Activation of γ-globin expression by hypoxia-inducible factor 1α.

Around birth, globin expression in human red blood cells (RBCs) shifts from γ-globin to ß-globin, which results in fetal haemoglobin (HbF, α2γ2) being gradually replaced by adult haemoglobin (HbA, α2ß2)1. This process has motivated the development of innovative approaches to treat sickle cell disease and ß-thalassaemia by increasing HbF levels in postnatal RBCs2. Here we provide therapeutically relevant insights into globin gene switching obtained through a CRISPR-Cas9 screen for ubiquitin-proteasome components that regulate HbF expression. In RBC precursors, depletion of the von Hippel-Lindau (VHL) E3 ubiquitin ligase stabilized its ubiquitination target, hypoxia-inducible factor 1α (HIF1α)3,4, to induce γ-globin gene transcription. Mechanistically, HIF1α-HIF1ß heterodimers bound cognate DNA elements in BGLT3, a long noncoding RNA gene located 2.7 kb downstream of the tandem γ-globin genes HBG1 and HBG2. This was followed by the recruitment of transcriptional activators, chromatin opening and increased long-range interactions between the γ-globin genes and their upstream enhancer. Similar induction of HbF occurred with hypoxia or with inhibition of prolyl hydroxylase domain enzymes that target HIF1α for ubiquitination by the VHL E3 ubiquitin ligase. Our findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during stress erythropoiesis and suggest a new therapeutic approach for ß-haemoglobinopathies.

Effective therapies for sickle cell disease: are we there yet?

Sickle cell disease (SCD) is a common genetic blood disorder associated with acute and chronic pain, progressive multiorgan damage, and early mortality. Recent advances in technologies to manipulate the human genome, a century of research and the development of techniques enabling the isolation, efficient genetic modification, and reimplantation of autologous patient hematopoietic stem cells (HSCs), mean that curing most patients with SCD could soon be a reality in wealthy countries. In parallel, ongoing research is pursuing more facile treatments, such as in-vivo-delivered genetic therapies and new drugs that can eventually be administered in low- and middle-income countries where most SCD patients reside.

Loss of miR-144/451 alleviates ß-thalassemia by stimulating ULK1-mediated autophagy of free α-globin.

Most cells can eliminate unstable or misfolded proteins through quality control mechanisms. In the inherited red blood cell disorder ß-thalassemia, mutations in the ß-globin gene (HBB) lead to a reduction in the corresponding protein and the accumulation of cytotoxic free α-globin, which causes maturation arrest and apoptosis of erythroid precursors and reductions in the lifespan of circulating red blood cells. We showed previously that excess α-globin is eliminated by Unc-51-like autophagy activating kinase 1 (ULK1)-dependent autophagy and that stimulating this pathway by systemic mammalian target of rapamycin complex 1 (mTORC1) inhibition alleviates ß-thalassemia pathologies. We show here that disrupting the bicistronic microRNA gene miR-144/451 alleviates ß-thalassemia by reducing mTORC1 activity and stimulating ULK1-mediated autophagy of free α-globin through 2 mechanisms. Loss of miR-451 upregulated its target messenger RNA, Cab39, which encodes a cofactor for LKB1, a serine-threonine kinase that phosphorylates and activates the central metabolic sensor adenosine monophosphate-activated protein kinase (AMPK). The resultant enhancement of LKB1 activity stimulated AMPK and its downstream effects, including repression of mTORC1 and direct activation of ULK1. In addition, loss of miR-144/451 inhibited the expression of erythroblast transferrin receptor 1, causing intracellular iron restriction, which has been shown to inhibit mTORC1, reduce free α-globin precipitates, and improve hematological indices in ß-thalassemia. The beneficial effects of miR-144/451 loss in ß-thalassemia were inhibited by the disruption of Cab39 or Ulk1 genes. Together, our findings link the severity of ß-thalassemia to a highly expressed erythroid microRNA locus and a fundamental, metabolically regulated protein quality control pathway that is amenable to therapeutic manipulation.

Clinical characteristics and outcomes of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis managed with different cytoreductive methods.

BACKGROUND: Hyperleukocytosis in patients with acute myeloid leukemia (AML) has been associated with worse outcomes. For cytoreduction, leukapheresis has been used but its clinical utility is unknown, and low-dose cytarabine (LD-cytarabine) is used as an alternative method. METHODS: Children with newly diagnosed AML treated between 1997 and 2017 in institutional protocols were studied. Hyperleukocytosis was defined as a leukocyte count of ≥100 × 109 /L at diagnosis. Clinical characteristics, early complications, survival data, and effects of cytoreductive methods were reviewed. Among 324 children with newly diagnosed AML, 49 (15.1%) presented with hyperleukocytosis. Initial management of hyperleukocytosis included leukapheresis or exchange transfusion (n = 16, considered as one group), LD-cytarabine (n = 18), hydroxyurea (n = 1), and no leukoreduction (n = 14). RESULTS: Compared with patients who received leukapheresis, the percentage decrease in leukocyte counts following intervention was greater among those who received LD-cytarabine (48% vs. 75%; p = .02), with longer median time from diagnosis to initiation of protocol therapy (28.1 vs. 95.2 hours; p < .001). The incidence of infection was higher in patients (38%) who had leukapheresis than those who receive LD-cytarabine (0%) or leukoreduction with protocol therapy (14%) (p = .008). No differences were noted in the outcomes among the intervention groups. Although patients with hyperleukocytosis had higher incidences of pulmonary and metabolic complications than did those without, no early deaths occurred, and the complete remission, event-free survival, overall survival rates, and outcomes of both groups were similar. CONCLUSION: LD-cytarabine treatment appears to be a safe and effective means of cytoreduction for children with AML and hyperleukocytosis.

RGL2 Deficiency Impairs Human Erythropoiesis By Altering Terminal Erythroid Differentiation and Apoptosis.

DISCLOSURES: No relevant conflicts of interest to declare.

Hereditary elliptocytosis-associated alpha-spectrin mutation p.L155dup as a modifier of sickle cell disease severity.

The broad phenotypic variability among individuals with sickle cell disease (SCD) suggests the presence of modifying factors. We identified two unrelated SCD patients with unusually severe clinical and laboratory phenotype that were found to carry the hereditary elliptocytosis-associated alpha-spectrin mutation c.460_462dupTTG (p.L155dup), a mutation enriched due to positive selective pressure of malaria, similar to the SCD globin mutations. A high index of suspicion for additional hematologic abnormalities may be indicated for challenging patients with SCD. These cases highlight the validity of specialized testing such as ektacytometry and next-generation sequencing for patients and family members to assess genotype/phenotype correlations.

Impact of crossing technique on the incidence of periprocedural myocardial infarction during chronic total occlusion percutaneous coronary intervention.

OBJECTIVES: We sought to evaluate the impact of crossing strategy on the incidence of periprocedural myocardial infarction (PMI) during chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: The optimal technique for crossing coronary CTOs remains controversial. METHODS: We retrospectively examined the incidence of PMI among 184 consecutive patients who underwent CTO PCI at our institution between 2012 and 2015. Creatine kinase-myocardial band fraction (CK-MB) and troponin were measured before and after PCI in all patients. PMI was defined as CK-MB increase ≥3× upper limit of normal (ULN). RESULTS: Mean age was 65 ± 8 years, 98% of patients were men, 57% had diabetes mellitus, 36% were current smokers, 38% had prior heart failure, 31% had prior coronary artery bypass graft surgery (CABG), and 55% had prior PCI. The retrograde approach was used in 38% of cases. As compared with antegrade wire escalation and antegrade dissection/re-entry, use of the retrograde approach was associated with higher J-CTO (Multicenter CTO Registry of Japan) scores (P < 0.0001), higher frequency of moderate or severe calcification (P = 0.0061), longer CTO length (P < 0.0001), more frequent proximal cap ambiguity (P < 0.0001), and lower technical (P = 0.0007) and procedural (P = 0.0014) success. The frequency of PMI for the antegrade-only and retrograde cases was 10% and 33%, respectively (P = 0.0001). On multivariate analysis, use of the retrograde approach and moderate/severe calcification were independently associated with higher incidence of PMI. CONCLUSIONS: As compared with antegrade-only crossing techniques, the retrograde approach is used in patients with more complex anatomy but may carry higher risk for PMI. © 2016 Wiley Periodicals, Inc.

Optimizing Radiation Safety in the Cardiac Catheterization Laboratory: A Practical Approach.

Reducing radiation exposure during cardiovascular catheterization is of paramount importance for both patient and staff safety. Over the years, advances in equipment and application of radiation safety protocols have significantly reduced patient dose and operator exposure. This review examines the current status of radiation protection in the cardiac and vascular catheterization laboratory and summarizes best practices for minimizing radiation exposure.

Determinants of operator and patient radiation exposure during cardiac catheterization: Insights from the RadiCure (RADIation reduction during cardiac catheterization using real-timE monitoring) trial.

BACKGROUND: In the RadiCure study 505 catheterization procedures were 1:1 randomized to use or no use of real-time radiation monitoring. Use of the Bleeper Sv monitor resulted in a significant reduction in operator radiation exposure. METHODS: We examined the association between several baseline and procedural parameters with operator and patient radiation exposure using univariable and multivariable analysis in the 505 patients that were enrolled in RadiCure. All baseline demographic and procedure characteristics recorded were included in the univariable analysis. RESULTS: Median fluoroscopy time was 6.2 (2.5-12.5) minutes, median patient air kerma dose was 0.908 (0.602-1.636) Gray and median first operator exposure was 10 (5-22) µSv. For analysis purposes, the 505 procedures were dichotomized based on the median operator exposure (10 µSv) and median patient radiation dose (0.908 Gray). On multivariable analysis, factors associated with high (above median or >10 µSv) first operator radiation exposure included radial access (odds ratio [OR] 5.44, 95% Confidence Interval [CI] 2.88-10.76), chronic total occlusion (CTO) intervention (OR 12.78, 95% CI 4.42-43.60), real-time radiation monitoring (OR 0.42, 95% CI 0.26-0.66), and use of a radioabsorbent drape (OR 0.53, 95% CI 0.28-0.96). High patient radiation dose (above median or >0.908 Gray) was associated with body mass index>30 kg/m2 (OR 3.22, 95% CI 1.99-5.29), prior MI (OR 2.26, 95% CI 1.29-4.04), prior cerebrovascular disease (OR 0.34, 95% CI 0.15-0.75), hypertension (OR 2.40, 95% CI 1.05-5.82), prior coronary artery bypass graft surgery (OR 2.46, 95% CI 1.40-4.39) and CTO intervention (OR 12.93, 95% CI 3.28-87.31), but was not associated with real-time radiation monitoring and use of a radioabsorbent drape. CONCLUSIONS: Several clinical and procedural factors are associated with higher patient and operator radiation exposure. Real-time radiation monitoring and use of disposable radiation shields were associated with lower operator, but not patient, radiation dose. © 2015 Wiley Periodicals, Inc.

Long-term outcomes with first- vs. second-generation drug-eluting stents in saphenous vein graft lesions.

BACKGROUND: As compared with bare metal stents, first-generation drug-eluting stents (DES) improved post-procedural outcomes in aortocoronary saphenous vein graft (SVG) lesions, but there is limited information on outcomes after use of second-generation DES in SVGs. METHODS: We compared the outcomes of patients who received first- (n = 81) with those who received second-generation (n = 166) DES in SVG lesions at our institution between 2006 and 2013. Major adverse cardiac events (MACE) were defined as the composite of all-cause death, myocardial infarction, and target vessel revascularization. RESULTS: Mean age was 66.0 ± 8.1 years and 97.6% of the patients were men. Mean SVG age was 11.1 ± 0.4 years. First-generation DES were sirolimus-eluting (n = 17) and paclitaxel-eluting (n = 64) stents. Second-generation DES were everolimus-eluting (n = 115) and zotarolimus-eluting (n = 51) stents. Median follow-up was 41 months. At 2-years post-procedure, patients with first- and second-generation DES had similar rates of death (20.91% vs. 20.27%, P = 0.916), target lesion revascularization (16.39% vs. 20.00%, P = 0.572), target vessel revascularization (20.97% vs. 23.16%, P = 0.747), myocardial infarction (26.15% vs. 23.00%, P = 0.644), and MACE (43.5% vs. 40.87%, P = 0.707), respectively. CONCLUSIONS: Outcomes with first- and second-generation DES in SVGs are similar. Novel stent designs are needed to further improve the clinical outcomes in this challenging patient and lesion subgroup. © 2015 Wiley Periodicals, Inc.

Successful management of a distal vessel perforation through a single 8-French guide catheter: Combining balloon inflation for bleeding control with coil embolization.

Coronary perforation is an infrequent, but serious complication of percutaneous coronary intervention (PCI), and is more likely to occur with complex (such as chronic total occlusion) PCI and use of atheroablative devices. For main vessel perforations, the "dual catheter" technique is usually employed in which a balloon is delivered over the first guide catheter to stop bleeding, whereas the covered stent is delivered through a second guide catheter. This is required because the large profile of the currently commercially available covered stents precludes fitting within even an 8-French guide together with a balloon. However, coil embolization for distal artery wire perforation and collateral vessel perforation can be achieved through a microcatheter that can fit along with a balloon within an 8-French guide catheter, obviating the need for a second guide catheter. We describe a case in which a distal artery wire perforation was successfully treated using a single 8-French guide catheter.

Comparison of radiation dose between different fluoroscopy systems in the modern catheterization laboratory: Results from bench testing using an anthropomorphic phantom.

BACKGROUND: Variations in radiation dose between various X-ray systems have received limited study. OBJECTIVE: We examined the impact of X-ray system type on patient radiation dose during cardiac catheterization. METHODS: An anthropomorphic phantom was used in a series of standardized experiments that involved 15 sec of continuous cineangiography in 7 projections. Three to seven experiments were performed in four commonly used X-ray systems: Innova IGS (GE Healthcare), Integris Allura FD20 (Philips), Allura Clarity (Philips), and Artis one (Siemens). Phantom radiation dose was measured with a dedicated X-ray dosimetry system (Gafchromic radiology film and Film QA XR software, Ashland) that was precalibrated at 0, 1, 2, 3, and 4 Gray, and with the X-ray system built-in functions. RESULTS: Radiation dose was lowest with the Allura Clarity system [average film dose 4.2±0.1 cGray, peak film dose 18.3±1.6 cGray, Air Kerma (AK) dose 0.310±0.002 Gray, Dose Area Product (DAP) dose 23.72±0.84 Gray*cm2], intermediate with the Integris Allura FD20 (average film dose 4.4±1.1 cGray, peak film dose 29.4±15.5 cGray, AK 0.482±0.189 Gray, DAP 45.18±21.90 Gray*cm2), and highest with the Artis one system (average film dose 7.4±0.8 cGray, peak film dose 66.9±0.09 cGray, AK 0.746±0.085 Gray, DAP 75.93±9.11 Gray*cm2) and the Innova IGS system (average film dose 7.2±1.0 cGray, peak film dose 49.3±28.9 cGray, AK 0.874±0.340 Gray, DAP 92.28±14.73 Gray*cm2; P=0.011 for average film dose, P=0.019 for maximum film dose, P=0.033 for AK, and P=0.008 for DAP). CONCLUSIONS: The X-ray system type has significant impact on patient radiation dose during cardiac catheterization.

Procedural failure of chronic total occlusion percutaneous coronary intervention: Insights from a multicenter US registry.

BACKGROUND: The hybrid approach to chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has significantly increased procedural success rates, yet some cases still fail. We sought to evaluate the causes of failure in a contemporary CTO PCI registry. METHODS: We examined 380 consecutive patients who underwent CTO-PCI at 4 high volume CTO PCI centers in the United States using the "hybrid" approach. Clinical, angiographic, complication, and efficiency outcomes were compared between successful and failed cases. Failed cases were individually reviewed by an independent reviewer to determine the cause of failure. RESULTS: Procedural success was 91.3%. Compared with patients in whom CTO PCI was successful, those in whom CTO PCI failed had similar baseline clinical characteristics, but were more likely to have longer occlusion length, more tortuosity, more proximal cap ambiguity and blunt stump, and higher mean J-CTO scores (2.8 ± 1.1 vs. 3.5 ± 1.0, P < 0.001), and less likely to have collaterals suitable for the retrograde approach (66% vs. 45%, P = 0.021). Failure was due to a complication in 10 cases (30%). In the remaining 23 cases (70%) failure was due to inability to wire the lesion (n = 21, 4 of which were CTOs due to in-stent restenosis), or poor antegrade flow after PCI (n = 5). CONCLUSIONS: Compared with successful cases, failed CTO-PCI cases are more likely to have higher J-CTO scores, longer occlusion length, ambiguous proximal cap and no appropriate collaterals for retrograde crossing. Development of novel CTO crossing techniques is needed to further increase CTO PCI success rates.

Gene Therapy and Gene Editing for ß-Thalassemia.

After many years of intensive research, emerging data from clinical trials indicate that gene therapy for transfusion-dependent ß-thalassemia is now possible. Strategies for therapeutic manipulation of patient hematopoietic stem cells include lentiviral transduction of a functional erythroid-expressed ß-globin gene and genome editing to activate fetal hemoglobin production in patient red blood cells. Gene therapy for ß-thalassemia and other blood disorders will invariably improve as experience accumulates over time. The best overall approaches are not known and perhaps not yet established. Gene therapy comes at a high cost, and collaboration between multiple stakeholders is required to ensure that these new medicines are administered equitably.

Selumetinib for Refractory Pulmonary and Gastrointestinal Bleeding in Noonan Syndrome.

A 15-year-old-boy with Noonan syndrome and status post orthoptic heart transplant developed mixed mitral valve disease and underwent mechanical mitral valve replacement 6 months before presentation with acute respiratory distress. He developed massive pulmonary hemorrhage that required veno-venous extracorporeal membrane oxygenation (ECMO) support. He had a prolonged anticoagulation free ECMO course of 4 weeks, with ongoing recurrent pulmonary hemorrhage and underwent several rounds of coil embolization of aortopulmonary collaterals. ECMO course was complicated by significant nasopharyngeal bleeding that required embolization of the sphenopalatine artery. Shortly after decannulation, he developed massive gastrointestinal and peritoneal hemorrhage that was treated by embolization of the left gastric artery and a branch of the internal iliac artery. His bleeding was attributed to neo-angiogenesis. Initial treatment with propranolol was unsuccessful. Subsequent treatment with interferon α 2b demonstrated efficacy, but severe neutropenia required cessation of therapy. Because functional alterations of the rat sarcoma virus-mitogen activated protein kinase signaling pathway and protein tyrosine phosphatase nonreceptor type (PTPN11) mutations in Noonan syndrome are known to be associated with neo-angiogenesis, we used the mitogen-activated protein kinase inhibitor selumetinib as a gene-targeted therapy with the hope of controlling bleeding and inhibiting neo-angiogenesis. After initiation of selumetinib, bleeding stopped and allowed the patient to be discharged from the hospital on dipyridamole as antiplatelet prophylaxis for his mechanical mitral valve. He had no further bleeding episodes through 1 year after hospital discharge.

Phase I Dose-Finding, Safety, and Tolerability Trial of Romiplostim to Improve Platelet Recovery After UCB Transplantation.

Platelet recovery is delayed after umbilical cord blood transplant (UCBT). Romiplostim is a thrombopoietin receptor agonist that has the potential to improve platelet engraftment after UCBT. The purpose of this study was to determine the safety profile and maximum tolerated dose (MTD) of romiplostim and to investigate whether romiplostim accelerates platelet recovery post-UCBT. It was a single-center, dose-finding, safety and tolerability phase I trial of weekly romiplostim in 20 adult patients who failed to achieve an un-transfused platelet count of 20 × 109/L by day +28 post-UCBT. Romiplostim was administered at the assigned dose as 6 weekly injections beginning by day +42 post-UCBT. Four dose levels (4, 6, 8, and 10 µg/kg per dose) were evaluated. The MTD of romiplostim was determined by the continual reassessment method, with a goal to identify a dose level with desired toxicity rate of ≤20%. Median age of the patients was 59.5 years, and 60% were female. Eleven patients received nonmyeloablative (NMA) double UCBT, seven patients received myeloablative single UCBT, and two patients received NMA single UCBT. Two patients received 4 µg/kg per dose, two received 6 µg/kg per dose, four received 8 µg/kg per dose, and the remaining 12 received 10 µg/kg per dose. Only five patients completed the full six doses of treatment. Of the 15 patients who received fewer than six doses, 12 were due to a platelet count of >100 × 109/L, two were due to platelet count of >400 × 109/L, and one was due to right upper extremity edema without thrombosis. All romiplostim-treated patients achieved platelet engraftment to 20 × 109/L at a median of 45 days post-UCBT compared to 90% of controls at a median of 45 days (P = .08). Similarly, 90% of romiplostim-treated patients achieved platelet engraftment to 50 × 109/L at a median of 48 days compared to 75% of controls at a median of 52 days (P = .09). All dose levels were effective with low toxicity; therefore, the MTD of romiplostim was 10 µg/kg per dose, and romiplostim is a safe and potentially effective therapy to counter delayed platelet recovery post-UCBT.

Predictors of Excess Patient Radiation Exposure During Chronic Total Occlusion Coronary Intervention: Insights From a Contemporary Multicentre Registry.

BACKGROUND: High patient radiation dose during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) might lead to procedural failure and radiation skin injury. METHODS: We examined the association between several clinical and angiographic variables on patient air kerma (AK) radiation dose among 748 consecutive CTO PCIs performed at 9 experienced US centres between May 2012 and May 2015. RESULTS: The mean age was 65 ± 10 years, 87% of patients were men, and 35% had previous coronary artery bypass graft surgery (CABG). Technical and procedural success was 92% and 90%, respectively. The median patient AK dose was 3.40 (interquartile range, 2.00-5.40) Gy and 34% of the patients received > 4.8 Gy (high radiation exposure). In univariable analysis male sex (P = 0.016), high body mass index (P < 0.001), history of hyperlipidemia (P = 0.023), previous CABG (P < 0.001), moderate or severe calcification (P < 0.001), tortuosity (P < 0.001), proximal cap ambiguity (P = 0.001), distal cap at a bifurcation (P = 0.006), longer CTO occlusion length (P < 0.001), blunt/no blunt stump (P < 0.001), and centre (P < 0.001) were associated with higher patient AK dose. In multivariable analysis high body mass index (P < 0.001), previous CABG (P = 0.005), moderate or severe calcification (P = 0.005), longer CTO occlusion length (P < 0.001), and centre (P < 0.001) were independently associated with higher patient AK dose. CONCLUSIONS: Approximately 1 in 3 patients who undergo CTO PCI receive high AK radiation dose (> 4.8 Gy). Several baseline clinical and angiographic characteristics can help predict the likelihood of high radiation dose and assist with intensifying efforts to reduce radiation exposure for the patient and the operator.

Accuracy of remote chest X-ray interpretation using Google Glass technology.

OBJECTIVES: We sought to explore the accuracy of remote chest X-ray reading using hands-free, wearable technology (Google Glass, Google, Mountain View, California). METHODS: We compared interpretation of twelve chest X-rays with 23 major cardiopulmonary findings by faculty and fellows from cardiology, radiology, and pulmonary-critical care via: (1) viewing the chest X-ray image on the Google Glass screen; (2) viewing a photograph of the chest X-ray taken using Google Glass and interpreted on a mobile device; (3) viewing the original chest X-ray on a desktop computer screen. One point was given for identification of each correct finding and a subjective rating of user experience was recorded. RESULTS: Fifteen physicians (5 faculty and 10 fellows) participated. The average chest X-ray reading score (maximum 23 points) as viewed through the Google Glass, Google Glass photograph on a mobile device, and the original X-ray viewed on a desktop computer was 14.1±2.2, 18.5±1.5 and 21.3±1.7, respectively (p<0.0001 between Google Glass and mobile device, p<0.0001 between Google Glass and desktop computer and p=0.0004 between mobile device and desktop computer). Of 15 physicians, 11 (73.3%) felt confident in detecting findings using the photograph taken by Google Glass as viewed on a mobile device. CONCLUSION: Remote chest X-ray interpretation using hands-free, wearable technology (Google Glass) is less accurate than interpretation using a desktop computer or a mobile device, suggesting that further technical improvements are needed before widespread application of this novel technology.

Impact of Crossing Strategy on Intermediate-term Outcomes After Chronic Total Occlusion Percutaneous Coronary Intervention.

BACKGROUND: There is ongoing controversy about the optimal crossing strategy selection for chronic total occlusion (CTO) percutaneous coronary intervention (PCI), especially regarding the relative merits of antegrade dissection/re-entry and the retrograde approach. METHODS: We retrospectively examined the clinical outcomes of 173 consecutive patients who underwent successful CTO PCI at our institution between January 2012 and March 2015. RESULTS: The mean age was 65 ± 8 years, and 98% of the patients were men with a high prevalence of diabetes (60%), previous coronary artery bypass grafting (CABG) (31%), and previous PCI (54%). The successful CTO crossing strategy was antegrade wire escalation in 79 patients (45.5%), antegrade dissection/re-entry in 58 patients (33.5%), retrograde wire escalation in 11 patients (6.4%), and retrograde dissection and re-entry in 25 patients (14.5%). The retrograde approach was more commonly used in lesions with interventional collaterals (P < 0.0001), moderate/severe calcification (P = 0.02), blunt stump (P = 0.01), and a higher Japan Chronic Total Occlusion score (P = 0.0002). Use of dissection and re-entry (both antegrade and retrograde) was associated with bifurcation and the distal cap (P = 0.004), longer CTO occlusion length (P < 0.0001), and longer stent length (P < 0.0001). Median follow-up was 11 months. The 12-month incidence of death, myocardial infarction, and the composite of acute coronary syndrome/target lesion revascularization/target vessel revascularization was 2.5%, 4.9%, and 24.4%, respectively, and was similar with intimal and subintimal crossing strategies. CONCLUSIONS: Antegrade dissection/re-entry and retrograde approaches are frequently used during CTO PCI and were associated with similarly favorable intermediate-term outcomes as antegrade wire escalation.

Near-Infrared Spectroscopy Analysis of Coronary Chronic Total Occlusions.

OBJECTIVE: To examine the presence and localization of lipid-core plaque (LCP) in coronary vessels with chronic total occlusions (CTOs) using near-infrared spectroscopy (NIRS). METHODS: NIRS imaging was performed after guidewire crossing of the occlusion in 15 patients with CTOs. LCP was defined as ≥2 adjacent 2 mm yellow blocks on the block chemogram. We also measured the maximum lipid-core burden index (LCBI) in a 4 mm length of artery (maxLCBI4mm). Large LCP was defined as maxLCBI4mm ≥500. RESULTS: Median patient age was 64 years (interquartile range [IQR], 61-67 years) and all patients were men with high prevalence of diabetes mellitus (64%) and prior coronary artery bypass graft surgery (27%). The CTO target vessel was the right coronary artery (46%), left anterior descending artery (27%), or circumflex artery (27%). Median occlusion length was 35 mm (IQR, 30-50 mm). LCP was present in 11 of 15 CTO vessels (73%) and a large LCP in 4 of 15 CTO vessels (27%). LCP was located at the proximal cap in 6 CTOs (55%), the CTO body in 6 CTOs (55%), and the distal cap in 2 CTOs (18%). The median overall LCBI and maxLCBI4mm were 145 (IQR, 79-243) and 415 (IQR, 267-505), respectively. All patients underwent successful stenting without any complications. The 12-month incidence of in-stent restenosis and target-lesion revascularization was 25%, and all patients who developed restenosis had an LCP at baseline. CONCLUSIONS: LCPs are commonly encountered in coronary CTO vessels, suggesting an active intraplaque atherosclerotic process. The impact of LCP on postintervention outcomes requires further study.