Ellen Thompson

Agonists of epoxyeicosatrienoic acids reduce infarct size and ameliorate cardiac dysfunction via activation of HO-1 and Wnt1 canonical pathway

Myocardial infarction (MI) is complicated by ventricular fibrosis and associated diastolic and systolic failure. Emerging studies implicate Wnt1 signaling in the formation of new blood vessels. Epoxyeicosatrienoic acids (EETs)-mediated up-regulation of heme oxygenase-1 (HO-1) protects against the detrimental consequences of MI in several animal models, however, the mechanism(s) by which this occurs remains unclear. The aim of this study was to examine these mechanisms in the LAD ligation animal model of post infarcted heart failure. Specifically, we sought to clarify the mechanistic basis of the interactions of the Wnt1 canonical pathway, HO-1 and associated angiogenesis. Human microvascular endothelial cells (HMECs) were exposed to anoxia and treated with the EET agonist, NUDSA, in the presence and absence of tin mesoporphyrin (SnMP). Increased capillary density, and Wnt1 and HO-1 expression occurred in cells treated with NUDSA. Anoxic HMECs treated with NUDSA and Wnt1 siRNA, exhibited decreased in the expression of β-catenin and the Wnt1 target gene, PPARδ (p<0.05 vs. NUDSA). Furthermore, blocking the Wnt 1 antagonist, Dickkopf 1, by siRNA increased β-catenin and PPARδ expression, and this effect was further enhanced by the concurrent administration of NUDSA. In in vivo experiments, C57B16 mice were divided into 4 groups: sham, mice with MI via LAD ligation and mice with MI treated with NUDSA, with and without SnMP. Increased fractional area change (FAC) and myocardial angiogenesis were observed in mice treated with NUDSA (p<0.05 vs. MI). Increased expression of HO-1, Wnt1, β-catenin, adiponectin, and phospho-endothelial nitric oxide synthetase (p-eNOS), and a decrease in the glycosylated subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, gp91(phox) expression occurred in cardiac tissue of mice treated with NUDSA (p<0.05 vs. MI). SnMP reversed these effects. This novel study demonstrates that increasing the canonical Wnt1 signaling cascade with the subsequent increase in HO-1, adiponectin and angiogenesis ameliorates fibrosis and cardiac dysfunction in a mouse model of MI and supports the hypothesis that HO-1 is an integral component of the EETs-adiponectin axis and is central for the control of resistance to fibrosis and vascular dysfunction and in part determine how they influence the cellular/vascular homeostasis and provides insight into the mechanisms involved in vascular dysfunction as well as potential targets for the treatment of CVD.

Diversion of the inferior vena cava following repair of atrial septal defect causing hypoxemia

Atrial septal defects (ASDs) are a common congenital abnormality, and operative repair is a routine, safe procedure. Diversion of the inferior vena cava (IVC) into the left atrium is an unusual complication following ASD closure. We report a case that illustrates the problem created by this right‐to‐left shunt. A middle‐aged woman underwent ASD repair. She developed hypoxemia postoperatively. A transthoracic echocardiogram confirmed a right‐to‐left shunt, found only with agitated saline injected into the femoral vein, not into the basilic vein. Surgical reexploration revealed a residual ASD diverting IVC flow into the left atrium, which was repaired with a pericardial patch. Echocardiography with agitated saline injected from the femoral vein is an easy method to diagnose this uncommon complication. (ECHOCARDIOGRAPHY, Volume 21, May 2004)

Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population.

Objectives: Diabetic cardiomyopathy (DCM) is an established complication of diabetes mellitus. In West Virginia, the especially high incidence of diabetes and heart failure validate the necessity of developing new strategies for earlier detection of DCM. Since most DCM patients remain asymptomatic until the later stages of the disease when the fibrotic complications become irreversible, we aimed to explore biomarkers that can identify early-stage DCM. Methods: The patients were grouped into 4 categories based on clinical diabetic and cardiac parameters: Control, Diabetes (DM), Diastolic dysfunction (DD), and Diabetes with diastolic dysfunction (DM+DD), the last group being the preclinical DCM group. Results: Echocardiography images indicated severe diastolic dysfunction in patients with DD+DM and DD compared to DM or control patients. In the DM and DM+DD groups, TNFα, isoprostane, and leptin were elevated compared to control (p<0.05), as were clinical markers HDL, glucose and hemoglobin A1C. Fibrotic markers IGFBP7 and TGF-β followed the same trend. The Control group showed higher beneficial levels of adiponectin and bilirubin, which were reduced in the DM and DM+DD groups (p<0.05). Conclusion: The results from our study support the clinical application of biomarkers in diagnosing early stage DCM, which will enable attenuation of disease progression prior to the onset of irreversible complications.

Creating a Biomarker Panel for Early Detection of Chemotherapy Related Cardiac Dysfunction in Breast Cancer Patients

Cardiotoxicity is an important issue for breast cancer patients receiving anthracycline-trastuzumab therapy in the adjuvant setting. Studies show that 3-36% of patients receiving anthracyclines and/or trastuzumab experience chemotherapy related cardiac dysfunction (CRCD) and approximately 17% of patients must stop chemotherapy due to the consequences of CRCD. There is currently no standardized, clinically verified way to detect CRCD early, but common practices include serial echocardiography and troponin measurements, which can be timely, costly, and not always available in areas where health care resources are scarce. Furthermore, detection of CRCD, before there is any echocardiographic evidence of dysfunction or clinical symptoms present, would allow maximal benefit of chemotherapy and minimize cardiac complications. Creating a panel of serum biomarkers would allow for more specificity and sensitivity in the early detection of CRCD, which would be easy to implement and cost effective in places with limited health care. Based on a review of the literature, we propose creating a biomarker panel consisting of topoisomerase 2β, serum troponin T/I, myeloperoxidase, NT-proBNP, miR-208b, miR-34a, and miR-150 in breast cancer patients receiving anthracyclines and/or trastuzumab to detect CRCD before any signs of overt cardiotoxicity are apparent.

Developing a panel of biomarkers and miRNA in patients with myocardial infarction for early intervention strategies of heart failure in West Virginian population

Background Myocardial infarction is the most common cause of heart failure. MI has been intricately linked to ventricular remodeling, subsequently leading to the reduction in the cardiac ejection fraction causing HF. The cumulative line of evidence suggests an important role of several biomarkers in modulating the cardiac vasculature, further contributing towards the progression of post-MI complications. Studies have demonstrated, yet not fully established, that an important biomarker, IL-10, has a causal relationship with MI and associated cardiac dysfunction. Hypothesis This study aims to establish the role of IL-10 as a prognostic marker for the cardiovascular outcomes and to develop a panel of biomarkers and circulating miRNAs that could potentially result in the early detection of HF resulting from MI, allowing for early intervention strategies. Methods and results Blood was withdrawn and echocardiography assessment was performed on a total of 43 patients that were enrolled, within 24 hours of the incidence of MI. Patients were divided in three main groups, based on the ejection fraction measurement from echocardiography: control (n = 14), MI with normal EF (MI+NEF, n = 13) and MI with low EF (MI+LEF, n = 16). Our results showed that TGFβ-1, TNF-α, IL-6 and MMP-9 were upregulated significantly in MI+NEF group and more so in MI+LEF group, as compared to control group (p<0.01). The circulating levels of miR-34a, miR-208b and miR-126 were positively correlated and showed elevated levels in the MI+NEF group, even higher in MI+LEF group, while levels of miR-24 and miR-29a were reduced in MI+NEF, and much lower in MI+LEF, as compared to the control group (p<0.01). Our results also demonstrated a direct correlation of IL-10 with the ejection fraction in patients with MI: IL-10 was elevated in MI+NEF group, however, the levels were significantly low in MI+LEF group suggesting an important role of IL-10 in predicting heart failure. Importantly, our study confirmed the correlation of IL-10 with EF by our follow-up echocardiography assessment that was performed 2 months after the incidence of MI. Conclusion Our results support the clinical application of these serum biomarkers to develop a panel for appropriate prognosis and management of adverse cardiac remodeling and development of heart failure post-myocardial infarction.