Serum Midkine as a Predictor of Cardiac Events in Patients With Chronic Heart Failure

doi:10.1016/j.cardfail.2009.12.014

Journal of Cardiac Failure

Volume 16, Issue 4, April 2010, Pages 308-313

https://doi.org/10.1016/j.cardfail.2009.12.014 Get rights and content

Abstract

Background

Midkine, a heparin-binding growth factor, has various functions such as migration of inflammatory cell and anti-apoptotic effect. Invasion of inflammatory cell and cardiomyocyte apoptosis are involved in development and progression of heart failure (HF). However, the relationship between midkine and HF has not been previously examined. Therefore, we examined clinical significance of serum midkine levels to determine the prognosis of HF patients.

Methods and Results

Serum levels of midkine were measured at admission in 216 consecutive patients hospitalized for HF and 60 control subjects. Patients were prospectively followed during a mean follow-up period of 653 ± 375 days with the end points of cardiac death and progressive HF requiring rehospitalization. Serum concentrations of midkine were significantly higher in patients with HF than in controls. Patients with cardiac events had significantly higher concentrations of midkine than those without cardiac events. Kaplan-Meier analysis revealed that cardiac event rates increased markedly as midkine levels rose. Furthermore in the multivariate analysis, after adjustment for age, gender ,and complications, midkine was the independent predictor of cardiac events.

Conclusion

Serum midkine levels are increased in HF patients, and midkine is a novel marker for risk stratifying HF patients.

Section snippets

Study Design and Participants

We prospectively studied 216 consecutive patients with HF (132 men, 84 women) who had been admitted for the treatment of worsening HF because of systolic dysfunction or diastolic dysfunction. And 60 age-matched normal subjects (35 men, 25 women; ages 65 ± 12 years) who were hospitalized for cardiac examinations without HF composed the control group. The diagnosis of HF was made by 2 senior cardiologists using the generally accepted Framingham criteria and information including a history of

Results

The baseline clinical characteristics of patients with HF and control subjects are listed in Table 1. Uric acid, C-reactive protein (CRP), brain natriuretic peptide (BNP), midkine, and echocardiographic left ventricular end-diastolic dimension (LVEDD) were significantly higher in patients with HF than in control subjects. The estimated GFR and left ventricular ejection fraction (LVEF) were significantly lower in patients with HF than in control subjects. There were no differences in midkine

Discussion

In the present study, we showed the following findings: (1) serum midkine levels were significantly elevated in patients with HF compared with healthy control subjects; (2) midkine levels increased with advancing NYHA functional class; (3) midkine levels were higher in patients with cardiac events compared with those without cardiac events; (4) multivariate Cox proportional hazard analysis demonstrated that midkine levels were the independent factor to predict adverse clinical outcomes in

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Furthermore, the serum levels of MK were shown to be increased in patients with heart failure and predicted risk of cardiac adverse events. As such, MK can become a new prognostic biomarker for risk stratification in patients with heart failure, or a novel diagnostic biomarker in patients with cardiac ischemia (Kitahara et al., 2010). The development of blood vessels is pivotal for organ growth in the embryo and repair of injured tissue in the adult.
Midkine is a recently identified new growth factor/cytokine with pleiotropic functions in the human organism. First discovered in the late eighties, midkines have now become the subject of numerous studies in cardiovascular, neurologic, renal diseases and also various types of cancers.
We summarize here the most important functions of midkine in cardiovascular diseases, emphasizing its role in inflammation and its antiapoptotic and proangiogenetic effects. Midkine has multiple roles in the organism, with the specific feature of being either beneficial or harmful depending on which tissue it acts on. Even though midkine has been shown to have cardiac protective effects against acute ischemia/reperfusion injury and to inhibit cardiac remodeling, it also promotes intimal hyperplasia and vascular stenosis. As such, different therapeutic strategies are currently being evaluated, consisting of administering either midkine proteins or midkine inhibitors depending on the desired outcome. More data is gathering to suggest that these novel therapies could become an adjunctive to standard cardiovascular therapy. Nonetheless, much is still to be learned about midkine. The encouraging results up till now require further studying in order to fully understand the complete profile of its mechanism of action and the clinical safety and efficacy of novel therapeutic opportunities offered by midkine molecular targeting.
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Midkine is a multifunctional growth factor, and its serum levels are increased with the functional severity of heart failure. This study aimed to examine the role of midkine in heart failure pathogenesis. Midkine expression levels were increased in the kidney and lung after transverse aortic constriction (TAC) surgery, but not sufficiently increased in the heart. After TAC, phosphorylation of extracellular signal-regulated kinase1/2 and AKT, and the expression levels of foetal genes in the heart were considerably increased in transgenic mice with cardiac-specific overexpression of midkine (MK-Tg) compared with wild-type (WT) mice. MK-Tg mice showed more severe cardiac hypertrophy and dysfunction, and showed lower survival rate after TAC than WT mice. We conclude that midkine plays a critical role in cardiac hypertrophy and remodelling.
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: Supported, in part, by a grant-in-aid for Scientific Research (No. 19590804, 19790513, 21590923, 21590935, and 21790701) from the Ministry of Education Culture, Sport, Science and Technology and a grant-in-aid from the global century center of excellence (COE) program of the Japan Society for the Promotion of Science.

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Clincial InvestigationSerum Midkine as a Predictor of Cardiac Events in Patients With Chronic Heart Failure

Abstract

Background

Methods and Results

Conclusion

Section snippets

Study Design and Participants

Results

Discussion

Brain Res Dev Brain Res

Ann Thorac Surg

Am J Pathol

Lab Invest

J Mol Cell Cardiol

Kidney Int

Roles of proteoglycans in reception of the midkine signal

Trends Glycosci Glycotechnol

A new family of heparin-binding growth/differentiation factors: increased midkine expression in Wilms' tumor and other human carcinomas

Cancer Res

Neointima formation in a restenosis model is suppressed in midkine-deficient mice

J Clin Invest

Midkine is involved in neutrophil infiltration into the tubulointerstitium in ischemic renal injury

J Immunol