HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Powell, J. T. Articles by Länne, T. Search for Related Content PubMed PubMed Citation Articles by Powell, J. T. Articles by Länne, T.

Influence of fibrillin-1 genotype on the aortic stiffness in men

¹University Hospitals of Coventry and Warwickshire, Walsgrave, Coventry; ²Department of Vascular Surgery, Imperial College at Charing Cross, London, United Kingdom; and ³Division of Clinical Physiology, Department of Medicine and Care, University Hospital, Linköping, Sweden

Submitted 28 May 2004 ; accepted in final form 4 May 2005

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Aortic stiffness is a predictor of cardiovascular mortality. The mechanical properties of the arterial wall depend on the connective tissue framework, with variation in fibrillin-1 and collagen I genes being associated with aortic stiffness and/or pulse pressure elevation. The aim of this study was to investigate whether variation in fibrillin-1 genotype was associated with aortic stiffness in men. The mechanical properties of the abdominal aorta of 79 healthy men (range 28–81 yr) were investigated by ultrasonographic phase-locked echo tracking. Fibrillin-1 genotype, characterized by the variable tandem repeat in intron 28, and collagen type I alpha 1 genotype characterized by the 2,064 G>T polymorphism, were determined by using DNA from peripheral blood cells. Three common fibrillin-1 genotypes, 2-2, 2-3, and 2-4, were observed in 50 (64%), 10 (13%), and 11 (14%) of the men, respectively. Those of 2-3 genotype had higher pressure strain elastic modulus and aortic stiffness compared with men of 2-2 or 2-4 genotype (P = 0.005). Pulse pressure also was increased in the 2-3 genotype (P = 0.04). There was no significant association between type 1 collagen genotype and aortic stiffness in this cohort. In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease.

blood pressure; collagen; elastin; mechanics

In a previous study, our laboratory demonstrated an association between arterial pulse pressure and variation in the fibrillin-1 gene in healthy middle-aged men (27). This study used the variable tandem nucleotide repeat in intron 28 of the fibrillin-1 gene to describe three common genotypes, 2-2 (present in over half the population), 2-3, and 2-4. Men of 2-3 genotype had the highest pulse pressure. Pulse pressure is an independent predictor of cardiovascular outcomes (2). Arterial stiffness is an important determinant for pulse pressure, and recently evidence has begun to emerge that aortic stiffness itself is an independent predictor of cardiovascular mortality in hypertensive patients (3, 4, 18, 20). These findings have awakened interest in genetic determinants of aortic stiffness. Recently, Medley and coworkers showed that fibrillin-1 genotype was associated with increased aortic stiffness in patients with coronary artery disease (21). In particular, using the same variable tandem nucleotide repeat (27), they showed, as a measure of aortic stiffness, that patients of the 2-3 fibrillin genotype had significantly higher input impedance and characteristic impedance than patients of 2-2 or 2-4 genotype (21). Similarly, pulse-wave velocity measurements have been used to demonstrate an association between a polymorphism in a Sp1 binding site of the first intron of the COL1A1 (type 1 collagen) gene and aortic stiffness in healthy young adults (5).

We have used a different, noninvasive technique, phase-locked echo tracking, to measure the stiffness of the abdominal aorta in healthy men. The aim of this study was to determine whether variation in the fibrillin-1 or type 1 collagen genes was associated with aortic stiffness in this cohort.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The majority of subjects studied (n = 50) were healthy male volunteers, aged 40–59 yr, who were first-degree relatives of patients with abdominal aortic aneurysm. In addition, 4 persons <40 yr and 25 persons >59 yr were investigated. Subjects with peripheral arterial disease (signified by an ankle brachial systolic pressure index <0.9) and maximum abdominal aortic diameter more than 2.5 cm were excluded. A questionnaire was administered to determine the history of previous myocardial infarction, angina, hypertension, diabetes, and smoking, and the use of any regular medications was noted. A blood sample was taken for the measurement of cholesterol and to provide peripheral blood cells for the preparation of genomic DNA. The staff performing ultrasonographic investigations were blinded to the clinical data and to the genotypes, which were evaluated later. Staff undertaking the genotyping were blinded to the physiological measurements. Each subject gave informed consent to the experiments, which were approved by the Ethics Committee at Lund University, Lund, Sweden.

Ultrasonic measurements of aortic distensibility.   The diameter and pulsatile diameter changes of the abdominal aorta were measured by means of echo-tracking ultrasonography (29). We used an electronic echo-tracking instrument (Diamove, Teltec AB, Lund, Sweden) capable of detecting vessel wall movements of <10 µm (19). With this equipment, pulsatile vessel diameter changes can be measured and, in combination with blood pressure measurements, form the basis for calculation of vessel wall stiffness (inversely related to vascular distensibility). The instrument was interfaced with a B-mode real-time ultrasound scanner (EUB-240, Hitachi, Tokyo, Japan) and fitted with a 3.5-MHz linear array transducer. A data acquisition system containing a personal computer type 386 (Express, Tokyo, Japan) and a 12-bit analog-to-digital converter (Analog Devices, Norwood, MA) was included to enable simultaneous monitoring of the electrocardiogram, arterial blood pressure, and vessel diameter. Briefly, two electronic markers automatically locked to the luminal interface of the echoes from the anterior and posterior vessel wall and followed the pulsatile movements of the vessel wall. The repetition frequency of the echo-tracking loops was 870 Hz, with a time resolution of 1.2 ms.

All measurements were performed with the subject in the supine position after at least 15 min of rest. Differences in blood pressure between left and right arm were excluded before the investigation. From the real-time picture, the abdominal aorta distal to the renal arteries was insonated in longitudinal section, and the echoes from the aortic wall were optimized before pulsatile diameter changes were recorded, 3.5 cm proximal to the iliac bifurcation. A sequence of at least five representative consecutive-diameter cycles was chosen manually, and mean vessel diameters and diameter changes were calculated. Indirect blood pressure measurements were performed immediately after measurements of the pulsatile aortic diameter with a sphygmomanometer and a standard cuff on the left arm. Mean arterial blood pressure (MAP) was taken as the brachial diastolic pressure plus one-third of the pulse pressure and assumed to be equal to the intra-arterial pressure in the abdominal aorta. Comparison between intra-arterial pressure in abdominal aorta and the brachial blood pressure obtained by the auscultatory method has shown a slight systematic underestimation of pulse pressure, which does not affect comparative studies of aortic stiffness between different groups of subjects (30).

Distensibility was expressed as the inverse relation of pressure strain elastic modulus and stiffness.

Pressure strain elastic modulus (Ep) was defined according to Peterson et al. (26) as:

(1)

Stiffness () was defined according to Kawasaki et al. (14) as

(2)

In these equations, P syst and P diast are the maximal systolic and end-diastolic blood pressure levels (mmHg). D syst and D diast are the corresponding vessel diameters (mm). Ep is measured in newtons per square meter. The factor (K) for converting millimeters of mercury to newtons per square meter is 133.3.

Each subject was examined three times with calculation of pressure strain elastic modulus and stiffness from the corresponding diameter, pulsatile diameter change, and blood pressures obtained by the auscultatory method. Mean values for each subject were calculated. By this technique, the variability for repeated measurements of the aortic diameter and pulsatile diameter changes were 5 and 15%, respectively (10).

Preparation and analysis of genomic DNA.   Isolation of genomic DNA was performed according to routine protocols, and DNA samples were typed for the (TAAAA)_n repeat in intron 28 of the fibrillin-1 gene on chromosome 15, using the primers CCT GGC TAC CAT TCA ACT CCC and GAG TAC ATA GAG TGT TTT AGGG as described previously (27). Polymorphism in the Sp1 binding site (in the first intron, 2064 G>T) of the COL1A1 gene was determined as described previously, using the polymerase chain reaction with a mismatched primer that introduces a diallelic restriction site for Bal1 (9).

Statistics.   Data are presented as means ± SD for all data, because these approximated to a normal distribution. Comparisons were performed by ² tests for categorical variables. Analysis of variance was used for the three-group analysis of continuous variables. Associations among genotype, aortic diameter, and aortic stiffness were adjusted for age, body mass index, mean blood pressure, and heart rate in a regression model.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The 79 men (mean age 55.3 yr, range 28–81) had mean aortic diameter 1.84 ± 0.16 cm and mean systolic pressure 138 ± 13 mmHg; 17 (22%) were current smokers, but no subject had diabetes.

The distribution of the fibrillin-1 genotypes for the (TAAAA)_n repeat was 1-2 (4), 1-3 (1), 1-4 (1), 2-2 (50), 2-3 (10), 2-4 (11), 3-3 (1), and 3-4 (1). Associations between genotype and aortic stiffness were investigated by using only the three common genotypes 2-2, 2-3, and 2-4 (total of 71 men, of whom 47 were middle-aged, 40–59 yr). The mean aortic stiffness was 13.30 ± 7.62. The demographic and measured data, according to fibrillin-1 genotype, are shown in Table 1. Seven subjects were being treated for hypertension (four 2-2, two 2-3, one 2-4). Subjects of 2-3 genotype had the highest pulse pressure, 61 ± 9, vs. 52 ± 9 and 51 ± 11 mmHg for those of 2-2 and 2-4 genotype, respectively (P = 0.04). Subjects of 2-3 genotype also had the highest aortic stiffness 18.66 ± 5.09, vs. 12.85 ± 7.10 and 11.49 ± 6.88 for those of 2-2 and 2-4 genotype, respectively (P = 0.001). Interestingly, the subject of 3-3 genotype had the highest aortic stiffness ( = 38.9). The subjects of 2-3 genotype also had the highest systolic blood pressure, pressure strain elastic modulus, and heart rate (Table 1). The association between aortic stiffness and 2-3 genotype remained highly significant after adjustment for age, body mass index, mean blood pressure, and heart rate (P = 0.005).

For the COL1A1 genotype, 58 men (74%) were homozygous for the G allele, 20 (25%) men were GT heterozygotes, and one man (1%) was homozygous for the T allele. Mean aortic stiffness for men of GG genotype was 12.67 ± 6.89 compared with 13.54 ± 7.20 for men of GT genotype (P = 0.35). Adjustment for age, body mass index, and heart rate had little effect (P = 0.32).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study has extended current information about the genetic contribution to aortic stiffness. Using phase-locked echo tracking to noninvasively measure aortic stiffness, we have shown that in men (predominantly middle-aged) those of fibrillin-1 2-3 genotype had stiffer abdominal aortas than men of the two other common genotypes (2-2 and 2-4). The strength of the association in a small population indicates the importance of this effect. In contrast, the polymorphism in the COL1A1 promoter had a nonsignificant effect on the stiffness of the abdominal aorta.

Expression and turnover of the elastic connective tissue matrix in the arterial wall may influence the elastic properties. As a constituent of extensible microfibrils, fibrillin-1 might be of importance. These microfibrils are associated with the elastin fibers and arranged in concentric elastic lamellae. By directing the orientation of the elastin fibers, fibrillin-1 microfibrils may play a vital role in load bearing (28). There are several indications that fibrillin-1 is an important factor in the regulation of mechanical properties in central arteries. Mutations in the fibrillin-1 gene have been associated with increased aortic stiffness as well as increase in central pulse pressure in Marfan syndrome (12, 13, 31). Furthermore, an association has been established between the fibrillin-1 polymorphism used in this study, with pulse pressure and aortic impedance, even though this polymorphism has not been reported to be functional (21, 27).

Because the pressure-diameter relationship of the arterial wall is nonlinear, pressure strain elastic modulus is pressure dependent (see Eq. 1). This might explain why the pressure strain elastic modulus value was 80% higher in the subjects of fibrillin-1 2-3 genotype than in those of fibrillin-1 2-2 and 2-4 genotypes, because mean blood pressure was higher in the 2-3 genotype (Table 1). However, stiffness index () is based on the observed linear relation between the logarithm of relative pressure and distension ratio (Eq. 2) and has been shown to be less pressure dependent (15). Nevertheless, stiffness was 60% higher in subjects of fibrillin-1 2-3 genotype than in those of fibrillin-1 2-2 and 2-4 genotypes. Furthermore, the association between aortic stiffness and 2-3 genotype remained highly significant also after adjustment for mean pressure, indicating the possibility of a structural difference in the aortic wall between the groups (Table 1).

Calculation of impedance provides an estimate of average stiffness distal to the point of measurement. In contrast, phase-locked echo tracking measures stiffness at a single point in the artery, the abdominal aorta in the present investigations. This differentiates our study from other recent studies (5, 20, 21). The cohorts also had very different characteristics: older patients with coronary artery disease and healthy young adults (5, 21). We confined our study to men because of the gender difference in aortic stiffness (29). Furthermore, because aortic stiffness also is dependent on age, we separately evaluated the middle-aged men (40–59 yr). Although the associations between aortic stiffness and fibrillin-1 genotype were demonstrated in both the complete cohort as well as the more restricted group, the association between pulse pressure and aortic stiffness only was significant in the complete cohort, probably because of sample size limitations.

All the men were selected by being first-degree relatives of patients with abdominal aortic aneurysm. It might be argued that an underlying genetic predisposition to aneurysmal disease might confound our results, because abdominal aortic aneurysms have a higher prevalence in near relatives of patients with abdominal aortic aneurysms than in the general population (34). Also, in patients with abdominal aortic aneurysm, those of fibrillin 2-3 genotype have highest systolic and pulse pressures and these patients have stiff aortic walls (16, 23). However, the frequency of the fibrillin-1 genotypes in our study was similar to those earlier described, both in healthy middle-aged men and in patients with coronary artery disease (21, 27). Furthermore, none of the subjects in our study had a dilated aorta, and aortic stiffness, diameter, blood pressure, and heart rate were within the ranges reported earlier (Table 1) (32). Therefore, any underlying genetic or cardiovascular disease bias to our study was likely to be minimal.

We observed a surprising, novel association between increased heart rate and the fibrillin-1 2-3 genotype in our cohort, the significance of which is uncertain (Table 1). An increased heart rate might alter cardiovascular regulation in several ways. It may lead to decreased pulse pressure due to a combination of an increase in diastolic decay and reduced diastolic time. An increase in sympathetic tone often accompanies an increase in heart rate, which leads to increased peripheral resistance (24). This, in turn, may result in changed pulse pressure amplification between central and peripheral arteries owing to a modification in the location of reflection sites, with an overestimation of central aortic pressure as consequence when only the peripheral blood pressure is measured (as in this study) (1, 35). Several recent papers have addressed the issue whether increased heart rate affects arterial stiffness and peripheral blood pressure. The pulse wave velocity, as well as the peripheral pulse pressure, were unaffected or lower in the studies by Albaladejo et al. (1) and Wilkinson et al. (35), indicating no change in arterial stiffness. In contrast, Lantelme et al. (17) found a significant increase in pulse-wave velocity but without any change in pressure. Thus the effect on arterial stiffness appears unresolved, and, when we adjusted for heart rate, the significance of the association between fibrillin-1 genotype and aortic stiffness remained. A high resting heart rate has been related to the development of coronary atherosclerosis and of cardiovascular events and death in several studies (8, 25, 33). In fact, the findings of both increased aortic stiffness with concomitant increase in pulse pressure and a significant increase in heart rate might indicate that individuals with the fibrillin-1 2-3 genotype are at additional high risk for cardiovascular events.

The mechanical properties of the wall of the aorta are determined mainly by elastin and collagens. The distensible elastin is load bearing at low pressures and the much stiffer collagen at high pressures, giving rise to a nonlinear pressure diameter curve, and it is clear that the collagen-to-elastin ratio is the principal determinant of wall mechanics (6). Because only a minor part of the collagen is load bearing in the physiological pressure range, however, the amount and function of elastin will probably have the largest impact on the outcome of the mechanics of the aortic wall (7, 11). Thus it is not surprising that, with a normal distribution of genotypes, no significant difference in aortic stiffness was found between COL1A1–2064 GT heterozygotes and GG homozygotes, although the trend was in the same direction as reported previously (5). This collagen polymorphism may be functional, because it lies within a Sp1 binding site. The importance of genetic regulation of the extracellular matrix components on aortic stiffness is supported by the recent observations that matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening (22).

In summary, our results provide further confirmation that variation in connective tissue genes, particularly fibrillin-1, is an important determinant of aortic stiffness. The findings of increased aortic stiffness, blood pressure, and heart rate in the individuals with fibrillin-1 2-3 genotype indicate the possibility of synergistic mechanisms increasing their risk of cardiovascular events.

	FOOTNOTES

 

Address for reprint requests and other correspondence: T. Länne, Division of Clinical Physiology, Dept. of Medicine and Care, Univ. Hospital, SE 581 85 Linköping, Sweden (E-mail: tosla{at}imv.liu.se)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Albaladejo P, Copie X, Boutouyrie P, Laloux B, Declere AD, Smulyan H, and Benetos A. Heart rate, arterial stiffness, and wave reflections in paced patients. Hypertension 38: 949–952, 2001.[Abstract/Free Full Text]
2. Benetos A, Safar M, Rudnichi A, Smulyan H, Richard JL, Ducimetiere P, and Guize L. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population. Hypertension 30: 1410–1415, 1997.[Abstract/Free Full Text]
3. Blacher J, Guerin A, Pannier B, Marchais S, Safar M, and London GM. Impact of aortic stiffness on survival in end-stage renal failure. Circulation 99: 2434–2439, 1999.[Abstract/Free Full Text]
4. Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, and Laurent S. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 39: 10–15, 2002.[Abstract/Free Full Text]
5. Brull DJ, Murray LJ, Boreham CA, Ralston SH, Montgomery HE, Gallagher AM, McGuigan FE, Davey Smith G, Savage M, Humphries SE, and Young IS. Effect of a COL1A1 Sp1 binding site polymorphism on arterial pulse wave velocity: an index of compliance. Hypertension 38: 444–448, 2001.[Abstract/Free Full Text]
6. Dobrin P. Vascular mechanics. In: Handbook of Physiology. The Cardiovascular System. Peripheral Circulation and Organ Blood Flow. Bethesda, MD: Am. Physiol. Soc., 1983, sect. 2, vol. 3, pt. 1, chapt. 3, p. 65–102.
7. Dobrin PB, Baker WH, and Gley WC. Elastolytic and collagenolytic studies of arteries. Implications for the mechanical properties of aneurysms. Arch Surg 119: 405–409, 1984.[Abstract/Free Full Text]
8. Gillman MW, Kannel WB, Belanger A, and D'Agostino RB. Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 125: 1148–1154, 1993.[CrossRef][Web of Science][Medline]
9. Grant SF, Reid DM, Blake G, Herd R, Fogelman I, and Ralston SH. Reduced bone density and osteoporosis associated with a polymorphic Sp1 binding site in the collagen type I alpha 1 gene. Nat Genet 14: 203–205, 1996.[CrossRef][Web of Science][Medline]
10. Hansen F, Bergqvist D, Mangell P, Rydén , Sonesson B, and Lanne T. Non-invasive measurement of pulsatile vessel diameter changes and elastic properties in human arteries: a methodological study. Clin Physiol 13: 631–643, 1993.[Web of Science][Medline]
11. Hayashi K, Sato H, Handa H, and Moritake K. Biomechanical study of the constitutive laws of vascular walls. Exp Mech 14: 440–444, 1974.[CrossRef]
12. Jeremy RW, Huang H, Hwa J, McCarron H, Hughes CF, and Richards JG. Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome. Am J Cardiol 74: 369–373, 1994.[CrossRef][Web of Science][Medline]
13. Jondeau G, Boutouyrie P, Lacolley P, Laloux B, Dubourg O, Bourdarias JP, and Laurent S. Central pulse pressure is a major determinant of ascending aorta dilation in Marfan syndrome. Circulation 99: 2677–2681, 1999.[Abstract/Free Full Text]
14. Kawasaki T, Sasayama S, Yagi S, Asakawa T, and Hirai T. Non-invasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res 21: 678–687, 1987.[Web of Science][Medline]
15. Lanne T and Ahlgren AR. Increased arterial stiffness in IDDM women —methodological considerations. Diabetologia 39: 871–872, 1996.[CrossRef][Medline]
16. Lanne T, Sonesson B, Bergqvist D, Bengtsson H, and Gustafsson D. Diameter and compliance in the male human abdominal aorta: influence of age and aortic aneurysm. Eur J Vasc Surg 6: 178–184, 1992.[CrossRef][Web of Science][Medline]
17. Lantelme P, Mestre C, Lievre M, Gressard A, and Milon H. Heart rate: an important confounder of pulse wave velocity assessment. Hypertension 39: 1083–1087, 2002.[Abstract/Free Full Text]
18. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, and Benetos A. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37: 1236–1241, 2001.[Abstract/Free Full Text]
19. Lindström K, Gennser G, Sindberg Eriksson P, Bentin M, and Dahl P. An improved echo-tracker for studies on pulse-waves in the fetal aorta. In: Fetal Physiological Measurements. London: Butterworths, 1987, p. 217–226.
20. Meaume S, Benetos A, Henry OF, Rudnichi A, and Safar ME. Aortic pulse wave velocity predicts cardiovascular mortality in subjects >70 years of age. Arterioscler Thromb Vasc Biol 21: 2046–2050, 2001.[Abstract/Free Full Text]
21. Medley TL, Cole TJ, Gatzka CD, Wang WY, Dart AM, and Kingwell BA. Fibrillin-1 genotype is associated with aortic stiffness and disease severity in patients with coronary artery disease. Circulation 105: 810–815, 2002.[Abstract/Free Full Text]
22. Medley TL, Kingwell BA, Gatzka CD, Pillay P, and Cole TJ. Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression. Circ Res 92: 1254–1261, 2003.[Abstract/Free Full Text]
23. MacSweeney ST, Skidmore C, Turner RJ, Sian M, Brown L, Henney AM, Greenhalgh RM, and Powell JT. Unravelling the familial tendency to aneurysmal disease: popliteal aneurysm, hypertension and fibrillin genotype. Eur J Vasc Endovasc Surg 12: 162–166, 1996.[CrossRef][Web of Science][Medline]
24. Narkiewicz K and Somers VK. Interactive effect of heart rate and muscle sympathetic nerve activity on blood pressure. Circulation 100: 2514–2518, 1999.[Abstract/Free Full Text]
25. Palatini P and Julius S. Heart rate and the cardiovascular risk. J Hypertens 15: 3–17, 1997.[CrossRef][Web of Science][Medline]
26. Peterson LH, Jensen RE, and Parnell J. Mechanical properties of arteries in vivo. Circ Res 8: 622–639, 1960.[Abstract/Free Full Text]
27. Powell JT, Turner RJ, Henney AM, Miller GJ, and Humphries SE. An association between arterial pulse pressure and variation in the fibrillin-1 gene. Heart 78: 396–398, 1997.[Abstract/Free Full Text]
28. Sherratt MJ, Wess TJ, Baldock C, Ashworth J, Purslow PP, Shuttleworth CA, and Kielty CM. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Micron 32: 185–200, 2001.[CrossRef][Web of Science][Medline]
29. Sonesson B, Hansen F, Stale H, and Lanne T. Compliance and diameter in the human abdominal aorta—the influence of age and sex. Eur J Vasc Surg 7: 690–697, 1993.[CrossRef][Web of Science][Medline]
30. Sonesson B, Lanne T, Vernersson E, and Hansen F. Sex difference in the mechanical properties of the abdominal aorta in human beings. J Vasc Surg 20: 959–969, 1994.[Web of Science][Medline]
31. Sonesson B, Hansen F, and Lanne T. Abnormal mechanical properties of the aorta in Marfan's syndrome. Eur J Vasc Surg 8: 595–601, 1994.[CrossRef][Web of Science][Medline]
32. Sonesson B, Lanne T, Hansen F, and Sandgren T. Infrarenal aortic diameter in the healthy person. Eur J Vasc Surg 8: 89–95, 1994.[CrossRef][Web of Science][Medline]
33. Thomas F, Bean K, Provost JC, Guize L, and Benetos A. Combined effects of heart rate and pulse pressure on cardiovascular mortality according to age. J Hypertens 19: 863–869, 2001.[CrossRef][Web of Science][Medline]
34. Van Vlijmen-van Keulen CJ, Pals G, and Rauwerda JA. Familial abdominal aortic aneurysm: a systematic review of a genetic background. Eur J Vasc Endovasc Surg 24: 105–116, 2002.[CrossRef][Web of Science][Medline]
35. Wilkinson IB, Mohammad NH, Tyrrell S, Hall IR, Webb DJ, Paul VE, Levy T, and Cockcroft JR. Heart rate dependency of pulse pressure amplification and arterial stiffness. Am J Hypertens 15: 24–30, 2002.[CrossRef][Web of Science][Medline]

This article has been cited by other articles:

				C Vlachopoulos, K Aznaouridis, and C Stefanadis Clinical appraisal of arterial stiffness: the Argonauts in front of the Golden Fleece Heart, November 1, 2006; 92(11): 1544 - 1550. [Abstract] [Full Text] [PDF]

				Yasmin, I. B. Wilkinson, K. M. O'Shaughnessy, T. Lanne, R. De Basso, and J. T. Powell Influence of fibrillin-1 genotype on aortic stiffness in men: a note of caution J Appl Physiol, April 1, 2006; 100(4): 1431 - 1432. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Powell, J. T. Articles by Länne, T. Search for Related Content PubMed PubMed Citation Articles by Powell, J. T. Articles by Länne, T.