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Background Peripheral arterial disease (PAD) is associated with considerable mortality and morbidity worldwide. The present study explored the risk factors for arterial calcification among the different sections of the lower extremity in patients with PAD and analyzed their correlations with the extent of arterial stenosis at the corresponding section. Methods This study enrolled symptomatic PAD patients from our hospital from March 2017 to March 2018. The lower extremity arterial calcification score (LEACS) and lower extremity arterial stenosis index (LEASI), representing the extent of arterial stenosis, were measured on computed tomography (CT) and the correlations between them were analyzed using Spearman’s correlation analysis. The relationships between risk factors and calcification were analyzed among the different sections of the lower extremity artery. Results In total, 209 patients were included. The LEACSs of the total lower extremity, aortoiliac artery, and femoropopliteal and infrapopliteal arteries were correlated with the LEASI (all P  < 0.05), but their correlation was relatively weak in the aortoiliac artery. Univariate analysis showed that hypertension was associated with the total ( P  = 0.019) and aortoiliac ( P  = 0.012) LEACSs. Diabetes was related to both femoropopliteal ( P  = 0.001) and infrapopliteal ( P  = 0.002) LEACSs. The infrapopliteal LEACS was higher in male patients ( P  = 0.011). After adjustment for age, the above relationships were maintained among the different sections, but not in the total lower extremity artery. Conclusions The LEACS is associated with the LEASI in all arterial sections, but that of the aortoiliac artery was relatively weak. Different factors have different effects on calcification among the various sections of the lower extremity artery.

Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of life. In the spectrum of heritable ectopic mineralization disorders are also generalized arterial calcification of infancy (GACI), with extremely severe arterial calcification diagnosed by prenatal ultrasound or perinatally, and arterial calcification due to CD73 deficiency (ACDC) manifesting with arterial and juxta-articular mineralization in the elderly; the latter disorders are caused by mutations in ENPP1 and NT5E, respectively. The unifying pathomechanistic feature in these three conditions is reduced plasma levels of inorganic pyrophosphate (PPi), a powerful endogenous inhibitor of ectopic mineralization. Several on-going attempts to develop treatments for these conditions, either with the goal to normalize PPi plasma levels or by means of preventing calcium hydroxyapatite deposition independent of PPi, are in advanced preclinical levels or in early clinical trials. This overview summarizes the prospects of treatment development for ectopic mineralization disorders, with PXE, GACI and ACDC as the target diseases, from the 2020 vantage point.

Generalized arterial calcification of infancy (GACI) is a rare disease characterized by arterial calcification. GACI is caused by a mutation in the ENPP1 or ABCC6 genes. GACI causes severe hypertension and heart failure, and approximately 50% of patients die within the first 6 months. In particular, preterm infants with GACI often die due to immature cardiac function. Bisphosphonates are effective in treating GACI; however, no standardized treatment regimen is available. We experienced a case of a preterm infant with GACI born at 30 weeks gestation. Ultrasonography showed high-intensity lesions in the arteries, and computed tomography revealed calcification of the arteries throughout the body, leading to the diagnosis of GACI. We administered intravenous pamidronate, and her cardiac contraction improved. The initial scheduled interval between drug administrations was 2 months. However, the cardiac contraction worsened 1 month after the pamidronate administration. Therefore, we decreased the dosing interval and administered a second course of pamidronate, which improved her cardiac function. We then switched to oral etidronate. To improve the morbidity and mortality rates of preterm infants with GACI, it is important to obtain an early diagnosis of GACI by investigating high-intensity lesions in the arteries and performing early administration of an appropriate type of bisphosphonate.

Background Generalized Arterial Calcification of Infancy (GACI) is a heritable ectopic mineralization disorder resulting in diffuse arterial calcifications and/or stenosis, mostly caused by mutations in the ENPP1 gene. Here we present a case report of GACI in a male infant with a new familial mutation of the ENPP1 gene and the clinical outcome after biphosphonates therapy. Case presentation The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. To investigate this atypical hypertension, a renal Doppler ultra-sonography was performed and diffuse echo-bright arteries were detected; then a low-dose whole-body computed tomography demonstrated extensive arterial calcifications, suggesting GACI. A novel homozygous mutation c.784A > G (p.Ser262Gly) was detected in the ENPP1 gene. The infant was administered four courses of bisphosphonates: arterial calcifications were found to decrease but severe refractory hypertension was persistent . Although GACI can be a rapidly fatal illness and frequently results in death in infancy, the patient was 24 months of age at the time of writing this report. Conclusions Three points of interest: the first one is to remind clinicians of this rare and atypical etiology in neonates with severe hypertension and in fetuses with cardiomyopathy and non-immune hydrops fetalis. The second point is the identification of a novel mutation in the ENPP1 gene associated with a clinical presentation of GACI. The third point is the fairly favourable outcome of our patient after bisphosphonates therapy, with calcifications regression but not hypertension.

Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disorder, characterized by calcification of the internal elastic lamina, fibrotic myointimal proliferation of muscular arteries and resultant arterial stenosis. Treatment with bisphosphonates has been proposed as a means of reducing arterial calcifications in GACI patients, although there is no formalized treatment approach. The case reported here was a patient with severe GACI diagnosed at three months of age who had no response to bisphosphonate treatment, but clinically improved after the initiation of magnesium and anti-phosphate (using calcium carbonate) treatments. In patients unresponsive to bisphosphonate, magnesium and anti-phosphate treatment may be attempted.

•Generalized arterial calcification in infancy (GACI) is a rare genetic disorder.•GACI is characterized by abnormal vascular calcification and marked myointimal proliferation.•GACI is often fatal due to complications of cardiac ischemia, hypertension and cardiac failure.•Postmortem Computed Tomography demonstrates abnormal vascular and soft tissue calcification. Generalized arterial calcification in infancy is a rare genetic disorder characterized by abnormal calcification of large and medium sized arteries and marked myointimal proliferation resulting in arterial stenosis. The condition is often fatal secondary to complications of cardiac ischemia, hypertension and cardiac failure. In this report we describe the findings at post mortem computed tomography, histology and autopsy.

Background Heart failure and peripheral artery disease (PAD) are the two most common cardiovascular diseases (CVD) in individuals with type 2 diabetes mellitus (T2DM). The T 50 calciprotein crystallization test measures the transformation of calciprotein particles type 1 (CPP1) into CPP2 in vitro and has been introduced as a low-cost biomarker for arterial calcification and CVD risk. We aimed to investigate the association between T 50 and (1) heart failure with preserved ejection fraction (HFpEF), (2) ankle-brachial index (ABI) as measure of PAD, (3) pulse wave velocity (PWV) as measure of central arterial stiffness and (4) arterial calcification in individuals with T2DM. Methods Cross-sectional data was used of 771 individuals with T2DM (64% men, 67 [63–71] years). T 50 was measured using nephelometry on non-fasting serum samples. Presence of HFpEF was assessed with echocardiography based on current guidelines. ABI was categorized as ≤ 0.9 (PAD), 0.9–1.4 (normal) and ≥ 1.4 (high). Central arterial stiffness was measured using carotid-femoral PWV. Lower-extremity and coronary calcification were measured using computed tomography and quantified using Agatston scores categorized into zero (reference category) and tertiles > 0. Multivariable-adjusted Poisson, multinomial and linear regression analyses were used to study the associations with aforementioned surrogate CVD risk markers. Results Mean T 50 was 355 ± 55 min. HFpEF and PAD were present in 36.6% and 5.8% of the cohort, respectively. Mean cfPWV was 12.9 ± 2.5 m/s. Median calcification scores in the coronary arteries and lower-extremities were 315 [40–1246] and 791 [64–3820] Agatston units, respectively. Every 60-min decrease in T 50 , indicating higher calcification risk, was associated with increased coronary arterial calcification (e.g. highest tertile OR = 1.63 [1.15–2.30], p  = 0.006), but not with lower-extremity arterial calcification (e.g. highest tertile OR = 1.28 [0.96–1.69], p  = 0.088). Moreover, T 50  ≤ 330 min versus T 50  ≥ 390 min was associated with PAD (OR = 3.04 [1.03–8.94], p  = 0.044). Finally, every 60-min decrease in T 50 was not associated with neither HFpEF (RR = 1.02 [0.90–1.17], p  = 0.736) nor cfPWV (β =  − 0.08 [ − 0.26–0.10], p  = 0.398). Conclusion Low T 50 was associated with increased risks of coronary arterial calcification and PAD (measured by ABI ≤ 0.9) in individuals with T2DM, but not with HFpEF, central arterial stiffness and lower-extremity arterial calcification. Further research is warranted to evaluate the additive value of T 50 in CVD risk stratification in clinical care.

Idiopathic infantile arterial calcification (IIAC) is a rare disorder characterized by extensive calcification of medium and large arteries. We report the case of a 32-week-old infant with hydrops fetalis and heart failure who died at 4 days of age. At autopsy the infant was found to have cardiomegaly, myocardial infarctions and multifocal calcifications of the aorta and arteries in the lungs, heart, thyroid, spleen, and testis. Calcification extended from the internal elastic lamina into the intima and media and was associated with a giant-cell reaction and smooth muscle proliferation. A search of the English language medical literature identified 161 IIAC case reports. Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory distress in a previously healthy infant. Significantly, 19 of 22 IIAC survivors presented at less than 2 weeks of age, and 15 survivors were treated with diphosphonates.

This meta-analysis was conducted to clarify the role of klotho and fibroblast growth factor 23 (FGF-23) in human arterial remodeling across recent studies, in terms of arterial calcification, thickness, and stiffness. A systematic literature search was conducted on five databases for articles up to December 2023. Arterial calcification, thickness, and stiffness were determined using the calcification score and artery affected, carotid intima–media thickness (CIMT), and pulse wave velocity (PWV), respectively. Sixty-two studies with a total of 27,459 individuals were included in this meta-analysis. Most studies involved chronic kidney disease patients. Study designs were mostly cross-sectional with only one case–control and nine cohorts. FGF-23 was positively correlated with arterial calcification (r = 0.446 [0.254–0.611], p < 0.0001 and aOR = 1.36 [1.09–1.69], p = 0.006), CIMT (r = 0.188 [0.02–0.354], p = 0.03), and PWV (r = 0.235 [0.159–0.310], p < 0.00001). By contrast, Klotho was inversely correlated with arterial calcification (r = − 0.388 [− 0.578 to − 0.159], p = 0.001) and CIMT (r = − 0.38 [− 0.53 to − 0.207], p < 0.00001). In conclusion, FGF-23 and Klotho were associated with arterial calcification, thickness, and stiffness, clarifying their role in arterial remodeling processes.

Purpose Generalized arterial calcification of infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods We performed deep phenotyping of 20 GACI survivors. Results Sixteen of 20 subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusion GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.