Serum Biomarkers of Endothelial Dysfunction in Fabry Associated Cardiomyopathy

Background: Fabry disease (FD) is characterized by early development of vasculopathy and endothelial dysfunction. However, it is unclear whether these findings also play a pivotal role in cardiac manifestation. As Fabry cardiomyopathy (FC) is the leading cause of death in FD, we aimed to gather a better insight in pathological mechanisms of the disease.Methods: Serum samples were obtained from 17 healthy controls, 15 FD patients with and 7 without FC. FC was defined by LV wall thickening of >12 mm in cardiac magnetic resonance imaging and serum level of proBNP, high sensitive Troponin T (hsT), and globotriaosylsphingosine (lyso-GB3) were obtained. A multiplex ELISA-Assay for 23 different angiogenesis markers was performed in pooled samples. Markers showing significant differences among groups were further analyzed in single samples using specific Elisa antibody assays. L-homoarginine (hArg), L-arginine, asymmetric (ADMA), and symmetric Dimethylarginine (SDMA) were quantified by liquid chromatography—mass spectrometry.Results: Angiostatin and matrix metalloproteinase 9 (MMP-9) were elevated in FD patients compared to controls independently of the presence of FC (angiostatin: 98 ± 25 vs. 75 ± 15 ng/mL; p = 0.001; MMP-9: 8.0 ± 3.4 vs. 5.0 ± 2.4 μg/mL; p = 0.002). SDMA concentrations were highest in patients with FC (0.90 ± 0.64 μmol/l) compared to patients without (0.57 ± 0.10 μmol/l; p = 0.027) and vs. controls (0.58 ± 0.12 μmol/l; p = 0.006) and was positively correlated with indexed LV-mass (r = 0.61; p = 0.003), hsT (r = 0.56, p = 0.008), and lyso-Gb3 (r = 0.53, p = 0.013). Accordingly, the ratio of L-homoarginine to SDMA (hArg/SDMA) was lowest in patients with FC (2.63 ± 1.78) compared to controls (4.16 ± 1.44; p = 0.005). For L-arginine, hArg and ADMA no significant differences among groups could be detected, although a trend toward higher ADMA and lower hArg levels could be observed in the FC group. Furthermore, a significant relationship between kidney and cardiac function could be revealed (p = 0.045).Conclusion: Elevated MMP-9 and angiostatin levels suggest an increased extracellular matrix turnover in FD patients. Furthermore, endothelial dysfunction may also be involved in FC, as SDMA and hArg/SDMA are altered in these patients

Structural alteration of lung parenchyma in patients with NF1: a phenotyping study using multidetector computed tomography (MDCT)

Background!#!Diffuse interstitial lung disease have been described in Neurofibromatosis type 1 (NF1), but its diversity and prevalence remain unknown. The aim of this study was to assess the prevalence and characteristics of (NF1)-associated lung manifestations in a large single-center study using multidetector computed tomography (MDCT) and to evaluate the smoking history, patients' age, genetics, and the presence of malignant peripheral nerve sheath tumors (MPNST) as potential influencing factors for lung pathologies.!##!Methods!#!In this retrospective study, 71 patients with NF1 were evaluated for the presence of distinctive lung manifestations like reticulations, consolidations, type of emphysema, pulmonary nodules and cysts. All patients underwent F-18-FDG PET/CT scans, which were reviewed by two experienced radiologists in consensus. Patients' subgroups were formed based on their smoking history (current smokers/previous smokers/never smokers), age (< 12 years, 12-18 years, > 18 years), and presence of MPNST (MPNST/no MPNST). In 57 patients (80%), genetic analysis of sequences coding for the neurofibromin on chromosome 17 was performed, which was correlated with different lung pathologies.!##!Results!#!Among all NF1 patients (33 ± 14 years, 56% females), 17 patients (24%) were current smokers and 62 patients (87%) were > 18 years old. Pulmonary cysts, nodules, and paraseptal emphysema were the most common pulmonary findings (35%, 32%, 30%). The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking. Cysts were observed only in adults, whereas no significant correlation between age and all other pulmonary findings was found (p > 0.05). Presence of MPNST was accompanied by higher rates of intrapulmonary nodules and pulmonary metastasis. Neither the presence nor absence of any of the specific gene mutations was associated with any particular lung pathology (p > 0.05).!##!Conclusions!#!All pulmonary findings in NF1 patients occurred independently from specific mutation subtypes, suggesting that many NF1 mutations can cause various pulmonary pathologies. The presence of pulmonary metastases, MPNST and centrilobular emphysema was associated with smoking, indicating the value of smoking secession or the advice not to start smoking in NF1 patients as preventive strategy for clinicians. For screening of pulmonary manifestations in NF1 patients, an MDCT besides medical history and physical examination is mandatory in clinical routine

Association of Asymmetric Dimethylarginine and Diastolic Dysfunction in Patients with Hypertrophic Cardiomyopathy

Despite genetic heterogeneity, early manifestation of diastolic dysfunction (DD) is common in hypertrophic cardiomyopathy (HCM). Nitric oxide (NO) may contribute to myocardial relaxation. NO synthases (NOS) use l-arginine (Arg) as a substrate, as asymmetric dimethylarginine (ADMA) is a direct endogenous inhibitor of NOS. This study aimed to analyze the association of Arg and its derivates, i.e., l-homoarginine (hArg), ADMA and symmetric dimethylarginine (SDMA), with DD in HCM patients. In 215 HCM patients (mean age 54 ± 15 years, 58% male) transmitral and mitral annulus velocities were echocardiographically analyzed. Plasma concentrations of Arg derivatives were measured by liquid chromatography tandem-mass spectrometry. In 143 (70%) patients suffering from DD, ADMA showed the strongest association with DD (0.66 ± 0.16, 0.72 ± 0.24, and 0.76 ± 0.26 µmol/L, p < 0.01 for trend). In linear regression analyses, positive association per standard deviation increase of ADMA was found with E-wave (beta coefficient (95% confidence interval): 4.72 (0.43–9.01); p < 0.05) and mean E/E’ (1.76 (0.73–2.79) p < 0.001). Associations were adjusted for age, sex, body mass index (BMI), diabetes mellitus, coronary artery disease, and arterial hypertension. Elevated ADMA is associated with the severity of DD in HCM. Higher ADMA level might lead to decreased NO production and thus an impaired myocardial relaxation pattern

Pre-interventional assessment of right renal to right adrenal vein distance: Impact on procedure time and radiation dose in adrenal vein sampling.

PurposeAdrenal vein sampling (AVS) is the reference standard for evaluation of lateralized hormone production in primary aldosteronism. We aimed to investigate the impact of pre-interventional right renal vein (RRV) to right adrenal vein (RAV) distance measurement on fluoroscopy time, contrast agent exposure and radiation dose during AVS.Materials and methodsForty-five patients with primary aldosteronism undergoing AVS were enrolled in our retrospective study and divided into three groups. In the group "ruler" (n = 14), RRV-RAV-distances were determined pre-interventionally by cross-sectional imaging (CT/MRI) and AVS was performed by one interventional radiologist with limited experience in AVS. CT/MRI-derived and fluoroscopy-derived RRV-RAV-distances were correlated for aimed cannulation of the RAV. Patients in group "no ruler" (n = 24, three interventional radiologists with limited experience in AVS) and in group "expert", (n = 7, one expert interventional radiologist) underwent AVS without pre-interventional estimation of RRV-RAV-distances. Procedure parameters (fluoroscopy time, contrast agent volume, radiation dose) of group "ruler" were compared to both other groups by Kruskal-Wallis rank-sum test.ResultsCorrelation of CT/MRI-derived and fluoroscopy-derived RRV-RAV-distances was good (r = 0.74;p = 0.003). The median RRV-RAV-distance was 4.5cm at CT/MRI (95%-CI:4.2-5.0cm) and 4.0cm at fluoroscopy (95%-CI:3.8-4.5cm). Fluoroscopy time (p0.05).ConclusionsCT/MRI-derived pre-interventional renal-adrenal vein distance measurements correlate well with angiographic distance measurements. Pre-interventional estimation of the RRV-RAV-distance allows for aimed cannulation of the RAV with potential reduction of fluoroscopy time, contrast agent exposure and radiation-dose during AVS

Inter- and Intraobserver reproducibility of T2 relaxation times of the discus interpubicus: A feasibility study at 3 Tesla.

OBJECTIVE:To quantify standard values of the discus interpubicus in healthy subjects and to determine reliability and repeatability using T2 relaxation time measurements at 3T. METHODS:20 asymptomatic participants (10 male, 10 female; mean age: 27.3 years ±4.1, BMI: 22.2 ±1.8) underwent a 3T Magnetic Resonance Imaging (MRI) of the pelvic region in a supine position. We included sagittal and para-axial T2w sequences centred over the pubic symphysis in order to identify the complete discus interpubicus. For quantitative analysis, a multi-echo Turbo Spin Echo (TSE) sequence (including 12 echo times between 6.4 and 76.8 ms) was acquired and analysed by using an in-house developed quantification plugin tool (qMapIt) extending ImageJ. Two readers in consensus defined three central slices of the pubic symphysis with the greatest length. For each slice, both readers separately placed three regions-of-interest (ROI) covering the whole discus interpubicus. Both readers repeated the ROI placements in identical fashion after a four-week interval on the original MRI images. Statistical analysis included intraclass correlation coefficient (ICC), nonparametric Wilcoxon test, Fisher exact test and mean relaxation time in ms and 95% confidence intervals. RESULTS:T2 relaxation time analysis was performed for all 20 participants. In total, a mean relaxation time of all analysed segments for both observers was 48.6 (±6.3 ms), with a mean relaxation time for observer 1 of 48.7 (±6.0 ms) and for observer 2 of 48.5 ms (±6.6ms). The calculated ICC comparing inter- and intrarater reproducibility was excellent in all segments (≥0.75). CONCLUSION:T2 mapping of the discus interpubicus demonstrates good inter- and intrarater repeatability as well as reliability. Mean relaxation times were calculated with 48.6ms in healthy volunteers