β-blocker is a commonly used drug class whose influence remains under-considered in the interpretation of CPET. In the present study, acute inhibition of cardio-specific β-adrenoreceptors had no effect on aerobic capacity or ventilatory response during exercise in healthy subjects. Preserved VO2max was possible since the β-blockers negative chronotropic and inotropic effects, assessed by lower resting and maximal HR and SBP with a 18% reduction in the HR/VO2 slope, was counter-balanced by increased O2 pulse probably through intrinsic cardiac and/or peripheral adaptative mechanisms. The present result also revealed a 23% increase in the early chronotropic recovery within the first end-exercise minute.
Beta-Blockade
The bisoprolol dose used in the present study respected the recommendations when initiating a treatment titrated to effect [21]. How much body-weight titration would have influenced the present results is unknown. After 2.5 mg bisoprolol, 97% of the subjects showed a clear chronotropic inhibition, > 10 bpm, indicating effective starting dose.
With 5 mg of bisoprolol, all subjects decrease HR at rest with no bradycardiac adverse events reported. 76% of the subjects reached the minimal tolerated HR (70 bpm) suggesting achievement of the target dose. It remains unknown if higher doses would have been more efficient the 24% other subjects.
Aerobic Capacity
Previous studies reported either an unchanged or a 5–7% VO2max alteration after 1 or 2 weeks of β-blocker intake [16, 17]. No altered VO2max was observed in the present study in accordance with other studies on healthy young subjects [22, 23], aortic aneurysm [14], or hypertension patients [24]. This general observation made in healthy or pathological conditions suggests that the negative inotropic and chronotropic effects of β-blocker promote multiple compensatory-dependent mechanisms such as; mechanical/intrinsic cardiac adaptation and/or according to Fick’s principle, enhanced O2 extraction in exercising muscles, etc. [15].
Chronotropic Response to Exercise
HR response to exercise is multi-factorial and depends on autonomic outflows (central command), reflex responses to skeletal muscle activation (exercise pressor reflex), hemodynamic changes, sinus node function, parasympathetic withdrawal and β-adrenoreceptor responsiveness [20]. At the onset of exercise, chronotropic response mainly depends on para-sympathetic drive reduction. Further exercising allows the catecholamines to stimulate nodal cells and cardiomyocytes β1-receptors which will in turn modify the membrane permeability to K+ and Ca++ resulting in increased cardiomyocytes excitability, frequency of excitation, impulse conduction and relaxation speed [20]. Pharmacological inhibition of the β1-receptors will therefore attenuate all those cardiac adrenergic responses during exercise and might also participate to the smoothened SBP response at exercise [20].
Chronotropic Index
Chronotropic incompetence, defined as the inability of the HR to increase during exercise, is diagnosed using the chronotropic index, the HR/VO2 slope or when the measured maximal HR does not reach 80% of the predicted maximal HR [20, 25].
Numerous studies showed an altered chronotropic index under chronic and acute β-blockers intakes [25,26,27]. However, the chronotropic index has also been shown to be inversely correlated to mortality in healthy men [28], congenital heart disease [29]. Also in patients with HF treated with β-blockers, an index below 0.6 increased mortality of + 17% at 24 months [30]. As illustrated in Fig. 3, 7 healthy subjects out of 21 (33%) showed a chronotropic index < 0.6 after 5.0 mg of bisoprolol intake. Hence in some circumstances, the chronotropic index might be more affected by the treatment than by the disease itself.
HR/VO2 Slope
The HR vs metabolism relationship, namely the HR/VO2 or HR/MET slopes, also evaluates the chronotropic response to exercise with the advantage to be physical fitness level independent. Normal values of HR/VO2 are between 3 to 4 b/ml/kg in healthy sedentary subjects [6] and is known to be influenced by age, sex, physical fitness or altitude [23, 31, 32]. The HR/VO2 slope is increased in cardiac affections such as Fontant patients (not on beta-blockers) or atrial septal defect and reduced in patients with heart failure with preserved ejection fraction treated by beta-blockers [33,34,35]. The presently healthy subjects exhibited a decreased HR/VO2 slope after bisoprolol intake reaching the lower limit of normal independently of the prescribed dose (Fig. 2). Our study highlights that a drug-related reduction in the HR/VO2 slope (average decrease of 0.5 b/ml/kg) has to be taken into account during CPET analysis, when beta-blockers are prescribed, at least acutely.
Chronotropic Post-Exercise Kinetics
HRR is often reported as an indirect estimation of cardio-vascular fitness. Indeed, HRR is enhanced in endurance athletes as compared to resistive training athletes [20]. Conversely, a delayed HRR, particularly when < 12 bpm decrease is observed within the first minute after maximal exercise, is associated with increased all-cause mortality in asymptomatic subjects and in pathological populations such as HF, chronic obstructive pulmonary disease or interstitial lung disease [6, 8, 36, 37]. Indeed, this early recovery phase is highly dependent on the reactivation of the parasympathetic tone, while later (slow recovery phase), HRR is influenced by the reduction of sympathetic activity and non-autonomic factors (α-adrenergic tone, atrial stretch or central temperature changes) [38].
The present increased HRR at 1 min post-exercise suggest that acute β1-adrenergic blockade may allow for an enhanced cardiac vagal reactivation. However, the involvement of non-autonomic mechanisms cannot be excluded [38].
Oxygen Pulse
IN the present study, maximal O2 pulse, a composite index reflecting maximal stroke volume and end-exercise peripheral O2 extraction, was increased by the intake of β1-blocker independently of the drug dose. As end-exercise peripheral O2 extraction has been shown to be unaltered following B1-selective blockade [12], increased maximal O2 pulse may reflect a decreased systemic resistance or left ventricular afterload and an intrinsic cardiac adaptation after β-adrenergic receptor blockade, resulting from the Frank-Starling mechanism when ventricular filling time is increased.
β1-selective blockade is also known to preserve the β2-receptor induced muscular vasodilation during exercise with one study reporting a 4% increase in end exercise CavO2 of CAD patients [13]. This suggests that this peripheral adaptation may partially contribute to the increased maximal O2 pulse and the VO2max preservation under β1-blockade.
Gas Exchange and Chemosensibility
The present result showed no influence of bisoprolol intake on the ventilatory response to exercise, preserving maximal ventilation but also ventilatory efficiency evaluated by the VE/VCO2 ratio at VT or the VE/VCO2 slope. This suggests little or no interference of β1-adrenergic effects on central or peripheral chemo-receptors or muscle metabo-receptors during exercise [39]. However, Beloka et al. previously showed smoothened VE/VCO2 slopes after chronic intake of bisoprolol in healthy subjects [17]. Because this was not associated with detectable changes in the sympathetic nervous system tone, metabosensitivity or chemosensitivity, the authors attributed the lower VE/VCO2 slopes to underlying hemodynamic mechanisms. Other studies showing lower hyperventilation response under β-blockers were realized under un-specific β blockade, suggesting an involvement of β2-adrenoreceptors rather than β1-receptors in the ventilatory response to exercise [39].
Clinical Relevance
From a clinically point of view, the present study highlights a potential risk of misinterpretation of CPET in subjects on beta-blockers. Firstly, it is interesting to note that VO2max is not or hardly affected by beta-blocker intake. Secondly, the maximal O2pulse value will be overestimated due to the negative chronotropic effect suggesting a cautious and contextualized interpretation. Thirdly, the chronotropic response to exercise (assessed by the chronotropic index or HR/VO2 slope) is reduced by an average of 0.5 b/mL/kg and should be taken into account in the interpretation, especially when the value approaches the limit of chronotropic incompetence (< 3 b/mL/kg). Finally, the pharmacologically-induced HRR acceleration with bisoprolol should be included in the interpretation of the recovery phase.
Limitation of the Study
There are several limitations in the present study that could have affected the results or conclusions. All tested subjects were healthy active young adults. The extrapolation of the present results to older subjects or to patient with cardiac diseases remains therefore uncertain. It is also important to underly that five subjects were precautionary excluded for high reactivity to bisoprolol with bradycardia and hypotension. This thus constitutes an inclusion bias in the present study.
Moreover, the present observed effects are the consequence of an acute β-blocker dose intake and it remains uncertain if more β1-receptors would be inhibited with a chronic β-blocker treatment or higher doses and if it would influence the present results.
Also, young men and women were recruited in the present study sample, but sex influence on chronotropic response under beta-blockade remains unknown. Although no sex differences appeared after an inter-sex comparison (not shown), a sex influence cannot be excluded in older or pathological populations.