M. Toelle

Renal Denervation for Refractory Hypertension – Technical Aspects, Complications and Radiation Exposure

PURPOSE To analyze procedural details, complications and radiation exposure in renal denervation (RDN) using the Medtronic Symplicity® device in the treatment of refractory hypertension. MATERIALS AND METHODS Fifty three consecutive patients underwent RDN. The number of ablations per artery, peri-procedural complications, procedure time (PT), fluoroscopy time (FT), dose-area product (DAP) and procedure-related complications were documented. Additionally, the radiation dose was compared between obese (body mass index ≥ 30 kg/m(2)) and non-obese patients. RESULTS Bilateral RDN was performed in 50/53 (94 %) cases and with a minimum of 4 ablations per artery in 33/50 (66 %), the mean count being 5.4 (range R: 2 - 13) on the right and 4.3 (R: 1 - 10) on the left. The FT and DAP decreased significantly over the first 12 procedures, reaching a steady state with a median FT of 11.2 min (R: 7.5 - 27) and a median DAP of 4796 cGy × cm(2) (R: 1076 - 21 371), resulting in an effective dose of 15.7 mSv. The median PT was 57 min (R: 40 - 70). Obese patients had a 3.3-fold higher radiation dose (p < 0.001). We observed one severe spasm and one imminent respiratory depression, both resolved without sequelae. CONCLUSION For an experienced interventionalist, RDN has a short learning curve with a low risk profile. The radiation dose does not exceed that of other renal artery interventions, but is explicitly higher in obese patients, who account for a large portion of patients with refractory hypertension.

A highly sensitive method for quantification of iohexol

Iohexol (1-N,3-N-bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl) acetamide-2,4,6-triiodobenzene-1,3-dicarboxamide) is used for accurate determination of the glomerular filtration rate (GFR) in chronic kidney disease (CKD) patients. However, high iohexol amounts might lead to adverse effects in organisms. In order to minimize the iohexol dosage required for the GFR determination in humans, the development of a sensitive quantification method is essential. Therefore, the objective of our preclinical study was to establish and validate a simple and robust liquid-chromatography-electrospray-mass-spectrometry (LC-ESI-MS) approach using the multiple reaction monitoring mode for iohexol quantification. In order to test whether a significantly decreased amount of iohexol is sufficient for reliable quantification, a LC-ESI-MS approach was assessed. We analyzed the kinetics of iohexol in rats after application of different amounts of iohexol (15 mg to 150 μg per rat). Blood sampling was conducted at four time points, at 15, 30, 60, and 90 min, after iohexol injection. The analyte (iohexol) and the internal standard (iothalamic acid) were separated from serum proteins using a centrifugal filtration device with a cut-off of 3 kDa. The chromatographic separation was achieved on an analytical Zorbax SB C18 column. The detection and quantification were performed on a high capacity trap mass spectrometer using positive ion ESI in the multiple reaction monitoring (MRM) mode. Furthermore, using real-time polymerase chain reaction (RTPCR) the effect of iohexol on early regulated gene expression in thyroid and renal cortex was tested to determine a threshold of physiological active iohexol concentrations. A linear correlation of the iohexol amount and mass-signal (MS) intensity was found in the range of 50 pg to 40 ng (r2 = 0.998). The lowest limit of quantification (LLOQ) was 50 pg. The intra- and inter-day accuracies were between 91.2% and 98.7%. The intra- and inter-day precisions were between 2.7% and 9.2%. The recovery rate of iohexol was determined in the range of 100.8 ± 10.9%. The gene expression test revealed that iohexol dosages exceeding 0.5 mg kg−1 induce a group of genes in thyroidal tissue that comprises transcription factors and genes of cellular stress response. Namely, Ptgs2, Smad7, Jun, Srf, Dusp1, Timp1 and others are up-regulated within 15 min after iohexol i.v. application. This mass-spectrometry based method has been proved to be sensitive, selective and suitable for the quantification of iohexol in serum. Due to high sensitivity of this novel method the iohexol application dose as well as the sampling time in the clinical routine could be reduced in the future in order to further minimize side effects in humans.

Beta Trace Protein does not outperform Creatinine and Cystatin C in estimating Glomerular Filtration Rate in Older Adults

Despite intense research the optimal endogenous biomarker for glomerular filtration rate (GFR) estimation has not been identified yet. We analyzed if ß-trace protein (BTP) improved GFR estimation in elderly. 566 participants aged 70+ from the population-based Berlin Initiative Study were included in a cross-sectional validation study. BTP, standardized creatinine and cystatin C were measured in participants with iohexol clearance measurement as gold standard method for measured GFR (mGFR). In a double logarithmic linear model prediction of mGFR by BTP was assessed. Analyses with BTP only and combined with creatinine and cystatin C were performed. Additionally, performance of GFR estimating equations was compared to mGFR. We found that the combination of all three biomarkers showed the best prediction of mGFR (r2 = 0.83), whereat the combination of creatinine and cystatin C provided only minimally diverging results (r2 = 0.82). Single usage of BTP showed worst prediction (r2 = 0.67) within models with only one biomarker. Subgroup analyses (arterial hypertension, diabetes, body mass index ≤23 and >30) demonstrated a slight additional benefit of including BTP into the prediction model for diabetic, hypertensive and lean patients. Among BTP-containing GFR equations the Inker BTP-based equation showed superior performance. Especially the use of cystatin C renders the addition of BTP unnecessary.

[PP.27.08] UTILISATION OF THE ARTERIAL STIFFNESS ASSESSMENT IN THE EVERYDAY CLINICAL PRACTICE

Objective: There is emerging evidence pointing out the arterial stiffness (AS) as an important independent predictor of cardiovascular events. Carotid-femoral pulse wave velocity (cfPWV) is a best-established surrogate parameter for assessment of AS. Measurement of cfPWV is considered to be gold standard for evaluating AS. Though it has been widely used in clinical and observational studies, its utilisation in the everyday clinical practice is scarce due to technical challenges and procedural pitfalls of the available non-invasive assessment techniques. Emerging oscillometric techniques seem to simplify assessment procedure. We thus aimed to evaluate the accuracy of performance and reproducibility with a new oscillometric device Tel-O-GRAPH® for measurement of PWV. Design and method: 89 patients were prospectively included in the study. Oscillometric calculation of cfPWV was performed with Tel-O-GRAPH® (I.E.M., Stolberg, Germany) and tonometric calculation with Sphygmocor® (AtCor Medical, West Ryde, NSW, Australia). The accuracy assessment was performed according to the requirements of ARTERY Society. Coefficients of variation and intraclass correlation coefficients were used to evaluate the reproducibility. Results: Mean study population age was 48.8 ± 19.1 years. 59.6% of the patients were male and 15.1% were smoker. The mean PWV measured with Tel-O-GRAPH® was 7.8 ± 2.3 m/s, the mean PWV measured with Sphygmocor® was 7.3 ± 1.7 m/s. The mean difference of PWV between devices was 0.49 ± 1.26 m/s (p < 0.0001) and Pearson correlation index was 0.86 (p < 0.0001). The coefficient of variation and intraclass correlation coefficients between single measured PWV values with Tel-O-GRAPH® and Sphygmocor® were 2.38 ± 6.13% vs. 6.3 ± 4.33% (p < 0.05) and 0.99;0.99;0.99 vs. 0,78;0.84;0.71 respectively. Conclusions: We observed that oscillometric calculation of cfPWV with Tel-O-GRAPH® can be done quickly and easy, with very high reproducibility of the values and adequate measurement accuracy compared to Sphygmocor®. Reported data suggest that oscillometry might evolve to a favoured method for assessment of the PWV in the everyday clinical practice and clinical studies due to its easiness of performance with concurrently remained reliability and accuracy.

INCREASED URIDINE ADENOSINE TETRAPHOSPHATE CONCENTRATIONS CAUSE INCREASED PROLIFERATION RATES OF IMT AND CORRELATE WITH BLOOD PRESSURE: PP.29.154

Background: Uridine adenosine tetraphosphate (Up4A) was been recently characterized as a potent vasoconstrictor. Up4A occurs in plasma from healthy subjects at concentrations suffi-cient to cause strong vasoconstrictive effects. In this study, Up4A concentrations in plasma from juvenile hypertensives and normotensives were determined. Methods: Up4A was purified to homogeneity by preparative reverse phase high performance liquid-chromatography (HPLC), affinity HPLC and analytic reverse phase HPLC from depro-teinized plasma of juvenile hypertensives and normotensives. Results and Discussion: Mean total plasma Up4A concentration was significantly increased in juvenile hypertensives compared to juvenile normotensives (33.0±25.4 vs. 3.7±0.9 nmol/L; mean±SEM, n = 40 and 38; respectively, p < 0.005). Accordingly, Up4A showed a significant association with juvenile hypertension (OR for ln(Up4A): 1.82; 95% CI 1.12, 2.95). Plasma Up4A concentrations correlated with left ventricular mass (Kendall-tau correlation coefficient 0.220, n = 40; p < 0.05) and intima media wall thickness (Kendall-tau correlation coefficient 0.296, n = 40; p < 0.05) in the hypertensives. Since the increased intima media thickness may be related to proliferative effects of Up4A, we studied the effects of Up4A on human vascular smooth muscle cell (VSMC) proliferation. The maximum proliferative effect of Up4A was 83.7±18.0% above control (p < 0.01). Conclusion: Circulating levels of Up4A are strongly associated with juvenile hypertension. The endothelium-derived vasoconstrictor Up4A may contribute to the early development of primary hypertension and is moreover an important risk factor of juvenile hypertension.