Metabolomic signatures of ideal cardiovascular health in black adults.

Plasma metabolomics profiling is an emerging methodology to identify metabolic pathways underlying cardiovascular health (CVH). The objective of this study was to define metabolomic profiles underlying CVH in a cohort of Black adults, a population that is understudied but suffers from disparate levels of CVD risk factors. The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity study cohort consisted of 375 Black adults (age 53 ± 10, 39% male) without known CVD. CVH was determined by the AHA Life's Simple 7 (LS7) score, calculated from measured blood pressure, body mass index (BMI), fasting blood glucose and total cholesterol, and self-reported physical activity, diet, and smoking. Plasma metabolites were assessed using untargeted high-resolution metabolomics profiling. A metabolome wide association study (MWAS) identified metabolites associated with LS7 score after adjusting for age and sex. Using Mummichog software, metabolic pathways that were significantly enriched in metabolites associated with LS7 score were identified. Metabolites representative of these pathways were compared across clinical domains of LS7 score and then developed into a metabolomics risk score for prediction of CVH. We identified novel metabolomic signatures and pathways associated with CVH in a cohort of Black adults without known CVD. Representative and highly prevalent metabolites from these pathways included glutamine, glutamate, urate, tyrosine and alanine, the concentrations of which varied with BMI, fasting glucose, and blood pressure levels. When assessed in conjunction, these metabolites were independent predictors of CVH. One SD increase in the novel metabolomics risk score was associated with a 0.88 higher LS7 score, which translates to a 10.4% lower incident CVD risk. We identified novel metabolomic signatures of ideal CVH in a cohort of Black Americans, showing that a core group of metabolites central to nitrogen balance, bioenergetics, gluconeogenesis, and nucleotide synthesis were associated with CVH in this population.

Associations Between Preimplant Cancer Type and Left Ventricular Assist Device Outcomes: An INTERMACS Registry Analysis.

We used the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database to examine whether history of a solid versus hematologic malignancy impacts outcomes after left ventricular assist device (LVAD) implantation. We included LVAD recipients (2007-2017) with cancer history reported (N = 14,799, 21% female, 24% Black). Multivariate models examined the association between cancer type and post-LVAD mortality and adverse events. Competing risk analyses compared death and heart transplantation between cancer types and those without cancer in bridge-to-transplant (BTT) patients. A total of 909 (6.1%) patients had a history of cancer (4.9% solid tumor, 1.3% hematologic malignancy). Solid tumors were associated with higher mortality (adjusted hazard ratio [aHR] = 1.31, 95% confidence interval [CI] = 1.09-1.57), major bleeding (aHR = 1.15, 95% CI = 1.00-1.32), and pump thrombosis (aHR = 1.52, 95% CI = 1.09-2.13), whereas hematologic malignancies were associated with increased major infection (aHR = 1.43, 95% CI = 1.14-1.80). Compared to BTT patients without a history of cancer, solid tumor patients were less likely to undergo transplantation (adjusted subdistribution HR [aSHR] = 0.63, 95% CI = 0.45-0.89) and hematologic malignancy patients were as likely to experience death (aSHR = 1.16, 95% CI = 0.63-2.14) and transplantation (aSHR = 0.69, 95% CI = 0.44-1.08). Cancer history and type impact post-LVAD outcomes. As LVAD utilization in cancer survivors increases, we need strategies to improve post-LVAD outcomes in these patients.

Predictors of 5-Year Mortality in Patients Managed With a Magnetically Levitated Left Ventricular Assist Device.

BACKGROUND: In advanced heart failure patients implanted with a fully magnetically levitated HeartMate 3 (HM3, Abbott) left ventricular assist device (LVAD), it is unknown how preimplant factors and postimplant index hospitalization events influence 5-year mortality in those able to be discharged. OBJECTIVES: The goal was to identify risk predictors of mortality through 5 years among HM3 LVAD recipients conditional on discharge from index hospitalization in the MOMENTUM 3 pivotal trial. METHODS: This analysis evaluated 485 of 515 (94%) patients discharged after implantation of the HM3 LVAD. Preimplant (baseline), implant surgery, and index hospitalization characteristics were analyzed individually, and as multivariable predictors for mortality risk through 5 years. RESULTS: Cumulative 5-year mortality in the cohort (median age: 62 years, 80% male, 65% White, 61% destination therapy due to transplant ineligibility) was 38%. Two preimplant characteristics (elevated blood urea nitrogen and prior coronary artery bypass graft or valve procedure) and 3 postimplant characteristics (hemocompatibility-related adverse events, ventricular arrhythmias, and estimated glomerular filtration rate <60 mL/min/1.73 m2 at discharge) were predictors of 5-year mortality. In 171 of 485 patients (35.3%) without any risk predictors, 5-year mortality was reduced to 22.6% (95% CI: 15.4%-32.7%). Even among those with 1 or more predictors, mortality was <50% at 5 years (45.7% [95% CI: 39.0%-52.8%]). CONCLUSIONS: Long-term survival in successfully discharged HM3 LVAD recipients is largely influenced by clinical events experienced during the index surgical hospitalization in tandem with baseline factors, with mortality of <50% at 5 years. In patients without identified predictors of risk, long-term 5-year mortality is low and rivals that achieved with heart transplantation, even though most were implanted with destination therapy intent. (MOMENTUM 3 IDE Clinical Study Protocol, NCT02224755; MOMENTUM 3 Pivotal Cohort Extended Follow-up PAS, NCT03982979).

Circulating progenitor cells and outcomes in patients with coronary artery disease.

BACKGROUND: Low quantities of circulating progenitor cells (CPCs), specifically CD34+ populations, reflect impairment of intrinsic regenerative capacity. This study investigates the relationship between subsets of CPCs and adverse outcomes. METHODS: 1366 individuals undergoing angiography for evaluation of coronary artery disease (CAD) were enrolled into the Emory Cardiovascular Biobank. Flow cytometry identified CPCs as CD45med blood mononuclear cells expressing the CD34 epitope, with further enumeration of hematopoietic CPCs as CD133+/CXCR4+ cells and endothelial CPCs as vascular endothelial growth factor receptor-2 (VEGFR2+) cells. Adjusted Cox or Fine and Gray's sub-distribution hazard regression models analyzed the relationship between CPCs and 1) all-cause death and 2) a composite of cardiovascular death and non-fatal myocardial infarction (MI). RESULTS: Over a median 3.1-year follow-up period (IQR 1.3-4.9), there were 221 (16.6%) all-cause deaths and 172 (12.9%) cardiovascular deaths/MIs. Hematopoietic CPCs were highly correlated, and the CD34+/CXCR4+ subset was the best independent predictor. Lower counts (≤median) of CD34+/CXCR4+ and CD34+/VEGFR2+ cells independently predicted all-cause mortality (HR 1.46 [95% CI 1.06-2.01], p = 0.02 and 1.59 [95% CI 1.15-2.18], p = 0.004) and cardiovascular death/MI (HR 1.50 [95% CI 1.04-2.17], p = 0.03 and 1.47 [95% CI 1.01-2.03], p = 0.04). A combination of low CD34+/CXCR4+ and CD34+/VEGFR2+ CPCs predicted all-cause death (HR 2.1, 95% CI 1.4-3.0; p = 0.0002) and cardiovascular death/MI (HR 2.0, 95% CI 1.3-3.2; p = 0.002) compared to those with both lineages above the cut-offs. CONCLUSIONS: Lower levels of hematopoietic and endothelial CPCs indicate diminished endogenous regenerative capacity and independently correlate with greater mortality and cardiovascular risk in patients with CAD.

Prediction of Survival After Implantation of a Fully Magnetically Levitated Left Ventricular Assist Device.

BACKGROUND: Clinical trials inform on average efficacy, but individualized risk assessments for outcome prediction are important in guiding treatment implementation. OBJECTIVES: The authors developed and validated a patient-specific risk score to predict survival at 1 and 2 years after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation. METHODS: The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial includes 2,200 HM3 LVAD patients in the pivotal trial and Continued Access Protocol study (2014-2018). The authors randomly assigned all patients to a derivation cohort (n = 1,540) or validation cohort (n = 660). Univariate mortality predictors were screened for potential model inclusion, stepwise selection was used to build the multivariable Cox proportional hazards regression model, and performance (discrimination and calibration) was evaluated. RESULTS: Age, prior cardiac surgery (coronary artery bypass grafting [CABG] or valve procedure), lower serum sodium, higher blood urea nitrogen (BUN), small left ventricular size, and right atrial pressure-to-pulmonary capillary wedge pressure (RAP/PCWP) ratio >0.6 were significant risk factors for mortality. Receiver-operating characteristic (ROC) analysis in the validation cohort demonstrated an area under the curve (AUC) of 0.76 (95% CI: 0.70-0.81) at 1 year and 0.71 (95% CI: 0.66-0.77) at 2 years. Calibration between predicted and observed survival of the risk quintiles was high, with Pearson correlation coefficients of 0.986 and 0.994 at 1 and 2 years, respectively. Patients were successfully stratified into tertiles with higher-than-average, average, and lower-than-average survival, and observed mortality risk increased by 2-fold from one tertile to the next. CONCLUSIONS: A practical, easy-to-use HM3 Survival Risk Score with 6 components was developed to accurately predict 1- and 2-year survival after HM3 LVAD implantation. The survival risk score can be used to provide individual survival estimates to facilitate shared decision making when considering HM3 LVAD therapy. (MOMENTUM 3 Trial Portfolio; NCT02224755, NCT02892955).

Oncogenic potential of ATAD2 in stomach cancer and insights into the protein-protein interactions at its AAA + ATPase domain and bromodomain.

ATAD2 has recently been shown to promote stomach cancer. However, nothing is known about the functional network of ATAD2 in stomach carcinogenesis. This study illustrates the oncogenic potential of ATAD2 and the participation of its ATPase and bromodomain in stomach malignancy. Expression of ATAD2 in stomach cancer is analyzed by in silico and in vitro techniques including western blot and immunofluorescence microscopy of stomach cancer cells (SCCs) and tissues. The oncogenic potential of ATAD2 is examined thoroughly using genetic alterations, driver gene prediction, survival analysis, identification of interacting partners, and analysis of canonical pathways. To understand the protein-protein interactions (PPI) at residue level, molecular docking and molecular dynamics simulations (1200 ns) are performed. Enhanced expression of ATAD2 is observed in H. pylori-infected SCCs, patient biopsy tissues, and all stages and grades of stomach cancer. High expression of ATAD2 is found to be negatively correlated with the survival of stomach cancer patients. ATAD2 is a cancer driver gene with 37 mutational sites and a predictable factor for stomach cancer prognosis with high accuracy. The top canonical pathways of ATAD2 indicate its participation in stomach malignancy. The ATAD2-PPI in stomach cancer identify top-ranked partners; ESR1, SUMO2, SPTN2, and MYC show preference for the bromodomain whereas NCOA3 and HDA11 have preference for the ATPase domain of ATAD2. The oncogenic characterization of ATAD2 provides strong evidence to consider ATAD2 as a stomach cancer biomarker. These studies offer an insight for the first time into the ATAD2-PPI interface presenting a novel target for cancer therapeutics. Communicated by Ramaswamy H. Sarma.

Emerging oncogene ATAD2: Signaling cascades and therapeutic initiatives.

ATAD2 is a promising oncoprotein with tumor-promoting functions in many cancers. It is a valid cancer drug-target and a potential cancer-biomarker for multiple malignancies. As a cancer/testis antigen (CTA), ATAD2 could also be a probable candidate for immunotherapy. It is a unique CTA that belongs to both AAA+ ATPase and bromodomain family proteins. Since 2007, several research groups have been reported on the pleiotropic oncogenic functions of ATAD2 in diverse signaling pathways, including Rb/E2F-cMyc pathway, steroid hormone signaling pathway, p53 and p38-MAPK-mediated apoptotic pathway, AKT pathway, hedgehog signaling pathway, HIF1α signaling pathway, and Epithelial to Mesenchymal Transition (EMT) pathway in various cancers. In all these pathways, ATAD2 participates in chromatin dynamics, DNA replication, and gene transcription, demonstrating its role as an epigenetic reader and transcription factor or coactivator to promote tumorigenesis. However, despite the progress, an overall mechanism of ATAD2-mediated oncogenesis in diverse origin is elusive. In this review, we summarize the accumulated evidence to envision the overall ATAD2 signaling networks during carcinogenesis and highlight the area where missing links await further research. Besides, the structure-function aspect of ATAD2 is also discussed. Since the efforts have already been initiated to explore targeted drug molecules and RNA-based therapeutic alternatives against ATAD2, their potency and prospects have been elucidated. Together, we believe this is a well-rounded review on ATAD2, facilitating a new drift in ATAD2 research, essential for its clinical implication as a biomarker and/or cancer drug-target.

Premature atherosclerotic peripheral artery disease: An underrecognized and undertreated disorder with a rising global prevalence.

Premature atherosclerotic peripheral artery disease (PAD) of the lower extremities is characterized by disease diagnosis before the age of 50 years. The global prevalence of premature PAD has increased, and the disease is often underdiagnosed given heterogenous patient symptoms. Traditional cardiovascular risk factors like smoking, diabetes, hypertension, and hyperlipidemia as well as non-traditional risk factors like elevated lipoprotein(a), family history of PAD, hypercoagulability, and systemic inflammation are associated with premature PAD. Patients with premature PAD tend to have an aggressive vascular disease process, a high burden of cardiovascular risk factors, and other concomitant atherosclerotic vascular diseases like coronary artery disease. Prevention of cardiovascular events, improvement of symptoms and functional status, and prevention of adverse limb events are the main goals of patient management. In this review, we discuss the epidemiology, risk factors, clinical evaluation, and management of patients with premature PAD.

Circulating Progenitor Cells in Patients With Coronary Artery Disease and Renal Insufficiency.

Patients with coronary artery disease and renal insufficiency (RI) (estimated glomerular filtration rate <60 ml/min/1.73 m2) are at an increased risk of cardiovascular events. The contribution of regenerative capacity, measured as circulating progenitor cell (CPC) counts, to this increased risk is unclear. CPCs were enumerated as cluster of differentiation (CD) 45med+ mononuclear cells expressing CD34+, CD133+, CXCR4+ (chemokine [C-X-C motif] receptor 4), and VEGF2R+ (vascular endothelial growth factor receptor 2) epitopes in 1,281 subjects with coronary artery disease (35% with RI). Patients with RI and low (median) were at a similar risk as those without RI.

HIF1α-dependent upregulation of ATAD2 promotes proliferation and migration of stomach cancer cells in response to hypoxia.

Stomach cancer is a difficult-to-treat disease. Lack of detection markers and limited understanding of the disease mechanisms contribute to the aggressive nature of stomach cancer cells (SCCs). Recently, an ATPase, ATAD2 has been found to be highly expressed in stomach cancer contributing to increased malignancy. However, nothing is known about the mechanism of ATAD2 upregulation and its involvement in stomach carcinogenesis. Since hypoxic microenvironment plays a crucial role in the progression of solid tumors like stomach cancer; we have examined the regulation and function of ATAD2 expression in hypoxic SCCs. ATAD2 is induced in hypoxia-treated SCCs. Stomach adenocarcinoma and metastatic tissues with high HIF1α level also show enhanced ATAD2 expression. In the absence of hypoxia-inducible factor HIF1α, ATAD2 protein level is found to be less indicating towards a potential correlation between them. We identify the presence of HIF1α-binding site (HBS) and HIF1α ancillary site (HAS) in the ATAD2 promoter. Using both in vitro and in vivo binding studies, we confirm that HIF1α binds with the ATAD2 promoter in hypoxic condition. ATAD2 upregulation promotes proliferation and migration of SCCs exposed to hypoxia. Thus, we identify ATAD2 as a hypoxia-responsive and HIF1α-regulated gene and elucidate that upregulated expression of ATAD2 enhances tumor-promoting functions in hypoxic SCCs. Therefore, we propose ATAD2 as a promising therapeutic target for stomach cancer.

Bacopa monnieri-Induced Protective Autophagy Inhibits Benzo[a]pyrene-Mediated Apoptosis.

Benzo[a]pyrene (B[a]P) is capable of inducing oxidative stress and cellular injuries leading to cell death and associates with a significant risk of cancer development. Prevention of B[a]P-induced cellular toxicity with herbal compound through regulation of mitochondrial oxidative stress might protect cell death and have therapeutic benefit to human health. In this study, we demonstrated the cytoprotective role of Bacopa monnieri (BM) against B[a]P-induced apoptosis through autophagy induction. Pretreatment with BM rescued the reduction in cell viability in B[a]P-treated human keratinocytes (HaCaT) cells indicating the cytoprotective potential of BM against B[a]P. Moreover, BM was found to inhibit B[a]P-mediated reactive oxygen species (ROS)-induced apoptosis activation in HaCaT cells. Furthermore, BM was found to preserve mitochondrial membrane potential and inhibited release of cytochrome c in B[a]P-treated HaCaT cells. Bacopa monnieri induced protective autophagy; we knocked down Beclin-1, and data showed that BM was unable to protect from B[a]P-induced mitochondrial ROS-mediated apoptosis in Beclin-1-deficient HaCaT cells. Moreover, we established that B[a]P-induced damaged mitochondria were found to colocalize and degraded within autolysosomes in order to protect HaCaT cells from mitochondrial injury. In conclusion, B[a]P-induced apoptosis was rescued by BM treatment and provided cytoprotection through Beclin-1-dependent autophagy activation. Copyright © 2016 John Wiley & Sons, Ltd.

Janus kinase signaling activation mediates peritoneal inflammation and injury in vitro and in vivo in response to dialysate.

Peritoneal membrane pathology limits long-term peritoneal dialysis (PD). Here, we tested whether JAK/STAT signaling is implicated and if its attenuation might be salutary. In cultured mesothelial cells, PD fluid activated, and the pan-JAK inhibitor P6 reduced, phospho-STAT1 and phospho-STAT3, periostin secretion, and cleaved caspase-3. Ex vivo, JAK was phosphorylated in PD effluent cells from long-term but not new PD patients. MCP-1 and periostin were increased in PD effluent in long term compared with new patients. In rats, twice daily, PD fluid infusion induced phospho-JAK, mesothelial cell hyperplasia, inflammation, fibrosis, and hypervascularity after 10 days of exposure to PD fluid. Concomitant instillation of a JAK1/2 inhibitor virtually completely attenuated these changes. Thus, our studies directly implicate JAK/STAT signaling in the mediation of peritoneal membrane pathology as a consequence of PD.

Maximizing the erythropoietin response: iron strategies.

Anemia is a significant cause of morbidity and lowers the quality of life of patients suffering from chronic kidney disease (CKD). Iron deficiency is the most important cause of erythropoietin (EPO) hyporesponsiveness in CKD. EPO administration significantly increases the costs of CKD management. It follows that paramount importance must be given to enhancing responsiveness to EPO thereby ensuring that the patient derives maximum benefit. Intravenous iron (IVI) administration has been used for decades to replenish body iron stores. Multiple preparations of Iron are available in the market. However, IVI administration is fraught with dangers like adverse drug reactions, susceptibility to infection, and, as recently postulated, direct cellular toxicity. Traditional approaches to IVI administration have focused on multiple administrations of lower doses for fear of adverse reactions. However, recent studies have demonstrated that higher doses can be safely administered in a single infusion, thereby reducing hospitalization costs and patient inconvenience. Newer preparations of IVI are relatively safer, easier to administer and efficacious. Preparations like Iron sucrose, ferumoxytol, ferric carboxymaltose and iron isomaltoside do not require test doses and allow higher doses to be administered at a time with cost and effect benefits.