Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension.

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and high-Na+ diets, conditional KO mice displayed decreased plasma aldosterone but normal Na+/K+ balance. Under a high-Na+ diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K+ channel (ROMK), and total and phosphorylated thiazide-sensitive Na+Cl- cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na+/K+ balance maintained by downregulation of ENaC activity and upregulation of ROMK.

Genetic dissection of sodium and potassium transport along the aldosterone-sensitive distal nephron: Importance in the control of blood pressure and hypertension.

In this review, we discuss genetic evidence supporting Guyton's hypothesis stating that blood pressure control is critically depending on fluid handling by the kidney. The review is focused on the genetic dissection of sodium and potassium transport in the distal nephron and the collecting duct that are the most important sites for the control of sodium and potassium balance by aldosterone and angiotensin II. Thanks to the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, three main classes of diuretic receptors (furosemide, thiazide, amiloride) and the main components of the aldosterone- and angiotensin-dependent signaling pathways were molecularly identified over the past 20years. This will allow to design rational strategies for the treatment of hypertension and for the development of the next generation of diuretics.

Therapy modifications in response to poorly controlled hypertension, dyslipidemia, and diabetes mellitus.

BACKGROUND: Poorly controlled cardiovascular risk factors are common. Evaluating whether physicians respond appropriately to poor risk factor control in patients may better reflect quality of care than measuring proportions of patients whose conditions are controlled. OBJECTIVES: To evaluate therapy modifications in response to poor control of hypertension, dyslipidemia, or diabetes in a large clinical population. DESIGN: Retrospective cohort study within an 18-month period in 2002 to 2003. SETTING: Kaiser Permanente of Northern California. PATIENTS: 253,238 adult members with poor control of 1 or more of these conditions. MEASUREMENTS: The authors assessed the proportion of patients with poor control who experienced a change in pharmacotherapy within 6 months, and they defined "appropriate care" as a therapy modification or return to control without therapy modification within 6 months. RESULTS: A total of 64% of patients experienced modifications in therapy for poorly controlled systolic blood pressure, 71% for poorly controlled diastolic blood pressure, 56% for poorly controlled low-density lipoprotein cholesterol level, and 66% for poorly controlled hemoglobin A1c level. Most frequent modifications were increases in number of drug classes (from 70% to 84%) and increased dosage (from 15% to 40%). An additional 7% to 11% of those with poorly controlled blood pressure, but only 3% to 4% of those with elevated low-density lipoprotein cholesterol level or hemoglobin A1c level, returned to control without therapy modification. Patients with more than 1 of the 3 conditions, higher baseline values, and target organ damage were more likely to receive "appropriate care." LIMITATIONS: Patient preferences and suboptimal adherence to therapy were not measured and may explain some failures to act. CONCLUSIONS: As an additional measure of the quality of care, measuring therapy modifications in response to poor control in a large population is feasible. Many patients with poorly controlled hypertension, dyslipidemia, or diabetes had their therapy modified and, thus, seemed to receive clinically "appropriate care" with this new quality measure.

16q24.1 microdeletion in a premature newborn: Usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn.

OBJECTIVE:: Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. DESIGN:: Descriptive case report. SETTING:: Genetic department and neonatal intensive care unit of a tertiary care children's hospital. INTERVENTIONS:: None. PATIENT:: We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. MEASUREMENTS AND MAIN RESULTS:: An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. CONCLUSIONS:: Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.

Blood pressure and LDL-cholesterol targets for prevention of recurrent strokes and cognitive decline in the hypertensive patient: design of the European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment randomized trial.

BACKGROUND AND OBJECTIVES: The SBP values to be achieved by antihypertensive therapy in order to maximize reduction of cardiovascular outcomes are unknown; neither is it clear whether in patients with a previous cardiovascular event, the optimal values are lower than in the low-to-moderate risk hypertensive patients, or a more cautious blood pressure (BP) reduction should be obtained. Because of the uncertainty whether 'the lower the better' or the 'J-curve' hypothesis is correct, the European Society of Hypertension and the Chinese Hypertension League have promoted a randomized trial comparing antihypertensive treatment strategies aiming at three different SBP targets in hypertensive patients with a recent stroke or transient ischaemic attack. As the optimal level of low-density lipoprotein cholesterol (LDL-C) level is also unknown in these patients, LDL-C-lowering has been included in the design. PROTOCOL DESIGN: The European Society of Hypertension-Chinese Hypertension League Stroke in Hypertension Optimal Treatment trial is a prospective multinational, randomized trial with a 3 × 2 factorial design comparing: three different SBP targets (1, <145-135; 2, <135-125; 3, <125 mmHg); two different LDL-C targets (target A, 2.8-1.8; target B, <1.8 mmol/l). The trial is to be conducted on 7500 patients aged at least 65 years (2500 in Europe, 5000 in China) with hypertension and a stroke or transient ischaemic attack 1-6 months before randomization. Antihypertensive and statin treatments will be initiated or modified using suitable registered agents chosen by the investigators, in order to maintain patients within the randomized SBP and LDL-C windows. All patients will be followed up every 3 months for BP and every 6 months for LDL-C. Ambulatory BP will be measured yearly. OUTCOMES: Primary outcome is time to stroke (fatal and non-fatal). Important secondary outcomes are: time to first major cardiovascular event; cognitive decline (Montreal Cognitive Assessment) and dementia. All major outcomes will be adjudicated by committees blind to randomized allocation. A Data and Safety Monitoring Board has open access to data and can recommend trial interruption for safety. SAMPLE SIZE CALCULATION: It has been calculated that 925 patients would reach the primary outcome after a mean 4-year follow-up, and this should provide at least 80% power to detect a 25% stroke difference between SBP targets and a 20% difference between LDL-C targets.

Transposition of great arteries and single coronary artery: a new surgical technique for the arterial switch operation.

A single coronary artery can complicate the surgical technique of arterial switch operations, impairing early and late outcomes. We propose a new surgical approach, successfully applied in a 2.1 kg neonate, aimed at reducing the risk of early and late compression and/or distortion of the newly constructed coronary artery system.

3B.01: Performance of targeted screening for the identification of hypertension in children

OBJECTIVE: As universal screening of hypertension performs poorly in childhood, targeted screening to children at higher risk of hypertension has been proposed. Our goal was to assess the performance of combined parental history of hypertension and overweight/obesity to identify children with hypertension. We estimated the sensitivity, specificity, negative and positive predictive values of overweight/obesity and parental history of hypertension for the identification of hypertension in children. DESIGN AND METHOD: We analyzed data from a school-based cross-sectional study including 5207 children aged 10 to 14 years from all public 6th grade classes in the canton of Vaud, Switzerland. Blood pressure was measured with a clinically validated oscillometric automated device over up to three visits separated by one week. Children had hypertension if they had sustained elevated blood pressure over the three visits. Parents were interviewed about their history of hypertension. RESULTS: The prevalence of hypertension was 2.2%. 14% of children were overweight or obese and 20% had a positive history of hypertension in either or both parents. 30% of children had either or both conditions. After accounting for several potential confounding factors, parental history of hypertension (odds ratio (OR): 2.6; 95% confidence interval (CI): 1.8-4.0), overweight excluding obesity (OR: 2.5; 95% CI: 1.5-4.2) and obesity (OR: 10.1; 95% CI: 6.0-17.0) were associated with hypertension in children. Considered in isolation, the sensitivity and positive predictive values of parental history of hypertension (respectively 41% and 5%) or overweight/obesity (respectively 43% and 7%) were relatively low. Nevertheless, considered together, the sensitivity of targeted screening in children with either overweight/obesity or paternal history of hypertension was higher (65%) but the positive predictive value remained low (5%). The negative predictive value was systematically high. CONCLUSIONS: Restricting screening of hypertension to children with either overweight/obesity or with hypertensive parents would substantially limit the proportion of children to screen (30%) and allow the identification of a relatively large proportion (65%) of hypertensive cases. That could be a valuable alternative to universal screening.