Vascular age: how can it be determined? What are its clinical applications?






Peter M. NILSSON, MD, PhD
Lund University, Malmö
SWEDEN

Vascular age: how can it be determined? What are its clinical applications?


by P. M. Nilsson, Sweden



Over the last few years, the concept of early vascular aging (EVA) has supported research and clinical applications that aim to initiate preventive efforts early enough to influence the risk of cardiovascular disease. For example, young members of families at increased cardiovascular risk that are diagnosed with arterial stiffness and negative changes in hemodynamic control could be candidates for preventive efforts. Such efforts may be based on improved lifestyle habits and even early drug treatment if the absolute risk is considered to be high enough. However, how should EVA be defined? This question is yet to be settled, but one way is to target subjects with a carotid-femoral pulse wave velocity that is more than 2 standard deviations from that of the background population stratified for age and gender. There is still no direct treatment of EVA, only recommendations for conventional cardiovascular risk factor control. However, new interventions are being developed, not only new antihypertensive drugs, but also resveratrol and new vasculoprotective drugs, eg, the selective angiotensin II type 2 (AT2) receptor agonist named Compound 21 (C21). Human studies are awaited. In France, the ongoing SPARTE study (Stratégie de Prévention Cardiovasculaire Basée sur la Rigidité Arterielle) aims to elucidate whether an intervention strategy targeting arterial stiffness is more beneficial in patients with hypertension than conventional and guidelines-directed treatment.

Medicographia. 2015;37:454-460 (see French abstract on page 460)



Research on atherosclerosis as a morphological precursor to cardiovascular events has been ongoing for many decades. Effective treatment of causative lipid abnormalities has been developed. For example, there is widespread use of statins for control of low-density lipoprotein (LDL) cholesterol, an evidence-based treatment documented in a 2013 Cochrane meta-analysis on primary prevention.1

However, recent years have seen an emerging interest dedicated to arterial stiffness (arteriosclerosis) and from 2008, development of the concept of early vascular aging (EVA), which is described in several reviews.2-5 It is noteworthy that the previous concept of metabolic syndrome has been heavily criticized since 2005, due to inherent problems with defining the syndrome and with application of the concept in daily clinical practice, but also due to the lack of specific treatment.6 Therefore, the door was open to new concepts in cardiometabolic medicine that would help understanding and early prevention of disease events. Emergence of the EVA concept was also supported by the development of a number of new devices for measurement of central hemodynamics and arterial stiffness, components of great importance for understanding EVA, as summarized in a 2006 review in the European Heart Journal.7 It is believed that arteriosclerosis precedes the development of atherosclerosis, even if the two conditions tend to develop in parallel in adult life and in the elderly.


Figure 1
Figure 1. Early
vascular aging
affecting all layers
of the vessel wall
of the elastic
arteries.

Abbreviation:
NO, nitric oxide.
Image from Servier
Medical Art. © 2015,
Les Laboratoires
Servier.


Arterial stiffness as the core of vascular aging

Arterial aging starts early in life and is a process that spans from normal aging8 to pathological aging and the profound changes related to atherosclerosis. This aging process involves all three layers of the arterial wall: (i) the intima, with endothelial dysfunction, decrease in nitric oxide (NO) production, local inflammation, and later on, fatty streaks as early signs of atherosclerosis9; (ii) the media, with decreasing levels of elastin and a relative increase in collagen content with cross-linkages enhanced by detrimental effects of protein glycosylation10; and finally (iii) the adventitia, with impairment of innervation and neuronal control,11 a less functional vasa vasorum and development of perivascular fat deposits that may increase local inflammatory actions that can negatively impact vasodilation.12





Thus, arterial aging should be understood as a general process involving many different components of the entire arterial wall, as shown in Figure 1. Furthermore, this aging process involves not only the large elastic arteries (with their elastic content of the media), but also other parts of the entire vascular system, for example, remodeling of small arteries due to an increase in blood pressure.13 There is also a negative impact on the microvasculature of stiff large arteries when the pulse wave energy is transmitted to the microcirculation, causing damage.14 Thus, the EVA concept goes beyond both atherosclerosis and arterial aging for a more holistic view on the vascular system undergoing aging with superimposed disease processes. This cross-talk between the macro- and microcirculation is evident in the origin of vascular brain damage15 and impaired cognitive function.16,17 Finally, it should be noted that structural changes in the vasculature corresponds with a number of hemodynamic changes associated with aging, what can be called hemodynamic aging in relation to EVA.18

How should EVA be defined?

Arterial aging was first named and systematically studied in Italy by Taddei et al19 and in the United States by Lakatta et al in the BLSA study (Baltimore Longitudinal Study of Aging).20 During the same period, and having already begun in the 1980s, researchers in Maastricht (Struijker-Bourdier, Stehouwer, et al),21 Ghent (Van Bortel, Rietzschel, Segers, et al),22 and Paris (Safar, London, Laurent, Benetos, Boutouyrie, Bla- cher, et al)23-25 contributed important findings to describe arterial stiffness and changes in central wave reflections shaping the hemodynamics of aging, as well as changes in the microcirculation. In recent years, Dzau, Safar, and O’Rourke coined the term “the cardiovascular aging continuum” to describe the long road from risk factors to cardiovascular events and post-event complications.26

The EVA concept, which emerged in 2008,2-5 is now being extensively studied in different population-based cohorts in Europe, Asia, Africa, and Latin America, but still no general definition has been agreed upon. A number of risk markers constitute the background knowledge of EVA, with arterial (aortic stiffness) as the core variable (Table I). One way to define EVA could therefore be to select the outliers according to the normal range of carotid-femoral pulse wave velocity (c-f PWV), ie, more than 2 standard deviations (SD) above the normal distribution of c-f PWV based on data from the European reference group.27 Another way to describe EVA is based on statistical methods when arterial stiffness (measured by c-f PWV)—a central aspect of EVA—is used as the dependent variable in multiple regression analyses, and a number of risk markers or characteristics are used as independent variables, based on data from population-based studies. As the influence of hemodynamic changes and sympathetic nervous system (SNS) stimulation on the arterial tone is substantial, the data are normally adjusted for mean arterial pressure (MAP) and heart rate, the latter being a marker of SNS activity. Such investigations in a population-based study of elderly subjects (n=3700; mean age, 71 years) in Malmö, Sweden, has revealed that markers of glucose metabolism and dyslipidemia (elevated triglycerides, low high-density lipoprotein [HDL] cholesterol levels), as well as waist circumference (a marker of active abdominal fat tissue with inflammatory action), are significantly associated with arterial stiffness (c-f PWV), but not LDL cholesterol, smoking, or cystatin-C, a marker of impaired renal function.28 The findings thus point to two different clusters of cardiovascular risk factors involved in development of arteriosclerosis and atherosclerosis, respectively. Levels of arterial stiffness were also higher in subjects with known or newly detected diabetes, as compared with nondiabetic subjects. In another set of analyses from the same cohort, it was shown that arterial stiffness, at least at the higher end of the distribution, is associated with impaired cognitive function as measured in a cross-sectional analysis, especially concerning testing of “speed and executive” function.29 Vascular aging is thus linked to brain and cognitive aging.


Table I
Table I. Proposed components (criteria) for definition of the early
vascular aging syndrome.

Abbreviations: HDL, high-density lipoprotein; SD, standard deviation; TG, triglycerides.



In northern Portugal, in the Gumarães study, Cunha and colleagues have screened more than 2500 local inhabitants from an area known for a high stroke incidence, one of the highest in the western part of Europe.30 In that study, the authors wanted to screen for the proportion of subjects with characteristics of EVA in that stroke-prone population. The method they used to define EVA subjects was the one based on c-f PWV more than 2 SDs above normal in the European database. The findings were remarkable, with a very high proportion defined as EVA subjects in the young, especially in young men.30 The causes are unknown; however, that finding calls for screening and treatment of cardiovascular risk factors, including blood pressure control and improved lifestyle, in these subjects.

Also, in the Belgian Asklepios study, arterial aging has been determined in a healthy population by use of measures of arterial stiffness and ultrasound examinations of large arteries.31 The findings showed that femoral arterial stiffness was higher in men than in women, but did not change with age and no age-gender interaction was evident. Carotid arterial stiffness increased with age and showed a significant age-gender interaction, with carotid stiffness increasing more rapidly in women than in men, crossing over around the age of 45 years. Aortic pulse wave velocity did not differ between men and women, but did increase with age. No age-gender interaction was evident. The authors concluded that the relation with age and gender of local and central stiffness measures is not the same over the age range of 35-55 in apparently healthy men and women. Whether age-gender effects, as evident in the carotid artery, are found centrally depends on the central stiffness parameter used.31

It is thus of great importance to have a number of population based studies to compare between, especially for characteristics of EVA and the prevalence rates in different age groups. Studies from other ethnic groups are also very much needed.

Prediction of cardiovascular disease based on arterial stiffness

Stiffening of the large arteries known as arterial stiffness (arteriosclerosis) has been shown to be an important risk marker for future cardiovascular events and mortality beyond well-known cardiovascular risk factors, based on two updated meta-analyses.32,33 The prediction of total mortality hints that arterial stiffness could be a marker of aging and frailty in gen- eral, including increased risk of many causes of mortality. Measurement of arterial stiffness is preferably performed by use of c-f PWV,34 with a risk threshold of 10 m/s according to an updated consensus document from 2012 published in the Journal of Hypertension.35 This can be achieved by both direct and indirect methods, which are reasonably well correlated with each other in most cases, even if the direct measurement (c-f PWV) is preferred. Arterial stiffness is known to be strongly associated with age and hypertension,36 findings also confirmed in a longitudinal study from the United States.37 The arterial aging is tightly intercorrelated with blood pressure and causes the increase in pulse pressure seen in aged individuals. In some individuals, the arterial stiffening seen with increasing age is more pronounced and occurs earlier in life, a marker of EVA. In fact, a number of nonhemodynamic components are thought to affect arterial aging, such as hyperglycemia and dyslipidemia. Several cross-sectional studies have shown an association between arterial stiffness and diabetes as well as with markers of impaired glucose metabolism.38,39 This is also evident in subjects with end-stage renal disease (ESRD) with an increased central arterial stiffness. However, results from studies investigating the association between arterial stiffness and other and milder stages of chronic kidney disease (CKD) have presented conflicting results.40 There is no doubt that a close link exists between CKD and cardiovascular disease (CVD) as well as with metabolic changes— for example, hypercholesterolemia—and that the degree of albuminuria is a marker of this increased risk, easy to quantify. More studies are needed for evaluation of vascular calcification as an important part of the arterial aging phenomenon in CKD patients.

How can we build awareness and interest in knowing one’s vascular age?

It is a common human finding that most people are interested in their health and would like to avoid disease if possible, especially for members of families at increased risk of cardio-metabolic disorders. Attempts have been made to develop models to show cardiovascular risk estimation; one example is based on the European Systemic COronary Risk Evaluation (SCORE).41 In both SCORE and the Framingham project, another model has been proposed, one that calculates the so called cardiovascular risk age,42 where conventional risk factors for coronary heart disease are used, not arterial stiffness (PWV) itself.

In recent years, many manufacturers of modern devices that estimate, either directly or indirectly, the stiffness of the aorta have launched models to calculate vascular age based on stiffness estimation. As the gold standard methods (Complior, SphygmoCor) for direct assessment of c-f PWV have until now been expensive to use—though becoming less so with time—other devices with various ways of indirect measurement have been marketed (Arteriograph, Mobil-O-Graph, the CAVI system [cardio-ankle vascular index], etc). The increasing attention to arterial stiffness and vascular aging, not only among physicians, but also among patients and lay people has led to the development of various ways to calculate the vascular age based on algorithms where background factors (age, sex, body mass index, blood pressure, smoking) are entered together with some kind of measure of aortic stiffness or central hemodynamics. In the end, it is possible to show an individual’s vascular age in relation to chronological age, or at least an approximation. If elevated, this sends a strong message that a discrepancy is present and that signs of early aging are detected. Patients may understand this to reflect not only vascular aging, but in a more general sense, biological aging, which may trigger different reactions, perhaps even fear and anxiety. However, if the physician-patient relationship is good and based on mutual trust and understanding, this can lead later on to positive changes in lifestyle. It may also encourage patients to accept new drug treatment for risk factors, for example, elevated blood pressure.

Poor adherence to preventive drug therapy is a well-described problem.43 If new pedagogical models can improve adherence, this could translate into a more solid cardiovascular risk reduction, for example, if somebody decides to quit smoking or to restart previously abandoned therapy for hypertension and hyperlipidemia. The estimates of vascular aging (arterial stiffness) can even be followed over time at repeat visits. That can provide the patient with useful feedback information further reinforcing healthy lifestyle changes and adherence to drug therapy. A similar, well-known approach is used with diabetic patients, who are taught and encouraged to follow their own fasting glucose levels via home measurements and to keep a diary of habits and plasma glucose levels, as well as their glycated hemoglobin A1c (HbA1c) levels.

In preventive cardiology, we need to find new ways to increase interest in cardiovascular risk and awareness to promote healthy changes. At the same time, we have to be cautious not to over exaggerate findings for risk markers that could be influenced by technical shortcomings. Due to methodological variation, which clinicians are very accustomed to and understand, it is better to rely on repeated measures rather than to put too much emphasis on single measurements.

Treatment of arterial stiffness

Different methods have been proposed to treat or retard the process of arterial stiffening as a reflection of vascular aging, and a number of suggested interventions are shown in Table II. So far, one observational analysis of 294 patients with a prolonged follow-up period has shown that, beyond blood pressure control, prolonged control of hypertension reverses early vascular changes and has a long-term beneficial influence on arterial stiffness with decreasing c-f PWV levels over time.44 It is suggested that blocking the renin-angiotensin system (RAS) or using calcium antagonists could be of special relevance, based both on experimental and clinical studies.

Only one large intervention study addressing arterial stiffness (as the core component of EVA) is currently ongoing. This is the randomized controlled SPARTE study (Stratégie de Prévention Cardiovasculaire Basée sur la Rigidité Arterielle) in France, aiming to compare a treatment strategy for reduction of arterial stiffness (c-f PWV) by different means, including drugs that specifically influence the RAS, with another treatment strategy (control) for controlling conventional risk factors, including blood pressure, as suggested inguidelines.45 SPARTE is planned to continue for a number of years, until a sufficient number of cardiovascular end points has accumulated in order to show potential differences in outcomes between the treatment arms. Recruitment is ongoing, eventually also for patients outside of France in collaboration with the European Society of Hypertension (ESH).

It is important to note that a number of new antihypertensive drugs are under development at various stages of preclinical and clinical studies, as reviewed by Laurent et al in the Lancet.46


Table II
Table II. Potential treatment modalities for early vascular aging
(and its core component, arterial stiffness).

Abbreviations: AGE, advanced glycation end products; GH, growth hormone;
IGF-1, insulin-like growth factor 1; MMP, matrix metalloproteinase; PARP-1,
poly(ADP-ribose) polymerase 1; RAS, renin-angiotensin system; TNF, tumor
necrosis factor.


Multiple cardiovascular risk factor control for EVA

As increased c-f PWV has been documented to be an independent risk marker for future cardiovascular events and total mortality in recent meta-analyses,32,33 there is a need to target it with multiple-risk-factor control, aiming for a c-f PWV measure under 10 m/s, the current threshold for increased risk. Whether this also holds true in patients with established type 2 diabetes is currently unknown. However, it is plausible and very likely that it takes a multidrug intervention to achieve positive results in these patients, because of the advanced stage of vascular disease and the combination of arteriosclerosis, atherosclerosis, and chronic inflammation further enhanced by hyperglycemia and insulin resistance. This strategy is also emphasized in the recent European guidelines on risk factor control in patients with diabetes, prediabetes, or impaired glucose metabolism.47 In clinical practice, this means that cardiovascular risk patients should be offered antihypertensive and lipid-lowering drugs (statins) as well as antidiabetic drugs if needed, but they should also stop smoking (facilitated by drugs if necessary) and take aspirin, the latter only in secondary prevention.

The treatment should also be patient-centered and based on motivation, information, and effective systems for clinical follow- up.

New and emerging therapies

There exist a number of potential therapeutic alternatives for treatment of vascular aging,48 but still no specific treatment directed against arterial stiffness itself (Table II). Recently, new discoveries for better understanding the RAS have led to the development of a selective angiotensin II type 2 (AT2) receptor agonist called Compound 21 (C21). This rather small molecule increases the physiological defense mechanism in the vascular system, providing some vascular protection based on anti-inflammatory and antiremodeling effects on the arterial wall. Still, only data from animal experiments are available,49 but these have shown a reduction in arterial stiffness in experimental models of induced hypertension.50 The interesting aspect is that the blood pressure effect is rather limited, so this could be a way to selectively improve arterial compliance. Other beneficial actions of C21 include neuroprotection and improved glucose metabolism. This means that the drug will also be tested in other animal models of disease. If these intervention effects can also be repeated in humans and with a positive tolerance profile, the drug could be used for vascular protection in combination with more conventional antihypertensive and lipid-lowering drugs. So far, the safety profile seems to be beneficial in animal experiments, even at supranormal dosages of C21. Human studies are planned to begin during 2015 or 2016.

There have been high hopes for dietary modification of vascular aging, for example, by use of resveratrol, an extract from red wine flavonoids.51 The benefits of the Mediterranean diet are well known, and one Dutch study showed beneficial influences in adolescence and early adulthood.52 The authors concluded that this kind of diet may be an important means of preventing arterial stiffness in adulthood.

Summary

EVA as a new concept for research and early prevention has sparked interest among many physicians, and offers new perspectives. Current medical and surgical therapies will be expanded in the future for better control of the pathological processes involved, even for the control of arterial aging. If stiffness of large arteries can be controlled, this may also benefit the microvasculature, as the transmission of pulse wave energy to the periphery will decrease. New interventions are needed to address the role of blood glucose and advanced glycation end products for worsening EVA, as are methods to counteract this detrimental influence on the arterial wall. A better control of arterial stiffness and central hemodynamics53 could eventually translate into improved prognosis and reduced risk of CVD events. What can be done now is to aim for an effective 24-hour blood pressure control, both for brachial and central blood pressure. This requires drug combination therapy in many patients, where RAS blockers and calcium antagonists should be preferred. If patients can be convinced that arterial and vascular aging is of concern to them, this will increase understanding and adherence to therapy, thereby contributing to cardiovascular prevention: the earlier, the better!

Acknowledgments. This review was supported by two grants from the Research Council of Sweden for research on early vascular aging and cardiovascular risk factors.


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Keywords: aging; arterial stiffness; blood pressure; C21; drugs; family; glycemia; hypertension; vascular