Stress Doppler echocardiography in relatives of patients with idiopathic and familial pulmonary arterial hypertension: results of a multicenter European analysis of pulmonary artery pressure response to exercise and hypoxia.
BACKGROUND
This large, prospective, multicentric study was performed to analyze the distribution of tricuspid regurgitation velocity (TRV) values during exercise and hypoxia in relatives of patients with idiopathic and familial pulmonary arterial hypertension (PAH) and in healthy control subjects. We tested the hypothesis that relatives of idiopathic/familial PAH patients display an enhanced frequency of hypertensive TRV response to stress and that this response is associated with mutations in the bone morphogenetic protein receptor II (BMPR2) gene.


RESULTS
TRV was estimated by Doppler echocardiography during supine bicycle exercise in normoxia and during 120 minutes of normobaric hypoxia (FIO(2)=12%; approximately 4500 m) in 291 relatives of 109 PAH patients and in 191 age-matched control subjects. Mean maximal TRVs were significantly higher in PAH relatives during both exercise and hypoxia. During exercise, 10% of control subjects but 31.6% of relatives (P<0.0001) exceeded the 90% quantile of mean maximal TRV seen in control subjects. Hypoxia revealed hypertensive TRV in 26% of relatives (P=0.0029). Among control subjects, TRV at rest was not related to age, sex, body mass index, systemic blood pressure, smoking status, or heart rate. Within kindreds identified as harboring deleterious mutations of the BMPR2 gene, a hypertensive TRV response occurred significantly more often compared with those without detected mutations.


CONCLUSIONS
Pulmonary hypertensive response to exercise and hypoxia in idiopathic/familial PAH relatives appears as a genetic trait with familial clustering, being correlated to but not caused by a BMPR2 mutation. The suitability of this trait to predict manifest PAH development should be addressed in long-term follow-up studies.
Grünig
Ekkehard
E
Department of Pneumology Thoraxclinic, University Hospital Heidelberg, Amalienstrasse 5, D-69126 Heidelberg, Germany. ekkehard.gruenig@thoraxklinik-heidelberg.de
Weissmann
Sylvia
S
Ehlken
Nicola
N
Fijalkowska
Anna
A
Fischer
Christine
C
Fourme
Thierry
T
Galié
Nazzareno
N
Ghofrani
Ardeschir
A
Harrison
Rachel E
RE
Huez
Sandrine
S
Humbert
Marc
M
Janssen
Bart
B
Kober
Jaroslaw
J
Koehler
Rolf
R
Machado
Rajiv D
RD
Mereles
Derliz
D
Naeije
Robert
R
Olschewski
Horst
H
Provencher
Steeve
S
Reichenberger
Frank
F
Retailleau
Kathleen
K
Rocchi
Guido
G
Simonneau
Gérald
G
Torbicki
Adam
A
Trembath
Richard
R
Seeger
Werner
W
D000328:Adult; D001794:Blood Pressure / Q000502:physiology; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D015150:Echocardiography, Doppler; D005060:Europe; D015444:Exercise / Q000502:physiology; D005080:Exercise Test; D005190:Family; D005260:Female; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000503:physiopathology; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012146:Rest / Q000502:physiology; D014262:Tricuspid Valve Insufficiency / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II