Cardiovascular Pharmacology

The NLRP3 inflammasome as pharmacological target NLRP3 is a cytosolic receptor member of the nucleotide-binding and oligomerization domain NOD-like receptor (NLR) family that surveys the intracellular environment for the presence of infection, pathogens, and metabolic alarms. While the surveillance activity of NLRP3 is required to protect the host from several pathogens, uncontrolled activity can be detrimental to the host. Pharmacological and genetic strategies limiting NLRP3 inflammasome activation have been shown to be beneficial in a wide range of experimental models, from common pathologies such as arthritis, cardiovascular disease, and metabolic syndromes, to rare genetic disorders such as cryopyrin-associated-periodic-syndrome (CAPS). Thus, compounds that prevent NLRP3 inflammasome activation are of common interest with relevant therapeutic potential. The focus of this review is recent developments in NLRP3 inflammasome inhibitors. Correspondence should be addressed to Carlo Marchetti Department of Medicine, University of Colorado Denver, Aurora, CO, USA. (carlo.marchetti@udenver.edu) Conflict of interest: the author declares no conflict of interest. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Preclinical and clinical effects of the flavanol kaempferol: Oxidative stress, myocardial inflammation, and the impact of human metabolism No abstract available

Correlation of Inhaled Long-acting Bronchodilators with Adverse Cardiovascular Outcomes in Patients with Stable COPD: A Bayesian Network Meta-Analysis of Randomized Controlled Trials A majority of existing studies have focused on the efficacy of inhaled long-acting bronchodilators (ILABs), such as long-acting muscarinic antagonists (LAMAs) and long-acting β2–agonists (LABAs), and LABAs combined with LAMAs in treating chronic obstructive pulmonary disease (COPD). The current meta-analysis aimed to investigate the correlation of ILABs with specific cardiovascular adverse events (CAEs). Five electronic databases, including PubMed, Embase, Cochrane Library, Scopus and Web of Science, were systematically retrieved. Finally, 16 randomized controlled trials (RCTs) were enrolled into the current meta-analysis. Typically, the efficacy of 3 major classes of drugs (LABAs, LAMAs, as well as LABAs combined with LAMAs), as well as 7 specific drugs (including Formoterol, Glycopyrrolate, Indacaterol, Olodaterol, Salmeterol, Tiotropium, and Vilanterol) for 4 CAEs, including myocardial infarction (MI), cardiac failure (CF), ischemic heart disease (IHD) and stroke in stable COPD patients, was examined. All the pooled results were analyzed through the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). The direct meta-analysis results suggested that LABAs could increase the risk of CF in patients with stable COPD compared with placebo controls (OR 1.70, 95%CI 1.00-2.90). In addition, network meta-analysis results indicated that LAMAs combined with LABAs would result in an increased risk of CF in patients with stable COPD (OR 2.31, 95%CI 1.10-5.09). According to the ILABs specific drug analysis, Formoterol might potentially have protective effects on IHD compared with placebo controls (OR 0.45, 95%CI 0.18-1.00). In conclusion, among these three kinds of ILABs, including LAMAs, LABAs, and LABAs /LAMAs, for stable COPD patients, LAMAs and LABAs are associated with the least possibility to induce MI and stroke, respectively. However, the application of LABAs will probably increase the risk of CF, they should be used with caution for stable COPD patients with CF. In addition, in specific-drug analysis, the use of formoterol can reduce the risk of treatment-related IHD. Nevertheless, more studies on different drug doses are needed in the future to further validate this conclusion. Corresponding author (R.Chang): Tel: +86 0971 8063179 E-mail address: qhschangrong@126.com (R.Chang) & These authors contributed equally to this work and should be considered co-first authors; Disclosures: The authors have no conflicts of interest to disclose. Sources of Funding: Sponsored by National Natural Science Foundation of China (No.81360301) and QingHai Department of Science and Technology (NO.2018-ZJ-904); Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Atorvastatin Attenuates Cold-induced Hypertension by Preventing Gut Barrier Injury Chronic exposure to cold causes arterial hypertension (CIH). Emerging data have indicted that gut barrier dysfunction is involved in the pathogenesis of hypertension. In this study we explored the effect of gut barrier dysfunction on vascular inflammation induced by cold exposure and the therapeutic effect of atorvastatin in a CIH rat model. The CIH was established by cold exposure for two weeks. Two groups of Sprague Dawley (SD) rats were exposed to moderate cold (4 ± 1 °C), while the control group was maintained at room temperature (RT) (23 ± 1 °C) (10 rats/group). The two groups were received atorvastatin or vehicle at beginning of cold exposure, respectively, for two weeks. Cold exposure increased mean arterial pressure (MAP) compared to RT group, indicating that animals developed arterial hypertension. Cold exposure induced vascular dysfunction due to decreasing phosphorylated eNOS protein expression in aorta, and these were blunted by atorvastatin. Cold exposure increased the levels of gut-derived inflammatory cytokines, TNF-α and IL-6 production in aorta, and resulted in vascular inflammation, while atorvastatin prevented these effects. Cold exposure also increased gut permeability, inhibited tight junction protein expression in proximal colon and resulted in gut barrier dysfunction. Interestingly, atorvastatin eliminated increasing of gut permeability, decreasing of tight junction protein expression, gut pathology and reversed gut barrier dysfunction. Atorvastatin attenuated CIH and improved gut barrier function, the beneficial effects might be via inhibiting gut-derived inflammatory cytokines and reversing cold-induced vascular inflammation, suggesting that gut barrier dysfunction may be involved in the pathogenesis of CIH. Correspondence: Yue Li and Bing Bai, Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Youzheng Street No. 23, Nangang District, Harbin 150001, China. Tel: +86 451 85555673; Fax: +86 451 53675733 E-mail addresses: ly99ly@vip.163.com (Yue Li) and baibing2910@163.com (Bing Bai) † Song Zhang and Yun Zhang contributed equally to this work. Declaration of Conflicting Interests: The author(s) declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Antithrombotic Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease Undergoing Percutaneous Coronary Intervention Aim: The objective of this manuscript is to review the contemporary literature on the concomitant use of antithrombotic and antiplatelet therapy in patients with atrial fibrillation (AF) and coronary artery disease (CAD) after undergoing percutaneous coronary intervention (PCI). Special consideration was given to the type and duration of therapy, treatment strategies for the elderly (≥65 years of age), and strategies to reduce bleeding. Methods: Relevant studies were searched through MEDLINE/PubMed, Web of Science, Cochrane Library, ClinicalTrials.gov and Google Scholar. Of the 236 publications retrieved, 76 were considered relevant including: 35 randomized controlled trials (RCTs), 17 meta-analyses, 16 observational studies and 8 published major guidelines. Results: Most trials, meta-analyses and guidelines support either 1 month of triple therapy (TT) with an oral anticoagulant (OAC), dual antiplatelet agents (DAPT) with aspirin (ASA)/clopidogrel and afterwards dual therapy (DT) with OAC and single antiplatelet agent for an additional 11 months or alternatively DT alone for 12 months post-PCI. Individual consideration is given to the risk and impact of both stent thrombosis (ST), thromboembolism, and bleeding. Several trials and meta-analyses have also suggested that shorter DAPT duration (≤6 months) may be safer than longer therapy (≥6 months) when weighing the risk of bleeding with ischemic outcomes, especially with newer generation drug-eluting stents (DES). The selective use of proton pump inhibitors (PPIs) in patients prone to gastrointestinal bleeding (GIB) who are subjected to prolonged exposure with TT or DT may be beneficial. In the elderly the risk of bleeding from TT, compared with DT, outweighs the benefit of reducing ischemic events. Conclusion: In conclusion, tailoring therapy to the individual patient is recommended considering the ischemic and bleeding risk as well as the risk for thromboembolism. For most AF patients 1 month of TT, and subsequently DT for additional 11 months is recommended. Corresponding Author: Abhishek Mishra MD Department of Cardiovascular Disease One Guthrie Square, The Guthrie Clinic/Robert Packer Hospital Sayre, PA 18840 Abhishek_110@hotmail.com * Authors share equal contribution to this manuscript. Disclosures: None of the authors has any disclosures relevant to the content of the manuscript Funding sources: No study specific funding was used to support this work. The authors are solely responsible for drafting and editing of the manuscript and its final contents. All authors had access to the data and a role in writing the manuscript. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Impact of Post-Discharge Bleeding on Long-Term Mortality in Percutaneous Coronary Intervention Patients Taking Oral Anticoagulants Although post-discharge bleeding (PDB) are known to negatively affect long-term outcome in patients undergoing percutaneous coronary intervention (PCI) with antiplatelet therapy (APT), the prognostic importance of PDB in patients who require both oral anticoagulant (OAC) and APT has not been fully elucidated. Among 3718 consecutive patients who underwent PCI, 302 patients were treated with both OAC and APT. We evaluated the association between PDB and 3-year all-cause mortality, as estimated by a time-updated Cox proportional hazard regression model. We performed nearest-neighbor matching on propensity score to adjust the differences of baseline characteristics. Among 302 patients treated with OAC and APT, PDB was observed in 98 patients at a median time of 239 days. Patients experienced PDB had significantly higher incidence of 3-year all-cause mortality in the overall cohort and 94 propensity-score matched pairs (hazard ratio [HR] 6.21, 95% confidence interval [CI] 3.29–11.72, p < 0.0001; and HR 6.13, 95% CI 2.68–14.02, p < 0.0001, respectively). The risk of subsequent mortality was the highest within 180 days after PDB (58.3% within 180 days, and 75.0 % within 1 year). In conclusion, PDB was significantly associated with long-term mortality in patients taking both OACs and APT after PCI. Corresponding Author: Ruka Yoshida, MD Department of Cardiology, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560 Japan.TEL: +81527412111; Fax: +81527442785 E-mail: lyoshida@hotmail.com Conflict of Interest: H.I. received lecture fees from Astellas Pharma Inc., Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Pharma Inc., and MSD K. K. T.M. received lecture fees from Bayer Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Pfizer Japan Inc., Sanofi-aventis K. K., and Takeda Pharmaceutical Co., Ltd. T.M. received unrestricted research grant for Department of Cardiology, Nagoya University Graduate School of Medicine from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Otsuka Pharma Ltd., Pfizer Japan Inc., Sanofi-aventis K. K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd. Other authors have nothing to declare. Research Funding: This study was supported by a grant from Aichi Kidney Foundation and Grant-in-Aid for Scientific Research (KAKENHI) (No. 1 7 K 0 9 4 9 3) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Japanese Society for the Promotion of Science (JSPA). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The pharmacodynamic effects of a dopamine-somatostatin chimera agonist on the cardiovascular system The quantification of the effect of pharmacological treatment on the cardiovascular system is complicated due to the high level of inter-individual and circadian variability. Recently, a dopamine-somatostatin chimera, BIM23B065, was under investigation to concurrently target the somatostatin and dopamine D2 receptors for the treatment of neuroendocrine tumors. However, both dopamine and somatostatin interact with different components of the cardiovascular system. This study established the response of the heart rate and the systolic blood pressure after administration of BIM23B065 in healthy male volunteers by analysis of the rate-pressure product (RPP), in a model informed analysis. The RPP in the supine position of placebo treated subjects showed a clear circadian component, best described by two cosine functions. The pharmacokinetics of BIM23B065 and its metabolite were best described using 2-compartment models with different forms of elimination kinetics. The administration of BIM23B065 gave a statistically significant reduction in the RPP, after which the effect diminished due to tolerance to the cardiovascular effects after prolonged exposure to BIM23B065. This model provided insight in the circadian rhythm of the RPP in the supine position and the level of inter-individual variability in healthy male volunteers. The developed population pharmacokinetic/pharmacodynamic model quantified the interaction between BIM23B065 and the RPP, informing on the clinical pharmacological properties of BIM23B065. Corresponding author: Koos Burggraaf, Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands Tel: +31 71 524 6400, E-mail: kb@chdr.nl Conflict of interest: MJVE: None, JS: None, FES: None, WMIDB: None, MD: Employee of Ipsen, PHVDG: None, JB: None. This study was funded by Ipsen. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The role of cytochrome p450 and soluble epoxide hydrolase enzymes and their associated metabolites in the pathogenesis of diabetic cardiomyopathy A plethora of studies have demonstrated that cardiomyopathy represents a serious source of morbidity and mortality in patients with diabetes. Yet, the underlying mechanisms of diabetic cardiomyopathy are still poorly understood. Of interest, cytochrome P450 2J (CYP2J) and soluble epoxide hydrolase (sEH) are known to control the maintenance of cardiovascular health through the regulation of cardioprotective epoxyeicosatrienoic acids (EETs) and its less active products, dihydroxyeicosatrienoic acids (DHETs). Therefore, we examined the role of the aforementioned pathway in the development of diabetic cardiomyopathy. Our diabetic model initiated cardiomyopathy as indexed by the increase in the expression of hypertrophic markers such as NPPA. Furthermore, diabetic cardiomyopathy was associated with a low level of cardiac EETs and an increase of DHETs/EETs ratio both in vivo and in cardiac cells. The modulation in EETs and DHETs was attributed to the increase of sEH and the decrease of CYP2J. Interestingly, the reduction of sEH attenuates cardiotoxicity mediated by high glucose in the cardiac cells. Mechanistically, the beneficial effect of sEH reduction might be due to the decrease of phosphorylated ERK1/2 and p38. Overall, the present work provides evidence that diabetes initiates cardiomyopathy through the increase in sEH, the reduction of CYP2J and the decrease of cardioprotective EETs. Corresponding Author: Faculty of Pharmacy & Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada T6G 2E1. Tel.: +1 780 492 3071; fax: +1 780 492 1217. E-mail address: aelkadi@ualberta.ca (A.O.S. El-Kadi). Conflict of interest: There is no conflict of interest. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Danhong Injection Attenuates High-fat-induced Atherosclerosis and Macrophage Lipid Accumulation by Regulating PI3K/AKT Insulin Pathway Abstract: Background and aims: High-fat diet (HFD) is reported to induce atherosclerosis and insulin resistance (IR). Macrophage lipid accumulation has been implicated as key mediators during the development of HFD-induced atherosclerosis. Traditional Chinese formula, which has long been used to improve disorder of glucose and lipid metabolism of patients, is now gradually being used as complementary therapy. The present study aimed to investigate the effect of Dan-hong injection (DHI), a Chinese medicine used for the treatment of coronary artery disease, on atherosclerosis and its underlying mechanisms. Methods and results: We observed the effects of DHI on HFD-induced atherosclerosis in mice model, macrophage lipid accumulation in ox-LDL stimulated macrophage model and the role of PI3K/AKT insulin pathway in process of DHI ameliorating atherosclerosis. The data demonstrated that DHI attenuated atherosclerosis by ameliorating blood lipids, reducing the atherosclerotic index and atherosclerotic plaque area in HFD-induced atherosclerotic mice, and inhibiting TC levels in ox-LDL-induced macrophage model. By estimating the levels of serum IR-related indexes and protein expression of GLUT-4, DHI treatment dramatically inhibited the levels of fasting serum NEFA and fasting serum insulin, and promoted the protein expression of GLUT-4 in aortas of the HFD-induced atherosclerotic mice. Moreover, according to the hints provided by Microarray-Based Transcriptional Profiling, the results demonstrated that DHI treatment also promoted the activation of PI3K/AKT insulin signaling pathway induced by IRS-1 in aortas of HFD-induced atherosclerotic mice. Furthermore, in ox-LDL-induced macrophage model, the activation of PI3k/AKT signaling pathway also effectively functioned in the process of DHI inhibiting macrophage lipid accumulation. Conclusions: These results highlight that DHI treatment attenuates atherosclerosis and macrophage lipid accumulation by promoting the activation of PI3K/AKT insulin signaling pathway. It provides new insights into the molecular mechanism of DHI and its therapeutic potential in the treatment of atherosclerosis. Corresponding author: Hongxu Liu, Beijing Hospital of Traditional Chinese Medicine,Capital Medical University,23 Backstreet of Art Gallery, East district, Beijing, China, Zip code: 100010, E-mail: lhx_@263.net Conflicts of Interest: The authors declare they have no conflicts of interest. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The pharmacological differences in anti-anginal effects of long-lasting calcium channel blockers: azelnidipine and amlodipine We examined anti-anginal effects of azelnidipine and amlodipine in an arginine vasopressin (AVP)-induced rat anginal model. Oral administration of azelnidipine or amlodipine produced long-lasting inhibition of AVP-induced ST-segment depression in ECG. The degrees of inhibition with azelnidipine at doses of 1 and 3 mg/kg were comparable to those with amlodipine at 3 and 10 mg/kg. Both drugs lowered mean blood pressure in a dose related manner, while only azelnidipine decreased heart rate. Azelnidipine at 3 mg/kg and amlodipine at 10 mg/kg produced a similar decrease in the rate pressure product, an index for cardiac oxygen consumption. Their inhibitory effects on calcium-induced vascular contraction were compared in isolated porcine coronary arteries. Both drugs produced a slow-developing inhibition of calcium-induced contraction. Although their inhibitory effects were similar, the way the both drugs inhibited calcium-induced contraction differed with each other. After removing the drug from bathing solution, the inhibitory effects of azelnidipine were not blunted but were sustained for a long time which indicates that azelnidipine has high vascular affinity. On the other hand, those of amlodipine were rapidly blunted. These results suggest that the mechanisms underlying anti-anginal effects of azelnidipine differ from those of amlodipine. The anti-anginal effect with azelnidipine may be accounted for by its high affinity to the coronary blood vessels and the heart rate slowing effect, both of which are not shared with amlodipine. Correspondence: Fujisawa Michio MS, Research and Development Division, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. e-mail: fujisawa.michio.ec@daiichisankyo.co.jp, Facsimile: 81-3-5436-8561, Telephone: 81-3-5740-3481 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.