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.

Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized, double-blind, active-controlled, multicenter phase 3 trial.

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are -19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and -11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.

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.

Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, in Mouse Macrophages Negatively Affects M1 Polarization and Inflammatory Responses.

A RhoA-specific guanine nucleotide exchange factor, p190RhoGEF, was first cloned and identified in neuronal cells. In immune cells, we first reported the role of p190RhoGEF in B cells: expression of p190RhoGEF increased after CD40 stimulation and was required for CD40-mediated B cell activation and differentiation. We also showed that over-expression of p190RhoGEF negatively affected dendritic cell function in response to bacterial lipopolysaccharide (LPS). In this study, we examined the role of p190RhoGEF in macrophages using p190RhoGEF over-expressing transgenic (TG) mice. We found macrophages from TG mice to be more round than those from control mice, with enriched polymerized actin at the edge attached to the glass. TG macrophages also responded less to LPS: production of reactive oxygen species, phagocytosis, chemokine-dependent migration, and pro-inflammatory cytokine secretion were all reduced compared with the responses of macrophages from littermate (LTM) control mice. Furthermore, the classical M1 subset population was observed less in the peritoneal macrophages of TG mice than the LTM control mice during LPS-elicited peritoneal inflammation. When the activity of RhoA was inhibited in TG macrophages, their morphology and LPS responses became similar to those of the LTM macrophages. These results suggest that over-expression of p190RhoGEF in macrophages could reduce M1 polarization and inflammatory responses by regulating the actin cytoskeleton.

Enpp2 Expression by Dendritic Cells Is a Key Regulator in Migration.

Enpp2 is an enzyme that catalyzes the conversion of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which exhibits a wide variety of biological functions. Here, we examined the biological effects of Enpp2 on dendritic cells (DCs), which are specialized antigen-presenting cells (APCs) characterized by their ability to migrate into secondary lymphoid organs and activate naïve T-cells. DCs were generated from bone marrow progenitors obtained from C57BL/6 mice. Enpp2 levels in DCs were regulated using small interfering (si)RNA or recombinant Enpp2. Expression of Enpp2 in LPS-stimulated mature (m)DCs was high, however, knocking down Enpp2 inhibited mDC function. In addition, the migratory capacity of mDCs increased after treatment with rmEnpp2; this phenomenon was mediated via the RhoA-mediated signaling pathway. Enpp2-treated mDCs showed a markedly increased capacity to migrate to lymph nodes in vivo. These findings strongly suggest that Enpp2 is necessary for mDC migration capacity, thereby increasing our understanding of DC biology. We postulate that regulating Enpp2 improves DC migration to lymph nodes, thus improving the effectiveness of cancer vaccines based on DC.

Translesional Fractional Flow Reserve is Related to Plaque Components in Coronary Artery Disease: A Study Combining Pressure Wire and NIRS-IVUS Analysis.

OBJECTIVES: It remains unclear whether atherosclerotic plaque structure or composition is related to translesional biomechanical stresses in coronary artery disease. The aim of this study was to evaluate the association between translesional pressure parameters (using a pressure wire) and plaque characteristics (using a combined near-infrared spectroscopy [NIRS] and intravascular ultrasound [IVUS] imaging catheter). METHODS: Fractional flow reserve (FFR), delta (Δ) FFR, and Δ pressure were obtained during adenosine-induced maximum hyperemic status. Lipid core burden index (LCBI) and maximum LCBI within 2 mm (maxLCBI2mm) and tomographic anatomy were evaluated by NIRS-IVUS. RESULTS: Sixty-six lesions from 57 patients were analyzed (57 lesions for FFR, 45 lesions for ΔFFR). There was a negative correlation between FFR and maxLCBI2mm (r=-0.264; P=.049) and a positive correlation between ΔFFR and maxLCBI2mm (r=0.299; P=.049). ΔFFR of lesions with maxLCBI2mm ≥500 was significantly higher than maxLCBI2mm <500 (0.159 ± 0.085 vs 0.104 ± 0.075, respectively; P=.04). By receiver-operating characteristic curve analysis, ΔFFR ≥0.1 was a predictor for maxLCBI2mm ≥500 (area under curve, 0.707; 95% confidence interval, 0.552-0.862; P=.03). On multivariate analysis, ΔFFR was the only predictor of maxLCBI2mm (ß=0.347; P=.03). CONCLUSION: ΔFFR across a coronary artery lesion is related to lipid core burden assessed using NIRS-IVUS and might be a meaningful predictor of high-risk plaque (plaque with high lipid content).

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.

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.

The Effect of the Tumor Microenvironment and Tumor-Derived Metabolites on Dendritic Cell Function.

Dendritic cells (DCs) have a critical effect on the outcome of adaptive immune responses against growing tumors. Recent studies on the metabolism on DCs provide new insights on the functioning of these critical controllers of innate and adaptive immunity. DCs within the tumor microenvironment (TME) often exist in an inactive state, which is thought to limit the adaptive immune response elicited by the growing tumor. Tumor-derived factors in the TME are known to suppress DC activation and result in functional alterations in DC phenotype. We are now beginning to appreciate that many of these factors can also induce changes in immune cell metabolism. In this review, we discuss the functional alternation of DC phenotype by tumor metabolites.

Rsad2 is necessary for mouse dendritic cell maturation via the IRF7-mediated signaling pathway.

Dendritic cells (DCs) are the most potent professional antigen presenting cells and inducers of T cell-mediated immunity. However, few specific markers of mature DCs (mDC) have been reported. A previous microarray analysis revealed expression of mDC-specific genes and identified Rsad2 (radical S-adenosyl methionine domain containing 2) as a candidate specific marker for DC maturation. Mouse bone marrow-derived DCs were transfected with Rsad2 siRNA and examined by flow cytometry, ELISA, western, and confocal microscopy. C57BL/6 mice received intravenously B16F10 cells to establish a pulmonary metastasis model. Tumor-bearing mice then received subcutaneously two injections of mDCs or Rsad2 knockdown DCs. The cytotoxic T lymphocyte (CTL) population was examined from splenocytes of DC-vaccinated mice by flow cytometry. Rsad2 was induced at high levels in LPS-stimulated mDCs and mDC function was markedly attenuated under conditions of Rsad2 knockdown. Moreover, Rsad2 was necessary for mDC maturation via the IRF7-mediated signaling pathway. The importance of Rsad2 was confirmed in an Rsad2 knockdown lung metastasis mouse model in which mDCs lost their antitumor efficacy. Data on the CTL population further supported the results as above. Taken together, Rsad2 was an obvious and specific marker necessary for DC maturation and these findings will be clearly helpful for further understanding of DC biology.

An Alcohol Dehydrogenase Gene from Synechocystis sp. Confers Salt Tolerance in Transgenic Tobacco.

Synechocystis salt-responsive gene 1 (sysr1) was engineered for expression in higher plants, and gene construction was stably incorporated into tobacco plants. We investigated the role of Sysr1 [a member of the alcohol dehydrogenase (ADH) superfamily] by examining the salt tolerance of sysr1-overexpressing (sysr1-OX) tobacco plants using quantitative real-time polymerase chain reactions, gas chromatography-mass spectrometry, and bioassays. The sysr1-OX plants exhibited considerably increased ADH activity and tolerance to salt stress conditions. Additionally, the expression levels of several stress-responsive genes were upregulated. Moreover, airborne signals from salt-stressed sysr1-OX plants triggered salinity tolerance in neighboring wild-type (WT) plants. Therefore, Sysr1 enhanced the interconversion of aldehydes to alcohols, and this occurrence might affect the quality of green leaf volatiles (GLVs) in sysr1-OX plants. Actually, the Z-3-hexenol level was approximately twofold higher in sysr1-OX plants than in WT plants within 1-2 h of wounding. Furthermore, analyses of WT plants treated with vaporized GLVs indicated that Z-3-hexenol was a stronger inducer of stress-related gene expression and salt tolerance than E-2-hexenal. The results of the study suggested that increased C6 alcohol (Z-3-hexenol) induced the expression of resistance genes, thereby enhancing salt tolerance of transgenic plants. Our results revealed a role for ADH in salinity stress responses, and the results provided a genetic engineering strategy that could improve the salt tolerance of crops.

Therapeutic Efficacy of Nanocomplex of Poly(Ethylene Glycol) and Catechin for Dry Eye Disease in a Mouse Model.

Purpose: We investigated the possibility of the nanocomplex of poly(ethylene glycol) (PEG) and catechin as a new biomedical material to treat dry eye disease. Methods: NOD.B10.H2b mice were exposed to an air draft and injected with scopolamine for 10 days. Ten days later, the mice were treated with normal saline (n = 11), 1% catechin (n = 11), 1% PEG (n = 11), and 1% catechin/PEG nanocomplex solution mixture containing catechin and PEG at weight ratios of 1:1 (CP1, n = 11), 1:5 (CP5, n = 11), and 1:10 (CP10, n = 11). All treatments were administered five times a day for 10 days. We estimated the effect of PEG/catechin nanocomplexes on inflammation, tear production, epithelium stabilization, and goblet cell density. Results: Desiccation stress significantly decreased tear production and increased the corneal irregularity score. Furthermore, desiccation stress markedly increased the detached epithelium and decreased the numbers of conjunctival goblet cells. In addition, the expression of proinflammatory-related factors was markedly induced by desiccation stress in the lacrimal glands. However, the PEG/catechin nanocomplex effectively induced an increase in tear production, stabilization of the corneal epithelium, and an increase in conjunctival goblet cells and anti-inflammatory improvements in a PEG dose-dependent manner. Conclusions: In this study, we found that PEG may increase bioavailability of catechin. Therefore, the PEG/catechin nanocomplex can be used as a new biomedical material to treat dry eye disease through stabilization of the tear film and inhibition of inflammation.

Late-acquired incomplete stent apposition after everolimus-eluting stent versus sirolimus-eluting stent implantation in patients with non-ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction.

AIMS: Our aim was to evaluate the incidence and clinical outcomes of late-acquired incomplete stent apposition (LAISA) after implantation of first- and second-generation drug-eluting stents in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: Late-Acquired incomplete stent aPPOsition after everolimus-eluting stent versus sirolimus-eluting Stent ImplanTatION in pAtients with non ST-segment elevation Myocardial Infarction and ST-segment elevation myocardial infarction (APPOSITION-AMI) was a prospective, randomised study comparing LAISA after everolimus-eluting stent (EES) and sirolimus-eluting stent (SES) implantation in AMI patients. Intravascular ultrasound examination was serially performed post-procedurally and at eight-month follow-up in 195 AMI patients (205 native coronary lesions: 100 EES; 105 SES). LAISA was observed in 6.0% and 16.2% of EES- vs. SES-treated lesions (p=0.021), respectively. In 64.7% of SES-treated lesions, LAISA was caused by positive remodelling, whereas thrombus dissolution or plaque reduction was observed in 66.7% of EES-treated lesions. Among patients with LAISA, MACE developed in one (4.5%) in the SES group with no ST in either group up to one year. CONCLUSIONS: The incidence of LAISA was lower in AMI patients treated with EES as compared to SES, mainly secondary to positive remodelling in SES- but not EES-treated lesions. Patients with LAISA in both groups showed a very low MACE incidence at one-year follow-up.

Incidence and Morphological Predictors of Intrastent Coronary Thrombus After Drug-Eluting Stent Implantation (from a Multicenter Registry).

The mechanisms responsible for late and very late stent thrombosis remain incompletely understood. This study aimed to evaluate the incidence and morphologic predictors of intrastent thrombus in patients after drug-eluting stent (DES) implantation using optical coherence tomography (OCT). A total of 208 patients with 262 DES who underwent follow-up OCT examination >6 months after DES implantation were included. The detailed vascular morphology including characteristics of neointima was analyzed. Thrombus was identified in 24 patients (11.5%) 11 months after DES implantation. Minimal lumen cross-sectional area was significantly smaller in the thrombus group than in the nonthrombus group (2.9 ± 1.7 vs 4.6 ± 2.0 mm(2); p <0.001). No difference was found in the frequency of uncovered or malapposed struts between the 2 groups. Thin-cap fibroatheroma (20.6% vs 0.1%; p <0.001) and heterogeneous neointima (22.2% vs 9.0%; p = 0.001) were more frequently detected in the thrombus group compared to the nonthrombus group. Second-generation DES showed lower incidence of thrombus, uncovered struts, and extrastent lumen compared with first-generation DES. In conclusion, the present OCT study revealed that smaller lumen cross-sectional area and neointimal morphology are important factors associated with intrastent thrombus. Second-generation DES demonstrated improved arterial healing and a lower incidence of intrastent thrombus compared with first-generation DES.

Point-of-care measurements of platelet inhibition after clopidogrel loading in patients with acute coronary syndrome: comparison of generic and branded clopidogrel bisulfate.

PURPOSE: Platelet-function suppression with antiplatelet therapy is effective in preventing and treating cardiovascular disease. Clopidogrel is a thienopyridine derivative that blocks platelet activation by adenosine diphosphate receptor binding. This study demonstrates the effects of generic clopidogrel bisulfate in comparison to branded clopidogrel bisulfate in patients with acute coronary syndromes. METHODS: This prospective, 2-arm, single-center, open-label trial used 1:1 randomization to assign patients to receive generic or branded clopidogrel bisulfate. Patients with unstable angina or non-ST-segment elevation myocardial infarction and scheduled to undergo coronary angiography were enrolled. Platelet function was measured with a P2Y12 assay and reported in P2Y12 reaction units (PRU) and aspirin reaction units (ARU) after randomization. Platelet function was measured at 2, 4, 8, and 24 hours after 600-mg clopidogrel loading. The clinical outcome was checked at 1 month after coronary angiography. FINDINGS: Ninety-five patients were enrolled and randomized to the generic or branded group. Ninety patients (62 men [69%], 28 women [31%]; mean age, 58 years) completed the study protocol. The clinical characteristics were similar between the 2 groups. The difference in the baseline PRU measurements between the generic and branded groups was not significant (274.8 [59.7] vs 285.4 [62.4], respectively; P = 0.414). There were significant differences in 2-hour PRU (231.1 [71.3] vs 266.9 [67.4]; P = 0.017) and 4-hour PRU (227.3 [80.4] vs 265.7 [71.0]; P = 0.020); however, 24-hour PRU (200.5 [82.1] vs 220.6 [75.8]; P = 0.253) was similar. No death, myocardial infarction, target lesion revascularization, stent thrombosis, or Thrombolysis in Myocardial Infarction-defined major bleeding complications were reported during in-hospital stay or 1-month follow-up. IMPLICATION: In patients with ACS, loading of generic clopidogrel bisulfate was associated with an antiplatelet effect comparable to that of branded clopidogrel bisulfate. ClinicalTrials.gov identifier: NCT02060786.

Relationship between intravascular ultrasound parameters and fractional flow reserve in intermediate coronary artery stenosis of left anterior descending artery: intravascular ultrasound volumetric analysis.

OBJECTIVES: The objective of this study was to assess the relationship between intravascular ultrasound (IVUS) parameters, including volumetric analysis, and fractional flow reserve (FFR). BACKGROUND: Although it is known that coronary atherosclerosis burden measured by IVUS volumetric analysis is related with clinical outcomes, its relationship with functional significance remains unknown. METHODS: Both IVUS and FFR were performed in 206 cases of intermediate stenosis of the left anterior descending artery (LAD). Myocardial ischemia was assessed by FFR and maximal hyperemia was induced by continuous intracoronary adenosine infusion. FFR < 0.80 was considered as significant inducible myocardial ischemia. We performed standard IVUS parameter measurements and volumetric analyses. IVUS parameter comparison was performed in the presence (n = 90) or absence (n =116) of significant myocardial ischemia. RESULTS: Lesions with minimal lumen area (MLA) ≥ 4.0 mm2 had FFR ≥ 0.80 in 91.4% of cases, while 50.9% of lesions with MLA < 4.0 mm2 had FFR < 0.80. The independent predictors of FFR < 0.80 were IVUS lesion length (odds ratio [OR]: 1.1, 95% confidence interval [CI] = 1.06­1.18, P < 0.001) and MLA significance according to the lesion location (OR: 7.01, 95% CI = 3.09­15.92, P = 0.001). FFR correlated with plaque volume (r = −0.345, P < 0.001) and percent atheroma volume (PAV) (r = −0.398, P < 0.001). Lesions with significant ischemia (FFR < 0.80) as compared to those with FFR > 0.80 were associated with larger plaque volume (181.8 ± 82.3 vs. 125.9 ± 77.9 mm3, P < 0.001) and PAV (58.9 ± 5.6 vs. 53.8 ± 7.9%, P < 0.001). CONCLUSIONS: IVUS parameters representing severity and extent of atheromatous plaque correlated with functional significance in LAD lesions with intermediate stenosis.

In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography.

OBJECTIVES: The aim of this study was to characterize the morphological features of plaque erosion and calcified nodule in patients with acute coronary syndrome (ACS) by optical coherence tomography (OCT). BACKGROUND: Plaque erosion and calcified nodule have not been systematically investigated in vivo. METHODS: A total of 126 patients with ACS who had undergone pre-intervention OCT imaging were included. The culprit lesions were classified as plaque rupture (PR), erosion (OCT-erosion), calcified nodule (OCT-CN), or with a new set of diagnostic criteria for OCT. RESULTS: The incidences of PR, OCT-erosion, and OCT-CN were 43.7%, 31.0%, and 7.9%, respectively. Patients with OCT-erosion were the youngest, compared with those with PR and OCT-CN (53.8 ± 13.1 years vs. 60.6 ± 11.5 years, 65.1 ± 5.0 years, p = 0.005). Compared with patients with PR, presentation with non-ST-segment elevation ACS was more common in patients with OCT-erosion (61.5% vs. 29.1%, p = 0.008) and OCT-CN (100% vs. 29.1%, p < 0.001). The OCT-erosion had a lower frequency of lipid plaque (43.6% vs. 100%, p < 0.001), thicker fibrous cap (169.3 ± 99.1 µm vs. 60.4 ± 16.6 µm, p < 0.001), and smaller lipid arc (202.8 ± 73.6° vs. 275.8 ± 60.4°, p < 0.001) than PR. The diameter stenosis was least severe in OCT-erosion, followed by OCT-CN and PR (55.4 ± 14.7% vs. 66.1 ± 13.5% vs. 68.8 ± 12.9%, p < 0.001). CONCLUSIONS: Optical coherence tomography is a promising modality for identifying OCT-erosion and OCT-CN in vivo. The OCT-erosion is a frequent finding in patients with ACS, especially in those with non-ST-segment elevation ACS and younger patients. The OCT-CN is the least common etiology for ACS and is more common in older patients. (The Massachusetts General Hospital Optical Coherence Tomography Registry; NCT01110538).

Dynamic nature of nonculprit coronary artery lesion morphology in STEMI: a serial IVUS analysis from the HORIZONS-AMI trial.

OBJECTIVES: The authors sought to report the temporal stability of an untreated, nonculprit lesion phenotype in patients presenting with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The temporal stability of the untreated, nonculprit lesion phenotype has been studied using intravascular ultrasound-virtual histology (IVUS) in patients with stable ischemic heart disease, but not in STEMI patients. METHODS: As part of a formal substudy of the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, baseline and 13-month follow-up IVUS was performed in 99 untreated nonculprit lesions in 63 STEMI patients. Lesions were classified as pathological intimal thickening (PIT), IVUS-derived thin-cap fibroatheroma (TCFA), thick-cap fibroatheroma (ThCFA), fibrotic plaque, or fibrocalcific plaque. RESULTS: The frequency of TCFA increased from 41% at baseline to 54% at follow-up, whereas ThCFAs decreased from 41% to 34% and PIT decreased from 16% to 8%. Among the 41 lesions classified at baseline as TCFA, at follow-up, 32 (78%) were still classified as TCFA, whereas 9 (22%) were classified as ThCFAs or fibrotic plaques. An additional 21 lesions at follow-up were newly classified as TCFA, developing from either PIT or ThCFA. TCFA at baseline that evolved into non-TCFAs trended toward a more distal location than TCFA that did not change (p = 0.12). In lesions classified as TCFA, the minimum lumen area (MLA) decreased from 8.1 (interquartile range [IQR]: 7.4 to 8.8) mm(2) at baseline to 7.8 (IQR: 7.2 to 8.4) mm(2) at follow-up, p < 0.05; this was associated with an increase in percent necrotic core at the MLA site (14% [IQR: 12 to 16] to 19% [IQR: 17 to 22], p < 0.0001) and over the entire length of the lesion (14% [IQR: 12 to 16] to 18% [IQR: 17 to 20], p < 0.0001). CONCLUSIONS: Untreated nonculprit lesions in STEMI patients frequently have TCFA morphology that does not change during 13-month follow-up and is accompanied by a decrease in MLA and an increase in necrotic core. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966).

The Relationship between coronary artery calcification as assessed by multi-detector computed tomography and arterial stiffness.

Pulse wave analysis and intima-media thickness (IMT) of carotid artery are the non-invasive indicators of subclinical atherosclerosis. Coronary artery calcification (CAC) score measured by multi-detector computed tomography (MDCT) is well known as a predictor of coronary heart disease (CHD). We investigated the association between coronary calcification assessed by MDCT and extracoronary atherosclerosis measured by pulse wave analysis and IMT of carotid artery. Arterial stiffness and carotid IMT were measured consecutively in 133 patients who underwent their first coronary MDCT angiography due to chest pain. Patients were divided into three groups according to the CAC score (group 1, score = 0, n = 62; group 2, 0 < score < 400, n = 58; group 3, score ≥ 400, n = 13). The classification of CAC score was associated with age, prevalence of hypertension and dyslipidemia, systolic blood pressure, pulse pressure, brachial-ankle pulse wave velocity, percentage of brachial mean artery pressure, upstroke time (UT), augmentation index, and carotid IMT. In a multivariate analysis, age (P = .048), hypertension (P = .007), dyslipidemia (P = .24), and mean ankle UT (P = .038) were independent variables for the classification of CAC score. The UT of pulse wave was significantly associated with the CAC score. The increased UT of pulse wave might provide incremental risk prediction in addition to that defined by conventional CHD risk assessment.