Cardiopulmonary Phenotypic Disconnects Are Common in Patients With Duchenne Muscular Dystrophy

Abstract

SESSION TITLE: Pediatrics SESSION TYPE: Original Investigation Slide PRESENTED ON: Sunday, October 29, 2017 at 03:15 PM - 04:15 PM PURPOSE: In Duchenne muscular dystrophy (DMD), a patient′s dystrophin mutation may not be expressed as a consistent phenotype with regard to both pulmonary and cardiac function. Instead, we have observed highly discordant cardiac and pulmonary function in some individuals with DMD. In this study, we examine the prevalence and clinical characteristics of these cardiopulmonary phenotypic disconnects. METHODS: Retrospective cohort study of DMD patients (pts) in our clinic. Inclusion criteria: DMD diagnosed clinically and genetically; age ≥18 years; alive; and with discordant cardiopulmonary function (either bad pulmonary function and good cardiac function; or, bad cardiac function and good pulmonary function). Bad cardiac function was defined as an ejection fraction (EF) <40%. Bad pulmonary function was defined as a forced vital capacity (FVC) <1 liter. Results are expressed as mean +/- SD. “p” values determined by t-test. RESULTS: Among the 74 eligible pts, 25 pts (34%) met criteria for cardiopulmonary phenotypic disconnects. Group A had bad pulmonary function and good heart function (n = 21 pts; mean FVC 0.18 +/- 0.3 liters; mean EF 50.0 +/- 7.9%). Group B had bad heart function and good pulmonary function (n = 4 pts; mean FVC 2.6 +/- 0.7 liters; mean EF 21.3 +/- 7.5%). In Group A, 15 of the 21 pts are ventilated 24 hours/day, compared with none in Group B. In Group A, 8 of 21 pts have a tracheostomy, compared with none in Group B. Overall, Group A pts are significantly older (30.5 ± 7.5 yrs versus 21.3 ± 2.9 yrs; p = 0.025), with significantly better heart function (p < 0.001), and significantly worse lung function (p < 0.001) compared with Group B. CONCLUSIONS: DMD pts with cardiopulmonary phenotypic disconnects are common in our clinic population (34% of the pts ≥18 yrs). Most of the disconnects manifest as good heart function and bad pulmonary function (Group A, 21 of 25 pts) . When their respiratory failure is treated with assisted ventilation (71% are ventilated 24 hrs/day), these pts can experience prolonged survival (mean age 30.5 ± 7.5 yrs). Group B patients have bad heart function and good pulmonary function. Compared with Group A, the Group B pts are significantly younger (21.3 ± 2.9 yrs). The rarity of older Group B patients may be explained by an increased incidence of early death from progressive cardiomyopathy. CLINICAL IMPLICATIONS: Our findings suggest that, for a significant subset of DMD pts, cardiopulmonary natural history is not reliably predicted by the patient's dystrophin mutation, since the patients' cardiac and pulmonary function are highly discordant over time. This finding has important implications for predicting patient prognosis and for the design and evaluation of DMD therapies. If disconnects are common, then DMD therapies must be evaluated in the context of the cardiac and pulmonary natural history of individual patients, and not with aggregate data. Regarding etiology, some genetic modifiers may selectively affect cardiac muscle alone, with beneficial modifiers producing unexpectedly good heart function (Group A), and detrimental modifiers producing unexpectedly poor heart function (Group B). Therapies that amplify beneficial cardiac genetic modifiers or that block detrimental modifiers could prolong patient survival. DISCLOSURE: The following authors have nothing to disclose: Justin Jin, Syeda Maqsood, David Birnkrant No Product/Research Disclosure Information