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Background: The relevance of the IMPROVE-IT trial on real-life practice has not been explored in patients with ACS., Methods: A prospective Swiss cohort of 6266 patients hospitalized for ACS between 2009 and 2017 with a one-year follow-up. The primary endpoints were the ezetimibe use overall or in combination with high-intensity statin at discharge and at one year after ACS. Secondary endpoint was LDL-C target achievement at one year in a subsample of 2984 patients. Relative Ratios (RR) were used to assess changes in primary endpoints before and after the publication of IMPROVE-IT, adjusting for age, sex, diabetes, prior myocardial infarction, LDL-C and attendance to cardiac rehabilitation., Results: The period following the publication of the IMPROVE-IT trial was associated with a steady increase in the use of ezetimibe at discharge (from 1.8% to 3.8%, P < 0.001, adjusted RR 2.85, 95% CI 1.90-4.25) and at one year (from 5.0% to 13.8%, P < 0.001, adjusted RR 3.00, 95% CI 2.40-3.75). The combination of high-intensity statin and ezetimibe rose from 0.9% to 2.1% at discharge (P < 0.001, adjusted RR 3.35, 95% CI 1.90-5.89) and from 2.1% to 7.8% at one year (P < 0.001, adjusted RR 3.98, 95% CI 2.90-5.47). The period following the publication of the IMPROVE-IT trial was associated with an improvement of LDL-C target <1.8 mmol/L (adjusted RR 1.37, 95% CI 1.12-1.68)., Conclusions: After the publication of the IMPROVE-IT trial, the use of ezetimibe was increased by three-fold in a large contemporary cohort of ACS patients, concomitant with an improved LDL-C target achievement., Competing Interests: Declaration of competing interest Prof. Lüscher reports receiving research grants to the institution from Abbott, Biosensors, Biotronik, Boston Scientific, Daichi Sankyo, Eli Lilly and Medtronic, and consultant payments from AstraZeneca, Boehringer Ingelheim, Bayer, Merck, and Pfizer, MSD, Roche and Servier. Prof. Matter received grants from MSD, Eli Lilly, AstraZeneca, Roche and Bayer; expert testimony from MSD; payment for lectures from MSD, AstraZeneca, and Roche; and patents from Mabimmune, CH. Prof. Windecker reports research contracts to the institution from Abbott, Biotronik, Boston Scientific, Biosensors, Cordis, Medtronic, St. Jude Medical. Prof Mach reports receiving research grants to the institution from Amgen, AstraZeneca, BMS, Eli Lilly, MSD, Sanofi, and Pfizer. All other authors report no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Hyperglycaemia-induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. Intensive glycaemic control (IGC) has failed to reduce risk of heart failure in patients with diabetes but the underlying mechanisms remain to be elucidated. The present study investigates whether epigenetic regulation of the pro-oxidant adaptor p66 Shc contributes to persistent myocardial dysfunction despite IGC., Methods and Results: p66 Shc expression was increased in the heart of diabetic mice, and 3-week IGC by slow-release insulin implants did not revert this phenomenon. Sustained p66 Shc upregulation was associated with oxidative stress, myocardial inflammation and left ventricular dysfunction, as assessed by conventional and 2D speckle-tracking echocardiography. In vivo gene silencing of p66 Shc , performed during IGC, inhibited ROS production and restored cardiac function. Furthermore, we show that dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 causes CpG demethylation and histone 3 acetylation on p66 Shc promoter, leading to persistent transcription of the adaptor. Altered DNMT3b/SIRT1 axis in the diabetic heart was explained by upregulation of miR-218 and miR-34a. Indeed, in human cardiomyocytes exposed to high glucose, inhibition of these miRNAs restored the expression of DNMT3b and SIRT1 and erased the adverse epigenetic signatures on p66 Shc promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66 Shc expression and ROS generation., Conclusions: In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66 Shc transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/purpose: Catheter-based renal sympathetic denervation (RDN) can reduce blood pressure (BP) and sympathetic activity in certain patients with uncontrolled hypertension. Less is known about the impact of renal anatomy and procedural parameters on subsequent BP response., Methods/materials: A total of 564 patients with resistant hypertension underwent bilateral RDN in 9 centers in Europe and Australia using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic). Anatomical criteria such as prevalence of accessory renal arteries (ARA), presence of renal artery disease (RAD), length, and diameter were analyzed blinded to patient's characteristics., Results: ARA was present in 171 patients (30%), and RAD was documented in 71 patients (13%). On average 11±2.7 complete 120-s ablations were performed, equally distributed on both sides. After 6months, BP was reduced by 19/8mmHg (p<0.001 for both). Change of systolic blood pressure (SBP) was not related to the presence of ARA (-18 vs. -20mmHg; p=NS) or RAD (-16 vs. -20mmHg; p=NS). Patients with a bilateral diameter≤4mm had a more pronounced reduction of SBP compared to patients with a unilateral diameter≤4mm or a bilateral diameter>4mm (-29 vs. -26 vs. -17mmHg; p<0.001). Neither the length of the renal artery nor the number of RF ablations influenced BP reduction after 6months., Conclusions: The diameter of renal arteries correlated with SBP change after RDN at 6-month follow-up. Change of SBP was not related to the lengths of the renal artery, presence of ARA, RAD, or the number of RF ablations delivered by a mono-electrode catheter., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Risk of diabetic complications continues to escalate overtime despite a multifactorial intervention with glucose-lowering drugs, anti-hypertensive agents and statins. In this perspective, a mechanisms-based therapeutic approach to vascular disease in diabetes represents a major challenge. Epigenetic signatures are emerging as important determinants of vascular disease in this setting. Methylation and acetylation of DNA and histones is a reversible process leading to dysregulation of oxidant and inflammatory genes such as mitochondrial adaptor p66(Shc) and transcription factor NF-kB p65. Epigenetic modifications associated with diabetes may contribute to the early identification of high risk individuals. Ongoing epigenomic analyses will be instrumental in identifying the epigenetic variations that are specifically associated with cardiovascular disease in patients with diabetes. Here, we describe a complex scenario of epigenetic changes and their putative link with diabetic vascular disease. Pharmacological reprogramming of diabetes-induced epigenetic signatures may be a promising option to dampen oxidative stress and inflammation, and thus prevent cardiovascular complications in this setting., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)