Table of contents

0.1 Associations between plaque characteristics and FFR

0.1 Associations between plaque characteristics and FFR

Several studies indicate that atherosclerotic Plaque features in particular high remodeling index and presence of low attenuation​ LAP volume and represent high risk features and is associated with acute coronary syndrome [1]. However the relation to ischemia and FFR is not that well understood. Below are some hypotheses of how plaque characteristics may relate to FFR:

Hypotheses:

• The presence of large necrotic cores (low attenuation​ plaque and positive remodeling) within the neointima is associated with the inability of the vessel to dilate and predispose to ischemia and abnormal FFR
• The studies by Lavi et al. [2], Gage et al. [3] and Nabel et al. [4] all report abnormal vasomotor response (reduction in cross-section) to acetylcholine, exercise test, cold pressor test and heart rate increase in atherosclerotic arteries (See the section 0.1.1 Atherosclerosis and plaque morphology and its relation to FFR for summaries). However only Lavi et al. [2] differentiate between different plaque characteristics, and the introduction of nitroglycerin to a great extent reversed such effects and was similar in atherosclerotic and normal segments. Thus, with the assumption that nitroglycerin is used during Coronary Computed Tomography Angiography (CCTA) and the response is the same as during Invasive Coronary Angiography (ICA) and FFR measurement, differences in response to Hyperemia must describe any other differences.
• The study by Park et al. [5] (See the section 0.1.2 Atherosclerotic Plaque Characteristics by CT Angiography Identify Coronary Lesions That Cause Ischemia: a Direct Comparison to Fractional Flow Reserve for summary) suggests that Positive remodeling is a predictor of ischemia both in obstructive \( > 50 \% \) and non-onstructive obstructive \( < 50 \% \) atherosclerotic lesions. In a study comprising the same patients they found that atherosclerotic plaque features, and especially positive remodeling improved identification and reclassification of coronary arteries which cause ischemia [6]. It is worth noting that 100 out 407 interrogated lesions did not receive sublingual nitroglycerin before CCTA. In another patient cohort the study by Gaur et al. [7] they found that plaque assessment and FFRCT provide improved discrimination of ischemia, however the addition of plaque features to FFRCT did not improve predictive power (all patients received sublingual nitroglycerin before CCTA).
• Plaque characteristics are strongly correlated with geometric lesion severity, thus they are indirectly indicating the degree to which a particular plaque obstructs flow
• In the study by Park et al. [5] both lesion length and plaque volume is bigger/higher in ischemic lesions also in the case of non-obstructive CAD based on stenosis degree < 50 \( \% \). However the stenosis degree obtained from ICA is higher (49.4 \( \% \)) in the ischemic group than in the non-ischemic group (36.5 \( \% \)). Thus patients with positive remodeling and low attenuation​ plaque might result in a bias/underprediction of stenosis degree from CCTA (difficulty in differentiation of lumen/plaque).
• Plaque characteristics reflect the health of the downstream vasculature and calcification/lack of lipids suggests the distal vasculature is unhealthy (late/stable stage) and thus never requires blood flow beyond what is possible for the heart to provide through these stenoses.
• Plaque characteristics incorporate information of cumulative/diffuse atheresclorotic states which are not easily/accurately incorporated through stenosis degree
• The presence of large necrotic cores (low attenuation​ plaque and positive remodeling) represent vulnerable and active atherosclerotic lesions in which the actual geometry/lumen might change/reduce from the time of acquisition of CCTA and ICA.

If plaque features are related to FFR, what are the underlying explanations and how can this be incorporated into a computational FFR model? In simple terms FFR is determined by the stenosis geometry and the flow. The flow is again determined by two things, baseline flow and response to hyperemia. Thus if plaque characteristics are associated with FFR this could be incoprorated in the model in a few different ways

Incoproration to a model

• If plaque characteristics are related to the ability of the vessel to dilate, and this effect is different from the time CCTA was performed to when ICA is performed
• Vessel segments with/without certain plaque features could be synthetically dilated/contracted
• If certain plaque characteristics are related to bias/underestimation/overestimation of diameter in CCTA
• Vessel segments with/without certain plaque features could be synthetically dilated/contracted
• If plaque characteristics reflect the health of the downstream vasculature
• vessel segments with certain plaque features could be given different responses to adenosine
• vessel segments with certain plaque features could be given different different baseline coronary flow.

0.1.1 Atherosclerosis and plaque morphology and its relation to FFR

In the review by Ahmadi et al. [8] the authors propose that the presence of large necrotic cores and low attenuation​ plaque may be associated with the inability of the vessel to dilate. Relation to coronary endothelial dysfunction and plaque characteristics was analysed by Lavi et al. [2]. They performed a coronary endothelial function test by administrating Acetylcholine at increasing doses. Normal endothelial function was characterized as having a less than 10 \( \% \) reduction in coronary artery diameter, whereas Endothelial dysfunction was characterized as visible angiographic constriction and > 10 \( \% \) coronary artery diameter reduction. On average diameter reduced approximately by 20 \( \% \) for regions with endothelial dysfunction and about 5 \( \% \) in regions with normal function. It is worth noting that coronary artery response to nitroglycerin was similar in both groups, with an increase in diameter of approximately 20 \( \% \) . VH-IVUS analysis showed that coronary artery sections with endothelial dysfunction had significantly larger areas of necrotic core and dense calcified plaque compared to those without endothelial dysfunction. However, only necrotic core area was associated with endothelial dysfunction (p<0.001) after adjusting for other measures.

In a study by Gage et al. [3] the vasomotivity of normal and diseaseed coronary arteries during dynamic exercise, symptom limited supine bicycle exercise during cardiac catheterization was performed on 18 patients with classic angina pectoris. The response of normal and stenotic coronary arteries luminal areas was assesed from biplane coronary angiograms made before, during and after exercise. 12 patients (group 1) performed bycylce exercise for an average 3.4 min (81 W), and received 1.6 mg sublingual nitroglycerin. 6 patients (group 2) was given 0.1 mg intracoronary nitroglycerin before the bicycle test of av average of 3.8 min (96 w) followed by sublingual nitroglycerine as in group 1. During exercise in group 1, luminal area of the coronary stenosis decreased to 71 \( \% \) of resting levels (p less than .001), while area of the normal coronary artery increased to 123 \( \% \) of control (p less than .001). After sublingual nitroglycerin at the end of exercise, area of the normal vessel further increased to 140 \( \% \) of control (p less than .001), while luminal area of the stenosis dilated to 112 \( \% \) of resting levels (p less than .001 vs exercise, NS vs rest). Pretreatment with intracoronary nitroglycerin increased both normal (121 \( \% \) ; p less than .05) and stenotic (122 \( \% \) ; p less than .05) luminal areas, while preventing the previously observed narrowing of stenosis during exercise (114 \( \% \) ; NS).

In a study by Nabel et al. [4] 8 patients with angiographically normal arteries (group 1), 13 patients with mild coronary atherosclerosis (less than 50% diameter narrowing) (group 2) and 13 patients with advanced coronary stenoses (greater than 50 \( \% \) diameter narrowing) (group 3) were analysed in terms of response to the cold pressor test. In 31 segments of the angiographically normal arteries in group 1 a n average 12 \( \% \) increase in diameter was observed. In group 2 , 27 irregular segments constricted with an average of 9 \( \% \) reduction in diameter while 10 smooth segments dilated with a mean increase of 19 \( \% \) . In group an average reduction in diameter of 24 \( \% \) was observed in 17 stenotic segments. Coronary blood flow increaseas by 65 \( \% \) on average in group 1, by 15 \( \% \) in group 2 and decreased by 39 \( \% \) in group 3. Similar responses were found in a later study by Nabel et al. [9] where the vasomotor activity in normal, mild atherosclerosic and severely atherosclerosisc arteries were analyzed in terms of their response to increased heart rate (atrial pacing).

0.1.2 Atherosclerotic Plaque Characteristics by CT Angiography Identify Coronary Lesions That Cause Ischemia: a Direct Comparison to Fractional Flow Reserve

In the study by Park et al. [5], 252 patients (17 centers, 5 countries) underwent coronary CTA, with FFR performed for 407 coronary lesions. Lesions were categorized as obstructive ( stenosis degree >50 \( \% \) ) or non-obstructive ( stenosis degree < 50 \( \% \) ) and ischemic (FFR < 0.8) and non-ischemic (FFR > 0.8). For all FFR interrogated lesions, several atherosclerotic plaque characteristics (APCs), based on CTA images, were gathered; Positive remodeling, PR (lesion diameter of vessel wall/reference diameter > 1.1), Low attenuation plaque, LAP and spotty calcification, CP. In addition percent aggregate plaque volume ( \( \% \) APV, plaque volume/total vesel volume) was measured from the coronary ostium to the distal end of the lesion. In multivariate analyses, a stepwise increased risk of ischemia was observed for 1 (OR: 4.0, p < 0.001) and ≥2 (OR: 12.1, p < 0.001) APCs. These findings were APC dependent, with PR (OR: 5.3, p < 0.001) and LAP (OR: 2.1, p = 0.038) associated with ischemia, but not SC. When examined by stenosis severity, PR remained a predictor of ischemia for all lesions, whereas \( \% \) APV and LAP were associated with ischemia for only ≥50 \( \% \) , but not for <50 \( \% \) , stenosis. In a parallel study by Nakazato et. al including the same population they reported improved discrimination of ischemia by adding plaque characteristics to stenosis severity and FFRCT [6].

0.1.3 Coronary plaque quantification and fractional flow reserve by coronary computed tomography angiography identify ischaemia-causing lesions

In the study by Gaur et al. [7], Coronary CTA stenosis, plaque volumes, FFRCT, and FFR were assessed in 484 vessels from 254 patients. Stenosis >50 \( \% \) was considered obstructive. Plaque volumes (non-calcified plaque [NCP], low-density NCP [LD-NCP], and calcified plaque [CP]) were quantified using semi-automated software. Optimal thresholds of quantitative plaque variables were defined by area under the receiver-operating characteristics curve (AUC) analysis. Ischaemia was defined by FFR or FFRCT ≤0.80. Low-density NCP and FFRCT yielded diagnostic improvement over stenosis assessment with AUCs increasing from 0.71 by stenosis >50 \( \% \) to 0.79 and 0.90 when adding LD-NCP ≥30 mm3 and LD-NCP ≥30 mm3 + FFRCT ≤0.80, respectively. The addition of Low-density NCP to FFRCT did not improve discrimination of ischemia. Plaque analysis in this study included all coronary segments ≥2 mm.

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

In the study by Nakazato et. al [10] the discriminatory power of aggregate plaque volume ( \( \% \) APV) to detect ischemia was analysed separately and in addition to stenosis degree, minimal diameter/area. \( \% \) APV was defined as the sum of plaque volume divided bu the sum of vessel volume from the ostium to the distal portion of the lesion. 58 patients (with 58 stenoses) from 2 centers were analysed, of whom 22 were identified to be ischemic (FFR <= 0.8). AUC was higher for \( \% \) APV (0.85) than diameter stenosis degree (0.68). Addition of \( \% \) APV showed significant reclassification over diameter stenosis (NRI 0.77).

0.1.5 Quantitative Relationship Between the Extent and Morphology of Coronary Atherosclerotic Plaque and Downstream Myocardial Perfusion

In the study by Naya et al. [11] 73 patients and 209 arteries was analysed in terms of the effects of coronary atherosclerosis morphology and extent on myocardial flow reserve (MFR) based on PET estimated myocardial blood flow. For each vessel with atherosclerosis, the plaque length was measured in addition to its's decomposition, predominantly calsified (HU>150), non-calsified or mixed, remodelling index (RI < 1.1: healthy, 1.1 < R1 < 1.29: mild to moderate remodeling and RI > 1.29 extensive remodeling). Finally, a modified Duke CAD index integrating the number of affected vessels and the location of disease with ≥50 \( \% \) stenosis was used to quantify the extent and severity of CAD on a per-patient level. Standard PET/CTA fusion software (HeartFusion, GE Healthcare) was used to facilitate ascertainment of the exact correspondence between the territorial region of interest used to estimate the MFRregional and the location of coronary stenoses. Each of the 17 PET myocardial segments was assigned to the corresponding coronary vessel by 2 expert readers. MFRregional was computed based on these assignments by averaging MBF reserve values involving all segments distal to the most severe angiographic stenosis, regardless of whether a perfusion defect was present. For vessels without any stenosis, all segments subtended by the vessel were averaged. MFR was calcualted as the ratio of MFR in stress to that at rest. Total plaque length, composition, and remodeling index were not associated with lower MFR. On a per-patient basis, the modified Duke CAD (coronary artery disease) index (p = 0.04) and the number of segments with mixed plaque (p = 0.01) were the best predictors of low MFR\_global.

0.1.6 Noncalcified Atherosclerotic Plaque Burden at Coronary CT Angiography: A Better Predictor of Ischemia at Stress Myocardial Perfusion Imaging Than Calcium Score and Stenosis Severity

In the study by Bauer et al. [12] the relation between coronary CT angiographic findigs of calcified and non-calcified plaque burden and stenosis severity to myocardial perfusion imaging was assessed. Coronary CT angiograms were analyzed for stenosis and noncalcified or mixed plaque in 72 patients. A plaque analysis tool (Aquarius, TeraRecon) was used to calculate the volume of noncalcified plaque components. SPECT images were analyzed for perfusion defects. Between vessels with and those without perfusion defects, there was no significant difference in Agatston or calcium volume score (p = 0.25), but there was a significant difference in noncalcified plaque volume (44 ± 77 vs 19 ± 58 mm3; p = 0.03). Multiple stepwise regression analysis showed noncalcified plaque volume was the only significant predictor of ischemia.

0.1.7 Vulnerable plaque features on coronary CT angiography as markers of inducible regional myocardial hypoperfusion from severe coronary artery stenoses

In the study by Shmilovich et al. [13] 49 patients which were found to have a 70-99 \( \% \) focal stenosis from predominantly non-calcified plaque were analysed. For each stenoses, the presence of LAP (< 30 HU), Positive remodeling (stenosed outer wall/reference outer wall diameter > 1.05) and presence of spotty calcifications were noted for each stenoses, and their correlation to hyperpofusion measeured by myocardial perfusion imaging was checked. Detected hyperpofusion increased from an Odds ratio, OD of 1.3 ± 1.2 \( \% \) in arteries with LAP-/PR- to 3.2 ± 4.3 \( \% \) with LAP+/PR− or LAP−/PR+ plaques to 8.3 ± 2.4 \( \% \) with LAP+/PR+ plaques.

0.1.8 Abnormal Epicardial Coronary Resistance in Patients With Diffuse Atherosclerosis but “Normal” Coronary Angiography

In the study by De Bruyne et al. [14] 10 patients and 37 arteries with normal coronary angiograms (group 1) without signs of myocardial ischemia were analysed. Exercise ECG, dobutamine stress echocardiography, and stress perfusion scientigraphy were normal in all of them. In group 2 62 patients with focal angiograpic stenosis in a coronary artery other than those investigated for the present study were analysed. In this group the coronary arteries investigated showed no sign of focal stenosis by visual examination on the angiogram, and were contralateral to the stenotic arteries. The proximal diameter of normal arteries in group 1 was significantly larger than that of the nonstenotic atheresclerotic arteries from group 2 patients. On average distal diamteres were similar in both groups, and thus a more severe tapering was observed in group 1. There was no relation between the FFR and proximal diameter, distal diameter or degree of tapering. In group 2 the FFR of the distal non-stenotic LAD (0.86 +- 0.09) was significantly lower than in the non-stenotic LCS (0.91 +- 0.08). Resting Pd/Pa and FFR was significantly lower in group 1 than in group 2 (median, 1 mm Hg; range, 0 to 2 mm Hg) vs (median, 3 mm Hg; range, 0 to 18 mm Hg) at rest and (median, 3 mm Hg; range, 1 to 7 mm Hg) vs (median, 8 mm Hg; range, 0 to 31 mm Hg) at hyperemia. No artery studied by slow pullback of the pressure wire showed a sudden increase in distal coronary pressure, indicating that the pressure gradient observed in the distal part of the artery was due to a continuous loss of pressure along the arterial length rather than to a focal narrowing not detected at angiography. The present study, therefore, suggests that in addition to the above mechanisms for myocardial ischemia, abnormal resistance of coronary arteries due to diffuse atherosclerosis without focal stenosis may contribute to stress-induced myocardial ischemia and flow maldistribution on perfusion scintigrams, even after vasodilation of the epicardial arteries by nitrates.

0.1.9 Computed Tomographic Angiography Characteristics of Atherosclerotic Plaques Subsequently Resulting in Acute Coronary Syndrome

In the study by Motoyama et al. [1] 1,059 patients who underwent CT angiography, atherosclerotic lesions were analyzed for the presence of 2 features: PR and LAP. The remodeling index, and plaque and LAP areas and volumes were calculated. The plaque characteristics of lesions resulting in ACS during the follow-up of 27 ± 10 months were evaluated. Of the 45 patients showing plaques with both PR and LAP (2-feature positive plaques), ACS developed in 10 (22.2 \( \% \)), compared with 1 (3.7 \( \% \) ) of the 27 patients with plaques displaying either feature (1-feature positive plaques). In only 4 (0.5 \( \% \)) of the 820 patients with neither PR nor LAP (2-feature negative plaques) did ACS develop. Among 2- or 1-feature positive segments, those resulting in ACS demonstrated significantly larger remodeling index plaque volume LAP volume and percent LAP/total plaque area. All patients with subsequent ACS in the present study had culprit lesions that were \( \leq 75 \% \) stenotic at the time of CCTA.

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