Strain and Paldánius Cardiovasc Diabetol (2018) 17:57 https://doi.org/10.1186/s12933-018-0703-2 Cardiovascular Diabetology REVIEW Open Access Diabetes, cardiovascular disease and the microcirculation W. David Strain1* and P. M. Paldánius2 Abstract Cardiovascular disease (CVD) is the leading cause of mortality in people with type 2 diabetes mellitus (T2DM), yet a signifcant proportion of the disease burden cannot be accounted for by conventional cardiovascular risk factors. Hypertension occurs in majority of people with T2DM, which is substantially more frequent than would be antici- pated based on general population samples. The impact of hypertension is considerably higher in people with diabetes than it is in the general population, suggesting either an increased sensitivity to its efect or a confounding underlying aetiopathogenic mechanism of hypertension associated with CVD within diabetes. In this contribution, we aim to review the changes observed in the vascular tree in people with T2DM compared to the general population, the efects of established anti-diabetes drugs on microvascular outcomes, and explore the hypotheses to account for common causalities of the increased prevalence of CVD and hypertension in people with T2DM. Keywords: Microcirculation, Type 2 diabetes mellitus, Hypertension, Cardiovascular disease, Microvascular changes, Microalbuminuria Background in T2DM and hypertension, which in turn have signif- Type 2 diabetes mellitus (T2DM) and hypertension cant implications with respect to future CV risk. are established risk factors for cardiovascular disease (CVD), and people with T2DM and hypertension have Vascular anatomy in cardiovascular disease an increased risk of cardiovascular (CV) mortality com- Although there is increasing evidence that the venous pared with those with either condition alone [1]. Tis tree regulates cardiac output and total body circulating excess risk is suggested to be due to the synergistic efect fuid, the majority of the pathology occurs within the on large and small blood vessels simultaneously, thereby arterial circulation. Broadly, the arterial tree spanning reducing the potential for compensatory collateraliza- from the large coronary artery to the minute capillar- tion protecting organs from the adverse consequences of ies is comprised of four components—elastic (conduit) damage to either vascular bed. Te principle role of the arteries, muscular conduit arteries, muscular resistance vasculature is to deliver oxygen and nutrients to the tis- arterioles and capillaries—each representing a distinct sues—whether that is the heart, the brain, or the kidney. vessel system (Fig. 1) with a distinct role to play in the Te functional changes occurring in T2DM and hyper- circulation [2]. Elastin and collagen, the major structural tensive conditions signifcantly alter the haemodynamic proteins of elastic and muscular conduit arteries, respec- stress on the heart and other organs. However, the dif- tively, provide mechanical strength to the vessel wall for ferent physiology, mechanisms and changes at the micro- the conduct of blood from the heart to peripheral organs vascular level difer from those at the macrovascular level [3]. Teir abundance along the longitudinal aortic axis is largely determined during the developmental stage and remains quite stable after that, due to the extremely low *Correspondence: [email protected] 1 Diabetes and Vascular Medicine Research Centre, NIHR Exeter Clinical turnover [2]. Te basic architecture of the arterial tree Research Facility and Institute of Biomedical and Clinical Science, displays a progressive change from predominantly elas- University of Exeter Medical School, Royal Devon & Exeter NHS tin and vascular smooth cells at the aortic arch, gradu- Foundation Trust, Barrack Road, Exeter EX2 5AX, UK Full list of author information is available at the end of the article ally giving way to a collagen rich media by the distal aorta © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Strain and Paldánius Cardiovasc Diabetol (2018) 17:57 Page 2 of 10 Elastic artery Muscular artery Arteriole Capillary Internal elastic layer Tunica Endothelium Intima Tunica externa Tunica media Smooth muscle Basement cells (Media) membrane Endothelium Basement membrane Capillary lumen Tunica media Endothelium Tunica Intima Endothelium Tunica externa Thickening of basement membrane Reduced lumen Hypertrophic Eutrophic diameter remodelling remodelling Smaller capillary area Type 2 diabetes Essential hypertension Essential hypertension/ Type 2 diabetes Fig. 1 Structural hierarchy of arterial tree in health and disease conditions (Table 1). Over the last fve centimetres of the thoracic Hypertensive target organ damage in people with diabetes aorta and aortic branches, there is a rapid transition to One of the hallmarks of hypertensive vascular damage is a predominantly collagen and vascular smooth cell mus- increased arterial stifness in the large elastic arteries [4]. cular artery. In the resistance arterioles and capillaries, Arterial stifness contributes to the pathogenesis of ath- vascular smooth muscle (VSM) cells become increas- erosclerosis and independently predicts CV death after ingly sparse until these are no more than one cell layer in adjustment for hypertension, age and gender in patients the terminal branches. VSM cells have difering embry- with end stage renal failure [4], essential hypertension [5] onic origins in the vessel beds, with proximal elastic and T2DM [6]. Greater arterial stifness [7] and vascular and muscular vessels derived from ectodermal tissue, endothelial cell dysfunction [8] were reported in patients whereas small muscle beds and arterioles have meso- with T2DM. Concomitant T2DM and hypertension is dermal origin. Tereby, the formation of microcircula- also associated with greater arterial stifness than either tion is a result of the complex process of angiogenesis condition alone, independent of conventional CV risk from these mesodermal tissues which takes place dur- factors such as gender, smoking history and ethnicity [9, ing embryonic development as well as during adulthood 10]. Furthermore, in people with diabetes, the cell types (e.g. during hypoxic conditions) [2]. Tese diferences in which maintain integrity of the vascular wall in the mac- embryology have potential pharmacological and clinical rocirculation are more prone to damage, particularly in consequences later in life as they are thought to trigger the presence of CV risk factors [11]. Tese macrovascu- diferential efects of certain classes of vasodilators such lar changes, however, are evident in the pre-diabetic and as calcium channel blockers or α-adrenoceptor antago- pre-hypertensive stages, raising the possibility of a vascu- nists on proximal versus distal VSM cells. lar aetiology in the pathogenesis of diabetes and hyper- tension [12, 13]. Table 1 Characteristics of components of the arterial tree Elastic arteries Muscular conduit arteries Muscular resistance arterioles Capillaries Diameter > 2 mm 150 µm–2 mm 8–150 µm < 8 µm Regulation Media structure > endothelium Media structure and endothelium Endothelium > media structure Endothelium only Function Conduit: elastic recoil (diastolic BP) Conduit: minor resistance Resistance Nutrient and waste exchange BP blood pressure Strain and Paldánius Cardiovasc Diabetol (2018) 17:57 Page 3 of 10 Several mechanisms have been proposed to account for microvascular dysfunction confrm presence of multiple the greater arterial stifness in patients with T2DM and predictors of microvasculopathy and health outcomes of hypertension. Elevated glycaemia is a major determinant macrovascular events: studies of skeletal muscle micro- of both arterial stifness and carotid intimal media thick- circulation in rat models indicate greater heterogeneity ness (IMT), the latter of which is another well-established in perfusion distribution and reduced fexibility in micro- measure of blood pressure (BP)-related damage indepen- vascular network, progressive decrease in NO bioavail- dently predictive of CV events [14, 15]. Chronic hyper- ability, arachidonic acid metabolism, as well as myogenic glycaemia is known to be associated with the build-up of activation and adrenergic constriction [26]. advanced glycation end-products (AGEs), which, lead to arteriosclerosis [16]. Tis could account for the impact The role of microcirculation is universal of glycaemia on endothelial function. A meta-analysis Te emphasis on large vessel diseases such as increased reported that an increase in carotid IMT by 0.13 mm arterial stifness and carotid IMT ignores the contribu- is associated with an increase in CV risk by nearly 40% tion of the microcirculation to CVD. Whilst the asso- in patients with T2DM compared with control subjects ciation between disease of the conduit or resistance [17]. arteries and CVD has been explored and well-charac- Oxidative stress is an alternative mechanism which has terised, much of the variance