Perivascular adipose tissue modulation of neurogenic vasorelaxation of rat mesenteric arteries Perivascular sympathetic-sensory interactions have been shown to regulate calcitonin gene-related peptide (CGRP)-mediated vasodilation in rats. We investigated whether perivascular adipose tissue (PVAT) modulates the neurogenic vasorelaxation of isolated rat mesenteric arteries. Mesenteric arterial rings were prepared with or without PVAT (PVAT+ or PVAT−) and with either an intact or denuded endothelium (EC+ or EC-). The results of myography analysis revealed that vasocontraction to phenylephrine was highest in EC-PVAT-, lowest in EC+PVAT+, and intermediate in EC-PVAT+ and EC+PVAT-. Transmural nerve stimulation (TNS) induced the tetrodotoxin-sensitive relaxation of the phenylephrine-precontracted mesenteric arteries. However, nicotine induced minor relaxation in EC-PVAT+, while vasorelaxation was significantly enhanced in EC-PVAT-. Nicotine-induced vasorelaxation was insensitive to propranolol and also significantly lower in sympathetically-denervated and guanethidine-treated EC-PVAT-, while TNS-induced vasorelaxation persisted. In EC-PVAT- depleted of CGRP via capsaicin, nicotine- and TNS-induced vasorelaxation was almost absent. Lowering the pH of Krebs’ solution using HCl led to pH-dependent vasorelaxation that was sensitive to CGRP8-37. Furthermore, nicotine-induced relaxation of EC-PVAT-, which was not affected by leptin, was blocked by methyl palmitate. Methyl palmitate did not affect TNS- or HCl-induced vasorelaxation. These results suggest that PVAT plays a modulatory role in regulating sympathetic-sensory interaction-mediated CGRPergic vasorelaxation via the release of methyl palmitate. Corresponding Author: Shang-Jen Chang, MD, MS, Taipei Tzu Chi Hospital, New Taipei,, TAIWAN E-mail: changhh@livemail.tw, E-mail: urolyang@tzuchi.com.tw, E-mail: krissygnet@yahoo.com.tw Sources of funding: This work was supported by grants from Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (TCRD-TPE-106-RT-6 and TCRD-TPE-107-51). Disclosures: No conflicts of interest, financial or otherwise, are declared by the authors. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Direct Oral Anticoagulant Use Following Transcatheter Aortic Valve Replacement: A Case Series Background: Use of an anticoagulant after transcatheter aortic valve replacement (TAVR) has been increasing in practice after noted leaflet thrombosis on dual antiplatelet therapy. As the use of anticoagulation increases so does the number of poor warfarin candidates or warfarin intolerant patients. While direct oral anticoagulant (DOAC) use is increasing for other indications there is a paucity of data for use post-TAVR. The objective of this case series is to add to the available evidence for patients who may require a DOAC following TAVR. Methods: A single-center, retrospective observational case series was conducted including adults 18 years of age and older who received a DOAC following TAVR between November 2008 and June 2018 at Mayo Clinic Hospital – Rochester. All patients were identified as part of the Society of Thoracic Surgeons database. Results: Twenty-one patients were identified as having received a DOAC post-TAVR. Median age was 83.5 years (IQR 77-87), with 71% males. Within this cohort, 20 patients (95.2%) had an alternative indication for anticoagulation of either atrial fibrillation or atrial flutter. Apixaban was prescribed in 66.7% of patients, followed by rivaroxaban (14.3%), dabigatran (9.5%), and edoxaban (4.8%). No thromboembolic events were reported. Three patients experienced a bleeding event, of which only 2 occurred in the 3 months immediately following TAVR. Conclusion: DOAC therapy after TAVR was generally safe and well tolerated. Taken in context of other retrospective studies this data suggests that the presence of valvular heart disease, specifically TAVR in this case, should not preclude the use of DOACs. Corresponding Author: Abby K. Hendricks, PharmD Mayo Clinic 200 First Street SW Rochester, MN 55905 Phone: 507-255-5732 Fax: 507-255-7556 Email: Hendricks.abby@mayo.edu Conflict of Interest: The authors declare that they have no conflicts of interest. Funding: No funding was provided to support this study. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Paul M. Vanhoutte, an Appreciation No abstract available

Inhibition of Endothelial Dysfunction by Dietary Flavonoids and Preventive Effects Against Cardiovascular Disease Cardiovascular disease (CVD), such as stroke, ischemic heart disease, and heart failure, accounts for many deaths, and its increasing incidence is a worldwide concern. Accumulating evidence suggests that the elevated risk of CVD caused by dysfunction of vascular endothelial cells and resultant arteriosclerosis can be mitigated by increased consumption of fruits and vegetables. These foods contain phytochemicals such as polyphenols and carotenoids, as well as dietary fiber. Flavonoids of the polyphenol class are found in vegetables, fruits, grains, bark, roots, stems, flowers, tea, and wine. Several studies have indicated that flavonoids reduce CVD mortality by inhibiting endothelial dysfunction. Flavonoids have a common carbon skeleton and are classified as flavonols, flavones, flavanols, flavanones, anthocyanidins, and isoflavones. In this review, we discuss recent progress in identifying the mechanisms by which dietary flavonoids improve vascular endothelial cell function. Further, we describe the beneficial role that these flavonoids may play in preventing CVD caused by endothelial dysfunction-related atherosclerosis. Corresponding author: Dr. Kazuo Yamagata Ph.D. Department of Food Bioscience and Biotechnology, College of Bioresource Science, Nihon University (UNBS), Fujisawa, Japan. Phone: +81-466-84-3986; Fax: +81-466-84-3986; E-mail: yamagata.kazuo@nihon-u.acj.jp Competing interests; The authors report no conflicts of interest. Funding; Not Consent for publication; Not applicable. Ethics approval and consent to participate; Not applicable. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Non-coding RNAs in atrial fibrillation: current status and prospect Atrial fibrillation (AF) is an important cause of cardiovascular morbidity and mortality. Current therapies for AF are ineffective, mainly due to incomplete understanding of the pathogenesis of AF. Atrial remodeling contributes to the occurrence and progression of AF, but molecular mechanisms underlying AF remain unclear. Non-coding RNAs, including microRNAs, long non-coding RNAs and circular RNAs, are now considered to play an important role in the pathophysiology of AF. In this review, we summarize recent evidence supporting the role of non-coding RNAs in AF and highlight their diagnostic and prognostic applications as potential biomarkers and therapeutic strategies. Corresponding author: Xiaosheng Hu, Department of Cardiology, The First Affiliated Hospital, Medical School of Zhejiang University, Zhejiang Province, 310000, China. Email: 1196017@zju.edu.cn Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

EFFECTS OF RIVAROXABAN ON PLATELET AGGREGATION Rivaroxaban is a direct oral anti-Factor Xa anticoagulant. It has recently been suggested that rivaroxaban may affect platelet function in vitro; however, little is known about the clinical impact of this likely antiplatelet effect and if this probable phenomenon is dose-dependent. Our aim was to determine whether rivaroxaban at four different doses inhibits direct platelet aggregation. We included adult patients of both genders and who were allocated to one of the following groups depending on the prescribed daily dose of rivaroxaban: 5, 10, 15, and 20 mg. In 80 patients (20 patients/group), the percentage of platelet aggregation was determined by means of platelet aggregometry tests before and after rivaroxaban use. Basal samples were obtained before starting rivaroxaban and 1 month after treatment, both 2 and 24 h after the last dose of the drug (12 h after in the case of rivaroxaban 5 mg). We used five platelet agonists: adenosine diphosphate, epinephrine, arachidonic acid, collagen, and thrombin. There were no significant changes in the percentage of platelet aggregation before and after rivaroxaban use independently of the dose administered and the agonist used. Our results clearly shown that rivaroxaban, even at a high dose, does not directly affect platelet aggregation. Address for correspondence: Abraham Majluf-Cruz, MD, PhD, FACP, Apartado Postal 12-1100 Mexico City, Mexico Tel/Fax: 0052-55-5574-5626 E-mail: abraham.majluf@imss.gob.mx Declarations of interest: none Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Potential of the Cardiovascular Drug Levosimendan in the Management of Amyotrophic Lateral Sclerosis: Overview of a Working Hypothesis Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly two decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on non-cardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a neuromuscular disorder characterised by progressive weakness and eventual paralysis. Previous attempts to improve the muscle response in ALS patients and thereby maintain respiratory function and delay progression of disability have produced some mixed results. Continuing this line of investigation, levosimendan has been shown to enhance in vitro the contractility of diaphragm muscle fibres of non-ALS patients, and to improve in vivo diaphragm neuromuscular efficiency in heathy subjects. Possible positive effects on respiratory function in people with ALS was seen in an exploratory Phase 2 study, and a Phase 3 clinical trial is now underway to evaluate the potential benefit of an oral form of levosimendan on both respiratory and overall functions in patients with ALS. Here we will review the various known pharmacologic effects of levosimendan, considering their relevance to people living with ALS. Corresponding author: Piero Pollesello, Orion Pharma, P.O.Box 65 FIN-02101, Espoo, Finland, e-mail: piero.pollesello@orionpharma.com; tel.:+358509664191. Conflicts of interest: AA-C is a consultant for Orion Pharma, and has been Principal Investigator for clinical trials sponsored or supported by Orion Pharma. ZP has received lecture honoraria from Orion Pharma; LH received a grant from Orion Pharma to run a clinical trial; PP is an employee of Orion Pharma, where levosimendan was discovered and developed. 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. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Nitric oxide in post-cardiac arrest syndrome Sudden cardiac arrest is a leading cause of death worldwide. Although the methods of cardiopulmonary resuscitation (CPR) have been improved, mortality is still unacceptably high, and many survivors suffer from lasting neurological deficits due to the post-cardiac arrest syndrome (PCAS). Pathophysiologically, generalized vascular endothelial dysfunction accompanied by platelet activation and systemic inflammation have been implicated in the pathogenesis of PCAS. Because endothelial-derived nitric oxide (NO) plays a central role in maintaining vascular homeostasis, the role of NO-dependent signaling has been a focus of the intense investigation. Recent preclinical studies showed that therapeutic interventions that increase vascular NO bioavailability may improve outcomes after cardiac arrest complicated with PCAS. In particular, NO inhalation therapy has been shown to improve neurological outcomes and survival in multiple species. Clinical studies examining the safety and efficacy of inhaled NO in patients sustaining PCAS are warranted. Correspondence to: Fumito Ichinose, M.D., Ph.D. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, Phone: 617-643-0987, Fax: 617-643-4490, Email: FICHINOSE@mgh.harvard.edu Conflicts of interest: Dr. Miyazaki and Dr. Ichinose have nothing to disclose. Sources of support that require acknowledgment: This work was supported by a National Institute of Health grant R01HL110378 to Dr. Ichinose. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Impact of continuous P2Y12 inhibition tailoring in acute coronary syndrome and genetically impaired clopidogrel absorption Clopidogrel is still widely used in acute coronary syndrome (ACS) despite the development of more potent P2Y12 inhibitors. Previously, we conducted a trial which evaluated serial clopidogrel dose adjustment based on platelet function testing in ACS patients with initial high on-treatment platelet reactivity (HTPR). In this sub-study we performed post hoc analysis of the effect of ABCB1 genetic variants C3435T and G2677T/A on platelet inhibition and outcomes. There were no differences in the proportion of HTPR patients among C3435T carriers and non-carriers in both interventional and control group. G2677T carriers expressed significantly higher proportion of HTPR pattern throughout 12-month follow-up in the control group with no difference in the interventional group. There was no difference in ischemic outcomes between C3435T and G2677T carriers and non-carriers in both groups of patients. The results indicate that ABCB1 genotyping is not useful to guide clopidogrel therapy tailoring to improve high risk patient management. Corresponding author: Sasa Pavasovic, tel. +38512367467; GSM: +385918833155; fax number: +38512367512; email: pavasovic.sasa@gmail.com Conflict of interest: All authors state they have no conflict of interest to declare. Postal address: University of Zagreb School of Medicine, Department for Cardiovascular Diseases, University Hospital Center Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Berberine Attenuates Cholesterol Accumulation in Macrophage Foam Cells via Suppressing AP-1 Activity and Activation of Nrf2/ HO-1 Pathway Atherosclerosis is a chronic inflammation condition resulting from the interaction between lipoproteins, monocyte-derived macrophages, T lymphocytes and other cellular elements in the arterial wall. Macrophage-derived foam cell plays a key role in both early and advanced stage of atherosclerosis. Previous studies have shown that berberine could inhibit foam cells formation and prevent experimental atherosclerosis. However, its underlying molecular mechanisms have not been fully clarified. In the present study, we explored the cholesterol-lowering effects of berberine in macrophage-derived foam cell and investigated its possible mechanisms in prevention and treatment of atherosclerosis. Here, we demonstrated that berberine could inhibit atherosclerosis in apolipoprotein E-deficient mice and induce cholesterol reduction as well as decrease the content of macrophage. Berberine can regulate oxLDL uptake and cholesterol efflux, thus, suppresses foam cells formation. Mechanisms study showed that berberine can suppress scavenger receptor expression via inhibiting the activity of AP-1 and up-regulate ATP-binding cassette transporter via activating Nrf2/HO-1 signaling in human macrophage. In summary, berberine significantly inhibits atherosclerotic diseases development by regulating lipid homeostasis and suppressing macrophage foam cell formation. Address for correspondence: Xiang-Fei Feng, Associate Professor, Department of Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China, Tel:+86-21-66785231; Fax: +86-21-66785231, Email: fengxfxh@126.com Declaration of Interest: The authors have no competing interest to declare. # These authors contributed equally to this work Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.