Leonard Y. Lee

Potential biomarkers for predicting outcomes in CABG cardiothoracic surgeries

The variations in recovery time, complications, and survival among cardiac patients who have undergone coronary artery bypass graft (CABG) procedures are vast. Many formulas and theories are used to predict clinical outcome and recovery time, and current prognostic predictions are based on medical and family history, lifestyle, co-morbidities, and performance status. The identification of biomarkers that provide concrete evidence supporting clinical outcome has greatly affected the field of medicine, helping clinicians in many medicine sub-specialties to forecast clinical course. Recent studies have discovered biomarkers that may be used as predictors of cardiac patients’ status post-cardiothoracic surgery, and the applications are numerous. In this review, we assess currently available cardiac biomarkers as predictors of clinical outcome for post-operative CABG patients. Data were collected from various studies in which cardiac biomarkers were measured in pre-operative and post-operative CABG patients.

Femoral cannulation: a safe vascular access option for cardiopulmonary bypass in minimally invasive cardiac surgery

Femoral cannulation during cardiopulmonary bypass has become a common approach for many cardiac procedures and serves as an important access option, especially during minimally invasive cardiac surgery. Opponents, however, argue that there is significant risk, including site-specific and overall morbidity, which makes the use of this modality dangerous compared to conventional aortoatrial cannulation techniques. We analyzed our institutional experience to elucidate the safety and efficacy of femoral cannulation. All data were collected from a single hospital’s cardiac surgery database. A total of 346 cardiac surgeries were evaluated from September 2012 to September 2013, of which 85/346 (24.6%) utilized a minimally invasive approach. Of the 346 operations performed, 72/346 (20.8%) utilized femoral cannulation while 274/346 (79.2%) used aortoatrial cannulation. Stroke occurred in 1/72 (1.39%) after femoral cannulation, specifically, in a conventional sternotomy patient, while it occurred in 6/274 (2.19%) [p=0.67] after aortoatrial cannulation. When comparing postoperative complications between the femoral cannulation and aortoatrial cannulation groups, the rates of atrial fibrillation [10/72 (13.9%) versus 46/274 (16.8%), p=0.55], renal failure [2/72 (2.78%) versus 11/274 (4.01%), p=0.62], prolonged ventilation time [4/72 (5.56%) versus 27/274 (9.85%), p=0.26] and re-operation for bleeding [3/72 (4.17%) versus 13/274 (4.74%), p=0.84] showed no significant difference. Selective femoral cannulation provides a safe alternative to aortoatrial cannulation for cardiopulmonary bypass and is especially important when performing minimally invasive cardiac surgery. When comparing aortoatrial and femoral cannulation, we found no significant difference in the postoperative complication rates and overall mortality.

Proteolytic Cleavage of AMPKα and Intracellular MMP9 Expression Are Both Required for TLR4-Mediated mTORC1 Activation and HIF-1α Expression in Leukocytes

LPS-induced TLR4 activation alters cellular bioenergetics and triggers proteolytic cleavage of AMPKα and HIF-1α expression in leukocytes. In human leukocytes, and more specifically neutrophils, AMPKα cleavage yields 55- and 35-kDa protein fragments. In this study, we address the mechanism by which AMPKα is cleaved and its relevance to human health. Our data indicate that AMPKα cleavage is linked to MMP9 expression and that both are required for mammalian target of rapamycin complex-1 and S6K1 activation and HIF-1α expression in LPS-stimulated human and mice leukocytes. Three key observations support this conclusion. First, no changes in AMPKα and TLR4 signaling intermediates (mammalian target of rapamycin complex-1/S6 kinase 1/HIF-1α) were detected in LPS-stimulated MMP9-deficient mice leukocytes. Second, rMMP9 cleaved human AMPKα ex vivo, producing degradation products similar in size to those detected following LPS stimulation. Third, MMP9 inhibitors prevented AMPKα degradation and HIF-1α expression in LPS-activated human leukocytes, whereas AMPK activators blocked MMP9 and HIF-1α expression. Significantly, AMPKα degradation, MMP9, and TLR4 signaling intermediates were all detected in leukocytes from patients with type 2 diabetes mellitus and patients following cardiopulmonary bypass surgery. Plasma from these two patient cohorts induced AMPKα cleavage and TLR4 signaling intermediates in healthy donor leukocytes and either a TLR4 inhibitor or polymyxin prevented these outcomes. Detection of AMPKα degradation, MMP9 expression, and TLR4 signaling intermediates described in this study in leukocytes, the most readily available human cells for clinical investigation, may provide a powerful tool for further exploring the role of TLR4 signaling in human diseases and lead to identification of new, context-specific therapeutic modalities for precision medicine.

Aortic root replacement in a patient following congenital aortico‐left ventricular tunnel repair in childhood

Congenital aortico‐left ventricular tunnel requires surgical repair during childhood. Long‐term surveillance is essential in these patients given the risk for aortic aneurysm development in adulthood. We describe an aortic root replacement for an aortic aneurysm five decades following the closure of an aortic‐left ventricular tunnel.

Insulin-Dependent Regulation of mTORC2-Akt-FoxO Suppresses TLR4 Signaling in Human Leukocytes: Relevance to Type 2 Diabetes.

Leukocyte signaling in patients with systemic insulin resistance is largely unexplored. We recently discovered the presence of multiple Toll-like receptor 4 (TLR4) signaling intermediates in leukocytes from patients with type 2 diabetes or acute insulin resistance associated with cardiopulmonary bypass surgery. We extend this work to show that in addition to matrix metalloproteinase 9, hypoxia-inducible factor 1α, and cleaved AMPKα, patient leukocytes also express IRS-1 phosphorylated on Ser312, Akt phosphorylated on Thr308, and elevated TLR4 expression. Similar signaling intermediates were detected in leukocytes and neutrophils treated with lipopolysaccharide (LPS), a ligand of TLR4, in vitro. In contrast, insulin, but not LPS, induced mammalian target of rapamycin complex 2 (mTORC2)–dependent phosphorylation of Akt on Ser473 and FoxO1/O3a on Thr24/32 in leukocytes and neutrophils. Insulin suppressed LPS-induced responses in a dose- and time-dependent manner. AS1842856, a FoxO1 inhibitor, also suppressed TLR4 signaling. We propose that insulin is a homeostatic regulator of leukocyte responses to LPS/TLR4 and that the signaling intermediates expressed in leukocytes of patients with type 2 diabetes indicate TLR4 signaling dominance and deficient insulin signaling. The data suggest that insulin suppresses LPS/TLR4 signals in leukocytes through the mTORC2-Akt-FoxO signaling axis. Better understanding of leukocyte signaling in patients with type 2 diabetes may shed new light on disease causation and progression.

Carotid Stenosis in Cardiac Surgery—No Difference in Postoperative Outcomes

Abstract Background Debate over revascularization of asymptomatic carotid stenosis before cardiac surgery is ongoing. In this study, we analyze cardiac surgery outcomes in patients with asymptomatic carotid stenosis at a single hospital. Methods In this study, 1,781 patients underwent cardiac surgery from January 2012 to June 2013; 1,357 with preoperative screening carotid duplex were included. Patient demographics, comorbidities, degree of stenosis, postoperative complications, and mortality were evaluated. Chi‐square test and logistic regression analysis were performed. Results Asymptomatic stenosis was found in 403/1,357 patients (29.7%; 355 moderate and 48 severe). Patients with stenosis, compared with those without, were older (71.7 ± 11 vs. 66.3 ± 12 years; p < 0.01). Females were more likely to have stenosis (odd ratio, = 1.7; 95% confidence interval, 1.4‐2.2); however, patients were predominantly male in both groups. There were no significant differences in the rates of mortality and postoperative complications, including stroke and transient ischemic attack (TIA). Postoperative TIA occurred in 3/1,357(0.2%); only one had moderate stenosis. Inhospital stroke occurred in 21/1,357 (1.5%) patients; stroke rates were 2.3% (8/355) with moderate stenosis and 2.1% (1/48) severe stenosis. There were 59/1,357 (4.3%) deaths; patients with stenosis had a mortality rate of 4.2% (17/403); however, no postoperative stroke lead to death. Multivariable logistic regression analysis with adjustment for age, gender, race, comorbidities, and postoperative complications did not show an impact of carotid stenosis on postoperative mortality and development of stroke after cardiac surgery. Conclusion This study suggests that patients with asymptomatic carotid stenosis undergoing cardiac surgery are not at increased risk of postoperative complications and mortality; thus, prophylactic carotid revascularization may not be indicated.

Interferon Lambda: Toward a Dual Role in Cancer

Interferon (IFN)-λ, a type III interferon (IFN), is a member of a new family of pleotropic cytokines that share high similarity with classical IFNs α and β (IFN-α/β), type I IFNs. IFN-λ acts as an antiviral agent and displays distinct biological functions, including tumor suppression. Although it activates the common Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways, similar to IFN-α/β, IFN-λ differentially induces the expression of IFN-stimulated genes (ISGs). Novel evidence indicates that IFN-λ acts quite differently from IFN-α/β under both homeostasis and pathological situations. In contrast to IFN-α/β, IFN-λ is not involved in over-stimulation of the immune response or exacerbation of inflammation. However, the emergence of unexpected characteristics of IFN-λ, in the control of inflammation and promotion of immune suppression and cancer, reveals novel challenges and offers more strategic opportunities in the context of cancer and beyond. In this article, we discuss new evidence and potential consequences associated with the biology of IFN-λ and provide a different vision for building novel therapeutic strategies in oncology.

Pericardial windows have limited diagnostic success

BackgroundPericardial effusion (PE) is a common finding in patients who have chronic cardiac failure, who had undergone cardiac surgery, or who have certain other benign and malignant diseases. Pericardial drainage procedures are often requested for both diagnostic and therapeutic purposes. The perceived benefit is that it allows for diagnosis of malignancy or infection for patients with PEs of unclear etiology. The purpose of the study is to determine the diagnostic yield of surgical drainage procedures.MethodsWe conducted a retrospective chart review of patients who underwent surgical drainage procedures of PEs from July 1st, 2011 to January 1st, 2017 at a single institution. The variables included data on preoperative, intraoperative, and postoperative findings; morbidity; and survival.ResultsA total of 145 patients with an average age of 61 ± 5 and primarily men (53%) were evaluated. All of the surgical drainage procedures were performed through the sub-xiphoid approach. Twenty-five of the 145 patients (17.2%) had diagnostic findings in either the pericardial tissue or fluid. The cytology alone was diagnostic in 4.8% (N = 7) of patients with mixed findings including adenocarcinoma of the lung and breast. The pathology was diagnostic for cancer in 1.4% (N = 2) of patients with Melanoma and Lung cancer identified. The cytology and pathology were concordant in 4.0% (N = 6) identifying cancers that included mesothelioma and adenocarcinoma. Infection was identified in the pericardial fluid in 6.9% (N = 10) of the patients.ConclusionSurgical pericardial drainage procedures allow for removal of PE that may lead to tamponade physiology and potential mortality. Although there is therapeutic benefit from these procedures there is only a small diagnostic benefit.

The Structure and biological function of CREG

The cellular repressor of E1A-stimulated genes (CREG) is a 220 amino acid glycoprotein structurally similar to oxidoreductases. However, CREG does not have enzymatic activities because it cannot bind to the cofactor flavin mononucleotide. Although CREG can be secreted, it is mainly an intracellular protein localized in the endocytic-lysosomal compartment. It undergoes proteolytic maturation mediated by lysosomal cysteine proteases. Biochemical studies have demonstrated that CREG interacts with mannose-6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R) and exocyst Sec8. CREG inhibits proliferation and induces differentiation and senescence when overexpressed in cultured cells. In Drosophila, RNAi-mediated knockdown of CREG causes developmental lethality at the pupal stage. In mice, global deletion of the CREG1 gene leads to early embryonic death. These findings establish an essential role for CREG in development. CREG1 haploinsufficient and liver-specific knockout mice are susceptible to high fat diet-induced obesity, hepatic steatosis and insulin resistance. The purpose of this review is to provide an overview of what we know about the biochemistry and biology of CREG and to discuss the important questions that remain to be addressed in the future.

Microgravity simulation activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis during vasculogenesis

Gravity plays an important role in normal tissue maintenance. The ability of stem cells to repair tissue loss in space through regeneration and differentiation remains largely unknown. To investigate the impact of microgravity on blood vessel formation from pluripotent stem cells, we employed the embryoid body (EB) model for vasculogenesis and simulated microgravity by clinorotation. We first differentiated mouse embryonic stem cells into cystic EBs containing two germ layers and then analyzed vessel formation under clinorotation. We observed that endothelial cell differentiation was slightly reduced under clinorotation, whereas vascular branch morphogenesis was markedly enhanced. EB-derived endothelial cells migrated faster, displayed multiple cellular processes, and had higher Cdc42 and Rac1 activity when subjected to clinorotation. Genetic analysis and rescue experiments demonstrated that Cdc42 but not Rac1 is required for microgravity-induced vascular branch morphogenesis. Furthermore, affinity pull-down assay and mass spectrometry identified Rap1GDS1 to be a Cdc42 guanine nucleotide exchange factor, which was upregulated by clinorotation. shRNA-mediated knockdown of Rap1GDS1 selectively suppressed Cdc42 activation and inhibited both baseline and microgravity-induced vasculogenesis. This was rescued by ectopic expression of constitutively active Cdc42. Taken together, these results support the notion that simulated microgravity activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis.