Negative interaction between nitrates and remote ischemic preconditioning in patients undergoing cardiac surgery: the ERIC-GTN and ERICCA studies

Abstract

Remote ischaemic preconditioning (RIPC) using transient limb ischaemia failed to improve clinical outcomes following cardiac surgery and the reasons for this remain unclear. In the ERIC-GTN study, we evaluated whether concomitant nitrate therapy abrogated RIPC cardioprotection. We also undertook a post-hoc analysis of the ERICCA study, to investigate a potential negative interaction between RIPC and nitrates on clinical outcomes following cardiac surgery. In ERIC-GTN, 185 patients undergoing cardiac surgery were randomized to: (1) Control (no RIPC or nitrates); (2) RIPC alone; (3); Nitrates alone; and (4) RIPC + Nitrates. An intravenous infusion of nitrates (glyceryl trinitrate 1 mg/mL solution) was commenced on arrival at the operating theatre at a rate of 2–5 mL/h to maintain a mean arterial pressure between 60 and 70 mmHg and was stopped when the patient was taken off cardiopulmonary bypass. The primary endpoint was peri-operative myocardial injury (PMI) quantified by a 48-h area-under-the-curve high-sensitivity Troponin-T (48 h-AUC-hs-cTnT). In ERICCA, we analysed data for 1502 patients undergoing cardiac surgery to investigate for a potential negative interaction between RIPC and nitrates on clinical outcomes at 12-months. In ERIC-GTN, RIPC alone reduced 48 h-AUC-hs-cTnT by 37.1%, when compared to control (ratio of AUC 0.629 [95% CI 0.413–0.957], p = 0.031), and this cardioprotective effect was abrogated in the presence of nitrates. Treatment with nitrates alone did not reduce 48 h-AUC-hs-cTnT, when compared to control. In ERICCA there was a negative interaction between nitrate use and RIPC for all-cause and cardiovascular mortality at 12-months, and for risk of peri-operative myocardial infarction. RIPC alone reduced the risk of peri-operative myocardial infarction, compared to control, but no significant effect of RIPC was demonstrated for the other outcomes. When RIPC and nitrates were used together they had an adverse impact in patients undergoing cardiac surgery with the presence of nitrates abrogating RIPC-induced cardioprotection and increasing the risk of mortality at 12-months post-cardiac surgery in patients receiving RIPC.

Cardioprotective effects of high-altitude adaptation in cardiac surgical patients: a retrospective cohort study with propensity score matching

“…For a considerable period, it has been recognized that transient hypoxic or ischemic preconditioning, remote ischemic preconditioning, and chronic hypoxia exposure offer protection to the heart against acute I-R injury in animals. Recent clinical trials have shown the limited improvement effect of transient limb remote ischemic preconditioning on clinical outcomes of surgical patients (3)(4)(5)(6)(7). Nonetheless, there are still doubts as to whether other hypoxic or ischemic methods can produce clinically significant myocardial protective effects.…”

“…Clinical practice does not allow for the application of many short-term pretreatment techniques, such as hypoxic or myocardial ischemic preconditioning, which significantly reduce myocardial I-R injury in animal experiments ( 2 ). Remote ischemic preconditioning has also been confirmed to be cardioprotective in animal studies, nonetheless, the results of several clinical studies have generated controversy ( 3 – 7 ). In a multicenter randomized clinical trial involving adult patients underwent cardiac surgery, there was no significant difference in the incidences of primary end point between the remote ischemic preconditioning group (14.3%) and the control group (14.6%) ( 8 ).…”

Pharmacological Cardioprotection against Ischemia Reperfusion Injury—The Search for a Clinical Effective Therapy

“…In addition, nitroglycerin administration in cardioplegia solution increased NO levels and decreased troponin T levels in CABG patients [208]. In contrast, treatment with glyceryl trinitrate did not affect cardiac troponin T levels and even abrogated the cardioprotective effect of RIPC in cardiac surgery patients [209]. Taken together, NO donors seem promising in protecting the heart via the vasculature during CPB; however, it should be taken into account that most NO donors have platelet inhibitory properties and might therefore have clinical consequences in terms of postoperative bleeding [210].…”

Reperfusion injury on computed tomography following endovascular revascularization of acute mesenteric ischemia: prevalence, risk factors, and patient outcome

“…Despite a substantial amount of preclinical data assessing the biological or pathological process of bowel RI [ 19 , 20 ], no clinical studies have been performed to date. Unlike in the field of myocardial [ 40 ] or cerebral ischemia [ 41 ], this significant gap between fundamental research and clinical practice is common in the field of mesenteric ischemia. Of course, AAMI is rare compared to ischemia in other organs [ 42 ], but more probably, this can be explained by the focus on bowel resection in historical surgical series [ 43 ].…”