SAH gene variants revisited in the European Project On Genes in Hypertension.

OBJECTIVE: Previous studies found significant association of hypertension and hypertension-related phenotypes with genetic variation in SAH (Spontaneously hypertensive rat-clone A-Hypertension-associated). We sought independent confirmation of these findings in the European Project On Genes in Hypertension. METHODS AND RESULTS: We randomly recruited 2603 relatives from 560 families and 31 unrelated subjects from six European populations (mean age 38.8 +/- 15.7 years; 52.1% women). We measured systolic/diastolic blood pressure (mean, 122.4/76.6 mmHg), body mass index (24.9 kg/m2), triceps skinfold (1.7 cm), waist-to-hip ratio (0.83 units), serum total and high-density lipoprotein (HDL) cholesterol (5.14 and 1.33 mmol/l), serum triglycerides (1.95 mmol/l) and blood glucose (4.90 mmol/l). We genotyped the G-1606A and -962del/ins polymorphisms. In all subjects, the allele frequencies were 11.8 and 29.5% for -1606A and -962del, respectively. Lewontin's D' was 0.97 (P < 0.0001). Haplotype frequencies were 58.8% for -1606G plus -962ins, 29.5% for -1606G plus -962del, and 11.7% for -1606A plus -962ins. Both before and after adjustment for covariates, none of the phenotype-genotype associations approached statistical significance. Our study had 80% power to detect on two-sided tests (P = 0.05), effect sizes of 1.8/1.3 mmHg for systolic/diastolic blood pressure, 0.52 kg/m2 for body mass index, 0.01 units for the waist-to-hip ratio, 0.96 mm for the triceps skinfold, 0.13 and 0.05 mmol/l for total and HDL cholesterol, 0.18 mmol/l for serum triglycerides, and 0.11 mmol/l for blood glucose. The family-based analyses did not reveal population stratification (P > or = 0.67). CONCLUSION: The evidence supporting an association of hypertension or hypertension-related phenotypes with the SAH gene remains equivocal in human studies.

Heritability and intrafamilial aggregation of arterial characteristics.

BACKGROUND: We investigated the heritability and familial aggregation of various indexes of arterial stiffness and wave reflection and we partitioned the phenotypic correlation between these traits into shared genetic and environmental components. METHODS: Using a family-based population sample, we recruited 204 parents (mean age, 51.7 years) and 290 offspring (29.4 years) from the population in Cracow, Poland (62 families), Hechtel-Eksel, Belgium (36), and Pilsen, the Czech Republic (50). We measured peripheral pulse pressure (PPp) sphygmomanometrically at the brachial artery; central pulse pressure (PPc), the peripheral augmentation indexes (PAIxs) and central augmentation indexes (CAIxs) by applanation tonometry at the radial artery; and aortic pulse wave velocity (PWV) by tonometry or ultrasound. In multivariate-adjusted analyses, we used the ASSOC and PROC GENMOD procedures as implemented in SAGE and SAS, respectively. RESULTS: We found significant heritability for PAIx, CAIx, PPc and mean arterial pressure ranging from 0.37 to 0.41; P < or = 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r > or = 0.12; P < or = 0.02) with the exception of PPc (r = -0.007; P = 0.90) in parent-offspring pairs. The sib-sib correlations were also significant for CAIx (r = 0.22; P = 0.001). The genetic correlation between PWV and the other arterial indexes were significant (rhoG > or = 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (rhoE = 0.10, P = 0.03). CONCLUSION: The observation of significant intrafamilial concordance and heritability of various indexes of arterial stiffness as well as the genetic correlations among arterial phenotypes strongly support the search for shared genetic determinants underlying these traits.

Sympathetic activity, assessed by power spectral analysis of heart rate variability, in white-coat, masked and sustained hypertension versus true normotension.

OBJECTIVE: To assess, in a population-based approach, sympathetic nervous system activity by the use of power spectral analysis of heart rate variability, in normotension, white-coat hypertension, masked hypertension and sustained hypertension. METHODS: The electrocardiographic RR interval was registered in the supine and standing positions and the low-frequency and high-frequency components of its variability were quantified. Cut-off values of 140/90 mmHg for conventional blood pressure and 135/85 mmHg for daytime ambulatory blood pressure were used to define the four blood pressure groups. RESULTS: After exclusion of patients with diabetes, myocardial infarction or treated hypertension, 1485 subjects with complete data remained for the analysis in the supine position. Age averaged 39 +/- 14 years; 54% were women. Conventional and ambulatory blood pressure averaged, respectively, 122 +/- 16/79 +/- 11 mmHg and 124 +/- 12/77 +/- 8 mmHg. After adjusting for demographic, anthropometric and lifestyle characteristics, the low-frequency to high-frequency ratio (geometric mean) averaged 0.81 in normotension and was significantly higher in white-coat hypertension (1.11; P < 0.001), based on a higher low-frequency component and a lower high-frequency component (P < 0.01). This ratio was not significantly different between normotension, masked hypertension (0.97) and sustained hypertension (0.93). The adjusted standing-to-supine ratio of the high-frequency component (geometric mean) was significantly higher in sustained hypertension (0.50) than in normotension (0.39; P < 0.01), but not in white-coat (0.40) and masked hypertension (0.45). CONCLUSION: The findings at rest are compatible with increased sympathetic activity and decreased parasympathetic modulation in white-coat hypertension, with normal autonomic cardiac regulation in masked and sustained hypertension. In addition, sustained hypertension is characterized by a blunted decrease of the high-frequency component on standing.

-391 C to G substitution in the regulator of G-protein signalling-2 promoter increases susceptibility to the metabolic syndrome in white European men: consistency between molecular and epidemiological studies.

BACKGROUND: The regulator of G-protein signalling-2 (RGS2) is a key factor in adipogenesis. We hypothesized that the metabolic syndrome, of which obesity is an important component, might be related to genetic variation in RGS2. METHODS AND RESULTS: We screened the human RGS2 gene. We tested the functionality of a common genetic variant in vitro, ex vivo, and in epidemiological study involving six European populations. The C to G substitution at position -391 in the RGS2 promoter was associated with enhanced RGS2 expression in vitro in transfected 3T3-L1 adipocytes and Chinese hamster cells and ex vivo in adipocytes from male, but not female, volunteers. In 2732 relatives from 512 families and 348 unrelated individuals, randomly recruited from six European populations, the prevalence of GG homozygosity was 54.1%. The metabolic syndrome score, a composite of six continuous traits making up this clinical entity, was 0.27 standardized units higher (P < 0.001) in 795 GG homozygous men compared with 683 men carrying the C allele. Transmission of the -391 G allele to male offspring was associated with a 0.20 unit increase in the score (P=0.039). These epidemiological relations were not significant in 1602 women. CONCLUSIONS: The C to G substitution at position -391 in the RGS2 promoter increases RGS2 expression in adipocytes and is associated with the metabolic syndrome in white European men. Further experimental and clinical research should establish whether this common polymorphism might be a target for preventive or therapeutic intervention.

The International Database of Ambulatory Blood Pressure in relation to Cardiovascular Outcome (IDACO): protocol and research perspectives.

OBJECTIVES: The International Database on Ambulatory Blood Pressure Monitoring (1993-1994) lacked a prospective dimension. We are constructing a new resource of longitudinal population studies to investigate with great precision to what extent the ambulatory blood pressure improves risk stratification. METHODS: The acronym IDACO refers to the new International Database of Ambulatory blood pressure in relation to Cardiovascular Outcome. Eligible studies are population based, have fatal as well as nonfatal outcomes available for analysis, comply with ethical standards, and have been previously published in peer-reviewed journals. In a meta-analysis based on individual patient data, composite and cause-specific cardiovascular events will be related to various indexes derived by ambulatory blood pressure monitoring. The analyses will be stratified by cohort and adjusted for the conventional blood pressure and other cardiovascular risk factors. RESULTS: To date, the international database includes 7609 patients from four cohorts recruited in Copenhagen, Denmark (n=2311), Noorderkempen, Belgium (n=2542), Ohasama, Japan (n=1535), and Uppsala, Sweden (n=1221). In these four cohorts, during a total of 69,295 person-years of follow-up (median 9.3 years), 1026 patients died and 929 participants experienced a fatal or nonfatal cardiovascular event. Follow-up in five other eligible cohorts, involving a total of 4027 participants, is still in progress. We expect that this follow-up will be completed by the end of 2007. CONCLUSION: The international database of ambulatory blood pressure in relation to cardiovascular outcome will provide a shared resource to investigate risk stratification by ambulatory blood pressure monitoring to an extent not possible in any earlier individual study.

Sodium excretion as a modulator of genetic associations with cardiovascular phenotypes in the European Project on Genes in Hypertension.

Hypertension is a chronic age-related disorder, affecting nearly 20% of all adult Europeans. This disease entails debilitating cardiovascular complications and is the leading cause for drug prescriptions in Europeans older than 50 years. Intensive research over the past two decades has so far failed to identify common genetic polymorphisms with a major impact on blood pressure or associated cardiovascular phenotypes, suggesting that multiple genes each with a minor impact, along with gene-gene and gene-environment interactions, play a role. The European Project on Genes in Hypertension (EPOGH) is a large-scale, family-based study in which participants from seven different populations were phenotyped and genotyped according to standardized procedures. This review article summarizes the initial 5-year findings and puts these observations into perspective against other published studies. The EPOGH demonstrated that phenotype-genotype relations strongly depend on host factors such as gender and lifestyle, in particular salt intake as reflected by the 24-h urinary excretion of sodium. The EPOGH therefore highlights the concept that phenotype-genotype relations can only be studied within a defined ecogenetic context.

Arterial characteristics in normotensive offspring of parents with or without a history of hypertension.

BACKGROUND: In this study we compared the arterial characteristics and blood pressure (BP) of normotensive offspring of two normotensive parents (OFF/NT) and normotensive offspring who had at least one hypertensive parent (OFF/HT). METHODS: A total of 174 OFF/HT (17 to 40 years of age) and 59 OFF/NT (16 to 34 years) were recruited in Cracow, Poland (n = 138) and Pilsen, Czech Republic (n = 95). Peripheral pulse pressure (PPp) was determined from conventional and 24-h ambulatory BP. A SphygmoCor device was used to measure the central (CAIx) and peripheral (PAIx) systolic augmentation indexes, central pulse pressure (PPc), and the aortic pulse wave velocity (PWV). In multivariate analyses family clusters and significant covariates were accounted for. RESULTS: The OFF/HT had higher (.14 < P < .0007) conventional BP and PPp on conventional BP measurement (121/75 v 114/71 mm Hg and 46 v 42 mm Hg) as well as on 24-h ambulatory monitoring (118/70 v 114/67 mm Hg and 48 v 47 mm Hg). OFF/HT, compared with OFF/NT, also had higher (.05 < P < .0008) PPc (28 v 26 mm Hg), PAIx (54.7% v 44.9%), CAIx (108.8% v 99.8%), and PWV (7.4 v 6.6 m/sec). However, complex adjustment including mean arterial pressure and age removed the differences between the offspring in the PAIx, CAIx, and PWV. CONCLUSIONS: Large-artery properties are altered in OFF/HT compared with OFF/NT. The findings from this cross-sectional study suggest that the alterations in arterial function in subjects with a family history of hypertension are determined mainly by an increased BP and age-related hemodynamic changes.

Reference values in white Europeans for the arterial pulse wave recorded by means of the SphygmoCor device.

Measurement of blood pressure together with applanation tonometry at the radial artery allows the reproducible assessment of various indexes of arterial stiffness, including the peripheral (PPp) and central pulse pressures (PPc) and the peripheral (Alp) and central augmentation indexes (Alc). We defined preliminary diagnostic thresholds, using the distributional characteristics of these hemodynamic measurements in a reference population. We randomly recruited 870 subjects from 3 European populations. PPp was the average difference between systolic and diastolic blood pressure measured five times at one home visit. For measurement of PPc, Alp and Alc, we used the SphygmoCor device. We selected subjects without hypertension, diabetes, dyslipidemia in need of medical treatment or previous or concomitant cardiovascular disease. The study population included 228 men and 306 women (mean age 34.9 years). All hemodynamic measurements were curvilinearly related to age, and Alp and Alc were lower in men than in women. In men at age 40, the upper 95% prediction bands of the relations of the hemodynamic measurements with age approximated 60 mmHg for PPp, 40 mmHg for PPc, 90% for Alp, and 30% for Alc. For PPc, Alp and Alc, these thresholds must be adjusted for age, leading to lower and higher thresholds at younger and older age, respectively. In addition, in women of any age, the Alp and Alc thresholds must be increased by 10% and 7%, respectively. Pending validation in prospective outcome studies, distributional characteristics of arterial stiffness indexes in a reference population can be used to generate operational thresholds for use in clinical practice.

[Growth factors and cytokines (TGFBeta, bFGF and IGF-1) and cardiac left ventricular hypertrophy in hypertension]. / Czynniki wzrostu i cytokiny (TGFBeta, bFGF i IGF-1) a przerost miesnia lewej komory serca w nadcisnieniu t tetniczym.

One of the most frequent types of organ damage developing in the course of hypertension is left ventricular hypertrophy (LVH). The percentage of hypertensive patients with LVH, assessed with echocardiographic method, amounts to 20-60%, depending on blood pressure level and duration of hypertension. This review includes current opinions on the role of transforming growth factor Beta1 (TGFP31), basic fibroblast growth factor (bFGF, FGF2), and insulin-like growth factor-1 (IGF-1) in the development of LVH in the course of hypertension. TGFBeta1 is a cytokine involved in the regulation of proliferation and cell differentiation. Its action is mainly directed towards the connective tissue cells, which it stimulates into production of collagen I and III. Increased levels of TGFbeta1 have been found both in animal models and in patients with hypertension and LVH. Growth factors bFGF and IGF-1 activate cell proliferation and have anti-apoptotic action. The role of bFGF and IGF-1 has been demonstrated in animal models; however, results of observations in subjects with hypertension and LVH are inconsistent. Discussed growth factors and cytokines and cell signalling pathways related to them might in future appear as targets for therapeutic intervention.

Left ventricular mass in relation to genetic variation in angiotensin II receptors, renin system genes, and sodium excretion.

BACKGROUND: In the European Project On Genes in Hypertension (EPOGH), we investigated in 3 populations to what extent left ventricular mass (LVM) was associated with genetic variation in the angiotensin II receptors type 1 (AGTR1 A1166C) and type 2 (AGTR2 G1675A) while accounting for possible gene-gene interactions with the angiotensin-converting enzyme (ACE D/I) and angiotensinogen (AGT -532C/T) polymorphisms. METHODS AND RESULTS: We randomly recruited 221 nuclear families (384 parents, 431 offspring) in Cracow (Poland), Novosibirsk (Russia), and Mirano (Italy). Echocardiographic LVM was indexed to body surface area, adjusted for covariates, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests in a population-based and family-based approach, respectively. For AGTR1 and AGTR2, there was no heterogeneity in the phenotype-genotype relations across populations. LVM index was unrelated to the AGTR1 A1166C polymorphism. In men, in the population- and family-based analyses, the allelic effects of the AGTR2 polymorphism on LVM index differed (P=0.01) according to sodium excretion. In women, this gene-environment interaction did not reach statistical significance. In untreated men, LVM index (4.2 g/m2 per 100 mmol) and left ventricular internal diameter (0.73 mm/100 mmol) increased (P<0.02) with higher sodium excretion in the presence of the G allele with an opposite tendency in A allele carriers. The ACE D/I polymorphism, together with the ACE genotype-by-sodium interaction term, significantly and independently improved the models relating LVM index to the AGTR2 polymorphism and the AGTR2 genotype-by-sodium interaction. CONCLUSIONS: The present findings support the hypothesis that in men the AGTR2 G1675A and the ACE D/I polymorphisms independently influence LVM and that salt intake modulates these genetic effects.

Epistatic interaction between alpha- and gamma-adducin influences peripheral and central pulse pressures in white Europeans.

BACKGROUND: Adducin is a membrane skeleton protein consisting of alpha- and beta- or alpha- and gamma-subunits. Mutations in alpha- and beta-adducin are associated with hypertension. In the European Project on Genes in Hypertension, we investigated whether polymorphisms in the genes encoding alpha-adducin (Gly460Trp), beta-adducin (C1797T) and gamma-adducin (A386G), alone or in combination, affected pulse pressure (PP), an index of vascular stiffness. METHODS: We measured peripheral and central PP by conventional sphygmomanometry and applanation tonometry, respectively. We randomly recruited 642 subjects (162 nuclear families and 70 unrelated individuals) from three European populations. In multivariate analyses, we used generalized estimating equations and the quantitative transmission disequilibrium test. RESULTS: Peripheral and central PP averaged 46.1 and 32.6 mmHg, respectively. Among carriers of the alpha-adducin Trp allele, peripheral and central PP were 5.8 and 4.7 mmHg higher in gamma-adducin GG homozygotes than in their AA counterparts, due to an increase in systolic pressure. gamma-Adducin GG homozygosity was associated with lower urinary Na/K ratio among alpha-adducin Trp allele carriers and with higher urinary aldosterone excretion among alpha-adducin GlyGly homozygotes. Sensitivity analyses in founders and offspring separately, and tests based on the transmission of the gamma-adducin G allele across families, confirmed the interaction between the alpha- and gamma-adducin genes. CONCLUSIONS: In alpha-adducin Trp allele carriers, peripheral and central PP increased with the gamma-adducin G allele. This epistatic interaction is physiologically consistent with the heterodimeric structure of the protein and its influence on transmembranous sodium transport.

Host and environmental determinants of heart rate and heart rate variability in four European populations.

OBJECTIVE: In a population-based sample of nuclear families recruited in the framework of the European Project on Genes in Hypertension (EPOGH), we investigated the association between heart rate (HR) and its variability (HRV), and gender, age, posture, breathing frequency, body mass index, systolic blood pressure, family history of hypertension and various lifestyle factors, such as smoking, alcohol and coffee consumption and physical activity. METHODS: RR interval and respiration were registered in the supine and standing positions (15 min each) in 1208 subjects in Bucharest (Romania, n= 267), Cracow (Poland, n= 323), Mirano (Italy, n= 323) and Novosibirsk (Russian Federation, n= 295). After exclusion of 199 participants on antihypertensive treatment and/or patients with diabetes mellitus (n= 40) or myocardial infarction (n= 4), 993 subjects were eligible for analysis. We evaluated 858 participants with high-quality recordings. Using fast Fourier transform, we decomposed HRV into low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.40 Hz) components, which were expressed in normalized units. RESULTS: Mean values were 35.3 years for age, 24.3 kg/m for body mass index (BMI) and 121.0/77.2 mmHg for blood pressure. The group included 462 (53.8%) women. Across four centres, HR and HRV were similarly and independently associated with gender, age and postural position (P <0.001). In the supine position, HR was higher in women than men (67.2 versus 63.7 bpm). Men had higher normalized LF power than women (48.8 versus 41.5), but lower HF power (40.6 versus 47.4). The normalized HF power decreased with age (r = -0.43), whereas LF power increased (r = 0.32). On standing, HR increased (83.3 versus 65.6 bpm), normalized HF power declined (19.2 versus 44.3) and LF power increased (67.4 versus 44.9). The independent effects of respiration frequency, systolic blood pressure, family history of hypertension, body mass index and lifestyle factors on HRV differed between populations, and explained no more than 8% of the total variance. CONCLUSIONS: Across four European populations, gender, age and posture were consistent and independent correlates of HR and HRV. Lifestyle seems to have small but varying influences on HR and/or HRV, probably depending on the environmental and cultural background of the population under study.

Relationship between left ventricular mass and the ACE D/I polymorphism varies according to sodium intake.

BACKGROUND: In the European Project on Genes in Hypertension (EPOGH), we investigated to what extent left ventricular mass (LVM) in populations and families relates to the angiotensin-converting enzyme (ACE D/I) and aldosterone synthase (CYP11B2 -344C/T) polymorphisms and urinary sodium excretion. METHODS: We recruited 219 nuclear families (382 parents and 436 offspring) randomly in Cracow (Poland), Novosibirsk (Russia) and Mirano (Italy). Echocardiographical LVM was indexed to body surface area, adjusted for covariables, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests, in a population-based and family-based approach, respectively. RESULTS: We found significant differences between the two Slavic centres and Mirano in left ventricular mass index (LVMI) (94.9 versus 80.3 g/m2), sodium excretion (229 versus 186 mmol/day), and the prevalence of the ACE D allele (52.1 versus 58.5%). There was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with the ACE gene, but not with the aldosterone synthase gene. In the two Slavic centres, ACE II homozygosity was significantly associated with higher LVMI, in population-based as well as in family-based analyses. By contrast, in Mirano, LVMI was slightly higher in DD homozygotes (P = 0.05), but only in the population-based approach. LVMI increased with higher sodium excretion in ACE II homozygous offspring of both Slavic and Italian extraction (+4.2 +/- 2.1 g/m2 per 100 mmol; P = 0.04) and in Slavic (+2.6 +/- 1.1 g/m2 per 100 mmol; P = 0.02), but not Italian (-3.3 +/- 3.2 g/m2 per 100 mmol; P = 0.29) D allele carriers. We did not find any association between LVMI and the aldosterone synthase -344C/T polymorphism. CONCLUSIONS: The relationship between LVMI and the ACE D/I polymorphism differs across populations, possibly as a consequence of intermediate regulatory mechanisms responsive to varying levels of salt intake.

Association of peripheral and central arterial wave reflections with the CYP11B2 -344C allele and sodium excretion.

OBJECTIVE: Angiotensin II and aldosterone, generated by the angiotensin-converting enzyme (ACE) and aldosterone synthase (CYP11B2), respectively, not only regulate sodium and water homeostasis, but also influence vascular remodeling in response to high blood pressure. In the European Project on Genes in Hypertension (EPOGH), we therefore investigated whether the ACE I/D and CYP11B2 C-344T polymorphisms influence early arterial wave reflections, a measure of vascular stiffness. METHODS: We measured the peripheral and central augmentation index of systolic blood pressure by applanation tonometry at the level of the radial artery in 622 subjects (160 families and 64 unrelated individuals) randomly recruited from three European populations, whose average urinary sodium excretion ranged from 196 to 245 mmol/day. In multivariate analyses, with sodium excretion analyzed as a continuous variable, we explored the phenotype-genotype associations by means of generalized estimating equations and the quantitative transmission disequilibrium test. RESULTS: The peripheral and central augmentation indexes were significantly higher in CYP11B2 -344C allele carriers than in -344T homozygotes. In offspring, early wave reflections increased with the transmission of the -344C allele. This effect of the CYP11B2 polymorphism occurred in subjects with a higher than median urinary sodium excretion (210 mmol/day). The ACE I/D polymorphism did not influence augmentation of systolic blood pressure. CONCLUSIONS: The CYP11B2 C-344T polymorphism affects arterial stiffness. However, sodium intake seems to modulate this genetic effect.

beta-Adducin polymorphisms, blood pressure, and sodium excretion in three European populations.

The associations of the beta-adducin C1797T polymorphism with blood pressure (BP) and various indexes of sodium homeostasis were investigated in 388 men and 456 women, aged 18 to 60 years, recruited from three European populations (Cracow, Poland, n = 300; Novosibirsk, Russian Federation, n = 274; Mirano, Italy; n = 270). Phenotypes included 24-h ambulatory BP and urinary excretion of electrolytes and aldosterone. Subjects were genotyped for the beta-adducin polymorphism. Both a population-based association study and a family-based analysis were performed. Urinary sodium excretion was higher in Cracow than in Mirano (241 v 185 mmol/24 h, P <.05) and intermediate in Novosibirsk (206 mmol/24 h). The beta-adducin T allele (15.2% v 9.1%, P <.0001) was more prevalent in Mirano than in the two Slavic centers. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with beta-adducin. In the Slavic centers, 24-h systolic BP was higher in T allele carriers than in CC homozygotes (122.3 v 119.7 mm Hg, P =.03), whereas this was not the case in Mirano (121.8 v 122.9 mm Hg, P =.42). In Slavic (212.6 v 233.1 mmol/24 h) as well as in Italian (166.1 v 191.5 mmol/24 h) participants, 24-h sodium excretion was lower (P =.01) in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test. In conclusion, the frequency of the beta-adducin T allele and salt intake differ across European populations. Thus, both variation in genetic background and salt intake may explain the observed heterogeneity in the phenotype-genotype relationships. Genetic determinants of complex quantitative traits such as BP can only be investigated within their epidemiologic context.

Blood pressure phenotypes in relation to the beta-adducin C1797T polymorphism in the European Project on Genes in Hypertension (EPOGH).

METHODS: The association of blood pressure (BP) with the beta-adducin C1797 T polymorphism was investigated in 388 men and 456 women aged 18-60 years recruited from three European populations (Cracow, Poland, n=300; Novosibirsk, Russian Federation, n=274; Mirano, Italy; n=270). Phenotypes included conventional measurements of BP obtained at the second contact with the subjects and 24-h ambulatory BP. Subjects were genotyped for the beta-adducin C1797 T polymorphism. Both a population-based association study and a family-based analysis were performed. RESULTS: Urinary sodium excretion was higher in Cracow than in Mirano (241 versus 185 mmol/day, P<0.05) and intermediate in Novosibirsk (206 mmol/day). The beta-adducin T allele (15.2 versus 9.1%, P<0.0001) was more prevalent in Mirano than in the two Slavic centres. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with beta-adducin. Adjusted population-based analyses demonstrated that in the two Slavic centres, values of systolic pressure obtained by 24-h, daytime and night-time ambulatory monitoring, but not those measured by conventional sphygmomanometry at home, were significantly higher in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test. CONCLUSIONS: Phenotype-genotype associations involving blood pressure are influenced by the technique and conditions of the BP measurement as well as by the overall ecogenetic context.

Genetic factors in hypertension. Angiotensin-converting enzyme polymorphism.

AIM: The key enzyme of the renin-angiotensin-aldosterone system angiotensin-converting enzyme (ACE), shows the genetic polymorphism responsible for the varying activity of this enzyme. In a study of randomly chosen families we analyzed the relationship between insertion/deletion (I/D) polymorphism of the ACE and ambulatory blood pressure (ABP), left ventricular mass index (LVMI) and carotid intima-media thickness (IMT). METHODS: The study population consisted of 127 parents and 167 offspring. All subjects underwent 24 hr ABP monitoring using a SpaceLabs 90207 device. 2D and M-mode echocardiograms were also obtained. The carotid intima-media thickness (IMT) was assessed by ultrasound. The I/D polymorphism of the ACE gene was measured with the use of PCR method. For statistical analysis, co-variables and correlations between relatives were taken into account. RESULTS: The frequency of genotypes was: 27.2% for DD homozygotes, 49.7% for DI heterozygotes and 23.1% for II homozygotes, being in Hardy-Weinberg equilibrium (P=0.97). There was no relationship between the ACE gene polymorphism and ABP, LVMI or carotid IMT in parents nor their offspring. The transmission disequilibrium tests for quantitative traits showed only a slight tendency towards the influence of the polymorphism on LVMI (P=0.06). CONCLUSIONS: In the study group of nuclear families, I/D polymorphism of the ACE gene did not influence blood pressure, left ventricular mass or carotid intima-media thickness.

[Phenotypes of the cardiovascular system and polymorphisms of the endothelial nitric oxide synthase]. / Wybrane fenotypy ukladu krazenia a zmiennosc genetyczna sródblonkowej syntazy tlenku azotu.

AIM: Reduced nitric oxide (NO) production is associated with pathological changes in the cardiovascular system. In our study we analyzed the relationship between two polymorphisms (Glu298Asp and VNRT in the intron 4) of the endothelial nitric oxide synthase (eNOS) and ambulatory blood pressure (ABP), left ventricular mass index (LVMI) and vascular phenotypes. METHODS: The study population consisted of 127 parents and 167 offspring. All subjects underwent 24 hr ABP monitoring using a SpaceLabs 90207 device. 2D and M-mode echocardiograms were obtained. Pulse wave velocity (PWV) between the common carotid and femoral artery was measured with the Complior device and the carotid intima-media thickness (IMT) was assessed by ultrasound. For statistical analysis co-variables and correlations between relatives were taken into account. RESULTS: There was no relationship between the eNOS gene polymorphisms and ABP or LVMI neither in parents nor their offspring. Among parents, who were carriers of the 298Asp allele higher IMT values were noted as compared with Glu/Glu homozygotes (0.94 vs. 0.70 mm; p = 0.007). Among offspring there was a similar tendency towards higher IMT (0.60 vs. 0.53 mm; p = 0.10), but also higher PWV in carriers of the 298Asp allele as compared with Glu/Glu homozygotes (8.47 vs. 8.17 m/sec; p = 0.14). Polymorphism VNRT in intron 4 was not associated with vascular phenotypes. CONCLUSION: The Glu298Asp polymorphism of eNOS gene identifies patients with larger carotid IMT.

[Heart rate variability in patients after coronary artery bypass grafting--early and long term effects of cardiac rehabilitation]. / Zmiennosc rytmu zatokowego serca u pacjentów po zabiegach pomostowania aortalno-wiencowego-wczesne i pózne wyniki rehabilitacji kardiologicznej.

Patients after coronary artery bypass grafting (CABG) have impaired heart rate variability (HRV) parameters. The clinical significance of impaired HRV and the influence of the cardiac rehabilitation on the HRV in this group of patients is not clear. We studied 103 patients (average age 52.2 +/- 7.8) after CABG, divided into group A (72 patients) who underwent cardiac rehabilitation (starting 15 days after the CABG) and group B (31 patients) who did not have rehabilitation. In all patients, a 24 hr ECG (including time and frequency domain HRV) was obtained before the onset of rehabilitation, after completion of the rehabilitation and after 6 months. Before the rehabilitation there were no differences in time-domain HRV between the groups, however frequency-domain HRV values were significantly higher in group A. In group A, the time-domain HRV parameters improved after 21 days of rehabilitation, whereas the frequency domain parameter components remained unchanged. At 6 months, improvement in time and frequency domain HRV parameters was noted, but the parameters were significantly higher in group A. In patients that underwent coronary artery bypass grafting, the cardiac rehabilitation time domain HRV showed improvement in both the short term (21 days) and long run (6 months). However, the frequency domain parameter was only increased over the long run. Cardiac rehabilitation speeds up the improvement of the time domain HRV and frequency domain parameters over long term observation (6 months).

[Heart rate variability in patients with hypertension and left ventricular hypertrophy]. / Zmiennosc rytmu serca u pacjentów z nadcisnieniem tetniczym i przerostem lewej komory miesnia sercowego.

The aim of the study was to analyse the heart rate variability (HRV) in patients with moderate essential hypertension complicated by left ventricular hypertrophy (LVH). Forty-two patients with untreated essential hypertension participated in the study group and 45 normotensives (16M, 29F, age 49.8 +/- 5.6 years) served as the controls. The hypertensives were divided into those with LVH (n = 25, 10M, 15F, age 50.1 +/- 5.9 years) and those without LVH (n = 17, 4M, 13F, age 52.0 +/- 3.4 years). HRV was recorded and analysed using the CardioPSA System, Medatec. In each subject, 30 min. of ECG recording was obtained: 15 min. in the supine, position and 15 min. in the upright position. Fast Fourier transform was used to analyse total power, low frequency (LF, 0.04-0.15 Hz) and high frequency components (HF, 0.15-0.40 Hz). Left ventricular mass was calculated from echocardiograms using the Deveraux formula. LVH was defined as a left ventricular mass index (LVM) > 134 g/m2 for men and > 110 g/m2 for women. A T-test was used to test for nter-group differences: p < 0.05 was considered as significant. In hypertensive patients with left ventricular hypertrophy, we observed decreased values of HF component, both in supine and upright positions, as compared to hypertensives without LVH. Components of HRV did not differ between the hypertensives without LVH and the normotensives. In hypertensives with a LVH the high frequency component of HRV was decreased, indicating impaired para-sympathetic activity.