Peripheral arterial disease


  • PAD is prevalent and associated with high morbidity and mortality but is frequently underdiagnosed.

  • Conventional approaches to diagnosis, including ABI and angiography (invasive and noninvasive), can only assess the extent and severity of macrovascular atherosclerosis.

  • There is growing recognition that microvascular abnormalities in PAD contribute to patient symptoms and portend adverse clinical outcomes, including wound healing, infection, and limb amputation.

  • Microvascular abnormalities and associated skeletal muscle remodeling are poorly captured by standard diagnostic modalities.

  • Radionuclide perfusion imaging with SPECT and PET provide accurate, quantitative assessments of tissue perfusion that complement angiographic data. As such, they can be used to identify potential therapeutic benefit from revascularization and medical management, including supervised exercise therapy.

  • Radionuclide imaging using targeted radiotracers are emerging as potential powerful tools for assessing novel cell and gene therapies for PAD.

Epidemiology and the natural history of peripheral arterial disease

Over the last several decades, cardiovascular imaging has expanded to incorporate peripheral vascular disease, which affects the arterial, venous, and lymphatic systems. The primary focus of this chapter will be on arterial disease of the lower extremities, a progressive atherosclerotic process that causes stenosis and occlusion.

In 2010, peripheral arterial disease (PAD) affected 200 million people worldwide with a prevalence that increased with age and in association with diabetes mellitus (DM). PAD is associated with an increased risk for cardiovascular disease and is the third leading cause of atherosclerotic cardiovascular comorbidity after coronary artery disease (CAD) and stroke. The increased morbidity and mortality risks are due to downstream clinical manifestations of intermittent claudication, nonhealing ulcers, the need for limb amputation, associated increased risk for cardiac events, and death. Patients with PAD experience a diminution in quality of life, largely attributable to impaired ambulatory physical function.

Despite the high prevalence and significant effect on patient quality of life and survival, PAD is frequently underdiagnosed. The challenges in identification of PAD are due to (1) underrecognition of symptoms, (2) the prevalence of asymptomatic or variable presentation of PAD, and (3) limitations in standard noninvasive diagnostic modalities, such as ankle-brachial index (ABI), ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). These standard imaging modalities have utility in assessing the macrovascular circulation, particularly for inflow disease and in the absence of extensive calcification. As such, these techniques are used to assess patency of the conduit lower-extremity arteries and surveillance after lower-extremity revascularization.

Similar to our evolving understanding of CAD, an expanded understanding of PAD beyond just macrovascular disease requires assessment of the microvascular circulation in the lower extremities, along with pairing of functional and anatomic assessments of PAD, characterization of the biology of the atherosclerotic plaque, a measure of the angiogenic and arteriogenic response, and assessment of the metabolic health of the downstream skeletal muscle. With their ability to image both perfusion and biologic processes, radionuclide imaging techniques offer promise to improve our understanding of pathophysiology, help with diagnosis, and guide in the treatment of PAD. Given that these emerging techniques are in development and not yet part of clinical practice, clinical insights are embedded in the text to highlight challenges in our current standard for assessment of PAD and opportunities that may exist for radionuclide techniques.

Compartments of peripheral arterial disease: Macrovasculature, microvasculature, angiosomes, and collateral vessels

In patients with PAD, reduced physical function, development of wounds, and tissue loss are because of insufficient blood flow and perfusion, resulting from impaired oxygen and nutrient supply to the lower extremity skeletal musculature. Reduced oxygen supply is traditionally attributed to progressive narrowing of the large arteries from atherosclerosis. The macrovascular arterial system is divided into inflow (conduit) arteries (i.e., aorta and iliac branches) and outflow arteries. The outflow arteries include the arteries above-the-knee (i.e., the superficial femoral artery) and the below-the-knee vasculature (i.e., the popliteal artery and infrapopliteal arteries—anterior tibial, posterior tibial, and peroneal arteries).

The angiosome concept of foot perfusion is based on anatomic studies of arterial circulation for planning of revascularization and/or amputation. Angiosomes are three-dimensional (3D) blocks of tissue that consist of skin, subcutaneous tissue, fascia, muscle, and bone. They are supplied by specific upstream infrapopliteal arteries (anterior tibial, posterior tibial, and peroneal arteries), which, in turn, supply downstream vascular runoff territories in the foot. There are six foot angiosomes, including three that originate from the posterior tibial artery, one from the anterior tibial artery, and two from the peroneal artery ( Fig. 31.1 ).

Fig. 31.1

Angiosomes of the foot and ankle.

Medial and lateral views of the main foot arterial trunks and associated angiosome territories are illustrated.

Adapted from Alexandrescu VA, Pottier M, Balthazar S, Azdad K. The foot angiosomes as integrated level of lower limb arterial perfusion: amendments for chronic limb threatening ischemia. J Vasc Endovasc Ther. 2019;4(1):6.

Critical limb ischemia (CLI) with complicating ischemic and neuroischemic foot ulcers is more common in patients with DM. The construct of angiosomes is applied in patients with DM and CLI to predict healing after revascularization because angiosome-directed revascularization has been associated with improvement in wound healing and limb salvage. Revascularization planning is informed by identification of the macrovascular level of stenosis, which is often multilevel. Although multivessel infrapopliteal disease is common, complete revascularization of all three infrapopliteal vessels is not always possible and is associated with poor long-term patency, whereas angiosome-directed revascularization allows for targeting of specific anatomic regions ( Fig. 31.2 ).

Fig. 31.2

Angiosome-directed revascularization for critical limb ischemia (CLI) in a patient with diabetes.

Digital subtraction angiography in a 63-year-old male with diabetes and CLI with nonhealing ulcers of the right foot first and second digits undergoing multivessel revascularization of the lower extremity (left). Patient was referred for angiosome-directed revascularization to achieve wound healing and limb salvage. An ankle-brachial index was uninterpretable because of calcified, noncompressible arteries. Angiographic images acquired before ( A ) and after ( B ) balloon angioplasty of the right popliteal artery, and before ( C ) and after ( D ) the balloon angioplasty of the right superficial femoral artery (SFA), demonstrate improvement in arterial patency after revascularization. Arrows denote segments of arterial stenosis targeted for balloon angioplasty. Single photon emission computed tomography (SPECT)/computed tomography (CT) perfusion imaging in a CLI patient before and after revascularization (right). Coregistered and fused SPECT/CT images demonstrate increased radiotracer uptake and improved microvascular perfusion in the foot in the axial ( A ), sagittal ( B ), and coronal ( C ) views after balloon angioplasty of the SFA and popliteal artery. There was a qualitative improvement in perfusion. In the region of the nonhealing ulcer, change in SPECT perfusion in the dorsal foot was 2.56%. SPECT/CT has the ability to demonstrate changes in perfusion in patients undergoing angiosome-directed revascularization for CLI.

Reproduced from Chou TH, Atway SA, Bobbey AJ, Sarac TP, Go MR, Stacy MR. SPECT/CT imaging: a noninvasive approach for evaluating serial changes in angiosome foot perfusion in critical limb ischemia. Adv Wound Care (New Rochelle). 2020;9(3):103-110.

Collateral reserve is an important natural “rescue system” to maintain perfusion in a diseased angiosome. The corollary is that collateral depletion, as has been documented in patients with DM and end-stage renal disease, may be operative in CLI. In patients with diabetic end-artery disease, so-called patchy atherosclerosis occurs, along with septic thrombosis and loss of small collaterals. As such, there is growing recognition that a dysfunctional microvascular system and loss of capillary density plays a critical role in abnormal perfusion to skeletal muscle. The small pedal arteries (1 to 2 mm in diameter) and the microvasculature (<100 μm) account for limb symptoms in patients with and without macrovascular PAD ( Fig. 31.3 ). It has been suggested that in patients with DM, the occurrence of the so-called diabetic foot is related to a combination of distal atherosclerotic macroangiopathy and an impairment of microcirculatory function, which is associated with neuropathy, reduced immune function, and local sepsis. As such, impairment in the microcirculation plays a significant role in lower-extremity ulceration and affects wound healing.

Fig. 31.3

Incidence of amputation in patients with macrovascular peripheral arterial disease (PAD), microvascular PAD, both, or none.

Reproduced from Beckman JA, Duncan MS, Damrauer SM, et al. Microvascular disease, peripheral artery disease, and amputation. Circulation. 2019;140(6):449-458.

Microvascular dysfunction represents a complex number of factors that contribute to lower-extremity disease in those with DM. Contributing factors include peripheral autonomic neuropathy, regional sepsis, endothelial dysfunction with associated atherosclerosis, and dysfunctional vascular smooth muscle cells. Microvascular dysfunction is worsened by autonomic dysfunction, with loss of autoregulatory function, an impaired hyperemic and inflammatory response, dysfunctional vasomotion, increased arteriovenous shunting, impaired oxygen diffusion, and leukocyte migration. These regulated biologic systems become dysfunctional and result in poor wound healing in diabetic patients. Radionuclide imaging offers promise as an assessment tool of the microvascular system and perfusion reserve ( Fig. 31.4 ).

Fig. 31.4

Sagittal view of 99m technetium-tetrofosmin single photon emission computed tomography imaging in a patient with nonhealing heal ulcer before ( A ) and after ( B ) lower-extremity revascularization and wound debridement shows increased tracer uptake in the heel and distal foot. Prerevascularization regions of ischemia are identified by white arrows, and improvements in postrevascularization perfusion are denoted by yellow arrows.

Reproduced from Stacy MR, Sinusas AJ. Novel applications of radionuclide imaging in peripheral vascular disease. Cardiol Clin. 2016;34(1):167-177.

Standard noninvasive evaluation of peripheral arterial disease

Standard noninvasive diagnostic modalities of PAD are best understood in the context of the anatomic classifications of PAD and primarily assess macrovascular arterial stenosis and occlusion. A brief summary of standard noninvasive diagnostic modalities is presented with categorization of modalities by (1) anatomic versus physiologic assessment, (2) macrovascular versus microvascular assessment, and (3) rest versus provocation assessment ( Table 31.1 ).

TABLE 31.1

Summary of Standard Noninvasive Modalities for Assessment of Peripheral Arterial Disease

Diagnostic Modality Categorization Advantages Limitations
Ankle-brachial index (ABI)

  • Macrovascular

  • Physiologic

  • Rest

  • Inflow macrovascular stenosis/obstruction;

  • Sensitive to establish or refute CLI

  • Overestimation in medial calcification, common in DM, ESRD, advanced age;

  • Limited in localizing disease;

  • Decreased sensitivity in microvascular disease;

  • Poor correlation with symptoms

Exercise ABI

  • Macrovascular

  • Physiologic

  • Provocation

Exercise-provoked drop in ABI to identify proximal inflow disease missed by resting ABI
Segmental pressure

  • Macrovascular

  • Physiologic

  • Rest

Provides anatomic localization of disease Overestimation in medial calcification, common in DM, ESRD, advanced age
Pulse volume recording (PVR)

  • Macrovascular

  • Physiologic

  • Rest

  • Useful in noncompressible vessels;

  • Provides anatomic localization of disease

Lacks quantification
Toe brachial index (TBI)

  • Macrovascular

  • Physiologic

  • Rest

  • Improved identification of runoff disease in the foot;

  • Useful in presence of noncompressible pedal arteries

  • Limited accuracy

  • Does not provide localization of disease

Transcutaneous oxygen pressure (TcPO 2 )

  • Microvascular/collateral assessment

  • Physiologic

  • Rest

Measure of superficial tissue viability

  • Insensitive to mild-moderate severity PAD;

  • Nonlinear relation to flow;

  • Affected by many nonvascular factors

Duplex ultrasonography

  • Macrovascular

  • Physiologic

  • Rest

  • Patency of peripheral stents and bypass grafts;

  • Assessment of large-vessel flow

  • Cannot assess collateral or microvascular flow;

  • Artifacts from calcification;

  • Limited to large vessels;

  • Limited depth penetration

Computed tomography angiography (CTA)

  • Macrovascular

  • Anatomic

  • Rest

  • Vessel morphology;

  • Localization of obstruction

  • Artifacts from calcification;

  • Lacks standard quantification

Magnetic resonance angiography (MRA)

  • Macrovascular

  • Anatomic

  • Rest

  • Vessel morphology;

  • Localization of obstruction

Limited spatial resolution

  • Emerging magnetic resonance techniques ,

  • Blood Oxygen Level-Dependent (BOLD)

  • Microvascular

  • Physiologic and anatomic

  • Provocation

  • Tissue perfusion and oxygenation;

  • Quantification;

  • Coregistration of flow measurements with angiosome anatomy

  • Research tool;

  • Provocation required for measurable signal

  • (exercise, pharmacologic, or reactive hyperemia)

CLI, Critical limb ischemia; DM, diabetes mellitus; ESRD , end-stage renal disease; PAD, peripheral arterial disease.

Radionuclide imaging techniques offer potential to overcome many of the limitations of standard noninvasive assessment of PAD. Although positron emission tomography (PET) has higher sensitivity than single photon emission computed tomography (SPECT) for targeted molecular imaging and lower levels of ionizing radiation through the use of isotopes with short half-lives, SPECT systems are more readily available. Unfortunately, SPECT and PET for molecular imaging have lower spatial resolution than CT and MRI. Given this limitation, hybrid imaging systems (PET/CT, SPECT/CT, PET/MRI) allow for the pairing of high-sensitivity physiologic images with quantification of radionuclide uptake in anatomic regions of interest and allow for topographic localization, attenuation correction, and correction for partial volume effects. Additionally, new targeted radiotracers can assess specific biologic processes that are attendant to the biologic underpinnings of PAD, such as atherosclerosis, angiogenesis, inflammation, thrombosis, and ischemia ( Table 31.2 ).

TABLE 31.2

Radiotracers for Perfusion and Molecular imaging of Peripheral Arterial Disease.

Adapted from Stacy MR, Sinusas AJ. Novel applications of radionuclide imaging in peripheral vascular disease. Cardiol Clin. 2016;34(1):167-177.

Application Modality Radionuclide Biologic Target Application
Skeletal muscle perfusion and blood flow SPECT 201 Thallium (Tl) Clinical
99m Technetium (Tc)-sestamibi Clinical
99m Tc-tetrofosmin Clinical ,
PET 15 O-water Clinical ,
C 15 O 2 Clinical
15 O 2 Clinical ,
13 N-ammonia Preclinical: mouse
Skeletal muscle angiogenesis SPECT 99m Tc-NC100692 ανβ3 integrin Preclinical: mouse
111 Indium (In)-VEGF121 VEGF receptor Preclinical: rabbit
125 1-c(RGB(I)yV) ανβ3 integrin Preclinical: mouse
PET 76 Br-nanoprobe ανβ3 integrin Preclinical: mouse
68 Ga-NOTA-RGB ανβ3 integrin Preclinical: mouse
64 Cu-DOTA-CANF-comb NPR-C Preclinical: mouse
64 Cu-DOTA-VEGF 121 VEGF receptor Preclinical: mouse
64 Cu-NOTA-TRC105 CD105 Preclinical: mouse ,
Peripheral atherosclerosis PET 18 F-FDG Macrophages Clinical
68 Ga-Dotate Somatostatin receptor-2 Preclinical
18 F-methylcholine ( 18 F-FMCH) Macrophage cell membranes Preclinical: mouse
11 C-PK11195 Translocator protein (TSPO) on macrophage Preclinical: mouse
18 F-Galacto-RGB ανβ3 integrin Preclinical: mouse
18 F-Fluciclatide ανβ3 integrin Preclinical
18 F-NaF Microcalcification Clinical: aorta, carotid, femoral
11 C-acetate Fatty Acid Synthesis Clinical; aorta, carotid, iliac
64 Cu-DOTA-CANF C-type atrial natriuretic factor Preclinical: rabbit
99m Tc-PBMC Peripheral blood mononuclear cell Clinical
18 F-fluoromisonidazole (FMSO) Hypoxia Clinical
18 F-HX4 Hypoxia Preclinical
64 Cu-ATSM Hypoxia Preclinical
Skeletal muscle metabolism PET 18 F-FDG Glucose analog Clinical
18 F-Fluoro-4-thia-octadec-9-enoate ( 18 F-FTO) Oleate-free fatty acid Clinical

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Nov 21, 2021 | Posted by in CARDIOVASCULAR IMAGING | Comments Off on Peripheral arterial disease
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