Currently, physiological assessment of coronary artery stenosis has become an important standard for decision making in percutaneous coronary intervention (PCI) (1–3). Indeed, it has been shown that up to 20% of patients with successful revascularization as evidenced by angiographic findings still suffer from subsequent adverse coronary events (4–6). Recently studies showed that these patients were likely to have residual or diffuse disease and/or stented segment, due to condition of anatomical revascularization, but not functional revascularization (4–6). Previous studies have shown that the relative increase and final fractional flow reserve (FFR) were reliable parameters for evaluating coronary functional revascularization and may confer prognostic efficacy for patients after PCI (4). Furthermore, recent studies suggest that quantitative flow ratio (QFR), a highly consistent parameter, with FFR indicating functional stenosis of coronary arteries, may also be a validated prognostic index after PCI (5–7). However, the current understanding of coronary artery disease (CAD) indicates that the progression of disease is not only determined by the anatomy or physiology of the coronary lesion alone but is also influenced by systemic factors, such as inflammation and autonomic dysfunction (8–10). In this regard, an integrated approach incorporating parameters of functional revascularization, such as QFR, may confer better prognostic implications in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) after PCI.

Our previous study revealed a significant association between parameters of heart rate variability (HRV), inflammation, and coronary artery physiology based on QFR (11). Specifically, the 24-hour deceleration capacity (DC 24h), a Holter-derived indicator of parasympathetic activity, has also been suggested as a strong predictor of mortality for patients with myocardial infarction (12). Physiologically, automatic nervous system (ANS) carries the essential function in the formation of the heart and critical regulator of vascular development during cardiovascular development (13). Moreover, pathologically, autonomic function, particularly the activity of the vagus nerve, has been correlated with systemic inflammation (13, 14) and vascular tension (15). Therefore, we hypothesized that an integrated approach incorporating the relative increase and final coronary physiology with DC 24h may improve the prognostic efficacy of current models based on clinical variables in NSTE-ACS patients who underwent complete and successful PCI.

In this retrospective cohort study, we included patients with NSTEMI who underwent complete revascularization with PCI and who had adequate information on pre- and post-procedural QFR and Holter-derived HRV data. We found that lower post-PCI QFR (≤0.88), smaller % QFR increase (≤23%), and lower DC 24h (≤2.42) at baseline were all independent predictors for the risk of MACCEs during follow up. Moreover, incorporation of relative increase and final QFR combined with DC may improve the predictive efficacy of existing models based on clinical variables for MACCEs in patients with NSTE-ACS.

Risk stratification remains challenging in patients with NSTE-ACS, particularly for those after PCI (22, 23). Although multiple large observational studies have suggested a potential role of post-PCI FFR as a predictor for adverse events in the future, the optimal cutoff remains unknown and may be variable according to the different patient populations included (24–26). More importantly, FFR can only be obtained via invasive procedures with the assistance of an additional pressure guidewire and the use of adenosine, which significantly limits its use in clinical practice (27). In comparison, QFR, as a noninvasive angiographically-derived FFR measurement is more applicable in clinical settings. Previous studies have confirmed that QFR is highly consistent with FFR and could be used as a validated indicator of functional coronary stenosis (28, 29). A previous study that included 602 patients who underwent complete and successful revascularization with a mean follow-up of 629 days showed that lower values of QFR might be a risk factor for the increased incidence of vessel-oriented adverse events (5). Alternatively, a retrospective study that included 771 vessels with post-PCI QFR suggested a predictive efficacy and independent correlation between post-PCI QFR and long-term vessel-related clinical outcomes in state of the PCI practice (6). Our results, which showed a possible prognostic role of post-PCI QFR for MACCEs in NSTE-ACS patients after PCI, is consistent with the findings of these studies. Nevertheless, neither pre-PCI FFR nor post-PCI QFR alone could fully discriminate the degree of relative contribution of stented and non-stented segment disease burden. Therefore, in order to discriminate the relative contribution of each component of coronary artery lesions, previous studies showed that the percentage of increase of the FFR value before and after PCI has also been independently and significantly correlated with poor long-term prognosis (4), and integration of the concept of percent FFR increase and post-PCI FFR value allowed a better discrimination of high-risk patients after complete and successful PCI (4). In our study, significant associations were observed between percent QFR increase and post-PCI QFR with MACCEs after PCI. However, all these findings are focused on the local interaction between stents and targeted lesions. It could be hypothesized that incorporating parameters that indicated the systematic burden of CAD, such as systematic inflammation and autonomic dysregulation, may further improve the prognostic efficacy of models based on current clinical variables.

Previous studies showed that the ANS is directly involved in cardiovascular development (30–32). Previous ex vivo studies showed that the imbalance of ANS may be an early marker of acute cardiovascular disease events (33–36). In addition, ANS is shown to have key effects on vasoconstriction and vasodilation, which influence vessel physiology (13, 37). Alternatively, the mechanism underlying persistently lowered shear stress appears to be the formation of vulnerable plaque (38). However, there remains scant evidence from literature to indicate the potential association between ANS, hydrodynamic shear forces and the vulnerability of coronary plaque. Our results therefore support the hypothesis that imbalance in cardiac ANS may affect local hydrodynamic shear forces and lead to vulnerability of coronary lesions, and may therefore play a key role in the pathogenesis of acute coronary events. Interestingly, our previous studies showed a significant interaction between ANS and immune inflammation on coronary physiology evaluated by QFR (11, 39). These findings support the incorporation of ANS imbalance for risk stratification of patients with CAD. Notably, measurement of DC is refractory to external factors and premature beat, which could therefore objectively reflect the modulation of heart rate by the ANS and quantitatively analyze vagal nerve activity compared with HRV (12, 19, 20).

Our overall findings are in line with a previous prospective study including 2,111 patients with acute myocardial infarction, which demonstrated that impaired DC was a strong predictor of mortality after myocardial infarction, and the predictive efficacy of DC was even stronger than the conventional measures of HRV (12). In this study, we found that incorporation of relative increase and final QFR combined with DC is associated with stronger predictive efficacy of existing models based on clinical variables for MACCEs in patients with NSTE-ACS. Briefly, acute myocardial ischemia might impair cardiac vagal nerve and induce the production of inflammatory cytokines (14), and subsequently lead to endothelial dysfunction, lipid dysregulation, vascular smooth muscle cell activation, macrophage infiltration, thus accelerating coronary artery plaque rupture of residual lesions and effects on the burden of coronary heart disease (40, 41). Although the exact molecular pathways remain to be determined, the results of our study support the incorporation of relative increase and final QFR combined with DC to improve the predictive efficacy of existing models based on clinical variables for MACCEs in patients with NSTE-ACS.

Due to the retrospective nature of the study, possible selection bias may overestimate the predictive value of DC 24h, post-PCI QFR or %QFR increase for MACCEs, particularly with the small sample size. In order to validate the predictive value of these parameters, prospective cohort studies with larger samples sizes will be required. Also, we evaluated the DC only once, on patient admission. It is unclear whether DC monitored for multiple times would be more valid as a predictor of MACCEs. In addition, it should be mentioned that the post-PCI QFR or %QFR increase has not yet been validated against post-PCI FFR or %FFR increase. Studies are warranted for further confirmation and optimization of the software and protocols for QFR measurement. Moreover, our findings might not be generalizable to other institutions due to the differences between offline and online analyses. Nevertheless, the concept regarding that “higher is better” for DC 24hr, post-PCI QFR or %QFR increase when undergoing complete revascularization with PCI is beyond doubt. In addition, intravascular ultrasound or optical coherence tomography may be considered to provide detailed assessment of culprit lesions and non-culprit lesions of the patients, and it might also improve the prognostic efficacy if parameters related to these examinations are incorporated. Due to methodological reasons, DC could not be applied to ACS patients with atrial fibrillation or other non-sinus rhythms. Finally, no inflammatory markers were analyzed because we did not measure these markers in the included patients.

In conclusion, the results of our study showed that the relative increase and final coronary physiology combined with DC may improve the predictive efficacy of existing models based on clinical variables for MACCEs in NSTE-ACS patients who underwent complete and successful PCI. These results support the incorporation of relative increase and final coronary physiology combined with DC for risk stratification in NSTE-ACS patients, although validation will require larger prospective studies.

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to LY, lileiyu@whu.edu.cn or HJ, hong-jiang@whu.edu.cn.

The studies involving human participants were reviewed and approved by the Ethics Committee of Renmin Hospital of Wuhan University (No. WDRY2021-K078). The Ethics Committee waived the requirement of written informed consent for participation.

LY and HJ: substantial contributions to conception and design, data acquisition, and data analysis and interpretation. JW, CL, FG, ZZ, HC, LZ, YW, HZ, ZL, SD, JS, QD, and SX: drafting the article or critically revising it for important intellectual content. JW, CL, and FG: final approval of the version to be published and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (81871486, 81970287, and 82100530).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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