Higher Sodium Excretion Research Articles

Neuroendocrine Changes and Natriuresis in Response to Social Stress in Rats

Sympathetic activation is detected by the tachycardic, hypertensive and hyperthermic responses during social conflicts in rodents and primates. Sympathetic nervous system activation promoting sodium retention has long been recognized to play a significant role in the development and maintenance of salt-sensitive hypertension. The objective was to investigate neuroendocrine activation and renal sodium excretion in response to chronic social stress. Male Wistar rats were subjected to social stress in accordance with the resident-intruder paradigm. Intruder rats were subjected to social confrontation once daily for 6 days. After the last confrontation, plasma corticosterone and urinary catecholamines were determined to assess the neuroendocrine activation. Plasma aldosterone, plasma and urinary creatinine, Na(+) , K(+) and urinary volume were also measured. Chronic social stress increased the urinary norepinephrine, dopamine and plasma corticosterone levels, with no changes in epinephrine levels. On the other hand, high plasma aldosterone levels and low urinary sodium excretion without differences in creatinine clearance were observed. In conclusion, social stress had a strong antinatriuretic effect, which is coincident with noradrenergic and corticoadrenal activation and an increase in plasma aldosterone levels. Activation of these factors may promote sodium retention, which has long been recognized to play a significant role in the development and maintenance of hypertension.

Effects of Testosterone on Renal Function in Salt-Loaded Rats

IntroductionThe objective of this study is to investigate the effects of androgen on renal sodium excretion and renal functional in sodium-loaded rats. MethodsSixty male Wistar rats aged 8 weeks were used, of which 48 underwent orchiectomy and the other 12 underwent a sham procedure. The 48 orchiectomized rats were randomly divided into 4 groups (12/group): castrated rats (Cas), testosterone-supplemented castrated rats (TC), flutamide (androgen receptor blocker)-treated castrated rats (FC) and flutamide-treated testosterone-supplemented castrated rats (FTC). The 12 sham-operated rats served as controls. All 60 rats were fed with 8% NaCl chow for 8 weeks. Systemic blood pressure (BP) was recorded at 0, 4 and 8 weeks. Sodium excretion, microalbuminuria and creatinine clearance were calculated before and at the end of the experiment. Circulating levels of testosterone and angiotensin II and plasma renin activity were measured by radioimmunological method at the end of the experiment. ResultsBP of controls and TC was higher at 8 weeks than at baseline; BP of Cas, FC or FTC was lower than that of controls. Plasma renin activity and angiotensin concentrations were lower in Cas, FC and FTC (groups with testosterone absent or blocked) than in controls and TC (groups with testosterone intact). Cas, FC and FTC displayed less microalbuminuria, higher sodium excretion and higher creatinine clearance than control and TC. ConclusionsIn salt-loaded rats, testosterone seems to activate the renin-angiotensin system, resulting in sodium retention, higher BP and renal injury.

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

Extrapolations from observational studies and short-term intervention trials suggest that population-wide moderation of salt intake might reduce cardiovascular events. To assess whether 24-hour urinary sodium excretion predicts blood pressure (BP) and health outcomes. 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). 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. 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. 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.

Eine alte Dame mit Hyponatriämie und rezidivierenden Stürzen

Hyponatremia is one of the most commonly seen electrolyte abnormalities in hospitalized patients. The differential diagnoses are complex once the typical causes for hyponatremia such as congestive cardiac failure, liver failure, hyperglycemia, thiazides, antipsychotic drugs or chemotherapy are excluded. Especially the differentiation between the syndrome of inappropriate ADH secretion and salt-wasting nephropathy as seen in cerebral salt wasting (CSW) can be difficult. The case of a 79-year-old lady is discussed who presented to the Emergency Department with extreme dizziness after having fallen off a ladder. Biochemistry studies revealed severe hyponatremia (Na 114 mmol/l) as well as hypochloremia (Cl 85 mmol/l), all other laboratory studies were unremarkable. The intake of a thiazide diuretic, an adrenal insufficiency and other common causes of hyponatremia were excluded. On examination, there were clinical signs of volume depletion. The serum sodium initially improved adequately after the infusion of intravenous normal saline (0.9%) only to fall again along with clinical signs of volume depletion after ceasing the infusion. A high urinary sodium excretion persisted despite hyponatremia and volume depletion. Due to the clinical course the syndrome of inappropriate ADH secretion was considered unlikely and the diagnosis of CSW established. Under therapy with fludrocortisone her sodium stabilized within the normal range and she remained free of symptoms. CSW is an important differential diagnosis of hyponatremia in the hypovolemic patient. It is due to an inadequately high urinary sodium excretion. The response to intravenous normal saline can make the diagnosis likely and distinguish it from SIADH. The exact pathophysiological mechanism behind CSW is not yet completely understood. Therapy consists of fluid and salt supplementation or mineralocorticoid substitution.

Transient type 1 pseudo-hypoaldosteronism: report on an eight-patient series and literature review

Eight boys aged 2-12 weeks with urinary tract malformations (UTMs) exhibited features of transient type 1 pseudo-hypoaldosteronism (TPHA1) in the course of urinary tract infection (UTI). Hyponatremia (120.9+/-5.8 mmol/l), hyperkalemia (6.9+/-0.9 mmol/l), metabolic acidosis (plasma bicarbonate 11+/-1.4 mmol/l), and a rise in serum creatinine levels (145+/-101 micromol/l) were associated with high urinary sodium (Na) and low potassium (K) excretion. Tubular resistance to aldosterone was indicated by high plasma aldosterone concentrations (170.4+/-100.5 ng/dl), high levels of the plasma aldosterone to potassium ratio (25.2+/-15.6), and diminished urinary K/Na values (0.31+/-0.19). With appropriate therapy, serum electrolytes, creatinine, and acid-base balance normalized within 2 weeks. A Medline search revealed another 85 cases of TPHA1 reported to date. All of the 93 patients were less than 7 months of age and 90% were less than 3 months of age, 90.3% suffered from UTM, with associated UTI in 89% of them, 11% had UTMin the absence of UTI, and 9.7% showed isolated UTI. These findings indicate that early infancy is the main contributing factor for TPHA1 to occur and that UTI and UTMare additional factors, with at least one being required for its development.

Independent Relations of Left Ventricular Structure With the 24-Hour Urinary Excretion of Sodium and Aldosterone

Previous studies reported on the association of left ventricular mass index (LVMI) with urinary sodium or with circulating or urinary aldosterone. We investigated the independent associations of LVMI with the urinary excretion of both sodium and aldosterone. We randomly recruited 317 untreated subjects from a white population (45.1% women; mean age 48.2 years). Measurements included echocardiographic left ventricular (LV) properties, the 24-hour urinary excretion of sodium and aldosterone, plasma renin activity (PRA), and proximal (RNa(prox)) and distal (RNa(dist)) renal sodium reabsorption, assessed from the endogenous lithium clearance. In multivariable-adjusted models, we expressed changes in LVMI per 1-SD increase in the explanatory variables, while accounting for sex, age, systolic blood pressure, and the waist-to-hip ratio. LVMI increased independently with the urinary excretion of both sodium (+2.48 g/m(2); P=0.005) and aldosterone (+2.63 g/m(2); P=0.004). Higher sodium excretion was associated with increased mean wall thickness (MWT: +0.126 mm, P=0.054), but with no change in LV end-diastolic diameter (LVID: +0.12 mm, P=0.64). In contrast, higher aldosterone excretion was associated with higher LVID (+0.54 mm; P=0.017), but with no change in MWT (+0.070 mm; P=0.28). Higher RNa(dist) was associated with lower relative wall thickness (-0.81x10(-2), P=0.017), because of opposite trends in LVID (+0.33 mm; P=0.13) and MWT (-0.130 mm; P=0.040). LVMI was not associated with PRA or RNa(prox.) In conclusion, LVMI independently increased with both urinary sodium and aldosterone excretion. Increased MWT explained the association of LVMI with urinary sodium and increased LVID the association of LVMI with urinary aldosterone.

Mutations in SPINT2 Cause a Syndromic Form of Congenital Sodium Diarrhea

Autosomal-recessive congenital sodium diarrhea (CSD) is characterized by perinatal onset of a persistent watery diarrhea with nonproportionally high fecal sodium excretion. Defective jejunal brush-border Na(+)/H(+) exchange has been reported in three sporadic patients, but the molecular basis of the disease has not been elucidated. We reviewed data from a large cohort of CSD patients (n = 24) and distinguished CSD associated with choanal or anal atresia, hypertelorism, and corneal erosions--i.e., a syndromic form of CSD--occurring in ten families from an isolated form--i.e., classic CSD--presenting in seven families. Patients from both groups have a high risk of mortality due to immediate electrolyte imbalances and complications from long-term parenteral nutrition in the first years of life, but survivors can eventually adapt to partial or complete enteral nutrition. A genome-wide SNP scan was applied and identified a homozygous c.593-1G-->A splicing mutation in SPINT2, encoding a Kunitz-type serine-protease inhibitor, in one extended kindred with syndromic CSD. The same mutation and four distinct, homozygous or compound heterozygous mutations (p.Y163C, c.1A-->T, c.337+2T-->C, c.553+2T-->A) were identified in all syndromic patients. No SPINT2 mutations were found in classic-CSD patients. SPINT2 mutations were associated with loss of protein synthesis or failure to inhibit the serine protease trypsin in vitro. We delineate syndromic CSD as a distinct disease entity caused by SPINT2 loss-of-function mutations. SPINT2 mutations might lead to an excess of yet unknown serine protease activity in affected tissues.

Acute renal dysfunction after cardiac surgery with cardiopulmonary bypass is associated with plasmatic IL6 increase

Background: Acute renal dysfunction (ARD) is common after cardiac surgery with cardiopulmonary bypass (CPB). CPB results in a sudden systemic inflammatory response. Systemic and local pro-inflammatory cytokines synthesis has been linked with sub-clinical renal injury, especially tubular lesions. Therefore, we sought to assess the systemic synthesis pro-inflammatory cytokines and its association with perioperative ARD after cardiac surgery with CPB. Methods: Sixty-two patients undergoing cardiac surgery with CPB were prospectively included. Four groups of patients were defined according to blood creatinine increase: no ARD (less than 25% increase), faint ARD (25–50% increase), moderate ARD (50–100% increase), severe ARD (more than 100% increase). Results: Within the 48 post-operative hours was ARD observed as no dysfunction (41.9%), faint (32.2%), moderate (16.1%), severe (9.6%). One patient had to undergo a dialysis. Pre-operative characteristics were homogenous between the four groups excepted the left ventricle ejection fraction. ARD was associated with a low urinary output with high sodium excretion fraction. Significant increase of IL-6 level occurred when patients underwent a severe ARD despite no significant differences for the CRP and TNF-α concentrations. Conclusion: Severe acute renal dysfunction after cardiac surgery with CPB is associated with a significant increased IL-6 systemic production.

Diet, obesity and obesogenic trends in two generations of Swedish women

Secular trends in obesity and related lifestyle factors are reported in two generations of 38- and 50-year old Swedish women. Specifically, we describe changes in obesity and fat patterning, while examining concurrent shifts in factors that are proposed to be causally related to the modern obesity epidemic. A total of 1,270 women aged 38 or 50 were selected from population registries and examined in 1968/69 (born 1930 or 1918) or 2004/05 (born 1966 or 1954). Anthropometric methods and lifestyle questions were unchanged between earlier and later surveys. Dietary comparisons were based on 24-h recall, with additional questions about usual alcohol and salt consumption patterns. In subgroups, 24-h urinary sodium was determined. Weight, height, waist circumference, waist-hip ratio, triceps and subscapular skinfold measures were all significantly higher in later-born cohorts, although BMI and obesity were not significantly changed. Higher sodium excretion was observed among later-born sub-groups, consistent with reports of increasing salt preference. Lower proportions of energy as fat and sucrose, but higher carbohydrate, protein and fiber concentrations were reported by later-born cohorts. There were shifts towards increased frequency of wine and liquor consumption, but decreased beer. Leisure time physical activity and perceived stress levels both increased significantly over 36 years. A number of anthropometric and lifestyle differences between two generations of Swedish women were observed. Increases in subcutaneous and abdominal fatness were detected without significantly increasing BMI. While some aspects of diet showed improvement, increases in salt preference and sodium excretion are cause for concern.

Sodium excretion in relation to sodium intake and aldosterone excretion in newborn pre-term and full-term infants.

The importance of aldosterone for the control of salt balance has been examined in pre-term infants (gestational age 28--34 weeks) and in full-term infants. The post-natal age has varied from 2--21 days. Eight-hour urinary specimens have been analysed with regard to sodium, potassium and aldosterone. The daily sodium intake has been recorded following determination of milk intake and analyses of sodium in breast milk. Due to variations of sodium content of breast milk, the daily sodium intake in pre-term infants was lower than in full-term infants during the first 10 days of life. The sodium excretion was significantly higher in pre-term infants than in full-term infants during the first six days of life. During the first week of life the sodium balance is negative in pre-term infants and positive in full-term infants. Aldosterone excretion is high during the first week of life and increases further from the 2nd to the 3rd week of life in both pre-term and full-term infants. The correlation between aldosterone excretion and urinary potassium/sodium quotient is 0.87 in full-term infants, 0.57 in pre-term infants aged 13--20 days and does not exist in pre-term infants aged 2--10 days. It is suggested that the high sodium excretion in newborn pre-term infants can in part be explained by an unresponsiveness to aldosterone at this developmental stage.

Cerebral Salt Wasting in a Child with Cervicothoracic Hematoma

Although the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is commonly observed in patients with acute or chronic central nervous system (CNS) disorders, cerebral salt wasting (CSW) that results in hyponatremia has rarely been reported in children. Both SIADH and CSW result in increased urinary sodium excretion and hyponatremia. However, the management protocols for these two conditions are quite different; volume restriction is used in treating SIADH, while volume expansion is necessary for the treatment of CSW. We present a case of CSW in a child with cervicothoracic hematoma secondary to head and cervicothoracic trauma, without evidence of brain edema. The child was diagnosed on the basis of high urinary sodium excretion resulting in hyponatremia and low serum osmolarity. Improvements in serum sodium levels after saline hydration confirmed this diagnosis. We believe that potentially dangerous cases of hyponatremia should be carefully evaluated in children with cervicothoracic hematoma secondary to trauma, including situations in which brain edema is absent.

Successful rescue of severe hypernatraemia (196 mmol/L) by treatment with hypotonic fluid

Hypernatraemia over 160 mmol/L is considered to be severe. This case reports a patient who developed extreme hypernatraemia with a serum sodium concentration of 196 mmol/L. The patient was known to have chronic renal impairment and was admitted with acute deterioration of renal function secondary to dehydration. This was considered to be secondary to poor oral fluid intake (related to depression) and lithium-induced nephrogenic diabetes insipidus with salt-losing nephropathy. The patient had a high urinary sodium excretion but was also in a pure water losing state as evidenced by an inappropriately low urine osmolality for the plasma osmolality and was successfully treated with hypotonic intravenous fluid and desmopressin.

High Sodium Intake Strengthens the Association of ACE I/D Polymorphism with Blood Pressure in a Community

Limited evidence is available on a gene-environment interaction of angiotensin-converting enzyme (ACE) gene I/D polymorphism and high blood pressure (BP) with salt intake among general populations. We hypothesized that persons with the I allele of the ACE gene have elevated BP levels in response to a higher sodium intake, and thus the association of ACE I/D polymorphism with BP levels was stronger among persons with a higher sodium intake than those with a lower sodium intake. We conducted a population-based cross-sectional study of 2823 men and women aged 30 to 74 years in a Japanese rural community to examine the association of the ACE I/D polymorphism with BP levels stratified by salt intake, as estimated by 24-h urine collection and dietary questionnaire. Polymorphism of the ACE I/D was detected by an allele-specific polymerase chain reaction. There was no significant difference in BP levels among DD, ID, and II groups for either sex or total samples. However, mean difference in diastolic BP levels for II versus DD groups was +3.0 mm Hg (P = .003) among persons with higher sodium excretion, +1.8 mm Hg (P = .04) among those with higher present sodium intake score, and +1.7 mm Hg (P = .06) among those with higher past sodium intake score. A high sodium intake strengthens the association of ACE I/D polymorphism with BP levels in community-based samples.

Aldosterone Synthase Gene T-344C Polymorphism, Sodium and Blood Pressure in a Free-Living Population: A Community-Based Study

There have been few epidemiological studies on the gene-environmental interaction between the aldosterone synthase gene (CYP11B2) T-344C polymorphism and sodium in relation to blood pressure in a free-living general population. We hypothesized a priori that persons with the T allele of CYP11B2 would have elevated blood pressure levels in response to a higher sodium intake, and thus the association between the T-344C polymorphism and blood pressure would be more evident among persons with a high sodium intake than among those with a low sodium intake. Study subjects were 2,823 men and women aged 30-74 in a Japanese community. We examined the associations between the T-344C polymorphism and blood pressure levels, stratified by sodium variables estimated by 24-h urinary sodium excretion and a dietary questionnaire. There was no significant difference in blood pressure levels among the CC, TC and TT groups for either or both sexes. However, among persons with higher sodium excretion, mean systolic blood pressure levels tended to be higher in those with the TC (+3.0 mmHg, p=0.06) and TT (+2.9 mmHg, p=0.07) genotypes than in those with the CC genotype, but this tendency was not seen among those with lower sodium excretion (-4.0 mmHg, p=0.03 for TC vs. CC; -3.0 mmHg, p=0.11 for TT vs. CC; p for interaction =0.006). In conclusion, we found no association between CYP11B2 and blood pressure for total subjects or for persons with a higher sodium intake. However, a possible gene-blood pressure association among persons with higher sodium intake needs to be explored further.

Refractory hyponatremia

Refractory hyponatremia

Cerebral salt wasting in tuberculous meningitis: treatment with fludrocortisone

Three cases of cerebral salt wasting complicating tuberculous meningitis are described. Diagnosis was based on hyponatraemia associated with high urinary sodium excretion and inappropriately high urine output in the presence of dehydration. Treatment with fludrocortisone resulted in sodium and fluid homeostasis.

Clinical and Genetic Correlates of Serum Aldosterone in the Community: The Framingham Heart Study

We investigated the environmental and genetic sources of interindividual variability in serum aldosterone level in a large, community-based sample. We examined the relation of serum aldosterone to vascular risk factors, urine sodium, and candidate single nucleotide polymorphisms in 2891 Framingham Offspring Study participants (53.2% women, mean age 59 years) using multivariable linear regression. Multivariable logistic regression was used to identify predictors of high (top quartile) and low (lowest quartile) serum aldosterone values. We estimated heritability of serum aldosterone via variance-component methods and evaluated linkage via a 10-cM-density genome scan. Clinical variables related to higher serum aldosterone level included female sex, diuretic treatment, and a higher total/high density lipoprotein cholesterol ratio. A high urinary sodium excretion, postmenopausal status (without hormone replacement therapy), increased pulse pressure, and prevalent cardiovascular disease were related to lower serum aldosterone values. Urinary sodium was the strongest correlate of serum aldosterone (R2= 10%). Serum aldosterone levels did not differ by genotype in the aldosterone synthase (CYP11B2c.1-344C>T) and the mineralocorticoid receptor (NR3C2c.754A>G) genes. The estimated heritability of serum aldosterone was 0.10. No chromosomal region attained a log-of-the-odds score >1 in multipoint linkage analysis. We observed a complex relation between serum aldosterone and vascular risk factors. The genetic contribution to serum aldosterone level was modest.

Low sodium diet protects from aldosterone-induced endothelial dysfucntion and left ventricular hypertrophy in subjects with resistant hypertension

Experimental models have demonstrated that aldosterone-induced cardiovascular damage requires concomitant high dietary sodium exposure. Studies from this and other laboratories have linked aldosteronism to endothelial dysfunction and left ventricular (LV) hypertrophy in human subjects. The current study was designed to determine if low sodium intake can blunt aldosterone-induced endothelial dysfunction and LV hypertrophy (LVH). Consecutive subjects (n=155) with resistant hypertension were prospectively evaluated with an early morning plasma aldosterone, renin and 24-hr urinary aldosterone and sodium. Changes in brachial artery diameter during hyperemia (flow-mediated dilation or FMD) were measured as an index for endothelial function. FMD was negatively correlated and LV end-diastolic diameter (LVDD) and LV mass (LVM) were positively correlated with aldosterone excretion (r=0.38, p<0.0001 and r=0.26, p=0.004). However the product of 24-hr sodium and aldosterone was an even stronger predictor of FMD and LVH than aldosterone alone (FMD: r=−0.59, p<0.0001, LVM: r=0.35, p<0.0001). Among subjects with high aldosterone excretion (> 12 μg/24-hr), low dietary sodium ingestion (<100 meq/24-hr) was associated with significantly less endothelial dysfunction and significantly less LVH. Three-month treatment with spironolactone significantly increased FMD and decreased LVH in subjects with and without aldosteronism, independent of blood pressure reduction level. However, these improvements were significantly greater in subjects with a high aldosterone and sodium excretion. These results are the first demonstration that low dietary sodium ingestion can protect from aldosterone-induced vascular and ventricular dysfunction in humans. Further, these results suggest that cardiovascular risk in subjects with resistant hypertension may be predicted by the product of urinary aldosterone and sodium excretion.

Left Ventricular Mass in Relation to Genetic Variation in Angiotensin II Receptors, Renin System Genes, and Sodium Excretion

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. 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. 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.

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

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. 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. 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. 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.