Enhanced Release of Endothelin-1 and Angiopoietin-2 During Experimentally-Induced Peripheral Venous Congestion is Associated with Heart Failure-Related Clinical Events

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Conference Proceeding

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J Heart Lung Transplant


Purpose: Growing evidence suggests that venous congestion (VC) is a contributor to the pathophysiology of heart failure (HF) progression by causing inflammation, vasoconstriction, oxidative stress and endothelial activation. We hypothesized that: 1) euvolemic HF with reduced ejection fraction (HFrEF) pts with a recent history of HF hospitalization have more pronounced phenotypic response to VC compared to pts not hospitalized; 2) greater phenotypic response to VC is associated with subsequent HF-related events.

Methods: Two matched groups of euvolemic NYHA Class II-III HFrEF pts, with and without history of HF hospitalization within prior 6 months, were studied. We modeled acute VC by inflating a cuff around the dominant arm, targeting ∼30 mmHg increase in venous pressure. Blood was sampled before and after 90 min of VC (Fig A). HF-related events were recorded during 4-y follow up.

Results: 44 pts were studied (53±12 yo; 32% female). During follow up, 16 pts had a HF hospitalization, 6 LVAD implant, 3 heart transplant and 3 died. Circulating endothelin-1 (ET-1), tumor necrosis factor-α, interleukin-6, isoprostane, angiotensin II, angiopoietin-2 (Ang-2), vascular cell adhesion molecule-1 and soluble CD146 were significantly increased in the congested vs. control arm after 90 min of VC. Higher ET-1 and Ang-2 response to VC was present in pts with vs. without recent HF hospitalization, and prospectively associated with incident HF-related events (Fig B-C). These results were confirmed after adjustment for age, sex, and history of recent (<6 months) HF hospitalization: ET-1 (HR 1.70, 95% CI 1.05-2.73) and Ang-2 (HR 2.37, 95% CI 1.12 -4.98).

Conclusion: A greater ET-1 and Ang-2 response to VC is: 1) present in euvolemic pts with vs. without a recent history of HF hospitalization, and 2) prospectively associated with more HF-related events. A distinct and sustained biological sensitivity to VC occurs in pts at high-risk for HF progression.





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