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.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Lewalle A,Land S,Merken JJ,Raafs A,Sepúlveda P,Heymans S,Kleinjans J,Niederer SAdoi
10.1016/j.bpj.2019.07.033subject
Has Abstractpub_date
2019-12-17 00:00:00pages
2337-2348issue
12eissn
0006-3495issn
1542-0086pii
S0006-3495(19)30622-8journal_volume
117pub_type
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