Carole Amant

D Allele of the Angiotensin I–Converting Enzyme Is a Major Risk Factor for Restenosis After Coronary Stenting

BACKGROUND Although intracoronary stent implantation significantly reduces restenosis compared with balloon angioplasty, a minority of patients still develop restenosis predominantly due to neointimal hyperplasia. Experimental studies suggest that the renin-angiotensin system is involved in neointimal hyperplasia after arterial injury. In humans, the plasma and cellular levels of ACE are associated with an I/D genetic polymorphism in the ACE gene, DD patients having higher levels. METHODS AND RESULTS We investigated a possible relation between the ACE I/D polymorphism and restenosis in 146 patients who underwent successful implantation of a Palmaz-Schatz stent and had 6-month follow-up angiography. The minimal lumen diameter (MLD) before and after the procedure did not differ significantly among the three groups of genotypes (DD, ID, and II). At follow-up, MLD had a significant inverse relationship to the number of D alleles present (DD, 1.65 +/- 0.71 mm; ID, 1.84 +/- 0.60 mm; II, 2.05 +/- 0.61 mm; P < .007). Late luminal loss during the follow-up period was significantly related to the number of D alleles (DD, 0.89 +/- 0.61 mm; ID, 0.60 +/- 0.52 mm; II, 0.40 +/- 0.53 mm; P < .0001). The relative risk of restenosis (defined as a > 50% diameter stenosis at follow-up) approximated by the adjusted odds ratio was 2.00 per number of D alleles (95% confidence interval, 1.03 to 3.88, P < .04). CONCLUSIONS The ACE I/D polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the renin-angiotensin system may be implicated in the pathogenesis of restenosis after coronary stenting.

THE ANGIOTENSIN II TYPE 1 RECEPTOR GENE POLYMORPHISM IS ASSOCIATED WITH CORONARY ARTERY VASOCONSTRICTION

OBJECTIVES This study sought to assess the potential association of the angiotensin-converting enzyme (ACE) and angiotensin II type 1 (AT1) receptor gene polymorphisms on coronary vasomotion in humans. BACKGROUND Abnormal coronary vasomotion plays a role in the clinical expression of coronary atherosclerosis. The components of the renin-angiotensin system are important determinants of vasomotor tone. Furthermore, epidemiologic evidence suggests that these components are involved in the pathogenesis of coronary artery disease. Indeed, two genetic polymorphisms of the ACE and AT1 receptor genes were synergistically associated with the occurrence of myocardial infarction. The influence of these genetic polymorphisms on the risk of myocardial infarction may be related, at least in part, to a deleterious effect on coronary vasomotion. METHODS We studied the response of angiographically normal human coronary arteries after intravenous injection of methylergonovine maleate, a potent vasoconstrictor whose effects have been previously explored in various aspects of coronary artery disease. We characterized the ACE and AT1 receptor genotypes in a consecutive series of 140 patients with normal coronary arteries. Coronary vasomotion was assessed with quantitative coronary angiography. RESULTS No effect of the ACE gene polymorphism was detected. Conversely, the patients carrying the AT1 receptor CC genotype (n = 13) had significantly greater vasoconstriction in distal coronary vessels (p < 0.009). CONCLUSIONS The AT1 receptor gene polymorphism is associated with coronary vasomotion in humans.

The deletion allele of the angiotensin I converting enzyme gene as a genetic susceptibility factor for cognitive impairment

Experimental evidences suggest an implication of the renin angiotensin system (RAS) as a potential determinant of cognitive functions. To explore this hypothesis, we compared the distribution of an insertion (I)/deletion (D) polymorphism of the gene coding for the angiotensin I converting enzyme (ACE), a key enzyme of the RAS, in 228 elderly with cognitive impairment to that of 255 controls. The ACE D allele frequency was higher in the group with cognitive impairment (0.594) than in controls (0.514) (P < 0.02). The ACE DD genotype carriers had an increased risk of cognitive impairment (OR = 1.60, 95% CI (1.04-2.36), P < 0.03), independent of other risk factors of cognitive impairment: age, gender and presence of the apolipoprotein E epsilon 4 allele. This association was stronger in men (OR = 3.25, 95% CI (1.40-7.58), P < 0.006). This result suggests a possible implication of the RAS in human brain and cognitive functions.

Polymorphism of the prion protein is associated with cognitive impairment in the elderly: The EVA study

Background: Little is known about the role of the prion protein (PrPsen/gene PRNP). PRNP knockout mice studies suggest that PrPsen may be involved in CNS degeneration. This observation prompted us to examine the influence of PRNP genetic variability on cognitive abilities in the elderly. Methods: In a community-based sample of 1,163 subjects aged 59 to 71 years, we characterized the valine (Val) and methionine (Met) allele of the PRNP polymorphism at codon 129. The effect of this polymorphism was estimated on the Mini-Mental State Examination (MMSE) and on a global composite score built from a battery of nine different neuropsychological tests. The results were adjusted for age, gender, education, and apolipoprotein E (apoE) polymorphism. Results: Cognitive impairment (MMSE score < 24) was present in 2.5% of the Met-Met individuals, 2.9% of the Met-Val individuals, and 7.0% of Val-Val subjects (p = 0.02). Subjects homozygous for the PRNP Val allele had a lower MMSE and global score than the two other genotypes (p< 0.003). This effect was of the same magnitude as that of the apoEϵ4 allele on cognitive performances. Both apoE ϵ4 and PRNP Val allelic effects were additive. Conclusion: This observation suggests that variability of the PRNP locus may be associated with cognitive performance in the elderly. This result, if confirmed, offers potential clues for the role of PRNP in the human brain.

Angiotensin II Type 1 Receptor Gene Polymorphism Is Associated with an Increased Vascular Reactivity in the Human Mammary Artery in vitro

A gene polymorphism of the angiotensin II (AII) type 1 receptor has been described previously (A to C transversion at position 1166). Besides the epidemiological studies needed to determine a possible relationship between the polymorphism and some cardiovascular diseases, no study has been conducted to determine the impact of the polymorphism on vascular functions. At subthreshold concentrations, within the physiological range, AII potentiates α-adrenergic-dependent vascular tone. We investigated phenylephrine-induced tone and its amplification by AII (10 pmol/l) in human internal mammary artery rings mounted in organ baths. We performed concentration-response curves to phenylephrine (0.1–100 µmol/l) before and after pretreatment with AII (10 pmol/l). Patients had the genotype AA (n = 20) or the A to C transversion (AC/CC, n = 30). Contractions to phenylephrine (0.1–100 µmol/l) were significantly higher in rings from AC/CC than from AA patients (maximum response: 1.47±0.07 vs. 1.22±0.06 mN/mg, p < 0.001). AII (10 pmol/l) induced a significant potentiation of phenylephrine-induced contraction (e.g. 58.9% increase in tone with 1 µmol/l phenylephrine, p < 0.001) which was significantly lower in the AC/CC than in the AA group (46±9 vs. 66±7% with 1 µmol/l phenylephrine, p < 0.01). Contractions to AII (1 or 100 nmol/l) were not significantly affected by the genotype. Although the study was performed in arteries from patients with a coronary artery disease, these changes in vascular reactivity might be of interest in the understanding of the relationship between a possible higher probability of cardiovascular disorder and the genetic polymorphism of the AII type 1 receptor.

Relation between the deletion polymorphism of the angiotensin-converting enzyme gene and late luminal narrowing after coronary angioplasty

BACKGROUND The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been implicated in the pathogenesis of coronary artery disease. The deletion allele is strongly associated with the level of circulating ACE and is a potent risk factor for myocardial infarction. Recently, the deletion allele was also associated with the occurrence of visually diagnosed restenosis after percutaneous transluminal coronary angioplasty (PTCA) in a selected population of patients with acute myocardial infarction. METHODS AND RESULTS We investigated the influence of the ACE I/D polymorphism on the occurrence of restenosis after PTCA with the use of quantitative coronary angiography. ACE I/D genotypes were characterized in 118 consecutive patients who had one-vessel disease and were undergoing systematic angiographic follow-up. Coronary angiograms were analyzed before and after PTCA and at follow-up (7.4 +/- 3.0 months). Before PTCA, there were no clinical or angiographic differences among the three groups of genotypes (DD, n = 39; ID, n = 62; II, n = 17). After PTCA, the mean differences in minimal luminal diameter between post-PTCA and pre-PTCA angiograms (acute gain) were identical in the three groups, as was the mean percent residual stenosis. At follow-up angiography, the mean difference in minimal coronary luminal diameter between post-PTCA and follow-up angiograms (late loss) was not significantly different in the three groups of genotypes. The percentage of patients with restenosis defined as a > 50% stenosis was identical in the three groups. CONCLUSIONS In this quantitative study, the I/D polymorphism of the ACE gene had no influence on the occurrence of restenosis after coronary angioplasty.

Association of angiotensin converting enzyme and angiotensin II type 1 receptor genotypes with left ventricular function and mass in patients with angiographically normal coronary arteries.

OBJECTIVE: To analyse the potential association of the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) gene polymorphisms on left ventricular function and mass in patients with normal coronary arteries. DESIGN: Consecutive sample. SETTING: University hospital. SUBJECTS: 141 consecutive white patients referred for coronary angiography and with angiographically normal coronary arteries. Patients with valvar diseases, cardiomyopathies, or a history of myocardial infarction were excluded. MAIN OUTCOME MEASURES: Left ventricular variables were measured for all patients. The ACE and AT1R genotypes were determined with a polymerase chain reaction based protocol using DNA prepared from white blood cells. A general linear model was used to compare data according to the ACE and to the AT1R genotypes. RESULTS: A strong association was observed between left ventricular mass and systemic hypertension (mean (SD) hypertension: 114 (31) g/m2; no hypertension 98 (23) g/m2; P < 0.003). However, no influence of ACE and AT1R polymorphisms on left ventricular mass was found, regardless of systemic hypertension. The subjects homozygous for the AT1R CC mutation had a significantly lower ejection fraction than those with allele A (AC+AA) (mean (SD) 62(12)% and 68(10)%, respectively, P < 0.05). No synergistic interaction of ACE and AT1R gene polymorphisms on left ventricular function and mass was found. CONCLUSIONS: These data do not support an association of the ACE and AT1R genotypes on left ventricular hypertrophy in white patients with normal coronary arteries.

Effect of the angiotensin I-converting enzyme I/D polymorphism on cognitive decline <

Several clinical, epidemiological, and pathological observations suggest that vascular risk factors are associated with cognitive performances. The renin-angiotensin system components, major determinants of the cardiovascular system, are expressed in the brain. To estimate their potential impact on cognitive performances, we studied the association between cognitive functioning and an insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene. In a sample of 1168 highly performing subjects (59–71 years), DD homozygotes had the lowest cognitive scores as evaluated by the Mini-Mental State Examination. Cognitive decline at 4-year follow-up (defined as the loss of at least 3 points in Mini-Mental State Examination score) was more prevalent in these subjects, the odds ratio being equal to 1.53 (95% CI: 1.04–2.24) with subjects ID as reference class. Moreover, the combined effect of the presence of at least one APOE ϵ4 allele and ACE DD homozygosity was a risk factor for cognitive decline. This report reinforces the hypothesis of an influence of cardiovascular risk factors on cognitive performances.

Paraoxonase Polymorphism (Gln192Arg) as a Determinant of the Response of Human Coronary Arteries to Serotonin

Background-Oxidation of LDL plays a role in endothelial dysfunction. Paraoxonase, an enzyme present on HDL, protects LDL against oxidation. Paraoxonase activity is genetically determined in part, and 3 genotypes have been described with variable enzymatic activity. We hypothesized that the paraoxonase polymorphism might influence endothelial function. Methods and Results-Twenty-seven patients with clinical manifestations of coronary artery disease underwent provocative testing by intracoronary administration of serotonin. None of the coronary arteries studied had significant (>50%) stenosis. Ten patients had the QQ genotype and 17 had the QR genotype. At proximal segments, the mean percentage reduction in lumen diameter in response to serotonin was greater in QQ patients than in QR patients (10(-5) mol/L: P<0.05; 10(-4) mol/L: P<0.006). Similarly, at distal segments, constriction in response to serotonin was greater in QQ patients than in QR patients (10(-6) mol/L: P<0. 03; 10(-5) mol/L: P<0.07). Conclusions-These results suggest a higher synthesis or release of endothelium-derived relaxing factors to counteract the vasoconstrictor effect of serotonin in patients with the R allele. These findings provide evidence that the paraoxonase polymorphism may play a role in the regulation of coronary vasomotor tone.

Dual determination of angiotensin-converting enzyme and angiotensin-II type 1 receptor genotypes as predictors of restenosis after coronary angioplasty

This study sought to assess the potential influence of the angiotensin-converting enzyme (ACE) and angiotensin II type 1 (AT1) receptor gene polymorphisms on restenosis after coronary balloon angioplasty. The authors conclude that screening for genetic suspectibility to restenosis based on genotyping of ACE and AT1 receptor polymorphisms before conventional balloon angioplasty is not clinically useful.