The conundrum of arterial stiffness, elevated blood pressure, and aging

Abstract

Isolated systolic hypertension is a major health burden that is expanding with the aging of our population. There is evidence that central arterial stiffness contributes to the rise in systolic blood pressure (SBP); at the same time, central arterial stiffening is accelerated in patients with increased SBP. This bidirectional relationship created a controversy in the field on whether arterial stiffness leads to hypertension or vice versa. Given the profound interdependency of arterial stiffness and blood pressure, this question seems intrinsically challenging, or probably naïve. The aorta's function of dampening the pulsatile flow generated by the left ventricle is optimal within a physiological range of distending pressure that secures the required distal flow, keeps the aorta in an optimal mechanical conformation, and minimizes cardiac work. This homeostasis is disturbed by age-associated, minute alterations in aortic hemodynamic and mechanical properties that induce short- and long-term alterations in each other. Hence, it is impossible to detect an "initial insult" at an epidemiological level. Earlier manifestations of these alterations are observed in young adulthood with a sharp decline in aortic strain and distensibility accompanied by an increase in diastolic blood pressure. Subsequently, aortic mechanical reserve is exhausted, and aortic remodeling with wall stiffening and dilatation ensue. These two phenomena affect pulse pressure in opposite directions and different magnitudes. With early remodeling, there is an increase in pulse pressure, due to the dominance of arterial wall stiffness, which in turn accelerates aortic wall stiffness and dilation. With advanced remodeling, which appears to be greater in men, the effect of diameter becomes more pronounced and partially offsets the effect of wall stiffness leading to plateauing in pulse pressure in men and slower increase in pulse pressure (PP) than that of wall stiffness in women. The complex nature of the hemodynamic changes with aging makes the "one-size-fits-all" approach suboptimal and urges for therapies that address the vascular profile that underlies a given blood pressure, rather than the blood pressure values themselves.

Figure 1. A schematic model illustrating the mechanism of TGF-β1 activation with loss of elasticity

TGF-β1 is secreted in a large latent complex, consisting of TGF-β1 associated with the latency associated peptide (LAP) and the latent TGF-β1–binding protein (LTBP-1). This structure links VSMCs to elastic fibers. In normal-functioning elastic arteries, VSCMs contraction pulls the whole compound with elastic fiber connected to it. With the loss of elasticity due to calcification, amyloidization, and other factors, the elastic fiber is less mobile and traction forces exerted by the stiffer VSMCs is transferred to LAP potentially resulting in activation of TGF-β1 and subsequent fibrosis. (Adapter from Blood Pressure and Arterial Wall Mechanics in Cardiovascular Diseases, Safar ME, O’Rourke MF, Frohlich ED, London, 2014)

Figure 2. Early age-related changes in aortic distensibility precede the changes in PWV

Aortic distensibility (triangles) decreases sharply between the 3^rd and 5^th decade of life after which there is a sharp rise in aortic pulse wave velocity (modified from Redheuil et al, Hypertension, 2010)

Figure 3. Conceptual model of arterial aging

Age-associated cellular disorders and cumulative mechanical stress lead to a state of chronic inflammation, elastin degradation, and endothelial and VSMC dysfunction. These processes interact and lead to arterial wall calcification, fibrosis, amyloid deposition, VSMCs proliferation, and increased intimal medial thickness. These structural changes lead to functional alterations resulting in widened pulse pressure. (Adapter from Blood Pressure and Arterial Wall Mechanics in Cardiovascular Diseases, Safar ME, O’Rourke MF, Frohlich ED, London, 2014)

Figure 4

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 (A) and women (B) from the SardiNIA project. (Adapted with modification from Scuteri et al, Hypertension, 2014)