N-terminal pro-brain natriuretic peptide: a powerful predictor of mortality in hypertension.

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.

Quantification of ventricular resynchronization reserve by radionuclide phase analysis in heart failure patients: a prospective long-term study.

BACKGROUND: Phase analysis, developed to assess dyssynchrony from ECG-gated radionuclide ventriculography, has shown promising results. We hypothesized that quantifying the cardiac resynchronization reserve, that is, the extent of response to cardiac resynchronization therapy (CRT), by radionuclide imaging could potentially identify patients who are best suited for CRT. METHODS AND RESULTS: Seventy-four patients ages 64.8±10.1 years were prospectively studied from July 2004 to July 2006, of whom 62.2% and 37.8%, respectively, were in New York Heart Association class 3 and 4. Mean QRS width was 173±25 ms. ECG-gated radionuclide ventriculography to quantify interventricular and intraventricular dyssynchrony was performed at baseline with and without CRT and at the 3-month follow-up visit. Amino-terminal-pro-brain natriuretic peptide (NT-pro-BNP) levels were also determined at baseline and at 3 months. During a mean follow-up of 10.1±7.6 months, there were 37 (50%) clinical events that defined the nonresponder group, including cardiac death or readmission for worsening heart failure. In multivariate Cox model analysis, higher NT-pro-BNP blood levels were associated with a significant increase in the risk for event (hazard ratio=1.085 for a 100 pg/L increase in NT-pro-BNP; 95% confidence interval, 1.014 to 1.161). Each 10° elevation in intraventricular dyssynchrony was associated with a decrease in the risk of events (hazard ratio=0.456, 95% confidence interval, 0.304 to 0.683). Receiver operating characteristic curve analysis demonstrated that an interventricular dyssynchrony cutoff value of 25.5° for intraventricular synchrony yielded 91.4% sensitivity and 84.4% specificity for predicting a good response to CRT. CONCLUSIONS: The quantification of interventricular dyssynchrony with radionuclide phase analysis suggests that early postimplantation interventricular dyssynchrony may provide identification of CRT responders.

N-terminal pro-brain natriuretic peptide--a promising biomarker for the diagnosis of left ventricular hypertrophy in hypertensive women.

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.

Insulin resistance and plasma triglyceride level are differently related to cardiac hypertrophy and arterial stiffening in hypertensive subjects.

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.

Significance of urinary angiotensinogen in essential hypertension as a function of plasma renin and aldosterone status.

OBJECTIVE: This study was performed to test the significance of urinary angiotensinogen (UAGT) in essential hypertensive patients stratified as a function of plasma renin and aldosterone. METHODS AND RESULTS: A sample of 248 essential hypertensives, investigated under their usual sodium diet and either off-medication or under a standardized treatment, was separated into two groups on the basis of upright plasma active renin and aldosterone medians. Patients with plasma active renin and aldosterone below medians are referred to as the low renin-aldosterone essential hypertensive group (LRA-EH). Others subjects are defined as other essential hypertensives (O-EH). Blood pressure (BP) was recorded by 24-h ambulatory monitoring. UAGT was measured by a specific enzyme-linked immunosorbent assay for total angiotensinogen. Because UAGT was markedly increased in the presence of overt proteinuria (>/= 300 mg/24 h), proteinuric patients (n = 29) were excluded from subsequent analyses. UAGT was a significant predictor of systolic and diastolic BP in LRA-EH females (P < 0.01 and P = 0.05, respectively) but not in males. By contrast, urinary sodium excretion (P < 0.001) and maintenance of treatment (P = 0.002) were significant predictors of systolic BP in males. These correlations were not observed in O-EH, whether males or females. CONCLUSIONS: In the present study, UAGT stands as a strong predictor of BP in women with low plasma renin/aldosterone, suggesting an involvement of the tubular renin-angiotensin system in these subjects. Higher sodium intake or the need to maintain treatment may account in part for the lack of a similar relationship in males.

[Renin-secreting tumour: about a new diagnosed case during pregnancy]. / Tumeur à rénine. A propos d'un nouveau cas diagnostiqué au cours d'une grossesse.

A 29 year-old female patient developed severe arterial hypertension in the beginning of her second pregnancy. Investigations performed at 16 weeks of amenorrhea showed hypokaliemia in relation to severe hyperreninism: plasma active renin was 25 fold normal value, 94% as prorenin (prorenin representing 94% of total renin). Radiological investigations including ultrasonography and MRI disclosed an homogenous and avascular tumor in the right kidney. Its ablation confirmed renin tumor, and allowed recovery from HTA and continuation of pregnancy. This is the 75th reported case in the literature, enabling to make a new statement about diagnostic and therapeutic procedures, which are modified during pregnancy by contra-indication to X-rays and renin-angiotensin-aldosteron axis inhibitors.

A1166C polymorphism of angiotensin II type 1 receptor, blood pressure and arterial stiffness in hypertension.

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.

Mapping the genetic determinants of hypertension, metabolic diseases, and related phenotypes in the lyon hypertensive rat.

The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat.

Ischemia induces early expression of a new transcription factor (6A3-5) in kidney vascular smooth muscle cells: studies in rat and human renal pathology.

Acute renal failure, characterized by rapid decline in glomerular filtration rate, is a major cause of morbidity and mortality. During the evolution of renal diseases chronic ischemia develops. Indeed, acute or chronic renal failure may occur as a result of renal ischemia, which induces cells to dedifferentiate, proliferate, or become apoptotic. In this study, we have investigated the expression of a newly identified transcription factor, 6A3-5, under in vitro and in vivo conditions. Proliferating vascular smooth muscle were investigated in response to different mitogenic agents. The 6A3-5 expression was then studied in ischemic rat kidney, induced by renal pedicle clamping, followed, or not, by reperfusion. Subsequently human renal biopsies from early kidney grafts and chronic renal diseases were also investigated for 6A3-5 protein expression by immunohistochemistry. In vitro study shows an over-expression of 6A3-5 following 2 to 4 hours stimulation by serum or Angiotensin II, of rat proliferating aortic smooth muscle cell. Moreover, in vivo study shows that this new protein is over expressed in rat kidney submitted to 45 minutes ischemia. An anti-6A3-5 antibody shows the protein to be expressed in smooth muscle cells of the arterioles and intermediate size arteries, in mesangial cells and interstitial myofibroblasts. In human biopsies of early kidney grafts and renal disease, the same up-regulation of 6A3-5, as in acute ischemic situation, is observed. This 6A3-5 expression is intimately associated with alpha-smooth muscle cell actin expression in mesangial cells, arteriolar smooth muscle cells as well as interstitial myofibroblasts. Transcription factor 6A3-5 could potentially be a novel early vascular marker of acute and chronic renal ischemic stress implicated in tissue remodeling.

Delayed maturation of catecholamine phenotype in nucleus tractus solitarius of rats with glial angiotensinogen depletion.

Cerebral catecholamines and angiotensins are both involved in the regulation of cardiovascular function. Recent in vitro studies have suggested that angiotensin II modulates noradrenergic neurotransmission by controlling both the expression and neuritic trafficking of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. To assess the potential existence of such mechanisms in vivo, we compared TH phenotype ontogeny in the nucleus tractus solitarius (NTS), which is the first central relay of the baroreflex, between control Sprague-Dawley rats and TGR(ASrAOGEN) rats (TG) with glial specific angiotensinogen (AOGEN) depletion. TG displayed a delayed increase in both TH-mRNA and TH protein levels, which sharply rises in the NTS of control rats within the fourth week. The delayed maturation of TH phenotype also affected the presence of TH protein in the neuropil, not only within the NTS region but also within the ventrolateral medulla. This was evidenced by a large decrease in the density of TH-containing neuronal processes in TG at 4 weeks only, without noticeable modification of the labeling of the neuritic marker MAP2, suggesting that neuritic trafficking of TH protein was transiently altered. These results indicate that glial AOGEN is crucial to coordinate within the fourth week the mechanisms driving the maturation of NTS catecholaminergic neurons and suggest that impairment of the central angiotensinergic system early in development can lead to cardiovascular dysfunction related to altered maturation of catecholaminergic neurons located in both the dorsal and the ventrolateral medulla.

Analysis of the role of the SA gene in blood pressure regulation by gene targeting.

The SA gene is expressed in the proximal tubule of the kidney and may be involved in blood pressure (BP) regulation. However, direct evidence for this is lacking. We constructed and analyzed an SA-null mouse in which exons 2 and 3 of the SA gene (including the start codon) had been deleted by homologous recombination. Basal BP and BP changes in response to increased salt and to treatment with losartan were compared between mice homozygous for the targeted SA allele (SA-/- mice) and littermates carrying the wild-type allele (SA+/+ mice). Molecular and biochemical analysis confirmed the lack of SA gene product in SA-/- mice. SA-/- mice grew normally, were fertile, and had no overt phenotype. With both indirect and direct techniques, basal BP was similar in SA-/- and SA+/+ mice. A high salt diet for 4 weeks caused a significant increase in BP in SA-/- and SA+/+, mice but there was no difference between the 2 strains. Losartan caused a significant decrease in BP, but again the response was similar between SA-/- and SA+/+ mice, as were their kidney renin mRNA levels. SA is not involved in the regulation of either basal or salt related BP, and the lack of differential effect in SA-/- mice is not a consequence of compensatory activation of the renin-angiotensin system.