Peripheral venous congestion causes time- and dose-dependent release of endothelin-1 in humans

Abstract

Endothelin-1 (ET-1) is a pivotal mediator of vasoconstriction and inflammation in congestive states such as heart failure (HF) and chronic kidney disease (CKD). Whether peripheral venous congestion (VC) increases plasma ET-1 at pressures commonly seen in HF and CKD patients is unknown. We seek to characterize whether peripheral VC promotes time- and dose-dependent increases in plasma ET-1 and whether these changes are sustained after decongestion. We used a randomized, cross-over design in 20 healthy subjects (age 30 ± 7 years). To experimentally model VC, venous pressure was increased to either 15 or 30 mmHg (randomized at first visit) above baseline by inflating a cuff around the subject's dominant arm; the nondominant arm served as a noncongested control. We measured plasma ET-1 at baseline, after 20, 60 and 120 min of VC, and finally at 180 min (60 min after cuff release and decongestion). Plasma ET-1 progressively and significantly increased over 120 min in the congested arm relative to the control arm and to baseline values. This effect was dose-dependent: ET-1 increased by 45% and 100% at VC doses of 15 and 30 mmHg, respectively (P < 0.05), and declined after 60 min of decongestion though remaining significantly elevated compared to baseline. In summary, peripheral VC causes time- and dose-dependent increases in plasma ET-1. Of note, the lower dose of 15 mmHg (more clinically relevant to HF and CKD patients) was sufficient to raise ET-1. These findings support the potentially contributory, not merely consequential, role of VC in the pathophysiology of HF and CKD.

Keywords: Congestive heart failure; endothelin; inflammation.

Figure 1

Plasma endothelin‐1 time response to venous congestion (VC) at a dose of 15 mmHg (A) and 30 mmHg (B); 30 mmHg data at 180 min in the test arm are based on a sample of 18 subjects; 15 mmHg data at 60 min in the control arm are based on a sample of 19 subjects. * P < 0.05 versus baseline; # P < 0.05 versus control arm.

Figure 2

Plasma endothelin‐1 changes from baseline according to time and venous congestion (VC) dose. Change is computed as endothelin‐1 differences between each time point and baseline levels in the test arm; 30 mmHg data at 180 min in the test arm are based on a sample of 18 subjects; 15 mmHg data at 60 min in the control arm are based on a sample of 19 subjects.