Journal of Human Hypertension (2001) 15, 447–454 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh REVIEW ARTICLE Peripheral vascular disease and hypertension: a forgotten association? A Makin1,2, GYH Lip1, S Silverman2 and DG Beevers1 1University Department of Medicine; 2Department of Vascular Surgery, City Hospital, Birmingham B18 7QH, UK Peripheral vascular disease (PVD) is associated with a ical associations, hypertension contributes to the high cardiovascular morbidity and mortality. Intermit- pathogenesis of atherosclerosis, the basic underlying tent claudication 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 death, increasing it by three-fold, and haemostasis and lipids, 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 risk factor for vas- hypertensive treatment trials have adequately cular disorders, including PVD. Of hypertensives at addressed whether a reduction in blood 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 infarction and stroke. 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 United States of America, 9.6% of ‘cardiovascular also associated with abnormalities of haemostasis events’ are due to PVD, requiring 63 000 hospital 1 and the lipid 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 asymptomatic 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 Artery 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 blood pressure 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 heart 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 necrosis.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 lesions occupying Ͼ5% of the intimal area of the ADAM study discovered an odds ratio of about the abdominal aorta 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.