Agnieszka Olszanecka

Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion

CONTEXT Extrapolations from observational studies and short-term intervention trials suggest that population-wide moderation of salt intake might reduce cardiovascular events. OBJECTIVE To assess whether 24-hour urinary sodium excretion predicts blood pressure (BP) and health outcomes. DESIGN, SETTING, AND PARTICIPANTS Prospective population study, involving 3681 participants without cardiovascular disease (CVD) who are members of families that were randomly enrolled in the Flemish Study on Genes, Environment, and Health Outcomes (1985-2004) or in the European Project on Genes in Hypertension (1999-2001). Of 3681 participants without CVD, 2096 were normotensive at baseline and 1499 had BP and sodium excretion measured at baseline and last follow-up (2005-2008). MAIN OUTCOME MEASURES Incidence of mortality and morbidity and association between changes in BP and sodium excretion. Multivariable-adjusted hazard ratios (HRs) express the risk in tertiles of sodium excretion relative to average risk in the whole study population. RESULTS Among 3681 participants followed up for a median 7.9 years, CVD deaths decreased across increasing tertiles of 24-hour sodium excretion, from 50 deaths in the low (mean, 107 mmol), 24 in the medium (mean, 168 mmol), and 10 in the high excretion group (mean, 260 mmol; P < .001), resulting in respective death rates of 4.1% (95% confidence interval [CI], 3.5%-4.7%), 1.9% (95% CI, 1.5%-2.3%), and 0.8% (95% CI, 0.5%-1.1%). In multivariable-adjusted analyses, this inverse association retained significance (P = .02): the HR in the low tertile was 1.56 (95% CI, 1.02-2.36; P = .04). Baseline sodium excretion predicted neither total mortality (P = .10) nor fatal combined with nonfatal CVD events (P = .55). Among 2096 participants followed up for 6.5 years, the risk of hypertension did not increase across increasing tertiles (P = .93). Incident hypertension was 187 (27.0%; HR, 1.00; 95% CI, 0.87-1.16) in the low, 190 (26.6%; HR, 1.02; 95% CI, 0.89-1.16) in the medium, and 175 (25.4%; HR, 0.98; 95% CI, 0.86-1.12) in the high sodium excretion group. In 1499 participants followed up for 6.1 years, systolic blood pressure increased by 0.37 mm Hg per year (P < .001), whereas sodium excretion did not change (-0.45 mmol per year, P = .15). However, in multivariable-adjusted analyses, a 100-mmol increase in sodium excretion was associated with 1.71 mm Hg increase in systolic blood pressure (P.<001) but no change in diastolic BP. CONCLUSIONS In this population-based cohort, systolic blood pressure, but not diastolic pressure, changes over time aligned with change in sodium excretion, but this association did not translate into a higher risk of hypertension or CVD complications. Lower sodium excretion was associated with higher CVD mortality.

Ambulatory Blood Pressure Monitoring in 9357 Subjects From 11 Populations Highlights Missed Opportunities for Cardiovascular Prevention in Women

To analyze sex-specific relative and absolute risks associated with blood pressure (BP), we performed conventional and 24-hour ambulatory BP measurements in 9357 subjects (mean age, 52.8 years; 47% women) recruited from 11 populations. We computed standardized multivariable-adjusted hazard ratios for associations between outcome and systolic BP. During a course of 11.2 years (median), 1245 participants died, 472 of cardiovascular causes. The number of fatal combined with nonfatal events was 1080, 525, and 458 for cardiovascular and cardiac events and for stroke, respectively. In women and men alike, systolic BP predicted outcome, irrespective of the type of BP measurement. Women compared with men were at lower risk (hazard ratios for death and all cardiovascular events=0.66 and 0.62, respectively; P<0.001). However, the relation of all cardiovascular events with 24-hour BP (P=0.020) and the relations of total mortality (P=0.023) and all cardiovascular (P=0.0013), cerebrovascular (P=0.045), and cardiac (P=0.034) events with nighttime BP were steeper in women than in men. Consequently, per a 1-SD decrease, the proportion of potentially preventable events was higher in women than in men for all cardiovascular events (35.9% vs 24.2%) in relation to 24-hour systolic BP (1-SD, 13.4 mm Hg) and for all-cause mortality (23.1% vs 12.3%) and cardiovascular (35.1% vs 19.4%), cerebrovascular (38.3% vs 25.9%), and cardiac (31.0% vs 16.0%) events in relation to systolic nighttime BP (1-SD, 14.1 mm Hg). In conclusion, although absolute risks associated with systolic BP were lower in women than men, our results reveal a vast and largely unused potential for cardiovascular prevention by BP-lowering treatment in women.

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.

The effect of hormone replacement therapy on arterial blood pressure and vascular compliance in postmenopausal women with arterial hypertension.

Arterial pathology is a major contributor to cardiovascular disease, morbidity and mortality. Women are at higher risk of cardiovascular disease after menopause. Arterial stiffness determined by pulse wave velocity, increases with age both in men and women, whereas arterial compliance in premenopausal women is greater than in men of similar age. This difference is lost in the postmenopausal years, with evidence of rapid decline in arterial compliance in the perimenopausal period. Loss of hormonal modulation is a likely explanation for reduced arterial compliance in postmenopausal women. Long-term treatment with hormone replacement therapy (HRT) may be expected to partially reverse the increase in arterial stiffness. The aim of the study was to analyse the effect of HRT on blood pressure and arterial compliance in postmenopausal women with arterial hypertension receiving hypotensive drugs. The results in the present study of postmenopausal women with mild to moderate arterial hypertension receiving HRT showed only a transient tendency towards lower blood pressure. In our study HRT was found to improve arterial compliance at 3 months after HRT, and the effect was maintained throughout 12 months. The increased arterial compliance in women receiving HRT was independent of blood pressure. In parallel with decreasing pulse wave velocity women receiving HRT had lower total and low-density lipoprotein cholesterol. The conclusions were that after 1 year HRT in postmenopausal women with arterial hypertension improves circadian blood pressure pattern, but it does not affect significantly blood pressure values and variability. The present study also shows that HRT significantly inhibits age-related rigidity of large arteries.

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.

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 ≤ 0.0001. The method of intrafamilial concordance confirmed these results; intrafamilial correlation coefficients were significant for all arterial indexes (r ≥ 0.12; P ≤ 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 (ρG ≥ 0.29; P < 0.0001). The corresponding environmental correlations were only significantly positive for PPp (ρE = 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.

Ambulatory blood pressure, left ventricular mass and vascular phenotypes in relation to the endothelial nitric oxide synthase gene Glu298Asp and intron 4 polymorphisms in a population-based family study

Reduced nitric oxide production is associated with pathological changes in the cardiovascular system. In a study of randomly chosen families, we analysed the relationship between two polymorphisms (Glu298Asp and intron 4) of the endothelial nitric oxide synthase (eNOS) and ambulatory blood pressure (ABP), left ventricular mass index (LVMI) and vascular phenotypes. The study population consisted of 127 parents and 167 offspring. All subjects underwent 24 h ABP monitoring using a SpaceLabs 90207 device. 2D and M-mode echocardiograms were obtained. Pulse wave velocity 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, covariables and correlations between relatives were taken into account. The frequency of genotypes was as follows: for Glu298Asp: 55.1%—Glu/Glu, 40.1%—Glu/Asp and 4.8%—Asp/Asp; for intron 4: 65.0%—4 b/b, 33.3%—4 b/a and 1.7%—4 a/a, being in Hardy–Weinberg equilibrium (P⩾0.29). There was no relationship between the eNOS gene polymorphisms and ABP or LVMI either in parents or their offspring. Among parents, carriers of the 298Asp allele had higher IMT values as compared with Glu/Glu homozygotes (0.94 vs 0.70 mm; P=0.007). Among offspring, there was a similar tendency (0.60 vs 0.53 mm; P=0.10), which was confirmed by transmission disequilibrium tests for quantitative variables (P⩾0.07). Our findings indicate that the Glu298Asp polymorphism of eNOS identifies patients with larger carotid IMT, also in younger subjects.Journal of Human Hypertension advance online publication, 03 March 2005; doi:10.1038/sj.jhh.1001837

Maternal and Paternal Influences on Left Ventricular Mass of Offspring

Abstract—Significant intrafamilial correlations of left ventricular mass exist in first-degree relatives. However, the specific maternal and paternal influences on left ventricular mass of offspring remain unknown. We therefore evaluated familial aggregation of left ventricular mass by type of familial relation in two European populations. A random sample of 159 nuclear families (250 parents and 321 offspring) was investigated in Cracow, Poland, and Novosibirsk, Russia. The mean age of parents and offspring was 51.4 years and 25.1 years, respectively. Two-dimensionally guided M-mode echocardiography was performed, and left ventricular mass was calculated. As a measure of concordance, we computed correlation coefficients for left ventricular mass between first-degree relatives and between spouse pairs. After adjustment for center, gender, age, height, body weight, systolic blood pressure, antihypertensive treatment, smoking, alcohol intake, and physical activity, the intrafamilial correlations for left ventricular mass were 0.06 (P =0.57) in 91 spouse-spouse pairs, 0.14 (P =0.002) in 500 parent-offspring pairs, and 0.32 (P <0.001) in 179 sib-sib pairs. Across the four parent-offspring relations, the intrafamilial correlations of left ventricular mass differed. The mother-son (n =140, r =0.27, P <0.001) and mother-daughter (n =161, r =0.28, P <0.001) correlations were significant, whereas the father-son (n =101, r =0.04, P =0.69) and father-daughter (n =98, r =−0.09, P =0.38) correlations were not different from zero. Overall, the mother-offspring correlation coefficient was significantly higher than the father-offspring correlation (r =0.28 versus r =−0.04;P =0.005). Thus, maternal factors appear to have more impact on left ventricular mass of offspring than do paternal influences. Further studies are required to elucidate the genetic, epigenetic, and ecogenetic mechanisms underlying these divergent parent-offspring correlations.

Myocardial perfusion in hypertensive patients with normal coronary angiograms.

Background Pressure-induced left ventricular hypertrophy is one of the mechanisms responsible for an impaired coronary vasodilating capacity leading to myocardial ischemia and angina. The aim of the study was to investigate myocardial perfusion using cardiovascular magnetic resonance in patients with arterial hypertension and a history of chest pain and normal coronary angiography, and to estimate the influence of left ventricular hypertrophy on the parameters of myocardial perfusion. Methods The study included 102 patients (mean age 55.4 ± 7.7 years) with well controlled hypertension and 12 healthy volunteers. In 96 patients, myocardial first-pass perfusion cardiovascular magnetic resonance both at rest and during an infusion of adenosine 140 μg/kg/min was performed. Semiquantitative perfusion analysis was performed by using the upslope of myocardial signal enhancement to derive the myocardial perfusion index and the myocardial perfusion reserve index. The study group was divided according to the presence of left ventricular hypertrophy in the cardiovascular magnetic resonance examination: group with left ventricular hypertrophy (n = 40) and without left ventricular hypertrophy (n = 56). Results Independent of the presence of left ventricular hypertrophy, there were significant differences in baseline myocardial perfusion index between hypertensive patients and controls (0.13 ± 0.07 vs. 0.04 ± 0.01; P < 0.001), and in stress myocardial perfusion index (hypertensive patients 0.21 ± 0.10 vs. controls 0.09 ± 0.03; P < 0.001). In hypertensive patients, the myocardial perfusion reserve index was reduced in the mid and apical portions of the left ventricle (1.71 ± 1.1 vs. 2.52 ± 0.83; P < 0.02). There was no significant correlation of myocardial perfusion reserve index with left ventricular mass or hypertrophy. Conclusion In patients with mild or moderate hypertension and a history of chest pain with normal coronary angiography, there is regional myocardial perfusion reserve impairment that is independent of the presence of left ventricular hypertrophy and may be a reason for angina.

Structure and function of large arteries in hypertension in relation to oxidative stress markers

BACKGROUND The relationship between hypertension and oxidative stress remains unexplained. Nevertheless, it is well established that reactive oxygen species have an influence on the arterial wall, endothelial function and therefore determine blood pressure. AIM The evaluation of selected oxidative stress markers in hypertensive patients and an assessment of the relationship between oxidative stress markers and the arterial structure and function. We also aimed to investigate whether the influence of oxidative stress on remodelling of arteries, their structural and functional changes is independent of hypertension or is related to hypertension. METHODS Altogether 217 subjects (114 female, 103 male) were enrolled from hypertensive families. The mean age was 45.5 ± 16 years, and the group included 155 hypertensives. In every subject, the pulse wave velocity and intima-media thickness (IMT) in carotid arteries were measured as well as selected oxidative stress markers such as asymmetric dimethylarginin (ADMA), symmetric dimethylarginin (SDMA), advanced oxidation protein products (AOPP) and oxidised low density lipoproteins (ox-LDL). RESULTS The results of multivariate analysis show that in hypertensive patients: the ADMA level increased with increasing peripheral pulse pressure (b = 0.003; p < 0.001), and AOPP was related to higher carotid IMT (b = 0.91; p = 0.036). In normotensive subjects, the following associations were found: between ADMA and central pulse pressure (b = 0.006; p = 0.008), between SDMA and the peripheral augmentation index (b = -0.03; p = 0.014), between AOPP and the peripheral augmentation index (b = 0.011; p = 0.04), and between ox-LDL/LDL ratio and the peripheral augmentation index (b = -0.025; p = 0.004). The SDMA/ADMA ratio was associated with estimated glomerular filtration rate in both groups (b = -0.0061; p < 0.0001 and b = -0.005; p < 0.017, respectively). In hypertensives, we observed a relation with peripheral pulse pressure (b = -0.0067; p = 0.0143). Moreover, in normotensives there was an association between the SDMA/ADMA ratio and uric acid (b = 1.3629; p = 0.046). CONCLUSIONS We found that the influence of oxidative stress on the structure and function of large arteries was independent of hypertension. Therefore oxidative stress may play a significant role in the development of arterial stiffness. Higher oxidative stress is associated with more advanced arterial remodelling in hypertension.