Early Vascular Ageing – A Concept in Development

European Endocrinology, 2015;11(1):26–31 DOI: http://doi.org/10.17925/EE.2015.11.01.26

Abstract:

Cardiovascular disease (CVD) is a prevalent condition in the elderly, often associated with metabolic disturbance and type 2 diabetes. For a number of years, research dedicated to understand atherosclerosis dominated, and for many good reasons, this pathophysiological process being proximal to the CVD events. In recent years, research has been devoted to an earlier stage of vascular pathology named arteriosclerosis (arterial stiffness) and the new concept of early vascular ageing (EVA), developed by a group of mostly European researchers. This overview describes recent developments in research dedicated to EVA and new emerging aspects found in studies of families at high cardiovascular risk. There are new aspects related to genetics, telomere biology and the role of gut microbiota. However, there is still no unifying definition available of EVA and no direct treatment, but rather only recommendations for conventional cardiovascular risk factor control. New interventions are being developed – not only new antihypertensive drugs, but also new drugs for vascular protection – the selective angiotensin-II (AT2) agonist Compound 21 (C21). Human studies are eagerly awaited. Even new functional food products could have the potential to positively influence cardiometabolic regulation, to be confirmed.
Keywords: Arterial ageing, arterial stiffness, blood pressure, C21, diet, drugs, glycaemia, hypertension, lipids, microbiota
Disclosure: Peter M Nilsson has no conflicts of interest to declare. No funding was received for the publication of this article. This review was supported by two grants from the Research Council of Sweden for research on vascular ageing and the family clustering of cardiometabolic disorders.
Received: February 04, 2015 Accepted March 13, 2015
Correspondence: Peter M Nilsson, Lund University, Department of Clinical Sciences, Skåne University Hospital, IM Nilssons gata 32, S-205 02 Malmö, Sweden. E: Peter.Nilsson@med.lu.se

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Thomas Sydenham, the great English seventeenth-century physician (see Figure 1), said that “A man is as old as his arteries”, a concept that has once again come into focus of cardiovascular research and clinical activities, which this review aims to describe.

In preventive cardiology there has long existed the need to target individuals at risk for preventive action based on lifestyle improvement and intervention related to conventional risk factors for cardiovascular disease (CVD) manifestations (hyperlipidaemia, hypertension, smoking, diabetes). This has been made possible by use of specific risk algorithms based on follow-up investigations of screened subjects for prediction of events in large population-based cohorts. Famous examples include the Framingham Risk Score (FRS)1 and the European SCORE, which originated with the Danish algorithm PRECARD,2 as well as other lessknown algorithms (PROCAM from Germany; Q-RISK from the UK). The SCORE system has been calibrated to national applications based on national cardiovascular statistics on CVD endpoints. Computer applications have been widely distributed, even when the clinical uptake is difficult to quantify.

At least the US-based FRS has been found to overestimate the cardiovascular risk in many European populations, providing a reasonfor using SCORE instead.3,4 Furthermore, new versions of SCORE, including high-density lipoprotein (HDL) cholesterol and not only total cholesterol, will reclassify patients more correctly for risk categories than does the traditional SCORE.5 For cardiovascular complications of type 2 diabetes, some other risk algorithms have been developed in newly detected patients, based mostly on the UK Prospective Diabetes Study (UKPDS) Risk Engine,6 but also based on national register data on treated patients with type 2 diabetes from Sweden.7 The endpoint most commonly used for these algorithms was cardiovascular events (fatal or non-fatal), generally caused by atherosclerosis, plaque rupture or thrombo-embolic mechanisms. In more recent years, the research activities dedicated to atherosclerosis also started to involve effects of acute or chronic inflammation mediating the risk of CVD – for example,in patients with the metabolic syndrome.8 Inflammation is often linked to abdominal obesity, insulin resistance and hepatic steathosis and supposed to be both general and local – that is, perivascular by origin. The modern genetic studies and discoveries of CVD and type 2 diabetes have contributed to our understanding of causal pathways for these disorders, as revealed by applying so-called causal inference (Mendelian randomisation) methodologies,9 but so far have not resulted in new drug developments. Even if substantial achievements have been accomplished both in pathophysiology and evidence-based treatment, there is need for deeper understanding of the early origins and features of cardiovascular and metabolic disease, as well as elucidation of why many of these disorders tend to cluster in families at risk not directly addressed in the conventional risk algorithms. This is a background for the emerging interest dedicated to arterial stiffness (arteriosclerosis) and the development of the concept of early vascular ageing (EVA) since 2008. It is noteworthy that the previous concept of the metabolic syndrome has been heavily criticised since 2005, mostly by diabetologists, for inherent problems with definitions and applications in daily practice, but also for the lack of specific treatment.10 Thus the arena was open to new concepts in cardiometabolic medicine to support understanding of pathophysiology and prevention. Such new concepts will one day also challenge the EVA construct and are a reflection of how science works in a critical way.

Arterial Stiffness as a Reflection of Vascular Ageing
Attempts have been made to define arterial ageing during the development from normal ageing of arteries to disease caused by superimposed atherosclerosis.11 Many researchers now consider arterial stiffness (arteriosclerosis) to represent an earlier step in vascular pathology during the life course than atherosclerosis, as arterial stiffness could possibly be influenced to a high degree by factors acting already in early life. Atherosclerosis leading to plaque formation and rupture, causing clinical disease events, is better defined and has been associated with a number of well-known risk markers or risk conditions.12 Among these are genetic factors, especially involving lipid metabolism, as well as adverse lifestyle factors (smoking, sedentary lifestyle, unhealthy diet) and traditional risk factors such as hypertension and diabetes, but also less-well-defined factors such as chronic inflammation and the influence of oxidative stress.

As every human being has once been pre-formed in utero, some hypotheses hold that early life influences could play a role in development of arterial function and vascular morphology, leading to increased risk of arteriosclerosis as visible at least in young adulthood. All components of the vascular tree may be affected – for example, the elastin content and thinness of the arterial wall; the development of the microcirculation, as can be studied in the retinal bed; and, finally, the number and functionality of capillaries.

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Keywords: Arterial ageing, arterial stiffness, blood pressure, C21, diet, drugs, glycaemia, hypertension, lipids, microbiota