#apaperaday: Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the Dystrophin-Deficient D2.B10-Dmdmdx/J Mouse

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Preserved Left Ventricular Function despite Myocardial Fibrosis and Myopathy in the dystrophin-Deficient D2.B10-Dmdmdx/J Mouse

Today’s paper from Hayes et al in the journal of oxidative medicine and cellular longevity. The paper studies heart function and pathology in d2/mdx mice. Doi 10.1155/2022/5362115

Duchenne patients experience respiratory & heart failure due to loss of dystrophin. To delay onset of cardiac problems standards of care include prophylactic use of ACE inhibitors.

Cardiac pathology includes fibrosis deposition, hypertrophy & mitochondrial dysfunction, resulting in oxidative stress & reduction of energy & cell death. Debio-025 protects mitochondria by preventing a pore permanently opening, the first step towards swelling & mitochondria death.

Authors used the d2/mdx model to test effects of debio, perindropril (ACE inhibitor) & a combination in the development of heart fibrosis and functional deficits. Authors used only male mice, groups of 8 and included the DBA wild type controls!

Treatment started when mice were 12 weeks. Analysis was done at week 18.Authors observed reduced muscle strength for d2/mdx compared to DBA wild types. Collagen levels were higher in diaphragm as well (sign of fibrosis). Treatment of Debio-25, perindopril or both had no effect.

Echo was used to study heart function. No differences were seen for left ventricular functioning between DBA and d2/mdx (vehicle or any treatment). Fibrosis was increased in d2/mdx, but reduced in the groups treated with perindopril.

Histologically the right ventricle was more affected. Sadly no functional measures were done for the right ventricle due to a difficult position for echo analysis. Note that we found the right ventricle to be more affected also in the regular mdx mice.

In humans the left ventricle is worse but they have assisted ventilation, which helps reduce the strain on the right ventricle if I understood correctly. Mdx mice & d2/mdx have a very fibrotic and not optimally functioning diaphragm, which exacerbates right ventricle pathology.

Back to the paper: d2/mdx mice have more inflammation in the heart for both vehicle & treatment groups. Authors discuss that with histology they observed pathology in the heart, functionally the left ventricle was performing normally.

They note this could be due to experimental set up. Mice were under anesthesia, which reduces strain. They see no functional treatment effects. But since they see no difference between d2/mdx & DBA WT, this is not unexpected. No deficit –> cannot measure a possible improvement.

Authors suggest that if they had started treatment earlier they might have seen a treatment effect. I do not think this is likely, see previous tweets. It is possible deficits would become visible later. However, with age also DBA wild type start having calcium deposits in the heart.

Authors suggest having other control groups as a way to correct for this. However it is crucial to include the DBA wild types! You need to know which pathology is there anyway & which is due to the lack of dystrophin in order to properly use the model & compare treatment effects.

I like how the authors used controls and largish groups. However I do not always agree with their line of thinking.

Pictures by Annemieke, used with permission.