Endothelin-1 and Cardiac Allograft Vasculopathy (CAV)

Impact of Endothelin-1 on the Development of Cardiac Allograft Vasculopathy in Heart Transplant Recipients: Endothelin Receptor Antagonism and Vasomotor Function

Many patients with end-stage heart failure, a condition in which the heart fails to pump enough blood to support the body's other organs, are fortunate enough to receive a heart transplant. However, despite taking medicines aimed at blunting the immune system's response to the donor heart, some of them will develop transplant-related disease in the coronary arteries supplying their hearts. Fifty years after the first human-to-human heart transplant, this disorder-cardiac allograft vasculopathy (CAV)-remains a leading cause of long-term death and has been coined the 'Achilles' Heel' of heart transplantation. Indeed, a better understanding of how CAV occurs and improved therapies to prevent and/or slow its development are desperately needed to meaningfully impact patient outcomes. Endothelin-1 (ET-1) is a key molecular regulator of arterial health, and our prior data suggests that it is associated with accelerated CAV. In this particular study of recent heart transplant recipients, we are asking: Does ET-1 contribute to the coronary artery's capacity to dilate/constrict? To answer this question, during the cardiac catheterization at 1 year post-transplant (standard of care), we will measure blood levels of ET-1 and perform an invasive evaluation of coronary vasomotor function inn a consecutive subset of patients who will have received a 1-week course of the oral endothelin receptor antagonist (macitentan) prior this catheterization, which will allow us to test how much ET-1 contributes to coronary responsiveness. The findings from this study may provide the necessary foundation to study whether endothelin receptor antagonists are able to effectively reduce the rate of accelerated CAV.

A consecutive subset of eligible patients based on inclusion/exclusion criteria will receive a 1-week course of Macitentan (10 mg po daily) prior to their routine 1-year coronary angiogram (7th and final dose of Macitentan will occur on the day of the angiogram).

Macitentan is a nonselective endothelin-receptor antagonist (ERA) that is approved for use in pulmonary arterial hypertension (PAH); the use of Macitentan in post-heart transplant patients is considered investigational.

ET-1 bioactivity as measured by contribution to vasomotor tone via the Macitentan:Nitroglycerin luminal volume dilation ratio on Intravascular Ultrasound (IVUS)

Inclusion Criteria: Within 4 months post-transplant ≥18 years old Have a serum creatinine < 2.0 mg/dL (to minimize risk of contrast-induced nephropathy) Able to provide informed written consent. Exclusion Criteria: Multi-organ transplant Transplant-related complications and comorbidities that preclude the ability to safely perform an invasive coronary evaluation in the cardiac catheterization laboratory Pregnant women due to possible fetal harm; all women of childbearing potential must have a negative pregnancy test within 1 week of starting Macitentan, and 30 days after completing the one-week course of Macitentan. Patients who are taking potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) as these drugs can expose one to higher levels of macitentan Cirrhosis or baseline liver function tests (AST/ALT) > 3x the upper limit of normal

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