Early Vascular Ageing Syndrome - could it be defined? Peter M Nilsson For more than 20 years the so called Metabolic syndrome has been in focus as a model to better understand the etiology of cardiovascular disease in relation to metabolic abnormalities. However, during the last few years an increasing wave of criticism has made the metabolic syndrome disputed and now some people think that it should better be abandoned [1]. Therefore there is a need to find new models for both theoretical understanding and intervention on increased cardiovascular risk in order to prevent cardiovascular disease manifestations. In this perspective it is therefore of interest to discuss the most important cardiovascular risk factor of all – the ageing process and more specifically vascular ageing. Cardiovascular risk is determined not only by conventional risk factors of importance in adult life, but also on early life programming based on intrauterine fetal growth retardation, often to be followed by rapid catch-up growth patterns [2]. This is called the early life developmental origins of cardiovascular disease [3], or sometimes even the “Mis-match� hypothesis [4], thereby depicting that there is a mis-match between the conditions that the fetus is programmed for in utero, and the environment that the new-born child meets in early postnatal life. There are several important consequences of this programming effect, as shown to influence glucose metabolism based both on changes in insulin sensitivity and beta-cell function [5,6], as well as haemodynamic control [7], neuroendocrine regulation [8,9] and also kidney function [10]. In addition, several reports have now documented that also vascular structure and function is more or less programmed in early life. This includes several mechanisms that can eventually lead to morphological and functional changes of importance for the development of adult cardiovascular risk. For example, it has been shown that an impaired fetal growth is associated with capillary rarefaction [11], endothelial dysfunction [12] and less arterial diameter [13], as compared to what has been recorded in children with normal fetal growth. One consequence of this development is an increased risk of elevated blood pressure and later on overt hypertension, as now documented in numerous studies. This is accompanied by a tendency for early arterial changes included in the new concept of an early vascular ageing [14,15], that can also be called the EVA syndrome [16]. One typical clinical example of this is the early arterial ageing
observed in young patients with essential hypertension. An increased “intrinsic” stiffness of the arterial wall material (Young’s elastic modulus) was found in younger hypertensive patients but not in middle-aged and older hypertensive patients compared with age- and gender-matched normotensive individuals. Several arguments favour an interaction between hypertension and diabetes to accelerate vascular aging and increase the cardiovascular risk [18].
Vascular ageing and arterial stiffening In normal ageing there is a well-known age-related arterial stiffening process (arteriosclerosis) due to quantitatively less elastin and more collagen, but also qualitative changes, in the content of the arterial vessel wall, in association with impaired endothelial-mediated vasodilation [15]. In patient with hyperglycaemia and overt type-2 diabetes, an additional component of glycaemic changes in vessel wall proteins (glycosylation) will add to the process of arterial stiffening, a process that is reflected not only by HbA1c levels, but also by the Advanced Glycation End (AGE) products [19]. AGE has recently been shown to predict cardiovascular events in Finnish women with type 2 diabetes, even if no correlation with plasma glucose levels or HbA1c was found [20]. Aging is the major determinant of all measurements and indirect evaluations of arterial stiffness and wave reflection. One measure of arterial stiffening is the increased pulse wave velocity (PWV), also known to predict cardiovascular events, based on data from more than 13,000 subjects in 12 studies [21,22]. The risk increases linearly with PWV but is especially increased above 12 m/sec that is now recommended to be a threshold for increased risk according to the 2007 Guidelines for the management of arterial hypertension. The measurement of pulse wave velocity (PWV) is generally accepted as the most simple, non-invasive, robust, and reproducible method with which to determine arterial stiffness. Carotid-femoral PWV is a direct measurement, and it corresponds to the widely accepted propagative model of the arterial system. Measured along the aortic and aorto-iliac pathway, it is the most clinically relevant, since the aorta and its first branches are what the left ventricle “sees”, and are thus responsible for most of the pathophysiological effects of arterial stiffness. PWV is usually measured using the foot-to-foot velocity method from various waveforms: PWV is thus calculated as the ratio between the distance covered by the wave (i.e. the surface distance between the two recording sites) and the transit time (i.e. the time delay measured between the feet of the two waveforms).
Ageing is the major determinant of PWV, explaining up to 33% of PWV variance in multivariate analysis. New ways are currently investigated to increase our knowledge on arterial stiffness and wave reflection in human hypertension, as summarised in a European expert consensus document [22] and further detailed in a recent review [23]. First, local arterial stiffness of superficial arteries can be determined using ultrasound devices. Carotid stiffness may be of particular interest, since in that artery atherosclerosis is frequent. All types of classical, bi-dimensional vascular ultrasound systems can be used to determining diameter at diastole and stroke changes in diameter, but most of them are limited in the precision of measurements because they generally use a video-image analysis. At present some researchers also measure local arterial stiffness of deep arteries like the aorta using magnetic resonance imaging (MRI). However, most of pathophysiological and pharmacological studies have used echotracking techniques. A major advantage is that local arterial stiffness is directly determined, from the change in pressure driving the change in volume, i.e. without using any model of the circulation. However, because it requires a high degree of technical expertise, and takes longer than measuring PWV, local measurement of arterial stiffness is only really indicated for mechanistic analyses in pathophysiology, pharmacology and therapeutics, rather than for epidemiological studies. In multivariate analysis, aging is the major determinant of carotid stiffness, and explains a larger part of the variance of carotid than aortic stiffness, up to 64% in normotensives.
Central aortic pressure. Central pulse wave analysis has recently gained a large amount of popularity, after the publication of the CAFÉ study, showing that a combination of a calcium channel blocker and an ACE inhibitor could be more effective for lowering aortic systolic blood pressure than a combination of a diuretic and a beta-receptor blocker, despite similar effect of brachial blood pressure. Central augmentation index and central pulse pressure have shown independent predictive values for all-cause mortality in patients with end-stage renal disease, and CV events in patients undergoing percutaneous coronary intervention and in the hypertensive patients of the CAFÉ study [24]. Central systolic and pulse pressures are influenced by aortic stiffness and the geometry and vasomotor tone of small arteries. In the case of stiff arteries, like in the elderly, PWV rises and the reflected wave arrives back at the central arteries earlier,
adding to the forward wave, and augmenting the systolic pressure. Indeed, the arterial pressure waveform is a composite of the forward pressure wave created by ventricular contraction and a reflected wave. Waves are reflected from the periphery, mainly at branch points or sites of impedance mismatch. Wave reflection can be quantified through the augmentation index (AIx) - defined as the difference between the second and first systolic peaks of the pressure wave, expressed as a percentage of the pulse pressure. Apart from a high PWV, also changes in reflection sites can influence the augmentation index. In clinical investigation, age is a major determinant of AIx and central PP, in addition to aortic PWV, DBP and height. Arterial pressure waveform should be analysed at the central level, i.e. the ascending aorta, since it represents the true load imposed to the left ventricle and central large artery walls [22]. Aortic pressure waveform can be estimated either from the radial artery waveform, using a transfer function, or from the common carotid waveform. On both arteries, the pressure waveform can be recorded non-invasively with a penciltype probe incorporating a high-fidelity Millar strain gauge transducer. The most widely used approach is to perform radial artery tonometry and then apply a transfer function to calculate the aortic pressure waveform from the radial waveform. In summary, various methodologies are available for determining arterial aging in individuals, under non-invasive conditions of clinical investigation, and for comparing observed data with reference values of a normal “aging� population.
The addition of atherosclerosis and inflammation Superimposed on the normal arterial ageing is pathological arterial ageing induced by chronic inflammation, lipid deposit and start of the atherosclerotic process. This is even more evident in patients with uncontrolled hypertension for whom the normal increase in pulse pressure above 60 years of age is more pronounced and can serve as an easy accessible measure of the combined effect of both processes: arteriosclerosis and superimposed atherosclerosis. Using the methodologies described above, it has been shown that markers of inflammation, e.g. hs-CRP and the primary pro-inflammatory cytokines TNF-Îą and IL6 are associated with morphological changes of both atherosclerosis and increased arterial stiffening. In addition, chronic inflammation, such as during rheumatoid arthritis or systemic lupus erythematosus, has been reported to stiffen the large arteries. This may occur through various mechanisms including endothelial
dysfunction, cell release of a number of inducible matrix metalloproteinases (including MMP-9), medial calcifications, changes in proteoglycan composition and state of hydration, and cellular infiltration around the vasa vasorum leading to vessel ischaemia. How to define EVA? Some controversy exists on how the EVA syndrome should best be defined. One might argue that there is no need of a definition as this concept is more like a biological model of understanding, and not a fixed model. On the other hand it should be possible to analyze the distribution of pulse wave velocity, as a marker of arterial stiffness and EVA, in various age-groups, stratified for gender. EVA could then be defined as the outliers more than highest +2SD of the distribution for a specific population and in relation to age-group and gender. This is something that will soon be accomplished based on European collaboration within an extensive data-base on PWV measurements (Laurent S, personal communication). Another way to define EVA would be to analyze the remaining part of PWV that is not explained by conventional cardiovascular risk factors in a multiple regression analysis, when adjustment is made for age, gender, blood pressure, hyperlipideamia, smoking, hyperglycaemia and drug treatment. This is still something that is not fully explored and work in progress. An important aspect is how PWV or arterial stiffness is measured as different methods exist (Complior, Sphygmocor, Arterigraph, ultrasound devices) and should be validated against each other.
In summary, the EVA syndrome is a useful concept to increase awareness of the pathophysiological consequences of a heavy cardiovascular risk factor burden for CVD [24,25]. It is measurable and can be followed over time, for example for changes in pulse wave velocity. The broad evaluation and treatment of risk factors is necessary to achieve long-terms benefits, as most visibly shown in the Steno-2 study for patients with type 2 diabetes. The goal for systolic blood pressure in diabetes is still, however, not well defined.
References 1. Borch-Johnsen K, Wareham N. The rise and fall of the metabolic syndrome. Diabetologia 2010;53:597-9. 2. Barker DJP (ed). Fetal and infant origins of adult disease. 1st edition. British Medical Journal. London, 1992. 3. Nilsson PM, Holmäng A. Introduction to Mini-symposium on developmental origins of adult disease. J Internal Med 2007;261:410-1. 4. Gluckman P, Hanson M. Developmental origins of health and disease. Cambridge University Press. Cambridge, 2006. 5. McKeigue PM, Lithell HO, Leon DA. Glucose tolerance and resistance to insulinstimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia 1998;41:1133-8. 6. Harder T, Rodekamp E, Schellong K, Dudenhausen JW, Plagemann A. Birth weight and subsequent risk of type 2 diabetes: a meta-analysis. Am J Epidemiol 2007;165:849-857. 7. Schreuder MF, van Wijk JA, Delemarre-van de Waal HA. Intrauterine growth restriction increases blood pressure and central pulse pressure measured with telemetry in aging rats. J Hypertens 2006;24:1337-43. 8. Ward AM, Syddall HE, Wood PJ, Chrousos GP, Phillips DI. Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis: low birth weight and central HPA regulation. J Clin Endocrinol Metab 2004;89:1227-33. 9. Seckl JR, Holmes MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal “programming” of adult pahophysiology. Nature Clinical Practice Endocrin Metab 2007;3:479-488. 10. Hershkovitz D, Burbea Z, Skorecki K, Brenner BM. Fetal programming of adult kidney disease: cellular and molecular mechanisms. Clin J Am Soc Nephrol 2007;2:334-342.
11. Pladys P, Sennlaub F, Brault S, Checchin D, Lahaie I, La NL, et al. Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero. Am J Physiol Regul Integr Comp Physiol. 2005;289:R1580-8. 12. Halvorsen CP, Andolf E, Hu J, Pilo C, Winbladh B, Norman M. Discordant twin growth in utero and differences in blood pressure and endothelial function at 8 years of age. J Intern Med 2006;259:155-63. 14. Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension 2005;46:454-62. 15. O´Rourke MF, Hashimoto J. Mechanical factors in arterial aging. A clinical perspective. J Am Coll Cardiol 2007;50:1-13. 16. Nilsson PM, Lurbe E, Laurent S. The early life origins of vascular ageing and cardiovascular risk: the EVA syndrome (review). J Hypertens 2008; 26:1049-1057. 17. Bussy C, Boutouyrie P, Lacolley P, Challande P, Laurent S. Intrinsic stiffness of the
carotid
artery
wall
material
in
essential
hypertensives.
Hypertension
2000;35:1049-1054. 18. Franklin SS. Do diabetes and hypertension interact to accelerate vascular ageing? J Hypertens 2002;20:1693-6. 19. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 2006;114:597-605. 20. Kilhovd BK, Juutilainen A, Lehto S, RĂśnnemaa T, Torjesen PA, Birkeland KI, et al. High serum levels of advanced glycation end products predict increased coronary heart disease mortality in nondiabetic women but not in nondiabetic men: a population-based 2005;25:815-20.
18-year
follow-up
study.
Arterioscler
Thromb
Vasc
Biol
21. Laurent S. Hypertension and macrovascular disease. ESH Newsletter 2007;8: no. 31. 22. Laurent S, Cockkroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006;27:2588-2605. 23. Laurent S, Boutouyrie P. Recent advances in arterial stiffness and wave reflection in human hypertension. Hypertension 2007;49:1202-1206. 24. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressurelowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213-25. 25. Minamino T, Komuro I. Vascular aging: insights from studies on cellular senescence, stem cell aging, and progeroid syndromes. Nat Clin Pract Cardiovasc Med. 2008;5:637-48. 26. Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: A tale of EVA and ADAM in cardiovascular risk assessment and prevention. (Brief Review) Hypertension. 2009; 54:3-10.