Cardiac remodeling after enzyme replacement therapy with acid alpha-glucosidase for infants with Pompe disease

Abstract

Background: Infantile Pompe disease (glycogen storage disease type 2) is a fatal disorder caused by deficiency of acid alpha-glucosidase. This deficiency results in glycogen accumulation in the lysosomes of many tissues including cardiac muscle. The disease is characterized by profound hypotonia, poor growth, organomegaly, and cardiomegaly. Severe hypertrophic cardiomyopathy often is present in early infancy, and most patients die of cardiac or respiratory failure in the first year of life. This report describes the cardiac response of infants with Pompe disease to a phase 2 trial of enzyme replacement therapy (ERT).

Methods: Eight patients with classical infantile Pompe disease were given intravenous recombinant human GAA (rhGAA) for 1 year. Cardiac monitoring included echocardiography, electrocardiograms (ECGs), chest radiographs, and clinical cardiac evaluation at 4, 8, 12, 24, 36, and 52 weeks. At 52 weeks, 6 patients were alive.

Results: Most of the treated patients had rapid regression of ventricular hypertrophy in response to ERT, with near normalization of posterior wall thickness, ventricular mass, and ventricular size. Systolic ventricular function was preserved despite rapid changes in ventricular mass and size. Concomitantly, ECGs documented lengthening of the PR interval and decreased ventricular voltages, whereas chest radiographs documented a decreased cardiothoracic ratio. Symptoms of pulmonary congestion were diminished, and survival was improved.

Conclusion: The cardiovascular system responds quickly and strikingly to ERT with rhGAA, suggesting rapid reversal of excessive glycogen storage in cardiac muscle cells. Changes in ventricular mass and function are maintained throughout 1 year of follow-up evaluation and associated with decreased morbidity and prolonged survival.

Fig. 1

Indexed left ventricular (LV) mass versus time. The graph shows the change in mass during the 52 weeks of therapy (p < 0.001). Note the rapid change in the indexed mass between the baseline and week 8 measurements. All eight patients are represented, but not all patients have a calculated mass for all seven time points due to technical limitations. The dotted line delineates the upper limits of normal in the normative database used for this analysis for children with a body surface area ranging from 0.2 to 0.6 m². The patient whose data ends at 12 weeks (inverted triangles) died 14 weeks into treatment

Fig. 2

Ventricular wall diameter versus time. Composite of the septal and posterior wall diameters during the 52 weeks of therapy. (a) The change in septal wall z-score. (b) The corresponding change in posterior wall z-score. Some data points are missing due to technical limitations. All five U.S. patients are represented in this data set, but only one of the European patients. The patient whose data ends at 12 weeks (inverted triangles) died 14 weeks into treatment

Fig. 3

Epicardial cross-sectional area and end diastolic diameter versus time. (a) The change in epicardial cross-sectional area measured at end diastole. Only the five U.S. patients are represented in this figure. (b) The change in intracavitary diameter at end diastole, measured from the M-mode data. All eight patients are represented in this graph. The patient whose data ends at 12 weeks died 14 weeks into treatment

Fig. 4

Left ventricular (LV) mass-to-volume ratio versus time. The change in LV mass-to-volume ratio. Only the five U.S. patients are represented in this figure. The dotted lines outline the approximate normal range for this parameter in children whose body surface area ranges from 0.2 to 0.6 m². The patient whose data ends at the 36-week time point died before the final data collection time point (open circles)

Fig. 5

Echocardiographic appearance of the left ventricle. (a) Image of the left ventricle at end diastole before the start of treatment. (b) Image from the same patient after 4 weeks of therapy. (c) Image of the same patient after 52 weeks of therapy

Fig. 6

Systolic function versus time. (a) Ejection fraction. Only the five U.S. patients are represented. The patient whose data ends at 36 weeks (open circle in both graphs) died before the 52-week data collection. (Normal range of ejection fraction is approximately 60% to 75% depending on age at the time of data collection). (b) Shortening fraction. All eight patients are represented in this graph, although not all time points are available for each patient due to technical limitations. The patient whose data ends at the 12-week time point (inverted triangle) died 14 weeks into treatment. (Normal range of the shortening fraction is approximately 32% to 45% depending on age at the time of data collection.) There is no significant change in the indices of systolic function between the start of therapy and the 52-week time point (p = 0.84)