Association of coronary inflammation with plaque vulnerability and fractional flow reserve in coronary artery disease.

BACKGROUND: The fat attenuation index (FAI) measured using coronary computed tomography angiography (CCTA) enables the direct evaluation of pericoronary adipose tissue composition and vascular inflammation. We aimed to investigate the association of fractional flow reserve (FFR) and plaque vulnerability with coronary inflammation. METHODS: Patients with suspected coronary artery disease (CAD) who underwent CCTA and invasive FFR measurements within 90-day were included. A cloud-based medical device, CaRi-Heart, serves as a surrogate tool for evaluating coronary inflammation based on FAI by analyzing CCTA images. The correlations between CCTA-defined plaque characteristics, invasive coronary angiographic and physiologic assessments, and CaRi-Heart risk were analyzed. The primary endpoint was the patient-oriented composite outcome (POCO) consisting of all-cause death, any myocardial infarction, and any revascularization. RESULTS: A total of 564 patients (median age 67.0 years; 75.4 â€‹% men) were included. There were no significant differences in quantitative and qualitative plaque characteristics or FFR between the high- and low-CaRi-Heart risk groups (i.e., ≥5 â€‹% and <5 â€‹%). During the median follow-up of 3.2 years [1.13-4.73 years], CaRi-Heart risk ≥5 â€‹% was associated with a significantly higher rate of POCO compared to CaRi-Heart risk <5 â€‹% (0.9 â€‹% vs. 10.1 â€‹%, P â€‹= â€‹0.037). The CaRi-Heart risk was an independent predictor of POCO as a continuous (adjusted HR 1.016, 95 â€‹% CI 1.005-0.027, P â€‹= â€‹0.004) and categorical variable (CaRi-Heart risk ≥5 â€‹%, adjusted HR 2.949, 95 â€‹% CI 1.182-7.360, P â€‹= â€‹0.021), regardless of high-risk plaque characteristics and FFR. CONCLUSION: Coronary inflammation risk assessed using CaRi-Heart risk provides independent prognostic information regardless of plaque vulnerability and physiologic stenosis in patients with CAD.

Impact of hyperaemic stenosis resistance on long-term outcomes of stable angina in the ILIAS Registry.

BACKGROUND: The hyperaemic stenosis resistance (HSR) index was introduced to provide a more comprehensive indicator of the haemodynamic severity of a coronary lesion. HSR combines both the pressure drop across a lesion and the flow through it. As such, HSR overcomes the limitations of the more traditional fractional flow reserve (FFR) or coronary flow reserve (CFR) indices. AIMS: We aimed to identify the diagnostic and prognostic value of HSR and evaluate the clinical implications. METHODS: Patients with chronic coronary syndromes (CCS) and obstructive coronary artery disease were selected from the multicentre ILIAS Registry. For this study, only patients with combined Doppler flow and pressure measurements were included. RESULTS: A total of 853 patients with 1,107 vessels were included. HSR more accurately identified the presence of inducible ischaemia compared to FFR and CFR (area under the curve 0.71 vs 0.66 and 0.62, respectively; p<0.005 for both). An abnormal HSR measurement was an independent and important predictor of target vessel failure at 5-year follow-up (hazard ratio 3.80, 95% confidence interval: 2.12-6.73; p<0.005). In vessels deferred from revascularisation, HSR seems to identify more accurately those vessels that may benefit from revascularisation rather than FFR and/or CFR. CONCLUSIONS: The present study affirms the theoretical advantages of the HSR index for the detection of ischaemia-Âinducing coronary lesions in a large CCS population. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry], ClinicalTrials.gov: NCT04485234).

Basal Coronary Microvascular Resistance Predicting Death and Heart Failure in Patients Without Functional Coronary Stenosis.

BACKGROUND: Abnormal coronary microcirculation is linked to poor patient prognosis, so the aim of the present study was to assess the prognostic relevance of basal microvascular resistance (b-IMR) in patients without functional coronary stenosis. METHODS AND RESULTS: Analyses of 226 patients who underwent intracoronary physiological assessment of the left anterior descending artery included primary endpoints of all-cause death and heart failure, as well as secondary endpoints of cardiovascular death and atherosclerotic vascular events. During a median follow-up of 2 years, there were 12 (5.3%) primary and 21 (9.3 %) secondary endpoints. The optimal b-IMR cutoff for the primary endpoints was 47.1 U. Kaplan-Meier curve analysis demonstrated worse event-free survival of the primary endpoints in patients with a b-IMR below the cutoff (χ2=21.178, P<0.001). b-IMR was not significantly associated with the secondary endpoints (P=0.35). A low coronary flow reserve (CFR; <2.5) had prognostic value for both endpoints (primary endpoints: χ2=11.401, P=0.001; secondary endpoints: (χ2=6.015; P=0.014), and high hyperemic microvascular resistance (≥25) was associated only with the secondary endpoints (χ2=4.420; P=0.036). Incorporating b-IMR into a clinical model that included CFR improved the Net Reclassification Index and Integrated Discrimination Improvement for predicting the primary endpoints (P<0.001 and P=0.034, respectively). CONCLUSIONS: b-IMR may be a specific marker of the risk of death and heart failure in patients without functional coronary stenosis.

Angiographic Findings and Post-Percutaneous Coronary Intervention Fractional Flow Reserve.

Importance: The associations between angiographic findings and post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) and their clinical relevance according to residual functional disease burden have not been thoroughly investigated. Objectives: To evaluate the association of angiographic and physiologic parameters according to residual functional disease burden after drug-eluting stent implantation. Design, Setting, and Participants: This cohort study population was from the International Post-PCI FFR registry, which incorporated 4 registries from Korea, China, and Japan. Patients who underwent angiographically successful second-generation drug-eluting stent implantation and post-PCI FFR measurement were included in the analysis. The patients were divided into 3 groups according to the residual disease burden (post-PCI FFR ≤0.80 [residual ischemia], 0.81-0.86 [suboptimal], and >0.86 [optimal]). The data were collected from August 23, 2018, to June 11, 2019, and the current analysis was performed from January 11, 2022, to October 7, 2023. Exposures: Angiographic parameters and post-PCI FFR. Main Outcomes and Measures: The primary outcome was target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction, and target vessel revascularization (TVR) at 2 years. Results: In this cohort of 2147 patients, the mean (SD) age was 64.3 (10.0) years, and 1644 patients (76.6%) were men. Based on the post-PCI physiologic status, 269 patients (12.5%) had residual ischemia, 551 (25.7%) had suboptimal results, and 1327 (61.8%) had optimal results. Angiographic parameters had poor correlations with post-PCI FFR (r < 0.20). Post-PCI FFR was isolated from all angiographic parameters in the unsupervised hierarchical cluster analysis. Post-PCI FFR was associated with the occurrence of TVF (adjusted hazard ratio [AHR] per post-PCI FFR 0.01 increase, 0.94 [95% CI, 0.92-0.97]; P < .001), but angiographic parameters were not. The residual ischemia group had a significantly higher rate of TVF than the suboptimal group (AHR, 1.75 [95% CI, 1.08-2.83]; P = .02) and the optimal group (AHR, 2.94 [95% CI, 1.82-4.73]; P < .001). The TVR in the residual ischemia group was predominantly associated with TVR in the nonstented segment (14 [53.8%]), unlike the other 2 groups (3 [10.0%] in the suboptimal group and 13 [30.2%] in the optimal group). Conclusions and Relevance: In this cohort study of the International Post-PCI FFR registry, a low degree of associations were observed between angiographic and physiologic parameters after PCI. Post-PCI FFR, unlike angiographic parameters, was associated with clinical events and the distribution of clinical events. The current study supports the use of post-PCI FFR as a procedural quality metric and further prospective study is warranted.

Prognostic Value of Microvascular Resistance Reserve Measured Immediately After PCI in Stable Coronary Artery Disease.

BACKGROUND: Microvascular resistance reserve (MRR) has been proposed as a specific metric to quantify coronary microvascular function. The long-term prognostic value of MRR measured in stable patients immediately after percutaneous coronary intervention (PCI) is unknown. This study sought to determine the prognostic value of MRR measured immediately after PCI in patients with stable coronary artery disease. METHODS: This study included 502 patients with stable coronary artery disease who underwent elective PCI and coronary physiological measurements, including pressure and flow estimation using a bolus thermodilution method after PCI. MRR was calculated as coronary flow reserve divided by fractional flow reserve times the ratio of mean aortic pressure at rest to that at maximal hyperemia induced by hyperemic agents. An abnormal MRR was defined as ≤2.5. Major adverse cardiac events (MACEs) were defined as a composite of all-cause mortality, any myocardial infarction, and target-vessel revascularization. RESULTS: During a median follow-up of 3.4 years, the cumulative MACE rate was significantly higher in the abnormal MRR group (12.5 versus 8.3 per 100 patient-years; hazard ratio 1.53 [95% CI, 1.10-2.11]; P<0.001). A higher all-cause mortality rate primarily drove this difference. On multivariable analysis, a higher MRR value was independently associated with lower MACE and lower mortality. When comparing 4 subgroups according to MRR and the index of microcirculatory resistance, patients with both abnormal MRR and index of microcirculatory resistance (≥25) had the highest MACE rate. CONCLUSIONS: An abnormal MRR measured immediately after PCI in patients with stable coronary artery disease is an independent predictor of MACE, particularly all-cause mortality.

Impact of sex on the assessment of the microvascular resistance reserve.

BACKGROUND: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women. AIM: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes. METHODS: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men. RESULTS: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men. CONCLUSION: The MRR seems to be equally applicable in both women and men with stable coronary artery disease.

Prognostic Implications of Individual and Combinations of Resting and Hyperemic Coronary Pressure and Flow Parameters.

Background: Coronary pressure- and flow-derived parameters have prognostic value. Objectives: This study aims to investigate the individual and combined prognostic relevance of pressure and flow parameters reflecting resting and hyperemic conditions. Methods: A total of 1,971 vessels deferred from revascularization after invasive pressure and flow assessment were included from the international multicenter registry. Abnormal resting pressure and flow were defined as distal coronary pressure/aortic pressure ≤0.92 and high resting flow (1/resting mean transit time >2.4 or resting average peak flow >22.7 cm/s), and abnormal hyperemic pressure and flow as fractional flow reserve ≤0.80 and low hyperemic flow (1/hyperemic mean transit time <2.2 or hyperemic average peak flow <25.0 cm/s), respectively. The clinical endpoint was target vessel failure (TVF), myocardial infarction (MI), or cardiac death at 5 years. Results: The mean % diameter stenosis was 46.8% ± 16.5%. Abnormal pressure and flow were independent predictors of TVF and cardiac death/MI (all P < 0.05). The risk of 5-year TVF or MI/cardiac death increased proportionally with neither, either, and both abnormal resting pressure and flow, and abnormal hyperemic pressure and flow (all P for trend < 0.001). Abnormal resting pressure and flow were associated with a higher rate of TVF or MI/cardiac death in vessels with normal fractional flow reserve; this association was similar for abnormal hyperemic pressure and flow in vessels with normal resting distal coronary pressure/aortic pressure (all P < 0.05). Conclusions: Abnormal resting and hyperemic pressure and flow were independent prognostic predictors. The abnormal flow had an additive prognostic value for pressure in both resting and hyperemic conditions with complementary prognostic between resting and hyperemic parameters.

Prognostic implications of unrecognized myocardial infarction and periprocedural myocardial injury on cardiac magnetic resonance imaging in patients with chronic coronary syndrome.

This study sought to evaluate the prognostic implications of the presence of preprocedural unrecognized myocardial infarction (UMI) and periprocedural myocardial injury (PMI) evaluated by delayed gadolinium enhancement cardiac magnetic resonance (DE-CMR) in patients with chronic coronary syndrome (CCS) undergoing elective percutaneous coronary intervention (PCI). We enrolled 250 CCS patients scheduled for elective PCI. UMI was defined as the presence of late gadolinium enhancement (LGE) detected by pre-PCI CMR in the region without medical history of revascularization and/or MI. Periprocedural new occurrence or increased volume of LGE in the target territory detected by post-PCI CMR (PPL) were used to assess PMI. In the final analysis of 235 patients, UMI and PPL were detected in 43 patients (18.3%) and 45 patients (19.1%), respectively. During follow-up for a median of 2.2 years, major adverse cardiac events (MACE) occurred in 31 (13.2%) patients. On multivariable analysis, UMI and PPL remained as significant predictors of MACE after adjusting confounding factors (HR 4.62, 95% CI 2.24-9.54, P < 0.001, HR 2.33, 95% CI 1.11-4.91, P = 0.026). In patients with CCS who underwent elective PCI, UMI and PPL were independent predictors of worse outcomes. UMI and PPL on DE-CMR might provide additional potential insight for the risk stratification of patients undergoing elective PCI.

Changes in microvascular resistance following percutaneous coronary intervention - From the ILIAS global registry.

BACKGROUND: Microvascular resistance (MR) has prognostic value in acute and chronic coronary syndromes following percutaneous coronary intervention (PCI), however anatomic and physiologic determinants of the relative changes of MR and its association to target vessel failure (TVF) has not been investigated previously. This study aims to evaluate the association between changes in MR and TVF. METHODS: This is a sub-study of the Inclusive Invasive Physiological Assessment in Angina Syndromes (ILIAS) registry which is a global multi-centre initiative pooling lesion-level coronary pressure and flow data. RESULTS: Paired pre-post PCI haemodynamic data were available in n = 295 vessels out of n = 828 PCI treated patients and of these paired data on MR was present in n = 155 vessels. Vessels were divided according to increase vs. decrease % in microvascular resistance following PCI (ΔMR % ≤ 0 vs. ΔMR > 0%). Decreased microvascular resistance ΔMR % ≤ 0 occurred in vessels with lower pre-PCI fractional flow reserve (0.67 ± 0.15 vs. 0.72 ± 0.09 p = 0.051), coronary flow reserve (1.9 ± 0.8 vs. 2.6 ± 1.8 p < 0.0001) and higher hyperemic microvascular resistance (2.76 ± 1.3 vs. 1.62 ± 0.74 p = 0.001) and index of microvascular resistance (24.4 IQ (13.8) vs. 15. 8 IQ (13.2) p = 0.004). There was no difference in angiographic parameters between ΔMR % ≤ 0 vs. ΔMR > 0%. In a cox regression model ΔMR % > 0 was associated with increased rate of TVF (hazard ratio 95% CI 3.6 [1.2; 10.3] p = 0.018). CONCLUSION: Increased MR post-PCI was associated with lesions of less severe hemodynamic influence at baseline and higher rates of TVF at follow-up.

Sex differences in prevalence and outcomes of the different endotypes of chronic coronary syndrome in symptomatic patients undergoing invasive coronary angiography: Insights from the global ILIAS invasive coronary physiology registry.

BACKGROUND AND AIMS: The management of chronic coronary syndrome (CCS) is informed by studies predominantly including men. This study investigated the relationship between patients sex and different endotypes of CCS, including sex-specific clinical outcomes. METHODS: In patients with CCS undergoing coronary angiography, invasive Fractional Flow Reserve (FFR) and Coronary Flow Reserve (CFR) were measured. Patients were stratified into groups: 1) obstructive coronary artery disease (oCAD) (FFR≤0.80, no revascularization), 2) undergoing revascularization, 3) non-obstructive coronary artery disease with coronary microvascular dysfunction (CMD) (FFR>0.80, CFR≤2.5), and 4) non-obstructive coronary artery disease without CMD (FFR>0.80 and CFR>2.5). RESULTS: 1836 patients (2335 vessels) were included, comprising 1359 (74.0%) men and 477 (26.0%) women. oCAD was present in 14.1% and was significantly less prevalent in women than in men (10.3% vs 15.5%, respectively p < 0.01). Revascularization was present in 30.9% and was similarly prevalent in women and men (28.2% vs. 31.9%, respectively p = 0.13). CMD was present in 24.2% and was significantly more prevalent in women than men (28.6% vs 22.6%, respectively p < 0.01). Normal invasive measurements were found in 564 patients (33.0% women vs 30.0% men, p = 0.23). Male sex was associated with an increased risk of target vessel failure compared to women (HR.1.89, 95% CI 1.12-3.18, p = 0.018), regardless of CCS-endotype. CONCLUSIONS: Sex differences exist in the prevalence and outcomes of different endotypes of CCS in symptomatic patients undergoing invasive coronary angiography. In particular, oCAD (and subsequent revascularization) were more prevalent in men. Conversely, CMD was more prevalent in women. Overall, men experienced a worse cardiovascular outcome compared to women, independent of any specific CCS endotype.

Microvascular resistance reserve: diagnostic and prognostic performance in the ILIAS registry.

AIMS: The microvascular resistance reserve (MRR) was introduced as a means to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of administration of potent vasodilators on aortic pressure. This study aimed to evaluate the diagnostic and prognostic performance of MRR. METHODS AND RESULTS: A total of 1481 patients with stable symptoms and a clinical indication for coronary angiography were included from the global ILIAS Registry. MRR was derived as a function of the coronary flow reserve (CFR) divided by the fractional flow reserve (FFR) and corrected for driving pressure. The median MRR was 2.97 [Q1-Q3: 2.32-3.86] and the overall relationship between MRR and CFR was good [correlation coefficient (Rs) = 0.88, P < 0.005]. The difference between CFR and MRR increased with decreasing FFR [coefficient of determination (R2) = 0.34; Coef.-2.88, 95% confidence interval (CI): -3.05--2.73; P < 0.005]. MRR was independently associated with major adverse cardiac events (MACE) at 5-year follow-up [hazard ratio (HR) 0.78; 95% CI 0.63-0.95; P = 0.024] and with target vessel failure (TVF) at 5-year follow-up (HR 0.83; 95% CI 0.76-0.97; P = 0.047). The optimal cut-off value of MRR was 3.0. Based on this cut-off value, only abnormal MRR was significantly associated with MACE and TVF at 5-year follow-up in vessels with functionally significant epicardial disease (FFR <0.75). CONCLUSION: MRR seems a robust indicator of the microvascular vasodilator reserve capacity. Moreover, in line with its theoretical background, this study suggests a diagnostic advantage of MRR over other indices of vasodilatory capacity in patients with hemodynamically significant epicardial coronary artery disease.

Relationship of OCT-defined plaque characteristics with CCTA-derived coronary inflammation and CMR-derived global coronary flow reserve in patients with acute coronary syndrome.

BACKGROUND: The relationship of layered plaque detected by optical coherence tomography (OCT) with coronary inflammation and coronary flow reserve (CFR) remains elusive. We aimed to investigate the association of OCT-defined layered plaque with pericoronary adipose tissue (PCAT) inflammation assessed by coronary computed tomography angiography (CCTA) and global (G)-CFR assessed by cardiac magnetic resonance imaging (CMR) in patients with acute coronary syndrome (ACS). METHODS: We retrospectively investigated 88 patients with first ACS who underwent preprocedural CCTA, OCT imaging of the culprit lesion prior to primary/urgent percutaneous coronary intervention (PCI), and postprocedural CMR. All patients were divided into two groups according to the presence and absence of OCT-defined layered plaque at the culprit lesion. Coronary inflammation was assessed by the mean value of PCAT attenuation (-190 to -30 HU) of the three major coronary vessels. G-CFR was obtained by quantifying absolute coronary sinus flow at rest and during maximum hyperemia. CCTA and CMR findings were compared between the groups. RESULTS: In a total of 88 patients, layered plaque was detected in 51 patients (58.0%). The patients with layered plaque had higher three-vessel-PCAT attenuation value (-68.58 ± 6.41 vs. -71.60 ± 5.21 HU, P = 0.021) and culprit vessel-PCAT attenuation value (-67.69 ± 7.76 vs. -72.07 ± 6.57 HU, P = 0.007) than those with non-layered plaque. The patients with layered plaque had lower G-CFR value (median, 2.26 [interquartile range, 1.78, 2.89] vs. 3.06 [2.41, 3.90], P = 0.003) than those with non-layered plaque. CONCLUSIONS: The presence of OCT-defined layered plaque at the culprit lesion was associated with high PCAT attenuation and low G-CFR after primary/urgent PCI in patients with ACS. OCT assessment of culprit plaque morphology and detection of layered plaque may help identify increased pericoronary inflammation and impaired CFR, potentially providing the risk stratification in patients with ACS and residual microvascular dysfunction after PCI.

Abnormal physiological findings after FFR-based revascularisation deferral are associated with worse prognosis in women.

The prognostic value of abnormal resting Pd/Pa and coronary flow reserve (CFR) after fractional flow reserve (FFR)-guided revascularisation deferral according to sex remains unknown. From the ILIAS Registry composed of 20 hospitals globally from 7 countries, patients with deferred lesions following FFR assessment (FFR > 0.8) were included. (NCT04485234) The primary clinical endpoint was target vessel failure (TVF) at 2-years follow-up. We included 1392 patients with 1759 vessels (n = 564 women, 31.9%). Although resting Pd/Pa was similar between the sexes (p = 0.116), women had lower CFR than men (2.5 [2.0-3.2] vs. 2.7 [2.1-3.5]; p = 0.004). During a 2-year follow-up period, TVF events occurred in 56 vessels (3.2%). The risk of 2-year TVF was significantly higher in women with low versus high resting Pd/Pa (HR: 9.79; p < 0.001), whereas this trend was not seen in men. (Sex: P-value for interaction = 0.022) Furthermore, resting Pd/Pa provided an incremental prognostic value for 2-year TVF over CFR assessment only in women. After FFR-based revascularisation deferral, low resting Pd/Pa is associated with higher risk of TVF in women, but not in men. The predictive value of Pd/Pa increases when stratified according to CFR values, with significantly high TVF rates in women in whom both indices are concordantly abnormal.Clinical Trial Registration: Inclusive Invasive Physiological Assessment in Angina Syndromes Registry (ILIAS Registry), NCT04485234.

Combined use of hyperemic and non-hyperemic pressure ratios for revascularization decision-making: From the ILIAS registry.

OBJECTIVE: The aim of this study is to evaluate the diagnostic and prognostic value of non-hyperaemic Pd/Pa and to determine its additional value when combined with the gold standard hyperaemic pressure ratio (FFR) to guide revascularization. METHODS: In a large, multi-center, retrospective registry, we included a total of 2141 patients with a clinical indication for coronary angiography providing physiological data in 2726 vessels. A classification was made based on the FFR (cut-off value: 0.80) and non-hyperaemic Pd/Pa (cut-off value: 0.92) values and the primary outcome was target-vessel failure (TVF) at 5-year follow-up. RESULTS: Mean age was 63 ± 10.0 and 75% of the study population were men. Regression analysis showed an overall good correlation between FFR and non-hyperaemic Pd/Pa (r = 0.73, p < 0.005) and discordance was present in 17% of the vessels. Resting Pd/Pa was independently associated with TVF at 5-year follow-up (HR 0.08, 95%CI: 0.02-0.27; p < 0.005). The risk for TVF was the lowest in vessles with concordant normal pressure ratio's, with the highest risk in vessels with any abnormal pressure ratio in which revascularization was deferred. In these vessels, there was no difference in risk for TVF between the discordant and concordant abnormal values. CONCLUSION: Abnormal pressure ratios in both non-hyperemic and hyperemic conditions portend important prognostic value. Combined application of FFR and non-hyperemic Pd/Pa efficiently identifies those vessels with concordant normal resting and hyperemic pressure ratios of which long-term clinical outcomes are excellent. These data lead to hypothesize that the decision to defer revascularization should potentially be based on combined non-hyperemic and hyperemic pressure ratios. CLINICAL TRIAL REGISTRATION: Inclusive Invasive Physiological Assessment in Angina Syndromes Registry (ILIAS Registry), NCT04485234.

Differences in Plaque Characteristics and Myocardial Mass: Implications for Physiological Significance.

Background: The mechanism of the fractional flow reserve (FFR) difference according to sex has not been clearly understood. Objectives: This study sought to evaluate sex differences in coronary stenosis, plaque characteristics, and left ventricular (LV) mass and their implications for physiological significance. Methods: This was a post hoc analysis of a pooled population of multicenter, international prospective cohorts. Patients (166 women and 489 men) underwent coronary computed tomography angiography (CCTA) within 90 days before invasive FFR measurements were included. The minimal lumen area, percent of plaque burden, whole vessel plaque volume by composition, high-risk plaque characteristics, and LV mass were analyzed from CCTA images. Results: Among 1,188 vessels analyzed, the FFR value was higher in women than that in men (0.85 ± 0.13 vs 0.82 ± 0.14; P = 0.001) despite a similar percentage of diameter stenosis between the sexes (45.9% ± 18.9% vs 46.1% ± 17.7%; P = 0.920). The composition of fibrofatty plaque + necrotic core (13.1% ± 16.9% vs 21.2% ± 19.9%; P < 0.001) and frequencies of low attenuation plaque (12.7% vs 24.5%; P < 0.001) and positive remodeling (33.8% vs 45.5%; P = 0.001) were lower in women than in men. Vessel, plaque, and lumen volumes were significantly smaller in women than that in men (all P < 0.001); however, no sex difference was observed in any of these parameters after adjustment for LV mass (all P > 0.10). Sex was not an independent predictor of the FFR value after adjustment for stenosis severity, plaque characteristics, and LV mass. Conclusions: Higher FFR values for the same stenosis severity in women can be explained by fewer high-risk plaque characteristics and smaller myocardial mass in women than that in men. (CCTA-FFR Registry for Risk Prediction; NCT04037163).

Impact of the downstream myocardial mass on values of coronary microvascular resistance.

The assessment of hyperemic microvascular resistance (HMR) may be dependent on the assessment location in the coronary artery and the amount of partial myocardial mass (PMM) distal to the assessment locations. The aim of this study was to investigate the differences in HMR values between the distal and proximal sites in the same coronary arteries as well as the relationship between HMR and PMM. Twenty-nine vessels from 26 patients who had undergone intracoronary physiological assessments including Doppler flow velocity at the distal third part and the proximal third part in the same vessels were assessed. The mean values of HMR and PMM at the distal sites were 2.08 ± 0.75 mmHg/cm/sec and 22.2 ± 10.4 g, respectively. At the proximal sites, the values of HMR and PMM were 1.19 ± 0.33 mmHg/cm/sec and 59.9 ± 18.3 g, respectively. All HMR values at the distal sites were significantly higher than those at the proximal sites (p < 0.001). Smaller PMM at the distal sites was significantly associated with higher HMR (r = -0.544, p = 0.002) and was the strongest factor affecting the HMR values (p = 0.009), while this relationship was not observed at the proximal sites (r = -0.262, p = 0.17). The impact of PMM on HMR was diminished at assessment locations where PMM was greater than 35 g. In conclusion, a small amount of downstream myocardial mass could be related to high HMR values. The assessment location around the proximal coronary artery with over 35 g of myocardium would be appropriate to assess HMR because it minimizes the influence of the assessment location.

Prognostic Impact of Coronary Flow Reserve in Patients With Reduced Left Ventricular Ejection Fraction.

Background Intracoronary physiologic indexes such as coronary flow reserve (CFR) and left ventricular ejection fraction (LVEF) have been regarded as prognostic indicators in patients with coronary artery disease. The current study evaluated the association between intracoronary physiologic indexes and LVEF and their differential prognostic implications in patients with coronary artery disease. Methods and Results A total of 1889 patients with 2492 vessels with available CFR and LVEF were selected from an international multicenter prospective registry. Baseline physiologic indexes were measured by thermodilution or Doppler methods and LVEF was recorded at the index procedure. The primary outcome was target vessel failure, which was a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization over 5 years of follow-up. Patients with reduced LVEF <50% (162 patients [8.6%], 202 vessels [8.1%]) showed a similar degree of epicardial coronary artery disease but lower CFR values than those with preserved LVEF (2.4±1.2 versus 2.7±1.2, P<0.001), mainly driven by the increased resting coronary flow. Conversely, hyperemic coronary flow, fractional flow reserve, and the degree of microvascular dysfunction were similar between the 2 groups. Reduced CFR (≤2.0) was seen in 613 patients (32.5%) with 771 vessels (30.9%). Reduced CFR was an independent predictor for target vessel failure (hazard ratio, 2.081 [95% CI, 1.385-3.126], P<0.001), regardless of LVEF. Conclusions CFR was lower in patients with reduced LVEF because of increased resting coronary flow. Patients with reduced CFR showed a significantly higher risk of target vessel failure than did those with preserved CFR, regardless of LVEF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Prognostic value of structural and functional coronary microvascular dysfunction in patients with non-obstructive coronary artery disease; from the multicentre international ILIAS registry.

BACKGROUND: Coronary microvascular dysfunction (CMD) is an important contributor to angina syndromes. Recently, two distinct endotypes were identified using combined assessment of coronary flow reserve (CFR) and minimal microvascular resistance (MR), termed structural and functional CMD. AIMS: We aimed to assess the relevance of the combined assessment of CFR and MR in patients with angina and no obstructive coronary arteries. METHODS: Patients with chronic coronary syndromes (CCS) and non-obstructive coronary artery disease (fractional flow reserve [FFR] ≥0.80) were selected (N=1,102). Functional CMD was defined as abnormal CFR in combination with normal MR and structural CMD as abnormal CFR with abnormal MR. Clinical endpoints were the incidence of major adverse cardiac events (MACE) and target vessel failure (TVF) at 5-year follow-up. RESULTS: Abnormal CFR was associated with an increased risk of MACE and TVF at 5-year follow-up. Microvascular resistance parameters were not associated with MACE or TVF at 5-year follow-up. The risk of MACE and TVF at 5-year follow-up was similarly increased for patients with structural or functional CMD compared with patients with normal microvascular function. There were no differences between both endotypes (p=0.88 for MACE, and p=0.55 for TVF). CONCLUSIONS: Coronary microvascular dysfunction, identified by an impaired CFR, was unequivocally associated with increased MACE and TVF rates over a 5-year follow-up period. In contrast, impaired MR was not associated with 5-year adverse clinical events. Moreover, there was no significant difference in the risk of MACE and TVF between a low CFR accompanied by pathologically increased MR (structural CMD) or not (functional CMD). CLINICALTRIALS: gov: NCT04485234.

Differential Impact of Coronary Revascularization on Long-Term Clinical Outcome According to Coronary Flow Characteristics: Analysis of the International ILIAS Registry.

BACKGROUND: Coronary pressure indices such as fractional flow reserve are the standard for guiding elective revascularization. However, considering additional coronary flow parameters could further individualize and optimize the decision on revascularization. We aimed to investigate the potentially differential prognostic associations of elective percutaneous coronary intervention (PCI) according to coronary flow properties represented by coronary flow reserve (CFR), coronary flow capacity (CFC), and baseline CFC (bCFC). METHODS: From the ILIAS Registry (Inclusive Invasive Physiological Assessment in Angina Syndromes) composed of 16 hospitals globally from 7 countries, patients with obstructive coronary artery disease who underwent invasive coronary physiological assessment were included (N=2370 vessels). We assessed effect measure modifications of the association of PCI and 5-year target vessel failure according to CFR, CFC, and bCFC either assessed by Doppler-technique or thermodilution-method. RESULTS: The mean age of the population was 63.3 years, and there were 1322 (73.6%) males. Median fractional flow reserve was 0.85, and PCI was performed in 600 (25.3%) vessels. Reduced CFR, CFC, and abnormal bCFC were defined in 988 (41.7%), 542 (22.9%), and 600 (25.3%) vessels, respectively. Significant effect measure modifications were observed by CFC either in odds ratio (P=0.0018), additive (P=0.029), and hazard ratio scale (P=0.0002). The absolute risk of 5-year target-vessel failure was higher if treated by PCI in vessels with normal CFC by 1.8 (-1.7 to 5.3) percent, while that was lower by -5.9 (-12 to -0.1) percent in those with reduced CFC. CFR and bCFC were not significant effect modifiers in any scales. Similar associations were observed in per-patient analyses, whereas the findings were less robust. CONCLUSIONS: We observed qualitative effect measure modification of PCI and 5-year clinical outcomes according to CFC status in additive scale. CFR and bCFC were not robust effect modifiers. Therefore, CFC could be potentially used to optimize the patient selection for elective PCI treatment combined with fractional flow reserve.