Preventing early vascular aging (EVA)




Peter M. NILSSON, MD, PhD
Department of Clinical Sciences
Lund University, Malmö
SWEDEN

Preventing early vascular aging (EVA)


by P. M. Nilsson, Sweden

In recent years, the new concept of early vascular aging (EVA) has emerged as a useful tool to aid understanding of how cardiovascular risk increases in relation to the biological aging process. The core feature of EVA is arterial stiffness, which can be measured as increased pulse wave velocity in relation to a subject’s chronological age and sex. Prevention of EVA should start early in life, as there is evidence that factors acting during fetal life, childhood, and adolescence all contribute to the development of EVA. Improved lifestyle is the first intervention to consider, followed in adults by drug therapy to control risk factors such as hypertension, increased blood pressure variability, hyperglycemia, and hyperlipidemia. Among the antihypertensive drugs to have been found of particular use are classes of agents that block the renin-angiotensin system. These have been shown to produce beneficial results regarding central blood pressure reduction, arterial wall remodeling, and reduction of cardiovascular risk in studies like HOPE (Heart Outcomes Prevention Evaluation), PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), HYVET (HYpertension in the Very Elderly Trial), ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), and LIFE (Losartan Intervention For Endpoint reduction in hypertension). Current developments involve attempts to find pathways that can interact with the vascular aging process, including ways to break glycemic linkages or manipulate telomere biology or endothelial function. This holds promise for the future.

Medicographia. 2012;34:11-16 (see French abstract on page 16)

In medicine, we constantly have to challenge old concepts and beliefs in order to push forward the frontiers of science and clinical practice. For more than 20 years, ever since the 1988 Banting lecture given by Gerald Reaven, the focus has been on the so-called metabolic syndrome as a model to help better understand the etiology of cardiovascular disease (CVD) as arising from metabolic and hemodynamic abnormalities.1 Over the past few years, however, an increasing wave of criticism and dispute has built up over this model, and today some people think that the concept of the metabolic syndrome would be better abandoned.2 Thus, there exists a need for new models, both for theoretical understanding and for intervention in cases of increased cardiovascular risk in order to prevent CVD manifestations. Against this backdrop, it is therefore interesting to discuss the most important cardiovascular risk factor of all—aging and the aging process in general, but more specifically, vascular aging. Cardiovascular risk is determined not only by conventional risk factors important in adult life, but also by early life programming arising from intrauterine fetal growth retardation, often followed by rapid catch-up growth patterns.3 This is called the early life developmental origins of CVD,4 or sometimes the “mismatch” hypothesis,5 whereby there is a mismatch between the conditions that the fetus is programmed for in utero, and the environment that the newborn child meets in early postnatal life.

There are several important consequences of this programming effect; it has been shown to influence glucose metabolism through changes in insulin sensitivity and β-cell function,6 as well as influencing hemodynamic control,7 neuroendocrine regulation,8 and kidney function.9

In addition, several reports have now documented that vascular structure and function are also to a certain extent determined via programming early in life. This includes several mechanisms that can eventually lead to morphological and functional changes important in the development of adult cardiovascular risk. For example, it has been shown that compared with normal fetal growth, impaired fetal growth is associated with capillary rarefaction,10 endothelial dysfunction,11 narrower arterial diameter, and increased aortic-intima media thickness.12 In addition, premature birth itself—without growth retardation—is associated with long-term negative consequences for the vascular system.13

As has now been documented in numerous studies, one consequence of this impaired development is an increased risk of elevated blood pressure, and later on, overt hypertension. This is accompanied by a tendency to exhibit early arterial changes, as included in the new concept of early vascular aging (EVA) that developed from arterial aging.14,15 EVA is also referred to as the EVA syndrome (see Table).16 One typical clinical example of EVA is the early arterial aging observed in young patients with essential hypertension. Compared with age- and gender-matched normotensive individuals, an increased “intrinsic” stiffness of the arterial wall material (Young’s elastic modulus) has been found in younger hypertensive patients, but not in middle-aged and older hypertensive patients. With increasing age, the content of elastin in the arterial wall decreases and the amount of collagen fiber increases, as do cross-linkages between fibers. Several arguments favor an interaction between hypertension and diabetes in the acceleration of vascular aging and increase in cardiovascular risk.17

Table
Table. Core characteristics of the early vascular aging (EVA)
syndrome.

One consequence of vascular aging is the development of target organ damage; most notably, left ventricular hypertrophy, microalbuminuria, and retinopathy, but also cognitive decline and peripheral arterial disease. One can also consider arterial stiffness, the core feature of the EVA syndrome, as a tissue biomarker less sensitive to temporary changes than some biomarkers in common use such as serum or plasma biomarkers like lipids, C-reactive protein, fibrinogen, N-terminal pro B-type natriuretic peptide, and others.

How should EVA be defined?

Some controversy exists as to how the EVA syndrome16 should best be defined. One might argue that there is no need for a definition, as this concept is currently more of a biological model of understanding than a fixed model. Nevertheless, it should be possible to analyze the distribution of pulse wave velocity (PWV) in various age groups, stratified for sex, as a marker of arterial stiffness and EVA. EVA could then be defined as the outliers located above the highest +2 standard deviation of the distribution for a specific population and in relation to age group and sex. This is something that was recently accomplished through European collaboration using an extensive database of PWV measurements.18 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, with adjustments made for age, gender, blood pressure, hyperlipidemia, smoking, hyperglycemia, and drug treatment.

Finally, it could be argued that the primary definition of EVA should be the highest quartile or quintile of the distribution of PWV in combination with the corresponding cutoff levels for an inflammatory marker such as C-reactive protein or some other marker of inflammation or endothelial dysfunction. This is something that has not been fully explored yet and is therefore still work in progress. An important element is how PWV or arterial stiffness is measured, as different methods exist (Complior, Sphygmocor, Arteriograph, ultrasound devices) that need to be validated against each other.

Cognitive decline and EVA

A new aspect of EVA to emerge is the link with cognitive decline starting in midlife and with increased risk for dementia later in life, especially that of vascular origin.19,20 It has been shown that the burden of vascular risk factors plays an important role in the development of cognitive decline, acting against a background of cognitive reserves shaped by neurocognitive development during early childhood and adolescence. With the help of modern medical devices, it is possible to measure PWV in retinal vessels or the intracranial circulation. This could provide new insights into the connection between vascular pathophysiology and age-related impairment of mental function.

In summary, the EVA syndrome is a useful concept for increasing our awareness of the pathophysiological consequences of a heavy burden of CVD risk factors where the core is arterial stiffness.21,22 It is measurable and can be followed over time—for example, through changes in PWV. Broad evaluation and treatment of risk factors is necessary to achieve long-term benefits, as has most visibly been shown in the Steno-2 study in patients with type 2 diabetes.23 However, the goal for systolic blood pressure in patients with diabetes is still not well defined. It was the subject of extensive discussion following the results of the ACCORD (Action to Control CardiOvascular Risk in Diabetes) blood pressure trial, in which no extra benefit was shown for the primary cardiovascular end point in patients achieving systolic blood pressure of <120 mm Hg compared with controls with <140 mm Hg.24

Prevention and treatment of EVA

Ideally, the different components of the EVA syndrome should be prevented early in life; firstly, during the fetal period, but also later on during childhood and adolescence. Normal fetal development and normal physiological and neurocognitive growth during childhood are factors of great importance in the control of vascular risk, and have also long been factors that are addressed in the course of regular maternal and child health care. One important factor is the support of physical activity and neurocognitive development through appropriate diet and mental stimulation. Another component is the prevention of development of obesity with its accompanying insulin resistance and blood pressure elevation.

_ The role of lifestyle in EVA prevention
The treatment of more established EVA in adult life should start with lifestyle interventions—most importantly, increased physical exercise and cessation of smoking. If possible, the patient should also be encouraged to adopt a healthy pattern of food intake based on what has been referred to as the Mediterranean diet.25 This includes a large amount of fruit and vegetables, but also fish, poultry, and a restricted amount of red meat. A glass of wine or two forms part of the cultural tradition of this diet. When obesity is a problem, the aim should be for weight stabilization in the first instance, and in some cases, weight reduction—a goal that is hard to achieve and maintain for many people. In selected cases, bariatric surgery can also be an option for weight loss in grossly obese subjects with a body mass index above 35 mg/m2.

_ Drug treatment for prevention of EVA
When it comes to drug therapy in patients with EVA, a multiple risk factor approach is of great importance, and the aim should be to control all of the classic risk factors for CVD. However, special attention should be given to the elevated blood pressure found in these patients, which most commonly engages the central circulation, with increased arterial stiffness and central pulse pressure.

There is emerging evidence that blood pressure variability is an independent CVD risk factor, and it is often linked with vascular properties, arterial stiffness, and aging, as pointed out by Rothwell et al.26 Furthermore, it is important to gain control of central blood pressure and newer aspects such as the reflected wave in the arterial tree27 and excess central pressure.28 In ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), a higher wave reflection predicted future cardiovascular events independent of conventional risk factors in people with treated hypertension.27 In an observational study in France, it was shown that it was possible to obtain a large and sustained decrease in aortic stiffness in 97 treated hypertensive patients under conditions of routine clinical practice. These changes likely represent a delayed response to the long-term normalization of blood pressure and cardiovascular risk factors through arterial remodeling.28

As there is crosstalk between the central circulation and peripheral circulation, there is also a case for improving the microcirculation.29 This goal can be achieved by combining different antihypertensive drugs, preferably with therapy based on an agent that blocks the renin-angiotensin system (RAS).

Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) seem to be beneficial in blocking RAS, but β-blockers are less useful for arterial stiffness because of the resultant vasoconstriction in the peripheral circulation of the arterioli. In the CAFE (Conduit Artery Function Evaluation) study, treatment with the calcium antagonist amlodipine, often combined with the ACE inhibitor perindopril, was associated with lower central blood pressure compared with β-blocker/thiazide diuretic therapy.30

Effective blood pressure control can lead to regression of arterial stiffness and a reduction in PWV—even more than would be predicted on the basis of the blood pressure lowering per se. This supports the notion that long-term risk factor control can reverse aspects of EVA. As the RAS is important in the remodeling of arteries, it is logical to use agents that block the RAS to counteract this process. Often, this is done in combination with the use of statins for lipid control and effective treatment of hyperglycemia in patients with impaired glucose metabolism or type 2 diabetes. Among the RAS blockers, some drugs have accumulated more evidence than others.

Examples are: (i) ramipril in HOPE (Heart Outcomes Prevention Evaluation) and ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial); (ii) perindopril in PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and HYVET (HYpertension in the Very Elderly Trial); (iii) losartan in LIFE (Losartan Intervention For Endpoint Reduction in hypertension); and (iv) telmisartan in ONTARGET (vide supra), to name some of the most well known. The aforementioned classic studies were aimed at assessing risk factor control in the first instance and not evaluation of the effect of the drug on arterial stiffness, although such an effect is likely to have contributed to the overall beneficial clinical effect of the drugs. In fact theoretically, differences in effects on arterial stiffness and central blood pressure could contribute to some of the observed variation in the effects of different RAS blockers, but this has still to be proven. In ONTARGET, no difference in clinical effects was observed between patients treated with ramipril or telmisartan, or the combination of these two drugs.31 This suggests that these two RAS blockers at least are clinically comparable.

It has further been suggested that inflammation plays an important role in hypertension and atherosclerosis, and that inflammatory changes induced even in prehypertensive subjects can lead to increased arterial stiffness. The effects of perindopril on both inflammatory and aortic elasticity markers were tested in 109 hypertensive patients not taking any antihypertensive therapy.32 Aortic strain, aortic distensibility, aortic stiffness index, and inflammatory markers, including C-reactive protein, interleukin (IL)-1α, IL-1β, and tumor necrosis factor-α, were measured in all patients before and after 20 weeks of perindopril therapy. While aortic strain and distensibility showed statistically significant increases with perindopril therapy, measures on the aortic stiffness index and inflammatory markers were found to decrease. The authors therefore concluded that perindopril therapy resulted in an improvement in aortic elastic properties. There was also an attenuation of the inflammatory status of patients, as reflected by lower inflammatory marker levels compared with pretreatment values.

_ New drugs for potential treatment of EVA
New drugs are under development for control of hypertension, hyperlipidemia, and diabetes. These drugs should also be tested for their ability to counteract arterial stiffness, endothelial dysfunction, vascular remodeling, and target organ damage.

Examples of such new drugs are: (i) renin antagonists, angiotensin AT2 receptor agonists, and vasopeptidase inhibitors for treatment of hypertension; (ii) cholesteryl ester transfer protein (CETP) antagonists for increasing high-density lipoprotein (HDL) cholesterol; and (iii) the new incretin-acting drugs for treatment of type 2 diabetes. The latter class of drugs is of special interest regarding characterization of incretin receptors for glucose-dependent insulinotropic poly-peptide (GIP) and glucagon-like peptide-1 (GLP-1) in the heart and vasculature. Other new drugs are being developed for enhancement of the regular vasodilatory effects of normal endothelium. All these drugs have to be evaluated in randomized control trials, and many such trials are ongoing already.33

Other more specific drugs for counteracting EVA and the aging process may be the so-called advanced glycation end product (AGE) modifiers, or AGE-breakers. So far, these have been shown to be more effective in animal studies than in human studies. Research activities are also ongoing regarding manipulation of more complex biological systems such as the Klotho system, and manipulation of telomerase function for regulation of telomere length, or testing of farnesyl transferase inhibitors in patients with Hutchinson-Gilford progeria, a complex disorder involving premature aging, although this is still at present futuristic.

Conclusions

The EVA syndrome has recently been proposed as a new concept in cardiovascular medicine to help better understand the importance of aging of the arterial tree and the CVD risk associated with this. It is important that we gain a better understanding of EVA, and find ways to define it if possible. Broad risk factor intervention is needed in patients at risk; for example, those with a positive family history of early-onset CVD manifestations. Control of hypertension is a high priority, and based on existing evidence, it appears that agents blocking the RAS are useful for counteracting arterial stiffness and remodeling of the arterial wall. ACE inhibitors and ARBs are now well-proven drugs for achievement of this, one such drug being perindopril, which has shown beneficial results on cardiovascular events and mortality reduction in several intervention trials when combined with indapamide. This approach brings “ADAM” (aggressive decrease of atherosclerosis modifiers) to EVA for risk factor control in subjects at increased risk34—and the earlier the better. _

References
1. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.
2. Borch-Johnsen K, Wareham N. The rise and fall of the metabolic syndrome. Diabetologia. 2010;53:597-599.
3. Barker DJP. The Fetal and Infant Origins of Adult Disease. 1st ed. London, England: BMJ Books; 1992.
4. Nilsson PM, Holmäng A. Introduction to mini-symposium on developmental origins of adult disease. J Intern Med. 2007;261:410-411.
5. Gluckman P, Hanson M. Developmental Origins of Health and Disease. Cambridge, England: Cambridge University Press; 2006.
6. McKeigue PM, Lithell HO, Leon DA. Glucose tolerance and resistance to insulin- stimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia. 1998;41:1133-1138.
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;24:1337-1343.
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;89:1227-1233.
9. 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.
10. Pladys P, Sennlaub F, Brault S, 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-R1588.
11. 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;259:155-163.
12. Cosmi E, Visentin S, Fanelli T, Mautone AJ, Zanardo V. Aortic intima media thickness in fetuses and children with intrauterine growth restriction. Obstet Gynecol. 2009;114:1109-1114.
13. Bonamy AK, Martin H, Jörneskog G, Norman M. Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm. J Intern Med. 2007;262:635-642.
14. Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor? Hypertension. 2005;46:454-462.
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. J Hypertens. 2008;26:1049-1057.
17. Franklin SS. Do diabetes and hypertension interact to accelerate vascular ageing? J Hypertens. 2002;20:1693-1696.
18. Reference Values for Arterial Stiffness’ Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: “establishing normal and reference values.” Eur Heart J. 2010;31:2338- 2350.
19. Scuteri A, Nilsson PM, Tzourio C, Redon J, Laurent S. Microvascular brain damage with aging and hypertension: pathophysiological consideration and clinical implications. J Hypertens. 2011;29:1469-1477.
20. Gorelick PB, Scuteri A, Black SE, et al; American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Vascular contributions to cognitive impairment and dementia. A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011; 42:2672-2713.
21. Laurent S, Cockcroft J, Van Bortel L, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27:2588-2605.
22. Laurent S, Boutouyrie P. Recent advances in arterial stiffness and wave reflection in human hypertension. Hypertension. 2007;49:1202-1206.
23. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-591.
24. The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1582.
25. Mente A, de Koning L, Shannon HS, Anand SS. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. Arch Intern Med. 2009;169:659-669.
26. Rothwell PM. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet. 2010;375: 938-948.
27. Manisty C, Mayet J, Tapp RJ, et al; ASCOT Investigators. Wave reflection predicts cardiovascular events in hypertensive individuals independent of blood pressure and other cardiovascular risk factors: an ASCOT (Anglo-Scandinavian Cardiac Outcome Trial) substudy. J Am Coll Cardiol. 2010;56:24-30.
28. Ait-Oufella H, Collin C, Bozec E, et al. Long-term reduction in aortic stiffness: a 5.3-year follow-up in routine clinical practice. J Hypertens. 2010;28:2336-2341.
29. Laurent S, Briet M, Boutouyrie P. Large and small artery cross-talk and recent morbidity-mortality trials in hypertension. Hypertension. 2009;54:388-392.
30. Williams B, Lacy PS, Thom SM, et al; CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213-1225.
31. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358: 1547-1559.
32. Koz C, Baysan O, Yokusoglu M, et al. The effects of perindopril on aortic elasticity and inflammatory markers in hypertensive patients. Med Sci Monit. 2009; 15:PI41-PI45.
33. Lesven S, Gautier JF, Maréchaud R. Treatment of type 2 diabetes: new clinical studies and effects of GLP-1 on macrovascular complications. Ann Endocrinol (Paris). 2010;71:505-510.
34. Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: a tale of EVA and ADAM in cardiovascular risk assessment and prevention. Hypertension. 2009;54:3-10.

Keywords: arterial stiffness; cardiovascular disease; EVA (early vascular aging); fetal development; hypertension; pulse wave velocity; renin-angiotensin system; vascular aging