(Hypertension. 1995;26:44-47.)
© 1995 American Heart Association, Inc.
Articles |
Influence of Angiotensin II Type 1 Receptor Polymorphism on Aortic Stiffness in Never-Treated Hypertensive Patients
From INSERM U337, Broussais Hospital (A. Benetos, J.T., S.G., R.A., M.S.), INSERM SC7 (S.R., O.P., F.C.), and INSERM U36, College de France (A. Bonnardeaux, F.S.), Paris, France.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Several clinical and experimental studies have suggested a significant role of angiotensin II in the development of alterations of small and large arteries. The present study was designed to assess the contribution of polymorphism (corresponding to an A1166
C transversion) of the
angiotensin II type 1 receptor (AT1) gene to
aortic stiffness. One hundred thirty-four never-treated hypertensive
patients were included in the study. Aortic distensibility was
evaluated by measuring carotid-femoral pulse wave velocity. Age,
systolic and diastolic pressure, and metabolic
parameters were similar in the three genotypes.
Pulse wave velocity was 11.4±2.5 m/s in AT1 AA
homozygotes, 12.5±3.2 m/s in AC heterozygotes, and 14.7±4.0 m/s in CC
homozygotes (P=.003, P<.001 after adjustment for
age, blood pressure, and body mass index). Moreover, an interaction was
found between AT1 genotype and the ratio of total
to high-density lipoprotein cholesterol in terms of the
development of aortic stiffness. Thus, a positive correlation was
observed between the ratio of total to high-density lipoprotein
cholesterol and pulse wave velocity in AC and CC
(r=.42, P<.001) but not AA patients. These
results suggest that the AT1 gene is involved in the
development of aortic stiffness in hypertensive patients and could
modulate the effects of lipids on large arteries.
Key Words: renin-angiotensin system • polymorphism (genetics) • receptors, angiotensin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The two major causes of increased stiffness in the large arteries are age and high blood pressure. Increased stiffness is associated with several structural changes of the arterial wall, including arterial thickening and changes in extracellular matrix. In addition to age and high blood pressure, local hormonal factors may play a role in the modification of the arterial wall, mainly by modifying cell growth or synthesis of the extracellular matrix.1 Among these factors angiotensin II might be of particular importance, since it induces hypertrophy of vascular smooth muscle cells in culture and increases collagen production by fibroblasts.2 3 In vivo administration of nonpressor doses of angiotensin II induces arterial thickening in rats,4 whereas in humans, higher levels of angiotensin I–converting enzyme have been observed in subjects with increased thickness of the carotid wall.5 Most of the actions of angiotensin II are mediated by the effects of this peptide on the angiotensin II type 1 receptors (AT1),6 7 and the recent identification of polymorphic DNA markers on the AT1 gene8 offers a good opportunity to study the involvement of the AT1 gene in arterial rigidity.
In the present cross-sectional study we investigated whether in never-treated hypertensive patients this genetic polymorphism is associated with aortic stiffness evaluated by the method of carotid-femoral pulse wave velocity (PWV).9 10 11
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
One hundred thirty-four white never-treated hypertensive patients aged 21 to 72 years were included in this study after they provided written informed consent. Subjects were recruited from the Broussais Hospital in Paris at the Hypertension Department during an ambulatory checkup for hypertension. They were selected according to the following criteria: (1) systolic blood pressure the morning of the study greater than 145 mm Hg and/or diastolic blood pressure greater than 90 mm Hg with both sphygmomanometer (mean of three measurements in the supine position, Korotkoff phase V sound) and an automatic oscillometric device (DINAMAP 845)12 ; (2) absence of clinical or biological signs of secondary hypertension; and (3) lack of any antihypertensive or vasodilatory treatment in the past.
The mean duration of hypertension was 5.1±6.0 years (range, 0 to 30 years). No subject had recent symptoms of coronary artery disease. Patients with diabetes type I or II were excluded from the study.
All the participants were examined in the morning after a fast of at least 12 hours, and all underwent the same procedure. After 15 minutes of rest in the supine position, aortic PWV was evaluated with the use of two pressure probes. This method has been extensively analyzed previously.13 Briefly, two pressure waves were recorded transcutaneously at two sites (at the base of the neck for the common carotid artery and over the right femoral artery). Pulse transit time was determined as the average of 10 consecutive beats. The distance traveled by the pulse wave was measured over the body surface as the distance between the two recording sites. Aortic PWV was calculated as the ratio of distance to transit time. The reproducibility of the measurement for aortic PWV (expressed as percent variation of the mean value) has been found to be 5.3±3.6%.13
During the procedure and for 5 minutes afterward, blood pressure was measured automatically every 2 minutes with a DINAMAP device. The mean of five consecutive measurements was calculated. An automatic method was chosen for the statistical analysis to avoid interobserver variations and diminish "white coat" reactivity.
At the end of this procedure, plasma was drawn for determination of serum potassium, plasma glucose, triglycerides, and total and high-density lipoprotein (HDL) cholesterol levels according to the standard methods. Metabolic parameter determination was not performed in patients receiving treatment for dyslipidemia.
Genotype Investigations
DNA was extracted according to standard methods.8
The A1166C polymorphism of the AT1 gene
was determined as previously described8 in all but three
subjects in whom genotyping was unsuccessful for technical reasons.
Statistical Analysis
One-way ANOVA was used to test differences in the means of
quantitative variables between genotypes before and after
adjustment of covariables (age, blood pressure, body mass index).
The comparison of the effects of age, blood pressure, and
metabolic parameters on PWV in the different
genotypes was performed with an interaction test (ANCOVA).
Hardy-Weinberg equilibrium was tested by a 
2 test
with 1 df.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The distributions of the AT1 A/C genotypes and allele frequencies were similar in men and women (Table 1). Age, blood pressure, duration of hypertension, body mass index, and metabolic parameters were similar in the three genotypes, whereas the mean values of PWV were significantly influenced by this polymorphism (P=.003) (Table 2). This effect was even stronger after adjustment for age, body mass index, and systolic or diastolic blood pressure (P<.001). Thus, AA patients showed lower, CC patients showed higher, and AC patients showed intermediate values of PWV (AA versus AC, P<.02; AA versus CC, P<.005; AC versus CC, P<.05). Interactions were also tested to establish whether the AT1 polymorphism might influence the relationship between known determinants of PWV (age, systolic blood pressure, diastolic blood pressure, body mass index, and the ratio of total to HDL cholesterol) and PWV. The only significant interaction (P<.02) involved the ratio of total to HDL cholesterol; the association between this ratio and PWV existed only in the presence of the AC or CC genotypes (Figure).
|
|
|
indicates AA patients; 
, AC and CC patients. The
interaction of TC/HDL and AT1 polymorphism on PWV was
statistically significant (P=.003). |
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In contrast to previous human studies focusing on the genetic determination of blood pressure, this cross-sectional study assessed the role of genetic factors in the development of large-artery stiffness in never-treated hypertensive patients. Arterial stiffness was assessed by measuring aortic PWV, a noninvasive, accurate, safe, and reproducible method suited to the screening of large populations. Aortic PWV is well correlated with left ventricular hypertrophy,13 14 general atherosclerosis,15 and especially coronary artery disease,11 so that patients with coronary heart disease have abnormally rigid aortas.16 17
As reported previously, aortic stiffness is positively correlated with age and systolic blood pressure in both normotensive and hypertensive subjects.18 19 The independent role of the renin-angiotensin system in the regulation of aortic stiffness in hypertensives has been suggested in pharmacological studies by comparing the effects of converting-enzyme inhibitors to other antihypertensive drugs. However, these results are not consistent and could be influenced by nonspecific effects of the different drugs. Moreover, anterior treatments may have residual effects on arterial structure and function, thereby modifying aortic distensibility.
The main result of our study is that the AT1 polymorphism seems to be involved in the regulation of aortic stiffness in never-treated hypertensive patients. This effect is codominant, ie, AT1 AC heterozygotes have a mean PWV that is intermediate between that of both types of homozygotes. Moreover, this association remains significant after adjustment for covariables strongly affecting PWV.
The AT1 A/C polymorphism corresponds to an
A1166C transversion located at the 5' end of the 3'
untranslated region of the gene.8 This polymorphism
does not seem to be functional but might be in linkage disequilibrium
with an unidentified functional variant. It has been shown that the
frequency of the C allele is increased in patients with severe
hypertension from 28% to 40%.8 In our study no
relationship was observed between the AT1 A/C
polymorphism and blood pressure level, and the frequency of the C
allele was 25%, which is comparable to the frequency observed by
Bonnardeaux et al8 in normotensives. The lack of
association of the AT1 C1166 allele with
hypertension in this study could be due to the noninclusion of patients
with severe hypertension. Although the
physiological role of the AT1 is well
defined, the mechanism of PWV increase associated with this genetic
polymorphism is unclear. First, because of the tissular
localization of the receptor, there is no modification of an
intermediate phenotype described in association with this
polymorphism. Further studies will be required to identify
intermediate phenotypes such as a modification of the number or
affinity of this receptor on accessible cells, such as platelets.
In a previous study no mutation in the coding sequence of the gene was
detected in a group of 50 hypertensive patients.8
Therefore, it is more likely that the nonfunctional marker we used in
this study is in linkage disequilibrium with a variant affecting either
the stability of the mRNA or the regulation of the expression of the
gene. It is conceivable that an increased number of receptors could
increase the effect of angiotensin II on the
arterial wall and hence increase arterial wall
stiffness.
In our study an interaction was found between AT1 genotype and the ratio of total to HDL cholesterol in terms of the development of aortic stiffness. Thus, in hypertensives a positive correlation was observed between ratio of total to HDL cholesterol and PWV in AC and CC but not AA patients. The role of the metabolic parameters, and especially plasma cholesterol, in the development of aortic stiffness is controversial. Some studies have shown that patients with lipid disturbances have decreased aortic elasticity, but these results were disputed by others.20 21 In the present study we did not find any significant relationship between PWV and ratio of total to HDL cholesterol when the whole population of patients was considered. These results suggest that the effects of lipids on large arteries may vary as a function of the AT1 genotype.
If these results are confirmed, AT1 gene polymorphism appears to be a particularly important risk predictor for arterial stiffness in hypertensive subjects. It is therefore important to identify the variant of the gene responsible for the biological effect. The implication of the renin-angiotensin system in this process, through the AT1 gene polymorphism, also suggests that blockade of the system might have beneficial effects on arterial wall structure and function.
|
Acknowledgments |
|---|
This study was supported by INSERM and the Claude Bernard Association. We thank Servier and Hoechst pharmaceutical companies for financial support. We are grateful to Dr Anne Charru, Dr Xavier Jeunemaitre, and members of the Groupe d'Etudes du Système Renine-Angiotensine for the advice and help provided. We also thank Andrée Neubauer, Josiane Anguill, Nadine Common, and Brigitte Laloux for their technical assistance.
|
Footnotes |
|---|
Reprint requests to Athanase Benetos, MD, Hôpital Broussais (Serv Médecine 1), 96 rue Didot, 75014 Paris, France.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Dzau VJ, Safar ME. Large conduit arteries in hypertension: role of the renin-angiotensin system. Circulation. 1988;77:947-953.
2.
Bunkenburg B, van Amelsvoort T, Rogg H, Wood JM.
Receptor-mediated effects of angiotensin II on
growth of vascular smooth muscle cells from spontaneously hypertensive
rats. Hypertension. 1992;20:746-754.
3. Naftilan AJ, Pratt RE, Dzau VJ. Induction of c-fos, c-myc and PDGF A chain gene expression by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1419-1424.
4.
Griffin SA, Brown WCB, Macpherson F, Macgrath JC,
Wilson VG, Korsgaard N, Mulvany M, Lever AF.
Angiotensin II causes vascular
hypertrophy in part by a nonpressor mechanism.
Hypertension. 1991;17:626-635.
5.
Bonithon-Kopp C, Ducimetiere P, Touboul PJ, Fève
JM, Billaud E, Courbon D, Héraud V. Plasma
angiotensin-converting enzyme activity and carotid wall
thickening. Circulation. 1994;89:952-954.
6. Rogg H, Schmid A, de Gasparo M. Identification and characterisation of angiotensin II receptor subtypes in rabbit ventricular myocardium. Biochem Biophys Res Commun. 1990;173:416-422. [Medline] [Order article via Infotrieve]
7. Dostal DE, Baker KM. Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart: mediation by the AT1 receptor. Am J Hypertens. 1992;5:276-280. [Medline] [Order article via Infotrieve]
8.
Bonnardeaux A, Davies E, Jeunemaitre X, Fery I, Charru
A, Clauser E, Tiret L, Cambien F, Corvol P, Soubrier F.
Angiotensin II type 1 receptor gene
polymorphisms in human essential hypertension.
Hypertension. 1994;24:63-69.
9. Avolio AP, Deng D, Fa-Quan D, Wei-Qiang L, Yao-Fei L, Zhen-Dong H, Lian-Fen X, O'Rourke MF. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Hypertension. 1985;71:202-210.
10. Nichols WW, O'Rourke MF. McDonald's Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles. 3rd ed. London, England: Edward Arnold Publishers, Ltd; 1990:77-142, 216-269, 283-359, 398-437.
11.
Farrar DJ, Bond MG, Riley WA, Sawyer JK.
Anatomic correlates of aortic pulse wave velocity and carotid
artery elasticity during atherosclerosis progression
and regression in monkeys. Circulation. 1991;83:1754-1763.
12.
Silas J, Barker A, Ramsay L. Clinical evaluation
of DINAMAP 845 automated blood pressure recorder. Br
Heart J. 1980;43:202-204.
13. London GM, Marchais SJ, Safar ME, Genest AF, Guerin AP, Metivier F, Chedid K, London AM. Aortic and large artery compliance in end-stage renal failure. Kidney Int. 1990;37:137-142. [Medline] [Order article via Infotrieve]
14. Bouthier JD, De Luca N, Safar ME, Simon ACh. Cardiac hypertrophy and arterial distensibility in essential hypertension. Am Heart J. 1985;109:1345-1352. [Medline] [Order article via Infotrieve]
15. Safar ME. Atherosclerotic hypertension: systolic hypertension and arterial compliance in patients with arteriosclerosis obliterans of the lower limbs. In: Safar ME, Fouad Tarazi F, eds. The Heart in Hypertension. Dordrecht, Netherlands: Kluwer Academic Publishers; 1989:123-133.
16.
Simonson E, Nakagawa K. Effect of age on pulse
wave velocity and `aortic ejection time' in healthy men and in men
with coronary artery disease.
Circulation. 1960;22:126-129.
17. Dart AM, Lacombe F, Yeoh JK, Cameron JD, Jennings GL, Laufer E, Esmore DS. Aortic distensibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplant. Lancet. 1991;338:270-273. [Medline] [Order article via Infotrieve]
18.
Smulyan H, Csermely TJ, Mookherjee S, Warner RA.
Effect of age on arterial distensibility in
asymptomatic humans.
Arteriosclerosis. 1983;3:199-205.
19. Asmar R, Benetos A, London G, Hugue C, Weiss Y, Topouchian J, Laloux B, Safar M. Aortic distensibility in normotensive, untreated and treated hypertensive patients. Blood Press. 1995;4:48-54. [Medline] [Order article via Infotrieve]
20. Dart AM, Lacombe F, Yeoh JK, Cameron JD, Jennings GL, Laufer E, Esmore DS. Aortic distensibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplant. Lancet. 1991;338:270-273.
21.
Relf IRN, Lo CS, Myers A, Wahlqvist ML.
Risk factors for changes in aorto-iliac arterial
compliance in healthy men.
Arteriosclerosis. 1986;6:105-108.
This article has been cited by other articles:
 |
|
 |
|
  P. Lacolley, P. Challande, M. Osborne-Pellegrin, and V. Regnault Genetics and pathophysiology of arterial stiffness Cardiovasc Res, March 1, 2009; 81(4): 637 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. T. Jones, A. R. Thompson, F. M. van Bockxmeer, H. Hafez, J. A. Cooper, J. Golledge, S. E. Humphries, P. E. Norman, and A. M. van Rij Angiotensin II Type 1 Receptor 1166C Polymorphism Is Associated With Abdominal Aortic Aneurysm in Three Independent Cohorts Arterioscler Thromb Vasc Biol, April 1, 2008; 28(4): 764 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Mitchell, M. E. Dunlap, W. Warnica, A. Ducharme, J. M. O. Arnold, J.-C. Tardif, S. D. Solomon, M. J. Domanski, K. A. Jablonski, M. M. Rice, et al. Long-Term Trandolapril Treatment Is Associated With Reduced Aortic Stiffness: The Prevention of Events With Angiotensin-Converting Enzyme Inhibition Hemodynamic Substudy Hypertension, June 1, 2007; 49(6): 1271 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Laurent, J. Cockcroft, L. Van Bortel, P. Boutouyrie, C. Giannattasio, D. Hayoz, B. Pannier, C. Vlachopoulos, I. Wilkinson, H. Struijker-Boudier, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications Eur. Heart J., November 1, 2006; 27(21): 2588 - 2605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Laurent, P. Boutouyrie, and P. Lacolley Structural and Genetic Bases of Arterial Stiffness Hypertension, June 1, 2005; 45(6): 1050 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-J. Mourad, G. Ducailar, A. Rudnicki, M. Lajemi, A. Mimran, and M. E Safar Age-related increase of pulse pressure and gene polymorphisms in essential hypertension: a preliminary study Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 109 - 115. [Abstract] [PDF]
|
|
|
|
|
|
O. Hanon, V. Luong, J. J. Mourad, L. A. Bortolotto, X. Jeunemaitre, and X. Girerd Aging, Carotid Artery Distensibility, and the Ser422Gly Elastin Gene Polymorphism in Humans Hypertension, November 1, 2001; 38(5): 1185 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Balkestein, J. A. Staessen, J.-G. Wang, J. J. van der Heijden-Spek, L. M. Van Bortel, C. Barlassina, G. Bianchi, E. Brand, S.-M. Herrmann, and H. A. Struijker-Boudier Carotid and Femoral Artery Stiffness in Relation to Three Candidate Genes in a White Population Hypertension, November 1, 2001; 38(5): 1190 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Brull, L. J. Murray, C. A. Boreham, S. H. Ralston, H. E. Montgomery, A. M. Gallagher, F. E.A. McGuigan, G. Davey Smith, M. Savage, S. E. Humphries, et al. Effect of a COL1A1 Sp1 Binding Site Polymorphism on Arterial Pulse Wave Velocity: An Index of Compliance Hypertension, September 1, 2001; 38(3): 444 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Izzo Jr Aging and Systolic Hypertension : Cluster Patterns and Problem-Solving Strategies to Answer the Genetic Riddle Hypertension, April 1, 2001; 37(4): 1067 - 1068. [Full Text] [PDF]
|
|
|
|
|
|
A. S. Wierzbicki, M. Lambert-Hammill, P. J. Lumb, and M. A. Crook Renin-Angiotensin System Polymorphisms and Coronary Events in Familial Hypercholesterolemia Hypertension, November 1, 2000; 36(5): 808 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Spiering, A. A. Kroon, M. M. J. J. Fuss-Lejeune, M. J. A. P. Daemen, and P. W. de Leeuw Angiotensin II Sensitivity Is Associated With the Angiotensin II Type 1 Receptor A1166C Polymorphism in Essential Hypertensives on a High Sodium Diet Hypertension, September 1, 2000; 36(3): 411 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Olivieri, E. Trabetti, S. Grazioli, C. Stranieri, S. Friso, D. Girelli, C. Russo, P. F. Pignatti, G. Mansueto, and R. Corrocher Genetic Polymorphisms of the Renin-Angiotensin System and Atheromatous Renal Artery Stenosis Hypertension, November 1, 1999; 34(5): 1097 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kainulainen, M. Perola, J. Terwilliger, J. Kaprio, M. Koskenvuo, A.-C. Syvanen, E. Vartiainen, L. Peltonen, and K. Kontula Evidence for Involvement of the Type 1 Angiotensin II Receptor Locus in Essential Hypertension Hypertension, March 1, 1999; 33(3): 844 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. I. Rice, C. A. Foy, and P. J. Grant Angiotensin converting enzyme and angiotensin II type 1-receptor gene polymorphisms and risk of ischaemic heart disease Cardiovasc Res, March 1, 1999; 41(3): 746 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nagai, C. J. Earley, M. K. Kemper, C. S. Bacal, and E.J. Metter Influence of age and postmenopausal estrogen replacement therapy on carotid arterial stiffness in women Cardiovasc Res, January 1, 1999; 41(1): 307 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Blacher, B. Pannier, A. P. Guerin, S. J. Marchais, M. E. Safar, and G. M. London Carotid Arterial Stiffness as a Predictor of Cardiovascular and All-Cause Mortality in End-Stage Renal Disease Hypertension, September 1, 1998; 32(3): 570 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Girerd, O. Hanon, J. J. Mourad, P. Boutouyrie, S. Laurent, and X. Jeunemaitre Lack of Association Between Renin-Angiotensin System, Gene Polymorphisms, and Wall Thickness of the Radial and Carotid Arteries Hypertension, September 1, 1998; 32(3): 579 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Castellano, M. L. Muiesan, M. Beschi, D. Rizzoni, A. Cinelli, M. Salvetti, G. Pasini, E. Porteri, G. Bettoni, R. Zulli, et al. Angiotensin II Type 1 Receptor A/C1166 Polymorphism: Relationships With Blood Pressure and Cardiovascular Structure Hypertension, December 1, 1996; 28(6): 1076 - 1080. [Abstract] [Full Text]
|
|
|
|
|
|
T. J. Brinton, M. T. Kailasam, R. A. Wu, J. H. Cervenka, S.-S. Chio, R. J. Parmer, A. N. DeMaria, and D. T. O'Connor Arterial Compliance by Cuff Sphygmomanometer: Application to Hypertension and Early Changes in Subjects at Genetic Risk Hypertension, October 1, 1996; 28(4): 599 - 603. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. Benetos, S. Gautier, S. Ricard, J. Topouchian, R. Asmar, O. Poirier, E. Larosa, L. Guize, M. Safar, F. Soubrier, et al. Influence of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor Gene Polymorphisms on Aortic Stiffness in Normotensive and Hypertensive Patients Circulation, August 15, 1996; 94(4): 698 - 703. [Abstract] [Full Text]
|
|
|
|
|
|
A. F. Dominiczak, A. M. Devlin, W. K. Lee, N. H. Anderson, D. F. Bohr, and J. L. Reid Vascular Smooth Muscle Polyploidy and Cardiac Hypertrophy in Genetic Hypertension Hypertension, March 1, 1996; 27(3): 752 - 759. [Abstract] [Full Text]
|
|
|
|
|
|
M. E. Safar and E. D. Frohlich The Arterial System in Hypertension : A Prospective View Hypertension, July 1, 1995; 26(1): 10 - 14. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. C. J. HUNT, J. E. BURLEY, C. M. L. CHAPMAN, and J. P. BEILBY A high-throughput MS-PCR method on MADGE gels for ANG II type-1 receptor A1166C polymorphism Physiol Genomics, August 31, 1999; 1(2): 71 - 73. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||