The effect of remote ischaemic conditioning and glyceryl trinitrate on perioperative myocardial injury in cardiac bypass surgery patients

BACKGROUND: Due to the aging population and increased prevalence of co-morbidities (such as diabetes, obesity and renal failure), higher risk patients are undergoing coronary artery bypass graft and/or valve (CABG±valve) surgery, increasing the risk of post-surgical complications (such as perioperative myocardial injury/infarction), and worse clinical outcomes. As such, novel cardioprotective strategies are required to protect the heart against perioperative myocardial injury (PMI) during CABG±valve surgery. A number of clinical studies have shown that remote ischaemic preconditioning (RIPC), in which the arm or leg is subjected to cycles of brief ischaemia and reperfusion, by inflating a cuff placed on the upper arm or thigh, can reduce peri-operative myocardial injury (PMI) during CABG±valve surgery. However, not all studies have been positive, and large clinical outcomes studies (ERICCA and RIPHeart) have reported no benefit with RIPC in this clinical setting. The reasons for this are unclear but may relate to co-medications used in this clinical setting including agents such as propofol anaesthesia, and morphine. In this thesis, I investigated whether glyceryl trinitrate (GTN), which is often given as an intra-operative intravenous (IV) infusion, is cardioprotective in its own right, and whether it attenuates the cardioprotective effect of RIPC in patients undergoing CABG±valve surgery. Primary hypothesis: The effect of RIPC on reducing PMI will be attenuated in the presence of GTN administered as an intra-operative IV infusion in patients undergoing CABG±valve surgery. Secondary hypothesis: GTN administered as an intra-operative IV infusion will reduce PMI in patients undergoing CABG±valve surgery. METHODOLOGY : The ERIC-GTN trial (http://www.clinicaltrials.gov: NCT01864252) was a single-site, double-blinded, randomised, placebo-controlled clinical study investigating whether an intra-operative IV GTN infusion attenuates the cardioprotective effect of RIPC in patients undergoing CABG±valve surgery. Consenting adult patients (age >18 years) undergoing elective CABG±valve surgery with blood cardioplegia were eligible for inclusion. Following anaesthetic induction, patients were randomised to receive one of the four treatment groups: Group 1 - Sham+Saline: a sham RIPC protocol (comprising simulated limb cuff inflations and deflations) followed by an intra-operative intravenous (IV) saline infusion. Group 2 - Sham+GTN: a sham RIPC protocol followed by an intra-operative IV GTN infusion. Group 3 - RIPC+Saline: a RIPC protocol (comprising three 5-minute cycles of simultaneous upper arm and thigh cuff inflations/deflations) followed by an intra-operative IV saline infusion. Group 4 - RIPC+GTN: a RIPC protocol followed by an intra-operative IV GTN infusion. The primary endpoint was PMI, as quantified by 72 hour area-under-the-curve (AUC) serum high-sensitivity Troponin T. RESULTS : The intended sample size was 260 patients, but following the results of an interim analysis of 189 patients, the ERIC-GTN trial was stopped. There was no difference in PMI in patients from Groups 1 (Sham+Saline) and 2 (Sham+GTN), suggesting that, in itself, an intra-operative GTN infusion was not cardioprotective. However, patients in Group 3 (RIPC+Saline) did sustain less PMI as evidenced by a 37% reduction in 72 hour AUC Troponin T release, when compared to patients in Group 1 (Sham+Saline), confirming the cardioprotective effects of RIPC. Interestingly, the beneficial effect of RIPC on reducing PMI in Group 3 (RIPC+Saline), was abrogated in the presence of GTN (Group 4, RIPC+GTN), suggesting a negative interaction between RIPC and intra-operative IV GTN infusion. CONCLUSIONS: The interim analysis of the ERIC-GTN study has shown a negative interaction between RIC and GTN, suggesting that an intra-operative GTN infusion, attenuated the cardioprotective effects of GTN, in terms of reducing PMI in patients undergoing CABG±valve surgery. This finding may, in part, explain the results of the ERICCA trial in which RIPC failed to reduce major adverse cardiovascular events in patients undergoing CABG±valve surgery

Reply to Sanfilippo et al. Caution Is Warranted When Assessing Diastolic Function Using Transesophageal Echocardiography. Comment on “Kyle et al. Consensus Defined Diastolic Dysfunction and Cardiac Postoperative Morbidity Score: A Prospective Observational Study. J. Clin. Med. 2021, 10, 5198”

We thank Sanfilippo and colleagues for their insightful comments about the assessment of diastolic function with transesophageal echocardiography (TEE) [...

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

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