1 2 aim

#apaperaday: The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy

Duchenne UK New Horizons special from @journal_nd by @LucaBello2 et al on a large retrospective analysis to find factors that influence the onset and severity and trajectory of cardiomyopathy in Duchenne DOI: 10.3233/JND-230129

Duchenne is caused by lack of dystrophin, which causes problems in skeletal muscle, brain (shoutout to @EU_BIND which has a meeting now too) & heart. All patients develop cardiomyopathy, but the age of onset and severity varies and seems not related to severity of muscle symptoms.

Standards of care indicate treatment with ace inhibitors and beta blockers proactively and also monitoring of pathology. Authors here focused on the ejection fraction of the left ventricle (pushing blood into the body). This is normally 50-55%.

Furthermore, they focused on shortening fraction, another measure for left ventricle output (28% or higher is normal) and end diastolic volume, where a volume over 70 mL/square meter body surface area indicated dilated cardiomyopathy. Authors used ECG analysis.

Authors performed retrospective analysis of a huge cohort: 819 patients, 541 from 11 Italian centers and the rest from the CINRG database. The average age at baseline was 12.5 years, but age varied between 0 and 45 years. Data was available from over 3000 ECGs!

However, not for all values did authors have data for each ECG. For ejection fraction almost 2900 measures were available, for shortening fraction almost 1200 and for volume 346 (so a lot less). Patients were monitored between 1984 and 2012 (Italian) or 2006-2016 (CINRG)

About 50% of patients were on steroids, while 25% were not and for 25% is was not known (the disadvantage of retrospective analysis is that sometimes things are not fully clear). 65% were on ace inhibitors and 30% on beta blockers.

For 22% of patients no genetic diagnosis was confirmed. However, authors specified that patients who had a muscle biopsy showing <3% dystrophin could be included. Given that some of the Italian data predates the ability to do genetic diagnosis this is acceptable to me.

Authors show with age ejection fraction and shortening fraction decrease at rates of 0.8% & 0.4% per year. For end diastolic volume a trend was seen (note that this is the aspect for which less data were available). Age inhibitor use slowed down ejection fraction decline by 0.1%.

Looking at genetic mutations authors see a protective effect of having an exon 44 skippable mutation. This was known for muscle function & motor milestones & correlates with exon 44 skipping levels that reframe the transcripts and allow low level dystrophin production in muscle.

However, lacking access to heart biopsies, we did not know whether this would also translate to slower cardiac pathology development. This seems to be the case. Authors also see that patients with variants before the Dp116 promotor (i.e. before exon 56) have worse pathology.

Finally, authors looked at genetic modifiers and found that the LTBP4 variant that is protective for skeletal muscle, also is protective for heart. In muscle we know that this variant leads to less TGFbeta signaling, ergo less fibrosis. We can speculate the same happens in heart.

Authors discuss for this type of natural history studies collaborations are crucial to get to high numbers. The challenge is the different cohorts had different standards of care (different time of collection and different areas), which will influence cardiomyopathy development.

The decline in ejection fraction was expected, but now there is quantitative data, that will allow better anticipation and also design of clinical trials. Why patients with a deletion before Dp116 have a worse pathology than dose after is not really understood.

It has been speculated that Dp116 may be expressed in the heart to bind with dystrophin protein binding partners, which is detrimental as it can link only on one end, but not to actin (like the full length dystrophin).

Authors outline the limitations: because it was retrospective datapoints were missing. Also ECG is less sensitive than MRI. However, for MRI a lot less data is available for now.