The Pressure of Aging

Abstract

Significant hemodynamic changes ensue with aging, leading to an ever-growing epidemic of hypertension. Alterations in central arterial properties play a major role in these hemodynamic changes. These alterations are characterized by an initial decline in aortic distensibility and an increase of diastolic blood pressure, followed by a sharp increase in pulse wave velocity (PWV), and an increase in pulse pressure (PP) beyond the sixth decade. However, the trajectories of PWV and PP diverge with advancing age. There is an increased prevalence of salt-sensitive hypertension with advancing age that is, in part, mediated by marinobufagenin, an endogenous sodium pump ligand.

Keywords: Age-dependent salt-sensitive hypertension; Aging; Angiotensin II; Arterial fibrosis; Arterial wall remodeling; Hemodynamics; Marinobufagenin; Pulse wave velocity.

Figure 1

Aortic strain (red) decreases sharply between the 3^rd and 5^th decade of life after which there is a sharp rise in aortic pulse wave velocity (blue) (A). Aortic strain and PWV plotted against each other showing an exponential increase in PWV with declining aortic strain with aging (B) Adapted from Redheuil A, Yu WC, Wu CO, et al. Reduced ascending aortic strain and distensibility: earliest manifestations of vascular aging in humans. Hypertension 2010;55(2):319–26; with permission.

Figure 2

Linear mixed-effects models predicted PWV and SBP values illustrating gender-specific cross-sectional differences “beginning of the splines” and the longitudinal changes (slopes of the splines) with aging (Rates of changes are illustrated in the lower panels) in men and women from the SardiNIA project. Adapted from Scuteri A, Morrell CH, Orru M, et al. Longitudinal perspective on the conundrum of central arterial stiffness, blood pressure, and aging. Hypertension 2014;64(6):1219–27; with permission.

Figure 3

Structures of marinobufagenin (MBG) (A) and Na/K-ATPase with binding sites for MBG (B). Interaction between RAAS and MBG in the pathogenesis of salt-sensitive hypertension (C). Adapted from Bagrov AY, Shapiro JI, Fedorova OV. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacological reviews 2009;61(1):9–38; with permission.

Figure 4

Effect of low and normal dietary salt intake on urinary MBG excretion (A), aortic pulse-wave velocity (PWV) (B), and correlation between urinary MBG and PWV (C) in older patients Adapted from Jablonski KL, Fedorova OV, Racine ML, et al. Dietary sodium restriction and association with urinary marinobufagenin, blood pressure, and aortic stiffness. Clin J Am Soc Nephrol 2013;8(11):1952–9; with permission.

Figure 5

Factors implicated in the modulation of cGMP-dependent phosphorylation / dephosphorylation of renal and vascular Na/K-ATPase (NKA).

Figure 6

Scheme of age-associated shift of the modulation of renal and vascular effects of MBG by ANP.

Figure 7

Pathways that participate in age-associated remodeling of large arteries. Ang II initiates both inflammatory and repair processes From Lakatta EG. The reality of aging viewed from the arterial wall. Artery research 2013;7(2):73–80; with permission.

Figure 8

Age-Associated Matrix Remodeling of Central Arteries. MBG – marinobufagenin; NKA – Na/K-ATPase (MBG receptor); EGFR – epidermal growth factor receptor; MT1 – metallothionein 1; MMP – matrix metalloprotease; TIMP – metalloprotease inhibitor; TGF-b1 – transforming growth factor beta 1; OPN – osteoponin; ON – osteonectine; ALP – alkaline phosphatase; MGP – matrix Gla protein. Numerous other molecules, not shown on that diagram, have important role in fibrosis, calcification and elastin fragmentation.