Abstract 13808: Role of Cardiac Specific Follistatin-Like 1 in Heart Failure with Preserved Ejection Fraction
Background: Heart failure (HF) with preserved ejection fraction (HFpEF), commonly known as “diastolic HF”, accounts for ∼50% of all HF presentations. Hypertension is a major cause of HFpEF. Similarly, aldosterone (ALDO) plays a pivotal role in HFpEF. Follistatin-like 1 (Fstl1), an extracellular glycoprotein, is expressed in the normal heart and is elevated in acute coronary syndrome and HF. Fstl1 also exerts anti-hypertrophic and anti-inflammatory effects. The aim of this study is to investigate the role of Fstl1 in ALDO-induced HFpEF.
Methods: Uninephrectomized, cardiomyocyte-specific Fstl1 knock-out (Fstl1cKO) mice and wild-type (WT) mice received a continuous infusion of either d-ALDO or saline and were maintained on 1% NaCl for 4 weeks. Thereafter, blood pressure (BP) measurement, echocardiography and qRT-PCR were performed. Isolated adult rat ventricular myocytes (ARVM) were treated with recombinant Fstl1 (rFstl1) and then stimulated with ALDO. pERK and MMP were determined by immunoblotting.
Results: BP was increased in both WT-ALDO and Fstl1cKO-ALDO (146±6 and 143±5mmHg; p<0.05 vs. respective shams). Left ventricular hypertrophy (LVH) was increased in WT-ALDO (HW/BW: 5.4±0.3 vs. 4.2±0.1mg/g; p<0.05 vs. WT-saline), but was further increased in Fstl1cKO-ALDO (HW/BW: 5.7±0.2mg/g). LV dimensions and ejection fraction were no different between WT-ALDO and Fstl1cKO-ALDO. As expected, the increased LVH in Fstl1cKO-ALDO was associated with an increased ANF and BNP expression vs. WT-ALDO. Myocardial fibrosis was increased but no different between WT-ALDO (8.7±1.0%) and Fstl1cKO-ALDO (9.0±2.2%). Collagen type I and III expression were increased 1.5-fold and 1.1-fold, respectively in Fstl1cKO-ALDO vs. WT-ALDO. In ARVM, ALDO increased pERK, MMP2 and MMP9 expression (p<0.05 for all vs. control). Pretreatment with rFstl1 modulated ALDO-induced pERK expression and MMP2/TIMP2 and MMP9/TIMP1 ratios (p<0.05 for all vs. ALDO alone).
Conclusions: Cardiac specific Fstl1 deficiency exacerbated the progression of ALDO-induced HFpEF. MMPs and their inhibitors are regulators of the extracellular matrix and are important in the development of HFpEF. Fstl1 may modulate the progression of HFpEF possibly via a mechanism involving ERK and the MMP axis.
- © 2011 by American Heart Association, Inc.