|
Sign In to gain access to subscriptions and/or personal tools.
|
Angiotensin-converting enzyme DD genotype in patients with primary pulmonary hypertension: increased frequency and association with preserved haemodynamics
William T Abraham
Divisions of Cardiology, University of Colorado School of Medicine Denver, abraham-1@ medctr.osu.edu
Mary V Raynolds
Divisions of Cardiology, University of Colorado School of Medicine Denver
David B Badesch
Division of Pulmonary Medicine, Department of Medicine, University of Colorado School of Medicine Denver, Colorado, USA
Kristine M Wynne
Division of Pulmonary Medicine, Department of Medicine, University of Colorado School of Medicine Denver, Colorado, USA
Bertron M Groves
Divisions of Cardiology, University of Colorado School of Medicine Denver
Robert L Roden
Divisions of Cardiology, University of Colorado School of Medicine Denver
Alastair D Robertson
Divisions of Cardiology, University of Colorado School of Medicine Denver
Brian D Lowes
Divisions of Cardiology, University of Colorado School of Medicine Denver
Lawrence S Zisman
Divisions of Cardiology, University of Colorado School of Medicine Denver
Norbert F Voelkel
Division of Pulmonary Medicine, Department of Medicine, University of Colorado School of Medicine Denver, Colorado, USA
Michael R Bristow
Divisions of Cardiology, University of Colorado School of Medicine Denver
M Benjamin Perryman
Divisions of Cardiology, University of Colorado School of Medicine Denver
Hypothesis/introduction
A polymorphic marker within the angiotensin-converting enzyme (ACE) gene has been associated with circulating and tissue ACE activity and with a variety of forms of cardiovascular disease. Since angiotensin II (Ang II) causes pulmonary vasoconstriction and vascular and myocardial remodelling, we postulated a role for the renin-angiotensin system and the ACE DD genotype in the pathophysiology of primary pulmonary hypertension (PPH) and in the right ventricular response to pressure overload in these patients.
Methods and results
The incidence of the ACE DD genotype was evaluated in 60 patients with severe PPH compared with two normal control populations, a group of healthy population-based controls (n=158) and subjects found suitable for cardiac organ donation (n=79). Genomic DNA extracted from peripheral leukocytes was amplified using the polymerase chain reaction to detect polymorphic markers. Haemodynamics were determined by right heart catheterisation in a subset of the PPH patients. The frequency of the ACE DD genotype was 45% in the patients with PPH, compared with 24% in the organ donors, and 28% in populationbased healthy controls (p=0.01 for chi-square test). Of the 32 PPH patients with baseline haemodynamics, 12 exhibited the ACE DD genotype and 20 were non-DD. While the mean pulmonary artery pressure and the duration of symptoms attributable to pulmonary hypertension was not different between the DD and non-DD groups, cardiac output was significantly lower (3.29±0.27 vs. 5.07±0.37 L/minute, p=0.002) and the trouvemean right atrial pressure tended to be higher (8.85±1.29 vs. 4.92±1.27 mmHg, p=0.08) in the non-DD group. The reduction in cardiac output seen in the non-DD group was not due to a difference in heart rate, but to a significant reduction in stroke volume, consistent with a decreased contractile state. In addition, non-DD patients exhibited a significantly worse functional capacity (NYHA Class 3.14±0.12 vs. 2.40±0.28, p=0.02).
Conclusions
1) The ACE DD genotype is significantly increased in patients with severe PPH compared with normal controls, suggesting that certain individuals may be genetically predisposed to developing pulmonary hypertension. 2) The ACE DD genotype is associated with preserved right ventricular function in PPH patients, supporting a compensatory myocardial or inotropic role for Ang II in the pressure overloaded right ventricle.
Key Words: angiotensin II • genetics • haemodynamics • polymerase chain reaction • pulmonary hypertension
References
- Jeunemaitre X., Soubrier F., Kotelevtsev YV et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 1992;71:169-80.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Ward K., Hata A., Jeunemaitre X. et al. A molecular variant of angiotensinogen associated with preeclampsia. Nature Genetics 1993;4:59-61.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hegele RA, Brunt JH, Connelly PW A polymorphism of the angiotensinogen gene associated with variation in blood pressure in a genetic isolate. Circulation 1994;90:2207-12.[Abstract/Free Full Text]
- Bonnardeaux A., Davies E., Jeunemaitre X. et al. Angiotensin II type 1 receptor polymorphisms in human essential hypertension. Hypertension 1994;24:63-9.[Abstract/Free Full Text]
- Rigat B., Hubert C., Corvol P., Soubrier F. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 1992;20:1433.[Free Full Text]
- Rigat B., Hubert C., Alhenc-Gelas F., Cambien F., Corvol P., Soubrier F. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86:1343-6.[Web of Science][Medline]
[Order article via Infotrieve]
- Tiret L., Rigat B.,Visvikis S. et al. Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 1992; 51:197-205.[Web of Science][Medline]
[Order article via Infotrieve]
- Danser AH, Schalekamp MA, Bax WA et al. Angiotensinconverting enzyme in the human heart: effect of the deletion/insertion polymorphism. Circulation 1995;92:1387-8.[Abstract/Free Full Text]
- Cambien F., Poirier O., Lecerf L. et al. Deletion polymorphism in thegene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature 1992;359:641-4.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Tiret L., Kee F., Poirier O. et al. Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction. Lancet 1993;341:991-2.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mattu RK, Needham EWA, Galton DJ, Frangos E., Clark AJL, Caufield M. A DNA variant at the angiotensin-converting enzyme gene locus associates with coronary artery disease in the Caerphilly Heart Study. Circulation 1995;91:270-4.[Abstract/Free Full Text]
- Raynolds MV, Bristow MR, Bush E. et al. The angiotensin converting enzyme D/D genotype frequency is increased in patients with ischemic or idiopathic dilated cardiomyopathy. Lancet 1993;342:1073-5.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Marian AJ, Yu Q-t, Workman R., Greve G., Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet 1993;342:1085-6.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Iwai N., Ohmichi N., Nakamura Y., Kinoshita M. DD genotype of the angiotensin-converting enzyme gene is a risk factor for left ventricular hypertrophy. Circulation 1994;90:2622-8.[Abstract/Free Full Text]
- Schunkert H., Hense H-W., Holmer SR et al. Association between a deletion polymorphism of the angiotensin converting-enzyme gene and left ventricular hypertrophy. N Engl J Med 1994;330:1634-8.[Abstract/Free Full Text]
- Pratt RE, Dzau VJ Trophic effects of angiotensin on blood vessels and heart. In: Robertson JI, Nicholls MG (eds.). The Renin-Angiotensin System. London: Gower Medical Publishing, 1993;1:31.1-31.7.
- Schmengler K., Stumpe KO Akut- und Langzeitbehandlung des schweren Lungenhochdrucks mit Captopril. In: Gross H (ed.). Hemmung des Angiotension-Konversionsenzyms (ACE): Ein neues Prinzip in der Behandlung der Hypertonie und der Herzinsuffizienz. Munich: MMV Medizin Verlag, 1983.
- Niarchos AP, Whitman HH, Goldstein JE, Laragh JH Hemodynamic effects of captopril in pulmonary hypertension of collagen vascular disease. Am Heart J 1982;104:834-8.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Voelkel NF Drug effects on the pulmonary circulation: an overview. Sem Respiratory Med 1985;7:141-5.
Journal of Renin-Angiotensin-Aldosterone System, Vol. 4, No. 1,
27-30 (2003)
DOI: 10.3317/jraas.2003.003
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
R. D. Machado, O. Eickelberg, C. G. Elliott, M. W. Geraci, M. Hanaoka, J. E. Loyd, J. H. Newman, J. A. Phillips III, F. Soubrier, R. C. Trembath, et al.
Genetics and genomics of pulmonary arterial hypertension.
J. Am. Coll. Cardiol.,
June 30, 2009;
54(1 Suppl):
S32 - S42.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Haddad, R. Doyle, D. J. Murphy, and S. A. Hunt
Right Ventricular Function in Cardiovascular Disease, Part II: Pathophysiology, Clinical Importance, and Management of Right Ventricular Failure
Circulation,
April 1, 2008;
117(13):
1717 - 1731.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Haworth
The cell and molecular biology of right ventricular dysfunction in pulmonary hypertension
Eur. Heart J. Suppl.,
December 1, 2007;
9(suppl_H):
H10 - H16.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. F. Voelkel, R. A. Quaife, L. A. Leinwand, R. J. Barst, M. D. McGoon, D. R. Meldrum, J. Dupuis, C. S. Long, L. J. Rubin, F. W. Smart, et al.
Right Ventricular Function and Failure: Report of a National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure
Circulation,
October 24, 2006;
114(17):
1883 - 1891.
[Full Text]
[PDF]
|
|
|
|
|
