Non-Invasive Hemodynamic Monitoring of Cocaine-Induced Changes in Cardiac Output and Systemic Vascular Resistance in Subjects with Chronic Cocaine Use Disorder Background. Cocaine use disorder (CUD) is a common problem in the United States and worldwide. The mechanisms by which cocaine induces acute cardiovascular toxicity are various. When systemically absorbed through inhaled or intravenous routes, cocaine induces an acute rise in heart rate (HR) and blood pressure (BP) leading to a significant increase in cardiac output (CO) and myocardial oxygen demand. Subjects with chronic CUD represent a special population that has experienced long-term cocaine exposure, often without showing signs of cardiovascular disease. We herein present prospectively collected data on the acute hemodynamic effects of intravenous cocaine in a cohort of non-treatment-seeking individuals with CUD without cardiovascular disease. Methods and Results. Baseline physiologic data were collected while participants underwent infusion of escalating doses of cocaine (10 mg, 20 mg, 40 mg administered over 2 minutes) at baseline and after receiving single-blind placebo treatment. Continuous non-invasive hemodynamic monitoring was performed throughout the infusion sessions using the ccNexfin finger cuffs (Edwards Lifesciences Corp, Irvine, CA). The recorded arterial BP tracings allowing measurement of beat-to-beat changes in HR, BP, stroke volume, CO, and systemic vascular resistance (SVR). None of the subjects experienced a treatment related serious adverse event. Cocaine produced significant dose-dependent increases in median HR, BP, CO, and +dP/dt (a measure of cardiac contractility) and a significant dose-dependent reduction in median SVR. Conclusions. Intravenous cocaine in a cohort of otherwise healthy subjects with CUD produced dose dependent increases in CO, largely explained by an increase in HR, accompanied by a dose-dependent decrease in SVR. Address for correspondence: F. Gerard Moeller, M.D. 1200 East Clay Street Richmond, Virginia 23298-0261 Frederick.moeller@vcuhealth.org Disclosures. Dr Moeller discloses grant funding from Indivior and Nektar therapeutics. All other authors have no disclosures to report. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The neglected role of neutrophils in the severity of aortic valve stenosis No abstract available

Dietary apigenin in the prevention of endothelial cell dysfunction The anti-carcinogenic effects of the polyphenol apigenin (4', 5, 7-trihydroxyflavone) have been amply documented and are currently assessed in clinical studies. Potential benefits against other inflammatory diseases, such as atherosclerosis, are also being uncovered Following their previous work in the field, Yamagata et al., report in the present issue that “Dietary apigenin reduces induction of LOX-1 and NLRP3 expression, leukocyte adhesion and acetylated low density lipoprotein uptake in human endothelial cells exposed to trimethylamine-N-oxide” The context of this molecular study and its potential for future breakthroughs in cardiovascular pharmacology are also discussed. Corresponding author: FGizard@yahoo.com 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.

Intrinsic Adaptation of Shr Right Atrium Reduces Heart Rate Hypertension represents an autonomic dysfunction, characterized by increased sympathetic and decreased parasympathetic cardiovascular tone leading to resting tachycardia. Therefore, studies assessing hypertension-associated changes in isolated cardiac tissues were conducted under electric field stimulation to stimulate the neurons. Herein we characterize the influence of the autonomic neurotransmitter on the baseline atrial chronotropism of unpaced isolated right atria of normotensive (NWR) and spontaneously hypertensive rats (SHR). Our results revealed a resting bradycardia in tissues from SHR in comparison to normotensive rats. The release of autonomic neurotransmitters, acetylcholine or norepinephrine, still occurs in the electrically unstimulated right atrium, after excision of the sympathetic nerve, which could explain differences in basal heart rate between NWR and SHR. Nicotine and the acetylcholinesterase inhibitor physostigmine reduced the chronotropism of right atria from either NWR or SHR. Conversely, the muscarinic receptor antagonist atropine did not affect the basal chronotropism of tissues from both strains. Furthermore, tyramine increased the chronotropism of NWR and SHR atria indicating availability of the neuronal stocks of noradrenaline. Although the monoamine uptake inhibitor cocaine increased right atrium chronotropism in both strains, the basal heart rate was not affected by the β-adrenoceptor antagonist propranolol. In summary, after acute section of the sympathetic nerve, autonomic neurotransmitters are still released either in resting conditions or upon pharmacological stimulation of right atria from both strains. Nevertheless, autonomic neurotransmission does not affect resting chronotropism, nor is the responsible for reduced basal heart rate of the isolated right atrium of hypertensive rats. Address for correspondence: Juliano Quintella Dantas Rodrigues, MSc/PhD, Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo (EPM/UNIFESP), Rua Três de Maio n° 100, 2° floor, Zip Code 04044-020, E-mail address: juliano.quintella@unifesp.br (J. Q. D. Rodrigues); Phone/Fax.: + 55 11 5576 4449. * These authors contributed equally to this paper. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

BaiJiu increases nitric oxide bioactivity of Chinese herbs used to treat CAD via the NO3--NO2--NO pathway BaiJiu (BJ) is a type of Chinese rice wine combined with the traditional Chinese herbs GuaLou (GL) and XieBai (XB), which have been used to treat and prevent coronary artery disease (CAD) for nearly 2,000 years in China. However, the mechanisms behind the compatibility of the components of this compound (GLXBBJ) have not been deeply investigated. In this study, the compatibility of the GLXBBJ compounds with nitric oxide (NO) bioactivity was evaluated in herbs, cells, and isolated aortic rings. Nitrate (NO3-) and nitrite (NO2-) concentrations were quantified by the Griess method. Nitric oxide (NO) was quantified by a multifunctional enzyme marker using a fluorescent probe. Qualitative analysis of L-arginine-endothelial NO synthase (eNOS) was performed by western blotting. The tension of aortic rings was measured by multi myograph system. The ability of BJ to reduce NO3- to NO2- and NO2- to NO was strongest under hypoxic conditions and was not affected by temperature. BJ-containing serum significantly decreased the NO3- content and increased the NO2- content in hypoxic cells. Combining BJ with GL, XB, or GLXB resulted in stronger vasodilation effects. These results demonstrate that BJ effectively reduces NO3-/NO2-, although only a small amount of NO3- is present. Once combined with GL, XB, or GLXB, which are rich in NO3-/NO2-, robust NO bioactivity was generated through the NO3--NO2--NO pathway. Therefore, this study supports the potential of using traditional Chinese herbs for promoting medical innovation and for future drug development. Corresponding author: (Yaoping Tang) E-mail: typqc@126.com; Tel: +86 18007802816; Fax: +86 7713946492 (Congxin Huang) E-mail: huangcongxin@vip.163.com; Tel: +86 13907131546 Conflict of interest: The authors declared that they have no conflicts of interest related to this work. Sources of support: This work was supported by the National Natural Science Foundation of China [grant # 81774115, 2018]; National Natural Science Foundation of China [grant # 81460721, 2015]; National Natural Science Foundation of China [grant # 30960487, 2010]; National Natural Science Foundation of China [grant # 31460243, 2015]; and Guangxi Autonomous Region Scientific Research and Technology Development and Chairman Technology Fund Project of China [No.1517-10].We thank Mr. Zhixiang Long and Mr. Xiaoguang Shi for their technical support of nitrate and nitrite measurements. We also appreciate Dr. Laijun Liu for the assistance in manuscript preparation. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Multiplicity of Nitric Oxide and Natriuretic Peptide Signalling in Heart Failure Heart failure (HF) is a common consequence of several cardiovascular diseases, and is understood as a vicious cycle of cardiac and haemodynamic decline. The current inventory of treatments either alleviate the pathophysiological features (e.g., cardiac dysfunction, neurohumoral activation, ventricular remodelling) and/or target any underlying pathologies (e.g., hypertension, myocardial infarction). Yet, since these do not provide a cure, the morbidity and mortality associated with HF remains high. Therefore, the disease constitutes an unmet medical need, and novel therapies are desperately needed. Cyclic guanosine 3’,5’-monophosphate (cGMP), synthesised by nitric oxide (NO)- and natriuretic peptide (NP)- responsive guanylyl cyclase (GC) enzymes, exerts numerous protective effects on cardiac contractility, hypertrophy, fibrosis, and apoptosis. Impaired cGMP signalling, which can occur following GC deactivation and the upregulation of cyclic nucleotide-hydrolysing phosphodiesterases (PDEs), promotes cardiac dysfunction. Herein we review the role that NO/cGMP and NP/cGMP signalling plays in HF. After considering disease aetiology, the physiological effects of cGMP in the heart are discussed. We then assess the evidence from pre-clinical models and patients that compromised cGMP signalling contributes to the HF phenotype. Finally, the potential of pharmacologically harnessing cardioprotective cGMP to rectify the present paucity of effective HF treatments is examined. To whom correspondence should be addressed. Email: m.e.j.preedy@qmul.ac.uk. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

cGMP Signaling and Modulation in Heart Failure Cyclic GMP (cGMP) represents a classic intracellular second messenger molecule. Over the past two decades, important discoveries have identified that cGMP signaling becomes deranged in heart failure, and that cGMP and its main kinase effector, Protein Kinase G, generally oppose the biological abnormalities contributing to heart failure, in experimental studies. These findings have influenced the design of clinical trials of cGMP-augmenting drugs in heart failure patients. At present, the trial results of cGMP-augmenting therapies in heart failure remain mixed. As detailed in this review, strong evidence now exists that Protein Kinase G opposes pathologic cardiac remodeling through regulation of diverse biological processes and myocardial substrates. Potential reasons for the failures of cGMP-augmenting drugs in HF may be related to biological mechanisms opposing cGMP, or due to certain features of clinical trials, all of which are discussed. Correspondence: Robert M. Blanton, MD. Molecular Cardiology Research Institute, Tufts Medical Center. 800 Washington Street, #080. Boston, MA, USA 02111. Telephone +1 617 636 7678 Fax +1 617 636 1444 Email: rblanton@tuftsmedicalcenter.org Sources of Support: NIH R01HL131831 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Research progress of mechanisms and drug therapy for atherosclerosis on TLR pathway Recent reports have established atherosclerosis (AS) as a major factor in the pathogenetic process of cardiovascular diseases like ischemic stroke and coronary heart disease. Although the possible pathogenesis of AS remains to be elucidated, a large number of investigations strongly suggest that the inhibition of Toll-like receptors (TLRs) alleviates the severity of AS to some extent by suppressing vascular inflammation and the formation of atherosclerotic plaques. As pattern recognition receptors (PRRs), TLRs occupy a vital position in innate immunity, mediating various signaling pathways in infective and sterile inflammation. This review summarizes the available data on the research progress of AS and the latest antiatherosclerotic drugs associated with TLR pathway. Corresponding author. E-mail address: yunmanlicpu@hotmail.com (Y.-m. Li) E-mail address: huyahui324@163.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

FSTL3 induces lipid accumulation and inflammatory response in macrophages and associates with atherosclerosis FSTL3 as adipokine take part in dyslipidemia and inflammatory response, but the association of FSTL3 with atherosclerosis is unclear. This study indicated that FSTL3 showed significantly higher level (Control: 7.68±3.10 ng/mL versus AS: 9.29±2.37 ng/mL; P<0.001) in atherosclerosis, and FSTL3 expressed higher in plaque of ApoE knockout mice and located in macrophages. OxLDL induced expression and secretion of FSTL3, meanwhile, FSTL3 promoted lipid accumulation in macrophages. The advanced study found that FSTL3 upregulated CD36 and LOX-1 expression with dose-dependent manner, however, FSTL3 also evoked interleukin 1-β (IL1-β), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α (TNFα) and matrix metalloproteinase-9 (MMP-9) secretion in macrophages. On the contrary that downregulated FSTL3 attenuated expression of oxLDL induced CD36, LOX-1 and inflammatory cytokines expressing. All of these results demonstrated that FSTL3 as novelty cytokine take part in process of atherosclerosis through increasing lipid accumulation and inflammation via regulating CD36 and LOX-1 expression. Corresponding author: Ding Wenjun, MD, PhD Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital 180 Feng Lin road Shanghai 200025 People’s Republic of China Tel: +86 21 64041990 Fax: +86 21 64041990 Email address: doctor_dingwj@163.com Co-corresponding author: Wang Chunsheng, MD, PhD Department of Cardiac Surgery, Shanghai Institute of Cardiovascular Diseases Zhongshan Hospital 180 Feng Lin road Shanghai 200025 People’s Republic of China Tel: +86 21 64041990 Fax: +86 21 64041990 Email address: doctor_wangcs@163.com 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.

Long non-coding RNA NEAT1 promotes myocardiocyte apoptosis and suppresses proliferation via regulation of miR-129-5p Recent studies have revealed the important role of long non-coding RNAs (lncRNAs) in heart development and pathogenesis. This study was aimed to investigate the role of NEAT1 in hypoxia-induced cardiac injury and explore its possible molecular mechanism. Real-time PCR (RT-PCR) was used to determine the relative RNA expression of NEAT1 and its potential target microRNA (miRNA), miR-129-5p, in the plasma of patients with acute myocardial infarction, heart failure, and angina, as well as in H2O2-treated H9c2 cells. The role of NEAT1 overexpression or inhibition in H9c2 cell migration and proliferation was assessed by transwell assay and Edu staining, respectively. Collagen deposition and apoptosis were evaluated by western blot detection of collagen and apoptotic proteins, including Capase3, Bax, and Bcl2. We showed that H2O2 treatment significantly decreased H9c2 cell migration and proliferation while increasing H9c2 cell apoptosis. Inhibition of NEAT1 attenuated the cell apoptosis and alleviated proliferation inhibition induced by hypoxia. Bioinformatics analysis showed that miR-129-5p was the direct target of NEAT1, which was confirmed by luciferase assay. NEAT1 upregulation aggravated apoptosis by downregulating miR-129-5p. In conclusion, we uncovered a novel NEAT1-miR129 axis and its implication in H2O2-induced heart failure. Correspondence author: Ling Qin, Department of Cardiology, The First Hospital of Jilin University, No.71 of Xinmin Street, Changchun City, Jilin Province, 130021, PR. China. Tel: 86 0431-84808227 Email: tx75452@163.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.