Nitric Oxide Inhalation is Associated with Decreased Incidence of Acute Rejection after Cardiac Transplantation

Abstract

Inhaled nitric oxide (iNO) has been shown to decrease ischemia-reperfusion injury (IRI) by several putative mechanisms, while preclinical studies have shown it to reduce acute rejections. In heart transplantation (HTx), iNO is routinely used to decrease pulmonary vascular resistance. However, iNO's effect on IRI after HTx and later outcomes on acute rejections remains unknown. We performed post hoc analysis on clinical data and plasma samples of 84 donor-recipient pairs collected in a prospective, double-blinded single-center trial. Recipient plasma was collected prior to HTx, and 1, 6, 12, and 24h after transplantation. In addition cardiac biopsies were collected before and 1h after reperfusion, and 2 weeks after HTx. We measured TnT, TnI, CKMBm, and proBNP as biomarkers for early organ-specific injury and function. Follow-up was conducted until one year for rejections and mortality. Of the 84 patients, 58.3% received iNO after HTx based on perioperative pulmonary vascular resistance. Preoperatively, iNO-treated patients had higher bilirubin and proBNP (P<0.01 and P<0.05), and a trend for higher transpulmonary gradient (P=0.058). Postoperatively, iNO-treated patients had higher TnT, TnI, and proBNP plasma levels (P<0.01-0.05), and an increased need for renal replacement therapy (P<0.001) compared to patients not receiving iNO. iNO-treated patients received more likely ATG, and therefore patients were divided to subgroups based on ATG and iNO treatment. In a 1-year follow-up, mortality between groups was similar. In groups without ATG treatment, iNO-treated patients had fewer biopsy-proven acute rejection episodes, and their 1-y freedom from rejection was higher (20% vs 52%) (both P<0.01). There was a similar, albeit statistically non-significant, trend for groups receiving ATG. iNO-treated patients were sicker pre- and postoperatively compared to patients not receiving iNO. Despite iNO-patients being overall sicker, iNO-treatment associated with less rejections. Our findings suggest that iNO may have some long-term cardioprotective effects after HTx. In ISHLT 2020 meeting we aim to present also results on the effect of iNO on early inflammatory cell influx to the graft, and on changes in cardiac transcriptome using IHC and next-generation sequencing from cardiac biopsies.