Take a Deep (Nitric Oxide) Breath and Follow the Reverse Translational Research Pathway

Manuel Lobo; Borja Ibanez


Eur Heart J. 2018;39(29):2726-2729. 

In This Article

Timing of iNO Initiation

The timing of therapy initiation deserves special attention. iNO in the NOMI trial was initiated soon before reperfusion for reasons of feasibility (the gas tanks were located in the catheterization laboratory). However, a previous study in a rat IRI model showed no benefit from iNO initiated at reperfusion, whereas earlier iNO initiation during the ischaemia period was associated with significant reductions in AAR-normalized infarct size.[19] This observation chimes with clinical experience with two therapies associated with infarct size reduction in STEMI patients; remote ischaemic conditioning (RIC)[20] and intravenous metoprolol[21] have been found to be more effective when initiated long before reperfusion than when initiated close to reperfusion.[22] In both cases, the link between therapy initiation time and cardioprotection observed in clinical trials has been confirmed experimentally in the pig model.[21,23] It is thus possible that early initiation of iNO during the ischaemia phase (e.g. during ambulance transit to the hospital) would have resulted in a stronger cardioprotective effect in the NOMI trial; however, while such an outcome is plausible, it remains a matter of speculation at present.

The NOMI trial should not be seen as the final nail in the coffin of NO-based therapies to reduce infarct size. Rather, the trial findings leave many open questions to be addressed in further studies. Inhaled NO seems a safe and easy to implement strategy and, given the strong mechanistic data supporting its potential efficacy, it is too early for the scientific community to give up on this therapy. The impact of iNO dose and timing should be re-evaluated in large animal models in an exercise of reverse translational research (from the bedside back to the bench); see Take home figure. Moreover, this exercise should not be restricted to this intervention, but should be extended to all infarct-limiting strategies. Given the growing evidence that the timing of initiation with therapies to reduce IRI influences their cardioprotective strength,[20,21,23] it is appropriate to question the dominant view that these therapies will be equally effective when applied at any time before reperfusion.

Take Home Figure.

In the classic view, translational research is viewed as a one-way transit from bench to bedside (translating basic discoveries into clinical applications). However, the reverse translational pathway (from clinic back to basic/experimental research) is increasingly acknowledged as a critical requirement for successful translational research. The reasons for neutral or inconclusive results in any step of the translational research pathway can often be identified and explained by returning to an earlier step. The figure shows the steps in the translational research pathway, together with the most important considerations for studies searching for infarct-limiting therapies. The translational journey can start with a basic research discovery or a clinical observation. Taking shortcuts in this pathway is usually a high-risk endeavour (e.g. performing an RCT after a positive small-animal study without first performing a large-animal pre-clinical trial). In the NOMI trial, a successful transition from basic research to pre-clinical models was followed by a pilot RCT, yielding a negative outcome: the hypothesis that iNO initiated soon before reperfusion would result in smaller infarctions was not confirmed. Important questions can be evaluated by returning to conduct new tests in the pre-clinical models, such as dose–response studies and different timings of iNO initiation. An alternative approach is to reconsider the cardioprotective target in new basic research studies. iNO, inhaled nitric oxide; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MVO, microvascular obstruction; RCT, randomized clinical trial.