Find information on thousands of medical conditions and prescription drugs.

Primary pulmonary hypertension

In medicine, pulmonary hypertension (PH) or pulmonary artery hypertension (PAH) is an increase in blood pressure in the pulmonary artery or lung vasculature. more...

Home
Diseases
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Arthritis
Arthritis
Bubonic plague
Hypokalemia
Pachydermoperiostosis
Pachygyria
Pacman syndrome
Paget's disease of bone
Paget's disease of the...
Palmoplantar Keratoderma
Pancreas divisum
Pancreatic cancer
Panhypopituitarism
Panic disorder
Panniculitis
Panophobia
Panthophobia
Papilledema
Paraganglioma
Paramyotonia congenita
Paraphilia
Paraplegia
Parapsoriasis
Parasitophobia
Parkinson's disease
Parkinson's disease
Parkinsonism
Paroxysmal nocturnal...
Patau syndrome
Patent ductus arteriosus
Pathophobia
Patterson...
Pediculosis
Pelizaeus-Merzbacher disease
Pelvic inflammatory disease
Pelvic lipomatosis
Pemphigus
Pemphigus
Pemphigus
Pendred syndrome
Periarteritis nodosa
Perinatal infections
Periodontal disease
Peripartum cardiomyopathy
Peripheral neuropathy
Peritonitis
Periventricular leukomalacia
Pernicious anemia
Perniosis
Persistent sexual arousal...
Pertussis
Pes planus
Peutz-Jeghers syndrome
Peyronie disease
Pfeiffer syndrome
Pharmacophobia
Phenylketonuria
Pheochromocytoma
Photosensitive epilepsy
Pica (disorder)
Pickardt syndrome
Pili multigemini
Pilonidal cyst
Pinta
PIRA
Pityriasis lichenoides...
Pityriasis lichenoides et...
Pityriasis rubra pilaris
Placental abruption
Pleural effusion
Pleurisy
Pleuritis
Plummer-Vinson syndrome
Pneumoconiosis
Pneumocystis jiroveci...
Pneumocystosis
Pneumonia, eosinophilic
Pneumothorax
POEMS syndrome
Poland syndrome
Poliomyelitis
Polyarteritis nodosa
Polyarthritis
Polychondritis
Polycystic kidney disease
Polycystic ovarian syndrome
Polycythemia vera
Polydactyly
Polymyalgia rheumatica
Polymyositis
Polyostotic fibrous...
Pompe's disease
Popliteal pterygium syndrome
Porencephaly
Porphyria
Porphyria cutanea tarda
Portal hypertension
Portal vein thrombosis
Post Polio syndrome
Post-traumatic stress...
Postural hypotension
Potophobia
Poxviridae disease
Prader-Willi syndrome
Precocious puberty
Preeclampsia
Premature aging
Premenstrual dysphoric...
Presbycusis
Primary biliary cirrhosis
Primary ciliary dyskinesia
Primary hyperparathyroidism
Primary lateral sclerosis
Primary progressive aphasia
Primary pulmonary...
Primary sclerosing...
Prinzmetal's variant angina
Proconvertin deficiency,...
Proctitis
Progeria
Progressive external...
Progressive multifocal...
Progressive supranuclear...
Prostatitis
Protein S deficiency
Protein-energy malnutrition
Proteus syndrome
Prune belly syndrome
Pseudocholinesterase...
Pseudogout
Pseudohermaphroditism
Pseudohypoparathyroidism
Pseudomyxoma peritonei
Pseudotumor cerebri
Pseudovaginal...
Pseudoxanthoma elasticum
Psittacosis
Psoriasis
Psychogenic polydipsia
Psychophysiologic Disorders
Pterygium
Ptosis
Pubic lice
Puerperal fever
Pulmonary alveolar...
Pulmonary hypertension
Pulmonary sequestration
Pulmonary valve stenosis
Pulmonic stenosis
Pure red cell aplasia
Purpura
Purpura, Schoenlein-Henoch
Purpura, thrombotic...
Pyelonephritis
Pyoderma gangrenosum
Pyomyositis
Pyrexiophobia
Pyrophobia
Pyropoikilocytosis
Pyrosis
Pyruvate kinase deficiency
Uveitis
Q
R
S
T
U
V
W
X
Y
Z
Medicines

Depending on the cause, it can be a severe disease with a markedly decreased exercise tolerance and right-sided heart failure. It was first identified by Dr Ernst von Romberg in 1891.

Signs and symptoms

A history usually reveals gradual onset of shortness of breath, fatigue, angina pectoris, syncope (fainting) and peripheral edema.

In order to establish the cause, the physician will generally conduct a thorough medical history and physical examination. A detailed family history is taken to determine whether the disease might be familial.

Diagnosis

Normal pulmonary arterial pressure in a person living at sea level has a mean value of 12-16mmHg. Definite pulmonary hypertension is present when mean pressures at rest exceed 25 mmHg. Although pulmonary arterial pressure can be estimated on the basis of echocardiography, pressure sampling with a Swan-Ganz catheter provides the most definite measurement.

Diagnostic tests generally involve blood tests, electrocardiography, arterial blood gas measurements, X-rays of the chest (generally followed by high-resolution CT scanning). Biopsy of the lung is usually not indicated unless the pulmonary hypertension is thought to be secondary to an underlying intrinsic lung disease. Clinical improvement is often measured in a "six-minute walking test", i.e. the distance a patient can walk in six minutes, and stability and improvements in this measurement correlate with reduced mortality.

Causes and mechanisms

Pulmonary hypertension can be primary (occurring without an obvious cause) or secondary (a result of other disease processes.)

Primary PH

Primary pulmonary hypertension (PPH) is considered a genetic disorder. Certain forms of PPH have been linked to mutations in the BMPR2 gene, which encodes a receptor for bone morphogenic proteins, as well as the 5-HT(2B) gene, which codes for a serotonin receptor. Recently, characteristic proteins of human herpesvirus 8 (also known for causing Kaposi sarcoma) were identified in vascular lesions of PPH patients. However, it is not understood what roles these genes and viral particles play in PPH. PPH has also been associated to the use of appetite suppressants (e.g. Fen-phen). While genetic susceptibility to adverse drug reactions is suspected, the cause of the disease is still largely unknown.

Read more at Wikipedia.org


[List your site here Free!]


Linkage analysis in a large family with primary pulmonary hypertension ; genetic heterogeneity and a second primary pulmonary hypertension locus on 2q31-32
From CHEST, 3/1/02 by Bart Janssen

Abbreviations: BMPR2 = bone morphogenetic protein receptor type II; DHPLC = denaturing high performance liquid chromotography; LOD = logarithm of the odds for linkage; PASP = pulmonary artery systolic pressure; PPH = primary pulmonary hypertension

**********

Primary pulmonary hypertension (PPH) is an autosomal dominant disorder with an estimated incidence of about one to two cases per million. The disease is characterized by increased resistance of precapillary pulmonary arteries and leads to sustained elevation of pulmonary arterial pressure (mean pressure > 25 mm Hg at rest or > 30 mm Hg during exercise). (1) The disease can occur at any stage throughout life from infancy onwards. The mean age at onset is 36 years, and the median length of survival without treatment is < 3 years after diagnosis. (2) Therefore, even in large families, there will never be a high number of living family members with manifest PPH at any one time point. As a consequence, linkage studies are hampered by low numbers of living patients. Despite these problems, American and British investigators managed to find the gene locus and to identify the trait-causing gene: the bone morphogenetic protein receptor type II (BMPR2) gene on chromosome 2q33. (3,4) The BMPR2 gene is mutated in a significant proportion of PPH patients, and studies on large cohorts have shown mutation detection rates ranging from 26% in sporadic PPH to 48% in familial cases. (5,6) Nevertheless, it appears to be impossible to find all or almost all mutations in a cohort of patients. Several plausible explanations for this problem can be mentioned, like a mutational hot spot in a regulatory element or undetected locus heterogeneity. So far, it was not possible to investigate the latter explanation due to the limited number of living patients.

Our echocardiographic studies have demonstrated that a predisposition to PPH can be diagnosed at an early stage of disease using stress Doppler echocardiography. (7) A pathologic rise of pulmonary artery systolic pressure (PASP) during supine bicycle exercise (> 40 mm Hg) was observed only in those family members who shared the risk haplotype with the index patients. To investigate the genetic cause in BMPR2-negative PPH patients, we analyzed a large family with PPH and a normal BMPR2 gene using linkage analysis, stress Doppler echocardiography and, in some family members, right-heart catheterization.

METHODS AND RESULTS

We studied a large German pedigree with four generations (Fig 1). The family has been described previously by Grunig et al. (7) Individuals were classified as carriers if they had a diagnosis of manifest PPH (pulmonary artery pressure > 25 mm Hg, or PASP > 35 mm Hg at rest, after excluding secondary PPH), or if stress Doppler echocardiography revealed a pathologic increase of PASP ([greater than or equal to] 45 mm Hg) during supine bicycle exercise. Family members with a maximum PASP of [less than or equal to] 35 mm Hg were classified as normal. All family members with intermediate PASP values (> 35 mm Hg and < 45 mm Hg) and family members suspected as having pulmonary hypertension due to secondary causes were classified as status unknown. The intermediate PASP range corresponds to the SD at high heart rates and was introduced to avoid the occurrence of false recombinations. In total, we studied 57 family members. A manifest PPH was diagnosed in two family members. A PPH carrier status was found by Doppler echocardiography in 12 individuals; in another 12 family members, the PASP values were normal. The remaining family members had secondary pulmonary hypertension, were not available for clinical investigation, revealed inadequate Doppler echocardiographic signals, or revealed intermediate PASP values and were therefore classified as status unknown. All adult cases with manifest PPH or a PPH carrier status were reinvestigated by right-heart catheterization. In each case, the stress echocardiographic data were confirmed.

[FIGURE 1 OMITTED]

BMPR2 mutations were excluded by DHPLC analysis. The family was genotyped for the markers shown in Figure 1, location scores (logarithm of the odds for linkage [LOD] scores, Z) were computed at 1-centimorgan intervals, and haplotypes were constructed manually.

The multipoint analysis showed high LOD scores in the proximal part of the PPH candidate region, whereas insignificant LOD scores (Z < 0.1) were obtained for the more distal markers linked to BMPR2 (locus PPH1). The haplotypes indicated that recombinations with the PPH1 locus occurred in one unaffected family member (V-7) and in two members who showed a pathologic increase of PASP (51 mm Hg and 47 mm Hg, respectively) during supine bicycle exercise (IV-2 and IV-7) [Fig 1]. The maximum LOD score for this family was found at the position of marker D2S2307 (Z maximum, 4.54). At the BMPR2-linked marker D2S307, the LOD score was 0.07.

A PASP of 40 mm Hg during supine bicycle exercise is generally accepted as maximal for normal individuals. (8,9) Based on these findings, we had to consider the individuals with pathologic PASP as genuine PPH carriers, despite the recombinant haplotypes.

CONCLUSION

The results of our study suggest linkage heterogeneity in PPH with a second locus, designated PPH2, located on chromosome 2q31-32. According to the haplotypes, the PPH2 locus maps in between the markers D2S335 and D2S2314 (Fig 1). Since PPH1 (BMPR2) and PPH2 lie only 15 to 19 centimorgans apart, many small families will show no recombination between the two regions. Therefore, it is not possible to classify small families by means of haplotype analysis. This might explain why several authors failed to find BMPR2 mutations in several families that showed marker data consistent with linkage to 2q33.

The genetic classification of our families would not have been possible without the novel diagnostic procedure involving stress Doppler echocardiography. Although we studied a PPH-related phenotype rather than PPH itself, the haplotype information demonstrates that the PPH2 locus is not the site of a modifier gene, modifying the PPH phenotype toward a trait detectable by stress Doppler echocardiography, but the site of a mutation that is the direct cause of PPH. We conclude that stress Doppler echocardiography enables the investigators to identify carriers of the disease, nearly independent of the state of the disease process. Although the use of an intermediate range ensures that we only counted genuine recombinations, we noticed that 15 noncarriers and only 2 carriers were excluded from the study due to intermediate PASP values. Therefore, the use of an intermediate range and the exact cutoff value needs further evaluation.

Our data indicate that a second PPH gene maps to 2q31-32. This map position is supported by a highly significant LOD score. We realize that more conclusive evidence should come from studies on larger numbers of families. Such a study is currently in progress in our institutions.

REFERENCES

(1) Rubin L. ACCP consensus statement: primary pulmonary hypertension. Chest 1993; 104:236-250

(2) D'Allonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991; 115:343-349

(3) Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67:737-744

(4) The International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF-[beta] receptor, cause familial primary pulmonary hypertension. Nat Genet 2000; 26:81-84

(5) Thomson JR, Machado RD, Pauciulo MW, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-[beta] family. J Med Genet 2000; 37:741-745

(6) Massague J, Chen Y. Controlling TGF-[beta] signaling. Genes Dev 2000; 14:627-644

(7) Grunig E, Janssen B, Mereles D, et al. Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000; 102:1145-1150

(8) Gurtner HP, Walser P, Fassler B. Normal values for pulmonary hemodynamics at rest and during exercise in man. Prog Respir Res 1995; 9:295-315

(9) Janosi A, Apor P, Hankoczy J, et al. Pulmonary artery pressure and oxygen consumption measurement during supine bicycle exercise. Chest 1998; 93:419-421

* From the Institute of Human Genetics (Drs. Janssen, Barth, Miltenberger-Miltenyi, and Bartram and Mr. Rindermann), University of Heidelberg, Heidelberg; Department of Cardiology (Drs. Mereles, Abushi, Kubler, and Grunig), University of Heidelberg, Heidelberg: and Department of Pneumonology (Dr. Seeger), University of Giessen, Giessen, Germany.

Correspondence to: Bart Janssen, PhD, Institute of Human Genetics, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany; e-mail: Bart_Janssen@med.uni-heidelberg.de

COPYRIGHT 2002 American College of Chest Physicians
COPYRIGHT 2002 Gale Group

Return to Primary pulmonary hypertension
Home Contact Resources Exchange Links ebay