Abstract 5095: The Role of Circulating Transforming Growth Factor-β in Vascular Ehlers-Danlos Syndrome: Implications for Drug Therapy

Objective: TGFβ signaling has been shown to play a major role in the pathogenesis of Marfan syndrome (MFS), leading to a novel treatment strategy through TGFβ inhibition using losartan. We hypothesized that circulating TGFβ levels may be elevated in disorders that disrupt arterial wall extracellular matrix, such as the vascular form of Ehlers-Danlos syndrome (VEDS). Patients and Methods: Circulating levels of TGFβ-1 were measured in EDTA plasma of 141 patients with MFS (n=21, mean age 43±16y), VEDS (n=41, 37±13y) and controls (n=79, 48±13y) using an electrochemoluminescence platform (LLOQ 4±2.6pg/ml). Results: In keeping with prior work, this study revealed increased circulating TGFβ in patients with MFS compared to control patients (9.2±1.2ng/ml vs. 2.5±0.4ng/ml, p<0.0001). Remarkably, the levels seen in patients with VEDS were also significantly higher than controls (8.0±1.0ng/ml vs. 2.5±0.4ng/ml, p<0.0001) and statistically indistinguishable from those seen in MFS (9.2±1.2ng/ml vs. 8.0±1.0ng/ml, p=0.5). In a bivariate logistic regression model, the odds ratio was 7.5 (p=0.02, CI 1.3– 43.3) when comparing quartiles of TGFβ values in VEDS patients with age, sex and BMI matched controls. There was a non-statistically significant trend for higher TGFβ levels in patients without cardiovascular medication (MFS, 11.4±3.0ng/ml; VEDS, 8.5±1.3ng/ml) compared to patients treated with ARBs and/or ACE-Is (MFS, 6.1±1.0ng/ml; VEDS, 4.6±0.8ng/ml), whereas β-blockers appeared to have some impact on TGFβ levels in MFS (9.0±1.7ng/ml) but not in VEDS patients (8.3±1.8ng/ml). The influence of age on TGFβ levels in the controls is statistically significant but weak (r=0.3, p=0.007). In the disease groups, TGFβ is inversely related to age (MFS, r=−0.7, p<0.0001; VEDS, r=−0.1, p=0.6), which is most likely due to ascertainment bias towards a less severe phenotype in the older patients and longer duration of medical therapy, especially in the MFS population. Conclusion: Further investigation is warranted to establish the role of TGFβ signaling in the pathogenesis of VEDS. The current results may help to provide a rationale for the use of TGFβ lowering drug therapy in this patient population as it is emerging in the MFS patient population.