Peripheral venous congestion causes inflammation, neurohormonal, and endothelial cell activation

Abstract

Aims: Volume overload and venous congestion are typically viewed as a consequence of advanced and of acute heart failure (HF) and renal failure (RF) although it is possible that hypervolaemia itself might be a critical intermediate in the pathophysiology of these diseases. This study aimed at elucidating whether peripheral venous congestion is sufficient to promote changes in inflammatory, neurohormonal, and endothelial phenotype similar to those observed in HF and RF.

Methods: To experimentally model peripheral venous congestion, we developed a new method (so-called venous stress test) and applied the methodology on 24 healthy subjects (14 men, age 35 ± 2 years). Venous arm pressure was increased to ∼30 mmHg above the baseline level by inflating a tourniquet cuff around the dominant arm (test arm). Blood and endothelial cells (ECs) were sampled from test and control arm (lacking an inflated cuff) before and after 75 min of venous congestion, using angiocatheters and endovascular wires. Magnetic beads coated with EC-specific antibodies were used for EC separation; amplified mRNA was analysed by Affymetrix HG-U133 Plus 2.0 Microarray.

Results: Plasma interleukin-6 (IL-6), endothelin-1 (ET-1), angiotensin II (AII), vascular cell adhesion molecule-1 (VCAM-1), and chemokine (C-X-C motif) ligand 2 (CXCL2) were significantly increased in the congested arm. A total of 3437 mRNA probe sets were differentially expressed (P < 0.05) in venous ECs before vs. after testing, including ET-1, VCAM-1, and CXCL2.

Conclusion: Peripheral venous congestion causes release of inflammatory mediators, neurohormones, and activation of ECs. Overall, venous congestion mimicked, notable aspects of the phenotype typical of advanced and of acute HF and RF.

Keywords: Congestive heart failure; Endothelin; Endothelium; Inflammation.

Figure 1

Venous stress test. Blood and endothelial cells were sampled from the antecubital or basilic vein of the non-dominant arm (control arm) at baseline and of the dominant arm (test arm) after 75 min of local venous congestion using angiocatheters and endovascular wires. Peripheral venous pressure was increased ∼30 mmHg above baseline levels by inflating a tourniquet cuff around the test arm, proximally, just below the shoulder. Blood was also obtained at 75 min from the control arm which was not exposed to venous congestion, thus serving as a control (*).

Figure 2

Heat map of the 72 probe sets with an absolute fold-change >2.0 and a false discovery rate <0.05. The green header bar refers to endothelial cell gene expression in samples prior to venous congestion and the red header bar represents endothelial cell gene expression in samples after experimental venous congestion. Blue-coloured cells in the matrix represent relative under expression (i.e. lower expression values) and yellow-coloured cells represent relative over expression (i.e. higher expression values). FC, fold-change.