Effects of AGTR1 A1166C gene polymorphism in patients with heart failure treated with candesartan.
BACKGROUND
The benefits of angiotensin II receptor blockers (ARBs) in patients with heart failure who are treated with standard pharmacotherapy, including an angiotensin-converting enzyme (ACE) inhibitor, were demonstrated in 2 large randomized trials. It is currently impossible to determine which patient will benefit from the addition of an ARB.


OBJECTIVE
To explore the impact of selected candidate genes on the hemodynamic, neurohormonal, and antiinflammatory effects of candesartan in patients with heart failure who are already being treated with an ACE inhibitor.


METHODS
We investigated the impact of 10 candidate genetic polymorphisms on the effects of candesartan in patients with heart failure who are treated with an ACE inhibitor. We evaluated their impact on acute (2 wk) and long-term (24 wk) changes in blood pressure and N-terminal proB-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) during treatment with candesartan.


RESULTS
Thirty-one patients were included. Homozygotes of the AGTR1 A1166 allele (n = 13) had a greater decrease in systolic (-9.1 +/- 4.7 vs 1.1 +/- 3.3 mm Hg; p = 0.04 by analysis of variance [ANOVA], adjusting for dose) and diastolic blood pressure (-5.1 +/- 1.5 vs 1.9 +/- 1.9 mm Hg; p = 0.005 by ANOVA, adjusting for dose) compared with C1166 allele carriers (n = 18) following 2 weeks of treatment. After 6 months of treatment, C1166 carriers experienced a greater decrease in NT-proBNP (-151.4 [-207; -19.8] ng/L vs 147.3 [-61.3; 882.9] ng/L; p = 0.03) and hsCRP (-0.8 [-2.2; -0.03] mg/L) vs 0.2 [-1.8; 5.3] mg/L; p = 0.09) compared with patients carrying the AA1166 genotype. No other significant association was found.


CONCLUSIONS
The results of this proof-of concept study provide the first evidence that the AGTR1 A1166C polymorphism could influence the response to candesartan in patients with heart failure who are receiving ACE inhibitors. Validation of these exploratory findings in larger populations is required before use of the AGTR1 A1166C genotype can be incorporated into clinical practice.
de Denus
Simon
S
Faculty of Pharmacy, University of Montreal, Montreal Heart Institute, Montreal, QC, Canada.
Zakrzewski-Jakubiak
Marcin
M
Dubé
Marie-Pierre
MP
Bélanger
François
F
Lepage
Serge
S
Leblanc
Marie-Hélène
MH
Gossard
Denis
D
Ducharme
Anique
A
Racine
Normand
N
Whittom
Lucette
L
Lavoie
Joel
J
Touyz
Rhian M
RM
Turgeon
Jacques
J
White
Michel
M
D000368:Aged; D000704:Analysis of Variance; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000187:drug effects; D010446:Peptide Fragments / Q000187:drug effects; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D002097:C-Reactive Protein; C081643:candesartan