DOCA/Salt: much more than a model of hypertension. Mineralocorticoid excess produces inflammation, hypertrophy, and fibrosis independently of its effects on sodium balance and blood pressure. Mineralocorticoids act through the mineralocorticoid receptor (MR) which mediates transcriptional and rapid non-genomic effects in non-epithelial cells including cardiomyocytes, vascular endothelial and smooth muscle cells, macrophages and T-cells, and neurons. DOCA, an inactive pro-drug, is converted to DOC with variable efficiency in different cells types. The affinities of DOC and aldo for the MR are similar; the affinity of DOC for the glucocorticoid receptor (GR) is greater than that of aldosterone. As DOC is rapidly inactivated in the kidney, doses of DOCA required to increase renal sodium and water resorption produce relatively greater non-renal effects and concentrations of DOC that activate both MR and GR. Thus the DOCA excess is not equivalent to endogenous aldosterone excess. Nonetheless, the mechanisms of both steroids that produce cardiovascular inflammation and remodeling are direct and independent of hypertension, as well as indirect, through increased blood pressure. Elise P. Gomez-Sanchez, DVM, PhD, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, phone (601) 984-1589, egomez-sanchez@umc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Ginsenoside Re preserves cardiac function and ameliorates left ventricular remodeling in a rat model of myocardial infarction Ginsenoside Re, an herbal ingredient from ginseng, has been demonstrated to protect the heart from various cardiovascular diseases. In the present study, we investigated the protective effects and mechanisms of ginsenoside Re (Gin-Re) on cardiac function and left ventricular remodeling in a rat model of myocardial infarction (MI). After ligating the left anterior descending coronary artery, Wistar rats were treated with Gin-Re (135 mg/kg) by gavage everyday for 4 weeks. Serological detection showed that Gin-Re significantly inhibited myocardial injury and attenuated oxidative stress in MI rats. Echocardiographic observation showed that Gin-Re significantly improved cardiac function and prevented left ventricular dilatation induced by MI. Pathological observation found that Gin-Re significantly decreased interstitial fibrosis in the left ventricle of MI rats. Compared with the MI group, Gin-Re treatment promoted AMPKα phosphorylation, decreased TGF-β1 expression and attenuated Smad2/3 activation. After Gin-Re treatment, the phosphorylation of FAK, PI3K p110α and Akt was enhanced in MI rats, while PI3K p110β showed no difference compared with the MI group. These results indicate that Gin-Re may improve MI-induced cardiac dysfunction and mitigate ventricular remodeling via regulation of the AMPK/TGF-β1/Smad2/3 and FAK/PI3K p110α/Akt signaling pathways. Correspondence to: Dr. Chenglong Wang, No.1 Xiyuan Playground; Haidian District, Beijing 100091, China. Email: wcl796@126.com Supported by grants from the National Natural Science Foundation of China (No. 81873934, 81874410). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Should we judge stroke risk by static or dynamic risk scores? A focus on the dynamic nature of stroke and bleeding risks in patients with atrial fibrillation. Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and a major risk factor for stroke. The number of patients with AF is predicted to increase in the next few decades. AF has also negative impact on quality of life as well as it significantly increases the risk of cardiovascular disease and overall mortality. As the stroke is a pivotal outcome of AF, its prevention with the use of anticoagulation therapy constitutes an important component of AF management. The decision on oral anticoagulants (OACs) prescription should be based on appropriate risk stratification to allow comprehensive assessment of benefit/hazard ratio of stroke and bleeding along with patients’ preference. Several risk scores for stroke and bleeding as well as for stroke and systemic embolism have been developed, mainly in patients on vitamin K antagonists (VKAs). AF guidelines stress the need for repetitive evaluation of thromboembolic and bleeding risks to tailor optimal AF management. Indeed, risk is not a static ‘one off’ process and it should be adjusted for dynamic nature of risk factors. However, most risk scores are calculated according to baseline characteristics of patients, but the older patients get, the more comorbidities they acquire, which influences stroke risk significantly. Hence, the default management of every patient with AF should include a regular reassessment of stroke and bleeding risk factors. Correspondence: Professor G. Y. H. Lip, gregory.lip@liverpool.ac.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Hexokinase II up-regulation contributes to asiaticoside-induced protection of H9c2 cardioblasts during oxygen-glucose deprivation/reoxygenation Asiaticoside (AS), one of the main functional components of Centella asiatica, has been reported to protect neurons from ischemia-hypoxia-induced injury. However, the role of AS in myocardial oxygen-glucose deprivation/reoxygenation (OGD/R) injury has not been investigated. The aim of this study was to investigate the role of AS in OGD/R-treated H9c2 cardiomyocytes and the underlying mechanism involved. Cell viability was detected using MTT assay. Cell apoptosis was measured using flow cytometry. The oxidative stress was assessed by detecting the malonaldehyde (MDA) content, and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). The glucose consumption and lactate production were determined to reflect glycolysis rate. The expression levels of hexokinase II (HK2) were detected using RT-qPCR and western blot. H9c2 cells were transfected with small interfering RNA targeting HK2 (si-HK2) to knockdown HK2. Results showed that AS improved cell viability and inhibited apoptosis in OGD/R-injured H9c2 cells. AS pretreatment prevented OGD/R-induced oxidative stress, as evidenced by the decreased MDA content, and increased activities of SOD, GSH-Px, and CAT. The decreased glucose consumption and lactate production in OGD/R-injured H9c2 cells were reversed after AS treatment. Mechanically, AS induced the expression of HK2 in OGD/R-injured H9c2 cells. Knockdown of HK2 abolished the protective effects of AS on OGD/R-injured H9c2 cells. In conclusion, the protective effects of AS on cardiomyocytes from OGD/R-induced injury was mediated at least partly by up-regulating HK2. Corresponding author (Xinwei Jia). Deparment of Vasculocardiology, Affiliated Hospital of Hebei University, No.212 Yuhuadong Road, Baoding 071000, China. Email: xinwjia@163.com. # These authors contributed equally to this work. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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”. Here, the context of this molecular study and its potential for future breakthroughs in cardiovascular pharmacology are discussed. Corresponding author: FGizard@yahoo.com 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.

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.