Scholarly article on topic '178 Circulating Micrornas for Predicting and Monitoring Response to Mechanical Circulatory Support from a left Ventricular Assist Device'

178 Circulating Micrornas for Predicting and Monitoring Response to Mechanical Circulatory Support from a left Ventricular Assist Device Academic research paper on "Basic medicine"

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Academic research paper on topic "178 Circulating Micrornas for Predicting and Monitoring Response to Mechanical Circulatory Support from a left Ventricular Assist Device"

BCS Abstracts 2014

LOS groups had significant reductions in diastolic blood pressure. In addition, the PRO group showed reduced basal HR (373 bpm ±13 x 421 bpm ± 42), and the ENL group presented reduced intrinsic pacemaker HR (308 bpm ± 26 x 343 bpm ± 30). The vehicle group showed sympathetic dominance in determining the basal HR, in contrast, the PRO group showed vagal dominance in determining the baseline HR when compared to the ENL, HCTZ and AML groups, considering that for these animals the chrono-tropic response after the administration of propranolol was significantly lower, when compared to the response obtained after the administration of atropine. For HRV, the pharmacologically treated group showed no significant difference in the values of low frequency band (LF; 0.2-0.75 Hz) and higher power in high frequency band (HF; 0.75-3.0 Hz), compared to the vehicle group. The analysis of systolic arterial pressure variability revealed that the ENL group showed a reduction in the LF band, compared to the vehicle, LOS, PRO and HCTZ groups. Conclusion None of the pharmacological treatment was able to completely attenuate the adverse effects of hypertension on the auto-nomic parameters in spontaneously hypertensive rats, however, the group treated with Enalapril showed a positive effect on the SAPV

THE ALPHA-KETOGLUTARATE RECEPTOR GPR99 REGULATES PATHOLOGICAL CARDIAC HYPERTROPHY

Ameh Omede*, Delvac Oceandy, Mamas Mamas, Elizabeth Cartwright, Min Zi, Sukhpal Prehar, Arfa Maqsood. Institute of Cardiovascular Sciences, University of Manchester

interstitial fibrosis and larger cell surface area compared to wildtype controls. The cardiac function as indicated by fractional shorting (FS) is significantly lower in the knockout mice compared to wildtype mice following TAC. To examine the mechanism we performed yeast two hybrid screening analysis and have identified CSN5, a member of the COP9 signalosome complex, as a novel interacting partner of the GPR99 receptor. COP9 is known as a regulator of protein degradation via the ubiquitin proteasome system. Adenoviral mediated overexpression of GPR99 in cardio-myocytes induced the ubiquitination and degradation of a prohypertrophic factor interferon regulatory factor 5 (IRF5). Consistently, in GPR99-/- mice expression of IRF5 was significantly increased following TAC, which might provide the possible mechanism responsible for the increased hypertrophy in these mice. Conclusion Our findings suggest that the alpha-ketoglutarate receptor GPR99 modulates pathological hypertrophic response by modulating ubiquitination of IRF5. Thus, GPR99 may become the possible target for heart failure treatment.

CIRCULATING MICRORNAS FOR PREDICTING AND MONITORING RESPONSE TO MECHANICAL CIRCULATORY SUPPORT FROM A LEFT VENTRICULAR ASSIST DEVICE

1Andrew Morley-Smith*, 2Adam Mills, 3Steven Jacobs, 3Bart Meyns, 3Filip Rega, 1Andre Simon, 1John Pepper, Alexander Lyon, 4Thomas Thum. 'Imperial College London and Royal Brompton/Harefield; 2Imperial College London; 3University Hospitals Leuven; 4Hannover Medical School and Imperial College London

10.1136/heartjnl-2014-306118.177

Introduction GPR99, a member of G-protein coupled receptor family, is expressed in the heart. Previous studies suggested that this receptor can bind to alpha-ketoglutarate, a metabolite that is elevated in the serum of heart failure (HF) patients. However, the functional role of GPR99 in cardiomyocytes is unknown. In this study, we investigated whether GPR99 regulates cardiac hypertrophy, a key process in the development of HF. Results Mice with genetic ablation of GPR99 (GPR99-/-) displayed an increased in hypertrophy following transverse aortic constriction (TAC) as indicated by heart weight/body weight ratio. Furthermore, GPR99-/- mice showed significantly increased

10.1136/heartjnl-2014-306118.178

Purpose There are few non-invasive techniques to predict and monitor patients' responses to left ventricular assist device (LVAD) therapy. MicroRNAs (miRs) are small noncoding RNAs with intricate roles in cardiovascular disease. They remain stable in the circulation, are readily quantified, and may be useful as new biomarkers. This study sought to identify candidate miR biomarkers for further investigation and to investigate whether these circulating miRs were of myocardial origin. Methods and Results We studied 55 serial plasma and myocar-dial samples from 19 patients who underwent HeartMate II LVAD implantation, and used a screening microarray to analyse

Abstract 178 Figure 1 Box plots showing changes miR-483-3p expression and NT-proBNP levels after 6 months LVAD therapy. There is upregulation of plasma (A) and myocardial (B) miR-483-3p expression, with fold change 2.32 (1.30-2.44;p = 0.021) and 1.799 (0.717-4.719; p 0.169) respectively. NT-proBNP shows a corresponding significant reduction. Outlier results are shown with -. *Significant to p

Heart 2014; 100(Suppl 3):A1-A138

BCS Abstracts 2014

the change in expression of 1,113 miRs from pre-implant and 6 months follow-up. Twelve miRs showed significant variation and underwent validation, with miR-1202 and miR-483-3p selected for further study. The key findings in the test cohort (n = 8) were: (1) miR-483-3p showed upregulation after 6 months of LVAD therapy in circulating plasma (median fold change 2.32 (1.30-2.44); p = 0.021) and in ventricular myocardium (median fold change 1.799 (0.717-4.719; p = 0.169). This mirrored the reduction in NT-proBNP levels at 6 months (fold change 0.30 (0.08-0.43); p = 0.004; see Figure). (2) Using change in NT-proBNP at 3 months as a marker of clinical response to LVAD therapy, baseline expression of plasma miR-1202 identified good versus poor LVAD responders (absolute expression 1.296 (1.293-1.306) vs. 1.311 (1.310-1.318) A.U.; p = 0.004). (3) Both miR-483-3p and miR-1202 are also enriched in ventricular myocardium suggesting the heart as the possible source of these plasma miRs.

Conclusions This is the first report of circulating miR bio-markers in LVAD patients. We demonstrate the feasibility of this approach, and report the potential for miR-483-3p and miR-1202 respectively to monitor and predict response to LVAD therapy. We suggest that changes in miR-483-3p expression could provide a more specific assessment of ventricular function that complements the changes in systemic neuroendocrine milieu recorded by serial measurement of natriuretic peptides, and suggest that miR-1202 could be valuable for judging the likelihood of good response to LVAD support. However, these conclusions are weakened by small sample size and retrospective analysis. We propose further work to study these hypotheses further and elucidate roles for miR-483-3p and miR-1202 in clinical practice and in underlying biological processes.

THE ROLE OF MICROPARTICLES IN CAROTID DISEASE

Andrew Schiro*, 2Fiona Wilkinson, 2Ria Weston, 3JVincent Smyth, 'Andrew JBoulton, 3Ferdinand Serracino-Inglott, 2Yvonne MAlexander. 'University of Manchester; 2Manchester Metropolitan University; 3Manchester Royal Infirmary

10.1136/heartjnl-2014-306118.179

Introduction Endothelial microparticles (EMPs) are released from dysfunctional endothelial cells. We hypothesised that patients with unstable carotid plaque have higher levels of circulating microparticles compared to patients with stable plaques which could be related to a specific cytokine profile. Methods Circulating EMPs and inflammatory cytokine levels were measured in seventy patients with significant carotid disease undergoing carotid endarterectomy and 20 healthy controls. Fifty one (73%) patients had symptomatic disease whilst 19 (27%) were asymptomatic. EMPs (CD31+/ Annexin V+ CD42b-) were quantified using flow cytometry. Immunohistological analysis of carotid plaques for CD68+, CD206+ macrophages, TNF-a smooth muscle actin and osteopontin was performed, together with Alizarin red staining for detection of calcific deposits. Bioplex assays were used for cytokine analysis. Plaques were graded according to the American Heart Association plaque scoring system. Results Significantly higher EMP levels were observed in symptomatic patients compared to controls, p = 0.01, while no differences were noted in EMP levels in asymptomatic vs controls p = 0.11. The higher EMP levels appeared to associate with the unstable plaques which also had a significantly higher level of CD68+ macrophages compared to stable plaques (AHA I-IV) and higher circulating levels of Chemokine ligand-9 (CXCL-9) (p < 0.004). Of note, macrophage inhibitory factor (MIF) was among the

chemokines that were elevated in the circulation of patients with stable plaques, whether a lack of this factor in unstable plaques has direct effects on phenotype remains to be elucidated. Other factors elevated in patients with stable plaques were IL-16, cutaneous T-cell attracting chemokine (CTACK), and stem-cell growth factor-b (SCGF-b) (p value of 0.05, 0.035 and 0.002 respectively). Conclusion Circulatory EMP and specific inflammatory cytokine levels are raised in patients with unstable plaques, while MIF, a potentially protective factor was elevated in serum of patients with stable plaques. These data could have major implications for the development of a diagnostic tool whereby EMPs together with markers of macrophage activity could act in a combined manner as biomarkers of plaque vulnerability and stroke susceptibility.

CAN NEUTROPHIL APOPTOSIS BE TARGETED THERAPEUTICALLY TO MODIFY INFLAMMATION DURING MYOCARDIAL INFARCT HEALING?

Xiaofeng Zhao*, David Dorward, Adriano Rossi, Gillian Gray. University of Edinburgh 10.1136/heartjnl-2014-306118.180

Neutrophils are rapidly recruited to infarct site in response to cardiomyocyte death. Apoptosis and phagocytosis by macrophages prevents further damage to host tissues, but can also polarise macrophages towards an anti-inflammatory phenotype, potentially enhancing repair and reducing infarct expansion after myocardial infarction. Pharmacological induction of neutrophil apoptosis by cyclin-dependent kinase inhibitor drugs (CDKi) has been shown to enhance resolution of inflammation in the murine lung (Rossi et al ., 2006). The present study study investigated the in vitro effects of a CDKi (AT7519) on mouse neutrophil apoptosis and determined its effects on agonist-induced Ca2+ flux.

Immature bone marrow-derived neutrophils (BMDNs) were isolated and inflammatory neutrophils obtained from the lavage of thioglycollate-induced peritonitis (TGNs). Apoptosis was assessed by flow-cytometric analysis of annexinV/propidium iodide (PI) binding, DNA incorporation of PI into permeablised cells (hyplodiploid peak) and morphological assessment of cyto-centrifuge preparations. Intracellular Ca2+ flux was assessed by spectrofluorimetric analysis of Fura-2 loaded cells.

BMDNs and TGNs underwent constitutive apoptosis at 6 and 20h, an effect enhanced by AT7519 in a concentration, time and caspase-dependent manner. For example, at 6h, apoptosis assessed by hypodiploid peak quantification was 6.7% in control BMDNs vs 15.2% in 1 pM AT7519 treated cells. In TGNs, apoptosis as assessed by annexinV/PI binding at 6 h were 6.2% in control vs 12.0% in 1pM AT7519 treated cells (n = 6). Interestingly, AT7519 did not directly induce Ca2+ fluxes in BMDNs or TGNs nor did it affect Ca2+ fluxes triggered by neutrophil agonists (fMLF and PAF).

Thus AT7519 enhances mouse neutrophil apoptosis without affecting early activation responses such as agonist-induced Ca2+ flux and therefore suggests that CDKi induce apoptosis even in the presence of stimuli found at inflammatory sites, which make it a promising anti-inflammatory agent to be used in the setting of MI.

This study was supported by a Chinese Scholarship Council/ University of Edinburgh Fellowship to XZ and by a BHF Centre of Research Excellence Award.

REFERENCE

Rossi AG, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Med 2006;12:1056-1064

Heart 2014;100(Suppl 3):A1-A138

178 Circulating Micrornas for Predicting and Monitoring Response to Mechanical Circulatory Support from a left Ventricular Assist Device

Andrew Morley-Smith, Adam Mills, Steven Jacobs, Bart Meyns, Filip Rega, Andre Simon, John Pepper, Alexander Lyon and Thomas Thum

Heart 2014 100: A100-A101

doi: 10.1136/heartjnl-2014-306118.178

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