Category: 2018

Follistatin-like protein 1 (FSTL1): A cardiokine that alters metabolism and reverses remodeling in tachy-pacing canine HF

FSTL1 is a molecule with tremendous potential. While already considered an important clinical biomarker and cardioprotective cardiokine (a molecule secreted by cardiac muscle), Recchia et al demonstrate that FSTL1 also serves as a regulator of energy substrate metabolism. Using a canine tachy-pacing HF model, infusion of recombinant human FSTL1 exhibited efficacy in reversing pathological cardiac metabolism and remodelling.

In HF patients, derangement in myocardial energy consumption have a negative impact on cardiac function. In TAC-induced HF mice, FSTL1 overexpression caused increased AMP-activated Kinase (AMPK) activation, which ultimately increases fatty acid oxidation, ketone body metabolism, and glucose uptake (likely protective mechanisms in HF).

27 total (14 tachy-pacing HF, 13 control dogs) were given either acute FSTL1 infusion (20ug/kg over 10 minutes) or FSTL1 chronic infusion (10ng/kg/min for 14 days). Tachy-pacing HF dogs were studied at spontaneous heart rate, with the pacemaker turned off. Control dogs were paced to match the spontaneous heart rate measured at baseline in HF dogs. Hemodynamics and arterial concentrations of FFA, glucose, lactate, and total ketone bodies were measured at 10, 30, and 60 minute intervals among the acute infusion group. These levels were also obtained in the chronic infusion group. In the chronic group, additional testing with dobutamine infusion was performed to compare hemodynamic data to historical groups of normal and HF dogs not subjected to any chronic treatment.

Acute infusion of FSTL1 led to significant hemodynamic improvements from baseline HF values as well as compared to control values (Table 1, p<0.05). FFA, glucose, and ketone body concentrations also significantly decreased in the acute infusion group (Table 2, p<0.05). The chronic infusion group experienced significant decreases in HR and LVEDD when compared to baseline (p<0.05). The chronic infusion group had significantly better contractility after dobutamine infusion than the historic HF control group.

Complementary in vitro experiments confirmed that FSTL1 stimulated oxygen consumption through AMPK activation.

The current study did not measure circulating plasma levels of endogenous FSTL1 in dogs, due to the unavailability of analytical tools sensitive to the protein. Furthermore, a dose response curve was lacking since only single dose was used for acute and chronic FSTL1 infusion.

In a heartbeat…

FSTL1 is a cardiokine that functions as a metabolic modulator in tachy-pacing canine HF. Further studies are needed to continue exploring the potential therapeutic role of FSTL1 in HF.

Study Link