Assessment of FFR-Negative Intermediate Coronary Artery Stenoses by Spectral Analysis of the Radiofrequency Intravascular Ultras

Baseline angiographic, physiologic and VH-IVUS characteristics.
Signature” plaque. (A) Relative plaque composition is preserved across a vessel in a given patient, in a pattern unique to each patient. Shown are longitudinal plots of 2 representative vessels (red, lipid core; dark green, fibrous; light green, fibrolipi
Figure 2ii
Figure 2iii
Table showing correlation values of percent plaque component at index stenosis frame versus adjacent frames for all plaque components. P < 0.01 for all r-values.
Clinical event rates for intermediate coronary artery stenoses.
Virtual histology morphologic plaque types. Plaques were classified as thin-cap fibroatheromas (TCFA), fibrous cap atheromas (FCA), fibrocalcific lesions (FC) and pathological intimal thickening (PIT).
Baseline clinical characteristics.

Jason H. Rogers, MD, Jacob Wegelin, PhD, Kori Harder, RN, Richard Valente, MD, Reginald Low, MD

Assessing the clinical importance of angiographically intermediate coronary artery stenoses (> 40% and < 70%) at the time of cardiac catheterization remains a challenge. Since not all intermediate stenoses are hemodynamically significant, determining fractional flow reserve (FFR) by pressure wire measurement is a validated method for determining the physiologic import of an intermediate lesion. FFR represents maximum achievable blood flow to the myocardium supplied by a stenotic artery as a fraction of normal maximum flow. Its normal value is 1.0, and a value of < 0.75 has been reported to identify stenoses associated with inducible ischemia. Both retrospective and prospective studies have shown that deferral of angioplasty in patients with FFR > 0.75 results in low target stenosis event rates.1–3
Intravascular ultrasound (IVUS) has demonstrated that the extent of coronary atherosclerosis is underestimated by coronary angiography, and IVUS permits direct measurements of the lumen, coronary artery wall and components of atherosclerotic plaques.4–6 IVUS-derived minimum lumen area (MLA) < 4.0 mm2 and/or minimum lumen diameter (MLD) < 2.0 mm have been shown to predict the probability of an adverse clinical event in follow up.7,8 Qualitative assessment of atheroma morphology has been shown to have clinical relevance in predicting vulnerable coronary plaques that may result in an acute coronary syndrome, although these studies have been limited by inadequate characterization of plaque components by traditional ultrasound technology.
Tissue characterization of atherosclerotic plaques by IVUS can be enhanced by analysis of the back-scattered radiofrequency (RF) ultrasound signal, which contains amplitude and frequency.9–12 In standard IVUS grayscale images, calcified regions of plaque and dense fibrous components generally reflect ultrasound energy well, and thus appear bright and homogenous, whereas regions of low echo-reflectance in IVUS images are usually labeled “soft” or “mixed” plaque. Unfortunately, utilizing such grayscale images to differentiate and quantify plaque components is technically difficult. Spectral analysis of the RF IVUS backscatter data offers an in vivo opportunity to easily assess plaque composition.13 The analyzed RF information is used to reconstruct tissue maps to provide “virtual histology” intravascular ultrasound (VH-IVUS) information about the vessel wall and atherosclerotic plaque. Spectral analysis of the RF ultrasound backscatter signals has been shown to have 80–92% accuracy in identifying the four possible basic tissue types in an atherosclerotic plaque: fibrous, fibrolipidic, calcified and lipid necrotic (core).13,14
The purpose of this pilot study was to examine the VH-IVUS morphologic characteristics of intermediate coronary artery stenoses and adjacent vessel segments with an FFR > 0.75. Since VH-IVUS is now widely available, the findings reported are relevant to the practicing interventional cardiologist.

Study population and trial design. Subjects (n = 30) were enrolled after obtaining informed consent through a protocol approved by our institutional review board. Baseline clinical information was collected. Inclusion criteria for participation were: (1) age >/= 18 years; (2) subjects referred for non-emergency cardiac catheterization; (3) presence of angiographically intermediate stenosis (> 40% and < 70% diameter stenosis by quantitative coronary angiography) in a native coronary artery with a reference diameter > 2.25 mm; and (4) stenosis FFR >/= 0.75. Patients were excluded if they had a stenosis FFR < 0.75 (percutaneous coronary intervention was performed), or if they had any contraindication to IVUS examination. Eligible subjects then went on to have VH-IVUS studies as described below. Clinical follow up was obtained and patients were re-enrolled in the study if they presented for clinically-indicated catheterization during the follow-up period, and repeat FFR and IVUS were performed if possible.
Angiographic analysis. Intracoronary nitroglycerin (100–200 mg) was administered prior to coronary angiography. Quantitative coronary angiography (QCA) was performed by a trained technician blinded to the VH-IVUS results using a computer-assisted automatic edge detection algorithm (Inturis Allura, version 9.0, Phillips Medical Systems, The Netherlands). With the outer diameter of the contrast-filled catheter as the calibration standard, the minimum lumen diameter in diastole, as measured from orthogonal projections, was recorded. The reference segment diameter was obtained from an angiographically normal segment proximal or distal to the lesion. Lesions were classified by CASS site and the modified American College of Cardiology/American Heart Association classification.15
Determination of fractional flow reserve. Pressure wire measurements were performed using a 0.014 inch SmartWire XT/WaveMap pressure guidewire (Volcano Therapeutics, Inc., Rancho Cordova, California). Intravenous heparin sufficient to achieve an activated clotting time of > 200 seconds was administered before the wire was advanced through a standard guiding catheter, normalized and advanced distal to the stenosis. Adenosine was administered to induce maximal hyperemia, either intravenously (140–180 mg/kg/minute) or high-dose intracoronary (30–60 µg in the right, and 60–100 mg in the left coronary artery). FFR was calculated as the minimum ratio of mean hyperemic distal coronary pressure measured by the pressure wire to the mean aortic pressure measured by the guiding catheter.
Qualitative and quantitative virtual histology-intravascular ultrasound analysis. IVUS was performed using a solid-state, linear array, 20 MHz, 2.9 Fr Eagle Eye IVUS imaging catheter (Volcano Therapeutics). The IVUS catheter was advanced over the pressure wire to a position at least 10 mm distal to the target lesion. The entire artery was then imaged retrograde to a position at least 10 mm proximal to the stenosis, and usually to the aorto-ostial junction at a motorized pullback speed of 0.5 mm/second. IVUS studies (grayscale and VH-IVUS) were acquired and recorded using an IVG3 IVUS digital data recorder (Version 1.3, Volcano Therapeutics, Inc.). Radiofrequency backscatter IVUS data acquisition was gated to the R-wave of the electrocardiogram for determination of “virtual histology” IVUS. Each gated acquisition was defined as a VH-IVUS “frame”, which is the unit of measurement used on the VH-IVUS console. Automatic border detection with manual confirmation was performed on grayscale images for determination of lumen and media-adventitial borders. A color-coded tomographic view of each IVUS image was generated, quantifying relative contributions of fibro-lipidic (light green), fibrous (green), calcific (white), and lipid necrotic core (red) components of the atherosclerotic plaque. Target stenosis” plaque composition was calculated as an average of the frame with the MLA, as well as of the immediate distal and proximal frames (3-frame average), unless otherwise specified. As previously described, atherosclerotic lesions were classified (Figure 1) as pathological intimal thickening (PIT, mainly fibrotic-fibrolipidic tissue with 0–3% lipid core CSA), fibrocalcific lesions (FC, mainly fibrotic plaques with some calcium and > 3%, but less than or equal to 10% CSA) plaques with overlying fibrous tissue], and VH-derived thin-cap fibroatheromas [VH-TCFA, lipid-rich (> 10% CSA)] plaques with no overlying fibrous tissue).16 All lesions interrogated in this study fell into one of these four categories. Note that the term “VH-TCFA” is used to distinguish this category from histologic TCFA. Since the axial resolution of VH-IVUS is ~150 microns, the prevalence of TCFA will be overestimated.
Statistical analysis. Continuous data are reported as mean ± standard deviation. To investigate the possibility that there could be consistent plaque composition over a vessel, we examined the relationship between plaque composition variables at the index stenosis and the averages of these variables over portions of the vessel adjacent to the index stenosis. The averages of adjacent segments were computed over the index stenosis along with the adjacent 2 frames, over the 20 adjacent frames, over the 40 adjacent frames and over the entire imaged vessel. Pearson correlations were computed between the plaque composition variables (calcified, fibrous, fibrolipidic and lipid core) at the index stenosis and these averages for each variable. Pearson correlations were also computed between: (1) HDL, LDL and total cholesterol versus plaque composition at the target stenosis; and (2) FFR and the minimum luminal diameter at the target stenosis. A p-value < 0.05 was considered statistically significant.

Baseline demographic data are presented in Table 1. Twelve patients (40%) underwent PCI on a lesion in another vessel at the time of study. In addition to the clinical characteristics described, all patients had a left ventricular ejection fraction (LVEF) > 40%, no patients had prior coronary artery bypass graft surgery (CABG), and diabetics were insulin-requiring (n = 2) or on oral hypoglycemics (n = 6). Angiographic, physiologic (FFR) and VH-IVUS data are summarized in Table 2. FFR did not significantly correlate with the contribution of any of the four plaque components to absolute or relative plaque area at the stenosis or in adjacent segments. FFR correlated weakly with the IVUS-derived minimum luminal diameter at the target stenosis (r = 0.35, p = 0.04), but not with the minimum luminal area at the target stenosis (r = 0.27, p = 0.11). Despite fairly homogeneous angiographic stenosis severity (> 40% and < 70%) and FFR values (all subjects >/= 0.75), there was marked heterogeneity in the composition of plaque at the stenosis sites. In order of decreasing frequency, the majority of intermediate stenoses were VH-derived thin-cap fibroatheromas (n = 22), followed by fibrocalcific atheromas (n = 7), fibrous-cap atheromas (n = 5), and pathological intimal thickening (n = 3). The relative contribution of each component in plaque remained relatively constant in the frames adjacent to the site of maximum stenosis, and correlated well at sites more distant from the index stenosis. The observation that plaque components are conserved in their relative contributions to plaque across adjacent segments is presented in Figure 2. The tightest correlation for a plaque component across a vessel was for lipid core. No significant relationships between lipid values and plaque composition were found, although this may be due to the fact that the majority of patients were on a statin at the time of study enrollment. Presumably for the same reason, high-sensitivity C-reactive protein did not correlate with the amount of calcium in the vessel, as determined by VH-IVUS.
Clinical follow up of 12 ± 2 months was available for 26 patients. Three patients (all with VH-TCFAs at index evaluation) experienced events in the follow-up period, but only 1 of these patients had an event at the index lesion (plaque progression resulting in angina requiring PCI). The second patient had plaque rupture at a site distant to the index stenosis, and the third patient had an unwitnessed death at home without the performance of an autopsy. The small study size precludes comment on VH-IVUS as a predictive tool, but the low specificity of TCFA for predicting events may be noted.

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