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Physiology in Medicine: Peripheral arterial disease
Matthew D. Muller, Amy B. Reed, Urs A. Leuenberger, and Lawrence I. Sinoway
Pennsylvania State University College of Medicine, Penn State Hershey Heart and Vascular Institute, Hershey, Pennsylvania
Submitted 1 August 2013; accepted in final form 19 August 2013
Muller MD, Reed AB, Leuenberger UA, Sinoway LI. Physiology in Medi-
cine: Peripheral arterial disease. J Appl Physiol 115: 1219–1226, 2013. First
published August 22, 2013; doi:10.1152/japplphysiol.00885.2013.—Peripheral ar-
terial disease (PAD) is an atherosclerotic condition that can provoke symptoms of
leg pain (“intermittent claudication”) during exercise. Because PAD is often
observed with comorbid conditions such hypertension, dyslipidemia, diabetes,
cigarette smoking, and/or physical inactivity, the pathophysiology of PAD is
certainly complex and involves multiple organ systems. Patients with PAD are at
high risk for myocardial infarction, stroke, and all-cause mortality. For this reason,
a better physiological understanding of the pathogenesis and treatment options for
PAD patients is necessary and forms the basis of this Physiology in Medicine
review.
ischemia; blood pressure; blood flow; claudication; exercise
PERIPHERAL ARTERIAL DISEASE (PAD) is typically caused by
progressive narrowing of the arteries in the lower extremities.
This condition affects 5–12 million Americans (43, 75), and
the hallmark symptom is exertional pain in the buttocks, thigh
or calf that promptly resolves with rest, termed “intermittent
claudication.” However, only 10–15% of patients have classic
claudication symptoms. In part because of the varied and often
nonspecific presentation of symptoms, PAD remains poorly
understood by the public, it is under-diagnosed in the primary
care setting, and patients rarely receive optimal treatment (43,
44). Because PAD is an atherosclerotic disease, it is not
surprising that patients with PAD are at high risk for myocar-
dial infarction, stroke, and all-cause mortality (20). Indeed,
patients with a history of PAD have the same relative risk of
cardiovascular death as patients with coronary or cerebrovas-
cular disease (19, 33). To further emphasize this fact, patients
with PAD are three times more likely to die over the next 10
years compared with healthy individuals (20). From a physio-
logical standpoint, the diagnosis and treatment of PAD in-
volves fundamentals of fluid dynamics, metabolism, auto-
nomic control of blood pressure, and the integration of multiple
body systems. In this report, we describe 1) the pathogenesis of
atherosclerosis (Fig. 1); 2) the clinical presentation and diag-
nosis of PAD; 3) the physiological consequences of chronic
limb ischemia (Table 1); and 4) the physiological basis of
current and future therapies in PAD (Table 2 and Fig. 2).
PATHOGENESIS OF ATHEROSCLEROSIS
As recently stated (30), “Atherosclerosis is a chronic im-
munoinflammatory, fibroproliferative disease of large and
medium-sized arteries fueled by lipid.” This all-encompassing
definition involves physiological processes at the cellular and
molecular levels. The basic steps in the formation of an
intraluminal thrombus (e.g., in the leg of a PAD patient) are as
follows. First, LDL cholesterol from the blood passes through
the dysfunctional endothelial cells and enters the intima media
where it is oxidized. Second, monocytes sense the local in-
flammation and migrate to the arterial wall. Third, monocytes
engulf the oxidized LDL and become foam cells, which appear
histologically as a fatty streak. When the foam cells die, they
release their lipid content, creating a lipid core. Fourth, smooth
muscle cells proliferate and form a fibrous cap over the lipid
core. Fifth, as more LDL accumulates, the external elastic
membrane will expand (i.e., outward remodeling) in an effort
to maintain blood flow. Eventually, the vessel will not be able
to compensate and the plaque will protrude into the lumen,
thereby raising both resistance and stiffness. Over time, sub-
clinical plaque rupture followed by normal healing is a major
physiological mechanism by which thrombi increase in size
and reduce perfusion to distal targets.
It is important to emphasize that environmental irritants
(e.g., cigarette smoking) and cardiometabolic risk factors (i.e.,
hypertension, hyperlipidemia, diabetes, and physical inactiv-
ity) as well as genetic factors contribute to the initial stages of
this process (Fig. 1). It should also be noted that there is
considerable overlap and redundancy between the stages. For
instance, oxidized LDL reduces the formation of nitric oxide
and potentiates the formation of endothelin-1 (78). The circu-
lating hormone angiotensin II promotes atherosclerosis by
forming reactive oxygen species (ROS) in macrophages, en-
dothelial cells, and vascular smooth muscle cells. These ROS
contribute to further oxidation of LDL cholesterol. Taken
together, a variety of cytokines, growth factors, hormones, and
adhesion molecules participate in the formation of an intralu-
minal thrombus. Why this process manifests itself in the lower
extremity of PAD patients is not entirely clear.
CLINICAL PRESENTATION AND DIAGNOSIS OF PAD
A patient with suspected PAD will undergo measurement of
the ankle-brachial index (ABI) at rest. Because perfusion to the
Address for reprint requests and other correspondence: M. D. Muller, Penn
State Univ. College of Medicine, Heart and Vascular Institute, H047, 500
Univ. Dr., Hershey, PA 17033 (e-mail: mmuller1@hmc.psu.edu).
J Appl Physiol 115: 1219–1226, 2013.
First published August 22, 2013; doi:10.1152/japplphysiol.00885.2013. Physiology in Medicine
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lower extremity is reduced in PAD, the ankle blood pressure
will be lower than the brachial blood pressure; lower ABIs
(i.e., more severe disease) correlate with mortality (20, 63). It
is interesting that in the current high-tech state of medicine, the
diagnosis of PAD is largely based on straightforward integra-
tive physiology techniques relating blood pressure and blood
flow. Prior large-scale studies have advocated that anyone �50
yr who is a smoker or diabetic and all people �70 yr receive
ABI measurements (1). Postexercise ABI measurements may
provide additional sensitivity (1). The qualitative Fontaine
stages (I � asymptomatic, II � claudication, III � ischemic
rest pain, IV � tissue loss or gangrene) and Rutherford stages
(0 � asymptomatic, 1 � mild claudication, 2 � moderate
claudication, 3 � severe claudication, 4 � ischemic rest pain,
5 � minor tissue loss, 6 � ulceration or gangrene) are used to
grade severity of limb ischemia (48, 64). In addition to symp-
toms of leg pain, PAD patients with advanced disease may also
present with skin atrophy, loss of hair, coldness, and nonpal-
pable pulses.
PHYSIOLOGICAL CONSEQUENCES OF CHRONIC LIMB ISCHEMIA
Metabolism in ischemic muscle. PAD is not solely a disease
of circulatory insufficiency. Because of the chronic low-flow
state, PAD patients have metabolic dysfunction within skeletal
muscle that makes them less able to utilize the oxygen that is
delivered. A series of studies were conducted demonstrating
that PAD patients accumulate acylcarnitines in both the plasma
and muscle during short duration exercise (5, 37). This indi-
cates that substrates are not effectively oxidized in PAD and
suggests that distal flow limitation alters oxygen utilization. In
fact, resting levels of acylcarnitine inversely correlate with
claudication-limited peak aerobic capacity (V̇O2 max) (41). Rel-
ative to control subjects, patients with PAD also have fewer
type I fibers, accumulate lactate at lower exercise intensities,
have reductions in some electron transport chain enzymes, and
have impaired oxygen uptake kinetics (5, 6). As noted in Table
2, exercise trainingcan restore many of these impairments. On
a physiological level, it is interesting that PAD patients have
increased mitochondrial content in skeletal muscle as well as
increased mitochondrial enzyme activity (39). Previous inves-
tigators have hypothesized that these adaptations might im-
prove oxygen utilization under low-flow conditions (5).
The physiological differences between acute and chronic
reductions in peripheral blood flow (i.e., ischemia) should be
1. LDL is oxidized
2. Monocytes migrate 
 to arterial wall
3. Foam cell formation
4. Smooth muscle cells 
 proliferate and form 
 fibrous cap
5. Outward remodeling
cigarette
smoking
high dietary 
sodium
high dietary 
cholesterol
high blood 
sugar
high blood 
pressure
genetic 
factors
Healthy Artery Artery with PAD
Fig. 1. Pathogenesis of peripheral arterial dis-
ease (PAD). Figure outlines the predisposing
factors and molecular pathways that convert
a health artery (left) into an artery with PAD
(right).
Table 1. Physiological consequences of chronic limb ischemia
Physiological Consequences
Already Determined
Number and size of type 1 muscle fibers 2
Capillary density in leg muscle 2
Muscle and blood levels of acylcarnitines 1
Muscle lactate accumulation during exercise 1
Maximal oxygen uptake 2
Endothelial function of limb blood vessels 2
Systemic markers of inflammation 1
Systemic markers of coagulation 1
Rise in arterial blood pressure during exercise 1
Possible Associations Not Yet Determined
Compensatory vasodilation of limb blood vessels
Neurovascular transduction of sympathetic outflow
Baroreflex sensitivity
Chemoreflex sensitivity
Coronary dilator capacity
Renin-angiotensin-aldosterone involvement
Table 2. Benefits of exercise training in humans with PAD
Benefits References
Functional Benefits
Improved maximal walking distance 31, 38–40, 61, 70
Improved pain free walking distance 31, 38–40
Increased quality of life 31, 71
Increased free-living physical activity 61, 70, 71
Physiological Benefits
Decreased systemic inflammation 80, 84
Increased endothelial function 8, 57
Increased skeletal muscle oxidative capacity 28, 38, 39
Increased maximal oxygen uptake 28, 31, 38–40, 70
PAD, peripheral artery disease.
Physiology in Medicine
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noted. Compared with acute ischemia via cuff occlusion or
intra-arterial balloon inflation, PAD is characterized by chronic
limb ischemia due to atherosclerosis as well as age-related
impairments in vascular compliance. Thus an impaired ABI is
due to the net effects of structural/mechanical changes within
the arterial wall, functional impairments in compensatory va-
sodilation, and physical blockage of flow by atherosclerotic
plaque (typically observed in large conduit arteries). Funda-
mentally, ischemia (and also hypoxemia) impairs O2 delivery
to skeletal muscle, and the local vasculature can dilate in an
attempt to increase blood flow and O2 availability. This classic
“supply and demand” balance is well established in both health
and disease and is a key concept of physiology (27).
Using an intra-arterial balloon catheter to impede blood flow
to the working forearm muscle in healthy subjects, Casey and
Joyner (12, 14) recently demonstrated that acute hypoperfusion
of the forearm leads to a compensatory vasodilation (i.e., to
balance the acute impairment in O2 delivery) at rest and during
low-intensity exercise. Indeed, the magnitude of flow restora-
tion correlated to the reduction in downstream vascular resis-
tance (13) and nitric oxide and adenosine both were involved
(12). The arterial balloon catheter model of Casey and Joyner
is an advanced experimental technique that allows researchers
to determine cause-and-effect mechanisms of acute limb ische-
mia beyond the use of external cuff compression. However,
this technique is invasive and does not study atherosclerotic
ischemia per se, but rather ischemia due to mechanical reduc-
tions in limb blood flow. Whether PAD patients are in a
chronic state of hypoperfusion that leads to local reduction in
vascular resistance (i.e., distal to a stenosis) is plausible but
needs to be experimentally tested.
Endothelial function and blood markers of vascular health.
The endothelium is a monolayer of cells within blood vessels
that participates in hemostasis, inflammation, and angiogene-
sis. Importantly, endothelial cells produce a myriad of factors
that can increase or decrease vasomotor tone (85). Endothelial
function can be experimentally tested in the limb and coronary
arteries using a variety of invasive and noninvasive approaches
(79). Epidemiological studies suggest that PAD patients have
severely compromised endothelial function in the limbs, and
this is likely due to the combined effects of oxidative stress,
inflammation, elevated serum lipids, and impaired ability of
endothelial cells to produce nitric oxide (9, 10). Indeed, levels
of fibrinogen and C-reactive protein are elevated in PAD (9,
50, 67). Additionally, Pellegrino et al. (66) demonstrated that
impairments in peripheral vascular endothelial function in PAD
patients (brachial artery flow-mediated dilation) correlate to cor-
onary flow reserve (i.e., a measure of coronary vasodilator capac-
ity). This linkage is important to understand because patients with
PAD have a high incidence of coronary disease (32).
Early PAD (Fontaine I-II)
Limb Arterial Inflow
Limb Venous Outflow
Resting ABI
Post-exercise ABI
Pain Free Walking Distance
Total Walking Distance
Quality of Life
Advanced PAD (Fontaine III-IV)
Limb Arterial Inflow
Rest Pain
Wound Healing
Amputations
ESTABLISHED BENEFITS OF 
INTERMITTENT 
PNEUMATIC CALF 
COMPRESSION (IPCC)
BENEFITS POSSIBLE 
BUT NOT YET 
CONFIRMED FOR 
REMOTE ISCHEMIC 
PRECONDITIONING 
(RIPC) AND 
ENHANCED EXTERNAL 
COUNTERPULSATION 
(EECP)
IPCC
EECP
RIPC
Fig. 2. Physiological basis of novel mechanical therapies
in PAD. Intermittent pneumatic calf compression (IPCC)
has been widely studied in patients with PAD ranging
from mild to severe leg symptoms (left). Remote ischemic
preconditioning (RIPC) and enhanced external counterpul-
sation (EECP) have not yet been prospectively tested in
PAD but there is strong physiological rationale for why
these therapies may improve leg symptoms and reduce
systemic cardiovascular disease risk. Taken together, me-
chanical therapies are likely to be an effective alternative
or adjunct therapy to dynamic exercise training in PAD.
Physiology in Medicine
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HDL cholesterol is typically lower and LDL cholesterol and
triglycerides are higher in PAD patients relative to healthy
controls. Plasma-antiplasmin complex, a hemostatic activation
marker, is elevated in PAD and may be able to identify patients
at a higher risk for future myocardial infarction (21, 67).
Cigarette smoking clearly enhances the progression of athero-
sclerosis (52). The renin-angiotensin-aldosterone system in
PAD patients has not been comprehensively studied, but it is
known that ACE inhibitors slow the progression of atheroscle-
rosis and may favorably benefit functional capacity (17). Taken
together, several pathophysiological processes are evident in
PAD that reflect systemic atherosclerosis in addition to local
reductions in blood flow.
Autonomic control of blood pressure and blood flow. The
sympathetic nervous system serves as the principal integrated
controller of myocardial function, regional distribution of
blood flow, and blood pressure. Many cardiovascular disease
states are associated with heightened sympathetic tone (11, 29).
Specifically, preclinical and clinicalstudies in hypertension,
heart failure, obstructive sleep apnea, and renal disease pro-
vided evidence that basal sympathetic activity as determined
by heart rate variability, circulating levels of the sympathetic
neurotransmitter norepinephrine, and directly measured sym-
pathetic vasoconstrictor nerve activity (via microneurography)
is increased and predicts cardiovascular risk (11, 29). A direct
consequence of enhanced sympathetic activity is increased
vasoconstrictor tone in the target organ(s), which decreases
regional blood flow unless it is counterbalanced by a commen-
surate increase in blood pressure (perfusion pressure). Further-
more, increased sympathetic tone may contribute to endothelial
dysfunction (42), a hallmark in the development of atheroscle-
rotic disease. However, it is important to appreciate that under
physiologic conditions, sympathetic activity to different target
tissues (skeletal muscle, kidneys, coronary arteries, etc.) may
be highly variable, and some of these target territories are very
difficult to study in humans (29).
An understanding of the specific role of sympathetic neural
control and dysregulation in PAD is very limited. Most patients
with PAD suffer from comorbid conditions such as hyperten-
sion, diabetes mellitus, and renal disease, and many are ciga-
rette smokers, conditions that by themselves are known to be
associated with sympathetic activation and vascular dysfunc-
tion (15, 29, 34, 62). Therefore, the pattern of sympathetic
neural regulation in PAD is likely the result of the integrated
effects of reflex interactions, altered central integration, and
vascular dysfunction and remodeling. To what extent sympa-
thetic overactivity and dysregulation are cause or consequence
of the underlying disease process, by what mechanism the
sympathetic nervous system is activated and modulated,
whether it directly contributes to disease progression, and how
it exerts its potential adverse effects on the cardiovascular
system in humans are topics of continued debate. One postu-
lated mechanism of sympathetic activation involves enhanced
central expression of angiotensin II and renin-angiotensin-
aldosterone system (RAAS) activity, promoting generation of
reactive oxygen species and inflammation that result in im-
paired baroreflex restraint and heightened peripheral chemore-
flex sensitivity (26, 65, 68, 86, 88). The contribution of renal
sympathetic nerves to this process in humans is an area of
active investigation (74). In another model of sympathetic
activation produced by intermittent hypoxia (68), downstream
effects of the generation of the transcription factor hypoxia-
inducible-factor (HIF)-1�, including oxidative stress, appear to
be crucial (76). This model is highly relevant to hypertension
in general and to the effects of smoking.
PAD patients have an augmented blood pressure response to
dynamic exercise (2, 3, 55). Our laboratory recently demon-
strated that this was due in part to an augmented muscle
mechanoreflex (relative to healthy controls) and that oxidative
stress may be involved (60). Recent studies provide evidence
that the muscle metaboreflex is also augmented in a rodent
model of PAD (82, 83, 87). As recently reviewed by Li and
Xing (54), alterations in metabolically sensitive muscle affer-
ent receptors (transient receptor potential vanilloid type 1,
purinergic P2X, acid sensing ion channel) appear to underlie
the augmented blood pressure response to muscle contraction
in this model. The augmented pressor response to exercise in
PAD may be a normal compensatory response to enhance skeletal
muscle blood flow, but high afterload may damage the brain and
heart over time. Prospective studies relating acute exercise adap-
tations to long-term medical outcomes are needed. Because dy-
namic exercise is the primary stimulus that provokes symptoms in
PAD and because patients with more severe disease have larger
pressor responses to exercise (60), we believe understanding this
process is of paramount physiological and medical importance.
Future work in PAD patients who also have diabetes may clarify
how an augmented pressor response to exercise influences limb
function.
In addition to the sympathetic nervous system, vagal activ-
ity, typically inversely related to sympathetic activity, may also
play a role. Vagal activity can exert important anti-inflamma-
tory effects, thus potentially inhibiting vascular inflammation
that underlies systemic atherosclerosis (81). Conversely, in a
hypertensive rodent model, sympathetic activation has been
shown to promote cardiac fibrosis (cardiac remodeling) via
effects on monocytes (53). Whether reduced sympathetic ac-
tivity or enhanced vagal activity would translate into anti-
inflammatory effects on blood vessels in humans with PAD is
unknown.
PHYSIOLOGICAL BASIS OF CURRENT AND FUTURE
THERAPIES IN PAD
Treatment for patients with PAD is aimed at improving
maximal walking distance and functional capacity as well as
reducing cardiovascular disease risk. Previous publications
have outlined the medical, surgical, and lifestyle management
of this progressive disease (36, 64). The following section will
focus on the physiological mechanisms by which the following
treatments are effective: 1) medical therapy; 2) surgical inter-
vention; 3) exercise training; and 4) mechanical therapy.
Medical therapy. Drug treatment with statins and antiplatelet
agents is necessary for the secondary prevention of coronary
and cerebrovascular disease in PAD patients. Because of the
prevalence of comorbid conditions, smoking cessation, blood
glucose management, and treatment of hypertension and obe-
sity is also required (36, 64). Medical management is aimed at
symptom relief and slowing progression of atherosclerotic
disease. Although there have been a number of drugs evaluated
for use in patients with claudication, efficacy is only noted for
cilostazol and antiplatelet agents (16, 72). Cilostazol is a
phosphodiesterase inhibitor that suppresses platelet aggrega-
Physiology in Medicine
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tion; it is also a direct vasodilator. Patients can note improve-
ment in maximal and pain-free walking distance in as short as
4 wk. Other phosphodiesterase inhibitors have been noted to
increase mortality in patients with advanced heart failure, thus
cilostazol is contraindicated in patients with any level of heart
failure (36). Taken together, these above medications are
physiologically effective if they improve blood flow to the
limb, prevent lipid accumulation and oxidation, and prevent
coagulation (i.e., preventing further progression of atheroscle-
rosis). However, epidemiological evidence suggests that many
patients do not receive symptom relief with medical therapy
alone; the physiological rationale is likely because drugs are
not able to enhance limb blood flow to the levels observed with
other therapies (listed below).
Surgical intervention. Restoration of limb blood flow can be
achieved through angioplasty (with or without the addition of
atherectomy), stenting, and lower extremity bypass. Percuta-
neous management has the advantage of being less invasive,
avoiding infection and incision and generally being performed
as an outpatient. When conservative measures fail and claudi-
cation becomes lifestyle limiting, angiography with intention
to treat becomes a logical next step. Femoral arterial access is
often utilized with 5–7 Fr. sheaths typical for intervention. If
percutaneous treatment is deemed not possible by the physi-
cian, proximal and distal targets will be identified on angiog-
raphy for lower extremity bypass planning. Autogenous con-
duits using great saphenous vein is preferred over prosthetic
graft that carries a higher risk of infection, thrombosis, and
decreased limb salvage compared withvein. Hybrid proce-
dures exist that can combine these two modalities—endovas-
cular and open vascular surgery—under one anesthetic. Hybrid
operating rooms are becoming increasingly common and offer
many advantages for the patient, including the ability often to
make the entire procedure less invasive, as well as combining
two procedures into one. On a physiological level, it is not
surprising that surgically removing an obstruction to flow
improves symptoms in PAD. How these standard of care
procedures influence other body systems (e.g., muscle metab-
olism, autonomic nervous system, inflammatory processes) is
an area for future investigation.
Exercise training. The benefits of exercise training in PAD
are well established and are outlined in Table 2. As noted by
Hamburg and Balady (35) in a recent review, the current
recommendations include treadmill walking 3–5 days/wk up to
the point of mild to moderate pain (35). Once pain is experi-
enced, subjects are encouraged to rest and repeat the bout of
exercise when symptoms resolve. In animals with experimen-
tally induced limb ischemia, exercise training leads to angio-
genesis and collateralization (35); whether this occurs in hu-
mans is unclear. Resistance training, arm ergometry, and mod-
ified cross country skiing have also shown positive benefits
(35). It is important to emphasize that supervised programs are
more effective than home-based programs (70). However,
unlike cardiac rehabilitation programs, health insurance typi-
cally does not cover exercise for PAD patients (35). Whether
exercise training is equal to or more effective than surgical
intervention has been debated (18, 56, 61). Nevertheless, there
is sufficient evidence that whole body dynamic exercise pro-
vides primary and secondary benefits in PAD. On a physiological
level, these benefits are due to complex interactions between
oxygen delivery and oxygen extraction in skeletal muscle.
Mechanical therapy. Patients with moderate to advanced
PAD (Fontaine II-IV) are often unwilling or unable to exercise
at the required intensity needed to achieve cardiovascular and
functional benefit. For this reason, several mechanical devices
have been developed that act on the arterial and/or venous
systems. The most commonly studied therapy is intermittent
pneumatic foot and calf compression (IPCC). Using the phys-
iological principles set for by Le Dentu in 1867 (51) IPCC
facilitates the venous emptying of the foot veins into the more
proximal leg veins. Inflation pressures ranging from 85 to 180
mmHg are delivered to the foot and/or calf for 2–4 s, and this
compression is followed by 16–20 s of rest (deflation). This
paradigm is recommended for 2–6 h/day and allows for sus-
tained flow while the veins refill (23–25, 46). Patients with
both claudication and critical limb ischemia have experienced
improvements in walking distance, improved quality of life,
improved ABI, reduced leg pain, and reduced incidence of
amputation (22, 45, 59). This is important for critical limb
ischemia patients because they would not normally be encour-
aged to participate in a dynamic exercise program. The mech-
anisms by which this occurs have been widely speculated (23,
24, 46, 49, 69) but until recently have not been directly tested:
1) increased arteriovenous pressure gradient; 2) production
of vasodilator substances due to increased shear stress; and
3) inhibition of the venoarteriolar reflex (which would nor-
mally act to impair blood flow when the limb is dependent).
Recent studies in rodents investigated the effect of intermittent
pneumatic leg compression on skeletal muscle performance,
exercise tolerance, blood flow, oxidative capacity, and capil-
lary contacts (73). The investigators found that 2 wk of daily
treatment enhanced exercise performance and increased blood
flow to the plantaris muscle compared with sham-operated
animals. Another study from the same group found that inter-
mittent compression transiently altered the expression of some
(e.g., CYR61 and CTGF), but not all (e.g., VEGF), genes in
human subjects (77). On a physiological level, these cited
studies importantly help clarify the mechanisms by which
intermittent compression provides clinical benefits.
Two other mechanical therapies include enhanced external
counterpulsation (EECP) and remote ischemic preconditioning
(RIPC). EECP is an effective therapy for the treatment of
refractory angina and utilizes principles of hemodynamics in
relation to each cardiac cycle (58). The patient is situated in the
semi-supine posture with cuffs on the lower legs, thighs, and
buttocks. During early diastole, the cuffs sequentially and
rapidly inflate to suprasystolic pressure (distal to proximal);
during end diastole the cuffs simultaneously deflate. This
occurs for 60 min, 5 times/wk for 7 wk. By unloading the
vasculature during systole and augmenting diastole, cardiac
output is increased. Additional benefits are long lasting and
include reduced proinflammatory markers, improved endothe-
lial function, and reduced arterial stiffness (58). A diagnosis of
PAD has been considered a relative contraindication for EECP
but recent studies have indicated its safety (7). Many of the
cardiac patients who benefit from EECP likely have systemic
atherosclerotic disease (i.e., beyond just refractory angina).
The concept that EECP might improve both limb and cardiac
function in PAD needs to be prospectively tested. We should
emphasize that the use of EECP in PAD patients must be
performed in a medically supervised facility, and discussion
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should progress to standardize prescreening tests (e.g., imag-
ing, blood panels) to minimize risk to the patient.
Similar to EECP, RIPC has gained attention in recent years,
albeit in patients with coronary disease, not necessarily PAD
(47). The fact that acute limb ischemia may protect against
future limb or coronary ischemia is an attractive notion for
patients who are unable to undergo exercise training or who do
not respond to medical therapy. By making an arm or leg
ischemic for 5 min, a cascade of hemodynamic and biochem-
ical events occur that appear to offer both short-term and
long-term systemic cardioprotection (4). Many of these studies
have been performed in nonhuman models, but recent evidence
suggests that 3–5 cycles of 5 min upper arm ischemia followed
by reperfusion reduces infarction size and reduces troponin
levels in cardiac patients (47). Whether a similar effect is seen
in PAD patients remains to be directly tested. Compared with
IPCC, EECP and RIPC modalities have not been comprehen-
sively investigated, but we believe there is a physiological
rationale for why they could/should be effective in PAD. RIPC
is the shortest duration stimulus and also the least expensive,
but the magnitude and duration of clinical benefits is currently
unknown.
SUMMARY AND FUTURE DIRECTIONS
PAD is a common and progressive atherosclerotic disease
that is closely linked with cardiac and cerebrovascular mortal-
ity. Its hallmark symptom, intermittent claudication, is pro-
voked by moderate to vigorous leg exercise, but less than 25%
of patients with PAD experience claudication, which makes the
disease challenging to diagnose and treat (43, 75). Despite
recent efforts, PAD is underdiagnosed in the primary care
setting (44). Because PAD is often observed with comorbid
conditions such as hypertension, dyslipidemia, diabetes, ciga-
rette smoking, and/or physical inactivity, the pathophysiology
of PAD is certainly complex (Fig. 1). At the present time, there
are few studies in PAD patients that isolate cause-and-effect
mechanisms of skeletal muscle metabolic dysfunction, endo-
thelial function, or autonomic circulatory control as the disease
progresses. Another gap in knowledge ishow and why me-
chanical therapies are effective. Lastly, understanding how the
coronary blood vessels and myocardium are altered in response
to chronic limb ischemia is a necessary area to pursue. It is
clear that the discipline of physiology will remain a driving
force for the diagnosis and management of PAD as this field
moves forward.
ACKNOWLEDGMENTS
The authors appreciate the help of Anne Muller in preparing the graphics
for this report. We also acknowledge the administrative guidance of Kris Gray
and Jen Stoner.
GRANTS
This work was supported by National Institutes of Health Grants P01
HL096570 (to L.I.S.), UL1 TR000127 (to L.I.S.), and R01 HL098379 (to
U.A.L.).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: M.D.M., A.B.R., U.A.L., and L.I.S. conception and
design of research; M.D.M., A.B.R., U.A.L., and L.I.S. analyzed data;
M.D.M., A.B.R., U.A.L., and L.I.S. interpreted results of experiments; M.D.M.
prepared figures; M.D.M. drafted manuscript; M.D.M., A.B.R., U.A.L., and
L.I.S. edited and revised manuscript; M.D.M., A.B.R., U.A.L., and L.I.S.
approved final version of manuscript.
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