HFSA ePoster Library

Rationale: Cardiovascular disease (CVD) is fast emerging as a significant source of morbidity and mortality in patients with Duchenne Muscular Dystrophy (DMD). Left ventricular dysfunction is a strong indicator of worsening prognosis in DMD patients. As such, left ventricular ejection fraction (LVEF) has been used to monitor cardiac health and guide therapy in this population. Evidence suggests that β₁-adrenoceptors (ADRB1) play a role in regulating cardiac function, whereby more functional ADRB1 genotype variants (e.g., Arg389) are associated with systemic hypertension, potentially contributing to poorer cardiac function and increased mortality risk in DMD patients with CVD. Additionally, patients expressing the Arg389 variant are more likely to be responders to ß-blocker therapy. Thus, the purpose of this study was to determine whether the longitudinal progression of decline in LVEF in DMD patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status.
Methods: Data from the CINRG Duchenne Natural History Study including 147 DMD patients (6-34 yrs) were analyzed with a focus on ADRB1 genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients (homozygous for Gly at amino acid 389; n = 80), and Arg389 patients (homozygous or heterozygous for Arg at amino acid 16; n = 67). A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use after controlling for demographics, corticosteroid-use, ambulatory status, and clinic site.
Results: Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 yrs). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype.
Conclusion: There was no influence of ADRB1 genotype on longitudinal LVEF in our cohort. There was, however, a negative influence of ß-blocker use on LVEF. These data suggest that DMD patients do not demonstrate a genotypic “responder” effect to ß-blockers, and that ß-blocker therapy may be detrimental to cardiovascular health in patients with DMD.