Cardiovascular Measures of All-Cause Mortality in Duchenne Muscular Dystrophy

Abstract

Background: Cardiopulmonary failure is the leading cause of death in Duchenne muscular dystrophy (DMD). Research into DMD-specific cardiovascular therapies is ongoing, but there are no Food and Drug Administration-approved cardiac end points. To adequately power a therapeutic trial, appropriate end points must be chosen and the rate of change for these end points reported. The objective of this study was to evaluate rate of change for cardiac magnetic resonance and blood biomarkers and to determine which measures associate with all-cause mortality in DMD. Methods: Seventy-eight DMD subjects underwent 211 cardiac magnetic resonance studies analyzed for left ventricular (LV) ejection fraction, indexed LV end diastolic and systolic volumes, circumferential strain, late gadolinium enhancement presence and severity (global severity score, and full width half maximum), native T1 mapping, T2 mapping, and extracellular volume. Blood samples were analyzed for BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), and troponin I. Cox proportional hazard regression modeling was performed with all-cause mortality as the outcome. Results: Fifteen subjects (19%) died. LV ejection fraction, indexed end systolic volumes, global severity score, and full width half maximum worsened at 1 and 2 years while circumferential strain and indexed LV end diastolic volumes worsened at 2 years. LV ejection fraction, indexed LV end diastolic and systolic volumes, late gadolinium enhancement full width half maximum, and circumferential strain associated with all-cause mortality ( P <0.05). NT-proBNP was the only blood biomarker that associated with all-cause mortality ( P <0.05). Conclusions: LV ejection fraction, indexed LV volumes, circumferential strain, late gadolinium enhancement full width half maximum, and NT-proBNP are associated with all-cause mortality in DMD and may be the best end points for use in cardiovascular therapeutic trials. We also report change over time of cardiac magnetic resonance and blood biomarkers.

Rate of Change in Cardiac Magnetic Resonance Imaging Measures Is Associated With Death in Duchenne Muscular Dystrophy

“…LV Ecc has been associated with LV dysfunction 28 , 29 , 30 and death. 14 Our findings further validate the previous use of Ecc as an outcome in some DMD trials. 31 , 32 , 33 Interestingly, a similar relationship was not observed with global Ecc.…”

“…Rate of change in LVEDVi and LVESVi was similarly higher in deceased subjects compared with living subjects. Two studies have previously demonstrated an association between LVESVi and death, 11 , 14 and only 1 study has demonstrated an association with LVEDVi. 14 Both volume metrics increase faster in deceased subjects early in the disease course (second decade) before becoming similar later in the course.…”

“…Two studies have previously demonstrated an association between LVESVi and death, 11 , 14 and only 1 study has demonstrated an association with LVEDVi. 14 Both volume metrics increase faster in deceased subjects early in the disease course (second decade) before becoming similar later in the course. This may suggest that these volumetric measurements are an important early measure of cardiac involvement and future death.…”

“… 13 Recent work within our patient cohort has also shown that additional CMR measures, including indexed left ventricular end‐diastolic (LVEDVi) and end‐systolic (LVESVi) volumes as well as circumferential strain (Ecc) associate with death. 14 …”

Imaging and Serum Biomarkers for Cardiomyopathy in Duchenne Muscular Dystrophy

“…A new article by Soslow et al 6 now describes cardiac magnetic resonance and serum biomarker measurements in DMD participants who were enrolled from 2 prospective observational cohorts who were mostly treated with steroids and some cardiac medications. The DMD cohort had a median age of 12.9 years (range, 7.4–27.5 years) at first imaging.…”