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• W2888394889 abstract "HomeHypertensionVol. 72, No. 4Interaction Between Hypertension and Arterial Stiffness Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBInteraction Between Hypertension and Arterial StiffnessAn Expert Reappraisal Michel E. Safar, Roland Asmar, Athanase Benetos, Jacques Blacher, Pierre Boutouyrie, Patrick Lacolley, Stéphane Laurent, Gérard London, Bruno Pannier, Athanase Protogerou, Véronique Regnault and for the French Study Group on Arterial Stiffness Michel E. SafarMichel E. Safar Correspondence to Michel E. Safar, Paris Descartes University, APHP, Centre de Diagnostic et de Thérapeutique, Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75181 Paris Cedex 04, France. Email E-mail Address: [email protected] From the Diagnosis and Therapeutics Center, Hôtel-Dieu Hospital, Paris, France (M.E.S., J.B.) Search for more papers by this author , Roland AsmarRoland Asmar Foundation-Medical Research Institutes, Geneva, Switzerland/Beirut, Lebanon (R.A.) Search for more papers by this author , Athanase BenetosAthanase Benetos Department of Geriatrics, Nancy University Hospital, Université de Lorraine, Inserm U1116, DCAC, France (A.B.) Search for more papers by this author , Jacques BlacherJacques Blacher From the Diagnosis and Therapeutics Center, Hôtel-Dieu Hospital, Paris, France (M.E.S., J.B.) Search for more papers by this author , Pierre BoutouyriePierre Boutouyrie Department of Pharmacology, Assistance Publique-Hôpitaux de Paris, Georges Pompidou European Hospital; Paris-Descartes University; PARCC-Inserm U970, Paris, France (P.B., S.L.) Search for more papers by this author , Patrick LacolleyPatrick Lacolley Université de Lorraine, Inserm U1116, DCAC, Nancy, France (P.L., V.R.) Search for more papers by this author , Stéphane LaurentStéphane Laurent Department of Pharmacology, Assistance Publique-Hôpitaux de Paris, Georges Pompidou European Hospital; Paris-Descartes University; PARCC-Inserm U970, Paris, France (P.B., S.L.) Search for more papers by this author , Gérard LondonGérard London PARCC-Inserm U970, Paris, France (G.L., B.P.); Department of Nephrology, Manhès Hospital, Fleury-Mérogis, France (G.L., B.P.) Search for more papers by this author , Bruno PannierBruno Pannier PARCC-Inserm U970, Paris, France (G.L., B.P.); Department of Nephrology, Manhès Hospital, Fleury-Mérogis, France (G.L., B.P.) Search for more papers by this author , Athanase ProtogerouAthanase Protogerou Cardiovascular Prevention and Research Unit, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Greece (A.P.). Search for more papers by this author , Véronique RegnaultVéronique Regnault Université de Lorraine, Inserm U1116, DCAC, Nancy, France (P.L., V.R.) Search for more papers by this author and for the French Study Group on Arterial Stiffness Search for more papers by this author Originally published20 Aug 2018https://doi.org/10.1161/HYPERTENSIONAHA.118.11212Hypertension. 2018;72:796–805Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 20, 2018: Ahead of Print Our current day understanding of the basic principles of hemodynamics and arterial stiffness has largely benefited from earlier seminal works of 19th-century physicists/physiologists/physicians1 and the development of noninvasive methodologies that provide accurate analysis of the pressure wave in normal and pathological conditions. The mechanical properties of large arteries are highly complex, and particularly difficult to measure, from both theoretical and technical perspectives. Arteries have marked anisotropy and nonlinear viscoelastic properties2,3 that are specific to a single arterial segment. Although it is difficult to extrapolate segmental arterial properties to the whole arterial tree, simple parameters derived from either the Windkessel model or that of arterial wave propagation have been elaborated. Safar and O’Rourke2,4 have contributed extensively to the clinical applications of these concepts, which have proven their relevance in predicting outcomes and refining therapies.The present review summarizes extensive research conducted over recent decades on the relation between hypertension and arterial stiffness. This critical analysis of major concepts has been developed by key French research groups in collaboration with numerous international research centers.Basic Concepts: Hypertension, Windkessel Model, and Aortic StiffnessIn the 1970s, research in the field of hypertension gave particular emphasis to cardiac output and particularly the extent to which it varied from the norm in patients with essential hypertension. Investigations were limited to the framework of the negative feedback loop of the Guyton model that was used to illustrate cardiac output, fluid volumes, and potentially kidney function in patients with normal or elevated blood pressure (BP).5 Although cardiac output levels were shown to be normal in the majority of hypertensive patients, it became clear that specific mechanisms—particularly to counteract the classically normal or low intravascular volume in this population—were at play to maintain effective output levels.6 Steady-state hemodynamic variables were thus defined from personal clinical adaptations of the Guyton model.7 We observed that, in the same way as hypertension and regardless of BP levels, arterial stiffening (demonstrated by reduced compliance and distensibility) emerged as another distinctive feature of cardiovascular risk, which was invariably observed concurrently with endothelial dysfunction.8The Windkessel model provides accurate assessment of the extent to which large arteries instantly adjust to the volume of blood ejected from the ventricles, store part of the stroke volume during each systole, and drain this volume during diastole, to maintain adequate cardiac output and continuous perfusion of peripheral organs and tissues.6,9Whereas the Windkessel model is a nonpropagative representation of arterial circulation, the Moens-Korteweg equation described both propagation and velocity. Given that pulse waves travel faster in stiffer arteries, it was suggested in 1987 that pulse wave velocity (PWV) would provide more reliable insight into arterial stiffness than the Windkessel model.10 PWV was measured in longitudinal portions of large arteries, typically between the carotid and femoral arteries, and considered almost rectilinear. Elevated PWV together with increased pulsatile diameter were identified as standard features of hypertension.11,12 Carotid-femoral PWV (cf-PWV) soon emerged as the gold standard for assessing aortic stiffness and one of the most valuable independent predictors of cardiovascular events.6,13,14Arterial stiffness increases progressively from the heart to the periphery. This, together with the tapering of the aortic diameter (impedance mismatch), induces wave reflections. Figure 1 describes the mechanisms through which impedance mismatch generates reflection of the pressure wave and protects small arteries from excessive pulsatility, and how this phenomenon is lost in hypertension.15 Clinical trials have demonstrated that young healthy individuals have lower central (carotid) than peripheral (brachial) systolic BP (SBP), whereas mean arterial pressure and diastolic BP (DBP) are relatively constant throughout the arterial tree.16 This hemodynamic characteristic is called pulse pressure (PP) amplification, though it actually refers to a pressure waveform distortion rather than an amplification, the latter erroneously implying an energy input into the system. PP amplification rapidly became a means to evaluate the aortic stiffness gradient, which, when it disappears, is an independent predictor of cardiovascular events that is quite distinct from aortic stiffening.16 These observations also confirmed the preservation of the Windkessel effect (Figure 1)15 in subjects with hypertension.Download figureDownload PowerPointFigure 1. Impedance mismatch and wave pressure reflection. In normotension (NT), the proximal aorta is more distensible than the distal aorta, thus leading to an arterial stiffness gradient (aortic pulse wave velocity (PWV) < distal aorta PWV). This gradient is equivalent to an impedance mismatch, generating wave reflections. Partial reflections occur upstream, at a distance from the microcirculation, and return at low PWV to the aorta during diastole. Because the reflected wave arrives late in systole, there is little superposition of reflected waves to incident waves, and systolic blood pressure (SBP) is not increased. Central-to-peripheral amplification is maintained. Partial reflections limit the transmission of pulsatile pressure energy to the periphery and protect the microcirculation. With the disappearance or inversion of the stiffness gradient (aortic PWV > peripheral PWV, less impedance mismatch), pulsatile pressure is insufficiently dampened and is transmitted, thus damaging the microcirculation. Less pressure waves are reflected, and although they travel backward at high velocity because of the elevated arterial stiffness, they arrive at the central aorta in early systole and are superimposed on the incident pressure wave, a phenomenon which increases SBP. In black, hypertension (HT); in grey, NT. Tapering of the aortic diameter is illustrated. The dotted lines schematically separate the segments of the arterial tree into proximal elastic aorta, distal less elastic aorta, resistance arteries, and microcirculatory network.Figure 1 shows how aortic PWV is lower than peripheral PWV; BP levels change abruptly between resistance arteries and the microcirculatory network, thus protecting the microcirculation.15 A model of elevated BP (hypertensive disease) illustrates the hypothesis whereby arteriolar modifications of the endothelium, of vascular smooth muscle (VSM), or both, operate as an adaptive mechanism to maintain low levels of capillary pressure, irrespective of BP levels.15,17 Proximal aortic PWV increases up to—and sometimes beyond—the level of aortic distal PWV, reducing or reversing the physiological stiffness gradient. This reduces proximal reflections and consequently, pulsatile pressure is inadequately dampened as it reaches the smaller arteries, causing hyperpulsatility and potential damage to the microcirculation.In elderly patients, and women in particular,18 these changes in the mechanical properties of vessels promote PP augmentation because of early arrival of pressure wave reflections and excessive PP transmission to the small vasculature, both triggering cardiovascular complications.2,17–20 Three parameters are largely preserved in subjects with hypertension, irrespective of sex: cardiac output level, low capillary pressure, and the Windkessel effect.Hypertension, Arterial Stiffness, and VSM CellsThe rationale for assessing aortic stiffness in clinical hypertension is based on 2 primary observations.21–23 First, there is no intrinsic stiffening of large arteries as assessed by distensibility-pressure curves or elastic modulus-wall stress curves in patients with essential hypertension.22,23 Second, for a given level of BP or circumferential wall stress, arterial wall hypertrophy typically occurs in the presence of normal arterial stiffness. Recent basic research has clearly established the role of VSM cells (VSMC) in arterial stiffness.24–26Glagov published his seminal work on the structural changes of the aorta in response to high BP in the early 1960s,27 and by the end of the 1980s, clinical measurements of arterial stiffness were relatively commonplace.6 Much later, abolition of VSM tone (by potassium cyanide poisoning) was seen to increase the elasticity of the rat carotid artery, thus highlighting the major role of VSMC.8 Animal studies showed that loss of vascular endothelium is correlated with increased carotid artery diameter and distensibility, both of which are less prominent in spontaneously hypertensive than in normotensive rats. Thus, in the presence of endothelial cells, powerful constrictive mechanisms were likely at play to maintain arterial properties through their equilibrium with nitric oxide bioactivity.8Research into cellular and molecular determinants of arterial stiffness has recently expanded the classical view attributing arterial stiffening to components of extracellular matrix (ECM; mainly elastin and collagen) to proteins regulating VSMC contractility and cell-ECM interactions, all now linked at focal adhesions (FA; Figure 2).25 The emerging concept of VSMC stiffness established their role in controlling arterial stiffness, which involves dynamic actin/myosin interactions with G-protein and the subsequent signaling pathways.28 VSMC plasticity is controlled by numerous growth factors and transcriptional pathways. Dedifferentiation to synthetic and proliferative states leads to ECM accumulation or hypertrophy of the vascular wall, which may directly affect arterial stiffness. The pivotal role of VSMC plasticity is exemplified in arterial calcification where a shift from a contractile to a secretory phenotype mediates a process similar to that of bone formation (see below).Download figureDownload PowerPointFigure 2. Vascular smooth muscle cell (VSMC) mechanotransduction in hypertension. In response to mechanical stimuli, the increase in extracellular matrix (ECM) stiffness promotes integrin activation and recruitment of talin leading to the formation of focal adhesion (FA) complexes. The talin-to-vinculin binding reinforces the actin-talin linkage and forms catch bonds. This process increases actin polymerization and cell migration. Activation of GPCRs (G-protein–coupled receptors) via RhoA-ROCK (ras homolog family member A/Rho-associated protein kinase) pathways results in cell contraction. PDGF (platelet-derived growth factor) and the SRF (serum response factor)/myocardin axis regulate specific genes encoding contractile proteins. PDGF also triggers VSMC proliferation and autophagy. FA activation and increased dynamic actomyosin interactions regulate VSMC stiffness. Hypertension-induced changes in these different signaling pathways (boxes) are highlighted at the level of elastic (EA) and muscular (MA) arteries. At the structural level, ECM, the number of musculo-elastic complexes and the elastic potential of the arterial wall are greater in EA than in MA, whereas vascular tone and density of VSMCs are greater in MA. Ang II indicates angiotensin II; CArG, CC(A/T)6GG; Elk-1, ETS-like transcription factor-1; and KLF4, Krüppel-like factor 4.FA are a dynamic process involving adhesion proteins, fibronectin, integrins, and the intracellular talin and vinculin linked to F-actin filaments (Figure 2).26 Proteins within FA undergo conformational changes that mediate cellular mechanotransduction. On a rigid ECM, the reinforcement of FA because of vinculin binding to talin constitutes a catch bond leading to a long FA lifetime. The current hypothesis is that catch bond formation plays a major role in arterial stiffening. To further investigate the relation between FA-size and the arterial stiffness gradient, Dinardo et al29 showed that VSMC from the thoracic aorta exhibit smaller FA than cells from the femoral artery.FA are linked to G-protein–related VSMC contractility.25 FA complexes are physically linked to the nucleus via interactions of the cytoskeleton with the nuclear matrix, in a process called nuclear mechanotransduction. Tension forces from ECM are transmitted to the nucleus via the link complex and the lamina scaffold and affect gene expression. This balances both extracellular and intracellular forces.30The assumption that FA site numbers increase the stiffness of wall components is substantiated by the spontaneously hypertensive rat model in which fibronectin- and α5β1 integrin-expression is greater in the media.31At the cellular level in spontaneously hypertensive rat, increased stiffness is only observed in elastic arteries and not in muscular arteries.32 The specific contribution of VSMC to arterial stiffening and modulation has yet to be elucidated in light of FA activation coupled with G-protein–regulated contractility.33End-Stage Renal Disease, Premature Aging, and Arterial CalcificationsYoung patients with end-stage renal disease (ESRD)—who rapidly develop significant arterial calcifications—were among the first hypertensive individuals to undergo extensive clinical investigations.Characteristic Features of ESRD PatientsPremature arterial aging is a characteristic feature of patients with ESRD and is typically associated with marked arterial stiffening (Figure 3) and a notable increase in the diameter of the terminal abdominal aorta. Variations in cf-PWV can be detected before the onset of overt cardiovascular disease. Aortic PWV is an independent predictor of all-cause and cardiovascular mortality in patients with ESRD, as well as in those with chronic kidney disease and hypertension, and as such, differs markedly from the minor changes in PWV that are observed in patients with mild-to-moderate hypertension (see above). Extreme increases in aortic stiffness lead to notable reductions in the stiffness gradient and aortic taper.34,35 Aortic stiffening causes early return of reflected waves, elevates aortic SBP and PP, reduces coronary perfusion pressure, the arterial stiffness gradient and the reflective properties of the arterial tree, and exposes small arteries to greater wave transmission toward the periphery, with subsequent damage to these vessels (Figure 1).35 Certain BP-lowering drugs, such as angiotensin-converting enzyme inhibitors that attenuate aortic stiffness, exert favorable effects and improve survival in ESRD.35 Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers also slow the progression of aortic stiffening in hypertensive patients with chronic kidney disease stages 2 to 5. However, neither of these drugs prevents the carotid artery remodeling and dilation that are associated with cardiovascular events.35 Variations in aortic geometry can reveal microvascular dysfunction and are reliable predictors of all-cause and cardiovascular mortality.13 Future investigations should provide clearer insight into the effects of different pharmacological agents in patients on hemodialysis and after renal transplantation.36 Indeed, Karras et al37 demonstrated that kidney transplantation was associated with reversal of aortic stiffening and normalization of carotid remodeling.Download figureDownload PowerPointFigure 3. Age-associated arterial stiffness in end-stage renal disease (ESRD). Correlations between age and (A) aortic PWV, (B) brachial PWV, and (C) brachial/aortic stiffness gradient in controls (red) and patients with ESRD (blue). Adapted from London et al35 with permission. Copyright © 2016, the American Society of Nephrology.Arterial Calcifications in ESRDOne distinctive feature of vascular damage in ESRD is the presence of arterial calcification—representing the process of repair and the formation of scar tissue—that is correlated with cardiovascular morbidity and mortality.38 Numerous experimental studies have highlighted similarities between bone development and the process of arterial calcification,39–41 which involves VSMC phenotype differentiation into osteoblast-like cells (with subsequent mineralization), and is induced and regulated by the equilibrium between factors that promote and factors such as fetuin-A, matrix Gla protein, and osteoprotegerin that inhibit calcification. Clinical data indicate that VSMC phenotype differentiation is influenced by several factors, such as inflammation, dyslipidemia, oxidative stress, estrogen deficiency, vitamin D and K deficiencies, hypercalcemia and hyperphosphatemia, characterized by the activation of Cbfa1/Runx2-factors that are essential for osteoblastogenesis of mesenchymal cells. Calcification develops in 2 stages: first, activation of macrophages, and second, inflammation and calcification.39 Arterial calcification develops in the intima and medial layers of large and medium-sized vessel walls, often concurrently at both sites. Calcification of the intima progresses with the evolution of atherosclerotic plaque. The diffuse mineral deposits in the arterial tunica media that characterize media calcification (Mönckeberg’s sclerosis) are frequently observed in the elderly but are more distinct in patients with metabolic disorders, such as metabolic syndrome, diabetes mellitus, or ESRD. Management of patients with evidence of arterial calcifications focuses mainly on prevention, or stabilization of existing calcifications, because regression is unlikely. Because intimal calcification is related to atherosclerosis, the usual treatment approach is nonspecific as in patients with atherosclerosis. Management of ESRD patients includes controlling serum calcium and phosphate levels, thereby avoiding oversuppression of parathyroid activity.Age-Related Changes in Arterial Stiffness and the BP CurveAge-Related Changes in Arterial Stiffness and the BP CurveThe prevailing characteristic of hypertension in elderly individuals is the progressive change in the BP curve, with both a higher SBP and a lower DBP.42 This is clearly shown in the DESIR (Data from an Epidemiologic Study on the Insulin Resistance Syndrome) study of 4293 nondiabetic and type 2 diabetic volunteers (age, 30–65 years).42 Mean annual SBP levels increased significantly with age and were higher in men than in women. Initially, changes in both DBP and SBP were the same, irrespective of sex, and reaching peak levels around the age of 45. Subsequently though, annual changes in DBP were less notable and were even significantly negative in individuals >60 years. Mean PP level increased markedly with age and was a significant predictor of cardiovascular risk,42 as was further PP amplification.43Because increased PP per se can be influenced by the extent of heart failure, aortic stiffening was recognized as a more appropriate marker of vascular damage than PP measurements.44 Increased aortic stiffness can be associated with decreased DBP; coronary ischemia and excessive DBP-lowering are therefore likely consequences, with cardiovascular accidents as a potential outcome.45 Furthermore, noninvasive assessment of cf-PWV has shown aortic stiffening to be consistently higher in patients with both hypertension and type 2 diabetes mellitus than in nondiabetic hypertensive subjects, for the same BP level (Figure 4).46,47 Arterial stiffening can therefore be positively correlated to overall and long-term cardiovascular risk, but also to the duration of diabetes mellitus in patients with concomitant hypertension and type 2 diabetes mellitus. In addition, age-induced increases in PWV favor the development of arterial calcifications and adhesive molecules in these patients.9,48,49 Arterial stiffness is related to age, heart rate, and mean arterial pressure, and in hypertensive diabetic subjects, to diabetes mellitus duration and insulin treatment, a finding that is of major importance.46,49Download figureDownload PowerPointFigure 4. Reference values for pulse wave velocity according to age and cardiovascular risk factors. Mean values are presented for each age decade according to the presence of diabetes mellitus (1032 subjects) or the number of cardiovascular risk factors (sex, dyslipidemia, and current smoking): no risk factors (2207 subjects), males (1080 subjects), dyslipidemia (6251 subjects), and current smokers (444 subjects). Threshold values for dyslipidemia were defined in the 2007 European Society of Cardiology/European Society of Hypertension guidelines (total cholesterol >5.0 mmol/L, HDL [high-density lipoprotein]-cholesterol <1.0 mmol/L for men and <1.2 mmol/L for women, LDL [low-density lipoprotein]-cholesterol >3.0 mmol/L or triglycerides >1.7 mmol/L). Adapted from the Reference Values for Arterial Stiffness’ Collaboration47 with permission. Copyright © 2010, the European Society of Cardiology.Although the impact of metabolic disorders on arterial stiffness is widely acknowledged, the role of high waist circumference remains questionable, particularly when arterial stiffness is assessed using the cardio-ankle vascular index.50,51 Recent studies have shown lower arterial stiffness values in subjects with increased waist circumference.BP and Arterial Stiffness in Elderly SubjectsThe majority of evidence relating to the risks of high BP and the benefits of BP-lowering is derived by extrapolating data from younger populations and more recent studies such as HYVET (Hypertension in the Very Elderly)52 and SPRINT (Systolic Blood Pressure Intervention Trial).53Interestingly, post hoc analysis of the HYVET trial found no relationships between the benefits of antihypertensive treatment and patient frailty.54 More recently, SPRINT53 showed that even in subjects ≥75 years, cardiovascular disease outcomes and total mortality were reduced with intensive treatment as compared with standard therapeutic strategies. However, both HYVET and SPRINT excluded the frailest subjects such as those with clinically significant cognitive decline, dementia, and other comorbidities.55 Nevertheless, in people with major frailty and loss of autonomy, the relationship between BP (both SBP and DBP) and cardiovascular events was absent or even negative.56 More recent studies showed that this negative relationship was mainly observed in individuals receiving BP-lowering drugs and was highly suggestive of reversed causality.57–59Interestingly, in these very old, frail individuals, arterial stiffness remains a determinant of cognitive decline, morbidity, and mortality.43,60 The impact of SBP levels and arterial stiffness can be very different, possibly because low SBP levels mainly reflect age-related comorbidities and conditions such as malnutrition, dehydration or frailty, whereas in relatively younger and more robust individuals, low SBP levels mainly reflect lower arterial stiffness and better arterial health.We can also hypothesize that people with marked frailty and polymorbidity may have impaired circulatory autoregulation, causing tissue hypoperfusion in the presence of low BP, especially when this low BP is the result of treatment with multiple antihypertensive drugs.These considerations may also at least partly explain why there is currently insufficient evidence about the benefits of BP-lowering treatment in frail, polymedicated octogenarians.61,62Interactions Between Hypertension and Arterial StiffnessArterial Stiffness as a Cause or a Consequence of HypertensionSpeculation continues as to whether arterial stiffness is a cause or a consequence of hypertension, and whether large or small arteries are damaged first (Figures 1 and 5).An insidious positive feedback loop between local mechanical and biological responses on one hand and global hemodynamic results on the other, may explain why central artery stiffening is both a cause of hypertension and one of its consequences.63 Intrinsic stiffness of the carotid artery was only seen to be elevated independently of BP in young hypertensives, and not in older patients.23 Longitudinal assessment of the temporal relationship between carotid and aortic stiffness,64 and incident hypertension, suggests that arterial stiffening is a precursor for future changes to the systolic hemodynamic load. However, in hypertension, arterial stiffness increases because of increases in distension pressure. Moreover, sustained increases in BP promote matrix synthesis causing subsequent increases in vascular thickness and structural stiffening. In addition, elevated BP increases the load of stiff components within the arterial wall, reorganizes the spatial distribution of VSMC and ECM,25 and increases arterial stiffness.Aortic stiffening may also be paralleled and possibly influenced by remodeling of small resistance arteries that are closely interdependent in sustained grade I hypertension, and likely during the early phases of prehypertension. Although it is difficult to establish a temporal relationship, the likely existence of a cross-talk (as opposed to a linear sequence) was previously suggested, whereby changes in small arteries affect the phenotype of larger arteries, and vice versa in a vicious circle.65 Damage to both small and large arteries contributes to the rise in central BP by favoring the generation of wave reflections and their propagation, respectively, as seen in hypertensive patients where both the media-to-lumen ratio of subcutaneous small resistance arteries and cf-PWV are independent determinants of central SBP. Increased resistance in small arteries elevates mean BP, and then increases arterial stiffness in the large elastic arteries which, concomitantly with more pressure wave reflections, increases central SBP and 24-hour ambulatory brachial BP variability, ultimately leading to target organ damage.65,66 The increased central BP pulsatility is, in turn, a factor of small resistance artery damage. This was initially reported in hypertensive animal models and later in hypertensive patients in whom brachial PP and more recently central SBP and PP were measured with applanation tonometry. Interestingly, the wall-to-lumen ratio of retinal arteries is significantly correlated with 24-hour SBP levels, and retinal microcirculation changes are already detectable in prehypertensive subjects.66Thus, whether hypertension causes or is caused by central arterial stiffening and whether large or small arteries are damaged first can be considered irrelevant. The main issue is that progressive aggravation is likely in both cases. The clinical comb" @default.
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• W2888394889 title "Interaction Between Hypertension and Arterial Stiffness" @default.
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