Prognostic Implications of Fractional Flow Reserve and Coronary Flow Reserve After Drug-Eluting Stent Implantation

Abstract

Background: Fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) provides prognostic information, but limited data are available regarding prognostication using post-PCI coronary flow reserve (CFR). In this study we aimed to assess the prognostic value of post-procedural FFR and CFR for target vessel failure (TVF) after PCI.

Methods and Results: This lesion-based post-hoc pooled analysis of previously published registry data involved 466 patients with chronic coronary syndrome with single-vessel disease who underwent pre- and post-PCI FFR and CFR measurements, and were followed-up to determine the predictors of TVF. The prognostic value of post-PCI CFR and FFR was compared with that of FFR or CFR alone. Post-PCI FFR/CFR discordant results were observed in 42.5%, and 10.3% of patients had documented TVF. Receiver-operating characteristic curve analysis revealed that the optimal cutoff values of post-PCI FFR and CFR to predict the occurrence of TVF were 0.85 and 2.26, respectively. Significant differences in TVF were detected according to post-PCI FFR (≤0.85 vs. >0.85, P=0.007) and post-PCI CFR (<2.26 vs. ≥2.26, P<0.001). Post-PCI FFR ≤0.85 and post-PCI CFR <2.26 were independent prognostic predictors.

Conclusions: After PCI completion, discordant results between FFR and CFR were not uncommon. Post-PCI CFR categorization showed incremental prognostic value for predicting TVF independent of post-PCI FFR risk stratification.

Fractional flow reserve (FFR) is a reliable metric for assessing the severity of functional stenosis in epicardial coronary artery disease based on the results of randomized clinical trials.¹ FFR supports correct decision making of revascularization for intermediate stenosis and provides improved clinical outcomes.^2,3 In addition, recent studies suggest that post-percutaneous coronary intervention (PCI) FFR has prognostic value, with an inverse relationship to worse outcomes.⁴ Coronary flow reserve (CFR) is another well-validated index that can assess coronary flow characteristics and impairment. CFR also provides prognostication in a variety of patient subsets.⁵ CFR reflects the integrated coronary disease burden, including epicardial functional stenosis severity and microvascular dysfunction.^5,6 Of interest, disagreements between pre-PCI FFR and CFR are commonly observed and are recognized as the results of different pathophysiological mechanisms between epicardial and microvascular function.^7–9 Given that PCI is optimally performed without significant complications, post-PCI CFR may better represent coronary flow characteristics or impairment because CFR is less susceptible to the effects of epicardial stenosis, leading to better prognostication by CFR than FFR. To test this hypothesis, we evaluated the prognostic implication of post-PCI FFR and CFR in patients who underwent successful newer-generation drug-eluting stent (DES) implantation.

Methods

The data that support the findings of this study are available from the corresponding author on reasonable request.

Study Design and Patient Population

This study analyzed individual participant data pooled from 4 recent studies, which have been previously reported (Supplementary Figure 1).^10–13 Briefly, the patients were enrolled in the institutional PCI physiology registry at Tsuchiura Kyodo General Hospital, which evaluated the clinical implications of physiological assessments. Patients for the present study were identified and enrolled on the following inclusion criteria: age >20 years, detection of an identifiable, single culprit lesion (>50% stenosis by visual assessment) located in the proximal portion of a native coronary artery, symptomatic ischemia or objective ischemia according to noninvasive stress testing and/or FFR measurements, pre- and post-PCI FFR and CFR measurements immediately after uncomplicated PCI, and a follow-up period >1 year. Exclusion criteria included angiographically significant left main disease, renal insufficiency with baseline serum creatinine level >1.5 mg/dL, cardiomyopathy, congestive heart failure, and periprocedural myocardial infarction as defined by the Fourth Universal Definition of Myocardial Infarction¹⁴ based on a blood sample taken an average of 20–24 h after PCI, symptoms, and other objective findings after PCI completion, which have been reported to affect prognosis.¹⁵ Patients with minor cardiac troponin elevation, without other manifestation required by the above-mentioned definition, were included in the final analysis. The study was conducted in compliance with the institutional ethics committee guidelines and received approval (TKGH #2022FY89). The present study also complied with the Declaration of Helsinki for investigation in human beings, and all patients provided written informed consent before the institutional registry enrollment for future investigations. Prompt guideline-directed medical therapy was initiated for all patients before PCI.

Pre- and Post-PCI Physiological Measurements and Analysis

Coronary angiography and PCI procedures were performed using standard techniques. Coronary angiograms were analyzed quantitatively using a CMS-MEDIS system (Medis Medical Imaging Systems, Leiden, The Netherlands). The PCI techniques and use of imaging devices, such as intravascular ultrasound or optical coherence tomography, were at the interventionalists’ discretion. The type of implanted stent was also selected from the newer-generation DES by the operator. Pre- and post-PCI FFR and CFR measurements were performed, as previously described.^16–19 Briefly, coronary physiological measurements were obtained by a 6F guiding catheter via the radial approach using a pressure temperature sensor guidewire and analyzing systems (PressureWire X Guidewire, Abbott Laboratories, IL, USA; RadiAnalyzer, St. Jude Medical, St. Paul, MN, USA; and CoroFlow, Coroventis Research AB, Uppsala, Sweden). After administration of a bolus of intracoronary nitrate (200 μg), the wire sensor was advanced and positioned as far distally in the target vessel as practical. Hyperemia was induced by infusion of adenosine or adenosine triphosphate into an antecubital vein at a rate of 140 μg/kg/min or 160 μg/kg/min, respectively. FFR was calculated as the ratio of distal coronary pressure to proximal pressure under stable hyperemia. CFR was obtained using the thermodilution method as the ratio of resting transit time divided by hyperemic transit time. The index of microcirculatory resistance at rest (IMR_rest) was calculated as the distal coronary pressure multiplied by the mean transit time at rest. IMR under hyperemia (IMR_hyper) was calculated as the distal coronary pressure multiplied by the mean transit time under hyperemia. Microvascular resistance reserve (MRR) was calculated as (CFR/FFR) × aortic pressure at rest/aortic pressure under hyperemia.²⁰ The resistive resistance ratio (RRR) was calculated as IMR_rest/IMR_hyper.²¹ Post-PCI physiological measurements were performed after post-stenting high-pressure dilatation using a noncompliant balloon and/or additional stenting guided by physiological evaluation and intravascular imaging at the operators’ discretion, and when the operator considered PCI was completed.

Definition of Clinical Outcomes and Data Collection

The primary clinical outcome of this study was TVF, defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization (TVR) during the follow-up period (median 4.2 years, range 2.5–5.0 years). Clinically driven remote TVR, >3 months after PCI, was defined as repeat PCI in the presence of angiographically significant stenosis with ≥1 of the following:(1) positive noninvasive myocardial perfusion imaging test results; (2) recurrence of anginal symptoms; and (3) positive FFR values. Clinical endpoints were determined by blinded assessment of hospital records or via telephone interviews. Time to event was calculated as the period between PCI and the first occurrence of TVF. Patients without TVF were censored at the time of the last follow-up.

Statistical Analysis

Statistical analyses were performed using R version 4.0.3 (The R Foundation for Statistical Computing, Vienna, Austria) and SPSS version 25.0 (IBM Corp., Armonk, NY, USA). Categorical data are expressed as numbers and percentages and compared by the chi-square or Fisher’s exact test. Continuous data are expressed as median (interquartile range) and analyzed using the Mann-Whitney U test. The analysis of variance was used for variables with non-normal and normal distributions to evaluate the difference between groups with and without TVF, respectively. Correlations between variables were assessed using Pearson’s correlation analysis. Receiver-operating characteristic curves (ROC) were analyzed to assess the best cutoff values of physiological and baseline characteristics for predicting TVF. The optimal cutoff value was determined by the Youden index. The cumulative incidence of clinical outcomes was estimated by Kaplan-Meier and compared using log-rank tests. All analyses were based on per-patient analysis, and a representative vessel was defined as a target vessel because all patients in this study had single-vessel disease. A Cox proportional hazards regression model was used to identify independent predictors of TVF. The covariates with P<0.05 in the univariate analysis were included in the multivariate analysis. A collinearity index was used for checking linear combinations among covariates, and the Akaike information criterion was used to avoid overfitting. A two-sided P<0.05 was considered statistically significant.

Results

Baseline Patient Characteristics, Angiographical, and Physiological Findings

A total of 466 patients with chronic coronary syndrome who underwent uncomplicated PCI with newer-generation DES and pre- and post-PCI FFR and CFR measurements were studied in the final analysis (Supplementary Figure 1). Baseline clinical, angiographic, and physiological data according to the presence or absence of TVF are presented in Table 1. The median age of the study population was 68.0 (61–73) years, and 83.3% were male. The median pre-PCI FFR and CFR were 0.70 and 2.00, respectively. The median post-PCI FFR and CFR were 0.87 and 2.74, respectively. FFR increased in all patients, in contrast to the decrease in post-PCI CFR by 30.3%. The distribution of pre- and post-PCI FFR are shown in Supplementary Figure 2, and the distribution of pre- and post-PCI CFR are presented in Supplementary Figure 3. A weak but significant correlation between post-PCI CFR and post-PCI high-sensitivity troponin I was found (r=−0.165, 95% confidence interval (CI) −0.252, −0.076, P<0.001) The prevalence of post-PCI FFR ≤0.80 was 13.7%, and of post-PCI CFR <2.0 and <2.5 were 28.3% and 44.2%, respectively. Discordant results between FFR and CFR were observed in 35.6% of patients before PCI and in 42.5% after PCI completion, using the thresholds of FFR=0.80 and CFR=2.5.

Table 1.

Patients’ Clinical, Angiographic, and Physiologic Characteristics

	Overall (n=466)	Patients with TVF (n=48)	Patients without TVF (n=418)	P value
Baseline characteristics
Age (years)	68 (61–73)	70 (62–78)	68 (61–73)	0.135
Male	388 (83)	40 (83)	348 (83)	1.000
Hypertension	328 (70)	32 (7)	296 (71)	0.617
Diabetes mellitus	187 (40)	21 (44)	166 (40)	0.642
LDL-cholesterol	94 (77–118)	100 (85–117)	94 (76–118)	0.456
Current smoker	102 (22)	6 (13)	96 (23)	0.138
eGFR	67 (55–81)	71 (40–87)	67 (56–79)	0.956
LVEF	64 (57–68)	61 (56–68)	64 (57–68)	0.353
SYNTAX score (pre-PCI, per pts)	9 (5–11)	10 (7–13)	8 (5–11)	0.031
Angiographic data (Pre-PCI)
Target vessel (RCA/LAD/LCX)	95/313/58 (20.4/67.2/12.4)	11/34/3 (24/70/7)	84/279/55 (20/67/13)	0.694/0.729/0.391
Lesion length	12.9 (9.2–18.6)	11.8 (8.5–17.3)	13.1 (9.3–19.0)	0.172
Diameter stenosis	59.7 (52.5–67.2)	58.2 (51.0–66.8)	59.8 (52.8–67.2)	0.386
Reference diameter	2.6 (2.2–3.0)	2.5 (2.2–2.9)	2.6 (2.3–3.0)	0.367
Minimum lumen diameter (mm)	1.0 (0.8–1.3)	1.0 (0.9–1.3)	1.1 (0.8–1.3)	0.981
Physiologic indices
Pre-PCI FFR	0.70 (0.63–0.75)	0.69 (0.59–0.74)	0.71 (0.63–0.75)	0.056
Pre-PCI CFR	2.00 (1.32–3.00)	1.76 (1.20–2.57)	2.00 (1.32–3.04)	0.108
Pre-PCI IMRhyper	22.0 (15.1–35.6)	21.1 (13.8–35.7)	22.1 (15.3–35.6)	0.532
Pre-PCI MRR	3.33 (2.36–4.64)	3.37 (2.30–4.27)	3.33 (2.36–4.72)	0.425
Pre-PCI RRR	2.84 (1.87–4.11)	2.66 (1.73–3.52)	2.84 (1.89–4.21)	0.218
Pre-PCI resting transit time (s)	0.84 (0.56–1.24)	0.73 (0.56–1.13)	0.87 (0.56–1.24)	0.242
Pre-PCI hyperemic transit time	0.39 (0.26–0.66)	0.40 (0.29–0.58)	0.39 (0.26–0.67)	0.739
Post-PCI FFR	0.87 (0.83–0.92)	0.85 (0.81–0.90)	0.87 (0.83–0.92)	0.018
Post-PCI CFR	2.74 (1.83–4.21)	1.94 (1.42–2.98)	2.85 (1.95–4.42)	<0.001
Post-PCI IMRhyper	17.2 (12.2–24.9)	17.0 (12.5–29.4)	17.2 (12.2–24.1)	0.666
Post-PCI MRR	3.68 (2.52–5.74)	2.75 (2.00–3.87)	3.83 (2.58–5.83)	0.002
Post-PCI RRR	3.51 (2.36–5.43)	2.54 (1.89–3.74)	3.71 (2.44–5.59)	<0.001
Post-PCI resting transit time	0.73 (0.48–1.04)	0.65 (0.38–0.93)	0.75 (0.48–1.07)	0.068
Post-PCI hyperemic transit time	0.24 (0.16–0.36)	0.29 (0.17–0.45)	0.23 (0.16–0.34)	0.272

Data are presented as n (%) or median (interquartile range). CFR, coronary flow reserve; FFR, fractional flow reserve; IMR_hyper, index of microcirculatory resistance at hyperemia; LAD, left anterior descending artery; LCX, left circumflex artery; LDL, low density lipoprotein; LVEF, left ventricular ejection fraction; MRR, microvascular resistance reserve; PCI, percutaneous coronary intervention; RCA, right coronary artery; RRR, resistive resistance ratio; TVF, target vessel failure.

Clinical Outcomes at Long-Term Follow-up

At a median follow-up of 4.2 years, the cumulative rate of TVF was 10.3% (48/466) (Table 2).

Table 2.

Incidence of Major Adverse Cardiac Events According to Post-PCI FFR and CFR Values

	Overall (n=466)	Post-PCI FFR ≤0.85, Post-PCI CFR <2.26 (n=76)	Post-PCI FFR ≤0.85, Post-PCI CFR ≥2.26 (n=98)	Post-PCI FFR >0.85, Post-PCI CFR <2.26 (n=100)	Post-PCI FFR >0.85, Post-PCI CFR ≥2.26 (n=192)	P value
Event
Cardiac death	15 (3.2)	4 (5.3)	2 (2.0)	5 (5.0)	4 (2.1)	0.394
TVMI	9 (1.9)	6 (7.9)	1 (1.0)	1 (1.0)	1 (0.5)	0.003
Composite outcome (cardiac death + TVMI)	24 (5.2)	10 (13.2)	3 (3.1)	6 (6.0)	5 (2.6)	0.007
TVR	24 (5.2)	9 (11.8)	5 (5.1)	6 (6.0)	4 (2.1)	0.013
TVF (cardiac death + TVMI + TVR)	48 (10.3)	18 (23.7)	8 (8.2)	12 (12)	9 (4.7)	<0.001

Data are presented as n (%). TVMI, target vessel myocardial infarction; TVR, target vessel revascularization. Other abbreviations as in Table 1.

Determinants of the Incidence of TVF

Patients with TVF showed significantly higher pre-PCI SYNTAX scores. Pre- and post-PCI FFR and CFR tended to be lower in patients with vs. without TVF (Table 1). Post-PCI FFR and CFR were significantly lower in patients with vs. without TVF, whereas the pre- and post-PCI IMR_hyper were similar between groups. Baseline mean transit time tended to be shorter in patients with TVF, but the hyperemic mean transit time was similar between groups. ROC analysis revealed the optimal cutoff values of post-PCI FFR and post-PCI CFR to predict TVF were 0.85 (area under the curve 0.61, sensitivity 0.56, specificity 0.65, positive predictive value 0.16, negative predictive value 0.93) and 2.26 (area under the curve 0.65, sensitivity 0.67, specificity 0.65, positive predictive value 0.18, negative predictive value 0.94), respectively. Event-free survival was significantly worse in patients stratified by the cutoff values of post-PCI FFR ≤0.85 and post-PCI CFR <2.26 (Figure 1A,B). Multivariable Cox proportional hazard analysis revealed that post-PCI CFR and post-PCI FFR were independently predictive of TVF (Table 3). Kaplan-Meier analysis indicated that both post-PCI FFR ≤0.85 and post-PCI CFR ≤2.26 were significantly associated with higher incidence of TVF (Figure 2). We added the analyses using previously validated physiological cutoff values. The results of the analyses using post-PCI FFR=0.86^22,23 and post-PCI CFR=2.5 as cutoff values indicated similar findings to those shown in Figure 3.

Figure 1.

Survival from TVF during 5-year follow-up according to the best cutoff post-PCI FFR and CFR values determined by ROC curve analysis. (A) Optimal post-PCI FFR value for TVF was 0.85 and the log-rank test revealed patients with lower post-PCI FFR values were associated with poor prognosis (P=0.002). (B) Optimal post-PCI CFR value for TVF was 2.26 and the log-rank test revealed patients with lower post-PCI CFR values were associated with poor prognosis (P<0.001). CFR, coronary flow reserve; FFR, fractional flow reserve; PCI, percutaneous coronary intervention; ROC, receiver-operating characteristic curve; TVF, target vessel failure.

Table 3.

Univariate and Multivariate Cox Regression Analysis to Predict TVF

	Univariate analysis			Multivariate analysis 1			Multivariate analysis 2
	HR	95% CI	P value	HR	95% CI	P value	HR	95% CI	P value
Age	1.03	1.00–1.06	0.070
Male	0.94	0.44–2.00	0.868
Diabetes mellitus	1.19	0.67–2.10	0.554
Current smoker	0.49	0.21–1.15	0.101
LVEF	0.99	0.97–1.02	0.518
Pre-PCI FFR	0.08	0.01–0.96	0.046
Post-PCI FFR	0.003	0.0001–0.13	0.003	0.005	0.0001–0.23	0.006	0.004	0.0001–0.21	0.006
Pre-PCI CFR	0.77	0.59–0.99	0.043
Post-PCI CFR	0.80	0.67–0.96	0.016	0.82	0.69–0.98	0.028
Pre-PCI IMRhyper	1.00	0.98–1.01	0.716
Post-PCI IMRhyper	1.01	0.99–1.02	0.297
Pre-PCI resting transit time	0.78	0.44–1.38	0.389
Post-PCI resting transit time	0.47	0.23–0.99	0.047				0.52	0.24–1.11	0.092
Pre-PCI hyperemic transit time	1.01	0.66–1.53	0.973
Post-PCI hyperemic transit time	0.99	0.77–1.27	0.932

CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.

Figure 2.

Kaplan-Meier analysis of TVF-free survival in 2 groups classified according to FFR and CFR values. Kaplan-Meier curves show survival from TVF comparing patients classified according to post-PCI FFR and CFR values based on receiver-operating characteristic curve analyses. CFR, coronary flow reserve; FFR, fractional flow reserve; PCI, percutaneous coronary intervention; TVF, target vessel failure.

Figure 3.

Kaplan-Meier analysis of survival from TVF during 5-year follow-up in the groups stratified by post-PCI cutoff values of FFR=0.86 and CFR=2.5. CFR, coronary flow reserve; FFR, fractional flow reserve; PCI, percutaneous coronary intervention; TVF, target vessel failure.

Discussion

In this study, we evaluated the prognostic significance of post-PCI physiological measurements, particularly focused on CFR, to predict TVF after uncomplicated PCI with newer-generation DES. The important findings of this study were: (1) both post-PCI FFR and CFR provided prognostic information after uncomplicated PCI using newer-generation DES; (2) the best cutoff values of post-PCI FFR and CFR to predict TVF were 0.85 and 2.26, respectively; and (3) compared with post-PCI CFR, post-PCI FFR provided limited reclassification ability for TVF. Among patients with lower post-PCI FFR, only patients with lower post-PCI CFR showed a significantly higher risk of TVF than those with higher post-PCI FFR.

FFR and CFR are both evidence-based physiological measures for myocardial ischemia and guide revascularization decision making.^1,5,24,25 A recent study suggested that post-PCI FFR showed prognostic value with an inverse relationship to adverse outcomes.⁴ FFR values allow assessment of the severity of epicardial functional stenosis. CFR provides an integrated measurement of coronary circulation including the epicardial coronary artery, diffuse atherosclerotic burden, and microvascular function. CFR measurement has been recommended as a diagnostic tool for microvascular disease by the European Society of Cardiology guidelines.²⁶ A recent meta-analysis has reported that low CFR confers an increased risk across a broad range of disease subgroups including both established epicardial coronary artery disease and microvascular dysfunction.⁵ Our results are in line with those findings and further extend the clinical significance of CFR to patients with successful revascularization by PCI. Of note, IMR_hyper, a metric representing microvascular function, was not predictive of TVF in this study. Although the exact mechanisms remain undetermined, this observation could be explained by the small number of TVF cases or the specific measurement time window (immediately after PCI completion) in our study. A recent study also reported no difference in prognosis between patients with low CFR and high IMR_hyper and those with low CFR and low IMR_hyper.²⁷ The clinical significance of IMR_hyper has been repeatedly reported in patients with STEMI, but no definitive results have been observed in patients treated with elective and successful PCI when patients with significant periprocedural myocardial injury were excluded. IMR_hyper may not be sensitive for TVF in patients with successful PCI without significant periprocedural myocardial injury.

In the majority of the patients in the present study, imaging-guided PCI (intravascular ultrasound or optical coherence tomography) was performed, although the use of imaging device was at the operator’s discretion. Optimal imaging-guided PCI might have resulted in less stent under-expansion and malapposition in this study, leading to less impact of post-PCI FFR on outcomes, as compared with post-PCI CFR, which might provide prognostication by integrated assessment of diffuse disease and microvascular dysfunction after epicardial lesion modification by PCI.

The post-PCI resting transit time was significantly shorter in patients with TVF as compared with that in those without TVF, whereas the post-PCI hyperemic transit time was not significantly different between these groups. Also, post-PCI MRR and RRR were significantly lower in patients with TVF compared with patients without TVF. This observation suggests that decreased resting microvascular resistance might be a signature of disturbed autoregulation at rest in patients with an increased risk of TVF, Kato et al²⁸ reported that resting coronary sinus flow measured by phase-contrast cine cardiovascular magnetic resonance may be a useful parameter for risk stratification. They argued that coronary flow was already elevated at rest, whereas the reserve capacity for pharmacological stress was decreased in patients with worse outcomes. A previous study using positron emission tomography²⁹ revealed that the resting flow significantly decreased, but peak flow did not significantly change, in patients with successful revascularization. After successful intervention, the microvasculature may return to near baseline levels. These findings suggest that resting coronary blood flow provides important prognostication after successful PCI, although resting transit time did not remain a significant predictor for TVF in the multivariate model (Table 3). This hypothesis is merely speculative and further validation should be performed in future studies.

Study Limitations

This was a single-center retrospective analysis of registered patients’ data included in published studies and thus is observational in nature, and has inherent limitations. First, rigorous exclusion criteria and the protocol for inclusion limited the number of study patients and may have resulted in a certain level of further selection bias. We could not exclude the possibility that some of the clinically indicated patients were excluded at the attending physicians’ discretion. Second, although this study included a relatively large population with pre- and post-PCI physiological data by wire-based invasively measured indices, the present sample size and the number of TVF cases still limited the confidence of the overall statistical analyses, as well as extensive subgroup analyses. Third, periprocedural myocardial infarction may be associated with coronary flow impairment. Although cases meeting the Fourth Universal Definition¹⁴ with clinical manifestations had already been excluded and we had no cases of post-PCI slow flow phenomenon, cases of minor troponin elevation might affect the results. Fourth, residual hyperemia and/or unstable hemodynamics immediately after PCI might affect the results, possibly leading to underestimation of post-PCI CFR.

Conclusions

Post-PCI CFR <2.5 occurred in 44.2% of patients treated after uncomplicated newer-generation DES implantation, and discordant results between FFR and CFR were not uncommon. Among patients with lower post-PCI FFR, only patients with lower post-PCI CFR showed significantly higher risk of TVF than those with higher post-PCI FFR. Thus, both measurement of post-PCI FFR and CFR showed incremental prognostic value compared with post-PCI FFR or CFR alone.

Conflict of Interest Statement / Funding Sources

None.

IRB Information

The present study was approved by Tsuchiura Kyodo General Hospital Ethics Committee. Reference number: #2022FY89.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-23-0293

References

• 1.   De Bruyne B, Fearon WF, Pijls NHJ, Barbato E, Tonino P, Piroth Z, et al. Fractional flow reserve-guided PCI for stable coronary artery disease. N Engl J Med 2014; 371: 1208–1217, doi:10.1056/nejmoa1408758.
• 2.   Xaplanteris P, Fournier S, Pijls NHJ, Fearon WF, Barbato E, Tonino PAL, et al. Five-year outcomes with pci guided by fractional flow reserve. N Engl J Med 2018; 379: 250–259, doi:10.1056/nejmoa1803538.
• 3.   Tonino PAL, De Bruyne B, Pijls NHJ, Siebert U, Ikeno F, van’t Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009; 360: 213–224, doi:10.1056/NEJMoa0807611.
• 4.   Johnson NP, Tóth GG, Lai D, Zhu H, Açar G, Agostoni P, et al. Prognostic value of fractional flow reserve: Linking physiologic severity to clinical outcomes. J Am Coll Cardiol 2014; 64: 1641–1654, doi:10.1016/j.jacc.2014.07.973.
• 5.   Kelshiker MA, Seligman H, Howard JP, Rahman H, Foley M, Nowbar AN, et al. Coronary flow reserve and cardiovascular outcomes: A systematic review and meta-analysis. Eur Heart J 2022; 43: 1582–1593, doi:10.1093/eurheartj/ehab775.
• 6.   Van De Hoef TP, Siebes M, Spaan JAE, Piek JJ. Fundamentals in clinical coronary physiology: Why coronary flow is more important than coronary pressure. Eur Heart J 2015; 36: 3312–3319, doi:10.1093/eurheartj/ehv235.
• 7.   Koo BK, Erglis A, Doh JH, Daniels DV, Jegere S, Kim HS, et al. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms: Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol 2011; 58: 1989–1997, doi:10.1016/j.jacc.2011.06.066.
• 8.   Lee JM, Jung JH, Hwang D, Park J, Fan Y, Na SH, et al. Coronary flow reserve and microcirculatory resistance in patients with intermediate coronary stenosis. J Am Coll Cardiol 2016; 67: 1158–1169, doi:10.1016/j.jacc.2015.12.053.
• 9.   Ahn SG, Suh J, Hung OY, Lee HS, Bouchi YH, Zeng W, et al. Discordance between fractional flow reserve and coronary flow reserve: Insights from intracoronary imaging and physiological assessment. JACC Cardiovasc Interv 2017; 10: 999–1007, doi:10.1016/j.jcin.2017.03.006.
• 10.   Hwang D, Lee JM, Yang S, Chang M, Zhang J, Choi KH, et al. Role of post-stent physiological assessment in a risk prediction model after coronary stent implantation. JACC Cardiovasc Interv 2020; 13: 1639–1650, doi:10.1016/j.jcin.2020.04.041.
• 11.   Misawa T, Kanaji Y, Sugiyama T, Hoshino M, Yamaguchi M, Hada M, et al. Effect of percutaneous coronary intervention on global hemodynamics and the prevalence of residual microvascular dysfunction. Microcirculation 2022; 29: 1–14, doi:10.1111/micc.12745.
• 12.   Yamaguchi M, Hoshino M, Sugiyama T, Kanaji Y, Nogami K, Nagamine T, et al. Preprocedural transthoracic Doppler echocardiography to identify stenosis associated with increased coronary flow after revascularisation. Sci Rep 2022; 12: 1–10, doi:10.1038/s41598-022-05683-0.
• 13.   Hada M, Hoshino M, Wakasa N, Sugiyama T, Kanaji Y, Yamaguchi M, et al. Early effect of percutaneous coronary intervention of non-left anterior descending artery on coronary flow velocity reserve of left anterior descending artery assessed by transthoracic Doppler echocardiography. PLoS One 2021; 16: 1–12, doi:10.1371/journal.pone.0256161.
• 14.   Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation 2018; 138: e618–e651, doi:10.1161/CIR.0000000000000617.
• 15.   Silvain J, Zeitouni M, Paradies V, Zheng HL, Ndrepepa G, Cavallini C, et al. Cardiac procedural myocardial injury, infarction, and mortality in patients undergoing elective percutaneous coronary intervention: A pooled analysis of patient-level data. Eur Heart J 2021; 42: 323–334, doi:10.1093/eurheartj/ehaa885.
• 16.   Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek J Koolen JJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996; 334: 1703–1708, doi:10.1056/NEJM199606273342604.
• 17.   Fearon WF, Balsam LB, Farouque HMO, Robbins RC, Fitzgerald PJ, Yock PG, et al. Novel index for invasively assessing the coronary microcirculation. Circulation 2003; 107: 3129–3132, doi:10.1161/01.CIR.0000080700.98607.D1.
• 18.   De Bruyne B, Pijls NH, Smith L, Wievegg M, Heyndrickx GR. Coronary thermodilution to assess flow reserve: Experimental validation. Circulation 2001; 104: 2003–2006, doi:10.1161/hc4201.099223.
• 19.   Matsuda J, Murai T, Kanaji Y, Usui E, Araki M, Niida T, et al. Prevalence and clinical significance of discordant changes in fractional and coronary flow reserve after elective percutaneous coronary intervention. J Am Heart Assoc 2016; 5: 1–14, doi:10.1161/JAHA.116.004400.
• 20.   De Bruyne B, Pijls NHJ, Gallinoro E, Candreva A, Fournier S, Keulards DCJ, et al. Microvascular resistance reserve for assessment of coronary microvascular function: JACC Technology Corner. J Am Coll Cardiol 2021; 78: 1541–1549, doi:10.1016/j.jacc.2021.08.017.
• 21.   Layland J, Carrick D, McEntegart M, Ahmed N, Payne A, McClure J, et al. Vasodilatory capacity of the coronary microcirculation is preserved in selected patients with non-ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2013; 6: 231–236, doi:10.1161/CIRCINTERVENTIONS.112.000180.
• 22.   Agarwal SK, Kasula S, Hacioglu Y, Ahmed Z, Uretsky BF, Hakeem A. Utilizing post-intervention fractional flow reserve to optimize acute results and the relationship to long-term outcomes. JACC Cardiovasc Interv 2016; 9: 1022–1031, doi:10.1016/j.jcin.2016.01.046.
• 23.   Hoshino M, Kanaji Y, Hamaya R, Kanno Y, Hada M, Yamaguchi M, et al. Prognostic value of post-intervention fractional flow reserve after intravascular ultrasound-guided second-generation drug-eluting coronary stenting. EuroIntervention 2019; 15: E779–E789, doi:10.4244/EIJ-D-18-01032.
• 24.   Pijls NHJ, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van’t Veer M, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER study. J Am Coll Cardiol 2007; 49: 2105–2111, doi:10.1016/j.jacc.2007.01.087.
• 25.   De Bruyne B, Pijls NHJ, Kalesan B, Barbato E, Tonino PAL, Piroth Z, et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012; 367: 991–1001, doi:10.1056/nejmoa1205361.
• 26.   Neumann FJ, Sechtem U, Banning AP, Bonaros N, Bueno H, Bugiardini R, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41: 407–477, doi:10.1093/eurheartj/ehz425.
• 27.   Boerhout CKM, de Waard GA, Lee JM, Meija-Renteria H, Lee SH, Jung JH, et al. Prognostic value of structural and functional coronary microvascular dysfunction in patients with non-obstructive coronary artery disease: From the multicentre international ILIAS registry. EuroIntervention 2022; 18: 719–728, doi:10.4244/EIJ-D-22-00043.
• 28.   Kato S, Fukui K, Kodama S, Azuma M, Nakayama N, Iwasawa T, et al. Prognostic value of resting coronary sinus flow determined by phase-contrast cine cardiovascular magnetic resonance in patients with known or suspected coronary artery disease. J Cardiovasc Magn Reson 2021; 23: 1–12, doi:10.1186/s12968-021-00790-9.
• 29.   Lichtenberg R. Importance of resting coronary blood flow as the main determinant of coronary flow reserve. J Am Coll Cardiol 2017; 70: 2839, doi:10.1016/j.jacc.2017.08.078.