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      Impaired Endothelial Function in Hereditary Angioedema During the Symptom-Free Period

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          Abstract

          Introduction: The presence of coronary endothelial dysfunction was previously shown in Hereditary Angioedema (HAE) patients. The aim of our study was to evaluate the effect of HAE on systemic endothelial function and whether there was a relationship among endothelial function, asymmetric dimethylarginine (ADMA) -which is a strong inhibitor of nitric oxide synthesis-, and disease severity scores.

          Methods: Twenty-four HAE patients (18 females, aged 47.9 ± 2 years) without factors known to interfere with endothelial function were studied and compared with 24 healthy peers age- and gender-matched. Endothelial function was assessed by means of non-invasive finger plethysmography (reactive hyperaemia index: RHI) and ADMA levels by high-performance liquid chromatography. HAE severity scores have been calculated according to published literature.

          Results: In HAE patients RHI was lower (2.03 ± 0.46 vs. 2.82 ± 0.34, p < 0.0001) and ADMA higher (0.636 ± 7 vs. 585 ± 5 micromol/L, p < 0.01) than in controls. A statistically significant inverse correlation was revealed between RHI and patients' ADMA levels ( r = −0.516, p = 0.009) as well as between RHI and patients' chronological age ( r = −0.49, p = 0.015). A statistically significant correlation between RHI and ADMA was confirmed even when excluding the possible influence of cholesterol ( r = −0.408, p = 0.048). No other significant correlations were found with the examined laboratory and clinical parameters (chronological age, age at disease onset, disease duration, severity scores, and gender).

          Conclusion: The dysfunction previously shown in HAE patients at the coronary arteries seems to involve the peripheral vessels as well, without a correlation with disease severity.

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          Most cited references35

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          Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction.

          This study attempted to assess whether coronary risk factors are associated with endothelial dysfunction in the systemic arteries of asymptomatic men and women. Endothelial dysfunction is present in adults with established atherosclerosis. It is not known whether risk factors interact to produce endothelial dysfunction in clinically well subjects early in the natural history. Using high resolution ultrasound, we measured arterial diameter at rest, after reactive hyperemia (with increased flow causing endothelium-dependent dilation) and after sublingual nitroglycerin (an endothelium-independent dilator). Arterial responses were studied noninvasively in 500 clinically well, nonhypertensive subjects (252 men, 248 women; mean [+/- SD] age 36 +/- 15 years, range 5 to 73), including 179 current and former smokers. The superficial femoral artery was studied in 46 subjects and the brachial artery in 454. Flow-mediated dilation ranged from -1% to +17%. All arteries dilated in response to administration of nitroglycerin (17 +/- 6%), suggesting an abnormality of endothelial function in subjects with impaired flow-mediated dilation. On univariate analysis, reduced flow-mediated dilation was significantly related to hypercholesterolemia, cigarette smoking, higher blood pressure, male gender, older age, family history of premature vascular disease and larger vessel size (p < 0.01). By multiple stepwise regression analysis, reduced flow-mediated dilation was independently associated with cigarette smoking, older age, male gender and larger vessel size (p < 0.005) but not with total cholesterol level, blood pressure or family history. A composite risk factor score was independently related to flow-mediated dilation (r = -0.30, p < 0.0001), suggesting risk factor interaction. Loss of endothelium-dependent dilation in the systemic arteries occurs in the preclinical phase of vascular disease and is associated with interaction of the same risk factors known to predispose to atherosclerosis and its complications in later life.
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            Plasma bradykinin in angio-oedema.

            Bradykinin is believed to be the main mediator of symptoms in hereditary (HA) and acquired (AA) angio-oedema due to C1 esterase inhibitor deficiency, as well as in angio-oedema that complicates treatment with inhibitors of angiotensin-converting enzyme (ACE). Difficulties in the measurement of kinin concentrations, however, have so far precluded the demonstration of an incontrovertible change in plasma bradykinin concentrations in these disorders. By developing a reliable assay we have been able to follow bradykinin concentrations during attacks and during remission in HA and in AA, and also in a patient treated with an ACE-inhibitor. Liquid-phase extraction, high-performance liquid chromatography, and RIA were used for specific measurement of plasma bradykinin concentrations in 22 patients with HA and in 22 healthy volunteers of similar age and sex distribution. Four patients with AA and one hypertensive patient treated with the ACE inhibitor captopril were also studied. Among the healthy volunteers plasma bradykinin concentration was inversely proportional to age. The geometric mean plasma bradykinin concentration in the healthy volunteers was 2.2 fmol/mL (SD 2.2), compared with 3.9 fmol/mL (3.7) among patients with HA during remission (p=0.095). Bradykinin was also high in the patients with AA (10.4 fmol/mL [1.6]). During acute attacks of oedema, in both HA and AA, plasma bradykinin rose to two to 12 times the upper limit of normal. Infusion of C1-esterase inhibitor (the deficient factor in both HA and AA) immediately lowered bradykinin concentrations. In the patient receiving the ACE-inhibitor captopril, bradykinin concentration was very high at 47 fmol/mL during an acute attack of angio-oedema, but normal at 3.2 fmol/mL in remission after withdrawal of the drug. A sensitive method for measurement of plasma bradykinin provided the means to show that concentrations of this peptide decrease with age in healthy people. Although the differences between patients in remission and healthy controls did not reach statistical significance, there were substantial rises in bradykinin during acute attacks of hereditary, acquired, or captopril-induced angio-oedema.
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              Hereditary angio-oedema.

              Hereditary angio-oedema is caused by a heterozygous deficiency of C1 inhibitor. This inhibitor regulates several inflammatory pathways, and patients with hereditary angio-oedema have intermittent cutaneous or mucosal swellings because of a failure to control local production of bradykinin. Swellings typically evolve in several hours and persist for a few days. In addition to orofacial angio-oedema, painless swellings affect peripheries, which causes disfigurement or interference with work and other activities of daily living. Angio-oedema affecting the gastrointestinal tract or abdominal viscera causes severe pain often with vomiting due to oedematous bowel obstruction. About 2% of swellings involve the larynx and can be fatal if untreated. About 50% of patients have laryngeal swellings that are potentially fatal despite prophylaxis. In this Seminar we review the clinical features, diagnosis, and management of hereditary angio-oedema, with specific emphasis on the new treatments available for acute swellings. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                16 May 2018
                2018
                : 9
                : 523
                Affiliations
                [1] 1Unit of Internal Medicine, Department of Medical Sciences and Public Health, Allergy and Clinical Immunology, University of Cagliari , Cagliari, Italy
                [2] 2Unit of Cardiology and Angiology, Department of Medical Sciences and Public Health, University of Cagliari , Cagliari, Italy
                [3] 3Sports Physiology Lab., Department of Medical Sciences and Public Health, University of Cagliari , Cagliari, Italy
                Author notes

                Edited by: Pasquale Pagliaro, Università degli Studi di Torino, Italy

                Reviewed by: Massimo Piepoli, Guglielmo da Saliceto Hospital, Italy; Fabio Mangiacapra, Università Campus Bio-Medico, Italy

                *Correspondence: Pier P. Bassareo piercard@ 123456inwind.it

                This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology

                †These authors have contributed equally to this work.

                Article
                10.3389/fphys.2018.00523
                5964294
                68a7b879-4dbc-4e73-bd7c-221265c6a8ec
                Copyright © 2018 Firinu, Bassareo, Zedda, Barca, Crisafulli, Mercuro and Del Giacco.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 05 January 2018
                : 24 April 2018
                Page count
                Figures: 1, Tables: 2, Equations: 0, References: 46, Pages: 7, Words: 4928
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                hereditary angioedema,bradykinin,nitric oxide,asymmetric dimethylarginine,endothelium,atherosclerosis,flow mediated dilation

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