Cardiovascular Pharmacology

Pulmonary Delivery of Antiarrhythmic Drugs for Rapid Conversion of New-Onset Atrial Fibrillation Pharmacologic management of atrial fibrillation (AF) is a pressing problem. This arrhythmia afflicts >5 million individuals in the United States and prevalence is estimated to rise to 12 million by 2050. While the pill-in-the-pocket regimen for self-administered AF cardioversion introduced over a decade ago has proven useful, significant drawbacks exist. Among these are the relatively long latency of effects in the range of hours along with potential for hypotension and other adverse effects. This experience prompted development of a new strategy for increasing plasma concentrations of anti-arrhythmic drugs rapidly and for a limited time, namely, pulmonary delivery. In preclinical studies in Yorkshire pigs, intratracheal administration of flecainide was shown to cause a rapid, reproducible increase in plasma drug levels. Moreover, pulmonary delivery of flecainide converted AF to normal sinus rhythm by prolonging atrial depolarization, which slows intra-atrial conduction and appears to be directly correlated with efficacy in converting AF. The rapid rise in plasma flecainide levels optimizes its anti-AF effects while minimizing adverse influences on ventricular depolarization and contractility. A more concentrated and soluble formulation of flecainide using a novel cyclodextrin complex excipient reduced net drug delivery for AF conversion when compared to the acetate formulation. Inhalation of the beta-adrenergic blocking agent metoprolol slows ventricular rate and can also terminate AF. In human subjects, oral inhalation of flecainide acetate with a hand-held, breath-actuated nebulizer results in signature prolongation of the QRS complex without serious adverse events. Thus, pulmonary delivery is a promising advance in pharmacologic approach to management of AF. Corresponding Author: Richard L. Verrier, Ph.D. Beth Israel Deaconess Medical Center, Division of Cardiovascular Medicine Harvard-Thorndike Electrophysiology Institute 99 Brookline Avenue, RN-301 Boston MA 02215-3908 Phone: 617-667-0733; FAX: 617-975-5270 Email address: rverrier@bidmc.harvard.edu Funding: No funding was received for the preparation of this review. Conflict of Interest Disclosures: Dr. Verrier is principal investigator of grants from InCarda Therapeutics to Beth Israel Deaconess Medical Center. Dr. Belardinelli is an employee of InCarda Therapeutics. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Essential role of the ELABELA-APJ signaling pathway in cardiovascular system development and diseases ELABELA (ELA), previously classified as a “non-coding” RNA, is a new endogenous peptidic ligand of apelin receptor (APJ/APLNR), a class A (rhodopsin-like) G protein-coupled receptor (GPCR). It has been identified to play a crucial role in diverse biological processes, especially in the normal and pathological cardiovascular system. In comparison with APJ’s first ligand apelin, ELA may play a key role at different time-points or heart regions. In this review, we summarized the roles of the ELA-APJ signaling pathway in cardiovascular system development and diseases. Corresponding authors: Sun CHEN, Fengyuan CHEN, Kun SUN, Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, 200092, Sun CHEN, No. 1665, Kongjiang Road, Yangpu District, Shanghai, China. Email: chensun@xinhuamed.com.cnTelephone number: +86 021-25078833 Conflict of Interest: none declared. Funding Information: This work was supported by the National Natural Science Foundation of China [grant numbers 81720108003, 81800281]; and the Shanghai Municipal Commission of Health and Family Planning [grant number 20184Y0062]. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The long non-coding RNA metastasis-associated lung adenocarcinoma transcript-1 regulates CCDC80 expression by targeting miR-141-3p/miR-200a-3p in vascular smooth muscle cells Objective: Our previous study showed that Coiled-Coil Domain Containing 80 (CCDC80) accelerates the development of atherosclerosis by decreasing lipoprotein lipase (LPL) expression and activity in apoE knockout mice. However, the regulatory mechanism for CCDC80 expression is unclear. This study was designed to evaluate whether non-coding RNAs involved the regulation of CCDC80 expression in vascular smooth muscle cells (VSMCs). Methods and Results: Bioinformatics prediction and luciferase reporter gene results showed that miR-141-3p/200a-3p bound to the 3’UTR of CCDC80. Further, miR-141-3p/200a-3p mimics decreased the expression of CCDC80 but increased LPL expression. Opposite results were observed with miR-141-3p/200a-3p inhibitors. We also found that lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) interacted with the sequences of miR-141-3p/200a-3p and decreased their expression. RT-qPCR and western blotting results showed that MALAT1 overexpression increased CCDC80 expression and decreased LPL expression, while MALAT1 knockdown displayed an opposite phenotype. The effects of both MALAT1 overexpression and knockdown were blocked by miR-141-3p/200a-3p mimics or inhibitors. Conclusions: Thus, we demonstrated that lncRNA MALAT1 regulates CCDC80 and LPL expression through miR-141-3p/200a-3p. Corresponding author: Wei-Dong Yin, Ph.D., Professor, Institute of Cardiovascular Research, University of South China, Hengyang, Hunan 421001, China Email: wdy20042004@126.com Tel: 86-734-8282554, Chao-Ke Tang, Ph.D., Professor, Institute of Cardiovascular Research, University of South China, Hengyang, Hunan 421001, China Email: tangchaoke@qq.com Tel: 86-734-8281853 # These authors contributed equally to this work. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Experience in Transitioning from Parenteral Prostacyclins to Selexipag in Pulmonary Arterial Hypertension Parenteral prostacyclin therapies remain first line therapy for patients with pulmonary arterial hypertension (PAH) with class IV symptoms. In selected patients who have been clinically stabilized, switching to selexipag, a chemically distinct prostacyclin receptor agonist, may alleviate risks associated with long-term parenteral therapy. We report our experience with transition of patients from parenteral prostacyclin therapy to selexipag. From January 2016 to July 2017 patients with PAH at Duke University Pulmonary Vascular Disease Center with functional class II symptoms on stable parenteral prostacyclin therapy were offered the opportunity to transition to selexipag. A standardized protocol was developed to guide titration of therapies. Patients underwent pre- and post-transition assessments of hemodynamics, echocardiography, laboratory biomarkers, and functional status. We studied 14 patients with PAH (11 women; median age 53 years) in total. Overall, 13 patients tolerated the switch to selexipag and remained on the drug at study completion and 1 patient passed away due to progressive liver failure. Surrogate markers including NT-proBNP, 6MWD, RV function, TAPSE, and right heart catheterization hemodynamics were similar pre- and post-transition. The transition from parenteral prostanoid therapy to oral selexipag was overall well-tolerated in patients with stable PAH and functional class II symptoms. Finally, doses of selexipag up to 3200 mcg twice daily were well-tolerated in patients who had been treated with prior parenteral prostacyclins. Address for Correspondence: Kishan S. Parikh, MD, Duke University Medical Center, Box 102351, NC 27710; telephone: 919-668-8820; fax: 919-681-0339; email: kishan.parikh@duke.edu. Funding Source: This was an investigator-initiated study (SR) funded by Actelion Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Cardiovascular risk and safety evaluation of a dual peroxisome proliferator-activated receptor-alpha/gamma agonist, aleglitazar, in type 2 diabetes patients: A meta-analysis This study evaluates the cardiovascular risk and safety of a dual peroxisome proliferator-activated receptor alpha and gamma (PPARα&γ), aleglitazar, for the management of type 2 diabetes mellitus. Studies were identified after a literature search in electronic databases and included in the meta-analysis according to eligibility criteria. Meta-analyses of mean differences in the changes from the baseline or odds ratios of selected indices between the aleglitazar- and the placebo/comparator-treated participants were performed. Seven studies (11832 individuals; age 59.3 years [95% confidence interval (CI) 56.4, 61.9]; body mass index 30.8 kg/m2 [95% CI 30.1, 31.7]; gender, 54% males [44, 64]) were included. In comparison with the placebo or pioglitazone, the aleglitazar treatment significantly improved %HbA1c, high-density lipoprotein-cholesterol (HDL-chol), and triglycerides. Aleglitazar also significantly decreased fasting plasma glucose and apolipoprotein B compared to the placebo. However, compared to the placebo or pioglitazone, aleglitazar significantly increased serum creatinine levels and significantly decreased the estimated glomerular filtration rate. In addition, the aleglitazar treatment was associated with a significantly increased body weight. Incidence of hypoglycemia, gastrointestinal hemorrhage, bone fractures, heart failure, cardiovascular death, and malignancy was higher in the aleglitazar group. Despite efficacy in glycemic and lipidic control, the aleglitazar treatment was associated with a poor safety profile. Corresponding author: Dr. Chang-Zhi Qu Department of Cardiology, Heilongjiang Province Hospital No. 405 Guogeli Street, Nan Gang District, Harbin 150001, China Fax: +86-0451-88025367 Tel: +86-13633649380 Email: qvchzh_med@163.com Funding: None Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Direct Oral Anticoagulants and Coronary Artery Disease: The Debacle of Aspirin Era? Longstanding aspirin is the cornerstone to prevent recurrence of thrombotic events in patients with ischemic heart disease. However, clopidogrel, a more potent antiplatelet agent, is preferred over aspirin in targeted populations including those with high risk of gastrointestinal bleeding. In addition, clopidogrel offers superior oral-tolerance and it may reduce the rates of intracranial hemorrhages as compared to aspirin. On the other hand, an extensive inhibition of coagulation cascade appears to be reasonable to minimize thrombotic events in such patients. After several failed exploratory investigations in the past with vitamin K antagonists, the newest direct oral anticoagulants may represent an alternative. In order to counterbalance bleeding complications, a low dose of these agents should be considered. Few publications have already showed promising results with the combination of clopidogrel and low-dose DOACs. Further investigations should be addressed to elucidate whether or not this is the downfall of the aspirin era for secondary prevention of atherosclerotic cardiovascular events. Address for correspondence: Dr. Juan J Badimon, FACC, FAHA, Director, Atherothrombosis Research Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Siani, email- juan.badimon@mssm.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Artemisinin attenuated atherosclerosis in high-fat diet-fed ApoE-/- mice by promoting macrophage autophagy via AMPK/mTOR/ULK1 pathway Artemisinin is an endoperoxide sesquiterpene lactone from Artemisia annua L with multiple beneficial effects, including anti-inflammation, anti-oxidant and vascular protection. Recent studies have found that inflammation along with autophagy deficiency in macrophages are the possible reasons for foam cell accumulation in the intima, which leads to atherosclerotic plaque formation. The primary aim of this study was to explore the inhibiting effect of artemisinin on atherosclerosis in high-fat diet (HFD)-fed ApoE-/- mice and investigate the probable mechanism. Artemisinin (50, 100 mg/kg, intragastric administration) treatment effectively inhibited foamy macrophage transformation and decreased atherosclerotic plaque formation in atherosclerotic mice. Moreover, artemisinin promoted AMP activated protein kinase (AMPK) activation, inhibited mammalian target of rapamycin (mTOR) and uncoordinated-51-like kinases 1 (ULK1) phosphorylation, increased LC-3II accumulation and P62 degradation, and thereby enhancing macrophage autophagy. Besides, the inhibiting effect of artemisinin on mTOR and ULK1 phosphorylation could be abrogated by AMPK knockdown, suggesting AMPK was the essential target of artemisinin on promoting macrophage autophagy. Our study indicated that artemisinin alleviated atherosclerotic lesions by accelerating macrophage autophagy via AMPK/mTOR/ULK1 pathway. Corresponding author: Prof. Xiaodong Li, Department of Cardiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, People’s Republic of China E-mail: Lxd1894021@126.com Tel: +24-96615-22111 Fax: 024-23899651 Funding: This study was supported by grants from the Science and Technology Development Project of Liaoning Province (No. 2017225007) and the Diagnostic and Therapeutic Capability Construction Project for Key Clinical Departments of Liaoning Provincial Hospital Reform (No. LNCCC-D10-2015). Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Beta-blocker Dose Stratifies Mortality Risk in a Racially Diverse Heart Failure Population Heart failure (HF) is highly prevalent and a major cause of death in the US. The effect of HF medications on survival has been predicted by validated models studied in populations predominantly of European descent. This study aimed to identify medications associated with survival in a racially diverse HF population. HF patients were recruited and followed from 2001 to 2015. Data were collected from electronic health records and the Social Security Death Index. The primary analysis tested the association between medication dose and all-cause mortality, with a secondary analysis assessing the composite outcome of death or cardiac-related hospitalization. Circulating concentration of the fibrotic marker procollagen type III N-terminal peptide (PIIINP) was also compared with medication doses in patients with concentrations available. The study population consisted of 337 patients, of which 23% died and 46% were hospitalized. Increased beta blocker (BB) dose was significantly associated with survival in the base model (HR=0.71, P=0.017), and marginally associated in the comprehensive model (HR=0.75, P= 0.068). BB dose was also associated with decreased risk of the composite endpoint in the base model (HR= 0.80, P=0.029) and to a lesser extent in the comprehensive model (HR=0.83, P=0.085). Further, increased BB dose was inversely associated with circulating PIIINP concentration (P=0.041). In conclusion, our study highlights the importance of BB dose escalation for survival and decreased hospitalization in patients with HF, regardless of race or HF type. It also suggests that benefits observed with high-dose BBs could be mediated, at least in part, by decreased cardiac fibrosis, however further research is needed. Corresponding Author: Julio D. Duarte, PharmD, PhD, FAHA Assistant Professor University of Florida College of Pharmacy HSC PO Box 100486 1600 SW Archer Road Gainesville, FL 32610 352-273-8132 juliod@cop.ufl.edu Sources of Funding: This project was funded in part by the University of Illinois at Chicago Office of the Vice Chancellor for Research as well as American Heart Association Midwest Affiliate Scientist Development Grant 0335361Z (LHC), NIH/NIA R03 AG033381 (LHC), NIH/NHLBI R01 HL141281 (AAD), and NIH/NIGMS K23 GM112014 (JDD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Disclosures None Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Genetic Variations of CYP19A1 Gene and Stroke Susceptibility: A Case-control Study in the Chinese Han Population Objective: This study aimed to explore the association between genetic variations of CYP19A1 and stroke susceptibility in the Chinese Han population. Methods: A total of 477 stroke patients and 480 healthy controls were recruited in this study. The genotyping of CYP19A1 polymorphisms (rs4646, rs6493487, rs1062033, rs17601876 and rs3751599) was performed by Agena MassARRAY platform. Under logistic regression models, we evaluated the associations of CYP19A1 polymorphisms and stroke susceptibility by odds ratio and 95% confidence intervals. Results: Our study showed that rs4646 (co-dominant: P = 0.020; recessive: P = 0.016) and rs17601876 (allele: P = 0.044; co-dominant: P = 0.011; dominant: P = 0.009; recessive: P = 0.046) significantly decreased the risk of stroke. In the stratification analysis, rs4646 is associated with decreased stroke risk among the individuals older than 64 (co-dominant: P = 0.028; recessive: P = 0.010) and female (co-dominant: P = 0.029; recessive: P = 0.029), whereas rs1062033 increased stroke risk in the subgroup of age ≤ 64 (recessive: P = 0.042). Rs17601876 has a strong relationship with stroke susceptibility, which is age- and gender-dependent. In haplotype analysis, we found one block (rs17601876 and rs3751599), and Ars17601876Grs3751599 haplotype is related to an increased stroke risk (P < 0.05). Additionally, CYP19A1 variations had effects on clinical characteristics. Conclusion: CYP19A1 polymorphisms were significantly associated with stroke susceptibility in the Chinese Han population. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

The effect of PPI withdrawal on dabigatran etexilate plasma levels in patients with atrial fibrillation: a washout study Background: Several studies demonstrated that proton pump inhibitors (PPI) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels. Aim of study: The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF. Methods: This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2 week period of PPI withdrawal with Hemoclot® Thrombin Inhibitor Assay. Results: The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after two weeks of PPI withdrawal (97.2±79.7 versus 163.8±105.5 ng/mL; p < 0.05). Moreover, significantly higher peak dabigatran levels were observed after two weeks of PPI withdrawal (142.4±102.8 versus 255±129.5 ng/mL; p ≤ 0.001). Conclusions: This study showed that a 2 week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF. Correspondence to:Matej Samoš, MD PhD, Department of Internal Medicine I, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Kollarova 2, 036 59 Martin, Slovak republic, e – mail: matej.samos@gmail.com, tel.: +421 907 612 943, +421 43 4203 820 Conflict of interest: The authors have no conflict of interest to declare. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.