s123 resources (HCR) and direct costs of HF care in three Middle Eastern countries: Egypt (EG), Saudi Arabia (SA) and the United Arab Emirates (UAE). Methods: Survey questionnaire was developed and used in interview with leading heart failure specialists, cardiologists and/or clinical pharmacists in each country to collect HCR and costs from their respective institutions in both private and public sectors. HCR (diagnostics, physician visits, medications, inpatient admission, ER, invasive procedures) used in routine management of their HF patients were included. National cost of HF was estimated by summing the total cost of HF in each sector, and was used to calculate the average annual cost per patient. Given the lack of epidemiology data on HF in the region, we used the US prevalence rate of 2.4% in > 20 years population adjusted for age distribution in the three ME countries. Costs were in local currency and converted to Unites States Dollars (USD) using current exchange rates for respective currencies. Results: An estimated 1.35 million patients are being treated for HF

Heart failure remains a major cause of hospitalization and death worldwide. Heart failure can be caused by abnormalities in the epigenome resulting from dysregulation of histone-modifying enzymes. While chromatin enzymes catalyzing lysine acetylation and methylation of histones have been the topic of many investigations, the role of arginine methyltransferases has been overlooked. In an effort to understand regulatory mechanisms implicated in cardiac hypertrophy and heart failure, we assessed the expression of protein arginine methyltransferases (PRMTs) in the left ventricle of failing human hearts and control hearts. Our results show a significant up-regulation of protein arginine methyltransferase 6 (PRMT6) in failing human hearts compared to control hearts, which also occurs in the early phase of cardiac hypertrophy in mouse hearts subjected to pressure overload hypertrophy induced by trans-aortic constriction (TAC), and in neonatal rat ventricular myocytes (NRVM) stimulated with the hypertrophic agonist phenylephrine (PE). These changes are associated with a significant increase in arginine 2 asymmetric methylation of histone H3 (H3R2Me2a) and reduced lysine 4 tri-methylation of H3 (H3K4Me3) observed both in NRVM and in vivo. Importantly, forced expression of PRMT6 in NRVM enhances the expression of the hypertrophic marker, atrial natriuretic peptide (ANP). Conversely, specific silencing of PRMT6 reduces ANP protein expression and cell size, indicating that PRMT6 is critical for the PE-mediated hypertrophic response. Silencing of PRMT6 reduces H3R2Me2a, a mark normally associated with transcriptional repression. Furthermore, evaluation of cardiac contractility and global ion channel activity in live NRVM shows a striking reduction of spontaneous beating rates and prolongation of extra-cellular field potentials in cells expressing low-level PRMT6. Altogether, our results indicate that PRMT6 is a critical regulator of cardiac hypertrophy, implicating H3R2Me2a as an important histone modification. This study identifies PRMT6 as a new epigenetic regulator and suggests a new point of control in chromatin to inhibit pathological cardiac remodeling.

Background: Dilated cardiomyopathy (DCM) is a common form of cardiomyopathy causing systolic dysfunction and heart failure. Rare variants in more than 30 genes mostly encoding sarcomeric proteins and proteins of the extracellular matrix have been implicated in familial DCM to date. We recently identified a novel mutation (Gly243Arg) in FBXO32 causing familial DCM through abnormal SKP1/CUL/F-BOX (SCF) complex formation and defects in proteins regulating the autophagy/lysosome machinery (Al-Yacoub, Genome Biology, 2016). Objective: To explore in more details the mechanisms by which the defective SCF FBXO32 complex leads to the development of DCM. Methodology: Using a PCR-based microarray, we screened for mRNAs significantly dysregulated in the heart of the patient carrying the FBXO32 mutation compared to control and idiopathic human hearts. Subsequently, we validated dysregulation of a candidate gene using immunoblot analysis and tested the effect of the mutant or wild-type FBXO32 on the novel candidate identified in primary neonatal rat cardiomyocytes. Results: We found a robust up-regulation in mRNA expression of the Activating transcription Factor 2 (ATF2), a member of the leucine zipper family of DNA binding proteins, which plays a critical role in cardiac development. ATF2 protein level was also strongly increased in the heart with the FBXO32 mutation compared to control hearts and to hearts of idiopathic origin. Expression of the mutant FBXO32 protein in primary cardiomyocytes enhanced ATF2 protein expression compared to cells expressing the wild-type FBXO32 protein. Since FBXO32 is member of the SCF complex and has ubiquitin ligase activity, experiments are now investigating whether FBXO32 directly regulates ATF2 protein stability and the role of ATF2 in autophagy flux regulation in dilated cardiomyopathy. Conclusion: Our results indicate that abnormal SCF activity due to the FBXO32 mutation stabilizes the AFT2 transcription factor and suggest a new mechanism by aberrant SCF activity causes DCM in human.