Influence of the Angiotensin II Type 1 Receptor Gene Polymorphism on the Effects of Perindopril and Nitrendipine on Arterial Stiffness in Hypertensive Individuals
Angiotensin-converting enzyme inhibitors improve arterial stiffness independently of blood pressure reduction. Since we have recently shown that in hypertensive individuals the A1166C polymorphism of the angiotensin II type 1 receptor (AT1-R) is an independent determinant of aortic stiffness, we designed the present study to assess the influence of this polymorphism on the changes of aortic stiffness after chronic treatment with the angiotensin-converting enzyme inhibitor perindopril and the calcium channel blocker nitrendipine. Forty perindopril- and 42 nitrendipine-treated hypertensive individuals were studied. We evaluated aortic stiffness by measuring the carotid-femoral pulse wave velocity. Carriers of the AT1-R C allele showed higher baseline values of pulse wave velocity than AA homozygotes (P<.05). In the perindopril group, a threefold greater reduction in pulse wave velocity was observed in carriers of the C allele than in AA homozygotes (−2.85±0.62 versus −0.94±0.32 m/s, respectively; P<.001), whereas in the nitrendipine group, pulse wave velocity decreased only in AA homozygotes and not in AT1-R C carriers (−1.38±0.35 versus +0.04±0.60 m/s, respectively; P<.01). These results indicate that according to the AT1-R A1166C genotype, an angiotensin-converting enzyme inhibitor and a calcium channel blocker affect pulse wave velocity in opposite ways. Since some evidence shows that increased pulse wave velocity may enhance cardiovascular risk, it might be useful for physicians to consider the AT1-R genotype when prescribing an angiotensin-converting enzyme inhibitor or calcium channel blocker to a hypertensive individual.
- renin-angiotensin system
- calcium channel blockers
- angiotensin-converting enzyme inhibitors
It is well established that ACEIs improve the stiffness and structure of large arteries independently of BP reduction,1 2 3 indicating that the renin-angiotensin system plays a major role in the hypertension-induced structural and functional alterations of the arterial wall.4 Recently, we have shown that in hypertensive individuals, the A1166C polymorphism of the AT1-R is a significant and independent determinant of aortic stiffness. The presence of the C allele was associated with increased arterial stiffness.5
In the present study, we assessed whether the AT1-R A1166C polymorphism also influences the BP response and change in arterial stiffness associated with ACEI therapy in human hypertension. We determined AT1-R genotype in 40 hypertensive individuals who received the ACEI perindopril for 2 months. To assess whether the influence of the AT1-R A1166C polymorphism was specific to ACE inhibition, we subsequently investigated the influence of this polymorphism on the antihypertensive and arterial effects of the calcium channel blocker nitrendipine.
Eighty-two white hypertensive subjects aged 38 to 65 years were studied. Subjects were recruited from the cohort of hypertensive individuals who were genotyped for the AT1-R polymorphism as part of our previously reported study.5
Forty subjects with mild to moderate essential hypertension (95<diastolic BP<115 mm Hg) entered a 2-week run-in phase followed by a 2-week placebo period and then received 4 mg perindopril daily for 2 months. BP and aortic stiffness were measured at the end of both the placebo and active treatment periods. Blood was drawn for DNA extraction. The AT1-R A1166C polymorphism was determined by DNA amplification with the polymerase chain reaction as previously described.6 BP and heart rate were measured every 2 minutes with an automatic oscillometric device (Dinamap 845, Critikon). Aortic stiffness was evaluated by measurement of carotid-femoral PWV, a noninvasive, accurate, safe, and reproducible method.7 8
Genotype analysis was performed in subjects in whom BP and aortic stiffness had been formerly evaluated during controlled pharmacological studies performed in our center of clinical investigation. For that purpose, we proposed a genotype analysis to 56 individuals who had formerly received the calcium channel blocker nitrendipine at the dose of 10 to 20 mg/d for 1 to 3 months. All subjects had mild to moderate, sustained, uncomplicated essential hypertension (95<diastolic BP<115 mm Hg). Forty-two of these 56 individuals agreed to undergo the analysis (mean dosage±SE, 14±2 mg/d; mean treatment duration, 2.2±0.4 months), and blood was drawn for genotype determination. In these subjects, hemodynamic parameters were evaluated after a 2-week placebo period (baseline) and at the end of nitrendipine treatment. BP and aortic stiffness had been evaluated following the same procedure as in the prospective study with perindopril. Genotypes were determined in all subjects after BP and PWV evaluation; investigators who did the genotype analysis did not have access to any clinical data on the subjects. Analysis of previous treatment regimens showed no difference in the four genotype treatment subgroups. All participants in the perindopril and nitrendipine studies gave written informed consent.
Results are expressed as mean±SE. Because of the relatively small number of CC homozygotes, subjects were classified according to the presence or absence of the AT1-R 1166C allele (AA versus AC+CC). The significance of any difference in mean value was tested with Student's t test. Because PWV is highly dependent on age and BP level, we used ANCOVA to adjust PWV baseline values and changes with treatment on age and BP. Statistical analysis was performed with the SAS statistical software (SAS Institute). Results were considered to be significant at a value of P<.05.
Table 1⇓ shows the distribution of the AT1-R A1166C genotype. Among the 18 subjects (45%) carrying the C allele, 1 was a CC homozygote. Mean values of age and body mass index and baseline BP values were similar in the AT1-R A1166C genotypes (Table 2⇓). By contrast, baseline PWV values were higher in subjects presenting the C allele (P<.01). BP and PWV (Table 2⇓ and Figure)⇓ were significantly reduced in both genotypes. BP changes with perindopril were larger in subjects with the C allele than in AA subjects (P<.05). The presence of the C allele was also associated with a greater reduction in PWV (−19.8%) compared with that observed in AA subjects (−7.5%). This association remained significant after adjustment for mean BP changes and age (P<.02).
The distribution of AT1-R A1166C genotypes in the nitrendipine group was similar to that observed in the perindopril group (Table 1⇑). Among the 17 subjects with the C allele, 2 were CC homozygotes. Mean values of age and body mass index and baseline BP values (Table 3⇓) were not statistically different between AT1-R A1166C genotype subgroups and were comparable to the values observed in the perindopril-treated subjects. Subjects with the C allele had higher baseline PWV values (P<.05). Systolic and diastolic BPs were significantly reduced in both genotypes. Nitrendipine-induced decreases in systolic and diastolic BPs were not significantly different between the two genotype subgroups (Table 3⇓). PWV was markedly reduced in AA homozygotes (−11.3%) but remained unchanged in carriers of the C allele (Table 3⇓ and Figure) (P<.01, AA versus AC+CC after adjustment for BP changes and age).
BP and the AT1-R Polymorphism
In this study, we found that the AT1-R genotype influences the effects of perindopril on BP and arterial stiffness. Thus, despite similar baseline BP levels across AT1-R A1166C genotypes, BP decreased to a greater extent in subjects carrying the C allele than in AA homozygotes. In the nitrendipine-treated subjects, the opposite tendency was observed, but the difference in BP changes according to the presence of the C allele was not statistically significant. It has been suggested that plasma levels of renin or ACE could be helpful in determining the type of drug therapy for hypertension and that ACEIs are more effective in individuals with high plasma renin activity.9 However, other studies showed that the BP-lowering effect of ACEIs was not correlated with basal plasma levels of renin-angiotensin system components.10 These inconsistent results can be related to the variability of the plasma levels and/or to the fact that plasma levels do not reflect the tissue activity of the renin-angiotensin system. It is possible that the AT1-R polymorphism could be a more reliable indicator than renin or ACE plasma levels for assessment of the activation of this system and prediction of ACEI efficacy.
Influence of AT1-R Genotype on Arterial Stiffness
We have previously reported in hypertensive individuals that the presence of the AT1-R C allele is independently associated with higher PWV values, suggesting the significant implication of this gene in the development of arterial stiffness.5 A new finding is that in individuals carrying the C allele, PWV following ACEI reduction was about threefold higher than in AA homozygotes; this difference between genotypes was highly significant even after adjustment for BP changes. The higher efficacy of the ACEI in reducing PWV in AC and CC individuals represents additional evidence for the implication of the renin-angiotensin system in the development of arterial stiffness in these individuals.
In contrast to what was observed with perindopril, nitrendipine induced a significant relative decrease of PWV in AA homozygotes but not in carriers of the C allele. Since a strong positive relationship exists between BP and aortic stiffness, the absence of change in PWV despite a BP reduction after nitrendipine in AC and CC subjects suggests that nitrendipine induces neurohumoral vasoactive changes, which by themselves blunt the improvement of arterial stiffness. Because we studied nitrendipine and perindopril separately, we cannot make comparisons between the two drugs. However, the design of the present study allowed us to evaluate the effect of the AT1-R A1166C polymorphism within each treatment group. Our study indicates that the AT1-R polymorphism influences in the opposite way changes in arterial stiffness after treatment with nitrendipine or perindopril.
The beneficial effects of perindopril in individuals with the C allele may be of particular interest because these individuals have an exaggerated arterial stiffness and may represent a high cardiovascular risk population among people with hypertension.11 12 The mechanisms and clinical implications of the lack of effectiveness of the calcium antagonist nitrendipine in this group of hypertensive individuals are still unknown. If our results were to be confirmed by larger, prospective, double-blind studies, the AT1-R genotype could be a useful indicator for anti-hypertensive drug strategy, especially in individuals with increased arterial stiffness.
Selected Abbreviations and Acronyms
|ACEI||=||angiotensin-converting enzyme inhibitor|
|AT1-R||=||angiotensin II type 1 receptor|
|PWV||=||pulse wave velocity|
This work was supported in part by INSERM, the Claude Bernard Association, and the Groupement de Recherche et d'Etudes sur les Genomes (GREG). The authors thank Servier Pharmaceutical Co for supporting the study. We also thank Isabelle Gautier for her excellent technical assistance.
Reprint requests to Athanase Benetos, MD, PhD, Hôpital Broussais (Serv Medecine 1), 96 rue Didot, 75014 Paris, France.
- Received March 18, 1996.
- Revision received April 2, 1996.
- Revision received May 13, 1996.
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