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.

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.

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.

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.