Peripheral artery disease (PAD) and diabetes mellitus (DM) are leading causes of nontraumatic lower limb amputation in the United States. Microvascular disease (MVD) was found to be associated with lower limb amputation, independently of PAD and DM status, a risk increased in a synergistic manner in individuals with comorbid PAD, according to a review published in Arteriosclerosis, Thrombosis, and Vascular Biology. This observation has potential implications for the treatment of PAD, MVD and concomitant disease, as well strategies to prevent amputations.

Patients with PAD have large vessel atherosclerosis that manifests as painful symptoms in some and reduced limb functionality in nearly all individuals. When conduit artery occlusive disease becomes severe enough to induce critical limb ischemia, lower limb amputation is often required. Definitive diagnosis of PAD relies on measurement of the ankle-brachial index (ABI), which provides a summary of limb artery occlusive disease. Ankle systolic pressure over 10% lower than that of the brachial artery is indicative of PAD. While accurate, ABI infrequently reflects symptom severity and poorly predicts limb outcomes.

In some patients with PAD successfully treated with endovascular procedures such as percutaneous transluminal angioplasty, subsequent amputation is still necessary. The review authors believe that such cases may result from persistent unrecognized MVD.

Research indicates that MVD may be systemic occurrence, so that identification of vessel disease in a single capillary bed (as in neuropathy, nephropathy or retinopathy) may represent more widespread microvascular dysfunction, as is the case in systemic atherosclerosis. MVD may therefore play an important role in limb dysfunction and adverse events in patients with PAD.


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I The risk for amputation was found to be 3.7-fold greater in individuals with vs without NVD (adjusted hazard ratio [HR], 3.74; 95% CI, 3.03-4.62; P <.0001), 14-fold higher in patients with vs without PAD (HR, 13.86; 95% CI, 11.25-17.07; P <.0001), and 22.7-fold higher in those with MVD and PAD vs neither condition (HR, 22.71; 95% CI, 18.34-28.12; P <.0001) in the Veteran’s Aging Cohort Study. The risk for amputation was also greater in patients with vs without DM, which commonly involves systemic MVD resulting in end-organ damage.

MVD may therefore potentiate the risk for amputation in patients with PAD. Impaired wound healing, which may result in serial ischemic-reperfusion injury and chronic inflammation, may contribute to subsequent need for amputation. The review authors advise that patients with PAD who are diagnosed with MVD should undergo strict foot surveillance and early wound therapy to mitigate the risk for amputation.

Functional limb improvement in patients with PAD requires an increase in microvasculature density in calf skeletal muscle, and moderate aerobic exercise may aid this process. MVD pharmacotherapy overlaps with that for microvascular ischemic heart disease, including antiplatelet medications and glucose- and lipid-lowering agents; exercise is also recommended. The need for revascularization of large-artery occlusions should be independent of the presence of MVD, as such interventions are necessary for optimal management of critical limb ischemia and avoidance of lower limb amputation.

Studies on the mechanisms underlying the synergistic effects of concomitant PAD and MVD on the risk for amputation may lead to the development of more targeted pharmacotherapies. In addition, identification of patients with comorbid PAD and MVD will allow risk stratification of future study participants, thus improving studies.

“Until biomarkers or new treatments become available, the higher risk [for] 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,” noted the authors.

Funding and Conflicts of Interest Disclosures:

JA 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.

Reference

Behroozian A, Beckman JA. Microvascular disease increases amputation in patients with peripheral artery disease. Arterioscler Thromb Vasc Biol. 2020;40(3):534-540. doi:10.1161/atvbaha.119.312859