A. de la Sierra

Urinary albumin excretion is associated with true resistant hypertension

Resistant (or refractory) hypertension (RH) is a clinical diagnosis based on blood pressure (BP) office measurements. About one third of subjects with suspected RH have indeed pseudo-resistant hypertension and 24-h ambulatory-blood pressure-monitoring aids to precisely identify them. Our aim was to determine those clinical, laboratory or echocardiographic variables that may be associated with subjects with sustained hypertension (namely true RH). We carried out a cross-sectional analysis of 143 patients consecutively enrolled with the clinical diagnosis of RH. All patients underwent clinical-demographic, laboratory evaluation, 2D-echocardiography and 24-h ambulatory-blood pressure-monitoring. Pseudo-resistant hypertension or white-coat RH was defined if office BP was ⩾140 and/or 90 mm Hg and 24-h BP <130/80 mm Hg. One-hundred and three (72%) patients had true RH and 40 (28%) patients had white-coat RH. True RH patients had significantly higher diabetes prevalence and higher office-systolic blood pressure (SBP) levels. Regarding target organ damage, left ventricular mass index (LVMI) and 24-h urinary albumin excretion (UAE) were also higher in true RH after adjustment for possible confounders (P=0.031 and P=0.012, respectively). In a logistic regression analysis, only office-SBP (multivariate OR (95%CI): 1.030 (1.003–1.057), P=0.030) and UAE (multivariate OR (95% CI): 2.376 (1.225–4.608), P=0.010) were independently associated with true RH. We conclude that true resistant hypertension is associated with silent target organ damage, especially UAE. In patients with suspected RH, assessment of 24 h ambulatory BP is the most accurate way to detect a population with high risk for target-organ damage.

Endothelial dysfunction is associated with increased levels of biomarkers in essential hypertension

To assess the correlation between endothelial dysfunction and the serum levels of biomarkers of inflammation, remodelling and oxidative stress in essential hypertension, 78 treatment-naïve essential hypertensives (mean age 43 years) underwent measurement of endothelial dysfunction, using the maximal acetylcholine-induced forearm vasodilation and serum levels of adhesion molecules, selectins, chemokines, metalloproteinases, copper, zinc, selenium, vitamins, homocysteine, malondialdehyde, erythrocyte glutathione peroxidase and erythrocyte superoxide dismutase. Mean (±s.e.m.) maximal acetylcholine-induced vasodilation was 367±20%. Patients with a more impaired acetylcholine-dependent vasodilation (first tertile) had increased levels of e-selectin (P=0.009), p-selectin (P<0.001), monocyte chemotactic protein type 1 (MCP-1; P=0.012) and the tissue inhibitor of metalloproteinases type 1 (TIMP-1; P=0.044), which in turn showed significant inverse correlations with maximal endothelium-dependent vasodilation. Serum levels of selenium (P=0.012), vitamin C (P=0.038), erythrocyte glutathione peroxidase (P<0.001) and superoxide dismutase (P=0.022) activities were reduced in patients with a more impaired endothelium-dependent vasodilation. Recently diagnosed treatment-naïve essential hypertensives showed a relationship between the endothelial dysfunction, serum markers of inflammation and remodelling and levels of antioxidant substances. These could be potentially helpful markers of high risk in hypertensive patients.

Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin–angiotensin system

This review is aimed at examining calcium channel blocker (CCB)-related oedema and how this can be attenuated through the use of agents that inhibit the renin-angiotensin system. CCBs are effective antihypertensive agents, but their propensity for causing oedema may reduce compliance. A review of the literature has indicated that the absolute incidence of this side effect is difficult to determine because reported rates vary widely, a factor that may stem from differences in the surveillance technique (active vs passive). In a recent trial incorporating active surveillance, 25% of patients who received amlodipine 10 mg per day experienced oedema. CCB-induced oedema is caused by increased capillary hydrostatic pressure that results from preferential dilation of pre-capillary vessels. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) cause post-capillary dilation and normalize hydrostatic pressure, and are thus ideally suited for prevention/reversal of CCB-induced oedema. The efficacy of this strategy was proven using both subjective and objective techniques. ARB/CCB and ACEI/CCB combination therapy is also more effective than CCB monotherapy in controlling blood pressure. These combinations represent an important advance in the management of hypertension.This review is aimed at examining calcium channel blocker (CCB)-related oedema and how this can be attenuated through the use of agents that inhibit the renin–angiotensin system. CCBs are effective antihypertensive agents, but their propensity for causing oedema may reduce compliance. A review of the literature has indicated that the absolute incidence of this side effect is difficult to determine because reported rates vary widely, a factor that may stem from differences in the surveillance technique (active vs passive). In a recent trial incorporating active surveillance, 25% of patients who received amlodipine 10 mg per day experienced oedema. CCB-induced oedema is caused by increased capillary hydrostatic pressure that results from preferential dilation of pre-capillary vessels. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) cause post-capillary dilation and normalize hydrostatic pressure, and are thus ideally suited for prevention/reversal of CCB-induced oedema. The efficacy of this strategy was proven using both subjective and objective techniques. ARB/CCB and ACEI/CCB combination therapy is also more effective than CCB monotherapy in controlling blood pressure. These combinations represent an important advance in the management of hypertension.

Methodology and technology for peripheral and central blood pressure and blood pressure variability measurement: Current status and future directions - Position statement of the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability

Office blood pressure measurement has been the basis for hypertension evaluation for almost a century. However, the evaluation of blood pressure out of the office using ambulatory or self-home monitoring is now strongly recommended for the accurate diagnosis in many, if not all, cases with suspected hypertension. Moreover, there is evidence that the variability of blood pressure might offer prognostic information that is independent of the average blood pressure level. Recently, advancement in technology has provided noninvasive evaluation of central (aortic) blood pressure, which might have attributes that are additive to the conventional brachial blood pressure measurement. This position statement, developed by international experts, deals with key research and practical issues in regard to peripheral blood pressure measurement (office, home, and ambulatory), blood pressure variability, and central blood pressure measurement. The objective is to present current achievements, identify gaps in knowledge and issues concerning clinical application, and present relevant research questions and directions to investigators and manufacturers for future research and development (primary goal).

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.

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.

Increased activity of the Mg2+/Na+ exchanger in red blood cells from essential hypertensive patients.

Epidemiological, clinical, and experimental evidence suggests a relation between Mg2+ metabolism and essential hypertension. The aim of the present study was the detection of abnormalities of the erythrocyte Mg2+/Na+ exchanger in essential hypertensive patients. We studied 66 untreated essential hypertensive patients and 36 normotensive control subjects. Maximal efflux rates of total Mg2+ efflux and the Na(+)-dependent and Na(+)-independent components of Mg2+ efflux were determined in Mg(2+)-loaded red blood cells. Mg2+/Na+ exchanger was calculated as the Na(+)-dependent component of the Mg2+ efflux. Mean values of Mg2+/Na+ exchanger were clearly elevated in hypertensive subjects with respect to normotensive control subjects [184.7 +/- 15.7 versus 84.4 +/- 6 mumol(L.cell.h)-1; P < .001]. This elevation was due primarily to the increased total Mg2+ efflux [324.2 +/- 21.9 versus 257.9 +/- 17.3 mumol(L.cell.h)-1; P < .05], whereas the Na(+)-independent component was not significantly different between the groups [154.5 +/- 11.8 versus 173.4 +/- 15.5 mumol(L.cell.h)-1; P = NS]. Moreover, total erythrocyte Mg2+ content was slightly reduced in hypertensive patients with respect to normotensive control subjects (1.84 +/- 0.04 versus 2.07 +/- 0.04 mmol/L.cell; P < .001). Using the 99% confidence limits of the normotensive population as the normal range, 30 (45.5%) hypertensive subjects showed values of Mg2+/Na+ exchanger higher than 160 mumol(L.cell.h)-1. The Mg2+/Na+ exchanger was inversely correlated with basal intraerythrocyte Mg2+ content (r = -.323; P = .001). From a clinical point of view, we found a positive correlation between diastolic blood pressure values and Mg2+/Na+ exchanger (r = .246; P < .05) in the sample of essential hypertensive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Resistant hypertension: patient characteristics, risk factors, co-morbidities and outcomes

Among the vast population of hypertensive subjects, between 10 and 15% do not achieve an adequate blood pressure (BP) control despite the use of at least three antihypertensive agents. This group, designated as having resistant hypertension (RH), represents one of the most important clinical challenges in hypertension evaluation and management. Resistant hypertensives are characterized by several clinical particularities, such as a longer history of hypertension, obesity and other accompanying factors, such as diabetes, left ventricular hypertrophy, albuminuria and renal dysfunction. In addition to other diagnostic and therapeutic maneuvers, such as excluding secondary hypertension, ensuring treatment adherence and optimizing therapeutic schemes, ambulatory BP monitoring (ABPM) is crucial in the clinical evaluation of patients with RH. ABPM distinguish between those with out-of-office BP elevation (true resistant hypertensives) and those having white-coat RH (WCRH; normalcy of 24-h BPs), the prevalence of the latter estimated in about one-third of the population with RH. True resistant hypertensives also exhibit more frequently other co-morbidities, more severe target organ damage and a worse cardiovascular prognosis, in comparison to those with WCRH. Some device-based therapies have recently been developed for treatment of RH. This requires a better characterization of a potential candidate population. A better knowledge of the clinical features of resistant hypertensive subjects, the confirmation of elevated BP values out of the doctor’s office, and improvements in the search for secondary causes would help to select those candidates for newer therapies, once the pharmacological possibilities have been exhausted.

Effect of long-term irbesartan treatment on endothelium-dependent vasodilation in essential hypertensive patients.

Abstract Endothelial dysfunction plays a pivotal role in the development of essential hypertension and its complications. The purpose of this study is to assess the effect of antihypertensive treatment with the angiotensin receptor blocker irbesartan on endothelial function in a group of essential hypertensive patients. Thirty-two untreated hypertensives are examined at baseline and at the end of a six-month period of irbesartan treatment. Endothelium-dependent and -independent responses are determined by measuring changes in forearm blood flow (FBF) by strain gauge plethysmography in response to intrarterial infusions of acetylcholine (endothelium-dependent vasodilation [EDV]), sodium nitroprusside (endothelium-independent vasodilation [EIV]), with and without the addition of the nitric oxide (NO) synthase inhibitor L-NMMA. Plasma endothelin, plasma and urinary nitrates and nitrites, and cyclic GMP are measured at baseline and at the end of treatment. Irbesartan promoted a significant increase in EDV (from 433±147% to 488±75%; P=0.027) and EIV (from 442±130% to 495±104%; P=0.041). L-NMMA-induced vasoconstriction was significantly enhanced after irbesartan treatment (relative decrease of FBF from 33.4±9.5% to 39.5±5.6%; P=0.001). Plasma concentrations of endothelin fell significantly after irbesartan treatment (from 5.78±1.86 to 4.16±1.52 pg/mL; P=0.001). We concluded that long-term irbesartan treatment enhances both endothelium-dependent and -independent vascular vasodilation capacity. In addition to this non-specific effect, irbesartan restores the vasoconstriction capacity of NO synthase inhibitors, suggesting a direct effect on tonic NO release, and decreases endothelin production. These actions may play an important role in the vascular protecting effects of irbesartan.

Lack of association between ACE gene polymorphism and left ventricular hypertrophy in essential hypertension.

The possible association between the insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene and left ventricular hypertrophy (LVH) was investigated in a group of essential hypertensive patients. Seventy-one essential hypertensive patients (35 men and 36 women), aged 51 ± 1 years, were genotyped by PCR for the I/D polymorphism of the ACE gene. Cardiac morphology and function were assessed by means of M-mode echocardiography. The relative frequencies of the three genotypes, DD, DI, and II, were respectively: 24%, 55%, and 21%. Mean values of left ventricular mass index were 145, 144, and 150 g/m2 for DD, DI, and II genotypes, without significant differences among them (P = 0.82). Likewise, the prevalence of LVH (76%, 64%, and 87%) was not significantly different among the three genotypes (P = 0.23). We conclude that the ACE gene I/D polymorphism is not associated with LVH in essential hypertension.