Arterial Stiffness, the Metabolic Syndrome, and the Brain

The so-called metabolic syndrome (MetS) has been a topic of controversy ever since a critical debate started in 2005 on whether it exists or not, its definitions, and treatment alternatives.1 Nevertheless, the constellation of cardiometabolic risk factors/markers in MetS is still a reality, even if the predictive ability of MetS for future cardiovascular events is not supposed to be more than the sum of its components. The most recent definition of MetS was presented in 20092 and is still not further revised. Recently the focus of interest in preventive cardiology has shifted to the role of arterial stiffness (arteriosclerosis) as a major driver of increased cardiovascular risk and increased total mortality, even adjusted for other cardiovascular risk factors/markers.3,4 Furthermore, some of the metabolic abnormalities associated with MetS (increased glycemia, insulin resistance, dyslipidemia) are also characteristics of increased arterial stiffness, as measured by pulse-wave velocity (PWV) in large, elastic arteries, even adjusted for hemodynamic factors such as mean arterial blood pressure and heart rate.5,6 In fact, these abnormalities have been included in the new concept of early vascular ageing7,8 that is now being screened for in various populations. The brain is an organ prone to disease complications caused by cardiovascular and metabolic risk factors. This includes not only cerebrovascular stroke but also impaired cognition associated with white matter lesions or white matter intensities and vascular dementia. MetS has been linked to increased risk of these abnormalities,9 and this is also the case for hypertension10 and type 2 diabetes11 alone. More recently, evidence has accumulated that increased arterial stiffness (PWV) is associated with impaired cognitive function in a nonlinear pattern,12 but not predictive of dementia in general,13 even if more prospective studies are needed. This could be explained by the hypothesis that cognitive development and later age-related impairment during the life course are separated from dementia as a specific disease entity.13 Almost all people experience impaired cognition with ageing, or at least slowed cognitive processing and exe cutive function, but only a minority will develop dementia. One important research area is to understand the early stages of this process and how cardiometabolic risk factors/markers affect the cerebral circulation, and whether this process is possible to prevent or to retard by improved risk factor control. An earlier study showed that different constellations of MetS components had different associations with aortic PWV in a large international multicenter study, mostly recruiting European subjects.14 However, no specific measurements were available to analyze such associations with arterial segments closer to the brain and their characteristics. In a new observational study, it was investigated whether MetS was associated with reduced cerebral blood flow at midlife, and if so, whether arterial stiffness was responsible for mediating their relation.15 In total, 83 middle-aged adults were studied and an MetS score was calculated for each subject. All subjects were free from cardiovascular or neurological disease. Middle cerebral artery hemodynamics were measured using transcranial Doppler ultrasound. Indices of aortic, systemic, and carotid artery stiffness were derived. The results showed that subjects had a constellation of subclinical MetS pathology that was inversely associated with cerebrovascular conductance (CVC: r = −0.26; P = 0.02). Carotid-femoral PWV, brachial-ankle PWV, and carotid artery distensibility fully mediated the direct association of MetS score and CVC. The authors concluded that arterial stiffness, particularly the stiffness of the carotid artery, mediated reductions in CVC related to MetS. Based on these findings, it is now better understood how MetS characteristics and vascular abnormalities are linked, of great importance for the development of brain pathology as influenced by arterial stiffness and reduced CVC. It is regretted that no measurement of cognitive function was carried out, but such variables could be of great importance to add when vascular changes (arterial stiffness) are linked to brain pathology (white matter lesions) and cognitive dysfunction, as was previously reported from the Reykjavik study.16 Another important aspect is the role of insulin sensitivity. It is suggested that impaired insulin sensitivity (insulin resistance) is the unifying factor for MetS components. We also know that insulin resistance may impair endothelial function and vasodilation. This could be one of the causative mechanisms behind the link between MetS and arterial stiffness resulting in lower CVC, but neither insulin sensitivity nor endothelial function was measured in the study. However, the authors hypothesize that elevated glucose levels, i.e., impaired glucose metabolism (involving insulin sensitivity), would be the MetS component with greatest contribution to arterial stiffness and CVC reductions. This should be further explored in future studies. In summary, the association described between MetS components and reduced CVC, as mediated by measures of arterial stiffness, is an important step to better understand the interplay between metabolic and hemodynamic factors for increased risk of impaired cognitive function and vascular dementia (Figure 1). This calls for preventive action, as summarized in the 2011 recommendation from a number of American organizations, such as the 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.17 In the future, more focus should also be put on the influence of a positive family history for cardiometabolic disease or traits for risk of arterial stiffness,18 and genetic factors that could increase the risk both of dementia and atherosclerotic disease such as ApoE4.19 As hypertension is a major risk factor for both cerebrovascular events and brain pathology (i.e., white matter lesions, white matter intensities), the screening and treatment of hypertension is of prime importance on a global scale, as recently pointed out by the Lancet Commission for Hypertension,20 where also the early vascular ageing concept was highlighted. Schematic representation of the proposed interrelationship between the metabolic syndrome, insulin resistance, vascular changes, and risk of impaired cognitive function and vascular dementia. CVC, cerebrovascular conductance; WMI, white matter intensities; WHL, white matter lesions. This work was supported by a grant from the Swedish Research Council for studies on arterial stiffness, metabolism, and impaired cognition.