Identification of gene signatures regulated by carvedilol in mouse heart.

Chronic treatment with the ß-blocker carvedilol has been shown to reduce established maladaptive left ventricle (LV) hypertrophy and to improve LV function in experimental heart failure. However, the detailed mechanisms by which carvedilol improves LV failure are incompletely understood. We previously showed that carvedilol is a ß-arrestin-biased ß1-adrenergic receptor ligand, which activates cellular pathways in the heart independent of G protein-mediated second messenger signaling. More recently, we have demonstrated by microRNA (miR) microarray analysis that carvedilol upregulates a subset of mature and pre-mature miRs, but not their primary miR transcripts in mouse hearts. Here, we next sought to identify the effects of carvedilol on LV gene expression on a genome-wide basis. Adult mice were treated with carvedilol or vehicle for 1 wk. RNA was isolated from LV tissue and hybridized for microarray analysis. Gene expression profiling analysis revealed a small group of genes differentially expressed after carvedilol treatment. Further analysis categorized these genes into pathways involved in tight junction, malaria, viral myocarditis, glycosaminoglycan biosynthesis, and arrhythmogenic right ventricular cardiomyopathy. Genes encoding proteins in the tight junction, malaria, and viral myocarditis pathways were upregulated in the LV by carvedilol, while genes encoding proteins in the glycosaminoglycan biosynthesis and arrhythmogenic right ventricular cardiomyopathy pathways were downregulated by carvedilol. These gene expression changes may reflect the molecular mechanisms that underlie the functional benefits of carvedilol therapy.

Long Non-Coding RNAs as Master Regulators in Cardiovascular Diseases.

Cardiovascular disease is the leading cause of death in the United States, accounting for nearly one in every seven deaths. Over the last decade, various targeted therapeutics have been introduced, but there has been no corresponding improvement in patient survival. Since the mortality rate of cardiovascular disease has not been significantly decreased, efforts have been made to understand the link between heart disease and novel therapeutic targets such as non-coding RNAs. Among multiple non-coding RNAs, long non-coding RNA (lncRNA) has emerged as a novel therapeutic in cardiovascular medicine. LncRNAs are endogenous RNAs that contain over 200 nucleotides and regulate gene expression. Recent studies suggest critical roles of lncRNAs in modulating the initiation and progression of cardiovascular diseases. For example, aberrant lncRNA expression has been associated with the pathogenesis of ischemic heart failure. In this article, we present a synopsis of recent discoveries that link the roles and molecular interactions of lncRNAs to cardiovascular diseases. Moreover, we describe the prevalence of circulating lncRNAs and assess their potential utilities as biomarkers for diagnosis and prognosis of heart disease.

Is Blush on CT Scan in Patients With Pelvic Fracture Associated With Embolization Rates and Outcomes?

INTRODUCTION: In trauma patients with pelvic fractures, computed tomography (CT) scans are a critical tool to evaluate life-threatening hemorrhage. Contrast extravasation, or "blush", on CT may be a sign of bleeding, prompting a consult for angiography and possible embolization. However, the utility of blush on CT is controversial. We sought to evaluate our experience with patients who sustained pelvic fractures and had blush on CT. METHOD: A retrospective review was performed for all patients with blunt pelvic fractures between January 1, 2017 and December 31, 2018. Demographic, clinical, radiographic, and injury data were obtained. Comparison of mortality, hospital length of stay (LOS), and intensive care unit (ICU) LOS was performed for 3 subgroups: angio versus no angio; embo versus no embo; prophylactic embo versus therapeutic embo. We also calculated the sensitivity, specify, positive predictive value (PPV), and negative predictive value (NPV) of CT blush to predict the need for embolization. RESULTS: 889 patients were found to have a blunt pelvic fracture. 51 patients had blush on CT scan. 29 (56.9%) underwent angiography. 17 (58.6%) of these 29 patients were found to have extravasation and were embolized. 12 patients had an angio with no extravasation, and 6 of these patients (50%) underwent prophylactic embolization. No significant difference was found for hospital LOS, ICU LOS, or mortality in our 3 groups. Sensitivity, specificity, PPV, and NPV for CT blush were 74%, 96%, 33%, 99%, respectively. CONCLUSION: Patients with active extravasation undergoing embolization had similar outcomes to patients without active extravasation. Blush on CT scan had low sensitivity and low PPV but high specificity and high NPV. Future studies need to include careful attention to the CT protocol utilized as well as patient selection.

Deletion of the Duffy antigen receptor for chemokines (DARC) promotes insulin resistance and adipose tissue inflammation during high fat feeding.

OBJECTIVE: Inflammation in adipose tissues in obesity promotes insulin resistance and metabolic disease. The Duffy antigen receptor for chemokines (DARC) is a promiscuous non-signaling receptor expressed on erythrocytes and other cell types that modulates tissue inflammation by binding chemokines such as monocyte chemoattractant protein-1 (MCP-1) and by acting as a chemokine reservoir. DARC allelic variants are common in humans, but the role of DARC in modulating obesity-related metabolic disease is unknown. METHODS: We examined body weight gain, tissue adiposity, metabolic parameters and inflammatory marker expression in wild-type and DARC knockout mice fed a chow diet (CD) and high fat diet (HFD). RESULTS: Compared to wild-type mice, HFD-fed DARC knockout mice developed glucose intolerance and insulin resistance independent of increases in body weight or adiposity. Interestingly, insulin sensitivity was also diminished in lean male DARC knockout mice fed a chow diet. Insulin production was not reduced by DARC gene deletion, and plasma leptin levels were similar in HFD fed wild-type and DARC knockout mice. MCP-1 levels in plasma rose significantly in the HFD fed wild-type mice, but not in the DARC knockout mice. Conversely, adipose tissue MCP-1 levels were higher, and more macrophage crown-like structures were detected, in the HFD fed DARC knockout mice as compared with the wild-type mice, consistent with augmented adipose tissue inflammation that is not accurately reflected by plasma levels of DARC-bound MCP-1 in these mice. CONCLUSIONS: These findings suggest that DARC regulates metabolic function and adipose tissue inflammation, which may impact obesity-related disease in ethnic populations with high frequencies of DARC allelic variants.