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      Apelin and Cardiac Function in Hemodialyzed Patients: Possible Relations?

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          Background: Apelin, a newly discovered adipocytokine, is produced by white adipose tissue and is also expressed in the kidney and heart. Increasing evidence suggests a role for apelin in the pathology of the cardiovascular system. Cardiovascular disease is a major contributor to the mortality and morbidity in patients with chronic renal failure. The aim of this study was to assess associations between apelin, coronary artery disease (CAD) and echocardiographic parameters in hemodialyzed patients. Patients and Methods: We investigated plasma apelin levels (using commercially available kits) in 81 nondiabetic, clinically stable hemodialyzed patients (38 females, 43 males) with and without CAD. Results: Patients with CAD were significantly older, with significantly increased left ventricular internal end-diastolic dimension (LVIDd), left ventricular internal end-systolic dimension (LVISd), right ventricle (RV), left atrium (LA), interventricular septum in diastole, left ventricle posterior wall in diastole (LVPW), aorta, pulmonary artery, significantly lower ejection fraction and apelin than patients without CAD. We observed statistically significant correlations between apelin and echocardiographic parameters: LVIDd, LVISd, RV, LA, right atrium, LVPW, aorta, and serum lipids: cholesterol, LDL, triglycerides. In multiple logistic regression analysis, the only associate of apelin was LVIDd. Conclusions: Apelin level was significantly lower in dialyzed patients with CAD and it was associated with cardiac function. Apelin might be involved in the pathophysiology of cardiovascular disease in chronic renal failure. Since apelin is an inotrope in normal and failing hearts, this finding may have clinical implications for future use of apelin as a novel inotropic agent also for patients with uremic cardiomyopathy.

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          Most cited references 15

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          Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999.

          Knowledge of the excess risk posed by specific cardiovascular syndromes could help in the development of strategies to reduce premature mortality among patients with chronic kidney disease (CKD). The rates of atherosclerotic vascular disease, congestive heart failure, renal replacement therapy, and death were compared in a 5% sample of the United States Medicare population in 1998 and 1999 (n = 1,091,201). Patients were divided into the following groups: 1, no diabetes, no CKD (79.7%); 2, diabetes, no CKD (16.5%); 3, CKD, no diabetes (2.2%); and 4, both CKD and diabetes (1.6%). During the 2 yr of follow-up, the rates (per 100 patient-years) in the four groups were as follows: atherosclerotic vascular disease, 14.1, 25.3, 35.7, and 49.1; congestive heart failure, 8.6, 18.5, 30.7, and 52.3; renal replacement therapy, 0.04, 0.2, 1.6, and 3.4; and death, 5.5, 8.1, 17.7, and 19.9, respectively (P < 0.0001). With use of Cox regression, the corresponding adjusted hazards ratios were as follows: atherosclerotic vascular disease, 1, 1.30, 1.16, and 1.41 (P < 0.0001); congestive heart failure, 1, 1.44, 1.28, and 1.79 (P < 0.0001); renal replacement therapy, 1, 2.52, 23.1, and 38.9 (P < 0.0001); and death, 1, 1.21, 1.38, and 1.56 (P < 0.0001). On a relative basis, patients with CKD were at a much greater risk for the least frequent study outcome, renal replacement therapy. On an absolute basis, however, the high death rates of patients with CKD may reflect accelerated rates of atherosclerotic vascular disease and congestive heart failure.
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            Apelin, a newly identified adipokine up-regulated by insulin and obesity.

            The results presented herein demonstrate that apelin is expressed and secreted by both human and mouse adipocytes. Apelin mRNA levels in isolated adipocytes are close to other cell types present in white adipose tissue or other organs known to express apelin such as kidney, heart, and to a lesser extent brown adipose tissue. Apelin expression is increased during adipocyte differentiation stage. A comparison of four different models of obesity in mice showed a large increase in both apelin expression in fat cells and apelin plasma levels in all the hyperinsulinemia-associated obesities and clearly demonstrated that obesity or high-fat feeding are not the main determinants of the rise of apelin expression. The lack of insulin in streptozotocin-treated mice is associated with a decreased expression of apelin in adipocytes. Furthermore, apelin expression in fat cells is strongly inhibited by fasting and recovered after refeeding, in a similar way to insulin. A direct regulation of apelin expression by insulin is observed in both human and mouse adipocytes and clearly associated with the stimulation of phosphatidylinositol 3-kinase, protein kinase C, and MAPK. These data provide evidence that insulin exerts a direct control on apelin gene expression in adipocytes. In obese patients, both plasma apelin and insulin levels were significantly higher, suggesting that the regulation of apelin by insulin could influence blood concentrations of apelin. The present work identifies apelin as a novel adipocyte endocrine secretion and focuses on its potential link with obesity-associated variations of insulin sensitivity status.
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              Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility.

              The orphan receptor APJ and its recently identified endogenous ligand, apelin, exhibit high levels of mRNA expression in the heart. However, the functional importance of apelin in the cardiovascular system is not known. In isolated perfused rat hearts, infusion of apelin (0.01 to 10 nmol/L) induced a dose-dependent positive inotropic effect (EC50: 33.1+/-1.5 pmol/L). Moreover, preload-induced increase in dP/dt(max) was significantly augmented (P<0.05) in the presence of apelin. Inhibition of phospholipase C (PLC) with U-73122 and suppression of protein kinase C (PKC) with staurosporine and GF-109203X markedly attenuated the apelin-induced inotropic effect (P<0.001). In addition, zoniporide, a selective inhibitor of Na+-H+ exchange (NHE) isoform-1, and KB-R7943, a potent inhibitor of the reverse mode Na+-Ca2+ exchange (NCX), significantly suppressed the response to apelin (P<0.001). Perforated patch-clamp recordings showed that apelin did not modulate L-type Ca2+ current or voltage-activated K+ currents in isolated adult rat ventricular myocytes. Apelin mRNA was markedly downregulated in cultured neonatal rat ventricular myocytes subjected to mechanical stretch and in vivo in two models of chronic ventricular pressure overload. The present study provides the first evidence for the physiological significance of apelin in the heart. Our results show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that the inotropic response to apelin may involve activation of PLC, PKC, and sarcolemmal NHE and NCX.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                May 2006
                02 June 2006
                : 26
                : 2
                : 121-126
                aDepartment of Nephrology, Medical University, Białystok, and bDialysis Unit, Działdowo, Poland
                92122 Am J Nephrol 2006;26:121–126
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 1, References: 23, Pages: 6
                Self URI (application/pdf):
                Original Report: Patient-Oriented, Translational Research

                Cardiovascular Medicine, Nephrology

                Hemodialysis, Cardiac function, Coronary artery disease, Apelin


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