Introduction
Age is one of the most important risk factors for cardiovascular disease,Reference Najjar, Scuteri and Lakatta1 although the exact mechanism, beyond a greater accumulation of exposure to environmental pathogens, by which ageing leads to cardiovascular events is not fully understood. As the absolute numbers and proportion of older adults increases across most of the developed world, a greater understanding of the aetiopathogenic mechanisms of the increased vascular risk and their therapeutic implications becomes essential to all clinicians assessing and managing the geriatric patient. The purpose of this review is to discuss what is currently understood about the role of the endothelium and microcirculation in the ageing process.
The endothelium
Endothelial dysfunction, a key vascular change observed with advancing age, is increasingly being recognized as an important early step in the process of clinical cardiovascular disease. The endothelium, that is the monolayer of cells forming the interface between circulating blood and the intima of all blood vessels, plays a vital role in maintaining vascular homeostasis.Reference Moncada, Palmer and Higgs2 The healthy endothelium is optimally placed and is able to respond to physical and chemical signals by production of a wide range of factors that regulate vascular tone, cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation.Reference Deanfield, Halcox and Rabelink3 In normal physiology the endothelium produces nitric oxide (NO), mainly in response to shear stress, but also by messengers such as bradykinin, vascular endothelial growth factor (VEGF), adenosine and serotonin. This acts as a vasodilator adapting tissue perfusion to changes in cardiac outputReference Corson, James, Latta, Nerem, Berk and Harrison4 whilst inhibiting inflammation, cellular proliferation and thrombosis, thereby maintaining the vascular wall in a quiescent state. Other vasodilatory mechanisms regulated by the endothelium include prostacyclinReference Higgs, Higgs, Moncada and Vane5 and endothelium-derived hyperpolarizing factor (EDHF).Reference Busse, Edwards, Félétou, Fleming, Vanhoutte and Weston6 EDHF can compensate for loss of NO-mediated vascular tone particularly in the microcirculation.Reference Halcox, Narayanan, Cramer-Joyce, Mincemoyer and Quyyumi7 All of these vasodilatory factors are reduced with advancing age.Reference Wang and Lakatta8–Reference Taddei, Virdis, Mattei, Ghiadoni, Gennari, Fasolo, Sudano and Salvetti10 Further, endothelial produced vasoconstrictors such as endothelin-1, prostanoids and angiotensin II, which in health help modulate vasomotion,Reference Kinlay, Behrendt, Wainstein, Beltrame, Fang, Creager, Selwyn and Ganz11, Reference Saye, Singer and Peach12 are up-regulated with increasing age. Additional work has demonstrated a pro-inflammatory and oxidative stress phenotypeReference Donato, Eskurza, Silver, Levy, Pierce, Gates and Seals13, Reference Taddei, Virdis, Ghiadoni, Salvetti, Bernini, Magagna and Salvetti14 in impaired endothelial function of carefully screened healthy, older people.
These impairments in endothelial function are mechanistically involved in the initiation and development of atherosclerosisReference Deanfield, Halcox and Rabelink3, Reference Davignon and Ganz15–Reference Vita and Keaney17 and predict future cardiovascular disease.Reference Halcox, Schenke, Zalos, Mincemoyer, Prasad, Waclawiw, Nour and Quyyumi18–Reference Suwaidi, Hamasaki, Higano, Nishimura, Holmes and Lerman20 Because of this, impaired vascular endothelial function with advancing age has been widely studied as a putative and potentially reversible mechanism by which age acts to increase cardiovascular risk.
Recognition of the importance of the endothelium has resulted in a considerable amount of research, mostly focusing on conduit arteries and resistance vessels, often using a forearm model. However, the majority of the vascular endothelium lies within the microvasculature, due to the large surface area of the nutritive vessels when compared with the conduit vessels. As such, the role of endothelial dysfunction in the microcirculation plays an important role in regulating tissue perfusion.
The microcirculation
The microcirculation comprises flow within the arterioles and venules <150 μm in diameter, which show a myogenic reduction in lumen diameter in response to increase in pressure, and capillaries.Reference Levy, Ambrosio, Pries and Struijker-Boudier21 It provides the interface for the delivery of oxygen and nutrients, the removal of waste products and carbon dioxide, transvascular exchange and tissue fluid economy.Reference Shore, Tooke and Lowe22 Organs, tissues and most cells depend on adequate perfusion by the microcirculation and thus adequate microvessel function is essential for the cardiovascular system to fulfil this fundamental role.Reference Shore, Tooke and Lowe22 As such, changes in microvessel function with age may have important consequences for organ function and overall human health. The structure and function of the microcirculation have been covered elsewhere in detail.Reference Shore, Tooke and Lowe22–Reference Serné, de Jongh, Eringa, IJzerman and Stehouwer24
The contribution of endothelial function to alterations in microvascular structure and function with advancing age has been the subject of increased interest in recent years. This is partly due to recognition of the importance of microcirculation in cardiovascular and metabolic diseases. Abnormalities of the microcirculation have been reported in a number of disease states including hypertension,Reference Feihl, Liaudet, Waeber and Levy25, Reference Tooke, Sandeman and Shore26 insulin resistance,Reference Serné, de Jongh, Eringa, IJzerman and Stehouwer24 and type I and II diabetes.Reference Tooke, Morris and Shore27 Framingham Risk Score is also associated with impaired skin microvessel endothelium-dependent vasodilatation in healthy older men and women.Reference Ijzerman, de Jongh, Beijk, van Weissenbruch, Delemarre-van de Waal, Serné and Stehouwer28
Clinically, elevated urinary albumin excretion rate (AER), an indirect marker of renal microvascular damage, independently predicts total and cardiovascular mortality in diabetes,Reference Mattock, Barnes, Viberti, Keen, Burt, Hughes, Fitzgerald, Sandhu and Jackson29 hypertensive patients,Reference Ljungman, Wikstrand, Hartford and Berglund30 postmenopausal women,Reference Roest, Banga, Janssen, Grobbee, Sixma, de Jong, de Zeeuw and van der Schouw31 elderly patients,Reference Damsgaard, Frøland, Jørgensen and Mogensen32 and the general (largely non-diabetic) population, right into the normal range of AER.Reference Yudkin, Forrest and Jackson33–Reference Gerstein, Mann, Yi, Zinman, Dinneen, Hoogwerf, Hallé, Young, Rashkow, Joyce, Nawaz and Yusuf35 Similarly, microvascular retinopathy is associated with a 3-fold increase in risk of heart failure even in people without pre-existing coronary heart disease, diabetes or hypertension.Reference Wong, Rosamond, Chang, Couper, Sharrett, Hubbard, Folsom and Klein36 Cerebral microvascular disease indicated by the presence of white matter lesions or leukoariaosis on magnetic resonance imagingReference Pantoni and Garcia37 were associated with increased risk of stroke in the Atherosclerosis Risk In Communities (ARIC) study. This study also showed that if retinopathy was also present the risk ratio rose from 2.6 to 18.1,Reference Wong, Klein, Sharrett, Couper, Klein, Liao, Hubbard and Mosley38 suggesting that greater risk might be conferred by systemically abnormal microvascular function.
Microvessel ageing across the human lifespan
Current evidence indicates that a number of factors contribute to alterations in microvascular function from birth to older age. These include genetic factors, developmental factors, age-related biological factors, environmental and lifestyle factors as well as the interaction of disease processes that probably combine to determine microcirculatory health.
Genetic factors
Studies of parents and offspring suggest that children of hypertensives have attenuated maximal cutaneous microvascular perfusion and capillary recruitment compared with those of normotensive parents, and offspring who go on to develop hypertension have further blunting of responses compared with those who remain normotensive.Reference Noon, Walker, Webb, Shore, Holton, Edwards and Watt39 As such, a genetic predisposition to poor microvessel function may constitute an important part of the inheritance and development of hypertension in these individuals. In contrast to children of hypertensive subjects, offspring of normotensive parents who themselves develop hypertension demonstrate no difference in microvessel function.Reference Noon, Walker, Webb, Shore, Holton, Edwards and Watt39
Ethnic differences in microvascular function also suggest a genetic component to microvascular function. Women of African-Caribbean descent have poorer maximal cutaneous microvascular perfusion than European counterparts, and men and women of African-Caribbean descent have poorer post-occlusive microvascular reactive hyperaemia (i.e. the microvascular response to tissue ischaemia) compared with European counterparts after correcting for conventional risk factors.Reference Strain, Chaturvedi and Shore40 Left ventricular hypertrophy is also greater in African-Caribbeans and some of this difference is explained by poorer microvessel function.Reference Strain, Chaturvedi, Leggetter, Nihoyannopoulos, Rajkumar, Bulpitt and Shore41 The mechanisms underlying inherited differences in microvessel function are uncertainReference Lee, Shore, Humphreys, Lowe, Rumley, Clark, Hattersley and Tooke42 but these inherited differences may have important implications for appropriate risk stratification and clinical management of disease.
Developmental factors
Foetal development may also influence microvessel function. Low birth-weight babies born at full term have lower maximal hyperaemia at 3 months of age compared with babies of higher birth-weight.Reference Goh, Shore, Quinn and Tooke43 This persists into childhoodReference Martin, Hu, Gennser and Norman44 and may contribute to increased cardiovascular risk associated with low birth-weight.Reference Leon, Lithell, Vâgerö, Koupilová, Mohsen, Berglund, Lithell and McKeigue45 Impaired endothelial function and increased arterial stiffness have also been reported in adults with low birth-weight,Reference Goodfellow, Bellamy, Gorman, Brownlee, Ramsey, Lewis, Davies and Henderson46 suggesting that low birth-weight is associated with systemically poor micro- and macrovascular function.
During puberty, microvascular function adapts during pubertal development probably because of the greater hydrostatic challenge incurred as a result of the growth spurt and progression towards adult height.Reference Shore, Price, Sandeman, Tripp and Tooke47 Lowering the leg from a supine position to below heart level induces vasoconstriction in healthy post- but not pre-pubertal children. Children with type I diabetes do not fully acquire this microcirculatory adaptation during puberty, even if they are free of diabetic complications.Reference Shore, Price, Sandeman, Tripp and Tooke47 Similarly, adult diabetics do not display this compensatory mechanism resulting in capillary hypertension upon standing,Reference Shore, Price, Sandeman, Tripp and Tooke47, Reference Rayman, Hassan and Tooke48 potentially leaving the foot microcirculation exposed to high hydrostatic pressures associated with upright posture, perhaps contributing to the pathophysiology of the diabetic foot. These findings suggest that microvascular function during development and childhood may have important implications for disease pathophysiology and importantly precede other indicators of cardiovascular and metabolic diseases.
Adult ageing and the influence of biological and lifestyle factors
A common misconception is that microvascular function is a marker, whether cause or effect, of brachial arterial hypertension. However, a study exploring young and older normotensive and hypertensive subjects demonstrated impairment in endothelial-dependent (but not endothelial-independent) cutaneous microvascular vasodilatation and an increased capillary pressure in the older normotensive adults compared with their younger counterparts, but importantly no difference in capillary pressures or vascular function between the older adults with and without hypertension.Reference James, Tullett, Hemsley and Shore49 This suggests strongly that microvascular dysfunction is independent of brachial artery blood pressure. Microvessel dilatation in response to skin heating, used as a measure of maximal physiological tissue perfusion, is also diminished with age.Reference Kenney, Morgan, Farquhar, Brooks, Pierzga and Derr50 This appears to be mediated at least partly through alterations to nitric oxide signalling, but non-nitric oxide signalling mechanisms were also important.Reference Minson, Holowatz, Wong, Kenney and Wilkins51
Increasing weight is a recognized consequence of western ageing,Reference Seals and Gates52 such that approximately 44% of over-65s in the UK are overweight and a third are obese. In women, obesity is associated with impaired capillary recruitment and endothelium-dependent vasodilatation both in the basal state and during experimental hyperinsulinaemia.Reference de Jongh, Serné, Ijzerman, de Vries and Stehouwer53 This attenuation of microvascular vasodilatation in response to insulin will necessarily attenuate nutritive supply to tissues and is thought to represent ‘vascular insulin resistance’Reference de Jongh, Serné, Ijzerman, de Vries and Stehouwer53 and contribute to the development of hypertension.Reference Serné, Gans, Maaten, Wee, Donker and Stehouwer54 Visceral adiposity appears to be particularly detrimental to microvessel function, most likely mediated by a pro-inflammatory state,Reference de Jongh, Ijzerman, Serné, Voordouw, Yudkin, de Waal, Stehouwer and van Weissenbruch55 although the associated elevated circulating free fatty acid concentrations also are likely to contribute.Reference de Jongh, Serné, Ijzerman, de Vries and Stehouwer56 Finally, although not directly related, the high dietary salt usually associated with increased calorific intake is thought to influence microvessel function, most likely through increased activation of the renin angiotensin aldosterone system.Reference de Jongh, Serné, Ijzerman and Stehouwer57 Angiotensin II acts on the endothelial cell wall to increase vasoconstriction through endothelin-1; however, at least part of this is mediated through the local angiotensin system, rather than the systemic renal controlled system.Reference Shore, Tooke and Lowe22, Reference Feletou and Vanhoutte58
Aerobic exercise has been reported to attenuate the age-related decline in resistance vessel endothelial function through a nitric oxide-dependent mechanism.Reference DeSouza, Shapiro, Clevenger, Dinenno, Monahan, Tanaka and Seals59 A similar finding has recently been reported in skin microvessels studied using microdialysis. Microvessel function was worse in older sedentary compared with older active or younger men and this was attributable to impaired nitric oxide signalling.Reference Black, Green and Cable60 An exercise training programme in the sedentary older cohort restored microvessel function and improved nitric oxide signalling.
In women, hormone status may impart important influences on microvessel function. Capillary pressure is lower in women compared with men below age 50 years but there is no difference between the sexes after age 50.Reference Shore, Sandeman and Tooke61 However, hormone replacement therapy does not appear to improve microvessel function in healthy post-menopausal women and may be detrimental to the microcirculation in diabetic women.Reference Gooding, MacLeod, Spyer, Ewings, Tooke and Shore62 Impaired cutaneous post-occlusive reactive hyperaemia predicts increased cardiovascular risk as assessed by the Framingham risk scores, although it is unclear whether this is simply confounded by obesity and insulin resistance.Reference Vuilleumier, Decosterd, Maillard, Burnier and Hayoz63 Clinical markers of microvascular dysfunction appear to play a stronger prognostic role in women than men. An elevated urinary albumin excretion rate after a myocardial infarction is associated with a 1.7-fold relative death risk in men, whereas in women, after all other conventional risk factors such as obesity, hypertension, lipid profile, renal function and smoking had been adjusted for, the relative death risk is 3.3, more than twice that of men. Similarly in normotensive type 2 diabetes the vascular event rate in women with microalbuminuria is over three times that of comparable men.Reference Zandbergen, Sijbrands, Lamberts and Bootsma64 These data suggest that the microcirculation may play a more important role in the pathogenic mechanisms of vascular disease in women.
Therapeutic implications
Risk stratification
Measuring surrogates for microvascular and endothelial function is now commonplace in the assessment of patients at higher cardiovascular risk, such as those with diabetes, hypertension and chronic kidney disease.Reference de Zeeuw, Remuzzi, Parving, Keane, Zhang, Shahinfar, Snapinn, Cooper, Mitch and Brenner65 Retinal microvascular changes due to ageing, hypertension and other processes appear to reflect cerebral microvascular diseaseReference Goto, Katsuki, Ikui, Kimoto and Mimatsu66 and are associated with stroke independent of other risk factors.Reference Wong, Klein, Couper, Cooper, Shahar, Hubbard, Wofford and Sharrett67 Although this is clearly in place caution should be exercised with interventions, particularly in the elderly, as currently the evidence for targeting microvascular and endothelial function remains in embryonic form.
Lifestyle modifications, including the prescription of aerobic exercise, dietary modifications, caloric restriction, and weight loss, can improve endothelial function.Reference Hambrecht, Wolf, Gielen, Linke, Hofer, Erbs, Schoene and Schuler68–Reference Raitakari, Ilvonen, Ahotupa, Lehtimäki, Harmoinen, Suominen, Elo, Hartiala and Raitakari70 These lifestyle modifications have also been reported to improve prognosis in a whole range of cardiovascular and other conditions; however, as yet the proportionate risk reduction due to this improvement in microvascular function is unclear.
Targeting microalbuminuria
The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study demonstrated reduction in albuminuria translated to a reduction in cardiovascular endpoints.Reference Ibsen, Olsen, Wachtell, Borch-Johnsen, Lindholm, Mogensen, Dahlöf, Devereux, de Faire, Fyhrquist, Julius, Kjeldsen, Lederballe-Pedersen, Nieminen, Omvik, Oparil and Wan71 This accounted for approximately 30% of the benefit that losartan provided over atenolol in the study and was independent of blood pressure control. This has also been demonstrated in diabetes and renal failure where reductions in microalbuminuria are proportionate to reductions in risk of future vascular events.Reference Wachtell, Ibsen, Olsen, Borch-Johnsen, Lindholm, Mogensen, Dahlöf, Devereux, Beevers, de Faire, Fyhrquist, Julius, Kjeldsen, Kristianson, Lederballe-Pedersen, Nieminen, Okin, Omvik, Oparil, Wedel, Snapinn and Aurup72 As such, microalbuminuria has become a therapeutic target in its own right in diabetes at least,Reference de Zeeuw73 by the routine use of ACE-inhibitors, angiotensin receptor blockers and recently the direct renin inhibitor, aliskiren. This latter class is of particular interest because as well as having its safety and tolerability assessed specifically in an elderly cohort,Reference Duprez, Munger, Botha, Keefe and Charney74 it has an antiproteinuric effect at least as good as the ACE-inhibitor or ARBReference Persson, Rossing, Reinhard, Juhl, Stehouwer, Schalkwijk, Danser, Boomsma, Frandsen and Parving75 and additional benefit, when added to the ARB, losartan, of 20% further reduction in urinary albumin excretion.Reference Parving, Persson, Lewis, Lewis and Hollenberg76 This benefit is independent of blood pressure and is thought to represent an effect on the aforementioned local renin-angiotensin activity. Additional therapy with non-dihydropyridine calcium channel blockers (i.e. verapamil and diltiazem) have consistently demonstrated reductions in proteinuria not achieved with the dihydropyridines (e.g. amlodipine, felodipine, nifedipine).Reference Bakris, Copley, Vicknair, Sadler and Leurgans77
From what has been presented thus far, it would be easy to imagine a simple argument that microvascular function declines with advancing age; ACE-inhibitors improve microvascular function, therefore all elderly patients should receive ACE-inhibitor therapy. Unfortunately this is not the case. The Antihypertensive and Lipid Lowering Treatment to prevent Heart Attack Trial (ALLHAT), the single biggest antihypertensive trial conducted, did not demonstrate any benefit from ACE-inhibitor-based therapy over thiazide-type diuretic or amlodipine.78 A potential explanation for this is the lack of diuretics used in the ACE-inhibitor arm of ALLHAT. It is well recognized that, in order to get maximal antihypertensive effect of ACE-inhibition or ARBs, the renin-angiotensin system must be first stimulated with a diuretic. This does challenge the hypothesis of ubiquitous ACE-inhibitor therapy to improve microvascular function though, rather it justifies a targeted approach for those who have persistent microalbuminuria after adequate blood pressure control.Reference Parving, Lehnert, Bröchner-Mortensen, Gomis, Andersen and Arner79
Statins or cholesterol reduction
Cholesterol reduction with statin therapy has become almost ubiquitous in patients at high cardiovascular risk; however, early studies exploring the effects of cholesterol reduction were less than conclusive. Indeed a meta-analysis of diet, cholestyramine and fibrate therapies could demonstrate no reduction in mortality and only a non-significant (P = 0.06) trend in reduced cardiovascular events.Reference Muldoon, Manuck and Matthews80 Subsequently many cholesterol-reducing studies using statins have demonstrated reductions in cardiovascular events and mortality,81–Reference Sever, Dahlöf, Poulter, Wedel, Beevers, Caulfield, Collins, Kjeldsen, Kristinsson, McInnes, Mehlsen, Nieminen, O'Brien and Ostergren83 and more recently have suggested benefits in conditions outside of the classic cardiovascular system such as Alzheimer's disease.Reference Rosenberg, Mielke, Tschanz, Cook, Corcoran, Hayden, Norton, Rabins, Green, Welsh-Bohmer, Breitner, Munger and Lyketsos84 The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial demonstrated a significant cardiovascular risk reduction despite all subjects having a ‘normal’ cholesterol but elevated high sensitivity C-reactive protein (hsCRP).Reference Ridker, Danielson, Fonseca, Genest, Gotto, Kastelein, Koenig, Libby, Lorenzatti, MacFadyen, Nordestgaard, Shepherd, Willerson and Glynn85 This hsCRP is a recognized marker of vascular inflammation that is tightly associated with endothelial dysfunction, suggesting the statin benefit was maximized in those with ongoing vascular damage, rather than absolute cholesterol concentration.
Endothelial function in diabetes
Endothelial dysfunction is common in diabetes and newer hypoglycaemic drugs have attempted to address this. The use of peroxisome proliferator-activated receptor-gamma agonists is associated with improved endothelial function;Reference Sidhu, Cowan and Kaski86 however, they also cause fluid retention, through mechanisms as yet unknown, and weight gain that has counteracted the potential benefits.
There has been recent interest in therapies that influence the glucagon-like peptide (GLP)-1 pathway. Endogenous GLP-1 has been demonstrated to improve endothelial function in those with diabetes,Reference Nyström, Gutniak, Zhang, Zhang, Holst, Ahrén and Sjöholm87 mediated directly through GLP-1 receptors located in the myocardium and vascular endothelium, and other, as yet unidentified, pathways.Reference Ban, Noyan-Ashraf, Hoefer, Bolz, Drucker and Husain88 Drugs that increase GLP-1, such as the DPP-4 inhibitors (gliptins) and GLP-1 analogues, are particularly useful in elderly patients as in addition to their potential benefits on endothelial function, they come with excellent tolerability in elderly and reduced hypoglycaemia risk.Reference Pratley, Rosenstock, Pi-Sunyer, Banerji, Schweizer, Couturier and Dejager89, Reference Ferrannini, Fonseca, Zinman, Matthews, Ahrén, Byiers, Shao and Dejager90 In animal models they have also been demonstrated to reduce endothelial reperfusion injuries post-myocardial infarction, leading investigators to consider their use as a vascular protection in normoglycaemic individuals.Reference Bose, Mocanu, Carr, Brand and Yellon91, Reference Bose, Mocanu, Carr and Yellon92
Conclusion
The role of endothelial and microcirculatory dysfunction is increasingly recognized as an early step in the pathogenesis of vascular target organ damage. Elderly patients are at elevated risk, due to increased exposure to environmental risk factors and accumulation of multiple co-morbid conditions each adversely affecting pathways within vascular homeostasis. Clinically available tools for assessing microvascular function, such as urinary albumin excretion rate, should be utilized as part of risk stratification processes, in the hope that early targeted treatment may prevent or delay progression of cardiovascular disease and maintain health into old age.
Conflicts of interest
There are no conflicts of interest for any author.
Acknowledgements
We would like to acknowledge support from the Peninsula NIHR Clinical Research Facility. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
