Background: Long-term outcomes of antiplatelet monotherapy in patients who receive percutaneous coronary intervention are unknown. The HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis–Extended Antiplatelet Monotherapy) Extended study reports the posttrial follow-up results of the original HOST-EXAM trial. Methods: From March 2014 through May 2018, 5438 patients who maintained dual antiplatelet therapy without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents were randomly assigned in a 1:1 ratio to receive clopidogrel (75 mg once daily) or aspirin (100 mg once daily). The primary end point (a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission attributable to acute coronary syndrome, and Bleeding Academic Research Consortium type 3 or greater bleeding), secondary thrombotic end point (cardiac death, nonfatal myocardial infarction, ischemic stroke, readmission attributable to acute coronary syndrome, and definite or probable stent thrombosis), and bleeding end point (Bleeding Academic Research Consortium type 2 or greater bleeding) were analyzed during the extended follow-up period. Analysis was performed on the per-protocol population (2431 patients in the clopidogrel group and 2286 patients in the aspirin group). Results: During a median follow-up of 5.8 years (interquartile range, 4.8–6.2 years), the primary end point occurred in 12.8% and 16.9% in the clopidogrel and aspirin groups, respectively (hazard ratio, 0.74 [95% CI, 0.63–0.86]; P <0.001). The clopidogrel group had a lower risk for the secondary thrombotic end point (7.9% versus 11.9%; hazard ratio, 0.66 [95% CI, 0.55–0.79]; P 5 years after randomization, clopidogrel monotherapy compared with aspirin monotherapy was associated with lower rates of the composite net clinical outcome in patients without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02044250.

The aim of this study was to compare the safety and efficacy of biodegradable-polymer (BP) drug-eluting stents (DES), bare metal stents (BMS), and durable-polymer DES in patients undergoing coronary revascularization, we performed a systematic review and network meta-analysis using a Bayesian framework. Study stents included BMS, paclitaxel-eluting (PES), sirolimus-eluting (SES), endeavor zotarolimus-eluting (ZES-E), cobalt–chromium everolimus-eluting (CoCr-EES), platinium–chromium everolimus-eluting (PtCr-EES), resolute zotarolimus-eluting (ZES-R), and BP biolimus-eluting stents (BP-BES). After a systematic electronic search, 113 trials with 90 584 patients were selected. The principal endpoint was definite or probable stent thrombosis (ST) defined according to the Academic Research Consortium within 1 year. Biodegradable polymer-biolimus-eluting stents [OR, 0.56; 95% credible interval (CrI), 0.33–0.90], SES (OR, 0.53; 95% CrI, 0.38–0.73), CoCr-EES (OR, 0.34; 95% CrI, 0.23–0.52), and PtCr-EES (OR, 0.31; 95% CrI, 0.10–0.90) were all superior to BMS in terms of definite or probable ST within 1 year. Cobalt–chromium everolimus-eluting stents demonstrated the lowest risk of ST of all stents at all times after stent implantation. Biodegradable polymer-biolimus-eluting stents was associated with a higher risk of definite or probable ST than CoCr-EES (OR, 1.72; 95% CrI, 1.04–2.98). All DES reduced the need for repeat revascularization, and all but PES reduced the risk of myocardial infarction compared with BMS. All DESs but PES and ZES-E were superior to BMS in terms of ST within 1 year. Cobalt–chromium everolimus-eluting stents was safer than any DES even including BP-BES. Our results suggest that not only the biodegradability of polymer, but the optimal combination of stent alloy, design, strut thickness, polymer, and drug all combined determine the safety of DES.

Background—: Cell-based therapies to augment endothelial cells (ECs) hold great therapeutic promise. Here, we report a novel approach to generate functional ECs directly from adult fibroblasts. Methods and Results—: Eleven candidate genes that are key regulators of endothelial development were selected. Green fluorescent protein (GFP)–negative skin fibroblasts were prepared from Tie2-GFP mice and infected with lentiviruses allowing simultaneous overexpression of all 11 factors. Tie2-GFP ⁺ cells (0.9%), representing Tie2 gene activation, were detected by flow cytometry. Serial stepwise screening revealed 5 key factors (Foxo1, Er71, Klf2, Tal1, and Lmo2) that were required for efficient reprogramming of skin fibroblasts into Tie2-GFP ⁺ cells (4%). This reprogramming strategy did not involve pluripotency induction because neither Oct4 nor Nanog was expressed after 5 key factor transduction. Tie2-GFP ⁺ cells were isolated using fluorescence-activated cell sorting and designated as induced ECs (iECs). iECs exhibited endothelium-like cobblestone morphology and expressed EC molecular markers. iECs possessed endothelial functions such as Bandeiraea simplicifolia -1 lectin binding, acetylated low-density lipoprotein uptake, capillary formation on Matrigel, and nitric oxide production. The epigenetic profile of iECs was similar to that of authentic ECs because the promoters of VE-cadherin and Tie2 genes were demethylated. mRNA profiling showed clustering of iECs with authentic ECs and highly enriched endothelial genes in iECs. In a murine model of hind-limb ischemia, iEC implantation increased capillary density and enhanced limb perfusion, demonstrating the in vivo viability and functionality of iECs. Conclusions—: We demonstrated the first direct conversion of adult fibroblasts to functional ECs. These results suggest a novel therapeutic modality for cell therapy in ischemic vascular disease.

Background— Despite the therapeutic potential of endothelial progenitor cells (EPCs) in ischemic vascular diseases, their insufficient numbers limit clinical applications. Peroxisome proliferator–activated receptor (PPAR)-δ belongs to the nuclear hormone receptor superfamily, and its functions in various tissues and cells are almost unexplored, especially with respect to vascular biology. Methods and Results— PPAR-δ activation in EPCs phosphorylated Akt, and this phosphorylation was mediated not only by genomic but also by nongenomic pathways through interaction with the regulatory subunit of phosphatidylinositol 3-kinase. PPAR-δ activation with agonist (GW501516 or L-165041) increased the proliferation of human EPCs and protected them from hypoxia-induced apoptosis. In addition, PPAR-δ activation enhanced EPC functions, such as transendothelial migration, and tube formation. These actions by PPAR-δ activation in EPCs were dependent on the phosphatidylinositol 3-kinase/Akt pathway. In ischemic hindlimb of mice models, transplantation of PPAR-δ agonist–treated human or mouse EPCs enhanced blood flow recovery to ischemic limbs compared with vehicle-treated EPCs. In EPCs from PPAR-δ–knockout mice, however, treatment with PPAR-δ agonist did not enhance in vivo vasculogenic potential. Systemic administration of PPAR-δ agonist increased hematopoietic stem cells in bone marrow and EPCs in peripheral blood, leading to improved vasculogenesis with incorporation of bone marrow–derived cells to new vessels in a corneal neovascularization model and limb salvage with better blood flow in an ischemic hindlimb model. Conclusions— The results of our study suggest that PPAR-δ agonist has therapeutic vasculogenic potential for the treatment of ischemic cardiovascular diseases.

Rationale:: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear. Objective:: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions. Methods and Results:: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested after injection of recombinant Wnt3a protein (r-Wnt3a) in the left ventricular free wall. Wnt signaling was found to decrease the proliferation of adult CSP cells, both in vitro and in vivo, through suppression of cell cycle progression. Wnt stimulation exerted its antiproliferative effects through a previously unappreciated activation of insulin-like growth factor binding protein 3 (IGFBP3), which requires intact IGF binding site for its action. Moreover, injection of r-Wnt3a after myocardial infarction in mice showed that Wnt signaling limits CSP cell renewal, blocks endogenous cardiac regeneration and impairs cardiac performance, highlighting the importance of progenitor cells in maintaining tissue function after injury. Conclusions:: Our study identifies canonical Wnt signaling and the novel downstream mediator, IGFBP3, as key regulators of adult cardiac progenitor self-renewal in physiological and pathological states.