Management of non-ST-segment elevation MI (NSTEMI) patients is a growing clinical challenge, representing nowadays the majority of acute MI in most contemporary registries [8], [9]. Moreover, NSTEMI patients have a dramatically high rate of in-hospital cardiovascular complications, almost similar to STEMI population. NSTEMI are also characterized by increased age, and further evidence of co-morbidities such as diabetes, most conditions that are known to reduce the beneficial effects of PIA in STEMI [10], [11]. However, the impact of PIA in the setting of NSTEMI patients is currently unknown.

Only small sample size study had analysed the impact of PIA in NSTEMI, suggesting decreased in hospital complications. [16] The high rate of PIA observed in our study (>40%) is consistent with the rate reported in STEMI. [6], [17] In a recent meta-analysis, PIA was observed in 35% of patients presenting a STEMI. [18] A higher rate of PIA in NSTEMI (vs. STEMI) has also been found in previous studies reporting that patients experiencing PIA were more likely to experience NSTEMI than STEMI. [19], [20]. In clinical situations, there is a wide heterogeneity of the timing onset of PIA before the acute MI, ranging from the first 24 hours to 2 months [1], [2]. In agreement with previous works [5], [21], our data strongly support a beneficial and protective role of PIA, when experienced within 7 days before the index event. Patients with PIA had similar risk profile than patients without PIA. However, they were more frequently obese, hypertensive and with family history of CAD, consistent with coronary angiographic findings showing a trend for more CAD extent in such group.

Angina occurring before a first STEMI has been suggested to confer multiple cardioprotective effects. TIMI-4 trial showed a significant decrease in hospital death (3 vs. 8%), severe congestive heart failure or shock (1 vs. 7%), and CK peak determining infarct size (119 vs. 154 IU/L) associated with PIA. [22], [23] TIMI-9 trial further reported that patients with angina onset within 24 hours of infarction had a lower 30-day cardiac event rate (including death, recurrent MI, heart failure, or shock) than those with onset of angina >24 hours (4% vs 17%) [1]. In-hospital VAs are rather uncommon but major life-threatening complication in acute MI [24], [25], [26], in particular in NSTEMI [15]. However, only few trials have assessed the impact of PIA on such arrhythmias, limited to out-of-hospital arrhythmias [7] or reperfusion arrhythmias [25]. In our work, PIA was associated with a decreased infarct size -by 28%, as measured by CK peak-, consistent with previous findings [1], [4], [23]. Our work also showed that conditioning the heart can confer additional benefit over current medical practice procedures. Moreover, our results from multivariate models showing a loss of prognostic capacity of PIA when CK was added to the model, interestingly suggest that PIA may have contributed to the decreased incidence of VAs, via a lower infarct size. However, the underlying mechanisms of the beneficial effects of PIA are not yet clarified.

The PIA-induced development of coronary collateral circulation from the non-ischemic areas has been suggested. Some authors also proposed that increases in pressure due to a subtotal occlusion during short episodes of angina could play an important role by opening and developing coronary collateral vessels, especially in diabetic patients [27]. However, in contrast to experimental studies, the involvement of coronary collateral circulation in the cardioprotective effect of PIA in humans remains controversial. In patients undergoing PCI, an antiarrhythmic effect of preconditioning can occur independently of collateral recruitment [28] Moreover, the protective role of PIA has been observed even in the absence of significant collateral circulation [2], [29]. In NSTEMI patients, where coronary arteries are not totally occluded, the involvement of such pathophysiological mechanism in the beneficial effects of PIA may be only modest.

Another potential cardioprotective mechanism relates to experimental ischemic preconditioning. Preconditioning the myocardium during brief episodes of ischemia, before a sustained occlusion, stimulates adenosine receptors, decreases the cellular influx of calcium, leading to a decrease in myocardial energy demands and limiting the extent of myocardial injury. [30] Transient mitochondrial permeability transition pore (mPTP) opening mediates preconditioning-induced protection, via a K+ ATP-dependent channel [31]–[33]. Experimental preconditioning has been shown to typically reduce infarct size and decrease in ischemia-reperfusion arrhythmias in most animal models. [34]–[36] Ischemic preconditioning could also induce antiarrhythmic protection in humans [37]–[41].

Finally, chronic treatment with CV drugs such as aspirin or nitrates, taken before the acute MI, may improve outcomes in patients experiencing PIA. The cardioprotective effect of such chronic preadmission treatments has been indirectly suggested, in a recent retrospective work showing that patients under chronic CV treatments (i.e. aspirin, β-blockers, ACE inhibitors, or statins) before hospital admission were less likely to develop STEMI than NSTEMI. [19] Interestingly, the risk proportionally decreased with the increasing number of medications used before acute MI, underlining the benefit of preventive medication in high-risk patients. Moreover, in the GRACE Study, a history of angina was more common among patients with NSTEMI than among those with STEMI, further lending support for the hypothesis that prior treatment may also modify the disease process and clinical presentation [20]. Nitroglycerin conferred cardioprotection against ischemia through a protein kinase C-dependent pathway [42], [43]. Recently, in a large multinational, unselected population over 50.000 MI patients, chronic nitrate use pre-infarction was associated with significantly lower levels of cardiac markers of necrosis, further suggesting a smaller extent of myocardial necrosis [44]. Hence, in our study, such treatments may have participated at least in part to the beneficial effect associated with PIA.