A Plasma Pyrophosphate Cutoff Value for Diagnosing Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disease responsible for a juvenile peripheral arterial calcification disease. The clinical diagnosis of PXE is only based on a complex multi-organ phenotypic score and/or genetical analysis. Reduced plasma inorganic pyrophosphate concentration [PPi]p has been linked to PXE. In this study, we used a novel and accurate method to measure [PPi]p in one of the largest cohorts of PXE patients, and we reported the valuable contribution of a cutoff value to PXE diagnosis. Plasma samples and clinical records from two French reference centers for PXE (PXE Consultation Center, Angers, and FAVA-MULTI South Competent Center, Nice) were assessed. Plasma PPi were measured in 153 PXE and 46 non-PXE patients. The PPi concentrations in the plasma samples were determined by a new method combining enzymatic and ion chromatography approaches. The best match between the sensitivity and specificity (Youden index) for diagnosing PXE was determined by ROC analysis. [PPi]p were lower in PXE patients (0.92 ± 0.30 µmol/L) than in non-PXE patients (1.61 ± 0.33 µmol/L, p < 0.0001), corresponding to a mean reduction of 43 ± 19% (SD). The PPi cutoff value for diagnosing PXE in all patients was 1.2 µmol/L, with a sensitivity of 83.3% and a specificity of 91.1% (AUC = 0.93), without sex differences. In patients aged <50 years (i.e., the age period for PXE diagnosis), the cutoff PPi was 1.2 µmol/L (sensitivity, specificity, and AUC of 93%, 96%, and 0.97, respectively). The [PPi]p shows high accuracy for diagnosing PXE; thus, quantifying plasma PPi represents the first blood assay for diagnosing PXE.

Vitamin D and Calcium Supplementation Accelerate Vascular Calcification in a Model of Pseudoxanthoma Elasticum.

Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by ABCC6 mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries. METHODS: we analyzed whether long-term exposure of Abcc6-/- mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6-/- and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining. RESULTS: at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6-/- mice. CONCLUSIONS: vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.

Vitamin D and Calcium Supplementation Accelerates Randall's Plaque Formation in a Murine Model.

Most kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth. We analyzed whether long-term exposure of Abcc6-/- mice (a murine model of Randall's plaque) to vitamin D supplementation, with or without a calcium-rich diet, would accelerate the formation of Randall's plaque. Eight groups of mice (including Abcc6-/- and wild type) received vitamin D alone (100,000 UI/kg every 2 weeks), a calcium-enriched diet alone (calcium gluconate 2 g/L in drinking water), both vitamin D supplementation and a calcium-rich diet, or a standard diet (controls) for 6 months. Kidney calcifications were assessed by 3-dimensional microcomputed tomography, µ-Fourier transform infrared spectroscopy, field emission-scanning electron microscopy, transmission electron microscopy, and Yasue staining. At 6 months, Abcc6-/- mice exposed to vitamin D and calcium supplementation developed massive Randall's plaque when compared with control Abcc6-/- mice (P < 0.01). Wild-type animals did not develop significant calcifications when exposed to vitamin D. Combined administration of vitamin D and calcium significantly accelerates Randall's plaque formation in a murine model. This original model raises concerns about the cumulative risk of vitamin D supplementation and calcium intakes in Randall's plaque formation.

ABCC6 Deficiency Promotes Development of Randall Plaque.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the ABCC6 gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models. METHODS: We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from Abcc6-/- mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications. RESULTS: Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques). Abcc6-/- mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls, Abcc6-/- mice had low urinary excretion of pyrophosphate. CONCLUSIONS: The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and Abcc6-/- mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones.

The ABCC6 Transporter: A New Player in Biomineralization.

Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed.

Assessment of endothelial function by acetylcholine iontophoresis: impact of inter-electrode distance and electrical cutaneous resistance.

OBJECTIVES: Endothelial function can be assessed by acetylcholine (ACh) iontophoresis with single current application. The effect of inter-electrode distance as well as electrical cutaneous resistance (ECR) on ACh dependent vasodilation has never been studied using single current application. The aims of this study are (i) to compare ACh-peak and ECR measured at different inter-electrode distances, (ii) to assess the relationship between ACh-peak and ECR, (iii) and to study the reproducibility of the ECR values. METHODS: Fourteen healthy subjects were included. Using laser speckle contrast imaging, ACh-iontophoreses (0.1 mA, 30s) were performed on the forearm at a 7-day interval with an inter-electrode distance set at 5 cm. Two other inter-electrode distances were also evaluated: 10 cm and 15 cm. ECR was measured during each ACh-iontophoresis as well as the ACh-peak. RESULTS: No statistical difference was found between the ACh-peak values obtained at 5 cm, 10 cm and 15 cm. ECRs were also not statistically different. An inverse relationship (r=-0.60) was found between the ACh-peak and ECR (p<0.05). The coefficient of variation of the inter-day reproducibility of the ECR values was 9.1% [6.5%-15.1%] with an intra-class-correlation coefficient of 0.93 [0.81-0.98]. CONCLUSION: Inter-electrode distance ranging from 5 cm to 15 cm changes neither the ACh-peak value nor the ECR value. ECR impacts ACh-peak values.

Response to statin therapy in obstructive sleep apnea syndrome: a multicenter randomized controlled trial.

RATIONALE: Accumulated evidence implicates sympathetic activation as inducing oxidative stress and systemic inflammation, which in turn lead to hypertension, endothelial dysfunction, and atherosclerosis in obstructive sleep apnea (OSA). Statins through their pleiotropic properties may modify inflammation, lipid profile, and cardiovascular outcomes in OSA. METHODS: This multicenter, randomized, double-blind study compared the effects of atorvastatin 40 mg/day versus placebo over 12 weeks on endothelial function (the primary endpoint) measured by peripheral arterial tone (PAT). Secondary endpoints included office blood pressure (BP), early carotid atherosclerosis, arterial stiffness measured by pulse wave velocity (PWV), and metabolic parameters. RESULTS: 51 severe OSA patients were randomized. Key demographics for the study population were age 54 ± 11 years, 21.6% female, and BMI 28.5 ± 4.5 kg/m(2). In intention to treat analysis, mean PAT difference between atorvastatin and placebo groups was 0.008 (-0.29; 0.28), P = 0.979. Total and LDL cholesterol significantly improved with atorvastatin. Systolic BP significantly decreased with atorvastatin (mean difference: -6.34 mmHg (-12.68; -0.01), P = 0.050) whereas carotid atherosclerosis and PWV were unchanged compared to the placebo group. CONCLUSION: In OSA patients, 3 months of atorvastatin neither improved endothelial function nor reduced early signs of atherosclerosis although it lowered blood pressure and improved lipid profile. This trial is registered with NCT00669695.

Pseudoxanthoma elasticum - Genetics, pathophysiology, and clinical presentation.

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6-gene are causative, coding for a transmembrane transporter mainly expressed in hepatocytes, which promotes the efflux of adenosine triphosphate (ATP). This results in low levels of plasma inorganic pyrophosphate (PPi), a critical anti-mineralization factor. The clinical phenotype of PXE is characterized by the effects of elastic fiber calcification in the skin, the cardiovascular system, and the eyes. In the eyes, calcification of Bruch's membrane results in clinically visible lesions, including peau d'orange, angioid streaks, and comet tail lesions. Frequently, patients must be treated for secondary macular neovascularization. No effective therapy is available for treating the cause of PXE, but several promising approaches are emerging. Finding appropriate outcome measures remains a significant challenge for clinical trials in this slowly progressive disease. This review article provides an in-depth summary of the current understanding of PXE and its multi-systemic manifestations. The article offers a detailed overview of the ocular manifestations, including their morphological and functional consequences, as well as potential complications. Lastly, previous and future clinical trials of causative treatments for PXE are discussed.

Quantification of the calcification phenotype of Abcc6-deficient mice with microcomputed tomography.

Pseudoxanthoma elasticum in humans and dystrophic cardiac calcification in mice are heritable disorders characterized by dystrophic calcification of soft connective tissues related to the defective function of the ABCC6 (human)/Abcc6 (mouse) transporter. Of particular interest is the finding of calcified vibrissae in Abcc6(-/-) mice, which facilitates the study of dystrophic calcification by histological techniques. We aimed to determine whether mice prone to dystrophic cardiac calcification (C3H/HeOuJ and DBA/2J strains) presented similar vibrissae changes and to evaluate the value of microcomputed tomography to quantify the extent of mystacial vibrissae calcifications. These calcifications were absent in DBA/2J and C57BL/6J control mice. In both Abcc6(-/-) and C3H/HeOuJ mice, calcifications progressed in a caudal-rostral direction with aging. However, the calcification process was delayed in C3H/HeOuJ mice, indicating an incomplete expression of the calcification phenotype. We also found that the calcification process in the cephalic region was not limited to mystacial vibrissae but was also present in other periorbital sensorial vibrissae. The vibrissae calcification was circular and encompassed the medial region of the vibrissae capsule, adjacent to the ring and cavernous sinuses (the areas adjacent to blood and lymphatic vessels). Collectively, our findings confirm that Abcc6 acts as an inhibitor of spontaneous chronic mineralization and that microcomputed tomography is a valuable noninvasive tool for the assessment of the calcification phenotype in Abcc6-deficient mice.

Calf muscle stimulation with the Veinoplus device results in a significant increase in lower limb inflow without generating limb ischemia or pain in patients with peripheral artery disease.

OBJECTIVE: Increase in arterial inflow to the lower limbs is important to obtain functional improvement in peripheral artery disease (PAD) patients with claudication. The aim of this study was to assess the effect of electrical stimulation of calf muscles on arterial inflow and tissue oxygen content in PAD in the area of stimulation. METHODS: Fifteen adult patients [mean (standard deviation) age, 62 (12 ) years; height, 165 (8)cm; weight, 76 (13) kg; lowest ankle-brachial index 0.66 (0.19)] with stable arterial claudication were recruited. All patients performed a treadmill test (3.2 km/h, 10% slope) associated with a transcutaneous oximetry test expressed as decrease from rest of oxygen pressure (DROP) index values (calf changes minus chest changes from rest) with a maximum walking distance (median [25th/75th percentiles]) of 295 [133-881] m. The DROP index on the symptomatic side was -25 [-18/-34] mm Hg. On another day the patients underwent electrical stimulation in the seated position on the leg that was the most symptomatic on the treadmill. After resting values were recorded, the gastrocnemius was stimulated for 20minutes at increasing contraction rates at 5-minute steps of 60, 75, 86, and 100bpm on the most symptomatic side. Arterial blood inflow with duplex Doppler ultrasound scanning of the femoral artery, DROP transcutaneous oxygen pressure value, and oxygen concentration (O2Hb) from the near-infrared spectroscopic signal of the calf were recorded on both sides. Patients were instructed to report eventual contraction-induced pain in the stimulated calf. Results are given as mean (standard deviation) or median [25th/75th percentiles] according to distribution, and the level of statistical significance was set at P < .05 on two-tailed tests. RESULTS: Lower limb inflow (mL/min) was 64 [48/86] vs 63 [57/81] (P> .05) before stimulation, 123 [75/156] vs 57 [44/92] (P < .01) at 60bpm, 127 [91/207] vs 49 [43/68] (P < .01) at 75bpm, 140 [84/200] vs 57 [45/71] (P < .01) at 86bpm, and 154 [86/185] vs 55 [46/94] (P < .01) at 100bpm on the stimulated vs nonstimulated limb, respectively. No apparent decrease or significant leg difference was observed in DROP index or O2Hb values. None of the patients reported contraction-induced pain in the leg. CONCLUSIONS: Electrical stimulation of calf muscle with the Veinoplus device results in a significant increase of arterial inflow without measurable muscle ischemia or pain. Potential use of this device as an adjuvant treatment to improve walking capacity in PAD patients remains to be evaluated.

Atherosclerosis Calcification: Focus on Lipoproteins.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids in the vessel wall, leading to the formation of an atheroma and eventually to the development of vascular calcification (VC). Lipoproteins play a central role in the development of atherosclerosis and VC. Both low- and very low-density lipoproteins (LDL and VLDL) and lipoprotein (a) (Lp(a)) stimulate, while high-density lipoproteins (HDL) reduce VC. Apolipoproteins, the protein component of lipoproteins, influence the development of VC in multiple ways. Apolipoprotein AI (apoAI), the main protein component of HDL, has anti-calcific properties, while apoB and apoCIII, the main protein components of LDL and VLDL, respectively, promote VC. The role of lipoproteins in VC is also related to their metabolism and modifications. Oxidized LDL (OxLDL) are more pro-calcific than native LDL. Oxidation also converts HDL from anti- to pro-calcific. Additionally, enzymes such as autotaxin (ATX) and proprotein convertase subtilisin/kexin type 9 (PCSK9), involved in lipoprotein metabolism, have a stimulatory role in VC. In summary, a better understanding of the mechanisms by which lipoproteins and apolipoproteins contribute to VC will be crucial in the development of effective preventive and therapeutic strategies for VC and its associated cardiovascular disease.

Impact of experimental conditions on noncontact laser recordings in microvascular studies.

Microcirculation, especially skin microcirculation, is a window toward systemic vascular function in magnitude and underlying mechanisms. Different techniques have been developed to assess the microcirculation. Among these techniques, laser technology is used to perform noninvasive microvascular assessments. In the 1970s, the laser Doppler flowmetry (LDF) technique was proposed to monitor microvascular blood flow. More recently, noncontact technologies including laser Doppler perfusion imaging (LDI) and laser speckle contrast imaging (LSCI) have improved the reproducibility of the microcirculation measurements and facilitated some clinical evaluations such as on wounds and ulcers. However, due to the absence of contact between tissue and sensors, it is likely that different technical and environmental conditions may interfere with microvascular recordings. This review presents major technical and environmental conditions, which may interfere with noncontact laser recordings in microvascular studies.

Aging reduces the accuracy of self-reported walking limitation in patients with vascular-type claudication.

BACKGROUND: The published correlations between treadmill performance and the Walking Impairment Questionnaire (WIQ) score are generally fair. We hypothesized that the slope of the relationship of maximal treadmill walking time to WIQ would be lower in older than in younger patients, resulting in (1) a fair correlation in the population considered as a whole and (2) different cutoff points of the WIQ score to predict the ability to complete 5 minutes of treadmill walking in different age groups. METHODS: A 9-month prospective study was performed among patients referred for vascular-type claudication. Patients were divided into three age groups by years: <60 (group 1, n = 91), 60 to 70 (group 2, n = 80), and >70 (group 3, n = 77). Patients self-completed the WIQ, which was corrected with a nurse, if necessary, and then completed a treadmill test. We calculated the correlation coefficient and slope of the relationship between the WIQ and maximal treadmill walking time. We used receiver operating characteristics curve analysis to estimate the accuracy of the WIQ score to determine the ability of the patients to complete 5 minutes of treadmill walking. RESULTS: Differences in slopes were significant between groups 1 vs 2 (P = .02), 2 vs 3 (P < .002), and 1 vs 3 (P < .001). The R(2) for the regression lines also tended to decrease but was only significant between two extremes (1 vs 2, P = .11; 2 vs 3, P = .07; 1 vs 3, P < .001). In patients aged <60 years (group 1), a WIQ score of 47 predicted the ability to complete a 5-minute test on treadmill with 86.8% accuracy (area under the receiver operating characteristics curve, 0.906; P < .001). The accuracy in predicting treadmill results from the WIQ score was fair in group 2 and nonsignificant in group 3. CONCLUSIONS: Prediction of treadmill walking capacity from the WIQ score should account for age. The TransAtlantic Inter-Society Consensus suggests that self-reported limitation has an equal weight as measured walking distance in the treatment choices and follow-up of patients with peripheral arterial disease. The WIQ should probably be used with caution in clinical routine, and constant-load treadmill testing is probably not the ideal candidate in elderly patients. New or adapted tools are likely needed in such patients but remain to be studied.

The IDEAL study : towards personalized drug treatment of hypertension.

OBJECTIVE: To identify markers (phenotypic, genetic, or environmental) of blood pressure (BP) response profiles to angiotensin converting enzyme inhibitors (ACEIs) and diuretics. METHODS: IDEAL was a crossover (two active and two wash out phases), double-blind, placebo-controlled trial. Eligible patients were untreated hypertensive, aged 25 to 70. After two visits, patients were randomized to one of four sequences. The main outcome was BP differences between the active treatment and placebo. RESULTS: One hundred and twenty-four patients were randomised: mean age 53, men 65%, family history of hypertension 60%. Average BP fall at each visit before randomisation was about 2% of the initial level reflecting both a regression to the mean and a placebo effect. CONCLUSION: The results are expected to improve knowledge in drug's mechanisms of action and pathophysiology of hypertension, and to help in personalizing treatment. The estimation of BP responses to each drug in standardized conditions provided a benefit to each participant.

Reference Probe for TcpO2 at Rest: A Systematic Review.

(1) Background: Transcutaneous oxygen pressure (TcpO2) is used to determine the severity of lower extremity arterial disease (LEAD). Many authors used a ratio of limb to chest TcpO2, also called the regional perfusion index (RPI), which should be independent of variations in oxygen delivery and reflective of local limb oxygen supply. The relevance of a reference probe-positioned TcpO2 electrode is debated. We aimed to review the relevance of the reference probe in previous studies using rest TcpO2. (2) Methods: We searched Medline and the Cochrane Central Register of Controlled Trials on 22 September 2022 using keywords related to TcpO2, reference probe and LEAD. (3) Results/Discussion: Fifteen studies were included in the review. Nine studies investigated LEAD severity (n = 9), amputation healing predication (n = 4), surgical outcome prediction (n = 2), therapeutic effect (n = 3) and difference according to diabetic status (n = 1). Four studies investigated more than 1 indication. Among 12 (16.7%) studies using RPI, only two authors found a benefit of using RPI instead of absolute TcpO2. Using only univariate analysis, one author reported that RPI was significantly related to viability at 1 year, while distal TcpO2 was not, on 13 limbs. The following year, the same author published a new study including 118 limbs that reported that RPI and absolute TcPO2 were both prognostic factors for limb viability at 1 year using a multivariate model. (4) Conclusions: Only one study firmly supporting the use of RPI, calculated using a reference probe on the arm, to predict BKA healing. Prospective studies are needed to validate this result; for other indications there is insufficient data supporting the use of a TcpO2 reference probe at rest.

Case Report, Practices Survey and Literature Review of an Under-Recognized Pediatric Vascular Disorder: The BASCULE Syndrome.

Introduction: Bier anemic spots, cyanosis, and urticaria-like eruption (BASCULE) syndrome is an underreported pediatric vascular disorder from the group of acrosyndromes. In children, these include paroxysmal acrosyndromes (Raynaud's phenomenon and chilblain-like lesions), permanent acrosyndromes (acrocyanosis), and transient acrosyndromes, in which their pathogeneses are associated with virus infections, Epstein-Barr virus, and, more recently, SARS-CoV-2, respectively. Methods: We reported a case of BASCULE syndrome associated with postural orthostatic tachycardia syndrome (POTS) and provided a narrative review of case reports describing the BASCULE syndrome in children. Moreover, we presented the results of a prospective practice survey that we performed in the French medical community. Results: A 14-years-old boy reported pruritic erythrocyanic lesions on the lower limbs, which occurred whenever he was in a standing position and fully resolved when he laid down. He reported asthenia and cramps. He presented a typical BASCULE syndrome associated with POTS confirmed by a tilt-test. Physical and vascular examinations were within the normal range. We identified 12 case reports, describing 21 pediatric cases since 2016. Most patients were adolescents between 12 and 19 years of age or were newborns. Furthermore, 20% of cases in the literature have presented POTS or orthostatic intolerance. Our survey among 95 French physicians confirmed that BASCULE syndrome is an underdiagnosed and under recognized disease in the general pediatric practice, at least in France. Among these physicians, 65% had already encountered patients with similar symptoms, but only 30% declared that they had knowledge of the BASCULE syndrome. Conclusion: The under-recognition of the clinical manifestations leads the patients to consult emergency rooms, with multiple unnecessary investigations performed. Therefore, we suggest that the diagnosis of BASCULE syndrome is based on clinical observations, without the need for laboratory tests, to avoid unnecessary health costs. We suggest physicians to perform a tilt-test when POTS is suspected.

Relationships between Plasma Pyrophosphate, Vascular Calcification and Clinical Severity in Patients Affected by Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE; OMIM 264800) is an autosomal recessive metabolic disorder characterized by progressive calcification in the skin, the Bruch's membrane, and the vasculature. Calcification in PXE results from a low level of circulating pyrophosphate (PPi) caused by ABCC6 deficiency. In this study, we used a cohort of 107 PXE patients to determine the pathophysiological relationship between plasma PPi, coronary calcification (CAC), lower limbs arterial calcification (LLAC), and disease severity. Overall, our data showed a deficit in plasma PPi in PXE patients compared to controls. Remarkably, affected females showed higher PPi levels than males, but a lower LLAC. There was a strong correlation between age and PPi in PXE patients (r = 0.423, p < 0.0001) but not in controls (r = 0.059, p = 0.828). A weak correlation was found between PPi and CAC (r = 0.266, p < 0.02); however, there was no statistically significant connection with LLAC (r = 0.068, p = 0.518) or a severity score (r = 0.077, p = 0.429). Surprisingly, we found no significant correlation between plasma alkaline phosphatase activity and PPi (r = 0.113, p = 0.252) or between a 10-year cardiovascular risk score and all other variables. Multivariate analysis confirmed that LLAC and CAC were strongly dependent on age, but not on PPi. Our data showed that arterial calcification is only weakly linked to circulating PPi levels and that time (i.e., age) appears to be the major determinant of disease severity and calcification in PXE. These data are important to better understand the natural history of this disease but also for the follow-up and management of patients, and the design of future clinical trials. Our results also show that PPi is not a good biomarker for the evaluation of disease severity and progression.

Assessment of the systolic rise time by photoplethysmography in peripheral arterial diseases: a comparative study with ultrasound Doppler.

Aims: Peripheral arterial disease (PAD) is a major public health burden requiring more intensive population screening. Ankle brachial index (ABI) using arm and ankle cuffs is considered as the reference method for the detection of PAD. Although it requires a rigorous methodology by trained operators, it remains time-consuming and more technically difficult in patients with diabetes due to mediacalcosis. Techniques based on the study of hemodynamic, such as the systolic rise time (SRT), appear promising but need to be validated. We retrospectively compared the reliability and accuracy of SRT using a photoplethysmography (PPG) technique to the SRT measured by ultrasound doppler (UD) in PAD patients diagnosed with the ABI (137 patients, 200 lower limbs). Methods and results: There was a significant correlation between SRT measured with UD (SRTud) compared with that with PPG (SRTppg, r = 0.25; P = 0.001). Best correlation was found in patients without diabetes (r = 0.40; P = 0.001). Bland and Altman analysis showed a good agreement between the SRTud and SRTppg. In contrast, there was no significant correlation between UD and PPG in diabetes patients. Furthermore, patients with diabetes exhibited a significant increase of SRTppg (P = 0.02) compared with patients without diabates but not with the SRTud (P = 0.18). The SRTppg was significantly linked to the arterial velocity waveforms, the type of arterial lesion but not vascular surgery revascularization technique. Conclusion: This monocentric pilot study shows that SRT measured with the PPG signal reliably correlates with SRT recorded with UD. The PPG is an easy to use technique in the hand of non-expert with a potential interest for general screening of PAD, especially in diabetes patients, due to its ease to use.

Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation.

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.