Lessons learned during a 30-year experience with simultaneous carotid endarterectomy and coronary artery bypass grafting.

OBJECTIVE: A simultaneous operative approach to patients with significant carotid and coronary disease has been suggested as a safe, lower cost, and more convenient alternative to a staged approach. During the last three decades, spanning the career of our senior author, our group has pursued simultaneous coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA) in limited circumstances. We previously reported on our results in series from 1984 to 1994 and 1994 to 1999. Based on these prior results and the current literature, we liberalized our inclusion criteria. We are now reporting on a contemporary cohort of 91 patients operated on from 2006 to 2018. METHODS: All patients who underwent combined CEA/CABG in 2006 to 2018 were entered into the Vascular Quality Initiative database. We compared the current series of 91 patients (group 3) with the 74 patients (group 2) from 1994 to 1999 and the 100 patients (group 1) from 1984 to 1994 who also underwent combined CEA/CABG. We examined demographic and comorbid factors, presence of cerebrovascular symptoms, degree of contralateral carotid stenosis, perioperative stroke, and death. Statistical comparison was made with χ2 analysis. RESULTS: The groups had similar demographics and comorbidities. Significant differences were noted in the preoperative diagnosis of hyperlipidemia (42%, 51%, 75%; P = .005) and the proportion of patients requiring urgent operations (24%, 47%, 56%; P = .002) during successive time periods. Patients in group 3 were much less likely to have preoperative symptoms from carotid stenosis before operation (55%, 31%, 4.4%; P < .001). Correspondingly, patients in group 3 were more likely to have asymptomatic unilateral carotid stenosis (20%, 55%, 78%; P < .001). The 30-day mortality rate remained stable compared with the first interval (8%, 3%, 2.2%; P = .11). Likewise, the overall stroke rate decreased in the later periods compared with the first series (9%, 1.4%, 2.2%; P = .016). Of the two perioperative strokes recorded for group 3, only one event was ipsilateral to the carotid artery operated on compared with the four ipsilateral strokes of nine total reported in group 1 and no ipsilateral stroke reported in group 2. CONCLUSIONS: Based on the favorable results of the previously reported series of CEA/CABG from our group, we continued to liberalize selection criteria for the combined procedure to essentially mirror the standard recommendations for CEA in patients without coronary disease. The current series using this treatment algorithm demonstrates the safety of this approach, with stroke and death rates equivalent to those of CABG alone. These excellent results were achieved in the face of increasingly urgent cardiac procedures. The fact that the majority of the perioperative strokes were contralateral to the carotid artery operated on reinforces the safety of our approach but underscores the significant burden of atherosclerosis in these patients.

Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias.

The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B-cell leukemia by inhibiting interferon regulatory factor 4 (IRF4) but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the messenger RNA (mRNA) level without altering the genomic DNA and induces B-cell leukemia via genetic deletion of the gene encoding IRF4.

Oncomir miR-125b regulates hematopoiesis by targeting the gene Lin28A.

MicroRNA-125b (miR-125b) is up-regulated in patients with leukemia. Overexpression of miR-125b alone in mice causes a very aggressive, transplantable myeloid leukemia. Before leukemia, these mice do not display elevation of white blood cells in the spleen or bone marrow; rather, the hematopoietic compartment shows lineage-skewing, with myeloid cell numbers dramatically increased and B-cell numbers severely diminished. miR-125b exerts this effect by up-regulating the number of common myeloid progenitors while inhibiting development of pre-B cells. We applied a miR-125b sponge loss of function system in vivo to show that miR-125b physiologically regulates hematopoietic development. Investigating the mechanism by which miR-125b regulates hematopoiesis, we found that, among a panel of candidate targets, the mRNA for Lin28A, an induced pluripotent stem cell gene, was most repressed by miR-125b in mouse hematopoietic stem and progenitor cells. Overexpressing Lin28A in the mouse hematopoietic system mimicked the phenotype observed on inhibiting miR-125b function, leading to a decrease in hematopoietic output. Relevant to the miR-125b overexpression phenotype, we also found that knockdown of Lin28A led to hematopoietic lineage-skewing, with increased myeloid and decreased B-cell numbers. Thus, the miR-125b target Lin28A is an important regulator of hematopoiesis and a primary target of miR-125b in the hematopoietic system.

Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathway in mice.

APCs are essential for innate and adaptive immunity as well as self-immune tolerance. Here, we show that the Cap'n'collar member Bach1 regulates the generation of APCs, specifically macrophages and dendritic cells, in mice. The impaired APC development in Bach1(-/-) mice was accompanied by defects in downstream T-cell responses and partial protection from experimental autoimmune encephalomyelitis. Genomewide analyses identified a panel of Bach1 target genes and ablation of the direct Bach1 target gene HO-1 exacerbated the impaired APC development observed in Bach1(-/-) mice. This was attributed to the impaired ability of HO-1(-/-)Bach1(-/-) double mutants to produce upstream APC progenitor cells, including common myeloid progenitor (CMP)-Flk2(+). By contrast, we observed an increase in hematopoietic stem-progenitor cells (HSPCs) in these mice, suggesting a developmental block in the progression of HSPCs to CMP-Flk2(+) and subsequently APCs.