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Hemodynamic folluw-up after heart failure surgery : systolic and diastolic function Brinke, E.A. ten

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systolic and diastolic function

Brinke, E.A. ten

Citation

Brinke, E. A. ten. (2011, September 29). Hemodynamic folluw-up after heart failure surgery : systolic and diastolic function. Retrieved from

https://hdl.handle.net/1887/17886

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/17886

Note: To cite this publication please use the final published version (if

applicable).

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