| BackgroundLeft ventricular hypertrophy(LVH)is a strong,independent risk factor for cardiovascular morbidity and all-cause mortality.The following factors,age,male,gender, postmenopausal status in women,life style and diabetes,have been known to contribute to the development of LVH.Although hypertension is a major cause of LVH,the degree of LVH does not parallel the level of blood pressure,the duration of hypertension,or reversal of hypertensive LVH by pharmacological treatments.Indeed,genetic factors account for 60%of blood pressure-independent cardiac mass variances,suggesting the important role played by genetic factors in the development of LVH in essential hypertension.Endothelial nitric oxide synthase(eNOS)plays a critical role in the development of ventricular remodeling and cardiac hypertrophy.The purpose of the study was to determine whether three common variants in the eNOS gene(NOS3)are associated with risk of LVH in patients with essential hypertension.In animal models, long-term systemic inhibition of NO production with the NOS inhibitor L-NAME or NOS3-deficient mice have been shown to induce greater LVH,fibrosis and dysfunction, especially concentric LVH.Restoration of eNOS in the heart of NOS3-deficient mice has been shown to attenuate LVH and dysfunction in transverse ascending aorta constriction (TAC)model,and also inhibits hypertrophy in the remote myocardium and preserves cardiac function after myocardial infarction.Furthermore,the expression of NOS3 has been shown to be increased in the ventricular myocardium of failing human hearts, suggesting that the endothelial NO/NOS pathway has an important role in left ventricular remodeling and LVH.ObjectivesThe purpose of the study was to determine whether three common variants in the eNOS gene(NOS3)are associated with risk of left ventricular hypertrophy(LVH)in patients with essential hypertension.MethodsThree NOS3 genetic variants,-T786C(rs2070744),eNOS4a/b and +G894T(rs1799983) were genotyped in two independent case-control studies:the first study consisted of 1,061 hypertensive patients with LVH and 1,118 hypertensive patients without LVH,and the second sample consisted of 120 patients with LVH and 223 patients without LVH. Echocardiographic measurements were obtained in all the hypertensive patients.ResultsOnly the+G894T(Glu298Asp)variant of NOS3 was associated with higher risk of LVH (OR=1.67,95%CI:1.19-2.36,P＜0.01)in the first population;and replicated in the second population(OR=1.41,95%CI:1.01-2.28,P＜0.05)in a recessive model. Compared with carriers of the G allele(GT+GG),patients carrying the TT genotype had increased septal wall thickness(16.2%,P＜0.01;11.7%,P＜0.01,respectively);left ventricular posterior wall thickness(8.3%,P＜0.01;7.1%,P＜0.01,respectively);left ventricular mass index(14.0%,P＜0.01;25.1%,P＜0.01,respectively)and relative wall thickness(13.1%,P＜0.01;16.2%,P＜0.01,respectively)in the first and second populations.ConclusionsOur results support that homozygosity for +G894T(Glu298Asp)in NOS3 is a genetic risk factor for the development of LVH in patients with hypertension. BackgroundLeft ventricular hypertrophy(LVH)is a strong,independent risk factor for cardiovascular morbidity and all-cause mortality.The following factors,age,male,gender, postmenopausal status in women,life style and diabetes,have been known to contribute to the development of LVH.Although hypertension is a major cause of LVH,the degree of LVH does not parallel the level of blood pressure,the duration of hypertension,or reversal of hypertensive LVH by pharmacological treatments.Indeed,genetic factors account for 60%of blood pressure-independent cardiac mass variances,suggesting the important role played by genetic factors in the development of LVH in essential hypertension.Since nitric oxide(NO)modulates the growth of the myocardium, Asymmetric dimethylarginine(ADMA),an endogenous inhibitor of nitric oxide synthase (NOS)has been shown to be significantly related to left-ventricular mass and inversely related to ejection fraction.The bulk of ADMA is degraded by an enzyme named dimethylarginine dimethylaminohydrolase 2(DDAH2),which is found in tissues that express endothelial isoforms of nitric oxide synthase.ADMA/NO pathway is important for the pathogenesis of LVH.ObjectivesThe purpose of the study was to determine whether the common variant in the dimethylarginine dimethylaminohydrolase 2(DDAH2)gene is associated with risk of left ventricular hypertrophy(LVH)in patients with essential hypertension.MethodsThe case-control study consisted of 1,135 hypertensive patients with LVH and 1,139 hypertensive patients without LVH,as well as 767 control subjects.We used a haplotype-tagging single nucleotide polymorphisms(SNPs)approach to identify tag SNPs in DDAH2.The tag SNPs were genotyped in case-control study.The effect of DDAH2 variants on gene expression was studiedby use of luciferase reporter assays. ResultsA promoter variant-449C/G(rs805305)was identified and found to be the only tag-SNP in completely linkage disequilibrium with other SNPs(rs707916,rs805304)in the region containing DDAH2.Compared with the carriers of the GG genotype,the hypertensive patients with LVH carrying the C allele(GC+CC)had an increase in the LV mass index (62.0±15.7 g/m2.7 vs.59.9±13.1 g/m2.7,P＜0.05),posterior wall thickness(12.1±2.9 mm vs.11.4±1.9 mm,P＜0.01),and relative wall thickness(47.9±12.9%vs.46.0±11.0%, P＜0.01).In addition,the C allele(GC±CC)of the -449 locus was associated with higher risk ofLVH(OR=1.26,95%CI:1.03-1.53,P＜0.01)in the study.The SNP-449C-bearing DDAH2 promoter exhibited 49.5%of lower transcription activity than the SNP-449G-bearing promoter.ConclusionsOur results support that the DDAH2 common variant is a genetic risk factor for the development of LVH in patients with essential hypertension.
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