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Publisher: Oxford University Press   (Total: 397 journals)

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Showing 1 - 200 of 397 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 53, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.434, CiteScore: 1)
African Affairs     Hybrid Journal   (Followers: 66, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 91, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 19, SJR: 1.376, CiteScore: 3)
American Entomologist     Full-text available via subscription   (Followers: 8)
American Historical Review     Hybrid Journal   (Followers: 161, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 45, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 168, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 190, SJR: 2.713, CiteScore: 3)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 19, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 8, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 16, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 22, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal   (Followers: 1)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 16, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 37, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 56, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 10, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 34, SJR: 0.728, CiteScore: 2)
Antibody Therapeutics     Open Access  
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 58, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
Arbitration Intl.     Full-text available via subscription   (Followers: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 44, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 52, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 327, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 29, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 179, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 65)
Brain     Hybrid Journal   (Followers: 68, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 51, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 36, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 600, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 85, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 6, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 33)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 65, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 11, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 2, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 14, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 46, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 18, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 5, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 10, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 27, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 1)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 70, SJR: 5.051, CiteScore: 5)
Communication Theory     Hybrid Journal   (Followers: 24, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 27, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 3, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 2)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 3, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 8, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 14, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 20, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 5, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 16, SJR: 0.139, CiteScore: 0)
Economic Policy     Hybrid Journal   (Followers: 42, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 54, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 15, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 3)
Environmental History     Hybrid Journal   (Followers: 27, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 3, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 19, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 63, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 3.625, CiteScore: 3)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 2)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. : Case Reports     Open Access  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 195, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 20, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 30, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 42, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 12)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 15, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 28, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 32, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 25, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 7, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 33, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 21, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 14, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 36, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 23, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 5, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 13, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 57, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 16, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 22, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 31, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 28, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 15, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access   (Followers: 1)
Human Reproduction Update     Hybrid Journal   (Followers: 20, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 62, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 56, SJR: 1.591, CiteScore: 3)
ICSID Review : Foreign Investment Law J.     Hybrid Journal   (Followers: 10)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 10, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 39, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 48, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.319, CiteScore: 2)
Interacting with Computers     Hybrid Journal   (Followers: 11, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 65, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 25)
Intl. Health     Hybrid Journal   (Followers: 6, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 36, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 64, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 240, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 38, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 11, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 40, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 23, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 48, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 25, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 16, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 46, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 15, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 5, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 40, SJR: 1.226, CiteScore: 2)
J. of Burn Care & Research     Hybrid Journal   (Followers: 10, SJR: 0.768, CiteScore: 2)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, SJR: 0.36, CiteScore: 1)
J. of Church and State     Hybrid Journal   (Followers: 12, SJR: 0.139, CiteScore: 0)
J. of Communication     Hybrid Journal   (Followers: 55, SJR: 4.411, CiteScore: 5)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 37, SJR: 0.33, CiteScore: 0)
J. of Complex Networks     Hybrid Journal   (Followers: 2, SJR: 1.05, CiteScore: 4)
J. of Computer-Mediated Communication     Open Access   (Followers: 29, SJR: 2.961, CiteScore: 6)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 13, SJR: 0.402, CiteScore: 0)
J. of Consumer Research     Full-text available via subscription   (Followers: 47, SJR: 5.856, CiteScore: 5)

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Journal Cover
Cardiovascular Research
Journal Prestige (SJR): 3.002
Citation Impact (citeScore): 5
Number of Followers: 14  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0008-6363 - ISSN (Online) 1755-3245
Published by Oxford University Press Homepage  [397 journals]
  • Scientists on the Spot: The future of genome editing in cardiovascular
    • Authors: Stellos K; Musunuru K.
      Abstract: Watch the interview here:
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
      DOI: 10.1093/cvr/cvy302
      Issue No: Vol. 115, No. 2 (2019)
  • Leaders in Cardiovascular Research: Barbara Casadei
    • Authors: Guzik T; Casadei B.
      Abstract: Watch the interview'v=MTm-LR_UBCs
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
      DOI: 10.1093/cvr/cvy303
      Issue No: Vol. 115, No. 2 (2019)
  • Challenges and advances of CRISPR-Cas9 genome editing in therapeutics
    • Authors: Stellos K; Musunuru K.
      Abstract: Commentary on ‘In vivo CRISPR editing with no detectable genome-wide off-target mutations’, by Akcakaya P et al., Nature, 2018.3
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
      DOI: 10.1093/cvr/cvy300
      Issue No: Vol. 115, No. 2 (2019)
  • What have we learned about using aspirin for primary prevention from the
           ASCEND and ARRIVE trials'
    • Authors: Tousoulis D.
      Abstract: Subjects with diabetes mellitus are at increased cardiovascular disease (CVD) risk.1 Particularly, diabetic patients with additional risk factors or target organ damage are considered as risk equivalent to patients with known coronary artery disease and are eligible for aggressive treatment prevention strategies. However, the role of aspirin in the primary prevention of CVD in diabetic patients remains an issue of controversy.2  In this setting, the results of the recently published ASCEND trial have been long awaited.2 ASCEND was a large clinical trial that randomized a total of 15 480 patients with diabetes mellitus with no known vascular disease to aspirin or placebo, with prospective follow-up for 7.4 years to test the effects of aspirin on vascular events (i.e. myocardial infarction, stroke or transient ischaemic attack, or death from any vascular cause, excluding any confirmed intracranial haemorrhage) and major bleeding events (i.e. intracranial haemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding).2 Although aspirin significantly lowered vascular events [relative risk (RR) = 0.88; 95% confidence interval (CI) 0.79–0.97], it also increased major bleeding events (RR = 1.29; 95% CI 1.09–1.52) mainly due to excess gastrointestinal bleeding and other extracranial bleeding. In pre-specified subgroup analyses there was no evidence of variation in the effect of aspirin according to baseline characteristics, the use of n-3 fatty acids or estimated vascular risk. Also, previous reports of greater benefit of aspirin use among persons with a body weight <70 kg were not confirmed. The effects of aspirin on all-cause mortality and cancer risk were neutral. Importantly, the incidence of a major bleeding event increased with baseline vascular risk, and thus the predicted number of serious vascular events that would be avoided by aspirin was closely balanced by the predicted number of bleeding event caused. Thus, overall any absolute benefits in the reduction of vascular events by preventive aspirin administration in diabetic persons were counterbalanced by an increase in bleeding events.2  Interestingly, similar negative findings were simultaneously reported by the ARRIVE trial,3 another randomized control trial on aspirin use in primary prevention; in a total of 12 546 patients at moderate cardiovascular risk with no diabetes or incident coronary artery disease, aspirin did not have any significant effects on cardiovascular events.3  A number of observations can be made about these findings relevant to CVD prevention. First, a remarkable finding in ASCEND was that, in contrary to opposite expectations, the majority of deaths in diabetic patients were due to non-vascular causes.2 This suggests that current risk management strategies with statins, antihypertensive medication, and possibly newer antidiabetic agents too, have radically changed the landscape and clinical course of diabetic patients, who are nowadays better protected against CVD development.  This was confirmed by the actual rate of events in these studies,2,3 which was lower than originally anticipated based on clinical risk score estimates. This is an important observation, which relates to the systematic overestimation of risk by the use of clinical risk score calculators. Notably, aspirin did reduce vascular events in diabetic patients, and therefore, the rationale for its use remains solid in these populations. However, the efficacy of preventive treatment interventions is highly dependent on the actual event risk of the population of interest.  Therefore, tools for more accurate risk assessment could be used to identify the subjects at the highest risk to guide the deployment of preventive measures such as aspirin. Recently, novel imaging modalities for the estimation of coronary inflammation and the residual inflammatory risk, such as perivascular fat attenuation index by standard coronary computed tomography angiography, could have a role in the risk stratification for coronary events, as recently suggested by the CRISP CT study.4 Certainly, more evidence is needed on this issue and further translational research in the field.  Another issue that warrants further investigation in basic research studies relates to aspirin non-responsiveness in patients with diabetes. A recent study suggested that the enteric coating of aspirin significantly reduces its bioavailability and its platelet inhibition efficacy in diabetes.5 Ways to maximize the platelet inhibitory effects of aspirin (without raising bleeding risks) and strategies to overcome aspirin resistance in patients with diabetes mellitus would be beneficial for millions of people worldwide.1  Interestingly, the postulated links between platelet activation and cancer were not confirmed by the ASCEND trial.2 Use of aspirin did not reduce the risk of gastrointestinal or any other form of cancer. US Preventive Services Task Force currently recommends aspirin for the primary prevention of colorectal cancer, but the cross-talk betw...
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
      DOI: 10.1093/cvr/cvy281
      Issue No: Vol. 115, No. 2 (2019)
  • Recent Cardiovascular Research highlights from the Americas
    • Authors: Smart C; Madhur M.
      Abstract: Cardiovascular Research is part of the European Society of Cardiology family of journals but is by no means restricted to European participation or distribution. Rather, Cardiovascular Research is expanding its global reach and to that end, features high-quality papers from around the world. In fact, a significant portion of the journal’s editorial board, particularly the Associate and Deputy Editors, is based in the United States. Almost 20% of all original research papers received by Cardiovascular Research in 2017 were from North, Central, or South America, marking an approximate 9% increase compared with the year prior. These submissions account for almost 25% of all original research papers published in the journal last year. In this commentary, we highlight the top five downloaded original research papers of 2017 from North, Central and South America. Collectively, these studies provide new insight into disease pathogenesis and provide novel therapeutic targets for many facets of cardiovascular disease including myocardial infarction (MI), cardiomyopathy, and pulmonary hypertension (PH).
      PubDate: Mon, 21 Jan 2019 00:00:00 GMT
      DOI: 10.1093/cvr/cvy229
      Issue No: Vol. 115, No. 2 (2019)
  • Testosterone to estradiol ratio and plaque inflammation: mechanistic
           insights and biomarker potential'
    • Authors: Figtree G; Ngo D, Bubb K.
      Pages: 255 - 257
      Abstract: This editorial refers to ‘Testosterone to oestradiol ratio reflects systemic and plaque inflammation and predicts future cardiovascular events in men with severe atherosclerosis’, by I.D. van Koeverden et al., pp. 453–462.
      PubDate: Mon, 05 Nov 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy260
      Issue No: Vol. 115, No. 2 (2018)
  • Natriuretic peptide receptors and atrial-selective fibrosis: potential
           role in atrial fibrillation
    • Authors: Nattel S.
      Pages: 258 - 260
      Abstract: This editorial refers to ‘Absence of natriuretic peptide clearance receptor attenuates TGF-β1-induced selective atrial fibrosis and atrial fibrillation’ by D. Rahmutula et al., pp. 357–372.
      PubDate: Wed, 21 Nov 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy287
      Issue No: Vol. 115, No. 2 (2018)
  • Cyclophilin D phosphorylation is critical for mitochondrial calcium
           uniporter regulated permeability transition pore sensitivity
    • Authors: Dhingra R; Lieberman B, Kirshenbaum L.
      Pages: 261 - 263
      PubDate: Wed, 31 Oct 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy270
      Issue No: Vol. 115, No. 2 (2018)
  • No hearty reception: infusion of CXCL4 impedes tissue repair by
           macrophages after myocardial infarction
    • Authors: Koenen R.
      Pages: 264 - 265
      Abstract: This editorial refers to ‘Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36 signalling to enhance post-myocardial infarction cardiac dilation and mortality’ by M.L. Lindsey et al., pp. 395–408.
      PubDate: Fri, 05 Oct 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy241
      Issue No: Vol. 115, No. 2 (2018)
  • Potential mechanisms underlying the cardiovascular benefits of sodium
           glucose cotransporter 2 inhibitors: a systematic review of data from
           preclinical studies
    • Authors: Chin K; Ofori-Asenso R, Hopper I, et al.
      Pages: 266 - 276
      Abstract: There is growing evidence from Phase III randomized clinical trials of the cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes mellitus. It is hypothesized that these benefits are mediated by mechanisms other than glucose control. To address this, we performed a systematic review of data from preclinical studies examining the direct cardioprotective effects of SGLT2 inhibitors. Medline, EMBASE, CINAHL, and International Pharmaceutical s databases were searched for preclinical studies that examined the potential cardioprotective effects of SGLT2 inhibitors. Submission documents to the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceutical and Medical Devices Agency for the registration of SGLT2 inhibitors were also reviewed. A total of 36 reports were included in the final analysis. The potential direct cardiovascular benefits of SGLT2 inhibitors include: augmentation of signal transducer and activator of transcription 3; inhibition of sodium hydrogen exchange; reduction of atherosclerosis; modulation of natriuretic peptides; vasodilation; modulation of sympathetic tone; and reduction of inflammation, oxidative stress, endoplasmic reticulum stress, and cardiac glucose uptake via down-regulation of SGLT1 expression. There are a number of mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits beyond glycaemic control.
      PubDate: Mon, 26 Nov 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy295
      Issue No: Vol. 115, No. 2 (2018)
  • The haematopoietic stem cell niche: a new player in cardiovascular
    • Authors: Al-Sharea A; Lee M, Purton L, et al.
      Pages: 277 - 291
      Abstract: Haematopoiesis, the process of blood production, can be altered during the initiation or progression of many diseases. Cardiovascular disease (CVD) has been shown to be heavily influenced by changes to the haematopoietic system, including the types and abundance of immune cells produced. It is now well established that innate immune cells are increased in people with CVD, and the mechanisms contributing to this can be vastly different depending on the risk factors or comorbidities present. Many of these changes begin at the level of the haematopoietic stem and progenitor cells (HSPCs) that reside in the bone marrow (BM). In general, the HSPCs and downstream myeloid progenitors are expanded via increased proliferation in the setting of atherosclerotic CVD. However, HSPCs can also be encouraged to leave the BM and colonise extramedullary sites (i.e. the spleen). Within the BM, HSPCs reside in specialized microenvironments, often referred to as a niche. To date in depth studies assessing the damage or dysregulation that occurs in the BM niche in varying CVDs are scarce. In this review, we provide a general overview of the complex components and interactions within the BM niche and how they influence the function of HSPCs. Additionally, we discuss the main findings regarding changes in the HSPC niche that influence the progression of CVD. We hypothesize that understanding the influence of the BM niche in CVD will aid in delineating new pathways for therapeutic interventions.
      PubDate: Mon, 24 Dec 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy308
      Issue No: Vol. 115, No. 2 (2018)
  • A thioredoxin-mimetic peptide exerts potent anti-inflammatory,
           antioxidant, and atheroprotective effects in ApoE2.Ki mice fed high fat
    • Authors: Canesi F; Mateo V, Couchie D, et al.
      Pages: 292 - 301
      Abstract: AimsOxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an anti-oxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. Here we analysed whether the thioredoxin-mimetic peptide (TxMP), CB3 might exert anti-oxidative, anti-inflammatory, and atheroprotective effects in ApoE2.Ki mice.Methods and resultsWe synthesized a small TxMP, Ac-Cys-Pro-Cys-amide, CB3 and characterized its antioxidant and anti-inflammatory effects on cultured peritoneal murine macrophages. CB3 significantly and dose-dependently reduced the level of reactive oxygen species in lipopolysaccharides (LPS)-activated macrophages. In addition, it efficiently lowered LPS-induced inflammatory process through NF-κB inhibition, as evidenced by the reduced secretion of monocyte chemoattractant protein-1, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α by macrophages. Nevertheless, CB3 did not affect cholesterol accumulation in macrophages. A daily-administered dose of 10 µg/g body weight CB3 to ApoE2.Ki mice on high fat diet did not affect plasma of total cholesterol and triglycerides levels but significantly reduced the plasma levels of pro-inflammatory cytokines (IL-33 and TNF-α) and oxidative markers. In contrast, it significantly induced the plasma levels of anti-inflammatory proteins (adiponectin, IL-10). In addition, CB3 reduced the number of pro-inflammatory M1 macrophages in spleen and decreased the ratio of M1/M2 macrophages in atherosclerotic lesion areas. Finally, CB3 significantly reduced the surface area of aortic lesions.ConclusionsOur results clearly showed that similar to the full length Trx-1, CB3 exerts protective effects, by reducing inflammation and oxidative stress in macrophages and in ApoE2.Ki mice. The atheroprotective effect of CB3 opens promising therapeutic approaches for treatment of atherosclerosis.
      PubDate: Fri, 13 Jul 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy183
      Issue No: Vol. 115, No. 2 (2018)
  • Immune system-mediated atherosclerosis caused by deficiency of long
           non-coding RNA MALAT1 in ApoE−/−mice
    • Authors: Gast M; Rauch B, Nakagawa S, et al.
      Pages: 302 - 314
      Abstract: AimsThe immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long non-coding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development.Methods and resultsHeterozygous MALAT1-deficient ApoE−/− mice displayed massive immune system dysregulation and atherosclerosis within 2 months even when kept on normal diet. Aortic plaque area (P < 0.05) and aortic root plaque size (P < 0.001) were increased in MALAT1-deficient vs. MALAT1-wildtype ApoE−/− mice. Serum levels of interferon-γ (IFN-γ), tumour necrosis factor (TNF), and interleukin 6 (IL6) were elevated (P < 0.001) in MALAT1-deficient animals. MALAT1-deficient bone marrow-derived macrophages showed enhanced expression of TNF (P = 0.001) and inducible NO synthase (NOS2) (P = 0.002), suppressed MMP9 (P < 0.001), and impaired phagocytic activity (P < 0.001) upon lipopolysaccharide stimulation. RNA-sequencing revealed grossly altered transcriptomes of MALAT1-deficient splenocytes already at baseline, with massive induction of IFN- γ, TNF, NOS2, and granzyme B; CC and CXC chemokines and CCR8; and innate immunity genes interferon-induced protein with tetratricopeptide repeats (IFIT)1/3, interferon-induced transmembrane protein (IFITM)1/3, ISG15. Multiple miRs were up to 45-fold upregulated. Further, selective ablation of the cytosolic part of the MALAT1 system only, the enzymatically MALAT1-derived mascRNA, resulted in massive induction of TNF (P = 0.004) and IL6 (P = 0.028) in macrophages. Northern analysis of post-myocardial infarction patient vs. control peripheral blood mononuclear cells showed reduced (P = 0.005) mascRNA in the patients. CHART-enriched RNA-sequencing reads at the genomic loci of MALAT1 and neighbouring nuclear enriched abundant transcript (NEAT1) documented direct interaction between these lncRNA transcripts.ConclusionThe data suggest a molecular circuit involving the MALAT1-mascRNA system, interactions between MALAT1 and NEAT1, and key immune effector molecules, cumulatively impacting upon the development of atherosclerosis. It appears reasonable to look for therapeutic targets in this circuit and to screen for anomalies in the NEAT1–MALAT1 region in humans, too, as possible novel disease risk factors.
      PubDate: Wed, 08 Aug 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy202
      Issue No: Vol. 115, No. 2 (2018)
  • Sex-specific regulation of collagen I and III expression by 17β-Estradiol
           in cardiac fibroblasts: role of estrogen receptors
    • Authors: Dworatzek E; Mahmoodzadeh S, Schriever C, et al.
      Pages: 315 - 327
      Abstract: AimsSex differences in cardiac fibrosis point to the regulatory role of 17β-Estradiol (E2) in cardiac fibroblasts (CF). We, therefore, asked whether male and female CF in rodent and human models are differentially susceptible to E2, and whether this is related to sex-specific activation of estrogen receptor alpha (ERα) and beta (ERβ).Methods and resultsIn female rat CF (rCF), 24 h E2-treatment (10−8  M) led to a significant down-regulation of collagen I and III expression, whereas both collagens were up-regulated in male rCF. E2-induced sex-specific collagen regulation was also detected in human CF, indicating that this regulation is conserved across species. Using specific ERα- and ERβ-agonists (10−7 M) for 24 h, we identified ERα as repressive and ERβ as inducing factor in female and male rCF, respectively. In addition, E2-induced ERα phosphorylation at Ser118 only in female rCF, whereas Ser105 phosphorylation of ERβ was exclusively found in male rCF. Further, in female rCF we found both ER bound to the collagen I and III promoters using chromatin immunoprecipitation assays. In contrast, in male rCF only ERβ bound to both promoters. In engineered connective tissues (ECT) from rCF, collagen I and III mRNA were down-regulated in female ECT and up-regulated in male ECT by E2. This was accompanied by an impaired condensation of female ECT, whereas male ECT showed an increased condensation and stiffness upon E2-treatment, analysed by rheological measurements. Finally, we confirmed the E2-effect on both collagens in an in vivo mouse model with ovariectomy for E2 depletion, E2 substitution, and pressure overload by transverse aortic constriction.ConclusionThe mechanism underlying the sex-specific regulation of collagen I and III in the heart appears to involve E2-mediated differential ERα and ERβ signaling in CFs.
      PubDate: Tue, 17 Jul 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy185
      Issue No: Vol. 115, No. 2 (2018)
  • Endoplasmic reticulum stress induces cardiac dysfunction through
           architectural modifications and alteration of mitochondrial function in
    • Authors: Prola A; Nichtova Z, Pires Da Silva J, et al.
      Pages: 328 - 342
      Abstract: AimsEndoplasmic reticulum (ER) stress has recently emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases. However, the molecular mechanisms by which ER stress leads to cardiac dysfunction remain poorly understood.Methods and resultsIn this study, we evaluated the early cardiac effects of ER stress induced by tunicamycin (TN) in mice. Echocardiographic analysis indicated that TN-induced ER stress led to a significant impairment of the cardiac function. Electron microscopic observations revealed that ultrastructural changes of cardiomyocytes in response to ER stress manifested extensively at the level of the reticular membrane system. Smooth tubules of sarcoplasmic reticulum in connection with short sections of rough ER were observed. The presence of rough instead of smooth reticulum was increased at the interfibrillar space, at the level of dyads, and in the vicinity of mitochondria. At the transcriptional level, ER stress resulted in a substantial decrease in the expression of the major regulator of mitochondrial biogenesis PGC-1α and of its targets NRF1, Tfam, CS, and COXIV. At the functional level, ER stress also induced an impairment of mitochondrial Ca2+ uptake, an alteration of mitochondrial oxidative phosphorylation, and a metabolic remodelling characterized by a shift from fatty acid to glycolytic substrate consumption. ConclusionsOur findings show that ER stress induces cytoarchitectural and metabolic alterations in cardiomyocytes and provide evidences that ER stress could represent a primary mechanism that contributes to the impairment of energy metabolism reported in most cardiac diseases.
      PubDate: Fri, 03 Aug 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy197
      Issue No: Vol. 115, No. 2 (2018)
  • Y-27632 preconditioning enhances transplantation of human-induced
           pluripotent stem cell-derived cardiomyocytes in myocardial infarction mice
    • Authors: Zhao M; Fan C, Ernst P, et al.
      Pages: 343 - 356
      Abstract: Aims The effectiveness of cell-based treatments for regenerative myocardial therapy is limited by low rates of cell engraftment. Y-27632 inhibits Rho-associated protein kinase (ROCK), which regulates the cytoskeletal changes associated with cell adhesion, and has been used to protect cultured cells during their passaging. Here, we investigated whether preconditioning of cardiomyocytes, derived from human-induced pluripotent stem cells (hiPSC-CM), with Y-27632 improves their survival and engraftment in a murine model of acute myocardial infarction (MI).Methods and results After MI induction, mice were subjected to intramyocardial injections of phosphate-buffered saline, hiPSC-CM cultured under standard conditions (hiPSC-CM–RI), or Y-27632-preconditioned hiPSC-CM (hiPSC-CM+RI). The resulting engraftment rate calculated 4 weeks after implantation was significantly higher and the abundance of apoptotic transplanted cells was significantly lower in hiPSC-CM+RI recipients than in hiPSC-CM–RI animals. In cultured hiPSC-CM, Y-27632-preconditioning reversibly reduced contractile activity and the expression of troponin genes, while increasing their attachment to an underlying mouse cardiomyocyte (HL1) monolayer. Y-27632 preconditioning also increased the expression of N-cadherin and integrin ß1, the two cell junction proteins. hiPSC-CM+RI were also larger in cell area with greater cytoskeletal alignment and a more rod-like shape than hiPSC-CM–RI, both after transplantation (in vivo) and in culture. The effects of Y-27632 preconditioning on contractile activity and morphology of hiPSC-CMs in culture, as well as on their engraftment rate and apoptotic death in MI mouse grafts, could be recapitulated by hiPSC-CM treatment with the L-type calcium-channel blocker verapamil.Conclusion Preconditioning with the ROCK inhibitor Y-27632 increased the engraftment of transplanted hiPSC-CM in a murine MI model, while reversibly impairing hiPSC-CM contractility and promoting adhesion.
      PubDate: Mon, 13 Aug 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy207
      Issue No: Vol. 115, No. 2 (2018)
  • Absence of natriuretic peptide clearance receptor attenuates
           TGF-β1-induced selective atrial fibrosis and atrial fibrillation
    • Authors: Rahmutula D; Zhang H, Wilson E, et al.
      Pages: 357 - 372
      Abstract: AimsTGF-β1 plays an important role in atrial fibrosis and atrial fibrillation (AF); previous studies have shown that the atria are more susceptible to TGF-β1 mediated fibrosis than the ventricles. Natriuretic peptides (NPs) play an important role in cardiac remodelling and fibrosis, but the role of natriuretic peptide clearance (NPR-C) receptor is largely unknown. We investigated the role of NPR-C in modulating TGF-β1 signalling in the atria.Methods and resultsMHC-TGF-β1 transgenic (TGF-β1-Tx) mice, which develop isolated atrial fibrosis and AF, were cross-bred with NPR-C knock-out mice (NPR-C-KO). Transverse aortic constriction (TAC) was performed in wild type (Wt) and NPR-C knockout mice to study. Atrial fibrosis and AF inducibility in a pathophysiologic model. Electrophysiology, molecular, and histologic studies were performed in adult mice. siRNA was used to interrogate the interaction between TGF-β1 and NP signalling pathways in isolated atrial and ventricular fibroblasts/myofibroblasts. NPR-C expression level was 17 ± 5.8-fold higher in the atria compared with the ventricle in Wt mice (P = 0.009). Cross-bred mice demonstrated markedly decreased pSmad2 and collagen expression, atrial fibrosis, and AF compared with TGF-β1-Tx mice with intact NPR-C. There was a marked reduction in atrial fibrosis gene expression and AF inducibility in the NPR-C-KO-TAC mice compared with Wt-TAC. In isolated fibroblasts, knockdown of NPR-C resulted in a marked reduction of pSmad2 (56 ± 4% and 24 ± 14% reduction in atrial and ventricular fibroblasts, respectively) and collagen (76 ± 15% and 35 ± 23% reduction in atrial and ventricular fibroblasts/myofibroblasts, respectively) in response to TGF-β1 stimulation. This effect was reversed by simultaneously knocking down NPR-A but not with simultaneous knock down of PKG-1.ConclusionThe differential response to TGF-β1 stimulated fibrosis between the atria and ventricle are in part mediated by the abundance of NPR-C receptors in the atria.
      PubDate: Tue, 18 Sep 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy224
      Issue No: Vol. 115, No. 2 (2018)
  • Telmisartan and thiorphan combination treatment attenuates fibrosis and
           apoptosis in preventing diabetic cardiomyopathy
    • Authors: Malek V; Gaikwad A.
      Pages: 373 - 384
      Abstract: AimsLCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s).Methods and resultsDiabetes was induced by administration of streptozotocin (55 mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1 mg/kg/day, p.o.) or telmisartan (10 mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-κB/MCP-1), profibrotic (TGF-β/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations.ConclusionThe protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.
      PubDate: Tue, 04 Sep 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy226
      Issue No: Vol. 115, No. 2 (2018)
  • Cyclophilin D-mediated regulation of the permeability transition pore is
           altered in mice lacking the mitochondrial calcium uniporter
    • Authors: Parks R; Menazza S, Holmström K, et al.
      Pages: 385 - 394
      Abstract: AimsKnockout (KO) of the mitochondrial Ca2+ uniporter (MCU) in mice abrogates mitochondrial Ca2+ uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice.Methods and resultsFirst, we examined whether cell death may occur via an upregulation in necroptosis in MCU-KO mice. However, our results show that neither RIP1 inhibition nor RIP3 knockout afford protection against ischaemia-reperfusion injury in MCU-KO as in wildtype (WT) hearts, indicating that the lack of protection cannot be explained by upregulation of necroptosis. Instead, we have identified alterations in cyclophilin D (CypD) signalling in MCU-KO hearts. In the presence of a calcium ionophore, MCU-KO mitochondria take up calcium and do undergo PTP opening. Furthermore, PTP opening in MCU-KO mitochondria has a lower calcium retention capacity (CRC), suggesting that the calcium sensitivity of PTP is higher. Phosphoproteomics identified an increase in phosphorylation of CypD-S42 in MCU-KO. We investigated the interaction of CypD with the putative PTP component ATP synthase and identified an approximately 50% increase in this interaction in MCU-KO cardiac mitochondria. Mutation of the novel CypD phosphorylation site S42 to a phosphomimic reduced CRC, increased CypD-ATP synthase interaction by approximately 50%, and increased cell death in comparison to a phospho-resistant mutant. ConclusionTaken together these data suggest that MCU-KO mitochondria exhibit an increase in phosphorylation of CypD-S42 which decreases PTP calcium sensitivity thus allowing activation of PTP in the absence of an MCU-mediated increase in matrix calcium.
      PubDate: Mon, 27 Aug 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy218
      Issue No: Vol. 115, No. 2 (2018)
  • Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36
           signalling to enhance post-myocardial infarction cardiac dilation and
    • Authors: Lindsey M; Jung M, Yabluchanskiy A, et al.
      Pages: 395 - 408
      Abstract: AimsMacrophage phagocytosis of dead cells is a prerequisite for inflammation resolution. Because CXCL4 induces macrophage phagocytosis in vitro, we examined the impact of exogenous CXCL4 infusion on cardiac wound healing and macrophage phagocytosis following myocardial infarction (MI).Methods and resultsCXCL4 expression significantly increased in the infarct region beginning at Day 3 post-MI, and macrophages were the predominant source. Adult male C57BL/6J mice were subjected to coronary artery occlusion, and MI mice were randomly infused with recombinant mouse CXCL4 or saline beginning at 24 h post-MI by mini-pump infusion. Compared with saline controls, CXCL4 infusion dramatically reduced 7 day post-MI survival [10% (3/30) for CXCL4 vs. 47% (7/15) for saline, P < 0.05] as a result of acute congestive heart failure. By echocardiography, CXCL4 significantly increased left ventricular (LV) volumes and dimensions at Day 5 post-MI (all P < 0.05), despite similar infarct areas compared with saline controls. While macrophage numbers were similar at Day 5 post-MI, CXCL4 infusion increased Ccr4 and Itgb4 and decreased Adamts8 gene levels in the infarct region, all of which linked to CXCL4-mediated cardiac dilation. Isolated Day 5 post-MI macrophages exhibited comparable levels of M1 and M4 markers between saline and CXCL4 groups. Interestingly, by both ex vivo and in vitro phagocytosis assays, CXCL4 reduced macrophage phagocytic capacity, which was connected to decreased levels of the phagocytosis receptor CD36. In vitro, a CD36 neutralizing antibody (CD36Ab) significantly inhibited macrophage phagocytic capacity. The combination of CXCL4 and CD36Ab did not have an additive effect, indicating that CXCL4 regulated phagocytosis through CD36 signalling. CXCL4 infusion significantly elevated infarct matrix metalloproteinase (MMP)-9 levels at Day 5 post-MI, and MMP-9 can cleave CD36 as a down-regulation mechanism.ConclusionCXCL4 infusion impaired macrophage phagocytic capacity by reducing CD36 levels through MMP-9 dependent and independent signalling, leading to higher mortality and LV dilation.
      PubDate: Wed, 29 Aug 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy211
      Issue No: Vol. 115, No. 2 (2018)
  • Microparticles harbouring Sonic hedgehog morphogen improve the
           vasculogenesis capacity of endothelial progenitor cells derived from
           myocardial infarction patients
    • Authors: Bueno-Betí C; Novella S, Soleti R, et al.
      Pages: 409 - 418
      Abstract: AimsEndothelial progenitor cells (EPC) play a role in endothelium integrity maintenance and regeneration. Decreased numbers of EPC or their impaired function correlates with an increase in cardiovascular events. Thus, EPC are important predictors of cardiovascular mortality and morbidity. Microparticles carrying Sonic hedgehog (Shh) morphogen (MPShh+) trigger pro-angiogenic responses, both in endothelial cells and in ischaemic rodent models. Here, we propose that MPShh+ regulates EPC function, thus enhancing vasculogenesis, and correcting the defects in dysfunctional EPC obtained from acute myocardial infarction (AMI) patients.Methods and resultsThe mechanisms underlying Shh pathway function and nitric oxide (NO) production in EPC were evaluated. MPShh+ increased both the in vitro and in vivo vasculogenic capacity of EPC isolated from adult human peripheral blood samples. MPShh+ treatment significantly increased the expression of Shh signalling pathway genes (PTCH1, SMO, and GLI1) and masters of pro-angiogenic genes (NOS3, VEGFA, KDR, and KLF2) in EPC. Moreover, MPShh+ increased both the protein expression and activity of eNOS, resulting in increased NO production. Most importantly, MPShh+ improved the vasculogenic capacity of EPC from AMI patients to levels similar to that of EPC from healthy patients. All these effects were due to the activation of Shh pathway.ConclusionMPShh+ increase both the vasculogenesis of EPC and their capacity to produce NO, including EPC from patients who have recently suffered an AMI. This study emphasizes MPShh+ and EPC as potential therapeutic tools for improving vascular regeneration as a treatment for cardiovascular ischaemic disease.
      PubDate: Tue, 14 Aug 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy189
      Issue No: Vol. 115, No. 2 (2018)
  • Peroxisome proliferator-activated receptor-gamma targeting nanomedicine
           promotes cardiac healing after acute myocardial infarction by skewing
           monocyte/macrophage polarization in preclinical animal models
    • Authors: Tokutome M; Matoba T, Nakano Y, et al.
      Pages: 419 - 431
      Abstract: AimsMonocyte-mediated inflammation is a major mechanism underlying myocardial ischaemia–reperfusion (IR) injury and the healing process after acute myocardial infarction (AMI). However, no definitive anti-inflammatory therapies have been developed for clinical use. Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, has unique anti-inflammatory effects on monocytes/macrophages. Here, we tested the hypothesis that nanoparticle (NP)-mediated targeting of pioglitazone to monocytes/macrophages ameliorates IR injury and cardiac remodelling in preclinical animal models.Methods and resultsWe formulated poly (lactic acid/glycolic acid) NPs containing pioglitazone (pioglitazone-NPs). In a mouse IR model, these NPs were delivered predominantly to circulating monocytes and macrophages in the IR heart. Intravenous treatment with pioglitazone-NPs at the time of reperfusion attenuated IR injury. This effect was abrogated by pre-treatment with the PPARγ antagonist GW9662. In contrast, treatment with a pioglitazone solution had no therapeutic effects on IR injury. Pioglitazone-NPs inhibited Ly6Chigh inflammatory monocyte recruitment as well as inflammatory gene expression in the IR hearts. In a mouse myocardial infarction model, intravenous treatment with pioglitazone-NPs for three consecutive days, starting 6 h after left anterior descending artery ligation, attenuated cardiac remodelling by reducing macrophage recruitment and polarizing macrophages towards the pro-healing M2 phenotype. Furthermore, pioglitazone-NPs significantly decreased mortality after MI. Finally, in a conscious porcine model of myocardial IR, pioglitazone-NPs induced cardioprotection from reperfused infarction, thus providing pre-clinical proof of concept.ConclusionNP-mediated targeting of pioglitazone to inflammatory monocytes protected the heart from IR injury and cardiac remodelling by antagonizing monocyte/macrophage-mediated acute inflammation and promoting cardiac healing after AMI.
      PubDate: Fri, 03 Aug 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy200
      Issue No: Vol. 115, No. 2 (2018)
  • Nintedanib improves cardiac fibrosis but leaves pulmonary vascular
           remodelling unaltered in experimental pulmonary hypertension
    • Authors: Rol N; de Raaf M, Sun X, et al.
      Pages: 432 - 439
      Abstract: AimsPulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH).Methods and resultsProliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib.ConclusionNintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.
      PubDate: Wed, 18 Jul 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy186
      Issue No: Vol. 115, No. 2 (2018)
  • Matrix sieving-enforced retrograde transcytosis regulates tissue
           accumulation of C-reactive protein
    • Authors: Li H; Liu X, Liu Y, et al.
      Pages: 440 - 452
      Abstract: AimsCirculating proteins larger than 3 nm can be transported across continuous endothelial barrier of blood vessels via transcytosis. However, excessive accumulation of serum proteins within the vessel walls is uncommon even for those abundant in the circulation. The aim of this study was to investigate how transcytosis regulates tissue accumulation of the prototypical acute-phase reactant C-reactive protein (CRP) and other serum proteins.Methods and resultsTranscytosis of CRP as well as of transferrin and low-density lipoprotein across aortic endothelial cells is bidirectional with directional preference from the apical (blood) to basolateral (tissue) direction both in vitro and in vivo. This directional preference is, however, reversed by the basement membrane (BM) matrix underlying the basolateral surface of endothelial cells. This is due to the sieving effect of the BM that physically hinders the diffusion of transcytosed proteins from the apical compartment towards underlying tissues, resulting in immediate retrograde transcytosis that limits basolateral protein accumulation. Conversely, CRP produced within vessel wall lesions can also be transported into the circulation.ConclusionOur findings identify matrix sieving-enforced retrograde transcytosis as a general mechanism that prevents excessive tissue accumulation of blood-borne proteins and suggest that lesion-derived CRP might also contribute to elevated serum CRP levels associated with increased risk for cardiovascular diseases.
      PubDate: Mon, 09 Jul 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy181
      Issue No: Vol. 115, No. 2 (2018)
  • Testosterone to oestradiol ratio reflects systemic and plaque inflammation
           and predicts future cardiovascular events in men with severe
    • Authors: van Koeverden I; de Bakker M, Haitjema S, et al.
      Pages: 453 - 462
      Abstract: AimsThe effects of testosterone on cardiovascular disease (CVD) as reported in literature have been ambiguous. Recently, the interplay between testosterone and oestradiol as assessed by testosterone/oestradiol (T/E2) ratio was suggested to be better informative on the normal physiological balance. Considering the role in CVD, we hypothesized that a low T/E2 ratio in men with CVD is associated with increased inflammation, a more unstable plaque and a worse cardiovascular outcome.Methods and resultsTestosterone and oestradiol concentrations were determined in blood samples of 611 male carotid endarterectomy patients included in the Athero-Express Biobank Study. T/E2 ratio was associated with baseline characteristics, atherosclerotic plaque specimens, inflammatory biomarkers, and 3 year follow-up information. Patients with low T/E2 ratio had more unfavourable inflammatory profiles compared with patients with high T/E2 as observed by higher levels of C-reactive protein [2.81 μg/mL vs. 1.22 μg/mL (P < 0.001)] and higher leucocyte counts [8.98*109/L vs. 7.75*109/L (P = 0.001)] in blood. In atherosclerotic plaques, a negative association between T/E2 ratio and number of neutrophils [B = −0.366 (P = 0.012)], plaque calcifications [OR: 0.816 (P = 0.044)], interleukin-6 (IL-6) [B = −0.15 (P = 0.009)], and IL-6 receptor [B = −0.13 (P = 0.024)] was found. Furthermore, in multivariate Cox regression analysis, low T/E2 ratio was independently associated with an increased risk for major cardiovascular events (MACE) during 3 year follow-up [hazard ratio 1.67 (95% confidence interval 1.02–2.76), P = 0.043]. In men with elevated body mass index (BMI), these effects were strongest.ConclusionIn male patients with manifest atherosclerotic disease, low T/E2 ratio was associated with increased systemic inflammation, increased inflammatory plaque proteins, and an increased risk of future MACE as compared to men with normal T/E2 ratio. These effects are strongest in men with elevated BMI and are expected to be affected by aromatase activity in white fat tissues. Normalization of T/E2 ratio may be considered as target for the secondary prevention of CVD in men.
      PubDate: Fri, 20 Jul 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy188
      Issue No: Vol. 115, No. 2 (2018)
  • Human peroxidasin 1 promotes angiogenesis through ERK1/2, Akt, and FAK
    • Authors: Medfai H; Khalil A, Rousseau A, et al.
      Pages: 463 - 475
      Abstract: AimsThe term angiogenesis refers to sprouting of new blood vessels from pre-existing ones. The angiogenic process involves cell migration and tubulogenesis requiring interaction between endothelial cells and the extracellular matrix. Human peroxidasin 1 (hsPxd01) is a multidomain heme peroxidase found embedded in the basement membranes. As it promotes the stabilization of extracellular matrix, we investigated its possible role in angiogenesis both in vitro and in vivo.Methods and resultsWe analysed the effects of peroxidasin 1 gene silencing and supplementation by recombinant hsPxd01 in TeloHAEC endothelial cells on cell migration, tubulogenesis in matrigel, and intracellular signal transduction as assessed by kinase phosphorylation and expression of pro-angiogenic genes as measured by qRT–PCR. We further evaluated the angiogenic potential of recombinant peroxidasin in a chicken chorioallantoic membrane model. RNA silencing of endogenous hsPxd01 significantly reduced tube formation and cell migration, whereas supplementation by the recombinant peroxidase promoted tube formation in vitro and stimulated vascularization in vivo through its catalytic activity. Moreover, recombinant hsPxd01 promoted phosphorylation of Extracellular signal-Regulated Kinases (ERK1/2), Protein kinase B (Akt), and Focal Adhesion Kinase (FAK), and induced the expression of pro-angiogenic downstream genes: Platelet Derived Growth Factor Subunit B (PDGFB), endothelial-derived Heparin Binding EGF-like growth factor (HB-EGF), CXCL-1, Hairy-Related Transcription Factor 1 (HEY-1), DNA-binding protein inhibitor (ID-2), Snail Family Zinc Finger 1 (SNAI-1), as well as endogenous hsPxd01. However, peroxidasin silencing significantly reduced Akt and FAK phosphorylation but induced ERK1/2 activation after supplementation by recombinant hsPxd01. While hsPxd01 silencing significantly reduced expression of HEY-1, ID-2, and PDGFB, it did not affect expression of SNAI-1, HB-EGF, and CXCL-1 after supplementation by recombinant hsPxd01.ConclusionOur findings suggest a role of enzymatically active peroxidasin 1 as a pro-angiogenic peroxidase and a modulator of ERK1/2, Akt and FAK signalling.
      PubDate: Wed, 04 Jul 2018 00:00:00 GMT
      DOI: 10.1093/cvr/cvy179
      Issue No: Vol. 115, No. 2 (2018)
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