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Inflammatory mechanisms are involved in initiation and progression of atherosclerotic lesions. Previous studies demonstrated antiinflammatory and consecutive antiatherosclerotic effects of the adenosine analogue 3-Deazaadenosine (c(3) Ado) on early lesion development. The present study evaluated the effect of long-term administration of c(3) Ado in a mouse model of advanced atherosclerosis. Apolipoprotein E-deficient mice (age, 35 weeks; n = 31) with already established advanced atherosclerotic lesions were fed either a diet supplemented with c Ado or a regular chow diet for 21 weeks. Treatment resulted in a significant reduction of serum homocysteine levels. Lesion size and lesion morphology, such as frequency of intraplaque hemorrhage, size of necrotic cores, thickness of fibrous caps, and macrophage content within the plaque, were not different between the groups. Lesion calcification, expression of alpha-actin, and intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, were inhibited by treatment with c(3) Ado. We could not detect any effect on serum concentrations of interleukin-10 (IL-10) and interleukin-1beta (IL-1beta) or on soluble adhesion molecules intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Electromobility shift assays of protein extracts isolated from aortas did not demonstrate different binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) after treatment with c Ado. Long-term treatment with the adenosine analogue 3-Deazaadenosine did not show significant effects on progression and stability of advanced atherosclerotic lesions in older apolipoprotein E-deficient mice. A potential antiatherosclerotic effect of c(3)Ado (eg, mediated through inhibition of adhesion molecules) might therefore be limited to prevention of early lesion formation and does not seem to play a relevant role in modifying advanced atherosclerotic disease.

Background: Patients undergoing maintenance hemodialysis (HD) with atrial fibrillation (AF) are at increased risk of ischemic stroke and bleeds. At present, vitamin K antagonists, e.g. warfarin, are predominantly used for anticoagulation in this patient population. In such patients, limited data are available on the use of non-vitamin K oral anticoagulants. Dabigatran etexilate (DE) is mainly (85%) renally eliminated, thus its half-life is prolonged in renal impairment. It has been established that 4-hour HD can remove up to 60% of dabigatran from the plasma. The aim of the presented study is to evaluate the dose-exposure relationship for DE in HD patients considering different dosages and HD modalities by pharmacokinetic modeling. The resulting data could inform DE dose selection in future clinical trials. Method: We compared modeled DE exposure at once- and twice-daily doses of 75 mg, 110 mg, 150 mg in HD patients from pre- and post-dialysis dosing, with values simulated from AF patients in the RE-LY ® trial, based on a previously characterized pharmacometric model. Furthermore, variations in non-renal clearance, and several dialysis settings were simulated. Exposure (area under the curve, AUC) was compared to those from typical clinical HD settings. Results: Twice-daily DE doses showed a 1.5- to 3.3-fold increase in AUC of dabigatran compared with a typical RE-LY ® patient. A once-daily dose of 75 mg given after dialysis or 110 mg given before dialysis achieved an AUC comparable (-13.3 and +4.4%, respectively) to typical RE-LY ® patients. Of the patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤ 31% change). Duration of dialysis, dialysate and blood flow rate changed exposure by ≤14%. Conclusion: Twice-daily dosing of all DE doses tested in this simulation resulted in exposures clearly above what can be seen in typical RE-LY ® patients and thus might not be recommendable, although this is based on modeling only and the clinical impact is unknown. In patients undergoing maintenance HD, DE 75 mg once daily (given after dialysis) or 110 mg once daily (given before dialysis), resulted in exposure comparable to that simulated in typical RE-LY ® patients.

Objective— Inflammatory mechanisms are involved in atherosclerotic plaque rupture and subsequent thrombin formation. Thrombin not only plays a central role in thrombus formation and platelet activation, but also in the induction of inflammatory processes. We assessed the hypothesis that melagatran, a direct thrombin inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions. Methods and Results— Melagatran (500 μmol/kg/d) or control diet was administered to apolipoprotein E–deficient mice (n=54) with advanced atherosclerotic lesions. Treatment reduced lesion progression in brachiocephalic arteries ( P P P 2 versus 126 819±51730 μm 2 ; P P P P Conclusions— The direct thrombin inhibitor melagatran reduces lesion size and may promote plaque stability in apolipoprotein E–deficient mice, possibly through reduced activation of proinflammatory transcription factors and reduced synthesis of MMP-9.

In recent years, transcatheter aortic valve implantation has become an emerging alternative for high-risk patients with severe aortic stenosis. Midterm outcomes compare favorably with conventional open heart surgery in selected patients. A promising new indication in this technology could be the interventional treatment of degenerated bioprostheses. Here, we report about a “valve in valve” implantation of the CoreValve prosthesis (Medtronic, Inc; Minneapolis, Minn) in a degenerative, Epic stented biological prosthesis (St Jude Medical; St Paul, Minn) in a patient with acute aortic regurgitation. A male patient aged 79 years with previous surgical valve replacement 5 years ago was admitted to the hospital with acute dyspnea (New York Heart Association class III to IV). At physical examination, a diastolic murmur (grade 4) and a blood pressure of 130/50 mm Hg were noted. Transthoracic and transesophageal echocardiography showed degeneration of the 23-mm Epic stented bioprosthesis with severe central aortic regurgitation …