Reduced trans-myocardial extraction of endothelin-1 in cardiac allograft vasculopathy

Abstract Introduction Cardiac allograft vasculopathy (CAV) is a major cause of graft failure due to microvascular dysfunction and ischaemia following heart transplant. Endothelin-1 (ET-1) is an endothelium derived vasoconstrictor peptide with multiple adverse effects including vascular smooth muscle proliferation and pro-inflammatory signalling. Elevated circulating ET-1 has been associated with accelerated CAV. We assessed the trans-myocardial gradient (TMG: coronary sinus minus coronary artery concentration: negative=extraction, positive=secretion) of ET-1 in heart transplant patients to determine correlations with angiographic, Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT) features of CAV. Methods 23 patients underwent invasive coronary angiography, 3-vessel grey scale IVUS (Opticross, 60mHz, Boston Scientific) and OCT (Dragonfly, Abbott Vascular) to define morphological features of vasculopathy 18±3 months post-transplant. Paired blood samples were obtained from the guide catheter and coronary sinus at the time of coronary imaging. Plasma was analysed using specific enzyme-linked immunosorbent assay for ET-1 peptide quantification. Survival was determined 98±5 months after initial assessment. Results ET-1 TMG distribution was mostly in the negative range reflecting net extraction across the coronary vascular bed (median [IQR]: -0.23 [-0.54, -0.02] pg/ml). However, vessels with more severe CAV demonstrated significantly more positive TMG i.e. less ET-1 trans-myocardial extraction (IVUS Stanford Grade IV: -0.05 [-0.21, 0.13] pg/ml versus Stanford Grade I-III: -0.31 [-0.64, -0.11] pg/ml, p = 0.01). ET-1 TMG was positively correlated with mean intimal thickness on both IVUS and OCT (IVUS: Kendall’s tau-b = 0.254, p=0.02 and OCT: Kendall’s tau-b = 0.344, p<0.0001). Patients who died had net ET-1 secretion compared with surviving patients (died: 0.21 [0.19 - 0.24] versus surviving: -0.28 [-0.52, -0.17], p = 0.01). Conclusions In heart transplant patients, coronary arteries with more intimal thickening had less trans-myocardial extraction, and more secretion of ET-1. ET-1 secretion in CAV may mediate the distal microvascular dysfunction commonly seen in this condition. These findings suggest a rationale for testing ET-1 receptor antagonists as a treatment for CAV.ET-1 TMG and IVUS Stanford Grade of CAVET-1 TMG and OCT derived MIT