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Biophys J. 2019 Jul 29. pii: S0006-3495(19)30622-8. doi: 10.1016/j.bpj.2019.07.033. [Epub ahead of print]

Balance of Active, Passive, and Anatomical Cardiac Properties in Doxorubicin-Induced Heart Failure.

Author information

1
Department of Biomedical Engineering, St Thomas's Hospital, King's College London, London, United Kingdom.
2
Department of Cardiology, Maastricht University, Maastricht, the Netherlands.
3
Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
4
Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.
5
Department of Biomedical Engineering, St Thomas's Hospital, King's College London, London, United Kingdom. Electronic address: steven.niederer@kcl.ac.uk.

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.

PMID:
31447110
DOI:
10.1016/j.bpj.2019.07.033
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