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ADVANCES IN VASCULAR BIOLOGY

Does endothelial dysfunction contribute to the


clinical status of patients with peripheral arterial
disease?
Joseph A Vita MD, Naomi M Hamburg MD

JA Vita, NM Hamburg. Does endothelial dysfunction contribute to La dysfonction endothliale contribue-t-elle


the clinical status of patients with peripheral arterial disease? Can J
Cardiol 2010;26(Suppl A):45A-50A. ltat clinique des patients atteints dune
maladie artrielle priphrique ?
Peripheral arterial disease leads to lower extremity ischemia and limb loss,
and is linked to cardiovascular events. The anatomical extent of lower Les maladies artrielles priphriques entranent une ischmie des membres
extremity atherosclerosis fails to fully explain ischemic symptoms or pre- infrieurs et une perte des membres et sont lies la coronaropathie.
dict the development of critical limb ischemia. Endothelial dysfunction is Ltendue anatomique de lathrosclrose des membres infrieurs nexplique
known to contribute to the pathogenesis and clinical expression of coro- pas tout fait les symptmes ischmiques et ne permet pas de prdire
nary artery disease, but the importance of endothelial dysfunction in lapparition dune ischmie critique des membres. On sait que la dysfonction
peripheral arterial disease remains incompletely understood. Endothelial endothliale contribue la pathogense et lexpression clinique des
dysfunction could contribute to lower extremity ischemia by impairing coronaropathies, mais on comprend mal limportance de la dysfonction
blood flow responses to ischemia, collateral formation and arterial remod- endothliale en cas de maladie artrielle priphrique. La dysfonction
elling, and by promoting vasospasm, thrombosis, plaque rupture and lesion endothliale pourrait contribuer une ischmie des membres infrieurs en
progression. There is a need for additional studies examining the contribu- nuisant la rponse du dbit sanguin lischmie, la formation collatrale
tion of endothelial dysfunction to the pathogenesis of peripheral arterial et au remodelage artriel et en favorisant le spasme vasculaire, la
disease, and the potential role of endothelial dysfunction as a surrogate thrombose, la rupture de la plaque et la progression des lsions. Dautres
marker with utility in the management of patients. tudes sont ncessaires pour examiner lapport de la dysfonction endothliale
sur la pathogense des maladies artrielles priphriques ainsi que le rle
Key Words: Critical limb ischemia; Endothelium; Inflammation; Nitric oxide; potentiel de la dysfonction endothliale comme marqueur de substitution
Peripheral arterial disease utile pour la prise en charge des patients.

PERIPHERAL ARTERIAL DISEASE life (1,16,17). Relevant to the present review, improved endothelial con-
Atherosclerotic peripheral arterial disease (PAD) is a major public trol of vascular tone, arterial remodelling, collateral formation and inflam-
health problem that affects approximately eight million Americans mation are believed to be important mechanisms accounting for the
and up to 20% of individuals older than 70 years of age (1-4). PAD benefits of exercise, statins and other risk reduction therapies (1,17-20).
produces considerable morbidity and health care expense because of Revascularization is indicated for uncontrolled symptoms and criti-
intermittent claudication, critical limb ischemia and amputation. In cal limb ischemia (3,21-23). Percutaneous revascularization is useful,
addition, patients with PAD have a four- to sixfold increased risk for particularly in the iliac arteries, although it is interesting that exercise
cardiovascular events (2), making detection and management of PAD training may be equally effective (24). Long-term results in more
an important public health priority. distal vessels have been disappointing despite the availability of drug-
PAD is associated with classical as well as more recently recognized eluting stents (16,23). Surgical revascularization with bypass grafting
cardiovascular risk factors (2,5,6). Accordingly, risk reduction therapy decreases symptoms and prevents limb loss in selected patients; how-
is the primary approach to management, particularly smoking cessa- ever, surgical procedures carry a risk of procedural cardiac events and
tion and lipid-lowering therapy. In randomized trials, statin treatment have a significant failure rate over time (21,22,25,26). Overall, only
has been shown to improve claudication and prevent cardiovascular 45% of patients with critical limb ischemia are alive with two limbs
events (3,7,8). Current guidelines also recommend aggressive treat- at one-year follow-up (3,16). Thus, there is a need to develop new
ment of other risk factors such as diabetes mellitus and hypertension to approaches for management. In this regard, it is important to consider
slow progression of PAD and to reduce coronary risk (3,9). It is impor- the mechanisms leading to intermittent claudication and critical limb
tant to point out, however, that risk factors for PAD are not identical ischemia.
to the risk factors for coronary artery disease (CAD) and stroke, sug-
gesting that there may be differences in pathophysiology (10,11). Pathogenesis of ischemia and limb complications in PAD
Other treatments for PAD have gained acceptance. In particular, anti- Leg ischemia in PAD has traditionally been attributed to obstruction
platelet therapy reduces the risk for cardiovascular disease events and graft of blood flow by fixed atherosclerotic lesions. Classical claudication,
occlusion (3,12-14). For patients with intermittent claudication, treat- with exercise-induced leg pain that is relieved by rest, could largely be
ment with the phosphodiesterase-3 inhibitor cilostazol (15) improves explained by such a demand ischemia model. Critical limb ischemia
walking distance, possibly due to vasodilator and antiplatelet effects. usually occurs in patients with multilevel atherosclerosis and could
Exercise programs particularly reduce symptoms and improve quality of reflect gradual progression of atherosclerotic lesions.
Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA
Correspondence: Dr Joseph A Vita, Section of Cardiology, Boston Medical Center, 88 East Newton Street, Boston, Massachusetts 02118, USA.
Telephone 617-638-8742, fax 617-638-8765, e-mail jvita@bu.edu
Received for publication July 14, 2009. Accepted September 25, 2009

Can J Cardiol Vol 26 Suppl A March 2010 2010 Pulsus Group Inc. All rights reserved 45A
Vita and Hamburg

blunts platelet aggregation, proliferation of vascular smooth muscle


and leukocyte adhesion, and is required for appropriate arterial remod-
elling and collateral development (48-50). In pathological states, loss
of nitric oxide and increased production of vasoconstrictors, such as
endothelin, limits blood flow and contributes to ischemia (51-53).
Under pathological conditions, the endothelium may also be
activated to express prothrombotic and proinflammatory factors,
including tissue factor, adhesion molecules, chemotactic factors and
cytokines (54-58) (Figure 1). In general, cardiovascular risk factors are
associated with an alteration of endothelial phenotype that promotes
atherosclerosis (42). Importantly, these observations have been trans-
lated to humans, and it is well known that patients with risk factors
and CAD have impaired endothelium-dependent dilation. However,
the contribution of an activated proinflammatory phenotype to
human disease is less well studied.
Endothelial dysfunction is firmly linked to the pathogenesis of
CAD and acute coronary events. On average, endothelium-dependent
vasodilation is lower in coronary disease patients than in controls
(20,42,59). It is important to note, however, that endothelial func-
tion varies widely even among patients with disease. Those with more
severely impaired endothelial function are more likely to have myo-
cardial ischemia on ambulatory electrocardiogram monitoring (60)
and have increased risk for myocardial infarction, unstable angina and
coronary death (61-67). Interventions proven to reduce cardiovascu-
lar risk also reverse endothelial dysfunction (20), and failure of the
endothelium to respond to therapy identifies patients at higher risk
(68,69). Thus, there is strong evidence linking endothelial dysfunc-
tion to CAD. However, it remains unknown whether endothelial
dysfunction contributes to clinical ischemia in the lower extremities
of patients with PAD.
Figure 1) Potential links between endothelial dysfunction and the clinical
expression of peripheral arterial disease (PAD). COX-2 Cyclooxygenase-2; Endothelial dysfunction and PAD
CRP C-reactive protein; eNOS Endothelial nitric oxide synthase; FMD Endothelial dysfunction could contribute to clinical status in PAD in
Flow-mediated dilation; ICAM-1 Intercellular adhesion molecule-1; IL-1 a number of ways. Loss of nitric oxide in skeletal muscle microvessels
Interleukin-1-beta; MCP-1 Monocyte chemoattractant protein-1; NFB blunts the hyperemic responses to exercise and ischemia, which would
Nuclear factor kappa B; ox-LDL Oxidized low-density lipoprotein; RH be expected to limit oxygen delivery under conditions of increased
Reactive hyperemia; ROS Reactive oxygen species; TNF- Tumor necrosis demand (45-47). As in epicardial coronary arteries, loss of nitric oxide
factor-alpha in the lower extremities could worsen the vasoconstrictor effects of
catecholamines and impair flow-mediated dilation, which might
worsen stenosis severity and increase resistance to blood flow during
Multiple lines of evidence, however, suggest that the pathogenesis
of limb ischemia in PAD is more complex. First, severe disease may be exercise (19,70-75). Importantly, such abnormalities can be reversed
present in asymptomatic patients (3,27,28). Second, intermittent over weeks to months with risk reduction therapy even if lesion regres-
claudication is a poor predictor of revascularization and limb amputa- sion does not occur (17,19,20,73,76). This time course corresponds to
tion (29-31). For example, only 15% to 20% of patients with intermit- improvement of claudication symptoms and reduction in cardiovascu-
tent claudication develop critical limb ischemia and only 10% require lar events during intervention studies.
amputation (32). Third, the anatomical severity of obstruction does As described by Glagov et al (77), outward remodelling helps
not predict clinical status. Thus, ankle-brachial index correlates maintain a patent arterial lumen as atherosclerotic plaques increase in
poorly with walking distance (33) and is a poor predictor of progressive size (77). Experimental studies have shown that compensatory remod-
limb ischemia, revascularization or cardiovascular events (30,34-36). elling depends on the activity of nitric oxide synthase (49,78,79), and
Furthermore, the observed benefits of vasodilators, antiplatelet agents the authors recently demonstrated that the remodelling response is
and exercise in PAD fit poorly with a demand ischemia model. In addi- blunted in patients with local endothelial dysfunction (80). Chronic
tion, interventions such as statin therapy and exercise act too quickly and recurrent limb ischemia stimulates compensatory collateral forma-
for meaningful regression to have occurred (1,8). tion (81-83) and this response depends on the bioavailabity of nitric
These findings raise the possibility that disturbances of vascular oxide (84-89). Thus, endothelial dysfunction may worsen clinical sta-
function may contribute to clinical status in PAD. Indeed, a number of tus in PAD because of impaired collateral formation and remodelling.
investigators have proposed that endothelial dysfunction, plaque rup- Endothelial activation with expression of proinflammatory and
ture, thrombosis and impaired collateral formation may all be impor- prothrombotic factors may also contribute to ischemia by promoting
tant (3,37-39). While the role of such mechanisms in the coronary plaque rupture (39,41). Studies completed by the authors and others
circulation for both stable angina and acute coronary syndromes has have shown that endothelial dysfunction predicts acute coronary
been well established (20,40-42), their specific role in PAD remains events in PAD patients, suggesting a relation with plaque rupture in
uncertain. the coronary circulation (65-67,90). Plaque rupture in the lower
extremities would produce an acute reduction in blood flow, and this
Endothelial dysfunction and CAD mechanism has been proposed to contribute to the development of
As has been reviewed by the authors and others, the vascular endothe- critical limb ischemia (39); the observed benefits of antiplatelet ther-
lium is a primary regulator of vascular homeostasis (20,42-44). Nitric apy supports this concept (3,12-14). Furthermore, thrombus reorgani-
oxide and other endothelium-derived vasodilators regulate blood flow zation following subacute rupture has been proposed as a mechanism
and maintain appropriate arterial tone (45-47). Nitric oxide also for lesion progression (39,91-93).

46A Can J Cardiol Vol 26 Suppl A March 2010


Endothelial dysfunction and PAD

Consistent with these potential mechanisms, several small cross- impaired endothelium-dependent vasodilation (133-135). The anti-
sectional studies have demonstrated loss of nitric oxide bioavailability inflammatory drug salsalate has been shown to inhibit IB kinase, and
in patients with PAD. For example, patients with PAD have blunted thus limit activation of NFB (132,136). Treatment of obese patients
vasodilator responses to acetylcholine (94,95) and impaired endothelium- with salsalate has been shown to reduce expression of p65, increase
dependent flow-mediated dilation of the brachial artery (96-98). Flow- detectable IB- and improve endothelium-dependent vasodilation
mediated dilation also has been reported to correlate inversely with (137), but the effects of anti-inflammatory therapy in PAD are
ankle-brachial index (98-100). Urine nitrate and cyclic GMP levels unknown.
are reduced in patients with PAD, suggesting decreased total body
nitric oxide production (101). Polymorphisms of nitric oxide synthase CONCLUSIONS AND IMPLICATIONS
genes correlate with ankle-brachial index (102). Finally, PAD is associ- PAD is an important public health problem because of the morbidity
ated with increased endothelin and plasminogen activator inhibitor-1 associated with lower extremity ischemia and limb loss, and because
(103-105). These studies support a link between endothelial dysfunc- PAD is linked with increased risk for CAD. The anatomical extent
tion and PAD, but do not address the question of whether endothelial of atherosclerosis and a demand model of ischemia fail to fully
dysfunction contributes to clinical status among PAD patients. explain ischemic symptoms in PAD or predict the development of
critical limb ischemia. Endothelial dysfunction, particularly loss of
Inflammation and endothelial dysfunction in PAD endothelium-dependent nitric oxide and activation of the endothe-
Atherosclerosis is a chronic inflammatory disease (40,57,58) and, not lium to a proinflammatory state, has convincingly been shown to
surprisingly, studies suggest systemic inflammation in PAD. For exam- play a role to the clinical expression of CAD. The pathogenesis and
ple, monocyte count (106), C-reactive protein and soluble intercellu- clinical manifestations of PAD and CAD are not identical, and the
lar adhesion molecule-1 predict future development of PAD contribution of endothelial dysfunction to clinical status and lower
(6,106,107). Polymorphisms in genes related to inflammation are also extremity ischemia in PAD is incompletely understood. There is a
associated with PAD (108). Patients with critical limb ischemia have need for studies examining the relative importance of the anatomical
immune activation (109,110) and increased blood and tissue levels of extent of atherosclerosis and endothelial dysfunction as determi-
inflammatory markers (111,112), although it is difficult to determine nants of clinical status in PAD and there is a need for investigation
whether inflammation is a cause or consequence of ischemia in this of whether endothelial dysfunction can serve as a surrogate for clini-
setting. Indeed, inflammatory markers decrease and endothelial func- cal status in intervention trials. We suggest that such studies would
tion improves following revascularization or limb amputation improve our understanding of the pathogenesis of clinical ischemia
(112,113). Interestingly, C-reactive protein correlates with functional in human PAD and may provide new information about novel
status of PAD patients, as measured by 6 min walk distance and 4 m approaches to management.
walking speed (114,115). Furthermore, an increase in C-reactive pro-
tein over time is associated with a decrease in 6 min walk distance
(116). ACKNOWLEDGEMENTS: Dr Vita is supported by grants from the US
The vascular endothelium is affected by and contributes to the National Institutes of Health (HL083269, HL083801, HL081587, and
inflammatory process (55). Endothelial cells can be activated by vari- HL75795) and the Boston University Medical Center Clinical and
ous relevant factors, including interleukin-1-beta (IL-1), tumor Translational Science Institute (1UL1RR025771). Dr Hamburg is sup-
necrosis factor-alpha (TNF-), oxidized LDL (ox-LDL), and C-reactive ported by the Boston University Leadership Program in Vascular Medicine
protein to promote an atherogenic phenotype (55,117-119). The acti- (K12 HL083781). The authors have no conflicts of interest to declare.
vated endothelium, in turn, expresses adhesion molecules, chemotac-
tic factors, cyclooxygenase-2 and other factors that accelerate the
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