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The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy
Luca Bello1, Daniele Sabbatini1, Aurora Fusto1
1Department of Neurosciences DNS, University of Padova, Padova, Italy.
Insights
Dilated cardiomyopathy in Duchenne muscular dystrophy (DMD) progresses with age. Specific dystrophin mutations and LTBP4 gene variants significantly impact cardiac function and disease progression in DMD patients.
Area of Science:
- Cardiology
- Genetics
- Neuromuscular Disorders
Background:
- Dilated cardiomyopathy (DCM) is a primary cause of mortality in Duchenne muscular dystrophy (DMD).
- The variability in DCM severity and progression in DMD is not well understood.
- Glucocorticoid treatments, mutation type, and genetic variants are potential modifying factors.
Purpose of the Study:
- To quantitatively describe the progression of systolic dysfunction in DMD.
- To investigate the impact of dystrophin mutations on cardiac function in DMD.
- To identify genetic factors influencing DCM in DMD patients.
Main Methods:
- Retrospective analysis of 3138 echocardiographic measurements from 819 DMD participants.
- Generalized estimating equation (GEE) models to assess changes in left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV).
- Multivariate GEE models to evaluate the effects of dystrophin mutations and LTBP4 gene variants.
Main Results:
- EF decreased by 0.80% and SF by 0.41% yearly; EDV showed no significant age-related increase.
- Mutations preserving C-terminal Dp71 expression correlated with decreased EDV (-11.01 mL/m2).
- Mutations affecting dp116 correlated with decreased EF (-4.14%).
- The rs10880 genotype in LTBP4 was associated with increased EF (+3.29%) and decreased EDV (-10.62 mL/m2) in a recessive model.
Conclusions:
- Systolic dysfunction progresses quantitatively in DMD patients.
- Distal dystrophin isoform expression influences the dystrophin-deficient heart.
- LTBP4 genotype significantly impacts DCM in DMD.
Background:
Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes.
Methods And Results:
We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model.
Conclusions:
We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.
