Transradial Versus Transfemoral Access for Bifurcation Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stent.

BACKGROUND: The benefits of transradial access (TRA) over transfemoral access (TFA) for bifurcation percutaneous coronary intervention (PCI) are uncertain because of the limited availability of device selection. This study aimed to compare the procedural differences and the in-hospital and long-term outcomes of TRA and TFA for bifurcation PCI using second-generation drug-eluting stents (DESs). METHODS: Based on data from the Coronary Bifurcation Stenting Registry III, a retrospective registry of 2,648 patients undergoing bifurcation PCI with second-generation DES from 21 centers in South Korea, patients were categorized into the TRA group (n = 1,507) or the TFA group (n = 1,141). After propensity score matching (PSM), procedural differences, in-hospital outcomes, and device-oriented composite outcomes (DOCOs; a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization) were compared between the two groups (772 matched patients each group). RESULTS: Despite well-balanced baseline clinical and lesion characteristics after PSM, the use of the two-stent strategy (14.2% vs. 23.7%, P = 0.001) and the incidence of in-hospital adverse outcomes, primarily driven by access site complications (2.2% vs. 4.4%, P = 0.015), were significantly lower in the TRA group than in the TFA group. At the 5-year follow-up, the incidence of DOCOs was similar between the groups (6.3% vs. 7.1%, P = 0.639). CONCLUSION: The findings suggested that TRA may be safer than TFA for bifurcation PCI using second-generation DESs. Despite differences in treatment strategy, TRA was associated with similar long-term clinical outcomes as those of TFA. Therefore, TRA might be the preferred access for bifurcation PCI using second-generation DES. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03068494.

Cutoff of the reverse shock index multiplied by the Glasgow coma scale for predicting in-hospital mortality in adult patients with trauma: a retrospective cohort study.

BACKGROUND: Early identification of patients at risk of potential death and timely transfer to appropriate healthcare facilities are critical for reducing the number of preventable trauma deaths. This study aimed to establish a cutoff value to predict in-hospital mortality using the reverse shock index multiplied by the Glasgow Coma Scale (rSIG). METHODS: This multicenter retrospective cohort study used data from 23 emergency departments in South Korea between January 2011 and December 2020. The outcome variable was the in-hospital mortality. The relationship between rSIG and in-hospital mortality was plotted using the shape-restricted regression spline method. To set a cutoff for rSIG, we found the point on the curve where mortality started to increase and the point where the slope of the mortality curve changed the most. We also calculated the cutoff value for rSIG using Youden's index. RESULTS: A total of 318,506 adult patients with trauma were included. The shape-restricted regression spline curve showed that in-hospital mortality began to increase when the rSIG value was less than 18.86, and the slope of the graph increased the most at 12.57. The cutoff of 16.5, calculated using Youden's index, was closest to the target under-triage and over-triage rates, as suggested by the American College of Surgeons, when applied to patients with an rSIG of 20 or less. In addition, in patients with traumatic brain injury, when the rSIG value was over 25, in-hospital mortality tended to increase as the rSIG value increased. CONCLUSIONS: We propose an rSIG cutoff value of 16.5 as a predictor of in-hospital mortality in adult patients with trauma. However, in patients with traumatic brain injury, a high rSIG is also associated with in-hospital mortality. Appropriate cutoffs should be established for this group in the future.

Over-Expression of p190RhoGEF Regulates the Formation of Atherosclerotic Plaques in the Aorta of ApoE-/- Mice via Macrophage Polarization.

The RhoA-specific guanine nucleotide exchange factor p190RhoGEF has been implicated in the control of cell morphology, focal adhesion formation, and cell motility. Previously, we reported that p190RhoGEF is also active in various immune cells. In this study, we examined whether over-expression of p190RhoGEF could affect atherosclerotic plaque formation in mouse aortae. For that purpose, transgenic (TG) mice over-expressing p190RhoGEF were cross-bred with atherosclerosis-prone apolipoprotein E (ApoE)-/- mice to obtain p190RhoGEF-TG mice with ApoE-/- backgrounds (TG/ApoE-/-). Aortic plaque formation was significantly increased in TG/ApoE mice-/- at 30 to 40 weeks of age compared to that in ApoE-/- mice. Serum concentrations of inflammatory cytokines (IL-6 and TNF-α) were greater in TG/ApoE-/- mice than in ApoE-/- mice at ~40 weeks of age. Furthermore, TG/ApoE-/- mice had a greater proportion of peritoneal macrophages within the M1 subset at 30 to 40 weeks of age, together with higher production of inflammatory cytokines and stronger responses to bacterial lipopolysaccharide than ApoE-/- mice. Collectively, these results highlight a crucial role of enhanced p190RhoGEF expression in atherosclerosis progression, including the activation of pro-inflammatory M1 macrophages.

Synthetic TGF-ß Signaling Agonist-Treated Dendritic Cells Induce Tolerogenicity and Antirheumatic Effects.

The newly synthesized compound TGF-ß signaling agonist (T74) is a small molecule associated with the TGF-ß receptor signaling pathway. Tolerogenic dendritic cells (tDCs) have been used to examine immunosuppressive and anti-inflammatory effects in multiple autoimmune disease models. The aim of this study was to investigate whether treatment of DCs with T74 has an antirheumatic effect in a mouse model of collagen-induced arthritis (CIA). Bone marrow-derived cells were obtained from DBA/1J mice and differentiated into DCs. T74-treated DCs (T74-DCs) were generated by treating bone marrow-derived DCs with LPS, type II collagen, and T74. T74-DCs expressed lower levels of surface molecules and inflammatory cytokines associated with antigen presentation and T cell stimulation. The ability of T74-DCs to differentiate effector T cells was lower than that of T74-untreated DCs (NT-DCs), but T74-DCs increased the regulatory T (Treg) cell differentiation in vitro. DBA/1J mice received two subcutaneous (s.c.) injections of type II collagen to establish CIA. Mice then received two s.c. injections of T74-DCs or NT-DCs. Joint inflammation was ameliorated in the paws of T74-DC-treated mice. Additionally, Treg populations in T74-DC-treated mice were higher than in NT-DC-treated or PBS-treated CIA mice. Taken together, these results demonstrate that T74 induces tolerance in DCs, and that T74-mediated DCs exert antirheumatic effects via induction of Tregs.

Long-Term Clinical Outcomes and Its Predictors Between the 1- and 2-Stent Strategy in Coronary Bifurcation Lesions　- A Baseline Clinical and Lesion Characteristic-Matched Analysis.

BACKGROUND: Differences in the impact of the 1- or 2-stent strategy in similar coronary bifurcation lesion conditions are not well understood. This study investigated the clinical outcomes and its predictors between 1 or 2 stents in propensity score-matched (PSM) complex bifurcation lesions.Methods and Results: We analyzed the data of patients with bifurcation lesions, obtained from a multicenter registry of 2,648 patients (median follow up, 53 months). The patients were treated by second generation drug-eluting stents (DESs). The primary outcome was target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction (TVMI), and ischemia-driven target lesion revascularization (TLR). PSM was performed to balance baseline clinical and angiographic discrepancies between 1 and 2 stents. After PSM (N=333 from each group), the 2-stent group had more TLRs (hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.42-6.97, P=0.005) and fewer hard endpoints (composite of cardiac death and TVMI; HR 0.44, 95% CI 0.19-1.01, P=0.054), which resulted in a similar TLF rate (HR 1.40, 95% CI 0.83-2.37, P=0.209) compared to the 1-stent group. Compared with 1-stent, the 2-stent technique was more frequently associated with less TLF in the presence of main vessel (pinteraction=0.008) and side branch calcification (pinteraction=0.010). CONCLUSIONS: The 2-stent strategy should be considered to reduce hard clinical endpoints in complex bifurcation lesions, particularly those with calcifications.

Triple-Networked Hybrid Hydrogels Reinforced with Montmorillonite Clay and Graphene Nanoplatelets for Soft and Hard Tissue Regeneration.

Hydrogel is a three-dimensional (3D) soft and highly hydrophilic, polymeric network that can swell in water and imbibe a high amount of water or biological fluids. Hydrogels have been used widely in various biomedical applications. Hydrogel may provide a fluidic tissue-like 3D microenvironment by maintaining the original network for tissue engineering. However, their low mechanical performances limit their broad applicability in various functional tissues. This property causes substantial challenges in designing and preparing strong hydrogel networks. Therefore, we report the triple-networked hybrid hydrogel network with enhanced mechanical properties by incorporating dual-crosslinking and nanofillers (e.g., montmorillonite (MMT), graphene nanoplatelets (GNPs)). In this study, we prepared hybrid hydrogels composed of polyacrylamide, poly (vinyl alcohol), sodium alginate, MMT, and MMT/GNPs through dynamic crosslinking. The freeze-dried hybrid hydrogels showed good 3D porous architecture. The results exhibited a magnificent porous structure, interconnected pore-network surface morphology, enhanced mechanical properties, and cellular activity of hybrid hydrogels.

TNF-α Induces Mitophagy in Rheumatoid Arthritis Synovial Fibroblasts, and Mitophagy Inhibition Alleviates Synovitis in Collagen Antibody-Induced Arthritis.

Mitophagy is a selective form of autophagy that removes damaged mitochondria. Increasing evidence indicates that dysregulated mitophagy is implicated in numerous autoimmune diseases, but the role of mitophagy in rheumatoid arthritis (RA) has not yet been reported. The aim of the present study was to determine the roles of mitophagy in patient-derived RA synovial fibroblasts (RASFs) and in the collagen antibody-induced arthritis mouse model. We measured the mitophagy marker PTEN-induced putative kinase 1 (PINK1) in RASFs treated with tumor necrosis factor-α (TNF-α) using Western blotting and immunofluorescence. Arthritis was induced in PINK1-/- mice by intraperitoneal injection of an anti-type II collagen antibody cocktail and lipopolysaccharide. RA severity was assessed by histopathology. PINK1 expression and damaged mitochondria increased in TNF-α treated RASFs via increased intracellular levels of reactive oxygen species. PINK1 knockdown RASFs decreased cellular migration and invasion functions. In addition, PINK1-/- mice with arthritis exhibited markedly reduced swelling and inflammation relative to wild-type mice with arthritis. Taken together, these findings suggest that regulation of PINK1 expression in RA could represent a potential therapeutic and diagnostic target for RA.

Whole blood RNA sequencing reveals a differential transcriptomic profile associated with cervical insufficiency: a pilot study.

BACKGROUND: The uterine cervix is a mechanical and immunological barrier against ascending infection during pregnancy. Cervical insufficiency (CI), a painless cervical dilation that occurs in the mid-trimester, is an important cause of extremely preterm birth. We hypothesized that women with CI have a differential transcriptomic profile. Therefore, we compared the transcriptomic profile of peripheral blood in women with CI and that of controls. METHODS: RNA sequencing was used to generate the global gene expression profiles of 11 women with CI and 4 controls, and differential expression analysis was performed to identify genes showing significant expression changes between the CI (n = 11) and control (n = 4) groups as well as between the CI-preterm (n = 7) and CI-term (n = 4) groups. Gene set enrichment was assessed in terms of Gene Ontology processes, and a subset of differentially expressed genes in CI was validated in a different sample-set by qRT-PCR and ELISA. RESULTS: Thirty genes were differentially expressed between the CI and control groups. Differentially upregulated genes in the CI group included neutrophil-mediated immunity-associated (DEFA3 and ELANE) and bicarbonate transport-related genes. The serum concentration of alpha defensin 3 was significantly higher in women with CI than in controls (P = 0.014). Analysis of differential gene expression according to pregnancy outcomes revealed 338 differentially expressed genes between the CI-term and CI-preterm groups. Immune and defense response to organism-associated genes and influenza A and NOD-like receptor signaling pathways were upregulated in the CI-term group. CONCLUSIONS: Our results revealed significant differences in the whole blood transcriptomic profiles of women with CI compared to those of controls. Different immune responses in women with CI may affect pregnancy outcomes.

Comparison of 2-Stenting Strategies Depending on Sequence or Technique for Bifurcation Lesions in the Second-Generation Drug-Eluting Stent Era　- Analysis From the COBIS (Coronary Bifurcation Stenting) III Registry.

BACKGROUND: It has not been determined which specific 2-stenting strategy is the best for bifurcation lesions. Our aim was to investigate the clinical outcomes of various 2-stenting strategies in the era of 2nd-generation drug-eluting stents (2G-DES).Methods and Results:We analyzed 454 patients who finally underwent 2-stenting for a bifurcation lesion, from among 2,648 patients enrolled in the COBIS III registry. The primary outcome was target lesion failure (TLF). Patients were analyzed according to stenting sequence (provisional [main vessel stenting first] vs. systemic [side branch stenting first]) and stenting technique (crush vs. T vs. culotte vs. kissing/V stenting). Overall, 4.4 years' TLF after 2-stenting treatment for bifurcation lesion was excellent: TLF 11.2% and stent thrombosis 1.3%. There was no difference in TLF according to 2-stenting strategy (11.1% vs. 10.5%, P=0.990 for provisional and systemic sequence; 8.6% vs. 14.4% vs. 12.9% vs. 12.2%, P=0.326 for crush, T, culotte, kissing/V technique, respectively). Only left main (LM) disease and a shorter duration of dual antiplatelet therapy (DAPT) were associated with TLF. The distribution of DAPT duration differed between patients with and without TLF, and the time-point of intersection was 2.5 years. Also, the side branch was the most common site of restenosis. CONCLUSIONS: The stenting sequence or technique did not affect clinical outcomes, but LM disease and shorter DAPT were associated with TLF, in patients with bifurcation lesions undergoing 2-stenting with 2G-DES.

Content Analysis and Quality Evaluation of Cesarean Delivery-Related Videos on YouTube: Cross-sectional Study.

BACKGROUND: YouTube is one of the most popular open-access video-sharing websites, and it is also used to obtain health care information. Cesarean delivery is the most common major surgical intervention in many countries. Videos related to cesarean delivery have also been uploaded to YouTube. However, no study has explored the overall quality of cesarean delivery videos on the platform. OBJECTIVE: The objective of this study was to analyze the content and evaluate the quality of the most frequently viewed videos related to cesarean delivery that are accessible on YouTube. METHODS: We searched for a total of 18 terms by combining the 6 terms retrieved from Google AdWords and the 3 terms c section, cesarean section, and cesarean delivery, which are used interchangeably. Videos were sorted by view count, and the 100 videos with the highest view counts were chosen. The number of views, duration, likes and dislikes, content type, and source of each video were recorded. In evaluating the quality of the videos, we referred to a previous study. Additionally, we developed a detailed scoring method that comprehensively evaluates the videos related to cesarean delivery by including the necessary information for each element of the cesarean delivery and whether scientific evidence was presented. RESULTS: Of the 100 videos analyzed, the most prevalent content (n=28) was videos that contained the actual surgical procedure of a cesarean delivery, and the most common source of cesarean delivery videos was physicians (n=30). Videos directly related to cesarean delivery, such as explanation of the surgery and the actual surgical procedure, were mainly uploaded by medical groups and scored higher than the videos indirectly related to cesarean delivery, which were mainly uploaded by nonmedical groups. In addition, videos directly related to cesarean delivery were more often uploaded earlier in time, with lower like ratios compared to indirect videos. CONCLUSIONS: YouTube is currently not an appropriate source for patients seeking information on cesarean delivery.

Functional Ambivalence of Dendritic Cells: Tolerogenicity and Immunogenicity.

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and inducers of T cell-mediated immunity. Although DCs play a central role in promoting adaptive immune responses against growing tumors, they also establish and maintain peripheral tolerance. DC activity depends on the method of induction and/or the presence of immunosuppressive agents. Tolerogenic dendritic cells (tDCs) induce immune tolerance by activating CD4+CD25+Foxp3+ regulatory T (Treg) cells and/or by producing cytokines that inhibit T cell activation. These findings suggest that tDCs may be an effective treatment for autoimmune diseases, inflammatory diseases, and infertility.

TGF-ß/IL-7 Chimeric Switch Receptor-Expressing CAR-T Cells Inhibit Recurrence of CD19-Positive B Cell Lymphoma.

Chimeric antigen receptor (CAR)-T cells are effective in the treatment of hematologic malignancies but have shown limited efficacy against solid tumors. Here, we demonstrated an approach to inhibit recurrence of B cell lymphoma by co-expressing both a human anti-CD19-specific single-chain variable fragment (scFv) CAR (CD19 CAR) and a TGF-ß/IL-7 chimeric switch receptor (tTRII-I7R) in T cells (CD19 CAR-tTRII-I7R-T cells). The tTRII-I7R was designed to convert immunosuppressive TGF-ß signaling into immune-activating IL-7 signaling. The effect of TGF-ß on CD19 CAR-tTRII-I7R-T cells was assessed by western blotting. Target-specific killing by CD19 CAR-tTRII-I7R-T cells was evaluated by Eu-TDA assay. Daudi tumor-bearing NSG (NOD/SCID/IL2Rγ-/-) mice were treated with CD19 CAR-tTRII-I7R-T cells to analyze the in vivo anti-tumor effect. In vitro, CD19 CAR-tTRII-I7R-T cells had a lower level of phosphorylated SMAD2 and a higher level of target-specific cytotoxicity than controls in the presence of rhTGF-ß1. In the animal model, the overall survival and recurrence-free survival of mice that received CD19 CAR-tTRII-I7R-T cells were significantly longer than in control mice. These findings strongly suggest that CD19 CAR-tTRII-I7R-T cell therapy provides a new strategy for long-lasting, TGF-ß-resistant anti-tumor effects against B cell lymphoma, which may lead ultimately to increased clinical efficacy.

Pdlim4 is essential for CCR7-JNK-mediated dendritic cell migration and F-actin-related dendrite formation.

Dendritic cells (DCs) are the most potent professional antigen (Ag)-presenting cells and inducers of T cell-mediated immunity. A previous microarray analysis identified PDZ and LIM domain protein 4 (Pdlim4) as a candidate marker for DC maturation. The aim of this study was to investigate whether Pdlim4 influences DC migration and maturation. Mouse bone marrow-derived DCs were transduced lentivirally with Pdlim4 short hairpin RNA and examined by confocal microscopy, flow cytometry, ELISA, and Western blotting. Pdlim4 was highly induced in LPS-stimulated mature DCs (mDCs). Pdlim4-knockdown mDCs showed reduced expression of molecules associated with Ag presentation and T-cell costimulation, reduced cytokine production, and functional defects in their ability to activate T cells. Moreover, Pdlim4 was necessary for mDC migration via C-C chemokine receptor type 7 (CCR7)-JNK in in vitro Transwell assays. The importance of Pdlim4 in DC migration was confirmed with an in vivo migration model in which C57BL/6 mice were injected with fluorescently labeled DCs in the footpad and migration to the popliteal lymph nodes was assessed by flow cytometry. Moreover, dendrite formation in mDCs was remarkably attenuated under Pdlim4 knockdown. Taken together, these results demonstrate that Pdlim4 is necessary for DC migration via CCR7-JNK, dendrite formation, and subsequent development of functional T-cell responses.-Yoo, J.-Y., Jung, N.-C., Lee, J.-H., Choi, S.-Y., Choi, H.-J., Park, S.-Y., Jang, J.-S., Byun, S.-H., Hwang, S.-U., Noh, K.-E., Park, Y., Lee, J., Song, J.-Y., Seo, H. G., Lee, H. S., Lim, D.-S. Pdlim4 is essential for CCR7-JNK-mediated dendritic cell migration and F-actin-related dendrite formation.

Usefulness of the trans-stent fractional flow reserve gradient for predicting clinical outcomes.

OBJECTIVES: We evaluated the usefulness of a fractional flow reserve (FFR) gradient across the stent (ΔFFRstent ) for long-term clinical outcomes after percutaneous coronary intervention (PCI) with a drug-eluting stent (DES). BACKGROUND: The clinical meaning of a trans-stent pressure gradient after DES implantation has not been estimated adequately. METHODS: FFR pull-back and intravascular ultrasound (IVUS) were performed after successful PCI in 135 left anterior descending artery lesions. ΔFFRstent was defined as the FFR gradient across the stent. The ΔFFRstent/length was defined as the ΔFFRstent value divided by the total stent length multiplied by 10. Major adverse cardiac events (MACEs) were the composite of all-cause death, target vessel-related myocardial infarction, and target lesion revascularization. RESULTS: Despite successful PCI, ΔFFRstent > 0 was observed in 98.5% of cases. ΔFFRstent ≥ 0.04 and ΔFFRstent/length ≥ 0.009 predicted suboptimal stenting defined as final minimal stent area < 5.5 mm2 . During 2,183 ± 898 days, the MACE-free survival rate was significantly lower in patients with ΔFFRstent ≥ 0.04 and ΔFFRstent/length ≥ 0.009 compared to those with lower values (69.6 vs. 93.4%, log-rank p = .031; 72.1 vs. 97.7%, log-rank p = .003, respectively). ΔFFRstent/length ≥ 0.009 (hazard ratio 10.1, p = .032) was an independent predictor of MACE. CONCLUSION: A trans-stent FFR gradient was frequently observed. ΔFFRstent and ΔFFRstent/length are related to long-term outcomes in DES-treated patients.

Over-expression of p190RhoGEF enhances B-cell activation and germinal center formation in T-cell-dependent humoral immune responses.

Previously, we reported induced expression of the p190 Rho guanine nucleotide exchange factor (p190RhoGEF, ARHGEF28) following CD40 stimulation of B cells isolated from mouse spleen. We also reported that p190RhoGEF and a downstream effector molecule RhoA are required for B-cell differentiation, especially for the induction of the plasma cell (PC) differentiation. This study investigates the role of p190RhoGEF in B-cell biology in vivo, using p190RhoGEF transgenic (TG) mice that overexpress a wild-type full gene in B cells. Immunization of these mice with T-cell-dependent antigen showed that populations of germinal center B cells and PCs were significantly increased in TG mice. Furthermore, similar results were shown in recombination activating 1 (Rag1) knockout mice that were reconstituted with B cells isolated from TG mice in combination with T cells isolated from littermate control mice. Analyses of isotype class switching and transcription factors involved in a germinal center reaction and PC differentiation also supported the findings from the cellular responses. These results suggest that p190RhoGEF may play a role in the stage of PC differentiation during T-cell-dependent humoral immune responses.

Impact of new-onset diabetes on clinical outcomes after ST segment-elevated myocardial infarction.

Objective. Patients with diabetes have higher mortality rate than patients without diabetes after ST-segment elevated myocardial infarction (STEMI). Prognosis of patients with new onset diabetes (NOD) after STEMI remains unclear. The aim of this study was to evaluate the prognosis of patients with NOD compared to that of patients without NOD after STEMI. Design. This study was a retrospective observational study. We enrolled 901 STEMI patients. Patients were divided into diabetic and non-diabetic groups at index admission. Non-diabetic group was divided into NOD and non-NOD groups. Kaplan-Meier analysis and Cox's proportional hazard regression models were used to compare major adverse cardiac events (MACE) free survival rate and hazard ratio for MACE between NOD and non-NOD groups. Results. Mean follow-up period was 59 ± 28 months. Diabetes group had higher MACE than non-diabetes group (p = .038). However, MACE was not different between NOD and non-NOD groups (p = 1.000). After 1:2 propensity score matching, incidence of MACE was not different between the two groups. In Kaplan-Meier survival curves, MACE-free survival rates were not statistically different between NOD and non-NOD groups either (p = .244). Adjusted hazard ratios of NOD for MACE, all-cause of death, recurrent myocardial infarction, and target vessel revascularization were 0.697 (95% confidence interval [CI]: 0.362-1.345, p = .282), 0.625 (95% CI: 0.179-2.183, p = .461), 0.794 (95% CI: 0.223-2.835, p = .723), and 0.506 (95% CI: 0.196-1.303, p = .158), respectively. Conclusion. This retrospective observational study with a limited statistical power did not show a different prognosis in patients with and without NOD.

Machine learning assessment of myocardial ischemia using angiography: Development and retrospective validation.

BACKGROUND: Invasive fractional flow reserve (FFR) is a standard tool for identifying ischemia-producing coronary stenosis. However, in clinical practice, over 70% of treatment decisions still rely on visual estimation of angiographic stenosis, which has limited accuracy (about 60%-65%) for the prediction of FFR < 0.80. One of the reasons for the visual-functional mismatch is that myocardial ischemia can be affected by the supplied myocardial size, which is not always evident by coronary angiography. The aims of this study were to develop an angiography-based machine learning (ML) algorithm for predicting the supplied myocardial volume for a stenosis, as measured using coronary computed tomography angiography (CCTA), and then to build an angiography-based classifier for the lesions with an FFR < 0.80 versus ≥ 0.80. METHODS AND FINDINGS: A retrospective study was conducted using data from 1,132 stable and unstable angina patients with 1,132 intermediate lesions who underwent invasive coronary angiography, FFR, and CCTA at the Asan Medical Center, Seoul, Korea, between 1 May 2012 and 30 November 2015. The mean age was 63 ± 10 years, 76% were men, and 72% of the patients presented with stable angina. Of these, 932 patients (assessed before 31 January 2015) constituted the training set for the algorithm, and 200 patients (assessed after 1 February 2015) served as a test cohort to validate its diagnostic performance. Additionally, external validation with 79 patients from two centers (CHA University, Seongnam, Korea, and Ajou University, Suwon, Korea) was conducted. After automatic contour calibration using the caliber of guiding catheter, quantitative coronary angiography was performed using the edge-detection algorithms (CAAS-5, Pie-Medical). Clinical information was provided by the Asan BiomedicaL Research Environment (ABLE) system. The CCTA-based myocardial segmentation (CAMS)-derived myocardial volume supplied by each vessel (right coronary artery [RCA], left anterior descending [LAD], left circumflex [LCX]) and the myocardial volume subtended to a stenotic segment (CAMS-%Vsub) were measured for labeling. The ML for (1) predicting vessel territories (CAMS-%LAD, CAMS-%LCX, and CAMS-%RCA) and CAMS-%Vsub and (2) identifying the lesions with an FFR < 0.80 was constructed. Angiography-based ML, employing a light gradient boosting machine (GBM), showed mean absolute errors (MAEs) of 5.42%, 8.57%, and 4.54% for predicting CAMS-%LAD, CAMS-%LCX, and CAMS-%RCA, respectively. The percent myocardial volumes predicted by ML were used to predict the CAMS-%Vsub. With 5-fold cross validation, the MAEs between ML-predicted percent myocardial volume subtended to a stenotic segment (ML-%Vsub) and CAMS-%Vsub were minimized by the elastic net (6.26% ± 0.55% for LAD, 5.79% ± 0.68% for LCX, and 2.95% ± 0.14% for RCA lesions). Using all attributes (age, sex, involved vessel segment, and angiographic features affecting the myocardial territory and stenosis degree), the ML classifiers (L2 penalized logistic regression, support vector machine, and random forest) predicted an FFR < 0.80 with an accuracy of approximately 80% (area under the curve [AUC] = 0.84-0.87, 95% confidence intervals 0.71-0.94) in the test set, which was greater than that of diameter stenosis (DS) > 53% (66%, AUC = 0.71, 95% confidence intervals 0.65-0.78). The external validation showed 84% accuracy (AUC = 0.89, 95% confidence intervals 0.83-0.95). The retrospective design, single ethnicity, and the lack of clinical outcomes may limit this prediction model's generalized application. CONCLUSION: We found that angiography-based ML is useful to predict subtended myocardial territories and ischemia-producing lesions by mitigating the visual-functional mismatch between angiographic and FFR. Assessment of clinical utility requires further validation in a large, prospective cohort study.

Myocardial Mass Contributes to the Discrepancy Between Anatomic Stenosis Severity Assessed by Intravascular Ultrasound and Fractional Flow Reserve in Intermediate Lesions of the Coronary Artery.

OBJECTIVES: The present study investigated the major contributors to the discrepancy between the minimal lumen area (MLA) and fractional flow reserve (FFR). BACKGROUND: There was considerable discrepancy between MLA or diameter stenosis (DS) and FFR. METHODS: We enrolled 744 patients with intermediate stenoses of the left anterior descending artery (LAD). Summed epicardial coronary artery length distal to the target stenosis was obtained from each longest view of the vessels on the coronary angiograms. Mismatching was defined as a lesion with FFR of >0.80 and MLA smaller than the best cut-off value (BCV) for predicting FFR of ≤0.80. Reverse mismatching was defined as a lesion with FFR of ≤0.80 and MLA larger than the BCV. RESULTS: Summed epicardial coronary artery length was longer at the lesions of proximal LAD than that of middle LAD (380 mm ± 82 mm vs. 341 mm ± 80 mm, P < 0.001). Reverse mismatching was found more frequently in the proximal than middle LAD (28.3% vs. 5.5%, P < 0.001). Independent predictors of FFR ≤ 0.80 were age, male, multi-vessel disease, proximal LAD lesion, MLA, DS, plaque burden at distal reference, lesion length and summed epicardial coronary artery length. Proximal LAD lesion was an independent predictor of reverse mismatching (hazard ratio 3.162, 1.858-5.382, P < 0.001). CONCLUSIONS: Myocardial mass subtended by a lesion is an important factor predicting FFR ≤0.80 and discrepancy between FFR and MLA. Myocardial mass subtended by a lesion should be considered when determining the revascularization therapy by intravascular ultrasound parameters. © 2017 Wiley Periodicals, Inc.

Impact of Age on the Functional Significance of Intermediate Epicardial Artery Disease.

BACKGROUND: The functional significance of an intermediate coronary lesion is crucial for determining the treatment strategy, but age-related changes in cardiovascular function could affect the functional significance of an epicardial stenosis. The aim of this study was therefore to investigate the impact of age on fractional flow reserve (FFR) measurements in patients with intermediate coronary artery disease (CAD). METHODS AND RESULTS: Intracoronary pressure measurements and intravascular ultrasound (IVUS) were performed in 178 left anterior descending coronary arteries with intermediate stenosis. The morphological characteristics and FFR of 91 lesions in patients <65 years old were compared with those of 87 patients ≥65 years old. There was no difference in lesion location, diameter stenosis, minimum lumen area, plaque burden, or lesion length between the 2 age groups. Elderly patients had higher FFR (0.81±0.06 vs. 0.79±0.06, P=0.004) and lower ∆FFR, defined as the difference between resting Pd/Pa and FFR (0.13±0.05 vs. 0.15±0.05, P=0.014). Age, along with the location and degree of stenosis, was independently associated with FFR and ∆FFR (ß=0.162, P=0.008; ß=-0.131, P=0.043, respectively). CONCLUSIONS: Elderly patients with intermediate CAD are more likely to have higher FFR and lower ∆FFR, despite a similar degree of epicardial stenosis, compared with younger patients. (Circ J 2016; 80: 1583-1589).