Long-term endothelin receptor antagonism attenuates coronary plaque progression in patients with early atherosclerosis

Abstract

Aim The purpose of the current study was to determine if long term treatment with an endothelin-A (ETA) receptor antagonist attenuates the progression of coronary plaques in patients with coronary endothelial dysfunction. Methods Thirty-five patients with non-obstructive coronary disease and coronary endothelial dysfunction were randomized in a double blind manner to treatment with placebo or ETA receptor antagonist Atrasentan (10 mg) for six months. Endothelial function was assessed by the change in coronary blood flow and coronary artery diameter in response to intracoronary acetylcholine. Normalized mean total atheroma volume (TAVMEAN), percent atheroma volume (PAV) and changes of atheroma volume were assessed by intravascular ultrasound (IVUS) at baseline and 6-month follow-up. Results In segments with coronary endothelial dysfunction, there was a significant decrease in normalized TAVMEAN and PAV at six months from baseline in the Atrasentan group compared to the placebo group median (IQR) −2.00 mm3 (−7.28, 2.53.) vs 9.11 mm3 (1.23, 14.05), p=0.0024 and 0.955% (−3.43, 1.70) vs 3.85% (−0.39, 14.59) p=0.010. There was no change in normalized TAV or PAV in the segments with normal endothelial function. Conclusion This study demonstrates that 6-month treatment with Atrasentan attenuates progression of coronary plaque in segments with endothelial dysfunction.

Preservation of Endothelium-Dependent Relaxation in Atherosclerotic Mice with Endothelium-Restricted Endothelin-1 Overexpression

“…ET-1 antagonists have been shown to decrease the size of atheroma in humans (Yoon et al, 2013). In a mouse model of endothelial ET-1 overexpression (eET-1), we showed that ET-1 is associated with vascular injury characterized by enhanced vascular remodeling, an increase in the formation of reactive oxygen species, and inflammation (Amiri et al, 2004(Amiri et al, , 2008.…”

Secondary Prevention Strategy of Cardiovascular Disease Using Endothelial Function Testing

“…A randomized study of endothelin-A receptor antagonist was reported recently by Yoon et al 41 In addition to its vasoconstrictive properties, endothelin has mitogenic properties, and plays an important role in the development of endothelial dysfunction and progression of atherosclerosis. 42 Plaque volume change was evaluated by intravascular ultrasound in patients with nonobstructive coronary artery disease (CAD) at baseline and 6-month follow-up, and in the coronary artery segments with endothelial dysfunction, significant plaque progression had occurred at the 6-month follow-up, but not in segments with normal endothelial function.…”

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

“…Recent genome‐wide association studies have implicated the ET A receptor as a genetic determinant of coronary artery disease,54, 55 carotid atherosclerosis,54 large‐artery stroke,55 and peripheral artery disease,56 suggesting a role of this receptor in atherogenesis across diverse arterial systems. These findings are supported by clinical and preclinical studies that suggest a direct role of the ET A receptor on the development of atherosclerosis 57, 58, 59, 60, 61. Recently, Gupta and colleagues demonstrated in a separate genome‐wide association study project that a single‐nucleotide polymorphism common in 5 vascular diseases, including coronary artery disease, promotes exaggerated endothelium‐derived ET‐1 and higher plasma ET‐1 62.…”