23
From: Clinical Hypertension and Vascular Diseases: Hypertension in the Elderly Edited by: L. M. Prisant © Humana Press Inc., Totowa, NJ
3 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 empha- sizes the importance of systolic blood pressure (SBP), especially in indi- viduals 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 patho- physiology. 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.
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 indus- trialized 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 hyper- tension (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 sug- gested 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).
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.)
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) com- ponent (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 accu- rately 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 antihyper- tensive treatment reduced coronary events (23%), strokes (30%), car- diovascular 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).
PATHOPHYSIOLOGY
Why is there such a great benefit of treating systolic hypertension?
The answer becomes clearer after a review of basic cardiovascular patho- physiology. Although it is currently fashionable to describe hyperten- sion as a complex metabolic syndrome that involves insulin resistance and other derangements; in the main, hypertension remains a hemody- namic 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 steady- state flow model has been used to approximate circulatory hemodynam- ics, 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 car- diac stroke volume in younger hypertensives (16).
Pulsatility and Blood Flow
To understand the pathophysiological relevance of systolic hyperten- sion, 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 pulsa- tile 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 proxi- mal 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,
Fig. 2. Components of blood pressure (BP) and cardiac load. Various param- eters are needed to describe pulsatile phenomena. DN, dicrotic notch, the divi- sion 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 pre- mature 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 deliv- ered 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 under- stood. The elastic behavior of arteries depends primarily on the composi- tion 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-
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 fun- damental 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, con- strictions, or areas of turbulence.
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 mea- sured centrally. This contrasts with MAP, which is relatively constant throughout the arterial tree. PP amplification is the result of the progres- sive 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- Fig. 4. Components of arterial pulse waves in older and younger subjects.
Because of the property of wave reflection, any pulse wave can be decom- posed 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.)
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 hyper- tension, 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 stiff- ness 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 Fig. 5. Pulse pressure (PP) amplification and wave reflection. In normal young individuals, PP is amplified as the wave travels downstream because of a pro- gressive 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 equiva- lent to central PP. (From ref. 27.)
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).
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 constric- tion (systemic vascular resistance). Peripheral arteriolar constriction directly increases diastolic BP and mean arterial pressure, whereas central artery stiff- ness 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.)
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 pres- sure 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 augmen- tation 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 atheroscle- rosis and probably contributes to rupture of unstable atherosclerotic plaques. The distal vasculature is also affected because increased pulsa- tile 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.
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.
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 reflec- tion are of increasing interest to researchers and clinicians. Because bra- chial 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 pri- mary prevention of CVD or improved therapeutic monitoring of antihy- pertensive drugs or new compounds that directly reduce arterial stiffness.
At present, all techniques that assess arterial stiffness should be consid- ered primarily research tools not ready for immediate clinical applica- tion (23–25).
REFERENCES
1. Kannel WB, Gordon T, Schwartz MJ. Systolic vs diastolic blood pressure and risk of coronary heart disease. Am J Cardiol 1971;27:335–345.
2. Izzo JL Jr, Levy D, Black HR. Clinical advisory statement: importance of systolic blood pressure in older Americans. Hypertension 2000;35:1021–1024.
3. Franklin SS, Jacobs MJ, Wong ND, L’Italien GJ, Lapuerta P. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives:
analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension 2001;37:869–874.
4. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure—JNC VII Express. JAMA 2003;289:2560–2572.
5. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Sur- vey, 1988–1991. Hypertension 1995;25:305–313.
6. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–1913.
7. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure more important than systolic blood pressure in predicting coronary heart disease events.
Circulation 1999;100:354–360.
8. Mitchell GF, Moye LA, Braunwald E, et al. Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocar-
dial infarction in patients with impaired left ventricular function. Circulation 1997;96:4254–4260.
9. Blacher J, London GM, Safar ME, Mourad JJ. Influence of age and end-stage renal disease on the stiffness of carotid wall material in hypertension. J Hypertens 1999;17:237–244.
10. Asmar R, Rudnichi A, Blacher J, London GM, Safar ME. Pulse pressure and aortic pulse wave are markers of cardiovascular risk in hypertensive populations. Am J Hypertension 2001;14:91–97.
11. Lloyd-Jones DM. Impact of systolic vs diastolic blood pressure level of JNC-VI blood pressure stage classification. Hypertension 1999;34:381–385.
12. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older patients with isolated systolic hypertension. JAMA 1991;265:
3255–3264.
13. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.
The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757–764.
14. Staessen JA, Wang JG, Thijs L, Fagard R. Overview of the outcome trials in older patients with isolated systolic hypertension. J Hum Hypertens 1999;13:859–863.
15. Fagard RH, Staessen JA, Thijs L, et al. Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hyperten- sion in Europe (Syst-Eur) Trial Investigators. Circulation 2000;102:1139–1144.
16. Julius S, Krause L, Schork NJ, et al. Hyperkinetic borderline hypertension in Tecumseh, Michigan. J Hypertens 1991;9:77–84.
17. Asmar R. Arterial pulse waves. In: Asmar R, ed. Arterial stiffness and pulse wave velocity: clinical applications. Amsterdam: Elsevier; 1999:17–23.
18. Nichols WW, O’Rourke MF. McDonald’s blood flow in arteries: theoretical, ex- perimental and clinical principles. 4th ed. London: Arnold; 1998:220–222.
19. Wilkinson IB, Franklin SS, Hall IR, Tyrrell S, Cockcroft JR. Pressure amplification explains why pulse pressure is unrelated to risk in young subjects. Hypertension 2001;38:1461–1466.
20. Koch-Weser J. Correlation of pathophysiology and pharmacology in primary hy- pertension. Am J Cardiol 1973;32:499–499.
21. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999;33:1111–1117.
22. Mitchell GF, Izzo JL Jr, Lacourciere Y, et al. Omapatrilat reduces pulse pressure and proximal aortic stiffness in patients with systolic hypertension: results of the conduit hemodynamics of omapatrilat international research study. Circulation 2002;105: 2955–2961.
23. Izzo JL Jr, Shykoff BE. Arterial stiffness: clinical relevance, measurement, and treatment. Rev Cardiovasc Med 2001;2:29–34, 37–40.
24. Izzo JL Jr, Manning TS, Shykoff BE. Office blood pressures, arterial compliance characteristics, and estimated cardiac load. Hypertension 2001;38:1467–1470.
25. Manning TS, Shykoff BE, Izzo JL Jr. Validity and reliability of diastolic pulse contour analysis (windkessel model) in humans. Hypertension 2002;39:963–968.
26. Williams TF, Foerster JE, Proctor JK, Hahn A, Izzo AJ, Elliott GA. A new double- layered launderable bed sheet for patients with urinary incontinence. J Am Geriatr Soc 1981;29:520–527.
27. Nichols WW, et al. Arterial vasodilation. Philadelphia; 1993:32.
28. Fleg/Kelly. Hypertension primer.
