Physicians' Academy for Cardiovascular Education

Heart rate reduction worsened exercise capacity in HFpEF patients

Literature - Pal N et al., Circulation. 2015

Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction

Pal N, Sivaswamy N, Mahmod M, et al.
Circulation. 2015;132:1719-1725


Patients with heart failure and preserved left ventricular ejection fraction (HFpEF) have similar mortality rates to patients with HF and reduced ejection fraction (HFrEF) [1,2,4]. Treatment options for HFpEF can improve signs and symptoms, however, none of them has shown to reduce morbidity and mortality in HF patients with ejection fraction ≥50% [2,3].
HFpEF has been associated with ventricular diastolic dysfunction that affects ventricular filling and coronary perfusion [5]. The reduction of heart rate in these patients is considered to be beneficial, since it leads to prolongation of diastole [6]. Guidelines have endorsed this therapeutic option [7].
On the other hand, increased heart rate contributes to higher cardiac output, supporting augmented metabolic demands of exercise in HF patients with or without reduced ejection fraction [8,9].
In this randomised, placebo-controlled, crossover study, the effects of short-term selective heart rate reduction on exercise performance of HFpEF patients was assessed. To lower heart rate, ivabradine was used at 7.5 mg twice daily versus placebo for 2 weeks, each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation. Ivabradine is an inhibitor of the sinoatrial pacemaker funny current (If ) that has no effect on cardiac contractility [10]. The comparison group consisted of 22 similarly treated matched asymptomatic hypertensive volunteers.

Main results

Response to exercise
Cardiopulmonary exercise testing of HFpEF patients at baseline revealed
  • significantly lower Vo2 peak (16.1 versus 27.0 mL・kg−1・min−1; P<0.0001) although the effort was satisfactory
  • significantly decreased anaerobic threshold (11.5 versus 20.6 mL・kg−1・min−1; P<0.0001)
  • significantly lower maximal workload achieved (4.5 versus 7.7 metabolic equivalents; P<0.0001)
  • increased ventilatory response to exercise (VE/Vco2)
compared with the hypertensive group.
Selective heart rate lowering with ivabradine in the HFpEF cohort
  • reduced the mean resting heart rate by 20 bpm (77 to 57 bpm; P<0.0001) without any effect on blood pressure or left ventricular EF
  • reduced the chronotropic response to exercise (peak heart rate, 129 versus 107 bpm; P<0.0001)
  • reduced peak oxygen consumption in the majority of HFpEF patients.
Selective heart rate lowering with ivabradine in the asymptomatic hypertensive cohort
As in the HFpEF group, ivabradine
  • significantly reduced resting heart rate compared with placebo (from 74 to 61 bpm; P=0.001)
  • lowered peak exercise heart rate (145 versus 127 bpm; P=0.003)
  • reduced (statistically nonsignificant) Vo2 peak (26 versus 24.5 mL・kg−1・min−1; P=0.47)


Ivabradine compared with placebo significantly worsened the change in peak Vo2 in the HFpEF cohort and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. These findings bring into question the value of systematic heart rate reduction in HFpEF patients with exercise limitation, and its role in improving their symptoms.

Editorial comment [11]

The results of this study is not a surprise, if the Fick equation is taken into consideration, according to which: Vo2 = (CO x Ca) – (CO x Cv), where CO = Cardiac Output = heart rate x stroke volume,
Ca = Oxygen concentration of arterial blood and Cv = Oxygen concentration of mixed venous blood.
In healthy humans, the increase in Vo2 during maximal exercise is due to a 40% increase in stroke volume, which occurs at the beginning of exercise, and a 150% increase in heart rate, which occurs at higher levels of exercise. Hence, heart rate is more important for the achievement of Vo2, compared to stroke volume.
Reduced exercise intolerance is a main reason for poor quality of life in patients with HFpEF, and can be measured with the use of peak Vo2, and this fact has not received adequate attention in HFpEF clinical trials.
Find this article online at Circulation


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