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BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients who had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomized patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 219 patients in the ticagrelor group and 224 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 9.6% (44 of 457 SVGs) versus 10.1% in the placebo group (50 of 497 SVGs; odds ratio, 0.87 [95% CI, 0.49–1.55]; P =0.64). SVG failure occurred in 32 patients (12.9%) in the ticagrelor group versus 32 patients (13.0%) in the placebo group (hazard ratio, 1.04 [95% CI, 0.63–1.69]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02352402. URL: https://eudract.ema.europa.eu/ ; Unique identifier: 2014-002142-50.

Observational and randomized evidence shows that arterial grafts have better patency rates than saphenous vein grafts (SVGs) in coronary artery bypass grafting. Observational studies suggest that the use of multiple arterial grafts is associated with longer postoperative survival, but this must be interpreted in the context of treatment allocation bias and hidden confounders intrinsic to the study designs. Recently, a pooled analysis of 6 randomized trials comparing the radial artery with the SVG as the second conduit and the largest randomized trial comparing the use of single and bilateral internal thoracic arteries have provided apparently divergent results about a clinical benefit with the use of >1 arterial conduit. However, both analyses have methodological limitations that may have influenced their results. At present, it is unclear whether the well-documented increased patency rate of arterial grafts translates into clinical benefits in the majority of patients undergoing coronary artery bypass grafting. A large randomized trial testing the arterial grafts hypothesis (ROMA [Randomized Comparison of the Clinical Outcome of Single Versus Multiple Arterial Grafts]) is underway and will report the results in a few years.

A 75-year-old man presented with dyspnea requiring home oxygen, on a background of partial colectomy for colon cancer, chronic renal failure, and coronary artery bypass graft surgery in 1978 (left internal mammary artery to left anterior descending graft and saphenous vein grafts [SVG] to the right coronary artery [RCA] and left circumflex artery). Clinically, he had jugular venous distension and bibasal crepitations, without overt ascites or peripheral edema. Chest x-ray demonstrated remote postoperative changes, cardiomegaly, mild pericardial calcification, and other radiographic findings of congestive heart failure, without apparent mediastinal mass (Figure 1). However, echocardiography revealed a large (9.4×8.7 cm), apparently extracardiac, mass compressing the right ventricle with severe functional tricuspid stenosis (mean gradient, 10 mm Hg) and turbulence of forward transtricuspid flow on color Doppler imaging (Figures 2A, 2B, and 3; Movie IA and IB in the online-only Data Supplement). Noncontrast cardiac MRI revealed a large (10.9×7.4×6.5 cm), relatively homogenous structure adjacent to the atrioventricular groove anteriorly, which was compressing the right heart and obstructing the tricuspid valve. The mass was distinct from adipose tissue, well circumscribed by overlying pericardium, and had no invasive characteristics. Cine imaging demonstrated flow within the mass. The structure location and characteristics were consistent with a partially thrombosed SVG aneurysm (Figure 4; Movie II …

Background— Coronary artery bypass grafting success is limited by vein graft failure (VGF). Understanding the factors associated with VGF may improve patient outcomes. Methods and Results— We examined 1828 participants in the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial undergoing protocol-mandated follow-up angiography 12 to 18 months post–coronary artery bypass grafting or earlier clinically driven angiography. Outcomes included patient- and graft-level angiographic VGF (≥75% stenosis or occlusion). Variables were selected by using Fast False Selection Rate methodology. We examined relationships between variables and VGF in patient- and graft-level models by using logistic regression without and with generalized estimating equations. At 12 to 18 months post–coronary artery bypass grafting, 782 of 1828 (42.8%) patients had VGF, and 1096 of 4343 (25.2%) vein grafts had failed. Demographic and clinical characteristics were similar between patients with and without VGF, although VGF patients had longer surgical times, worse target artery quality, longer graft length, and they more frequently underwent endoscopic vein harvesting. After multivariable adjustment, longer surgical duration (odds ratio per 10-minute increase, 1.05; 95% confidence interval, 1.03–1.07), endoscopic vein harvesting (odds ratio, 1.41; 95% confidence interval, 1.16–1.71), poor target artery quality (odds ratio, 1.43; 95% confidence interval, 1.11–1.84), and postoperative use of clopidogrel or ticlopidine (odds ratio, 1.35; 95% confidence interval, 1.07–1.69) were associated with patient-level VGF. The predicted likelihood of VGF in the graft-level model ranged from 12.1% to 63.6%. Conclusions— VGF is common and associated with patient and surgical factors. These findings may help identify patients with risk factors for VGF and inform the development of interventions to reduce VGF. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00042081.

Background— Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis. Methods and Results— The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O 2 − ) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O 2 − production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O 2 − and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ–dependent mechanism. Conclusions— We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.

Despite ongoing advances in percutaneous revascularization, coronary artery bypass grafting (CABG) continues to be performed in a large number of patients, with >400 000 operations reported in 2007 in the United States alone.1 Although arterial conduits are generally preferred, saphenous vein grafts (SVGs) continue to be used regularly. First described by Riahi and colleagues2 in 1975, aneurysmal dilatation of aortocoronary SVGs remains a rare yet widely reported phenomenon. Indeed, subsequent literature on the topic consists almost exclusively of case reports and small case series. Thus, the precise incidence of aortocoronary SVG aneurysms (SVGAs) remains difficult to ascertain, although in 1 case series, an incidence of 0.07% was estimated from a review of >5500 grafts at a single institution.3 However, this likely underestimates the true number because SVGAs often remain clinically silent and no guidelines exist to screen for their development. Given the infrequent identification of SVGAs, our current understanding of the epidemiology and pathogenesis of these aneurysms remains limited. Aneurysms are generally defined as a focal dilatation of vessels >1.5 times the proximal reference diameter; however, aneurysmal dilatation of aortocoronary SVGs has led to “giant” aneurysm formation, with reports of cases exceeding 10 cm.4–6 SVGAs are often incidentally identified on imaging, but cases of rupture,7 fistula formation with neighboring anatomy,8 and hemodynamic compromise resulting from compression of adjacent cardiac and vascular structures have been reported.9 To date, 2 reviews have been published that briefly summarize 108 cases of SVGAs.10,11 Traditionally, their management has been surgical—generally resection of the aneurysm with or without bypass of the affected territory. However, with refinement of percutaneous techniques, including the use of Amplatzer devices, covered stents, and arterial coiling, the management options …

Background— The Department of Veterans Affairs Randomized On/Off Bypass (ROOBY) trial compared clinical and angiographic outcomes in off-pump versus on-pump coronary artery bypass graft (CABG) surgery to ascertain the relative efficacy of the 2 techniques. Methods and Results— From February 2002 to May 2007, the ROOBY trial randomized 2203 patients to off-pump versus on-pump CABG. Follow-up angiography was obtained in 685 off-pump (62%) and 685 on-pump (62%) patients. Angiograms were analyzed (blinded to treatment) for FitzGibbon classification (A=widely patent, B=flow limited, O=occluded) and effective revascularization. Effective revascularization was defined as follows: All 3 major coronary territories with significant disease were revascularized by a FitzGibbon A-quality graft to the major diseased artery, and there were no new postanastomotic lesions. Off-pump CABG resulted in lower FitzGibbon A patency rates than on-pump CABG for arterial conduits (85.8% versus 91.4%; P =0.003) and saphenous vein grafts (72.7% versus 80.4%; P P P ≤0.001). The 1-year adverse cardiac event rate was 16.4% in patients with ineffective revascularization versus 5.9% in patients with effective revascularization ( P Conclusions— Off-pump CABG resulted in significantly lower FitzGibbon A patency for arterial and saphenous vein graft conduits and less effective revascularization than on-pump CABG. At 1 year, patients with less effective revascularization had higher adverse event rates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00032630.

Background— Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes. Methods and Results— Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21–2.06; P =0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71–1.52; P =0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77–1.53; P =0.65). Conclusions— VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.

Background— Limited information exists on the intermediate-term graft patency and 5-year clinical outcomes of patients receiving saphenous vein grafts with multiple (m-SVG) versus single distal targets (s-SVG) during coronary artery bypass graft (CABG) surgery in the current era. Methods and Results— We studied the association of the use of m-SVG versus s-SVG conduits with 1-year SVG failure (defined as ≥75% angiographic stenosis) and 5-year clinical events (death; death or myocardial infarction [MI]; and death, MI, or revascularization) in 3014 patients undergoing their first CABG surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV. Of 3014 patients enrolled in PREVENT IV, 1045 (34.7%) had ≥1 m-SVGs during CABG. Vein graft failure at 1-year was higher for m-SVG compared with s-SVG (adjusted odds ratio 1.24, 95% confidence interval 1.03 to 1.48). At 5 years, the adjusted composite of death, MI (including perioperative MI), or revascularization (hazard ratio 1.15, 95% confidence interval 1.00 to 1.31) and death or MI (hazard ratio 1.21, 95% confidence interval 1.03 to 1.43) were significantly higher in patients receiving m-SVGs. Conclusions— In patients undergoing first CABG surgery, the use of m-SVG was associated with a higher 1-year vein graft failure rate and trends toward worse clinical outcomes. Additional studies are needed to better understand the most appropriate conduit to improve long-term graft patency and clinical outcomes of patients undergoing CABG surgery. In the meantime, these data should encourage the use of s-SVG over m-SVG when feasible.

Background— Use of endoscopic saphenous vein harvesting has developed into a routine surgical approach at many cardiothoracic surgical centers. The association between this technique and long-term morbidity and mortality has recently been called into question. The present report describes the use of open versus endoscopic vein harvesting and risk of mortality and repeat revascularization in northern New England during a time period (2001 to 2004) in which both techniques were being performed. Methods and Results— From 2001 to 2004, 8542 patients underwent isolated coronary artery bypass grafting procedures, 52.5% with endoscopic vein harvesting. Surgical discretion dictated the vein harvest approach. The main outcomes were death and repeat revascularization (percutaneous coronary intervention or coronary artery bypass grafting) within 4 years of the index admission. The use of endoscopic vein harvesting increased from 34% in 2001 to 75% in 2004. In general, patients undergoing endoscopic vein harvesting had greater disease burden. Endoscopic vein harvesting was associated with an increased adjusted risk of bleeding requiring a return to the operating room (2.4 versus 1.7; P =0.03) but a decreased risk of leg wound infections (0.2 versus 1.1; P Conclusions— During 2001 to 2004 in northern New England, the use of endoscopic vein harvesting was not associated with harm. There was a nonsignificant increase in repeat revascularization, and survival was not decreased.

Background— Clopidogrel inhibits intimal hyperplasia in animal studies and therefore may reduce saphenous vein graft (SVG) intimal hyperplasia after coronary artery bypass grafting. The Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) study was undertaken to evaluate whether the addition of clopidogrel to aspirin inhibits SVG disease after coronary artery bypass grafting, as assessed at 1 year by intravascular ultrasound. Methods and Results— In this double-blind phase II trial, 113 patients undergoing coronary artery bypass grafting with SVGs were randomized to receive aspirin 162 mg plus clopidogrel 75 mg daily or aspirin 162 mg plus placebo daily for 1 year. The primary outcome was SVG intimal hyperplasia (mean intimal area) as determined by intravascular ultrasound at 1 year. Secondary outcomes were graft patency, major adverse cardiovascular events, and major bleeding. One-year intravascular ultrasound and coronary angiography were performed in 92 patients (81.4%). At 1 year, SVG intimal area did not differ significantly between the 2 groups (4.1±2.0 versus 4.5±2.1 mm 2 , aspirin-clopidogrel versus aspirin-placebo, P =0.44). Overall 1-year graft patency was 95.2% in the aspirin-clopidogrel group compared with 95.5% in the aspirin-placebo group ( P =0.90), and SVG patency was 94.3% in the aspirin-clopidogrel group versus 93.2% in the aspirin-placebo group ( P =0.69). Freedom from major adverse cardiovascular events at 1 year was 92.9±3.4% in the aspirin-clopidogrel group and 91.1±3.8% in the aspirin-placebo group ( P =0.76). The incidence of major bleeding at 1 year was similar for the 2 groups (1.8% versus 0%, aspirin-clopidogrel versus aspirin-placebo, P =0.50). Conclusions— Compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia 1 year after coronary artery bypass grafting. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00228423.

Background— Radial artery (RA) aortocoronary bypass grafts anastomosed to a branch of the circumflex coronary artery have significantly better patency rates than saphenous vein (SV) grafts at 5 years, but the physiological characteristics and mechanisms involved are not clearly defined. We compared RA and SV graft vasomotor and flow responses to endothelium-dependent and -independent stimuli 5 years after surgery in a subgroup of patients enrolled in the Radial artery versus Saphenous Vein Patency (RSVP) trial. Methods and Results— Twenty-seven patients were included in the study (RA, n=15; SV, n=12). Graft blood flow was calculated from flow velocity, measured by intracoronary Doppler, and luminal diameter, measured by quantitative coronary angiography, before and after intragraft infusions of adenosine, acetylcholine, and isosorbide dinitrate. At rest, RA luminal diameters were significantly smaller than SV luminal diameters ( P =0.029), blood flow velocity was greater in RA than SV ( P =0.008), and volume blood flows were similar. RA but not SV dilated in response to adenosine and isosorbide dinitrate (all P Conclusions— Five years after surgery, RA coronary bypass conduits grafted to a single coronary territory demonstrated preserved flow-mediated vasodilatation, whereas SV grafts did not. Our results may provide insight into the more favorable patency of RA grafts over SV grafts. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00139399.

Background— Clinical trials in ischemic patients showed the safety and benefit of autologous bone marrow progenitor cell transplantation. Non–bone marrow progenitor cells with proangiogenic capacities have been described, yet they remain clinically unexploited owing to their scarcity, difficulty of access, and low ex vivo expansibility. We investigated the presence, antigenic profile, expansion capacity, and proangiogenic potential of progenitor cells from the saphenous vein of patients undergoing coronary artery bypass surgery. Methods and Results— CD34-positive cells, negative for the endothelial marker von Willebrand factor, were localized around adventitial vasa vasorum. After dissection of the vein from surrounding tissues and enzymatic digestion, CD34-positive/CD31-negative cells were isolated by selective culture, immunomagnetic beads, or fluorescence-assisted cell sorting. In the presence of serum, CD34-positive/CD31-negative cells gave rise to a highly proliferative population that expressed pericyte/mesenchymal antigens together with the stem cell marker Sox2 and showed clonogenic and multilineage differentiation capacities. We called this population “saphenous vein–derived progenitor cells” (SVPs). In culture, SVPs integrated into networks formed by endothelial cells and supported angiogenesis through paracrine mechanisms. Reciprocally, endothelial cell–released factors facilitated SVP migration. These interactive responses were inhibited by Tie-2 or platelet-derived growth factor-BB blockade. Intramuscular injection of SVPs in ischemic limbs of immunodeficient mice improved neovascularization and blood flow recovery. At 14 days after transplantation, proliferating SVPs were still detectable in the recipient muscles, where they established N-cadherin–mediated physical contact with the capillary endothelium. Conclusions— SVPs generated from human vein CD34-positive/CD31-negative progenitor cells might represent a new therapeutic tool for angiogenic therapy in ischemic patients.

Background— Saphenofemoral junction (SFJ) ligation has been a major component of surgical intervention for varicose veins; however, recurrence occurs in as many as 40%. Neovascularization with reconnection of the venous channels at the transected SFJ has been identified as the major cause of this recurrence. This randomized controlled study sought to evaluate mechanical suppression of neovascularization at the SFJ, with the use of a synthetic patch, to prevent recurrence after ligation surgery. Methods and Results— A total of 389 limbs (from 292 patients) were randomized into either control (SFJ ligation surgery) or patch (SFJ ligation with polytetrafluoroethylene patch of the transected SFJ) groups. All patients underwent clinical assessment, duplex imaging, and air plethysmography studies preoperatively and at 1, 6, 12, and 36 months postoperatively. The patch consistently halved the recurrence rate to 3 years postoperatively in all clinical subgroups. In those patched SFJs that still developed recurrence, evidence of neovascularization circumventing the polytetrafluoroethylene patch was observed by both ultrasound and histology. Conclusions— This study demonstrates that use of a polytetrafluoroethylene patch is an effective mechanical suppressant of neovasculogenesis at the SFJ and can be safely used as a strategy to improve long-term outcome of varicose vein surgery.

Background— Graft patency is a fundamental predictor of long-term survival after coronary artery bypass surgery. Left and right internal thoracic artery (arterial) graft patency has been shown to be superior to that of saphenous vein grafts. More recently, the radial artery has been used as an aortocoronary graft, but little is known about the midterm and long-term patency of this conduit. We performed a single-center prospective randomized trial comparing the angiographic patency of radial artery and saphenous vein aortocoronary bypass grafts at 5 years after surgery. Methods and Results— We enrolled 142 patients randomized at a single center to have either the radial artery or saphenous vein grafted to a stenosed branch of the native left circumflex coronary artery. The primary end point was angiographic graft patency 5 years postoperatively. At 5 years, 134 patients were alive and eligible for reangiography (5-year survival, 94.4%). Angiography was performed in 103 patients (77%); 98.3% of radial artery grafts and 86.4% of saphenous vein grafts were patent ( P =0.04). Graft narrowing occurred in 10% of patent radial artery grafts and 23% of patent saphenous vein grafts ( P =0.01). Conclusions— Radial artery aortocoronary bypass grafts to a stenosed branch of the circumflex coronary artery have an excellent patency rate at 5 years. This was significantly better than the patency rate for saphenous vein grafts and comparable to reported patency rates for internal thoracic artery grafts.

Background— Tetrahydrobiopterin (BH 4 ) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH 4 levels are altered in human atherosclerosis and the importance of BH 4 bioavailability in determining endothelial function and oxidative stress remain unclear. We sought to define the relationships between plasma and vascular biopterin levels in patients with coronary artery disease and to determine how BH 4 levels affect endothelial function, eNOS coupling, and vascular superoxide production. Methods and Results— Samples of saphenous veins and internal mammary arteries were collected from 219 patients with coronary artery disease undergoing coronary artery bypass grafting. We determined plasma and vascular levels of biopterins, vasomotor responses to acetylcholine, and vascular superoxide production in the presence and absence of the eNOS inhibitor N G -nitro- l -arginine methyl ester. High vascular BH 4 was associated with greater vasorelaxations to acetylcholine ( P 4 was associated with lower vasorelaxations in response to acetylcholine ( P P 4 was associated with reduced total and N G -nitro- l -arginine methyl ester–inhibitable superoxide, suggesting improved eNOS coupling. Finally, plasma but not vascular biopterin levels were correlated with plasma C-reactive protein levels ( P Conclusions— An inverse association exists between plasma and vascular biopterins in patients with coronary artery disease. Vascular but not plasma BH 4 is an important determinant of eNOS coupling, endothelium-dependent vasodilation, and superoxide production in human vessels, whereas plasma biopterins are a marker of systemic inflammation.

Background— Mutations in the FOXC2 gene cause lymphedema distichiasis, an inherited primary lymphedema in which a significant number of patients have varicose veins. Because lymphedema distichiasis is believed to be caused by lymphatic valve failure (reflux), and FOXC2 is highly expressed on venous valves in mouse embryos, we tested the hypothesis that FOXC2 mutations may be linked to venous valve failure and reflux. Methods and Results— The venous system of the leg was investigated with Duplex ultrasound. Pathological reflux was recorded by color Duplex ultrasound in all 18 participants with a FOXC2 mutation, including 3 without lymphedema. Every participant with a mutation in FOXC2 showed reflux in the great saphenous vein (n=18), compared with only 1 of 12 referents (including 10 family members; P Conclusions— FOXC2 is the first gene in which mutations have been strongly associated with primary venous valve failure in both the superficial and deep veins in the lower limb. This gene appears to be important for the normal development and maintenance of venous and lymphatic valves.

A 65-year-old woman was admitted with shortness of breath and chest pain. A computed tomographic angiogram of the chest performed for suspected pulmonary embolism showed a filling defect in the left atrium, concerning for a tumor or thrombus (Figure, A). Transesophageal echocardiography revealed a large mobile mass in the left atrium attached to the interatrial septum with a very short pedicle (Figure, B and Movie I in the online-only Data Supplement). The patient had a history of surgical patent foramen ovale closure with a Prolene suture, mitral valve repair, and saphenous vein bypass graft to the right coronary …

Supplemental Digital Content is available in the text., Background— Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. Methods and Results— Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle–induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. Conclusions— These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.