Right ventricular and pulmonary vascular reserve in asymptomatic BMPR2 mutation carriers

https://doi.org/10.1016/j.healun.2016.06.018Get rights and content

Background

Non-invasive estimates have suggested that asymptomatic BMPR2 mutation carriers may have an abnormal pulmonary vascular response to exercise and hypoxia. However, this has not been assessed with “gold standard” invasive measures.

Methods

Eight controls and 8 asymptomatic BMPR2 mutation carriers underwent cardiac magnetic resonance imaging with simultaneous invasive pressure recording during bicycle exercise in normoxia, hypoxia and after sildenafil administration. Abnormal pulmonary vascular reserve was defined as an increase in mean pulmonary artery pressure relative to cardiac output (P/Q slope) >3 mm Hg/liter/min.

Results

During normoxic exercise, BMPR2 mutation carriers had a similar P/Q slope when compared with healthy subjects. Only 1 of 8 BMPR2 mutation carriers had a P/Q slope >3 mm Hg/liter/min. During exercise in hypoxia, 3 of 8 BMPR2 mutation carriers had P/Q slopes >3 mm Hg/liter/min compared with none of the controls. Sildenafil decreased the P/Q slope both in controls and BMPR2 mutation carriers. The exercise-induced increase in right ventricular ejection fraction was similar between groups. None of the BMPR2 mutation carriers developed pulmonary arterial hypertension within 2 (range 1.3 to 2.8) years.

Conclusions

The presence of a BMPR2 mutation, per se, is not associated with an abnormal pulmonary vascular and right ventricular functional response to exercise in asymptomatic individuals. Longer follow-up will be required to determine whether a P/Q slope of >3 mm Hg/liter/min during exercise in normoxia or hypoxia is a sign of pre-clinical disease expression.

Section snippets

Subjects

Between 2012 and 2014, all consecutive BMPR2 mutation carriers assessed at our institute who were asymptomatic and had normal resting mean pulmonary artery pressure (mPAP) of <25 mm Hg were invited to participate in this study. Eleven subjects fulfilled the inclusion criteria and 8 were included in the study.

Eight control subjects volunteered to participate after responding to local advertisements. All subjects were: (1) healthy; (2) had no history of cardiovascular disease, symptoms or risk

Baseline characteristics

The baseline characteristics of the study population are depicted in Table 1. Controls and BMPR2 mutation carriers were of similar age and gender. All subjects were asymptomatic and none had been receiving negative chronotropic medications or pulmonary vasodilator therapy. Exercise capacity in the BMPR2 mutation carriers was reduced, as reflected by their low peak volume of oxygen consumption (VO2, 88 ± 24% of predicted for age and gender) and tended to be lower than in the controls (Table 1).

Discussion

Using contemporary invasive pressure and CMR-derived volume measurements with improved sensitivity to test our hypothesis of an association between BMPR2 mutation status and sub-clinical pulmonary vascular and RV dysfunction, we found that only a minority of mutation carriers had hemodynamic responses to exercise that could be considered abnormal. Thus, the presence of a mutation in BMPR2 by itself is not sufficient to develop pulmonary vascular disease. During hypoxic exercise, 3 of 8 BMPR2

Disclosure statement

M.D. has served as investigator, speaker, consultant or steering committee member for Actelion, Bayer, Eli Lilly, GlaxoSmithKline, Pfizer and United Therapeutics, and has received research grants from Actelion, GlaxoSmithKline and Pfizer. H.H. is on the speakers’ bureau and advisory board of Bayer, Boehringer-Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Merck, Biotronik and St. Jude Medical.

The remaining authors have no conflicts of interest to disclose.

This study was funded by a

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    • 1

    Contributed equally as first authors.

    2

    Contributed equally as senior authors.

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    © 2016 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.