(Chest. 2005;128:630S-633S.)
© 2005
American College of Chest Physicians
Enhanced Hypoxic Pulmonary Vasoconstriction in Families of Adults or Children With Idiopathic Pulmonary Arterial Hypertension*
Ekkehard Grünig, MD
;
Christoph Dehnert, MD;
Derliz Mereles, MD;
Rolf Koehler, PhD;
Horst Olschewski, MD;
Peter Bärtsch, MD and
Bart Janssen, PhD
* From the Department of Cardiology (Drs. Grünig and Mereles), Institute of Sports Medicine (Drs. Dehnert and Bärtsch), Institute of Human Genetics (Drs. Koehler and Janssen), University of Heidelberg, Heidelberg, Germany; and the Department of Pneumology (Dr. Olschewski), University of Giessen, Giessen, Germany.
These authors contributed equally to this study.
Correspondence to: Ekkehard Grünig, MD, Department of Cardiology and Pneumology, University Hospital of Heidelberg, INF 410, 69120 Heidelberg, Germany; e-mail: ekkehard_gruenig{at}med.uni-heidelberg.de
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Introduction
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Idiopathic pulmonary arterial hypertension (IPAH) is a rare life-threatening disease that is characterized by the sustained elevation of pulmonary artery pressure without demonstrable cause.1 The disease is chronically progressive and is believed to evolve slowly, with an asymptomatic increase in pulmonary arterial constriction and remodeling for some years. In most patients, signs and symptoms appear when pulmonary artery pressure is markedly elevated.2 Since the identification of mutations of the bone morphogenetic protein receptor II (BMPR2) gene in patients with IPAH,345 methods aimed at the identification of persons at risk for the disease have gained attention. In previous studies67 performed in families with IPAH, we demonstrated that healthy individuals who shared the risk haplotype (RH) with the index patient (the IPAH gene) have an increased pulmonary artery systolic pressure (PASP) during exercise. We hypothesized that healthy carriers of the IPAH trait would not only have an abnormal increase in pulmonary artery pressure during exercise but also during exposure to hypoxia.
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Materials and Methods
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PASP was estimated at 30, 60, 90, and 120 min of normobaric hypoxia (fraction of inspired oxygen, 12%) and during supine bicycle exercise in normoxia as described previously68 using Doppler echocardiography in 38 family members of 5 adult index patients, in 37 family members of 5 children with IPAH, and in 56 control subjects. Linkage analysis and screening for BMPR2 mutations was performed in all families, as described previously.67 In all index patients, the diagnosis was made according to the World Health Organization criteria.1 The control group consisted of 56 aged-matched subjects (11 men and 45 women; mean [± SD] age, 24 ± 5 years; mean weight, 63 ± 9 kg; mean height, 172 ± 8 cm) who were recruited from the employees of the hospital. The sonographers who estimated PASP during hypoxia (C.D.) had no knowledge of the PASP values obtained during exercise (E.G. and D.M.) and vice versa. Recordings were analyzed off-line in random order and in a blinded fashion. In relatives or control subjects with abnormal PASP values, secondary reasons were excluded by a cascade of clinical examinations, including laboratory tests, chest roentgenography, pulmonary function tests, and the measurement of arterial blood gases. The clinicians were blinded to the results of genetic analysis.
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Results
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In the 5 families with adult IPAH, 21 members shared a RH or a BMPR2 mutation with the index patients and were classified as gene carriers. Seventeen members with different haplotypes and no BMPR2 mutation were classified as non-gene carriers. The mean maximal PASP was significantly greater in the 21 IPAH gene carriers both during hypoxia (48 ± 10 mm Hg) and during exercise (50 ± 8 mm Hg; p < 0.0001) than in the 17 non-gene carriers (during hypoxia, 38 ± 5 mm Hg; during exercise, 40 ± 5 mm Hg; p < 0.0001) and in the control subjects (33 ± 7 and 38 ± 7 mm Hg, respectively; p < 0.0001). In the families of adult patients, we observed that in 18 of 21 RH carriers (85.7%), but in only 4 members of the control group (7%) and 2 non-RH carriers (11.7%), the PASP response to hypoxia exceeded 40 mm Hg (range, 41 to 69 mm Hg) without secondary reasons. This increase was greatest after 90 to 120 min of hypoxia (change in PASP: RH carriers, 21 ± 9 mm Hg; non-RH carriers, 14 ± 5 mm Hg; p = 0.003). Three of the 21 RH carriers had PASP-values of < 40 mm Hg during hypoxia but abnormal values during exercise. The PASP values obtained during hypoxia were significantly correlated with those obtained during supine bicycle exercise using linear regressions (r = 0.74; standard error of estimate, 8.7 mm Hg; p < 0.001) and Bland-Altman analysis. RH carriers, non-RH carriers, and control subjects did not differ significantly in their mean oxygen saturation and heart rate during hypoxia, in age, body weight and height, mean maximal workload, mean maximal cardiac output, rate-pressure-product, mean maximal heart rate, and percent of age-predicted heart rate at maximal exercise.
None of the five children with IPAH had a BMPR2 mutation or deletion. Both parents of the index patient and/or members of both branches revealed an abnormal PASP response to exercise and hypoxia (Fig 1
).
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Figure 1. Pedigree of a consanguineous IPAH family investigated using stress echocardiography and echocardiography during hypoxia. In this family, the index patient is a child (V:1) with severe IPAH and idiopathic thrombocytopenia in whom a diagnosis had been made at 2.5 years of age. She died at 4 years of age. The medical history revealed no family history of an aggregation of the disease; the genetic screening did not reveal a BMPR2 gene mutation. In the clinical assessment, both parents and family members of both sides (III-1, III-3, IV-1, IV-3, IV-8, and IV-9) revealed a high PASP response to exercise and/or hypoxia (half-filled symbols). None of them had cardiopulmonary symptoms. In five family members (question mark symbol), PASP could not be assessed. The cooccurrence of individuals with a high PASP response in the paternal and maternal side of the pedigree is typical for families with infantile IPAH.12 This phenomenon, together with the existence of consanguineous families, suggests that, at least in some cases, infantile IPAH may have a recessive mode of inheritance.12
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Discussion
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The main finding of this study was an abnormal PASP response to prolonged hypoxia in family members who shared the RH or the BMPR2 mutation with the IPAH patients. The sensitivity and specificity for the identification of RH carriers was highest when the maximal PASP values during prolonged hypoxia and supine bicycle exercise were used. Under both conditions, a cutoff value of 40 mm Hg distinguished best between RH carriers and non-RH carriers.
In 6 of the 21 RH carriers, a twofold to threefold increase in PASP up to 55 to 69 mm Hg was documented. Since there were no significant differences of oxygen saturation, workload, BP-heart rate product, and cardiac output between the RH carriers and non-RH carriers, this abnormal PASP response could not be explained by an enhanced cardiac output or more severe hypoxemia.
The cutoff values that discriminate best between RH carriers and non-RH carriers during exercise fit well with earlier invasive9 and noninvasive10 studies showing that PASP in healthy individuals did not exceed 40 mm Hg when workloads did not exceed 200 W. However, this cutoff level might not be adequate in subjects with a mean age of > 40 years. At higher workloads, PASP can also exceed 40 mm Hg.11 PASP in persons with the RH was in a range observed in individuals susceptible to high altitude pulmonary edema.8 Thus, the question arises of whether RH carriers are prone to develop high altitude pulmonary edema.
Interestingly, the PASP response to exercise correlated highly with the response to hypoxia, suggesting that in RH carriers the abnormal vasoreactivity to exercise and hypoxia might be linked to or associated with the IPAH gene. One possible explanation for an underlying mechanism is an increased pulmonary vasoconstriction in IPAH gene carriers, which is induced by hypoxia or an increase in cardiac output on exercise. The clinical identification of RH carriers may be valuable because at present genetic screening will detect only some IPAH gene carriers; namely, those with BMPR2 mutations.5
Due to the incomplete penetrance, the number of individuals identified as IPAH gene carriers by genetic analysis and/or PASP measurements may be much higher than the number of subjects who will eventually develop the disease. Therefore, the obtained PASP values as well as the genetic results must be discussed very cautiously with the assessed relatives. Follow-up assessments in the relatives of IPAH patients may help to clarify the natural course of the disease and may lead to an early diagnosis, especially in family members who are at risk for IPAH.
We conclude that IPAH gene carriers may have an abnormal pulmonary vascular response not only to supine bicycle exercise at normoxia but also to prolonged hypoxia. Thus, enhanced hypoxic pulmonary vasoconstriction in the family members of IPAH patients may be genetically determined by the IPAH genes. The estimation of PASP by Doppler ultrasound during supine bicycle exercise or prolonged hypoxia may be useful and widely available screening methods for identifying patients at risk for IPAH. These methods need, however, to be validated in a larger group of subjects before they can be recommended for clinical practice.
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Footnotes
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The study was funded by the University of Heidelberg, Germany.
Abbreviations: BMPR2 = bone morphogenetic protein receptor II; IPAH = idiopathic pulmonary arterial hypertension; PASP = pulmonary artery systolic pressure; RH = risk haplotype
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References
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Introduction
Materials and Methods
