Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Abstract

The lymphatic circulation is an important component of the circulatory system in humans, playing a critical role in the transport of lymph fluid containing proteins, white blood cells, and lipids from the interstitial space to the central venous circulation. The efficient transport of lymph fluid critically relies on the rhythmic contractions of collecting lymph vessels, which function to “pump” fluid in the distal to proximal direction through the lymphatic circulation with backflow prevented by the presence of valves. When rhythmic contractions are disrupted or valves are incompetent, the loss of lymph flow results in fluid accumulation in the interstitial space and the development of lymphedema. There is growing recognition that many pharmacological agents modify the activity of ion channels and other protein structures in lymph muscle cells to disrupt the cyclic contraction and relaxation of lymph vessels, thereby compromising lymph flow and predisposing to the development of lymphedema. The effects of different medications on lymph flow can be understood by appreciating the intricate intracellular calcium signaling that underlies the contraction and relaxation cycle of collecting lymph vessels. For example, voltage-sensitive calcium influx through long-lasting (“L-type”) calcium channels mediates the rise in cytosolic calcium concentration that triggers lymph vessel contraction. Accordingly, calcium channel antagonists that are mainstay cardiovascular medications, attenuate the cyclic influx of calcium through L-type calcium channels in lymph muscle cells, thereby disrupting rhythmic contractions and compromising lymph flow. Many other classes of medications also may contribute to the formation of lymphedema by impairing lymph flow as an off-target effect. The purpose of this review is to evaluate the evidence regarding potential mechanisms of drug-related lymphedema with an emphasis on common medications administered to treat cardiovascular diseases, metabolic disorders, and cancer. Additionally, although current pharmacological approaches used to alleviate lymphedema are largely ineffective, efforts are mounting to arrive at a deeper understanding of mechanisms that regulate lymph flow as a strategy to identify novel anti-lymphedema medications. Accordingly, this review also will provide information on studies that have explored possible anti-lymphedema therapeutics.

Recellularized lymph node scaffolds with human adipose-derived stem cells enhance lymph node regeneration to improve lymphedema

“…The lymphatic circulation plays an important role in transporting lymph fluid, including leukocytes, proteins, and lipids, from the interstitial space to the central venous circulation 16 . Lymphatic vessels contract rhythmically, transporting lymph and inhibiting reflux by valves.…”

“…When there is a problem with the lymphatic circulation, fluid accumulates in the interstitial space 17 . Recently, the incidence of lymphedema is increasing due to surgery and radiotherapy related to malignant neoplasms 11 , 16 . Most of the standard treatment for lymphedema is physiotherapy such as lymphatic drainage and compression bandage.…”

The Effect of Pharmaceutical Agents on Lymphedema

“…Calcium channel blockers (CCBs) are a commonly used pharmaceutical to treat cardiac arrhythmias and vascular disease including hypertension and angina. 5 Peripheral edema is a potential side effect of CCBs and ranges from 5% to 70% based on the drug, 21,22 time of intake, 23 patient age, 24 and duration of therapy. 21 CCBs cause vasodilation of the arterioles in the absence of venous dilation, resulting in increased capillary pressure.…”

“…25 In addition, it is postulated that CCBs inhibit the contractions of the lymphatic system, which could result in the reduction of lymphatic flow and subsequent development of lymphedema. 5 Hypertension and/or its treatment are risk factors associated with lymphedema. 26 In a nested casecontrol study, Stolarz et al 6 found that CCBs were significantly associated with an increased risk of lymphedema in patients with breast cancer.…”

“…3,4 As part of the initial evaluation, the treating clinician should also conduct a review of the patient' s medications as peripheral edema can be a common side effect. 5,6 The major mechanisms through which drugs can be involved in causing peripheral edema are disruption of lymphatic drainage, increased capillary permeability, increased capillary hydrostatic pressure, and increased capillary hydrostatic pressure. 7 The purpose of this clinical conversation is to describe how different pharmaceutical agents may impact patients with a diagnosis of lymphedema.…”