Chen J-H, Yip CYY, Sone ED, Simmons CA. Arterial calcification impairs vascular resistance, thereby contributing to heart failure, and increases atherosclerotic plaque rupture risk contributing to heart … doi: 10.1007/s10753-012-9579-6. JACC Cardiovasc. VECs have been shown to signal the activation and calcification of VICs through the regulation of NO (75, 76), an important inhibitor of calcification (77–79). View all Huang H, Virmani R, Younis H, Burke AP, Kamm RD, Lee RT. Biol Trace Elem Res. (2016) 19:603–13. doi: 10.1084/jem.20020911, 91. doi: 10.1016/j.atherosclerosis.2008.07.010, 126. 10.1016/j.jcmg.2018.02.015 The purinergic … Recent progress in the treatment of vascular calcification. The oscillatory shear stresses experienced by VECs on the fibrosa side of the valve can lead to endothelial layer disruption as well as specific changes in cellular pathway expressions. (2015) 35:A582–2. 10.3390/ijms20153708 As described below, some studies propose that the process of activated VICs remodeling their surroundings causes these crystals, while others focus on endothelial disruption allowing calcium phosphate from the blood into the tissue. Due to a lack of organ donors, bioprosthetic implants are mostly made from porcine or bovine tissue. When vascular calcification is seen with atherosclerosis, statins have are used to reduce the rate of disease progression (122). Due to insensitive testing modalities, early calcification is also difficult to study in vitro as extremely low calcium levels are difficult to distinguish from background noise. Dynamic and complex molecular networks participate in vascular calcification [].Traditional single-mechanism experiments are relatively one-sided and cannot use big data to describe a state of disease … The cellular components found within the interior of valves and vasculature are vastly different and are likely key contributors to their pathologies as described later. TEHVs are generally created through a combination of ECM scaffolding populated with cells. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Batlivala SP, Emani S, Mayer JE, McElhinney DB. (2016) 118:692–702. Nissen SE, Nicholls SJ, Sipahi I. Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, et al. This results in valves that can neither open or close fully, which reduces mean ejection fraction and increases regurgitation. also show that WSS varies across the leaflet orientation, with radial WSS being significantly a higher component to the total WSS than is circumferential. While specifics are unclear, it is now well-accepted that there is a complex crosstalk between cells, ECM, biochemical cues and biomechanical changes during CAVD, and that these interactions drive mineralization. Di Vito A, Donato A, Presta I, Mancuso T, Brunetti FS, Mastroroberto P, Amorosi A, Malara N, Donato G. Int J Mol Sci. Atherosclerosis (2016) 253:124–7. J Mol Cell Cardiol. When the aortic valve is compromised by calcification, pulse pressure in arteries are markedly lower than in the physiologically healthy system (9, 84). Inactivation of the osteopontin gene enhances vascular calcification of matrix gla protein–deficient mice. doi: 10.1002/term.1964, 96. Carotid endarterectomies are common practice when patient's carotid artery is severely calcified (>70% reduction in diameter) to remove material from the artery. For instance, both a reduction in NO production and the disruption of the endothelial layer are shown to be initiators of severe valvular and vascular calcification. doi: 10.1161/01.ATV.5.3.293, 87. Treatment options specific to combatting vascular calcification are not a current clinical prospect, although treatments are currently under investigation in animal studies. Stephens EH, Chu C-K, Grande-Allen KJ. Despite this change at the geometric variation, overall the majority of stresses are unidirectional and constant. eCollection 2018. Histological structure of the aortic valve. doi: 10.1007/s10439-006-9163-z, 119. Overview of Similarities and Differences of Calcification in Valves and Vasculature. doi: 10.1016/S0140-6736(00)02844-0, 110. Based on the research presented in this review, treatment options targeting CAVD should be investigated using either aspects of the disease that are unique to calcified valves, or bona fide commonalities between the two diseases. Front. Med. (8.0 in.) (2007) 362:1421–36. Diastolic and systolic forces on the valve leaflets. A majority of individuals over the age of 60 have calcification exhibiting as enlarging calcium deposits found in their arteries (6). HHS Cardiovasc Pathol. Studies of the long-term performance of trans-catheter valves show this implementation method improves outcomes for high risk patients by circumventing the need for open heart surgery while still maintaining the implant integrity (110, 111). While it is now accepted that calcification is not due to passive degradation throughout patient lifetime, aging is still the best predictor of disease onset. 14. These cells directly interact with blood and the shear forces associated with its flow through the valve. (2018) 75:52–62. doi: 10.1093/eurheartj/ehx075, 121. These inflammatory cells, which are predominantly macrophages, can play active roles in the progression of calcification and remodeling of surrounding ECM (72, 73). doi: 10.1152/physrev.00047.2009, 49. 41. (2002) 196:1047–55. The presence and burden of coronary artery calcium (CAC) is a strong predictor of cardiovascular events. -, Alushi B., Beckhoff F., Leistner D., Franz M., Reinthaler M., Stahli B. E., et al. Similar to their roles in valves, elastin provides elastic recoil, extensibility and load bearing to the vasculature whereas collagen also affects tissue strength and extensibility. In a more recent study, post-menopausal women, who are at greater risk for vascular calcification, were shown to have a decreased risk of coronary calcification with increased vitamin K2 intake (125). doi: 10.3389/fendo.2012.00095, 10. doi: 10.1016/j.jbiomech.2017.10.014, 60. (2009) 42:1804–24. 12 doi: 10.1007/s10558-009-9089-9, 69. The heart is comprised of four chambers that are separated from one other and from nearby vasculature by four valves. Mathieu P, Bossé Y, Huggins GS, Corte A Della, Pibarot P, Michelena HI, et al. Valvular endothelial cells and the mechanoregulation of valvular pathology. doi: 10.1002/jcb.24031, 64. Changes in cellular expression can change the macro structure of the valve leaflets, which creates a positive feedback loop instigating calcification. Dynamic stiffening of poly(ethylene glycol)-based hydrogels to direct valvular interstitial cell phenotype in a three-dimensional environment. J Biomed Mater Res Part A (2009) 90A:1043–53. While there are no non-surgical treatments for CAVD, the progression of vascular calcification can be hindered by treating the preceding disease that instigated the calcification. 2020 Oct 9;21(20):7434. doi: 10.3390/ijms21207434. Paranya G, Vineberg S, Dvorin S, Kaushal S, Roth SJ, Rabkin E, et al. Crystallization of hydroxyapatite results in depositions of calcium in the medial layer, leading to the arterial stiffening. Although both heart valves and vasculature exhibit calcification and share some of the underlying processes leading toward mineralization, few significant correlations between the two have been made. However, on the non-coronary leaflet there is no outlet and thus the blood pools and exerts significant oscillatory shear forces. (1985) 5:293–302. Both occur as a result of an incident during the enamel’s formation period. (2013). J Cell Biochem. The authors would like to acknowledge Dr. Jennifer Connell for helping in editing the manuscript. Eriksen HA, Satta J, Risteli J, Veijola M, Väre P, Soini Y. Wang D, Uhrin P, Mocan A, Waltenberger B, Breuss JM, Tewari D, et al. Figure 2. Annu Rev Cell Dev Biol. Physiol Rev. Usually, calcification originates at the line of attachment where the leaflet meets the valve wall or in the belly region of the leaflet (52). The underlying pathophysiological pathways that go from inflammation to calcification and, finally lead to severe stenosis, remain, however, incompletely understood. doi: 10.1016/j.yjmcc.2015.01.006, 26. NOTCH1 regulates matrix gla protein and calcification gene networks in human valve endothelium. (2013) 22:1–8. Freeman RV, Otto CM. Calcification in the aortic valve can appear as osteogenic nodules similar to that found in bone (51). doi: 10.1152/physrev.00041.2008. Recent studies suggested that a lower serum thyroid hormone level is associated with more vascular calcification. CAVD begins as a mild sclerosis of the valve that worsens to stenosis and late-stage calcification. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MHJ, Meer IM, et al. Ge L, Sotiropoulos F. Direction and magnitude of blood flow shear stresses on the leaflets of aortic valves: is there a link with valve calcification? In vivo studies in rats have shown that areas of elastin breaks in vessels were significantly correlated with higher levels of calcium depositions (84, 97). Fibrosa, spongiosa, and, ventricularis are the three layers that make up the structure of a normal aortic valve. 5:197. doi: 10.3389/fcvm.2018.00197. NIH The initiation of these crystals is still being investigated. Calcification is the irregular deposition of mineralized crystals that change both the micro- and macro-scale properties of tissue. Cardiovasc. Proteins dependent on vitamin K have been studied to potentially inhibit vascular calcification, such as MGP. Vitamin D deficiency or insufficiency, has been associated with atopy and lack of asthma control. (2015) 1:195–206. (2011) 91:327–387. Bioprosthetic valves have an average life span of 15 years before failure due to structural deterioration, requiring reoperation to replace the valve again (107). (2010) 78:1232–9. J Biomech. Figure 3. (2007) 50:1205–13. Aggarwal S. R., Clavel M. A., Messika-Zeitoun D., Cueff C., Malouf J., Araoz P. A., et al. Ann Biomed Eng. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. In arteries, the tunica media makes up the thickest layer, about 50% of the dry weight, as greater musculature is needed to distribute blood throughout the entire body. 20 (15), 3708. In vasculature, atherosclerosis is the most common occurrence of calcification. doi: 10.1038/nrm809, 82. Broom ND. The aortic valve has a tri-layered structure with more collagen than elastin owing to the demanding need of mechanical strength while still maintaining elastic recoil. Understanding the key differences between vascular and valvular calcification along with the role of mechanical force in their progression will help pinpoint strategies for highly specific treatment options. During systole, blood pumps from the ventricle out to the aorta causing the AV leaflets to separate and bend toward the sinuses of Valsalva (Figure 3B). Cham: Springer (2017). Introduction. At branches in the vasculature and directly downstream of the branches, these stresses shift to become more oscillatory, lower magnitude shear stresses. Nature 504 (7480), 451–455. In the present review, we analyze and discuss the CAVD pathophysiology and future therapeutic strategies, focusing on the real and putative role of inflammation, calcification, and microbiome. VECs help to maintain physiological balances between the valve and its environment but are often considered one of the first mechanisms in valve calcification. |, Variation in Disease Prediction and Treatment, Creative Commons Attribution License (CC BY), Department of Bioengineering, Rice University, Houston, TX, United States. Common conditions such as diabetes, osteoporosis, kidney failure, and menopause are associated with vascular calcification (8, 9). -, Aryal B., Rotllan N., Fernandez-Hernando C. (2014). Sci Transl Med. Patterns and risk factors for systemic calcified atherosclerosis. Prevention and treatment information (HHS). (2006) 12:2131–40. Cao K, BukaC M, Sucosky P. Three-dimensional macro-scale assessment of regional and temporal wall shear stress characteristics on aortic valve leaflets. The capillaries of the vasa are mainly comprised of endothelial cells. See this image and copyright information in PMC. The fibrosa layer of AV leaflets is consistently proposed to be the initiation point for calcific nodules (58), since it is directly exposed to the bidirectional oscillatory shear forces at the valve/blood interface. J Am Coll Cardiol. Surgical treatments are an option for late-stage vascular calcification. doi: 10.1146/annurev-fluid-010313-141309, 88. Deficiency of natriuretic peptide receptor 2 promotes bicuspid aortic valves, aortic valve disease, left ventricular dysfunction, and ascending aortic dilatations in mice. The remaining leaflet is denoted as the non-coronary leaflet. However, it has been rarely evaluated whether lower thyroid hormone levels affect the calcification of thyroid cancer and there is a relationship between calcification patterns of papillary thyroid carcinoma (PTC) and coronary artery calcification … Jian B, Jones PL, Li Q, Mohler ER, Schoen FJ, Levy RJ. (2004)134:3100–5. Quiescent VICs (qVICs) are the most abundant in healthy adult valve tissue. Mechanical or biologic prostheses for aortic-valve and mitral-valve replacement. Mice deficient in osteoprotegerin were found to have calcification of the aorta and renal arteries (94). doi: 10.1101/gad.12.9.1260, 95. doi: 10.1016/j.biomaterials.2015.01.047, 81. Sex differences in aortic valve calcification measured by multidetector computed tomography in aortic stenosis. J Pathol Clin Res. Calcific aortic valve disease (CAVD) is the most common valve disease worldwide (Nkomo et al., 2006).Epidemiological studies show that 2.8% of adults over 75 years old have some CAVD degree, and as many as 25% of adults over 65 years old have at least valvular sclerosis (Miller et al., … In summary, valvular and vascular calcification requires further study to explore proper treatment options. J Am Coll Cardiol. Butcher JT, Nerem RM. 40. Circ Cardiovasc Genet: 489–498, 2009. Thus, the emergence of TEHVs would be a valuable addition to the range of commercially available valve implants. Coté N, Mahmut A, Bosse Y, Couture C, Pagé S, Trahan S, Boulanger MC, Fournier D, Pibarot P, Mathieu P. Inflammation. doi: 10.1161/CIRCULATIONAHA.107.743161, 85. Nat Rev Mol Cell Biol. aVICs can further differentiate into osteoblastic VICs (oVICs), which produce higher levels of alkaline phosphatase and can lead to calcification (34–36). doi: 10.1111/j.1748-1716.2009.01964.x, 50. Lancet (2000) 356:1403–5. Predictors of outcome in severe, asymptomatic aortic stenosis. Vitamin K, specifically vitamin K2, has been found to be inversely related to severe aortic calcification (124). The tunica media, the middle layer, consists of concentric elastic fibers, circumferentially aligned collagen, and vascular smooth muscle cells (39, 40). Puri R, Auffret V. Bioprosthetic valve thrombosis. Increasing intake of this vitamin therefore has the potential to prevent the progression of calcification (124). Valvular stenosis and calcification can be predicted through their risk factors of diabetes, smoking, hypertension, abundance of lipids in the blood system, and various metabolic syndromes (100). Inflammation is associated with the remodeling of calcific aortic valve disease. Am J Cardiol. 15. Rajamannan NM, Subramaniam M, Stock SR, Stone NJ, Springett M, Ignatiev KI, et al. doi: 10.1161/CIRCRESAHA.115.306751, 93. Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization. doi: 10.1161/CIRCRESAHA.115.306361, 42. Circulation (2001) 103:1522–8. As the valve closes for the ventricle to be refilled during diastole, the AV leaflets coapt under axial pressure, generating a tensile strain along the length of the leaflets in the VICs (Figure 3A). -. (2017) 377:1847–57. (2011) 109:564–77. doi: 10.1098/rstb.2007.2125, 6. Understanding the key differences and similarities between these two anatomic areas where calcification occurs may guide research efforts toward better treatments for both. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. Tarbell JM, Shi Z-D, Dunn J, Jo H. Fluid Mechanics, Arterial disease, and gene expression. Circulation (2005) 111:3316–26. Oxidative-mechanical stress signals stem cell niche mediated Lrp5 osteogenesis in eNOS–/– null mice. J Thorac Cardiovasc Surg. Rana Daggubati finally opened about his severe illness on Samantha Akkineni’s new chat show, Sam Jam, This is What He Has To Say. VECs line the surface of the valve leaflets on the ventricularis and fibrosa sides. Avolio A, Jones D, Tafazzoli-Shadpour M. Quantification of alterations in structure and function of elastin in the arterial media. The intensity of shear stress faced by vasculature differs based on both the shape of the vessel and the location of the vessel within the body (Figure 4). doi: 10.1056/NEJM200008313430903, 51. IL-6, interleukin 6; NF-κB, nuclear factor κ-light-chain enhancer of activated B cells; ox-LDL, oxidized low-density lipoprotein; SCFA, short-chain fatty acid; TMAO-Trimethylamine-N oxide; VECs, valve endothelial cells; VICs, vascular interstitial cells. (A) Forces experienced during diastole include compression and oscillatory shear on the fibrosa VECs and tensile strain on the VICs. As stated earlier, vascular calcification is very rarely found in isolation. doi: 10.1146/annurev-cellbio-100814-125610, 25. VSMCs in the intima produce fibrillar collagen, which, over time, contribute to atherosclerotic plaque (46, 47). Human cell derived off-the-shelf Tissue engineered heart valves for next generation transcatheter aortic valve replacement: a proof-of-concept study in adult sheep. Cardiovasc. doi: 10.1001/jama.295.13.jpc60002, 124. Clipboard, Search History, and several other advanced features are temporarily unavailable. In fact, while these conditions are seemingly similar, treatments that help reduce calcification in vasculature have been shown to have no effect on valvular calcification. Early clinical attempts at TEHVs, however, have suffered from fibrosis-like failure due to the continuous activation of the reseeded cells causing rampant collagen formation (115). GAG, glycosaminoglycans; VIC, valve interstitial cell. Wagenseil JE, Mecham RP. (2017) 38:619–21. The emerging role of valve interstitial cell phenotypes in regulating heart valve pathobiology. Although VSMCs are normally found in an ECM rich in elastin, the rate of synthesis of elastic fibers by adult VSMCs is very low, which is detrimental in diseases involving degradation of elastin (95). Mohler ER, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Vascular extracellular matrix and arterial mechanics. Allison DD, Grande-Allen KJ. Annu Rev Physiol. Chiu J-J, Chien S. 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VICs have multiple phenotypes that can be found in the valve (28–31). At bifurcations and curved regions, oscillatory shear (shown with yellow dashed arrows) is experienced at lower pressures and leads to calcification. doi: 10.1016/0021-9290(92)90249-Z, 45. Calcification is a prevalent disease in most fully developed countries and is predominantly observed in heart valves and nearby vasculature. Circulation (2001) 103:1051–6. The production of NO is stimulated through constant, pulsatile shear stress.