|
Table 1 decision-making on coronary revascularization via FFR. 16
Table 2 An overview of study design, populations, and estimates of FFRCT diagnostic performance in these 3 trials.17
Table 3 The quantitative accuracy of the workflow is described below31
Table 4 Baseline characteristics of study patients42
Table 5 Baseline Characteristics of study vessels42
Table 6 Closely correlated in pre-and post-adenosine FFR, RTCVD, pre- and post -stenosis length44
Chapter 1 Introduction
Cardiovascular disease, especially CAD remains the leading cause of morbidity and mortality in the world despite rapid improvement of medication and diagnostic tool.2 The widespread prevalence of CAD and multitude of diagnostic tests and therapies makes it one of the major contributors to burgeoning healthcare costs.3 The evaluation of a patient for coronary disease is problematic, as the sensitivity of traditional stress testing is only around 85%, and ICA is more time consuming, costly, and comes with some inherent risks.4 ICA frequently over-estimates the severity of coronary stenosis while underestimating lesion length.5 Furthermore, ICA does not reliably discern ischemia-provoking lesions from hemodynamically non-significant lesions.6 As a result of inaccurate diagnostic discrimination associated with the use of current noninvasive testing modalities, 60% or more of patients referred for ICA on a suspicion of CAD do not have obstructive disease7, and the majority of patients having revascularization performed do not have evidence of ischemia.8 ICA is the gold standard for anatomical detection of obstructive CAD, but it has limited capacity to determine the hemodynamic significance of stenosis, which is determined by decreased fractional flow reserve (FFR) 9. However, FFR is another invasive tool for CAD detection. New non-invasive technologies as Fractional flow reserve derived from coronary computed tomography angiography (FFRCT), virtual reality (VR), vascular robotic systems (VRS), and three-dimensional printing are suspended to improve the diagnosis, treatment and safety of patients with cardiovascular disease1and to identify high-risk subsets of individuals with “vulnerable” plaque before percutaneous treatment strategies.1 Our research focuses on the potential clinical impact each of these invasive and non-invasive modalities will have, as well as speculating on synergies that use of them together may achieve the highest diagnostic rate of CAD.
Chapter 2 Review
In this chapter, we will review the mechanism, current evidence, comparison with other modalities of CAD detection
2-1 Fractional Flow Reserve (FFR)
FFR is t a alternative pressure-derived estimate of coronary flow impairment based on the assumption that coronary pressure is linearly proportional to coronary flow when coronary resistance is minimal.
2-1.1 Introduction of Fractional Flow Reserve
Revascularization in stable ischemic heart disease (IHD) is indicated in patients on optimal medical therapy with angina and/or demonstrable ischemia and a significant
stenosis in one or more epicardial coronary arteries. However, angiography alone cannot truthfully determine the hemodynamic significance of coronary lesions, particularly those of intermediate stenosis severity. Morphological luminal narrowing of the coronary artery on coronary angiogram does not always cause myocardial ischemia.10 PCI of functionally insignificant coronary artery lesions may have serious consequences; therefore it is very important to show that a stenosis is capable to induce myocardial ischemia prior to intervention. FFR has emerged as a powerful tool for this purpose. In this review, we will briefly discuss the principle of FFR, and rationale supporting its use, and comparison with other modalities.11
Traditionally, visually estimated coronary stenosis has been used to guide PCI but FFR has turned the tide after FAME study published. FFR is a well validated evidence-based tool to objectively measure the physiologic significance and functional assessment of epicardial coronary arterial stenosis. The FFR is a lesion-specific index measured as the ratio of pressure in the diseased epicardial coronary artery to the pressure in ‘normal’ coronary arteries during maximal hyperemia. Compared to angiography, FFR to guide revascularization has been shown to reduce morbidity and cost of care in patients with intermediate grade stenosis.12 As recent clinical study, FFR is an independent prognosticator in patients with CAD and the gold standard for decision making in PCI.13
The FAME (Fractional Flow Reserve vs Angiography for Multi-vessel Evaluation) study is the most significance research about FFR and it displayed that invasive FFR-guided decisions about PCI improve event-free survival compared with coronary angiography-guided decisions alone.14 Consequently, FFR is the acknowledged reference standard for assessing the functional significance of CAD in a lesion-specific manner,15 resulting in the incorporation of FFR-guided intervention for intermediate stenosis in interventional guidelines with a Class IIA, Level of Evidence A, recommendation by The American College of Cardiology Foundation/American Heart Association/Society for Cardiac Angiography and Interventions (ACCF/AHA/SCAI).16 Similarly, the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery (ESC/EACTS) in their 2014 guidelines recommended utilization of FFR in hemodynamically relevant coronary lesions in stable patients when evidence of ischemia is not available as a class IA recommendation. A class IIA recommendation was made regarding the use of FFR guided PCI in patients with multi-vessel disease.17 As a result, FFR guidance during PCI has received a class 1A recommendation from the European Society of Cardiology18 and a class IIA recommendation from the American College of Cardiology.19 Taiwan national health insurance guidelines recommend FFR as a reasonable option to assess angiographic intermediate coronary lesions (50–70 %)and for guiding revascularization decisions (Figure 2-1). Until recently, invasive angiography has been considered a gold standard for obstructive disease and need for revascularization, but these intervention trials clearly show that functional ischemia, as defined by FFR, improves outcomes.
Figure 2-1 Taiwan national health insurance guideline
2-1.2 Mechanism of Fractional Flow Reserve
Measurement of FFR is obtained using a coronary pressure wire advanced distal to the coronary stenosis of target and dividing it by the mean aortic pressure measured through the guiding catheter during maximum coronary hyperemia and minimal coronary resistance20 (Figure 2-2). If lack of an epicardial stenosis, no pressure drop will occur along the vessel and FFR will be normal or close to1.0.11 The generally accepted cutoff value for an abnormal FFR is 0.80. Current guidelines, together with Taiwan, for revascularization recommend intervention in cases of coronary stenosis with FFR ≤0.8.11,17 Less than 10 % of lesions fall into a gray area between 0.75 and 0.8, and that these lesions almost invariably are able to induce myocardial ischemia, and a value of >0.8 is almost never associated with exercise-induced ischemia and warrants safe deferral of PCI20 (Figure 2-3). FFR measurements are extremely reproducible due the capability of the microvasculature to repeatedly vasodilate to exactly the same extent. The contribution of collaterals both anterograde and retrograde is taken into account when calculating FFR. FFR is also an extremely important tool for prognosis following PCI. Revascularization of a FFR positive stenosis is associated with significant decrease in ischemia with improved outcome.21 In addition, FFR post-stenting is an independent predictor of adverse outcomes. Patients with a normalized FFR (>0.95) post-PCI with stenting have the lowest 6-month event rates. As the post-PCI FFR decreases, there is a graded increase in adverse events.22 Moreover, the meta-analysis investigating outcomes based threshold reports increased clinical events as FFR decreased and a larger net benefit with revascularization for lower 3-baseline FFR values.23
Figure 2-2 Principle of coronary FFR20
Figure 2-3 Cut-off value of FFR
An example of use of fractional flow reserve (FFR) for assessment of intermediate coronary artery stenosis: LAD lesion appeared of intermediate severity on the angiogram (a). Resting gradient was 0.93 (b) and post-hyperemia gradient was 0.85 (c). PCI was deferred on basis of this information (Figure 2-4).
Figure 2-4 An example of FFR in real world of PCI and result in decision making of PCI.
Despite the widespread use of FFR, there are certain pitfalls that need to be considered. FFR can have false negatives and false positives. Falsely negative FFR, due to non-technical reasons, can be seen in cases with well-developed collaterals or a small perfusion territory. Falsely positive FFR can be seen in serial intermediate severity stenosis and when large areas are involved.24 FFR values also need to be interpreted with caution in certain scenarios like chronic total occlusion, elevated left ventricular end diastolic pressures, and consumption of coffee prior to FFR done with adenosine. In cases with chronic total occlusion with multiple collaterals, the interpretation of FFR must be done with caution. It is essential to confirm lack of a pressure drop in such scenarios.25 Similarly in patients with elevated left ventricular diastolic pressure, the FFR can be elevated especially in low blood pressures.26 Caffeine has been shown to prevent adenosine-induced hyperemia.27 Signal drift also occurs during the procedure; the maximal acceptable drift is ≤5 mmHg/h. So ideally, a pullback curve is most ideal only when done during maximal hyperemia.28
2-1.3 Clinical research of Fractional Flow Reserve
Three major prospective randomized trials have demonstrated the clinical utility of FFR, including of Deferral of percutaneous coronary intervention (DEFER), Fractional Flow reserve Versus Angiography for Multi-vessel Evaluation (FAME), and FAME 2.11 The DEFER trial enrolled 325 patients with stable IHD scheduled for PCI that had an intermediate lesion by angiography. Those that had an abnormal FFR with provocative testing, defined as less than 0.75, underwent PCI (n =144). The remaining 181 patients with an FFR ≤0.75 were randomized to PCI versus deferral of PCI. Based on similar event-free survival and rates of angina out to 5 years, the DEFER trial supports the practice of deferring PCI in clinically stable patients with a non-functionally significant lesion.29
The next step of comparing FFR and angiography guided PCI was explored in the landmark FAME trial. Among 1005 patients with stable IHD, unstable angina, or NSTEMI and multi-vessel disease, the patients randomized to FFR guided PCI had significantly lower rates of the primary endpoint (death, nonfatal myocardial infarction (MI), or revascularization) at 1 year.30 At the end of 2 years, lower mortality or MI attack continued to favor the FFR group (8.4 vs. 12.9 %, p=0.02).31. Finally, with the FAME 2 trial, FFR was used to identify functionally significant lesions (cutoff value of 0.8) and PCI was compared to optimal medical therapy alone.32 The trial, after enrolling 888 patients, was stopped early because of the significant benefit in favor of PCI due to the decreased need for urgent revascularization. With the results from these three trials, the role of FFR as a tool for guiding PCI was firmly established. Subsequently, FFR was also found to have a favorable impact on resource utilization.33 FAME 2 showed that patients receiving PCI with proven ischemia by FFR had 66 % fewer primary endpoint events including death, MI, and urgent vascularization than those patients treated with medical therapy alone. The Registry arm also showed that patients with a negative FFR suggesting absence of ischemia did very well being treated with optimal medical therapy and no intervention. However, real-world verifying similar results with longer follow-up are definitely warranted.
Gray zone area of FFR between 0.75 and 0.79 is another big issue. Although management in this area is left at the discretion of the treating clinician, further guidance is needed to decrease the variability in the management. A lot of parameters may alter the pressure gradient then affect the final FFR value, including of stenosis degree, subtended myocardial territory, diffuse disease superimposed on a focal stenosis and micro-vascular resistance.34 Contemporary revascularization guidelines advocate the use of FFR in stenosis of intermediate angiographic severity. Routine measurement of FFR in daily practice seemed to be linked with fewer stent implanted then result in improvement of cardiovascular outcomes.35 However, few clinical situations, like left ventricular hypertrophy (LVH) and micro-vascular disease do not have trustworthy FFR value and should be cautiously practical. In patients with severe LVH, the growth of vascular bed is unequal to the muscle mass growth. The traditional cutoff value of 0.75 is consequently not appropriate.36 Similarly, it may not be completely reliable in cases with severe micro-vascular disease. The use of FFR is essentially limited by its invasiveness and costs. Moreover, lesions as in-stent restenosis, left main coronary artery or side branch lesions, Thrombolysis In Myocardial Infarction flow <3, thrombus-containing lesions, tandem lesions, extreme tortuosity and/or coronary calcification, and cases in which the intravascular ultrasound (IVUS) imaging catheter or FFR guidewire failed to cross the lesion has some limitation of performing FFR. These issues highlight the need for more invasive or noninvasive diagnostic tests for gate keeping to the catheterization laboratory.9 Newer technologies such as FFRCT and instantaneous wave-free ratio (iFR) have been shown to be feasible and safer alternatives to FFR37. However, their prognostic role and impact needs further definition and many ongoing investigation focus on iFR/FFR hybrid strategy.
Clinical use of IVUS-minimal lumen area (MLA) thresholds of 2.0 to 4.0 mm2 has been restricted because of their poor diagnostic accuracy of 60% to 70% and low PPVs of 27% to 67%.34 The visual-functional mismatch was associated with older age, female, and a smaller body surface area and left ventricular mass and with having non-LAD lesions, a smaller vessel size, and shorter lesion length.34 Although IVUS is generally used to assess coronary lesion morphology and disease severity, its role in the clinical decision to treat or not to treat non-left main coronary stenosis has been limited. Because the hemodynamic significance is determined not only by the degree of stenosis but also by the size of the myocardial territory a, including previous discussed functional deficiency. So IVUS-MLA, as an anatomical parameter, is incorrect for identifying a ischemia-producing lesion with a FFR ≤ 0.75 to 0.80.38 Thus, IVUS measurement may be useful to decide how to treat the lesions with a large myocardial volume. Furthermore, development of invasive coronary angiography- derived myocardial segmentation may facilitate the practical use of IVUS for decision making.34 Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. Larger plaque volume and necrotic core (NC) areas could be estimated by invasive virtual histology intravascular ultrasound (VH-IVUS) and higher serum levels of fibrinogen degradation products (FDP) is an independent predictor of larger plaques (P=0.03) and greater plaque NC (P=0.02).39 The prospective study of coronary atherosclerosis (PROSPECT) trial has shown a higher rate of major adverse cardiovascular events in patients with larger plaques or more vulnerable plaque phenotypes, namely thin-cap fibro- atheroma40(TCFA). Those characteristics of vascular plaque with FDP level are described in Figure 2-5. Moreover, acute coronary events are thought to occur when a vulnerable plaque co-exists with circulating thrombosis-promoting factors.39 An elevated FDP level may be an indication of subclinical plaque rupture and/or erosion, and thus an indicator of a pro-atherogenic coronary environment.39 However, plaque composition data derived from VH-IVUS is not true histology, and its accuracy has been evaluated in both ex vivo human coronary histology studies39 and in vivo directional coronary atherectomy specimens,41 with predictive accuracies of 87% to 97%39. The findings of this study provide mechanistic insight into our understanding of adverse outcomes associated with vulnerable plaques. Prospective trials are warranted to further explore the role of FDP in identifying patients with coronary atherosclerosis at risk of developing ACS.
Figure 2-5 Intravascular ultrasound exam- ples of plaques from 2 patients with high and low serum FDP Levels. (A) Grayscale and VH-IVUS images of large lipid-rich plaque from a patient with a high serum FDP level. (B) Grayscale and VH-IVUS images of a smaller fibrous-rich plaque from a patient with a low serum FDP level.40
In addition, FFR is determined by many clinical and local factors, such as age, gender, body surface area, lesion length, LAD involvement, lesion location, and vessel size.34 Most of these factors reflect the size of the supplied myocardium and it remains challenging to quantitatively assess the amount of the subtended myocardium till now. Using the coronary artery based myocardial segmentation method, total left ventricular myocardial volume (V total), myocardial volume subtended by the stenotic coronary segment (V sub), and V ratio (the ratio of the Vsub to the V total) were assessed for the correction of anatomic stenosis and functional deficiency. Both V sub > 30.7 cm3 and V ratio >25.4% were determinants of FFR≤ 0.75 (area under the curve [0.696 and 0.744]). Overall, among lesions with IVUS-MLA ≤ 2.83 mm2 predicted FFR ≤ 0.75 with a sensitivity 88% and specificity 73%. Among lesions with IVUS-MLA ≤ 2.83 mm2 and FFR > 0.75, 89% showed Vsub < 30.7 cm.34 Lesions with Vsub > 30.7 cm3, an IVUS-MLA ≤ 2.85 mm2 predicted FFR ≤ 0.75 with sensitivity 85%, specificity 92%, positive predictive value(PPV) 92%, and negative predictive value(NPV) 85%. Conversely, lesions with a Vsub ≤ 30.7 cm3,IVUS-MLA ≤ 2.67 mm2 showed sensitivity 100%, specificity 69%, PPV 38%, and NPV 100% for predicting FFR ≤ 0.75.34
Recently-introduced ultrafast cardiac myocardial perfusion imaging (MPI) cameras with cadmium zinc telluride (CZT)-based detectors may provide superior image quality allowing faster acquisition with reduced radiation doses but the diagnostic performance of MPI is still caution as poor concordance with MPI and FFR identified ischemic territories.42
Except epicardial coronary artery stenosis, clinical studies show that micro-vascular disease is an independent predictor of poor clinical outcomes in patients with macro-vascular disease, especially acute MI.43 However, clinical events occur even in patients with high FFR.44 Coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) may provide additional diagnostic and prognostic insights for patients with ischemic heart disease, but the clinical implications of CFR and IMR measurements in patients who have undergone FFR measurement remain unclear. Cutoff values were FFR ≤ 0.80 (low FFR) and CFR ≤ 2 (low CFR), as previously described.43 Different cutoff value of high IMR was defined as values ≥75th percentile of IMR corr IMR corr ≥ 23 U. The presence of low CFR with high IMR corr was the most powerful independent predictor for patient-oriented composite outcome in patients with high FFR (HR: 4.914; 95% CI: 1.541 to 15.663; p = 0.007)43 (Figure 2-6). Measurement of CFR and IMR in patients with high FFR provided information regarding the microvascular system that was not evident by clinical or angiographic characteristics. Other independent prognostic factors in patients with high FFR were diabetes mellitus, and multi-vessel disease. These findings suggest that the integration of CFR and IMR with FFR may improve risk stratification for patients with high FFR and further study is warranted to determine the IMR cutoff value that has independent prognostic impact.43
Figure 2-6 Low CFR with high IMR (Line D) was associated with poor prognosis.43
Contrast induced nephropathy is independently associated with adverse events including death, MI, and bleeding.45so cardiologist try hard to reduce the amount of contrast usage while performing invasive PCI and FFR. Various pharmacological and cardiac interventional approaches have been examined to reduce the risk of contrast-induced nephropathy (CIN)46 but no specific measures for patients with advanced chronic kidney disease (CKD) have been determined. Established approaches to prevent CIN include peri-procedural hydration47and minimizing contrast volume46. However, CIN and procedure-related renal replacement Therapy (RRT) can inhibit the performance of revascularization in patients with advanced CKD, especially those approaching end-stage renal diseases. Pre-existent renal disease is the strongest independent predictor for development of CIN and the requirement for RRT, which develop in 27 and 4% of patients with severe CKD, respectively.48 The feasibility, safety, and clinical utility of percutaneous coronary intervention (PCI) without radio-contrast medium in patients with advanced chronic kidney disease (CKD) are unknown and specific strategy for ‘zero contrast’ PCI with the aims of preserving renal function and preventing the need for RRT in patients with advanced CKD was advocated.45
The FAME 2 trial was halted prematurely after a mean follow up of 7 months due to the significantly higher rate of primary outcome (death, MI, or urgent revascularization) in patients assigned to the medical therapy group32(4.3 vs. 12.7 %; P<0.001). However, the question arises whether benefits are worth the costs of FFR-guided PCI in patients with stable CAD. Although there is an early disadvantage of upfront costs primarily related to procedure, professional fees, hospitalization, and cath lab costs, follow-up and overall costs were noted to be higher for the medical therapy arm due to increased costs of follow-up revascularization. FFR-mediated PCI saved money by reducing the need for repeat revascularization, including PCI and CABG. This proves the cost-effectiveness of using FFR. COURAGE trial which compared optimal medical therapy with or without PCI in stable CAD patients failed to show cost-effectiveness of ICA-guided PCI, but FAME 2 differed by being FFR-guided and was thus cost-effective.49
There is also a growing concern about detrimental long term effects of radiation associated with diagnostic procedures. Non-invasive diagnostic procedures including CCTA and single photon emission computed tomography (SPECT) when compared to invasive strategy including ICA and FFR measurement showed cumulative radiation dose being lowest when a first positive test is followed by an invasive strategy.50 However, the combination of CA and FFR is associated with lower effective radiation dose than the combination of CCTA and SPECT.11
FFR is defined as the ratio of maximum hyperemic flow in the presence of coronary artery disease to normal maximum flow, and it can be obtained by the ratio of the hyperemic distal coronary artery pressure (Pd) to the aortic pressure51(Pa). However, FFR with enough hyperemia status is another important issue of accurate measurement. Although continuous intravenous (IV) adenosine or adenosine 50-triphosphate (ATP) via central vein is a gold standard for the induction of hyperemia for invasive FFR, but there are some concerns about the variability of FFR measurement (short half-life, effect of caffeine, cyclic change). It is difficult to confirm sufficient maximum hyperemia after ATP infusion. Recent studies reported that nicorandil (NIC) could be an alternative to ATP as a hyperemic agent. Although a strong linear correlation was observed between FFR with ATP and NIC, some cases indicated relatively large FFR discrepancy between ATP and NIC.52 Additional IC NIC might be useful to confirm sufficient maximum hyperemia after IV ATP infusion in daily clinical practice. Furthermore, IC NIC could reduce cyclic change in FFR; thus, physicians might find it easier to determine FFR value during the procedure.53
Despite known limitation of FFR as invasiveness, radiation or costs, the use of FFR play an important role in decision making of PCI. Moreover, FFR cannot always be measured in vessels owing to extreme tortuosity and/or coronary calcification. These issues underscore the need for more accurate noninvasive diagnostic tests for gatekeeping to the catheterization laboratory.
2-2 Fractional flow reserve derived from coronary computed tomography angiography (FFRCT)
ICA plays a significant role in diagnostic algorithms for CAD, but serious complications such as coronary dissection, stroke, and myocardial infarction cannot be avoided completely as invasive procedure.54 According to current guidelines, CCTA is appropriate for excluding obstructive CAD in patients with low-to-intermediate cardiovascular risk55 because previous studies show outstandingly high NPV of CCTA to rule out CAD56. However, lower PPV and overestimation of coronary lesion severity present clinical limitation, compared with invasive route57 (Figure 2-7).Thus, determining hemodynamic relevance of anatomic coronary artery stenosis remains challenging in FFRCT. Disadvantages of FFRCT include the requirement for separate test (many patients will require CA anyway), and that CCTA is limited in the context of calcific CAD, irregular heart rhythm, tachycardia or motion artifact. We describe a systemic review of FFRCT below.
Figure 2-7 Per-patient diagnostic performance of both CR scans and invasive angiography.57
2-2.1 Introduction of FFRCT
CCTA is well established as the noninvasive standard for anatomic assessment of CAD.58 With improvements in spatial and temporal resolution, both mechanical and software-based, as well as implementation of large detector scanners the field of coronary CTA has seen progressive improvements over the last 10 years.58 In addition to image quality improvements, multiple scanner advances in both image acquisition and reconstruction have enabled CCTA to be performed consistently with radiation dose exposure in the 1–5 mSv range58. Despite the rapid technology progression, resting CCTA remains a strictly anatomic test and, as such, similar to conventional ICA, it lacks the physiologic information to guide PCI59 (Figure 2-8).
Figure 2-8 Coronary computed tomographic angiography demonstrates a high-grade lesion in the proximal right coronary artery as seen with(A)3-dimensional reconstruction(arrow)and
(B)a multiplanar reformatted image(arrow).(C)The severity is suggested by the complex nature of the plaque, with both soft and calcific portions, as well as the compensatory expansion of the artery within the most severe area.(D and E).An invasive coronary angiogram confirmed the high-grade lesion in the right coronary artery(arrow).(F)A stent was selected to cover not only the high-grade area, but also the more moderate plaque proximal and distal to the most severe portions of the lesion.59
Invasive FFR during catheterization is the reference standard for assessing lesion-specific ischemia55 and is powerfully associated to the clinical outcome via FAME study.58 However, FFR is limited by its invasiveness and cost, and hence in real-world practice it is used for coronary revascularization decision-making in a minority of patients.58 Recent data suggest that CTCA is more accurate than MPI SPECT stress testing for the presence of clinically relevant CAD in symptomatic individuals, while exposing patients to less radiation1. Non-invasive FFR derived from CCTA (called FFRCT) may provide incremental diagnostic value over CCTA alone by combining anatomic and functional information. Several studies show high discriminatory accuracy of FFRCT to detect hemodynamically significant stenosis compared to invasive FFR.55 Recent investigations proposed additional functional parameters obtained from FFRCT may enhance diagnostic performance when detecting hemodynamically significant CAD.55 In addition, FFRCT based CCTA could provide additional markers, including plaque morphology, volume, and composition compared with ICA alone55 (Figure 2-9 ). However, a comparison predicting FFR abnormalities (inferring lesion-specific ischemia) based on noninvasive CCTA and ICA has not been well evaluated contemporarily in a large-scale multicenter study.
Figure 2-9 CCTA provides additional markers, including plaque morphology, volume, and composition, compared with ICA.55
2-2.2 Mechanism of FFRCT
With recent technological and scientific advancements, noninvasive methods to calculate FFR have been developed. The integration of computational fluid dynamics and quantitative anatomic and physiologic modeling now enables simulation of patient-specific hemodynamic parameters including blood velocity, pressure, pressure gradients, and FFR from standard acquired coronary CT datasets58.
Once computed tomography became fast enough to obtain clear images of the beating heart, it has been used for obtaining non-invasive diagnostic images of the coronary arteries as well as the larger structures of the heart.1 In addition to morphologic identification of the presence of coronary atherosclerosis, new techniques such as FFRCT allow even finer discrimination between those plaques that are and are not functionally stenotic, similar to invasive FFR in the cath lab.1 Once a patient has been identified as having plaque that is flow limiting (or theoretically unstable) and in need of stenting, FFRCT functional testing data can be used by the interventional cardiologist prior to the patient ever entering the cath lab to plan their percutaneous strategy.57
FFR can be derived from coronary CTA image data acquired using standard acquisition protocols without the need for additional imaging, medication, or radiation. FFRCT analysis uses mathematical models of blood flow derived from patient-specific data extracted from coronary CTA images and solved on high-performance computers. Any mathematical
model of blood flow in the circulation includes at least 3 elements: first, a description of the anatomic region of interest; second, the mathematical “governing equations” enumerating the physical laws of blood flow within the region of interest; and third, “boundary conditions” to define physiologic relationships between variables at the boundaries of the region of
interest.58 The integration of computational fluid dynamics and quantitative anatomic
and physiologic modeling now enables simulation of patient-specific hemodynamic parameters including blood velocity, pressure, pressure gradients, and FFR from standard
CCTA dataset.
Computed tomographic angiography is performed on 64–or higher detector row scanners with prospective or retrospective electrocardiographic gating in accordance with Society of Cardiovascular Computed Tomography guidelines. Computed tomographic angiograms are collected and transferred to a central core laboratory for blinded interpretation using an 18- or higher segment coronary model. Different researches evaluate CTs for maximal patient-, vessel-, and segment-based diameter stenosis.60 However, different study used different core laboratory or different software for accessing FFRCT so we cannot compare the difference of those FFRCT study. Calculations of FFRCT are performed by computational fluid dynamic (CFD) modeling after semi-automated segmentation of coronary arteries and left ventricular mass. Many methods are required to create 3-dimensional coronary blood flow, including newtonian fluid using incompressible Navier-Stokes equations, finite element method on a parallel supercomputer or others without disclosed. This process of transforming CCTA to FFRCT required approximately 6- or more hours per case so this is a big problem of time-wasting step in clinical use. Since coronary flow and pressure were unknown a priori, a method to couple lumped parameter models of the microcirculation to the outflow boundaries of the 3-dimensional model was used. Another difficult issue is the detection of blood pressure difference. Traditionally coronary blood flow was simulated under conditions modeling adenosine-mediated coronary hyperemia via invasive route. The FFRCT ratio was obtained by dividing the mean pressure distal to the coronary stenosis by the mean aortic pressure. Similar to invasive FFR, default FFRCT values of 0.50 and 0.90 were assigned to subtotally and totally occluded arteries or non-stenotic coronary arteries, respectively58 ( Table 1).
Table 1 decision-making on coronary revascularization via FFR. 58
2-2.3 Clinical research of FFRCT
Coronary CTA allows for a surrogate FFR measure to be derived (FFRCT), which adds to the diagnostic potential of coronary CTA without additional scanning, radiation, or contrast injection. The progressive development of FFRCT has led to studies being performed to evaluate the diagnostic accuracy of FFRCT compared with invasive FFR because recent studies demonstrated the huge gap between invasive FFR and FFRCT.
The Diagnosis of Ischemia-Causing Stenoses Obtained via Non-invasive Fractional Flow Reserve (DISCOVERFLOW), Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO), and Analysis of Coronary Blood Flow Using CT Angiography: Next Steps (NXT) trials suggests that FFRCT is a useful surrogate for invasive FFR and is clearly associated with lower costs and increased patient safety.11,57 FFRCT can help with combined anatomic–physiological evaluation of coronary artery stenosis with the help of a computer software. These trials showed similar sensitivity rates to FFR. However, the specificity and diagnostic accuracy rates of CCTA were lower as compared to FFR. A total of 609 patients and 1050 vessels have been investigated. An overview of study design, populations, and estimates of FFRCT diagnostic performance in these 3 trials58 is presented in Table 2.
Table 2 An overview of study design, populations, and estimates of FFRCT diagnostic performance in these 3 trials.
In the 3 trials, FFRCT revealed high per-patient and per-vessel discrimination
for the presence of ischemia with blinded comparison to measured FFR. However, in the DeFACTO trial, the accuracy of FFRCT was not met the lower limit of the 95 % confidence interval (67 %–78 %) and it did not exceed 70 % actually.61 Moreover, the diagnostic specificity of FFRCT was rather low for clinical use.(42 % for CCTA vs 54 % for FFRCT).
However, FFRCT demonstrated higher per-patient and per-vessel discrimination of ischemia compared with coronary CTA alone with AUC’ of 0.81 vs 0.68 (P< 0.001) and 0.81 vs 0.75 (P < 0.001).61 Several possible causes resulted in the lower accuracy and specificity, including of early generation FFRCT analysis algorithm and not enough use of pre-acquisition beta-blockers or nitroglycerin. Inadequate nitroglycerin induced hyperemia resulted in underestimation of the coronary artery diameter with a resultant increase in false positive FFRCT62 and beta-blockers were not used in almost one-third of patients, potentially adversely affecting CT image quality and increasing discordance between FFRCT and FFR.58
The most recent and largest study, the NXT trial incorporated knowledge from the previous 2 trials, including use of the latest generation of FFRCT analysis software.58 In the NXT trial, the per-patient diagnostic accuracy of FFRCT in predicting lesion-specific ischemia was superior to anatomic assessment by CCTA, 81 % vs 53 % (P< 0.001) arising from an increase in specificity from 34 % to 79 % (P< 0.001).63 The improved diagnostic performance of FFRCT in the NXT trial compared with the DeFACTO trial reflects major enhancement in FFRCT technology and physiologic modeling.58
In the NXT trial, there was a good direct correlation of FFRCT to invasively measured FFR (r = 0.82), with a slight underestimation of FFRCT (mean difference = 0.03) compared with FFR. The reproducibility of repeated FFRCT calculations are high with a coefficient of variation between 1.4 % and 4.6 % 58. Examples illustrating the clinical utility of FFRCT in patients with CAD with or without ischemia is shown in Figure 2-10 and 2-11.
Figure 2-10 Patient examples illustrating the clinical utility of FFRCT in patients with CAD with ischemia.58
Figure 2-11 Patient examples illustrating the clinical utility of FFRCT in patients with CAD without ischemia58
Various quantitative stenosis markers derived from CCTA could be used for improving accuracy of FFRCT : Corrected coronary opacification (CCO), transluminal attenuation gradient (TAG), remodeling index (RI), FFRCT, lesion length (LL), vessel volume (VV), total plaque volume (TPV), and calcified and non-calcified plaque volume (CPV and NCPV). Discriminatory power of these markers for flow-limiting versus non-significant coronary stenosis was assessed against invasive FFR as the reference standard55. Morphological parameters, as TPV and NCPV have the highest predictive value to determine hemodynamic relevance, showing higher sensitivity and specificity of 88% and 74%, and 92% and 81%, respectively. TPV and NCPV demonstrated significant correlation and performance compared with invasive FFR to diagnose lesion-specific ischemia (AUC 0.78, p = 0.013 and AUC 0.79, p = 0.009). Among those functional parameters, FFRCT and CCO are the strongest predictors for ischemia, showing sensitivity and specificity of 64% and 86%, and 100% and 90%, respectively.55
High coronary calcium scores are associated with an increased burden of atherosclerotic disease and impair the utilization of CTA to detect and rule out CAD64. When patients were divided using a cut-off for the Agatston score of either 100 or 400, the AUC for patients with an Agatston score >100 (AUC of 0.75 versus 0.85, p =0.1475) and an Agatston score >400 (0.75 versus 0.82, p =0.299) were lower, mainly driven by a loss of specificity64 (Figure 2-12). In clinical practice, un-interpretable segments found on CTA are often considered interpreted as a positive result even though their functional significance is unknown64. FFRCT has high diagnostic performance in the presence of coronary calcification, compared CTA alone.58 In a NXT trial sub-study including 214 patients (333 vessels), there was no difference in diagnostic accuracy, sensitivity, or specificity of FFRCT across Agatston score quartiles, including the highest quartile of patients with Agatston scores ranging between 416 and 359958. In vessels with the highest Agatston scores, FFRCT showed significant improved discrimination of ischemia compared with coronary CTA alone (0.91 vs 0.71, P = 0.004), corresponding to 60 % correct reclassification of cases when moving from coronary CTA to FFRCT58. In contrast, CCTA stenosis assessment relies on identification of segmental changes with resultant reduction in lumen interpretability so the presence of artifacts may have a greater impact on interpretation.
Figure 2-12 Role of CT angiography and perfusion imaging on the assessment of coronary artery disease e impact of coronary artery calcium and rate of uninterpretable exams.64
2-2.4 Cost Effectiveness, and Quality of Life (QOL) of FFRCT
In the context of rising global healthcare costs, greater attention is focused on cost-effectiveness of procedures with outcome improvement. Total medical costs were derived from the number of diagnostic tests, invasive procedures, hospitalizations, and medications during follow-up period. Accordingly, the “Outcomes of Anatomic vs Functional testing for Coronary Artery Disease” (PROMISE) trial, compared CCTA with frontline noninvasive ischemia testing and demonstrated an almost 50 % increase in downstream referrals to ICA and a doubling in PCI rate which, however, did not translate into improved outcomes.58 This findings emphasize the need of accurate noninvasive gate keeping to the catheterization laboratory beyond anatomic assessment. The study “Prospective Longitudinal Trial of FFRCT: Outcome and Resource impacts” (PLATFORM) trial examined the clinical cost effectiveness impact of a strategy using FFRCT to guide CAD management compared with the usual testing strategy in 11 European centers.58 Study results showed high rates of finding no obstructive CAD by ICA in both the planned noninvasive and planned ICA groups. In the planned ICA group, 73%of usual care patients had no obstructive CAD compared with only 12 % of patients guided by FFRCT.58 .The angiogram was cancelled in 61 % of patients with planned ICA noticeably after receiving functional data from FFRCT. The PLATFORM study highlights that FFRCT guidance for selection of ICA and decision-making on PCI may reduce costs in stable CAD and improve QOL at the same time.58
2-2.5 Limitations of FFRCT Testing
CCTA provide anatomic and pathologic benefits compared with ICA alone. Like high-risk left main pathology or abnormal takeoff of coronary ostium can be identified before PCI.1 During the last 5 years, FFRCT has undergone remarkable advancements in technology, and its support in the clinical community challenging conventional CCTA and ischemia testing.58 A particular strength of the computational methods used to derive FFRCT lies in the possibility of altering the patient anatomic or physiological model to predict the anticipated benefit of treatments. Although no special imaging protocols are required for FFRCT assessment, significant CT imaging artifacts such as motion, low contrast, or blooming from coronary calcification may impair the diagnostic performance of CCTA and thus of FFRCT. In the DeFACTO and NXT trials, 11 % and 13 % of the patients had non-evaluable coronary CTA images58. Poor quality of CCTA can be minimized by administration of heart-rate lowering medication and sublingual nitrates before image acquisition58. In the DeFACTO trial, administration of a pre-scan beta-blocker increased FFRCT diagnostic specificity from 51 % to 66 % (P = 0.03), whereas nitroglycerin pretreatment within 30 minutes of CT was associated with improved specificity from 54 % to 75 % (P = 0.01). Currently, FFRCT testing requires offsite computer processing requiring 2 to 6 hours at least so longer processing time is another big issue. However, significantly faster FFRCT-testing processing times resulting from software improvements are expected in the near future and fast (<1 hour) FFRCT has shown interesting results in small, single-center, retrospective studies.58 Importantly, invasive angiography should remain the dominant diagnostic strategy in high risk individuals, where pre-test probability of obstructive disease is very high.
There are a variety of different biomechanical forces that act on blood vessels arising from internal pressure and flow and external tissue support. These applied forces result in stress acting on the surface or within blood vessels, where stress is defined as force per unit area. In addition to external applied forces, blood vessels have intrinsic, or residual, stresses emanating from growth and remodeling.58 These residual stresses are present
even in the absence of external applied forces.
Wall shear stress (WSS) is defined as the tangential force per unit area acting on the luminal surface. Axial plaque stress (APS) is defined as the axial component of the hemodynamic stress acting on stenotic lesions.65 APS and WSS both result from hemodynamic forces acting on the luminal surface, but have important differences. APS is strongly related to the absolute pressure on the surface of the plaque, whereas WSS is independent of the absolute pressure but closely coupled to flow and the pressure-gradient. APS is much larger than WSS65 (approximately 40 times larger than the maximum WSS even in tight stenosis and under hyperemic conditions where WSS is maximal). Both WSS and APS can be derived from the velocity and pressure fields calculated by patient-specific modeling of coronary blood flow derived from CT data. Image-based computational methods have been used to compute wall shear stress noninvasively in the human abdominal aorta, the extra-cranial and intra-cranial cerebral arteries, and the pulmonary arteries.58
WSS plays a role in maintaining endothelial function and is likely to influence plaque initiation and progression.58 WSS is the product of the blood viscosity and the gradient of the velocity field at the luminal surface. WSS is sensed by the endothelium and in turn influences normal endothelial function, as well as atherosclerosis localization and progression. Image-based modeling techniques have also been used to evaluate wall shear stress in the human coronary arteries based on invasive data58, and to a lesser extent using noninvasive data.58 Whereas the mechanical influence of WSS is confined to a narrow zone of the vessel wall near the endothelium, APS acts throughout the entire thickness of the plaque and is likely to play a more direct role in plaque rupture. In a recent publication, Choi et al. described the potential role of APS in plaque rupture and its relationship with lesion geometry.65 APS was found to uniquely characterize the stenotic segment and differentiate forces acting on upstream and downstream segments of a plaque. While WSS and pressure were consistently higher in upstream than in downstream segments, APS could be higher at the downstream than upstream segment in some lesions, thus potentially explaining why some plaques rupture at the downstream segments. Figure 2-13 depicts the FFRCT result and the APS for a patient experiencing a cardiac arrest, and primary percutaneous coronary intervention of an occluded left anterior descending artery lesion occurring 1 year after a coronary CTA examination.58 The FFRCT and APS analyses were performed retrospectively based on the CCTA data acquired 1 year prior to the myocardial infarction, indicating a very low FFRCT result and high APS on the segment upstream of the minimum lumen area.65 The utility of FFRCT and axial plaque stress for predicting plaque rupture are currently being evaluated in the “Exploring the Mechanism of the Plaque Rupture in Acute Myocardial Infarction” (EMERALD) trial.
Figure 2-13 Case example FFRCT and APS analysis computed under simulated hyperemic conditions performed retrospectively on coronary CTA data acquired one year prior to a subsequent cardiac arrest and revascularization of a LAD lesion. (a) FFRCT analysis indicates a markedly functionally significant lesion in the mid-LAD (b) Coronary CTA images reveal a mixed non-calcified and calcified plaque (c) APS values are elevated in the upstream segment of the lesion.58
First-pass CT myocardial perfusion imaging (MPI) has resulted in significant interest with strong early results compared with both noninvasive and invasive measures of ischemia.58 Although a promising technique, CT perfusion requires the administration of a pharmacologic stress agent and a repeat CT acquisition, thereby increasing both the time required and the radiation exposure to the patient. Furthermore, CT perfusion provides data analogous to coronary flow reserve, which has known limitations in isolating epicardial coronary disease that is treatable with revascularization from microvascular disease without any established therapy.
CTA is an excellent method for detecting CAD, although it is still challenging in cases with heavy calcification and intermediate stenotic lesion. First-pass CT myocardial perfusion imaging (MPI) without stress is simultaneously obtained from the same raw data used for CCTA and requires no additional contrast medium and radiation exposure. CT myocardial perfusion imaging may represent an opportunity to overcome this limitation.64 CT myocardial perfusion analysis is an increasingly used imaging modality that detects inducible perfusion defects by assessing differences in contrast distribution between normal and hypoperfused myocardium.64 The addition of MPI to CTA increases the global accuracy of CT for the detection of functionally significant CAD.64 Retrospective image reconstruction was performed at 5% phase increments throughout the cardiac cycle. A total of 20 image data sets were reconstructed. The slice was 3-mm thick. The short-axis images were reconstructed from 20 image data sets using the standard double oblique method and were finally expressed in a bull’s eye map, which could be an easy-to-understand format for general physicians. Assignment of the left ventricular segment was based on the 16 myocardial segment models, excluding the apical segment.39 Warm colors represented hyper-enhanced areas with high CT values and cold colors represented hypo-enhanced areas with low CT values. From the tone of the cold colors and ratio of the cold color area, the hypo-enhanced areas were graded on a three-point scale of mild, moderate and severe. When first-pass CT-MPI without stress showed moderate or severe perfusion attenuation, corresponding vessels were considered to have significant stenosis9. CCTA in combination with first-pass CT MPI has a better diagnostic performance than CCTA alone, compared with invasive coronary angiography as the reference standard. First-pass CT-MPI without stress correctly reclassified 38% of CCTA false-positive vessels as true negative. First-pass CT-MPI without stress combined with CCTA demonstrated excellent diagnostic accuracy, compared with invasive FFR as the reference standard9 (Figure 2-14) and could be used as an adjunct to the diagnosis of ischemia-causing CAD as comprehensive non-invasive anatomical and functional assessment9 (Figure 2-15).
Figure 2-14 Reclassification criteria. Before CT-MPI analysis, non-evaluable with CCTA was defined as positive for stenosis using the following criteria: those with no vessel wall definition owing to marked motion artifacts or heavy calcification that precluded acquisition of diagnostic information.
Figure 2-15 Case examples of CCTA, CT-MPI without stress, coronary angiography, and invasive FFR.
Case 1. CCTA showed significant coronary artery calcification in the proximal LAD (yellow arrow). CT-MPI without stress showed no perfusion defect. Coronary angiography confirmed no significant stenosis in the LAD with invasive FFR = 0.86.
Case 2. CCTA showed significant coronary artery calcification in the left main trunk and proximal LAD (yellow arrow). CT-MPI without stress showed perfusion defects in the anterior (yellow arrow) and inferior (green arrow) walls. Coronary angiography confirmed 58% luminal stenosis in the LAD with invasive FFR = 0.78 (yellow line) and 56% stenosis in the RCA (green arrow).
Case 3. CCTA showed diffuse stenosis <50% in the middle of the LAD (yellow arrow). CT-MPI without stress showed perfusion defects in the anterior (yellow arrow) and inferolateral (green arrow) walls. Coronary angiography confirmed diffuse 55% stenosis in the LAD with invasive FFR = 0.75 (yellow line) and 69% of luminal stenosis in the LCX9.
2-3 Instantaneous wave-free ratio (iFR)
FFR is a validated index of coronary stenosis severity. FFR-guided PCI improves clinical outcomes compared to angiographic guidance alone. iFR has been proposed as a new index of stenosis severity that can be measured without adenosine. However, most published data have been based on off-line analyses of pressure recordings in a core laboratory.66
2-3.1 Introduction of iFR
FFR has demonstrated the inaccuracy of angiography for evaluating the functional
significance of coronary lesions with a 50% to 90% diameter stenosis.67 In the FAME trial, only 14% of patients with angiographic 3-vessel disease had functional 3-vessel disease, while 43% had 2-vessel disease, 34% suffered from single-vessel disease, and 9% had no functionally relevant coronary artery disease at all.67 In another recent study, FFR guidance was associated with reclassification of revascularization strategy in about half of the patients.66 Furthermore, FFR guided percutaneous coronary intervention has been shown to improve clinical outcome and procedural cost-effectiveness.55 In 2012, the instantaneous wave-free ratio (iFR) was introduced as an adenosine-independent index of coronary stenosis severity. While FFR is time-averaged over several cardiac cycles, iFR is calculated as the ratio of the distal transstenotic pressure to the proximal coronary or aortic pressure during a specific diastolic wave-free period in a single cardiac cycle, when coronary resistance is most stable and minimized over the cardiac cycle.66 A good classification agreement between iFR and FFR has been demonstrated, and the optimal calculated iFR cut-off was 0.83 to 0.89 for predicting an FFR value of 0.8.68,69
2-3.2 Mechanism of iFR
The cornerstone of FFR is the linear relationship between pressure and flow under conditions of constant (and minimized) intracoronary resistance70. Under such conditions, pressure and flow are assumed to be directly proportional, and a decrease in pressure across a stenosis reflects a decrease in blood flow to the dependent myocardium. However, even after administration of potent pharmacologic agents such as adenosine, intracoronary resistance is not static, but instead fluctuates in a phasic pattern throughout the cardiac cycle70 (Figure 2-16 and 2-17). These fluctuations reflect the interaction between the myocardium and microvasculature during systole (high intracoronary resistance, compression of microvasculature) and diastole (lower intracoronary resistance, decompression of the microvasculature).71 Accordingly, to minimize these effects, FFR is calculated during hyperemia (maximal flow to the vascular bed) and time averaged over several cardiac cycles to ensure constant and minimal intracoronary resistance.70Although time-averaging and the administration of pharmacologic vasodilators were a pragmatic solution to achieving appropriate conditions in which to calculate FFR when computational power was limited, it may now be unnecessary if a time period could be identified from the resting pressure waveform when resistance is naturally constant and minimized. Theoretically, during such a period in the cardiac cycle, intracoronary pressure and flow would be proportional. Consequently, a ratio of trans-stenotic pressures during this time would provide a measure of the severity of a coronary stenosis.
Figure 2-16 Identification of Wave-Free Period in the Cardiac Cycle70. Wave-intensity analysis (A) demonstrates the proximal and microcirculatory (distal) originating waves generated during the cardiac cycle. A wave-free period can be seen in diastole when no new waves are generated (shaded). This corresponds to a time period in which there is minimal microcirculatory (distal)– originating pressure (B), minimal and constant resistance (C), and a nearly constant rate of change in flow velocity (D). (Separated pressure above diastole is the residual pulsatile separated pressure component after subtraction of the diastolic pressure.)
Figure 2-17 Coronary Velocity, Aortic and Coronary Pressures, and Resistance in the Right Coronary Artery.70 Stable intracoronary resistance is subsequently achieved in diastole phase.
iFR is a pressure-derived adenosine-free functional measurement of coronary stenosis
and it has been proposed as an index of stenosis severity that is independent of hyperemia.69 The concept of iFR is based on the hypothesis that there is a diastolic “wave-free” period (WFP) when microvascular resistance is already constant and minimal. After the coronary angiogram was obtained, the pressure wire was zeroed, equalized, and positioned with the sensor. iFR was calculated as the mean pressure distal to the stenosis during the diastolic WFP (Pd wave-free period) divided by the mean aortic pressure during the diastolic WFP
(Pa wave-free period) (Figure 2-18). All analyses were performed in a fully automated manner, eliminating the need or manual selection of data time points.
Figure 2-18 iFR equal to Pd wave-free period divided by Pa wave-free period
The hypothesis underlying iFR depends on accepting that mean resting myocardial resistance during the WFP of diastole is minimal and equivalent to mean resistance during maximal hyperemia over the complete cardiac cycle. Blood flow at rest in a normal coronary artery is low during systole (because of high resistance) and occurs primarily in diastole. During adenosine-induced maximal hyperemia, coronary blood flow and trans-stenotic pressure gradient increase in both phases of the cardiac cycle but much more so during diastole than systole, compared with resting phase without adenosine.69 (Figure 2-19 and 2-20).
Figure 2-19 Pressure Tracings of 2 Sequential Heartbeats at hyperemia.69
Figure 2-20 Pressure Tracings of 2 Sequential Heartbeats at Rest.69
The iFR provides a beat-to-beat pressure ratio during the wave-free window, comparing each distal pressure with its corresponding aortic pressure. This ensures accuracy regardless of arrhythmia or variations in blood pressure and heart rate.70 An iFR value of ≦0.83 to 0.89 has been suggested as having diagnostic accuracy comparable to the commonly used FFR cutoff of≦0.80.68,69 In the “Adenosine Vasodilator Independent Stenosis Evaluation (ADVISE II)“ trial, iFR has demonstrated a high correlation to FFR and is a useful alternative to FFR in patients who cannot tolerate adenosine. Moreover, it appears to be more cost-effective and less time consuming.
Figure 2-21 Stability of the iFR During Hemodynamic Perturbation(A) sinus rhythm (B) tachycardia with respiratory variation.70
2-3.3 Clinical research of iFR
Receiver-operating characteristic analysis identified an optimal iFR cut-off value of 0.896 for categorization based on an FFR cut-off value 0.8.69 “Comparison of instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) — First real world experience” compared two different iFR-based diagnostic strategies (iFR-only and hybrid iFR–FFR) with standard FFR. They found that the iFR-only strategy showed good classification agreement (83.4%) with standard FFR. Use of the hybrid iFR–FFR strategy, assessing lesions in an iFR-gray zone of 0.86 to 0.93 by FFR, improved classification accuracy to 94.7%, and diagnosis would have been established in 61% of patients without adenosine-induced hyperemia. Real-time iFR measurements are easily performed, have excellent diagnostic performance and confirm available off-line core laboratory data. The excellent agreement between repeated iFR measurements demonstrates the reliability of single measurements. Combining iFR with FFR in a hybrid strategy enhances diagnostic accuracy, exposing fewer patients to adenosine. Overall, iFR is a promising method, but still requires prospective clinical endpoint trial evaluation66. After positioning the guide wire, automated online calculation of iFR was very fast (less than 5 s), and repeated measurements showed excellent short-term reproducibility. These findings agree with the recently published ADVISED-in-practice study.70 The existence of a WFP in diastole when
coronary resistance is constant and minimal opens the possibility of performing pressure-derived stenosis assessment without the need for pharmacologic vasodilation.
2-3.4 Cost effectiveness of iFR
In addition, adenosine-dependent procedural costs would drop, because both
the drug itself and the administration equipment would be unnecessary. Furthermore, considering adenosine contraindications and side effects, more patients could undergo functional assessment, and patient comfort would improve significantly. In the light of these advantages, iFR is a promising tool which may increase acceptance and use of invasive
functional assessment of coronary stenosis.66 In order to determine whether iFR was independent of hyperemia, mean Pd/Pa during this period was also measured during adenosine infusion (“hyperemic” iFR) in the study "VERIFY (VERification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in EverydaY Practice)”.69 The results show a moderate overall correlation between FFR and iFR but only a weak correlation in the clinically important range for decision making of 0.60 to 0.90. Besides, the study found iFR.
did in fact change markedly during adenosine-induced hyperemia, a finding which challenges the underlying concept and clinical applicability of iFR.69 Minimal diastolic resistance at rest (whether measured during the whole of diastole or only during the WFP) is generally 50% to 100% higher than the average resistance over the complete heart cycle during hyperemia, as is apparent from our observation of an average decrease in iFR from rest to hyperemia of more than 100% relative to the reduction of iFR from its normal value of 1.0.69 In
addition to these considerations, the geometry of a stenosis determines the relative magnitude of the friction coefficient (f) and the separation coefficient (s), as described
by the equation △P = fQ + sQ2, where P =pressure and Q =flow.69 In short, minimal resting gradients of severe lesions can increase substantially during hyperemia, whereas in long moderate lesions, large resting gradients may increase only minimally during hyperemia. They concluded that iFR is not independent of hyperemia, correlates poorly with FFR, and has not been validated experimentally or relative to any of the established noninvasive techniques for identifying reversible myocardial ischemia, including the true gold standard of repeat testing before and after revascularisation.69 Consequently, they believe that iFR cannot be recommended for clinical decision making in patients with coronary artery disease.
2-4 Virtual design
Virtual reality (VR) created a strong collection with medical filed recently, particularly in the fields of procedural training and robotic surgery. Recently, VR technology was involved in the peri- procedural or re-construction of cardiac anatomy, especially PCI and fluid medicated images as FFRCT.1 3D CTA coronary vasculature reconstructed images projected in a wearable VR device base on Google Glass (Google) could be an optical head-mounted display. So combination of these new technologies will help cardiologist for pre-operative evaluation and treatment of chest pain or any heart disease.
Figure 2-22 The future of virtual reality in coronary atherosclerosis
PCI guided by FFR is superior to standard assessment alone but fewer patients used FFR in real world population as many causes. Developing a computer model (different from FFRCT) that could accurately predict FFR from angiographic images only is a big challenge. Generic boundary conditions for CFD analysis are applied in the reconstruction and the knowledge of CFD is improving gradually. The outstanding study “Virtual Fractional Flow Reserve From Coronary Angiography: Modeling the Significance of Coronary Lesions” created a new way of leadless FFR, called virtual FFR(vFFR).72 Two clear projections, from similar phases of the cardiac cycle—as close to 90° apart as was possible with good vessel opacification and contrast— were selected to reconstruct the arteries. All 1212-dimensional images from each RoCA were exported to a Philips 3-dimensional (3D) workstation where the coronary reconstructions were created as a virtual reality modeling language file to the developed workflow (based upon Graphical Interface for Medical Image Analysis and Simulation software).So vFFR was created virtually via CFD mediated software and compared the accuracy with measured fractional flow reserve (mFFR), golden standard data from invasive FFR wire. The closed surface of vessel was “meshed” into approximately 1 million internal tetrahedra, in preparation for the CFD simulation.72 Generic downstream boundary conditions were developed via Windkessel model and choose an a posteriori correction as distal impedance reference . The Windkessel model is an electrical analogue of arterial vasculature, in which the downstream resistance is calculated from the pressure and flow over the heart cycle. As lack of downstream micro-vascular resistance and compliance values from invasive pressure measurement, they produce a generic value by averaged the resistance and compliance values. The accuracy of the vFFR with these averaged boundary conditions would be lower than that obtained using individually tuned parameters. Only 19 patients with stable CAD were studied for vFFR and there was a high level agreement between mFFR and vFFR. Diagnostic accuracy of vFFR (95% CI) was evaluated as follows; sensitivity 86% (0.48 to 0.97), specificity 100% (0.87 to 1.00), PPV 100% (0.60 to 1.00), and NPV 97% (0.82 to 0.99). The overall diagnostic accuracy of vFFR was 97%. Applying the more stringent threshold of significance for FFR (<0.75) lesions, the sensitivity was 71% (2 false negatives), specificity 100%, PPV 100%, NPV 93% and the overall diagnostic accuracy was 94%. The quantitative accuracy of the workflow is described in Table 3.72 The mean difference between mFFR and vFFR was +0.02 (SD = 0.08). The average absolute error of vFFR, when compared with mFFR, was ±0.06 (±8.1%). The Bland-Altman plot is shown in Figure 2-23.72 The correlation coefficient of the vFFR values with the mFFR values was 0.84 (Figure 2-24). The model reliably quantifies FFR to within ±0.06. This is the first in vivo study to report such accurate CFD-based measurements within the coronary circulation72 (Figure 2-25).
Table 3 The quantitative accuracy of the workflow is described below.72
Figure 2-23 Bland-Altman plot. Demonstrating the difference between the virtual fractional flow reserve (vFFR) and measured fractional flow reserve (mFFR) plotted against the mean value. The 2 dark lines indicate the limits of agreement, 2 SD above and below the mean delta.
Figure 2-24 Correlation Between vFFR and mFFR. With a line of best fit passing through the origin (R = 0.84).72
Figure 2-25 Example of vFFR in a Left Anterior Descending Artery72. Images from Patient #11, a 50-year-old man with chronic stable angina and a stenosis in the proximal left anterior descending artery. Two rotational angiograms were recorded, 1 with cranial, and the other with caudal tilt. (A and B) Single frames from the cranial rotation, in the posteroanterior (A) and right anterior oblique (B) projections. The arrows identify the stenosis. The baseline mFFR was 0.51. The angiographic data were processed for anatomic and physiological reconstruction, which is displayed in C. The colors represent pressure (Pa) according to the scale shown. The vFFR was 0.60. A 4 x 12 mm stent was implanted. The rotational angiogram was repeated, and the mFFR was 0.95. The corresponding images, taken from the post-implantation angiogram and the reconstruction, are shown in D, E, and F. The vFFR post-implantation was 0.96.
Compared with mFFR, there is no need for the induction of hyperemic flow, or additional procedure time, or the hazard of passing an intracoronary wire, or additional equipment, training or cost in vFFR. A computational tool such as vFFR would improve operator in physiologically guided decision making immediately. This method only relies on vessel geometry alone from invasive CA without unnecessary estimation of myocardial mass or computed tomography. As like as mFFR, microcirculatory resistance still presents a challenge to vFFRR. Alterations in downstream microcirculation resistance might limit the rise in blood flow after vasodilatation is induced and therefore might restrict the corresponding pressure drop distal to the stenosis in the epicardial artery.72 Consequently, the severity of the stenosis might be underestimated if the resistance is high. This model makes assumptions about the downstream resistance and applies a “one-size fits all” approach. Consequently, in cases with abnormally high microcirculatory resistance or when maximal hyperemia has not been achieved, the vFFR is more likely to deviate from the mFFR. It is recognized that mFFR might not be reliable in cases with microvascular damage. Similarly, collateral circulation is a confounding factor that might also interfere with the estimation, although it is unusual to find collaterals in all but the most severe stenoses, whose physiological significance is usually apparent. Despite amazing correlation between vFFR and mFFR, there are still some limitations in clinical use, including small sample size (35 datasets), generic boundary conditions, unavailable software (Philips) for image segmentation and up to 24 h of computational time required.
Chapter 3 Methods and materials
3-1、Study design
This was a single site, observational, analytical study carried out at the Mackay Memorial Hospital, Hsinchu branch .The study protocol was approved by the local ethics committee.
3-2、Study population
Between September 2014 and March 2016, patients who underwent elective PCI and clinically indicated FFR testing were included. Intermediate stenosis(50% to 69 % by visual and quantitative assessment) were enrolled from Mackay Memorial Hospital, Hsin-chu branch. Patients were eligible if they were older than 18 years had angiographically confirmed, relatively simple native vessel coronary disease (ideally Type A lesions) ,scheduled to undergo clinically indicated non-emergent ICA. FFR was measured in one or more coronary artery in each patient after the operator had identified potential targets for PCI.
Patients were excluded if they had serious comorbidity; previous MI; were unable to
provide informed consent; had significant left main stem disease; had a chronic total occlusion; could not receive intracoronary nitrate, or known anaphylactic reaction to iodinated contrast; contraindication to adenosine (including second- or third-degree heart block; sick sinus syndrome; long QT syndrome; severe hypotension, severe asthma, severe, or bronchodilator-dependent chronic obstructive pulmonary disease), had previously undergone coronary artery bypass graft surgery ; were too obese for RoCA to be performed (Body mass index > 35 kg/m2); requirement for an emergent procedure; suspicion of acute coronary syndrome (acute myocardial infarction and unstable angina); recent prior myocardial infarction within 40 days of ICA; Known complex congenital heart disease; prior pacemaker or internal defibrillator lead implantation; prosthetic heart valve; significant arrhythmia or tachycardia; pregnancy or unknown pregnancy status; Evidence of ongoing or active clinical instability, including acute chest pain (sudden onset), cardiogenic shock, unstable blood pressure with systolic blood pressure less than 90 mm Hg, and severe congestive heart failure (New York Heart Association Class III or IV) or acute pulmonary edema. Any active, serious, life-threatening disease with a life expectancy less than 2 months was also excluded.
3-3、Procedure protocol
Coronary angiography was performed with bi-plane axis RoCA (SIEMENS, Artis Zee Biplane) after iso-centering in posterior-anterior and lateral planes( as close to 90° apart as possible). Angiographic views were obtained after intra-coronary isosorbide dinitrate (100 or 200 µg) administered for vasodilatation effect. A hand injection of 10 to 20 ml contrast was injected through a 6- or 7-F guiding catheter for ensuring optimal vessel opacification.
Intermediate stenosis (50% to 69 % by visual and quantitative assessment) was indicated for FFR testing as Taiwan incurrence. After “equalizing” was performed with the pressure wire sensor positioned at the guiding catheter tip, we advanced a pressure-sensitive angioplasty wire (Volcano, PrimeWire PRESTIGE / St. Jude medical, Pressure Wire “ Certus” ) distal to the stenosis. Hyperemia was induced by an intra-coronary infusion of adenosine (Right coronary artery: 48µg and left coronary artery: 240 to 480µg). The FFR was measured in the diseased vessels and its FFR result was recorded as golden standard. The illustration of standard FFR testing was described as FFR procedure I, II and III (Figure 3-1, 3-2 and 3-3) .Stent implantation proceeded according to normal practice on the basis of the angiogram and the FFR. After stent implantation, RoCA and physiological measurements were repeated.
Figure 3-1 Equalization of pressure wire: the first, most important step for the balance of Pa and Pd pressure.
Figure 3-2 Insertion of FFR wire to the distal part of stenosis. Try to make sure that FFR wire is not placed on small branch. After maximal hyperemia and vasodilatation by adenosine and nitrate, FFR could be estimated after 3 to 5 seconds later.
Figure 3-3 Pullback FFR wire to the ostial site of coronary vessel. The acceptable resting FFR level is within 0.95 to 1.0. If the data is below 0.95, repeating the initial step of equalization is suggested then recheck FFR again.
The image collection of “real-time coronary velocity deficiency (RTCVD)” was performed after performing traditional, invasive FFR. A hand injection of 10 to 20 ml contrast was also injected through a 6- or 7-F guiding catheter after maximum hyperemia (10 seconds later) by intra-coronary adenosine (the same dosage as previous dosage of FFR testing). The distance, before and after stenosis, was calculated by radiologist immediately after procedure. The RTCVD was obtained using the distance after stenosis and dividing it by the distance before stenosis (Figure 3-4). The frame time (1/30 seconds per X-ray frame) was the same in the before and after stenosis distance calculated. The real-time coronary velocity deficiency was made for with and without adenosine images. The illustration of RTCVD was described as Figure 3-5 and 3-6. We used the standard valve of FFR, with and without adenosine to compared the correction of RTCVD and fractional Flow reserve from Coronary angiography.
Figure 3-4 Our hypothesis of RTCVD to predict the myocardial status, compared with golden standard of FFR data.
Figure 3-5 Compared pre-adenosine RTCVD and FFR. In the case of LAD, middle segment with 55 % stenosis. The standard value of resting FFR was 0.94 . The resting RTCVD (0.91) was calculated from 12.01 divided by 8.65+8.52.
Figure 3-6 Compared post-adenosine RTCVD and FFR. In the same case of LAD, middle segment with 55 % stenosis. The standard value of post-hyperemia FFR was 0.84 . The post-hyperemia RTCVD (0.81) was calculated from 7.13+5.47 divided by5.67+6.96+2.74.
3-4、Study medication and machine requirement
3-4.1 Mediation:
(A)Adenosine( 6mg/2ml Vial) : Hyperemia effect(Figure 3-7)
(B) Isosorbide dinitrate (Angidil) (10mg/10ml Amp ) :Vasodilation effect(Figure3-8)
(C) Iopamiro 370: Iopamidol 755mg/ml
(100ml / bottle ) : Contrast solution(Figure3-9)
3-4.2 Pressure-sensitive angioplasty wire:
Designed to replicate the performance of standard PCI guidewires, the PressureWire technology is available in both the Aeris and Certus models. In 2012, the next generation of FFR measurement technology, the PressureWire™ Agile Tip, entered the market offering improved responsiveness and steerability for easy handling in difficult anatomies. The PressureWire Agile tip technology also includes a new proprietary hydrophilic coating to reduce friction; making it easier for doctors to deploy stents and coronary balloons.
The PressureWire Aeris is a first-of-its-kind wireless FFR system that doesn’t require additional equipment or cabling in the cardiac catheterization laboratory. The system integrates FFR technology directly into a wide array of recording systems to immediately and securely display, measure and save FFR data.
PressureWire Aeris also integrates FFR results into a patient’s existing record, allowing the severity of coronary lesions to be documented together with other procedural data and angiographic imagery. The market-leading PressureWire Certus provides an FFR measurement without increasing procedural time. It is the only guidewire on the market to provide a combined measurement of pressure and temperature, which enables calculations of FFR, Coronary Flow Reserve (CFR) and an Index of Microcirculatory Resistance (IMR). Two pressure wire system,Volcano,PrimeWire PRESTIGE.(Figure 3-10) and St.Jude medical,PressureWire “ Certus” (Figure 3-11), are available in MacKay Memorial hospital and are choosen in our study.
Figure 3-10 Volcano,PrimeWire PRESTIGE.
Figure 3-11 St.Jude medical,PressureWire “ Certus”
3-4.3 Rotational Coronary angiography (RoCA) images
Figure 3-12 Coronary angiography was performed with bi-plane axis RoCA (SIEMENS, Artis Zee Biplane System)
3-4.4. Institutional review board (IRB):
our large study will be performed after IRB allowed.
3-5、Statistical analysis
Data were analyzed on a per-patient basis for clinical characteristics and on a per-vessel basis for other factors. Of the14 patients, Pearson correlation was used to calculate clinical relation of FFR vs RTCVD in pre- and post- adenosine status.
Chapter 4 Results
4-1 Patient and clinical characteristics:
Fourteen matched anatomical and physiological datasets were obtained: 4 right coronary arteries (RCA) and 10 left coronary arteries (LCA). There baseline characteristic of study patients, as patient age, gender and ECG rhythm were also recorded and are presented in table 4. The mean age of the group was 59 (range 44 to 86) years. Twelve vessels were male (86%).None had prior coronary disease or stent history. Of the 14 vessels, 7 left anterior descending artery (LAD), 3 left circumflex artery (LCX) and 4 right coronary artery (RCA) are enrolled in the study. 2 vessels were indicated for stent implantation after FFR measured.
Table 5 details the lesion characteristics, including gender, age, vessel lesion, ECG rhythm, adenosine dose (ug), FFR (pre- and post-adenosine), pre-adenosine pre-and post stenosis length (mm), post-adenosine pre-and post stenosis length (mm), and pre-and post–adenosine RTCVD.
Table 4 Baseline characteristics of study patients
Age Mean 59 y/o (44 -86 age)
Gender
-Male12
-Female 2
Lesion territory
-LAD7
-LCX3
-RCA4
ECG rhythm
-NSR13
-Atrial fibrillation 1
FFR (Pre-adenosine ) 0.953±0.036
FFR (Post -adenosine ) 0.896±0.069
FFR related PTCA 2
LAD = left anterior descending artery, LCX= left circumflex artery, RCA= right coronary artery
Table 5 Baseline Characteristics of study vessels
Vessel NumberGenderAgeVessel lesionECGFFR
(Pre-adenosine)FFR
(Post-adenosine)Adenosine
Dose
(ug)Pre-adenosine pre-stenosis length(mm)Pre-adenosine post-stenosis length(mm)RTCVD (Pre-Adenosine)Post-adenosine pre-stenosis length(mm)Post-adenosine post-stenosis length(mm)RTCVD (Post-Adenosine )
1M52m-LAD 50%AF0.940.894805.995.80.968.277.580.91
2M44m-RCA 60%NSR0.980.91489.369.260.9816.1815.290.94
3F62p- LAD 58%NSR0.950.8824019.3918.750.9624.0220.940.87
4F62p- LCX 55%NSR0.950.882408.428.020.9512.1411.20.92
5M53m-LAD 60%NSR0.920.794808.387.860.9314.0712.570.81
6M86m-LCX 55%NSR0.940.932409.389.190.9711.6811.290.96
7M86m-LAD 30%NSR0.870.8424013.4211.510.8513.4111.30.84
8M65p-LAD 60%NSR0.930.7524016.1615.580.9623.4816.790.72
9M39m-RCA52%NSR1.000.99486.526.490.9910.8310.010.92
10M59d-LCX 60%NSR1.000.992406.266.210.999.629.480.99
11M59m-LAD 35%NSR0.950.922409.089.010.9911.1110.550.95
12M49m-RCA 52%NSR0.980.95484.334.300.9920.9719.70.94
13M58m-LAD 55%NSR0.940.8724013.1712.010.9115.3712.60.81
14M61m-RCA 55%NSR1.000.9524010.3610.100.9715.2714.680.96
4-2 Quantitative accuracy of RTCVD.
Lesions were stratified into 2 groups: those with pre-adenosine status; and
those with post-adenosine status. The RTCVD was stratified in the same way, and the results were compared with FFR. There are closely correlated in pre-and post-adenosine FFR(0.953±0.036, 0.896±0.069, P=0.01), pre-and post-adenosine RTCVD (0.958±0.039, 0.895±0.076, P=0.01), pre-and post-adenosine pre-stenosis length(mm) (10.02±4.2,
14.74±4.95, P=0.01), and pre-and post-adenosine post-stenosis length (mm) (9.58±3.91,13.14±3.88, P=0.02) (Table 6).The correlation coefficient of the pre-adenosine FFR values with the pre-adenosine RTCVD values was 0.836(Figure 4-1). The correlation coefficient of the post-adenosine FFR values with the post-adenosine RTCVD values was 0.894 (Figure 4-2). Each individual FFR is compared with its corresponding RTCVD in two group of pre-adenosine and post-adenosine in Figure 4-3 and 4-4.
Table 6 Closely correlated in pre-and post-adenosine FFR, RTCVD, pre- and post -stenosis length
Pre-adenosinePost-adenosineP valve
FFR 0.953±0.0360.896±0.0690.01
RTCVD 0.958±0.0390.895±0.0760.01
Pre-stenosis length(mm) 10.02±4.214.74±4.950.01
Post-stenosis length(mm) 9.58±3.9113.14±3.880.02
Figure 4-1 Pearson correlation for pre-adenosine FFR and RTCVD: rs=0.836, p<0.001
Figure 4-2 Pearson correlation for post-adenosine FFR and RTCVD: rs =0.894, p<0.001
Figure 4-3 Pre-adenosine FFR compared with RTCVD. Pre-adenosine FFR (blue) compared with RTCVD (red).
Figure 4-4 Post-adenosine FFR compared with RTCVD. Pre-adenosine FFR (blue) compared with RTCVD (red).
Chapter 5 Discussion
We have developed a simple coronary workflow that demonstrates the feasibility of using image analysis and CFD techniques to predict clinically useful physiological measures within a diseased coronary circulation solely from angiographic images only. The workflow has been developed to create a simplified, 2D virtual coronary image from a single RoCA. Compared with previous detecting tools, our model doesn’t need extra-CFD solver, data of generic boundary conditions, or the pressure and flow solution within easy calculation. The results allow assessment of 1 or more coronary stenosis while estimation. The correlation coefficient of the pre-adenosine FFR values with the pre -adenosine RTCVD values was 0.836. The correlation coefficient of the post-adenosine FFR values with the post -adenosine RTCVD values was 0.894.This is the first in vivo study to report such accurate CFD-based
measurements within the coronary circulation. Previous FFR research and virtual FFR focused on 3D anatomic reconstruction of whole vessel (proximal to distal part) under continuous hyperemia by intravenous adenosine.72 However, this method wasted much time for longer vessels 3D reconstruction, including non-significant and significant stenosis. Besides, higher procedural cost was noted because intravenous route need more adenosine use. However, our hospital chose intracoronary bolus adenosine route for immediate hyperemia (short-acting time) and measured FFR difference in focal coronary stenosis. Good correlation of intracoronary bolus and continuous intravenous adenosine had been noted already in the past except tandem or diffuse lesion.74 By this way, we also chose intracoronary bolus adenosine route for RoCA image and RTCVD evaluation, compared with FFR via intracoronary bolus adenosine. During adenosine-induced maximal hyperemia, coronary blood flow and trans-stenotic pressure gradient increase in both phases of the cardiac cycle66.This could explained that we found the significant length difference in both pre-stenosis and post-stenosis after intra-coronary adenosine infusion. Increasing coronary flow with trans-stenotic pressure after maximal hyperemia is an important step to our study. The model will now be optimized with greater patient numbers and with more complex cases after reconstruction of 2D or 3D workflow.
5-1 Advantages of RTCVD
There are several advantages offered by using physiological measures derived from our CFD workflow. The model only requires knowledge of vessel geometry. There is no need for additional procedure time, the hazard of passing an intracoronary wire, or additional equipment, training, or cost. Images of RoCA need to be performed with bi-plane axis after iso-centering in posterior-anterior and lateral planes (as close to 90° apart as possible) or proper angle for straight vessel anatomy as patient’s condition. Besides, enough contrast amount will have better image density, usually 6 to 8 ml for LCA and 4 to 6 ml for LCA. The frame time should be the as low as different X-ray setting and we choose 1/30 seconds per X-ray frame for better image quality. A computational tool such as RTCVD would improve operator and patient access to physiologically guided decision making with potential impact on clinical outcome and cost. The current workflow will be simplified for use by a nonspecialist cardiologist or radiographer for use at the time of diagnostic angiography to plan revascularization strategy. A further advantage of RTCVD is that the effects of multiple lesions or critical stenosis can be included in the simulation.
5-2 Alternative approaches and disadvantages of RTCVD
The main disadvantage of our approach is that it requires a rotational coronary angiogram. Other disadvantages included (1) over- or under-estimation of length while poor quality of coronary image or tortuous vessels (2) it still needs medication of vaso-dilatation and hyperemia for maximal coronary flow. Both the CCTA and our RTCVD succeed in inferring the physiological significance of coronary lesions by applying CFD to reconstructed cardiovascular anatomy. However, our method relies on vessel geometry alone from invasive CA and does not involve an estimation of myocardial mass or computed tomography. In the case 13, post-adenosine RTCVD (values=0.81) was smaller than post-adenosine FFR (valve =0.87). Higher rotation of heart beat result in big error of calculating RTCVD then result in calculated gap between RTCVD and FFR. We did not perform PCI for this patient as high FFR value as NHI guideline.
5-3 Challenges with RTCVD
Microcirculatory resistance presents a challenge, although this is common to FFR. The FFR represents the fraction of the normal maximal myocardial flow that can be achieved despite the epicardial stenosis. Alterations in the resistance of the downstream microcirculation might limit the rise in blood flow after vasodilatation is induced and therefore might restrict the corresponding pressure drop distal to the stenosis in the epicardial artery.72 If inadequate drop of pressure occurred, the velocity deficiency of coronary flow could be decreased as high downstream microcirculation resistance then RTCVD might be over-estimated as smaller velocity deficiency. Consequently, the severity of the stenosis might be underestimated if the resistance is high. Other investigators have attempted to predict the
physiological significance of CAD from luminal geometry. Quantitative coronary angiography, intravascular ultrasound (IVUS) and optical coherence tomography
(OCT) have all been used to predict indexes of intracoronary physiology but have yielded disappointing results.72 Gonzalo et al73 compared the use of OCT and IVUS in predicting an FFR of < 0.8. There was no significant difference between OCT and IVUS, and diagnostic accuracy was described as “modest” (sensitivity 82%, specificity 63%). Similar to previous studies, our methodology requires geometric knowledge of the vessel only without considering boundary conditions(on the basis of multiple arterial resistance and compliance measurements and a Windkessel model). Calculations exclude upstream or downstream pressure and try to decreasing downstream resistance and compliance via invasive FFR route over a full heart cycle. Although we believe that knowledge of microvascular compliance and resistance would improve accuracy, this paper, like those of Koo et al and Min et al, seems to challenge the notion that anatomical data cannot be used to reliably predict the physiological significance of coronary lesions.72
5-4 study limitations.
First, the number of cases is modest, and we selected simple lesions in stable patients for this proof-of-concept study. The number of subjects was smaller, given that this study was performed in a single institution. However, the hypothesis-generating results are encouraging, and the data are sufficient to warrant a larger study. Second, RoCA provides only a few images in each projection, which limits those taken at end diastole. Third, the majority of lesions were intermediate in appearance (Table 4), only a limited subgroup of cases (n = 2) had an FFR falling between 0.70 and 0.80, the range that representing the lesions for intervention. So we need to develop a model predicting “RTCVD index” for fast functional assessment of intermediate coronary lesions” after collecting enough cases. We hope that the RTCVD index would have high correlation, accuracy, PPV and NPV, compared with golden FFR index.
Chapter6 Conclusion
Our RTCVD had high Pearson correlation with FFR and it could be a pre-FFR test before invasive FFR testing. RTCVD might combine with other invasive or non-invasive tools to predict the accuracy of myocardial ischemia individually. The model will now need the 3D reconstruction of coronary flow velocity to determine its effect and clinical indication with more complex cases.
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