Background and purpose: 1-methylnicotinamide (MNA) has been considered to be an inactive metabolite of nicotinamide. Here we assessed the anti-thrombotic activity of MNA in vivo. Experimental approach: Antithrombotic action of MNA was studied in normotensive rats with extracorporeal thrombus formation (thrombolysis), in renovascular hypertensive rats with intraarterial thrombus formation (arterial thrombosis) and in a venous thrombosis model in rats (venous thrombosis). Key results: MNA (3-100 mg kg À1 ) induced a dose-dependent and sustained thrombolytic response, associated with a rise in 6-keto-PGF 1a in blood. Various compounds structurally related to MNA were either inactive or weaker thrombolytics. Rofecoxib (0.01-1 mg kg À1 ), dose-dependently inhibited the thrombolytic response of MNA, indomethacin (5 mg kg À1 ) abolished it, while L-NAME (5 mg kg À1 ) were without effect. MNA (3-30 mg kg À1 ) also reduced arterial thrombosis and this effect was abrogated by indomethacin (2.5 mg kg À1 ) as well as by rofecoxib (1 mg kg À1 ). MNA, however, did not affect venous thrombosis. In vitro MNA did not modify platelet aggregation nor induce vasodilation. Conclusions and implications: MNA displayed a profile of anti-thrombotic activity in vivo that surpasses that of closely related compounds. MNA inhibited platelet-dependent thrombosis by a mechanism involving cyclooxygenase-2 and prostacyclin. Our findings suggest that endogenous MNA, produced in the liver by nicotinamide N-methyltransferase, could be an endogenous activator of prostacyclin production and thus may regulate thrombotic as well as inflammatory processes in the cardiovascular system.

BACKGROUND The arrhythmic role of the left atrial appendage (LAA) has been implicated in the maintenance of persistent atrial fibrillation. LAA isolation with catheter ablation has been successful but is limited by the risk of tamponade and electromechanical dissociation with the potential for LAA thrombus formation. OBJECTIVE To assess whether LAA ligation results in LAA electrical isolation. METHODS A total of 68 patients with contraindication or intolerance to oral anticoagulation therapy underwent LAA ligation with the LARIAT suture delivery device. Patients had unipolar [n = 30 (44%)] or bipolar [n = 38(56%)] voltage measurements pre- and post-LAA ligation. RESULTS All 68 patients underwent successful LAA ligation. There was a statistically significant reduction in the mean LAA voltage from pre-ligation (unipolar pre-ligation voltage 1.1 ± 0.53 mV; bipolar pre-ligation voltage 4.7 ± 2.83 mV) to post-ligation (unipolar post-ligation voltage 0.3 ± 0.38 mV; bipolar post-ligation voltage 0.6 ± 0.27 mV). Ninety-four percent of the patients had a reduction in the LAA voltage after the closure of the snare, with 10 of 30 (33%) of the patients having complete elimination of LAA voltage with the initial tightening of the suture. Pacing from the LAA after the closure of the snare resulted in lack of capture of the left atrium in 28 of 31 patients. CONCLUSIONS The snare closure of the LAA using the LARIAT device produces an acute reduction in the LAA voltage and inhibits the capture of the left atrium during LAA pacing. Future studies are needed to determine whether LAA ligation affects atrial fibrillation burden.

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IntroductionLeft atrial appendage closure (LAAC) with LARIAT offers an alternative to oral anticoagulation (OAC) for patients with atrial fibrillation. The aim of this study was to present long-term clinical outcomes of LAAC in these patients (AF).Material and methodsA prospective, single-center study was performed in 139 patients undergoing LAAC with Lariat. Thromboembolic events, severe bleeding and mortality rate were recorded. The reduction in risk of thromboembolism and bleeding after LAAC was calculated.ResultsThe mean CHADS2-score was 1.8 ± 1.0, mean CHA2DS2-VASc score was 2.9 ± 1.6 and HAS-BLED score was 3.1 ± 1.1. After 428.4 patient-years of follow-up (mean 4.2±1.0 years), the thromboembolism rate was 0.6% with a calculated thromboembolism risk reduction of 81%. The severe bleeding rate was 0.8%; calculated bleeding risk reduction was 78%. The overall mortality rate was 1.6%.ConclusionsLong-term outcomes show that LAAC with Lariat is a safe and effective treatment for stroke prevention and bleeding risk reduction in AF patients with a high level of underlying risk.

Background: Patients surviving an initial stroke present a significantly increased risk for further strokes. Left atrial appendage closure (LAAC) became an alternative treatment to pharmacological therapy for stroke prevention in atrial fibrillation (AF) patients. Objective: To evaluate the long-term efficacy of LAAC in primary and secondary stroke prevention in patients with AF. Methods: This retrospective study enrolled 139 patients following LAAC who were divided into 2 groups: 37 patients with prior stroke (Stroke Group) and 102 patients without stroke (Control Group). Overall, cumulative follow-up was 530.1 patient-years. Results: Mean CHADS2, CHA2DS2-VASc scores, and HAS-BLED score were higher in patients with prior stroke compared to patients without stroke (3.0 vs. 1.4, p < 0.0001 and 4.6 vs. 2.3, p < 0.0001, 4.0 vs. 2.8, p < 0.0001, respectively). There were no significant differences between other patient factors (sex, heart failure, hypertension, previous stroke/transient ischemic attack, peripheral vascular disease), which may increase the risk of thromboembolism based on the CHA2DS2-VASc score. Average follow-up was 51.3 months in patients with previous stroke and 50 months in patients without previous stroke. Thromboembolic event rate was 0.8 vs. 0.5 (p = 0.72), bleeding event rate was 0 years vs. 1.4 (p = 0.25), and mortality rates were 0.8 vs. 2.1 (p = 0.38) between the Stroke Group and the Control Group. The estimated reductions in thromboembolic and bleeding risks were 89 and 100%, respectively, in Stroke Group, and 91 and 81%, respectively, in Control Group. Conclusion: Patients with prior stroke may be the preferred group for LAAC regardless of the presence or absence of contraindications for anticoagulant therapy.

Results LAA occlusion was performed in 139 patients. At the time of the procedure, 82 patients were aged 64 years or younger, 44 patients were aged 65 to 74 years, and 13 patients were aged 75 or older (P <0.001). Patients aged 75 years

1-Methylnicotinamide (MNA), a major endogenous metabolite of nicotinamide, possesses anti-thrombotic and anti-inflammatory activity, and reverses endothelial dysfunction. In the present work, we investigated whether such a vasoprotective profile of MNA activity affords anti-diabetic action in rats. Diabetes was induced by streptozotocin (STZ) in Sprague-Dawley rats. Eight weeks after STZ injection in untreated or MNA-treated rats (100 mg kg(-1) daily), development of diabetes (plasma concentrations of fasting and non-fasting glucose, HbA(1c), peptide C), development of oxidant stress (lipid peroxidation, carbonylation of plasma proteins), as well as NO-dependent endothelial function in aorta, coronary and mesenteric vessels were analyzed. Finally, the effect of chronic treatment with MNA on long-term survival of diabetic rats was determined. Chronic treatment with MNA profoundly lowered fasting glucose concentrations in plasma, displayed mild effects on plasma HbA(1c) and peptide C concentrations, while having no effects on non-fasting glucose. On the other hand, MNA treatment considerably lowered lipid peroxidation, protein carbonylation, completely prevented impairment of endothelium-dependent vasodilatation in the aorta that was mediated entirely by NO, but failed to affect endothelial function in resistant vessels, which was mediated only partially by NO. Most importantly, chronic treatment with MNA prolonged the long-term survival of diabetic rats. In conclusion, MNA displayed a significant anti-diabetic effect that may be linked to its vasoprotective activity.

Background Left atrial appendage closure (LAAC) with LARIAT has emerged as one of the alternatives to oral anticoagulation (OAC) in patients with nonvalvular atrial fibrillation (AF). Our aim was to study long‐term outcomes in patients undergoing LARIAT procedure. Methods We analyzed patients screened for LARIAT device in four centers between December 2009 and June 2012. Out of these, patients who didn't undergo LAAC with the LARIAT device due to unfavorable LAA morphology and other preprocedural contraindications were included in control group. We analyzed thromboembolism, bleeding events, and mortality between LAA and control group. Results About 153 patients were screened. Out of these, 108 (70.6%) patients underwent LARIAT placement (LAA arm) and 45 (29.4%) excluded patients were included in control arm. There were no differences in CHADS2 and CHA2DS2‐VASc score. Mean HAS‐BLED score was significantly higher in the LARIAT group (3.5 ± 1.06 vs 3.09 ± 1.22, P = .04). Mean follow‐up time (in years) was 6.56 ± 0.84 in LAA and 6.5 ± 1.26 in control arm. During follow‐up period, the LARIAT group was associated with significantly less thromboembolic events (1.9% vs 24%, P < .001), bleeding events (9.2% vs 24.4%, P = .03), and mortality (5.6% vs 20%, P = .01) as compared with the control group. Conclusions Long‐term data from routine clinical practice from our study suggests that LAA exclusion with LARIAT device is an effective treatment in management of nonvalvular AF patients with high risk of stroke, bleeding, and mortality. Further randomized trials, such as aMAZE, will provide more insight in this expanding field.