Inflammatory Reprogramming Mediates Changes in Three-Dimensional Strain Capacity and Cardiac Function in Beagle Dogs with Doxorubicin-Related Cardiomyopathy

TL;DR

This study uses beagle dogs to show that doxorubicin causes heart damage, especially in the right ventricle, linked to inflammation and changes in heart function.

Contribution

A new beagle dog model was developed to study doxorubicin-induced cardiotoxicity and its link to inflammatory reprogramming.

Findings

Right ventricular strain and function declined earlier and more severely than left ventricular in DOX-treated dogs.

Inflammatory gene levels increased significantly in DOX-treated dogs, correlating with cardiac dysfunction.

Right ventricular damage showed stronger correlations with inflammatory reprogramming than left ventricular damage.

Abstract

The cardiotoxicity of doxorubicin (DOX) limits its use in
cancer treatment. To address this limitation, we developed a novel animal model
that uses beagle dogs to investigate DOX-induced cardiac disorders.
Unfortunately, the lack of effective cardioprotection strategies against
DOX-induced cardiotoxicity poses a significant challenge. To
establish a canine model for low-mortality DOX-induced cardiac dysfunction and
explore the relationship between inflammatory reprogramming and DOX-related
cardiotoxicity.

Twenty male beagle dogs aged two years were
randomly assigned into the DOX (N = 10) and control (CON) (N = 10) groups. DOX
was infused (1.5 mg/kg) every two weeks until doses cumulatively reached 12
mg/kg. Serum biomarkers and myocardial pathology were evaluated, while real-time
fluorescence-based quantitative polymerase chain reaction (RTFQ-PCR), two- and
three-dimensional echocardiography (2DE and RT3DE), functional enrichment, and
matrix correlation were also performed.

In the DOX group,
high-sensitive cardiac troponin T (hs cTnT) and N-terminal pro-brain natriuretic
peptide (NT-proBNP) were significantly increased. Myocardial pathology indicated
early to medium myocardial degeneration via a decreased cardiomyocyte
cross-sectional area (CSA). Increased levels of inflammatory gene transcripts
(interleukin 6 (IL6), tumor necrosis factor (TNF), transforming growth factor
β (TGFβ), intercellular adhesion molecule 1 (ICAM1), interleukin
1 (IL1), interleukin 1β (IL1β), and interleukin 8 (IL8)), of
collagen metabolism and deposition regulatory genes (matrix metalloproteinase
(MMP) family and tissue inhibitor of matrix metalloproteinase (TIMP) family), and
the natriuretic peptide family (NPS) (natriuretic peptide A, B and C (NPPA, NPPB,
and NPPC)) were observed. Strain abnormalities in the right ventricular
longitudinal septal strain (RVLSS), right ventricular longitudinal free-wall
strain (RVLFS), left ventricular global longitudinal strain (LVGLS), and left
ventricular global circumferential strain (LVGCS) were detected at week 28 (vs.
week 0 or CON group, p
< 0.05, respectively). A significant decline in
RVLSS and RVLFS occurred at week 16, which was earlier than in the corresponding
left ventricular areas. A significant right ventricular ejection fraction (RVEF)
decline was noted at week 16 (vs. week 0, 33.92 ± 3.59% vs. 38.58 ±
3.58%, p
< 0.05), which was 12 weeks earlier than for the left
ventricular ejection fraction (LVEF), which occurred at week 28 (vs. week 0,
49.02 ± 2.07% vs. 54.26 ± 4.38%, p
< 0.01). The right
ventricular strain and functional damages correlated stronger with inflammatory
reprogramming (most R from 0.60 to 0.90) than the left ones (most R from
0.30 to 0.65), thereby indicating a more pronounced correlation.

Inflammatory reprogramming mediated disorders of strain
capacity and cardiac function predominantly in the right side of the heart in the
newly established DOX-related cardiomyopathy beagle dog model.

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