In children with IOPD, long-term cardiac function stable after ERT
Findings undermine previous observations that skeletal muscle function declines over time
Cardiac function normalized within a year of starting enzyme replacement therapy (ERT) for children with classic infantile-onset Pompe disease (IOPD) and remained stable over about 10 years, a study found.
The findings were confirmed with standard and more advanced techniques to look at cardiac function.
In light of the fact that there was no “clinically relevant decline in cardiac function,” the authors said cardiac follow-ups could be less frequent, but not stopped altogether, once a patient has stabilized on ERT.
The study, published in the International Journal of Cardiology was titled, “Effects of enzyme replacement therapy on cardiac function in classic infantile Pompe disease.”
Classic IOPD is Pompe disease in its most severe form, with symptoms of generalized muscle weakness emerging in the first months of life. Patients also have hypertrophic cardiomyopathy, wherein the heart’s muscle becomes thickened, making it harder to pump blood. Left untreated, classic IOPD patients usually don’t survive past their first year due to cardiac or respiratory failure.
Lifelong ERT is a mainstay treatment with an established ability to prolong survival and improve motor and heart function for patients. In the long-term, however, patients can have residual skeletal muscle weakness and it’s still being investigated if the same is true of the cardiac muscle.
Researchers previously found ERT normalized classic IOPD patients’ left ventricular mass index (LVMI), a surrogate marker of cardiac hypertrophy, which was sustained for up to 13 years.
In that study, heart function was measured with echocardiography (ECG), a standard test that uses sound waves to image the heart.
Improved cardiac function over time
Here, the researchers wanted to get a more detailed picture of heart function over time using a type of ECG analysis called myocardial deformation, which looks directly at the heart muscle.
The study involved 27 patients (59% female), comprising all classic IOPD patients treated with ERT in the Netherlands since 1998. Fourteen of them overlapped with the previous study.
ERT was initiated three days to 8.3 months after birth and cardiac function was monitored repeatedly by conventional ECG over a median follow-up of 9.9 years and up to 22 years.
Myocardial deformation analysis was conducted in retrospect on ECG images collected from 2004 or later. Earlier images weren’t of high enough quality to be analyzed. Parameters were compared with data from 103 healthy children (median age, 10.8).
Six children died during the follow-up, the most common cause being respiratory failure.
Conventional ECG measures indicated mean LVMI was significantly reduced after a year on ERT, reflecting a reduction in hypertrophy. At that time, 21 of 23 children had normal LVMI.
That remained stable over the follow-up. As of the last measurement, the mean LVMI for patients and healthy children was in the normal range.
Shortening fraction, a measure of the left ventricle’s systolic function — its ability to contract during a heartbeat — was normal before ERT and throughout the study.
All measures of myocardial deformation indicated diminished heart function before starting ERT, which were mostly normalized within the first year of treatment and remained relatively stable over the follow-up.
Despite limitations related to the small sample size — a common problem in rare disease research — the findings across both analyses indicate ERT leads to improved cardiac function that remains stable over time.
That could mean “cardiac follow-up frequency using echocardiogram can most likely be reduced once cardiac function has normalized,” the researchers wrote, noting, however, that intermittent assessments in adulthood using the more sensitive myocardial deformation analysis should be used to detect any subtle changes in cardiac function.
These cardiac findings are in sharp contrast to previous observations that skeletal muscle function declines over time after starting ERT, according to the scientists, who said why cardiac cells might be more responsive to treatment still remains to be answered and called for further in-depth mechanistic studies.