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

Abstract and Introduction


Timely blood flow restoration (reperfusion) is the cornerstone of therapeutic strategies for ST-segment elevation myocardial infarction (STEMI).[1] Reperfusion salvages the myocardium subtended by the occluded artery in a time-dependent manner, such that the longer the duration of coronary occlusion, the smaller the amount of salvageable myocardium. Wide implementation of reperfusion strategies has massively reduced mortality: in-hospital mortality of patients with MI was close to 25% in the 1970s and in less than three decades has been reduced to ~5%.[2] The development of reperfusion therapy for STEMI is thus one of the most successful stories in the history of medicine.[3] However, despite this progress, STEMI still frequently results in significant loss of myocardial mass, and infarct size has been confirmed as the main determinant of long-term post-STEMI mortality and morbidity.[4] There is therefore a need for complementary therapeutic strategies to reduce further infarct size and improve long-term outcomes.

Paradoxically, an important determinant of infarct size is reperfusion itself. This is because the reperfusion procedure, despite being essential for myocardial salvage, induces additional myocardial damage. Final infarct size is thus the combined result of injury caused by ischaemia and injury caused by reperfusion to restore blood flow, and is therefore termed ischaemia/reperfusion injury (IRI).[5] The dominant current view is that ischaemia-related damage can be reduced only by shortening the duration of coronary occlusion, whereas reperfusion-related damage, occurring at the time of blood flow restoration, could in principle be reduced by interventions at any time before reperfusion, including in the catheterization lab immediately before opening the occluded vessel. This latter strategy is logistically very attractive and has garnered major interest. Many interventions tackling reperfusion-related injury have been shown to be beneficial in animal models; however, translation to the clinic has generally been disappointing.[6] The idea of using inhaled nitric oxide (iNO) to reduce infarct size unfortunately appears to have joined this list of failed translations of intervention strategies.

NO is synthesized within the myocardium mainly by isoforms of NO synthase. Evidence from several laboratories has clearly demonstrated that endogenous NO protects against IRI,[7] and several interventions that reduce IRI have been shown to act via NO pathways.[8] The clear ability of NO production to increase myocardial tolerance to ischaemia and reduce IRI led several investigators to test the benefits of delivering exogenous NO.[9] The wide range of mechanisms through which NO limits IRI include cardiomyocyte mitochondrial protection, preservation of endothelial function, and inhibition of platelet aggregation and neutrophil–endothelium interactions. Among the various proposed NO-based therapies, iNO is especially attractive because of its ease of administration. Several independent studies have reported the positive infarct-limiting effects of iNO in different experimental models, including mice, rats, and pigs undergoing reperfused MI.[9]

Encouraged by this robust pre-clinical evidence, some generated in their own laboratory,[10] Stefan Janssens and colleagues launched the Nitric Oxide for Inhalation in ST-Elevation Myocardial Infarction (NOMI) trial, the first randomized clinical trial (RCT) testing a therapeutic iNO strategy to reduce MI size in STEMI patients, which is published in this issue of the journal.[11] In this pilot trial, 250 STEMI patients undergoing primary coronary intervention (PCI) were recruited at four hospitals in three countries and were randomized in a double-blind, placebo-controlled manner to inhale oxygen supplemented with NO (80 ppm; active arm) or without supplementation (control). Inhalations were initiated upon the patient's arrival in the catheterization lab and were maintained for 4 h. The primary efficacy endpoint was the extent of late gadolinium enhancement cardiac magnetic resonance [LGE CMR, % left ventricular (LV) mass], a surrogate for infarct size, 48–72 h (day 2–3) after MI. Key secondary efficacy endpoints included LGE relative to the high signal intensity area on T2W CMR (a surrogate for the extent of oedema), microvascular obstruction, and intramyocardial haemorrhage on day 2–3 CMR. The main results of the trial are that NO inhalation in STEMI patients is safe but has no impact on infarct size or any other endpoint. A pre-specified subgroup analysis revealed significant interaction between iNO and the use of parenteral nitroglycerin, a known pharmacological NO donor. In nitroglycerin-naive patients (55% of the population), iNO was associated with smaller infarcts. The effect of nitroglycerin in this trial is difficult to explain, since in the control arm (no iNO) nitroglycerin use was associated with an infarct size reduction similar to that produced with iNO in nitroglycerin-naive patients, an unexpected outcome according to current knowledge.

Janssens and colleagues are to be commended for their outstanding work in identifying a potential cardioprotective strategy in experimental models[10] and moving these findings to the clinical arena by leading the first human trial.[11] In face of the natural disappointment of the authors and the wider research and clinical community, it is important to consider potential factors that may have contributed to the failed translation.