Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure.

AIMS: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be due to mutations in the genes encoding ß-myosin heavy chain (MYH7) or cardiac myosin-binding protein C (MYBPC3). The aim of the present study was to determine the prevalence and spectrum of mutations in both genes in German HCM and DCM patients and to establish novel genotype-to-phenotype correlations. METHODS AND RESULTS: Coding exons and intron flanks of the two genes MYH7 and MYBPC3 of 236 patients with HCM and 652 patients with DCM were sequenced by conventional and array-based means. Clinical records were established following standard protocols. Mutations were detected in 41 and 11% of the patients with HCM and DCM, respectively. Differences were observed in the frequency of splice site and frame-shift mutations in the gene MYBPC3, which occurred more frequently (P< 0.02, P< 0.001, respectively) in HCM than in DCM, suggesting that cardiac myosin-binding protein C haploinsufficiency predisposes to hypertrophy rather than to dilation. Additional novel genotype-to-phenotype correlations were found in HCM, among these a link between MYBPC3 mutations and a particularly large thickness of the interventricular septum (P= 0.04 vs. carriers of a mutation in MYH7). Interestingly, this correlation and a link between MYH7 mutations and a higher degree of mitral valve regurgitation held true for both HCM and DCM, indicating that the gene affected by a mutation may determine the magnitude of structural and functional alterations in both HCM and DCM. CONCLUSION: A large clinical-genetic study has unravelled novel genotype-to-phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use.

Pantoprazole does not influence the antiplatelet effect of clopidogrel-a whole blood aggregometry study after coronary stenting.

Recent attention has been drawn to a potential drug-drug interaction observed between clopidogrel and proton pump inhibitors (PPIs). However, this potential interaction may not be a class effect of PPIs. We investigated if pantoprazole, which has a different metabolism than omeprazole, diminishes the effectiveness of clopidogrel. Our study included 336 patients (mean age 64.6 years; 106 women) 48 hours after percutaneous coronary stent implantation with a loading dose of 600 mg clopidogrel hydrogensulfate and 500 mg aspirin, followed by 75 mg clopidogrel and 100 mg aspirin daily. Whereas 188 patients (59 women) were not given any PPI comedication, 122 patients received pantoprazole and 26 either omeprazole or esomeprazole. The platelet aggregation followed by impedance aggregometry (in Ohm) was induced by 5 mmol/L adenosine diphosphate. The percentage of clopidogrel low-response (CLR) was similar between the non-PPI group [2.75 Ohm (confidence interval, CI: 2.25-3.26); 21.9% CLR] and the pantoprazole group [2.33 Ohm (CI: 1.79-2.87); 16.4% CLR] but higher in patients treated with omeprazole/esomeprazole (3.00 Ohm (CI: 1.49-4.51); 30.8% CLR). Multivariate regression analysis reveals that the risk of CLR in the pantoprazole comedication group was not increased compared with the group without any PPI [odds ratio 0.59 (CI: 0.31-1.13) 0.11]. Our data suggest that pantoprazole does not diminish the antiplatelet effectiveness of clopidogrel early after coronary stenting. Therefore, the use of pantoprazole seems preferable in patients treated with clopidogrel when a concomitant medication with a PPI is indicated.

Unrecognized secondary causes of hypertension in patients with hypertensive urgency/emergency: prevalence and co-prevalence.

BACKGROUND: Hypertensive urgency/emergency occurs frequently, yet no prospective data on common secondary causes, including sleep apnea (SA), renal artery stenosis (RAS), and hyperaldosteronism, are available. METHODS: Patients presenting to the emergency room for over 1 year with systolic blood pressure > or =180 mmHg and/or diastolic blood pressure > or =100 mmHg and typical symptoms were included. RAS was diagnosed by direct duplex/Doppler ultrasound of the renal artery, resistance index, and imaging. The aldosterone/renin ratio (ARR) was determined from morning blood samples taken with the patients supine after > or =2 h of rest. A positive ARR (>50) was followed by saline infusion to exclude primary hyperaldosteronism. SA was evaluated by nasal breathing flow screening; when positive [apnea/hypopnea index (AHI) >5/h], complete polysomnography was performed. RESULTS: Of 161 patients (age, 66.0 +/- 13.1 years; BMI, 28.6 +/- 5.1 kg), 131 had previously identified hypertension (duration, 12.7 +/- 11.5 years; 1.9 +/- 1.5 antihypertensive medications). SA was found in 114 (70.8%) patients [18% mild (AHI: 5-15/h), 26.8% moderate (15.1-30/h), and 24.2% severe (>30/h)]. Aldosterone levels exceeded 160 pg/ml in 22 of 23 patients with hyperaldosteronism; 4 had primary and 12 had secondary hyperaldosteronism. Thirteen (8.1%) patients had RAS. Three secondary causes were found in 1 patient (0.6%), > or =2 in 25 (15.5%), and > or =1 in 124 patients (77.0%). Of 150 detected secondary causes, only 5 were recognized previously. CONCLUSIONS: Secondary causes of hypertension are common and predominantly unrecognized in patients with hypertensive urgency/emergency. Co-prevalence of secondary causes occurs in about 15% and should be considered before therapeutic intervention.

Effect of protein A immunoadsorption on T cell activation in patients with inflammatory dilated cardiomyopathy.

BACKGROUND: Immunoadsorption (IA) is used in patients with inflammatory dilative cardiomyopathy (iDCM) to remove cardiotoxic autoantibodies, and to improve myocardial function. Even if IA is used only once, the level of anti-cardiac antibodies remains low over time. Changes in cell-mediated immunity after IA may contribute to this observation. The aim of this study is to investigate the effect of IA on cell-mediated immunity especially on regulatory and early activated T cells. METHODS: Ten patients (50.1 ± 9.3 years) with chronic iDCM (with signs of myocardial inflammation in biopsies, but without persistence of virus genome), reduced left ventricular ejection fraction (EF < 35%) underwent IA. Blood samples were drawn before and after an IA course of 5 days, and 1, 3, and 6 months after IA. Leukocyte subpopulations were quantified by FACS analysis. RESULTS: Left ventricular systolic function improved on average at 6 months from 25.6 ± 4.9 to 37.3 ± 10.1% (p < 0.05). The left ventricular end-diastolic diameter was reduced after 6 months (63.3 ± 3.1 vs. 57.1 ± 4.1 mm; p < 0.05). IA therapy led to an increase of regulatory T cells (CD4(+), CD25(+) and CD127(low)) over time (up to 6 months). This was associated with a decrease of activated T cells (CD4(+)/CD69(+) and CD8(+)/CD69(+) cells) and CD28(+) T cells (co-stimulatory cells), which was detectable for at least 6 months after IA. CONCLUSION: It is suggested that changes in cell-mediated immunity contribute to the beneficial effect of IA on myocardial function, and on maintenance of reduced blood levels of cardiotoxic autoantibodies.

Upregulation of platelet CD40, CD40 ligand (CD40L) and P-Selectin expression in cigarette smokers: a flow cytometry study.

Cigarette smoking is a well known risk factor for cardiovascular disease with a great impact on mortality. Studies have linked smoking to inflammation, platelet activation and enhanced atherosclerosis. The present study investigated the activation and expression of proinflammatory markers on platelets obtained from smokers. The expression of P-selectin (CD62P) (as a marker of activation) and CD40/CD40L (as a marker for proinflammatory processes) were quantified in platelets by flow cytometry. Platelet-rich plasma was obtained from 34 apparent healthy volunteers (19 cigarette smokers, 15 age-matched control persons). Basal measurements and the response to stimulation with ADP and TRAP (10, 30, 100 micromol/l) were evaluated. Values given (mean fluorescence index, MFI) are mean +/- standard deviation. The basal values of platelet bound CD40 (3.20 +/- 0.50 vs. 2.71 +/- 0.28; P = 0.002), CD40L (1.10 +/- 0.12 vs. 0.95 +/- 0.12; P = 0.005) and P-selectin (0.70 +/- 0.21 vs. 0.55 +/- 0.11; P = 0.012) were significantly elevated in smokers as compared to controls. In addition, higher values were noted on stimulation with ADP or TRAP in smokers, although these different values were without statistical significance. According to our data cigarette smoking activates platelets (P-selectin expression) and stimulates the CD40-CD40L-pathway in otherwise healthy volunteers. These findings emphasize that cigarette smoking leads to a proinflammatory and prothrombotic state thus contributing to accelerated atherosclerosis.

The CYP2J2 G-50T polymorphism and myocardial infarction in patients with cardiovascular risk profile.

BACKGROUND: Cytochrome P450 (CYP) enzyme 2J2, an epoxygenase predominantly expressed in the heart, metabolizes arachidonic acid to biologically active eicosanoids. One of the CYP2J2 products, 11, 12-epoxyeicosatrienoic acid, has several vasoprotective effects. The CYP2J2-G-50T-promotor polymorphism decreases gene expression and is associated with coronary artery disease. This association supports the vascular protective role of CYP-derived eicosanoids in cardiovascular disease. In the present study, we investigated the influence of this polymorphism on survived myocardial infarction in two study groups of patients with on average high cardiovascular risk profile. METHODS: The CYP2J2 polymorphism was genotyped in two groups of patients that were collected with the same method of clinical data collection. Data from 512 patients with sleep apnoea (group: OSA) and on average high cardiovascular risk profile and from another 488 patients who were admitted for coronary angiography (CAR-group) were evaluated for a potential correlation of the CYP2J2 polymorphism G-50T and a history of myocardial infarction. The G-50T polymorphism of the CYP2J2 gene was genotyped by allele specific restriction and light cycler analysis. RESULTS: The T-allele of the polymorphism was found in 111 (11.1%; CAR-group: N = 65, 13.3%; OSA: N = 46, 9.0%). 146 patients had a history of myocardial infarction (CAR: N = 120, 24.6%; OSA: N = 26, 5.1%). Cardiovascular risk factors were equally distributed between the different genotypes of the CYP2J2 G-50T polymorphism. In the total group of 1000 individuals, carriers of the T-allele had significantly more myocardial infarctions compared to carriers of the wild type (T/T or G/T: 21.6%; G/G: 13.7%; p = 0.026, odds ratio 1.73, 95%-CI [1.06-2.83]). In the multivariate logistic regression analysis the odds ratio for a history of myocardial infarction in carriers of the T-allele was 1.611, 95%-CI [0.957-2.731] but this trend was not significant (p = 0.073). CONCLUSION: In presence of other risk factors, the CYP2J2 G-50T failed to show a significant role in the development of myocardial infarction. However, since our result is close to the border of significance, this question should be clarified in larger, prospective studies in the future.

Circulating endothelial microparticles correlate inversely with endothelial function in patients with ischemic left ventricular dysfunction.

BACKGROUND: Bone-marrow derived endothelial progenitor cells (CD34+ and VEGFR2+ KDR+ EPC) and endothelial-derived microparticles (CD 31+Annexin V+, EMP; indicator for endothelial apoptosis) were examined in the peripheral blood of 35 male, clinically stable patients with 3-vessel coronary artery disease (CAD). The patients were divided in 2 groups, those with preserved or normal function (n = 17; EF 65 +/- 6%) and those with reduced left ventricular (LV) function (n = 18; EF 36 +/- 11%). METHODS AND RESULTS: The number of circulating EPCs was decreased by 25% (P = .07) and the number of EMPs was increased by 109 % (P < .05) in patients with LV dysfunction compared with those with normal or preserved LV function. EPCs were positively correlated (r = 0.24 for patients with LV dysfunction and r = 0.28 for patients with preserved LV function) with endothelial function as assessed by flow-mediated vasodilatation. In contrast, EMPs were inversely correlated (r = -0.42 for patients with LV dysfunction and r = -0.49 for patients with preserved LV function). CONCLUSIONS: CAD patients with significant LV dysfunction show an increased index of endothelial cell damage. This decrease (or lack of compensatory elevation) of EPCs may result in a reduced potential for repair and thus contribute at least in part to the pathogenesis of endothelial dysfunction.

Continuous positive airway pressure treatment of mild to moderate obstructive sleep apnea reduces cardiovascular risk.

RATIONALE: Obstructive sleep apnea (OSA) is linked to increased cardiovascular risk, but the impact of mild forms of OSA and their treatment on cardiovascular outcomes remains controversial. OBJECTIVES: To prospectively investigate cardiovascular outcomes in treated versus untreated patients with OSA. METHODS: Consecutive sleep laboratory patients with all degrees of OSA were included. Endpoints were nonfatal (myocardial infarction, stroke, and acute coronary syndrome requiring revascularization procedures) and fatal (death from myocardial infarction or stroke) cardiovascular events. MEASUREMENTS AND MAIN RESULTS: Comparison of event-free survival rates in treated versus untreated patients (Kaplan-Meier estimates, log-rank test). Of 449 patients enrolled (age, 56.0 +/- 10.5 years; body mass index, 30.8 +/- 5.4 kg/m(2)), 364 patients received OSA treatment, and 85 patients remained untreated. Median follow-up was 72.0 months (range, 1-156). Mean apnea-hypopnea index before treatment was 30.9 +/- 21.8/hour in treated and 15.3 +/- 13.0/hour in untreated patients, but there were no differences in cardiovascular comorbidities or risk factors. In patients with mild-moderate OSA (n = 288), events were more frequent in untreated patients (estimated event-free survival at 10 yr, 51.8 vs. 80.3% [P < 0.001]; absolute risk reduction, 28.5%; number needed to treat to prevent one event/10 yr, 3.5). After adjustment for age, gender, cardiovascular risk factors, and comorbidities at baseline, OSA treatment was an independent predictor for events (hazard ratio, 0.36; 95% confidence interval, 0.21-0.62; P < 0.001). CONCLUSIONS: OSA treatment was associated with a cardiovascular risk reduction of 64% independent from age and preexisting cardiovascular comorbidities. OSA treatment should be considered for primary and secondary cardiovascular prevention, even in milder OSA.

Hormonal status modulates circulating endothelial progenitor cells.

OBJECTIVE: Endothelial progenitor cells (EPCs) may have an important role in vascular homeostasis and repair. METHODS: We examined the level of circulating EPCs in pre- (n = 22; mean age 28.7 years), and postmenopausal healthy females without (n = 30; mean age 61.6 years) or under current hormone replacement therapy (HRT) (n = 19; mean age 59.8 years). RESULTS: Premenopausal females had the highest level of circulating EPCs (0.147 +/- 0.076 per thousand of polymorphnuclear cells). The level of EPCs was lowest in postmenopausal females (0.094 +/- 0.058 per thousand), and increased significantly with HRT on average by 25.5%. In addition, the proliferative capacity of circulating EPCs was assessed under cell culture conditions. This capacity was significantly increased in EPCs isolated from postmenopausal subjects under current HRT as compared to corresponding samples obtained from postmenopausal females without HRT. CONCLUSIONS: This observation is in line with the hypothesis that the hormonal status in females modulates the cardiovascular risk and that circulating EPCs could be involved in this phenomenon.

Risk factors and myocardial infarction in patients with obstructive sleep apnea: impact of beta2-adrenergic receptor polymorphisms.

BACKGROUND: The increased sympathetic nervous activity in patients with obstructive sleep apnea (OSA) is largely responsible for the high prevalence of arterial hypertension, and it is suggested to adversely affect triglyceride and high-density lipoprotein (HDL) cholesterol levels in these patients. The functionally relevant polymorphisms of the beta2-adrenergic receptor (Arg-47Cys/Arg16Gly and Gln27Glu) have been shown to exert modifying effects on these risk factors in previous studies, but results are inconsistent. METHODS: We investigated a group of 429 patients (55 +/- 10.7 years; 361 men, 68 women) with moderate to severe obstructive sleep apnea (apnea/hypopnea index (AHI) 29.1 +/- 23.1/h) and, on average, a high cardiovascular risk profile (body mass index 31.1 +/- 5.6, with hypertension in 60.1%, dyslipidemia in 49.2%, and diabetes in 17.2% of patients). We typed the beta2-adrenergic receptor polymorphisms and investigated the five most frequent haplotypes for their modifying effects on OSA-induced changes in blood pressure, heart rate, and lipid levels. The prevalence of cardiovascular risk factors and coronary heart disease (n = 55, 12.8%) and survived myocardial infarction (n = 27, 6.3%) were compared between the genotypes and haplotypes. RESULTS: Multivariate linear/logistic regressions revealed a significant and independent (from BMI, age, sex, presence of diabetes, use of antidiabetic, lipid-lowering, and antihypertensive medication) influence of AHI on daytime systolic and diastolic blood pressure, heart rate, prevalence of hypertension, and triglyceride and HDL levels. The beta2-adrenergic receptor genotypes and haplotypes showed no modifying effects on these relationships or on the prevalence of dyslipidemia, diabetes, and coronary heart disease, yet, for all three polymorphisms, heterozygous carriers had a significantly lower relative risk for myocardial infarction (Arg-47Cys: n = 195, odds ratio (OR) = 0.32, P = 0.012; Arg16Gly: n = 197, OR = 0.39, P = 0.031; Gln27Glu: OR = 0.37, P = 0.023). Carriers of the most frequent haplotype (n = 113) (haplotype 1; heterozygous for all three polymorphisms) showed a five-fold lower prevalence of survived myocardial infarction (OR = 0.21, P = 0.023). CONCLUSION: Our study showed no significant modifying effect of the functionally relevant beta2-adrenergic receptor polymorphisms on OSA-induced blood pressure, heart rate, or lipid changes. Nevertheless, heterozygosity of these polymorphisms is associated with a lower prevalence of survived myocardial infarction in this group with, on average, a high cardiovascular risk profile.

Modifying effects of the R389G beta1-adrenoceptor polymorphism on resting heart rate and blood pressure in patients with obstructive sleep apnoea.

OSA (obstructive sleep apnoea) stimulates sympathetic nervous activity and elevates resting HR (heart rate) and BP (blood pressure). In the present study in a cohort of 309 untreated OSA patients, the resting HR and BP during the daytime were correlated with AHI (apnoea/hypopnea index) and compared with patients with R389R (n = 162), R389G (n = 125) and G389G (n = 22) genotypes of the beta1-adrenoreceptor R389G polymorphism. We analysed the impact of the genotype on the decline of HR and BP in a subgroup of 148 patients (R389R, n = 86; R389G, n = 54; G389G, n = 8) during a 6-month follow-up period under CPAP (continuous positive airway pressure) therapy during which cardiovascular medication remained unchanged. In untreated OSA patients, we found an independent relationship between AHI and resting HR (beta = 0.096, P < 0.001), systolic BP (beta = 0.09, P = 0.021) and diastolic BP (beta = 0.059, P = 0.016). The resting HR/BP, however, did not differ among carriers with the R389R, R389G and G389G genotypes. CPAP therapy significantly reduced HR [-2.5 (-1.1 to -4.0) beats/min; values are mean difference (95% confidence intervals)] and diastolic BP [-3.2 (-1.5 to -5.0) mmHg]. The decline in HR was more significantly pronounced in the R389R group compared with the Gly(389) carriers [-4.1 (-2.3 to -5.9) beats/min (P < 0.001) compared with -0.2 (2.1 to -2.6) beats/min (P = 0.854) respectively; Student's t test between groups, P = 0.008]. Diastolic BP was decreased significantly (P < 0.001) only in Gly389 carriers (R389G or G389G) compared with R389R carriers [-5.0 (-2.3 to -7.6) mmHg compared with -2.0 (0.4 to -4.3) mmHg respectively]. ANOVA revealed a significant difference (P = 0.023) in HR reduction between the three genotypes [-4.1 (+/-8.4) beats/min for R389R, -0.5 (+/-9.3) beats/min for R389G and +1.9 (+/-7.2) beats/min for G389G]. In conclusion, although the R389G polymorphism of the beta1-adrenoceptor gene did not influence resting HR or BP in untreated OSA patients, it may modify the beneficial effects of CPAP therapy on these parameters.

Doppler echocardiographic prediction of recurrent atrial fibrillation following cardioversion.

BACKGROUND: Cardioversion for atrial fibrillation (AF) is associated with impairment of left atrial mechanical function and increased risk of thrombus formation with subsequent embolisation. Measuring atrial mechanical function is of interest to determine the individual risk of thromboembolism and the risk of recurrent AF. METHODS: We included 112 consecutive patients with AF and planned cardioversion. Serial echocardiographic measurements of left atrial size and Doppler measurement of mitral valve peak A wave velocities were obtained at days 0, 1, 2, 3, and 28 following cardioversion. These measurements and clinical parameters were related to clinical events and recurrent AF within 4 weeks following cardioversion. Cardioversion was achieved in 100 patients. RESULTS: AF-recurrence within 4 weeks was 23.9% and 45.8% for patients with < or = and > 6 weeks AF-duration, respectively (p=0.04). Peak A wave velocities were significantly lower up to 2 days following cardioversion in patients with AF-recurrence. A peak A wave velocity < 52 cm/s at day 1 resulted in an odds ratio of 5.0 (95% CI: 1.4-18.6) for recurrence of AF. In multiple logistic regression analysis, peak A wave velocity at day 1 remained the only independent predictor of recurrent AF. Left atrial diameter did not correlate with recurrence of AF. CONCLUSIONS: A single measurement of mitral peak A wave velocity 1 day following cardioversion is predictive of AF recurrence. This method is feasible for risk estimation with potential therapeutic implications.

Obstructive sleep apnea and blood pressure. Interaction between the blood pressure-lowering effects of positive airway pressure therapy and antihypertensive drugs.

BACKGROUND: There is increasing evidence that obstructive sleep apnea is an independent risk factor for arterial hypertension. Previous studies on the antihypertensive effects of positive airway pressure therapy on daytime blood pressure (BP) revealed inconsistent results. METHODS: The relations between the apnea/hypopnea index (AHI) and BP or heart rate (HR) were investigated in a cohort of 540 consecutive patients (age, 55.4 +/-11.1 years) with moderate or severe obstructive sleep apnea (OSA). The mean AHI was 28.2 +/- 22.0 events/h before OSA therapy. A group of 196 patients in whom antihypertensive medication was kept unchanged was followed for 6 months during bilevel or continuous positive airway pressure (Bi-/CPAP) therapy. RESULTS: Significant associations were found between AHI and systolic BP (beta = 0.078, P = .014), diastolic BP (beta = 0.056, P = .003), HR (beta = 0.096, P < .001), and the prevalence of arterial hypertension (odds ratio = 0.015, P = .003), independent of age, body mass index, and gender. During the follow-up period with effective Bi-/CPAP therapy, the mean daytime systolic BP decreased from 130.7 +/- 15.5 mm Hg to 128.6 +/- 15.9 mm Hg (P = .051), diastolic BP from 80.2 +/- 9.3 mm Hg to 77.5 +/- 9.5 mm Hg (P = .001), and HR from 77.7 +/- 8.8 to 75.7 +/- 8.1 beats/min (P = .001). Multiple linear regression analysis revealed that the absence of antihypertensive drugs and the level of the initial BP are significant and independent predictors for the lowering effect of Bi-/CPAP therapy on systolic and diastolic BP. CONCLUSIONS: This study confirms an independent relationship between the severity of OSA and BP/HR. Absence of BP-lowering medication and BP values before treatment are independent predictors for the reduction of BP with Bi-/CPAP therapy.

Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2.

BACKGROUND: Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. However, it is not known whether genetic polymorphisms of CYP2J2 are associated with increased cardiovascular risks. METHODS AND RESULTS: All 9 exons of the CYP2J2 gene and its proximal promoter were sequenced in 132 patients to identify potential variants. Functional consequence of a single nucleotide polymorphism (SNP) in the promoter of CYP2J2 was further evaluated by use of transcription factor-binding and reporter assays. A total of 17 polymorphisms were identified. One of the most relevant polymorphisms in terms of frequency and functional importance is located at -50 (G-50T) in the proximal promoter of CYP2J2. Screening of 289 patients with coronary artery disease and 255 control subjects revealed 77 individuals with the G-50T SNP (17.3% of coronary artery disease patients, 10.6% of control subjects; P=0.026). The association of the G-50T polymorphism remained significant after adjustment for age, gender, and conventional cardiovascular risk factors (OR, 2.23; 95% CI, 1.04 to 4.79). The G-50T mutation resulted in the loss of binding of the Sp1 transcription factor to the CYP2J2 promoter and resulted in a 48.1+/-2.4% decrease in CYP2J2 promoter activity (P<0.01). Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP. CONCLUSIONS: A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary artery disease.