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Negative interaction between nitrates and remote ischemic preconditioning in patients undergoing cardiac surgery: the
Ashraf Hamarneh1, Andrew Fu Wah Ho2,3, Heerajnarain Bulluck4,5
1Institute of Cardiovascular Sciences, The Hatter Cardiovascular Institute, University College London, London, WC1E 6HX, UK.
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.
Insights
Remote ischaemic preconditioning (RIPC) alone reduced heart injury in cardiac surgery patients. However, combining RIPC with nitrates negated this benefit and increased mortality risk.
Area of Science:
- Cardiology
- Cardiovascular Surgery
- Pharmacology
Background:
- Remote ischaemic preconditioning (RIPC) is a technique to protect organs from injury during surgery.
- Previous studies have shown inconsistent results regarding RIPC's effectiveness in cardiac surgery.
- The interaction between RIPC and nitrate therapy in cardiac surgery is not well understood.
Purpose of the Study:
- To evaluate if nitrate therapy abrogates the cardioprotective effects of RIPC.
- To investigate a potential negative interaction between RIPC and nitrates on clinical outcomes after cardiac surgery.
Main Methods:
- ERIC-GTN study: 185 patients randomized to control, RIPC alone, nitrates alone, or RIPC + nitrates.
- Primary endpoint: peri-operative myocardial injury (PMI) measured by 48-h AUC-hs-cTnT.
- ERICCA study: Post-hoc analysis of 1502 patients to assess 12-month clinical outcomes.
Main Results:
- RIPC alone reduced PMI by 37.1% in ERIC-GTN (p=0.031).
- Nitrate therapy abrogated RIPC's cardioprotective effect in ERIC-GTN.
- In ERICCA, RIPC + nitrates showed a negative interaction, increasing 12-month mortality and peri-operative myocardial infarction risk.
Conclusions:
- Concomitant nitrate therapy abrogates RIPC-induced cardioprotection in cardiac surgery.
- The combination of RIPC and nitrates has an adverse impact, increasing mortality risk.
- Further research is needed to clarify the mechanisms behind this interaction.
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