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Fractional Flow Reserve and Coronary Computed Tomographic Angiography
A Review and Critical Analysis
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Invasive fractional flow reserve (FFR) is now the gold standard for intervention. Noninvasive functional imaging analyses derived from coronary computed tomographic angiography (CTA) offer alternatives for evaluating lesion-specific ischemia. CT-FFR, CT myocardial perfusion imaging, and transluminal attenuation gradient/corrected contrast opacification have been studied using invasive FFR as the gold standard. CT-FFR has demonstrated significant improvement in specificity and positive predictive value compared with CTA alone for predicting FFR of ≤0.80, as well as decreasing the frequency of nonobstructive invasive coronary angiography. High-risk plaque characteristics have also been strongly implicated in abnormal FFR. Myocardial computed tomographic perfusion is an alternative method with promising results; it involves more radiation and contrast. Transluminal attenuation gradient/corrected contrast opacification is more controversial and may be more related to vessel diameter than stenosis. Important considerations remain: (1) improvement of CTA quality to decrease unevaluable studies, (2) is the diagnostic accuracy of CT-FFR sufficient? (3) can CT-FFR guide intervention without invasive FFR confirmation? (4) what are the long-term outcomes of CT-FFR–guided treatment and how do they compare with other functional imaging-guided paradigms? (5) what degree of stenosis on CTA warrants CT-FFR? (6) how should high-risk plaque be incorporated into treatment decisions? (7) how will CT-FFR influence other functional imaging test utilization, and what will be the effect on the practice of cardiology? (8) will a workstation-based CT-FFR be mandatory? Rapid progress to date suggests that CTA-based lesion-specific ischemia will be the gatekeeper to the cardiac catheterization laboratory and will transform the world of intervention.
- atherosclerotic plaque
- cardiac catheterization
- coronary angiography
- myocardial perfusion imaging
- sensitivity and specificity
Background: Invasive Fractional Flow Reserve
Obstructive coronary artery disease (CAD) produces symptoms and increases the risk of adverse cardiac outcomes. However, determining whether a particular coronary stenosis is responsible for causing myocardial ischemia can be challenging, even with invasive coronary angiography (ICA). To help guide decisions in the cardiac catheterization laboratory, Pijls et al1 and De Bruyne et al2 introduced the concept of myocardial fractional flow reserve (FFR) more than 20 years ago.
FFR is defined as the ratio between the maximum myocardial blood flow in the presence of an epicardial coronary stenosis and the maximum myocardial blood flow in the theoretical absence of the stenosis.1 Briefly, when both epicardial and myocardial resistances are minimized by administering vasodilators and assuming microvascular resistance is similar in the presence and absence of an epicardial stenosis, coronary flow becomes proportional to coronary pressure. Because there is little pressure loss along a normal epicardial coronary artery, the proximal coronary pressure of a diseased artery is a reflection of what the distal pressure would be in the absence of disease. Hence, FFR can be defined as the distal coronary pressure divided by the proximal coronary pressure during maximal hyperemia. Traditionally, FFR is determined invasively in the cardiac catheterization laboratory with a coronary pressure wire in the vessel measuring distal pressure and a guiding catheter measuring the proximal pressure during hyperemia induced with adenosine.
FFR has several unique attributes that separate it from other indices, such as coronary flow reserve.3 First, it has an unequivocal normal value of 1.0 in every patient and every vessel. Second, it has a well-defined ischemic cutpoint of 0.80 with a gray zone from 0.75 to 0.80. Third, because FFR is measured during maximal hyperemia, it is not affected by changes in heart rate and blood pressure and is extremely reproducible. Fourth, FFR incorporates the contribution of collateral blood supply because distal pressure takes into account both antegrade flow and collateral flow. Noninvasive assessments of FFR do not account for collateral flow in the same manner.
Finally, FFR specifically interrogates the epicardial vessel independent of the microvasculature, assuming the microvascular dysfunction if present is fixed and chronic. For example, in the setting of an old myocardial infarction, a residual stenosis, despite its angiographic appearance may have little pressure gradient and a nonischemic FFR during maximal hyperemia because it supplies nonviable myocardium. In this setting, FFR remains accurate and informs the clinician that there is no benefit in relieving the stenosis because it is not responsible for inadequate myocardial blood flow. However, in the setting of an acute myocardial infarction, in which case transient and reversible degrees of microvascular damage occur, FFR may not be reliable.
FFR was first validated by measuring it in 45 patients with intermediate single-vessel coronary disease and comparing the FFR value to the result from 3 different noninvasive stress tests.4 Because there is no true gold standard for identifying myocardial ischemia, if any one of the noninvasive tests was abnormal, then the lesion was felt to be capable of producing myocardial ischemia. Because each test has an accuracy of roughly 80%, applying sequential Bayesian analysis, the combination of all 3 tests provides an accuracy of >95%. In this study, the investigators found at a cutoff value of 0.75, FFR had 100% specificity, 88% sensitivity, and an accuracy of 93%. To improve the sensitivity of FFR, the more recent clinical trials have used an FFR cutoff value of 0.80.
Several multicenter, randomized clinical trials have provided further validation of FFR as an index, which can predict clinical outcome. The DEFER trial established the safety of deferring percutaneous coronary intervention (PCI) on coronary stenoses, which were not functionally significant based on FFR.5 Patients with intermediate lesions and FFR value of ≥0.75 were randomized to performance of PCI anyway or to deferral of intervention and continued medical therapy. The study demonstrated the safety of medical therapy for functionally nonsignificant lesions because the event-free survival rate at 2 years was similar between the 2 groups (89% versus 83% for the deferral versus performance groups, respectively; P=0.27), as was the degree of angina. This cohort has now been followed for 15 years with no significant increase in revascularization rate in the deferral patients and a significantly lower rate of myocardial infarction (2.2 versus 10%, P=0.03).6 Other observational registries have confirmed the safety of deferring revascularization of coronary disease, which is not significant based on FFR, even if involving the proximal left anterior descending artery7 or the left main coronary.8
The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trial was a large, multicenter, randomized study that further confirmed the safety of deferring PCI of lesions that are not hemodynamically significant, but more importantly demonstrated the safety, cost-effectiveness, and clinical benefit of routinely measuring FFR in patients with multivessel CAD undergoing PCI.9 The FAME study included 1005 patients with 2- or 3-vessel CAD eligible for PCI and randomized them to either angiography-guided PCI, in which case the operator performed PCI based on the angiographic appearance of the CAD, or FFR-guided PCI, in which case only those lesions with an FFR of ≤0.80 underwent PCI. The FFR-guided patients received significantly fewer stents; yet, they had similar relief of angina and a significantly lower rate of the primary end point: death, myocardial infarction, or repeat revascularization at 1 year (13.2 versus 18.3, P=0.02). The rate of death or myocardial infarction was also significantly lower at both 1 and 2 years.10 Most of this benefit was because of better assessment of stenoses between 50% and 90% narrowed because the vast majority of those stenoses >90% narrowed had an ischemic FFR value. A cost-effectiveness study showed that the FFR-guided strategy was a cost-saving approach, leading to a lower event rate and utilizing fewer resources.11 By 5 years, there was a durable benefit from FFR-guided PCI.12 The FAME trial showed that functional angioplasty, performing PCI on lesions responsible for ischemia, while treating lesions medically that are not hemodynamically significant results in excellent clinical outcomes by maximizing the benefit of PCI while minimizing its risks.
One of the criticisms of the FAME trial was that it did not include a medical therapy arm. Some argued that medical therapy alone would have performed as equally well as FFR-guided PCI. The goal of the FAME 2 trial was to compare outcomes in patients who had stable CAD, which was functionally significant based on FFR, and who were randomized to either guideline-directed medical therapy alone or to PCI and best medical therapy.13 In this manner, FAME 2 was the mirror image of the DEFER trial. The key difference between the FAME 2 trial and previous studies comparing medical therapy to PCI in stable patients was that FFR was measured first, so only those patients with significant myocardial ischemia were randomized. Patients with CAD but no functionally significant lesions received guideline-directed medical therapy alone and formed a reference group.
Enrollment in the FAME 2 trial was stopped early by the data safety monitoring board after a mean follow-up of 7 months because of a highly significant increase in the primary end point of death, myocardial infarction, or the need for hospitalization and urgent revascularization in the patients assigned to medical therapy alone (12.7% versus 4.3%, P<0.001). This was driven primarily by an increase in the need for urgent revascularization in the medical therapy patients. The death and myocardial infarction rate was numerically higher, but not statistically significant in the best medical therapy alone patients (3.9% versus 3.4%, P=0.22). The complete 2-year follow-up showed similar findings with a significantly higher rate of the primary end point in the medically treated patients (19.5% versus 8.1%, P<0.001).14 A landmark analysis evaluating the rate of death or myocardial infarction occurring 7 days after enrollment (eliminating the periprocedural myocardial infarctions occurring in the PCI group) demonstrated a significantly higher rate of death or myocardial infarction in the medically treated patients (8.0% versus 4.6%, P=0.04). Importantly, in the patients in the reference group who had stable CAD that was not functionally significant based on FFR and who received medical treatment alone, the event rate was low and similar to the PCI group of patients. A cost-effectiveness analysis from FAME 2 found that FFR-guided PCI was attractive at $36 000 per quality-adjusted life years.15 Historically, FFR use in the United States has been low; however, as a result of the above data and an increased emphasis on appropriate application of PCI, the percentage of cases involving FFR has been increasing on a yearly basis and is now ≈20%.16 Because of this increased usage of FFR, there is interest in streamlining the measurement. One proposed method is to eliminate the need for hyperemia by measuring only resting gradients, such as the resting ratio of distal pressure to proximal pressure or the instantaneous wave-free ratio that is the ratio of resting distal pressure to proximal pressure during the so-called diastolic wave–free period. Unfortunately, multiple large, multicenter studies have shown that these indices are only ≈80% accurate when compared with FFR.17,18
The FAME 2 trial highlighted an important concept that the greater the burden of ischemia-producing CAD, the higher the event rate with medical therapy alone. Other studies have also found a relationship between the FFR value across the lesion and the risk of adverse events with medical therapy alone, which is attenuated by revascularization,19 even when focusing only on the gray zone of FFR values.20 These data emphasize the need to focus our noninvasive evaluation of CAD on both anatomy and ischemia. One of the limitations of the traditional method for measuring FFR is that it requires an invasive procedure. Recently, there has been great interest in developing a noninvasive method for assessing FFR by using the anatomic data derived from coronary computed tomographic angiography (CTA).
Noninvasive FFR
FFR derived from CTA (CT-FFR) has the potential to be a game changer in the noninvasive assessment of the significance of coronary artery stenoses by providing the proverbial one stop shop of anatomy and function in a single low-dose scan.21 The notion of noninvasive measurement of CT-FFR seems, on the surface, to be ludicrous. How could FFR be derived noninvasively from a resting CTA, without the administration of a vasodilator? The application of computational fluid dynamics to the CTA data set has allayed these fears and initiated a series of studies, which may fundamentally transform the cardiac catheterization laboratory into a truly interventional rather than diagnostic facility.
Why We Need CT-FFR
The National Cardiovascular Data Registry highlighted the need for a more reliable gatekeeper to the cardiac catheterization laboratory by evaluating the percentage of 661 063 patients undergoing elective catheterization who had >50% stenosis.22 Preprocedural noninvasive testing was performed in 64% of patients; of those, 51.9% were abnormal. The percentages of patients correctly identified as having >50% stenosis ranged from 44% to 45% for exercise treadmill testing, stress echocardiography, stress myocardial perfusion imaging (MPI), and stress magnetic resonance imaging (MRI); for resting CTA, the percentage was 70%. The inadequacy of the commonly used functional tests may be explained by their validation paradox: exercise treadmill testing, single-photon emission computed tomographic MPI, and stress echocardiography have used >50% stenosis on ICA as the gold standard, on which their sensitivities and specificities were validated. Unfortunately, >50% stenosis is a severely flawed gold standard, correlating well neither with intravascular ultrasound nor with invasive FFR, which is validated by the gold standard of outcomes. Functional imaging is even more problematic because it uses the test to judge the results of the gold standard by which it is validated. For instance, a normal stress echocardiogram in a patient with an 80% proximal left anterior descending stenosis is by definition a false-negative finding. However, the overwhelmingly more likely interpretation in the noninvasive community would be a nonischemic stenosis, on the erroneous assumption that the stress test is the gold standard.
The National Cardiovascular Data Registry suggests that anatomy trumps function for the identification of patients with >50% stenosis, a finding confirmed by numerous nonrandomized studies, and 3 prospective randomized controlled trials. In the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial,23 10 000 symptomatic patients were randomized to CTA or functional testing (MPI, 67.5%; stress echocardiography, 22.4%; and treadmill testing, 10.2%). The percentage of patients undergoing catheterization with <50% stenosis was 3.4% for CTA versus 4.3% for functional testing (P=0.02). The Coronary CT Angiography in Patients With Recent Acute-Onset Chest Pain (CATCH) trial24 randomized 576 patients with chest pain to CTA versus usual care (treadmill testing, 76% and MPI, 22%). In those undergoing catheterization, 29% of the CTA arm and 64% of the functional arm had <50% stenosis (P=0.002). In the Cardiac CT for the Assessment of Chest Pain and Plaque (CAPP) trial25 of 488 patients with chest pain randomized to CTA or treadmill testing, 30% of the CTA arm and 65% of the functional arm that had catheterization had <50% stenosis. In the Scottish Computed Tomography of the HEART (SCOT-HEART) trial26 of 4146 subjects randomized to CTA versus standard care, similar numbers of patients underwent invasive angiography, but the percentage with normal coronary arteries was 4.8% for CTA versus 14.0% for usual care (P<0.001), and the percentage with >50% stenosis was 69.2% for CTA versus 57.3% for usual care (P=0.005).
From the prognostic perspective, in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial of patients randomized to intervention plus optimal medical therapy versus optimal medical therapy alone, 621 patients had MPI.27 The odds ratio for prediction of acute events was 1.01 (95% confidence interval, 0.98–1.03; P=0.54) for ischemic burden versus 1.05 (95% confidence interval, 1.02–1.08; P=0.002) for atherosclerotic burden by quantitative coronary angiography. In addition to demonstrating the superiority of CTA over functional testing in identifying >50% diameter stenosis (DS), the randomized controlled trials are suggestive of the beneficial effect on prognostic outcomes of CTA versus functional testing–guided management. The PROMISE trial23 revealed a better outcome at 12 months for CTA versus functional-guided treatment (hazard ratio, 0.66; P=0.049) for death plus MI, although there was no difference at 36 months. In the SCOT-HEART trial,26 there was a 50% reduction (hazard ratio, 0.50; 95% confidence interval, 0.28–0.88; P=0.02) in fatal and nonfatal myocardial infarction in the CTA-guided group. The Long-Term Clinical Impact of CATCH trial24 also noted a 38% reduction in the primary end point of cardiac death, myocardial infarction, unstable angina, late revascularization, and chest pain readmissions (11% versus 16%, P=0.04).
Thus, the anatomic superiority of CTA to functional testing in identifying obstructive disease and producing better outcomes in relatively short-term randomized trials, plus the prognostic superiority of anatomy to ischemia in the Courage trial, provides support for the increasing use of CTA. However, the ascendancy of functional invasive FFR as the gold standard, with outcome-based superiority of FFR-guided intervention to anatomy-guided intervention, would seem discordant with the above discussion. In reality, there may be no contradiction because FFR is not simply another functional test that infers ischemia by stress-induced perfusion defects or wall motion abnormalities. Rather, as discussed in detail above, it is a direct measure of flow inadequacy. A recent meta-analysis (Table 1) highlighted the inferior accuracy of MPI and stress echocardiography to CTA alone for identifying invasive FFR of ≤0.80 and may explain the better outcomes discussed above for CTA-guided treatment.28 In addition, in a study of 67 patients with multivessel disease, MPI was particularly suboptimal, with 61% sensitivity, 69% specificity, 47% positive predictive value (PPV), and 80% negative predictive value (NPV).29 Interestingly, stress MRI and positron emission tomography (PET) performed at least as well as CTA alone, but these technologies are expensive and are not widely used. Whether the ability of CTA to improve outcomes by identifying abnormal invasive FFR will be further enhanced by adding FFR capabilities, paralleling the improved outcomes after invasive FFR-guided treatment, is yet to be determined and is the focus of this article.
Computed Tomography–Fractional Flow Reserve
Fractional flow reserve form computed tomography (FFRCT; HeartFlow, Inc, Redwood City, CA) is the first noninvasive functional test to use an outcome-based gold standard, that is, invasive FFR, rather than one fundamentally based on coronary stenosis measurement. Computational fluid dynamics are used for the calculation of FFR at any point in the vascular tree, based on projected adenosine-induced vasodilation, from a CTA of at least moderate quality acquired at rest without adenosine infusion; the step by step methodology and clinical examples are presented in Figure 1.30
The brief history of CT-FFR trials is summarized in Tables 2 and 3 and reveals somewhat discordant results for the 2 multicenter FFRCT trials, attributed to technical issues as will be discussed. Because of these differences, pooled values are not presented. The initial report (DISCOVER-FLOW [Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve]) of 159 vessels in 103 patients from multiple centers undergoing FFRCT and ICA with FFR yielded remarkable improvements in specificity (25%–82%) and PPV (58%–85%) in both patients and vessels compared with CTA alone, with invasive FFR as the gold standard, without differences in sensitivity and NPV.31 The study met its primary end point to detect a relative improvement in diagnostic accuracy of ≥25% for FFRCT when compared with CTA stenosis.
A larger multicenter study (DeFACTO [Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography]) of 615 vessels in 252 patients yielded different results.32 The sensitivity and NPV were similar for CTA and FFRCT, as in DISCOVER-FLOW, but there were no significant improvements in specificity (42%–54%) and PPV (61%–67%). A subgroup analysis restricted to 150 vessels in 82 patients with intermediate stenoses of 30% to 69% revealed improved sensitivity (34%–72%) and NPV (78%–90%) compared with CTA.33 There was no improvement in specificity (72%–67%) and the PPV, while improved, (27%–41%) was unacceptably low. The study did not achieve its prespecified primary outcome goal for the level of per-patient diagnostic accuracy of >70% of the lower bound of the 95% confidence interval.
Pursuant to the disappointing DeFACTO results, the investigators addressed the perceived technical and methodologic shortcomings. Better lumen boundary identification was achieved by improved automated image processing methods. Physiological models of microcirculatory resistance that yielded better diagnostic performance than the previous studies were used. In particular, more aggressive rate control and universal nitroglycerin administration were mandated to strictly adhere to the best practices for image acquisition. The results of the third multicenter study (NXT [Analysis of Coronary Blood Flow Using CT Angiography: Next Steps]) results reflect the remedies.34 In 484 vessels in 254 patients, FFRCT significantly improved the per-patient specificity and PPV (32%–84% and 40%–65%, respectively) and the per-vessel specificity and PPV (60%–86% and 33%–67%, respectively) compared with CTA. There were no significant changes in sensitivity and NPV. Similarly, the area under the receiver-operating characteristic curve increased from 0.81 to 0.90 (P=0.0008) for the per-patient analysis (Table 2). In the 235 patients with intermediate stenoses in the 30% to 70% range, the per-patient specificity and PPV improved from 32% to 79% and 37% to 63%, respectively, compared with CTA. The study met its primary end point per-patient diagnostic performance as assessed by the area under the receiver-operating characteristic curve of FFRCT (≤0.80) versus CTA (stenosis>50%) for the diagnosis of hemodynamically significant stenosis (FFR≤0.80) in patients with CTA stenosis of 30% to 90%. The sensitivity, specificity, and accuracy of FFRCT persisted across the quartiles of coronary artery calcium score, as did its superior specificity and accuracy compared with CTA.35 Inclusion of the 12% of studies deemed nonanalyzable because of calcium blooming, and other artifacts might have decreased the accuracy.
The ability of FFRCT to predict a nonischemic invasive FFR response to stenting was evaluated by recalculating the FFRCT after projected improvement of the stenosis by percutaneous intervention. In 44 lesions in 44 patients, they reported 100% sensitivity, 96% specificity, 50% PPV, and 100% NPV.33
In addition to the prospective, multicenter FFRCT reports, there are several studies that use local workstation-based computational fluid dynamics algorithms. In a retrospective single-center study by Renker et al,37 with <60 minutes analysis time and invasive FFR of <0.80 as the gold standard, 67 lesions were retrospectively evaluated in 53 patients. They reported 85% sensitivity and specificity, PPV of 71%, and NPV of 93% on a per-lesion basis, with the area under the receiver-operating characteristic curve of 0.92 compared with 0.72 (P=0.0049) for CTA alone. On a per-patient basis, the area under the receiver-operating characteristic curve was of borderline superiority to CTA alone (0.91 versus 0.78, P=0.078), with 94% sensitivity, 84% specificity, 71% PPV, and 97% NPV. In a prospective single-center workstation-based study with a 20-minute processing time, Kruk et al38 analyzed 96 lesions in 90 patients with invasive FFR of <0.80 as the gold standard. They reported 76% sensitivity, 72% specificity, 67% PPV, and 80% NPV compared with 100% sensitivity, 2% specificity, 43% PPV, and 100% NPV for CTA alone.
Important CT-FFR Considerations
CTA Quality
The importance of strict adherence to quality guidelines cannot be overemphasized because the ability to calculate CT-FFR is dependent on the quality of the study. In the 2 multicenter trials, 11% and 13% of the CTA studies were unsuitable for technical reasons.31–34 Because scanner temporal and spatial resolution continue to improve and strict adherence to quality guidelines increases, motion and calcium blooming artifacts should be less problematic and the percentage of analyzable studies should increase, although this remains to be demonstrated. Unfortunately, there will always be nondiagnostic studies, as there are for all imaging modalities.
Test Accuracy
Are the CT-FFR sensitivity and specificity, which characterize the accuracy of the test compared with the invasive FFR gold standard, sufficiently robust? The NXT sensitivity and specificity were 86% and 79% for CT-FFR versus 94% and 34% for CTA alone.34 The benefits clearly reside in the reduced false positives compared with CTA alone, with the concomitant reduction in unnecessary ICA. In this context, evaluation of FFRCT as a gatekeeper to ICA will be examined by Coronary Computed Tomographic Angiography for Selective Cardiac Catheterization (CONSERVE).30 However, the 79% specificity is still suboptimal, and the lower sensitivity is of concern. The PPV and NPV, which are dependent on the prevalence of ischemic lesions in the specific patient population and cannot be easily extrapolated to the community at large, were 65% and 93% for CT-FFR versus 40% and 92% for CTA alone.34 In the NXT population, therefore, there was no benefit compared with CTA alone for identifying those patients whose invasive FFR will warrant intervention, and 35% of the abnormal results were false positives. In addition, the discrepancies between the specificities of CTA for invasive FFR of ≤0.80 in the FFRCT trials (patients 25%–42% and vessels 40%–60; Table 3)31–34 and those reported in a meta-analysis (patients 80% and vessels 86%; Table 2)28 are striking and require explanation. Although head to head comparisons in the same group of patients are more compelling than meta-analyses, and even assuming that there may have been a disproportionate number of patients with extensive calcification and, therefore, more false positives in the FFRCT trials, the discrepancies need to be further elucidated. Moreover, the CTA specificities are considerably inferior to the meta-analysis reported specificities for single-photon emission computed tomographic MPI and stress echocardiography,28 a surprising result.
Nonetheless, CT-FFR implementation will be warranted if it proves to be superior to other functional tests in head to head comparisons in studies evaluating the triage of patients to ICA. Future trials to address this critical issue are underway or are being planned. Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia (CREDENCE)30 will be a direct comparison of CTA plus FFRCT against MPI and positron emission tomography. PERFECTION will pit FFRCT against single-energy CT rest/stress perfusion imaging30 and Dual Energy CT for Ischemia Determination Compared to "Gold Standard" Non-Invasive and Invasive Technique (DECIDE-Gold) will compare FFRCT and dual-energy CT rest/stress perfusion imaging.30 However, these are trials of diagnostic performance, rather than patient outcomes.
CT-FFR, Decision Making, and Outcomes
Application of population-based accuracy to the individual is far from straightforward, and decision making is always easiest at the extremes. For instance, it is a simple choice to proceed to ICA with a CT-FFR of 0.65 and to defer ICA with a value of 0.90. Intermediate values present more difficult choices and closer to 0.80, the more likely is a false negative or false positive compared with invasive FFR. There is no obvious remedy for the uncertainty of the middle ground other than to temper expectations of the agreement with invasive FFR in this range. However, there are more complicated issues than simple triage to ICA.
1. Below what CT-FFR value will invasive FFR confirmation be unnecessary before proceeding to intervention, thereby resulting in cost savings incremental to those associated with avoiding unnecessary ICA? Current practice requires confirmation of CT-FFR by invasive FFR because CT-FFR is not yet guideline recommended, and there are no ongoing or proposed trials to evaluate the outcomes of proceeding to intervention based on CT-FFR without invasive FFR confirmation. In the meantime, FFRCT has been approved by the FDA and is being used for triage to the catheterization laboratory without long-term trials demonstrating improved outcomes with this approach. Interestingly, intervention is already deemed appropriate after abnormal MPI and stress echocardiography without requiring confirmation by invasive FFR, with which their correlation is suboptimal. Thus, logic would dictate that abnormal CT-FFR, which correlates well with invasive FFR as discussed above, should also suffice for intervention. However, as noted, it is not yet the standard of care, and should be discouraged until the requisite outcome data are available.
b. Although CTA has been shown to increase the revascularization rate compared with usual care,24,25 the incremental role of CT-FFR on the number of revascularizations is unknown, and there are no outcome studies to determine the beneficial effect of CT-FFR–guided revascularization. The prognostic significance of FFRCT will be evaluated by Assessing Diagnostic Value of Non-Invasive FFRCT in Coronary Care (ADVANCE)30 in a prospective longitudinal registry.
2. There are short-term outcome,39 quality of life, and resource utilization data.40 In the PLATFORM study of 380 patients for whom ICA was planned but were instead randomized to usual care versus FFRCT-guided care, the major adverse coronary event rate at 90 days was 0% versus 1%, a nonsignificant difference.39 There were also no differences in event rate at 90 days for the 204 patients for whom a noninvasive testing strategy was planned but were randomized to usual versus FFRCT-guided care; there were no events in either group. Significant differences were noted in the percentage of patients with <50% stenosis on ICA (the primary end point), in the planned invasive arm for the FFRCT (12%) and usual care (73%) groups, and ICA was cancelled in 61% of the FFRCT-guided care group. In the same patient cohort of 584 patients, costs and quality of life issues were addressed.40 With projected charges for the FFRCT ranging from none to 7× the cost of the CTA (there is currently no insurance reimbursement), 90-day costs were 32% lower in the FFRCT patients in the planned invasive group than in the usual care patients ($7343 versus $10 734 P<0.0001) at no charge for the FFRCT, with no differences in the planned noninvasive group. The lower cost persisted with FFRCT charges ≤7× the CTA ($8619 versus $ 10 734; P<0.0001). Three quality of life scores improved more in the FFRCT arm of the planned invasive strategy without differences in the noninvasive cohort.
CT-FFR Lesion Candidates
Which CTA stenoses should be evaluated with CT-FFR? CTA uses the traditional >50% DS cutoff for a significant lesion, on which its sensitivity and specificity using ICA as the gold standard to ICA are determined. Patients with stenoses <50% are traditionally not referred for further evaluation. Unfortunately, the percent DS does not correlate well with FFR. In FAME,9,41 only one third of 50% to 70% lesions demonstrated FFR of ≤0.80 and one fifth of 71% to 90% stenoses were associated with FFR of >0.80. In another report,42 FFR of >0.80 was noted in more than half of >50% stenoses and 1 in 7 to lesions <50% lesions had FFR of ≤0.80. Therefore, it would be reasonable to perform CT-FFR on all stenoses in the 30% to 90% range to minimize both unnecessary ICA and the failure to detect potentially ischemic stenoses in the lower range. The subsets of bifurcation and complex lesions have not been addressed in any study other than to be excluded from the study by Renker et al.37
CTA Plaque Characteristics and FFR
It has become evident that high-risk CTA plaque characteristics influence outcomes and ischemia. Patients with low-attenuation plaque and positive remodeling (2 feature positive plaques) accounted for ≈50% of acute coronary syndromes in both short- and long-term studies43–45 with no differences in DS between those plaques with and without ischemic events. Several studies have confirmed the relationship between CTA plaque characteristics and FFR. CTA and invasive FFR were obtained in 58 patients with intermediate (30%–69%) stenosis.46 The area under the receiver operator characteristics curve for ischemic FFR was highest (P=0.001) for total atherosclerotic plaque volume (0.85), followed by minimum luminal area (0.78), minimum luminal diameter (0.75), DS (0.68), and area stenosis (0.66).
In the much larger and more detailed second study,47 a multicenter evaluation of 407 lesions in 252 patients undergoing CTA and invasive FFR, there was a 50% increased risk of FFR of ≤0.80 per additional 5% atherosclerotic plaque volume compared with a 30% increased risk per 5% lumen area stenosis. In multivariate analysis of adverse plaque characteristics, positive remodeling, low attenuation plaque, and spotty calcification were associated with odds ratios for ischemic FFR of 5.4 (P<0.001), 2.2 (P=0.028), and 1.6 (0.177), respectively. The presence of 1 and ≥2 characteristics was associated with odds ratios of 4.5 (P<0.001) and 13.2 (P<0.001), respectively. Finally, in the equally large and detailed third study,48 484 vessels in 254 patients were evaluated with FFR and FFRCT using optimal plaque thresholds derived from area under the receiver operator characteristics curves. Low-density noncalcified plaque, total noncalcified and total plaque volume, positive remodeling, and plaque length were all significantly related to FFR of ≤0.80 in univariate analysis; only low-density noncalcified plaque volume was significant (relative risk, 4.3; P<0.001) in multivariate analysis, independent of the degree of stenosis. The area under the receiver operator characteristics curve for detection of FFR of <0.80 was 0.71 for >50% stenosis and increased to 0.79 with the addition of low-density noncalcified plaque volume (P<0.001), and it was further increased by FFRCT of <0.80 (P<0.001).
Endothelial dysfunction secondary to the oxidative stress imposed by the necrotic lipid core has been thought to be the pathogenesis of the ischemic response.49–52 Thus, stenoses in or below the lower range of presumed significance should be evaluated with CT-FFR in the setting of high-risk plaque characteristics. In addition, it has been proposed that borderline normal invasive FFR values, for example, 0.81, be regarded in a less benign light when accompanied by 2 feature positive plaques in a suggestive clinical setting (Figure 2).53
Impact of CT-FFR on Noninvasive Imaging
There are already multiple outcome studies demonstrating the superiority of CTA alone to functional testing.23,24,26 The publication of additional positive CT-FFR data, particularly outcome and cost effectiveness studies compared with other functional imaging technologies, will likely significantly decrease the use of MPI, stress echocardiography, and stress MRI. These will be reserved for those patients with renal dysfunction and contrast anaphylaxis for whom CTA is contraindicated and for institutions without CT-FFR capability. The additional time, contrast load, and radiation of computed tomographic stress MPI (CTP) may also dampen enthusiasm. On a cardiology community level, as noninvasive functional imaging provides a substantial proportion of the private cardiologists' income, its further decline will likely accelerate the rapidly ongoing hospital acquisition of private practices with all the implications thereof. This is particularly salient if insurers mandate CTA and CT-FFR as the first test in the evaluation of chest pain.
Practical Issues
Although immediate access to CT-FFR results is not imperative in stable angina patients, convenience and cost favor an on-site workstation solution, provided that the FFR values are as accurate as the FFRCT of Heartflow, which must be sent out for derivation. Ultimately, all vendors will likely develop on-site CT-FFR, with the additional cost absorbed by insurers at a level not likely to exceed the cost of the CTA itself. Whether it will be a purchasable software upgrade or a per use fee is yet to be determined.
Reliance on Invasive FFR
The remarkably rapid ascendancy of invasive FFR to the gold standard for intervention as a class 1 (level of evidence A) recommendation is predicated on the results of the FAME and DEFER trials.6,9,10,12–14 In the unlikely event that this role is downgraded, CT-FFR will suffer accordingly. Of note, the clinical use of CT-FFR is not yet guideline recommended.
Other CTA Functional Testing
Although not measuring FFR itself, there are other CTA modalities that have been compared with invasive FFR: CTP and transluminal attenuation gradient/corrected contrast opacification (TAG/CCO).
CT Myocardial Perfusion Imaging
Similar to single-photon emission computed tomographic MPI, static CTP requires both rest and stress acquisitions, with the order determined by the pretest likelihood of significant obstructive disease. Adenosine, regadenoson, and dipyridamole have been used as the stress agent, with semiquantitative comparison of rest and stress myocardial perfusion to determine the extent of ischemia (Figure 3).54 There are extensive CTP data favorably comparing its accuracy to ICA, MPI, and stress MRI for the detection of >50% stenosis by ICA.55–58 The ability to reduce false-positive findings by discounting perfusion abnormalities in the distribution of normal vessels offers an advantage over the other functional tests, all of which lack an anatomic component. There are several studies comparing CTP with invasive FFR (Table 4). In 195 vessels in 65 patients undergoing invasive FFR, CTP yielded 95% sensitivity, 74% specificity, 49% PPV, and 98% NPV compared with 98% sensitivity, 54% specificity, 37% PPV, and 99% NPV for CTA alone.59 Ko et al,60 in 86 vessels in 42 patients, reported 76% sensitivity, 84% specificity, 82% PPV, and 79% NPV for CTP. The values for CTA alone were 93%, 60%, 68%, and 90%, respectively. The combination of computed tomographic myocardial perfusion (CTMP) defect and CTA >50% stenosis improved the specificity (98%) and PPV (97%) but decreased the sensitivity to 68%. CTP was compared with FFR in 101 patients, only 27 of whom had directly measured FFR with the remainder imputed from total occlusions of severely stenotic lesions. CTP alone was associated with 68% sensitivity, 93% specificity, 88% PPV, and 79% NPV. With the addition of CTP to CTA, they reported sensitivity, specificity, PPV, and NPV of 89%, 83%, 80%, and 90%, respectively.61 Wong et al62 reported 89% sensitivity, 65% specificity, 57% PPV, and 92% NPV in 127 vessels in 75 patients undergoing FFR. The addition of CTP to the CTA resulted in sensitivity, specificity, PPV, and NPV of 76%, 89%, 78%, and 88%, respectively.62 Finally, Choo et al63 noted that the addition of CTP to CTA improved specificity from 83% to 94% and PPV from 75% to 90% without change in sensitivity and NPV.
The variable results of CTMP compared with CT-FFR, as well as the additional radiation, contrast, and scan time inherent in 2 separate acquisitions, are current disadvantages of this modality. Dynamic CTMP, and dual-energy CT that reduces beam-hardening artifacts, may improve the accuracy of CTMP.64,65
Transluminal Attenuation Gradient/Corrected Contrast Opacification
Resting flow impairment measured by differences in resting CTA contrast densities proximal and distal to a stenosis, with or without CCO to correct for the downstream decreases in attenuation inherent in studies not acquired with a single beat, has been evaluated in multiple studies with initially favorable results, despite an expected reduction in resting flow only with stenosis >90% (Figure 4).54 Subsequent data have not been supportive of additive value. TAG is defined as the linear regression coefficient between luminal contrast attenuation (Hounsfield units [HU]) and length from the ostium (cm).
The diagnostic performance of TAG and CCO is summarized in Table 5. Although the sensitivity, specificity, PPV, and NPV of TAG were inferior to CTA alone (77%, 74%, 67%, and 86% versus 94%, 66%, 64%, and 94%) in 54 patients and 78 vessels with invasive FFR as the gold standard, the addition of TAG to CTA provided incremental value.66 In a second study of 97 vessels in 63 patients with invasive FFR, the sensitivity, specificity, PPV, and NPV of TAG were 48%, 91%, 79%, and 71%, respectively; TAG was additive to CTA alone (c-statistic increased from 0.726–0.809, P=0.025).67 For CCO, the corresponding values were 65%, 61%, 54%, and 71%, and it did not significantly increase the c-statistic of CTA (0.726 versus 0.784, P=0.09). Comparison of TAG with CTA and FFRCT was performed in 53 patients and 82 vessels from the DISCOVER-FLOW trial; TAG sensitivity was 38% versus 72% for CTA >70% DS and 81% for FFRCT.68 Evaluation of well-developed collateral flow in the setting of chronic total occlusions by TAG yielded 65% sensitivity, 73% specificity, 52% PPV, and 82% NPV, as well as accurately differentiating between retrograde and antegrade flow.69
A subsequent comparison with invasive FFR revealed no incremental value for TAG (69% sensitivity, 44% specificity, 27% PPV, and 83% NPV) over CTA alone (95% sensitivity, 75% specificity, 54% PPV, and 98% NPV) in 253 vessels in 85 patients; the addition of CCO and exclusion of calcified segments only slightly improved the results.70 Finally, in a 3 part study of phantoms, dogs and 152 vessels in 62 patients undergoing ICA, no significant TAG differences were noted between stenotic and normal vessels. Proximal to distal decreases in attenuation were a function of vessel diameter rather than stenosis.71 The variable TAG results may reflect the use of 64 detector scanners that do not provide the isotemporal, single-beat acquisition best suited for TAG, as emphasized by Lardo et al72 in their pilot animal and human study in which they calculated coronary blood flow using CT transluminal attenuation flow encoding. They found a strong correlation with microsphere myocardial blood flow (R2=0.90, P<0.001) in the animal model and appropriate values in patients.
The profound impact of invasive FFR on intervention has had major repercussions on the world of noninvasive imaging. It is no longer acceptable to gauge the efficacy of an imaging modality by its ability to identify a >50% DS. Rather, its diagnostic accuracy for the detection of an invasive FFR of ≤0.80 is paramount and will remain so for as long as invasive FFR remains the gold standard. In this regard, the most commonly used modalities of MPI and stress echocardiography are clearly inferior to CTA alone, which, in turn seems to be inferior to CT-FFR in specificity and PPV. In addition, the ability of CTA to analyze plaque characteristics offers a clear advantage over nonanatomic functional imaging. Considerable work remains to be done:
Longer-term outcome studies of major cardiac events and cost effectiveness of CT-FFR–guided treatment compared with the other imaging modalities, including MRI and positron emission tomography, which seem to have diagnostic performance rivaling CTA alone and CT-FFR.
Outcome studies comparing CT-FFR leading directly to intervention without confirmation by invasive FFR versus requiring confirmation by invasive FFR.
Development of the most accurate and cost-effective CT-FFR workstation-based technology.
The potential effects of successful trials, aside from reduced events and costs, are obvious and potentially disruptive: reduction in unnecessary ICA with transformation of the catheterization laboratory into a purely interventional suite and dramatic reduction in the standard functional imaging tests with the inevitable accompanying major decline in private practice and hospital income. Until the trials are completed, CT-FFR will likely be slowly incorporated into practice, notwithstanding the absence of guideline recommendation. A futuristic algorithm based on further validation and acceptance of CT-FFR as the standard of care is presented in Figure 5.
Dr Hecht is a consultant to Philips medical Systems and Heartflow. Dr Fearon received research support from Medtronic and St. Jude and he is a consultant to Medtronic and HeartFlow. The other author report no conflicts.
This Review is in a thematic series on Cardiovascular Imaging, which includes the following articles:
T1 Mapping in Characterizing Myocardial Disease: A Comprehensive Review
Fractional Flow Reserve and Coronary Computed Tomographic Angiography: A Review and Critical Analysis
Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease: Anatomy, Physiology, or Morphology?
Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis
Transcathether Valve Replacement and Valve Repair: Review of Procedures and Intraprocedural Echocardiographic Imaging
Advances in Echocardiographic Imaging in Heart Failure With Reduced and Preserved Ejection Fraction
Viability: Is it Still Attractive?
Guest Editors: Jagat Narula and Y. Chandrashekhar
- Nonstandard Abbreviations and Acronyms
- coronary computed tomographic angiography
- computed tomographic stress myocardial
- Fractional Flow Reserve Versus Angiography for Multivessel Evaluation
- fractional flow reserve
- fractional flow reserve form computed tomography
- myocardial perfusion imaging
- magnetic resonance imaging
- negative predictive value
- percutaneous coronary intervention
- positive predictive value
- Received February 24, 2016.
- Revision received May 18, 2016.
- Accepted May 25, 2016.
- © 2016 American Heart Association, Inc.
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- Fractional Flow Reserve and Coronary Computed Tomographic AngiographyHarvey S. Hecht, Jagat Narula and William F. FearonCirculation Research. 2016;119:300-316, originally published July 7, 2016https://doi.org/10.1161/CIRCRESAHA.116.307914
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PLD improves indigenous literacy in remote community area: Speech Pathology Australia case study.
In my time travelling to different schools and conducting seminars with educators, I often highlight the fact that attendance at school is important and essential for children to learn. However it's important to point out that on its own, attendance will not raise literacy standards. This is particularly the case for remote schools and those […]Read More


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I used the fabulous Izzy's Christmas Friends, which you can find in the Christmas section of Di's Digi Stamps website.
This card is also for
Stamps: Izzy's Christmas Friends from Di's Digi Designs
Papers: Bermuda Bay, Whisper White & Winter Frost DSP (Retired) all from Stampin' Up, Super Smooth Card from That Craft Place
Ink: Copic Markers
Accessories: Gems from Poundland, Shimmering Snowflakes Dies from Memory Box, Peeking Snowflake Dies from Creative Expressions, White Liquid Applique
Copics Used:
Skin - E000, E00, E21, E11, E04, R20, R30
Hair - E53, E55, E57
Green - BG34, BG13, B15
Pink - RV10, RV11, RV13
Turquoise - B01, BG01, BG02
Red - R24, R27, R29
Bear - W00, W1, C5, C7, C9, R20, R30
Penguin - W00, W1, W5, W7, W9, YR15, YR18
And that's all from me for this post folks! Thanks for stopping by and don't forget to pop on over to Di's Digi Designs Challenge blog and check out all the other gorgeous cards from the DT and why not join in the fun whilst you are there too?!


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Hellooo!! My name is Amber Bernhard and I am an Admission Counselor for the Texas Hill Country. I am a recent graduate of Schreiner University class of 2014 with my Bachelor of Arts in Communication Studies. I loved my experience here so much that I couldn't help but come back.
In my free time, I enjoy spending time with friends, completing DIY projects, exploring the great outdoors, and binge watching TV shows on Netflix.
Schreiner is a fantastic place to find yourself and figure out your next steps in life. With a small class size and an opportunity to get involved, Schreiner is a perfect fit for students that are looking for a one-of-a-kind experience specific for what you want to do. Come take a visit and enjoy the Texas Hill Country air! Hope to see you soon!
Amber Bernhard
Admission Counselor


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Hello all!
This week's Midweek Throwdown from Operation Write Home (OWH) is a color challenge – White on White …..
At first I thought ….. ugh …. what can I do with that! wedding card? or maybe a wedding shower? How much call is there going to be for those cards? This is not going to be fun – maybe I should start cleaning the house in anticipation of company coming tomorrow for Thanksgiving dinner….
Man-o-man, was I wrong! Thank you OWH for once again encouraging me to try something different!
Although there are always things that are either in-use or have recently been used and aren't put back in their place, I'm more than a bit of a nerd or geek, or whatever the proper term is, when it comes to having things organized. When I get an idea (which sometimes … ok, often …. takes me a LONG time) I don't want to have to spend a lot of time digging around trying to find this or that.
This attitude also extends to my papers – sorted by color family and within that between patterned or plain. I do have a nice variety of white papers – flat, sparkly, textured, lightweight, heavyweight (you get the idea) – all sorted and stacked. So I grabbed the pile of white and thought, well, I guess I can emboss something and make it acceptable. But as I started flipping through the papers to find the right weight and finish, I was reminded how many 'colors' of white there are ~ I don't mean cream or beige or even off-white (which I have sorted and stacked separately) but, when it stands on it's own, is a color that I consider to be white. Now this is definitely a non-scientific assessment and is based only on how my eye sees things, but I have a lot of different whites! Of course, I knew that – after all, I did sort them in the first place, but it's not something I really give much thought to on a day-to-day basis. Now the challenge was becoming a bit more interesting and a bit less daunting.
So I set the papers aside and started thinking in reverse – not about what paper do I want to use and then find an embossing folder that would work, but instead about a design and then I'll fit the papers to it. I settled on what I guess would be called a modified tri-fold card. A2 size but with the front flap folded over again. My first thought was to do a partial die cut and layer the cut area with a different white than the card base – and so I set about trying to find the perfect die. I found a lovely detailed die called Renaissance Heart from Hero Arts – I gave it a go. It was ok but it wasn't what I had envisioned and layering would be tough. So I tried again and this time I did a partial die cut using a Spellbinder's Classic Hearts die about the same size as the Renaissance Heart and then found a pearlized white paper (it may look off-white or cream in the photo, but I swear that, on it's own, it is very white). I cut the pearlized paper with the Renaissance Heart die and layered over the top of solid heart cut into the card base. That worked! WOO HOO!! But I still wasn't happy with the overall results of the card – it was still a bit too plain, so I took some more of the pearlized paper and another Spellbinders die (Lattice Rectangles) and cut a layer for the inside of the card. That was the answer!
I know that the sample card had a sentiment stamped in a pastel color, but with the partial die cut, the only writing surface is the inside panel so I wanted to leave that open. I tried a couple of things on the front using the Stamp-a-ma-jig to try out different placements but I didn't find anything I thought really worked. I hope it stands well enough on its own.
Now things were falling into place, so why not another card? I liked the tri-fold approach but how about going back to the original embossing idea? I have the Spellbinders Wonderful Wings set and had also considered a butterfly for the first card – and the two papers worked well together – so I cut and layered the butterfly. I would pop that up with some foam tape but what do do for the embossing? For me, butterflies and flowers just belong together. I have a great die from Memory Box called Fairytale Flower Border that was the perfect fit! I used the die to emboss both the inside of the card base and a strip of the pearlized paper that was left over. I'm disappointed that the embossing doesn't show up better in the photo because it is so pretty in person. I adhered the pearlized paper to the front of the card, layered on the butterfly and ta-da! a second card!
I hope you like them both!
Wishing you all a very Happy Thanksgiving~


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Looking For an Arab Muslim or Black Man
My name is Sofia. I just recently turned 19. I have deep feelings towards black and Arab Muslim men.
They seem to turn me on whenever I think of them and see them.
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Please do come to Europe, there are many other white girls like myself who want you, and who are tired of white men.


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This system combines the automatic adjustment capabilities of torque and the typical speed of a hydraulic drive, with the advantages of an electric drive. These are the main features:
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Maintenance – Drastic reduction of routine maintenance costs (filters and oil in control unit) and significant reduction of extraordinary maintenance costs (hydraulic valves, pumps and motors).
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TÜV Rheinland Group is a leading provider of technical services worldwide. We assist manufacturers, importers and retailers from the product development stage to market approval with our testing, inspection, and certification services. TÜV Rheinland offers a one-stop solution for clothing, textiles, and protective equipment. Our advanced equipment and technical expertise will help your products meet all major domestic and international regulations and standards. The features of our service include fast turnaround time and excellent follow-up.
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River Pointe has everything you want, at a price you can afford. Spacious apartments featuring renovated kitchens and baths, combined with updated hallways and entries, create a home you`ll be proud of. At the center of our community, the clubhouse features an indoor pool, fitness center and party room. Outside, wrapped in loads of green grass is our relaxing outdoor pool, play lot, and picnic area. A place everyone can enjoy! Add the convenience of the nearby Northtown shopping area (one mile) and it is easy to see why River Pointe is the perfect place for you to call home.
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Chambéry is a beautiful town in the Rhône-Alpes region of France. Chambéry is the birthplace and historic capital of Savoie. Throughout history, it has been both Italian and French. It lies in a valley in the Alps surrounded by the Bauges and Chartreuse mountain ranges and provides almost 360-degree views of the French Alps. To the north, it is bordered by Lac du Bourget, the largest natural lake in France. Chambéry has long been a "crossroads to the Alps" dating all the way back to the 11th century. For many years, it was ruled by the Duchy of Savoie before being annexed to the King of France. Jean-Jacques Rousseau wrote the Declaration of the Rights of Man (the French version of the Bill of Rights) while living in Chambéry.
Chambéry is a charming, peaceful place to visit with beautiful architecture, good food and wine, and friendly people. There are many vineyards in the area that visitors can enjoy, and on Saturdays, the city public market is abuzz with the freshest cheeses, meats, and local produce from the Alps. The area offers many recreational activities to choose from in all seasons, from skiing and snowshoeing, to sailing and rock climbing. The famous Tour de France bicycle race comes through the area in the summer. Chambéry also boasts the Savoie Technolac research park and the Universite de Savoie, and a mountain research center.
Get in[edit]
By plane[edit]
There is a small local airport, Chambéry-Savoie Airport (IATA: CMF, ICAO: LFLB), 10km north of the city, next to Lac du Bourget, that is served by a number of cheap airlines, especially during the winter months.
A little further away is Lyon–Saint-Exupéry Airport (IATA: LYS), which is also served by international flights. There are 2 daily TGV train services in each direction between Lyon airport (station name: Lyon-Saint Exupéry TGV) and Chambéry with a journey time of 1 hour. Alternatively, there is a bus service operated by Transdev Haute-Savoie [1] with a journey time of 1 hour.
By train[edit]
Chambéry has direct TGV from Paris and other trains (TER, Train Express Regional) to all major destinations of the region. It takes 3.5 hours to get to Chambery on the direct TGV. Chambéry is easily accessible to Lyon, Grenoble, Chamonix, Geneva (Switzerland), and Turin (Italy.)
By road[edit]
It is linked by motorways to
Get around[edit]
Chambéry is compact in size and is easily explored on foot in a short amount of time. The medieval section of the town is quite well preserved. There are also local and regional buses. If you wish to explore the mountains or go on a wine tour, car rentals are available in town.
If you want a bit of exercise, you can also rent a bicycle and explore a bit further. Bicycles can be rented from the Vélostation in front of the train station: Agence Ecomobilité http://agence.ecomobilite.free.fr/ Only 3 euros for a half day and 5 euros for a full day. Open Monday-Friday 6:30 am to 7 pm and from 9 am to 7 pm on weekends and holidays.
Cycle paths: a cycle route goes from the centre of town north to the Lac du Bourget (mostly a cycle lane which is separate from the road) and another goes south into the vineyards (mixture of separate cycle lane and quiet country roads).
See[edit][add listing]
Do[edit][add listing]
Shopping, eating, drinking, visiting vineyards, hiking, boating, skiing, snowshoeing, rock climbing, horseback riding
Buy[edit][add listing]
A light, yet sturdy knife from local company "Opinel"
Cheap shoes and clothing from the store Axo. Hard to find (ask the locals for directions) and terribly disorganized, but the prices are very good. A pair of ballerina flats usually goes for around 8 euros.
Eat[edit][add listing]
Fondue savoyarde, tartiflette, crêpes, goats cheese
Drink[edit][add listing]
Vins de Savoie, Chartreuse, Génépi, O'Cardinal's Pub
Located: 9, rue Denfert Rochereau, 73000 Chambery
It is situated in the centre of Chambéry near the Savoy University. It includes 40 soundproof bedrooms on three floors, which all include bathroom, telephone, satellite TV and car space in front of the hotel to deposit luggage. English, Spanish, French and Italian is spoken. The hotel also includes an indoor swimming pool, tennis, skating rink and an equestrian centre.
Hotel facilities: Internet - wireless internet is available in all rooms and is free of charge, Guest parking - Private parking is possible at a location nearby and cost roughly EUR 6.00 ($9.60) per day.
Children and extra beds: Maximum capacity of extra beds in a room is 1
Price: EUR 90 ($144) per day
Check-In: 12.00 hours
Check-Out: 11.00 hours
All rooms are non-smoking.
CHÂTEAU DE CANDIE (90~160 Euros + Restaurant, 23~55 Euros) Address: 38, rue Bobby Sands, 73000, Chambéry-le-Vieux (5 km from Chambéry) Tel.: (33)(4)79966300 Fax: (33)(4)79966310 Five minutes from the centre of Chambéry, this massive XIVth Century Château had its beautiful rooms elegantly renovated. The cuisine is inspired by its Savoy roots: sautéed mushrooms and crawfish, omble chevalier meunière, beef fillet seasoned with Szechuan pepper. Great cheeses and wines. All food served in the "Orangerie".
L'ESSENTIEL (27~53 Euros) Address: 183, place de la Gare, 73000, Chambéry. Tel.: (33)(4)79969727 Fax: (33)(4)79961778 Closed on Saturday Lunches & all Sundays. A contemparary decor and inventive regional cuisine, served with local Savoy wines.
L'HYPOTÉNUSE (14~35 Euros) Address: Carré Curial, 73000, Chambéry. Tel.: (33)(4)79858015 Fax: (33)(4)79858018 Closed on Saturday lunches & all Sundays as well as July 15th~August 15th. In a space full of silence and fresh air, this restaurant offers a seasonal cuisine created with locally grown products at a reasonable price.
AUX PIÉTONS Address: Place Monge, 73000, Chambéry. Tel.: (33)(4)79855245 Closed on Sundays & Tuesday nights. Gearty local specialties: cheese fondue, tartiflette and brasérade.
LE TONNEAU (17~35 Euros) Address: 2, rie Saint-Antoine, 73000, Chambéry. Tel.: (33)(4)79337826 Fax: (33)(4)79854969 Closed on Sunday evenings & all Sundays. An elegant restaurant with a shaded terrace for summer dining. Great service and food.
LE SAINT REAL RESTAURANT Address: Place Pierre Dumas, 73000 Chambéry Telephone Number: 04 79 70 09 33 Website: http://www.restaurant-saint-real.com/en/ Situated in the heart of the Old Town of Chambéry, near the famous Fontaine des Elephants. Le Saint Real Restaurant caters for any occasion including; business meals, romantic dinners, birthday meals and family dinners, take your time to discover high quality food within an elegant and exquisite setting.
Menu Suggestions: - The fresh duck stove foie gras with the Victoria pineapple white rum and ice - Hazel nuts fried of roe deer Corsican juice to currents - Rack of lamb roasted in a nuts crust - Selection of fresh and refined cheese - Selection of delicious desserts
Get out[edit]
Aix-les-Bains, Annecy, La Feclaz


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Research Library | Digital Repository
Karyotypes and evolution of the spinosus group of lizards in the genus Sceloporus. American Museum novitates ; no. 2431
Scientific Publications
American Museum Novitates
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Karyotypes and evolution of the spinosus group of lizards in the genus Sceloporus. American Museum novitates ; no. 2431
Cole, Charles J.
"Karyotypes of all the species in the spinosus group of lizards of the genus Sceloporus were analyzed by means of the colchicine, hypotonic citrate, air-dried technique, employing both bone marrow and testicular tissues. The following cytogenetic phenomena were found within this species group: interspecific and intraspecific variation in chromosome number and morphology; polymorphism in local populations; cytologically recognizable sex chromosomes; and natural chromosomal aberrations. There are four general karyotypes in the species group, though some exhibit relatively minor variations. Diploid chromosome numbers range from a high of 40 (with nearly all chromosomes telocentric) to a low of 22 (with all or nearly all chromosomes metacentric or submetacentric). The cytogenetic data, together with ecological, behavioral, and biogeographic data, indicate that speciation within the group has produced several phylads. Karyotypic evolution primarily involved chromosomal centric fusion (whole-arm translocation). The proposed phylogeny of the group is strongly compatible with the evidence that desert-dwelling species were derived from ancestors occurring in tropical to subtropical forests"--P. 41-42.
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American Museum Novitates
Novitates (Latin for "new acquaintances"), published continuously and numbered consecutively since 1921, are short papers that contain descriptions of new forms and reports in zoology, paleontology, and geology. New numbers are published at irregular intervals.
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The Yoruba socio-cultural group, the Oodua People's Congress (OPC), has sued for peace in the raging faceoff over the October 1 ultimatum that a coalition of Arewa youths issued last week, ordering Ndigbo to vacate Northern Nigeria.
In a statement released in Lagos at the weekend, Founder and President of the Oodua People's Congress (OPC), Dr. Frederick Fasehun, said that considering the current travails Nigeria was going through, everyone owed it a duty not to complicate matters by opening new vistas of trouble.
"What would happen should the Yoruba decide to issue this same ultimatum to Northerners living in the South-West? And what if the Igbo give a deadline to the Hausa-Fulani and the Yoruba living in the South-East? And the Middle-Belters now decide they do not want to see the Hausa-Fulani and Igbo groups?"
He thought it paradoxical that while the great Nationalist, Dr. Nnamdi Azikiwe, wanted a united Africa, his followers and disciples were clamouring for a shredded Nigeria.
"Any call to division is unfair, uncalled for and ill-advised in this age of anomie, when Nigeria needs everyone's energy, cooperation and prayers to build a nation where peace, happiness and plenty will reign.
"As small nations can only aspire to become great, not vice versa, Nigeria's greatness will come about as a function of the mutual understanding, love and cooperation of her people. Let us all bear in mind that no nation or part thereof is great without pervasive cooperation among her citizens."
Reacting to the spokesman of Arewa's Elders, Dr. Ango Abdullahi's backing of the ultimatum; Fasehun said old politicians ought to offer peace instead of fanning the embers of division.
Addressing the youths, Fasehun said: "Nigeria belongs to the youth. They should not keep quiet while their fathers are busy shredding Nigeria."
He called on Nigerians to use the period of the holy month of Ramadan for national prayers, as the country could not survive the current buffeting without the intervention of the Creator.
He said: "Those who govern us have been unkind to all and each of us. Individual reprisals will be a burden too great to hand out to an innocent country. Let the anger of the furious come down so that the joy of the joyous may be pervasive and common.
"General Buhari's government should not be true to type. Too many people for too long have been wronged. If we all cry over division of the polity, we shall at the end become a laughing stock and finally end up with nothing to divide."
Rather, the OPC leader said this time in the nation's history demanded all hands to be united against prevailing challenges like terrorism, insurgency and poverty.
Declaring that the 2014 National Conference addressed the need for restructuring, the Yoruba socio-cultural group, said, "We cannot just bury the report of such a landmark achievement, sweep it under the carpet and pretend it does not exist. Nigeria needs to dig up that report and activate its provisions, which represent the sine qua non, the irreducible minimum, for building a strong and united Nigeria."


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Free Partnershipeement Form Elegant Friendly Loan Sample Contracts Template Of Australia
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Welcoming Wellness: Exploring Creative Ideas to Addressing Law School Stress
Thursday, November 30, 2017 6:00 pm to 7:30 pm
This group is being offered to all UConn Law students. It meets weekly on Thursdays beginning November 9th through December 14th. Please drop in for all or part of the group depending on your schedule. Creative ways to reduce stress, improve wellness, and reduce feelings of overwhelm will be explored through a variety of activities and group discussion. Refreshments will be served.
Yvonne Tafuto
If you require reasonable accommodations for a disability, please contact the Law School at 860-570-5130 or via email at firstname.lastname@example.com at least two weeks in advance.