# 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.

## Key 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.