should be measured in younger subjects with ISH. Surprisingly, the editorialist of the Chicago study42 set aside authoritative scientific information and came to a different conclusion that supports the status quo, ie, that ISH should be regarded as a disease and that all persons irrespective of age should be treated. Treatment of aortic stiffening is also of interest to surgeons— application of elastic material over segments of the aorta could take over its elastic role, while at the same time reducing aortic diameter to its size in earlier adult life. this is likely to find some role in the future, not only for treating refractory hypertension, but for treating aneurysmal dilation of the aorta at the same time.43,44

Central aortic and upper limb pressure: outcome studies

Up until the late 1990s, all clinical trials of hypertension were based on brachial cuff pressures. Measurement of central pressure was first used in REASON (pREterax in regression of Arterial Stiffness in a contrOlled double-bliNd study),45 where a perindopril/low-dose indapamide drug combination was compared to atenolol. this showed greater benefit with the perindopril/indapamide combination for reduction of central, but not brachial, pressure and for reduction in lV mass over 12 months.46

Similar results found in the CAFE (Conduit Artery Function Evaluation)47 substudy of ASCOt (Anglo-Scandinavian Cardiac Outcomes trial) were associated with reduction of a prespecified composite outcome in the amlodipine±perindopril group compared with the atenolol±bendroflumethiazide group. Similar results were seen in the J-CORE (Japan-Combined treatment with Olmesartan and a calcium channel blocker versus olmesartan and diuretics Randomized Efficacy) study.48 All these studies, which were small, were followed by a series of studies and meta-analyses that have shown there is an advantage of central aortic pressure compared with brachial pressure for the prediction of outcomes.49-53

Although contrary opinions still exist, there is an emerging consensus that central aortic pressure, measured with validated devices, warrants use in future trials of antihypertensive therapies, especially those which deal with aging and aortic stiffening. The ESH has encouraged support of this view,40 and the most respected group of cardiovascular epidemiologists in the USA have presented the strongest evidence to date.41

The first century of hypertension was launched in Chicago by Fischer with his Journal of the American Medical Association article on actuarial data for the life insurance industry.8 the second century was launched by Greenland, Stamler, and colleagues, also from Chicago, with their questioning of guidelines for treatment of systolic BP in young subjects,37 and then in their groundbreaking follow-up study of 27 000 persons over 31 years.41 life insurance companies are expected to confirm or deny the Chicago views in the very near future. n

Conflict of interest: Michael O’Rourke is a founding director of AtCor Medical Pty limited, manufacturer of systems for analyzing the arterial pulse and Aortic Wrap Pty limited, developer of devices to improve aortic distensibility, and a consultant to Novartis and Merck.


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Keywords: Aortic function, aortic stiffness, pulse wave velocity, wave reflection, augmentation pressure, augmentation index, radial pulse wave, aortic pulse waveform, elasticity, impedance, arteriosclerosis