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.

Numerical simulation on the effects of drug eluting stents at different Reynolds numbers on hemodynamic and drug concentration distribution.

BACKGROUND: The changes of hemodynamics and drug concentration distribution caused by the implantation of drug eluting stents (DESs) in curved vessels have significant effects on In-Stent Restenosis. METHODS: A 3D virtual stent with 90° curvature was modelled and the distribution of wall shear stress (WSS) and drug concentration in this model were numerically studied at Reynolds numbers of 200, 400, 600, 800. RESULTS: The results showed that (1) the intensity of secondary flow at the 45° cross-section was stronger than that at the 90° cross-section; (2) As the Reynolds number increases, the WSS decreases. When the Reynolds number reaches 600, the low-WSS region only accounts for 3% of the total area. (3) The effects of Reynolds number on drug concentration in the vascular wall decreases in proportionally and then the blood velocity increased 4 times, the drug concentration in the vascular wall decreased by about 30%. (4) The size of the high drug concentration region is inversely proportional to the Reynolds number. As the blood velocity increases, the drug concentration in the DES decreases, especially at the outer bend. CONCLUSIONS: It is beneficial for the patient to decrease vigorous activities and keep calm at the beginning of the stent implantation, because a substantial amount of the drug is released in the first two months of stent implantation, thus a calm status is conducive to drug release and absorption; Subsequently, appropriate exercise which increases the blood velocity is helpful in decreasing regions of low-WSS.

Acute thrombosis of drug eluting stent following protamine: a case report.

Reversal of anticoagulant effect of heparin to treat coronary perforation after bare metal stent implantation is an accepted practice. However this practice may not be safe following drug eluting stent implantation. We report a case of acute stent thrombosis following protamine administration for coronary perforation after drug eluting stent implantation.

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.

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.

Cocaine-induced very late stent thrombosis.

Cocaine misuse is a known cause of acute coronary syndrome (ACS). Management of these patients has always been a challenge due to medication compliance and eventual risk of stent thrombosis. However, even cocaine misusers who are compliant with dual antiplatelet therapy have been reported to have stent thrombosis. All cases of cocaine-induced stent thrombosis reported in the literature have occurred within first year of stent placement (acute, subacute or late). We report a first case of very late stent thrombosis in a 54-year-old active cocaine misuser who presented with ST segment elevation myocardial infarction, which was successfully managed with percutaneous transluminal coronary angioplasty. A review of all the reported cases of cocaine-induced stent thrombosis is also discussed. Given the high mortality associated with stent thrombosis, treatment option for cocaine misusers presenting with ACS should be conservative when possible. If percutaneous coronary intervention is needed, bare metal stent should be preferred.

Adverse effects of high dose aspirin on platelet adhesion to experimental autogenous vein grafts.

Prostacyclin (PGI2) production and platelet adhesion were studied in veins grafted into the arterial system of rabbits. Animal groups consisted of: no treatment; low dose aspirin (ASA) (0.5 mg . kg-1 X 24 h-1) plus dipyridamole (2 mg . kg-1 X 6 h-1); high dose ASA (40 mg . kg-1 X 24 h-1) plus dipyridamole (2 mg . kg-1 X 6 h-1); dipyridamole (2 mg . kg-1 X 6 h-1) alone. Results showed that vein grafts from animals treated with high dose ASA plus dipyridamole produced significantly less PGI2 than the other three groups (p less than 0.05 compared with the dipyridamole group; p less than 0.01 compared with the other two groups). In addition, there was significantly greater platelet deposition on the vein grafts from this high dose ASA group as compared to the low dose ASA group (p less than 0.05). By contrast, animals treated with dipyridamole alone had significantly less platelet deposition compared to both the control and high dose ASA groups (p less than 0.05). High dose ASA given to prevent thrombotic occlusion following coronary artery bypass grafting may, by reducing PGI2, result in enhanced platelet deposition. This in turn is likely to increase intimal hyperplasia as has been demonstrated previously with high dose ASA. Clinical studies, which have shown the early anti-thrombotic benefits of high dose ASA plus dipyridamole, have not measured graft intimal thickness. Since this process is an important cause of graft narrowing, ASA, in high dose, may adversely affect long-term graft survival.

Aprotinin in aortocoronary bypass surgery: increased risk of vein-graft occlusion and myocardial infarction? Supportive evidence from a retrospective study.

To assess the thrombotic risk of aprotinin in aortocoronary bypass surgery, we retrospectively analyzed the results of a trial, originally designed to compare the effects of one-year treatment with various antithrombotic drugs in the prevention of vein-graft occlusion. Graft patency at one year was assessed by angiography. Myocardial infarction, thromboembolism, major bleeding, and death were clinical endpoints. Of 948 randomized patients, 42 received aprotinin, all enrolled by one of the participating centres. Occlusion rates of distal anastomoses were 20.5% in the aprotinin group and 12.7% in the non-aprotinin group (p = 0.091). The proportions of patients with occluded grafts were 44.1% versus 26.3% (p = 0.029). Perioperative myocardial infarction occurred in 14.3% and 7.0%, respectively (p = 0.12). Mean postoperative blood loss was 451 ml in the aprotinin group compared with 1039 ml in the non-aprotinin group (p < 0.0001). Mean transfusion requirements were 1.1 U versus 2.1 U of red blood cells (p = 0.004). Aprotinin decreases blood loss and transfusion requirement. Our data suggest that this benefit may be associated with a reduction of graft patency and an increased risk of myocardial infarction.

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.

A new manifestation and treatment alternative for heparin-induced thrombosis.

We treated a coronary artery bypass patient whose postoperative course was complicated by heparin-induced thrombocytopenia and resultant pulmonary artery and saphenous vein graft thromboses. The pulmonary thromboemboli were found first, and pulmonary blood flow was restored with intravenously administered tissue plasminogen activator (tPA). A short time later, the vein grafts were found to be occluded, and we subsequently performed multivessel percutaneous transluminal coronary angioplasty (PTCA) using tPA as an adjuvant to oral warfarin sodium therapy with excellent results. We conclude that heparin-induced thromboses in the pulmonary arteries are amenable to thrombolytic therapy, including tPA, whereas this regimen appears to have little effect on saphenous vein grafts. We also found that a combination of warfarin and thrombolytic therapy is an alternative regimen for heparin-intolerant patients who require PTCA.

Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. A multicenter, randomized, double-blind, placebo-controlled study.

The purpose of this study was to evaluate the efficacy and safety of aprotinin in a U.S. population of patients undergoing coronary artery bypass grafting. Early vein graft patency rates were assessed by ultrafast computed tomography. A total of 216 patients at five centers were randomized to receive either high-dose aprotinin or placebo during the operation; 151 patients underwent primary operation, and 65 underwent repeat procedures. Total blood product exposures in the primary group were 2.2 per patient receiving aprotinin as compared with 5.7 per patient receiving placebo (p = 0.010). The repeat group had 0.3 exposures per patient receiving aprotinin as compared with 10.7 per patient receiving placebo (p = < 0.001). Consistent reductions in the percent of patients requiring donor red blood cells and in the number of units of platelets, fresh frozen plasma, and cryoprecipitate required were associated with the use of aprotinin in both primary and repeat groups. Mortality was 5.6% in the aprotinin group and 3.7% in the placebo group (p = 0.517). In the primary group, clinical diagnoses of myocardial infarction were made in 8.9% of patients receiving aprotinin as compared with 5.6% of the patients receiving placebo (p = 0.435). In the repeat group, infarctions occurred in 10.3% of patients receiving aprotinin and 8.3% of patients receiving placebo (p = 1.000). Secondary analysis of electrocardiograms and available enzyme data showed no significant difference in infarction rates between the treatment groups. There was no difference in clinically significant renal dysfunction. The early vein graft patency rates were 92.0% in the aprotinin group and 95.1% in the placebo group (p = 0.248). In this study, aprotinin was effective in reducing bleeding and blood product transfusion rates, and its use was not associated with an increase in complications. An adverse effect on early vein graft patency rates was not demonstrated, but the number of grafts assessed was insufficient for absolute conclusions in this regard.

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.

No difference among modern contrast media's effect on neointimal proliferation and restenosis after coronary stenting in pigs.

RATIONALE AND OBJECTIVES: Recent clinical trials indicate that the choice of radiographic contrast media (CM) may influence the late outcome of coronary interventions. This might be explained by the different effects of various CM on neointimal proliferation. METHODS: The effect of a 1-hour incubation of bovine aortic smooth muscle cells in ioxaglate or iopromide solution on in vitro cell division was tested. Furthermore, in 12 pigs randomized into 3 groups (iopromide, ioxaglate, and iosimenol; a novel nonionic dimer), coronary angiography was performed followed by implantation of stents. After 28 days, restenosis was assessed by quantitative angiography and histomorphometry. RESULTS: Compared with saline, CM did no change cell counts up to 15 days after incubation. Baseline parameters in the pigs indicated no difference between the test groups. After 28 days, the test groups showed no significant differences in the parameters characterizing in-stent restenosis. CONCLUSIONS: Under the experimental conditions iopromide, ioxaglate, and iosimenol had no or very similar direct or otherwise mediated effect on cell proliferation and restenosis.

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.

Erythropoietin therapy improves graft patency with no increased incidence of thrombosis or thrombophlebitis.

BACKGROUND: Recombinant human erythropoietin (rHuEPO) for the treatment of severe anemia in patients with end-stage renal disease (ESRD) is suggested to improve rehabilitation and cognitive function. The criticism is the alleged increase in the failure rate of arteriovenous (AV) access grafts and in the incidence of lower-extremity deep venous thrombophlebitis (DVT). This study addressed the longevity of AV grafts and the incidence of DVT. STUDY DESIGN: We reviewed 481 consecutive patients with ESRD on dialysis with PTFE access grafts, including 173 consecutive patients who were receiving rHuEPO and 308 who were not. rHuEPO was administered during dialysis titrated against the hematocrit to achieve a level of 33% to 38%. The rHuEPO-ESRD group included 173 patients with a mean age of 58 years, including 54% women; 84% of the grafts were in the upper extremity. In the control group of 308 patients, 57% were women. Diabetes and hypertension were controlled in both groups. RESULTS: Forty-five of 173 rHuEPO patients (26%) experienced graft thrombosis within 1 year. Among 88 episodes of thrombosis, 14 patients experienced multiple episodes. Primary patency was 8.9 months; secondary patency was 11.2 months. In the control population, 95 of 308 patients (31%) experienced graft thrombosis; 27 patients had multiple episodes. Primary patency was 7.8 months and secondary patencywas 9.8 months. The hematocrit improved from a mean of 23% in the control group to 34% in the treated rHuEPO group. Two patients in the control group and one patient receiving rHuEPO experienced DVT in the lower extremity. CONCLUSIONS: Primary and secondary AV fistula patency rates were improved by 10% with rHuEPO. rHuEPO did not increase DVT.