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Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh–Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = −0.57, p = 0.001, n = 29) and FIB-4 (r = −0.47, p = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, p = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; p < 0.0001, n = 20). ALBI, MELD, and Pugh–Child scores correlated negatively with [PPi]pl (r = −0.60, p = 0.0005; r = −0.56, p = 0.002; r = −0.41, p = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, p = 0.02, n = 16; r = 0.58, p = 0.009, n = 20; r = 0.41, p = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, p = 0.02, n = 16; r = 0.67, p = 0.002, n = 20; r = 0.61, p = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, p = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37–44] vs. 35 [30–40], p = 0.009) and [PPi]pl was normalized (1.40 [1.07–1.86] vs. 0.68 [0.53–0.80] µmol/L, p = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters.

Introduction: Pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder caused by pathogenic ABCC6 variants, is characterized by skin, ocular and cardiovascular (CV) symptoms. Due to striking phenotypic variability without genotype-phenotype correlations, modifier genes are thought to play a role in disease variability. In this study, we evaluated the collective modifying effect of rare variants on the cardiovascular phenotype of PXE.Materials and Methods: Mixed effects of rare variants were assessed by Whole Exome Sequencing in 11 PXE patients with an extreme CV phenotype (mild/severe). Statistical analysis (SKAT-O and C-alpha testing) was performed to identify new modifier genes for the CV PXE phenotype and enrichment analysis for genes significantly associated with the severe cohort was used to evaluate pathway and gene ontology features.Results Respectively 16 (SKAT-O) and 74 (C-alpha) genes were significantly associated to the severe cohort. Top significant genes could be stratified in 3 groups–calcium homeostasis, association with vascular disease and induction of apoptosis. Comparative analysis of both analyses led to prioritization of four genes (NLRP1, SELE, TRPV1, and CSF1R), all signaling through IL-1B.Conclusion This study explored for the first time the cumulative effect of rare variants on the severity of cardiovascular disease in PXE, leading to a panel of novel candidate modifier genes and disease pathways. Though further validation is essential, this panel may aid in risk stratification and genetic counseling of PXE patients and will help to gain new insights in the PXE pathophysiology.

IntroductionPatients on dialysis and kidney transplant recipients (KTR) present the syndrome of mineral and bone disorders (MBD), which share common traits with monogenic calcifying diseases related to disturbances of the purinergic system. Low plasma levels of inorganic pyrophosphate (PPi) and ectopic vascular calcifications belong to these two conditions. This suggests that the purinergic system may be altered in chronic kidney disease with MBD. Therefore, we perform a transversal pilot study in order to compare the determinants of PPi homeostasis and the plasma levels of PPi in patients on dialysis, in KTR and in healthy people.Patients and MethodsWe included 10 controls, 10 patients on maintenance dialysis, 10 early KTR 3 ± 1 months after transplantation and nine late KTR 24 ± 3 months after transplantation. We measured aortic calcifications, plasma and urine levels of PPi, the renal fractional excretion of PPi (FePPi), nucleoside triphosphate hydrolase (NPP) and ALP activities in plasma. Correlations and comparisons were assessed with non-parametric tests.ResultsLow PPi was found in patients on dialysis [1.11 (0.88–1.35), p = 0.004], in early KTR [0.91 (0.66–0.98), p = 0.0003] and in late KTR [1.16 (1.07–1.45), p = 0.02] compared to controls [1.66 (1.31–1.72) μmol/L]. Arterial calcifications were higher in patients on dialysis than in controls [9 (1–75) vs. 399 (25–526) calcium score/cm2, p < 0.05]. ALP activity was augmented in patients on dialysis [113 (74–160), p = 0.01] and in early KTR [120 (84–142), p = 0.002] compared to controls [64 (56–70) UI/L]. The activity of NPP and FePPi were not different between groups. ALP activity was negatively correlated with PPi (r = −0.49, p = 0.001).DiscussionPatients on dialysis and KTR have low plasma levels of PPi, which are partly related to high ALP activity, but neither to low NPP activity, nor to increased renal excretion of PPi. Further work is necessary to explore comprehensively the purinergic system in chronic kidney disease.

We determined whether early changes in central haemodynamics, as determined by transthoracic impedance, induced by a 70 degrees head-up tilt (HUT) test could predict syncope. Heart rate, arterial blood pressure and central haemodynamics [pre-ejection period and rapid left ventricular ejection time ( T (1)), slow ejection time ( T (2)) and d Z /d t (max) (where Z is thoracic impedance), assessed by the transthoracic impedance technique], were recorded during supine rest and during a 45 min 70 degrees HUT test in 68 patients (40+/-2 years) with a history of unexplained recurrent syncope. We found that 38 patients (42+/-3 years) had a symptomatic outcome to 70 degrees HUT (fainters) and 30 (39+/-2 years) had a negative outcome (non-fainters). When measured between 5 and 10 min of 70 degrees HUT, T (2) had increased significantly only in the fainters, and a change in T (2) of40 ms from baseline predicted a positive outcome with a sensitivity of 68% and a specificity of 70%. During supine rest prior to 70 degrees HUT, the fainters exhibited a shorter T (2) than non-fainters (183+/-10 compared with 233+/-14 ms; P0.01), and a T (2) of199 ms predicted a positive outcome to 70 degrees HUT with a sensitivity of 68% and a specificity of 63%. Incorporation of the changes that occurred from rest to 70 degrees HUT in other haemodynamic variables (heart rate11 beats/min, systolic pressure2 mmHg, diastolic pressure7 mmHg and pulse pressure-3 mmHg) increased the specificity to 97% and the positive predictive value to 93%. Thus transthoracic impedance could detect differences in central haemodynamics between fainters and non-fainters during supine rest and during the initial period of 70 degrees HUT with a consistent sensitivity and specificity when combined with peripheral haemodynamic variables.

This study compared spontaneous baroreflex sensitivity (BRS) estimates obtained from an identical set of data by 11 European centers using different methods and procedures. Noninvasive blood pressure (BP) and ECG recordings were obtained in 21 subjects, including 2 subjects with established baroreflex failure. Twenty-one estimates of BRS were obtained by methods including the two main techniques of BRS estimates, i.e., the spectral analysis (11 procedures) and the sequence method (7 procedures) but also one trigonometric regressive spectral analysis method (TRS), one exogenous model with autoregressive input method (X-AR), and one Z method. With subjects in a supine position, BRS estimates obtained with calculations of α-coefficient or gain of the transfer function in both the low-frequency band or high-frequency band, TRS, and sequence methods gave strongly related results. Conversely, weighted gain, X-AR, and Z exhibited lower agreement with all the other techniques. In addition, the use of mean BP instead of systolic BP in the sequence method decreased the relationships with the other estimates. Some procedures were unable to provide results when BRS estimates were expected to be very low in data sets (in patients with established baroreflex failure). The failure to provide BRS values was due to setting of algorithmic parameters too strictly. The discrepancies between procedures show that the choice of parameters and data handling should be considered before BRS estimation. These data are available on the web site ( http://www.cbi.polimi.it/glossary/eurobavar.html ) to allow the comparison of new techniques with this set of results.

L'invention concerne un procédé de mesure d'un indice (Ira) de la rigidité locale de la paroi d'une artère de conduction véhiculant le sang d'un sujet. Selon l'invention, un tel procédé comprend au moins : - une étape de mesure, en un unique point de mesure, de la variation d'impédance électrique (&Dgr; Z) d'un volume (V) du sang circulant dans ladite artère ; - une étape de détermination d'au moins deux indices intermédiaires (RP%, PCPA%) chacun représentatif d'une caractéristique distincte mise en jeu dans la rigidification de ladite paroi, au moins un desdits indices intermédiaires (RP , PCPA ) étant obtenus à partir de ladite mesure de la variation d'impédance électrique (&Dgr; Z) ; - une étape de détermination dudit indice (Ira) de la rigidité locale en fonction desdits au moins deux indices intermédiaires (RP , PCPA ).