Follistatin like 1 Regulates Hypertrophy in Heart Failure with Preserved Ejection Fraction

JACC Basic Transl Sci. 2016 Jun;1(4):207-221. doi: 10.1016/j.jacbts.2016.04.002. Epub 2016 Jun 27.


Objective: We sought to determine whether Fstl1 plays a role in the regulation of cardiac hypertrophy in HFpEF.

Background: Heart failure (HF) with preserved ejection fraction (HFpEF), accounts for ~50% of all clinical presentations of HF and its prevalence is expected to increase. However, there are no evidence-based therapies for HFpEF; thus, HFpEF represents a major unmet need. Although hypertension is the single most important risk factor for HFpEF, with a prevalence of 60-89% from clinical trials and human HF registries, blood pressure therapy alone is insufficient to prevent and treat HFpEF. Follistatin like 1 (Fstl1), a divergent member of the follistatin family of extracellular glycoproteins, has previously been shown to be elevated in HF with reduced ejection fraction (HFrEF) and associated with increased left ventricular mass.

Methods and results: In this study, blood levels of Fstl1 were increased in humans with HFpEF. This increase was also evident in mice with hypertension-induced HFpEF and adult rat ventricular myocytes stimulated with aldosterone. Treatment with recombinant Fstl1 abrogated aldosterone-induced cardiac myocyte hypertrophy, suggesting a role for Fstl1 in the regulation of hypertrophy in HFpEF. There was also a reduction in the E/A ratio, a measure of diastolic dysfunction. Furthermore, HFpEF induced in a mouse model that specifically ablates Fstl1 in cardiac myocytes (cFstl1-KO), showed exacerbation of HFpEF with worsened diastolic dysfunction. In addition, cFstl1-KO-HFpEF mice demonstrated more marked cardiac myocyte hypertrophy with increased molecular markers of anp and bnp expression.

Conclusions: These findings indicate that Fstl1exerts therapeutic effects by modulating cardiac hypertrophy in HFpEF.

Keywords: cardiac hypertrophy; follistatin like 1; heart failure with preserved ejection fraction.