Association Between 3D-Angiography Based Fractional Flow Reserve and Non-Invasive Myocardial Ischemia Testing: The FAST ISCHEMIA Study.

BACKGROUND: In order to facilitate fractional flow reserve (FFR)-guided lesion assessment, several 3-dimensional (3D)-angiography-based physiological indices have been recently validated. Thus far, limited data are available on the association of these indices with conventional forms of ischemia testing. AIM: The aim of the study was to determine the association between 3D-angiography-based vessel-FFR (vFFR) and myocardial ischemia as assessed by exercise electrocardiography (ECG) testing, dobutamine stress echocardiography, single photon emission computed tomography myocardial perfusion imaging (SPECTMPI), and stress cardiovascular magnetic resonance imaging (stress CMR). METHODS: FAST ISCHEMIA is a retrospective, single-center cohort study including patients who underwent non-invasive myocardial ischemia testing and subsequent coronary angiography (≤3 months). A total of 145 patients (340 vessels) were analyzed. The overall patient-based sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) of vFFR ≤0.80 in any vessel for ischemia was 64% (95% confidence interval [CI], 53-74), 71% (95% CI, 54-84), 83% (95% CI, 72-91), 46% (95% CI, 33-60), 2.16 (95% CI, 1.25-3.74), and 0.52 (95% CI, 0.36-0.74), respectively. Multivariable logistic regression showed that vFFR ≤0.80 was significantly associated with ischemia on a patient level (odds ratio, 8.13; 95% CI, 2.51-30.06; P<.001) and on a vascular territory level (odds ratio, 2.75; 95% CI, 1.17-6.44; P<.01). CONCLUSION: Our study suggests that vFFR ≤0.80 has a modest association with non-invasive myocardial ischemia testing using either exercise ECG or stress imaging modalities. After correcting for independent confounders, vFFR was independently associated with ischemia on a non-invasive myocardial ischemia detection test.

Machine-learning-derived radiomics signature of pericoronary tissue in coronary CT angiography associates with functional ischemia.

Objectives: To determine the association between radiomics signature (Rad-signature) of pericoronary tissue (PCT) in coronary computed tomography angiography (CCTA) and CT-derived fractional flow reserve (CT-FFR), and explore the influential factors of functional ischemia. Methods: We retrospectively included 350 patients who underwent CCTA from 2 centers, consisting of the training (n = 134), validation (n = 66), and testing (with CCTA and invasive coronary angiography, n = 150) groups. After evaluating coronary stenosis level in CCTA (anatomical CT), pericoronary fat attenuation index (FAI), and CT-FFR, we extracted 1,691 radiomic features from PCT. By accumulating and weighting the most contributive features to functional ischemia (CT-FFR ≤ 0.8) the Rad-signature was established using Boruta integrating with a random forest algorithm. Another 45 patients who underwent CCTA and invasive FFR were included to assure the performance of Rad-signature. Results: A total of 1046 vessels in 350 patients were analyzed, and functional ischemia was identified in 241/1046 (23.0%) vessels and 179/350 (51.1%) patients. From the 47 features highly relevant to functional ischemia, the top-8 contributive features were selected to establish Rad-signature. At the vessel level, the area under the curve (AUC) of Rad-signature to discriminate functional ischemia was 0.83, 0.82, and 0.82 in the training, validation, and testing groups, higher than 0.55, 0.55, and 0.52 of FAI (p < 0.001), respectively, and was higher than 0.72 of anatomical CT in the testing group (p = 0.017). The AUC of the combined model (Rad-signature + anatomical CT) was 0.86, 0.85, and 0.83, respectively, significantly higher than that of anatomical CT and FAI (p < 0.05). In the CCTA-invasive FFR group, using invasive FFR as the standard, the mean AUC of Rad-signature was 0.83 ± 0.02. At the patient level, multivariate logistic regression analysis showed that Rad-signature of left anterior descending (LAD) [odds ratio (OR) = 1.72; p = 0.012] and anatomical CT (OR = 3.53; p < 0.001) were independent influential factors of functional ischemia (p < 0.05). In the subgroup of nonobstructive (stenosis <50% in invasive coronary angiography) and obstructive (≥50%) cases of the testing group, the independent factor of functional ischemia was FAI of LAD (OR = 1.10; p = 0.041) and Rad-signature of LAD (OR = 2.45; p = 0.042), respectively. Conclusion: The machine-learning-derived Rad-signature of PCT in CCTA demonstrates significant association with functional ischemia.

Lesion-Specific Peri-Coronary Fat Attenuation Index Is Associated With Functional Myocardial Ischemia Defined by Abnormal Fractional Flow Reserve.

Background: The association between abnormal invasive fractional flow reserve (FFR) and the fat attenuation index (FAI) of lesion-specific peri-coronary adipose tissue (PCAT) is unclear. Method: Data of patients who underwent coronary computed tomography angiography (CTA) and subsequent invasive coronary angiography (ICA) and FFR measurement within 1 week were retrospectively included. Lesion-specific FAI (FAIlesion), lesion-free FAI (FAInormal), epicardial adipose tissue (EAT) volume and attenuation was collected, along with stenosis severity and plaque characteristics. Lesions with FFR <0.8 were considered functionally significant. The association between FFR and each parameter was analyzed by logistic regression or receiver operating characteristic curve. Result: A total of 227 patients from seven centers were included. EAT volume or attenuation, traditional risk factors, and FAInormal (with vs. without ischemia: -82 ± 11 HU vs. -81 ± 11 HU, p = 0.65) were not significantly different in patients with or without abnormal FFR. In contrast, lesions causing functional ischemia presented more severe stenosis, greater plaque volume, and higher FAIlesion (with vs. without ischemia: -71 ± 8 HU vs. -76 ± 9 HU, p < 0.01). Additionally, the CTA-assessed stenosis severity (OR 1.06, 95%CI 1.04-1.08, p < 0.01) and FAIlesion (OR 1.08, 95%CI 1.04-1.12, p < 0.01) were determined to be independent factors that could predict ischemia. The combination model of these two CTA parameters exhibited a diagnostic value similar to the invasive coronary angiography (ICA)-assessed stenosis severity (AUC: 0.820 vs. 0.839, p = 0.39). Conclusion: It was FAIlesion, not general EAT parameters, that was independently associated with abnormal FFR and the diagnostic performance of CTA-assessed stenosis severity for functional ischemia was significantly improved in combination with FAIlesion.

Design of the Japanese Comprehensive Health-Economic Assessment for Appropriate Cardiac Imaging Strategy Including Outcome and Cost-Effectiveness in Stable Coronary Artery Disease Study (J-CONCIOUS).

Background: The evaluation of stable coronary artery disease (SCAD) has evolved, and contemporary clinical practice guidelines emphasize the importance of in-depth consideration of procedure indications, risk stratification, and results of non-invasive imaging tests. However, little is known about the appropriate selection of imaging modalities for ischemia evaluation and the comparative cost-effectiveness in real-world clinical practice. Methods and Results: The Japanese Comprehensive Health-Economic Assessment for Appropriate Cardiac Imaging Strategy including Outcome and cost-effectiveness in Stable Coronary Artery Disease Study (J-CONCIOUS), a multicenter observational study, was designed to prospectively enroll 2,500 patients with suspected or known SCAD, register clinical information and administrative records, and follow patients for 3 years. Any diagnostic or cardiac imaging modality (including stress tests using electrocardiography, echocardiography, or myocardial perfusion imaging; coronary computed tomographic angiography; and/or invasive coronary angiography with or without fractional flow reserve assessment) is acceptable. Clinical endpoints, such as all-cause mortality, cardiac death, and non-fatal myocardial infarction, will be obtained, along with quality of life assessment using the Seattle Angina Questionnaire. The cost-effectiveness of individual assessment patterns will be quantified by analysis of Diagnosis Procedure Combination (DPC) data, and quality-adjusted life years and the incremental cost-effectiveness ratio will be calculated. Conclusions: J-CONCIOUS is expected to establish a risk-based and cost-effective imaging strategy for the detection and evaluation of functional myocardial ischemia and/or anatomical coronary imaging in Japan.

Dystrophin R16/17 protein therapy restores sarcolemmal nNOS in trans and improves muscle perfusion and function.

BACKGROUND: Delocalization of neuronal nitric oxide synthase (nNOS) from the sarcolemma leads to functional muscle ischemia. This contributes to the pathogenesis in cachexia, aging and muscular dystrophy. Mutations in the gene encoding dystrophin result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). In many BMD patients and DMD patients that have been converted to BMD by gene therapy, sarcolemmal nNOS is missing due to the lack of dystrophin nNOS-binding domain. METHODS: Dystrophin spectrin-like repeats 16 and 17 (R16/17) is the sarcolemmal nNOS localization domain. Here we explored whether R16/17 protein therapy can restore nNOS to the sarcolemma and prevent functional ischemia in transgenic mice which expressed an R16/17-deleted human micro-dystrophin gene in the dystrophic muscle. The palmitoylated R16/17.GFP fusion protein was conjugated to various cell-penetrating peptides and produced in the baculovirus-insect cell system. The best fusion protein was delivered to the transgenic mice and functional muscle ischemia was quantified. RESULTS: Among five candidate cell-penetrating peptides, the mutant HIV trans-acting activator of transcription (TAT) protein transduction domain (mTAT) was the best in transferring the R16/17.GFP protein to the muscle. Systemic delivery of the mTAT.R16/17.GFP protein to micro-dystrophin transgenic mice successfully restored sarcolemmal nNOS without inducing T cell infiltration. More importantly, R16/17 protein therapy effectively prevented treadmill challenge-induced force loss and improved muscle perfusion during contraction. CONCLUSIONS: Our results suggest that R16/17 protein delivery is a highly promising therapy for muscle diseases involving sarcolemmal nNOS delocalizaton.

Lower Level of Low Density Lipoprotein Cholesterol is Associated with a Higher Increase in the Fractional Flow Reserve in Patients with Fixed-dose Rosuvastatin.

AIM: Fractional flow reserve (FFR) reflects on the diffuse atherosclerosis per coronary artery. It is unknown whether the statin therapy affects long term FFR after stenting. The aim of this study was to evaluate the long term FFR after stent implantation in patients who are intaking fixed-dose rosuvastatin. METHODS: A total of 22 patients with stable angina pectoris were enrolled. The values of FFR were measured before, immediately after, and 18 months after (follow-up day) the implantation of everolimus eluting stent (EES; Promus ElementTM or Promus Element PlusTM). A fixed dose of rosuvastatin at 5 mg/day was administrated to all patients. RESULTS: Of the 22 patients, 2 were excluded because of adverse effect of rosuvastatin and in-stent total occlusion after EES implantation. Overall, the values of FFR immediately after and 18 months after EES implantation did not show significant change (from 0.90±0.05 to 0.88±0.06, p=0.16). However, there was a significant negative correlation between low density lipoprotein (LDL) cholesterol level at follow-up day and changes in the value of FFR (p=0.01, r =－0.74). There was an increase in the FFR value after stenting in 8 out of 9 patients with LDL cholesterol level below 75 mg/dl (area under the curve 0.92, p=0.0005). CONCLUSIONS: LDL cholesterol level was associated with the change in the FFR value in patients following stent implantation. Lower LDL cholesterol tended to improve in the long-term FFR, underscoring the importance of lowering LDL cholesterol to prevent the progression of coronary atherosclerosis.

How to Utilize Coronary Computed Tomography Angiography in the Treatment of Coronary Artery Disease.

Coronary computed tomography angiography (CCTA) has high negative predictive power for detecting coronary artery disease. However CCTA is limited by moderate positive predictive power in the detection of myocardial ischemia. This is not unexpected because the diameter of a stenosis is a poor indicator of myocardial ischemia and discrepancy between the severity of stenosis and noninvasive tests is not uncommon. The value of stenosis for predicting future development of acute coronary syndrome represented by plaque rupture has been questioned. CCTA identifies the characteristics of high-risk plaque including positive remodeling, low density plaque and spotty or micro-calcification. Also, additional evaluation of myocardial ischemia using computational flow dynamics, and luminal attenuation gradient are expected to increase both diagnostic performance for hemodynamically significant stenosis and the predictive power for future cardiovascular risk. Technical advances in CCTA would enable evaluation of both coronary artery stenosis and myocardial ischemia simultaneously with high predictive performance, and would improve vastly the clinical value of CCTA.

How to Utilize Coronary Computed Tomography Angiography in the Treatment of Coronary Artery Disease

Coronary computed tomography angiography (CCTA) has high negative predictive power for detecting coronary artery disease. However CCTA is limited by moderate positive predictive power in the detection of myocardial ischemia. This is not unexpected because the diameter of a stenosis is a poor indicator of myocardial ischemia and discrepancy between the severity of stenosis and noninvasive tests is not uncommon. The value of stenosis for predicting future development of acute coronary syndrome represented by plaque rupture has been questioned. CCTA identifies the characteristics of high-risk plaque including positive remodeling, low density plaque and spotty or micro-calcification. Also, additional evaluation of myocardial ischemia using computational flow dynamics, and luminal attenuation gradient are expected to increase both diagnostic performance for hemodynamically significant stenosis and the predictive power for future cardiovascular risk. Technical advances in CCTA would enable evaluation of both coronary artery stenosis and myocardial ischemia simultaneously with high predictive performance, and would improve vastly the clinical value of CCTA.