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AIMS: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation. METHODS AND RESULTS: General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte specific Brap deletion using tamoxifen induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity this causes developmental arrest, whereas in adult hearts loss of BRAP induced apoptosis. This is explained by altered signaling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis. CONCLUSION: By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.

Key PointsQuestionWhat are the benefits and risks of continuing aspirin in addition to P2Y12 receptor inhibition with ticagrelor among patients with acute coronary syndrome between 1 month and 12 months after percutaneous coronary intervention? FindingsIn this nonprespecified, post hoc analysis of the GLOBAL LEADERS randomized clinical trial, beyond 1 month after percutaneous coronary intervention in acute coronary syndrome, aspirin was associated with increased bleeding risk and appeared not to add to the benefit of ticagrelor on ischemic events. MeaningThe findings of this hypothesis-generating analysis pave the way for further trials evaluating aspirin-free antiplatelet strategies after percutaneous coronary intervention. ImportanceThe role of aspirin as part of antiplatelet regimens in acute coronary syndromes (ACS) needs to be clarified in the context of newer potent P2Y12 antagonists. ObjectiveTo evaluate the benefit and risks of aspirin in addition to ticagrelor among patients with ACS beyond 1 month after percutaneous coronary intervention (PCI). Design, Setting, and ParticipantsThis is a nonprespecified, post hoc analysis of GLOBAL LEADERS, a randomized, open-label superiority trial comparing 2 antiplatelet treatment strategies after PCI. The trial included 130 secondary/tertiary care hospitals in different countries, with 15991 unselected patients with stable coronary artery disease or ACS undergoing PCI. Patients had outpatient visits at 1, 3, 6, 12, 18, and 24 months after index procedure. InterventionsThe experimental group received aspirin plus ticagrelor for 1 month followed by 23-month ticagrelor monotherapy; the reference group received aspirin plus either clopidogrel (stable coronary artery disease) or ticagrelor (ACS) for 12 months, followed by 12-month aspirin monotherapy. In this analysis, we examined the clinical outcomes occurring between 31 days and 365 days after randomization, specifically in patients with ACS who, within this time frame, were assigned to receive either ticagrelor alone or ticagrelor and aspirin. Main Outcomes and MeasuresThe primary outcome was the composite of all-cause death or new Q-wave myocardial infarction. ResultsOf 15968 participants, there were 7487 patients with ACS enrolled; 3750 patients were assigned to the experimental group and 3737 patients to the reference group. Between 31 and 365 days after randomization, the primary outcome occurred in 55 patients (1.5%) in the experimental group and in 75 patients (2.0%) in the reference group (hazard ratio [HR], 0.73; 95% CI, 0.51-1.03; P=.07); investigator-reported Bleeding Academic Research Consortium-defined bleeding type 3 or 5 occurred in 28 patients (0.8%) in the experimental group and in 54 patients (1.5%) in the reference arm (HR, 0.52; 95% CI, 0.33-0.81; P=.004). Conclusions and RelevanceBetween 1 month and 12 months after PCI in ACS, aspirin was associated with increased bleeding risk and appeared not to add to the benefit of ticagrelor on ischemic events. These findings should be interpreted as exploratory and hypothesis generating; however, they pave the way for further trials evaluating aspirin-free antiplatelet strategies after PCI. Trial RegistrationClinicalTrials.gov identifier: NCT01813435. This secondary analysis of the GLOBAL LEADERS randomized clinical trial evaluates the benefit and risks of aspirin in addition to ticagrelor among patients with acute coronary syndrome beyond 1 month after percutaneous coronary intervention.

Zu den selteneren Ursachen einer Dysphagie gehören degenerative Veränderungen der Halswirbelsäule (HWS). Eine eingeschränkte Beweglichkeit von Hals und Schultergürtel sowie schmerzhafter Hartspann der Nackenmuskulatur sind mögliche Begleitsymptome.In unserer Dysphagiesprechstunde werden Patienten einer videoendoskopisch kontrollierten Mehrfarben-Schluckdiagnostik, einer Ultraschalluntersuchung der Halsweichteile, einer Röntgenuntersuchung von Thorax und HWS und fakultativ einer Videofluoroskopie zugeführt.Innerhalb dieses Routineprogramms wurden 6 Patienten mit solchen für den Schluckvorgang relevanten Veränderungen der HWS gefunden. Insbesondere Verkalkungen des vorderen Längsbandes und Spondylophytenbildungen waren bedeutend. Zunehmende Dysphagie und in einem Falle Heiserkeit aufgrund mechanischer Behinderung der Kehlkopfmotilität veranlassten bei zwei der untersuchten Patienten eine chirurgische Entfernung der Spondylophyten. Postoperativ zeigte sich eine eindeutige Verminderung der Schluckbeschwerden.Degenerative Veränderungen der Halswirbelsäule sollten in der Abklärung einer Dysphagie nicht nur beim Fehlen sonstiger Ursachen differentialdiagnostisch bedacht werden. Die einfach durchzuführende Übersichtsaufnahme der Halswirbelsäule hat sich als ein wertvolles Instrumentarium für Screening-Untersuchungen erwiesen. In geeigneten Fällen kann evtl. frühzeitig eine operative Behandlung Linderung verschaffen.