Visualizing Vascular Mechanisms of Lipedema

This work will address clinical unmet needs for patients with lipedema using advanced magnetic resonance imaging (MRI) methods, in sequence with portable clinical tools, by testing fundamental hypotheses regarding potential screening methods, lymphatic therapy, and vascular dysfunction in patients with lipedema.

Lipedema is a disease marked by disproportionate subcutaneous adipose tissue (SAT) accumulation in the lower extremities that is accompanied by somatic pain and edema. Importantly, lipedema is commonly misdiagnosed as obesity and has been estimated to affect a high 11% of women. However, symptoms are refractory to diet, exercise, and other interventions for obesity leading to a mean delayed diagnosis of 22 years, high physical morbidity, and lifelong distress. Despite growing awareness of lipedema as a distinct clinical entity and a recent call to action for lipedema research, fundamental gaps persist in knowledge regarding both disease mechanisms and treatment options for this debilitating disease. Over the past four years, multi-disciplinary study from investigators in radiology, vascular medicine, and physical therapy has demonstrated that lipedema has distinct characteristics from obesity. Using whole-body fat-and-water MRI, lipedema is characterized by a 42% higher lower-extremity SAT deposition compared to BMI-matched females without lipedema (p\<0.001). Using noninvasive sodium MRI technologies, skin sodium is also elevated in patients with lipedema compared to controls (14.9±2.9 vs. 11.9±2.0 mmol/L, p=0.01) in the lower extremities, but not upper extremities. Importantly, skin sodium decreases following 6-weeks of lymphatic stimulation by complete decongestive therapy (CDT) in preliminary study of patients with lipedema. These tissue signatures are consistent with those of patients with known lymphatic insufficiencies (i.e., secondary lymphedema). Recent findings of elevated arterial perfusion and inflammatory profiles in lipedema raise significant questions about how blood and lymphatic circulation are involved in lipedema. The critical barrier to interrogating these systems, and more broadly addressing clinical unmet needs for evidence-based therapies for patients with lipedema, is that noninvasive lymphatic imaging strategies are traditionally underdeveloped. To address this barrier, non-tracer based MR lymphangiography is capable of visualizing lymphatic dilation and stasis in unilateral lymphedema, and similar features of lymphatic insufficiency are observed in the lower extremities of patients with lipedema. This study will apply these MRI tools together with standard clinical tools to test the following hypotheses: Hypothesis 1A: Ultrasound can be used as an accessible alternative to MRI for measuring subcutaneous fat deposition to distinguish lipedema from obesity. Hypothesis 1B: Ultrasound measurement of fat deposition together with bedside tools for measuring water deposition have improved ability than ultrasound alone for distinguishing lipedema from controls. Hypothesis 2: Tissue sodium is reduced following CDT in the lower extremities, but not in the untreated upper extremities, of patients with lipedema consistent with improved patient-reported outcomes. Hypothesis 3: Lymphatic flow velocity is reduced, while arterial blood flow is elevated, in the legs of patients with lipedema compared to controls.