In patients with STEMI and MVD, the current recommendations state that primary PCI should be limited to the culprit vessel with the exception of cardiogenic shock in the presence of multiple, critical stenosis or highly unstable lesions, and if there is persistent ischemia after PCI on the supposed culprit lesion [3]. If staged PCI to non-culprit vessels is being considered, non-invasive stress testing (myocardial perfusion scintigraphy, stress echocardiography, positron emission tomography or magnetic resonance imaging) should be used for ischemia and viability testing prior to a decision to proceed with PCI [4].

Fractional flow reserve is a well-validated technique to guide coronary intervention by identification of lesion-level ischemia. In the DEFER study, the prognosis of intermediate lesions with an FFR of > 0.75 was excellent if treated medically, with a < 1 % risk of any AMI after 5 years of follow-up [5]. However, studies to date have mainly involved stable patients outside of acute myocardial infarction (AMI) [5‐8]. The use of FFR to assess culprit and non-culprit lesions in the setting of acute ischemia represents a controversial area, although there is an increasing evidence base to support the role of FFR-guided strategy in acute coronary syndrome (ACS) [9].

The physiological principles underlying FFR are critically dependent on the ability to achieve maximal hyperaemia. In patients with AMI, pathophysiological disturbances in the microvasculature can have a potential impact on the ability to induce maximal hyperaemia, and thereby compromise the accuracy of FFR assessments in non-culprit vessels, theoretically leading to false negative results [10]. The 2011 ESC Guidelines for the management of ACS without ST-segment elevation [11] recommend that FFR should be ideally performed more than 5 days after the acute event in order to minimize the impact of any microvascular disturbance. The 2012 ESC Guidelines for the management of STEMI [4] state the staged revascularization approach for STEMI with MVD can be guided by FFR if performed several days or weeks after primary PCI. In the case report presented, the functional assessment of the mid-LAD lesions was made 3 weeks later than the primary PCI, in concordance to the current guidelines.

One of the most important studies about the use of FFR in ACS was from Ntalianis et al. [12] who studied 75 acute STEMI patients and 26 NSTEMI patients (<72 h post onset) and measured FFR in the non-culprit stenosis immediately following PCI of the culprit vessel and then repeated the FFR at 35 ± 4 days post initial procedure. The FFR value remained unchanged between the acute and follow-up phases in patients with STEMI (0.78 ± 0.10 vs. 0.76 ± 0.10, p = NS) and NSTEMI (0.77 ± 0.10 vs. 0.77 ± 0.20, p = NS). In only 2 patients, the FFR value was higher than 0.80 at the acute phase and lower than 0.75 at follow-up. The authors stated the data support that FFR measurements are safe and reliable for evaluating the severity of non-culprit stenosis in the acute phase of ACS, even during primary PCI.

A more recent study from Cuculi et al. [13] performed an invasive assessment of coronary physiology in 82 STEMI patients, immediately following PCI of the culprit vessel and 6 months later, associated with a contrast-enhanced cardiac magnetic resonance imaging evaluation of microvascular obstruction. Baseline Pd/Pa remained stable over time, but FFR reduced significantly between primary PCI and 6 months (p = 0.008); this reduction was mainly observed in patients with microvascular obstruction. Therefore, the authors stated that coronary microcirculation recovery progresses further by 6 months, suggesting that using FFR soon after STEMI might underestimate the degree of non-culprit vessel stenosis in almost half of patients.

The index of microcirculatory resistance (IMR) is a validated invasive wire-based measure of microvasculature function [14] and could be useful to assess the status of the coronary microcirculation in the setting of AMI [15], which may be used to validate an FFR result. The other potential caveat in a FFR-guided strategy in ACS patients, as it was done in our case report, is the possible existence of vulnerable coronary plaques in absence of flow limitation [9]. In the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study [16], patients presenting with ACS in whom PCI was successful, underwent 3-vessel radiofrequency intravascular ultra-sound (IVUS) imaging, and were followed for a median of 3.4 years for the incidence of MACE. In this study, the non-culprit lesions that led to MACE were frequently mild on angiographic assessment, but most were characterized by a large plaque burden, a small luminal area and were thin-cap fibroatheromas (TCFA); no MACE arose from untreated segments with a plaque burden resulting in less than 40 % loss of cross-sectional luminal area. Using data from PROSPECT study, some authors stated that clinical and angiographic characteristics had poor predictive accuracy in identifying patients with untreated high-risk plaques, at least not enough to obviate the need for intracoronary-imaging, although they assume that it is unrealistic to applicate 3-vessel invasive imaging in every clinical setting [17]. Others authors divided the same cohort into quartiles according to baseline angiographic diameter stenosis and concluded that the triad of predictors of future MACE increased in frequency with increasing angiographic diameter stenosis [18].

Some points of controversy involve the risk assessment of future MACE: do we have a cross-link between ischemia and plaque vulnerability? Can we expect that plaques with higher FFR values are stable and that lower FFR, with repetitive ischemia and high shear stress, induce vulnerability? Or do we have a diagnostic gap of vulnerable plaque between physiology and morphology? A study from Versteeg et al. [19] demonstrated that monocyte toll-like receptors 2 and 4 related to plaque vulnerability were significantly higher in patients with FFR < 0.75 than in patients with an FFR measurement of > 0.80, suggesting that vulnerability may be preceded by ischemia. In the Fractional Flow Reserve and Intravascular Ultrasound Relationship Study (FIRST) [20], the aim was to evaluate the correlation between FFR, IVUS, and virtual histology (VH) in intermediate coronary lesions. Minimal lumen area obtained by IVUS showed a moderate correlation with FFR measurements and the optimal cut-off for a FFR of < 0.80 varied depending on the vessel size. Plaque composition assessed by VH-IVUS identified only plaque burden as having any correlation with FFR values. Lesions without TCFA had better correlation with FFR compared with lesions with TCFA. A study from Hüseyinova et al. [21] evaluated 48 non-ST-elevation ACS patients having paired hemodynamic and morphological data of the culprit vessel. It was demonstrated that for a given stenosis, FFR values decrease with an increase in necrotic core and dense calcium contents of the physiologically significant coronary plaques. However, plaque composition did not exert any influence on the hemodynamic effect generated by physiologically non-significant stenosis.

The COMPARE ACUTE trial is an ongoing study enrolling MVD patients undergoing primary PCI and randomly allocates patients to receive either FFR-guided PCI or culprit vessel-only PCI in the setting of STEMI [22]. This trial may help to define the role of FFR in STEMI patients with MVD.