We read the article by Niccoli et al, regarding the influence of microvascular resistance on fractional flow reserve (FFR) measurements in patients with stable coronary artery disease versus patients with non–ST-segment elevation myocardial infarction. The investigators should be complimented for their effort to outline the influence of global cardiac microvascular dysfunction on the physiological assessment of nonculprit lesions in the setting of acute coronary syndromes (ACS), a quandary that yet remains unsolved.

Recently, we have similarly described the obscuring influence of microcirculatory disease on FFR-guided identification of stenosis severity, in which the coronary flow reserve (CFR) was applied as a combined measure of stenosis and microcirculatory disturbance. Because the change in microvascular resistance from baseline to hyperemia dictates CFR, the discordance between FFR and the hyperemic stenosis resistance index (HSR) described by the investigators conceivably represents the same phenomenon as the FFR/CFR discordance previously reported by our groups. On this basis, the frequency of FFR/HSR discordance in patients with non–ST-segment elevation myocardial infarction reported by the investigators—threefold of that generally observed in patients with stable coronary artery disease—leading to a substantial underestimation of physiological severity by FFR is worrisome, particularly in an era in which we are increasingly confronted with patients with ACS and in which FFR use in ACS is expanding while clinical evidence in this setting remains scarce and nonconclusive.

The investigators’ approach of using HSR as a standard of reference, an index less sensitive to changes in the microcirculation but which requires the concomitant assessment of coronary flow in addition to coronary pressure, is physiologically sound and significantly advances our understanding of functional stenosis severity in complex clinical settings such as ACS. Their findings add to the growing body of evidence suggesting that its susceptibility toward microcirculatory dysfunction might well be an important limitation of FFR-only diagnostic strategies and that a significant proportion of vessels exhibiting “negative” FFR values are not healthy but present with disturbed hemodynamics beyond the FFR domain that have pertinent clinical sequelae. However, because our current understanding of the complex pathophysiology of coronary artery disease largely relies on FFR and CFR, it would be of high value if the investigators provide the discordance of FFR with CFR particularly in their non–ST-segment elevation myocardial infarction cohort. These additional data would simplify comparisons with existing literature and would substantially enrich cumulating evidence suggesting that the combined assessment of the coronary circulation by means of both pressure and flow provides a more comprehensive yet required intracoronary evaluation of ischemic heart disease, particularly in clinical settings where microcirculatory dysfunction is to be expected.