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Aim: Primary aldosteronism could exert a negative feedback on prorenin secretion, of possibly different magnitude, whether it is related to an aldosterone-producing adenoma (APA) or an idiopathic hyperaldosteronism (IHA). The objectives of this study were to evaluate the level of prorenin in three subgroups: APA, IHA, and essential hypertension; and the performance of the aldosterone-to-prorenin ratio (APR) for the diagnosis of an APA., Methods: Seven hundred and forty-six hypertensive patients with a standardized work-up, including a prorenin measurement, were considered. Ninety-six patients without neutral treatment and 38 patients with other forms of secondary hypertension were excluded. APA and IHA were categorized according to computed tomography scan, adrenal venous sampling, pathological analysis and improvement of hypertension after surgery., Results: Thirty-five patients had a diagnosis of APA, 57 of IHA and 504 of essential hypertension. Prorenin was lower in APA and IHA than in essential hypertension (32.9, 40.4 and 50.3  pg/ml, respectively; P < 0.001). APR was higher in patients with APA and IHA than in those with essential hypertension (24.0, 11.8, and 4.0  pmol/l per pg/ml, respectively; P < 0.001). The APR was more discriminant than the aldosterone-to-renin ratio to identify APA compared to IHA (area under the receiver operating curve at 0.750 and 0.639, respectively; P = 0.04). The optimal cut-off values were 22  pmol/l per pg/ml for APR (sensitivity 57.0%, specificity 93.0%) and 440  pmol/l per pg/ml for aldosterone-to-renin ratio (sensitivity 54.3%, specificity 82.5%)., Conclusion: Primary aldosteronism and particularly its most caricatural form, that is APA, seems associated with a lower level of prorenin than essential hypertension. The APR could be included in the diagnostic strategy of APA.

Current antihypertensive strategies do not take into account that individual characteristics may influence the magnitude of blood pressure (BP) reduction. Guidelines promote trial-and-error approaches with many different drugs. We conducted the Identification of the Determinants of the Efficacy of Arterial blood pressure Lowering drugs (IDEAL) Trial to identify factors associated with BP responses to perindopril and indapamide. IDEAL was a cross-over, double-blind, placebo-controlled trial, involving four 4-week periods: indapamide, perindopril and two placebo. Eligible patients were untreated, hypertensive and aged 25-70 years. The main outcome was systolic BP (SBP) response to drugs. The 112 participants with good compliance had a mean age of 52. One in every three participants was a woman. In middle-aged women, the SBP reduction from drugs was -11.5 mm Hg (indapamide) and -8.3 mm Hg (perindopril). In men, the response was significantly smaller: -4.8 mm Hg (indapamide) and -4.3 (perindopril) (P for sex differences 0.001 and 0.015, respectively). SBP response to perindopril decreased by 2 mm Hg every 10 years of age in both sexes (P=0.01). The response to indapamide increased by 3 mm Hg every 10 years of age gradient in women (P=0.02). Age and sex were important determinants of BP response for antihypertensive drugs in the IDEAL population. This should be taken into account when choosing drugs a priori.

Despite a wide choice of effective antihypertensive treatments, blood pressure (BP) in roughly half of hypertensive subjects is not controlled. Resistant hypertension is defined as an uncontrolled BP despite optimal doses of three antihypertensive treatments, including a diuretic. After confirmation of resistant BP using home BP measurement or 24-hour ambulatory BP monitoring (ABPM), patients usually go through a work-up to rule out secondary hypertension. If secondary hypertension is ruled out, the recent European guidelines on hypertension consider baroreceptor stimulation or renal denervation to be possible options. The prevalence of resistant primary hypertension may reach up to 10% in specialized centres. The two proposed non-pharmacological therapeutic strategies have been developed recently to inhibit sympathetic overactivity in resistant hypertension. Among them, baroreceptor activation therapy (BAT) is an innovative approach that interferes with baroreflex function. The first-generation BAT device (Rheos(®); CVRx, Inc., Minneapolis, MN, USA) demonstrated good efficacy in lowering office BP and ABPM, but had an insufficient safety profile due to complex surgery. The second-generation BAT device (Barostim neo™ system; CVRx, Inc.) seems to share the same BP-lowering efficacy but has a better safety profile. We report the first French case of baroreceptor stimulation for hypertension using the Barostim neo™ system. We also discuss the pathophysiological features of and current levels of evidence for this technique., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Aim: We report the first experience of Lyon's university hospital regarding renal denervation to treat patients with resistant essential hypertension., Patients and Methods: Over a one-year period, 17 patients were treated (12 men, 5 women) with renal denervation. Baseline characteristics were as follows: age 56.5±11.5 years, BMI 33±5kg/m(2) and ambulatory blood pressure 157±16/87±13mmHg with 4.2±1.5 anti-hypertensive treatment., Results: We did not observe intra-operative or early complications. After a median follow-up of 3 months and with the same anti-hypertensive treatment, office systolic blood pressure (SBP) and diastolic blood pressure (DBP) decrease respectively of 20±15 (P<0.001) and 10±13mmHg (P=0.014) (n=17). After six months of follow-up, ambulatory blood pressure (ABPM) decrease of 17.5±14.9mmHg (P=0.027) for SBP and of 10.5±9.6mmHg (P=0.029) for DBP (n=6). Among these patients, five of them were controlled (ABPM inferior to 130/80mmHg) and electrical left ventricular hypertrophy indexes decreased: R wave in aVL lead of 4±3mm (P=0.031), Sokolow index of 3±3mm (P=0.205), Cornell voltage criterion of 9±7mm (P=0.027) and Cornell product of 1310±1104 (P=0.027)., Conclusion: Our results are in accordance with data from other centers. On average blood pressure decreases significantly but important inter individual variations are observed. The procedure seems safe., (Copyright © 2014. Published by Elsevier SAS.)

Objectives: The voltage of R wave in lead aVL (RaVL) seems to be more tightly correlated with left ventricular mass and cardiovascular events than any other ECG criterium of left ventricular hypertrophy. We hypothesized that RaVL could be an independent predictor of all-cause and cardiovascular death in hypertensive individuals., Methods: The baseline clinical and biological variables as well as ECG recordings were analyzed in a prospective cohort of 589 hypertensive individuals., Results: After 10 years of follow-up, we observed 95 deaths of which 53 had a cardiovascular cause. The optimal RaVL voltages to predict all-cause and cardiovascular mortality were 0.8 and 0.6  mV, respectively. In a multivariate adjusted Cox model, having an RaVL voltage superior to these cutoffs was associated with increased risks of all-cause death [hazard ratio: 2.04, 95% confidence interval (CI): (1.30-3.22)] and of cardiovascular death [hazard ratio: 2.89, 95% CI: (1.47-5.68)]. In the whole cohort and with the same adjusted Cox regression model, each 0.1  mV increment would increase the risk of all-cause death by 1.07 times [95% CI: (1.02-1.12)] and that of cardiovascular death by 1.13 times [95% CI: (1.06-1.20)]. After excluding in turn patients with positive Sokolow index, Cornell voltage, or Cornell product, the results remained statistically significant, meaning that RaVL was still able to pick-up high-risk patients when other classical and more sophisticated indices were not observable., Conclusion: The present results strengthen previous reports that demonstrated a strong role of RaVL voltage in risk stratification in hypertension.

The aim of this study was to compare the diagnostic performance of N-terminal pro-brain natriuretic peptide (NT-proBNP), electrocardiographic (ECG) criteria and transthoracic echocardiography (TTE) versus cardiac magnetic resonance imaging in detecting left ventricular hypertrophy (LVH). The study included 42 hypertensive subjects with mean±s.d. age 48.1±12.3 years, 57.1% men, 24-h ambulatory blood pressure 144/89 mm Hg, left ventricular ejection fraction >50%, without symptoms of heart failure, and not taking any drugs that interfere with hormonal regulation. The accuracies of the methods in detecting LVH were compared at two diagnostic LVH cutoffs: low, 83 g m(-2) in men and 67 g m(-2) in women; and high, 96 g m(-2) in men and 81 g m(-2) in women. With the low and high LVH cutoffs, the areas under the receiver-operating characteristic curves and the optimal values for NT-proBNP were 0.761, 0.849, 200 and 421 pg ml(-1), respectively. An NT-proBNP level under 30 pg ml(-1) ruled out LVH with 100% sensitivity. The optimal values and literature-based values of NT-proBNP allowed a correct classification of 73-81% of the subjects. In 80-90% of the cases, the diagnostic accuracy of NT-proBNP was close to that of ECG criteria but lower than that of TTE criteria. Interestingly, combining ECG criteria and NT-proBNP level improved the diagnostic performance to be at least comparable to that of TTE: the percentages of correctly classified subjects were 73-95% vs. 67-86%, respectively. Of note, the range considers both diagnostic LVH cutoffs. The simultaneous use of ECG criteria and NT-proBNP plasma levels seemed to be powerful enough to detect LVH in most hypertensive subjects.

Objectives: Our study aimed at determining the interaction between the prognostic value of diastolic blood pressure (DBP) and aortic atherosclerosis (ATS)., Background: With aging, equal systolic blood pressures (SBPs) become associated with low DBPs; i.e., high pulse pressures (PPs) become associated with a high risk of cardiovascular death. This association is usually ascribed to aortic stiffening with age but the precise impact of low DBP per se is yet uncertain., Methods: 938 hypertensive patients recruited in the seventies had an aortic ATS score at pretreatment aortography. All-cause and cardiovascular deaths were assessed 20 years later. The prognostic values of DBP and SBP were assessed by a multivariate Cox regression model and their interactions with ATS examined., Results: In the presence of ATS, an increase of 10 mmHg in DBP was associated with a protective effect: hazard ratios 0.84 [0.72-0.99] for cardiovascular death and 0.88 [0.78-1.00] for all-cause death. However, in the absence of ATS, DBP had no prognostic value: hazard ratios 1.05 [0.89-1.23] for cardiovascular death and 0.99 [0.88-1.11] for all-cause death (p for interaction: 0.061 and 0.087, respectively). No interaction was found between SBP and ATS (p for interaction > 0.40)., Conclusions: The prognostic values of DBP and aortic atheroma are not superimposable; yet, they are tightly connected: a low DBP is disadvantageous only in the presence of a pathologic aorta. Aortic atherosclerosis may explain, at least partly, in some high risk populations, the J-shape of the already reported DBP-outcome relationship., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Although some epidemiological studies have advocated a prognostic value of heart rate (HR) in hypertensive patients, the influence of vascular damages on this prognostic value has not been tested yet., Methods: HRs were collected by pulse palpation in 1204 primary hypertensive patients in sinus rhythm without cardiac-slowing drugs. Aortic damages were assessed by aortography, whereas cardiac disease was assessed by medical history, symptoms and electrocardiogram., Results: In a multivariable Cox model adjusted for major confounders, HR was of prognostic significance for all-cause [hazard ratio 1.12 (1.06-1.19) for 10 bpm increment and 1.39 (1.18-1.64) for HR ≥82 vs. <82 bpm] and cardiovascular death [hazard ratio 1.10 (1.02-1.20) for 10 bpm increment and 1.37 (1.09-1.72) for HR ≥82 vs. <82 bpm] after 35 years of follow-up. This association was particularly manifested at 15 years of follow-up. At that time, with the same multivariable survival model, the association between HR and cardiovascular death was stronger in patients with aortic atheroma [2.76 (1.47-5.18) for an HR ≥82 vs. <82 bpm] than in patients without [hazard ratio 1.36 (0.76-2.43) for an HR ≥82 vs. <82 bpm, P for interaction = 0.054]. Similarly, the association between HR and cardiovascular death was stronger in patients with an overt cardiac disease than those without (P for interaction = 0.044)., Conclusion: In hypertensive patients, the prognostic significance of HR for cardiovascular outcome is modulated by the presence of aortic atherosclerosis or cardiac disease. This should prompt us to a thorough examination of cardiovascular damages in hypertensive patients when HR is elevated.

Background: The impact of various methods of travel distance estimation on the prognostic value of pulse wave velocity (PWV) and on the adequacy of cut-offs has never been addressed within a single population of hypertensive patients., Methods: Four carotid-femoral PWVs were calculated from four different travel distances (Direct, Real, Subtracted, and Estimated) divided by the same travel time in 426 hypertensives (mean age 51.2 ± 13.8 years, mean systolic blood pressure 155.6 ± 21.1 mm Hg). The incidence of death from any cause and major cardiovascular events was studied. PWV predictive accuracies were determined using C-index analysis. Hazard ratios (HRs) associated with specific values of PWV were determined with Cox model analyses using cubic splines., Results: Mean PWV ranged from 8.3 ± 2.3 m/s for the Subtracted one to 11.6 ± 3.0 m/s for the Direct one (P < 0.001). When included as continuous variables in a Cox model, the four PWVs were significantly associated with outcome (all P < 0.001), and had similar C-index (0.608-0.617). In multivariable analysis, the HR calculated for a Direct PWV of 12 m/s was neutral (HR = 1.02). In contrast, the same analysis provided HR ranging from 1.79 to 2.90 with the other PWVs., Conclusions: Different travel distances markedly impact PWV values and prognostic cut-offs. PWV cut-offs should consequently be ascertained jointly with the method of measurement used. There is an urgent need for standardization of PWV assessment before implementing this parameter in the routine management of hypertensives.

Objective: To identify markers (phenotypic, genetic, or environmental) of blood pressure (BP) response profiles to angiotensin converting enzyme inhibitors (ACEIs) and diuretics., Methods: IDEAL was a crossover (two active and two wash out phases), double-blind, placebo-controlled trial. Eligible patients were untreated hypertensive, aged 25 to 70. After two visits, patients were randomized to one of four sequences. The main outcome was BP differences between the active treatment and placebo., Results: One hundred and twenty-four patients were randomised: mean age 53, men 65%, family history of hypertension 60%. Average BP fall at each visit before randomisation was about 2% of the initial level reflecting both a regression to the mean and a placebo effect., Conclusion: The results are expected to improve knowledge in drug's mechanisms of action and pathophysiology of hypertension, and to help in personalizing treatment. The estimation of BP responses to each drug in standardized conditions provided a benefit to each participant., (© 2012 Société Française de Pharmacologie et de Thérapeutique.)

Over the past years, natriuretic peptides have been recognised not only as important contributors to cardiovascular regulation but also as valuable markers in overt cardiac disease, including heart failure or coronary disease. More recently, these markers have shown their ability to detect preclinical cardiac alterations in different settings. In this respect, natriuretic peptides offer a new perspective for risk stratification in hypertension. They are correlated to various features of cardiac remodelling provoked by hypertension. They also depend on vascular properties, including blood pressure level and aortic stiffness. In addition to being integrative markers of cardiovascular alterations, several studies have shown their value in predicting all-cause mortality or cardiovascular mortality and morbidity in the general population. At least three consistent studies are now available in hypertension also showing this prognostic value. This performance, together with the ease of measurement, low cost and widespread availability, should prompt the wide use of natriuretic peptides for risk stratification in hypertension, at least in patients with normal electrocardiography, but also in most hypertensive patients., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Natriuretic peptides are controregulatory hormones associated with cardiac remodeling, namely, left ventricular hypertrophy and systolic/diastolic dysfunction. We intended to address the prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in hypertension. We prospectively studied the relationship between plasma NT-proBNP and all-cause mortality in 684 hypertensive patients with no history or symptoms of heart failure referred for hypertension workup in our institution from 1998 to 2008. After a mean duration of 5.7 years, we observed 40 deaths (1.04 deaths per 100 patients per year). After adjustment for traditional cardiovascular risk factors, including ambulatory blood pressure and serum creatinine, the risk for all-cause mortality more than doubled with each increment of 1 log NT-proBNP (hazard ratio: 2.33 [95% CI: 1.36 to 3.96]). The risk of death of patients with plasma NT-proBNP≥133 pg/mL (third tertile of the distribution) was 3.3 times that of patients with values<50.8 pg/mL (first tertile; hazard ratio: 3.30 [95% CI: 0.90 to 12.29]). This predictive value was independent of, and superior to, that of 2 ECG indexes of left ventricular hypertrophy, the Sokolov-Lyon index and the amplitude of the R wave in lead aVL. In addition, it persisted in patients without ECG left ventricular hypertrophy, which allowed refining risk stratification in this relatively low-risk patient category. In this large sample of hypertensive patients, plasma NT-proBNP appeared as a strong prognostic marker. This performance, together with the ease of measurement, low cost, and widespread availability of NT-proBNP test kits, should prompt a wide use of this marker for risk stratification in hypertension.

Cardiac remodeling was assessed both in the pressure-overloaded left ventricle and in the normotensive right ventricle of hypertensive transgenic rats (mRen2)27 (TGR27). The present study combined histology, electrophysiology, molecular biology and biochemistry techniques. A significant increase in action potential (AP) duration was recorded both in right and left ventricular myocytes wheareas only in the latter ones were hypertrophic. The increase in AP duration is mainly supported by the reduction of the transient outward K current (I(to)) density since no significant modification was observed for the L-type calcium current (I(Ca,L)), the sodium-calcium exchange current (I(NCX)), the delayed rectifier current (I(K)) and the inward rectifier current (I(K1)). The lower amplitude of I(to) current was associated with a lower Kv4.3 protein expression both in right and left ventricles while Kv4.3 mRNA levels was decreased only in left ventricle. Thus, a differential ventricular remodeling takes place in the TGR27 model. The possible cause of electrical remodeling in right ventricular myocytes of TGR27 is discussed.

Introduction: No agreement has been reached regarding the best strategy to detect left ventricular hypertrophy (LVH). This study examined the role of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of LVH in hypertensive patients and the potential factors that may influence its diagnostic performance., Methods: The global accuracy of NT-proBNP in diagnosing LVH was assessed using a receiver-operating characteristic (ROC) curve. The influence of patients' characteristics on test accuracy was studied with a ROC regression based on a probit model. Ninety-three subjects were included. All had NT-proBNP measured and underwent electrocardiography and echocardiography, with calculation of the left ventricular mass index (LVMI)., Results: The diagnostic performance of NT-proBNP in LVH varied slightly depending on the indexation mode of LVMI. In cases of body surface area indexation, the area under the ROC curve of 81.6% suggested a good performance. The accuracy of the marker was significantly higher in women than in men (p<0.0001). There were no significant effects of age, treatment, body mass index, left ventricular mass index, 24-h systolic blood pressure, or creatinine clearance on the test performance. Slight differences were observed when an indexation to height(2.7) instead of body surface area was used., Conclusions: The present results may lead to a new strategy for risk stratification in hypertension: in women, NT-proBNP alone or preferably in combination with electrocardiography seems sufficient to confirm or exclude diagnosis of LVH. In men, echocardiography would only be needed in cases of negative electrocardiography and NT-proBNP test.

Background: Arterial stiffness is a strong predictor of cardiovascular events and particularly of stroke. A likely explanation is the development of atherosclerotic lesions at the carotid level, favored by increased local stiffness. Another possibility involves cardiac consequences of aortic stiffness and particularly left atrial dilatation with its subsequent risk of atrial fibrillation (AF) and cerebral embolism., Aims: The present study investigated the link between arterial stiffness, pulse pressure and left atrial size, a determinant of AF risk., Methods: Arterial stiffness was determined from pulse wave velocity (PWV) and pulse pressure (PP). Left atrial size was also measured. Several potential confounders were taken into account including indices of ventricular remodeling and diastolic function (estimated by NT-Pro brain natriuretic peptide (NT-proBNP) levels)., Results: Three-hundred and ten hypertensive patients, aged 53 +/- 13 years, were included. Mean 24-h blood pressure (BP) was 154 +/- 20 over 93 +/- 13 mmHg. Significant relationships were found between left atrial diameter (LAD) and PWV (r=0.27, P<0.001) and between LAD and 24-h PP (r=0.32, P<0.001). LAD was also correlated significantly, although not always tightly, with left ventricular dimensions, geometry and NT-proBNP. In two different multivariate models, LAD remained significantly correlated with PWV or with 24-h PP, independently of classical determinants like age, gender, body mass index, ventricular remodeling (i.e. dimensions and geometry) and filling pressure., Conclusion: These results led us to propose AF as a new possible pathophysiological link between arterial stiffness and stroke. These results also emphasize the cardiac consequences of arterial stiffness which can fuel a new approach to AF prevention.

Left ventricular hypertrophy (LVH) is commonly associated with hypertension and represents an independent cardiovascular risk factor. The aim of this study was to test the hypothesis that the cardiac overload related to hypertension is associated to a specific gene expression pattern independently of genetic background. Gene expression levels were obtained with microarrays for 15,866 transcripts from RNA of left ventricles from 12-wk-old rats of three hypertensive models [spontaneously hypertensive rat (SHR), Lyon hypertensive rat (LH), and heterozygous TGR(mRen2)27 rat] and their respective controls. More than 60% of the detected transcripts displayed significant changes between the three groups of normotensive rats, showing large interstrain variability. Expression data were analyzed with respect to hypertension, LVH, and chromosomal distribution. Only four genes had significantly modified expression in the three hypertensive models among which a single gene, coding for sialyltransferase 7A, was consistently overexpressed. Correlation analysis between expression data and left ventricular mass index (LVMI) over all rats identified a larger set of genes whose expression was continuously related with LVMI, including known genes associated with cardiac remodeling. Positioning the detected transcripts along the chromosomes pointed out high-density regions mostly located within blood pressure and cardiac mass quantitative trait loci. Although our study could not detect a unique reprogramming of cardiac cells involving specific genes at early stage of LVH, it allowed the identification of some genes associated with LVH regardless of genetic background. This study thus provides a set of potentially important genes contained within restricted chromosomal regions involved in cardiovascular diseases.

Objective: The frequent association between the type 2 diabetes mellitus and cardio-vascular diseases suggests that metabolic factors may contribute to cardio-vascular remodeling. The aim of our study was to examine the relationships between left ventricular posterior wall thickness (LVPWT), pulse wave velocity (PWV), and the metabolic abnormalities of insulin resistance syndrome, in hypertensive patients., Methods: In 227 consecutive hypertensives, we examined the relationships between LVPWT, PWV, and metabolic factors: plasma glucose, insulin, total cholesterol, high density lipoprotein (HDL)-cholesterol, triglycerides levels as well as the homeostasis model assessment of insulin resistance (HOMA). The Pearson correlation coefficient and multiple regression analysis (including age, gender, body mass index, and 24-hour systolic blood pressure) were used as statistical tests., Results: In univariate analysis, glucose, HDL-cholesterol, and triglycerides levels were related to LVPWT (r = 0.19, p < 0.05; r = -0.26, p < 0.001; r = 0.31, p < 0.001, respectively); all metabolic variables, except HDL-cholesterol, correlated to PWV (plasma glucose r = 0.25, p < 0.001; total cholesterol r = 0.22, p < 0.01; triglycerides r = 0.20, p < 0.01; insulin r = 0.19, p < 0.01; HOMA r = 0.27; p < 0.001). In the multivariate model, plasma triglycerides remained correlated with LVPWT (beta = 0.19, p < 0.02) independently of systolic blood pressure, plasma aldosterone, and normetanephrine. Only HOMA and insulin level remained associated with PWV (beta = 0.14; beta = 0.13 respectively, p < 0.05)., Conclusions: These data suggest that among typical metabolic abnormalities of insulin resistance syndrome, plasma triglycerides, and insulin as well as degree of insulin resistance may contribute to cardiac hypertrophy and arterial stiffening independently of hemodynamic and hormonal factors.

Cytokines from the interleukin-6 (IL-6) family have been reported to play an important synergistic role with angiotensin II in the development of pathological cardiac hypertrophy. Whether their expression pattern changes in vivo, in an angiotensin I-dependent hypertrophied myocardium has not been reported. In this study, we addressed that issue using two animal models of angiotensin II-dependent cardiac hypertrophy. Heterozygous transgenic TGR(mRen2)27 (TGR) with an overactive cardiac renin angiotensin system and the closely related spontaneously hypertensive rats (SHR) were compared to their respective control rats. The mRNA levels of IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1) as well as their receptor subunits, glycoprotein 130 (gp130), IL-6 receptor (IL-6R), LIFR, and CNTFR, were measured by semi-quantitative RT-PCR. The protein levels of IL-6, LIF and CT-1 were investigated by western blot. TGR and SHR both displayed significant over expression of mRNA and protein levels for IL-6 and LIF. In TGR, the increased level of LIF was accompanied by a decrease in mRNA levels for LIFR and CNTFR. In SHR, a higher level of mRNA IL-6R was observed. By contrast, the mRNA and protein levels for CT-1 and the mRNA level for gp130 did not vary in these two models. These findings suggest that IL-6 and LIF, but not CT-1, contribute to angiotensin II-dependent left ventricular hypertrophy in the two hypertensive rat models, TGR(mRen2)27 and SHR.

Objective: To study the association of the AC polymorphism of angiotensin II type 1 receptor gene (AGTR1) with blood pressure and central arterial stiffness in a population of hypertensive patients referred to hospital for further work-up., Methods: One hundred and eighty-five patients, referred to our department from April 1998 to February 2002, were included. Blood pressure was measured by conventional and 24-h ambulatory methods, and arterial stiffness by carotid-femoral pulse wave velocity (PWV) determination. Genotyping for the AGTR1 AC polymorphism was performed by polymerase chain reaction., Results: AGTR1 AC polymorphism was not associated with systolic or diastolic blood pressure, measured either by conventional (P=0.89 and P=0.67, respectively) or by 24-h ambulatory (P=0.57 and P=0.56, respectively) methods. Conversely, this polymorphism was significantly associated with PWV (P=0.006) and had a dose-allele effect, PWV increasing with the number of A alleles (10.6 +/- 2.4 m/s in CC, 11.9 +/- 2.5 m/s in AC and 12.7 +/- 2.7 m/s in AA patients, P=0.002). Multiple regression analysis showed that AC polymorphism was still independently associated with PWV (P=0.01) and was the third most important determinant of PWV after age (P <0.0001) and 24-h mean blood pressure (P <0.0001)., Conclusion: In our study population, central arterial stiffness assessed by PWV was significantly and independently associated with the AC polymorphism, increased PWV being associated with the presence of the A allele. Further investigations are required for identification of the underlying mechanisms.

Introduction: The aim of this work was to identify new renin target genes in left ventricular hypertrophy during hypertension., Materials and Methods: We compared left ventricle gene expression from four transgenic TGR(mRen2)27 (TG+/-) rats and four non-transgenic littermates (TG-/-) using cDNA macroarray. Hybridisation signals were quantified with a phosphorimager, and normalised to an external scale. Data analysis was performed with Statistical Analysis for Microarrays (SAM 1.21) software. The mRNA levels of candidate genes were determined by semi-quantitative RT-PCR in three different hypertensive rats: TG+/-, spontaneously hypertensive (SHR) and genetically Lyon hypertensive (LH) rats, compared to their respective controls (TG-/-, Wistar-Kyoto, Lyon low blood pressure rats)., Results: Out of 1,200 genes present on the macroarray, 233 were reliably measured and only three were overexpressed (Biglycan, beta1-adenosine monophosphate-activated protein kinase [AMPK] and amyloid precursor like protein 2 [APLP2]) and 19 were underexpressed in the left ventricle of TG+/- compared with TG-/-. APLP2 is a member of the amyloid precursor protein (APP) family. APLP2 and APP mRNA levels were increased in TGR(mRen2)27 but significantly decreased in LH rats, while only APP was increased in SHR rats., Conclusions: We report new genes associated with renin-dependent left ventricular hypertrophy. Moreover, this work shows for the first time that the APP family gene expression could be altered in response to high renin activity and this effect is independent of cardiac remodelling and hypertension.

Unlabelled: Our goal was to study the relative influence of systolic blood pressure (SBP) and plasmatic markers of sympathetic and renin-aldosterone systems (RAS) activities to left atrial diameter (LAD), left ventricular posterior wall thickness (LVPWT) and pulse wave velocity (PWV), which reflect cardiovascular remodeling in hypertension., Methods: In 227 consecutive patients with hypertension (mean age +/- SD: 53.3 years +/- 13.4, 126 men), we measured: PWV, LAD, LVPWT, mean 24-hours SBP, plasma renin activity, and plasma aldosterone and catecholamine levels. Multiples linear regression analyses were performed to test statistical associations between hemodynamic and neurohumoral factors, and cardiovascular remodeling parameters, after adjustment for age, gender and body mass index., Results: LVPWT was positively correlated to SBP as well as to plasma aldosterone and meta-noradrenaline (p < 0.001). LAD and PWV were related to SBP but not to any of the biological variables. Moreover, LAD correlated to PWV independently of SBP (p < 0.05), whereas after SBP inclusion in the model, there was not significant correlation between LAD and LVPWT nor between LVPWT and PWV., Conclusion: In hypertension, the development of cardiac hypertrophy depends on SBP and the sympathetic and renin-aldosterone systems activities. The RAS is not involved in the PWV nor LAD modifications. Strong association between LAD and PWV suggest that left atrial enlargement, that may be considered as a marker of diastolic function, may results more from arterial stiffness than from ventricular hypertrophy.

In a narrow meaning, responders to a therapy are all those who will react as expected following the administration of this therapy. However, a wider definition is worth considering: all those for whom the administration of the therapy will be beneficial. Innovative therapies are increasingly expensive and hazardous, and limiting prescriptions to responders is both economically and ethically compulsory. The theoretical basis for such an approach exists. The process of defining the profile of responders consists of identifying the characteristics of the patients that interact with the size of the effect and integrating them quantitatively in a predictive model. The effect model, which is the relation between the risks of the event with and without the treatment, can be used for the prediction. It can integrate interactions of the efficacy with risk factors and/or genes. The data to be used to achieve both the identification of the interactions and the building of the predictive model are those from the studied population, the set of patients enrolled in clinical trials. Hence, the process of defining the therapy is an extrapolation from the studied population. To carry out the extrapolation process one can use various available techniques, of which none fully fits the purpose. No method is currently both fully adequate and validated. Finally, the predictive models, which we need to identify responders, do not exist in practice. Fortunately, new research approaches have been developed recently.

To study whether the brain renin-angiotensin system plays a role in the long-term and short-term control of blood pressure and heart rate variability, we examined in transgenic rats [TGR(ASrAOGEN)] with low brain angiotensinogen levels the 24-hour variation of blood pressure and heart rate. Telemetry recordings were made during basal and hypertensive conditions induced by a low-dose subcutaneous infusion of angiotensin II for 7 days. Short-term blood pressure and heart rate variability were evaluated by spectral analysis, and as a measure of baroreflex sensitivity, the average transfer gain between the pressure and heart rate variations was calculated. During the angiotensin II infusion in control but not TGR(ASrAOGEN) rats, the 24-hour rhythm of blood pressure was inverted (5.8+/-2 versus -0.4+/-1.8 mm Hg/group of day-night differences of blood pressure, P<0.05, respectively). In both the control and TGR(ASrAOGEN) rats, the 24-hour heart rate rhythms remained unaltered and paralleled those of locomotor activity. The transfer gain between 0.3 to 0.6 Hz was significantly higher in TGR(ASrAOGEN) than in control rats during control (0.71+/-0.1 versus 0.35+/-0.06, P<0.05) but not during angiotensin II infusion (0.6+/-0.07 versus 0.4+/-0.1, P>0.05). These results demonstrate that the brain renin-angiotensin system plays an important role in mediating the effects of angiotensin II on the circadian variation of blood pressure. Furthermore, these data indicate that a permanent deficiency in the brain renin-angiotensin system alters the reflex control of heart rate in rats.

B1 receptors are inducible receptors expressed only in stressful conditions. The aim of this study was to determine if, in (mREN2)27 transgenic rats, hypertension is associated with the presence of B1 receptors in the cardiovascular system and if a heat stress inducible effect is preserved during hypertension. Age-matched (16 weeks old) heterozygous hypertensive transgenic (mREN2)27 rats (HT rats) and the normotensive control animals (homozygous Sprague-Dawley rats, NT rats) were used. The study was conducted in two parts: in the first part the responsiveness of B1 receptors was studied in rats submitted to heat stress (42 degrees C rectal temperature, 20 min) or sham anaesthesia 24 h before, by recording changes in isometric tension in aortic rings in response to [des-Arg9]-bradykinin, a B1 receptor agonist. In the second part, we studied whether B1 receptor mRNA was present in aorta, heart and kidneys, using a semi-quantitative RT-PCR technique. [des-Arg9]-Bradykinin induced a concentration-dependent relaxation of aortic rings only from animals submitted to prior heat stress. This response was significantly higher in aortic rings from heat stressed HT rats than from heat stressed NT ones. B1 receptor mRNA was undetectable in organs from rats not submitted to heat stress but they were present 5 h after heat stress in aorta, heart and kidneys from both NT and HT rats. In conclusion, arterial hypertension observed in (mREN2)27 rats is not associated with the presence of B1 receptors. However, after heat stress, we observed an increase in responsiveness from HT rat aortas compared to NT ones.

Objective: Heat stress (HS) is known to confer protection against ischaemia-reperfusion injury, including mechanical dysfunction and myocardial necrosis. However, the effects of disease states on this HS-induced cytoprotective response are less known. Therefore, we investigated the effects of prior heat stress on the infarct size in the isolated rat heart and on the myocardial heat stress protein (HSP) 72 synthesis, in transgenic [(mREN-2)27] hypertensive (TGH) rats or normotensive (NT) controls., Methods: TGH or NT rats were either heat stressed (42 degrees C for 15 min) or sham anaesthetised. After 24 h, their hearts were isolated, perfused using the Langengorff technique, and subjected to a 35-min occlusion of the left coronary artery followed by 120 min of reperfusion. Myocardial HSP72 content was measured 24 h after HS or sham treatment using electrophoresis coupled with Western blot analysis., Results: Infarct-to-risk (I/R) ratio was significantly reduced in HS (15.5 +/- 1.2%) compared to sham (42.2 +/- 2.1%) hearts of NT rats. This reduction in infarct size was maintained in TGH hearts (I/R: 20.0 +/- 1.0 vs. 48.0 +/- 3.8%). Risk zones were similar between all experimental groups. The incidence of ventricular arrhythmias during ischaemia and reperfusion periods was not different between the four experimental groups. Western blot analysis of the myocardial HSP72 content showed a heat stress-induced increase of this protein, in both TGH and NT animals., Conclusion: These results demonstrate that the myocardial protective effect induced by heat stress could extend to a pathological animal model like the transgenic [(mREN-2)27] hypertensive rat and is correlated with a myocardial HSP72 induction.

It has been shown in various mammal species that clonidine, a well known centrally acting hypotensive agent, acts through the activation of imidazoline receptors (IRs) in the nucleus reticularis lateralis (NRL) of the brainstem. Specific binding sites sensitive to imidazolines and insensitive to catecholamines have been detected in rat and bovine, as well as human brains. An endogenous ligand, other than catecholamines, should exist for these IRs. Such a ligand could play a role in the pathophysiology of human essential hypertension. Therefore, we developed two RIAs with polyclonal and monoclonal anticlonidine antibodies. These antibodies presented specificity spectra similar to that of the IRs: they bound imidazolines and not catecholamines at all. These RIAs were used to detect imidazoline-like immunoreactivity in the human serum. Immunoreactive substance was measured in 26 normotensive subjects' sera, and specificity of interaction between antibodies and sera was verified. None of the known endogenous substances tested so far were able to interact with the two antibodies. Immunoreactivity in 32 essential hypertensive patients' sera proved higher in approximately 30% of cases. Values of immunoreactivity positively correlated with the mean arterial pressure values. This study demonstrates the existence of an "imidazoline-like" immunoreactive substance in the human serum with high levels in some hypertensive patients.

Studies of the central hypotensive mode of action of the imidazolines of which clonidine is the leading molecule suggest the presence of non-catecholamine binding sites called imidazoline receptors. Our group showed that neither the endogenic ligand of alpha-adrenergic receptors, noradrenaline, nor any other tested catecholamine or phenylethylamine have hypotensive effects at the site of action of all imidazolines, the lateral reticular nucleus of the brainstem. In addition, a population of membrane binding sites which take up labelled clonidine and which are insensitive to noradrenaline have been demonstrated in the lateral reticular nucleus. An endogenic non-catecholamine substance whose structure is currently under identification and which is recognised by these receptors has been isolated from the brain tissues of various mammals. All this experimental evidence supports the hypothesis that the hypotensive effects of imidazoline-like substances are related to their action on brainstem receptors specific to this endogenic ligand which we propose to call endazoline. Rilmenidine, which has a chemical structure similar to that of the imidazolines, has a higher relative selectivity for the imidazoline binding sites than the reference molecule (clonidine). A central antihypertensive agent without the classical sedative effects associated with this class of drug could result. A study of the structure-activity relationship is needed to confirm this hypothesis.

Aim: We report the first experience of Lyon's university hospital regarding renal denervation to treat patients with resistant essential hypertension. Patients and methods: Over a one-year period, 17 patients were treated (12 men, 5 women) with renal denervation. Baseline characteristics were as follows: age 56.5 ± 11.5 years, BMI 33 ± 5 kg/m² and ambulatory blood pressure 157 ± 16/87 ± 13 mmHg with 4.2 ± 1.5 anti-hypertensive treatment. Results: We did not observe per procedural and early complications. After a median follow-up of 3 months and with the same anti-hypertensive treatment, office systolic blood pressure (SBP) and diastolic blood pressure (DBP) decrease respectively of 20 ± 15 (P < 0.001) and 10 ± 13 mmHg (P = 0.014) (n = 17). After six months of follow-up, ambulatory blood pressure (ABPM) decrease of 17.5 ± 14.9 mmHg (P = 0.027) for SBP and of 10.5 ± 9.6 mmHg (P = 0.029) for DBP (n = 6). Among these patients, five of them were controlled (ABPM inferior to 130/80 mmHg) and electrical left ventricular hypertrophy indexes decreased: R wave in aVL lead of 4 ± 3 mm (P = 0.031), Sokolow index of 3 ± 3 mm (P = 0.205), Cornell voltage criterion of 9 ± 7 mm (P = 0.027) and Cornell product of 1310 ± 1104 (P = 0.027). Conclusion: Our results are in accordance with data from other centers. On average blood pressure decreases significantly but important inter individual variations are observed. The procedure seems safe. [ABSTRACT FROM AUTHOR]