Low-grade inflammation and arterial stiffness in the elderly

Increased arterial stiffness is a hallmark of the aging process and the consequence of many disease states including diabetes, atherosclerosis and a variety of autoimmune diseases [1–3]. It is a marker for increased cardiovascular disease risk, including myocardial infarction, heart failure, stroke, dementia, renal disease and total mortality [4]. Arterial stiffness not only contributes to these clinical scenarios but also lowers the threshold for their symptoms. Stiffness is not uniformly disseminated throughout the vascular tree but is often patchy, occurring in central and conduit arteries [5]. Common diseases such as hypertension amplify the vascular changes that result in arterial stiffness. Vascular stiffness develops from a complex interaction between stable and dynamic changes involving structural and cellular elements of the arterial wall. Histologically, the intima of stiffened arteries can exhibit abnormal and disarrayed endothelial cells, increased collagen, frayed and broken elastin molecules, expansion of vascular smooth muscle cells, infiltration of macrophages and mononuclear cells. In the media, vascular smooth muscle and collagen are increased and elastin is reduced, whereas in the adventitia, fibroblast numbers and collagen are increased; nonenzymatic protein glycation results in irreversible cross-links between long-lived extracellular matrix molecules such as collagen and inhibition of matrix-degrading enzymes such as metalloproteinase-2, which also contribute to arterial stiffness [6,7]. In addition to structural changes, arterial stiffness is strongly affected by endothelial cell signalling and vascular smooth muscle cell tone, modified by mechanostimulation or by paracrine mediators such as nitric oxide, angiotensin II, endothelin or reactive oxygen species [8,9]. Clinically, functional assessment of arterial stiffness using various noninvasive methodologies such as ultrasound or applanation tonometry has provided strong associations between greater arterial stiffness and biomarkers of low-grade inflammation and/or endothelial dysfunction. In young healthy adults, greater arterial stiffness has been associated with markers of low-grade inflammation but not endothelial dysfunction [10], whereas in the middle-aged populations, associations have been obtained with low-grade inflammation [11,12]. In older adults, mean age 71 years, Mattace-Raso et al.[13] could find no significant association between C-reactive protein and carotid distensibility. In this issue of Journal of Hypertension, van Bussel et al.[14] reexamine in a much more critical manner associations between low-grade inflammation and carotid artery stiffness and endothelial dysfunction and carotid artery stiffness in an elderly population. The average age was 68 years; the group exhibited varying degrees of impaired glucose metabolism and a high prevalence of cardiovascular disease. The authors use multiple markers of low-grade inflammation including C-reactive protein and cytokines interleukin (IL) 6, IL-8 and TNF-α as well as multiple markers of endothelial dysfunction and indices of carotid artery stiffness derived from ultrasonography including Young's elastic modulus and β-stiffness index. They grade low-grade inflammation using z-scores into tertiles and after adjustment for confounding variables, they demonstrate a strong positive association of low-grade inflammation with aortic stiffness defined by Young's elastic modulus; low-grade inflammation was also associated with β-stiffness index but lost after adjustment for glucose tolerance status. This positive association between low-grade inflammation and Young's elastic modulus was via a greater carotid artery diameter. Pathophysiologically, the greater diameter may represent remodelling of the arterial wall associated with atherosclerosis [15,16]; most of the inflammatory markers used to assess low-grade inflammation in this study have been either implicated in the development of atherosclerosis or associated with atherosclerosis [17–20]. It may also reflect structural damage to cellular and extracellular matrix components of the arterial wall. The study group exhibited various degrees of glucose impairment and glycated haemoglobin levels were positively associated with increasing z-scores of low-grade inflammation. Advanced glycation end products, whose formation is accelerated under conditions of hyperglycaemia, may cross-link elastin increasing the susceptibility of elastic laminae to rupture, thereby increasing diameter [21]. Together, the data in the study provide strong evidence for an association between low-grade inflammation and carotid artery stiffness due to increased vessel diameter; a larger carotid diameter has also been associated with increased mortality risk [22]. In the study, the authors also examine associations between endothelial dysfunction and carotid artery stiffness. They find no association between endothelial dysfunction z-score using multiple measures of dysfunction including flow-mediated dilatation and carotid artery stiffness. This is not totally surprising, as one might expect structural changes in the carotid to be the main determinant of stiffness in an elderly population. In younger age, healthy humans in whom structural changes in vessels would be expected to be less pronounced, endothelial dysfunction has been associated with increases in large artery stiffness [23]. The study of van Bussel et al. is cross-sectional in nature and any inferences about causality, that is, that low-grade inflammation plays a role in mediating carotid artery stiffness and remodelling needs to be made with caution. As measurements assessing inflammation were only made once, it is also unclear as to the persistence of the inflammation. However, given that there was a high prevalence of cardiovascular disease in the study group, persistent inflammation might be expected. Furthermore, recent evidence from a longitudinal study supports a role for low-grade inflammation in development of arterial stiffness. Patients with early-elevated markers of low-grade inflammation exhibited increased arterial stiffness after 15 years [24]. Given the associations between increased arterial stiffness and mortality risk and low-grade inflammation, it will be important to assess any potential benefits of specifically targeting low-grade inflammation therapeutically. In apparently healthy people without hyperlipidemia but with elevated C-reactive protein levels, one of the inflammatory markers used in the present study, rosuvastatin significantly reduced the incidence of major cardiovascular events [25]. In summary, the study of van Bussel et al. demonstrates significant associations between low-grade inflammation and increased arterial stiffness in an elderly population, which has also been reported in young healthy adults and middle-aged populations [10–12]; structural changes in vessels appear to account for the increase in stiffness, a major risk factor for various cardiovascular disorders and even dementia [4]. Additional studies will be required to determine whether therapeutically treating low-grade inflammation is beneficial in the elderly. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.