Arterial Aging. A Review of the Pathophysiology and Potential for Pharmacological Intervention REVIEW ARTICLE. Contents. Abstract

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1 REVIEW ARTICLE Drugs Aging 2011; 28 (10): X/11/ /$49.95/0 ª 2011 Adis Data Information BV. All rights reserved. Arterial Aging A Review of the Pathophysiology and Potential for Pharmacological Intervention Michael F. O Rourke, 1,2,3 Audrey Adji, 1,4 Mayooran Namasivayam 1,2 and Jonathan Mok 1 1 St Vincent s Clinic, Sydney, NSW, Australia 2 University of New South Wales, Sydney, NSW, Australia 3 Victor Chang Cardiac Research Institute, Sydney, NSW, Australia 4 Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia Contents Abstract Perspective Arterial Aging Mechanical Effects of Arterial Aging Clinical Consequences of Arterial Aging Heart Large Arteries Microvessels Potential for Pharmacological Intervention Wave Reflection as a Target for Drug Therapy Major Pharmaceutical Studies Hypertension Cardiac Failure Non-Pharmacological Therapies Conclusions Abstract This review begins with a perspective on the effects of arterial aging on society and world events over the past century. Until recently, the use of just one technique to measure blood pressure non-invasively limited progress in understanding the mechanisms involved and the potential of antihypertensive drug therapies. New methods for extracting information from the arterial waveform have followed the (re)introduction of arterial tonometry into clinical practice, together with mathematical analysis in the frequency and time domains. These new methods have exposed the phenomenon of aortic stiffening with age, and early wave reflection arising therefrom, and identified it as the major cause of cardiovascular degeneration. Such findings point to arterial aging as a logical target for the treatment and prevention not only of cardiac, aortic and large artery disease, but also of damage to microvessels in the brain and kidney, which in turn leads insidiously to dementia and renal failure, respectively.

2 780 O Rourke et al. 1. Perspective The last 80 years has seen an enormous increase in community expectations with regard to life expectancy, coupled with changes in the way that cardiovascular disease of aging presents, is characterized and is treated. The sudden death in 1945 of the American President Franklin D. Roosevelt from cerebral haemorrhage, [1] preceded by progressive but undisclosed elevation of arterial pressure (figure 1), was the principal spur to the establishment of the National Heart Institute (now Heart, Lung, and Blood Institute) within the National Institutes of Health in Washington, DC, USA. FDR had been elected to his fourth term as President, and although just 61 years old at the time of his death, his passing and his erratic behaviour in the last months of life as in the Yalta negotiations led to a constitutional change that no US president could serve for more than two terms. Thereby it was hoped that the subtle effects of cardiovascular aging, including decline in cognitive and executive function, would not pose the problem that it had at the end of World War II, and almost certainly did at the end of the World War I, when President Woodrow Wilson, whose arterial pressure was not known, appeared to have suffered a series of small strokes prior to discussions with European leaders on a League of Nations. The major cardiovascular disorder of aging was seen traditionally as elevated arterial pressure (hypertension) and its effects on the heart, kidneys and brain. But there were no effective drugs for treating elevated pressure, and those that did exist had such serious adverse effects that few were prepared to take them, especially if they had no symptoms. Treatment was reserved for those who had entered the malignant phase with systolic and diastolic pressure spiralling upwards, and with evidence of hypertensive encephalopathy or acute renal failure, characterized by acute damage to small blood vessels in the brain or kidney, or with acute left ventricular (LV) failure. Small blood vessel damage in the brain and kidney caused rupture or partial rupture of tiny arteries, oedema or spasm of arterial walls with thrombosis and increased vascular resistance in these organs. The clinical features of this process were seen as haemorrhages and exudates in the optic fundi and papilloedema. [2] 350 Systolic 300 D-Day Election Yalta Arterial blood pressure (mmhg) ECG: LVH Proteinuria: + ++ M A M J J A S O N D J F M Time (y, mo) A Diastolic Fig. 1. Diastolic and systolic brachial blood pressure of US President Franklin D. Roosevelt from 1935 until his death on 12 April Data are from the diary of his cardiologist, Dr Howard G. Bruen (reproduced from Messerli, [1] with permission, ª Copyright 1995 Massachusetts Medical Society). LVH = left ventricular hypertrophy.

3 Arterial Aging 781 In this malignant phase, with cerebral and renal resistance increased, it made little sense to reduce arterial pressure with vasodilators or any other drug therapy. The classic studies of Harvey Cushing [3] were quoted as showing that when intracranial pressure is raised, elevation of systemic arterial pressure is a compensatory mechanism to force blood through the brain, and so maintain perfusion and oxygen delivery. In New Zealand, one crusty and determined clinical investigator (Sir Horace Smirk) showed that gentle, steady reduction of arterial pressure over hours and days could relieve the malignant phase of hypertension, leading to return of consciousness, relief of renal failure and disappearance of evidence of oedema and haemorrhage in the optic fundi. [4,5] This work took a long time to be accepted around the world, with physicians in the US more sceptical than most. [5] Following World War II, in Sydney, the Englishman Frank Byrom recommenced his studies of arterial pressure in rats, which had been interrupted at the beginning of World War II, [6] and integrated these with clinical studies on patients through the Pathology Department at St Vincent s Hospital, Sydney, NSW, Australia. [7,8] Through his work with rats, observing microscopic changes in pial blood vessels through acrylic windows in the skull, Byrom established that it was elevation of arterial pressure alone that caused small arteries to narrow and to bleed, not the other way around. [8] He showed that abnormalities of the blood vessels were resolved permanently by a reduction in arterial pressure, and with a variety of methods. He showed that the inflammation accompanying fibrinoid necrosis of the arterial wall was secondary, and part of the process of repair. [7,8] By providing an explanation for Smirk s clinical results, Byrom became equally controversial in his field, although the work of both men was strongly supported by Sir George Pickering, then the father of hypertension in Great Britain. [2] Pickering, in the subtle introduction to his book High Blood Pressure in 1968, was caustically critical of his colleagues, especially in the US, who were reluctant to believe that there could be such a simple explanation for such a devastating disease. Table I. List of trial abbreviations and definitions Trial abbreviation ACCOMPLISH ALLHAT ASCOT CAFE HOPE J-CORE LIFE SHEP Trial definition Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Anglo-Scandinavian Cardiac Outcomes Trial Conduit Artery Functional Endpoint Heart Outcomes Prevention Evaluation Japan-Combined Treatment with Olmesartan and a Calcium Channel Blocker versus Olmesartan and Diuretics Randomized Efficacy Study Losartan Intervention For Endpoint reduction in hypertension Systolic Hypertension in the Elderly Program Byrom is generally credited now for the modern treatment of hypertension s malignant phase, [9] but his other work on the vicious circle was perhaps more important. [10] He was able to show through his rat experiments and clinical studies with Dodson and others, that hypertension begets hypertension through a renal mechanism. [7,8,10] His optimism and confidence that (with a few caveats) hypertension was reversible, even in its most severe form, begat research into, and production of, the highly effective antihypertensive drugs that are employed today. The North American contributions have principally been in the development of drugs and their use in large clinical trials. With the conquest of malignant hypertension established by Smirk and Pickering, the Veterans Affairs trials in patients with severe, [11] then less severe, [12] hypertension followed, and in turn were followed by the SHEP study (see table I for a list of trial names), [13] which established the value of treating elevated systolic pressure even when diastolic pressure is normal or low. For many years, therapy of hypertension was serendipitous, with the success of b-adrenoceptor antagonists (b-blockers) and diuretics not envisaged when they were first introduced. The most successful antihypertensive drugs now used ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), renin

4 782 O Rourke et al. inhibitors (RIs), calcium channel antagonists (calcium channel blockers [CCBs]), aldosterone receptor antagonists have been synthesized to interact with known pathophysiological mechanisms. The most successful act predominantly as arterial vasodilators, reducing tone in conduit arteries with lesser effect on peripheral resistance, thus reducing pulsatile as well as mean blood pressure. [14] With new knowledge of the underlying mechanisms and treatment of hypertension, and with widespread measurement of arterial pressure by general medical practitioners, the presentation of the condition has changed. This was well described by a pioneer of new applications, Harriet Dustan, [15] in 1989, as follows: It is really not surprising that up until this time the focus was on diastolic hypertension. From a 1989 perspective, it is hard to realize what a serious problem diastolic hypertension was before the era of anti-hypertensive drug therapy. This condition affected middle-aged persons at the height of their productivity. It either killed them suddenly by cerebral haemorrhage or slowly and miserably by cardiac or renal failure. No one was concerned about elderly persons with ISH [isolated systolic hypertension], particularly those who had lived longer than 70 years. However, when the effectiveness of anti-hypertensive drug treatment for diastolic hypertension was shown, the stage was set for a change in attitude towards ISH. The Framingham study has played a major role in our understanding of how arterial pressure changes with age. [16] It is now established that systolic pressure reaches a plateau at about age 35 years and then rises progressively with age, whereas diastolic pressure rises steadily to around age 50 years, then falls with increasing age, so that brachial pulse pressure (systolic minus diastolic) increases steeply with age (figure 2). [17] Framingham established the association between cardiovascular events and diastolic pressure up to age 40 years, the high association with pulse pressure above age 60 years, [18] and the continuing association of systolic pressure and events throughout life (figure 3). [19] Exhortations from the Framingham director and investigators led to the SHEP trial [13] being conducted and proof that in older subjects (aged >50 years), systolic pressure when elevated warrants treatment even when diastolic pressure is normal or low. In the past, it has been usual to consider changes in arteries due to aging as quantifiable from brachial artery pressure. Researchers are now aware of the unexplained inaccuracy of brachial cuff sphygmomanometers in measuring systolic and especially diastolic pressure under different conditions. [20] Awareness of aortic stiffening with age has led to non-invasive [21] measurement of aortic stiffness as carotid-femoral pulse wave velocity (PWV). Aortic stiffness is the major cause of increasing systolic pressure with age, but it acts directly by increasing the initial wave generated in the aorta during LV ejection, and indirectly by causing early return (in systole rather than diastole) of the reflected wave from peripheral sites. [20,22] Measurements of aortic stiffness as PWV and wave reflection as augmentation index or wave amplification show far greater change with age than brachial systolic pressure, and will be used increasingly in the future to characterize changes due to aging and to tailor appropriate drug therapy. [20,23] Such discussion follows. 2. Arterial Aging Arterial aging is often confused with atherosclerosis, which it is not. [24-26] The arterial changes due to aging have been best characterized in mainland China, where the diet is largely vegetarian, cholesterol levels are low, and atherosclerosis is uncommon. [27,28] Studies in different regions of China with high and low prevalence of hypertension also have helped to clarify the effects of aging separately from those of elevated blood pressure. [28] Arterial aging affects predominantly and almost exclusively the proximal thoracic aorta and proximal parts of the aortic arch branches to the head and upper limbs. These dilate and stiffen progressively with age. [24-28] Such changes are associated with progressive fragmentation and rupture of elastin fibres in the medial coat of the aorta. This is caused by repetitive pulsations of

5 Arterial Aging a b 88 SBP <120 mmhg SBP mmhg SBP mmhg SBP 160 mmhg All subjects Deaths, MI and CHF excluded MAP (mmhg) c Age (y) PP (mmhg) d Age (y) DBP (mmhg) Age (y) SBP (mmhg) Age (y) Fig. 2. Framingham longitudinal data showing change in arterial pressure with age. (a) Mean arterial pressure (MAP), (b) pulse pressure (PP), (c) diastolic blood pressure (DBP) and (d) systolic blood pressure (SBP) measured from the brachial artery for each subject at 5-year age intervals. In each SBP subgroup (based on index examination), data were averaged for all subjects and with deaths, non-fatal myocardial infarction (MI) and congestive heart failure (CHF) excluded (reproduced from Franklin et al., [17] with permission). the aorta. The elastic arteries are most affected since they stretch so much (by around 20% in early life) with each beat of the heart, and in contrast to the muscular conduit arteries such as the abdominal aorta and iliac, femoral and brachial arteries, which stretch by <3% with each beat. Elastin is the most inert non-living material in the body, with a half-life of decades. [20,29,30] It appears to respond to the same physical laws that determine change in crystalline structure, fragility and then fracture as other non-living materials, including rubber and steel. Fracture depends on the cumulative number of strain cycles (expressed logarithmically), and on the extent of strain (expressed directly). Natural rubber stretched by 10% is apt to fracture at cycles (corresponding to 30 years at 70 beats/min) and by 5% at cycles (corresponding to 100 years at 70 beats/min). These physical principles explain why the distensible proximal aorta shows early degeneration with age, whereas the muscular arteries show little or no degeneration

6 784 O Rourke et al. over a full life span of 100 years. Other aging changes include an increase in aortic wall thickness, principally in the intima, but this is not load-bearing and has little effect on mechanical properties. It does pose, however, a barrier to nitric oxide diffusion from endothelial cells at the blood interface to muscle cells in the media; this is the probable reason for impaired endothelial function with age. [31,32] The classic method of studying changes due to aging non-invasively has been measurement of the speed of travel of the arterial pulse along an arterial segment. [33] This has been done for almost 100 years in humans. The usual way to measure aortic wave velocity is to measure the wave foot at the aortic arch and at the femoral artery, measure the distance between these two sites and calculate the velocity as the distance divided by the delay of the wave foot. Typical values are 400 cm/sec at 18 years of age and 1200 cm/sec at 80 years of age. [20,33,34] Aortic PWV is related to aortic elasticity by the Moens- Korteweg equation (equation 1): [20] sffiffiffiffiffiffiffi Eh PWV ¼ (Eq: 1Þ 2r where PWV is in cm/sec, h is the thickness of the load-bearing media, 2r is the internal diameter of the vessel, r is blood density, and E is Young s modulus. A 2.5-fold increase in stiffness (as PWV) corresponds to a 6.25-fold increase in Young s modulus of elasticity. Such measurement of stiffness includes a length of iliac and femoral artery in which PWV remains relatively constant with age (at around 800 cm/sec). MRI measures of proximal aortic stiffness show even greater increases in PWV with age. [34] However expressed, these changes due to aging are huge and totally out of proportion to the mean 20 mmhg (~15%) increase in brachial systolic pressure seen between ages 18 and 80 years (figure 2). 2.1 Mechanical Effects of Arterial Aging Stiffening of the proximal aorta causes an increase in pressure that is generated by each beat of the heart. One can relate the pressure rise to the flow velocity within the artery by the characteristic impedance of the aorta through the waterhammer formula (equation 2): [20,35] P ¼ V Z c (Eq: 2Þ where P is pressure in dyne/cm 2, V is velocity in cm/sec and Z c is characteristic impedance in dyne sec/cm3. At peak flow velocity averaging 80 cm/sec in the aorta, and with characteristic impedance of 400 cm/sec (similar numerically to aortic PWV), a pressure wave of dyne/cm 2 will be created. This corresponds to a pressure 3.0 a b 3.0 CHD HR SBP 170 mmhg (p = ) SBP 150 mmhg (p = ) SBP 130 mmhg (p = ) SBP 110 mmhg (p = ) DBP (mmhg) CHD HR SBP 110 mmhg (p = ) SBP 130 mmhg (p = ) PP (mmhg) SBP 150 mmhg (p = ) SBP 170 mmhg (p = ) Fig. 3. Framingham data showing the separate influence of brachial systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) on coronary heart disease (CHD) events. (a) Joint influences of SBP and DBP on CHD risk. Hazard ratios (HRs) were determined from the level of DBP within SBP groups (reference value of 1.0 for SBP of 130 mmhg and DBP of 80 mmhg). (b) Joint influences of SBP and PP on CHD risk. HRs were determined from the level of PP within SBP groups (reference value of 1.0 for SBP of 130 mmhg and PP of 50 mmhg) [reproduced from Franklin et al., [18] with permission].

7 Arterial Aging 785 wave of 24 mmhg at peak aortic flow in an 18-year-old man. This is amplified by wave reflection in the upper limb and is measured as around 36 mmhg in the brachial arteries (i.e. if diastolic pressure is 80 mmhg, brachial systolic pressure will be 116 mmhg). [20] Flow into the aorta is exclusively confined to ventricular systole, with no flow in the remaining part of the cycle (around 600 msec at a heart rate of 67 beats/min). [20] The aortic pressure wave, however, shows a secondary boost, which can only be attributed to wave reflection at multiple sites in the circulation (principally where low-resistance conduit arteries terminate in high-resistance arterioles). As seen from the ascending aorta, this site appears to be approximately 50 cm distant, [20,35] corresponding to the origin of the coeliac arteries in the upper abdomen. At an aortic PWV of 400 cm/sec, wave reflection would be expected 0.25 seconds after the initial wave foot in the ascending aorta. The peak of aortic flow occurs at around 100 msec, so that wave reflection is expected in the later part of systole and throughout diastole in the 18-year-old man. This is an ideal situation for wave reflection. It does not increase peak systolic pressure at rest, but it does augment pressure during diastole when the coronary arteries can be perfused, and this is improved further during fight or flight when heart rate increases to perhaps 120 beats/min and ejection duration decreases to 0.25 seconds (figure 4). Design of the arterial system is optimal at age 18 years and through the procreative years that follow, but evolution in humans has no answer to the mischief that arises as the aorta degenerates and stiffens, and as aortic characteristic impedance and PWV increase with advancing years. The reflected wave returns earlier and earlier, with wave reflection effects apparent as a late systolic peak, from a wave that is seen closer to the peak of flow into the aorta (around 100 msec after onset) rather than near cessation of flow (around 300 msec after onset). This is exactly what would be expected if the reflection site remained unchanged and wave velocity increased 3-fold, from 400 to 1200 cm/sec, at age 80 years. The effect of aging then causes two ill-effects: an increase in the height of the primary pressure a Fig. 4. Schematic representations of the ascending aortic pressure wave superimposed on the left ventricular (LV) pressure wave in (a) a young individual and (b) an older person. In the older person, myocardial oxygen demand, represented by the pressure-time integral during systole (vertically hatched area), is increased by the higher LV and aortic systolic pressure and by the longer duration of systole (vertically hatched area). In the older person, supply of myocardial oxygen is reduced by the shorter duration of diastole (horizontally hatched area), the lower aortic pressure during diastole, and the increased LV pressure during diastole as a result of LV dysfunction (reproduced from O Rourke and Hashimoto, [24] with permission). wave and the addition of a secondary pressure wave of almost identical height from wave reflection (figure 5). Aortic dilation from degenerative changes causes peak flow reduction from 80 to perhaps 50 cm/sec by 80 years of age. [20] At this age, amplification of the pressure wave is reduced to around 5% from 50%, so that an aortic pulse pressure of 72 mmhg will appear as 76 mmhg at the brachial artery, and brachial systolic pressure will be 136 mmhg if diastolic pressure is 60 mmhg. The foregoing discussion, expanded in figure 5, shows how marked change in LV load is brought about by aging, but how this can be underestimated or overlooked by conventional measurements of brachial blood pressure by cuff. In figure 5, a 3-fold increase in aortic pulse pressure is associated with just a 9 mmhg or 7.5% increase in brachial systolic pressure. 2.2 Clinical Consequences of Arterial Aging Ill-effects of arterial stiffening are seen on the left ventricle of the heart, on the large arteries and on the smallest fragile arteries of highly perfused organs the brain and kidneys. b

8 786 O Rourke et al. a Pressure (mmhg) Pressure (mmhg) b Young Young 0.5 sec Middle Middle Old Old 0.5 sec Fig. 5. Pressure waveforms (a) measured in the radial artery and (b) synthesized for the ascending aorta in three women of the same family, aged 18 years (young), 48 years (middle) and 97 years (old). Pulse pressure is increased almost 4-fold in the ascending aorta and 2-fold in the upper limb (time calibration 0.5 sec) [reproduced from O Rourke and Hashimoto, [24] with permission] Heart As explained in section 2.1, aortic stiffening increases the primary wave caused by LV ejection. This wave is then augmented by early return of wave reflection from peripheral sites. Both contribute to increases in aortic and LV systolic pressure of mmhg. [20] This increases LV load, increases LV oxygen and blood demand and predisposes to LV hypertrophy and LV failure. Hypertrophy further increases LV demand, and causes slower and longer duration of ejection [20,36-38] and slower ventricular relaxation. [38] Ultimate adverse effects are myocardial ischaemia, even in the absence of coronary artery disease (particularly in older women), and heart failure, particularly from impaired ventricular filling during diastole. These problems are accompanied by lower aortic pressure during diastole. This further predisposes to myocardial ischaemia by reducing the coronary perfusion gradient during diastole, when the LV coronary arteries can be perfused. This is enhanced by a reduction in diastolic perfusion time by hypertrophy or by an increase in heart rate. Arterial aging is thus a set up for cardiac failure, both of systolic and diastolic type, and for myocardial ischaemia. [24-26] Large Arteries Aging itself through multiple cycles of expansion damages the aorta and causes it to dilate and elongate (particularly the ascending aorta), [39] as well as stiffen. Secondary consequences described in section 2.1 cause an increase in pulse pressure (up to 3-fold) with greater stretch with each cycle, and accelerated degeneration. High aortic pulse pressure predisposes to atherosclerosis [24-26,40] and to medionecrosis and aortic dissection. Such high pulse pressure also causes stretching of weakened parts of arteries, usually at branching points, and hastens dilation, aneurysm formation and rupture. [20] Microvessels The smallest arterial vessels proximal to thickwalled arterioles are fragile and normally carry blood with minimal pulsatile expansion and at steady constant flow velocity. In the 18-year-old man, pulsations are absorbed upstream in the

9 Arterial Aging 787 distensible aorta and blood passes into the arterioles in a steady stream. This is also the situation in (young) experimental animals. With progressive stiffening of the aorta with age, these pulsations are not absorbed upstream, and pass on into the microvessels, particularly those with high resting flow, which have arteries of supply that are and remain dilated. High pulsations in the microvessels of brain and kidneys cause damage to the endothelium with shedding of endothelial cells (the ultimate endothelial dysfunction), causing subsequent thrombosis and micro-infarction. [33] High pulsatile pressure also stretches and damages these vessels, with results similar to those seen in malignant hypertension as described in section 1. [2,7,8] The combination of micro-infarction and microhaemorrhage can explain lacunar brain infarcts, the amyloid deposits in the brain that result from micro-haemorrhage, [41,42] and the white matter hyperintensities on MRI, which are common in persons with Alzheimer s dementia. [43,44] Similar lesions occur in the kidney and can explain renal deterioration with age, albuminuria and haematuria. [44] The microvessels of the brain and kidney appear to be particularly susceptible to the aging changes since they gain no protection from the ravages in the aorta upstream. The microvessels in the LV of the heart are protected by contraction of the myocardium around them when pressure is highest during ventricular systole, while the liver, which also has a large blood supply, receives most of this blood from the portal vein rather than the hepatic artery. Microvessels in the lungs have adapted to pulsatile flow at low pressure through the pulmonary arteries. However, when pulsatile flow is markedly increased, even when mean pressure is low, as in patent ductus arteriosus or ventricular septal defect, a similar pathological process emerges with damage to the endothelium and media of small arterial vessels and with a combination of occlusion and haemorrhage resulting in pulmonary hypertension. [44,45] 3. Potential for Pharmacological Intervention Understanding the pathophysiological mechanism provides a basis for better management of cardiovascular aging and its consequences. At the origin, the basic problem of aortic stiffening is inevitable so long as the heart beats, and the arteries expand. This expansion, particularly of the proximal aorta, causes the fatigue and fracture of elastin in the same way that cycles of landing and take-off cause fatigue of the wing-spars of aircraft and determine maintenance programmes and their replacement. [20] As with the aorta, the wing-spars are especially vulnerable since they bend more than any other component of the aircraft. At least they are replaceable, whereas the elastin in the aorta is not. But ultimately the whole aircraft frame becomes fragile and subject to failure, as does the hull of a ship after a period of years at sea. Having considered the physical disorganization of the aorta in older humans, it seems impossible to envisage that drug therapy would have any benefit on aortic elasticity. This is the predominant belief, although benefits of cross-link breakers or similar therapy have been proposed. [46,47] Surgical therapy appears more feasible with substitution or wrapping of a degenerated aortic segment with an elastic graft. [48,49] While direct therapy of the degenerate aorta appears to carry little promise, indirect therapy carries great promise and can be credited with achieving many of the benefits seen with modern therapy of hypertension. This was first addressed in 1967 [49,50] and is discussed in the next section. This is particularly applicable in the treatment of ISH, which is the clinical syndrome caused by aortic stiffening with age. The clinical syndrome of essential hypertension, as seen in the past, is still with us, as are the syndromes of secondary hypertension due to adrenal tumours, primary renal disease, aortic coarctation, etc. In all of these conditions, elevated blood pressure begets further elevation in arterial pressure via the renin-angiotensin system, as described by Byrom. [8,10] In these conditions, peripheral resistance is elevated and progression is caused by a further increase in peripheral resistance. Appropriate attention entails measurement of arterial pressure as a routine practice in the population as individuals visit general practitioners for other ailments. Once a person is identified,

10 788 O Rourke et al. therapy is desirable to prevent the spiral to the high levels seen in the past. This has been so great a success that it is often taken for granted. 3.1 Wave Reflection as a Target for Drug Therapy As explained in section 2.1, the aging process, with an increase in aortic stiffening, increases systolic and pulse pressure by the following two mechanisms: (i) an increase in the initial pressure peak caused by LV ejection; and (ii) augmentation of this by early return of wave reflection from peripheral sites. Improvement in the primary wave can be achieved by reduction of arterial pressure itself, as a reduction in aortic PWV by around 100 cm/sec is associated with a 10 mmhg reduction in diastolic pressure. [20,51] This is seen as a benefit of all drugs that decrease diastolic pressure. Long-term reduction in arterial stiffness has recently been described by Laurent et al. [21] and Ait-Oufella et al., [52] but the benefits of this approach appear to pale in comparison with those achievable by a reduction in wave reflection. The benefits of a reduction in wave reflection were first described by Yaginuma et al. [53] in relation to nitroglycerin. The reduction in wave reflection is, however, apparent in the sphygmograms published by Murrell [54] in his classic paper on use of this drug to relieve angina pectoris. Yaginuma et al. [53] showed that reductions in central aortic systolic pressure and ascending aortic impedance at low frequency (up to 3 Hz) occurred without any change in aortic characteristic impedance or peripheral resistance and were attributable to dilation of small peripheral arteries with trapping of wave reflection in the peripheral circulation, such that the reflection returning to the heart was markedly reduced (figure 6). This explanation for the action of nitroglycerin was confirmed by other invasive and non-invasive studies and was the subject of a book published in [55] The explanation had not been apparent to those who had sought to interpret nitrate action solely on the basis of brachial sphygmomanometer cuff recordings. It was also not readily apparent when brachial or a b Initial pulse wave Reflected wave Reflected wave Fig. 6. The proposed mechanism for reduction in wave reflection with nitrates: (a) control condition and (b) after nitrate administration.wave reflection at the peripheral arterioles is unchanged; however, the amplitude of the reflected wave observed in central arteries is decreased markedly at arterial branches when daughter branches show greater dilation with nitrate than the parent artery (reproduced from Yaginuma et al., [53] with permission from Oxford University Press). radial pressure waves were recorded alone, but was described first by Kelly et al. [56] and effectively confirmed by Takazawa et al. [57] in Tokyo and Simkus and Fitchett [58] in Montreal. The introduction of pulse waveform analysis using applanation tonometry and measurement of aortic pressure and indices of wave reflection confirmed the beneficial effect of nitroglycerin on wave reflection (i.e. a reduction) and the subsequent decreases in central systolic and pulse pressures. Similar effects were apparent with other drugs, including ACE inhibitors, ARBs and CCBs, [59-63] and are supported by invasive studies of cardiac catheterization. [64-70] 3.2 Major Pharmaceutical Studies Hypertension A benefit from reducing high blood pressure with drugs was first shown by Smirk and

11 Arterial Aging 789 Alstad [71] in 1951 in patients with malignant hypertension, who were treated with ganglionblocking agents. Subsequently, the Veterans Affairs studies in the US [11,12] confirmed the reduction in mortality and morbidity in patients with severe (diastolic pressure >115 mmhg) and less severe (diastolic pressure >90 mmhg) hypertension. Again in the US, the SHEP trial [13] showed the benefit of treating ISH (i.e. elevated systolic hypertension with normal or low diastolic pressure in elderly persons). This is an exaggeration of the aging phenomenon and is attributable to aortic stiffening with normal or near normal peripheral arteriolar resistance. These trials followed multiple studies that compared the value of different drugs in the treatment of elevated arterial pressure. At the time these studies were conducted, attention was directed to the relationship between a reduction in arterial pressure (systolic and diastolic) and clinical events. The mechanism of action of drugs was of lesser priority because the effectiveness of the drugs primarily used in practice (b-blockers and diuretics) could not be satisfactorily explained. The largest government-sponsored antihypertensive trial ALLHAT [72] showed that use of an a- adrenoceptor antagonist (which dilates arterioles predominantly) was deleterious, such that this arm of the study was ceased, leaving comparison of the diuretic chlortalidone against an ACE inhibitor and a CCB. [73] The diuretic appeared superior to either ACE inhibitor or CCB. This was a surprising finding, since for primary use, the ACE inhibitors and CCBs were preferred over diuretics by prescribers. Pharmaceutical studies that followed publication of ALLHAT compared new CCBs, ACE inhibitors or ARBs against the older agents with the comparator, usually atenolol. Among the first of these was HOPE, [74] which compared the ACE inhibitor ramipril against atenolol in highrisk patients, usually with elevated arterial pressure. Ramipril appeared superior to atenolol, although the reductions in brachial systolic and diastolic pressures were similar. From this arose the hypothesis that the benefits of the new ACE inhibitor ramipril were unique, and were achieved without the decrease in arterial pressure customarily seen with ACE inhibitors. In New England Journal of Medicine correspondence, the authors rejected the view that these benefits were attributable to reductions in aortic and LV systolic pressure, i.e. that they were due to reductions in pressure beyond the brachial artery. [75] Hirata et al. [60] subsequently showed in persons with risk factors for cardiovascular disease that use of ramipril compared with atenolol in the doses used in HOPE led to a greater reduction (mean around 5 mmhg) in central aortic pressure than in brachial systolic pressure. The next major study was LIFE, [76] which compared the ARB losartan with atenolol. Again, as in HOPE, there was significant benefit for losartan over atenolol in outcomes, and again there was no difference in brachial systolic or diastolic pressure between the two groups. Again, benefits beyond blood pressure lowering were claimed. The LIFE investigators, when questioned at meetings, could only say that measurement of central aortic pressure was not in the agreed protocol. Much smaller studies were initiated in Paris by Asmar et al. [51] and de Luca et al., [77] with the support of a French company, to investigate changes in arterial stiffness and wave reflection together with central pressures (carotid, and aortic synthesized from the radial artery), brachial pressures and outcome (reduction in LV hypertrophy) when a combination of perindopril and low-dose diuretic was compared with atenolol over a 12-month period. As in HOPE and LIFE, the reductions in brachial pressures were similar in the two arms of the study, as was aortic (carotid-femoral) PWV, whereas mean central (carotid and aortic) systolic and pulse pressures were 4 5 mmhg lower than the brachial pressure. [59] There was no difference in carotid-femoral PWV (the gold standard of aortic stiffness) with perindopril/indapamide compared with the b-blocker. An outcome benefit was shown for the ACE inhibitor/diuretic combination in terms of a reduction in LV mass over 12 months. [77] Further studies have confirmed the benefits of drugs that reduce central aortic pressure in hypertensive patients. The CAFE [61] substudy of

12 790 O Rourke et al. ASCOT [78] attributed the benefit of amlodipinebased therapy over atenolol-based therapy in the major trial to the greater (mean 4 5 mmhg) reduction in aortic compared with brachial systolic pressure. Similar results were seen in the J-CORE [63] study, which compared the effects of a CCB with those of a diuretic when added to an ARB. There was again a mean difference of 4 5 mmhg between aortic systolic and brachial systolic pressure in favour of the ARB/CCB combination compared with a diuretic. This appeared to explain the results of the large ACCOMPLISH trial, [79] which had shown superiority for an ACE inhibitor/ccb combination over an ACE inhibitor/diuretic combination, and supported the results of a small trial that had shown a greater mean reduction of 3 4 mmhg for an ACE inhibitor over a diuretic in the reduction of central compared with brachial systolic pressure. [62] A meta-analysis of the many studies that have been conducted to date comparing central and brachial pressure reduction by antihypertensive therapy showed superiority for drugs that reduce wave reflection and central systolic pressure compared with those that reduce brachial pressure. [80] High blood pressure, together with aging, has been implicated in the development of small blood vessel disease in the brain, and with intellectual deterioration and dementia, [24,44] as discussed in section Drug therapy, particularly with ACE inhibitors, ARBs and CCBs, appears to decrease the rate of development of these lesions and conditions. [20] This has not been confirmed to complete satisfaction, but if it is, it will constitute another reason for early detection and treatment of arterial hypertension Cardiac Failure Cardiac failure is a very common mechanism of death in the elderly. Like cardiac arrest, it is regarded as a mechanism, and so is not recognized in death certificates and national mortality statistics. In the elderly, cardiac failure commonly presents as diastolic heart failure (or heart failure with normal systolic function) and is attributable to long-standing elevation of aortic systolic pressure due to aortic stiffening and early wave reflection. A less common presentation is with systolic heart failure, attributable to weakening of the left ventricle and impaired ventricular ejection; such patients have low (<35%) ejection fraction, myocardial scarring and often coronary artery disease. The two mechanisms are often combined. Commonly, diastolic dysfunction is the end result of chronically elevated systolic pressure and ISH. [20,81] The underlying abnormalities are aortic stiffening and early wave reflection. It is not yet established that such patients benefit from the same treatments as those administered for systolic heart failure. But usual treatments are similar and include ACE inhibitor or ARB drugs to reduce central aortic pressure to the lowest level tolerated, together with diuretics and vasodilating b-blockers. Many patients with diastolic heart failure were included in the trials previously described for hypertension, so that a particular value from drugs that reduce wave reflection is likely. The further benefit comes from reduction in late systolic pressure since this can partially offset the major defect in this condition, which is slow relaxation of the ventricle in late systole and early diastole. [36,37] In systolic heart failure, a reduction in wave reflection has a different effect, [81] and one that is harder to measure in terms of aortic stiffening (since blood pressure is usually low but PWV remains high [20] ) or in terms of wave reflection as aortic pressure augmentation. In patients with severe systolic dysfunction from myocardial weakening, there is usually no discernible late systolic pressure wave, and the ejection duration is usually short. [20,82] Evidence of (pressure) wave reflection may be seen as a prominent diastolic wave, i.e. apparent only after the aortic valve has shut. [20,81] The apparent anomaly here is readily explained in physical terms the wave reflection is still present, but cannot be manifest as pressure during ventricular systole because the ventricle is too weak to eject against any raised pressure. [81] Wave reflection is thus seen as a reduction in ventricular ejection and aortic flow in late systole with premature closure of the aortic valve. [81] In systolic heart failure, a reduction in wave reflection is apparent as an increase in stroke

13 Arterial Aging 791 volume caused by prolonged elevation of ventricular ejection. [36,37] Drugs used to accomplish this are ACE inhibitors and ARBs, sometimes long-acting dihydropyridine CCBs such as amlodipine, nitrates and vasodilating b-blockers. Diuretics are used for their customary action of reducing the expanded extracellular fluid volume through salt and water excretion. Reducing the wave reflection is the major strategy in diseases of aging, where one wishes to decrease LV load without reducing peripheral resistance. Nitrates are ideal since they cause predominant arterial, and little arteriolar, dilation but decrease systolic pressure augmentation and increase systolic flow augmentation in central arteries. [53,83,84] Nitrates, however, are associated with problems of tolerance and poor absorption from the digestive tract. The beneficial effect of nitrate therapy may not be apparent in conventional sphygmomanometric measurement of blood pressure in the brachial artery. [56-58] 4. Non-Pharmacological Therapies Surgical relief of aortic stiffening [48] can reduce aortic systolic and pulse pressure, and so improve LV function [85] and hopefully microvascular disease in cerebral and renal arteries. This strategy is, at least in theory, more logical than using drugs to treat the degenerate thoracic aorta. [20] It is relatively simple to stiffen the thoracic aorta through the application of rigid sleeves or ferrules, [49] but it is more difficult to accomplish the opposite and make the degenerate aorta less stiff. Novel techniques under investigation entail aortic wrapping; these may first find application in wrapping of aortic aneurysms, in conjunction with coronary artery bypass surgery. It has been well documented that physical exercise improves endothelial function [86] and thereby reduces wave reflection from the periphery of the body. [87,88] Reductions in wave reflection from the trunk and lower limbs can be achieved by leg exercise as part of walking sessions, conducted for minutes per day over a 4-week period. [89,90] The benefits are additional to those of drug therapy, and should be part of the management of older adults with hypertension and cardiac failure. They should also be encouraged in the younger population as a way of delaying the ill-effects of aortic stiffening on both the heart and the large and small arterial vessels. 5. Conclusions Aging is associated with gross changes in the structure and function of the large elastic arteries, particularly the proximal ascending aorta, the arch and the descending thoracic aorta. These changes involve the large elastic lamellae, which cushion pressure and flow fluctuations so effectively in youth, and result in almost steady flow through the arterioles and capillaries throughout the body. Repetitive pulsations resulting in about 20% stretching of the elastic arteries with each heart beat lead to changes in the crystalline structure of elastin, such that it becomes brittle and breaks, with the aorta dilating as stresses are transferred to the less extendable collagen fibres. Histologically, these changes are seen in the aorta of all older humans, but their implications have been understated when gauged by changes in brachial cuff pressures. Stiffening of the aorta leads to generation of higher pressure in early systole at the peak of flow, but also to early return of wave reflection from peripheral arterioles. This causes augmentation of pressure in late systole a finding that was recognized 100 years ago from the pulse at the wrist as a sign of aging. Stiffening of the thoracic aorta with age increases aortic systolic and LV pressure, resulting in LV hypertrophy and increased oxygen demands, predisposing to LV failure, and the decrease in aortic pressure throughout diastole lowers coronary perfusion pressure, predisposing to myocardial ischaemia. Greater aortic pulse pressure predisposes to atherosclerosis in major arteries. Inability of the aorta to cushion pulsations generated by the LV results in these pulsations extending into the fragile microvessels in the brain and kidneys, causing endothelial damage with thrombosis and medial damage with micro-haemorrhage, such

14 792 O Rourke et al. as that previously seen acutely in the malignant phase of hypertension. These abnormalities in aortic structure and function reveal more logical ways of treating the ill-effects of aging on the vascular system. Such effects are incompletely characterized by the label of ISH. The changes in the aorta are degenerate and permanent and do not present a target for medical treatment. The stiffened aorta is, however, more distensible when arterial pressure is lowered by any treatment but this effect is minor. Surgical therapies are possible but have not yet been tackled. The most logical treatment is to target the muscular arteries that comprise the bulk of the arterial tree. These arteries dilate with use of nitrates, ARBs, ACE inhibitors and CCBs. Such arterial dilation traps wave reflection in the small peripheral arteries and prevents this returning to the heart. The late systolic boost to pressure is markedly reduced by these drugs, but the benefit is not fully apparent from measurement of brachial pressure. The arterial pressure wave, however, shows characteristic changes, as first noted by Murrell with nitroglycerin 130 years ago. [54] These principles explain the greater benefits of new over old antihypertensive agents in reducing cardiovascular events and in slowing the progression of renal damage and dementia. Acknowledgements No sources of funding were used to assist in the preparation of this review. Michael O Rourke is the founding director of AtCor, manufacturer of Pulse Wave Analysis System. The other authors have no conflicts of interest that are directly relevant to the content of this review. References 1. Messerli FH. This day 50 years ago. N Engl J Med 1995; 332: Pickering G. High blood pressure. 2nd ed. London: J & A Churchill, Cushing H. Concerning a definite regulatory mechanism of the vaso-motor centre which controls blood pressure during cerebral compression. Bull Johns Hopkins Hosp 1901; 12: Smirk FH. High arterial pressure. Oxford: Blackwell, Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. New York: Raven Press, Byrom FB, Wilson C. A plethysmographic method for measuring systolic blood pressure in the intact rat. J Physiol 1938; 93: Byrom FB, Dodson LF. The causation of acute arterial necrosis in hypertensive disease. J Pathol Bacteriol 1948; 60: Byrom FB. The hypertensive vascular crisis: an experimental study. London: Heinemann, Kaplan NM. Clinical hypertension. 5th ed. Baltimore (MD): Williams & Wilkins, Ledingham JM. The vascular fault in hypertension: Byrom s work revisited. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. New York: Raven Press, 1995; VA Cooperative Study Group. Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202: VA Cooperative Study Group. Effects of treatment on morbidity in hypertension, II: results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: Systolic Hypertension in Elderly Program Cooperative Research Group (SHEP). Implications of the systolic hypertension in the elderly program. Hypertension 1993; 21: O Rourke MF, Kelly RP, Avolio AP, et al. Effects of arterial dilator agents on central aortic systolic pressure and on left ventricular hydraulic load. Am J Cardiol 1989; 63: Dustan HP. Isolated systolic hypertension: a long-neglected cause of cardiovascular complications. Am J Med 1989; 86: Levy D, Brink S. A change in heart. New York: Vintage Books, Franklin SS, Gustin 4th W, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. Circulation 1997; 96: Franklin SS, Khan SA, Wong ND, et al. Is pulse pressure useful in predicting risk for coronary heart disease? Circulation 1999; 100: Kannel WB, Wolf PA, McGee DL, et al. Systolic blood pressure, arterial rigidity and risk of stroke. JAMA 1981; 245: Nichols WW, O Rourke MF, Vlachopoulos C. McDonald s blood flow in arteries. 6th ed. London: Hodder Arnold, Laurent S, Cockcroft J, Van Bortel L, et al., on behalf of the European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27: Namasivayam M, McDonnell BJ, McEniery CM, et al., on behalf of the Anglo-Cardiff Collaborative Trial Study Investigators. Does wave reflection dominate age-related change in aortic blood pressure across the human life span? Hypertension 2009; 53: Salvi P, Safar ME, Labat C, et al., PARTAGE Study Investigators. Heart disease and changes in pulse wave velocity and pulse pressure amplification in the elderly over 80 years: the PARTAGE Study. J Hypertens 2010; 28: