V. Giner

Renin-Angiotensin System Genetic Polymorphisms and Salt Sensitivity in Essential Hypertension

We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.

Increased insulin resistance in salt sensitive essential hypertension.

Objective: To determine the possible relationship between insulin resistance and salt sensitivity in essential hypertension.Design and methods: We studied 17 non-obese, essential hypertensive patients (24-h blood pressure: 149 ± 15/94 ± 5 mm Hg) with normal glucose tolerance. Salt sensitivity was diagnosed in the presence of a significant increase (P < 0.05, more than 4 mm Hg) in 24-h mean blood pressure (MBP) when patients switched from a low-salt intake (50 mmol/day of Na+) to a high-salt intake (240 mmol/day of Na+), each period lasting 7 days. The insulin sensitivity index was determined by the euglycaemic hyperinsulinaemic clamp.Results: Six patients were classified as salt sensitive (24-h MBP increase: 6.2 ± 1.1 mm Hg), and 11 as salt resistant (24-h MBP increase: −1.2 ± 3.8 mm Hg). No significant differences were observed between salt sensitive and salt resistant patients regarding baseline characteristics, fasting serum insulin, fasting serum glucose, glycosilated haemoglobin, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, uric acid and microalbuminuria. Salt sensitive patients exhibited a reduced insulin sensitivity index compared with salt resistant patients (1.7 ± 1.1 vs 3.5 ± 1.2 mg/kg/min; P = 0.009). An inverse relationship (r −0.57; P = 0.016) between the insulin sensitivity index and 24-h MBP increase with high salt intake was found.Conclusion: Salt sensitive essential hypertensive patients are more insulin resistant than salt resistant patients when both salt sensitivity and insulin resistance are accurately measured. Indirect measures of both insulin and salt sensitivity and/or the presence of modifying factors, such as obesity or glucose intolerance, may account for differences in previous studies.

Association of the G protein β3 subunit T allele with insulin resistance in essential hypertension

A polymorphism (C825T) in the gene encoding the G protein β3 subunit (GNB3) has recently been associated with hypertension and obesity in several populations. The aim of the study was to analyse the relationship between this polymorphism and insulin sensitivity, an hypothesised unifying factor for hypertension and obesity. One hundred thirty unrelated patients with essential hypertension, 70 female and 60 male, aged 58±1 years with systolic blood pressure of 173±2 mm Hg and diastolic blood pressure of 105±1 mm Hg, were genotyped for the GNB3 polymorphism by PCR and restriction digestion with BseDI, and classified in two groups according to the genotypes CC and CT+TT. Body mass index (BMI) was significantly higher in patients with the T allele as compared with patients without the T allele (29.3±0.4 vs. 26.7±0.6 kg/m2, p<0.001). On the contrary, there were no differences in the level of systolic or diastolic blood pressure among the genotypes. Insulin sensitivity was measured in a subgroup of 35 patients by means of an euglycemic hyperinsulinemic clamp test. In this subgroup, patients with the T allele displayed lower insulin sensitivity index (1.6±0.3 vs. 2.7±0.3 mg/kg/min, p=0.022), higher fasting serum insulin (121±16 vs. 77±11 pmol/L, p=0.032), higher serum glucose 120 min after 75 g load (9.8±1.2 vs. 7.0±0.5 mmol/L, p=0.038), and higher glycosilated haemoglobin (5.7±0.4 vs. 4.7±0.2%; p=0.042) as compared with patients without the T allele. A regression analysis showed that the association between the T allele and insulin sensitivity was independent of BMI (β coefficient −0.386, p=0.022). These results suggest a relationship between the 825T allele of GNB3 and insulin resistance in the essential hypertensive patients studied, which seems to be independent of BMI.

Lack of correlation between two methods for the assessment of salt sensitivity in essential hypertension.

The existence of a heterogeneous blood pressure (BP) response to salt intake, a phenomenon known as salt sensitivity, has increasingly become a subject of clinical hypertension research, and has important clinical and prognostic implications. However, two different methodologies are currently used to diagnose salt sensitivity. The aim of the present study was to compare the BP response to intravenous sodium load and depletion on the one hand, and to changes in dietary salt intake on the other, in order to assess salt sensitivity in a group of essential hypertensive patients. Twenty-nine essential hypertensives underwent two different procedures separated by 1 month: a dietary test consisting of a 2-week period of low (20 mmol/day) and high (260 mmol/day) salt intakes, and an intravenous test consisting of a 2 litre saline load over a 4-h period, followed by 1 day of low (20 mmol) salt intake and furosemide (40 mg/8 h orally) administration. BP was registered at the end of every period using 24-h ambulatory BP monitoring. In the whole group of hypertensive patients studied, both low salt intake and furosemide administration significantly (P < 0.01) decreased mean BP. Correlation coefficients of BP changes obtained using the two methodologies were between 0.3 and 0.4. Moreover, coefficients of agreement between the oral and the intravenous tests, using several cut points for BP changes, were systematically below 0.5, thus indicating a misclassification of salt sensitivity greater than 50%, depending on the method used. None of the cut points for BP changes during furosemide administration showed a good combination of sensitivity and specificity compared with changes in response to low dietary salt. The present results indicate that the diagnosis of salt-sensitive hypertension should be based on the BP response to changes in dietary salt intake, while BP response to saline and furosemide administration leads to a systematic misclassification of more than 50% of patients, even using different cutpoints for changes in BP.

Polymorphisms of the angiotensinogen gene and the outcome of microalbuminuria in essential hypertension: a 3-year follow-up study.

Background: The objective of this study was to analyse the relationship of polymorphisms of the angiotensinogen (AGT) gene with the changes in microalbuminuria during 3 years of antihypertensive treatment in a group of young adults with essential hypertension.Methods: Essential hypertensives, less than 50 years old, never previously treated with antihypertensive drugs and in the absence of diabetes mellitus were included. After the initial evaluation, patients were treated using only nonpharmacological measures (n=23), only β-blockers (n=26), only angiotensin-converting enzyme inhibitors (ACEi) (n=57) or a combination of treatments (n=25). The office blood pressure, biochemical profile and urinary albumin excretion (UAE) were measured at the beginning and then yearly. The polymorphism A-6G of the AGT gene located in the promoter region was analysed.Results: In total, 131 patients, 35 (27%) microalbuminurics, were included. Although no significant differences in systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose and UAE were observed among genotypes at the initial examination, during the 3 years of antihypertensive treatment the slope values for the DBP, fasting glucose and UAE differed significantly despite no differences in the distribution of treatments being present. The subjects carrying the AA-6 genotype had the largest DBP decrease, but the lowest UAE reduction and the highest slope of glucose. Out of 35 initially microalbuminuric patients, 24 became normoalbuminuric and the lowest reduction rates were observed in subjects who carried the allele A-6. No interaction between the type of treatment and genotype was observed on the changes in UAE, BP or glucose values. In the subset of 57 patients treated with ACEi, the changes in UAE, BP and glucose had the same trend as was observed in the total population.Conclusions: Subjects carrying the AA genotype of the A-6G AGT gene polymorphism are resistant to a reduction of microalbuminuria. Whether this can be attributed to a predisposition to glucose metabolic disturbance or not needs to be confirmed in further studies.