Cardiovascular Pharmacology

Direct Oral Anticoagulants in octogenarians with atrial fibrillation: it's never too late. Abstract: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, and age is one of the strongest predictors/risk factors for ischaemic stroke in patients with AF. Elderly patients, in particular patients ≥ 80 years old, are at higher risk of both ischemic and bleeding events compared to younger patients. Vitamin K antagonists reduce the risk of ischemic stroke, especially in the elderly, but increases the bleeding risk. In addition, frequent international normalized ratio monitoring is needed, to ensure the optimal level of anticoagulation. Furthermore, vitamin K antagonists have multiple drug and food interactions. Direct oral anticoagulants have recently emerged as alternatives to Vitamin K Antagonists and are gradually increasing their popularity mainly because of their fewer drug and food interactions and ease of use. Their effectiveness and safety have been well-established in the general population but the benefit in the very elderly (≥80 years old) is still unclear. Data about the safety and the effectiveness of DOACs in patients >75 years old are available in literature, but the evidences of the use of DOACs in ≥80 years old are lacking. This review aims to give light to the differences, in terms of benefits and safety, of the DOACs in this subset of patients. Corresponding author: Dr Vincenzo Russo, Chair of Cardiology, University of Campania "Luigi Vanvitelli", Monaldi Hospital, AORN dei Colli, via Leonardo Bianchi 1, 80131 Napoli, e-mail: v.p.russo@libero.it Conflict of interests: none. Author contributions: Russo V and Carbone A designed the research, performed research and wrote the paper; Rago A, Golino P and Nigro G reviewed the paper. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cyclodextrin ameliorates the progression of atherosclerosis via increasing HDL-C plasma levels and anti-inflammatory effects in rabbits Abstract: To investigate the therapeutic effects of cyclodextrin on the development of atherosclerosis in rabbits, we evaluated the effects of (2-hydroxypropyl)-β-cyclodextrin(HPβCD)therapy on the organ coefficient, lipid profiles, inflammatory cytokines and atherosclerotic plaques in rabbits fed a high-fat diet. Our results demonstrated that HPβCD therapy reduced plasma triglyceride levels and inflammatory cytokine levels but increased plasma high-density lipoprotein cholesterol (HDL-C) levels. HPβCD therapy produced a significant decrease in the atherosclerotic lesion area and reduced macrophage and collagen content in the lesions. The expression levels of inflammatory genes in aortic plaques were significantly reduced by HPβCD treatment, but the expression of ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) in aortic plaques and livers increased significantly. HPβCD therapy may produce additional anti-atherosclerotic benefits likely via increasing HDL-C levels. Correspondence: Prof. Xiaochun Tang, E-mail: xiaochuntang@jlu.edu.cn, Tel: (86) 0431-87836175; Fax: (86) 0431-86758018 The authors report no conflicts of interest. This work was financially supported by the National atural Science Foundation of China (Grant No. 31472053 and 31572345). The Program for JLU Science and Technology Innovative Research Team (JLUSTIRT, No. 2017TD-28), the Fundamental Research Funds for the Central Universities. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Real Life Indications to Sacubitril/Valsartan Treatment in Patients with Chronic Systolic Heart Failure Objective. International guidelines recommend the introduction of sacubitril/valsartan in patients with heart failure and reduced ejection fraction who remain symptomatic despite optimal up-titrated therapy. The purpose of the following analysis is to verify the real-life eligibility for sacubitril/valsartan in a population of patients suffering from chronic heart failure, regularly monitored in a single heart failure clinic and treated according to guideline-directed medical therapy. Methods. From a total of 1070 patients regularly monitored in our HF Clinic between January-2011 and September-2017, the clinical records of 224 patients with heart failure and reduced ejection fraction on optimized guidelines directed medical therapy were retrospectively analyzed. Results. Out of 224 analyzed patients, 75 improved their ejection fraction or were asymptomatic after up-titration of guideline-directed medical therapy during follow up; 50 were not on angiotensin converting enzyme inhibitor or angiotensin receptor blocker for different reasons; 13 patients had systolic blood pressure ≤100 mmhg, so they were not eligible for sacubitril/valsartan introduction. The remaining patients were still symptomatic (NYHA ≥2) and therefore sacubitril/valsartan introduction was indicated in these 86 patients (38.4%) out of 224 enrolled. Conclusion. In patients with heart failure and reduced ejection fraction, where guideline-directed medical therapy is appropriately achieved, indication to sacubitril/valsartan treatment is around 38%. Address for correspondence: Gabriele Fragasso, MD Department of Clinical Cardiology, Heart Failure Clinic Istituto Scientifico San Raffaele, Via Olgettina 60, 20132 Milano – Italy e.mail gabriele.fragasso@hsr.it Phone: +390226437366; Fax: +390226437358 Conflicts of Interest: The Authors declare that there are no financial or other relations that could lead to a conflict of interest. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Ligustilide ameliorates the permeability of the blood-brain barrier model in vitro during oxygen-glucose deprivation injury through HIF/VEGF pathway Abstract Chuanxiong rhizome has been widely used for the treatment of cerebral vascular disease in traditional Chinese medicine. The integrity of blood-brain barrier (BBB) is closely linked to the cerebral vascular disease. The protective effects of ligustilide, the major bioactive component in Chuanxiong rhizome, on cerebral blood vessel has been reported previously, but its effects and potential mechanism on BBB has not been entirely clarified. In the current work, the effects of ligustilide on BBB permeability and the underlying molecular mechanisms had been investigated using the model of BBB established by co-culturing astrocytes and brain microvascular endothelial cells isolated from the rat brain. The ischemia-damaged model of BBB has been established with oxygen and glucose deprivation (OGD). Our results indicated that OGD significantly increased the permeability in the co-culture BBB model. This OGD-induced increase in permeability could suppress by ligustilide in a concentration dependent manner. Also, ligustilide promoted both gene and protein expression of tight junction proteins. Ligustilide suppressed the up-regulation of HIF-1α, VEGF and AQP-4 in the BBB model induced by OGD. Collectively, all results have demonstrated that ligustilide is capable of reducing the permeability of BBB in vitro model induced by OGD through HIF-1α/VEGF pathway and AQP-4, which provide a new target for the clinical application of ligustilide on BBB after stroke in future. Corresponding author: Prof. Ning Wang, Department of Pharmacy, Anhui University of Chinese Medicine, NO.1 Qian Jiang Road, Hefei, 230012, China. Tel:+86-551-68128186 Fax: + 86-0551-68129028 E-mail: wnsci123@163.com The authors report no conflicts of interest. The study was supported by the National Natural Science Foundation of China (No. 81773933, 81374005). The key projects of overseas visits of outstanding young backbone talents from universities in Anhui Province (gxfxZD2016117), Academic assistance program for the top-notch innovative talents from universities in 2017 provided by Anhui Province Office of Education (gxbjZD15). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Allopurinol administration for the prevention of contrast-induced nephropathy: a network meta-analysis with trial sequential analysis Contrast-induced nephropathy represents a major source of morbidity in patients undergoing coronary angiography. Various preventive measures have been proposed, although the optimal one remains still unknown. The aim of the present meta-analysis is to accumulate current literature knowledge and evaluate the renoprotective effects of allopurinol administration prior to contrast medium exposure. To achieve this, Medline, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov. and Google Scholar databases were searched from inception to November 8, 2018. Statistical meta-analysis was conducted with Review Manager 5.3, TSA 0.9.5.5 and R-3.4.3. Six studies were included with a total of 918 patients. Quantitative synthesis revealed that allopurinol lead to significantly reduced incidence of contrast-induced nephropathy compared to hydration alone (OR: 0.29, 95% CI: [0.09-0.90]). Trial sequential analysis suggested that Z-curve crossed the O'Brien–Fleming significance boundaries, although required information size was not reached. Network meta-analysis indicated that allopurinol had the highest probability (81.2%) to rank as the most effective intervention compared to hydration and N-acetyl cysteine; however, significant overlap with the rest treatments was noted. In conclusion, the present meta-analysis suggests that allopurinol may represent a promising measure for the prevention of acute kidney injury following coronary angiography. Future large-scale randomized controlled trials should verify this finding, while combinations of allopurinol with other novel interventions should be evaluated in order to define the most effective strategy to be implemented in the clinical setting. Corresponding author: Ioannis Bellos, MD, 15Β, Ag. Thoma str., Athens 115 27, Greece, e-mail: bellosg@windowslive.com, Tel: 0030 6947470441 Funding: None Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Effects of low-dose sacubitril/valsartan on different stages of cardiac hypertrophy in salt-loaded hypertensive rats Background: Sacubitril/valsartan was shown to attenuate the development of cardiac hypertrophy with enhanced blood pressure (BP) reduction compared to valsartan alone in animal models. We investigated whether a low dose sacubitril/valsartan has BP-independent effects on cardiac hypertrophy and pulmonary edema using a rat model of hypertension and obesity. Methods and results: In plan 1, male SHR/NDmcr-cp rats fed normal or phased-increased high salt were treated with vehicle, 6 mg/kg sacubitril/valsartan or 3 mg/kg valsartan, for 6 months. In plan 2, after high salt loading for 6 months, drugs were administered for 4 months. Antihypertensive effects of the two drugs were similar during all study periods. In plan 1 with normal salt, there were no differences between treatments in the left ventricle weight/body weight (VW/BW), or lung weight/BW as an index of cardiac hypertrophy or pulmonary edema, respectively. These indexes were smaller in high-salt-fed rats with sacubitril/valsartan than vehicle. In plan 2, both indexes did not differ between vehicle and sacubitril/valsartan. VW/BW was lower in valsartan than sacubitril/valsartan. In plan 2, gene markers of cardiac dysfunction were upregulated by sacubitril/valsartan compared to the other groups. Conclusion: Low-dose Sacubitril/valsartan may have different effects depending on the stage of cardiac hypertrophy in rats. Corresponding author: Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan, E-mail: kyamamoto@geriat.med.osaka-u.ac.jp Source of funding: This study was financially supported by Novartis Pharma K.K., Japan. Sacubitril/valsartan and valsartan were provided by Novartis AG. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

ALDH2 activation inhibited cardiac fibroblast-to-myofibroblast transformation via TGF-β1/Smad signaling pathway Pathological stimulus-triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert protective role in cardiovascular disease and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we employed transforming growth factor-β1 (TGF-β1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-β1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased α-SMA and periostin expression, reduced HCF derived-myofibroblast proliferation, collagen production and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-β1-induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1-induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via TGF-β1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Correspondence to: Ping Guo, Qilu Hospital, Shandong University, No. 107 Wenhua Xi Road, Jinan 250012, China; Tel: +86-531-82166844; Fax: +86-531-86927544; E-mail: 13953100732@163.com. The authors declare no conflict of interest. * These authors contributed equally to this work. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Number of ECG Replicates Influences the Estimated QT Prolonging Effect of a Drug Introduction: The present analysis addressed the effect of the number of ECG replicates extracted from a continuous ECG on estimated QT interval prolongation for different QT correction formulas. Methods: For one hundred healthy volunteers, who received a compound prolonging the QT interval, 18 ECG replicates within a 3 minute window were extracted from 12-lead Holter ECGs. Ten QT correction formulas were deployed and the QTc interval was controlled for baseline and placebo and averaged per dose level. Results: The mean prolongation difference was >4 ms for single and > 2 ms for triplicate ECG measurements compared to the 18 ECG replicate mean value. The difference was <0.5ms after 14 replicates. In contrast, concentration-effect analysis was independent of replicate count and also of QT correction formula. Conclusion: The number of ECG replicates impacted the estimated QT interval prolongation for all deployed QT correction formulas. However, concentration-effect analysis was independent of both the replicate number and correction formula. Address for correspondence: Prof. dr. J. Burggraaf Centre for Human Drug Research Zernikedreef 8 2333 CL Leiden E: kb@chdr.nl T: + 31 71 5246 400F: + 31 71 5246 499 Conflict of Interest: No Funding: No Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prognostic Impact of Angiotensin Converting Enzyme Inhibitors and Receptor Blockers on Recurrent Ventricular Tachyarrhythmias and ICD Therapies This study sought to assess the prognostic impact of treatment with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) on recurrences of ventricular tachyarrhythmias in recipients of implantable cardioverter defibrillators (ICD). Using a large retrospective registry including consecutive ICD recipients with documented episodes of ventricular tachycardia (VT) or fibrillation (VF) from 2002 to 2016, those patients treated with ACEi/ARB were compared to patients without (non-ACEi/ARB). The primary prognostic endpoint was first recurrences of ventricular tachyarrhythmias and related ICD therapies at 5 years. Multivariable Cox regression analyses were applied within the entire cohort, and thereafter Kaplan-Meier analyses were performed in propensity-matched subgroups. A total of 592 consecutive ICD recipients were included (81% treated with ACEiARB and 19% without). Although ACEi/ARB was associated with no differences of overall recurrence of ventricular tachyarrhythmias, ACEi/ARB was especially associated with improved freedom from appropriate ICD therapy within multivariable Cox regressions (HR=0.666; p=0.043), especially in patients with index episodes of VF, LVEF <35%, coronary artery disease, secondary preventive ICDs and GFR <45 ml/min/1.73m2. In the propensity-matched sub-group, ACEi/ARB still prolonged freedom from appropriate ICD therapies (HR=0.380; 95% CI 0.193-0.747; p=0.005). In conclusion, ACEi/ARB therapy was associated with improved freedom from appropriate ICD therapies. Corresponding author: Michael Behnes, First Department of Medicine, University Medical Center Mannheim (UMM), Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Phone: (+49) 621-383-6239; E-mail: michael.behnes@umm.de. No conflict of interest for all authors. Supported by the DZHK (Deutsches Zentrum fur Herz-Kreislauf-Forschung - German Centre for Cardiovascular Research). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The NLRP3 Inflammasome Inhibitor, OLT1177 (Dapansutrile), Reduces Infarct Size and Preserves Contractile Function After Ischemia Reperfusion Injury in the Mouse Background: Activation of the NLRP3 inflammasome is a primary driver of sterile inflammation in response to myocardial ischemia reperfusion. Pharmacologic inhibitors of the NLRP3 inflammasome are being developed. We proposed that OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could preserve myocardial function after ischemia reperfusion injury in the mouse. Methods: We used an experimental murine model of myocardial ischemia reperfusion injury through transient ligation of the left coronary artery, and measured the effects of OLT1177 (6, 60 or 600 mg/kg intraperitoneal dose) on infarct size at pathology and on systolic cardiac function at echocardiography. To simulate a clinical scenario, we investigated the time window of therapeutic intervention with OLT1177 (60 mg/kg) administered 60, 120, or 180 minutes after reperfusion. Results: OLT1177 was rapidly detectable in the plasma following intraperitoneal injection and had no effect on cardiac function in healthy mice. OLT1177 treatment at reperfusion showed significant dose-dependent reduction in infarct size (-36%, -67% and -62% for 6, 60 and 600 mg/kg, respectively; P<0.001 for linear trend, P=0.010 vs vehicle for 6 mg/kg and P<0.001 vs vehicle for 60 and 600 mg/kg) and preserved cardiac systolic function measured as LV fractional shortening (LVFS) at 24 hour and 7 days after injury (P=0.015 for 6 mg/kg and P<0.01 for 60 and 600 mg/kg). OLT1177 reduced infarct size also when given after 60 minutes of reperfusion (-71%, P<0.001 versus vehicle). Conclusion: OLT1177 (dapansutrile), a NLRP3 inflammasome inhibitor, limits infarct size and prevents LV systolic dysfunction when given within 60 minutes following ischemia reperfusion injury in the mouse. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Address for correspondence: Stefano Toldo, PhD Assistant Professor of Medicine Virginia Commonwealth University, VCU Pauley Heart Center, Box 980281, 1200 E. road St., Richmond, VA, 23298 - USA Stefano.toldo@vcuhealth.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com