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      Mediation of Arterial Stiffness for Hyperuricemia-Related Decline of Cardiac Systolic Function in Healthy Men

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          Background: This prospective observational study examined whether hyperuricemia may be associated with impaired left ventricular (LV) systolic function and increased cardiac load resulting from increased arterial stiffness.

          Methods and Results: In 1,880 middle-aged (mean [±SD] age 45±9 years) healthy men, serum uric acid (UA) levels, pre-ejection period/ejection time (PEP/ET) ratio, serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and brachial-ankle pulse wave velocity (baPWV) were measured at the start and end of the 3-year study period. Linear regression analysis revealed that serum UA levels measured at baseline were significantly associated with the PEP/ET ratio, but not with serum NT-proBNP levels, measured at baseline (β=0.73×10 −1, P<0.01) and at the end of the study period (β=0.68×10 −1, P<0.01). The change in the PEP/ET ratio during the study period was significantly greater in the High-UA (UA >7 mg/dL in 2009 and 2012) than Low-UA (UA ≤7 mg/dL in 2009 and 2012) group. Mediation analysis demonstrated both direct and indirect (via increases in baPWV) associations between serum UA measured at baseline and the PEP/ET ratio measured at the end of the study period.

          Conclusions: In healthy middle-aged Japanese men, hyperuricemia may be associated with an accelerated decline in ventricular systolic function, both directly and indirectly, via increases in arterial stiffness.

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          Most cited references 34

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          2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

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            Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells.

            Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling. Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease. In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease. For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling. It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein constitutively, revealing that vascular cells are another source of CRP production. UA (6 to 12 mg/dl) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media. Inhibition of p38 or extracellular signal-regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA. UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by 3H-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression. UA also increased HVSMC migration and inhibited HUVEC migration. In HUVEC, UA reduced nitric oxide (NO) release. Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling. This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells. The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease.
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              Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging.

              Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF). For the derivation study, 112 patients with CHF (age 59+/-12 years, peak oxygen consumption [Vo2] 17+/-7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (n=182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (n=120). In the derivation study, the best mortality predicting UA cutoff (at 12 months) was 565 micromol/L (9.50 mg/dL) (independently of age, peak Vo2, left ventricular ejection fraction, diuretic dose, sodium, creatinine, and urea; P or=565 micromol/L predicted mortality (hazard ratio, 7.14; P or=565 micromol/L, left ventricular ejection fraction

                Author and article information

                Circ Rep
                Circ Rep
                Circulation Reports
                The Japanese Circulation Society
                18 March 2021
                9 April 2021
                : 3
                : 4
                : 227-233
                [1) ] Department of Cardiology, Tokyo Medical University Tokyo Japan
                Author notes
                Mailing address

                Hirofumi Tomiyama, MD, PhD

                Department of Cardiology and Division of Pre-emptive Medicine for Vascular Damage, Tokyo Medical University 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023Japan tomiyama@ 123456tokyo-med.ac.jp
                Copyright © 2021, THE JAPANESE CIRCULATION SOCIETY

                This article is licensed under a Creative Commons [Attribution-NonCommercial-NoDerivatives 4.0 International] license.

                Original article
                Heart Failure


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