Long noncoding RNA H19-derived miR-675 aggravates restenosis by targeting PTEN.

Restenosis is mainly attributed to excessive proliferation of vascular smooth muscle cells (VSMCs). Noncoding RNAs have been identified as key regulators of diverse pathological processes. We reported that the long noncoding RNA H19 (LncRNA H19) and LncRNA H19-derived microRNA (miR-675) are overexpressed in neointima of balloon-injured artery. Thus, the present study aims to evaluate the role of LncRNA H19 on VSMCs proliferation. To determine the changes of LncRNA H19 and miR-675 expression in the injured arterial wall, the standard rat carotid artery balloon injury model was used. In vivo studies demonstrated that both LncRNA H19 and miR-675 were upregulated after vascular injury. Correlation analysis revealed a positive relationship between LncRNA H19/miR-675 and the ratio of intima to media. Gain-of-function studies showed that the overexpression of LncRNA H19 accelerated T/G HA-VSMC proliferation in vitro. We further validated that PTEN is the target gene of miR-675 as demonstrated by luciferase assay. Finally, the results of the rescue experiment indicated that LncRNA H19 promoted the proliferation of T/G HA-VSMC in a miR-675-dependent manner. This finding not only reveal a novel function of LncRNA H19, but also has important diagnostic and therapeutic implications in the setting of restenosis and perhaps other vascular proliferative disorders as well.

Heparin-Induced Thrombocytopenia Associated with a Heparin-Bonded Stent Graft.

We describe a case of heparin-induced thrombocytopenia (HIT) in association with heparin-bonded stent grafts. A 61-year-old man with claudication secondary to a left superficial femoral artery (SFA) occlusion was treated with 2 heparin-bonded polytetrafluorethylene (hep-PTFE) grafts. Despite the use of antiplatelet medication, he presented with thrombosed hep-PTFE grafts 1 week after initial treatment. An additional hep-PTFE graft was placed at the SFA origin because of migration of the first graft. He was discharged on anticoagulation; however, he presented again 2 weeks later with recurrent SFA thrombosis and a platelet count of 60,000, raising suspicion for HIT. All exogenous forms of heparin were discontinued, and he was started on an alternative anticoagulant. The patient returned again 5 days after being discharged with recurrent symptoms of acute limb ischemia. He underwent a left femoropopliteal artery bypass with autogenous conduit and removal of the grafts. He has since had an uneventful recovery. We believe HIT should be considered as a potential cause of hep-PTFE graft thrombosis. Diagnosis and management of these patients is complex and may require explantation of the graft.

Heme oxygenase-1 alleviates cigarette smoke-induced restenosis after vascular angioplasty by attenuating inflammation in rat model.

Cigarette smoke is not only a profound independent risk factor of atherosclerosis, but also aggravates restenosis after vascular angioplasty. Heme oxygenase-1 (HO-1) is an endogenous antioxidant and cytoprotective enzyme. In this study, we investigated whether HO-1 upregulating by hemin, a potent HO-1 inducer, can protect against cigarette smoke-induced restenosis in rat's carotid arteries after balloon injury. Results showed that cigarette smoke exposure aggravated stenosis of the lumen, promoted infiltration of inflammatory cells, and induced expression of inflammatory cytokines and adhesion molecules after balloon-induced carotid artery injury. HO-1 upregulating by hemin treatment reduced these effects of cigarette smoke, whereas the beneficial effects were abolished in the presence of Zincprotoporphyrin IX, an HO-1 inhibitor. To conclude, hemin has potential therapeutic applications in the restenosis prevention after the smokers' vascular angioplasty.

Anti-platelet factor 4/heparin antibodies in patients with impaired graft function after liver transplantation.

BACKGROUND: Heparin, the standard perioperative anticoagulant for the prevention of graft vessel thrombosis in patients undergoing liver transplantation (LT), binds to the chemokine platelet factor 4 (PF4). Antibodies that are formed against the resulting PF4/heparin complexes can induce heparin-induced thrombocytopenia. LT is a clinical situation that allows the study of T-cell dependency of immune responses because T-cell function is largely suppressed pharmacologically in these patients to prevent graft rejection. OBJECTIVES: To investigate the immune response against PF4/heparin complexes in patients undergoing LT. PATIENTS AND METHODS: In this prospective cohort study, 38 consecutive patients undergoing LT were systematically screened for anti-PF4/heparin antibodies (enzyme immunoassay and heparin-induced platelet aggregation assay), platelet count, liver function, and engraftment. RESULTS: At baseline, 5 (13%) of 38 patients tested positive for anti-PF4/heparin IgG (non-platelet-activating) antibodies. By day 20, an additional 5 (15%) of 33 patients seroconverted for immunoglobulin G (two platelet-activating) antibodies. No patient developed clinical heparin-induced thrombocytopenia. Two of six patients with graft function failure had anti-PF4/heparin IgG antibodies at the time of graft function failure. Graft liver biopsy samples from these patients showed thrombotic occlusions of the microcirculation. CONCLUSIONS: Anti-PF4/heparin IgG antibodies are generated despite strong pharmacologic suppression of T cells, indicating that T cells likely have a limited role in the immune response to PF4/heparin complexes in humans.

In vitro effects of lidocaine hydrochloride on coronary artery bypass grafts.

AIM: Coronary artery bypass grafting (CABG) is one of the most common procedures performed to improve blood supply to myocardium. The characteristics of grafts, mechanical stress and pharmacological agents have substantial influence on the short and long term graft patency. Lidocaine is among the most frequently used antiarrhythmic agents perioperatively. The aim of this study was to evaluate the in vitro effects of lidocaine on internal mammarian artery (IMA), radial artery (RA) and saphenous vein (SV) grafts. METHODS: Using standard tissue bath techniques, responses to increasing concentrations of lidocaine hydrochloride were obtained, in segments of IMA, RA and SV grafts. Twenty patients were enrolled in the study with a total number of 48 grafts (16 for IMA, RA and SV grafts each). In vitro lidocaine concentrations between 10(-9)M and 10(-3.5)M were studied to represent therapeutic plasma concentration of 1.5-5 mcg/mL. RESULTS: In IMA and RA grafts, lidocaine hydrochloride caused vasodilatation (40.5±1.9% and 39.1±2.6 % respectively) at concentrations between 10(-9) to 10(-7.5) M while causing a dose dependent vasoconstriction response at concentrations above 10(-7.5) M. In SV graft samples, lidocain hydrochloride caused vasodilatation (24.4±1.9 %) at concentrations between 10(-9) to 10(-7) M while causing dose dependent vasoconstriction at concentrations above 10(-7) M. For vasoconstriction effect, mean±SD values for E(max) were calculated as: 120.1±6.6% in IMA, 83.35±5.06% in RA, and 154.0±13.8% in SV. The vasoconstriction in the SV samples was higher than in the RA and IMA. The mean ±SD LogEC(50) values were -5.15±0.27, -5.76±0.11 and -5.56±0.19 for SV, IMA and RA grafts respectively.) There was a statiscally significant differences in the Log EC(50) values between SV, IMA and RA (P<0.005) CONCLUSION: Based on the results of our study, we conclude that, increasing doses of lidocaine in the perioperative period may cause vasospasm in IMA, RA and SV grafts. Thus, avoiding high doses may have a role in improving perioperative and long term mortality.

Occlusion of modified Blalock-Taussig shunt after clopidogrel cessation.

It has been suggested previously that rebound hypercoagulability may be responsible for morbidity and mortality following clopidogrel cessation in adults with acute coronary syndrome. We report a case of acute occlusion of a modified Blalock-Taussig shunt in an infant after clopidogrel discontinuation.

Recombinant factor VIIa affects anastomotic patency of vascular grafts in a rabbit model.

OBJECTIVE: Recombinant factor VIIa can decrease postoperative bleeding after cardiac surgery. However, the potential for recombinant factor VIIa to cause early vascular graft occlusion at the site of new vascular anastomoses has not been fully explored. We hypothesized that recombinant factor VIIa would cause a dose-dependent reduction in vascular graft patency in rabbits. METHODS: Reversed end-to-end interpositional vein grafts were sutured into the carotid artery of heparinized rabbits, and then recombinant factor VIIa (300 µg/kg, 90 µg/kg, or 20 µg/kg intravenously) or placebo was administered (n = 16/group). Graft patency was assessed at 24 hours using a vascular ultrasound probe. Factor VII activity levels were measured using a prothrombin time-based assay. In different rabbits, the patency of venous end-to-side anastomoses and simple carotid arterial repairs was assessed (recombinant factor VIIa, 300 µg/kg vs placebo, n = 8/group). Data were analyzed using Fisher's exact test, t tests, or analysis of variance. RESULTS: Physiologic variables (activated clotting time, hemoglobin, pH, Pao(2)) and vessel diameter were not different between groups. Vein graft patency was reduced (93.8%, 81.2%, 13.8%, and 6.3%) as factor VII activity levels increased (1.8 ± 0.4, 4.4 ± 2.1, 11.8 ± 4.7, and 23.6 ± 16.9 U/mL, respectively) with increasing doses of recombinant factor VIIa administered (0, 20, 90, and 300 µg/kg, respectively, P < .05). Patency in the arterial repairs and end-to-side venous grafts was also reduced in recombinant factor VIIa-treated rabbits (P < .05 for both). CONCLUSIONS: This study suggests that recombinant factor VIIa is associated with a dose-dependent increase in fresh vascular graft occlusion. Higher doses of recombinant factor VIIa may be associated with increased thrombotic outcomes.

Serious acute coronary thrombosis associated with heparin-induced thrombocytopenia in off-pump coronary artery bypass grafting.

A 72-year-old female underwent off-pump coronary bypass grafting one month after heparin exposure. Immediately after protamine administration, she developed hypotension due to acute graft failure. Grafting to left anterior descending branch was revised under intra-aortic balloon pump insertion and she was transferred to intensive care unit under stable hemodynamic condition. However, she gradually developed low cardiac output syndrome and echocardiography showed new onset of myocardial infarction. Coronary angiography on the first postoperative day revealed diffuse serious coronary thrombosis involving all grafts and grafted native coronary arteries. Emergent percutaneous coronary intervention (PCI) was performed for native vessels. Laboratory examination revealed severe progressive thrombocytopenia and she was clinically diagnosed as heparin-induced thrombocytopenia (HIT). After cessation of all heparins and alternative anticoagulation with argatroban, thrombocytopenia was improved and some of occluded grafts were recanalized. She was discharged on the 51st postoperative day. Acute graft thrombosis, especially caused by HIT, is a serious complication, which sometimes results in mortality. This is a successful case treated by PCI followed by an alternative anticoagulation.

Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study.

It has been suggested that preoperative fibrinogen plasma concentration is independently associated to postoperative blood loss after cardiac surgery. Theoretically, prophylactic infusion of fibrinogen concentrate may thus reduce postoperative bleeding, but this has not previously been investigated. Twenty elective coronary artery bypass graft (CABG) patients with preoperative plasma fibrinogen levels <3.8 g/l were included in a prospective randomised pilot study. Patients were randomised to receive an infusion of 2 g fibrinogen concentrate (FIB group) or no infusion before surgery (control group). Primary endpoint was safety with clinical adverse events and graft occlusion assessed by multi-slice computed tomography. Predefined secondary endpoints were postoperative blood loss, blood transfusions, haemoglobin levels 24 hours (h) after surgery, and global haemostasis assessed with thromboelastometry, 2 and 24 hours after surgery. Infusion of 2 g fibrinogen concentrate increased plasma levels of fibrinogen by 0.6 +/- 0.2 g/l. There were no clinically detectable adverse events of fibrinogen infusion. Computed tomography revealed one subclinical vein graft occlusion in the FIB group. Fibrinogen concentrate infusion reduced postoperative blood loss by 32% (565 +/- 150 vs. 830 +/- 268 ml/12 h, p=0.010). Haemoglobin concentration was significantly higher 24 h after surgery in the FIB group (110 +/- 12 vs. 98 +/- 8 g/l, p=0.018). Prophylactic fibrinogen concentrate infusion did not influence global postoperative haemostasis as assessed by thromboelastometry. In conclusion, in this pilot study preoperative fibrinogen concentrate infusion reduced bleeding after CABG without evidence of postoperative hypercoagulability. Larger studies are necessary to ensure safety and confirm efficacy of prophylactic fibrinogen treatment in cardiac surgery.

Extravascular perivenous fibrin support leads to aneurysmal degeneration and intimal hyperplasia in arterialized vein grafts in the rat.

BACKGROUND AND AIMS: External support of vein grafts by fibrin glue possibly prevents overdistension, vascular remodeling, and neointimal hyperplasia. Previous animal models of neointimal hyperplasia showed conflicting results. Here, long-term effects of external fibrin glue support were studied in a new rat model of jugular vein to abdominal aorta transposition. MATERIALS AND METHODS AND METHODS: In male Wistar rats (250-300 g) right jugular vein (1.0-1.5 cm) was transposed to the infrarenal aorta. Fibrin glue (0.25 ml) covered the vein before releasing the vascular clamps (n = 6). Control vein grafts were exposed directly to blood pressure. After 16 weeks vein grafts were pressure-fixed for histology. Intima thickness, luminal and intimal area were measured by planimetry and elastic fibers demonstrated by Elastica van Giesson staining. RESULTS: Intimal thickness (74.04 +/- 6.7 microm vs 1245 +/- 187 microm, control vs fibrin treatment; p < 0.001), intimal area (2517.16 +/- 355 mm(2) vs 18424 +/- 4927 mm(2), control vs fibrin treatment; p < 0.05) and luminal area (2184.75 +/- 347 mm(2) vs 7231.85 +/- 1782 mm(2), control vs fibrin treatment; p < 0.05) were significantly increased, elastic fibers in the vessel wall were diminished and the vessel wall infiltrated by mononuclear cells in fibrin glue supported veins. CONCLUSION: External support of vein grafts by fibrin glue leads to aneurysmal degeneration and intimal hyperplasia, thereby possibly jeopardizing long-term graft patency.

Is tranexamic acid safe in patients undergoing coronary endarterectomy?

BACKGROUND: Patients undergoing coronary endarterectomy during coronary artery bypass grafting (CABG) are at increased risk of perioperative myocardial infarction due to coronary intimal disruption. Data assessing the safety of the antifibrinolytic drug tranexamic acid (TA) in patients undergoing this procedure are lacking. METHODS: From September 1997 to December 1999, 221 patients underwent nonemergency primary CABG with endarterectomy of the right coronary artery alone in 149, the left anterior descending in 35, or both right and left anterior descending in 27. TA was administered intraoperatively to 87 patients (TA group: average total dose 62 +/- 4.4 mg/kg; range 20 to 109 mg/kg), and was not administered to 134 patients (No TA group). RESULTS: The patient characteristics of the 2 groups were similar. In-hospital mortality consisted of 2 patients in the TA group and 4 patients in the No TA group. Perioperative myocardial infarction rates were 2% and 5% in the TA and No TA groups, respectively (p = 0.49). The relative risk for any type of perioperative cardiac ischemic event in the TA group versus the No TA group was 0.77 (95% CI; 0.4, 1.2). Patients in the TA group had a significant reduction in postoperative chest tube drainage (685 versus 894 mL in the TA versus No TA groups, respectively) and in the use of fresh-frozen plasma (p = 0.03). CONCLUSIONS: These results suggest that the clinical effectiveness of tranexamic acid in reducing postoperative blood loss in patients undergoing coronary endarterectomy is not associated with a higher incidence of myocardial ischemia-related complications.

Influence of hormone replacement therapy on graft patency after femoropopliteal bypass grafting.

OBJECTIVE: Thromboembolic events are more frequent in women with established cardiovascular disease who are receiving hormone replacement therapy (HRT). The effect of HRT on the outcome of women undergoing infrainguinal bypass grafting is unknown. The purpose of this study was to estimate the influence of risk factors, in particular HRT, on the outcome of women undergoing femoropopliteal bypass grafting. METHODS: During a 5-year period (between 1993 and 1998), 131 femoropopliteal bypass graft procedures were performed in 106 women. The criteria prepared by the Ad Hoc Committee on Reporting Standards (Society for Vascular Surgery/North American Chapter of the International Society for Cardiovascular Surgery) were followed. Both univariate (Kaplan-Meier method) and multivariate analyses (Cox proportional hazards model) were used to determine the association among preoperative variables, graft patency, limb salvage, and survival. RESULTS: The average age of the patients was 66.4 years; 26% of the patients were receiving HRT. Indications for femoropopliteal bypass grafting were limb salvage (80%) and disabling claudication (20%). Autogenous vein was used in 48% of procedures, polytetrafluoroethylene (PTFE) in 49%, and PTFE-vein composite grafts in 3%. Distal popliteal anastomosis was above the knee in 52% and below the knee in 48%. Overall primary patency rate was 81% at 1 year, 65% at 3 years, and 56% at 5 years. Primary patency rates at 1, 3, and 5 years were 75%, 45%, and 23%, respectively, for HRT users and 84%, 72%, and 65%, respectively, for nonusers of HRT. Overall, cumulative 1- and 5-year limb salvage results were 96% and 92%, respectively, and long-term survival at 1, 3, and 5 years was 96%, 86% and 74%, respectively. With univariate and Cox regression analyses, HRT was identified as the only independent predictor of reduced primary graft patency (Kaplan-Meier method, log-rank test, P =.004; relative risk, 2.5; 95% CI, 1.3-4.8). Women receiving HRT who underwent a procedure with PTFE had the lowest primary graft patency rates (relative risk, 3.4; 95% CI, 1. 5-7.8; P =.006). CONCLUSIONS: Women undergoing femoropopliteal bypass graft procedures who are receiving HRT have significantly reduced primary graft patency rates. The risk of graft failure increases when prosthetic materials are used.

Multiple coronary artery graft occlusion in a fatal case of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening condition when immune-mediated platelet aggregation results in thromboembolic complications. A case is detailed of multiple saphenous vein graft thromboses and cardiac mural thrombi in a patient who died from complications of HIT.

Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial.

OBJECTIVE: We examined the effects of aprotinin on graft patency, prevalence of myocardial infarction, and blood loss in patients undergoing primary coronary surgery with cardiopulmonary bypass. METHODS: Patients from 13 international sites were randomized to receive intraoperative aprotinin (n = 436) or placebo (n = 434). Graft angiography was obtained a mean of 10.8 days after the operation. Electrocardiograms, cardiac enzymes, and blood loss and replacement were evaluated. RESULTS: In 796 assessable patients, aprotinin reduced thoracic drainage volume by 43% (P < .0001) and requirement for red blood cell administration by 49% (P < .0001). Among 703 patients with assessable saphenous vein grafts, occlusions occurred in 15.4% of aprotinin-treated patients and 10.9% of patients receiving placebo (P = .03). After we had adjusted for risk factors associated with vein graft occlusion, the aprotinin versus placebo risk ratio decreased from 1.7 to 1.05 (90% confidence interval, 0.6 to 1.8). These factors included female gender, lack of prior aspirin therapy, small and poor distal vessel quality, and possibly use of aprotinin-treated blood as excised vein perfusate. At United States sites, patients had characteristics more favorable for graft patency, and occlusions occurred in 9.4% of the aprotinin group and 9.5% of the placebo group (P = .72). At Danish and Israeli sites, where patients had more adverse characteristics, occlusions occurred in 23.0% of aprotinin- and 12.4% of placebo-treated patients (P = .01). Aprotinin did not affect the occurrence of myocardial infarction (aprotinin: 2.9%; placebo: 3.8%) or mortality (aprotinin: 1.4%; placebo: 1.6%). CONCLUSIONS: In this study, the probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion.