Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice

Abstract

Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success.

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…2). 13, 33, 34 However, other possibilities also include lack of proliferation or increased apoptosis, which seem unlikely based on current observations,9, 10 and abnormal expression of homing chemokines 16…”

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

“…Burgheron mutants succumbing in the survival study died abruptly and not of progressive neuromuscular decline. Multiple groups have reported some degree of cardiac dysfunction encompassing bradycardia, dilated cardiomyopathy with decreased contractility, and sympathetic innervation deficiency across multiple SMA mouse models (27)(28)(29)(30). To assess cardiac function in Burgheron mice, we studied mutant and control mice by echocardiography and electrocardiography at PND 25, 35, 60, 90, and 120.…”

Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

“…Cardiomyopathic changes can be rooted or result in rhythm disturbances, which (eg, bradycardia) have been extensively described and seem to be a consistent feature in SMA mice. 42,43,64 In humans, cardiac involvement has been described in the form of congenital malformations (predominantly SMA type I) and case reports of cardiomyopathy (predominantly SMA type III). 41,44,[65][66][67] The question remains whether our observations are due to autonomous nerve involvement or muscle development or affection.…”

“…The remaining 50% are healthy SMA carriers (Smn þ / À ; SMN2 tg/0 ) and used as controls. 30 Recent reports suggest that abnormal heart development in mice and human [41][42][43][44] as well as defects in skeletal muscle 45 and skeletal muscle vasculature 46 of mice are part of the phenotype and that SMA may be not a pure motoneuron disease. In addition, decreased levels of hepatic insulin-like growth factor binding protein acid labile subunit 18 possibly account for some of the dwarfism observed consistently across different SMA mouse models.…”