Constitutively Enhanced Lymphatic Pumping in the Upper Limbs of Women Who Later Develop Breast Cancer-Related Lymphedema

Abstract

Background: It has previously been shown that the lymph drainage rate in both upper limbs is greater in

The relationship between lymphangion chain length and maximum pressure generation established through in vivo imaging and computational modeling

“…By fitting our computational model to experimental measurements of the pumping pressure at multiple locations along the tail, we can estimate the average force generation for the chain of lymphatics, decoupling the intrinsic function of that vessel from other extrinsic factors such as interstitial fluid pressure at the injection site. Although measurement of the maximum pumping pressure is known to have the potential as a clinical diagnostic approach for lymphedema (11,63), this study suggests that any measurement of the maximum pumping pressure should be interpreted in the context of chain length; hence, measurements should be performed at multiple locations to provide sufficient information on lymphatic muscle activity in the limb of interest. Because this approach is noninvasive, the potential as a clinical diagnostic in lymphatic health is promising, and future trials in humans are warranted to establish feasibility.…”

“…Although significant advances have been made toward understanding the molecular regulation of lymphatic contractility in both isolated vessels and small animal models, there remains a significant gap in our understanding of how networks of lymphangions work across long distances to move fluid against the unfavorable pressure gradients that exist in vivo. Recent advances by several groups have demonstrated the ability to measure lymphatic pumping pressure in both clinical and animal research settings (7,11,43,45,53,63,66). Similar to blood pressure, which provides a measurement of cardiac pump function, the technique has been suggested to be indicative of the combined capacity of the intrinsic and extrinsic lymphatic pump.…”

“…The simulation results suggest that both the degree of smooth muscle cell activation and the number of working lymphangions directly influence this relationship between flow and outflow pressure. In the context of lymphedema, it has been suggested that patients with a higher lymph load are predisposed to disease (1,11), motivating further studies that explore how prolonged elevated demand on the intrinsic lymphatic pump might drive fatigue of lymphatic muscle force generation and thus lymphedema. Although smooth muscle force generation of lymphatics likely exhibits regional and species variations, the values for the model that best fit the in vivo data are within the range of those measured experimentally from other tissues tested ex vivo (Table 2), but interestingly are lower than rat lymphatics from other tissue beds.…”

Lymphatic Vessel Network Structure and Physiology

“…In more advanced lymphedema, evidence of impaired contraction of collecting lymphatics has been reported (714, 1019). Women who displayed higher lymphatic pumping pressures and lymph transport in their arms prior to breast cancer surgery were found to more likely develop secondary lymphedema (190). Blockage of collecting lymphatic vessels due to improper overgrowth and invasion of the smooth muscle layer into the lumen has also been reported in patients with leg secondary lymphedema (781).…”

New and Emerging Treatments for Lymphedema

“…23,24 Patients with LE have decreased lymphatic pumping pressures. 25 The perilymphatic inflammatory cell infiltrate that characterizes LE upregulates the expression of induced nitric oxide synthase (iNOS), disrupting the intrinsic NO gradient, thereby decreasing collecting lymphatic contractility and lymphatic fluid transport. iNOS causes a reduction in the strength of lymphatic contraction through excessive relaxation of collecting lymphatic vessels and inhibition of iNOS-producing cells significantly restores lymphatic contraction.…”