Despite the dramatic improvements of revascularization therapies occurring in the past decades, a relevant percentage of patients treated with percutaneous coronary intervention (PCI) still develops stent failure due to neo-atherosclerosis (NA). This histopathological phenomenon following stent implantation represents the substrate for late in-stent restenosis (ISR) and late stent thrombosis (ST), with a significant impact on patient’s long-term clinical outcomes. This appears even more remarkable in the setting of drug-eluting stent implantation, where the substantial delay in vascular healing because of the released anti-proliferative agents might increase the occurrence of this complication. Since the underlying pathophysiological mechanisms of NA diverge from native atherosclerosis and early ISR, intra-coronary imaging techniques are crucial for its early detection, providing a proper in vivo assessment of both neo-intimal plaque composition and peri-strut structures. Furthermore, different strategies for NA prevention and treatment have been proposed, including tailored pharmacological therapies as well as specific invasive tools. Considering the increasing population undergoing PCI with drug-eluting stents (DES), this review aims to provide an updated overview of the most recent evidence regarding NA, discussing pathophysiology, contemporary intravascular imaging techniques, and well-established and experimental invasive and pharmacological treatment strategies.

The critical role of the coronary microvascular compartment and its invasive functional assessment has become apparent in light of the significant proportion of patients presenting signs and symptoms of myocardial ischemia, despite the absence of epicardial disease, or after the adequate treatment of it. However, coronary microvascular dysfunction (CMD) represents a diagnostic challenge because of the small dimensions of the coronary microvasculature, which prevents direct angiographic visualization. Several diagnostic tools are now available for the invasive assessment of the coronary microvascular function, which, in association with the physiological indices used to investigate the epicardial department, may provide a comprehensive evaluation of the coronary circulation as a whole. Recent evidence suggests that the physiology-guided management of CMD, although apparently costly and time-consuming, may offer a net clinical benefit in terms of symptom improvement among patients with angina and ischemic heart disease. However, despite the results of several observational studies, the prognostic effect of the physiology-driven management of CMD within this population is currently a matter of debate, and therefore represents an unmet clinical need that urgently deserves further investigation.

Simple visual estimation of coronary angiography is limited by several factors that can hinder the proper classification of coronary lesions. Fractional flow reserve (FFR) is the most widely used tool to perform a physiological evaluation of coronary stenoses. Compared to isolated angiography, FFR has been demonstrated to be more effective in selecting those lesions associated with myocardial ischemia and, accordingly, impaired outcomes. At the same time, deferring coronary intervention in those lesions that do not show ischemic FFR values has proven safe and not associated with adverse events. Despite a major randomized clinical trial (RCT) and several non-randomized studies showing that FFR-guided revascularization could be superior to isolated angiography in improving clinical outcomes, subsequent RCTs have reported conflicting results. In this review, we summarize the principles behind FFR and the data currently available in the literature, highlighting the main differences between randomized and non-randomized studies that investigated this topic.