Joon-Hyung Doh

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

OBJECTIVES The aim of this study was to determine the diagnostic performance of a new method for quantifying fractional flow reserve (FFR) with computational fluid dynamics (CFD) applied to coronary computed tomography angiography (CCTA) data in patients with suspected or known coronary artery disease (CAD). BACKGROUND Measurement of FFR during invasive coronary angiography is the gold standard for identifying coronary artery lesions that cause ischemia and improves clinical decision-making for revascularization. Computation of FFR from CCTA data (FFR(CT)) provides a noninvasive method for identifying ischemia-causing stenosis; however, the diagnostic performance of this new method is unknown. METHODS Computation of FFR from CCTA data was performed on 159 vessels in 103 patients undergoing CCTA, invasive coronary angiography, and FFR. Independent core laboratories determined FFR(CT) and CAD stenosis severity by CCTA. Ischemia was defined by an FFR(CT) and FFR ≤0.80, and anatomically obstructive CAD was defined as a CCTA with stenosis ≥50%. Diagnostic performance of FFR(CT) and CCTA stenosis was assessed with invasive FFR as the reference standard. RESULTS Fifty-six percent of patients had ≥1 vessel with FFR ≤0.80. On a per-vessel basis, the accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 84.3%, 87.9%, 82.2%, 73.9%, 92.2%, respectively, for FFR(CT) and were 58.5%, 91.4%, 39.6%, 46.5%, 88.9%, respectively, for CCTA stenosis. The area under the receiver-operator characteristics curve was 0.90 for FFR(CT) and 0.75 for CCTA (p = 0.001). The FFR(CT) and FFR were well correlated (r = 0.717, p < 0.001) with a slight underestimation by FFR(CT) (0.022 ± 0.116, p = 0.016). CONCLUSIONS Noninvasive FFR derived from CCTA is a novel method with high diagnostic performance for the detection and exclusion of coronary lesions that cause ischemia.

Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI

Background Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave‐free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. Methods We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR‐guided or FFR‐guided coronary revascularization. The primary end point was the 1‐year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. Results At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, ‐0.2 percentage points; 95% confidence interval [CI], ‐2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). Conclusions Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE‐FLAIR ClinicalTrials.gov number, NCT02053038.)

Noninvasive Diagnosis of Ischemia-Causing Coronary Stenosis Using CT Angiography : Diagnostic Value of Transluminal Attenuation Gradient and Fractional Flow Reserve Computed From Coronary CT Angiography Compared to Invasively Measured Fractional Flow Reserve

OBJECTIVES The aim of this study was to compare the diagnostic performance of coronary computed tomography angiography (CCTA)-derived computed fractional flow reserve (FFR(CT)) and transluminal attenuation gradient (TAG) for the diagnosis of lesion-specific ischemia. BACKGROUND Although CCTA is commonly used to detect coronary artery disease (CAD), it cannot reliably assess the functional significance of CAD. Novel technologies based on CCTA were developed to integrate anatomical and functional assessment of CAD; however, the diagnostic performance of these methods has never been compared. METHODS Fifty-three consecutive patients who underwent CCTA and coronary angiography with FFR measurement were included. Independent core laboratories determined CAD severity by CCTA, TAG, and FFR(CT). The TAG was defined as the linear regression coefficient between intraluminal radiological attenuation and length from the ostium; FFR(CT) was computed from CCTA data using computational fluid dynamics technology. RESULTS Among 82 vessels, 32 lesions (39%) had ischemia by invasive FFR (FFR ≤0.80). Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratio of TAG (≤ -0.654 HU/mm) for detection of ischemia were 38%, 88%, 67%, 69%, 3.13, and 0.71, respectively; and those of FFR(CT) were 81%, 94%, 90%, 89%, 13.54, and 0.20, respectively. Receiver-operating characteristic curve analysis showed a significantly larger area under the curve (AUC) for FFR(CT) (0.94) compared to that for TAG (0.63, p < 0.001) and CCTA stenosis (0.73, p < 0.001). In vessels with noncalcified plaque or partially calcified plaque, FFR(CT) showed a larger AUC (0.94) compared to that of TAG (0.63, p < 0.001) or CCTA stenosis (0.70, p < 0.001). In vessels with calcified plaque, AUC of FFR(CT) (0.92) was not statistically larger than that of TAG (0.75, p = 0.168) or CCTA stenosis (0.80, p = 0.195). CONCLUSIONS Noninvasive FFR computed from CCTA provides better diagnostic performance for the diagnosis of lesion-specific ischemia compared to CCTA stenosis and TAG.

Aggregate Plaque Volume by Coronary Computed Tomography Angiography Is Superior and Incremental to Luminal Narrowing for Diagnosis of Ischemic Lesions of Intermediate Stenosis Severity

OBJECTIVES This study examined the performance of percent aggregate plaque volume (%APV), which represents cumulative plaque volume as a function of total vessel volume, by coronary computed tomography angiography (CTA) for identification of ischemic lesions of intermediate stenosis severity. BACKGROUND Coronary lesions of intermediate stenosis demonstrate significant rates of ischemia. Coronary CTA enables quantification of luminal narrowing and %APV. METHODS We identified 58 patients with intermediate lesions (30% to 69% diameter stenosis) who underwent invasive angiography and fractional flow reserve. Coronary CTA measures included diameter stenosis, area stenosis, minimal lumen diameter (MLD), minimal lumen area (MLA) and %APV. %APV was defined as the sum of plaque volume divided by the sum of vessel volume from the ostium to the distal portion of the lesion. Fractional flow reserve ≤ 0.80 was considered diagnostic of lesion-specific ischemia. Area under the receiver operating characteristic curve and net reclassification improvement (NRI) were also evaluated. RESULTS Twenty-two of 58 lesions (38%) caused ischemia. Compared with nonischemic lesions, ischemic lesions had smaller MLD (1.3 vs. 1.7 mm, p = 0.01), smaller MLA (2.5 vs. 3.8 mm(2), p = 0.01), and greater %APV (48.9% vs. 39.3%, p < 0.0001). Area under the receiver operating characteristic curve was highest for %APV (0.85) compared with diameter stenosis (0.68), area stenosis (0.66), MLD (0.75), or MLA (0.78). Addition of %APV to other measures showed significant reclassification over diameter stenosis (NRI 0.77, p < 0.001), area stenosis (NRI 0.63, p = 0.002), MLD (NRI 0.62, p = 0.001), and MLA (NRI 0.43, p = 0.01). CONCLUSIONS Compared with diameter stenosis, area stenosis, MLD, and MLA, %APV by coronary CTA improves identification, discrimination, and reclassification of ischemic lesions of intermediate stenosis severity.

A Novel Noninvasive Technology for Treatment Planning Using Virtual Coronary Stenting and Computed Tomography-Derived Computed Fractional Flow Reserve

OBJECTIVES This study sought to determine whether computational modeling can be used to predict the functional outcome of coronary stenting by virtual stenting of ischemia-causing stenoses identified on the pre-treatment model. BACKGROUND Computed tomography (CT)-derived fractional flow reserve (FFR) is a novel noninvasive technology that can provide computed (FFRct) using standard coronary CT angiography protocols. METHODS We prospectively enrolled 44 patients (48 lesions) who had coronary CT angiography before angiography and stenting, and invasively measured FFR before and after stenting. FFRct was computed in blinded fashion using coronary CT angiography and computational fluid dynamics before and after virtual coronary stenting. Virtual stenting was performed by modification of the computational model to restore the area of the target lesion according to the proximal and distal reference areas. RESULTS Before intervention, invasive FFR was 0.70 ± 0.14 and noninvasive FFRct was 0.70 ± 0.15. FFR after stenting and FFRct after virtual stenting were 0.90 ± 0.05 and 0.88 ± 0.05, respectively (R = 0.55, p < 0.001). The mean difference between FFRct and FFR was 0.006 for pre-intervention (95% limit of agreement: -0.27 to 0.28) and 0.024 for post-intervention (95% limit of agreement: -0.08 to 0.13). Diagnostic accuracy of FFRct to predict ischemia (FFR ≤ 0.8) prior to stenting was 77% (sensitivity: 85.3%, specificity: 57.1%, positive predictive value: 83%, and negative predictive value: 62%) and after stenting was 96% (sensitivity: 100%, specificity: 96% positive predictive value: 50%, and negative predictive value: 100%). CONCLUSIONS Virtual coronary stenting of CT-derived computational models is feasible, and this novel noninvasive technology may be useful in predicting functional outcome after coronary stenting. (Virtual Coronary Intervention and Noninvasive Fractional Flow Reserve [FFR]; NCT01478100).

Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis.

BACKGROUND The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear. OBJECTIVES The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement. METHODS Patients with high FFR (>0.80) were grouped according to CFR (≤2) and IMR (≥23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient-oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days). RESULTS A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]). CONCLUSIONS CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093).

Usefulness of Noninvasive Fractional Flow Reserve Computed from Coronary Computed Tomographic Angiograms for Intermediate Stenoses Confirmed by Quantitative Coronary Angiography

Coronary lesions of intermediate severity often cause ischemia, and fractional flow reserve (FFR)-guided revascularization for these coronary lesions is safe and effective. FFR derived from coronary computed tomography (FFR(CT)) is a noninvasive method for diagnosis of lesion-specific ischemia, but its performance for intermediate stenoses has not been examined to date. We examined the performance of FFR(CT) versus FFR at the time of invasive angiography in 66 vessels of 60 patients who were identified as having an intermediate stenosis, defined by quantitative coronary angiographic percent diameter stenosis 40% to 69%. Ischemia for FFR(CT) and FFR was defined as ≤0.80. Diagnostic performance of FFR(CT) was determined compared to an invasive FFR standard. Mean age of the study group was 63.5 ± 8.1 years (81% men). Thirty-one patients (47%) demonstrated ischemia with an FFR ≤0.80, with 2 of 16 (12.5%), 21 of 37 (56.8%), and 8 of 13 (61.5%) lesions of 40% to 49%, 50% to 59%, and 60% to 69% stenosis causal of ischemia, respectively. At an FFR ≤0.80 cutoff for lesion-specific ischemia, accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of FFR(CT) were 86.4%, 90.3%, 82.9%, 82.4%, and 90.6%, respectively, with an area under the receiver operator characteristics curve of 0.95 (p <0.001) and good correlation to FFR (0.60, p <0.0001). No biases between FFR(CT) and FFR were noted by Bland-Altman analysis (0.03 ± 0.12, p = 0.054). In conclusion, FFR(CT) is a novel noninvasive method for diagnosis of lesion-specific ischemia of coronary lesions of intermediate stenosis severity.

Clinical and Physiological Outcomes of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention in Patients With Serial Stenoses Within One Coronary Artery

OBJECTIVES This study was performed to evaluate the physiological and clinical outcomes of fractional flow reserve (FFR)-guided revascularization strategy with drug-eluting stents in serial stenoses within the same coronary artery. BACKGROUND Identifying a functionally significant stenosis is difficult when several stenoses exist within 1 coronary artery. METHODS A total of 131 patients (141 vessels and 298 lesions) with multiple intermediate stenoses within the same coronary artery were assessed by FFR with pullback pressure tracings. In vessels with an FFR <0.8, the stenosis that caused the largest pressure step-up was stented first. Major adverse cardiac events were assessed during follow-up. RESULTS FFR was measured 239 times and there were no procedure-related complications. There was a weak negative correlation between FFR and angiographic percent diameter stenosis (r = -0.282, p < 0.001). In total, 116 stents were implanted and revascularization was deferred in 61.1% (182 of 298) of lesions. When the vessels with an initial FFR <0.8 were divided into 2 groups according to FFR after first stenting (FFR ≥0.8 vs. FFR <0.8), there were no differences in baseline angiographic and physiological parameters between the 2 groups. During the mean follow-up of 501 ± 311 days, there was only 1 target vessel revascularization due to in-stent restenosis. There were no events related to deferred lesions. CONCLUSIONS FFR-guided revascularization strategy using pullback pressure tracing in serial stenoses was safe and effective. This strategy can reduce unnecessary intervention and maximize the benefit of percutaneous coronary intervention with drug-eluting stents in patients with multiple stenoses within 1 coronary artery.

Safety and efficacy of a novel hyperaemic agent, intracoronary nicorandil, for invasive physiological assessments in the cardiac catheterization laboratory.

AIMS Maximal hyperaemia is a key element of invasive physiological studies and adenosine is the most commonly used agent. However, infusion of adenosine requires additional venous access and can cause chest discomfort, bronchial hyper-reactivity, and atrioventricular conduction block. The aim of this study was to evaluate the feasibility and efficacy of intracoronary (IC) nicorandil as a novel hyperaemic agent for invasive physiological studies. METHODS AND RESULTS We enrolled 210 patients who underwent fractional flow reserve (FFR) measurement. Hyperaemic efficacy of the following methods was compared: IC bolus injection of adenosine; intravenous (i.v.) infusion of adenosine (140 μg/kg/min); and IC bolus of nicorandil (1 and 2 mg). In 70 patients, the index of microcirculatory resistance was also measured. Hyperaemic efficacy of IC nicorandil 2 mg was non-inferior to that of i.v. adenosine infusion (FFR: 0.82 ± 0.10 vs. 0.82 ± 0.10; P for non-inferiority < 0.001). There was a strong correlation between FFRs measured by i.v. adenosine and IC nicorandil (R² = 0.934). Nicorandil produced fewer changes in blood pressure, heart rate and PR interval, and less chest pain than adenosine (all P-values < 0.05). Atrioventricular block occurred in 12 patients with IC adenosine, 4 patients with i.v. adenosine and none with IC nicorandil. The index of microcirculatory resistance was 18.3 ± 8.7 with i.v. adenosine and 17.2 ± 7.6 with IC nicorandil (P = 0.126). CONCLUSION This study suggests that IC bolus injection of nicorandil is a simple, safe, and effective way to induce steady-state hyperaemia for invasive physiological evaluations. Clinicaltrials.gov number: NCT01331902.

Coronary Artery Axial Plaque Stress and its Relationship With Lesion Geometry : Application of Computational Fluid Dynamics to Coronary CT Angiography

OBJECTIVES The purpose of this study was to characterize the hemodynamic force acting on plaque and to investigate its relationship with lesion geometry. BACKGROUND Coronary plaque rupture occurs when plaque stress exceeds plaque strength. METHODS Computational fluid dynamics was applied to 114 lesions (81 patients) from coronary computed tomography angiography. The axial plaque stress (APS) was computed by extracting the axial component of hemodynamic stress acting on stenotic lesions, and the axial lesion asymmetry was assessed by the luminal radius change over length (radius gradient [RG]). Lesions were divided into upstream-dominant (upstream RG > downstream RG) and downstream-dominant lesions (upstream RG < downstream RG) according to the RG. RESULTS Thirty-three lesions (28.9%) showed net retrograde axial plaque force. Upstream APS linearly increased as lesion severity increased, whereas downstream APS exhibited a concave function for lesion severity. There was a negative correlation (r = -0.274, p = 0.003) between APS and lesion length. The pressure gradient, computed tomography-derived fractional flow reserve (FFRCT), and wall shear stress were consistently higher in upstream segments, regardless of the lesion asymmetry. However, APS was higher in the upstream segment of upstream-dominant lesions (11,371.96 ± 5,575.14 dyne/cm(2) vs. 6,878.14 ± 4,319.51 dyne/cm(2), p < 0.001), and in the downstream segment of downstream-dominant lesions (7,681.12 ± 4,556.99 dyne/cm(2) vs. 11,990.55 ± 5,556.64 dyne/cm(2), p < 0.001). Although there were no differences in FFRCT, % diameter stenosis, and wall shear stress pattern, the distribution of APS was different between upstream- and downstream-dominant lesions. CONCLUSIONS APS uniquely characterizes the stenotic segment and has a strong relationship with lesion geometry. Clinical application of these hemodynamic and geometric indices may be helpful to assess the future risk of plaque rupture and to determine treatment strategy for patients with coronary artery disease. (Evaluation of FFR, WSS, and TPF Using CCTA; NCT01857687).