OBJECTIVES: The aim of this study was to test the effects of treatment with 
ivabradine on exercise capacity and left ventricular filling in patients with 
heart failure with preserved ejection fraction (HFpEF).
BACKGROUND: Because symptoms of HFpEF are typically exertional, optimization of 
diastolic filling time by controlling heart rate may delay the onset of 
symptoms.
METHODS: Sixty-one patients with HFpEF were randomly assigned to ivabradine 5 mg 
twice daily (n = 30) or placebo (n = 31) for 7 days in this double-blind trial. 
Cardiopulmonary exercise testing with echocardiographic assessment of myocardial 
function and left ventricular filling were undertaken at rest and after 
exercise.
RESULTS: The ivabradine group demonstrated significant improvement between 
baseline and follow-up exercise capacity (4.2 ± 1.8 METs vs. 5.7 ± 1.9 METs, p = 
0.001) and peak oxygen uptake (14.0 ± 6.1 ml/min/kg vs. 17.0 ± 3.3 ml/min/kg, p 
= 0.001), with simultaneous reduction in exercise-induced increase in the ratio 
of peak early diastolic mitral flow velocity to peak early diastolic mitral 
annular velocity (3.1 ± 2.7 vs. 1.3 ± 2.0, p = 0.004). Work load-corrected 
chronotropic response (the difference in heart rate at the same exercise time at 
the baseline and follow-up tests) showed a slower increase in heart rate during 
exercise than in the placebo-treated group. Therapy with ivabradine (β = 0.34, p 
= 0.04) and change with treatment in exertional increase in the ratio of peak 
early diastolic mitral flow velocity to peak early diastolic mitral annular 
velocity (β = -0.30, p = 0.02) were independent correlates of increase in 
exercise capacity, and therapy with ivabradine (β = 0.32, p = 0.007) was 
independently correlated with increase in peak oxygen uptake.
CONCLUSIONS: In patients with HFpEF, short-term treatment with ivabradine 
increased exercise capacity, with a contribution from improved left ventricular 
filling pressure response to exercise as reflected by the ratio of peak early 
diastolic mitral flow velocity to peak early diastolic mitral annular velocity. 
Because this patient population is symptomatic on exertion, therapeutic 
treatments targeting abnormal exercise hemodynamic status may prove useful. (Use 
of Exercise and Medical Therapies to Improve Cardiac Function Among Patients 
With Exertional Shortness of Breath Due to Lung Congestion; 
ACTRN12610001087044).