Mohapradeep Mohan

Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status

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Identification of novel biomarkers in plasma for prediction of treatment response in patients with heart failure.

BACKGROUND Heart failure is a complex clinical syndrome that occurs at the end stage of heart disease. Despite advances in therapy for heart failure, improvement of clinical outcomes remains a challenge for physicians. The identification of treatment response early in the course of disease would be useful to improve management of these patients. The aim of this study was to identify novel biomarkers in plasma that could predict treatment response in patients with heart failure. METHODS Patients with heart failure who met inclusion and exclusion criteria according to the guidelines of the European Society of Cardiology were recruited. Uptitration of angiotensin-converting enzyme inhibitors and β blockers was performed over 6 months. Patients were followed up for clinical events within the next 24 months. Plasma proteins in patients who responded to standard treatment (responders) were compared with patients who died or were re-admitted for heart failure (non-responders). Plasma samples were depleted of 14 high abundance proteins with a multiple affinity removal system column (MARS). Then plasma samples were analysed on two-dimensional liquid chromatography coupled to a tandem mass spectrometry (2D LC-ESI-MS/MS) in high definition mode (HDMS(E)) to identify and quantify the different expression of proteins in plasma. Finally, ELISA was used to verify candidate biomarkers. FINDINGS Participants were 100 patients with heart failure matched for sex and age (50 responders [25 women], 50 non-responders [25 women], mean age 76·6 years [SD 8·1]). Of the non-responders, 18 died and 32 were re-admitted to hospital. 2D LC-ESI-MS/MS showed that the expression of neurotrimin (NTM) was highly upregulated, by 26·5 times (p<0·0001), in the responder group compared with the non-responder group. ELISA in the verification phase showed that the concentrations of NTM in plasma were significantly higher in the responders and lower in the non-responders (mean 4·73 log10 relative light units [SD 0·07] vs 4·70 [0·08], p=0·036). When ANOVA with Bonferroni post-hoc comparisons was used in three outcome subgroups (responders, patients re-admitted to hospital, and deaths), NTM concentrations were significantly different between death and the other groups (higher in responder vs death group, p<0·0001; higher in re-admission vs death group, p=0·001). INTERPRETATION Our findings suggest that NTM as a novel biomarker in heart failure will not only add information to understand the pathophysiological mechanisms of heart failure better, but also might provide a more accurate prediction of treatment response to guide medical therapy. In addition, a novel therapeutic target could be identified for design of drugs to improve outcomes. Futher work is required in larger populations to confirm this biomarker. FUNDING European Unions Seventh Framework Programme (BIOSTAT-CHF), John and Lucille van Geest Foundation.

EFFECT OF GLYCAEMIC CONTROL ON OUTCOME IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND CHRONIC HEART FAILURE

Controversy exists regarding the importance of glycaemic control in patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) based on conflicting previous reports that had used a single baseline HbA1c. HbA1c variability has also been linked to vascular complications in T2DM. We

PROGNOSTIC ROLE OF NEUTORPHIL TO LYMPHOCYTE RATIO IN PREDICTING OUTCOMES IN PATIENTS WITH CHRONIC HEART FAILURE

Background: Inflammatory cytokines such as interleukin-6 (IL-6) have been implicated in chronic heart failure (CHF) progression & development, mediating adverse cardiac remodeling. Neutrophils and lymphocytes are cellular components of systemic inflammation that are regulated by cytokines especially

P13 Anti-inflammatory effects of metformin – useful in cardiovascular disease?

Background Metformin is the first line drug treatment for type 2 diabetes (T2D). Along with its anti-hyperglycaemic properties, metformin is also associated with beneficial effects in cardiovascular disease (CVD). In observational studies, metformin has been associated with fewer adverse CV events.1 How metformin induces these effects is unclear as its mechanism of action is still to be determined. Inflammation, including NF-κB signalling, has been recognised as a contributing factor to both diabetes and CVD with metformin recently reported to have effects upon inflammatory signalling.2,3 In this study, we have utilised primary cells and human plasma to investigate the anti-inflammatory effects of metformin and how this may be useful in CVD. Results In mouse hepatocytes, TNFα-dependent IκB degradation and expression of pro-inflammatory mediators were inhibited by metformin and the IKKβ inhibitor BI605906. These effects upon NF-κB signalling could be separated from metabolic effects as BI605906 did not replicate metformin’s actions upon lipogenic gene expression, glucose production or AMPK activation. Analysing the plasma from a non-diabetic heart failure cohort,4 metformin use was associated with suppression of several plasma cytokines. Conclusion This study has demonstrated that the anti-inflammatory effects of metformin are separate from its anti-hyperglycaemic actions. This knowledge indicates that metformin may be harnessed for use in ‘at risk’ CVD groups irrespective of diabetes status. References Evans, et al. Diabetologia 2006;49:930–6 Isoda, et al. Arteriosclerosis, Thrombosis, and Vascular Biology 2006;26:611–7 Woo, et al. PLoS One 2014;9:e91111 Wong, et al. European Journal of Heart Failure 2012;14:1303–10

PROGNOSTIC ROLE OF COMBINED PLATELET COUNT AND NEUTROPHIL-TO-LYMPHOCYTE RATIO IN PREDICTING OUTCOME IN PATIENTS WITH CHRONIC HEART FAILURE

Inflammatory cytokines such as interleukin-6 (IL-6) have been implicated in chronic heart failure (CHF) progression, mediating adverse cardiac remodelling. Neutrophil-to-lymphocyte ratio (NLR) and reactive thrombocytosis are cellular components of systemic inflammation that are regulated by

INSULIN RESISTANCE IS ASSOCIATED WITH ALL-CAUSE MORTALITY AND ACCELERATES THE RISK OF PROGRESSION TO DIABETES IN NON DIABETIC HEART FAILURE PATIENTS

Heart failure is an insulin resistant state. Insulin resistance is highly prevalent in non-diabetic patients with heart failure. The impact of insulin resistance on the development of diabetes mellitus and mortality has not been fully defined. The purpose of this study was to investigate whether

60 Insulin Resistance is Associated with All-cause Mortality and Accelerates the Risk of Progression to Diabetes in Non-diabetic Heart Failure Patients

Background Heart failure is an insulin resistant state. Insulin resistance is highly prevalent in non-diabetic patients with heart failure. The impact of insulin resistance on the development of diabetes mellitus and mortality has not been fully defined. Objectives The purpose of this study was to investigate whether insulin resistance is associated with all-cause mortality in a group of non-diabetic patients with heart failure. We have also investigated the impact of insulin resistance on the conversion to diabetes mellitus in these patients. Methods Insulin resistance, defined by fasting Insulin resistance index (FIRI ≥ 2.7) was assessed in 121 consecutive CHF patients (69 ± 10, 22 % females, 81% ischaemic, 61% insulin resistant and FIRI of 4.19 ± 3.8 at baseline) and was followed up for their most recent HbA1c/FPG measurements and mortality data using the electronic linkage system in Dundee, UK. The primary outcome for these cohorts of patients was all cause mortality and secondary outcome was the development of diabetes mellitus. Cox proportional hazard models were used with FIRI as a continuous variable. Results After a 6.6 years (IQR 4.7–6.9) median follow-up period, 46 (38%) patients died. A cox proportional hazard model adjusted for relevant covariates showed that the degree of insulin resistance, was significantly associated (HR 1.09, CI 95% 1.02–1.16), p = 0.008) with all-cause mortality. Of the 81 patients we followed up for the development of diabetes, 29% of Insulin resistant-CHF patients developed diabetes, compared to 10% of non-IR-CHF patients. Conclusion In conclusion, higher FIRI relates to higher all-cause mortality in heart failure patients. We also found out that heart failure patients with IR are at high risk of developing diabetes.