Abstract
BackgroundMyostatin is a negative regulator of skeletal muscle mass whose activity is upregulated in adult heart failure (HF); however, its role in congenital heart disease (CHD) is unknown.MethodsWe studied myostatin and IGF-1 expression via Western blot in cardiac tissue at varying degrees of myocardial dysfunction and after biventricular support in CHD by collecting myocardial biopsies from four patient cohorts: A) adult subjects with no known cardiopulmonary disease (left ventricle, LV), (Adult Normal), (n = 5); B) pediatric subjects undergoing congenital cardiac surgery with normal RV size and function (right ventricular outflow tract, RVOT), (n = 3); C) pediatric subjects with worsening but hemodynamically stable LV failure [LV and right ventricle (LV, RV,)] with biopsy collected at the time of orthotopic heart transplant (OHT), (n = 7); and D) pediatric subjects with decompensated bi-ventricular failure on BiVAD support with biopsy collected at OHT (LV, RV, BiVAD), (n = 3).ResultsThe duration of HF was longest in OHT patients compared to BIVAD. The duration of BiVAD support was 4.3±1.9 days. Myostatin expression was significantly increased in LV-OHT compared to RV-OHT and RVOT, and was increased more than double in decompensated biventricular HF (BiVAD) compared to both OHT and RVOT. An increased myostatin/IGF-1 ratio was associated with ventricular dysfunction.ConclusionsMyostatin expression in increased in CHD, and the myostatin/IGF-1 ratio increases as ventricular function deteriorates. Future investigation is necessary to determine if restoration of the physiologic myostatin/IGF-1 ratio has therapeutic potential in HF.
Highlights
Myostatin, a member of the TGF-b family of proteins, has been well-established as a negative regulator of skeletal muscle mass [1]
Normal adult subjects had an average age of 39.866.2 years, while right ventricular outflow tract (RVOT) patients were much younger than both orthotopic heart transplantation (OHT) and biventricular HF after mechanical unloading (BiVAD) patients (8.263.0, 105.9638.4, 89.4627.7 months, respectively)
One RVOT patient was maintained on a single diuretic, in distinct contrast to a much sicker OHT and BiVAD population which required multiple diuretics, inotropes, and maximal vasopressors (BiVAD)
Summary
A member of the TGF-b family of proteins, has been well-established as a negative regulator of skeletal muscle mass [1]. Myostatin has been demonstrated to be upregulated in myocardial tissue in both small and large animal models of heart failure (HF) [2,3,4], where it has been proposed to play a role in the regulation of cardiac remodeling. Other investigators have reported that myostatin is increased in the serum [7], heart [8], and skeletal muscle [9] of adult HF patients. Myostatin is a negative regulator of skeletal muscle mass whose activity is upregulated in adult heart failure (HF); its role in congenital heart disease (CHD) is unknown
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