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Yoon S, Kim DY, Chu MK. Nitrous oxide abuse unmasking anti-phospholipid syndrome in a 24-year-old male with cerebral venous thrombosis and pulmonary thromboembolism: a case report. BMC Neurol 2025; 25:220. [PMID: 40420018 PMCID: PMC12105173 DOI: 10.1186/s12883-025-04237-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 05/13/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND The abuse of nitrous oxide (N2O) as a recreational drug has become a growing concern, manifesting in various medical complications. Here, we report the first Korean case of cerebral venous thrombosis (CVT) and pulmonary thromboembolism (PTE) caused by nitrous oxide abuse and anti-phospholipid syndrome. CASE PRESENTATION A 24-year-old Korean man studying abroad in the USA presented to the emergency department with altered sensorium, gait disturbance, and involuntary leg movements. His history revealed escalating nitrous oxide inhalation from occasional use to daily intake of 100 balloons over six months. The patient's symptoms were initially attributed to cobalamin deficiency due to N2O abuse, leading to hyperhomocysteinemia and subsequent venous thrombosis, particularly CVT and PTE. However, the presence of Lupus Anticoagulant (LA) indicated a potential autoimmune or inflammatory process contributing to thrombotic complications, complicating the diagnosis. The patient's treatment involved cobalamin supplementation, anticoagulation therapy, and addressing associated substance abuse and depression. Notably, subsequent tests revealed persistent positive LA, highlighting the complexity of the case and the multifactorial nature of N2O-induced complications. CONCLUSIONS The mechanisms underlying N2O-induced thrombotic complications are elucidated, primarily involving the oxidation of cobalamin to its inactive form, leading to hyperhomocysteinemia and endothelial dysfunction. The association with LA suggests a potential autoimmune or inflammatory component, adding another layer of complexity to pathophysiology. This case underscores the importance of recognizing and managing the systemic thrombotic risk associated with N2O abuse. It highlights the need for heightened vigilance in diagnosing and managing associated complications, including CVT, and emphasizes the importance of comprehensive diagnostic and treatment approaches addressing both medical and psychiatric aspects. In conclusion, this case serves as a poignant reminder of the serious medical consequences of N2O abuse and underscores the importance of early recognition, comprehensive management, and ongoing surveillance to mitigate its adverse effects on individual health and public well-being.
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Affiliation(s)
- Sojung Yoon
- Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Yu Kim
- Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Min Kyung Chu
- Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
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Lanas-Gimeno A, Lanas Á. Adverse events in patients with cardiovascular disease taking proton pump inhibitors. Expert Opin Drug Saf 2024; 23:1381-1391. [PMID: 39354720 DOI: 10.1080/14740338.2024.2409702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/21/2024] [Accepted: 09/24/2024] [Indexed: 10/03/2024]
Abstract
INTRODUCTION Proton pump inhibitors (PPIs) rank among the most frequently prescribed medications to treat acid-related diseases. Mounting concerns surround the potential for serious adverse events, including cardiovascular events, associated with their prolonged use/misuse. AREAS COVERED This comprehensive review explores cardiovascular adverse events linked to PPI use among high-risk cardiovascular patients. A structured search was conducted on PubMed. EXPERT OPINION Many patients with cardiovascular disease who require antiplatelet treatment will require long-term PPI treatment. Interpreting the published data is not straightforward. First, because there is no plausible mechanistic explanation for PPIs to induce cardiovascular events apart from the potential interaction with the metabolism of thienopyridines. Although several observational studies have shown an increased cardiovascular risk and mortality in patients taking long-term PPIs, most available clinical trials and meta-analyses of available studies do not. However, the absence of firm evidence of this link does not necessarily imply that this association does not exist, and other hypothesis must be explored. Anemia is a common event in patients who take antiplatelet therapy and PPIs, and it is a factor associated with cardiovascular events and death. Anemia in these patients is often attributed to erosive lesions of the small intestine, where PPI may play a key role by modifying the microbiota.
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Affiliation(s)
| | - Ángel Lanas
- Servicio de Aparato Digestivo, Hospital Clínico Universitario, Zaragoza, Spain
- Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
- CIBERehd, Madrid, Spain
- Universidad de Zaragoza, Zaragoza, Spain
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Pizov NA, Baranova NS. Cardioembolic stroke and endothelial dysfunction in men aged between 30 and 50 years. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2024:78-83. [DOI: 10.21518/ms2024-301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Introduction. Stroke in young adults is associated with high-level socioeconomic components, and patients face the lifelong effects of the vascular catastrophe. Young patients with cardioembolic stroke make up an important subgroup of ischemic stroke patients globally. A key to optimizing treatment and preventing relapses is identifying the causes and risk factors for ischemic stroke in young adults.Aim. To assess risk factors and endothelial function status in young men with cardioembolic strokeMaterial and methods. A total of 19 patients aged 30-50 years with cardioembolic stroke underwent clinical and instrumental examinations. All patients were admitted to the Yaroslavl Vascular Center before the COVID-19 pandemic. The severity of clinical symptoms and stroke were assessed using the NIHSS scales, Modified Rankin Scale, and Rivermead Mobility Index. The main risk factors for IS including the presence of high- or moderate-risk sources of cardioembolism were reviewed. All patients underwent brain neuroimaging, ultrasound imaging, electrocardiogram, echocardioscopy, and laboratory blood testing. An ultrasound guided tourniquet test was performed to assess the brachial artery endothelial vasomotor function. Results. The average age of patients with cardioembolic stroke was 43.2 ± 6.4 years. Mechanical valve prostheses (21.1%) and isolated atrial fibrillation (42.0%) are the most common sources of cardioembolism. Other commonly identified risk factors included hypertension (73.7%), dyslipidemia (42.1%), smoking (52.6%), and prior acute myocardial infarction (42.1%). The ultrasound guided tourniquet test showed normal dilation of the brachial artery in 26.3% patients, insufficient dilatation in 42.1% patients and vasoconstriction in 31.6% patients. Statistically significant associations between the main vascular risk factors, serum markers of endothelial dysfunction and ultrasound guided tourniquet test indices were identified.Conclusion. This study demonstrated a variety of risk factors for cardioembolic stroke in young men. Lifestyle modification is responsible for the occurrence of traditional risk factors in young adults.
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Bima C, Parasiliti-Caprino M, Rumbolo F, Ponzetto F, Gesmundo I, Nonnato A, Fornengo P, Vaula G, Ghigo E, Mengozzi G, Settanni F. Asymmetric and symmetric dimethylarginine as markers of endothelial dysfunction in cerebrovascular disease: A prospective study. Nutr Metab Cardiovasc Dis 2024; 34:1639-1648. [PMID: 38570234 DOI: 10.1016/j.numecd.2024.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 03/07/2024] [Accepted: 03/11/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND AND AIM Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been proposed as mediators of endothelial dysfunction. In this study, we aimed to investigate the diagnostic and prognostic role of ADMA and SDMA in acute cerebrovascular disease. METHODS AND RESULTS A prospective case-control study was performed, enrolling 48 patients affected by ischemic stroke with no cardioembolic origin, 20 patients affected by TIA, 40 subjects at high cardiovascular risk and 68 healthy subjects. ADMA levels were significantly lower in high-risk subjects (18.85 [11.78-22.83] μmol/L) than in patients with brain ischemic event, both transient (25.70 [13.15-40.20] μmol/L; p = 0.032) and permanent (24.50 [18.0-41.33] μmol/L; p = 0.001). SDMA levels were different not only between high-risk subjects and ischemic patients, but also between TIA and stroke patients, reaching higher levels in TIA group and lower levels in stroke group (1.15 [0.90-2.0] vs 0.68 [0.30-1.07] μmol/L; p < 0.001). SDMA was also correlated with short-term prognosis, with lower levels in case of adverse clinical course, evaluated by type of discharge (p = 0.009) and need of prolonged rehabilitation (p = 0.042). CONCLUSIONS The present study highlights the relationship between l-arginine, ADMA, SDMA and acute cerebrovascular events. Therefore, our results suggested a potential role of SDMA as a specific marker of transient ischemic damage and as a short-term positive prognostic marker.
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Affiliation(s)
- Chiara Bima
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Mirko Parasiliti-Caprino
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy.
| | - Francesca Rumbolo
- Clinical Biochemistry Laboratory, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Federico Ponzetto
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Iacopo Gesmundo
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonello Nonnato
- Clinical Biochemistry Laboratory, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Paolo Fornengo
- Internal Medicine 3, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giovanna Vaula
- Stroke Unit, Department of Neuroscience "Rita Levi Montalcini", University of Turin, Turin, Italy
| | - Ezio Ghigo
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giulio Mengozzi
- Clinical Biochemistry Laboratory, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Fabio Settanni
- Clinical Biochemistry Laboratory, Department of Medical Sciences, University of Turin, Turin, Italy
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Palomo I, Wehinger S, Andrés V, García‐García FJ, Fuentes E. RhoA/rho kinase pathway activation in age-associated endothelial cell dysfunction and thrombosis. J Cell Mol Med 2024; 28:e18153. [PMID: 38568071 PMCID: PMC10989549 DOI: 10.1111/jcmm.18153] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 04/05/2024] Open
Abstract
The small GTPase RhoA and the downstream Rho kinase (ROCK) regulate several cell functions and pathological processes in the vascular system that contribute to the age-dependent risk of cardiovascular disease, including endothelial dysfunction, excessive permeability, inflammation, impaired angiogenesis, abnormal vasoconstriction, decreased nitric oxide production and apoptosis. Frailty is a loss of physiological reserve and adaptive capacity with advanced age and is accompanied by a pro-inflammatory and pro-oxidative state that promotes vascular dysfunction and thrombosis. This review summarises the role of the RhoA/Rho kinase signalling pathway in endothelial dysfunction, the acquisition of the pro-thrombotic state and vascular ageing. We also discuss the possible role of RhoA/Rho kinase signalling as a promising therapeutic target for the prevention and treatment of age-related cardiovascular disease.
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Affiliation(s)
- Iván Palomo
- Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Medical Technology School, Thrombosis and Healthy Aging Research CenterUniversidad de TalcaTalcaChile
| | - Sergio Wehinger
- Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Medical Technology School, Thrombosis and Healthy Aging Research CenterUniversidad de TalcaTalcaChile
| | - Vicente Andrés
- Centro Nacional de Investigaciones Cardiovasculares (CNIC)MadridSpain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV)MadridSpain
| | - Francisco J. García‐García
- Department of Geriatric MedicineHospital Universitario de Toledo, Instituto de Investigación de Castilla La Mancha (IDISCAM), CIBERFES (ISCIII)ToledoSpain
| | - Eduardo Fuentes
- Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Medical Technology School, Thrombosis and Healthy Aging Research CenterUniversidad de TalcaTalcaChile
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Chang G, Shih HM, Pan CF, Wu CJ, Lin CJ. Effect of Low Protein Diet Supplemented with Ketoanalogs on Endothelial Function and Protein-Bound Uremic Toxins in Patients with Chronic Kidney Disease. Biomedicines 2023; 11:biomedicines11051312. [PMID: 37238983 DOI: 10.3390/biomedicines11051312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/21/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023] Open
Abstract
Studies have demonstrated that a low-protein diet supplemented with ketoanalogs (KAs) could significantly retard progression of renal function in patients with chronic kidney disease (CKD) stages 3-5. However, its effects on endothelial function and serum levels of protein-bound uremic toxins remain elusive. Therefore, this study explored whether a low-protein diet (LPD) supplemented with KAs affects kidney function, endothelial function, and serum uremic toxin levels in a CKD-based cohort. In this retrospective cohort, we enrolled 22 stable CKD stage 3b-4 patients on LPD (0.6-0.8 g/day). Patients were categorized into control (LPD only) and study groups (LPD + KAs 6 tab/day). Serum biochemistry, total/free indoxyl sulfate (TIS/FIS), total/free p-cresyl sulfate (TPCS/FPCS), and flow-mediated dilation (FMD) were measured before and after 6 months of KA supplementation. Before the trial, there were no significant differences in kidney function, FMD, or uremic toxin levels between the control and study groups. When compared with the control group, the paired t-test showed a significant decrease in TIS and FIS (all p < 0.05) and a significant increase in FMD, eGFR, and bicarbonate (all p < 0.05). In multivariate regression analysis, an increase in FMD (p < 0.001) and a decrease in FPCS (p = 0.012) and TIS (p < 0.001) remained persistent findings when adjusted for age, systolic blood pressure (SBP), sodium, albumin, and diastolic blood pressure (DBP). LPD supplemented with KAs significantly preserves kidney function and provides additional benefits on endothelial function and protein-bound uremic toxins in patients with CKD.
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Affiliation(s)
- George Chang
- Division of Nephrology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan
| | - Hong-Mou Shih
- Division of Nephrology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan
- Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100001, Taiwan
| | - Chi-Feng Pan
- Division of Nephrology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan
| | - Chih-Jen Wu
- Division of Nephrology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei 220001, Taiwan
| | - Cheng-Jui Lin
- Division of Nephrology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan
- Department of Medicine, Mackay Medical College, New Taipei 220001, Taiwan
- Department of Medicine, Mackay Junior College of Medicine, Nursing and Management, Taipei 100001, Taiwan
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Mutual effect of homocysteine and uric acid on arterial stiffness and cardiovascular risk in the context of predictive, preventive, and personalized medicine. EPMA J 2022; 13:581-595. [PMID: 36505895 PMCID: PMC9727018 DOI: 10.1007/s13167-022-00298-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/26/2022] [Indexed: 12/15/2022]
Abstract
Background Arterial stiffness is a major risk factor and effective predictor of cardiovascular diseases and a common pathway of pathological vascular impairments. Homocysteine (Hcy) and uric acid (UA) own the shared metabolic pathways to affect vascular function. Serum uric acid (UA) has a great impact on arterial stiffness and cardiovascular risk, while the mutual effect with Hcy remains unknown yet. This study aimed to evaluate the mutual effect of serum Hcy and UA on arterial stiffness and 10-year cardiovascular risk in the general population. From the perspective of predictive, preventive, and personalized medicine (PPPM/3PM), we assumed that combined assessment of Hcy and UA provides a better tool for targeted prevention and personalized intervention of cardiovascular diseases via suppressing arterial stiffness. Methods This study consisted of 17,697 participants from Beijing Health Management Cohort, who underwent health examination between January 2012 and December 2019. Brachial-ankle pulse wave velocity (baPWV) was used as an index of arterial stiffness. Results Individuals with both high Hcy and UA had the highest baPWV, compared with those with low Hcy and low UA (β: 30.76, 95% CI: 18.36-43.16 in males; β: 53.53, 95% CI: 38.46-68.60 in females). In addition, these individuals owned the highest 10-year cardiovascular risk (OR: 1.49, 95% CI: 1.26-1.76 in males; OR: 7.61, 95% CI: 4.63-12.68 in females). Of note, males with high homocysteine and low uric acid were significantly associated with increased cardiovascular risk (OR: 1.30, 95% CI: 1.15-1.47), but not the high uric acid and low homocysteine group (OR: 1.02, 95% CI: 0.90-1.16). Conclusions This study found the significantly mutual effect of Hcy and UA on arterial stiffness and cardiovascular risk using a large population and suggested the clinical importance of combined evaluation and control of Hcy and UA for promoting cardiovascular health. The adverse effect of homocysteine on arteriosclerosis should be addressed beyond uric acid, especially for males. Monitoring of the level of both Hcy and UA provides a window opportunity for PPPM/3PM in the progression of arterial stiffness and prevention of CVD. Hcy provides a novel predictor beyond UA of cardiovascular health to identify individuals at high risk of arterial stiffness for the primary prevention and early treatment of CVD. In the progressive stage of arterial stiffness, active control of Hcy and UA levels from the aspects of dietary behavior and medication treatment is conducive to alleviating the level of arterial stiffness and reducing the risk of CVD. Further studies are needed to evaluate the clinical effect of Hcy and UA targeted intervention on arterial stiffness and cardiovascular health. Supplementary Information The online version contains supplementary material available at 10.1007/s13167-022-00298-x.
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Kutluana U, Kutluana E, Alpua M, Özen M. Effects of Long-term Use of Proton Pump Inhibitors on Systemic Arterial Stiffness and Pulse Wave Velocity. Curr Vasc Pharmacol 2022; 20:439-446. [PMID: 35392785 DOI: 10.2174/1570161120666220407115457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND AND AIM Proton pump inhibitors (PPIs) are among the most widely prescribed agents. Although PPIs are widely regarded as harmlesss, long-term use of PPIs (LTUPPI) can have the potential to increase the risk of developing cardiovascular (CV) disease (CVD). Pulse wave velocity (PWV) is a good indicator of arterial stiffness. Several studies show a relationship between LTUPPI and CVD. However, the association between LTUPPI and PWV or arterial stiffness has not been reported. PATIENTS AND METHODS Patients (n=64) with LTUPPI and controls (n=91) were included. PWV, glucose, creatinine, total cholesterol, triglyceride, low-density lipoprotein cholesterol, cholesterol, highdensity lipoprotein cholesterol, and magnesium levels were measured. RESULTS In the LTUPPI group, PWV was greater than in controls (9.08±2.04 vs. 7.77±1.52 m/s, respectively, p=0.01); 34.4% of patients and 8.8% of controls had PWV levels >10 m/s (p=0.000). Multiple logistic regression analysis showed age (p<0.001) and LTUPPI (p=0.024) as predictors of elevated PWV. CONCLUSION PWV values are increased in patients with LTUPPI compared to controls independently of conventional CV risk factors. Measurement of PWV and other arterial stiffness parameters in cases with LTUPPI may be useful to predict possible CVD. Studies involving greater numbers are needed to confirm these findings.
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Affiliation(s)
- Ufuk Kutluana
- Faculty of Medicine, Pamukkale University, Internal Medicine and Gastroenterology Department, Denizli, Turkey
| | - Ecem Kutluana
- Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey
| | - Mehmet Alpua
- Faculty of Medicine, Pamukkale University, Internal Medicine and Gastroenterology Department, Denizli, Turkey
| | - Mert Özen
- Faculty of Medicine, Emergency Medical Department, Pamukkale University, Denizli, Turkey
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Pablo-Moreno JAD, Serrano LJ, Revuelta L, Sánchez MJ, Liras A. The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V. Int J Mol Sci 2022; 23:ijms23158283. [PMID: 35955419 PMCID: PMC9425441 DOI: 10.3390/ijms23158283] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 11/27/2022] Open
Abstract
The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.
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Affiliation(s)
- Juan A. De Pablo-Moreno
- Department of Genetics, Physiology and Microbiology, School of Biology, Complutense University, 28040 Madrid, Spain; (J.A.D.P.-M.); (L.J.S.)
| | - Luis Javier Serrano
- Department of Genetics, Physiology and Microbiology, School of Biology, Complutense University, 28040 Madrid, Spain; (J.A.D.P.-M.); (L.J.S.)
| | - Luis Revuelta
- Department of Physiology, School of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain;
| | - María José Sánchez
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas (CSIC), Junta de Andalucía, Pablo de Olavide University, 41013 Sevilla, Spain;
| | - Antonio Liras
- Department of Genetics, Physiology and Microbiology, School of Biology, Complutense University, 28040 Madrid, Spain; (J.A.D.P.-M.); (L.J.S.)
- Correspondence:
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Sena CM, Gonçalves L, Seiça R. Methods to evaluate vascular function: a crucial approach towards predictive, preventive, and personalised medicine. EPMA J 2022; 13:209-235. [PMID: 35611340 PMCID: PMC9120812 DOI: 10.1007/s13167-022-00280-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 05/02/2022] [Indexed: 11/06/2022]
Abstract
Endothelium, the gatekeeper of our blood vessels, is highly heterogeneous and a crucial physical barrier with the ability to produce vasoactive and protective mediators under physiological conditions. It regulates vascular tone, haemostasis, vascular inflammation, remodelling, and angiogenesis. Several cardio-, reno-, and cerebrovascular diseases begin with the dysfunction of endothelial cells, and more recently, COVID-19 was also associated with endothelial disease highlighting the need to monitor its function towards prevention and reduction of vascular dysfunction. Endothelial cells are an important therapeutic target in predictive, preventive, and personalised (3P) medicine with upmost importance in vascular diseases. The development of novel non-invasive techniques to access endothelial dysfunction for use in combination with existing clinical imaging modalities provides a feasible opportunity to reduce the burden of vascular disease. This review summarises recent advances in the principles of endothelial function measurements. This article presents an overview of invasive and non-invasive techniques to determine vascular function and their major advantages and disadvantages. In addition, the article describes mechanisms underlying the regulation of vascular function and dysfunction and potential new biomarkers of endothelial damage. Recognising these biomarkers is fundamental towards a shift from reactive to 3P medicine in the vascular field. Identifying vascular dysfunction earlier with non-invasive or minimally invasive techniques adds value to predictive diagnostics and targeted prevention (primary, secondary, tertiary care). In addition, vascular dysfunction is a potential target for treatments tailored to the person.
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Affiliation(s)
- Cristina M. Sena
- Institute of Physiology, Faculty of Medicine, University of Coimbra, Subunit 1, Polo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Lino Gonçalves
- Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Department of Cardiology, Coimbra’s Hospital and University Centre (CHUC), Coimbra, Portugal
| | - Raquel Seiça
- Institute of Physiology, Faculty of Medicine, University of Coimbra, Subunit 1, Polo 3, Azinhaga de Santa Comba, Celas, 3000-354 Coimbra, Portugal
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Homocysteine as a potential indicator of endothelial dysfunction and cardiovascular risk in female patients with borderline personality disorder. Borderline Personal Disord Emot Dysregul 2022; 9:11. [PMID: 35255991 PMCID: PMC8900342 DOI: 10.1186/s40479-021-00171-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 11/24/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND There is increasing evidence suggesting that patients with Borderline Personality Disorder (BPD) are at greater risk of developing cardiovascular diseases (CVD) compared to the general population. Homocysteine (Hcy) has been discussed as a serum marker for endothelial dysfunction as a mechanism involved in CVD and has been shown to be associated with numerous psychiatric conditions. Pathophysiologically, there seems to be a link between Hcy and psychological stress mediated by abnormal activity of the autonomic nervous system. Accordingly, the present study sought to examine Hcy in BPD and to explore possible associations with clinical parameters. METHODS Plasma Hcy levels as well as conventional cardiovascular risk factors, such as blood pressure, BMI, smoking habits, HbA1c, HDL, LDL, and cholesterol, were examined in 49 young female in-patients diagnosed with BPD and 50 psychologically healthy control subjects matched for age and sex. Assessment of borderline symptom severity, childhood trauma, exposure to chronic stress, and quality of sleep was performed using self-reported questionnaires. RESULTS BPD patients showed significantly higher mean plasma Hcy concentrations compared to controls, though below ranges considered pathological. Moreover, Hcy correlated significantly with the severity of childhood trauma, chronic stress, and subjective sleep disturbances. In a regression model BPD diagnosis was found to predict Hcy levels best. CONCLUSION In conclusion, young female BPD patients with no history of CVD show higher, though non-pathological, Hcy levels compared to healthy controls. Our findings seem to support the assumption that BPD is associated with increased risk of CVD, and that Hcy could serve as potential marker for risk evaluation of midlife CVD in BPD patients.
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Ding WY, Gupta D, Lip GYH. Atrial fibrillation and the prothrombotic state: revisiting Virchow’s triad in 2020. Heart 2020; 106:1463-1468. [DOI: 10.1136/heartjnl-2020-316977] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 02/05/2023] Open
Abstract
Atrial fibrillation (AF) is characterised by an increased risk of pathological thrombus formation due to a disruption of physiological haemostatic mechanisms that are better understood by reference to Virchow’s triad of ‘abnormal blood constituents’, ‘vessel wall abnormalities’ and ‘abnormal blood flow’. First, there is increased activation of the coagulation cascade, platelet reactivity and impaired fibrinolysis as a result of AF per se, and these processes are amplified with pre-existing comorbidities. Several prothrombotic biomarkers including platelet factor 4, von Willebrand factor, fibrinogen, β-thromboglobulin and D-dimer have been implicated in this process. Second, structural changes such as atrial fibrosis and endothelial dysfunction are linked to the development of AF which promote further atrial remodelling, thereby providing a suitable platform for clot formation and subsequent embolisation. Third, these factors are compounded by the presence of reduced blood flow secondary to dilatation of cardiac chambers and loss of atrial systole which have been confirmed using various imaging techniques. Overall, an improved understanding of the various factors involved in thrombus formation will allow better clinical risk stratification and targeted therapies in AF.
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Sgarra L, Bortone AS, Potenza MA, Nacci C, De Salvia MA, Acquaviva T, De Cillis E, Ciccone MM, Grimaldi M, Montagnani M. Endothelial Dysfunction May Link Interatrial Septal Abnormalities and MTHFR-Inherited Defects to Cryptogenic Stroke Predisposition. Biomolecules 2020; 10:861. [PMID: 32512924 PMCID: PMC7355772 DOI: 10.3390/biom10060861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 05/22/2020] [Accepted: 06/02/2020] [Indexed: 12/21/2022] Open
Abstract
We explored the significance of the L-Arginine/asymmetric dimethylarginine (L-Arg/ADMA) ratio as a biomarker of endothelial dysfunction in stroke patients. To this aim, we evaluated the correlation, in terms of severity, between the degree of endothelial dysfunction (by L-Arg/ADMA ratio), the methylene tetrahydrofolate reductase (MTHFR) genotype, and the interatrial septum (IAS) phenotype in subject with a history of stroke. Methods and Results: L-Arg, ADMA, and MTHFR genotypes were evaluated; the IAS phenotype was assessed by transesophageal echocardiography. Patients were grouped according to the severity of IAS defects and the residual enzymatic activity of MTHFR-mutated variants, and values of L-Arg/ADMA ratio were measured in each subgroup. Of 57 patients, 10 had a septum integrum (SI), 38 a patent foramen ovale (PFO), and 9 an ostium secundum (OS). The L-Arg/ADMA ratio differed across septum phenotypes (p ≤ 0.01), and was higher in SI than in PFO or OS patients (p ≤ 0.05, p ≤ 0.01, respectively). In the PFO subgroup a negative correlation was found between the L-Arg/ADMA ratio and PFO tunnel length/height ratio (p ≤ 0.05; r = - 0.37; R2 = 0.14). Interestingly, the L-Arg/ADMA ratio varied across MTHFR genotypes (p ≤ 0.0001) and was lower in subgroups carrying the most impaired enzyme with respect to patients carrying the conservative MTHFR (p ≤ 0.0001, p ≤ 0.05, respectively). Consistently, OS patients carried the most dysfunctional MTHFR genotypes, whereas SI patients the least ones. Conclusions: A low L-Arg/ADMA ratio correlates with impaired activity of MTHFR and with the jeopardized IAS phenotype along a severity spectrum encompassing OS, PFO with long/tight tunnel, PFO with short/large tunnel, and SI. This infers that genetic MTHFR defects may underlie endothelial dysfunction-related IAS abnormalities, and predispose to a cryptogenic stroke. Our findings emphasize the role of the L-Arg/ADMA ratio as a reliable marker of stroke susceptibility in carriers of IAS abnormalities, and suggest its potential use both as a diagnostic tool and as a decision aid for therapy.
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Affiliation(s)
- Luca Sgarra
- Department of Biomedical Sciences and Human Oncology—Section of Pharmacology, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.S.); (M.A.P.); (C.N.); (M.A.D.S.)
| | - Alessandro Santo Bortone
- Department of Emergency and Organ Transplantation—Section of Cardiovascular Diseases, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.S.B.); (T.A.); (E.D.C.); (M.M.C.)
| | - Maria Assunta Potenza
- Department of Biomedical Sciences and Human Oncology—Section of Pharmacology, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.S.); (M.A.P.); (C.N.); (M.A.D.S.)
| | - Carmela Nacci
- Department of Biomedical Sciences and Human Oncology—Section of Pharmacology, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.S.); (M.A.P.); (C.N.); (M.A.D.S.)
| | - Maria Antonietta De Salvia
- Department of Biomedical Sciences and Human Oncology—Section of Pharmacology, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.S.); (M.A.P.); (C.N.); (M.A.D.S.)
| | - Tommaso Acquaviva
- Department of Emergency and Organ Transplantation—Section of Cardiovascular Diseases, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.S.B.); (T.A.); (E.D.C.); (M.M.C.)
| | - Emanuela De Cillis
- Department of Emergency and Organ Transplantation—Section of Cardiovascular Diseases, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.S.B.); (T.A.); (E.D.C.); (M.M.C.)
| | - Marco Matteo Ciccone
- Department of Emergency and Organ Transplantation—Section of Cardiovascular Diseases, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.S.B.); (T.A.); (E.D.C.); (M.M.C.)
| | - Massimo Grimaldi
- General Hospital “F. Miulli” Acquaviva delle Fonti, 70021 Bari, Italy;
| | - Monica Montagnani
- Department of Biomedical Sciences and Human Oncology—Section of Pharmacology, Medical School, University of Bari “Aldo Moro”, 70124 Bari, Italy; (L.S.); (M.A.P.); (C.N.); (M.A.D.S.)
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Toya T, Sara JD, Lerman B, Ahmad A, Taher R, Godo S, Corban MT, Lerman LO, Lerman A. Elevated plasma homocysteine levels are associated with impaired peripheral microvascular vasomotor response. IJC HEART & VASCULATURE 2020; 28:100515. [PMID: 32322661 PMCID: PMC7171522 DOI: 10.1016/j.ijcha.2020.100515] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 12/23/2022]
Abstract
Homocysteine > 10 μmol/L is associated with peripheral microvascular endothelial dysfunction (PMED). Homocysteine > 10 μmol/L was associated with PMED in older, obese, or hypertensive patients. The association of homocysteine and PMED was prominent in patients with B-vitamins. Homocysteine > 10 μmol/L was associated with higher major cardiovascular events in univariate analysis. Background Hyperhomocysteinemia (HHcy) has been proposed as an important cardiovascular risk factor (cRF). However, little is known about the association between plasma homocysteine levels and peripheral microvascular endothelial dysfunction (PMED), which is an integrated index of vascular health. Methods This cross-sectional and retrospective cohort study included patients who underwent non-invasive PMED assessment using reactive hyperemia peripheral arterial tonometry (RH-PAT). The association between HHcy and PMED, and its impact on MACE (all-cause mortality and atherosclerotic cardiovascular events) was investigated. Results A total of 257 patients were enrolled (HHcy > 10.0 µmol/L, N = 51; lower levels of homocysteine [LHcy] ≤ 10 µmol/L, N = 206). Patients with HHcy were older, predominantly males, and with more comorbidities than patients with LHcy (p < 0.05 for all). RH-PAT index was lower in patients with HHcy versus LHcy (p = 0.01). A significant association between HHcy and PMED was observed in older (≥60 years), obese (≥30 kg/m2), present/past smokers and hypertensive patients. HHcy was significantly associated with PMED even after adjusting for other cRF and B-vitamins supplementation. HHcy was associated with an increased risk of MACE with a hazard ratio of 3.65 (95% CI 1.41–9.48, p = 0.01) and an adjusted hazard ratio of 2.44 (95% CI 0.91–6.51, p = 0.08) after adjustment for age (≥60 years). Conclusion HHcy was independently associated with PMED after adjusting for cRF and B-vitamins supplementation. Thus, the link between homocysteine and MACE could be mediated by endothelial dysfunction, and will require further clarification with future studies.
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Affiliation(s)
- Takumi Toya
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.,Division of Cardiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, Japan
| | - Jaskanwal D Sara
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Ben Lerman
- School of Medicine, St. George's University, St George's, West Indies, Grenada
| | - Ali Ahmad
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Riad Taher
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Shigeo Godo
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Michel T Corban
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
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15
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Zaric B, Obradovic M, Trpkovic A, Banach M, Mikhailidis DP, Isenovic ER. Endothelial Dysfunction in Dyslipidaemia: Molecular Mechanisms and Clinical Implications. Curr Med Chem 2020; 27:1021-1040. [DOI: 10.2174/0929867326666190903112146] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 08/23/2019] [Accepted: 08/23/2019] [Indexed: 12/13/2022]
Abstract
The endothelium consists of a monolayer of Endothelial Cells (ECs) which form
the inner cellular lining of veins, arteries, capillaries and lymphatic vessels. ECs interact with
the blood and lymph. The endothelium fulfils functions such as vasodilatation, regulation of
adhesion, infiltration of leukocytes, inhibition of platelet adhesion, vessel remodeling and
lipoprotein metabolism. ECs synthesize and release compounds such as Nitric Oxide (NO),
metabolites of arachidonic acid, Reactive Oxygen Species (ROS) and enzymes that degrade
the extracellular matrix. Endothelial dysfunction represents a phenotype prone to atherogenesis
and may be used as a marker of atherosclerotic risk. Such dysfunction includes impaired
synthesis and availability of NO and an imbalance in the relative contribution of endothelialderived
relaxing factors and contracting factors such as endothelin-1 and angiotensin. This
dysfunction appears before the earliest anatomic evidence of atherosclerosis and could be an
important initial step in further development of atherosclerosis. Endothelial dysfunction was
historically treated with vitamin C supplementation and L-arginine supplementation. Short
term improvement of the expression of adhesion molecule and endothelial function during
antioxidant therapy has been observed. Statins are used in the treatment of hyperlipidaemia, a
risk factor for cardiovascular disease. Future studies should focus on identifying the mechanisms
involved in the beneficial effects of statins on the endothelium. This may help develop
drugs specifically aimed at endothelial dysfunction.
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Affiliation(s)
- Bozidarka Zaric
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Milan Obradovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Andreja Trpkovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Lodz, Poland
| | - Dimitri P. Mikhailidis
- Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, United Kingdom
| | - Esma R. Isenovic
- Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia
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16
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Manolis AA, Manolis TA, Melita H, Katsiki N, Manolis AS. Proton pump inhibitors and cardiovascular adverse effects: Real or surreal worries? Eur J Intern Med 2020; 72:15-26. [PMID: 31796246 DOI: 10.1016/j.ejim.2019.11.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 11/21/2019] [Accepted: 11/24/2019] [Indexed: 02/06/2023]
Abstract
Proton pump inhibitors (PPIs) are among the most widely prescribed agents, either for treatment or prophylaxis of gastrointestinal (GI) disease, that are often administered for prolonged or chronic use. Patients with cardiovascular (CV) disease frequently receive PPIs for prophylaxis against GI bleeding due to common use of antithrombotic drugs. Over the last several years there is a growing number of reports associating chronic PPI use with a variety of serious CV and non-CV adverse effects. In this context, PPI use has been independently associated with an increased risk of CV morbidity (myocardial infarction, stroke, other CV events) and mortality. However, the critique remains that these data do not largely derive from randomized controlled trials. On the other hand, in certain conditions, the benefits of PPIs may outweigh the risks of adverse CV effects. As the indications for prolonged, particularly lifelong, prophylactic use of PPIs are not compelling and in the light of evidence of serious CV and other adverse effects, clinicians have to reconsider such long-term use of these drugs. Importantly, histamine 2 blockers have not been found to be associated with increased CV risk and thus may be an alternative therapeutic option in certain patients. These issues are amply discussed together with the potential mechanisms of these pleiotropic and off-target effects of PPIs, which are also depicted in an illustrative schema; data are also presented on differential effects of specific agents involved, alternative modes of therapy available, and relevant current guidelines on this issue.
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Affiliation(s)
| | | | | | - Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology and Metabolism, Diabetes Center, Medical School, AHEPA University Hospital, Thessaloniki, Greece
| | - Antonis S Manolis
- Third and First Department of Cardiology, Athens University School of Medicine, Ippokrateio Hospital, Vas. Sofias 114, Athens 115 27, Greece.
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17
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Wiciński M, Malinowski B, Puk O, Górski K, Adamkiewicz D, Chojnacki G, Walczak M, Wódkiewicz E, Szambelan M, Adamska P, Skibińska K, Socha M, Słupski M, Pawlak-Osińska K. Possible Effects of Proton Pump Inhibitors on Hearing Loss Development. BIOMED RESEARCH INTERNATIONAL 2019; 2019:4853695. [PMID: 31915695 PMCID: PMC6935450 DOI: 10.1155/2019/4853695] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 05/24/2019] [Accepted: 07/09/2019] [Indexed: 12/14/2022]
Abstract
Considered safe and often available as over-the-counter (OTC) drugs, proton pump inhibitors (PPI) are one of the most frequently used medicines. Over recent years much research analyzing PPI has been conducted and these studies shed light on PPI side effects and the mechanisms of these processes. In this study we summarize the findings of these studies and through deduction present some hypotheses on the impact of PPI on health. Of particular interest is the impact of PPI on hearing loss development. However, despite this side effect being localized, its mechanisms are complex, systemic and involve changes in whole body. This paper summarizes how through, inter alia, alterations in the circulatory system, respiratory system, central nervous system and metabolism PPI can cause hearing impairment, which can occur in every age group and is connected with long-term use of this group of drugs. This article also discusses the role PPI plays in the acceleration of presbycusis development, in relation to the fact that older people are the group who most frequently use PPI in long term. Hearing loss negatively impacts affects quality of life, especially among older patients who are also the most afflicted group; administration of PPI should therefore be considered carefully, taking into consideration all potential benefits and side effects.
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Affiliation(s)
- Michał Wiciński
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Bartosz Malinowski
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Oskar Puk
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Karol Górski
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Dawid Adamkiewicz
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Grzegorz Chojnacki
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Maciej Walczak
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Eryk Wódkiewicz
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Monika Szambelan
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Paulina Adamska
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Kamila Skibińska
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Maciej Socha
- Department of Obstetrics, Gynecology and Gynecological Oncology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Ujejskiego 75, 85-168 Bydgoszcz, Poland
| | - Maciej Słupski
- Department of Hepatobiliary and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Katarzyna Pawlak-Osińska
- Department of Pathophysiology of Hearing and Balance System, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
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18
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Fang P, Li X, Shan H, Saredy JJ, Cueto R, Xia J, Jiang X, Yang XF, Wang H. Ly6C + Inflammatory Monocyte Differentiation Partially Mediates Hyperhomocysteinemia-Induced Vascular Dysfunction in Type 2 Diabetic db/db Mice. Arterioscler Thromb Vasc Biol 2019; 39:2097-2119. [PMID: 31366217 PMCID: PMC6761027 DOI: 10.1161/atvbaha.119.313138] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 07/23/2019] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Hyperhomocysteinemia (HHcy) is a potent risk factor for diabetic cardiovascular diseases. We have previously reported that hyperhomocysteinemia potentiates type 1 diabetes mellitus-induced inflammatory monocyte differentiation, vascular dysfunction, and atherosclerosis. However, the effects of hyperhomocysteinemia on vascular inflammation in type 2 diabetes mellitus (T2DM) and the underlying mechanism are unknown. Approach and Results: Here, we demonstrate that hyperhomocysteinemia was induced by a high methionine diet in control mice (homocysteine 129 µmol/L), which was further worsened in T2DM db/db mice (homocysteine 180 µmol/L) with aggravated insulin intolerance. Hyperhomocysteinemia potentiated T2DM-induced mononuclear cell, monocyte, inflammatory monocyte (CD11b+Ly6C+), and M1 macrophage differentiation in periphery and aorta, which were rescued by folic acid-based homocysteine-lowering therapy. Moreover, hyperhomocysteinemia exacerbated T2DM-impaired endothelial-dependent aortic relaxation to acetylcholine. Finally, transfusion of bone marrow cells depleted for Ly6C by Ly6c shRNA transduction improved insulin intolerance and endothelial-dependent aortic relaxation in hyperhomocysteinemia+T2DM mice. CONCLUSIONS Hyperhomocysteinemia potentiated systemic and vessel wall inflammation and vascular dysfunction partially via inflammatory monocyte subset induction in T2DM. Inflammatory monocyte may be a novel therapeutic target for insulin resistance, inflammation, and cardiovascular complications in hyperhomocysteinemia+T2DM.
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Affiliation(s)
- Pu Fang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
| | - Xinyuan Li
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia PA
| | - Huimin Shan
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
| | - Jason J Saredy
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
| | - Ramon Cueto
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
| | - Jixiang Xia
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
| | - Xiaohua Jiang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
| | - Xiao-Feng Yang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
- Department of Pharmacology, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
- Department of Pharmacology, Lewis Kats School of Medicine, Temple University, Philadelphia, PA
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19
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Relationship of reduced glomerular filtration rate with alterations in plasma free amino acids and uric acid evaluated in healthy control and hypertensive subjects. Sci Rep 2019; 9:10252. [PMID: 31311955 PMCID: PMC6635408 DOI: 10.1038/s41598-019-46598-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 07/02/2019] [Indexed: 12/22/2022] Open
Abstract
The potential association between altered levels of plasma free amino acids (PFAAs) and uric acid (UA) with estimated glomerular filtration rate (eGFR) remains unknown among patients with hypertension. A total of 2804 healthy controls and 2455 hypertensive patients were included in the current analysis. eGFR was defined as reduced when it was <60 ml/min/1.73 m2. The associations between reduced eGFR and individual PFAAs and UA in the healthy control and hypertension groups were explored by logistic regression analyses adjusted for potential confounding variables. Results show that UA had a significant positive association with reduced eGFR in both healthy control and hypertension groups (P < 0.001). Among the PFAAs, citrulline, glycine and phenylalanine showed significant positive associations with reduced eGFR in both healthy control (P < 0.01 to 0.001) and hypertension (P < 0.001) groups. Moreover, alanine, asparagine and methionine achieved significant positive associations with reduced eGFR only in the hypertension group (P < 0.01 to 0.001). Conversely, serine showed significant inverse associations with reduced eGFR in the hypertension group only (P < 0.001). Our findings provide first evidence for a strong relationship between distinct patterns of PFAAs and elevated UA with reduced eGFR in hypertension. The findings may appear useful in developing effective strategies for the prevention or early detection and treatment of declined kidney function in hypertension.
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20
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Sarecka-Hujar B, Szołtysek-Bołdys I, Kopyta I, Dolińska B, Sobczak A. Concentrations of the Selected Biomarkers of Endothelial Dysfunction in Response to Antiepileptic Drugs: A Literature Review. Clin Appl Thromb Hemost 2019; 25:1076029619859429. [PMID: 31238702 PMCID: PMC6714895 DOI: 10.1177/1076029619859429] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Epilepsy is a disease arising from morphological and metabolic changes in the brain. Approximately 60% of patients with seizures can be controlled with 1 antiepileptic drug (AED), while in others, polytherapy is required. The AED treatment affects a number of biochemical processes in the body, including increasing the risk of cardiovascular diseases (CVDs). It is indicated that the duration of AED therapy with some AEDs significantly accelerates the process of atherosclerosis. Most of AEDs increase levels of homocysteine (HCys) as well as may affect concentrations of new, nonclassical risk factors for atherosclerosis, that is, asymmetric dimethylarginine (ADMA) and homoarginine (hArg). Because of the role of these parameters in the pathogenesis of CVD, knowledge of HCys, ADMA, and hArg concentrations in patients with epilepsia treated with AED, both pediatric and adult, appears to be of significant importance.
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Affiliation(s)
- Beata Sarecka-Hujar
- 1 Department of Pharmaceutical Technology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Sosnowiec, Poland
| | - Izabela Szołtysek-Bołdys
- 2 Department of General and Inorganic Chemistry, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Sosnowiec, Poland
| | - Ilona Kopyta
- 3 Department of Pediatric Neurology, School of Medicine in Katowice, Medical University of Silesia in Katowice, Katowice, Poland
| | - Barbara Dolińska
- 1 Department of Pharmaceutical Technology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Sosnowiec, Poland
| | - Andrzej Sobczak
- 2 Department of General and Inorganic Chemistry, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Sosnowiec, Poland
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21
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Dymara-Konopka W, Laskowska M. The Role of Nitric Oxide, ADMA, and Homocysteine in The Etiopathogenesis of Preeclampsia-Review. Int J Mol Sci 2019; 20:ijms20112757. [PMID: 31195628 PMCID: PMC6600256 DOI: 10.3390/ijms20112757] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 05/27/2019] [Accepted: 05/28/2019] [Indexed: 12/18/2022] Open
Abstract
Preeclampsia is a serious, pregnancy-specific, multi-organ disease process of compound aetiology. It affects 3–6% of expecting mothers worldwide and it persists as a leading cause of maternal and foetal morbidity and mortality. In fact, hallmark features of preeclampsia (PE) result from vessel involvement and demonstrate maternal endothelium as a target tissue. Growing evidence suggests that chronic placental hypoperfusion triggers the production and release of certain agents that are responsible for endothelial activation and injury. In this review, we will present the latest findings on the role of nitric oxide, asymmetric dimethylarginine (ADMA), and homocysteine in the etiopathogenesis of preeclampsia and their possible clinical implications.
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Affiliation(s)
- Weronika Dymara-Konopka
- Department of Obstetrics and Perinatology, Medical University of Lublin, Poland, 20-950 Lublin, Jaczewskiego 8, Poland.
| | - Marzena Laskowska
- Department of Obstetrics and Perinatology, Medical University of Lublin, Poland, 20-950 Lublin, Jaczewskiego 8, Poland.
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Catalpol Inhibits Homocysteine-induced Oxidation and Inflammation via Inhibiting Nox4/NF-κB and GRP78/PERK Pathways in Human Aorta Endothelial Cells. Inflammation 2019; 42:64-80. [PMID: 30315526 PMCID: PMC6394570 DOI: 10.1007/s10753-018-0873-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hyperhomocysteinemia (HHCY) has been recognized as an independent risk factor for atherosclerosis and plays a vital role in the development of atherosclerosis. Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa, can produce anti-inflammatory, anti-oxidant, anti-tumor, and dopaminergic neurons protecting effects. This study aimed to determine the protecting effects of catalpol against homocysteine (HCY)-induced injuries in human aortic endothelial cells (HAECs) and uncover the underlying mechanisms: 1. HAECs were cultured with different concentrations of HCY (3 mM) and catalpol (7.5 μΜ, 15 μΜ, 30 μΜ) for 24 h. (1) The level of MDA and GSH as well as LDH release was measured with colorimetric assay. (2) Reactive oxygen species (ROS) were detected by flow cytometry analysis. (3) Western blotting analysis was performed to detect the expression of Nox4, p22phox, ICAM-1, MCP-1, VCAM-1, IκB, nucleus p65, p65 phosphorylation, caspase-3, −9, bax, bcl-2, and ER stress-related proteins. (4) The expressions of CHOP, ATF4 were measured by qRT-PCR. (5) Mitochondrial membrane potential in HCY-treated HAECs was measured by rhodamine 123 staining, and the samples were observed by confocal laser scanning microscopy. 2. DPI, PDTC, and TUDCA were used to determine the interaction among Nox4/ROS, NF-κB, and endoplasmic reticulum stress. 3. TUDCA or Nox4 siRNA were used to investigate whether the effect of catalpol inhibiting the over-production of ROS were associated with inhibiting ER stress and Nox4 expression. Catalpol significantly suppressed LDH release, MDA level, and the reduction of GSH. Catalpol reduced HCY-stimulated ROS over-generation, inhibited the NF-κB transcriptional activation as well as the protein over-expressions of Nox4, ICAM-1, VCAM-1, and MCP-1. Catalpol elevated bcl-2 protein expression and reduced bax, caspase-3, −9 protein expressions in the HCY-treated HAECs. Simultaneously, catalpol could also inhibit the activation of ER stress-associated sensors GRP78, IRE1α, ATF6, P-PERK, P-eIF2α, CHOP, and ATF4 induced by HCY. In addition, the extent of catalpol inhibiting ROS over-generation and NF-κB signaling pathway was reduced after inhibiting Nox4 or ER stress with DPI or TUDCA. The inhibitor of NF-κB PDTC also reduced the effects of catalpol inhibiting the expressions of Nox4 and GRP78. Furthermore, the effect of catalpol inhibiting the over-generation of ROS was reduced by Nox4 siRNA. Catalpol could ameliorate HCY-induced oxidation, cells apoptosis and inflammation in HAECs possibly by inhibiting Nox4/NF-κB and ER stress.
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Walker DI, Lane KJ, Liu K, Uppal K, Patton AP, Durant JL, Jones DP, Brugge D, Pennell KD. Metabolomic assessment of exposure to near-highway ultrafine particles. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2019; 29:469-483. [PMID: 30518795 PMCID: PMC6551325 DOI: 10.1038/s41370-018-0102-5] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 09/06/2018] [Accepted: 11/12/2018] [Indexed: 05/17/2023]
Abstract
Exposure to traffic-related air pollutants has been associated with increased risk of adverse cardiopulmonary outcomes and mortality; however, the biochemical pathways linking exposure to disease are not known. To delineate biological response mechanisms associated with exposure to near-highway ultrafine particles (UFP), we used untargeted high-resolution metabolomics to profile plasma from 59 participants enrolled in the Community Assessment of Freeway Exposure and Health (CAFEH) study. Metabolic variations associated with UFP exposure were assessed using a cross-sectional study design based upon low (mean 16,000 particles/cm3) and high (mean 24,000 particles/cm3) annual average UFP exposures. In comparing quantified metabolites, we identified five metabolites that were differentially expressed between low and high exposures, including arginine, aspartic acid, glutamine, cystine and methionine sulfoxide. Analysis of the metabolome identified 316 m/z features associated with UFP, which were consistent with increased lipid peroxidation, endogenous inhibitors of nitric oxide and vehicle exhaust exposure biomarkers. Network correlation analysis and metabolic pathway enrichment identified 38 pathways and included variations related to inflammation, endothelial function and mitochondrial bioenergetics. Taken together, these results suggest UFP exposure is associated with a complex series of metabolic variations related to antioxidant pathways, in vivo generation of reactive oxygen species and processes critical to endothelial function.
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Affiliation(s)
- Douglas I Walker
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of Medicine, Emory University, Atlanta, GA, USA
- Department of Civil and Environmental Engineering, Tufts University, Medford, MA, USA
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kevin J Lane
- Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA
| | - Ken Liu
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | - Karan Uppal
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | | | - John L Durant
- Department of Civil and Environmental Engineering, Tufts University, Medford, MA, USA
| | - Dean P Jones
- Clinical Biomarkers Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, School of Medicine, Emory University, Atlanta, GA, USA
| | - Doug Brugge
- Department of Civil and Environmental Engineering, Tufts University, Medford, MA, USA
- Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA
- Jonathan M. Tisch College of Civic Life, Tufts University, Medford, MA, USA
| | - Kurt D Pennell
- Department of Civil and Environmental Engineering, Tufts University, Medford, MA, USA.
- School of Engineering, Brown University, Providence, RI, USA.
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24
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Chen WT, Shie CB, Yang CC, Lee TM. Blockade of Cardiac Proton Pump Impairs Ventricular Remodeling Through a Superoxide-DDAH-Dependent Pathway in Infarcted Rats. ACTA CARDIOLOGICA SINICA 2019; 35:165-178. [PMID: 30930564 DOI: 10.6515/acs.201903_35(2).20180917a] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Proton pump inhibitors (PPIs) are frequently used to prevent or treat peptic ulcers. Recently, PPIs have been shown to increase the risk of myocardial infarction. The purpose of this study was to determine whether PPIs adversely affect ventricular remodeling in infarcted rats. Methods Male Wistar rats were randomly assigned to receive either vehicle, omeprazole, omeprazole + vitamin C, omeprazole + olmesartan, or famotidine treatment for 4 weeks starting 24 hours after inducing myocardial infarction by ligating coronary arteries. Results Compared with vehicle-treated infarcted rats, omeprazole-treated infarcted rats had significant changes with reduced myocardial vitamin C levels, increased oxidant production, and decreased dimethylarginine dimethylaminohydrolase 2 (DDAH2) activity, which in turn increased asymmetric dimethylarginine (ADMA) levels and impaired ventricular remodeling. With gastric protection similar to omeprazole, the H2 blocker famotidine had no effect on ventricular remodeling. In contrast to the in vivo results, the ex vivo study showed similar superoxide and DDAH2 protein levels between vehicle- and omeprazole-treated infarcted rats, suggesting involvement of gastric vitamin C uptake rather than myocardial vitamin C in mediating the impaired axis of vitamin C-superoxide-DDAH2 in the in vivo measurements. The administration of PPIs was associated with impaired DDAH2 expression and increased myocardial ADMA, which impaired ventricular remodeling after infarction. These effects were prevented by the coadministration of vitamin C or olmesartan. Conclusions Our results indicate that the administration of PPIs was associated with impaired DDAH2 expression and increased myocardial ADMA by reducing gastric vitamin C uptake, which impaired ventricular remodeling after infarction.
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Affiliation(s)
| | - Chang-Bie Shie
- Gastrointestinal Section, Department of Medicine, China Medical University-An Nan Hospital, Tainan
| | | | - Tsung-Ming Lee
- Cardiovascular Institute.,Department of Medicine, School of Medicine, China Medical University, Taichung.,Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan
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25
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Samadi MT, Khorsandi H, Bahrami Asl F, Poorolajal J, Tayebinia H. Long-term exposures to Hypersaline particles associated with increased levels of Homocysteine and white blood cells: A case study among the village inhabitants around the semi-dried Lake Urmia. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 169:631-639. [PMID: 30496995 DOI: 10.1016/j.ecoenv.2018.11.074] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 11/16/2018] [Accepted: 11/18/2018] [Indexed: 06/09/2023]
Abstract
The dried bed of the world's second largest permanent Hypersaline lake, Lake Urmia, acts as a Hypersaline particle emission source. In the present study we aim to assess the health impact of this disaster and examine the association of Hypersaline particles with total and differential white blood cell counts (WBC) and homocysteine (Hcy), the biomarkers of cardiovascular diseases, in the residents around Lake Urmia. Based on the previous study three regions were selected as clean and polluted regions for ambient particulate matter (APM) from 2008 to 2015. Concentration of APM (PM10, PM2.5 and PM1; particulate matter with aerodynamic diameter of less than 10, 2.5 and 1 µm, respectively) was measured in the selected regions and totally, 123 participants were selected randomly from villagers who have lived in the selected regions for at least eight years. Biomarkers and covariates were measured in the selected regions and were analyzed using multiple linear regression models. We found a statistically significant association between APM and selected biomarkers (Hcy, total WBC, neutrophil, monocyte, lymphocyte and basophile) in the polluted regions. These results are consistent with our hypothesis that long-term exposure to Hypersaline particles originated from drying Urmia Hypersaline Lake is related to increased cardiovascular risk biomarkers.
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Affiliation(s)
- Mohammad Taghi Samadi
- Research Center for Health Sciences and Department of Environmental Health Engineering, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Hassan Khorsandi
- Department of Environmental Health Engineering, School of Public Health, Urmia University of Medical Sciences, Urmia, Iran.
| | - Farshad Bahrami Asl
- Department of Environmental Health Engineering, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Jalal Poorolajal
- Research Center for Health Sciences and Department of Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Heidar Tayebinia
- Department of Clinical Biochemistry, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Higher maternal plasma folate, vitamin B 12 and homocysteine levels in women with preeclampsia. J Hum Hypertens 2019; 33:393-399. [PMID: 30647465 DOI: 10.1038/s41371-019-0164-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 12/05/2018] [Accepted: 12/21/2018] [Indexed: 12/16/2022]
Abstract
Micronutrients like vitamin B12 and folate play an important role in nucleic acid metabolism, cell growth, and are important determinants of fetal growth. The present study examined the levels of maternal and cord plasma folate, vitamin B12, homocysteine, and their association with birth outcome in women with preeclampsia (PE). This study includes 450 normotensive control (NC) and 350 women with PE. PE women were further classified into women delivering at term (n = 224) and preterm (n = 126). Maternal and cord blood was collected at delivery. The levels of maternal vitamin B12 (p < 0.05), folate (p < 0.01), and homocysteine (p < 0.01) were higher in the PE group as compared to the NC group. Maternal folate levels were higher in both term and preterm groups, while vitamin B12 levels were higher only in the preterm group as compared to NC group. In contrast, homocysteine was higher only in the term PE group. Similar changes were also observed in the cord plasma. There was a positive association of maternal plasma homocysteine with systolic (r = 0.151, p = 0.000, n = 578) and diastolic blood pressure (r = 0.213, p = 0.000, n = 578) in the whole cohort. A negative association of maternal folate with systolic blood pressure (r = -0.105, p = 0.048, n = 352) while a positive association with baby weight in the NC group (r = 0.116, p = 0.029, n = 352). The present study suggests that maternal and cord micronutrient levels are altered in women with PE.
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Hisazaki K, Hasegawa K, Kaseno K, Miyazaki S, Amaya N, Shiomi Y, Tama N, Ikeda H, Fukuoka Y, Morishita T, Ishida K, Uzui H, Tada H. Endothelial damage and thromboembolic risk after pulmonary vein isolation using the latest ablation technologies: a comparison of the second-generation cryoballoon vs. contact force-sensing radiofrequency ablation. Heart Vessels 2018; 34:509-516. [DOI: 10.1007/s00380-018-1257-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 08/31/2018] [Indexed: 10/28/2022]
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Li D, Misialek JR, Huang F, Windham GB, Yu F, Alonso A. Independent Association of Plasma Hydroxysphingomyelins With Physical Function in the Atherosclerosis Risk in Communities (ARIC) Study. J Gerontol A Biol Sci Med Sci 2018; 73:1103-1110. [PMID: 29053806 PMCID: PMC6037051 DOI: 10.1093/gerona/glx201] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 10/16/2017] [Indexed: 11/13/2022] Open
Abstract
Background Plasma metabolites such as phosphatidylcholines and sphingomyelins (SMs) are associated with an age-related cognitive decline. However, their relations to age-related physical function decline remain largely unknown. Methods We examined the cross-sectional relations of 12 plasma metabolites (including four phosphatidylcholines and four SMs) with physical function in 383 older adults in the At herosclerosis Risk in Communities Study at the fifth exam (2011-2013, mean age [standard deviation (SD)]: 78.0 [5.5], 54.4% women, 28.3% African Americans). Physical function was assessed using grip strength, Short Physical Performance Battery, and 4-m walking speed. Individual metabolites were log-transformed and standardized. Multivariable linear regression was performed to account for demographics, APOE genotype, cardiovascular risk factors, comorbidities, use of antihypertensive and lipid-lowering medications, depressive symptoms, and cognition. Results Lower concentrations of asymmetric dimethylarginine and higher concentrations of SM (OH) C22:1, SM (OH) C22:2, and SM (OH) C24:1 were associated with physical function measures. In particular, SM (OH) C22:1 and SM (OH) C24:1 were associated with all three measures of physical function: β-coefficients (95% confidence interval) with grip strength were 0.89 kg (0.00, 1.78) and 0.86 kg (0.10, 1.61) per 1 SD higher concentration, respectively; with Short Physical Performance Battery score, were 0.61 (0.34, 0.88) and 0.41 (0.19, 0.63) per 1 SD difference, respectively; with 4-m walking speed were 0.035 m/s (0.013, 0.056) and 0.035 m/s (0.028, 0.047), respectively. Conclusions Plasma SM (OH)s may be independently associated with physical function in older adults.
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Affiliation(s)
- Danni Li
- Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis
| | - Jeffrey R Misialek
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis
| | - Fangying Huang
- Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis
| | - Gwen B Windham
- Department of Medicine, University of Mississippi Medical Center, Jackson
| | - Fang Yu
- School of Nursing, University of Minnesota, Minneapolis
| | - Alvaro Alonso
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
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Portelli M, Baron B. Clinical Presentation of Preeclampsia and the Diagnostic Value of Proteins and Their Methylation Products as Biomarkers in Pregnant Women with Preeclampsia and Their Newborns. J Pregnancy 2018; 2018:2632637. [PMID: 30050697 PMCID: PMC6046127 DOI: 10.1155/2018/2632637] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Accepted: 05/15/2018] [Indexed: 12/11/2022] Open
Abstract
Preeclampsia (PE) is a disorder which affects 1-10% of pregnant women worldwide. It is characterised by hypertension and proteinuria in the later stages of gestation and can lead to maternal and perinatal morbidity and mortality. Other than the delivery of the foetus and the removal of the placenta, to date there are no therapeutic approaches to treat or prevent PE. It is thus only possible to reduce PE-related mortality through early detection, careful monitoring, and treatment of the symptoms. For these reasons the search for noninvasive, blood-borne, or urinary biochemical markers that could be used for the screening, presymptomatic diagnosis, and prediction of the development of PE is of great urgency. So far, a number of biomarkers have been proposed for predicting PE, based on pathophysiological observations, but these have mostly proven to be unreliable and inconsistent between different studies. The clinical presentation of PE and data gathered for the biochemical markers placental growth factor (PlGF), soluble Feline McDonough Sarcoma- (fms-) like tyrosine kinase-1 (sFlt-1), asymmetric dimethylarginine (ADMA), and methyl-lysine is being reviewed with the aim of providing both a clinical and biochemical understanding of how these biomarkers might assist in the diagnosis of PE or indicate its severity.
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Affiliation(s)
- Maria Portelli
- Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida MSD2080, Malta
| | - Byron Baron
- Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida MSD2080, Malta
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30
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Endothelial factors in the pathogenesis and treatment of chronic kidney disease Part II. J Hypertens 2018; 36:462-471. [DOI: 10.1097/hjh.0000000000001600] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Association of plasma free amino acids with hyperuricemia in relation to diabetes mellitus, dyslipidemia, hypertension and metabolic syndrome. Sci Rep 2017; 7:17616. [PMID: 29247200 PMCID: PMC5732272 DOI: 10.1038/s41598-017-17710-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 11/29/2017] [Indexed: 12/22/2022] Open
Abstract
Previous studies demonstrated independent contributions of plasma free amino acids (PFAAs) and high uric acid (UA) concentrations to increased risks of lifestyle-related diseases (LSRDs), but the important associations between these factors and LSRDs remain unknown. We quantified PFAAs and UA amongst Japanese subjects without LSRDs (no-LSRD, n = 2805), and with diabetes mellitus (DM, n = 415), dyslipidemia (n = 3207), hypertension (n = 2736) and metabolic syndrome (MetS, n = 717). The concentrations of most amino acids differed significantly between the subjects with and without hyperuricemia (HU) and also between the no-LSRD and LSRD groups (p < 0.05 to 0.001). After adjustment, the logistic regression analyses revealed that lysine in DM, alanine, proline and tyrosine in dyslipidemia, histidine, lysine and ornithine in hypertension, and lysine and tyrosine in MetS demonstrated significant positive associations with HU among the patients with LSRDs only (p < 0.05 to 0.005). By contrast, arginine, asparagine and threonine showed significant inverse associations with HU in the no-LSRD group only (p < 0.05 to 0.01). For the first time, we provide evidence for distinct patterns of association between PFAAs and HU in LSRDs, and postulate the possibility of interplay between PFAAs and UA in their pathophysiology.
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Proton Pump Inhibitors and Cardiovascular Events: A Systematic Review. Heart Lung Circ 2017; 27:443-450. [PMID: 29233498 DOI: 10.1016/j.hlc.2017.10.020] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 10/15/2017] [Accepted: 10/26/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are a commonly prescribed medication that recent data has linked to an increased risk of cardiovascular morbidity and all cause morbidity. The current study sought to perform a systematic review to investigate the link between PPIs and morbidity and mortality METHODS: A systematic review was carried out as per the PRISMA guidelines, with information databases including Pubmed, Medline, and the Cochrane Review Database. English-language studies of all types published from January 1990 to October 2016 were considered. Dichotomous analysis generating odds ratios was performed using RevMan Version 5.3. RESULTS Thirty-seven studies were considered, of which five directly compared the effect of PPI use on mortality and/or cardiovascular morbidity (including 22,427 patients in mortality datasets, and 354,446 patients in morbidity datasets). For patients taking PPIs, all cause mortality (OR 1.68 [95% CI 1.53-1.84], p<0.001) and rate of major cardiovascular events (OR 1.54 [95% CI 1.11-2.13], p=0.01) were significantly higher. CONCLUSIONS The current systematic review demonstrates that, in patients using PPIs, there was a significant increase in morbidity due to cardiovascular disease. Careful consideration should be given to the prescription of PPIs while clinical equipoise remains. Further research in the area is required.
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Ameta K, Gupta A, Kumar S, Sethi R, Kumar D, Mahdi AA. Essential hypertension: A filtered serum based metabolomics study. Sci Rep 2017; 7:2153. [PMID: 28526818 PMCID: PMC5438387 DOI: 10.1038/s41598-017-02289-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 04/13/2017] [Indexed: 02/07/2023] Open
Abstract
Despite the easy and reliable methods of blood pressure measurement, the screening of essential hypertension (EH) is usually ignored due to delayed onset of symptoms. A probe into the biochemical changes in hypertension would serve as a welcome asset to provide insight into the mechanistic aspects of EH. Filtered serum samples from 64 EH patients and 59 healthy controls (HC) were analysed using 800 MHz nuclear magnetic resonance (NMR) spectroscopy. Application of principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) following receiver operating characteristic (ROC) curve of NMR data reveals significantly perturbed metabolites: alanine, arginine, methionine, pyruvate, adenine, and uracil. This set of metabolites correctly classified 99% of cases from HC and also showed excellent correlation in both isolated elevated diastolic blood pressure (DBP) cases and combined elevated systolic-diastolic blood pressure cases. Proton NMR metabolomics of EH may prove helpful in defining associated biomarkers and serve as an alternate diagnostic tool with judicious clinical assessment.
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Affiliation(s)
- Keerti Ameta
- Department of Biochemistry, King George's Medical University, Lucknow, India
| | - Ashish Gupta
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India.
| | - Sudeep Kumar
- Department of Cardiology, SGPGIMS, Lucknow, India
| | - Rishi Sethi
- Department of Cardiology, King George's Medical University, Lucknow, India
| | - Deepak Kumar
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George's Medical University, Lucknow, India
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Zhang Z, Zhu LL, Jiang HS, Chen H, Chen Y, Dai YT. Demethylation treatment restores erectile function in a rat model of hyperhomocysteinemia. Asian J Androl 2017; 18:763-8. [PMID: 26585696 PMCID: PMC5000801 DOI: 10.4103/1008-682x.163271] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Methylation modification is an important cellular mechanism of gene expression regulation. Dimethylarginine dimethylaminohydrolase-2 (DDAH-2) protein is a pivotal molecular for endothelium function. To explore the effects of 5-aza-deoxycytidine (5-aza), a demethylation agent, in hyperhomocysteinemia (hhcy)-related erectile dysfunction (ED) rats, 5-aza (1 mg kg−1) was administrated to Sprague-Dawley hhcy-rats induced by supplemented methionine chow diet. Erectile function, nitric oxide-cyclic guanosine monophosphate (NO-cGMP) levels, expression of DDAH-2 protein and promoter methylation status of DDAH-2 were studied in the corpora cavernosa. We found that supplemented methionine diet induced a high homocysteine level after 6 weeks of treatment. DDAH-2 protein was down-regulated in the corpora cavernosa while the administration of 5-aza up-regulated DDAH-2 expression and restored erectile function. The methionine-fed rats showed high methylation levels of DDAH-2 promoter region while the group treated with 5-aza demonstrated lower-methylation levels when compared to the methionine-fed group. Besides, the administration of 5-aza improved NO and cGMP levels in methionine-fed rats. Therefore, the methylation mechanism involves in ED pathogenesis, and demethylation offers a potential new strategy for ED treatment.
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Affiliation(s)
- Zheng Zhang
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Lei-Lei Zhu
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - He-Song Jiang
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Hai Chen
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Yun Chen
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Yu-Tian Dai
- Department of Andrology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, China
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Rai V. Methylenetetrahydrofolate Reductase (MTHFR) C677T Polymorphism and Alzheimer Disease Risk: a Meta-Analysis. Mol Neurobiol 2017; 54:1173-1186. [PMID: 26820674 DOI: 10.1007/s12035-016-9722-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 01/13/2016] [Indexed: 01/08/2023]
Abstract
Methylenetetrahydrofolate reductase (MTHFR) is key enzyme of folate/homocysteine pathway. Case control association studies on MTHFR C677T polymorphism and Alzheimer's disease (AD) have been repeatedly performed over the last two decades, but the results are inconclusive. The aim of the present study was to assess the risk of MTHFR C677T polymorphism for AD. Forty-one studies were identified by a search of PubMed, Google Scholar, Elsevier, and Springer Link databases, up to January 2015. Odds ratios (ORs) with corresponding 95 % confidence interval (CI) were calculated using fixed effect model or random effect model. The subgroup analyses based on ethnicity were performed. MTHFR C677T polymorphism had a significant association with susceptibility to AD in all genetic models (for T vs C OR = 1.29, 95 % CI = 1.07-1.56, p = 0.003; for TT + CT vs CC OR = 1.29, 95 % CI = 1.19-1.40, p = 0.0004; for TT vs CC OR = 1.31, 95 % CI = 1.16-1.48, p = 0.001; for CT vs CC OR = 1.24, 95 % CI = 1.13-1.35, p < 0.004; and for TT vs CT + CC OR = 1.13, 95 % CI = 1.00-1.28, p = 0.02). Results of present meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of AD.
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Affiliation(s)
- Vandana Rai
- Department of Biotechnology, Human Molecular Genetics Laboratory, VBS Purvanchal University, Jaunpur, 222003, UP, India.
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Yokoyama Y, Nishimura K, Barnard ND, Miyamoto Y. Blood Pressure and Vegetarian Diets. VEGETARIAN AND PLANT-BASED DIETS IN HEALTH AND DISEASE PREVENTION 2017:395-413. [DOI: 10.1016/b978-0-12-803968-7.00022-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abstract
Elevated plasma concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) are found in various clinical settings, including renal failure, coronary heart disease, hypertension, diabetes and pre eclampsia. In healthy people acute infusion of ADMA promotes vascular dysfunc tion, and in mice chronic infusion of ADMA promotes progression of atherosclerosis. Thus, ADMA may not only be a marker but also an active player in cardiovascular disease, which makes it a potential target for therapeutic interventions. This review provides a summary and critical discussion of the presently available data concern ing the effects on plasma ADMA levels of cardiovascular drugs, hypoglycemic agents, hormone replacement therapy, antioxidants, and vitamin supplementation. We assess the evidence that the beneficial effects of drug therapies on vascular func tion can be attributed to modification of ADMA levels. To develop more specific ADMA-lowering therapies, mechanisms leading to elevation of plasma ADMA con centrations in cardiovascular disease need to be better understood. ADMA is formed endogenously by degradation of proteins containing arginine residues that have been methylated by S-adenosylmethionine-dependent methyltransferases (PRMTs). There are two major routes of elimination: renal excretion and enzymatic degrada tion by the dimethylarginine dimethylaminohydrolases (DDAH-1 and -2). Oxidative stress causing upregulation of PRMT expression and/or attenuation of DDAH activity has been suggested as a mechanism and possible drug target in clinical conditions associated with elevation of ADMA. As impairment of DDAH activity or capacity is associated with substantial increases in plasma ADMA concentrations, DDAH is likely to emerge as a prime target for specific therapeutic interventions.
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Affiliation(s)
- Renke Maas
- Institute of Experimental and Clinical Pharmacology,
University Hospital Hamburg-Eppendorf, Hamburg, Germany
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Abstract
Endothelium-derived nitric oxide (NO) is the most potent endogenous vasodilator and, by virtue of its anti-inflammatory and anti-thrombotic effects, it is an endogenous anti-atherogenic agent. Accordingly, impairment of NO synthesis or bioactivity may increase the risk of vascular disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the NO synthase pathway. Plasma levels of ADMA are increased in patients with vascular disease, or with risk factors for vascu lar disease. Preclinical and clinical studies indicate that ADMA may mediate the adverse effects of traditional risk factors on endothelial vasodilator function. By impairing endothelial function, ADMA may contribute to pulmonary or systemic hypertension, as well as to vascular disease. Several drugs known to treat cardiovas cular disease also reduce plasma ADMA levels, such as angiotensin receptor antag onists, converting enzyme inhibitors, and insulin sensitizing agents. Plasma ADMA may be a common mediator of endothelial dysfunction induced by vascular risk factors. Insights into the mechanisms by which plasma ADMA is regulated may lead to new therapeutic knowledge.
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Affiliation(s)
- John P Cooke
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, CA 94305-5406, USA.
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40
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Abstract
The plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is the resultant of many processes at cellular and organ levels. Post-translational methylation of arginine residues of pro teins plays a crucial role in the regulation of their functions, which include processes such as transcription, translation and RNA splicing. Because protein methylation is irreversible, the methylation signal can be turned off only by proteolysis of the entire protein. Consequently, most methylated proteins have high turnover rates. Free ADMA, which is formed during proteolysis, is actively degraded by the intracellular enzyme dimethylarginine dimethylaminohydrolase (DDAH). Some ADMA escapes degradation and leaves the cell via cationic amino acid transporters. These trans porters also mediate uptake of ADMA by neighboring cells or distant organs, thereby facilitating active interorgan transport. Clearance of ADMA from the plasma occurs in small part by urinary excretion, but the bulk of ADMA is degraded by intracellular DDAH, after uptake from the circulation. This review discusses the various processes involved in ADMA metabolism: protein methylation, proteolysis of methylated proteins, metabolism by DDAH, and interorgan transport. In addition, the role of the kidney and the liver in the clearance of ADMA is highlighted.
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Affiliation(s)
- Tom Teerlink
- 1Department of Clinical Chemistry, VU University Medical
Center, Amsterdam, The Netherland
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Abstract
Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Like many other cardiovascular risk factors, hyperhomocysteinemia produces endothelial dysfunction due to impaired bioavailability of endothelium-derived nitric oxide (NO). The molecular mechanisms responsible for decreased NO bioavailabil ity in hyperhomocysteinemia are incompletely understood, but emerging evidence suggests that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, may be a key mediator. Homocysteine is produced during the synthesis of ADMA and can alter ADMA metabolism by inhibiting dimethylarginine dimethy laminohydrolase (DDAH). Several animal and clinical studies have demonstrated a strong association between plasma total homocysteine, plasma ADMA, and endothelial dysfunction. These observations suggest a model in which elevation of ADMA may be a unifying mechanism for endothelial dysfunction during hyper homocysteinemia. The recent development of transgenic mice with altered ADMA metabolism should provide further mechanistic insights into the role of ADMA in hyperhomocysteinemia.
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Abstract
Endothelium-derived nitric oxide (NO) is the most potent endogenous vasodilator and, by virtue of its anti-inflammatory and anti-thrombotic effects, it is an endogenous anti-atherogenic agent. Accordingly, impairment of NO synthesis or bioactivity may increase the risk of vascular disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of the NO synthase pathway. Plasma levels of ADMA are increased in patients with vascular disease, or with risk factors for vascular disease. Preclinical and clinical studies indicate that ADMA may mediate the adverse effects of traditional risk factors on endothelial vasodilator function. By impairing endothelial function, ADMA may contribute to pulmonary or systemic hypertension, as well as to vascular disease. Several drugs known to treat cardiovascular disease also reduce plasma ADMA levels, such as angiotensin receptor antagonists, converting enzyme inhibitors, and insulin sensitizing agents. Plasma ADMA may be a common mediator of endothelial dysfunction induced by vascular risk factors. Insights into the mechanisms by which plasma ADMA is regulated may lead to new therapeutic knowledge.
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Affiliation(s)
- John P Cooke
- Stanford University School of Medicine, Stanford, CA, USA,
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Sydow K, Hornig B, Arakawa N, Bode-Böger SM, Tsikas D, Münzel T, Böger RH. Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc Med 2016; 9:93-101. [PMID: 15521698 DOI: 10.1191/1358863x04vm538oa] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Hyperhomocysteinemia is associated with an enhanced risk for cardiovascular disease. Patients with peripheral arterial disease (PAD) show an increased prevalence of hyper-homocysteinemia. A decreased biological activity of nitric oxide (NO) may contribute to homocysteine-associated endothelial dysfunction. This study was designed to investigate whether elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) are involved in endothelial dysfunction in patients with chronic hyperhomocysteinemia and PAD. A total of 76 patients (58 males and 18 females; mean age 65.2 2.0 years) with PAD were included in the analysis and characterized according to demographic variables and cardiovascular risk factors. Flow-dependent vasodilation (FDD) was determined by high-resolution ultrasound in the radial artery. Total plasma homocysteine (plasma tHcy) and ADMA levels were measured by HPLC. Urinary nitrate was quantified using gas chromatography-mass spectrometry. Patients with plasma tHcy in the highest tertile (n 1/4 27; i.e. >10.6 mmol=l) had a mean plasma level of 14.4 1.2 mmol=l compared with 9.9 0.1 mmol=l in those patients in the middle tertile (n 1/4 22; p < 0.05) and 9.4 0.1 mmol=l in those in the lowest tertile (n 1/4 27; i.e. <9.6 mmol=l; p < 0.05). The hyperhomocysteinemic individuals (highest tertile) had a significantly decreased FDD compared with healthy age-matched controls (n 1/4 15) (7.6 1.0 vs 13.0 0.4%; p < 0.05), higher plasma ADMA concentrations (4.0 0.3 vs 2.6 0.3 mmol=l; p < 0.05), and a lower urinary nitrate excretion rate (89.5 13.4 vs 131.3 17.9 mmol=mmol creatinine; p < 0.05) compared with patients with plasma tHcy in the lowest tertile. Multivariate regression analysis including plasma tHcy, ADMA, total cholesterol, diabetes mellitus, smoking, and systolic blood pressure revealed ADMA as the only significant factor determining FDD (p < 0.05). In conclusion, we demonstrated a stronger relationship between impaired endothelial function and elevated ADMA levels in comparison with plasma tHcy concentrations in patients with PAD and chronic hyperhomocysteinemia. This may raise the question of whether different therapeutical options that interact indirectly with plasma tHcy, i.e. treatment with ACE inhibitors and AT1-receptor blockers to reduce ADMA plasma concentrations or L-arginine, could be a beneficial tool for treating patients with hyperhomocysteinemia.
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Affiliation(s)
- Karsten Sydow
- Division of Cardiology, University Hospital Hamburg-Eppendorf, Germany.
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Peng H, Chen L, Huang X, Yang T, Yu Z, Cheng G, Zhang G, Shi R. Vascular peroxidase 1 up regulation by angiotensin II attenuates nitric oxide production through increasing asymmetrical dimethylarginine in HUVECs. ACTA ACUST UNITED AC 2016; 10:741-751.e3. [DOI: 10.1016/j.jash.2016.06.036] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/05/2016] [Accepted: 06/18/2016] [Indexed: 12/17/2022]
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Gilinsky MA, Johnston TP, Zhukova NA, Dubrovina NI, Latysheva TV, Naumenko SE, Sukhovershin RA. Methylated arginine analogues: their potential role in atherosclerosis and cognition using the poloxamer-407-induced mouse model of dyslipidemia. Can J Physiol Pharmacol 2016; 94:1122-1131. [PMID: 27454106 DOI: 10.1139/cjpp-2016-0104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
An experimental mouse model of dyslipidemia and atherosclerosis was utilized to study the generation of methylarginines in vivo, as well as any potential behavioral changes in mice associated with the production of excess methylarginines. Following 14 weeks of poloxamer 407 treatment, mice developed atherosclerosis and the plasma concentrations of monomethylarginine and asymmetric dimethylarginine were found to be significantly greater than corresponding concentrations in control mice. This finding may have contributed to the development of aortic atherosclerotic lesions in poloxamer-treated mice by interfering with nitric oxide availability and, hence, normal function of vascular endothelium. Poloxamer-407-treated mice also showed a significant decrease in locomotor and exploratory activity, together with signs of emotional stress and anxiety relative to controls. Passive avoidance testing to assess learning and memory provided suggestive evidence that poloxamer-treated mice could potentially be characterized as having undergone a disruption in the process of forgetting about an aversive event, specifically, a foot shock, when compared with control mice. Thus, it is also suggested that the increase in both plasma monomethylarginine and asymmetric dimethylarginine in poloxamer-407-treated mice may somehow influence learning and memory, because endothelial dysfunction caused by reduced nitric oxide availability has been hypothesized to negatively influence cognitive function.
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Affiliation(s)
- Michael A Gilinsky
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Thomas P Johnston
- b Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108-2718, USA
| | - Natalia A Zhukova
- c Voroztzov N.N. Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Prosp. Acad. Lavrentjev, 630090, Novosibirsk, Russian Federation
| | - Nina I Dubrovina
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Tatyana V Latysheva
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Sergey E Naumenko
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
| | - Roman A Sukhovershin
- a Scientific Research Institute of Physiology and Basic Medicine, 4 Timakova St., 630117, Novosibirsk, Russian Federation
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Abstract
Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.
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47
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Morris CR. New strategies for the treatment of pulmonary hypertension in sickle cell disease : the rationale for arginine therapy. ACTA ACUST UNITED AC 2016; 5:31-45. [PMID: 16409014 DOI: 10.2165/00151829-200605010-00003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Nitric oxide (NO) is inactivated in sickle cell disease (SCD), while bioavailability of arginine, the substrate for NO synthesis, is diminished. Impaired NO bioavailability represents the central feature of endothelial dysfunction, and is a key factor in the pathophysiology of SCD. Inactivation of NO correlates with the hemolytic rate and is associated with erythrocyte release of cell-free hemoglobin and arginase during hemolysis. Accelerated consumption of NO is enhanced further by the inflammatory environment of oxidative stress that exists in SCD. Based upon its critical role in mediating vasodilation and cell growth, decreased NO bioavailability has also been implicated in the pathogenesis of pulmonary arterial hypertension (PHT). Secondary PHT is a common life-threatening complication of SCD that also occurs in most hereditary and chronic hemolytic disorders. Aberrant arginine metabolism contributes to endothelial dysfunction and PHT in SCD, and is strongly associated with prospective patient mortality. The central mechanism responsible for this metabolic disorder is enhanced arginine turnover, occurring secondary to enhanced plasma arginase activity. This is consistent with a growing appreciation of the role of excessive arginase activity in human diseases, including asthma and PHT. Decompartmentalization of hemoglobin into plasma consumes endothelial NO and thus drives a metabolic requirement for arginine, whose bioavailability is further limited by arginase activity. New treatments aimed at maximizing both arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, or oral arginine supplementation may represent novel therapeutic strategies.
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Affiliation(s)
- Claudia R Morris
- Department of Emergency Medicine, Children’s Hospital and Research Center at Oakland, Oakland, California, USA
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van Dijk SC, de Jongh RT, Enneman AW, Ham AC, Swart KMA, van Wijngaarden JP, van der Zwaluw NL, Brouwer-Brolsma EM, van Schoor NM, Dhonukshe-Rutten RAM, Lips P, de Groot CPGM, Smulders YM, Blom HJ, Feskens EJ, Geleijnse JM, van den Meiracker AH, Mattace Raso FUS, Uitterlinden AG, Zillikens MC, van der Velde N. Arterial stiffness is not associated with bone parameters in an elderly hyperhomocysteinemic population. J Bone Miner Metab 2016; 34:99-108. [PMID: 25804313 DOI: 10.1007/s00774-015-0650-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 12/25/2014] [Indexed: 10/23/2022]
Abstract
Several studies have observed positive associations between bone disease and cardiovascular disease. A potential common pathway is hyperhomocysteinemia; however, to date, there is a lack of data regarding hyperhomocysteinemic populations. Therefore, we examined both cross-sectionally and longitudinally, whether there is an association between bone parameters and arterial stiffness in a hyperhomocysteinemic population, and investigated the potential common role of homocysteine (hcy) level on these associations. Cross-sectional and longitudinal data of the B-PROOF study were used (n = 519). At both baseline and 2-year follow-up we determined bone measures-incident fractures and history of fractures, bone-mineral density (BMD) and quantitative ultrasound (QUS) measurement. We also measured arterial stiffness parameters at baseline-pulse wave velocity, augmentation index and aortic pulse pressure levels with applanation tonometry. Linear regression analysis was used to examine these associations and we tested for potential interaction of hcy level. The mean age of the study population was 72.3 years and 44.3 % were female. Both cross-sectionally and longitudinally there was no association between arterial stiffness measures and BMD or QUS measurements or with incident fractures (n = 16) within the 2-3 years of follow-up. Hcy level did not modify the associations and adjustment for hcy did not change the results. Arterial stiffness was not associated with bone parameters and fractures, and hcy neither acted as a pleiotropic factor nor as a mediator. The potential association between bone and arterial stiffness is therefore not likely to be driven by hyperhomocysteinemia.
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Affiliation(s)
- S C van Dijk
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
| | - R T de Jongh
- Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
- Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
| | - A W Enneman
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - A C Ham
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - K M A Swart
- Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
| | - J P van Wijngaarden
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
| | - N L van der Zwaluw
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
| | - E M Brouwer-Brolsma
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
| | - N M van Schoor
- Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
| | | | - P Lips
- Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
- Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands
| | - C P G M de Groot
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
| | - Y M Smulders
- Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
- Institute for Cardiovascular Research ICaR-VU, VU University Medical Center, Amsterdam, The Netherlands
| | - H J Blom
- Institute for Cardiovascular Research ICaR-VU, VU University Medical Center, Amsterdam, The Netherlands
- Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
| | - E J Feskens
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
| | - J M Geleijnse
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
| | - A H van den Meiracker
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - F U S Mattace Raso
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - A G Uitterlinden
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Netherlands Consortium of Healthy Ageing, Rotterdam and Leiden, The Netherlands
| | - M C Zillikens
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - N van der Velde
- Section of Geriatrics, Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Section of Geriatrics, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
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Tsuda K. Plasma Homocysteine Levels and Endothelial Dysfunction in Cerebro- and Cardiovascular Diseases in the Metabolic Syndrome. Am J Hypertens 2015; 28:1489. [PMID: 26163180 DOI: 10.1093/ajh/hpv112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 06/25/2015] [Indexed: 11/13/2022] Open
Affiliation(s)
- Kazushi Tsuda
- Cardiovascular Medicine, Cardiovascular and Metabolic Research Center, Kansai University of Health Sciences, Osaka, Japan.
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50
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Asymmetric dimethylarginine predicts left atrial appendage thrombus in patients with non-valvular atrial fibrillation. Thromb Res 2015; 136:1156-9. [DOI: 10.1016/j.thromres.2015.10.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 10/08/2015] [Accepted: 10/09/2015] [Indexed: 11/21/2022]
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