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Jim 1427mourad012005

  1. 1. Journal of Internal Medicine 2005; 257: 93–99Age-related increase of pulse pressure and plasminogenactivator inhibitor-1 I/D gene polymorphism in essentialhypertensionJ.-J. MOURAD1, G. DU CAILAR2, E.-M. NAZAL1, M. E. SAFAR3 AND A. MIMRAN2From the 1Department of Internal Medicine, Avicenne Hospital-AP-HP, Bobigny; 2Department of Internal Medicine, Lapeyronie Hospital,Montpellier; and 3Diagnosis Center, Hotel Dieu Hospital, Paris, FranceAbstract. Mourad J-J, du Cailar G, Nazal E-M, Safar between age and PP in subjects with never treatedME, Mimran A (Avicenne Hospital-AP-HP, Bobigny; essential hypertension.Lapeyronie Hospital, Montpellier; and Hotel Dieu Results. In the studied population, the genotypeHospital, Paris, France). Age-related increase of deletion (D)/D at position )675 of the PAI-1pulse pressure and plasminogen activator insertion (I)/D gene polymorphism was associatedinhibitor-1 I/D gene polymorphism in essential with a significant increase in the adjusted slope ofhypertension. J Intern Med 2005; 257: 93–99. the curve relating age to PP by comparison with the two other genotypes. No comparable difference inBackground. Pulse pressure (PP), a marker of cyclic age-related changes in systolic, diastolic or meanstrain on the arterial wall, is a significant predictor blood pressure was found.of cardiovascular (CV) risk, particularly regarding Conclusion. In subjects with essential hypertension,the incidence of coronary arterial stenosis. Genes the PAI-1 I/D gene polymorphism modulates therelated to haemostatic and/or fibrinolytic factors are age-mediated increase of PP, suggesting newconsistently influenced in vitro by mechanical insights on the complex interactions betweenstrain. genes, mechanical factors and CV risk.Objective. The goal of the present study was todetermine, in the three genotypes of the plasminogen Keywords: ageing, hypertension, plasminogen acti-activator inhibitor (PAI)-1 gene polymorphism, the vator inhibitor-1 gene polymorphism, pulse pressure.gender-adjusted difference in the relationships pathophysiological mechanisms. First, increasedIntroduction aortic SBP influences the level of end-systolicIncreased brachial systolic blood pressure (SBP) stress and promotes cardiac hypertrophy [1, 3,and pulse pressure (PP) are independent predictors 5]. Secondly, reduced DBP impairs coronary per-of cardiovascular (CV) risk, mainly for myocardial fusion and therefore favours myocardial ischaemiainfarction [1–6]. The predictive value of PP is [1–6].simultaneously influenced by an increase of SBP Long-term follow up of large populations hasand a decrease of diastolic blood pressure (DBP). In shown that the rate of increase of SBP, PP andlarge populations over 50 years of age, cross- arterial stiffness with age contributes greatly to CVsectional and longitudinal studies have shown that risk [9, 10]. The demonstration of wide intersubjectCV mortality is not only positively correlated to variations in the slope of the curve relating SBP orthe level of SBP [7, 8], but also that, at any given PP to age suggests that a number of environmentalvalue of SBP, CV mortality is higher when DBP is or genetic factors or the combination of both mightlower [8]. In fact, the predictive value of SBP and substantially influence this relationship [9–14].PP in CV mortality may result from two different Because a hereditary predisposition has previouslyÓ 2005 Blackwell Publishing Ltd 93
  2. 2. 94 J . - J . M O U R A D et al.been postulated for both PP and arterial stiffness mercury sphygmomanometer (mean of three meas-[12], some investigations have suggested that gen- urements made with patients in the supine position)etic factors play a role in the mechanism(s) of the and an automatic oscillometric device (see below)age-related increase of SBP and PP [13, 14]. on the morning of the study; (iv) no clinical or Perusse et al. [15] showed that particular geno- biological signs of secondary hypertension, astypes determined by single genes were associated previously defined [10]; and (v) no recent symp-with a steeper increase in SBP and hence PP with toms of coronary artery disease, heart failure,age amongst males and females in the general stroke, and/or peripheral arterial disease. Finally,population. According to this observation, it seems 97 men and 75 women, all Caucasian, from 19 tolikely that the age-related increase of PP might be 75 years old (mean: 47 years) were investigated instatistically influenced by genes potentially involved this study. Mean body weight and height andin longevity and CV mortality. Till the recent years, clinical and biological characteristics are indicatedmost of the results have been focused on gene in Table 1. Noninsulin diabetes was defined as apolymorphisms related to the renin-angiotensin fasting plasma glucose >7 mmol L)1 and/or by thesystem [13, 14, 16]. Few studies have been per- presence of antidiabetic agents (metformine and/orformed on gene polymorphisms related to fibrino- biguanids).lytic and/or haemostatic factors. However, All participants were examined in the morningalterations of fibrinolysis play a role in the CV risk after fasting for at least 12 h, and all underwentof myocardial infarction [17–19] and plasminogen the same procedure after providing written con-activator inhibitor (PAI)-1 release as well as corres- sent. After 20 min of rest in the supine position,ponding genes are significantly influenced in vitro by BP was measured automatically every 2 min withcyclic strain [20, 21]. Furthermore, changes in PAI- the Dinamap device (Model 845, Critikon, Tampa,1 plasma levels, sodium diet and renin-angiotensin FL, USA) [10]. The mean of five consecutivesystem are highly interrelated in the pathophysio- measurements was calculated. This automaticlogical mechanisms of hypertension and athero- method was chosen for the statistical analysis tosclerotic diseases [22]. avoid interobserver variations and to minimize The objective of the present study was to investi- ‘white-coat’ phenomenon. At the end of thisgate whether the PAI-1 insertion (I)/deletion (D) procedure, blood was drawn for determination ofgene polymorphism might influence the relation- standard biochemical measurements and DNAships between age and PP in men and women with extraction [10].never treated sustained essential hypertension. Table 1 Population description (n ¼ 172): mean ± SD (1 SD)Patients and methods and extremes (minimum–maximum)The study was performed in patients which entered Mean (±SD) Extremesthe Department of Internal Medicine of Lapeyronie Gender (men : women) 97 : 75Hospital, Montpellier, France, for a CV check-up Age (years) 47.1 ± 11.6 19–75ordered by their general practitioner or their cardi- Body height (cm) 167.7 ± 9.1 147–191ologist because of the presence of one or several CV Body weight (kg) 75.5 ± 17.1 44–163 BMI (kg m)2) 26.7 ± 5.2 18.5–58.6risk factors involving high BP, smoking, dyslipidae- Tobacco consumption 65 : 35mia, diabetes mellitus, and/or a family history of (no : yes) (%)premature CV disease. From this overall population Plasma total cholesterol (g L)1) 2.26 ± 0.42 1.20–3.45of patients, 172 consecutive subjects with never- Plasma creatinine (mmol L)1) 84.11 ± 15.32 54–123 SBP (mmHg) 163.0 ± 17.8 134–220treated sustained essential hypertension were DBP (mmHg) 96.9 ± 10.9 72–136enrolled in the present investigation. MAP (mmHg) 118.9 ± 12.0 93–159 Hypertensive subjects were selected according to PP (mmHg) 66.1 ± 13.6 40–118the following criteria: (i) a history of hypertension; HR (bpm) 67.5 ± 9.2 44–92(ii) no antihypertensive or vasodilator treatments BMI, body mass index; SBP, systolic blood pressure; DBP, diastolicprior to the start of the study; (iii) SBP >140 mmHg blood pressure; MAP, mean arterial pressure; PP, pulse pressure;and/or DBP >90 mmHg as measured with both HR, heart rate. Ó 2005 Blackwell Publishing Ltd Journal of Internal Medicine 257: 93–99
  3. 3. PULSE PRESSURE AND PAI-1 GENE POLYMORPHISM 95 Genomic DNA was prepared by standard salting- Resultsout techniques. The set of primers used for ampli-fication of relevant DNA regions, the probes and the Table 2 shows the mean values (adjusted to age andmethods used to detect the gene polymorphisms gender) of the different BP measurements accordinghave been described previously [13, 14]. In all cases, to the studied gene polymorphism. There was nopolymerase chain reaction amplification was used. difference between the three genotypes.The deletion (4G)/insertion (5G) polymorphism at Table 3 shows the adjusted slopes of the age–BPposition )675 of the PAI-1 promotor was studied curves in the three genotypes. Regarding PP, thereaccording to standard methods published in detail were significant differences (P1 < 0.034) (indicatedelsewhere [23, 24]. as P1) between the three studied genotypes. For the The statistical analyses was conducted using data DD genotype, PP represented 36% of the variance.collected from patients without any missing values. This interslope difference was not observed for theAllele and genotype frequencies were analysed using age–SBP, age–DBP and age–MAP relations.the gene-counting method. The Hardy–Weinberg Figure 1 shows the age–PP relationships (adjustedequilibrium, checked by chi-square test [13, 14] was on gender) for the DD + ID genotypes (lower panel)considered to be maintained. Quantitative data were versus the II genotype (upper panel). The presence ofexpressed as means ± SD (1 SD). Mean comparisons D allele was associated with a significant increase inwere made with adjustment to gender by anova the slope of the relationships between age and PP byusing the F-test to evaluate whether the mean comparison with the I allele.values of BP and other variables differed accordingto the different genotypes. The aim of the study was Discussionto show an intergroup difference in the slope of thecurve relating age and BP [either SBP or DBP or In this study, conducted in a population of never-mean arterial pressure (MAP) or PP] according to treated subjects with sustained essential hyperten-gender and, in a given gender, according to the sion, an increase of the slope of the age versus PPdifferent genotypes of a given gene. For this a test of curve was associated with the presence of the D/Dheterogeneity of slopes was used, which represents a variant of the PAI-1 gene polymorphism. Thisnatural extension of covariance analysis. This finding would have been even more meaningful ifmethod involves features from both anova and the result had been demonstrated using the alter-multiple regression. In a first step, the relationship native approach of longitudinal analysis. However, abetween age and BP in each genotype was explored number of previous reports have already identifiedby a multiple regression analysis in order to evaluate an adequate parallelism of the age–SBP and age–PPthe slope value. To do so, regression coefficients were relationship evaluated either from cross-sectional orthe least-squares estimates of the parameters. All longitudinal investigations [3, 7, 9, 10, 13, 14]. Onthese coefficients were adjusted to the standard CV the contrary, long-term follow up would have takenrisk factors, including: body mass index (BMI), many years and raised ethical concerns in view ofplasma total and high-density lipoprotein (HDL) the availability of drug treatment (mainly blockadecholesterol, triglycerides, diabetes (yes or no) and of the renin-angiotensin system) that might offsetsmoking habits (yes or no). After the slopes of theage–BP curves have been calculated for each geno-type, a slope comparison test was applied to evaluate Table 2 Blood pressures (age- and gender-adjusted) mean values and standard error according to genotypeswhether or not the age- and gender-adjustedregression coefficients of the age–BP relationship II (n ¼ 45) ID (n ¼ 82) DD (n ¼ 45)differed amongst the three groups. A F-test was used SBP (mmHg) 161.5 ± 2.5 164.4 ± 1.9 161.1 ± 2.6to determine the difference in the slopes. The result DBP (mmHg) 96.2 ± 1.7 96.4 ± 1.2 97.0 ± 1.7of the test (indicated P1 in Table 3) was considered MAP (mmHg) 118.0 ± 1.8 119.0 ± 1.3 118.4 ± 1.8as the principal outcome measure of the study. PP (mmHg) 65.3 ± 2.0 67.9 ± 1.5 64.1 ± 2.0Analyses were performed with sas software version SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP,6.7 (Cary, NC, USA) under Windows NT 98. A value mean arterial pressure; PP, pulse pressure; I, insertion; D, dele-of P £ 0.05 was considered significant. tion.Ó 2005 Blackwell Publishing Ltd Journal of Internal Medicine 257: 93–99
  4. 4. 96 J . - J . M O U R A D et al.Table 3 Blood pressures regression on age (adjusted on gender) in plasminogen activator inhibitor (PAI)-1 I/D gene polymorphismaccording to genotypes II (n ¼ 45) ID (n ¼ 82) DD (n ¼ 45) 2 2 R (%) Slope ± SE P-value R (%) Slope ± SE P-value R2 (%) Slope ± SE P-value P1-valueSBP 2 0.244 ± 0.255 0.344 9 0.472 ± 0.147 0.002 14 0.791 ± 0.271 0.006 0.394DBP 4 )0.025 ± 0.174 0.887 4 0.185 ± 0.092 0.048 3 )0.098 ± 0.172 0.572 0.257MAP 4 0.061 ± 0.178 0.732 7 0.286 ± 0.102 0.006 2 0.199 ± 0.192 0.305 0.550PP 2 0.269 ± 0.214 0.216 7 0.286 ± 0.105 0.008 36 0.889 ± 0.184 0.0001 0.034BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; HR,heart rate; R2, partial adjusted explanation of blood pressure variance by age and gender; Slope, regression coefficient; SE, standard error ofregression coefficient; n, sample size.P-value: probability of regression between blood pressure and age.P1-value: probability of interslope comparison between genotypes (see text). (a) and positively correlated in human populations, the Pulse pressure (mmHg) 130 120 110 haemodynamic data should be interpreted with 100 90 caution [1–7]. However, in the present study, this 80 70 issue raised minor concern since the modulating 60 50 influence of the gene polymorphisms studied on the 40 age–BP relationship was observed exclusively for PP 30 20 and not for SBP, DBP or MAP. 15 25 35 45 55 65 75 85 Age (years) In the present population, we observed that the P(Univariate Reg.) = 0.22 r (Univariate Corr.) = 0.19 slope of the age versus PP curve was enhanced in subjects with the D/D genotype of the PAI-1 gene 130 (b) r (Univariate Corr.) = 0.34 polymorphism. Studies of this polymorphism have Pulse pressure (mmHg) 120 shown a higher plasma PAI-1 activity in subjects 110 100 90 with the D than with the I allele in patients with 80 70 myocardial infarction, non insulin-dependent dia- 60 50 betes mellitus, insulin resistance and even in the 40 y = 0.38x + 49 general populations [17, 18, 27–33]. A relationship 30 20 between fibrinolysis and blood pressure was first 15 25 35 45 55 65 75 85 Age (years) described in the northern Sweden MONICA project P(Univariate Reg.) = 0.0001 [34], but when excluding groups of patients whoFig. 1 Age and pulse pressure relationships between plasminogen would be expected to have high PAI-1 levels, theactivator inhibitor (PAI)-1 II (a) and DD+ID (b) genotypes. Reg, association was lost. On the contrary, it is widelyregression; Corr, correlation. accepted that plasma PAI-1 levels are positively (but inconstantly) associated with increased risk forany deleterious consequences resulting from a atherosclerotic coronary disease [17–19, 35, 36]variant genotype [22, 25]. and mostly with increased SBP and DBP levels [37, In many reports, the hypothesis that genetic 38]. Since, in large populations, the slope of thevariability could lead to hypertension has been plasma PAI-1 level versus SBP or DBP is steeper fortested on the comparison of DBP mean values of SBP than for DBP [37], a positive and significantpatients with different genotypes (see review in [12, statistical link is expected between PP and the26]). In this investigation, we exclusively tested the plasma PAI-1 level. Our finding of a steeper slope ofhypothesis that genes might modulate the age- the age versus PP relationship for the D/D genotypeinfluence on PP and therefore play a role in CV risk (Fig. 1) agrees with this possibility and suggeststhrough an alteration in the course of this mechan- subtle links between increased PP, CV risk andical factor. Since PP represents the difference prothrombotic state [34–36]. Indeed, subjects withbetween SBP and DBP, and PP and SBP are strongly the 4G allele might have the higher values of PAI-1 Ó 2005 Blackwell Publishing Ltd Journal of Internal Medicine 257: 93–99
  5. 5. PULSE PRESSURE AND PAI-1 GENE POLYMORPHISM 97and of prothrombotic factors. They may have also a Acknowledgementssteeper increase of PP with age and, accordingly,the higher risk for myocardial infarction. Finally, This study was performed with the help of INSERM,impaired fibrinolytic balance is a feature of many ´ ´ ´ Societe Francaise d’Hypertension Arterielle and ¸patient populations including postmenopausal wo- GPH-CV (Groupe de Pharmacologie et d’Hemody- ´men and individuals with hypertension, insulin namique Cardiovasculaire), Paris. Authors thankresistance, type 2 diabetes and hypertriglyceridae- Mrs Anne Safar for her skilful secretarial help.mia, all of them having an increased risk for CVevents [37, 39]. We suggest that PP may be the Referencesmain mechanical factor enabling to establish aconsistent link between these different populations. 1 Darne B, Girerd X, Safar M, Cambien F, Guize L. Pulsatile versus steady component of blood pressure: a cross-sectionalOthers and we have shown that the level of aortic analysis and a prospective analysis on cardiovascular mor-PP (but not of SBP or DBP) is significantly and tality. Hypertension 1989; 13: 392–400.positively related with the number of arterial 2 Madhavan S, Ooi WL, Cohen H, Alderman MH. Relation ofcoronary stenosis in subjects with coronary ischae- pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 1994; 23: 395–401.mic disease and preserved cardiac function [40– 3 Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse42]. pressure useful in predicting risk for coronary heart disease? In the present study, the age–PP relationship of The Framingham Heart Study. Circulation 1999; 100:the D/D genotype could not be explained on the 354–60. 4 Millar JA, Lever AF, Burke V. Pulse pressure as a risk factorbasis of cardiac factors which are poorly related to for cardiovascular events in the MRC mild hypertension trial.fibrinolytic and/or haemostatic agents. The age–PP J Hypertens 1999; 17: 1065–72.relationship was rather modulated by vascular 5 Benetos A, Safar M, Rudnichi A et al. Pulse pressure: a pre-factors as arterial stiffness and wave reflections. dictor of long-term cardiovascular mortality in a French male population. Hypertension 1997; 30: 1410–5.This observation is consistent with previous inves- 6 Mitchell GF, Moye LM, Braunwald E et al. Sphygmomano-tigations in the past where we showed subtle but metrically determined pulse pressure is a powerful inde-consistent statistical links between plasma PAI-1, pendent predictor of recurrent events after myocardialarterial stiffness and wave reflections, the two latter infarction in patients with impaired left ventricular function. Circulation 1997; 96: 4254–60.factors being the main determinants of PP. Indeed, 7 Benetos A, Zureik M, Morcet J et al. A decrease in diastolicelevated plasma PAI-1 levels are significantly asso- blood pressure combined with an increase in systolic bloodciated with reduced carotid distensibility and/or pressure is associated with high cardiovascular mortality.altered PP amplification, both in subjects with J Am Coll Cardiol 2000; 35: 673–80. 8 Blacher J, Gasowski J, Staessen JA et al. Pulse pressure – nothypertension and overweight and in patients with mean pressure – determines cardiovascular risk in olderchronic renal disease [43–45]. hypertensive patients. Arch Intern Med 2000; 160: 1085–9. This study had several limitations: the cohort is 9 Franklin SS, Gustin W IV, Wong ND et al. Hemodynamicrelatively small, and therefore required that the patterns of age-related changes in blood pressure. The Fra- mingham Heart Study. Circulation 1997; 96: 308–15.findings should be constantly adjusted to age and 10 Benetos A, Adamopoulos C, Bureau JM et al. Determinants ofsex. On the contrary, and for the same reason, gene– accelerated progression of arterial stiffness in normotensivegene interactions were not evaluated, particularly subjects and in treated hypertensive subjects over a 6-yearwith the renin-angiotensin system [14, 39, 46]. period. Circulation 2002; 105: 1202–7. 11 du Cailar G, Mimram A, Fesler P, Ribstein J, Blacher J, Safar In conclusion, the results of present study have ME. Dietary sodium and pulse pressure in normotensive andshown a possible influence of PAI-1 polymorphism essential hypertensive subjects. J Hypertens 2004; 22: 697–on the increase of PP with age in hypertensive 703.subjects. Because PP is a consistent and independent 12 Avolio A. Genetic and environmental factors in the function and structure of the arterial wall. Hypertension 1995; 26:predictor of CV mortality [1–7], this result gives a 34–7.new insight on the relationship between genes, 13 Lajemi M, Labat C, Gautier S et al. Angiotensin II type 1mechanical factors and CV risk. receptor )153A/G and 1166A/C gene polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens 2001; 19: 407–13.Conflict of interest statement 14 Safar ME, Lajemi M, Rudnichi A, Asmar R, Benetos A. Angiotensin-converting enzyme D/I gene polymorphism andNo conflict of interest was declared.Ó 2005 Blackwell Publishing Ltd Journal of Internal Medicine 257: 93–99
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  7. 7. PULSE PRESSURE AND PAI-1 GENE POLYMORPHISM 99 sclerosis in a healthy male population. J Epidemiol 2000; 10: ˆ Correspondence: Prof. Michel Safar, Diagnosis Center, Hopital 34–41. ˆ Hotel-Dieu, 1, place du Parvis Notre-Dame, 75181 Paris Cedex46 Moore JH, Lamb JM, Brown NJ, Vaughan DE. Comparison of 04, France. combinatorial partitioning and linear regression for the (fax: +33 1 42 34 86 32; e-mail: michel.safar@htd.ap-hop- detection of epistatic effects of the ACE I/D and PAI-1 4G/5G paris.fr). polymorphisms on plasma PAI-1 levels. Clin Genet 2002; 62: 74–9.Ó 2005 Blackwell Publishing Ltd Journal of Internal Medicine 257: 93–99