SummaryBackground Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest antiischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT).

Key Points Question What is the clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) for chronic heart failure (CHF) owing to ischemic origin? Findings In this cohort study, CHIP had a high prevalence in 200 investigated patients with CHF. While no clinical baseline characteristics associated with CHF were different between CHIP carriers and non-CHIP carriers, except for the mean age, harboring mutations in the most prevalent driver genes associated with CHIP, namely DNMT3A and TET2 , was associated with a significant and profound increase in death and rehospitalization for heart failure. Meaning Clonal hematopoiesis of indeterminate potential is presented as a newly identified risk factor for impaired long-term survival and increased disease progression in patients with CHF that may be well targetable as a valuable approach to precision medicine in patients with CHF carrying specific mutations encoding for clonal hematopoiesis.

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Abstract-Transplantation of bone marrow cells as well as circulating endothelial progenitor cells (EPC) enhancesneovascularization after ischemia. The chemokine receptor CXCR4 is essential for migration and homing of hematopoietic stem cells. Therefore, we investigated the role of CXCR4 and its downstream signaling cascade for the angiogenic capacity of cultured human EPC. Ex vivo, differentiated EPC derived from peripheral blood abundantly expressed CXCR4. Incubation of EPC from healthy volunteers with neutralizing antibodies against CXCR4 profoundly inhibited vascular endothelial growth factor-and stromal-derived factor-1-induced migration as well as EPC-induced angiogenesis in an ex vivo assay. Preincubation of transplanted EPC with CXCR4 antibody reduced EPC incorporation and impaired blood-flow recovery in ischemic hindlimbs of nude mice (57Ϯ4% of normal perfusion versus untreated EPC: 80Ϯ11%, PϽ0.001). Bone marrow mononuclear cells (BM-MNC) or EPC of heterozygous CXCR4 ϩ/Ϫ mice displayed reduced CXCR4 expression and disclosed impaired in vivo capacity to enhance recovery of ischemic blood flow in nude mice (blood flow 27Ϯ11% versus 66Ϯ25% using wild-type cells, PϽ0.01). Importantly, impaired blood flow in ischemic CXCR4 ϩ/Ϫ mice was rescued by injection of wild-type BM-MNC. Next, we investigated the role of CXCR4 for functional capacities of EPC from patients with coronary artery disease (CAD). Surface expression of CXCR4 was similar in EPC from patients with CAD compared with healthy controls. However, basal Janus kinase (JAK)-2 phosphorylation was significantly reduced and less responsive to stromal-derived factor-1 in EPC from patients with CAD compared with healthy volunteers, indicating that CXCR4-mediated JAK-2 signaling is dysregulated in EPC from patients with CAD. The CXCR4 receptor signaling profoundly modulates the angiogenic activity and homing capacity of cultured human EPC. Disturbance of CXCR4 signaling, as demonstrated by reduced JAK-2 phosphorylation, may contribute to functional impairment of EPC from patients with CAD. Stimulating CXCR4 signaling might improve functional properties of EPC and may rescue impaired neovascularization capacity of EPC derived from patients with CAD. (Circ Res. 2005;97:1142-1151.) Key Words: coronary artery disease Ⅲ endothelium Ⅲ angiogenesis Ⅲ EPC C irculating endothelial progenitor cells (EPC) play a crucial role in postnatal neovascularization. 1-3 Increasing evidence suggests that transplantation of cultureexpanded progenitor cells or bone marrow-derived progenitor cells successfully promotes therapeutic neovascularization in both ischemic hindlimbs as well as acute myocardial infarction models. 4 -7 Moreover, recent clinical pilot studies suggest that not only restoration of blood flow in peripheral artery disease but also functional regeneration and left ventricular remodeling can be enhanced after autologous transplantation of bone marrow-derived cells or cultured EPC in patients with coronary atherosclerosis. 8 -11 Further evidence indicates that no...

Cell isolation protocols have a major impact on the functional activity of bone marrow-derived progenitor cells. The assessment of cell number and viability may not entirely reflect the functional capacity of cells in vivo. Additional functional testing appears to be mandatory to assure proper cell function before embarking on clinical cell therapy trials.

Emergency ultrasound is suggested to be an important tool in critical care medicine. Time-dependent scenarios occur during preresuscitation care, during cardiopulmonary resuscitation, and in postresuscitation care. Suspected myocardial insufficiency due to acute global, left, or right heart failure, pericardial tamponade, and hypovolemia should be identified. These diagnoses cannot be made with standard physical examination or the electrocardiogram. Furthermore, the differential diagnosis of pulseless electrical activity is best elucidated with echocardiography. Therefore, we developed an algorithm of focused echocardiographic evaluation in resuscitation management, a structured process of an advanced life support-conformed transthoracic echocardiography protocol to be applied to point-of-care diagnosis. The new 2005 American Heart Association/European Resuscitation Council/International Liaison Committee on Resuscitation guidelines recommended high-quality cardiopulmonary resuscitation with minimal interruptions to reduce the no-flow intervals. However, they also recommended identification and treatment of reversible causes or complicating factors. Therefore, clinicians must be trained to use echocardiography within the brief interruptions of advanced life support, taking into account practical and theoretical considerations. Focused echocardiographic evaluation in resuscitation management was evaluated by emergency physicians with respect to incorporation into the cardiopulmonary resuscitation process, performance, and physicians' ability to recognize characteristic pathology. The aim of the focused echocardiographic evaluation in resuscitation management examination is to improve the outcomes of cardiopulmonary resuscitation.

Background— Critical limb ischemia due to peripheral arterial occlusive disease is associated with a severely increased morbidity and mortality. There is no effective pharmacological therapy available. Injection of autologous bone marrow-derived mononuclear cells (BM-MNC) is a promising therapeutic option in patients with critical limb ischemia, but double-blind, randomized trials are lacking. Methods and Results— Forty patients with critical limb ischemia were included in a multicenter, phase II, double-blind, randomized-start trial to receive either intraarterial administration of BM-MNC or placebo followed by active treatment with BM-MNC (open label) after 3 months. Intraarterial administration of BM-MNC did not significantly increase ankle-brachial index and, thus, the trial missed its primary end point. However, cell therapy was associated with significantly improved ulcer healing (ulcer area, 3.2±4.7 cm 2 to 1.89±3.5 cm 2 [ P =0.014] versus placebo, 2.92±3.5 cm 2 to 2.89±4.1 cm 2 [ P =0.5]) and reduced rest pain (5.2±1.8 to 2.2±1.3 [ P =0.009] versus placebo, 4.5±2.4 to 3.9±2.6 [ P =0.3]) within 3 months. Limb salvage and amputation-free survival rates did not differ between the groups. Repeated BM-MNC administration and higher BM-MNC numbers and functionality were the only independent predictors of improved ulcer healing. Ulcer healing induced by repeated BM-MNC administration significantly correlated with limb salvage ( r =0.8; P <0.001). Conclusions— Intraarterial administration of BM-MNC is safe and feasible and accelerates wound healing in patients without extensive gangrene and impending amputation. These exploratory findings of this pilot trial need to be confirmed in a larger randomized trial in patients with critical limb ischemia and stable ulcers. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00282646.

Background-Transplantation