30 A randomised double-blind placebo-controlled study of fenofibrate as a metabolic modulator to augment cardiac physiology in moderate-severe aortic stenosis

Background

Pressure overload in aortic stenosis (AS) is associated with reduced cardiac fatty acid oxidation (FAO) and evidence of myocardial steatosis and impaired myocardial energetics. Here, we investigated whether modulating myocardial metabolism to increase FAO with a PPARα agonist, Fenofibrate in moderate-severe AS had effects on cardiac metabolism and physiology.

Methods

67participants with asymptomatic moderate-severe AS were prospectively randomised (double-blinded) to receive either Fenofibrate 200mg once daily (N= 54) or placebo (N=13) for 6 months (180 ± 7 days duration). Follow-up data was available in 42 patients. Primary endpoint was reduction in myocardial triglyceride content (MTG) measured using proton magnetic resonance spectroscopy (MRS). Secondary endpoints included cardiac PCr/ATP measured by 31P-MRS and LV strain assessed using MR tagging.

Results

There was significant reduction in MTG content (-0.40%, CI -0.74 to -0.06, p= 0.022), with a no significant reduction seen in placebo. (-0.46, CI -1.1 to 0.17, p= 0.13) A significant increase in venous butyrate levels was seen in the fibrate group (+0.09 mmol/l CI 0.006 to 0.17, p= 0.036) in line with increased fatty acid oxidation. No change in cardiac energetics was seen in either group. No change in cardiac function was seen in either group, global longitudinal strain (-0.07%, p 0.89 Fibrate vs -0.31%, p 0.67 Placebo), circumferential strain ( -0.15%, p 0.80 Fibrate vs 1.71%, p 0.07 Placebo).

Conclusions

Fenofibrate can potentially upregulate fatty acid oxidation in hypertrophied AS hearts reducing myocardial lipid content, but this did not have any measurable beneficial physiological effect in moderate-severe AS