Pathophysiology and Treatment of Critical Limb Ischemia

R. Kevin Rogers, MD MSc and William R. Hiatt, MD

Introduction
Peripheral arterial disease (PAD) is one of the major manifestations of systemic
atherosclerosis affecting 12% of the adult population and up to 20% of elderly persons. The
most severe form of PAD, critical or limb-threatening ischemia (CLI), occurs when arterial blood
flow is restricted so severely that perfusion of capillary beds is inadequate to sustain tissue
viability. Many patients do not progress sequentially along predefined stages from claudication
to CLI. As described in select longitudinal studies, some patients with symptomatic PAD have
been shown to develop CLI,1,2 while data from other studies have shown that many patients are
asymptomatic prior to the development of CLI.3,4 Ordinarily, compensatory mechanisms,
including capillary sprouting as well as arteriogenesis,5 alleviate the effects of blood flow
deprivation, but in patients with CLI, these mechanisms have been exhausted and/or are
defective. Inadequate perfusion of the skin and surrounding tissues leads to endothelial
dysfunction, chronic inflammation,6 and muscle damage.7,8 The net effect of these changes is
the occurrence of rest pain, chronic nonhealing wounds, and gangrene. At presentation, 20% to
25% of patients with CLI undergo primary amputation, 50% to 60% have vascular reconstruction
(surgical and/or endovascular), and 25% are treated medically.9 The 5-year mortality rate for
populations with CLI is 60%,10 exceeding that of prostate cancer (<1%),11 breast cancer
(11%),12 acute myocardial infarction (20%),13 colorectal cancer (36%),14 and stroke (41%).15
Though there are multiple treatment options for patients with CLI, limitations of individual
treatment modalities, difficulty in patient selection for various therapies, and lack of consensus
for overall treatment strategies offer room for improvement in the care of patients with CLI.
Currently, treatment for patients with CLI usually begins with an assessment of the index limb
for suitability of revascularization using surgical bypass or endovascular methods. For those
patients without an option for revascularization or with a nonsalvageable limb, primary
amputation may be considered. The major treatment goals for CLI include:

pain control

wound healing

limb salvage

improvement of quality of life, including maintaining ambulatory status

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reduction of overall cardiac risk

Understanding the multiple pathophysiologic mechanisms associated with CLI is

essential in the overall management of patients with limb-threatening ischemia and the
development of potential new therapies.
Pathophysiology of CLI
Hemodynamic abnormalities in CLI. Severe PAD is often the result of multisegment
occlusive disease in the arteries supplying the lower extremity. While the aorta, iliac, femoral,
and popliteal arteries may be involved, there is a particularly high prevalence of tibioperoneal
and pedal disease in patients with CLI, the small caliber of which can complicate successful
revascularization (Figure 1)

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Figure 1.

Examples of Different Levels of Obstructive PAD

Panel A shows a stenosis of the left

external iliac artery

Panel D Distal posterior tibial artery

occlusion extending into lateral plantar
artery

Panel B shows several stenoses in the

superficial femoral artery

Panel C shows extensive disease of the

tibial vessels in the calf.

Panel E following angioplasty

Factors that influence blood flow to affected tissues include the location, degree, and
length of the stenosis or occlusion, blood viscosity, blood flow velocity, perfusion pressure, and
extent of angiogenesis and arteriogenesis. These hemodynamic factors are diseased in
patients with CLI, leading to a decrease in ankle blood pressure. Evidence of severe PAD is
suggested when a patient has ulcers or gangrene with ankle systolic pressure <70 mm Hg or

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toe systolic pressure <50 mm Hg. Rest pain can occur when the ankle systolic pressure is
<50 mm Hg or toe systolic pressure is <30 mm Hg. Assessing hemodynamics in patients with
nonhealing wounds is important to guide care. Often patients with diabetes are classified as
having a diabetic foot ulcer, when in fact up to 50% have underlying PAD.16
While the macrovascular changes associated with PAD are often the initial events of
limb-threatening ischemia, the response to chronic ischemia also results in microvascular
dysfunction. There is an alteration in structure and function of endothelial cells and the
activation of white blood cells and inflammation. Ischemia with endothelial trauma results in
increased free radical production, inappropriate platelet activation, and leukocyte adhesion.17
Oxidative stress in PAD. Muscle ischemia is associated with an increase in oxidative
stress.

18

Oxidative stress occurs when the cell or tissue fails to detoxify the free radicals

produced during metabolic activity. Free radicals damage proteins, lipids and nucleic acids.
The production of oxygen-free radicals may be a unifying mechanism of vascular and skeletal
muscle injury in PAD. Repeated episodes of ischemia and reperfusion during recovery may
promote oxidative injury to endothelial cells, muscle mitochondria, muscle fibers, and distal
motor axons. Mitochondria are the major source of free radicals within the cell and, therefore,
somatic mutations in mitochondrial DNA are an important marker of oxidant injury. These
mutations are readily demonstrated in muscle from patients with PAD. For example, patients
with PAD have an increased frequency of mitochondrial DNA 4977 bp deletion mutation.19
Thus, they have increased levels of both local and systemic oxidative stress that, over time,
contribute to the functional limitations seen in these patients.
Alterations in skeletal muscle metabolism. Mitochondria perform a number of critical
tasks in the cell including acting as the cells power plant (housing the pathways of oxidative
phosphorylation, respiration, Krebs cycle, and fatty acid oxidation), and playing a central role in
intercellular communication and cell-death pathways. Muscle mitochondrial content and
mitochondrial enzyme activities reflect the functional status of the individual. In healthy subjects,
muscle mitochondrial content positively correlates with peak oxygen uptake, indicating the
importance of muscle oxidative capacity in determining exercise performance in the individual.20
In PAD, the marked limitation in walking activity and resultant sedentary behavior would be
expected to result in a decrease in muscle mitochondrial enzyme content and activity
(detraining). In contrast, several studies have revealed increased mitochondrial content in
muscle of patients with PAD.21,22,23 This increased mitochondrial expression appears to be a

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direct consequence of, and is proportional to, the severity of the occlusive disease as assessed
by leg hemodynamics.21 Thus, alterations in skeletal muscle mitochondria in PAD appear to
reflect the severity of the underlying occlusive disease process. Increased mitochondrial
content might improve oxygen extraction under ischemic conditions or could reflect a
compensatory mechanism for any intrinsic abnormality in mitochondrial oxidative capacity.
Patients with PAD may develop changes in the activity of enzymes critical for oxidative
metabolism in the affected skeletal muscle. A potential site of such impairment is the electron
transport chain, which is vulnerable to free radical injury.24 Skeletal muscle from legs affected
by PAD has reduced mitochondrial NADH dehydrogenase of complex I and ubiquinolcytochrome c oxidoreductase (complex III) activity.25 These observations suggest that electron
transport chain activity is affected by ischemia reperfusion injury in PAD and may contribute to
metabolic dysfunction in PAD.
The changes in enzyme activities and electron transport chain function might be
expected to reduce the ability to perform oxidative metabolism. During normal metabolic
conditions, fuel substrates such as fatty acids, protein, and carbohydrates are converted to acylCoA intermediates for complete oxidation in the Krebs cycle. During periods of metabolic
disruption, incomplete oxidation of acyl-CoA leads to their accumulation causing inhibition of the
metabolic pathways involved in acyl-CoA production. To prevent this event, the CoA-coupled
intermediates are linked to the cellular carnitine pool to serve as a buffer by collecting the
excess acyl groups through the formation of acylcarnitines. Thus, conditions of metabolic stress
leads to accumulation of corresponding acylcarnitine in the tissues and plasma where they can
be measured as markers of metabolic stress.26
Patients with PAD have alterations in carnitine metabolism. This phenomenon is evident
by the accumulation of short-chain acylcarnitines in plasma as well as skeletal muscle in legs
affected by arterial disease.27,28 Importantly, acylcarnitine accumulation may have functional
significance in that patients with the greatest accumulation have the most reduced treadmill
exercise performance.28 Thus, the degree of metabolic abnormality (as defined by acylcarnitine
accumulation) is a better predictor of treadmill exercise performance than the ankle brachial
index (ABI), emphasizing the importance of altered skeletal muscle metabolism in the
pathophysiology of PAD.
An overall pathophysiologic scheme is proposed in Figure 2. Atherosclerotic occlusions
of the peripheral arteries limit arterial perfusion to the lower extremities. The resultant oxygen

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supply/metabolic demand mismatch is associated with critical limb ischemia that severely limits
functional ability, threatens the limb, and affects quality of life. An additional consequence is
ischemia-reperfusion-induced oxidant stress injury throughout the vascular bed. Muscle
denervation and alterations in muscle metabolism further limit performance.
Figure 2.

Pathophysiology of Critical Limb Ischemia

Treatment of CLI
Prevention. As with many diseases, prevention should be the cornerstone of managing
patients with CLI or those with hemodynamics predisposing to CLI. Primary prevention of
wounds should be addressed at serial patient care visits. Secondary prevention of
atherosclerotic events is crucial with smoking cessation, blood pressure control, lipid lowering,
and antiplatelet agents. Many patients with CLI do not receive intensive risk factor modification.
Wound care. Though beyond the scope of this review, fastidious wound care is critical
for patients with CLI and ulcers. Underlying infection should be treated and necrotic tissue
debrided. Topical therapies with recombinant growth factors and hyperbaric oxygen are being
investigated.29
Medical therapy. In addition to secondary prevention of myocardial infarction and
stroke, there are medical options for patients with ischemic rest pain or ulcers in the form of
prostanoids. In a Cochrane systematic review of 20 trials, a small but statistically significant
benefit was seen for prostanoids in relief of ischemic rest pain and short-term ulcer healing.

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There was not a statistical benefit in limb salvage or mortality. Agents studied were
prostaglandin E1, prostacyclin, and iloprost.30 Given the lack of evidence for this drug class to
promote limb salvage or prolong life, they cannot be recommended.
Revascularization. For patients with severe PAD, revascularization (bypass surgery or
endovascular techniques) is widely regarded as the cornerstone of treatment. However,
revascularization is often inadequate as a stand-alone therapy given the aforementioned
complex pathophysiology of this disease. When discussing revascularization for CLI, the focus
is often on the tibioperoneal and pedal circulation, given the high prevalence of atherosclerotic
occlusive disease at this level.
In the BASIL trial, 452 patients with CLI who had infrainguinal disease amenable to
surgical or endovascular revascularization were randomized to a surgery-first or endovascularfirst strategy.31 Follow-up was up to 5.5 years for the primary outcome of amputation-free
survival (AFS). The trial was adequately powered yet there was no clinically or statistically
significant difference in the primary outcome. The BASIL trial suffers from limited
generalizability; no distinction was made for outcomes for infrapopliteal interventions and
endovascular therapy consisted of balloon angioplasty alone.
Contemporary revascularization acknowledges the angiosome concept. That is, the
tibioperoneal or pedal artery that directly supplies the wound is prioritized for revascularization.
Current endovascular techniques involve tibiopedal access and subintimal recanalization of
chronic tibioperoneal occlusions. Novel endovascular devices include re-entry devices,
dedicated pedal access equipment, dedicated 0.014 crossing wires, and drug-eluting balloons.
Drug-eluting, balloon-expandable stents designed for use in coronary arteries are also showing
promise in tibioperoneal revascularization. Across 18 observational studies of 640 patients with
CLI, the 12-month primary patency for drug-eluting coronary stents in the tibioperoneal vessels
was approximately 80%, which translated into a limb salvage rate of over 95%.32
With the advancement of endovascular techniques, the number of patients treated using
endovascular methods has grown steadily.33 In a recent study using the Nationwide Inpatient
Sample database, percutaneous transluminal angioplasty (PTA) increased 3-fold between 1999
and 2007 for limb threat patients, while bypass graft operations decreased by almost half.34
However, surgical techniques are also progressing with bypass to more distal targets
and exposure of crural arteries for hybrid revascularization. Surgical and endovascular

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therapies should be viewed as complementary, rather than competing, modalities for the
treatment of patients with CLI.
Therapeutic neovascularization. Therapeutic neovascularization is an exciting
upcoming modality in the treatment of patients with CLI. The term neovascularization
encompasses angiogenesis (sprouting of new capillaries in existing capillary beds),
arteriogenesis (growth of arterial conduits large enough to be seen on catheter-based
angiography), and vasculogenesis (formation of blood vessels from vascular or endothelial
progenitor cells).35 Various types of gene and cell-based therapies that promote
neovascularization are being investigated in patients with CLI.
Gene therapy for CLI has primarily focused on genes coding for angiogenic growth
factors. In particular, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF),
hepatocyte growth factor (HGF), and hypoxia inducible factor 1a (HIF-1a) have been studied.
Gene transfer to target cells can involve viral and non-viral vectors and intra-arterial,
intramuscular, and in vitro routes of delivery. Overall, clinical results have been mixed over a
variety of endpoints including changes in hemodynamics, transcutaneous oxygen tension, pain,
ulcer healing, amputation, and survival. Results from a number of phase 1 and 2 trials were
relatively promising; however, evidence of benefit in phase 3 trials are lacking.36 For example,
in the Phase 3 trial TAMARIS, there was no difference in the primary outcome of AFS in
patients with CLI randomized to treatment with non-viral fibroblast growth factor 1 and
placebo.37
Multiple cell-based therapies are also under investigation for the treatment of CLI.
Several meta-analyses, including a Cochrane review, of phase 1 and 2 trials of cell-based
therapies suggest that these treatments are safe and potentially beneficial over a similar
spectrum of outcomes as those studied in gene therapy trials for CLI.38,39 However, multiple
issues remain regarding the administration of cell-based therapy, including the optimal dosage
of cells, the best cell type (CD34+, CD133+, G-CSF-mobilized, mesenchymal-expanded), the
most appropriate cell source (autologous or allogenic, bone marrow-derived or peripheral
blood), and the preferred route of administration (intramuscular, intra-arterial, or both).40
Several phase 3 randomized trials are underway that will help address these unanswered
questions.41
Other treatments. Spinal cord stimulation, lumbar sympathectomy, and intermittent
pneumatic compression have been evaluated as treatment options for CLI patients who cannot

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be revascularized.42 In a meta-analysis of 6 trials comprising 450 patients, those treated with

spinal cord stimulation had improved rates of amputation and less pain compared to controls.43
However, there was no difference in ulcer healing and a relatively high complication rate with
spinal cord stimulation, resulting in a number needed to harm of 6. In several small trials and
observational studies of lumbar sympathectomy, there is a signal for pain relief but not reduction
in amputation or mortality in patients with CLI.44 In a small retrospective observational study of
48 patients, improvement in limb salvage and hemodynamics was seen in those treated with
intermittent pneumatic compression compared to unmatched controls.45
Summary
The pathophysiology of CLI is complex and involves both macrovascular and
microvascular pathology. Thus, not surprisingly, therapeutic modalities are multifold, spanning
many health care specialties and requiring substantial institutional infrastructure to provide
optimal patient care. Though challenging, the future of CLI treatment is exciting with increasing
focus on optimal wound care and prevention, improving revascularization results with novel
endovascular and surgical techniques and devices, and ongoing investigation into promising
therapies like therapeutic angiogenesis.

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