HomeCirculationVol. 131, No. 11Circulation: Clinical Summaries Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCirculation: Clinical SummariesOriginal Research Put Into Perspective for the Practicing Clinician Originally published17 Mar 2015https://doi.org/10.1161/CIR.0000000000000167Circulation. 2015;131:965–966Dabigatran and Rivaroxaban Use in Atrial Fibrillation Patients on HemodialysisDabigatran and rivaroxaban are new oral anticoagulants that are easier to administer than warfarin. Their use in dialysis patients is contraindicated because these medications are cleared by the kidney and the drugs can bioaccumulate to precipitate inadvertent bleeding. We followed a cohort of 29 977 hemodialysis patients with atrial fibrillation and found 5.9% of anticoagulated dialysis patients were started on dabigatrian or rivaroxaban. Our adjusted survival analysis associated dabigatran and rivaroxaban with a statistically significant 48% and 38% increased risk for serious bleeding referent to warfarin; furthermore, the excess risk of fatal bleeding was even larger. Compared with warfarin, the risk of death from hemorrhage was 78% greater with dabigatran and 71% greater with rivaroxaban, and these novel anticoagulants have no antidote that can quickly reverse the bleeding effect of these drugs. More dialysis patients are being started on dabigatran and rivaroxaban, even when their use is contraindicated; there are no studies to support that the benefits outweigh the risks of these drugs in end-stage renal disease. See p 972.Doing the Right Things and Doing Them the Right Way: Association Between Hospital Guideline Adherence, Dosing Safety, and Outcomes Among Patients With Acute Coronary SyndromeWe studied 39 291 patients from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry with non–ST-segment elevation acute coronary syndromes and found that guideline adherence and appropriate dosing of antithrombotic/antiplatelet agents appeared to provide independent and complementary information on in-hospital bleeding and mortality Thus, our data suggest that future research efforts should be directed to explore the feasibility of developing a standardized composite matrix incorporating both guideline adherence and proper dosing of high-risk medications that would have the best correlation with outcomes. See p 980.Temporal Trends in the Incidence and Prognosis of Aortic Stenosis: A Nationwide Study of the Swedish PopulationThe aging of Western populations can be expected to result in an increased burden of aortic valve stenosis, which is strongly correlated with age. However, declining age-adjusted incidence and mortality have recently been reported for other major heart diseases, and prospective studies of aortic stenosis are rare. Here, we used nationwide registers to study temporal trends in the incidence, clinical characteristics, and prognosis of aortic stenosis in the entire Swedish population between 1989 and 2009. We observed a decrease in age-adjusted incidence and improved prognosis for aortic stenosis to an extent similar to that for acute myocardial infarction and heart failure. These trends were broadly consistent across diverse subgroups (patients >75 and <75 years of age, inpatients and outpatients), and decreased mortality was seen both in patients who underwent valve replacement and in patients who did not. The median age at diagnosis increased over time, as expected, whereas the proportion of patients undergoing aortic valve replacement surgery increased in the elderly. Postoperative mortality at 30 days declined, despite the increased median age at diagnosis. Our study provides novel data suggesting that increased use of aortic valve replacement in the elderly and a reduction in perioperative mortality for aortic valve replacement, potentially in combination with improved risk factor control and cardiovascular therapy in comorbid conditions such as myocardial infarction and heart failure, have translated into favorable effects for patients with aortic stenosis. See p 988.Deficiency of Endothelium-Specific Transcription Factor Sox17 Induces Intracranial AneurysmCatastrophic rupture of intracranial aneurysm (IA) is the most frequent cause of hemorrhagic stroke. Neurosurgeons execute high-risk invasive operations such as craniotomy for IA treatment because drugs targeting IA are nonexistent. The present study conceives a potential to fill this long-standing drug vacancy by introducing an IA disease model. Previous genomic analyses identified significant disequilibrium at the Sox17 loci of patients with IA. However, how endothelium-specific transcription factor Sox17 can be involved in IA formation featuring weak outer vessel walls remains unanswered. We found robust Sox17 expression in healthy intracerebral arteries. In contrast, angiotensin II–induced hypertensive stress caused IA in Sox17-deficient intracerebral arteries, suggesting Sox17 mutation as an inherent factor working together with acquired risk factors for IA occurrence. Sox17 deletion and angiotensin II infusion jointly decreased junctional stability and reactive proliferation of endothelial cells within intracerebral arteries, implying disturbed transcriptional regulation and subsequent defects of endothelial cells as the basis of IA pathology. Reduced Sox17 expression and damaged endothelium observed in biopsies of multiple aneurysms highlight the clinical relevance of our results. IA consists largely of saccular and fusiform aneurysms on a morphological basis. In this study, the resemblance of IA occurring in a Sox17-deficient context to fusiform aneurysm can be of clinical interest because fusiform aneurysm, compared with saccular aneurysm, is more obscure in pathogenesis and more incurable. Development of related biomarkers can also contribute to a more subdivided diagnosis of IA by complementing current radiological imaging techniques. Our study modeling IA in mice triggers drug development for noninvasive IA therapy. See p 995.Endothelial-to-Mesenchymal Transition in Pulmonary HypertensionPulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. Pulmonary endothelial cells are involved in pulmonary vascular remodeling through their ability to control vascular tone. Effective therapies have been developed that promote vasodilation (epoprostenol and derivatives, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors). Although these drugs allow clinical, functional, and hemodynamic improvements, the prognosis of PAH patients remains poor. Another critical aspect of endothelial cell dysfunction in PAH is the excessive release of paracrine factors that act as growth factors to induce pulmonary artery smooth muscle cell proliferation. Accordingly, antiproliferative agents, such as tyrosine kinase inhibitors, have been investigated in PAH. Because safety concerns have curtailed the clinical application of these drugs, the need to identify new therapeutic targets has remained. To this end, we explored an unrevealed pathogenic mechanism in PAH, called endothelial-to-mesenchymal transition. We demonstrated that, in addition to promoting vascular remodeling though their cross-talk with smooth muscle cells, endothelial cells can directly contribute to the myofibroblastic core of PAH lesions by transitioning into a mesenchymal phenotype. We identified molecular actors of this pathological transition, including twist overexpression, vimentin phosphorylation, and BMPR2 gene mutation, a gene mutated in 70% of cases of familial PAH and in 10% to 40% of cases of idiopathic PAH. We also demonstrated that rapamycin partially reversed the protein expression patterns of endothelial-to-mesenchymal transition and improved experimental PAH. Hence, endothelial-to-mesenchymal transition is druggable, and this finding may have therapeutic implications. See p 1006. Previous Back to top Next FiguresReferencesRelatedDetails March 17, 2015Vol 131, Issue 11 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/CIR.0000000000000167 Originally publishedMarch 17, 2015 PDF download Advertisement