Christian D. Peters

Effects of phosphodiesterase-5 inhibition by sildenafil in the pressure overloaded right heart

Sustained pressure overload of the right ventricle (RV) causes RV hypertrophy and failure. Cyclic‐GMP has previously been shown to modulate left ventricular hypertrophy.

Increased Apical Targeting of Renal Epithelial Sodium Channel Subunits and Decreased Expression of Type 2 11β-Hydroxysteroid Dehydrogenase in Rats with CCl4-Induced Decompensated Liver Cirrhosis

It was hypothesized that dysregulation of renal epithelial sodium channel (ENaC) subunits and/or 11beta-hydroxysteroid dehydrogenase (11betaHSD2) may play a role in the increased sodium retention in liver cirrhosis (LC). Experimental LC was induced in rats by CCl(4) (1 ml/kg, intraperitoneally, twice a week) for 12 wk (protocol 1) or for 11 wk (protocol 2). In both protocols, one group of rats with cirrhosis showed significantly decreased urinary sodium excretion and urinary Na/K ratio (group A), whereas a second group exhibited normal urinary sodium excretion (group B) compared with controls, even though extensive ascites was seen in both groups of rats with cirrhosis. In group A, protein abundance of alpha-ENaC was unchanged, whereas beta-ENaC abundance was decreased in the cortex/outer stripe of outer medulla compared with controls. The gamma-ENaC underwent a complex change associated with increased abundance of the 70-kD band with a concomitant decrease in the main 85-kD band, corresponding to an aldosterone effect. In contrast, no changes in the abundance of ENaC subunit were observed in group B. Immunoperoxidase microscopy revealed an increased apical targeting of alpha-, beta-, and gamma-ENaC subunits in distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical and medullary collecting duct segments in group A but not in group B. Immunolabeling intensity of 11betaHSD2 in the DCT2, CNT, and cortical collecting duct was significantly reduced in group A but not in group B, and this was confirmed by immunoblotting. In conclusion, increased apical targeting of ENaC subunits combined with diminished abundance of 11betaHSD2 in the DCT2, CNT, and cortical collecting duct is likely to play a role in the sodium retaining stage of liver cirrhosis.

Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial

Background: Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP. Method: We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA). Results: We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 ± 12 mmHg (RDN) and 159 ± 14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [−6.2 ± 18.8 mmHg (RDN) vs. −6.0 ± 13.5 mmHg (SHAM)] and at 6 months [−6.1 ± 18.9 mmHg (RDN) vs. −4.3 ± 15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 ± 2.7 (RDN) vs. 7.0 ± 2.5 (SHAM)]. RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial. Conclusion: Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques.

No significant effect of angiotensin II receptor blockade on intermediate cardiovascular end points in hemodialysis patients

Agents blocking the renin-angiotensin-aldosterone system are frequently used in patients with end-stage renal disease, but whether they exert beneficial cardiovascular effects is unclear. Here the long-term effects of the angiotensin II receptor blocker, irbesartan, were studied in hemodialysis patients in a double-blind randomized placebo-controlled 1-year intervention trial using a predefined systolic blood pressure target of 140 mm Hg (SAFIR study). Each group of 41 patients did not differ in terms of age, blood pressure, comorbidity, antihypertensive treatment, dialysis parameters, and residual renal function. Brachial blood pressure decreased significantly in both groups, but there was no significant difference between placebo and irbesartan. Use of additional antihypertensive medication, ultrafiltration volume, and dialysis dosage were not different. Intermediate cardiovascular end points such as central aortic blood pressure, carotid-femoral pulse wave velocity, left ventricular mass index, N-terminal brain natriuretic prohormone, heart rate variability, and plasma catecholamines were not significantly affected by irbesartan treatment. Changes in systolic blood pressure during the study period significantly correlated with changes in both left ventricular mass and arterial stiffness. Thus, significant effects of irbesartan on intermediate cardiovascular end points beyond blood pressure reduction were absent in hemodialysis patients.

Invasive Validation of Arteriograph Estimates of Central Blood Pressure in Patients With Type 2 Diabetes

BACKGROUND Central blood pressure (BP) has attracted increasing interest because of a potential superiority over brachial BP in predicting cardiovascular morbidity and mortality. Several devices estimating central BP noninvasively are now available. The aim of our study was to determine the validity of the Arteriograph, a brachial cuff-based, oscillometric device, in patients with type 2 diabetes. METHODS We measured central BP invasively and compared it with the Arteriograph-estimated values in 22 type 2 diabetic patients referred to elective coronary angiography. RESULTS The difference (invasively measured BP minus Arteriograph-estimated BP) in central systolic BP (SBP) was 4.4±8.7 mm Hg (P = 0.03). The limits of agreement were ±17.1 mm Hg. CONCLUSIONS Compared with invasively measured central SBP, we found a systematic underestimation by the Arteriograph. However, the limits of agreement were similar to the previous Arteriograph validation study and to the invasive validation studies of other brachial cuff-based, oscillometric devices. A limitation in our study was the large number of patients (n = 14 of 36) in which the Arteriograph was unable to analyze the pressure curves. In a research setting, the Arteriograph seems applicable in patients with type 2 diabetes. CLINICAL TRAIL REGISTRATION ClinicalTrials.gov ID NCT01538290.

Pressure Load: The Main Factor for Altered Gene Expression in Right Ventricular Hypertrophy in Chronic Hypoxic Rats

Background The present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading. Methodology/Principal Findings To distinguish hypoxia from pressure-induced alterations, a group of rats underwent banding of the pulmonary trunk (PTB), sham operation, or the rats were exposed to normoxia or chronic, hypobaric hypoxia. Pressure measurements were performed and the right ventricle was analyzed by Affymetrix GeneChip, and selected genes were confirmed by quantitative PCR and immunoblotting. Right ventricular systolic blood pressure and right ventricle to body weight ratio were elevated in the PTB and the hypoxic rats. Expression of the same 172 genes was altered in the chronic hypoxic and PTB rats. Thus, gene expression of enzymes participating in fatty acid oxidation and the glycerol channel were downregulated. mRNA expression of aquaporin 7 was downregulated, but this was not the case for the protein expression. In contrast, monoamine oxidase A and tissue transglutaminase were upregulated both at gene and protein levels. 11 genes (e.g. insulin-like growth factor binding protein) were upregulated in the PTB experiment and downregulated in the hypoxic experiment, and 3 genes (e.g. c-kit tyrosine kinase) were downregulated in the PTB and upregulated in the hypoxic experiment. Conclusion/Significance Pressure load of the right ventricle induces a marked shift in the gene expression, which in case of the metabolic genes appears compensated at the protein level, while both expression of genes and proteins of importance for myocardial function and remodelling are altered by the increased pressure load of the right ventricle. These findings imply that treatment of pulmonary hypertension should also aim at reducing right ventricular pressure.

Assessment of Central Blood Pressure in Patients With Type 2 Diabetes: A Comparison Between Sphygmocor and Invasively Measured Values

BACKGROUND The SphygmoCor is used for noninvasive assessment of ascending aortic blood pressure (BP). However, the validity of the SphygmoCor transfer function has not been tested in an exclusively type 2 diabetic patient sample. Calibration with systolic (SBP) and diastolic (DBP) brachial BP has previously been associated with substantial imprecision of central BP estimates. We hypothesized that different noninvasive calibration strategies might improve the accuracy of the estimated ascending aortic BPs. METHODS In 34 patients with type 2 diabetes we estimated ascending aortic SBP and DBP using the SphygmoCor device and compared these data with invasively recorded data. The validity of the transfer function was assessed by calibrating with invasively recorded DBP and mean BP (MBP). The influence of noninvasive calibration strategies was assessed by calibrating with brachial oscillometric SBP+DBP vs. DBP+MBP using a form factor (ff) of 0.33 and 0.40, respectively. RESULTS When calibrating with invasive BP, the difference between estimated and invasively measured ascending aortic SBP and DBP was -2.3±5.6/1.0±0.9 mm Hg. When calibrating with oscillometric brachial BPs, the differences were -9.6±8.1/14.1±6.2 mm Hg (calibration with SBP and DBP), -8.3±11.7/13.9±6.1 mm Hg (DBP and MBP; ff = 0.33), and 1.9±12.2/14.1±6.2 mm Hg (DBP and MBP; ff = 0.40), respectively. Calibration with the average of 3 brachial BPs did not improve accuracy. CONCLUSIONS The SphygmoCor transfer function seems valid in patients with type 2 diabetes. Noninvasive calibration with DBP and MBP (ff = 0.40) enables accurate estimation of mean ascending aortic SBP at the group level. However, the wide limits of agreement indicate limited accuracy in the individual patient. CLINICAL TRIALS REGISTRATION Clinical Trials No. NCT01538290.

Aortic pulse wave velocity results depend on which carotid artery is used for the measurements.

Objective: Aortic pulse wave velocity (aPWV) is a gold standard noninvasive marker of arterial stiffness. aPWV is usually obtained as carotid–femoral pulse wave velocity by measurements on the common carotid artery and the femoral artery. The carotid arteries branch slightly differently from the aorta towards the right and left side of the neck. Theoretically, using the right or left carotid artery could influence aPWV results and there are no clear guidelines to support the choice of side. The aim of this study was to investigate whether aPWV results depend on right or left side carotid artery measurements in a group of healthy individuals. Methods and results: Two different observers examined 50 individuals without known cardiovascular disease between 23 and 66 years of age. The measurements were performed with the SphygmoCor equipment using both right and left carotid arteries. We found that use of the right carotid artery provided significantly higher aPWV values compared with the left carotid artery, also when using different methods to estimate the travel length of the pulse wave (pooled data, subtracted distance: 0.2 ± 0.4 m/s, P = 0.003; direct distance: 0.2 ± 0.5 m/s, P = 0.001). Conclusion: Using right or left carotid artery affects aPWV, as right-side measurements provided higher values. Attention to this side difference and use of the same carotid artery will increase the strength of intervention studies using aPWV as a surrogate endpoint.

Preserving residual renal function in dialysis patients: an update on evidence to assist clinical decision making

It has been documented that preservation of residual renal function in dialysis patients improves quality of life as well as survival. Clinical trials on strategies to preserve residual renal function are clearly lacking. While waiting for more results from clinical trials, patients will benefit from clinicians being aware of available knowledge. The aim of this review was to offer an update on current evidence assisting doctors in clinical practice.

AlphaLISA versus ELISA-based detection of interleukin 18 in healthy subjects and patients with end-stage renal disease.

Background. Interleukin 18 (IL-18) is an important pro-inflammatory cytokine investigated in end-stage renal disease (ESRD) and several autoimmune and inflammatory diseases. The quantitative colorimetric sandwich ELISA test kit from MBL is the most frequently used ELISA kit for IL-18 detection. Recently, a new bead-based proximity assay named AlphaLISA was developed. The aim of this study was to compare the performance of these two kits and to evaluate aspects of sample handling on IL-18 measurements. Methods. Measurements of IL-18 were performed on plasma samples from 11 ESRD-patients in regular haemodialysis treatment and 10 healthy volunteers. Results. We found a significant difference between assays corresponding to a factor of 6.4 (6.0; 6.7), p < 0.0001. Agreement was excellent with intra-class correlation coefficient 0.95. MBL had lower inter-assay variation, batch-to-batch variation and day-to-day variation. Spiking with recombinant IL-18 resulted in a mean recovery of 91 ± 7 (MBL) vs. 135 ± 17% (AlphaLISA), p < 0.0001. Both kits performed equally well when linearity was investigated. IL-18 was stable over a period of 424 days when plasma samples were stored at − 80°C. When blood samples were stored at room temperature mean IL-18 concentration changed significantly between 0, 1, 6, and 24 hours after sampling (p = 0.0213). No significant change was found with storage at 5°C. Severe haemolysis affected IL-18 measurements, whereas repeated freezing and thawing showed no effect. Mean IL-18 concentration was significantly higher in ESRD-patients compared to healthy subjects regardless of assay. Conclusion. Assay performance was best with the MBL-kit, although AlphaLISA was less time consuming when measuring plasma IL-18.