Editorial: Cardiovascular calcification: disease mechanisms, clinical phenotypes and therapeutic strategies

Highlighting the importance of extracellular vesicles in CVC pathogenesis, Li and colleagues revealed that bone marrow mesenchymal stem cell-derived exosomes containing microRNA-335 attenuate CVC by inhibiting SP1 and RUNX2 expression 7 . AgomiR-335 treatment in a rat model significantly reduced aortic calcification burden. This study shows that multi-organ mechanisms are involved in CVC pathophysiology, demonstrating an important cross-talk between the bone marrow and arterial blood vessels.Excessive inflammatory responses drive the formation of atherosclerotic plaques and subsequent calcification. Interferon regulartory factors (IRFs) play a crucial role in modulating these inflammatory mechanisms, as described in the review article of Wang and colleagues 8 . IRF8 in particular has been shown to regulate CVC by stimulating the transdifferentiation of vascular smooth muscle cells towards macrophages, promoting matrix degradation through MMP9, forming a nidus on which calcium crystal deposition can occur. Indeed, the pathogenic role of MMP9 in CVC is widely recognized, as indicated by earlier studies in the Mendelian disorder PXE 9,10 . Similar to the interferon family of cytokines, interleukins have been shown to be an integral part of immune signaling-related pathological mineralization as described by Zhao et al 11 . In a clinical context, interleukins can be easily targeted by monoclonal antibodies such as ziltivekimab, an IL-6-inhibiting protein whose efficacy in reducing cardiovascular disease is currently under investigation in the multinational placebo-controlled ZEUS trial (NCT05021835) including patients with established atherosclerotic cardiovascular disease, CKD and systemic inflammation 12 .Extracellular matrix components, in particular elastic fibers, play a fundamental role in CVC pathogenesis by forming a scaffold on which calcium crystal formation can be initiated. In their comprehensive review article, Lofaro and colleagues provide an overview on elastic fiber homeostasis and disruption in CVC and highlight the importance of elastic fiber-associated molecules such as fibrillins and proteoglycans 13 . Interestingly, treatment with nanoparticles containing calcium chelating agents and which are coated with antibodies specifically binding to degraded elastin has shown promising results in CVC models 14 . These nanoparticles carry potential for becoming the first therapy which can effectively resolve already existing hydroxyapatite crystal deposits, partially restoring the physiological biomechanical and molecular signaling properties of elastic fibers.At the clinical level, the work from Deng and Qin shed further light on the association between obesity and CVC 15 . The authors found an inverse U-shaped association between lipid accumulation product index and abdominal aortic calcification in a national cohort of nearly 3000 participants. While hormonal disturbances, including altered leptin levels, have been shown to contribute to CVC pathogenesis by increasing osteochondrogenic transdifferentiation of vascular smooth muscle cells and activating RUNX2, it remains unknown why a very high lipid accumulation product index seems to protect individuals from CVC 16 .Similarly, Tan and colleagues showed that the Naples prognostic score, comprising serum albumin and total cholesterol levels as well as leukocyte ratios, significantly and positively associated with severe abdominal aortic calcification 17 . These leukocyte ratios are of particular interest, as excessive inflammation is a known risk factor for CVC development. Additionally, impaired resolution of the inflammation response has also been identified in calcific aortic valve disease (CAVD) and atherosclerosis 18 .CAVD is a major cause of structural heart disease and identifying its genetic architecture may improve understanding and treatment. Using bulk RNA sequencing, Wang et al. identified 16 hub genes, including ITGB3, ITGAV, and MMP9 and demonstrated good diagnostic performance for CAVD 19 . Furthermore, MMP9 and PLAU likely contribute to disease progression by promoting inflammatory responses in monocytes and macrophages.Preclinical models play a pivotal role to study CAVD. In their extensive review Lafosse and colleagues assessed their strengths and limitations and how they can be used to investigate the cellular and molecular mechanisms involved in CAVD 20 . The central role of macrophages in CAVD was reviewed by Issa et al., highlighting the opposing effects of inflammatory macrophages -which promote the osteogenic transformation of valvular interstitial cells (VIC) though the release of numerous cytokines -and immunomodulatory macrophages, which release PPi hence protecting against valvular calcification 21 .The potential of nutrient restriction (NR) to mitigate VIC calcification through the ubiquitinproteasome system (UPS) was studied by Phadwal and co-authours 22 . NR significantly downregulated osteogenic markers and decreased calcium deposition in rat VICs. This study highlights NR as a promising non-invasive intervention for preventing VIC calcification by modulating the UPS.As highlighted by O'Brien et al., medial vascular calcification remains a major unmet therapeutic challenge, particularly in genetic disorders, diabetes mellitus, and CKD 23 . Central to emerging strategies is restoration of PPi homeostasis and approaches ranging from direct PPi supplementation and bisphosphonates to recombinant ENPP1 replacement and alkaline phosphatase inhibition illustrate a shift toward mechanism-based therapies aimed at correcting metabolic drivers of calcification. Adjunctive strategies including phosphate binders, magnesium, and vitamin K further emphasize the multifactorial nature of mineral imbalance in ectopic calcification.Beyond prevention, advances in interventional cardiology are reshaping management of established calcified lesions. Zhang et al. demonstrate that intravascular lithotripsy may preserve coronary microvascular function more effectively than rotational atherectomy, as reflected by lower post-procedural microvascular resistance following PCI in heavily calcified vessels 24 . Although clinical event differences were not statistically significant, these findings suggest that plaque-modifying technologies can influence downstream microvascular biology, highlighting the importance of procedural strategies that minimize embolization and inflammatory injury associated with calcium disruption.In a broader context of vascular health, the study by Feng and colleagues revealed that aging and prolonged cold exposure synergistically impair vascular healing after drug-eluting stent implantation in elderly patients, leading to delayed endothelialization and excessive neointimal growth, ultimately increasing the risk of major adverse cardiovascular events 25 . Using serial optical coherence tomography imaging and environmental data, the authors propose a novel 4D risk score for personalized risk stratification.Finally, Bergeon et al. expand the therapeutic scope by linking CAVD with inflammation and autonomic dysregulation, proposing preoperative transcutaneous vagus nerve stimulation as a novel preventive strategy for postoperative atrial fibrillation 26 . By enhancing parasympathetic tone and promoting resolution of inflammation, neuromodulation may address both arrhythmogenic substrates and inflammatory pathways associated with CAVD.To conclude, we would like to highlight the importance of multinational interdisciplinary research collaborations in the field of CVC, which can greatly accelerate research progress. Both the International Network on Ectopic Calcification (INTEC, www.itnintec.com) and the International Scientific Society of Ectopic Calcification (ISSEC, www.issec.org) have been created to this end and comprise both basic and clinical researchers as well as patient advocacy groups and representatives from the pharmaceutical industry. Scientific work of multiple INTEC/ISSEC members has been included in this Research Topic. These networks may significantly advance fundamental and clinical research discoveries and their translation towards the ultimate objective: a safe, affordable, and effective treatment for patients with CVC disorders.