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G.P.9.05 The role of ACE inhibitor therapy in presymptomatic cardiomyopathy in Duchenne muscular dystrophy
816
Abstracts / Neuromuscular Disorders 17 (2007) 764–900
of cardiac function and proper treatment following early diagnosis of heart problems is necessary in patients with DMD, because they possibly have severely affected cardiac problems without representing any clinical symptoms. BNP level monitoring may assist of early diagnosis of cardiomyopathy in patients with DMD. doi:10.1016/j.nmd.2007.06.184
G.P.9.05 The role of ACE inhibitor therapy in presymptomatic cardiomyopathy in Duchenne muscular dystrophy Kinali, M. 1,*; Robinson, R. 1; Sagi, L. 1; Nihoyannopoulos, P. 2; Manzur, A. 1; Muntoni, F. 1 1 Hammersmith Hospital, Dubowitz Neuromuscular Centre, London, United Kingdom; 2 Hammersmith Hospital, Department of Cardiology, London, United Kingdom Progressive cardiomyopathy is a common feature of Duchenne muscular dystrophy (DMD). Although echocardiographic evidence of left ventricular dysfunction may be present before the age of 10 years, cardiac symptoms only develop in the advanced stages of cardiomyopathy. There is some evidence that ACE inhibitor therapy can slow the deterioration of cardiac function, but this remains the subject of much debate. The aim of this study was to evaluate the effect of ACE inhibitor therapy in DMD boys with presymptomatic cardiomyopathy. Sixty-six boys with DMD and echocardiographic evidence of left ventricular dysfunction (fractional shortening (FS) <29% or regional wall motion abnormalities) were identified at the Dubowitz Neuromuscular Centre, Hammersmith Hospital. All patients had serial monitoring with echocardiography. The treated group comprised 54 patients who had been commenced on ACE inhibitor therapy following an abnormal echocardiogram. Thirteen of these patients were also treated with a beta blocker. The remaining 12 patients were untreated during their period of observation and served as the control group. The rate of change in FS (measured as change in percentage per year) for each patient was determined by linear regression. The mean rate of change of FS in the treated group was compared with that in the control group by the independent samples t-test (SPSS software). Treatment was well tolerated in all patients. The mean age at the first abnormal echocardiogram was 14.06 years in the treated group and 16.1 years in the control group. The mean rate of change of FS was 0.35 per year in the treated group and 6.77 per year in the control group. The difference in means assessed by the independent samples t-test (equal variances not assumed) was significant (p = 0.022). This study provides supportive evidence that ACE inhibitor therapy is well tolerated and can slow the progression of cardiomyopathy in presymptomatic DMD patients. The independent contribution of beta blockers or steroid therapy has not been assessed in this study and will require further investigation. doi:10.1016/j.nmd.2007.06.185
G.P.9.06 Impaired response to low-dose dobutamine stress in Duchenne muscular dystrophy Markham, L. 1; Khoury, P. 1; Witt, S. 1; Wong, B. 2; Benson, D. 3; Cripe, L. 1,* 1 Cincinnati Children’s Hospital Medical Center, Pediatric Cardiology, Cincinnati, United States; 2 Cincinnati Children’s Hospital Medical Center, Neurology, Cincinnati, United States; 3 Cincinnati Children’s Hospital Medical Center, Pediatric Cardiology/Cardiovascular Genetics, Cincinnati, United States Duchenne muscular dystrophy (DMD) cardiac phenotype develops without symptom. Neither genotype nor cardiac imaging at rest has pre-
dicted early onset of cardiac phenotype. Determine cardiac response to stress in DMD subjects with normal resting cardiac function. We hypothesized that shortening fraction (SF) response to low-dose Dobutamine stress echocardiography (DSE) would illicit early cardiac dysfunction in DMD. Low-dose DSE protocol was performed at rest and during infusion of Dobutamine at 10 and 20 mcg/kg/min. After consent, 9 DMD boys with normal resting function by echocardiography and no cardiac symptoms underwent DSE. Comparison was made to 6 age-matched boys undergoing DSE for clinical indications remote from Kawasaki disease (no coronary artery abnormalities and normal resting function). Variables analyzed by t-tests and repeated measures. DMD and control did not differ in age (10.4 ± 1.4 vs. 8.1 ± 3.8 years; p = 0.32) or resting shortening fraction (33 ± 6 vs. 36 ± 5%; p = 0.29). Both groups showed an incremental increase in shortening fraction with each dose which was significantly different by t-tests (10 mcg/kg/min: 40 ± 8 vs. 49 ± 5%; p = 0.03 and 20 mcg/kg/min: 42 ± 8 vs. 53 ± 4%; p = 0.01). No subject had wall motion abnormalities. The studies were well tolerated without significant side effect. Due to the small sample size, repeated measures analysis did not confirm a significant difference in response to Dobutamine. Despite normal resting systolic function, the DMD myocardium does not respond normally to stress as evidence by less of an incremental increase in shortening fraction during low-dose DSE. This blunted DSE response may be an early marker for the cardiomyopathy of DMD. To conclude a normal cardiac phenotype associated with genetic neuromuscular diseases additional modes of investigation should be considered. Shortening fraction (% increase from rest)
DMD (N = 9) Control (N = 6)
Baseline (%)
10 mcg/kg/min
20 mcg/kg/min
33 36
40% (+121%) 49% (+136%)
42% (+127%) 53% (+147%)
doi:10.1016/j.nmd.2007.06.186
G.P.9.07 MRI in Duchenne muscular dystrophy: Quantification of fat infiltration and gadolinium uptake using whole-muscle regions of interest Garrood, P. 1,*; Hollingsworth, K. 2; Thelwall, P. 2; Birchall, D. 3; Eagle, M. 1; Bushby, K. 1; Straub, V. 1 1 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom; 2 Newcastle Magnetic Resonance Centre, University of Newcastle, Newcastle upon Tyne, United Kingdom; 3 Regional Neurosciences Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom To date, there are no MRI studies of the degree and pattern of fat infiltration in steroid-treated boys, or the role of gadolinium in delineating changes in muscle water content. Our aim was to evaluate the use of signal intensity for whole-muscle regions of interest for the quantitative investigation of fat infiltration on T1-weighed scans and of muscle water content before and after exercise on contrast-enhanced scans. Nine steroid-treated ambulant boys with DMD (6.6–9.9 years) and five adult male volunteers (29.6–35 years) were scanned using a 3T Philips Achieva scanner. Boys were scanned before and 4 days after stepping exercise and adults 4 days after stepping exercise. Axial T1-weighted images and fat-saturated preand post-gadolinium contrast (OmniscanÒ) images of the calves, thighs and pelvis were obtained. Regions of interest were drawn defining muscles at mid-calf, thigh and pelvis. On T1-weighted images, mean signal intensities for all muscles studied were greater for the children than for the adults. This reached significance for 5/8 muscles. Post-exercise scans using signal intensity change as an index of contrast uptake showed significant differences between adults and children for 5/7 muscles. Although mean post-exercise signal changes after contrast were greater than those preexercise for all muscle groups in DMD boys, some boys’ showed a
Abstracts / Neuromuscular Disorders 17 (2007) 764–900
of cardiac function and proper treatment following early diagnosis of heart problems is necessary in patients with DMD, because they possibly have severely affected cardiac problems without representing any clinical symptoms. BNP level monitoring may assist of early diagnosis of cardiomyopathy in patients with DMD. doi:10.1016/j.nmd.2007.06.184
G.P.9.05 The role of ACE inhibitor therapy in presymptomatic cardiomyopathy in Duchenne muscular dystrophy Kinali, M. 1,*; Robinson, R. 1; Sagi, L. 1; Nihoyannopoulos, P. 2; Manzur, A. 1; Muntoni, F. 1 1 Hammersmith Hospital, Dubowitz Neuromuscular Centre, London, United Kingdom; 2 Hammersmith Hospital, Department of Cardiology, London, United Kingdom Progressive cardiomyopathy is a common feature of Duchenne muscular dystrophy (DMD). Although echocardiographic evidence of left ventricular dysfunction may be present before the age of 10 years, cardiac symptoms only develop in the advanced stages of cardiomyopathy. There is some evidence that ACE inhibitor therapy can slow the deterioration of cardiac function, but this remains the subject of much debate. The aim of this study was to evaluate the effect of ACE inhibitor therapy in DMD boys with presymptomatic cardiomyopathy. Sixty-six boys with DMD and echocardiographic evidence of left ventricular dysfunction (fractional shortening (FS) <29% or regional wall motion abnormalities) were identified at the Dubowitz Neuromuscular Centre, Hammersmith Hospital. All patients had serial monitoring with echocardiography. The treated group comprised 54 patients who had been commenced on ACE inhibitor therapy following an abnormal echocardiogram. Thirteen of these patients were also treated with a beta blocker. The remaining 12 patients were untreated during their period of observation and served as the control group. The rate of change in FS (measured as change in percentage per year) for each patient was determined by linear regression. The mean rate of change of FS in the treated group was compared with that in the control group by the independent samples t-test (SPSS software). Treatment was well tolerated in all patients. The mean age at the first abnormal echocardiogram was 14.06 years in the treated group and 16.1 years in the control group. The mean rate of change of FS was 0.35 per year in the treated group and 6.77 per year in the control group. The difference in means assessed by the independent samples t-test (equal variances not assumed) was significant (p = 0.022). This study provides supportive evidence that ACE inhibitor therapy is well tolerated and can slow the progression of cardiomyopathy in presymptomatic DMD patients. The independent contribution of beta blockers or steroid therapy has not been assessed in this study and will require further investigation. doi:10.1016/j.nmd.2007.06.185
G.P.9.06 Impaired response to low-dose dobutamine stress in Duchenne muscular dystrophy Markham, L. 1; Khoury, P. 1; Witt, S. 1; Wong, B. 2; Benson, D. 3; Cripe, L. 1,* 1 Cincinnati Children’s Hospital Medical Center, Pediatric Cardiology, Cincinnati, United States; 2 Cincinnati Children’s Hospital Medical Center, Neurology, Cincinnati, United States; 3 Cincinnati Children’s Hospital Medical Center, Pediatric Cardiology/Cardiovascular Genetics, Cincinnati, United States Duchenne muscular dystrophy (DMD) cardiac phenotype develops without symptom. Neither genotype nor cardiac imaging at rest has pre-
dicted early onset of cardiac phenotype. Determine cardiac response to stress in DMD subjects with normal resting cardiac function. We hypothesized that shortening fraction (SF) response to low-dose Dobutamine stress echocardiography (DSE) would illicit early cardiac dysfunction in DMD. Low-dose DSE protocol was performed at rest and during infusion of Dobutamine at 10 and 20 mcg/kg/min. After consent, 9 DMD boys with normal resting function by echocardiography and no cardiac symptoms underwent DSE. Comparison was made to 6 age-matched boys undergoing DSE for clinical indications remote from Kawasaki disease (no coronary artery abnormalities and normal resting function). Variables analyzed by t-tests and repeated measures. DMD and control did not differ in age (10.4 ± 1.4 vs. 8.1 ± 3.8 years; p = 0.32) or resting shortening fraction (33 ± 6 vs. 36 ± 5%; p = 0.29). Both groups showed an incremental increase in shortening fraction with each dose which was significantly different by t-tests (10 mcg/kg/min: 40 ± 8 vs. 49 ± 5%; p = 0.03 and 20 mcg/kg/min: 42 ± 8 vs. 53 ± 4%; p = 0.01). No subject had wall motion abnormalities. The studies were well tolerated without significant side effect. Due to the small sample size, repeated measures analysis did not confirm a significant difference in response to Dobutamine. Despite normal resting systolic function, the DMD myocardium does not respond normally to stress as evidence by less of an incremental increase in shortening fraction during low-dose DSE. This blunted DSE response may be an early marker for the cardiomyopathy of DMD. To conclude a normal cardiac phenotype associated with genetic neuromuscular diseases additional modes of investigation should be considered. Shortening fraction (% increase from rest)
DMD (N = 9) Control (N = 6)
Baseline (%)
10 mcg/kg/min
20 mcg/kg/min
33 36
40% (+121%) 49% (+136%)
42% (+127%) 53% (+147%)
doi:10.1016/j.nmd.2007.06.186
G.P.9.07 MRI in Duchenne muscular dystrophy: Quantification of fat infiltration and gadolinium uptake using whole-muscle regions of interest Garrood, P. 1,*; Hollingsworth, K. 2; Thelwall, P. 2; Birchall, D. 3; Eagle, M. 1; Bushby, K. 1; Straub, V. 1 1 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom; 2 Newcastle Magnetic Resonance Centre, University of Newcastle, Newcastle upon Tyne, United Kingdom; 3 Regional Neurosciences Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom To date, there are no MRI studies of the degree and pattern of fat infiltration in steroid-treated boys, or the role of gadolinium in delineating changes in muscle water content. Our aim was to evaluate the use of signal intensity for whole-muscle regions of interest for the quantitative investigation of fat infiltration on T1-weighed scans and of muscle water content before and after exercise on contrast-enhanced scans. Nine steroid-treated ambulant boys with DMD (6.6–9.9 years) and five adult male volunteers (29.6–35 years) were scanned using a 3T Philips Achieva scanner. Boys were scanned before and 4 days after stepping exercise and adults 4 days after stepping exercise. Axial T1-weighted images and fat-saturated preand post-gadolinium contrast (OmniscanÒ) images of the calves, thighs and pelvis were obtained. Regions of interest were drawn defining muscles at mid-calf, thigh and pelvis. On T1-weighted images, mean signal intensities for all muscles studied were greater for the children than for the adults. This reached significance for 5/8 muscles. Post-exercise scans using signal intensity change as an index of contrast uptake showed significant differences between adults and children for 5/7 muscles. Although mean post-exercise signal changes after contrast were greater than those preexercise for all muscle groups in DMD boys, some boys’ showed a