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Heart failure (HF) screening strategies require biomarkers to predict disease manifestation to aid HF surveillance and management programmes. The aim of this study was to validate a previous proteomics discovery programme that identified Tetranectin as a potential HF biomarker candidate based on expression level changes in asymptomatic patients at future risk for HF development. The initial study consisted of 132 patients, comprising of HF (n = 40), no-HF controls (n = 60), and cardiac surgery patients (n = 32). Serum samples were quantified for circulating levels of Tetranectin and a panel of circulating fibro-inflammatory markers. Cardiac tissue served as a resource to investigate the relationship between cardiac Tetranectin levels and fibrosis and inflammation within the myocardium. An independent cohort of 224 patients with or without HF was used to validate serum Tetranectin levels. Results show that circulating Tetranectin levels are significantly reduced in HF patients (p

Cancer therapeutics-related cardiac dysfunction (CTRCD) has emerged as a major cause of morbidity and mortality in cancer survivors. Effective clinical management of CTRCD is impeded by a lack of sensitive diagnostic and prognostic strategies. Circulating molecular markers could potentially address this need as they are often indicative of cardiac stress before cardiac damage can be detected clinically. A growing understanding of the underlying physiological mechanisms for CTRCD has inspired research efforts to identify novel pathophysiologically relevant biomarkers that may also guide development of cardio-protective therapeutic approaches. The purpose of this review is to evaluate current circulating biomarkers of cardiac stress and their potential role in diagnosis and management of CTRCD. We also discuss some emerging avenues for CTRCD-focused biomarker investigations.

Background The purpose of this study was to investigate the utility of BNP, hsTroponin-I, interleukin-6, sST2, and galectin-3 in predicting the future development of new onset heart failure with preserved ejection fraction (HFpEF) in asymptomatic patients at-risk for HF. Methods This is a retrospective analysis of the longitudinal STOP-HF study of thirty patients who developed HFpEF matched to a cohort that did not develop HFpEF (n = 60) over a similar time period. Biomarker candidates were quantified at two time points prior to initial HFpEF diagnosis. Results HsTroponin-I and BNP at baseline and follow-up were statistically significant predictors of future new onset HFpEF, as was galectin-3 at follow-up and concentration change over time. Interleukin-6 and sST2 were not predictive of future development of new onset HFpEF in this study. Unadjusted biomarker combinations of hsTroponin-I, BNP, and galectin-3 could significantly predict future HFpEF using both baseline (AUC 0.82 [0.73,0.92]) and follow-up data (AUC 0.86 [0.79,0.94]). A relative-risk matrix was developed to categorize the relative-risk of new onset of HFpEF based on biomarker threshold levels. Conclusion We provided evidence for the utility of BNP, hsTroponin-I, and Galectin-3 in the prediction of future HFpEF in asymptomatic event-free populations with cardiovascular disease risk factors.

Introduction: Recent evidence suggests that transcriptional reprogramming is involved in the pathogenesis of cardiac remodeling (cardiomyocyte hypertrophy and fibrosis) and the development of heart failure. 5-Azacytidine (5aza), an inhibitor of DNA methylation approved for hematological malignancies, has previously demonstrated beneficial effects on cardiac remodeling in hypertension. The aim of our work was to investigate whether pressure overload is associated with alterations in DNA methylation and if intervention with low-dose 5aza can attenuate the associated pathological changes. Methods and Results: C57Bl6/J mice underwent surgical constriction of the aortic arch for 8 weeks. Mice began treatment 4 weeks post-surgery with either vehicle or 5aza (5 mg/kg). Cardiac structure and function was examined in vivo using echocardiography followed by post mortem histological assessment of hypertrophy and fibrosis. Global DNA methylation was examined by immunostaining for 5-methylcytosine (5MeC) and assessment of DNA methyltransferase expression. The results highlighted that pressure overload-induced pathological cardiac remodeling is associated with increased DNA methylation (elevated cardiac 5MeC positivity and Dnmt1 expression). Administration of 5aza attenuated pathological remodeling and diastolic dysfunction. These beneficial changes were mirrored by a treatment-related reduction in global 5MeC levels and expression of Dnmt1 and Dnmt3B in the heart. Conclusion: DNA methylation plays an important role in the pathogenesis of pressure overload-induced cardiac remodeling. Therapeutic intervention with 5aza, at a dose 5 times lower than clinically given for oncology treatment, attenuated myocardial hypertrophy and fibrosis. Our work supports the rationale for its potential use in cardiac pathologies associated with aberrant cardiac wound healing.

Pathological remodelling of the myocardium, including inflammation, fibrosis and hypertrophy, in response to acute or chronic injury is central in the development and progression of heart failure (HF). While both resident and infiltrating cardiac cells are implicated in these pathophysiological processes, recent evidence has suggested that endothelial cells (ECs) may be the principal cell type responsible for orchestrating pathological changes in the failing heart. Epigenetic modification of nucleic acids, including DNA, and more recently RNA, by methylation is essential for physiological development due to their critical regulation of cellular gene expression. As accumulating evidence has highlighted altered patterns of DNA and RNA methylation in HF at both the global and individual gene levels, much effort has been directed towards defining the precise role of such cell-specific epigenetic changes in the context of HF. Considering the increasingly apparent crucial role that ECs play in cardiac homeostasis and disease, this article will specifically focus on nucleic acid methylation (both DNA and RNA) in the failing heart, emphasising the key influence of these epigenetic mechanisms in governing EC function. This review summarises current understanding of DNA and RNA methylation alterations in HF, along with their specific role in regulating EC function in response to stress (e.g. hyperglycaemia, hypoxia). Improved appreciation of this important research area will aid in further implicating dysfunctional ECs in HF pathogenesis, whilst informing development of EC-targeted strategies and advancing potential translation of epigenetic-based therapies for specific targeting of pathological cardiac remodelling in HF.

Background Hypertension and/or myocardial infarction are common causes of heart failure in Type 2 diabetes. Progression to heart failure is usually preceded by ventricular dysfunction, linked to matrix metalloproteinase (MMP) mediated extracellular matrix changes. We hypothesise that the minor allele of genetic variant rs3918242 in the promoter region of the MMP-9 gene is associated with hypertension and/or myocardial infarction, with resultant progression of dysfunctional cardiac remodelling in patients with diabetes without symptomatic heart failure. Methods We genotyped 498 diabetes patients participating in the St Vincent’s Screening TO Prevent Heart Failure (STOP-HF) follow-up programme for the rs3918242 single nucleotide polymorphism and investigated associations with the co-primary endpoints hypertension and/or myocardial infarction using a dominant model. We also evaluated resulting cardiometabolic phenotype and progression of ventricular dysfunction and cardiac structural abnormalities over a median follow-up period of 3.5 years. Results The CT/TT genotype comprised 28.1% of the cohort and was associated with a twofold higher risk of myocardial infarction (17.9% vs 8.4%), a reduction in ejection fraction and greater left ventricular systolic dysfunction progression [adjusted OR = 2.56 (1.09, 6.01), p = 0.026] over a median follow-up of 3.5 years [IQR 2.6, 4.9 years]. Conversely, rs3918242 was not associated with hypertension, blood pressure, pulse pressure or left ventricular mass index at baseline or over follow up. Conclusions Diabetes patients with the minor T allele of rs3918242 in the STOP-HF follow up programme have greater risk of myocardial infarction, lower ejection fraction and greater progression of left ventricular systolic abnormalities, a precursor to heart failure. These data may support further work on MMP-9 as a biomarker of ventricular dysfunction and the investigation of MMP-9 inhibitors for heart failure prevention in diabetes, particularly in the post-infarction setting. ClinicalTrials.gov Identifier: NCT00921960

While it is well established that the haemodynamic cause of hypoxic pulmonary hypertension is increased pulmonary vascular resistance, the molecular pathogenesis of the increased resistance remains incompletely understood. Macrophage migration inhibitory factor is a pleiotropic cytokine with endogenous tautomerase enzymatic activity as well as both intracellular and extracellular signalling functions. In several diseases, macrophage migration inhibitory factor has pro-inflammatory roles that are dependent upon signalling through the cell surface receptors CD74, CXCR2 and CXCR4. Macrophage migration inhibitory factor expression is increased in animal models of hypoxic pulmonary hypertension and macrophage migration inhibitory factor tautomerase inhibitors, which block some of the functions of macrophage migration inhibitory factor, and have been shown to attenuate hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. However, because of the multiple pathways through which it acts, the integrated actions of macrophage migration inhibitory factor during the development of hypoxic pulmonary hypertension were unclear. We report here that isolated lungs from adult macrophage migration inhibitory factor knockout ( MIF –/– ) mice maintained in normoxic conditions showed greater acute hypoxic vasoconstriction than the lungs of wild type mice ( MIF +/+ ). Following exposure to hypoxia for three weeks, isolated lungs from MIF –/– mice had significantly higher pulmonary vascular resistance than those from MIF +/+ mice. The major mechanism underlying the greater increase in pulmonary vascular resistance in the hypoxic MIF –/– mice was reduction of the pulmonary vascular bed due to an impairment of the normal hypoxia-induced expansion of the alveolar capillary network. Taken together, these results demonstrate that macrophage migration inhibitory factor plays a central role in the development of the pulmonary vascular responses to chronic alveolar hypoxia.

Remodeling of cardiac tissue architecture is essential for normal organ development and maintaining homeostasis after injury. Injurious insults to the heart, such as hypertension and myocardial infarction, promote cellular responses including stimulation of resident inflammatory cells, activation of endothelial cells and recruitment of immune cells, hypertrophy of cardiomyocytes, and activation of fibroblasts. The physiological goal of this coordinated cellular response is to repair damaged tissue while maintaining or restoring cardiac contractile function. Persistent uncontrolled inflammation, hypertrophy, and fibrosis in the heart due to hyperactive wound healing are detrimental and impair cardiac performance, facilitating the progression to heart failure. Abnormal changes in gene expression promote acquisition of aberrant cellular phenotypes that drive cardiac remodeling. DNA methylation and histone modifications are epigenetic mechanisms that critically regulate chromatin structure and gene expression, and are essential for normal physiology and development. Increasing clinical and experimental evidence suggests that these epigenetic mechanisms are involved in driving aberrant wound healing and the development of heart failure. While most of our knowledge to date is on the heart as a whole, the precise contribution of DNA methylation and histone modifications in regulating aberrant cardiac remodeling at the cellular level is less defined. Therefore, this overview aims to summarize the role of DNA methylation and histone modifications (acetylation and methylation) in heart failure and to comprehensively dissect the role these mechanisms play in regulating the function of cardiomyocytes, fibroblasts, and immune cells in response to injury. © 2018 American Physiological Society. Compr Physiol 8:451-491, 2018.

Heart failure (HF) is growing at alarming rate worldwide, largely due to increased prevalence of obesity and type-2 diabetes mellitus (T2DM). It is recognised that clinical prognosis for DM patients diagnosed with HF, is significantly worse than that of non-DM HF patients. Diabetic cardiomyopathy (DCM) is defined as the presence of diabetic-associated diastolic dysfunction in the absence of explicit coronary artery disease or other typical cardiovascular risk factors. DCM significantly increases the risk of chronic HF, but is commonly considered an underlying condition with subclinical cardiac dysfunction, and therefore is frequently underdiagnosed. An effective strategy for prevention and treatment of DCM has yet to be established. Therefore it is imperative we identify clear pathophysiological mechanisms of DCM so as to ultimately determine potential diagnostic advancements and therapeutic targets. Investigating pathological pathways involved in development of DCM is impossible without the foundation of reliable experimental models. Inducing experimental T2DM in vivo is commonly accomplished via delivery of streptozotocin (STZ) or the use of high-fat diet (HFD). Standard STZ induction produces a metabolic phenotype representative of T2DM with consistent cardiac fibrosis and diastolic dysfunction, but also causes acute pancreatic inflammation more in line with type-1 DM; limiting the suitability of the model. HFD induction is more relevant in terms of obesity-related DM, with more chronic progression of pathological features; however it does not develop consistent diastolic dysfunction. Therefore, the objective of this study was to characterise an improved experimental model of T2DM with reliable development of DCM characteristics, more reflective of human disease. Several groups use a hybrid model combining HFD with a single dose of STZ (opposed to multiple doses). However, the precise protocols used are variable and poorly characterised with regard to cardiac fibrosis and diastolic dysfunction. The majority of previous studies deliver a 50–100 mg/kg dose of STZ following 3–4 weeks of HFD. We fed 4 week old, male C57BL6 mice HFD for an overall period of 10 months; experimental groups received 100 mg/kg STZ (or vehicle only) at either week 8 or week 12 of the diet. Mice were monitored in parallel with untreated mice on normal diet throughout the study. Weights were recorded weekly, blood glucose levels and cardiac function (measured by echocardiography) were recorded monthly. At the end of the study, mice were sacrificed at which point blood and excised heart tissue were collected and analysed. Results of this study indicate that a single dose of STZ at week 8 of the HFD is adequate to induce T2DM, providing evidence of cardiac fibrosis and diastolic dysfunction progression. We believe the data generated represents a reliable model of DCM and we propose that this model could be employed as the basis of future mechanistic and therapeutic studies.

Background Cardiac Ischemia caused by coronary artery disease and myocardial infarction (MI) and its complications such as heart failure, arrhythmias and sudden death, are collectively the leading cause of mortality worldwide. Ischaemic injury to the myocardium leads to the development of aberrant ventricular remodelling and fibrosis. This occurs partly through the accumulation of hyperactive fibroblasts that promote enhanced extracellular matrix deposition and aberrant scar tissue formation. Understanding the cellular mechanisms that promote this ischemia induced-hyperactive fibrotic phenotype may yield novel anti-remodelling therapies for ischaemic cardiac pathologies. We have recently shown that human myocardial tissue hypoxia is associated with an enhanced pro-fibrotic gene profile in the tissue and, more significantly, that hypoxia-induced pro-fibrotic changes in cardiac fibroblasts are associated with global DNA hypermethylation. Based on this epigenetics data, we have conducted a gene-specific methylation study to investigate methylation changes that occur in hypoxic ventricular fibroblasts and to gain novel insights into mechanisms that may contribute to post-ischemic cardiac remodelling. Methods Human ventricular cardiac fibroblasts were exposed to 1% oxygen for up to 8 days. Global methylation changes were assessed using anti-5-methylcytosine (5MeC) staining, flow cytometry, QPCR, and western blot. Gene-specific methylation changes associated with hypoxia and an increased fibrotic state were determined by 5MeC immunoprecipitation and GeneChip human promoter arrays (Affymetrix), and validated by bisulphite genomic sequencing (BGS). Results Hypoxia-induced pro-fibrotic changes in cardiac fibroblasts included increased cell proliferation and increased alpha smooth muscle actin, collagen 1, DNMT1 and DNMT3B expression which associated with global DNA hypermethylation. Array analysis revealed 37 gene-specific hypermethylation changes and 133-hypomethylation changes occurred in response to chronic hypoxia. Conclusion Epigenetic modifications and changes in the DNA methylation identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu in the heart during disease. The application of epigenetic-based therapy, such as pharmacological DNA methylation modifiers, to target the hyperactive fibroblast phenotype may serve as a treatment option for cardiac pathologies associated with fibrosis and ischemia.

Background Limited knowledge exists of the extent of epigenetic alterations, such as DNA methylation, in Heart Failure (HF). We conducted targeted DNA methylation sequencing to identify DNA methylation alterations in coding and non-coding RNA across different etiological sub-types of HF. Methods and results A targeted bisulfite sequence capture sequencing platform was applied to DNA extracted from cardiac interventricular septal tissue of 30 male HF patients encompassing etiologies including Hypertrophic Obstructive Cardiomyopathy (HOCM, n=12), Ischemic Cardiomyopathy (ISCM, n=9), Dilated Cardiomyopathy (DCM, n=9), and 9 control patients with non-failing hearts (NF). We detected 62,678 differentially methylated regions (DMR) in the studied HF cohort. By comparing each HF sub-group to the NF control group we identified 195 unique DMRs: 5 in HOCM, 151 in DCM, and 55 in ISCM. These translated to 4 genes/1 non-coding RNA (ncRNA) in HOCM, 131 genes/17 ncRNA in DCM, and 51 genes/5 ncRNA in ISCM. Subsequent gene/ncRNA expression analysis was assessed using qRT-PCR and revealed 6 genes: 4 hypermethylated (HEY2, MSR1, MYOM3, COX17), 2 hypomethylated (CTGF, MMP2); and 2 microRNA: 1 hypermethylated (miR-24–1), 1 hypomethylated (miR-155) with significantly up- or down-regulated expression levels consistent with the direction of methylation in the particular HF sub-group. Conclusions For the first time DNA methylation alterations and associated gene expression changes were identified in etiologically-variant pathological heart failure tissue. The methylation-sensitive and disease-associated genes/non-coding RNA identified from this study represent a unique cohort of loci that demonstrate a plausible potential as a novel diagnostic and/or therapeutic target in HF and warrant further investigation. Acknowledgement/Funding Enterprise Ireland; European Regional Development Fund under Ireland's European Structural and Investment Funds Programmes 2014-2020

Background Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome associated with significant morbidity and mortality. Microvascular inflammation, endothelial dysfunction and increased extracellular matrix (ECM) deposition have been proposed as major pathophysiological factors, where the systemic pro-inflammatory state arising from co-morbidities such as obesity, diabetes and hypertension is predictive for HFpEF. Lysosomal proteases, such as the cathepsin family, play an important role in degradation of cellular substrates and remodelling of the extracellular matrix (ECM). Cathepsin S (CatS) is thought to be a particularly potent cysteine protease cleaving elastin and generating bioactive elastin peptides. Recent reports have highlighted altered levels of CatS in conditions of cardiac stress, remodelling, and dysfunction, however, whether alterations of CatS are present in the clinical scenario of HFpEF remains to be determined. Purpose: This study investigated whether levels of CatS are altered in HFpEF patients and if there is an association with CatS and pathophysiological cardiac processes such as inflammation and fibrosis. Methods This work spanned three different cohorts. Cohort 1: Levels of CatS were examined in serum samples of n=199 non heart failure (non-HF) and n=70 HFpEF patients by ELISA. Cohort 2: Gene expression of CatS and inflammatory markers were examined in monocytes isolated and purified from peripheral blood of n=30 non-HF and n=17 HFpEF patients. Cohort 3: Myocardial tissue and peripheral serum samples were procured from n=37 stable patients undergoing elective cardiac-bypass surgery. Samples were analysed for CatS levels and fibro-inflammatory markers relevant to cardiac fibrosis by qPCR, ELISA and radio-immuno assays. Results HFpEF patients had significantly higher levels of serum CatS compared with non-HF controls. CatS gene expression in isolated peripheral monocytes significantly correlated with markers of both classical (CCR2) and alternative (CD163, CX3CR1 and matrix metalloproteinase 9) activation. Myocardial CatS gene expression was positively correlated with the hypoxia marker carbonic anhydrase IX, tumour necrosis factor alpha, procollagen C-proteinase, matrix metalloproteinase 1, and lysyl oxidase gene expression. Similarly, serum levels of CatS correlated with both pro-inflammatory (IL-6, IL-8, MCP-1 and TNFα) and pro-fibrotic (PICP, PIINP and TIMP-1) markers. Conclusion Cathepsin S is significantly elevated in the sera of HFpEF patients and correlates with pathological processes including inflammation, hypoxia and ECM remodelling. Therapeutically targeting this cysetine protease may yield a novel strategy for the treatment of HFpEF.

Introduction Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodelling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. We have recently shown that human myocardial tissue hypoxia is associated with an enhanced pro-fibrotic gene profile in the tissue and, more significantly, that hypoxia-induced pro-fibrotic changes in cardiac fibroblasts are associated with global DNA hypermethylation. Purpose Based on this epigenetics data, we have conducted a gene-specific methylation study to investigate methylation changes that occur in hypoxic ventricular fibroblasts and to gain novel insights into mechanisms that may contribute to post-ischemic cardiac remodelling. Methods Human ventricular cardiac fibroblasts were exposed to 1% oxygen for up to 8 days. Global methylation changes were assessed using anti-5-methylcytosine (5MeC) staining, flow cytometry, QPCR, and western blot. Gene-specific methylation changes associated with hypoxia and an increased fibrotic state were determined by 5MeC immunoprecipitation and GeneChip human promoter arrays (Affymetrix), and validated by bisulphite genomic sequencing (BGS). Results Hypoxia-induced pro-fibrotic changes in cardiac fibroblasts included increased cell proliferation and increased alpha smooth muscle actin, collagen 1, DNMT1 and DNMT3B expression which associated with global DNA hypermethylation. Array analysis revealed 37 gene-specific hypermethylation changes and 133-hypomethylation changes occurred in response to chronic hypoxia. Conclusion Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu in the heart during disease. The application of epigenetic-based therapy, such as DNA methylation modifiers, as a treatment option for cardiac pathologies associated with fibrosis and ischemia may provide therapeutic benefit. Conflict of interest None

Background: Limited knowledge exists of the extent of epigenetic alterations, such as DNA methylation, in heart failure (HF). We conducted targeted DNA methylation sequencing to identify DNA methylation alterations in coding and noncoding RNA (ncRNA) across different etiological subtypes of HF. Methods and Results: A targeted bisulfite sequence capture sequencing platform was applied to DNA extracted from cardiac interventricular septal tissue of 30 male HF patients encompassing causes including hypertrophic obstructive cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and 9 control patients with nonfailing hearts. We detected 62 678 differentially methylated regions in the studied HF cohort. By comparing each HF subgroup to the nonfailing control group, we identified 195 unique differentially methylated regions: 5 in hypertrophic obstructive cardiomyopathy, 151 in dilated cardiomyopathy, and 55 in ischemic cardiomyopathy. These translated to 4 genes/1 ncRNA in hypertrophic obstructive cardiomyopathy, 131 genes/17 ncRNA in dilated cardiomyopathy, and 51 genes/5 ncRNA in ischemic cardiomyopathy. Subsequent gene/ncRNA expression analysis was assessed using quantitative reverse transcription polymerase chain reaction and revealed 6 genes: 4 hypermethylated ( HEY2 , MSR1 , MYOM3 , and COX17 ), 2 hypomethylated ( CTGF and MMP2 ); and 2 microRNA: 1 hypermethylated (miR-24-1), 1 hypomethylated (miR-155) with significantly upregulated or downregulated expression levels consistent with the direction of methylation in the particular HF subgroup. Conclusions: For the first time DNA methylation alterations and associated gene expression changes were identified in etiologically variant pathological HF tissue. The methylation-sensitive and disease-associated genes/ncRNA identified from this study represent a unique cohort of loci that demonstrate a plausible potential as a novel diagnostic and therapeutic target in HF and warrant further investigation.

Demodex mites are the largest and most complex organisms of the skin microflora. How they interact with the innate and adaptive immune systems is unknown. Their potential to have a pathogenic role in the causation of human skin disorders causes continued speculation. With growing interest in the microflora of human skin and its relevance to cutaneous health, the role of Demodex mites needs to be better understood. The main challenges facing scientists investigating the role of these organisms and possible solutions are reviewed under the following headings: (1) Determining the mite population in skin, (2) Transporting, extracting and imaging live mites, (3) Maintaining mites viable ex vivo and (4) Establishing methods to determine the immune response to Demodex mites and their internal contents.

Rosacea is a common facial skin disorder affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as important. The Demodex mite population in the skin of these patients is significantly higher than in subjects with normal skin suggesting they may be of etiological importance in this disorder. Little is known of the role of these mites in human skin and their potential to interact with the host immune system has not been elucidated. Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalised SZ95 sebocyte line. Time and mite dose dependent experiments were performed. Direct Demodex effects and the effects of medium in which Demodex had been cultured were evaluated on the TLR-signalling pathway on both a gene and protein expression level. Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards down modulation of genes in this pathway was observed. A subsequent switch to positive gene up-regulation was recorded after 48 hours of co-culture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced pro-inflammatory cytokine secretion whereas lower numbers did not. Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalised human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced IL8 secretion by these cells. This article is protected by copyright. All rights reserved.

Heart failure with preserved ejection fraction (HFpEF) is emerging as a metabolic disease. HFpEF initiation and progression is associated with the pro-inflammatory state found in conditions such as hypertension, obesity and diabetes. Although the role of dietary fat in the genesis of metabolic disorders and tissue inflammation has been characterised, dietary fat induced cardiac pathology and inflammation in the context of pressure-overload is less well defined. In this study, we reveal the cardioprotective effects of saturated fat intake on cardiac phenotype and cardiac inflammation in an established rat model of hypertension. Ten week old male normotensive Wistar (WKY), control rats (n=10), and matched SHR (n=20), were split into low-10%kcal and high-45%kcal fat chow. After 16 wks of diet intake, bodyweight profiles were similar among all groups (p=NS). Unconscious tail-cuff plethysmography confirmed elevated arterial pressure (>140mmHg) in both SHR dietary groups, (SBP in 45%kcal; 154.4 ± 21.7 mmHg, p+ macrophage infiltration was increased (10%kcal; 122.5 cells/mm 2 , & 45%kcal; 151.1 cells/mm 2 , p