Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients

Q: What are the key findings of this study?

Bisoprolol therapy reduced heart rate from 80 to 69 bpm (p<0.0001) but did not alter right ventricular sympathetic activity ([11C]HED retention index 3.20 vs 3.15 at baseline) in IPAH patients.

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Idiopathic pulmonary arterial hypertension (IPAH) (n=13). Intervention: Bisoprolol vs. Placebo (and baseline). Primary outcome: Right ventricular [11C]-hydroxyephedrine retention index (RV [11C]HED RI).

Q: What does this research mean for the field?

Bisoprolol therapy reduces heart rate but fails to reduce local right ventricular sympathetic activity or improve right ventricular function in patients with pulmonary arterial hypertension. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Mischa T. Rijnierse; Joanne A. Groeneveldt; Jasmijn S.J.A. van Campen; Karin Boer; Cathelijne E.E. van der Bruggen; Hendrik J. Harms; Pieter G. Raijmakers; Adriaan A. Lammertsma; Paul Knaapen; Harm Jan Bogaard; Berend E. Westerhof; Anton Vonk Noordegraaf; Cornelis P. Allaart; Frances S. de Man

doi:10.1177/2045894019873548

August 14, 2019Pulmonary CirculationOpen Access

Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients

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Key result

Bisoprolol lowers heart rate but fails to alter right ventricular sympathetic activity in IPAH.

n=13

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Why the study?

Beta-blocker therapy improved RV function in animal studies but yielded disappointing clinical results; whether it alters RV sympathetic activity in PAH remained unknown.

Does bisoprolol therapy reduce right ventricular sympathetic activity in patients with idiopathic pulmonary arterial hypertension?

Key Points

To determine whether beta-blocker therapy with bisoprolol reduces right ventricular sympathetic activity and improves right ventricular function in patients with pulmonary arterial hypertension.
Evaluated 13 patients with idiopathic pulmonary arterial hypertension (NYHA functional class II and III) treated with bisoprolol uptitrated to a maximal tolerated dose.
Assessed right ventricular ejection fraction, hemodynamics, and local sympathetic nerve activity at baseline and after bisoprolol treatment using cardiac magnetic resonance imaging, right heart catheterization, and [11C]-hydroxyephedrine positron emission tomography ([11C]HED PET).
Bisoprolol significantly reduced heart rate from 80 ± 8.8 bpm at baseline to 69 ± 6.3 bpm (p<0.0001), but right ventricular sympathetic activity remained unchanged (RV [11C]HED retention index was 3.15 ± 0.80 at baseline vs 3.20 ± 1.04 after bisoprolol).
Right ventricular [11C]HED retention index was lower than left ventricular uptake (p<0.01) and significantly related to systolic wall tension (R 2 = 0.4731, p<0.01) and right ventricular function (R 2 = 0.44, p = 0.01).
Right ventricular wall stress, right ventricular ejection fraction, and local sympathetic activity showed no functional improvement following bisoprolol administration.

Study Design

Type

RCT (n=13)

Blinding

Double-blind

Randomization

1:1 cross-over

Multicenter

No

Structured PICO

Does bisoprolol therapy reduce right ventricular sympathetic activity in patients with idiopathic pulmonary arterial hypertension?

P

Population

13 patients (median age 43 years, 92% female) with stable idiopathic pulmonary arterial hypertension in NYHA functional class II or III and sinus rhythm, treated for 6 months per cross-over period.

I

Intervention

Bisoprolol therapy uptitrated to a maximal tolerated dose

C

Comparator

Baseline (pre-treatment)

O

Outcome

Right ventricular sympathetic activity measured by [11C]-hydroxyephedrine positron emission tomography ([11C]HED PET) retention indexsurrogate

Main Result

Absolute Event Rate: 3.2% vs 3.15%

In patients with idiopathic pulmonary arterial hypertension, bisoprolol therapy does not improve right ventricular function or reduce right ventricular sympathetic activity despite lowering heart rate.

Limitations

[11C]HED images only presynaptic sympathetic activity and does not represent postsynaptic activity at the cardiomyocyte level
Relatively small sample size (n=13 analyzed out of 18 enrolled due to technical issues with 5 PET scans)
Lack of healthy control group due to low spatial resolution of the [11C]HED tracer in thin-walled normal right ventricles
Potential partial volume effects affecting [11C]HED uptake evaluation in the right ventricular free wall
Patients may not have tolerated the bisoprolol dosage required to achieve a change in RV sympathetic activity due to heart rate-limiting contraindications

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Implication

Bisoprolol should not target right ventricular sympathetic activity in IPAH despite heart rate reduction; leaves open beta-blocker effects on outcomes in randomized trials.

Abstract

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta‐blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta‐blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta‐blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]‐hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p<0.01) and was related to systolic wall tension (R 2 = 0.4731, p<0.01) and RV function (R 2 = 0.44, p = 0.01). In RV failure, the tolerated dosage of bisoprolol did not result in an improvement of RV function nor in a reduction in RV sympathetic activity.

Discussion

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Cite This Study

Rijnierse et al. (2019) conducted an RCT in Idiopathic pulmonary arterial hypertension (IPAH) (n=13). Bisoprolol vs. Placebo (and baseline) was evaluated on Right ventricular [11C]-hydroxyephedrine retention index (RV [11C]HED RI). Bisoprolol therapy reduced heart rate from 80 to 69 bpm (p<0.0001) but did not alter right ventricular sympathetic activity ([11C]HED retention index 3.20 vs 3.15 at baseline) in IPAH patients.

synapsesocial.com/papers/6a75a1466e15464cba6a35c7 https://doi.org/10.1177/2045894019873548

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Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Bisoprolol therapy does not reduce right ventricular sympathetic activity in pulmonary arterial hypertension patients

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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