Early vascular modifications in hypertension: pathophysiological considerations






Gary F. MITCHELL, MD
Cardiovascular Engineering
Inc., Norwood, MA, USA

Early vascular modifications in hypertension: pathophysiological considerations


by G. F. Mitchell, USA



Over the past half century, hypertension research has been dominated by a steady-flow hemodynamic model that posited a primary abnormality in resistance vessel structure and function as the key element in the pathogenesis of hypertension. Accordingly, drugs used to treat hypertension were designed and approved based on their ability to reduce peripheral vascular resistance or cardiac output, resulting in a reduction in mean arterial pressure. Large artery stiffness was found to be abnormal in hypertension, but the abnormalities were thought to be secondary to elevation of mean arterial pressure, resulting in excessive wear and tear and accelerated aging. Recent studies have demonstrated that abnormalities in aortic stiffness precede and contribute to the pathogenesis of hypertension, particularly wide pulse pressure hypertension, which is highly prevalent and difficult to control. Increased aortic stiffness and excessive pressure and flow pulsatility also play a major role in target organ damage. A greater awareness of the contribution of aortic stiffness to the pathogenesis of hypertension will facilitate efficient use of existing drugs and rational design of new agents that target primary abnormalities in aortic structure and function

Medicographia. 2015;37:373-379 (see French abstract on page 379)



Although hypertension is a prototypical complex disease with multiple potential contributors to pathogenesis, vascular structure and function obviously play a major role. Hemodynamic research and drug discovery in hypertension has traditionally focused on microvascular structure and function and on the contributions of peripheral vascular resistance and cardiac output to development of hypertension through elevation of mean arterial pressure. Accordingly, all drugs currently used to treat hypertension were developed and approved based on their ability to reduce mean arterial pressure.

Despite the traditional focus on small vessels as a primary driver of pathogenesis of hypertension, pioneering work some four decades ago by Safar and colleagues in France demonstrated that large artery stiffness is abnormal in patients with hypertension.1 However, at that time, aortic stiffness was largely considered a consequence rather than a cause of hypertension, and was thought to represent “accelerated aging” of the aorta because of exaggerated hemodynamic stress in the presence of increased mean arterial pressure. Recent evidence suggests that aortic stiffness may precede and actively contribute to the pathogenesis of hypertension and may contribute substantially to our inability to control systolic blood pressure, particularly after midlife, when wide pulse pressure hypertension is overwhelmingly predominant. Additionally, target organ damage and risk for adverse outcomes may be related more strongly to pressure pulsatility than to mean arterial pressure. The dissociation between available drugs that target mean arterial pressure and pathophysiology that includes a substantial contribution from pulse pressure contributes to treatment failures and adverse events and suggests that a new approach to drug design and treatment algorithms is needed.

Epidemiology of hypertension in the modern era

The distribution of hypertension subtypes has undergone complex shifts over the past several decades. For example, in the Multiple Risk Factor Intervention Trial (MRFIT) screening cohort recruited from 1973 through to 1975, the overall prevalence of hypertension was 35% and comprised 11% isolated diastolic, 16% mixed systolic and diastolic, and only 8% isolated systolic hypertension (ISH).2 In contrast, recent surveys have demonstrated a predominance of wide pulse pressure hypertension. ISH is by far the predominant subtype of hypertension among individuals on treatment with uncontrolled blood pressure.3 As age increases, hypertension becomes markedly more prevalent, the proportion of cases with ISH increases, and, unfortunately, the proportion of treated patients whose blood pressure is controlled to target falls.4 Failure to control blood pressure largely represents failure to control pulse pressure.

At the opposite end of the age spectrum, Zachariah et al found that development of obesity was associated with a marked increase in pulse pressure in children.5 McEniery et al found that ISH (8%) was twice as prevalent as diastolic hypertension (4%) in young adults (17 to 27 years of age).6 Grebla et al found that the prevalence of ISH in young adults has increased and that obesity was associated with higher odds of ISH in young adults.6,7 Wide pulse pressure in children may reflect a limited ability of the aorta to remodel in response to the increase in hemodynamic demand associated with obesity. The combination of aortic remodeling—in response to a substantial increase in cardiac output that accompanies obesity—and ongoing remodeling stress—associated with somatic growth— may transiently overwhelm the ability of the aorta to remodel, resulting in a mismatch between aortic diameter and flow and wide pulse pressure. Alternatively, obesity may have direct adverse effects on properties of the aortic wall.





Elastic lamellae in the aorta develop at an early age and must then remodel throughout the remainder of life. Remodeling of this fixed pool of elastin to a larger diameter necessarily increases stress on the elastic fibers, resulting in increased strain. Higher strain leads to engagement of additional collagen fibers that are normally loosely woven into the structure of the aortic wall. Since collagen is several orders of magnitude stiffer than elastin, aortic wall stiffness necessarily increases as collagen is engaged. The long-term consequences of a population wide increase in pulse pressure in children and young adults is unknown and gives cause for concern, particularly in light of our limited ability to control systolic blood pressure in older adults.

A brief overview of arterial stiffness measures

The term “arterial stiffness” is imprecise, and putative measures of “stiffness” are often misinterpreted. The present gold standard measure of aortic wall stiffness is carotid-femoral pulse wave velocity (CFPWV), which is assessed by performing tonometry of the carotid and femoral arteries in order to measure the transit time between the two sites. CFPWV is then simply transit distance divided by transit time. CFPWV is readily measured in a clinical setting with modest equipment and expertise and is easily interpreted: higher CFPWV is associated with higher risk for target organ damage and adverse clinical events, including incident hypertension. An extensive body of evidence and two recent meta-analyses have demonstrated strong, consistent, graded relations between CFPWV and risk for adverse outcomes, particularly in younger adults.8,9 Importantly, several studies have provided evidence that CFPWV may be amenable to treatment.10-17

An alternative measure of aortic “stiffness” is achieved by examining relations between pulsatile pressure and flow in the proximal aorta. Analysis of pressure and flow allows for calculation of aortic characteristic impedance (Zc), which is a measure of the pulsatile pressure produced by a given pulsatile flow in the proximal aorta in early systole, prior to arrival of reflected waves from the periphery. Aortic inflow during systole interacts with Zc to produce a forward traveling pressure wave (Pf) that accounts for most of the variance in pulse pressure across the full adult lifespan.18 Measurement of central aortic pressure and flow provides a comprehensive assessment of vascular load. However, the test is more difficult than measuring CFPWV alone and requires limited echocardiography and hence a specialized setting and equipment. Zc and Pf were recently shown to predict events in models that consider standard risk factors, including CFPWV, in the Framingham Offspring cohort.19 There is evidence that Zc and Pf are amenable to treatment.20-22

Various measures of wave reflection have been proposed. Augmentation index (AI) is a widely cited, pressure-only measure of relative wave reflection that is often presented as a measure of aortic stiffness.


Figure 1
Figure 1. Wave separation analysis.

When pressure and flow are both measured, forward (Pf) and reflected or backward (Pb) waves can be separated and assessed. The two cases shown in this figure have similar Pf and Pb amplitude and similar arrival time of the reflected wave. Yet the case on the left has no augmentation, whereas the case on the right has a substantial late systolic augmented pressure (AP), resulting in high augmentation index (AI = AP/PP [pulse pressure] = 22%). Markedly greater augmentation on the right is attributable to differences in the shape of Pf and Pb, rather than timing and amplitude of Pb. The case on the right has prolonged ejection, with a Pf peak in late systole (straight arrow) as well as a steeper Pb upstroke (curved arrow). Overlap of the prolonged Pf with the steeper upstroke of Pb produces marked pressure augmentation. A pressure-only analysis would predict markedly greater wave reflection in the case on the right, which is incorrect.



However, relations between AI and aortic stiffness are complex and, as a result, AI should not be considered a measure of aortic stiffness.23-25 Because wave reflection can either augment pressure or decelerate flow, one must measure pressure and flow in order to assess wave reflection accurately (Figure 1). For example, a failing heart will produce minimal pressure augmentation, whereas a concentrically hypertrophied heart will produce marked pressure augmentation for the same reflected wave. When pressure and flow are both known, it is possible to use wave separation analysis to assess the amplitudes of Pf and the reflected or backward wave (Pb).26 However, when interpreting Pb, it is important to acknowledge that the strongest determinant of Pb is Pf. Therefore, changes in Pb must be interpreted in the context of the associated Pf that gave rise to the reflected component. This is readily achieved by computing the reflection coefficient (RC = Pb/ Pf). RC and Pb are reduced markedly by vasodilator drugs or nitrates.27 However, as noted below, the clinical implications of a pharmacologic reduction in wave reflection remain to be determined.

Much has been written regarding the relative merits of central as compared to peripheral systolic and pulse pressure as the best measure to predict risk and monitor therapy. While some studies have shown a slightly stronger relation between central pressures and measures of target organ damage, the incremental value of central pressure remains unclear.28 However, conventionally assessed brachial pulse pressure together with CFPWV provides a complementary and powerful combination for assessing abnormalities in aortic structure and function.

Hemodynamic correlates of rising pulse pressure with advancing age

The substantial burden of disease associated with ISH provides an imperative to better understand factors that are associated with wide pulse pressure hypertension. A number of investigators have insisted that higher pulse pressure is predominantly attributable to premature return of Pb and higher AI.29 In the Framingham Heart Study cohort, AI increased markedly between 20 and 50 years of age.18 However, pulse pressure actually fell during this interval (Figure 2, page 376), as has been shown in other cohorts.30 After midlife, a marked increase in pulse pressure was paralleled by a similar increase in Pf, whereas AI fell. In the Framingham study, approximately 90% of the variance in central and peripheral pulse pressure was attributable to variability in Pf, with most of the remaining 10% of variance associated with the RC. Timing of wave reflection played a minor role. These basic observations suggest that premature wave reflection plays a minor role in age-related widening of pulse pressure.

The falls in pulse pressure, Pf, and Zc between 20 and 50 years of age contrasts with an accompanying increase in CFPWV during the same period (Figure 2).18,30 Dissociation between CFPWV and Zc has been attributed to alterations in aortic diameter.31 CFPWV and Zc are both directly related to wall stiffness and inversely related to diameter. However, Zc is much (5x) more sensitive to diameter. If stiffening of the aorta is associated with an increase in lumen diameter, Zc can fall even as CFPWV increases. In contrast, a combination of stiffening and a reduction in diameter will result in a disproportionate increase in Zc. A resulting mismatch between aortic diameter and flow gives rise to higher Pf and pulse pressure.32 In the Enigma cohort, ISH was associated with a 50% higher pulse pressure, which was attributed in part to a 12% higher stroke volume and 8% higher CFPWV, whereas AI was actually lower in the ISH group as compared to the normotensive group. The gap between 50% higher pulse pressure versus a combined 20% higher stroke volume and CFPWV suggests a contribution from abnormal Zc beyond the effect that was attributable to wall stiffness per se (as assessed by CFPWV), again suggesting that aortic geometry contributed to differences in pulse pressure. Because of potential dissociation between CFPWV and Zc (or pulse pressure), these measures provide complementary information regarding aortic structure and function, as noted earlier.


Figure 2
Figure 2. Pulsatile hemodynamics across the human lifespan in Framingham
Heart Study participants.

In these cross-sectional observations, pulse pressure (PP) falls modestly between young adulthood
and midlife and rises rapidly thereafter (panel A). In contrast, augmentation index (AI)
increases rapidly prior to midlife and falls thereafter, suggesting that pressure augmentation is
not the main explanation for rising pulse pressure with advancing age after midlife (panel B).
The age relations of pulse pressure are closely paralleled by characteristic impedance computed
in the time domain (ZcTD) (panel C) and forward wave amplitude (Pf). In contrast to PP,
Pf, and ZcTD, carotid-femoral pulse wave velocity (CFPWV) increases monotonically with age;
thus, the age-related increase in CFPWV appears to precede the increase in PP in cross-sectional
analyses. Data are from reference 18.



Aortic remodeling is a lifelong process.33 In children, the combination of somatic growth and obesity may overwhelm the ability of the aorta to remodel, resulting in higher pulse pressure.5 Similarly, in the oldest of old, the balance between wall stiffness, lumen diameter, and ambient flow in the proximal aorta determines pulse pressure.32,34 Whether stiffening stimulates remodeling or remodeling increases stiffness is debatable. However, evidence suggests that attenuated aortic remodeling is associated with wider pulse pressure at any given level of stiffness.

Crosstalk between aortic stiffness, pressure and flow pulsatility, and microvascular structure and function

Several lines of evidence suggest that increased aortic stiffness and excessive pressure and flow pulsatility are associated with adverse effects on microvascular structure and function. In the forearm, resting resistance is higher and reactive hyperemia in response to ischemia is markedly lower in the presence of higher aortic stiffness.35 Excessive pressure and flow pulsatility are associated with higher resting tone, remodeling, and vessel loss in the microcirculation, which increases peripheral vascular resistance and may drive up mean arterial pressure.36

Wave reflection in the arterial system is often portrayed as harmful. Indeed, excessive wave reflection may augment systolic pressure and increase load on the left ventricle during late systole. However, wave reflection at the interface between aorta and muscular arteries limits penetration of pulsatility into the downstream microcirculation of various vascular beds.37 High local resistance in precapillary arterioles of some vascular beds produces additional wave reflection that further limits the penetration of potentially harmful pulsatile energy into the microcirculation. The brain and kidneys, however, have limited distal protection from excessive pulsatility because they are obligate high-flow, low-impedance organs. A greater proportion of pulsatile power penetrates into the microcirculation in low impedance vascular beds. When the aorta stiffens, impedance mismatch at the interface with stiff muscular arteries is diminished and proximal wave reflection at this interface is diminished. As a result of increased transmission of pulsatile power into the periphery, the microcirculation may be dam- aged, resulting in microvascular lesions in surrounding tissue and reduced function in brain and kidneys.37,38 Pharmacologic manipulation of peripheral resistance by vasodilator drugs, particularly in patients with ISH who may have little or no abnormality in mean arterial pressure, may unnecessarily expose the microcirculation to additional pulsatile stress and damage. Vasodilator therapy should be avoided in such patients, particularly if mean arterial pressure and diastolic pressure are already normal or low.

Early vascular remodeling in hypertension

Recent evidence has refocused the debate regarding the role of the aorta as passive victim or active contributor in the pathogenesis of hypertension. Prospective findings in the middle- aged and older Framingham Offspring cohort demonstrated that higher CFPWV at baseline was associated with increased risk for blood pressure progression and incident hypertension during 7 years of follow-up.39 In contrast, once baseline CFPWV was considered in a multivariable model, no blood pressure measure was associated with progression of aortic stiffness. These analyses indicate that in the age range studied, aortic stiffness antedates and contributes to the pathogenesis of hypertension. Importantly, various other measures of vascular structure and function, including forward wave amplitude, augmentation index, brachial artery flow mediated dilation, and resting forearm blood flow, were also associated with increased risk for hypertension when considered together in a single multivariable model, confirming that even among vascular traits, hypertension is a multifactorial disease, with contributions from large and small arteries and endothelial function.

Observations in an obesity model of hypertension in the mouse recapitulate many of the findings of the foregoing Framingham analysis and strengthen the concept that aortic stiffening actively contributes to the development of hypertension. When normal mice were fed a diet high in sucrose and fat, they developed obesity, insulin resistance, and increased aortic pulse wave velocity within 1 month of initiation of the diet, at a time when blood pressure remained unchanged.40 The mice subsequently developed elevated blood pressure 6 months after initiation of the diet. A high-fat diet was associated with oxidative stress, upregulation of proinflammatory mediators, and reduced bioavailability of NO in the aortic wall within 2 months. Reduced bioavailability of NO was associated with increased activity of transglutaminase 2, an NO-sensitive enzyme,41 resulting in increased cross-linking of structural proteins in the aortic wall. Importantly, when mice were reverted to a normal diet, weight returned to baseline within 2 months and was associated with a reduction in aortic pulse wave velocity and blood pressure to the normal range. The findings in this mouse model of diet-induced hypertension and vascular inflammation are highly relevant in light of the present obesity epidemic and underscore the contribution of aortic pathology to pathogenesis of hypertension. The study raises hope that dietary interventions may be effective in reversing a component of the aortic pathology observed in obese patients, as has been demonstrated in clinical studies.10,12,13

Additional work in animal models and humans has underscored the potential contribution of inflammation to aortic stiffening and development of hypertension. CFPWV is associated with levels of various proinflammatory markers, including C-reactive protein and interleukin 6.42-45 In addition, treatment with anti-inflammatory drugs reduces inflammation and CFPWV.46,47 In a mouse model of vascular inflammation and hypertension induced by chronic infusion of low doses of angiotensin II, development of aortic stiffening and hypertension can be prevented by knocking out the adaptive immune system.48 Adoptive transfer of T cells restores sensitivity to angiotensin II–induced vascular inflammation, aortic stiffening, and hypertension, suggesting that T cell–mediated damage plays a critical role in the pathogenesis of aortic stiffening and hypertension in this model. Importantly, in the largest genome wide association study of CFPWV, the region of strongest association was in a gene desert on chromosome 14.49 The locus corresponds to the location of a gene enhancer for the BCL11B gene, the master regulator of T-cell fate, which is in volved in selection and maintenance of T-cell identity.50 However, the BCL11B gene product, COUP-TF (chicken ovalbumin upstream promoter transcription factor) interacting protein 2, is a transcription factor with many functions that might impact aortic structure and function.49


Figure 3
Figure 3. The vicious cycle of aortic
stiffening, microvascular dysfunction,
and target organ damage.

Various vascular risk factors have been identified
that may stiffen the aorta. Increased aortic stiffness
imposes pulsatile stress on the microcirculation.
The microcirculation remodels, ostensibly
to protect the capillaries from pulsatile damage.
However, microvascular remodeling and rarefaction
impairs reactivity and increases peripheral
resistance. Impaired reactivity increases susceptibility
to microvascular ischemia in target organs.
Increased peripheral resistance drives up mean
arterial pressure, resulting in additional stiffening
of the aorta. If left unopposed, this vicious cycle
culminates in clinically evident hypertension and
major clinical events.
Abbreviations: CHF, chronic heart failure; LVH,
left ventricular hypertrophy; MI, myocardial infarction.


Summary

In light of the foregoing, one can hypothesize the potential for a vicious cycle involving aortic stiffness, microvascular dysfunction, hypertension, and target organ damage (Figure 3, page 377). In the early stages of disease, risk factors may increase aortic stiffness directly by various mechanisms. Aortic stiffening increases pressure pulsatility and reduces protective wave reflection at the interface between the normally compliant aorta and stiff muscular arteries, resulting in greater transmission of potentially harmful pulsatility into the microcirculation, particularly in high-flow organs like the brain and kidneys. Microvascular remodeling in response to pulsatile stress impairs reactivity and increases susceptibility to microvascular ischemic damage.

Remodeling and loss of microvessels also increases peripheral vascular resistance, which will increase mean arterial pressure if cardiac output is maintained. The resulting increase in mean arterial pressure further stiffens the aorta and accelerates the vicious cycle. If the cycle is allowed to progress, patients will ultimately develop hypertension and various other forms of target organ damage mediated directly by aortic stiffness or indirectly through the effects of pulsatile stress on microvascular structure and function. Alternatively, if we identify aortic stiffening at an early stage and target existing or novel treatments at the root cause of the pathophysiologic cycle portrayed in Figure 3, we can potentially arrest the cycle at an early stage and prevent development of hypertension and target organ damage.

Disclosures: Dr. Mitchell is the owner of Cardiovascular Engineering, Inc., a company that develops and manufactures devices to measure vascular stiffness, and serves as a consultant to and receives honoraria from Novartis, Merck, and Servier and is funded by research grants HL094898, DK082447, HL107385, and HL104184 from the National Institutes of Health.



References
1. Simon AC, Safar ME, Levenson JA, London GM, Levy BI, Chau NP. An evaluation of large arteries compliance in man. Am J Physiol. 1979;237:H550- H554.
2. Domanski M, Mitchell G, Pfeffer M, et al. Pulse pressure and cardiovascular disease-related mortality: follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 2002;287:2677-2683.
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. Wong ND, Lopez VA, L’Italien G, Chen R, Kline SE, Franklin SS. Inadequate control of hypertension in US adults with cardiovascular disease comorbidities in 2003-2004. Arch Intern Med. 2007;167:2431-2436.
5. Zachariah JP, Graham DA, de Ferranti SD, Vasan RS, Newburger JW, Mitchell GF. Temporal trends in pulse pressure and mean arterial pressure during the rise of pediatric obesity in US children. J Am Heart Assoc. 2014;3:e000725.
6. McEniery CM, Yasmin, Wallace S, et al. Increased stroke volume and aortic stiffness contribute to isolated systolic hypertension in young adults. Hypertension. 2005;46:221-226.
7. Grebla RC, Rodriguez CJ, Borrell LN, Pickering TG. Prevalence and determinants of isolated systolic hypertension among young adults: the 1999-2004 US National Health And Nutrition Examination Survey. J Hypertens. 2010;28:15-23.
8. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318-1327.
9. Ben-Shlomo Y, Spears M, Boustred C, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol. 2014;63:636-646.
10. Dengo AL, Dennis EA, Orr JS, et al. Arterial destiffening with weight loss in overweight and obese middle-aged and older adults. Hypertension. 2010;55: 855-861.
11. Orr JS, Dengo AL, Rivero JM, Davy KP. Arterial destiffening with atorvastatin in overweight and obese middle-aged and older adults. Hypertension. 2009; 54:763-768.
12. Petersen KS, Blanch N, Keogh JB, Clifton PM. Effect of weight loss on pulse wave velocity: systematic review and meta-analysis. Arterioscler Thromb Vasc Biol. 2015;35:243-252.
13. Wildman RP, Farhat GN, Patel AS, et al. Weight change is associated with change in arterial stiffness among healthy young adults. Hypertension. 2005; 45:187-192.
14. Mitchell GF, Dunlap ME, Warnica W, et al. Long-term trandolapril treatment is associated with reduced aortic stiffness: the prevention of events with angiotensin- converting enzyme inhibition hemodynamic substudy. Hypertension. 2007;49:1271-1277.
15. Laurent S, Boutouyrie P. Dose-dependent arterial destiffening and inward remodeling after olmesartan in hypertensives with metabolic syndrome. Hypertension. 2014;64:709-716.
16. Boutouyrie P, Beaussier H, Achouba A, Laurent S. Destiffening effect of valsartan and atenolol: influence of heart rate and blood pressure. J Hypertens. 2014;32:108-114.
17. Ong KT, Delerme S, Pannier B, et al. Aortic stiffness is reduced beyond blood pressure lowering by short-term and long-term antihypertensive treatment: a meta-analysis of individual data in 294 patients. J Hypertens. 2011;29:1034- 1042.
18. Mitchell GF, Wang N, Palmisano JN, et al. Hemodynamic correlates of blood pressure across the adult age spectrum: noninvasive evaluation in the Framingham Heart Study. Circulation. 2010;122:1379-1386.
19. Cooper LL, Rong J, Benjamin EJ, et al. Components of hemodynamic load and cardiovascular events: the Framingham Heart Study. Circulation. 2015;131: 354-361.
20. 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.
21. Mitchell GF, Arnold JM, Dunlap ME, et al. Pulsatile hemodynamic effects of candesartan in patients with chronic heart failure: The CHARM Program. Eur J Heart Fail. 2006;8:191-197.
22. Satheesan S, Figarola JL, Dabbs T, Rahbar S, Ermel R. Effects of a new advanced glycation inhibitor, LR-90, on mitigating arterial stiffening and improving arterial elasticity and compliance in a diabetic rat model: aortic impedance analysis. Br J Pharmacol. 2014;171:3103-3114.
23. Vyas M, Izzo JL Jr, Lacourciere Y, et al. Augmentation index and central aortic stiffness in middle-aged to elderly individuals. Am J Hypertens. 2007;20:642-647.
24. Fok H, Guilcher A, Li Y, et al. Augmentation pressure is influenced by ventricular contractility/relaxation dynamics: novel mechanism of reduction of pulse pressure by nitrates. Hypertension. 2014;63:1050-1055.
25. Torjesen AA, Wang N, Larson MG, et al. Forward and backward wave morphology and central pressure augmentation in men and women in the Framingham Heart Study. Hypertension. 2014;64:259-265.
26. Westerhof N, Sipkema P, Van Den Bos GC, Elzinga G. Forward and backward waves in the arterial system. Cardiovasc Res. 1972;6:648-656.
27. Ting CT, Chen JW, Chang MS, Yin FC. Arterial hemodynamics in human hypertension. Effects of the calcium channel antagonist nifedipine. Hypertension. 1995;25:1326-1332.
28. Mitchell GF. Central pressure should not be used in clinical practice. Artery Res. 2015;9:8-13.
29. O’Rourke MF, Nichols WW. Aortic diameter, aortic stiffness, and wave reflection increase with age and isolated systolic hypertension. Hypertension. 2005;45: 652-658.
30. Segers P, Rietzschel ER, De Buyzere ML, et al. Noninvasive (input) impedance, pulse wave velocity, and wave reflection in healthy middle-aged men and women. Hypertension. 2007;49:1248-1255.
31. Mitchell GF, Lacourciere Y, Ouellet JP, et al. Determinants of elevated pulse pressure in middle-aged and older subjects with uncomplicated systolic hypertension: the role of proximal aortic diameter and the aortic pressure-flow relationship. Circulation. 2003;108:1592-1598.
32. Torjesen AA, Sigurdsson S, Westenberg JJ, et al. Pulse Pressure Relation to Aortic and Left Ventricular Structure in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. Hypertension. 2014;64:756-761.
33. Lam CS, Xanthakis V, Sullivan LM, et al. Aortic root remodeling over the adult life course: longitudinal data from the Framingham Heart Study. Circulation. 2010;122:884-890.
34. Mitchell GF, Gudnason V, Launer LJ, Aspelund T, Harris TB. Hemodynamics of increased pulse pressure in older women in the community-based Age, Gene/ Environment Susceptibility-Reykjavik Study. Hypertension. 2008;51:1123-1128.
35. Mitchell GF, Vita JA, Larson MG, et al. Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: the Framingham Heart Study. Circulation. 2005;112:3722-3728.
36. Mitchell GF. Effects of central arterial aging on the structure and function of the peripheral vasculature: implications for end-organ damage. J Appl Physiol. 2008;105:1652-1660.
37. Mitchell GF, van Buchem MA, Sigurdsson S, et al. Arterial stiffness, pressure and flow pulsatility and brain structure and function: the Age, Gene/Environment Susceptibility—Reykjavik study. Brain. 2011;134:3398-3407.
38. Woodard T, Sigurdsson S, Gotal JD, et al. Mediation analysis of aortic stiffness and renal microvascular function. J Am Soc Nephrol. 2015;26:1181-1187.
39. Kaess BM, Rong J, Larson MG, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012;308:875-881.
40. Weisbrod RM, Shiang T, Al Sayah L, et al. Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hypertension. 2013;62:1105-1110.
41. Santhanam L, Tuday EC, Webb AK, et al. Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness. Circ Res. 2010;107:117-125.
42. London GM, Marchais SJ, Guerin AP, Metivier F, Adda H, Pannier B. Inflammation, arteriosclerosis, and cardiovascular therapy in hemodialysis patients. Kidney Int Suppl. 2003;S88-S93.
43. Mattace-Raso FU, van der Cammen TJ, van der Meer IM, et al. C-reactive protein and arterial stiffness in older adults: the Rotterdam Study. Atherosclerosis. 2004;176:111-116.
44. Mahmud A, Feely J. Arterial stiffness is related to systemic inflammation in essential hypertension. Hypertension. 2005;46:1118-1122.
45. Schnabel R, Larson MG, Dupuis J, et al. Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection. Hypertension. 2008;51:1651-1657.
46. Maki-Petaja KM, Hall FC, Booth AD, et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by anti-tumor necrosis factor-alpha therapy. Circulation. 2006;114:1185-1192.
47. Angel K, Provan SA, Gulseth HL, Mowinckel P, Kvien TK, Atar D. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study. Hypertension. 2010;55:333-338.
48. Wu J, Thabet SR, Kirabo A, et al. Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circ Res. 2014;114:616-625.
49. Mitchell GF, Verwoert GC, Tarasov KV, et al. Common genetic variation in the 3′-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium. Circ Cardiovasc Genet. 2012;5:81-90.
50. Ikawa T, Hirose S, Masuda K, et al. An essential developmental checkpoint for production of the T cell lineage. Science. 2010;329:93-96.


Keywords: aortic stiffness; carotid-femoral pulse wave velocity; pulse pressure; characteristic impedance; microvascular target organ damage