T. Kuznetsova

Environmental exposure to cadmium, forearm bone density, and risk of fractures : prospective population study

BACKGROUND Chronic low-level exposure to cadmium may promote calcium loss via urinary excretion. We undertook a prospective population study to investigate whether environmental exposure to cadmium lowers bone density and increases risk of fractures. METHODS We measured urinary cadmium excretion, a biomarker of lifetime exposure, in people from ten districts of Belgium, of which six districts bordered on three zinc smelters. We also measured cadmium in soil and in vegetables from the districts, and collected data on incidence of fractures and height loss. Bone density was measured at the forearm just above the wrist by single photon absorptiometry, and calculated as the mean of six proximal and four distal scans. FINDINGS Mean cadmium excretion at baseline was 8.7 nmol daily. Across the ten districts, mean cadmium concentration in soil ranged from 0.8 to 14.7 mg/kg, and from 0.1 to 4.0 mg/kg dry weight in vegetables. Median follow-up was 6.6 years. Mean forearm bone density in proximal and distal scans was 0.54 g/cm2 and 0.43 g/cm2 in men, and 0.44 g/cm2 and 0.34 g/cm2 in women. In postmenopausal women, a twofold increase in urinary cadmium correlated with 0.01 g/cm2 decrease in bone density (p<0.02). The relative risks associated with doubled urinary cadmium were 1.73 (95% CI 1.16-2.57; p=0.007) for fractures in women and 1.60 (0.94-2.72, p=0.08) for height loss in men. Cadmium excretion in districts near smelters was 22.8% higher (p=0.001) than in other districts, with fracture rates of 16.0 and 10.3 cases per 1000 person-years, respectively, and a population-attributable risk of 35.0%. INTERPRETATION Even at a low degree of environmental exposure, cadmium may promote skeletal demineralisation, which may lead to increased bone fragility and raised risk of fractures.

M235T angiotensinogen gene polymorphism and cardiovascular renal risk.

OBJECTIVE In this meta-analysis, we attempted to derive pooled estimates for the putative associations between various cardiovascular-renal disorders and the M235T polymorphism of the angiotensinogen gene. METHODS Case-control studies were combined, using the Mantel and Haenszel approach. Joint P values for continuous variables were calculated by Stouffers method. Continuous measurements reported in different units were expressed on a percentage scale using the intrastudy mean of the MM genotype as denominator. RESULTS The computerized database used for this analysis included 69 reports with an overall sample size of 27,906 subjects. Overall, possession of the T allele was associated with an increased risk of hypertension. In comparison with the MM reference group (number of studies, n = 32), the excess risk was 31% (P = 0.001) in TT homozygotes and 11% (P = 0.03) in TM heterozygotes. The sensitivity analysis showed that this association was present only in whites (T allelic frequency, f = 42.2%), but not in blacks (f = 77.0%) or Asians (f = 78.0%). Atherosclerotic complications (n = 12), renal microvascular disorders (n = 13), cardiomyopathy (n = 2) or diabetic retinopathy (n = 3) were not correlated with the M235T polymorphism. Publication bias was observed for hypertension, but not for coronary heart disease, including myocardial infarction, and for microvascular nephropathy. Furthermore, in comparison with the MM control group, the circulating angiotensinogen levels (n = 8) were raised by 11 and 7% (P = 0.01) in TT and TM subjects, respectively. In contrast, plasma levels of the angiotensin I converting enzyme (n = 4) and body mass index (n = 15) were not associated with the T allele. CONCLUSION The T allele encoding angiotensinogen is not associated with atherosclerotic or microvascular complications, but in Caucasians behaves as a marker for hypertension. This association, which may have been inflated by publication bias, does not necessarily imply causality.OBJECTIVES The Hypertension Optimal Treatment (HOT) Study had two objectives: (1) to define the optimal target blood pressure when treating hypertensive patients (i.e. the level of blood pressure associated with the lowest incidence of major cardiovascular events such as fatal and non-fatal stroke and myocardial infarction and other cardiovascular mortality); and (2) to assess the effect of a low dose of acetylsalicylic acid (aspirin) compared with placebo on major cardiovascular events. METHODS The HOT study recruited 18 790 hypertensive subjects aged 50 to 80 years with diastolic blood pressure (DBP) between 100 and 115 mmHg (mean DBP 105 mmHg). Subjects were randomly assigned to be treated with the goal of reaching one of three target DBPs: < or = 90 mmHg (n = 6264), < or = 85 mmHg (n = 6264), or < or = 80 mmHg (n = 6262) using felodipine as initial therapy with the addition of other agents according to a 5-step regimen. In addition, subjects were randomly assigned to receive either 75 mg/day aspirin (n = 9399) or placebo (n = 9391). RESULTS DBP was reduced by 20.3, 22.3, and 24.3 mmHg in the < or = 90, < or = 85, and < or = 80 mmHg target groups, respectively. The incidence of all major cardiovascular events (fatal and non-fatal stroke, myocardial infarction, and other cardiovascular mortality) decreased, although not significantly, in relation to the randomized target blood pressure. There were 84, 64, and 61 fatal and non-fatal myocardial infarctions in the < or = 90 mmHg, < or = 85 mmHg, and < or = 80 mmHg groups, respectively (P = 0.05). The overall effect of aspirin on cardiovascular events was positive, most noticeably on fatal and non-fatal myocardial infarctions; aspirin reduced events by 36%. There were seven fatal episodes of bleeding (two cerebral) in the aspirin group compared with eight (three cerebral) in the placebo group, and 129 versus 70 non-fatal major episodes of bleeding in the two groups, respectively. The lowest incidence of all major cardiovascular events combined was found at an achieved DBP of 82.6 mmHg and at an achieved systolic blood pressure (SBP) of 138.5 mmHg. In the subgroup with diabetes mellitus at baseline (n = 1501), the effect of intensive lowering of blood pressure was especially noticeable. CONCLUSIONS Most cardiovascular end-points showed a declining frequency in relation to target blood pressure. The optimal protection against combined major cardiovascular end-points was observed in the range 80-85 mmHg for DBP and in the range 130-140 mmHg for SBP. It is worth noting that 92% of all subjects reached a DBP of < or = 90 mmHg and that side-effects gradually declined from 16.9% at 3 months to 2.2% at the end of the study. A substudy showed that quality of life was linked to the level of blood pressure obtained: the lower the blood pressure, the better the quality of life.

Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study

This prospective population study investigated in a random sample of 692 subjects (age 20-83 years) how changing environmental exposure to cadmium influenced blood pressure (BP) and the incidence of hypertension. At baseline (1985 to 1989; participation rate, 78%) and follow-up (1991 to 1995; re-examination rate, 81%), blood pressure was measured by conventional sphygmomanometry (CBP; 15 readings in total) and, at follow-up, also by 24-h ambulatory blood pressure monitoring (ABP). Systolic/diastolic CBP at baseline averaged 128.4/77.3 mm Hg. At baseline, blood cadmium concentration (B-Cd) and urinary cadmium excretion (U-Cd) averaged (geometric means) 11.1 nmol/L and 10.2 nmol/24 h. Over 5.2 years (median follow-up), B-Cd fell by 29.6% and U-Cd by 15.2%. B-Cd fell less in subjects living closer to three zinc smelters and in premenopausal women. During follow-up, systolic CBP decreased by 2.2 mm Hg in men and remained unchanged in women, and diastolic CBP increased by 1.8 mm Hg in both sexes. No relationship could be demonstrated between the secular trends in CBP and B-Cd or U-Cd or between B-Cd or U-Cd at baseline and the incidence of hypertension. In addition, in cross-sectional analyses involving the average of all available CBP measurements in each participant or 24-h ABP at follow-up (mean, 119.1/71.4 mm Hg), blood pressure was not correlated with B-Cd or U-Cd. In conclusion, environmental exposure to cadmium was not associated with higher CBP or 24-h ABP or with increased risk for hypertension. The lesser fall in B-Cd in the residents living closer to the zinc smelters or in premenopausal women underscores the necessity to sanitize cadmium-polluted areas and to systematically reinforce the preventive measures to be adopted by exposed communities to reduce cadmium uptake.

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.

Normality of ambulatory blood pressure

An operational threshold for making clinical decision on the basis of ambulatory blood pressure monitoring must be defined. This requires that the relationship between the ambulatory pressure and the incidence of cardiovascular complications be clarified beyond present understanding. Preliminary cut-off points for ambulatory monitoring were derived by averaging the 95th percentiles of the ambulatory blood pressure measurements for the normotensive subjects enrolled in various large-scale studies. According to this approach, the upper limits of normotension, calculated by rounding downwards, would be 130/80mmHg for the 24h blood pressure and 135/85 and 120/70mmHg for the daytime and night-time blood pressures. Abnormality, obtained by rounding upwards, would be blood pressure levels exceeding 135/85, 140/90 and 125/75mmHg, respectively.

1A.04: CORRELATES OF PERIPHERAL BLOOD MITOCHONDRIAL DNA COPY NUMBER IN A GENERAL POPULATION.

Objective: Mitochondrial DNA (mtDNA) molecules are highly susceptible to oxidative stress. Accumulation of mtDNA mutations leads to alterations of mitochondrial biogenesis and function that might result in decrease of mtDNA content within cells. This implies a possible role of mtDNA content as a potential biomarker in processes associated with oxidative stress and inflammation. However, data on correlates of the mtDNA content in a general population are sparse. Therefore, the objectives of the present study were to describe in a randomly recruited population sample the distribution and determinants of the peripheral blood mtDNA content. Design and method: We examined 689 individuals (50.4% women, mean age, 54.4 years), randomly selected from a Flemish population. Relative mtDNA copy number compared to nuclear DNA was measured by quantitative real-time PCR in peripheral blood. Results: There was a curvilinear relationship between the relative mtDNA copy number and age. Indeed, mtDNA content increased until the fifth decade of life and declined in older subjects (P age2 = 0.0005). Moreover, the mtDNA content significantly and independently increased with female sex (P = 0.0078) and platelet count (P < 0.0001), whereas it decreased with white blood cell count (WBC) (P < 0.0001). We also observed a slightly decrease in mtDNA content in women using oestroprogestogens (P = 0.044). Conclusions: In conclusion, we demonstrated in a general population that peripheral blood mtDNA content is significantly associated with sex and age. In addition, blood mtDNA content is influenced by platelet and WBC counts and intake of oestroprogestogens. Further studies are required to clarify the impact of inflammation and hormone therapy on mitochondrial function.

Heritability and other determinants of left ventricular diastolic function in the family-based population study.

Background: Understanding to what extent genetic factors influence diastolic Doppler indexes is an important issue in view of the relation of left ventricular diastolic dysfunction with outcome. We, therefore, investigated the heritability of left ventricular diastolic traits and the composite diastolic score in nuclear families recruited from the general population. Methods: In a random sample of 316 nuclear families (452 parents and 600 offspring, mean age, 58.5 and 33.3 years), we measured transmitral early and late diastolic velocities (E and A) by pulsed wave Doppler, and mitral annular velocities (e’ and a’) by tissue Doppler. Using principal component analysis, we summarized seven Doppler indexes – namely, E, A, e’ and a’ velocities, and their ratios – into a single diastolic score. To calculate the heritability of diastolic indexes, we used variance decomposition in nuclear families and offspring as implemented in SOLAR and SAS, and the regression slope of offspring on mid-parent residual values. Results: In variance decomposition analyses in nuclear families, the abovementioned traits with adjustment for covariables had moderate heritability ranging from 0.27 to 0.43 (P < 0.0001 for all). The parent–offspring concordances of all diastolic indexes were significant and ranged from 0.17 for A (P = 0.009) to 0.42 for e’ (P < 0.0001). In nuclear families and offspring, the heritability estimates of the composite diastolic score were 0.42 and 0.64, respectively (P < 0.0001). Conclusion: Our study demonstrated moderate heritability of various indexes reflecting left ventricular diastolic function in nuclear families. The observation highlights the necessity of further research into the genes that affect left ventricular diastolic function.

FATAL AND NONFATAL OUTCOMES, INCIDENCE OF HYPERTENSION, AND BLOOD PRESSURE CHANGES IN RELATION TO URINARY SODIUM EXCRETION IN WHITE EUROPEANS: 2C.01

Stolarz-Skrzypek K, Kuznetsova T, Thijs L, et al; European Project on Genes in Hypertension (EPOGH) Investigators: Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion. JAMA. 2011;305(17):1777-1785. eTable 1. Characteristics of Women in the Outcome Cohort by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline eTable 2. Characteristics of Men in the Outcome Cohort by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline eTable 3. Characteristics of Women in the Hypertension Cohort by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline eTable 4. Characteristics of Men in the Hypertension Cohort by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline eTable 5. Characteristics of the Participants in the Blood Pressure Cohort at Baseline and at Follow-up by Country eTable 6. Causes of Cardiovascular Mortality and Morbidity in the Outcome Cohort eTable 7. Multivariable-Adjusted Hazard Ratios for Mortality and Cardiovascular Events by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline in 3194 Participants Younger Than 60 Years eTable 8. Multivariable-Adjusted Hazard Ratios for Mortality and Cardiovascular Events by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline in 487 Participants 60 Years or Older eTable 9. Multivariable-Adjusted Hazard Ratios for Mortality and Cardiovascular Events by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline Excluding Any Adjustment for Blood Pressure eTable 10. Multivariable-Adjusted Hazard Ratios for Mortality and Cardiovascular Events by Tertiles of the 24-Hour Urinary Sodium-to-Potassium Ratio at Baseline eTable 11. Multivariable-Adjusted Hazard Ratios for Cardiovascular Mortality by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline after Censoring of Follow-up at 6, 9, 12, 15, 18 and 21 Years eTable 12. Multivariable-Adjusted Hazard Ratios for Incidence of Hypertension by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline eTable 13. Multivariable-Adjusted Cross-Sectional Associations Between Blood Pressure and 24-Hour Urinary Sodium by Study Population and Study Phase eFigure 1. Incidence of Mortality and Cardiovascular Events eFigure 2. Kaplan-Meier Estimates for the Incidence of Hypertension by Tertiles of the 24-Hour Urinary Sodium Excretion at Baseline eFigure 3. Distribution of the Absolute (A, C, E) and Relative (B, D, F) Changes in Systolic Blood Pressure (A, B), Diastolic Blood Pressure (C, D), and 24-Hour Urinary Sodium Excretion (E, F) in 1499 Participants of the Blood Pressure Cohort Followed Up for a Median of 6.1 Years eFigure 4. Change in Systolic Blood Pressure During Follow-Up By Deciles of the Change in the 24-Hour Urinary Sodium Excretion in the Blood Pressure Cohort (n=1499) eFigure 5. Change in Diastolic Blood Pressure During Follow-Up by Deciles of the Change in 24-Hour Urinary Sodium Excretion in the Blood Pressure Cohort (n=1499)

[PP.14.13] THE NATURAL HISTORY OF LEFT VENTRICULAR LONGITUDINAL STRAIN IN A GENERAL POPULATION: CLINICAL CORRELATES AND IMPACT ON CARDIAC REMODELLING

Objective: Recent studies demonstrated an independent prognostic role of left ventricular (LV) global longitudinal deformation (strain; LS) in patients and population. However, there are few data on changes in LS over time in the general population. We, therefore, investigated in the population cohort clinical correlates of longitudinal changes in LV end-systolic LS analyzed as continuous measures. In addition, we explored the potential impact of reduced LS on LV volumes. Design and method: We measured LV end-systolic (ESV) and end-diastolic (EDV) volumes by conventional echocardiography and global, basal-mid and apical LS by 2D speckle tracking in 627 participants (mean age 50.7 years, 51.4% women; 41.3% hypertensives) at baseline and after 4.7 years. In our analyses we used the absolute values of LS (magnitude of end-systolic deformation). Results: At baseline, means (±SD) of global, basal-mid and apical LS were 19.7 ± 2.4%, 18.5 ± 2.3% and 23.5 ± 4.2%, respectively. Over follow-up, the 5th to 95th percentile of change in global, basal-mid and apical LS were −3.9% to 3.7%, −3.2% to 3.8% and −8.8% to 5.9%, respectively. In stepwise regression, the magnitude of decrease in global, basal-mid and apical LS over time was greater in men than in women (P < 0.0001). Higher baseline mean blood pressure (MBP) as well as an increased MBP during follow-up were related to larger decreases in global as well as in level-specific LS. An increase in apical LS was significantly correlated with baseline age and change in pulse pressure over time. Furthermore, in the multivariable-adjusted analysis, we observed the significant inverse correlation between baseline ESV and global LS (P < 0.0001). Similarly, lower baseline global LS and a decreased LS over follow-up were significant predictors of longitudinal increase in ESV during follow-up (P < 0.0001 for both). No significant associations have been found between EDV and global LS measured at baseline and follow-up. Conclusions: The key findings of this study are that significant decrease in LS over time was associated with male sex, higher baseline MBP and an increase in MBP. Moreover, alteration in global LS leads to increase in LV systolic volume, which might be an early sign of adverse LV remodelling.

[PP.24.10] LEFT VENTRICULAR DIASTOLIC FUNCTION IN RELATION TO HEMODYNAMIC LOAD COMPONENTS IN A GENERAL POPULATION

Objective: It was suggested that the contribution of central pulsatility to left ventricular (LV) diastolic dysfunction might be mediated by the hemodynamic loads of forward and backward (reflected) pulse waves and their ratio. Therefore, in the general population study, we investigated the relation between echocardiographic indexes of LV diastolic function and central hemodynamic components derived by flow-independent wave separation analysis. Design and method: In 755 participants, using echocardiography, we assessed LV dimensions, transmitral blood flow and mitral annular tissue Doppler velocities. From the central pressure waveform obtained by radial applanation tonometry, we derived central pulse pressure (cPP). Forward (Pf) and backward (Pb) wave amplitudes and their ratio (i.e. reflection magnitude, RM) were derived using triangular-flow wave separation analysis as implemented in SphygmoCor® software. Despite good quality of pulse wave recordings, the wave separation algorithm failed to retrieve Pf and Pb in 139 subjects (18.4%). Thus, this analysis included 616 subjects (46.1% women; mean age, 49.2 years). Results: Age explained most of the variance in cPP (24.6%), Pb (33.2%) and RM (36.1%; P < 0.0001 for all), but was not correlated with Pf. We also observed that age altered direct correlation between Pf and Pb (Pint < 0.0001). Other independent clinical correlates of cPP, Pf, Pb and RM were body mass index, heart rate, mean arterial pressure and use of antihypertensive drugs. In multivariable-adjusted analyses, transmitral early (E) and late (A) diastolic peak velocity and E/e’ ratio (reflecting LV filling pressure) increased with amplitudes of cPP, Pf and Pb in both men and women (P < 0.025). Of all LV diastolic indexes, only E/A ratio was independently associated with RM in men (P = 0.019). After full adjustment, LV mass index increased with cPP and Pb in men only (P < 0.040). Conclusions: Low feasibility of yielding Pf and Pb amplitudes from pulse curves by the current triangular-flow algorithm might limit the clinical utility of this approach. We demonstrated that LV diastolic function indexes were related to both forward and backward wave amplitudes, favoring the use of the composite central pulse wave for prediction of LV diastolic dysfunction.