Mechanisms, Pathophysiology, and Therapy of Arterial Stiffness

Abstract

Abstract-Arterial stiffness is a growing epidemic associated with increased risk of cardiovascular events, dementia, and death. Decreased compliance of the central vasculature alters arterial pressure and flow dynamics and impacts cardiac performance and coronary perfusion. This article reviews the structural, cellular, and genetic contributors to arterial stiffness, including the roles of the scaffolding proteins, extracellular matrix, inflammatory molecules, endothelial cell function, and reactive oxidant species. Additional influences of atherosclerosis, glucose regulation, chronic renal disease, salt, and changes in neurohormonal regulation are discussed. A review of the hemodynamic impact of arterial stiffness follows. A number of lifestyle changes and therapies that reduce arterial stiffness are presented, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, natriuretic peptides, insulin modulators, as well as novel therapies that target advanced glycation end products. Key Words: arterial stiffness Ⅲ isolated systolic hypertension Ⅲ mechanisms Ⅲ therapeutics Ⅲ pathophysiology I ncreased central arterial stiffening is a hallmark of the aging process and the consequence of many disease states such as diabetes, atherosclerosis, and chronic renal compromise. Accordingly, there is a marked increase in the incidence and prevalence of clinical surrogate markers of vascular stiffness, such as pulse pressure and isolated systolic hypertension, with age and these associated conditions. [1][2][3][4][5][6] Arterial stiffening is also a marker for increased cardiovascular disease risk, including myocardial infarction, heart failure, and total mortality, as well as stroke, dementia, and renal disease. [7][8][9][10][11][12][13][14] This has been recently reviewed by Safar et al. 15 By altering the resting and stress-induced hemodynamics and energy expenditure, vascular stiffness not only contributes to these clinical repercussions and lowers the threshold for their symptoms but also likely contributes to more dyspnea with exertion and orthostatic hypotension in older adults. Although the structural and cellular changes that underlie arterial stiffness may predispose the vasculature to further insult by atherosclerotic disease, the mechanisms explaining this link are still undergoing investigation. Wang and Fitch provide a recent summary of the putative relationship between arterial stiffness and atherosclerosis. 16 Earlier work on arterial properties focused on fluid mechanics and the impact of hemodynamic and reflective wave properties on the development of arterial stiffness and the arterial waveforms. 17,18 The development of methods to measure and assess specific aspects of arterial stiffness, as recently reviewed by Oliver and Webb,19 greatly facilitated understanding of its role in cardiovascular disease. Here, we build on this earlier review to discuss more recent theories on the mechanisms co...

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

“…Collagen (type I) is the primary load‐bearing protein in the arterial wall, and its abundance is increased with advancing age (Zieman et al ., 2005; Diez, 2007; Fleenor et al ., 2012b). In contrast, elastin, the main structural protein conferring elasticity, is reduced in old arteries (Zieman et al ., 2005; Diez, 2007; Fleenor et al ., 2012b).…”

“…Collagen (type I) is the primary load‐bearing protein in the arterial wall, and its abundance is increased with advancing age (Zieman et al ., 2005; Diez, 2007; Fleenor et al ., 2012b). In contrast, elastin, the main structural protein conferring elasticity, is reduced in old arteries (Zieman et al ., 2005; Diez, 2007; Fleenor et al ., 2012b). We have previously shown in mice (Fleenor et al ., 2012a) and cultured aortic fibroblasts (Fleenor et al ., 2010) that oxidative stress contributes to some or all of the age‐associated structural changes seen within the arteries.…”

The association between aortic augmentation index and cardiovascular risk factors in a large unselected population

“…Systemic inflammation stimulates the age-dependant breakdown of elastic fibres and replacement by collagen in the central elastic arteries. 32 Most studies have reported an association between arterial stiffness measured by AIx 33,34 and high levels of markers of inflammation including hs-CRP, although some only found hs-CRP to be associated with PWV. 35 Current smoking was associated with at higher AIx in young women compared with young men and also with a faster attenuation of this relationship with increasing age in women compared with men.…”

Tissue elasticity and the ageing elastic fibre

“…In the same study, the authors present evidence that alterations in the microstructure of elastic fibre are likely to play an important role in determining tissue mechanical properties and that, as a consequence, the model of elastin as an isotropic solid is over-simplified. The proteolytic, oxidative and cross-linking mechanisms which are thought to compromise the structure of elastic fibres in skin and the lungs are also thought to be major factors in arterial ageing (Watanabe et al 1996;Zieman et al 2005). In addition to these chemical and biochemical mechanisms, the extreme mechanical demands made on tissues such as the aorta may promote the mechanical failure of elastic fibres (O'Rourke and Hashimoto 2007).…”