Author + information
- Komei Tanaka, MD, PhDa,
- María Valero-Muñoz, PhDa,
- Richard M. Wilson, BSa,
- Eric E. Essick, PhDa,
- Conor T. Fowler, BSa,
- Kazuto Nakamura, MD, PhDa,
- Maurice van den Hoff, PhDb,
- Noriyuki Ouchi, MD, PhDc and
- Flora Sam, MDa,d,∗ ()
- aWhitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts
- bAcademic Medical Center, Heart Failure Research Center, Department of Anatomy, Embryology & Physiology, Amsterdam, the Netherlands
- cDepartment of Molecular Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- dCardiovascular Section and Evans Department of Medicine, Heart Failure Program, Boston University School of Medicine, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Flora Sam, Whitaker Cardiovascular Institute, Cardiovascular Section, Boston University School of Medicine, 700 Albany Street, W507, Boston, Massachusetts 02118.
• Fstl1, also known as transforming growth factor-β–stimulated clone 36, is an extra-cellular glycoprotein implicated in the pathophysiology of cardiac disease.
• Fstl1 acts in a noncanonical manner relative to other follistatin family members, but its functions remain poorly understood.
• Circulating Flst1 levels are increased in humans with chronic stable HFpEF.
• Fstl1 treatment modulates cardiomyocyte hypertrophy in vitro and in vivo.
• Cardiac myocyte deletion of Fstl1 worsens the HFpEF phenotype in mice.
• These studies indicate that Fstl1 may be therapeutically effective in HFpEF by modulating cardiac hypertrophy and improving parameters of diastolic dysfunction.
Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of all clinical presentations of heart failure, (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% to 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 and associated with increased left ventricular mass. 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 (cardiac myocyte-specific Fstl1 knockout [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 atrial natriuretic peptide and brain natriuretic peptide expression. These findings indicate that Fstl1 exerts therapeutic effects by modulating cardiac hypertrophy in HFpEF.
This work was supported by a grant from the National Institutes of Health (HL117153) to Dr. Sam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Tanaka and Valero-Muñoz contributed equally to this work.
- Received November 11, 2015.
- Revision received March 12, 2016.
- Accepted April 6, 2016.
- The Authors