Early heart failure in the SMNΔ7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery

TLDR

SMA is a neurological disorder characterized by lower motor neuron death and skeletal muscle atrophy, but cardiovascular abnormalities have also been reported, indicating that the disease may affect non‑neuromuscular systems. The study aims to determine whether cardiovascular dysfunction in SMA requires therapeutic targeting and to evaluate the clinical relevance of these findings in human patients. Left ventricular function was assessed in SMNΔ7 mice and their littermates at 7 and 14 days of age using electrocardiography and echocardiography. SMA pups exhibit early bradycardia and progressive dilated cardiomyopathy, which are largely rescued by postnatal delivery of an SMN‑1 transgene via scAAV9, suggesting autonomic dysfunction contributes to cardiac compromise.

Abstract

Proximal spinal muscular atrophy (SMA) is a debilitating neurological disease marked by isolated lower motor neuron death and subsequent atrophy of skeletal muscle. Historically, SMA pathology was thought to be limited to lower motor neurons and the skeletal muscles they control, yet there are several reports describing the coincidence of cardiovascular abnormalities in SMA patients. As new therapies for SMA emerge, it is necessary to determine whether these non-neuromuscular systems need to be targeted. Therefore, we have characterized left ventricular (LV) function of SMA mice (SMN2+/+; SMNΔ7+/+; Smn−/−) and compared it with that of their unaffected littermates at 7 and 14 days of age. Anatomical and physiological measurements made by electrocardiogram and echocardiography show that affected mouse pups have a dramatic decrease in cardiac function. At 14 days of age, SMA mice have bradycardia and develop a marked dilated cardiomyopathy with a concomitant decrease in contractility. Signs of decreased cardiac function are also apparent as early as 7 days of age in SMA animals. Delivery of a survival motor neuron-1 transgene using a self-complementary adeno-associated virus serotype 9 abolished the symptom of bradycardia and significantly decreased the severity of the heart defect. We conclude that severe SMA animals have compromised cardiac function resulting at least partially from early bradycardia, which is likely attributable to aberrant autonomic signaling. Further cardiographic studies of human SMA patients are needed to clarify the clinical relevance of these findings from this SMA mouse.