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Follistatin like 1 Regulates Hypertrophy in Heart Failure with Preserved Ejection Fraction
Komei Tanaka1, María Valero-Muñoz1, Richard M Wilson1
1Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Insights
Follistatin like 1 (Fstl1) may treat heart failure with preserved ejection fraction (HFpEF). Elevated Fstl1 levels in HFpEF patients suggest a therapeutic role in modulating cardiac hypertrophy and diastolic dysfunction.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Heart failure with preserved ejection fraction (HFpEF) is a prevalent condition with limited therapeutic options.
- Hypertension is a major risk factor for HFpEF, but blood pressure management alone is insufficient.
- Follistatin like 1 (Fstl1) is elevated in heart failure with reduced ejection fraction (HFrEF) and linked to increased cardiac mass.
Purpose of the Study:
- To investigate the role of Fstl1 in the regulation of cardiac hypertrophy in HFpEF.
- To determine if Fstl1 has therapeutic potential in HFpEF.
Main Methods:
- Measured Fstl1 blood levels in human HFpEF patients and in mouse models of hypertension-induced HFpEF.
- Stimulated adult rat ventricular myocytes with aldosterone and assessed the effects of recombinant Fstl1.
- Generated a cardiac myocyte-specific Fstl1 knockout (cFstl1-KO) mouse model to study HFpEF.
- Assessed cardiac myocyte hypertrophy, diastolic dysfunction (E/A ratio), and expression of molecular markers (ANP, BNP).
Main Results:
- Fstl1 levels were elevated in human HFpEF, hypertensive HFpEF mice, and aldosterone-stimulated myocytes.
- Recombinant Fstl1 treatment reduced aldosterone-induced cardiac myocyte hypertrophy and improved the E/A ratio.
- cFstl1-KO mice with HFpEF exhibited exacerbated cardiac hypertrophy and worsened diastolic dysfunction.
- cFstl1-KO-HFpEF mice showed increased ANP and BNP expression, indicating cardiac stress.
Conclusions:
- Fstl1 plays a significant role in modulating cardiac hypertrophy in HFpEF.
- Fstl1 demonstrates therapeutic potential for HFpEF by mitigating cardiac hypertrophy and diastolic dysfunction.
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.
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