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Valve replacement is the main therapy for valvular heart disease, in which a diseased valve is replaced by mechanical heart valve (MHV) or bioprosthetic heart valve (BHV). Since the 2000s, BHV surpassed MHV as the leading option of prosthetic valve substitute because of its excellent hemocompatible and hemodynamic properties. However, BHV is apt to structural valve degeneration (SVD), resulting in limited durability. Calcification is the most frequent presentation and the core pathophysiological process of SVD. Understanding the basic mechanisms of BHV calcification is an essential prerequisite to address the limited-durability issues. In this narrative review, we provide a comprehensive summary about the mechanisms of BHV calcification on 1) composition and site of calcifications; 2) material-associated mechanisms; 3) host-associated mechanisms, including immune response and foreign body reaction, oxidative stress, metabolic disorder, and thrombosis. Strategies that target these mechanisms may be explored for novel drug therapy to prevent or delay BHV calcification.

Ectopic calcification (EC) of myofibers is a pathological feature of muscle damage in Duchenne muscular dystrophy (DMD). Mineralisation of muscle tissue occurs concomitantly with macrophage infiltration, suggesting a link between ectopic mineral deposition and inflammation. One potential link is the P2X7 purinoceptor, a key trigger of inflammation, which is expressed on macrophages but also up-regulated in dystrophic muscle cells. To investigate the role of P2X7 in dystrophic calcification, we utilised the Dmd mdx- βgeo dystrophin-null mouse model of DMD crossed with a global P2X7 knockout ( P2rx7 −/− ) or with our novel P2X7 knockin-knockout mouse ( P2x7 KiKo ), which expresses P2X7 in macrophages but not muscle cells. Total loss of P2X7 increased EC, indicating that P2X7 overexpression is a protective mechanism against dystrophic mineralisation. Given that muscle-specific P2X7 ablation did not affect dystrophic EC, this underlined the role of P2X7 receptor expression on the inflammatory cells. Serum phosphate reflected dystrophic calcification, with the highest serum phosphate levels found in genotypes with the most ectopic mineral. To further investigate the underlying mechanisms, we measured phosphate release from cells in vitro , and found that dystrophic myoblasts released less phosphate than non-dystrophic cells. Treatment with P2X7 antagonists increased phosphate release from both dystrophic and control myoblasts indicating that muscle cells are a potential source of secreted phosphate while macrophages protect against ectopic mineralisation. Treatment of cells with high phosphate media engendered mineral deposition, which was decreased in the presence of the P2X7 agonist BzATP, particularly in cultures of dystrophic cells, further supporting a protective role for P2X7 against ectopic mineralisation in dystrophic muscle.

Previous CKD-animal models primarily focused on a certain histological abnormality but lacked investigations of the interplay of EC in various tissues. This study compared calcified deposition in several tissues during CKD progression in mice, which was closely related. The severity of CKD was unparalleled with the development of ectopic calcification. Glomerular and tubular basement membrane calcification was detected in CKD mice, which has been considered extremely rare in clinical. Ectopic calcification (EC) involves multiple organ systems in chronic kidney disease (CKD). Previous CKD-animal models primarily focused on a certain histological abnormality but did not show the correlation with calcified development among various tissues. This study compared calcified deposition in various tissues during CKD progression in mice. Male 8-week-old C57BL/6J mice were randomly allocated to the seven groups: a basic, adenine, high-phosphorus, or adenine and high-phosphorus diet for 12-16 weeks (Ctl16, A12, P16, or AP16, respectively); an adenine diet for 4-6 weeks; and a high-phosphorus or adenine and high-phosphorus diet for 10-12 weeks (A6 + P10, A4 + P12, or A4 + AP12, respectively). Compared to the Ctl16 mice, the P16 mice only displayed a slight abnormality in serum calcium and phosphorus; the A12 mice had the most serious kidney impairment; the A4 + P12 and A6 + P10 mice had similar conditions of CKD, mineral abnormalities, and mild calcification in the kidney and aortic valves; the A4 + AP12 and AP16 groups had severe kidney impairment, mineral abnormalities and calcification in the kidneys, aortic valves and aortas. Furthermore, calcium-phosphate particles were deposited not only in the tubulointerstitial compartment but in the glomerular and tubular basement membrane. The elemental composition of EC in various tissues matched the calcification of human cardiovascular tissue as determined by energy dispersive spectroscopy. The severity of CKD was unparalleled with the progression of mineral metabolism disorder and EC. Calcification was closely related in different tissues and observed in the glomerular and tubular basement membranes.

Summary Type V osteogenesis imperfecta (OI) is a form of OI characterized by radial head dislocation (RHD), calcification of interosseous membrane (CIM), and hyperplastic callus (HPC). In this study, we characterized the clinical features of 28 type V OI patients. We presented that dysfunctions of elbow, hip joint, and abnormal epiphyseal growth plate were associated with ectopic calcification and summarized the history of HPC progression and treatment. Introduction The current study aims to systematically characterize the skeletal phenotypes of patients with type V OI and suggested possible surgical solutions. Methods A total of 28 patients were admitted for inpatient care at The Hong Kong University-Shenzhen Hospital diagnosed with type V OI (either clinically diagnosed or genetically confirmed with the IFITM5 c.-14C > T mutation). Results Prevalence of type V radiological features was comparable to previous literatures (RHD, 100%; CIM, 100%; HPC, 44%; and scoliosis, 50%). Novel skeletal phenotypes were presented including extension of coronoid process, acetabular labrum, acetabular protrusion, spontaneous autofusion of the hip, bulbous epiphysis, and popcorn calcification. Significant increase in BMD was observed in patients with bisphosphonate treatment. Twenty-five percent (3/12) of patients with preoperative use of indomethacin developed HPC postoperatively, and HPCs were absorbed in 2 young patients 2 years later. Conclusion This retrospective study summarized the clinical features and highlighted the abnormalities in elbow, hip joint, and growth plate in type V OI patients. Our study contributed to a more comprehensive clinical spectrum of type V OI. We also characterized the natural progression of HPC formation and resorption in patients in different ages. The use of bisphosphonate treatment is effective in improving bone mineral density in type V OI patients, and whether indomethacin can reduce incidence of HPC formation deserves further investigation.

Vascular calcifications are characterized by the ectopic deposition of calcium and phosphate in the vascular lumen or wall. They are a common finding in computed tomography scans or during autopsy and are often directly related to a pathological condition. While the pathogenesis and functional consequences of vascular calcifications have been intensively studied in some peripheral organs, vascular calcification and its pathogenesis in the central nervous system is poorly characterized and understood. Here, we review the occurrence of vessel calcifications in the brain in the context of aging and various brain diseases. We discuss the pathomechanism of brain vascular calcification in primary familial brain calcification as an example of brain vessel calcification. A particular focus is the response of microglia to the vessel calcification in the brain and their role in the clearance of calcifications.

We report a 64-year-old Japanese woman with a history of progressive loss of motor function and painful swelling of large joints. At the age of 54, profound calcification appeared around the shoulder and hip joints, which did not heal after repeated surgical resections. Iliac bone biopsy revealed osteomalacic changes. Laboratory data showed low serum alkaline phosphatase (ALP) activity and a high urine phosphoethanolamine (PEA) concentration with normal serum calcium, phosphate, and fibroblast growth factor 23 (FGF23) levels. Subsequent genetic analysis of the ALPL gene confirmed the diagnosis of hypophosphatasia (HPP) with the identification of a heterozygous single nucleotide deletion, c.1559delT (p.Leu520ArgfsX86). We started a mineral-targeted enzyme replacement therapy, asfotase alfa (AA), to treat the patient’s musculoskeletal symptoms. A follow-up bone biopsy after 12 months of AA treatment showed improvement of osteomalacia. Calcified deposits around the large joints were unchanged radiographically. To our knowledge, this is the first report of a patient with an adult-onset HPP who presented with profound calcification around multiple joints. Nonspecific clinical signs and symptoms in patients with adult-onset HPP often result in delayed diagnosis or misdiagnosis. We propose that bone biopsy and genetic analysis should be considered along with laboratory analysis for all patients with ectopic calcification around joints of unknown etiology for accurate diagnosis and better treatment.

Osteocalcin (OC) is the main non-collagenous hydroxyapatite-binding protein synthesized by osteoblasts, odontoblasts, and hypertrophic chondrocytes. It has a regulatory role in mineralization and it is considered a marker of bone cell metabolism. Recent findings evidenced new extra-skeletal roles for OC, depicting it as a real hormone. OC shares many functional features with the common hormones, such as tissue-specific expression, circadian rhythm, and synthesis as a pre-pro-molecule. However, it has some peculiar features making it a unique molecule: OC exists in different forms based on the degree of carboxylation. Indeed, OC has three glutamic acid residues, in position 17, 21, and 24, which are subject to γ-carboxylation, through the action of a vitamin K-dependent γ-glutamyl carboxytransferase. The degree of carboxylation, and thus the negative charge density, determines the affinity for the calcium ions deposited in the extracellular matrix of the bone. The modulation of the carboxylation could, thus, represent the mechanism by which the body controls the circulating levels, and hence the hormonal function, of OC. There are evidences linking OC, and the bone metabolism, with a series of endocrine (glucose metabolism, energy metabolism, fertility) physiological (muscle activity) and pathological functions (ectopic calcification). Aim of this review is to give a full overview of the physiological roles of OC by collecting the newest experimental findings on this intriguing molecule.

Pseudoxanthoma elasticum (PXE (OMIM 264800)) is an autosomal recessive connective tissue disorder mainly caused by mutations in the ABCC6 gene. PXE results in ectopic calcification primarily in the skin, eye and blood vessels that can lead to blindness, peripheral arterial disease and stroke. Previous studies found correlation between macroscopic skin involvement and severe ophthalmological and cardiovascular complications. This study aimed to investigate correlation between skin calcification and systemic involvement in PXE. Ex vivo nonlinear microscopy (NLM) imaging was performed on formalin fixed, deparaffinized, unstained skin sections to assess the extent of skin calcification. The area affected by calcification (CA) in the dermis and density of calcification (CD) was calculated. From CA and CD, calcification score (CS) was determined. The number of affected typical and nontypical skin sites were counted. Phenodex + scores were determined. The relationship between the ophthalmological, cerebro- and cardiovascular and other systemic complications and CA, CD and CS, respectively, and skin involvement were analyzed. Regression models were built for adjustment to age and sex. We found significant correlation of CA with the number of affected typical skin sites ( r  = 0.48), the Phenodex + score ( r  = 0.435), extent of vessel involvement ( V -score) ( r  = 0.434) and disease duration ( r  = 0.48). CD correlated significantly with V -score ( r  = 0.539). CA was significantly higher in patients with more severe eye ( p  = 0.04) and vascular ( p  = 0.005) complications. We found significantly higher CD in patients with higher V -score ( p  = 0.018), and with internal carotid artery hypoplasia ( p  = 0.045). Significant correlation was found between higher CA and the presence of macula atrophy ( β  = − 0.44, p  = 0.032) and acneiform skin changes ( β  = 0.40, p  = 0.047). Based on our results, the assessment of skin calcification pattern with nonlinear microscopy in PXE may be useful for clinicians to identify PXE patients who develop severe systemic complications.

Background Ectopic calcification, especially in soft tissues such as subcutaneous adipose tissue, is a rare and serious complication in chronic kidney disease (CKD) patients. It is commonly associated with cardiovascular morbidity and mortality. This case report highlights the occurrence of multiple ectopic calcifications in a patient with end-stage renal disease (ESRD) on peritoneal dialysis, emphasizing the role of inflammatory cytokines in the pathogenesis of this condition. Early and appropriate intervention can facilitate partial reversibility, highlighting the importance of regular follow-ups and the optimization of prescriptions, particularly in ensuring intensified high-quality, goal-oriented dialysis. Case presentation A 68-year-old female patient with diabetic nephropathy had been on maintenance peritoneal dialysis for four years. She presented with multiple subcutaneous nodules, particularly in the abdomen and lower limbs, for over a month. Ultrasound and non-contrast CT imaging revealed hyperechoic lesions and calcifications in the subcutaneous tissue, along with vascular and kidney calcifications. Laboratory results indicated inadequate dialysis, hypocalcemia, hyperphosphatemia, and significantly elevated serum parathyroid hormone (PTH) and inflammatory cytokines, including IL-6. The biopsy of the subcutaneous nodule from the lower abdomen revealed calcification and inflammation, accompanied by pronounced IL-6 expression. Treatment included intensified automated peritoneal dialysis (APD) combined with icodextrin peritoneal dialysis solution for long-term retention in the abdomen, cinacalcet, phosphate binders, calcitriol, and nutritional support. After one month, the patient’s condition showed significant improvement, with reduced calcification confirmed by follow-up ultrasound. Conclusions This case underscores the rarity of subcutaneous adipose tissue calcification in ESRD patients and highlights the crucial role of inflammatory factors, particularly IL-6, in the development of ectopic calcifications. Early, targeted interventions, especially high-quality, goal-directed dialysis, can significantly improve outcomes, illustrating the importance of regular monitoring and tailored treatment in preventing and managing calcification in CKD patients. Clinical trial number Not applicable.