Microvascular Disease Increases Amputation in Patients With Peripheral Artery Disease
Arteriosclerosis, Thrombosis, and Vascular Biology
Graphical Abstract
Abstract
It is estimated that >2 million patients are living with an amputation in the United States. Peripheral artery disease (PAD) and diabetes mellitus account for the majority of nontraumatic amputations. The standard measurement to diagnose PAD is the ankle-brachial index, which integrates all occlusive disease in the limb to create a summary value of limb artery occlusive disease. Despite its accuracy, ankle-brachial index fails to well predict limb outcomes. There is an emerging body of literature that implicates microvascular disease (MVD; ie, retinopathy, nephropathy, neuropathy) as a systemic phenomenon where diagnosis of MVD in one capillary bed implicates microvascular dysfunction systemically. MVD independently associates with lower limb outcomes, regardless of diabetic or PAD status. The presence of PAD and concomitant MVD phenotype reveal a synergistic, rather than simply additive, effect. The higher risk of amputation in patients with MVD, PAD, and concomitant MVD and PAD should prompt aggressive foot surveillance and diagnosis of both conditions to maintain ambulation and prevent amputation in older patients.
Highlights
•
Peripheral artery disease is a limb manifestation of large vessel atherosclerosis and a leading cause of nontraumatic amputations.
•
Microvascular disease independently associates with limb amputation after controlling for traditional atherogenic risk factors.
•
Concomitant presence of microvascular disease and peripheral artery disease synergistically amplifies the risk of amputation.
•
The implication of these findings suggests a new emerging importance of microvascular disease in consideration of limb salvage strategies.
Introduction
It is estimated that ≈185 000 amputations are performed annually in the United States leading to a current amputation prevalence of >2 million people.1,2 Amputation is a source of significant morbidity and mortality. The most common causes of amputation include vascular disease, diabetes mellitus, trauma, and cancer. More than half of amputees require a contralateral limb amputation within 3 years, and overall prognosis of is poor with mortality ranging as high as 50% within 5 years of first amputation.3,4 Patients experience depression, neglect, and job loss to the detriment of quality of life.5 Peripheral artery disease (PAD) begets amputation via conduit artery occlusive disease severe enough to be incapable of meeting basal tissue homeostasis in the lower extremities. Diabetes mellitus causes neuropathy, increases infection susceptibility, and impairs wound healing. Together, PAD and diabetes mellitus account for over half of all amputations and are the 2 primary nontraumatic causes of all amputations. Recently, microvascular disease (MVD) has been demonstrated in patient populations beyond diabetic people and linked to systemic microvascular dysfunction. This review will examine the roles of vascular disease, in both conduit and microvessels, on amputation.
Please see www.ahajournals.org/atvb/atvb-focus for all articles published in this series.
Peripheral Artery Disease
In 2010, it was estimated that >200 million people had PAD worldwide—a prevalence that rises as the population grows.6 PAD is a target organ manifestation of atherosclerosis in the lower limb.7 The majority of patients with PAD have decreased limb function despite the presence of classic intermittent claudication in only ≈20%. Regardless of symptomatology, nearly all patients with PAD experience reductions in ambulatory activity, daily functional capacity, and quality of life.8,9 One study showed a near 60% reduction in peak treadmill performance in participants with PAD, when compared with healthy individuals of the same age.10 Patients with claudication have a similar reduction in physical functioning as patients with severe congestive heart failure.11 The most severe limb manifestation of PAD is critical limb ischemia—a condition defined by ischemic pain at rest or the presence of ischemic skin lesions (ie, gangrene or ulcerations), which is associated with a significant risk of amputation.
The diagnosis of PAD requires the reduction in perfusion pressure at the ankle of ≥10% compared with the brachial artery systolic pressure. The ankle-brachial index (ABI)—a noninvasive hemodynamic assessment to compare blood pressures at the arm and ankle—is the standard method for PAD diagnosis.12,13 The ABI integrates all occlusive disease in the limb to create a summary value of limb artery occlusive disease. Despite its accuracy in diagnosis, the ABI is limited in its ability to predict limb outcomes.14,15 For example, in a longitudinal observational study of the natural history of 1244 claudicants, the rate of incident ischemic ulceration doubled as the ABI declined from 0.9 to 0.1 but was 3-fold higher at every level when the participant also had diabetes mellitus. The severity of conduit artery atherosclerosis by ABI captures only a part of the risk for major adverse limb events or amputations.16,17
The incongruity between ABI reduction and symptom severity is found in revascularization studies as well. In the randomized controlled IN.PACT DEEP trial (Randomized Amphirion DEEP DEB Versus Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia), ≈29% of patients with critical limb ischemia had an ABI >0.9, and only 10% met the criteria for severe disease with an ABI of <0.4.18 A multicenter study in Michigan recorded preintervention ankle-brachial indices in over half of 10 700 patients who underwent endovascular or surgical revascularization for critical limb ischemia.19 Twenty-five percent of those who underwent any type of revascularization for critical limb ischemia had normal ankle-brachial indices.19 Although arterial calcification artifact, pedal occlusive disease, and an inadequate atherosclerotic burden to lower ankle perfusion pressure must be mentioned, the mechanism that explains these observations remains unclear but may be related to MVD. Analysis of amputation outcomes despite successful lower limb conduit artery revascularization may shed further light on this subject.
Endovascular procedures that restore arterial perfusion to the target limb, such as percutaneous transluminal angioplasty, improve transcutaneous oxygen tension in the distal revascularized limb. Patients who required amputation post-percutaneous transluminal angioplasty had no change in transcutaneous oxygen tension after initial restoration while those who did have progressive increase in transcutaneous oxygen tension over the subsequent weeks had 100% limb salvage suggesting blood flow delivery to the distal tissue at risk is required for success.20 Amputations still occur in patients who receive surgical interventions in the absence of procedural complication. In a retrospective review of 69 distal arterial surgical reconstructions performed in 53 patients with end-stage renal disease during a mean follow-up period of 14 months, 59% of the 22 postsurgical revascularizations had amputations for foot ischemia despite patent bypass grafts and lack of infection.21 We suspect one underlying explanation for necessary amputations despite successful intervention without postprocedural complications is the presence of persistent microvascular dysfunction.
Microvascular Disease
MVD includes vessels from the capillary through arteriole, that is, those ≈100 um. The microvascular system can be thought of as partnered or paired to the organ or tissue with which it associates through oxygen and nutrient delivery, wound healing, end-organ metabolite exchange, hormonal signaling, and regulation of systemic blood pressure. We believe that the tissue and microvasculature should be considered as a functional unit, where dysfunction of one may induce or exacerbate the function of its partner. As a result, tissue dysfunction may begin with microvascular impairment. Examples of this include retinopathy and neuropathy. Examples of systemic illnesses that may first induce MVD before tissue dysfunction include hypertension, diabetes mellitus, vasculitides, blood dyscrasias, and chronic viral infections.22,23 Microvascular dysfunction has been characterized by impaired autoregulation of blood flow and vascular tone resulting in impaired oxygen delivery to the tissue, increased oxidative stress, and capillary rarefaction. Decreased microvascular density in calf muscle better predicts lower limb function than either severity of atherosclerotic disease.24–27 Reductions in microvascular density may be a mechanism of limb dysfunction common to disease states that limit leg function. Reductions in skeletal muscle microvascular density of the lower extremity play a similarly important role in decreased exercise tolerance found in congestive heart failure.28 MVD participates importantly in the development of adverse limb function and events in patients with PAD.
Recent data support the concept that the diagnosis of an MVD in one bed implicates microvascular dysfunction systemically. Investigators reported a significant correlation between coronary and lower extremity microvascular endothelium-dependent vasodilation in response to acetylcholine challenge.29 Others have shown that both skin arteriolar and retinal arteriolar dysfunction directly associate with albuminuria, regardless of diabetic status.30 Similarly, retinopathy31 and nephropathy32,33 associate inversely with coronary flow reserve. With particular relevance to the complications of PAD, both retinopathy and nephropathy associate directly with diminished skin microvessel function and lower limb amputation.34–36 These examples demonstrate a link between MVD and dysfunction in remote microvascular beds. We surmise that MVD is a systemic process akin to atherosclerosis.
Remote MVD has been associated with amputations. Proteinuria in nondiabetic patients was associated with an increased risk of amputation in a prospective cohort of >4600 patients with PAD followed over a 10-year period after controlling for the presence of diabetes mellitus.37 The risk for developing critical limb ischemia, including amputation, was increased (hazard ratio, 3.1–6.5) during a median follow-up of 19 years of >9000 patients from the ARIC cohort (Atherosclerosis Risk in Communities) after controlling for the presence of diabetes mellitus.38 The presence of proteinuria independently associated with the need for renal replacement therapy in patients with atherosclerotic renal artery stenosis.39 Although MVD is likely a systemic process, the mechanism(s) underlying the location of initial clinical presentation remains unclear and requires further research. Recent work supports, in part, a genetic component for initial clinical manifestation of atherosclerotic disease in the coronary, cerebral, or peripheral arterial beds that could imply an analogous process for MVD.40 In summary, the presence of MVD independently predicts lower limb outcomes.
MVD, PAD, and Amputation
The prevailing paradigm in limb salvage for decades had focused on surgical large vessel revascularization.41 The role of MVD in limb complications has been most commonly discussed in diabetic foot ulceration and neuropathy but limited in PAD.42 In a recent state-of-the-art review of critical limb ischemia, MVD was unmentioned.43 The role of MVD and PAD, with respect to lower extremity outcomes, was previously treated as separate and additive. We investigated the impact of an aggregate MVD phenotype on the risk of amputation in the Veterans Aging Cohort Study—a 125 000 patient cohort followed longitudinally for ≈9 years. “Using time-updated Cox proportional hazards regression, we analyzed the effect of prevalent microvascular disease (retinopathy, neuropathy, and nephropathy) and peripheral artery disease status on the risk of incident amputation events after adjusting for demographics and cardiovascular risk factors.” In this study, MVD, per se, increased the amputation risk 3.7-fold, PAD 14-fold, and the combination of MVD and PAD increased the risk of amputation 22.7-fold (95% CI, 18.3–28.1) when compared with participants with neither disease process after adjustment (Table).44 Indeed, 1 of 6 below-knee amputations occurred in the setting of MVD alone. The combination of PAD and MVD accounted for 45% of all amputations despite this latter group representing only ≈4% of the study population. This work shows that MVD may act as an aggregate clinical phenotype, confer an independent risk of amputation, be responsible for ≈18% of all amputations, and potentiate the amputation risk in patients with macrovascular disease. The presence of MVD in the setting of PAD highlights a patient population at the greatest risk (Figure).
| Group | Person-Years | Events | Incidence Rate per 1000 PY | Unadjusted Model | Adjusted Model | ||
|---|---|---|---|---|---|---|---|
| Hazard Ratio (95% CI) | P Value | Hazard Ratio (95% CI) | P Value | ||||
| No MVD or PAD | 795 802 | 182 | 0.23 | 1.00 | … | 1.00 | … |
| MVD | 130 584 | 207 | 1.59 | 6.84 (5.60–8.35) | <0.0001 | 3.74 (3.03–4.62) | <0.0001 |
| PAD | 58 395 | 265 | 4.54 | 19.68 (16.25–23.83) | <0.0001 | 13.86 (11.25–17.07) | <0.0001 |
| MVD and PAD | 40 182 | 531 | 13.22 | 56.92 (47.80–67.78) | <0.0001 | 22.71 (18.34–28.12) | <0.0001 |
Adjusted model includes age, sex, race, HIV, prevalent CVD, hypertension, diabetes mellitus, LDL cholesterol, HDL cholesterol, triglycerides, smoking status, hepatitis C virus infection, renal failure, BMI, anemia, total bilirubin, alcohol abuse or dependence, cocaine abuse or dependence, and chronic obstructive pulmonary disease. BMI indicates body mass index; CVD, cardiovascular disease; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MVD, microvascular disease; PAD, peripheral artery disease; and PY, person years.
Adapted from Beckman et al44 with permission. Copyright © 2019, American Heart Association, Inc.
It should be noted that this risk pattern was observed in patients with and without diabetes mellitus. Prediabetes, type 2 diabetes mellitus, and measures of hyperglycemia are independently associated with impaired microvascular function in the retina and skin in the Maastricht Study, reinforcing the concept that MVD is a systemic phenomenon.30 The Centers for Disease Control estimates that 84 million Americans have prediabetes creating a large population at risk.45 Diabetes mellitus represents a common pathway to MVD but is far from the only disease process to cause it. Hypertension has been shown to be a more common pathway to nephropathy. In 3000 subjects with abnormal urinary albumin excretion enrolled in the PREVEND study (Prevention of Renal and Vascular Endstage Disease), only 21% had hypertension, 7% had diabetes mellitus, and 82% had neither as an attributable cause of proteinuria.46 Furthermore, vascular outcomes have been linked to MVD in follow-up analysis of the PREVEND cohort, which demonstrated an 8% increase in myocardial infarction for every doubling of albuminuria.47 Diabetes mellitus and hypertension represent highly prevalent chronic diseases that lead to systemic MVD and dysfunction with consequent end-organ damage.
We postulate that one mechanism by which MVD increases amputation risk is through compromised wound healing. Proliferating microvascular endothelial cells play a pivotal role in the process of cutaneous wound healing via deposition of extracellular matrix in the peri- and intrawound area.48,49 The microvasculature delivers blood-borne cells, nutrients, and oxygen to actively remodeling areas. Microvascular remodeling is central to angiogenic induction and regulation. This process is dependent on capillary endothelial cell and pericyte interactions.50
Impairment of this process coupled with decreased perfusion pressures in PAD causes serial ischemic-reperfusion injuries that creates an inflammatory milieu. Levels of inflammation have been shown to predict amputation after lower extremity revascularization in patients with critical limb ischemia.51 We believe that once MVD is diagnosed, in any of the common locations, the risk of amputation rises significantly and mandates aggressive foot surveillance and early treatment of wounds.
Treatment of MVD
Recent data suggest that moderate aerobic exercise significantly improves microvascular function of the leg in older adults.52 An increase in calf skeletal muscle microvascular density appears to be necessary and precedes functional limb improvement in PAD during exercise treatment.53,54 The Centers for Medicare and Medicaid Services recently approved supervised exercise therapy for treatment of symptomatic PAD55 as it is the most effective therapy to increase ambulation in patients with PAD.56,57 This therapy may improve ambulation, in part, through improvements in microcirculatory density and function.
Pharmacological treatments of MVD are similar to that of microvascular ischemic heart disease and are limited to modification of lifestyle or existing atherogenic risk factors (ie, antiplatelet agents, lipid-lowering or glucose-lowering therapies) and exercise. The use of cilostazol—a phosphodiesterase-3 inhibitory antiplatelet agent with vasodilatory properties—has been demonstrated to improve walking distance, reduce restenosis, and 1-year amputation after either surgical or endovascular revascularization in the lower limb.58 In a randomized controlled trial of 90 patients with nephropathy and PAD, cilostazol slowed the progression of renal dysfunction.59 Cilostazol is thought to exert its effects by attenuating proinflammatory pathways. Its pleotropic effects have demonstrated benefit in mouse models of retinopathy, and although it does not demonstrate reversal of neuropathy, patients derive functional benefit from its use.60
We would note that our work does not suggest that revascularization be withheld based on the presence or absence of MVD. In fact, revascularization in the setting of significant reductions in large-artery perfusion is a key component of management in critical limb ischemia to avoid amputation.
Future Frontiers
The emerging data that patients with both PAD and concomitant MVD experience a significantly greater risk of lower limb amputation than those with PAD or MVD alone may suggest a new way to approach reducing adverse limb events in PAD. The concept that large conduit peripheral artery atherosclerotic disease burden explains limb dysfunction and critical limb ischemia may not incorporate all the vascular pathologies underlying these outcomes. Elucidation of these mechanisms may lay the foundation for future work to discover new drug targets or serum biomarkers that allow clinicians to noninvasively assess disease severity in hopes of improving patient quality of life and survival. It will be important to develop animal models of atherosclerotic PAD to investigate mechanisms and novel therapies experimentally. Similarly, the lack of easy-to-use methods to study microvascular function will limit easy study and evaluation of large series of patients. We would note that tools like magnetic resonance imaging for coronary artery flow reserve, retinal artery flicker light response, and laser Doppler flowmetry are cumbersome for large-scale clinical trials. New, easy-to-use tools, like the ABI for PAD, will enhance research in this area.
By identifying this unique subgroup of patients with PAD and concomitant MVD, clinical investigators can risk stratify patients in future analyses to determine whether medical or nonpharmacological interventions may benefit this particularly vulnerable population. The presence of PAD is often subclinical but carries with it a high morbidity. Early recognition and intervention, be it nonpharmacological or otherwise, could augment quality of life and overall survival. As of July 2018, the US Public Service Task Force does not recommend screening ABIs in asymptomatic patients because of insufficient data to determine benefit.61 Until biomarkers or new treatments become available, the higher risk of amputation in patients with MVD, PAD, and particularly concomitant MVD and PAD disease should prompt aggressive foot surveillance to maintain ambulation and prevent amputation in at risk patients.
Acknowledgments
We would like to thank Ben C. Smith for his contribution to the graphic illustration.
Footnote
Nonstandard Abbreviations and Acronyms
- ABI
- ankle-brachial index
- ARIC
- Atherosclerosis Risk in Communities
- IN.PACT DEEP
- Randomized Amphirion DEEP DEB Versus Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia
- MVD
- microvascular disease
- PAD
- peripheral artery disease
- PREVEND
- Prevention of Renal and Vascular Endstage Disease
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© 2020 American Heart Association, Inc.
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Received: 16 August 2019
Accepted: 16 December 2019
Published online: 20 February 2020
Published in print: March 2020
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Disclosures
J.A. Beckman reports consulting with AstraZeneca, Bristol-Myers Squibb, Amgen, Merck, Novo Nordisk, Sanofi, and Antidote Pharmaceutical. He serves on the Data Safety Monitoring Committee for Bayer and Novartis. The other author reports no conflicts.
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This work was supported by American Heart Association Strategically Focused Research Network in Vascular Disease grant 18SFRN33960373 (to J.A. Beckman).
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