Percutaneous renal denervation for the treatment of resistant essential hypertension; the first Dutch experience

Background

In a subpopulation of patients with essential hypertension, therapeutic targets are not met, despite the use of multiple types of medication. In this paper we describe our first experience with a novel percutaneous treatment modality using renal artery radiofrequency (RF) ablation.

Methods

Patients who were resistant to at least three types of antihypertensive medical therapy (office systolic blood pressure?≥?160 mmHg; n?=?9) or who did not tolerate medication (n?=?2) were selected. Between July and November 2010, a total of 11 patients received percutaneous RF treatment. Patients were followed up for 1 month after treatment. Urine and blood samples were taken to evaluate the effects on renal function and neurohumeral factors.

Results

No periprocedural complications or adverse events during follow-up were noted. A reduction of mean office blood pressure was seen from 203/109?±?32/19 mmHg at baseline to 178/97?±?28/21 mmHg at 1 month follow-up (mean difference 25?±?12 mmHg, p?<?0.01). Also, we noted a significant decrease in aldosterone level (391?±?210 pmol/L versus 250?±?142 pmol/L; p?=?0.03), while there was no decrease in plasma renin activity (190?±?134 fmol/L/s versus 195?±?163 fmol/L/s; p?=?0.43). No change in renal function was noted.

Conclusion

Catheter-based renal denervation seems an attractive novel minimally invasive treatment option in patients with resistant hypertension, with a low risk of serious adverse events.     

Redox proteomics identification of oxidatively modified myocardial proteins in human heart failure: implications for protein function

Increased oxidative stress in a failing heart may contribute to the pathogenesis of heart failure (HF). The aim of this study was to identify the oxidised proteins in the myocardium of HF patients and analyse the consequences of oxidation on protein function. The carbonylated proteins in left ventricular tissue from failing (n?=?14) and non-failing human hearts (n?=?13) were measured by immunoassay and identified by proteomics. HL-1 cardiomyocytes were incubated in the presence of stimuli relevant for HF in order to assess the generation of reactive oxygen species (ROS), the induction of protein carbonylation, and its consequences on protein function. The levels of carbonylated proteins were significantly higher in the HF patients than in the controls (p<0.01). We identified two proteins that mainly underwent carbonylation: M-type creatine kinase (M-CK), whose activity is impaired, and, to a lesser extent, α-cardiac actin. Exposure of cardiomyocytes to angiotensin II and norepinephrine led to ROS generation and M-CK carbonylation with loss of its enzymatic activity. Our findings indicate that protein carbonylation is increased in the myocardium during HF and that these oxidative changes may help to explain the decreased CK activity and consequent defects in energy metabolism observed in HF.     

Biochemical effects of supplemented long-chain polyunsaturated fatty acids in hyperphenylalaninemia

Hyperphenylalaninemic (HPA) children display low levels of long-chain polyunsaturated fatty acids (LCPUFA), particularly docosahexaenoic acid (DHA), in circulating lipids and erythrocytes. We have investigated the effects on the blood fatty acid status and lipid picture of a balanced supplementation with LCPUFA in HPA children through a double-blind, placebo-controlled trial. A total of 20 well-controlled HPA, school-age children were randomized to receive through a 12-month trial fat capsules supplying either 26% fatty acid as LCPUFA (including 4.6%gamma -linolenic acid, 7.4% arachidonic acid, AA, 5.5% eicosapentaenoic acid and 8% DHA) or placebo (olive oil). The study supplementation was administered in order to provide 0.3-0.5% of the individual daily energy requirements as LCPUFA. Reference data were obtained from healthy children of comparable age. Among HPA children (whose DHA status was poor at baseline), those supplemented with LCPUFA showed an increase of around 100% in the baseline DHA levels in plasma phospholipids and erythrocytes. No changes of AA levels were observed. Blood lipid levels did not significantly change. A balanced supplementation with LCPUFA in treated HPA children may improve the DHA status without adversely affecting the AA status.     

The yeast kinase Swe1 is required for proper entry into cell cycle after arrest due to ribosome biogenesis and protein synthesis defects

Sda1 is an essential protein required for cell cycle progression in Saccharomyces cerevisiae. Here, we show that the sda1-1 mutation causes a defect in the formation and nuclear export of 60S ribosomal subunits. Moreover, the sda1-1, but also other mutants defective in ribosome biogenesis (e.g., rix1-1 and tif6Delta), exhibit a G1 arrest, which could be the consequence of impaired ribosome biogenesis. Interestingly, additional deletion of the non-essential Swe1 kinase, the homolog of S. pombe Wee1, causes a pronounced delay in entering a new cell cycle in sda1-1, rix1-1 and tif6Delta cells, when shifted back from restrictive to permissive conditions. However, such a prolonged delay is independent of the Tyr19 phosphorylation in Cdc28. Moreover, the lack of Swe1 causes delay in budding and DNA replication in cells released from the G1 arrest due to the block of protein synthesis. Our data suggest that Swe1 is required for timely entry into cell cycle after a G1 arrest caused by impairment in pre-60S biogenesis and in protein synthesis. Therefore we propose that Swe1, which is required for coordination of cell growth and cell division in G2/M, also has a role in the beginning of the cell cycle.     

Apolipoprotein B gene polymorphism and plasma lipid levels in phenylketonuric children

The associations of apolipoprotein B (apoB) gene polymorphisms with blood lipid levels, also accounting for apo E polymorphisms, were assessed in 82 phenylketonuric (PKU) children on diet (34 girls, 48 boys, age 4-12 years, median 8 years). Dietary and plasma biochemical assessments were performed at six-month intervals from the age of 24 months onwards. Apo B (XbaI, MspI, EcoRI restriction sites) and apo E (E2, E3, E4) gene polymorphisms were determined by restriction-enzyme analysis after DNA extraction from blood. Subgroups of apoB polymorphisms were similar for energy intake, dietary lipids and distribution of apo E polymorphisms. Children carrying XbaI X+ / X+ showed higher plasma levels of LDL cholesterol than children carrying X- / X-/+. This gene-related response to dietary habits might play a role also in non-PKU individuals fed low-fat, low-cholesterol diets.     

Valine 114 replacements in archaeal elongation factor 1 alpha enhanced its ability to interact with aminoacyl-tRNA and kirromycin

Valine 114 in the D(109)AAILVVA sequence of elongation factor 1alpha from the archaeon Sulfolobus solfataricus (SsEF-1alpha) was substituted with an acidic (V114E), basic (V114K), or cavity-forming (V114A) residue, and the effects on the biochemical properties of the factor were investigated. This sequence is well-conserved among most of eukaryal and eubacterial counterparts, and in the three-dimensional structure of SsEF-1alpha, V114 is located in a hydrophobic pocket near the first GDP-binding consensus sequence G(13)XXXXGK[T,S] [Vitagliano, L., Masullo, M., Sica, F., Zagari, A., and Bocchini, V. (2001) EMBO J. 20, 5305-5311]. These mutants displayed functions absent in the wild-type factor. In fact, although they exhibited a rate in poly(Phe) incorporation almost identical to that of SsEF-1alpha, V114K and V114A exhibited an affinity for GDP and GTP higher and a capability to bind heterologous aa-tRNA stronger than that elicited by SsEF-1alpha but similar to that of eubacterial EF-Tu. V114E instead displayed not only a weaker binding capability for aa-tRNA but also a lower affinity for GDP. The intrinsic GTPase activity of V114E was drastically reduced compared to those of SsEF-1alpha, V114K, and V114A. Interestingly, the decreased intrinsic GTPase activity of V114E was partially restored by kirromycin, an effect already observed for the G13A mutant of SsEF-1alpha [Masullo, M., Cantiello, P., de Paola, B., Catanzano, F., Arcari, P., and Bocchini, V. (2002) Biochemistry 41, 628-633]. Finally, the V114A substitution showed only a marginal effect on both the thermostability and thermophilicity of SsEF-1alpha, whereas V114K and V114E replacements strongly destabilized the molecule.     

CO binding to hemoglobin and myoglobin in equilibrium with a gas phase of low PO2 value

The aim of this paper was to measure the binding of CO to myoglobin and hemoglobin at various PO2 values. For this purpose we have studied an "in vitro" system made up of solutions of hemoglobin and myoglobin equilibrated in two connected tonometers with the same gas phase of various PO2 and PCO. The results indicate that a significant proportion of CO is released by hemoglobin and binds myoglobin at low PO2 values (approximately 2-3 Torr), in qualitative agreement with the predictions of a previous computer simulation of the "in vivo" system.