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).

Ten-Year Outcome of Recanalization or Medical Therapy for Concomitant Chronic Total Occlusion After Myocardial Infarction.

BACKGROUND: The EXPLORE (Evaluating Xience and Left Ventricular Function in PCI on Occlusions After STEMI) trial was the first and only randomized trial investigating chronic total occlusion (CTO) percutaneous coronary intervention (PCI) early after primary PCI for ST-segment-elevation myocardial infarction, compared with medical therapy for the CTO. We performed a 10-year follow-up of EXPLORE to investigate long-term safety and clinical impact of CTO PCI after ST-segment-elevation myocardial infarction, compared with no-CTO PCI. METHODS AND RESULTS: In EXPLORE, 302 patients post-ST-segment-elevation myocardial infarction with concurrent CTO were randomized to CTO PCI within ≈1 week or no-CTO PCI. We performed an extended clinical follow-up for the primary end point of major adverse cardiac events, consisting of cardiovascular death, coronary artery bypass grafting, or myocardial infarction. Secondary end points included all-cause death, angina, and dyspnea. Median follow-up was 10 years (interquartile range, 8-11 years). The primary end point occurred in 25% of patients with CTO PCI and in 24% of patients with no-CTO PCI (hazard ratio [HR], 1.11 [95% CI, 0.70-1.76]). Cardiovascular mortality was higher in the CTO PCI group (HR, 2.09 [95% CI, 1.10-2.50]), but all-cause death was similar (HR, 1.53 [95% CI, 0.93-2.50]). Dyspnea relief was more frequent after CTO PCI (83% versus 65%, P=0.005), with no significant difference in angina. CONCLUSIONS: This 10-year follow-up of patients post-ST-segment-elevation myocardial infarction randomized to CTO PCI or no-CTO PCI demonstrated no clinical benefit of CTO PCI in major adverse cardiac events or overall mortality. However, CTO PCI was associated with a higher cardiovascular mortality compared with no-CTO PCI. Our long-term data support a careful weighing of effective symptom relief against an elevated cardiovascular mortality risk in CTO PCI decisions. REGISTRATION: URL: https://www.trialregister.nl; Unique identifier: NTR1108.

Comparison of the Diagnostic Yield of Intracoronary Acetylcholine Infusion and Acetylcholine Bolus Injection Protocols During Invasive Coronary Function Testing.

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina with no obstructive coronary arteries in patients. Both can be diagnosed by invasive coronary function testing (ICFT) using acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared with a 1-minute ACh bolus injection protocol in testing CED and CAS. We evaluated 220 consecutive patients with angina and no obstructive coronary arteries who underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion, and thereafter 110 patients using 1-minute bolus injections, because of a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low-dose ACh and CAS according to the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%, p = 0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3 vs 1-minute protocol (24% vs 44%, p = 0.004). Including T-wave abnormalities in the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as a diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as a diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

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.

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.

Post-spastic flow recovery time to document vasospasm induced ischemia during acetylcholine provocation testing.

Background: Intracoronary acetylcholine (ACh) provocation is an established method for diagnosing epicardial and microvascular vasospasm in contemporary clinical practice. We hypothesize that ACh-induced vasospasm is followed by post-spastic reactive hyperemia (PSRH), which is measured as an increased flow-recovery time. Objectives: To assess flow-recovery time, indicative of ischemia, among the diagnostic endotypes that follow ACh provocation testing. Methods: Patients with angina and non-obstructive coronary artery disease on angiography who underwent ACh provocation testing were included in this analysis. Doppler flow was continuously measured during the procedure and used to determine the flow-recovery time, which was calculated as time between cessation of ACh infusion and the point of flow recovery. Results: Conventional provocation testing according to the COVADIS criteria diagnosed vasospasm in 63%(77/123), an equivocal result in 22%(27/123) and a negative result in 15%(19/123) of patients. In reaction to the highest-dose of ACh, flow-recovery time was significantly extended and similar in the epicardial, microvascular and equivocal test results compared to the negative result (all p < 0.001) indicative of PSRH. Conclusion: Flow-recovery time in patients with an equivocal result is similar to patients with vasospasm, which indicates the occurrence of myocardial ischemia and therefore, these patients may benefit from medical treatment.

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.

Single antiplatelet therapy directly after percutaneous coronary intervention in non-ST-segment elevation acute coronary syndrome patients: the OPTICA study.

BACKGROUND: Early P2Y12 inhibitor monotherapy has emerged as a promising alternative to 12 months of dual antiplatelet therapy following percutaneous coronary intervention (PCI). AIMS: In this single-arm pilot study, we evaluated the feasibility and safety of ticagrelor or prasugrel monotherapy directly following PCI in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: Patients received a loading dose of ticagrelor or prasugrel before undergoing platelet function testing and subsequent PCI using new-generation drug-eluting stents. The stent result was adjudicated with optical coherence tomography in the first 35 patients. Ticagrelor or prasugrel monotherapy was continued for 12 months. The primary ischaemic endpoint was the composite of all-cause mortality, myocardial infarction, definite or probable stent thrombosis or stroke within 6 months. The primary bleeding endpoint was Bleeding Academic Research Consortium type 2, 3 or 5 bleeding within 6 months. RESULTS: From March 2021 to March 2022, 125 patients were enrolled, of whom 75 ultimately met all in- and exclusion criteria (mean age 64.5 years, 29.3% women). Overall, 70 out of 75 (93.3%) patients were treated with ticagrelor or prasugrel monotherapy directly following PCI. The primary ischaemic endpoint occurred in 3 (4.0%) patients within 6 months. No cases of stent thrombosis or spontaneous myocardial infarction occurred. The primary bleeding endpoint occurred in 7 (9.3%) patients within 6 months. CONCLUSIONS: This study provides first-in-human evidence that P2Y12 inhibitor monotherapy directly following PCI for NSTE-ACS is feasible, without any overt safety concerns, and highlights the need for randomised controlled trials comparing direct P2Y12 inhibitor monotherapy with the current standard of care.

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.

Haemodynamic characterisation of different endotypes in coronary artery vasospasm in reaction to acetylcholine.

BACKGROUND: Vasoreactivity testing with high-dose acetylcholine is considered vasospasm provocation and low-dose as endothelial function testing. AIMS: To assess the changes in reaction to low- and high-dose acetylcholine in the endotypes of CAS as defined by the Coronary Vasomotor Disorders International Study Group (COVADIS) working group. METHODS: Changes in coronary epicardial diameter, coronary blood flow (CBF) and vascular resistance were determined at low-dose acetylcholine. RESULTS: A total of 88 ANOCA patients were included in this analysis. In the negative group (n = 14) incremental infusion of acetylcholine produced a progressive increase in CBF (p = 0.008). In reaction to low-dose acetylcholine, the epicardial vasospasm group (n = 30) is characterised by epicardial vasoconstriction that is significantly more severe compared to the microvascular vasospasm group (p = 0.004)(n = 23). The equivocal group (n = 21) is characterised by an increase in CBF and reduction in vascular resistance that are both significantly different compared to the epicardial vasospasm group (p = 0.036 and p = 0.007, respectively). High-dose acetylcholine decreased epicardial diameter and CBF significantly in the epicardial vasospasm, microvascular vasospasm and in the equivocal group (all p < 0.05. Vascular resistance increased significantly in the epicardial vasospasm group (p < 0.001) and equivocal group (p = 0.009). CONCLUSION: In reaction to low-dose acetylcholine the negative and equivocal endotype has haemodynamic changes that suggest intact endothelium. In reaction to high-dose acetylcholine the epicardial vasospasm, microvascular vasospasm and equivocal endotype have hemodynamic changes that suggest VSMC-hyperreactivity. These results suggest that the equivocal endotype is a positive test comparable to microvascular vasospasm in the presence of normal endothelial function.

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.

Presence of Coronary Endothelial Dysfunction, Coronary Vasospasm, and Adenosine-Mediated Vasodilatory Disorders in Patients With Ischemia and Nonobstructive Coronary Arteries.

BACKGROUND: Coronary function testing in patients with ischemia and nonobstructive coronary arteries (INOCA) commonly includes assessment of adenosine-mediated vasodilation and acetylcholine spasm provocation. The purpose of this study was to evaluate the diagnostic value of additional endothelial function testing for the diagnosis of vasomotor dysfunction in patients with INOCA. METHODS: In this retrospective cohort study, we included patients with INOCA who underwent clinically indicated comprehensive coronary function testing. Endothelial dysfunction was defined as a <50% increase in coronary blood flow, determined by Doppler flow, and/or epicardial vasoconstriction compared to baseline, in response to low-dose acetylcholine. Coronary artery spasm (CAS) was defined as vasospastic angina or microvascular angina in response to coronary high-dose acetylcholine. An impaired adenosine-mediated vasodilation was defined as a coronary flow reserve <2.5 and/or hyperemic microvascular resistance ≥2.5. RESULTS: Among all 110 patients, 79% had endothelial dysfunction, 62% had CAS, and 29% had an impaired adenosine-mediated vasodilation. Endothelial dysfunction was present in 80% of patients who tested positively for CAS and/or an impaired adenosine-mediated vasodilation. Endothelial function testing increases the diagnostic yield of coronary function testing that only incorporates adenosine testing and spasm provocation by 17% to 92%. Of patients with normal adenosine-mediated vasodilation and no inducible CAS, 68% had endothelial dysfunction. CONCLUSIONS: Concomitant endothelial dysfunction was prevalent in the vast majority of patients with INOCA with inducible CAS and/or an impaired adenosine-mediated vasodilation. In patients with INOCA without inducible CAS and normal adenosine-mediated vasodilation, two-thirds had endothelial dysfunction. These results indicate the relevance to perform endothelial function testing in patients with INOCA in view of its therapeutic implication.

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.

Combined Assessment of FFR and CFR for Decision Making in Coronary Revascularization: From the Multicenter International ILIAS Registry.

OBJECTIVES: The aim of this study was to demonstrate the clinical implications of combined assessment of fractional flow reserve (FFR) and coronary flow reserve (CFR). BACKGROUND: Combined assessment of FFR and CFR allows detailed characterization of pathophysiology in chronic coronary syndromes. Data on the clinical implications of distinct FFR and CFR patterns are limited, leading to uncertainty regarding their relevance. METHODS: Patients with chronic coronary syndromes and obstructive coronary artery disease were selected from the multicenter ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry. Patients were classified into 4 groups on the basis of FFR ≤0.80 and CFR <2.0. The endpoint was the 5-year target vessel failure (TVF) rate. RESULTS: A total of 2,143 patients with 2,725 lesions were included. Compared with normal FFR/normal CFR, low FFR/low CFR carried the highest risk for TVF (HR: 5.4; 95% CI: 3.2-9.3; P < 0.001), significantly higher than in revascularized vessels (P = 0.007). Discordance, with either low FFR/normal CFR or normal FFR/low CFR, was associated with increased TVF rates compared with normal FFR/normal CFR (low FFR/normal CFR: HR: 3.5 [95% CI: 2.2-5.4; P < 0.001]; normal FFR/low CFR: HR: 3.0 [95% CI: 1.9-4.7; P < 0.001]). No difference in 5-year TVF was observed between the 2 discordant groups (P = 0.57) or between the discordant groups and the revascularized group (P = 0.26 vs low FFR/normal CFR; P = 0.60 vs normal FFR/low CFR). CONCLUSIONS: Impaired coronary hemodynamics are uniformly associated with increased 5-year TVF rates. Nonrevascularized vessels with discordant FFR and CFR are associated with 5-year event rates that are equivalent to those of vessels that undergo revascularization, whereas vessels with combined low FFR and CFR exhibit event rates that are significantly higher than after revascularization. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry]; 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.

Clinical Relevance of Ischemia with Nonobstructive Coronary Arteries According to Coronary Microvascular Dysfunction.

Background In the absence of obstructive coronary stenoses, abnormality of noninvasive stress tests (NIT) in patients with chronic coronary syndromes may indicate myocardial ischemia of nonobstructive coronary arteries (INOCA). The differential prognosis of INOCA according to the presence of coronary microvascular dysfunction (CMD) and incremental prognostic value of CMD with intracoronary physiologic assessment on top of NIT information remains unknown. Methods and Results From the international multicenter registry of intracoronary physiologic assessment (ILIAS [Inclusive Invasive Physiological Assessment in Angina Syndromes] registry, N=2322), stable patients with NIT and nonobstructive coronary stenoses with fractional flow reserve >0.80 were selected. INOCA was diagnosed when patients showed positive NIT results. CMD was defined as coronary flow reserve ≤2.5. According to the presence of INOCA and CMD, patients were classified into 4 groups: group 1 (no INOCA nor CMD, n=116); group 2 (only CMD, n=90); group 3 (only INOCA, n=41); and group 4 (both INOCA and CMD, n=40). The primary outcome was major adverse cardiovascular events, a composite of all-cause death, target vessel myocardial infarction, or clinically driven target vessel revascularization at 5 years. Among 287 patients with nonobstructive coronary stenoses (fractional flow reserve=0.91±0.06), 81 patients (38.2%) were diagnosed with INOCA based on positive NIT. By intracoronary physiologic assessment, 130 patients (45.3%) had CMD. Regardless of the presence of INOCA, patients with CMD showed a significantly lower coronary flow reserve and higher hyperemic microvascular resistance compared with patients without CMD (P<0.001 for all). The cumulative incidence of major adverse cardiovascular events at 5 years were 7.4%, 21.3%, 7.7%, and 34.4% in groups 1 to 4. By documenting CMD (groups 2 and 4), intracoronary physiologic assessment identified patients at a significantly higher risk of major adverse cardiovascular events at 5 years compared with group 1 (group 2: adjusted hazard ratio [HRadjusted], 2.88; 95% CI, 1.52-7.19; P=0.024; group 4: HRadjusted, 4.00; 95% CI, 1.41-11.35; P=0.009). Conclusions In stable patients with nonobstructive coronary stenoses, a diagnosis of INOCA based only on abnormal NIT did not identify patients with higher risk of long-term cardiovascular events. Incorporating intracoronary physiologic assessment to NIT information in patients with nonobstructive disease allowed identification of patient subgroups with up to 4-fold difference in long-term cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Differential Prognostic Value of Revascularization for Coronary Stenosis With Intermediate FFR by Coronary Flow Reserve.

OBJECTIVES: The authors sought to evaluate comparative prognosis between deferred versus performed percutaneous coronary intervention (PCI) according to coronary flow reserve (CFR) values of patients with intermediate fractional flow reserve (FFR). BACKGROUND: For coronary stenosis with intermediate FFR, the prognostic value of PCI remains controversial. The prognostic impact of PCI may be different according to CFR in patients with intermediate FFR. METHODS: From the ILIAS Registry (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry, N = 2,322), 400 patients (412 vessels) with intermediate FFR (0.75-0.80) were selected. Patients were stratified into preserved CFR (>2.0, n = 253) and depressed CFR (≤2.0, n = 147) cohorts. Per-vessel clinical outcomes during 5 years of follow-up were compared between deferred versus performed PCI groups in both cohorts. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization. RESULTS: Among the study population, PCI was deferred for 210 patients (219 vessels, 53.2%) (deferred group) and performed for 190 patients (193 vessels, 46.8%) (performed group). The risk of TVF was comparable between the deferred and performed groups (12.8% vs 14.2%; adjusted HR: 1.403; 95% CI: 0.584-3.369; P = 0.448). When stratified by CFR, PCI was performed in 39.1% (100/261 vessels) of the preserved CFR cohort and 61.9% (93/151 vessels) of the depressed CFR cohort. Within the preserved CFR cohort, the risk of TVF did not differ significantly between the deferred and performed groups (11.0% vs 13.9%; adjusted HR: 0.770; 95% CI: 0.262-2.266; P = 0.635). However, in the depressed CFR cohort, the deferred group had a significantly higher risk of TVF than the performed group (17.2% vs 14.2%; adjusted HR: 4.932; 95% CI: 1.312-18.53; P = 0.018). A significant interaction was observed between CFR and the treatment decision (interaction P = 0.049). Results were consistent after inverse probability weighting adjustment. CONCLUSIONS: In patients with intermediate FFR of 0.75 to 0.80, the prognostic value of PCI differed according to CFR, with a significant interaction. PCI was associated with a lower risk of TVF compared with the deferral strategy when CFR was depressed (≤2.0), but there was no difference when CFR was preserved (>2.0). CFR could be used as an additional risk stratification tool to determine treatment strategies in patients with intermediate FFR. (Inclusive Invasive Physiological Assessment in Angina Syndromes Registry [ILIAS Registry]; NCT04485234).