Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study.
The objective was to study whether coronary blood flow or its response to pravastatin are affected by genetic variation in the endothelial nitric oxide synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. Its formation is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in intron 4 (4a/b). Some clinical studies have suggested an association of the rare a-allele of eNOS with coronary artery disease and myocardial infarction. We carried out a double-blind placebo-controlled study involving 43 men (aged 35+/-4 years), who were randomized to receive either 40 mg/day pravastatin ( n=21) or placebo ( n=22) for 6 months. Myocardial blood flow was measured by positron emission tomography (PET) using (15)O-labeled water. PET was performed at rest and after stimulation by adenosine infusion. PET and lipid analyses were carried out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline there were no differences in basal or adenosine-stimulated coronary blood flow between subjects with either eNOS bb or ba genotypes. At the end of the study genotypes reacted differently between pravastatin and placebo groups with respect to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically, after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in men with the eNOS ba genotype, whereas in the men with the bb genotype no significant change in flow was observed ( P=0.002 for ba versus bb). In the placebo group there were no significant changes in blood flow from the baseline values ( P=0.916 for ba versus bb). After pravastatin treatment both genotype groups showed a similar decrease in serum total cholesterol and low-density lipoprotein cholesterol ( P<0.00001 for both). Our results suggest that adenosine-stimulated myocardial perfusion improves after treatment with pravastatin in subjects with the eNOS ba genotype but not in those with the bb genotype. This effect is not dependent on the decrease of serum cholesterol.
Kunnas
Tarja A
TA
University of Tampere, Department of Clinical Chemistry, Center for Laboratory Medicine, Tampere University Hospital and Medical School, Tampere, Finland.
Lehtimäki
Terho
T
Laaksonen
Reijo
R
Ilveskoski
Erkki
E
Janatuinen
Tuula
T
Vesalainen
Risto
R
Nuutila
Pirjo
P
Karhunen
Pekka J
PJ
Knuuti
Juhani
J
Nikkari
Seppo T
ST
D000328:Adult; D000483:Alleles; D000924:Anticholesteremic Agents / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology; D005838:Genotype; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D010919:Placebos; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000494:pharmacology*; D011897:Random Allocation; D014055:Tomography, Emission-Computed
D000924:Anticholesteremic Agents; D010919:Placebos; D004247:DNA; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin