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Journal of Human (2001) 15, 447–454  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh REVIEW ARTICLE Peripheral vascular and hypertension: a forgotten association?

A Makin1,2, GYH Lip1, S Silverman2 and DG Beevers1 1University Department of ; 2Department of Vascular , City Hospital, Birmingham B18 7QH, UK

Peripheral (PVD) is associated with a ical associations, hypertension contributes to the high cardiovascular morbidity and mortality. Intermit- pathogenesis of , the basic underlying tent is the most common symptomatic pathological process underlying PVD. Hypertension, in manifestation of PVD, but is also an important predictor common with PVD, is associated with abnormalities of of cardiovascular , increasing it by three-fold, and haemostasis and , leading to an increased ather- increasing all-cause mortality by two to five-fold. Hyper- othrombotic state. Nevertheless, none of the large anti- tension is a common and important for vas- hypertensive treatment trials have adequately cular disorders, including PVD. Of hypertensives at addressed whether a reduction in pressure presentation, about 2–5% have intermittent claudi- causes a decrease in PVD incidence. There is therefore cation, with this prevalence increasing with age. Simi- an obvious need for such outcome studies, especially larly, 35–55% of patients with PVD at presentation also since the two conditions are commonly encountered have hypertension. Patients who suffer from hyperten- together. sion with PVD have a greatly increased risk of myocar- Journal of Human Hypertension (2001) 15, 447–454 dial and . Apart from the epidemiolog-

Keywords: hypertension; peripheral vascular disease; atherosclerosis

Introduction associations, hypertension also contributes to the pathogenesis of atherosclerosis, which is the basic Peripheral vascular disease (PVD) is the cause of a underlying pathological process underlying PVD.12– large number of hospitalisations each year. In the 14 Indeed, hypertension, in common with PVD, is of America, 9.6% of ‘cardiovascular also associated with abnormalities of haemostasis events’ are due to PVD, requiring 63 000 hospital 1 and the profile. admissions every year. In addition, PVD is associa- Although it seems logical that the treatment of ted with a significant morbidity and mortality. In a hypertension should lead to a reduction in the inci- study in Finland, for example, patients with inter- dence of PVD, none of the large placebo-controlled mittent claudication had a three-fold excess risk of antihypertensive treatment trials have adequately death over 5 years from cardiovascular causes, when 2 addressed this question as a primary outcome meas- compared to men without claudication. This high ure. There is therefore an obvious need for more adverse outcome is also illustrated by an Israeli information on such outcomes especially since the study, where 44% of all men with intermittent two conditions are both common and closely claudication died within 21 years, when compared related. with 29% without PVD.3 Hypertension is a common and important risk fac- tor for all vascular disorders, including PVD.4,5 In Epidemiology of PVD hypertensive patients at presentation, between 2– 5% have intermittent claudication, with this preva- Intermittent claudication is the most common symp- lence increasing with age.6 Similarly, 35–55% of tomatic manifestation of PVD. Nevertheless these patients with PVD at presentation also have hyper- patients represent the tip of the iceberg as many tension.7–11 Apart from these epidemiological more patients have PVD (Table 1). The methods of case ascertainment with differing criteria for diagnosis and the diverse populations of Correspondence: Dr GYH Lip, E-mail: g.y.h.lipȰbham.ac.uk varying ages which have been studied may explain This paper was submitted to and dealt with by the USA Office of the Journal of Human Hypertension. the wide variation in the prevalence of PVD in the Received 1 February 2001; revised 6 February 2001; accepted 20 world literature. February 2001 In the Edinburgh Study, which studied a Peripheral vascular disease and hypertension A Makin et al 448 Table 1 Examples of studies demonstrating the prevalence of intermittent claudication compared to peripheral vascular disease

Country Reference No. Age IC PVD

Edinburgh Fowkas et al82 1592 55–74 4.5% 26.2%

Italy (ADEP) Violi et al11 613 (mean) 66 1.7% (f) 27.7% 2.2% (m) Sardinia Binaghi et al7 577 over 20 0.38% (f) 2.06% (f) 1.5% (m) 8.43% (m) Rotterdam Meijer et al17 4629 (f) over 55 1.2% (f) 20.5% (f) 3086 (m) 2.2% (m) 16.9% (m) Scandanavia Reunanan et al2 5224 (f) 30–59 1.8% (f) — 5738 (m) 2.1% (m) Israel Bowlin et al19 10059 (m) 40–65 2.7% (m) —

Framingham USA Kannel et al28 19501 (f) 29–74 0.24% (f) — 15290 (m) 0.52% (m)

f, female; m, male; IC, intermittent claudication; PVD, peripheral vascular disease (symptomatic and asymptomatic).

population of 1592 subjects aged 55 to 74 years, predict disease progression in patients with estab- 4.6% had intermittent claudication but in addition, lished PVD.20 In the Quebec Cardiovascular Study, 6.6% had major asymptomatic PVD diagnosed clini- 4570 men between the ages of 35 and 64 were fol- cally and 15% had minor asymptomatic disease.4 In lowed up for 12 years. During this period, 188 a Sardinian population of people aged over 20 years, developed intermittent claudication for the first 4.7% had PVD, measured using a standard question- time, this being an annual incidence of 41/10 000 naire together with Doppler blood flow studies per year. Those developing intermittent claudi- although only 18.5% of these were symptomatic at cation were significantly more likely to have elev- the time of examination.7 ated than the non-PVD examinees.21 Variable findings have been noted in other stud- The 38-year data from The Framingham Study ies. In an American study of 613 men and women, reported an increase in incidence of intermittent the prevalence of large vessel disease was 11.7%, claudication from 0.9% over 4 years in men aged small vessel disease 16% and combined large and 45–54 to 2.5% in men aged 65–75 until the 75 to small vessel involvement was present in 5.2% of 84-year-old cohort, where the incidence decreased participants.15 In a different study, the same authors to 1.9% over 4 years. Importantly, this change was reported that patients with severe PVD had signifi- very strongly correlated with the presence of Stage cantly elevated systolic blood pressure, although 2 (or higher) hypertension (systolic blood pressure they fail to define what the term ‘severe’ meant.16 In Ͼ160 mm Hg or diastolic blood pressure over 100).22 the Rotterdam Study of 7715 men and women aged over 55 years, PVD was present in 16.9% of men Hypertension as a contributor to PVD and 20.5% of women but symptomatic disease was only reported in 2.2% and 1.2% respectively;17 simi- Hypertension, and particularly the height of the sys- larly in Limburg, PVD was present in 8.6% of 3650 tolic blood pressure, is a well established risk factor subjects but was symptomatic in only 3.8%.18 In a for disease and stroke.4,5 As far back as 1962 Scandinavian sample of 10 962 aged 30–59 years, actuarial studies demonstrated that, as is now intermittent claudication was present in 2.1% of accepted, these complications are more closely asso- men and 1.8% of women2 and in 10 059 Israeli men ciated with the systolic rather than the diastolic aged 40–65 years, 2.7% responded positively when blood pressure elevation.23 In the Glasgow Blood asked about intermittent claudication symptoms.19 Pressure Clinic, it was even shown that there was One retrospective study of women from Belgium no relationship between change in diastolic blood showed that of 45 proven cases of PVD, 16 (36%) pressure and cardiovascular death.24 Whilst the had asymptomatic disease, whilst 19 (42%) had mortality from all causes is reduced by a reduction intermittent claudication and 10 (22%) had rest pain in systolic blood pressure, it remains 2–5 times and .12 higher than the mortality in the surrounding general Whilst there are much data on the prevalence of population,25 although there has been a recent trend PVD, few studies have specifically addressed the for the cardiovascular mortality in hypertensive incidence of PVD in large populations at follow up. patients to return to that of the population at The data from the TransAtlantic Inter-society large.26,27 Consensus (TASC) reveals that although hyperten- Follow-up data from the Framingham Study sion is a risk factor for development of PVD and is found a 2.5 to four-fold increased risk of PVD in men predictor of mortality in these patients it is not the and women with hypertension.5,28 In a post mortem most significant. Furthermore it does not seem to study of 1164 young men aged 15–34 years, 13.7%

Journal of Human Hypertension Peripheral vascular disease and hypertension A Makin et al 449 had renal changes indicative of hypertension and approximately twice as common in hypertensive they had a higher prevalence of raised atheroscler- patients compared with normotensives. In addition otic occupying Ͼ5% of the intimal area of the ADAM study discovered an odds ratio of about the abdominal of between 1.3 and 1.6-fold, 1.2 of having an undiagnosed AAA in hypertensives compared to the normotensive group.29 In these compared to normotensives in a population of 50– patients, the prevalence of abdominal aortic raised 79 year olds.32 This data also shows a much lower lesions was greater than that of raised lesions in the prevalence of AAA (defined as an abdominal aorta right coronary artery, which was somewhat unex- greater than 4.0 cm in diameter) in this age group pected, as hypertension is usually perceived as a (1.4%) than the other studies. It has great power hav- greater risk factor for .5,28 ing been conducted in 73 451 subjects, by far the Nevertheless not all studies demonstrate a clear largest. Although not all are atheroscler- relation between hypertension and PVD. For otic they are clearly so in the vast majority and thus example, the Reykjavik Study found a 55% decrease this aetiology has to be considered. As with most in the incidence of PVD in Icelandic men aged 60– peripheral atherosclerotic disease, there is a male 70 years old, which was greater than the decrease in predominance at any age. The presence of the incidence of coronary heart disease, although mellitus appears paradoxically to have a protective the presence of systolic or diastolic hypertension effect with very few patients developing aneur- were shown to be not significantly different.30 In an ysms.32,33 analysis from the Glasgow Blood Pressure clinic, of 1357 hypertensive men, 75 (5.5%) had probable or definite intermittent claudication and the preva- An important consideration is the association of lence was very clearly related to increasing age. PVD with both known and previously undiagnosed However, intermittent claudication showed no atherosclerotic (ARAS). It has relationship with the severity of the hypertension.6 been shown that 40% of patients undergoing Is hypertension therefore a significant risk factor abdominal arteriography for PVD have ARAS which at presentation for PVD? In a large study from Italy, was also present in 30% of patients undergoing cor- 35% of 1011 patients with PVD had hypertension at onary ,34,35 in contrast, the prevalence in presentation and importantly, having both hyperten- those with PVD and hypertension was 34%.36 sion and PVD produced an odds ratio of 1.48 It is apparent, however, that ARAS (unlike fibro- (P = 0.0056) for subsequent cardiovascular events.11 muscular dysplasia) is unlikely to be the cause of This study showed that from all causes were hypertension per se but poor renal perfusion leading more frequent in patients with an ankle/brachial to activation of the --system more pressure ratio below 0.8. This observation was also probably exaggerates the hypertension. While the confirmed in the SHEP ( in the effect of renal artery repair or on the Elderly Programme) study where a low ankle arm control of blood pressure has been disappointing, index (less than 0.9) in an older population as well there is evidence that these procedures may help to as hypertension predicted a two to three-fold preserve renal function.37,38 Several studies have increased risk of cardiovascular mortality.31 also reported that renal artery revascularisation, Of 510 Chinese patients with PVD in Hong Kong, with or without stenting has no advantages over oral 55% had hypertension which was exceeded only by antihypertensive in the management of high the prevalence of and elevated LDL choles- blood pressure.39 terol.8 In a small study from Belgium of 45 female An important consideration is the effect of the patients with proven PVD, arterial hypertension also treatment of hypertension in patients with ARAS. In proved to be a predictive risk factor.12 An Italian particular, angiotensin converting inhibi- case control study also showed a significantly tors (ACE-I) should be used with caution in patients greater prevalence of arterial hypertension (51.9 vs with known PVD because of the possibility of con- 9.8%) in PVD patients,10 which was confirmed by current renal artery stenosis leading to over-rapid Binaghi et al7 where 21.6% of 27 patients with PVD falls in blood and a deterioration in renal function.40 had arterial hypertension. Finally, treated or Whilst this problem is probably overstated, and usu- untreated hypertension was found to be present in ally reversible, great caution is needed, therefore, 40% of a population 84 patients with PVD aged when prescribing ACE-I in patients with peripheral, under 65 years old with angiographically or labora- coronary, and for that matter, carotid artery disease, tory-proven disease9 (Table 2). particularly if they are smokers. Renal function should also be assessed before and after a few days Hypertension and of the of starting ACE-I, even if excessive falls in blood abdominal aorta pressure are not encountered. There has been some debate as to the prevalence of abdominal (AAA) in hypertensive Diabetes mellitus patients. Table 3 shows a clear relationship between As would be expected, the prevalence of PVD in AAA and increased blood pressure, with AAA being patients suffering from diabetes mellitus (DM)

Journal of Human Hypertension Peripheral vascular disease and hypertension A Makin et al 450 Table 2 Prevalence of hypertension in patients with proven peripheral vascular disease proven by reduced ABPI or angiography

Population Reference No. in study Proportion Age (years) hypertensive

Italy (ADEP) Violi et al11 1011 35% — Hong Kong Cheng et al8 510 55% av. 72 Italy Novo et al10 102 51.9% av. 57.2 Toronto (Canada) Johnston et al9 84 40% Ͻ65 Sardinia Binaghi et al7 27 21.6% Ͼ20

Table 3 Prevalence of abdominal aortic aneurysm in subjects with hypertension

Population Reference Prevalence Prevalence Numbers in study Age (years) AAA in of AAA hypertensives % overall % Cases Controls

America (SHEP) Schiffrin et al81 11.9 6.5 143 123 av. 73 United Kingdom Vardulaki et al83 4.8 3.3 1028 4014 65–79 Spittell et al84 6.5 — 200 — av. 71 Denmark Lindholt et al85 17.8 4.2 213 men — 65–73 United Kingdom Williams et al86 5.2 men — 744 — Ͼ60 0.1% women 584 Ͼ65 United Kingdom Grimshaw et al87 7.7 3.8 — — 60–64

increases in the presence of systolic hypertension in clerotic disease. It has been shown in vitro that all racial groups.41–44 It has also been shown that, when low-density (LDL) are in contact at the time of diagnosis, patients with non- with endothelial cells, they become oxidised to the dependent diabetes mellitus (NIDDM) were shown active peroxide form. The oxidised LDL is avidly to have no greater prevalence of macrovascular PVD taken up by monocytes48,49 which attach to the than non-diabetics and that the vascular compli- endothelial cells on the molecules E-sel- cation rate is associated with an increasing duration ectin and intracellular adhesion molecule-1 (ICAM- of the disease.45 Furthermore there is evidence that 1) and migrate between them. Phagocytosis then if hypertension in diabetics is controlled, then the occurs and the are transformed into the progression of PVD can be slowed.46 characteristic foam cells, the precursor of athero- sclerosis.50 An accumulation of these foam cells gen- Pathophysiological considerations erates the so-called ‘’ in the intima. Although play no part in the initiation of Atherosclerotic lesions seem to occur at specific the plaque51 when the fatty streak becomes of suf- sites in patients with predetermined risk factors ficient size for the covering endothelial layer to be even if the exact mechanisms of their development disrupted platelets stick to the underlying matrix. is not completely clear. One contributing factor to The activated platelets release a number of factors, the initiation of the plaque would appear to be including -derived growth factor (PDGF).52 haemodynamic forces and especially shear stresses. This causes proliferation of cells and Most atherosclerotic disease in the peripheral cir- their migration towards the intima, which causes culation tends to occur in places where there would further growth of the plaque and formation of the be an expected change in the haemodynamic state; fibrous cap. The mature plaque thus has a covering the abnormal flow state is accompanied by a known of secreted by migrated smooth muscle decrease in arterial compliance and increased blood cells, covered with and a lipid interior. velocity.14,47 These ‘pro-atherogenic’ places are, Rupture of the cap exposing the collagen matrix to broadly speaking, at bifurcations in notably the blood causes formation that may carotid, aortic and femoral, and the risk of obstruct the vessel or become, once more, covered developing these lesions is greatly increased in with a fibrous coat leading to further propagation of hypertensive patients. the . The overall atherogenic process, however, is pre- Patients with hypertension demonstrate abnor- dominantly initiated and maintained by plaque lip- malities of vessel wall ( or ids. In view of this, it is not surprising that dyslipi- damage), blood constituents (abnormal levels of hae- daemic states, such as that which occurs in mostatic factors, platelet activation and fibrinolysis) association with hypertension as well as diabetes and blood flow (rheology and flow reserve) suggest- mellitus, causes an increased incidence of atheros- ing that hypertension does confer a prothrombotic

Journal of Human Hypertension Peripheral vascular disease and hypertension A Makin et al 451 or hypercoagulable state.53 These components analysis of the trials of beta-blockers in patients with appear to be related to target damage, long- intermittent claudication demonstrated that in term prognosis and are altered by treatment.53,54 patients with mild or moderate claudication beta- Many studies have also demonstrated abnormalities blockers have no detrimental effect on the in factors, platelets and the endothelium distance.65 Nevertheless, patients with rest pain or in patients with PVD, where they are predictive of gangrene should certainly not be given beta-block- adverse outcome. For example, elevated fibrin D- ers. Overall, beta-blockers should be administered dimer levels, an index of thrombogenesis and fibrin with some caution in patients with proven severe turnover,55 have been found in patients with PVD, PVD.66 which correlate with clinical, haemodynamic and The ACE inhibitors are widely used in the treat- angiographic severity.56 In one cross-sectional study ment of hypertension and . In patients of patients with carotid atherosclerosis, patients with PVD and hypertension they have been shown with increased intima-media thickness of carotid to increase the peripheral perfusion and walking arteries on B-mode ultrasound scanning also had distance and therefore appear useful in this set- higher fibrin D-dimer levels compared to controls.57 ting.67–69 Furthermore, the HOPE trial demonstrated The increased fibrin turnover in -smoking that ACE inhibitors given to high risk cardiovascular (the major risk factor for PVD) is likely to be one patients without heart failure was beneficial in pre- mechanism by which smoking contributes to PVD. venting cardiovascular end points.70 This group The measurement of fibrin D-dimer has been demonstrated a relative risk of about 0.75 for shown to have prognostic implications in patients patients with PVD treated with compared with PVD. In a study of 617 patients with claudi- to those on placebo. However, caution is advised if cation, baseline fibrin D-dimer levels were closely associated renal artery stenosis is present, as such related to future coronary events (both fatal and non- patients may develop significant and fatal, with a relative risk of 4.4 between upper and an acute deterioration in renal function. lower quintiles) and also with haemodynamic pro- The alpha receptor antagonists, such as gression of peripheral arterial disease.58 This risk is or , are used widely in combination treat- similar to that seen in healthy men.59 ment for high blood pressure, although as a class of Perhaps infection may be a common contributor drugs they do not appear to have a significant effect to both hypertension and PVD. Indeed, associations on symptoms of peripheral artery disease.71,72 Simi- have been reported between Chlamydia pneumon- lar comments can be made for the , iae infection and both hypertension and atheroscler- which generally have little effect on PVD, and are osis.60,61 Indeed C. pneumoniae is a pathogen which safe. is well recognised to be associated with atheroscler- The channel antagonists are effective in otic plaques and .60 In the the reduction of blood pressure in hypertensives. study by Cook et al,61 35% of hypertensive patients Some trials have shown significant benefit using and 17.9% of matched control subjects had antibody these agents on PVD symptoms73–75 although others titre levels consistent with C. pneumoniae infection, have demonstrated no improvement.64,76 Calcium with an odds ratio of 2.5 (95% confidence interval, channel antagonists therefore are certainly not 1.3 to 4.7). Nevertheless there were no significant contraindicated in PVD and their use might even differences in antibody levels between patients with be beneficial.77 left ventricular hypertrophy and hypercoagulability or endothelial dysfunction in this study. Interventions Therapeutic considerations Hypertension has repeatedly been shown as a risk factor for coronary artery disease and stroke but also Treatment of hypertension in patients symptomatic by treatment of hypertension, the incidence of these of PVD needs careful consideration (Table 4). Cur- complications and all their sequelae, are signifi- rent guidelines recommend an individualised cantly reduced. However, intervention trials in approach towards using antihypertensive agents, hypertension often do not include PVD or its symp- although it is recognised that the greatest trial tomatic manifestations, such as intermittent claudi- experience is with the beta-blockers and diuretics.62 cation, in the outcomes. One exception may be a For example, beta-blockers are recommended as small follow-up trial after the SHEP study, which ‘first-line’ treatment for hypertension, especially in showed a decrease in mortality from cardiovascular the presence of associated coronary disease. Never- causes for treated patients with known PVD.78 Per- theless has shown to reduce the walking haps it is time that more trials addressed this issue, distance in claudicants in one study63 but this does especially since the two conditions (that is, hyper- not seem to be a class effect, as the same study found tension and PVD) are commonly encountered an increase in walking distance with celiprolol. One together but the association is often forgotten. randomised placebo-controlled trial found no sig- Therapeutic interventions may affect smaller ves- nificant change in claudication distance in patients sels. For example, hypertension may affect small- with randomised to beta-blockers.64 A meta- artery structure, with correlations between

Journal of Human Hypertension Peripheral vascular disease and hypertension A Makin et al 452 Table 4 classes and peripheral vascular disease

Class Effect on PVD Uses Cautions Conclusion

Beta-blockers Potentially reduces Recommended for Contraindicated in Should be used with claudication distance protection of heart critical ischaemia caution Alpha-blockers Little effect Wide indications in None Can be used where beta- hypertension blockers are contraindicated ACE inhibitors Increase peripheral perfusion Heart failure and Suspected renal artery Useful and effective and claudication distance hypertension stenosis Some trials show reduction in Hypertension None Not contraindicated and antagonists symptoms may be beneficial

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