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Balance of active, passive, and anatomical cardiac properties in doxorubicin-induced heart failure

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Alexandre Rene Marie Lewalle, Sander Land, Jort Merken, Anne Raafs, Pilar Sepulveda, Stephane Heymans, Jos Kleinjans, Steven Alexander Niederer

Original languageEnglish
Pages (from-to)2337-2348
JournalBiophysical Journal
Volume117
Issue number12
Early online date29 Jul 2019
DOIs
Publication statusPublished - 17 Dec 2019

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Abstract

Late-onset heart failure (HF) is a known side effect of doxorubicin chemotherapy. Typically, patients are diagnosed when already at an irreversible stage of HF, which allows few or no treatment options. Identifying the causes of compromised cardiac function in this patient group may improve early patient diagnosis and support treatment selection. To link doxorubicin-induced changes in cardiac cellular and tissue mechanical properties to overall cardiac function, we apply a multiscale biophysical biomechanics model of the heart to measure the plausibility of changes in model parameters representing the passive, active, or anatomical properties of the left ventricle for reproducing measured patient phenotypes. We create representative models of healthy controls (N = 10) and patients with HF induced by (N = 22) or unrelated to (N = 25) doxorubicin therapy. The model predicts that HF in the absence of doxorubicin is characterized by a 2- to 3-fold stiffness increase, decreased tension (0–20%), and ventricular dilation (of order 10–30%). HF due to doxorubicin was similar but showed stronger bias toward reduced active contraction (10–30%) and less dilation (0–20%). We find that changes in active, passive, and anatomical properties all play a role in doxorubicin-induced cardiotoxicity phenotypes. Differences in parameter changes between patient groups are consistent with doxorubicin cardiotoxicity having a greater dependence on reduced cellular contraction and less anatomical remodeling than HF not caused by doxorubicin.

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