Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis
Abstract
:1. Introduction
2. Relevance of Lp(a) in AVS
3. Pathophysiology of Lp(a)-Induced AVS
4. The Notch and Wnt-Mediated Calcific Regulatory Pathways
5. Future Perspective
6. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
- Otto, C.M.; Lind, B.K.; Kitzman, D.W.; Gersh, B.J.; Siscovick, D.S. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N. Engl. J. Med. 1999, 341, 142–147. [Google Scholar] [CrossRef] [PubMed]
- Lindroos, M.; Kupari, M.; Heikkila, J.; Tilvis, R. Prevalence of aortic valve abnormalities in the elderly: An echocardiographic study of a random population sample. J. Am. Coll. Cardiol. 1993, 21, 1220–1225. [Google Scholar] [CrossRef]
- Joseph, J.; Naqvi, S.Y.; Giri, J.; Goldberg, S. Aortic Stenosis: Pathophysiology, Diagnosis, and Therapy. Am. J. Med. 2017, 130, 253–263. [Google Scholar] [CrossRef]
- Bonow, R.O.; Greenland, P. Population-wide trends in aortic stenosis incidence and outcomes. Circulation 2015, 131, 969–971. [Google Scholar] [CrossRef] [PubMed]
- Osnabrugge, R.L.J.; Mylotte, D.; Head, S.J.; Van Mieghem, N.M.; Nkomo, V.T.; LeReun, C.M.; Bogers, A.J.J.C.; Piazza, N.; Kappetein, A.P. Aortic stenosis in the elderly: Disease prevalence and number of candidates for transcatheter aortic valve replacement: A meta-analysis and modeling study. J. Am. Coll. Cardiol. 2013, 62, 1002–1012. [Google Scholar] [CrossRef]
- Desai, C.S.; Roselli, E.E.; Svensson, L.G.; Bonow, R.O. Transcatheter aortic valve replacement: Current status and future directions. Semin. Thorac. Cardiovasc. Surg. 2013, 25, 193–196. [Google Scholar] [CrossRef]
- Yutzey, K.E.; Demer, L.L.; Body, S.C.; Huggins, G.S.; Towler, D.A.; Giachelli, C.M.; Hofmann-Bowman, M.A.; Mortlock, D.P.; Rogers, M.B.; Sadeghi, M.M.; et al. Calcific aortic valve disease: A consensus summary from the Alliance of Investigators on Calcific Aortic Valve Disease. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 2387–2393. [Google Scholar] [CrossRef]
- Mohler, E.R., 3rd; Gannon, F.; Reynolds, C.; Zimmerman, R.; Keane, M.G.; Kaplan, F.S. Bone formation and inflammation in cardiac valves. Circulation 2001, 103, 1522–1528. [Google Scholar] [CrossRef] [PubMed]
- Stewart, B.F.; Siscovick, D.; Lind, B.K.; Gardin, J.M.; Gottdiener, J.S.; Smith, V.E.; Kitzman, D.W.; Otto, C.M. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J. Am. Coll. Cardiol. 1997, 29, 630–634. [Google Scholar] [CrossRef]
- Kamstrup, P.R.; Tybjaerg-Hansen, A.; Nordestgaard, B.G. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J. Am. Coll. Cardiol. 2014, 63, 470–477. [Google Scholar] [CrossRef] [PubMed]
- Cowell, S.J.; Newby, D.E.; Prescott, R.J.; Bloomfield, P.; Reid, J.; Northridge, D.B.; Boon, N.A. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N. Engl. J. Med. 2005, 352, 2389–2397. [Google Scholar] [CrossRef] [PubMed]
- Rossebo, A.B.; Pedersen, T.R.; Boman, K.; Brudi, P.; Chambers, J.B.; Egstrup, K.; Gerdts, E.; Gohlke-Barwolf, C.; Holme, I.; Kesaniemi, Y.A.; et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 2008, 359, 1343–1356. [Google Scholar] [CrossRef]
- Chan, K.L.; Teo, K.; Dumesnil, J.G.; Ni, A.; Tam, J. Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: Results of the aortic stenosis progression observation: Measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010, 121, 306–314. [Google Scholar] [CrossRef] [PubMed]
- Berg, K. A new serum type system in man--the lp system. Acta Pathol. Microbiol. Scand. 1963, 59, 369–382. [Google Scholar] [CrossRef] [PubMed]
- Romagnuolo, R.; DeMarco, K.; Scipione, C.A.; Boffa, M.B.; Koschinsky, M.L. Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen on the surface of vascular endothelial and smooth muscle cells. Thromb. Res. 2018, 169, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Gotoh, T.; Kuroda, T.; Yamasawa, M.; Nishinaga, M.; Mitsuhashi, T.; Seino, Y.; Nagoh, N.; Kayaba, K.; Yamada, S.; Matsuo, H. Correlation between lipoprotein(a) and aortic valve sclerosis assessed by echocardiography (the JMS Cardiac Echo and Cohort Study). Am. J. Cardiol. 1995, 76, 928–932. [Google Scholar] [CrossRef]
- Thanassoulis, G.; Campbell, C.Y.; Owens, D.S.; Smith, J.G.; Smith, A.V.; Peloso, G.M.; Kerr, K.F.; Pechlivanis, S.; Budoff, M.J.; Harris, T.B.; et al. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 2013, 368, 503–512. [Google Scholar] [CrossRef]
- Arsenault, B.J.; Boekholdt, S.M.; Dube, M.-P.; Rheaume, E.; Wareham, N.J.; Khaw, K.-T.; Sandhu, M.S.; Tardif, J.-C. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: A prospective Mendelian randomization study and replication in a case-control cohort. Circ. Cardiovasc. Genet. 2014, 7, 304–310. [Google Scholar] [CrossRef]
- Bergmark, C.; Dewan, A.; Orsoni, A.; Merki, E.; Miller, E.R.; Shin, M.-J.; Binder, C.J.; Horkko, S.; Krauss, R.M.; Chapman, M.J.; et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J. Lipid Res. 2008, 49, 2230–2239. [Google Scholar] [CrossRef]
- Van Der Valk, F.M.; Bekkering, S.; Kroon, J.; Yeang, C.; Van Den Bossche, J.; Van Buul, J.D.; Ravandi, A.; Nederveen, A.J.; Verberne, H.J.; Scipione, C.; et al. Oxidized phospholipids on Lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 2016, 134, 611–624. [Google Scholar] [CrossRef]
- Thanassoulis, G. Lipoprotein (a) in calcific aortic valve disease: From genomics to novel drug target for aortic stenosis. J. Lipid Res. 2016, 57, 917–924. [Google Scholar] [CrossRef] [PubMed]
- Que, X.; Hung, M.-Y.; Yeang, C.; Gonen, A.; Prohaska, T.A.; Sun, X.; Diehl, C.; Maatta, A.; Gaddis, D.E.; Bowden, K.; et al. Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice. Nature 2018, 558, 301–306. [Google Scholar] [CrossRef] [PubMed]
- O’Donoghue, M.L.; Morrow, D.A.; Tsimikas, S.; Sloan, S.; Ren, A.F.; Hoffman, E.B.; Desai, N.R.; Solomon, S.D.; Domanski, M.; Arai, K.; et al. Lipoprotein(a) for risk assessment in patients with established coronary artery disease. J. Am. Coll. Cardiol. 2014, 63, 520–527. [Google Scholar] [CrossRef] [PubMed]
- Vongpromek, R.; Bos, S.; Ten Kate, G.-J.R.; Yahya, R.; Verhoeven, A.J.M.; de Feyter, P.J.; Kronenberg, F.; Roeters van Lennep, J.E.; Sijbrands, E.J.G.; Mulder, M.T. Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia. J. Intern. Med. 2015, 278, 166–173. [Google Scholar] [CrossRef]
- Zheng, K.H.; Arsenault, B.J.; Kaiser, Y.; Khaw, K.-T.; Wareham, N.J.; Stroes, E.S.G.; Boekholdt, S.M. apoB/apoA-I Ratio and Lp(a) Associations With Aortic Valve Stenosis Incidence: Insights From the EPIC-Norfolk Prospective Population Study. J. Am. Heart Assoc. 2019, 8, e013020. [Google Scholar] [CrossRef]
- Tsimikas, S.; Brilakis, E.S.; Miller, E.R.; McConnell, J.P.; Lennon, R.J.; Kornman, K.S.; Witztum, J.L.; Berger, P.B. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N. Engl. J. Med. 2005, 353, 46–57. [Google Scholar] [CrossRef]
- Saleheen, D.; Haycock, P.C.; Zhao, W.; Rasheed, A.; Taleb, A.; Imran, A.; Abbas, S.; Majeed, F.; Akhtar, S.; Qamar, N.; et al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: A mendelian randomisation analysis. Lancet. Diabetes Endocrinol. 2017, 5, 524–533. [Google Scholar] [CrossRef]
- Taleb, A.; Witztum, J.L.; Tsimikas, S. Oxidized phospholipids on apoB-100-containing lipoproteins: A biomarker predicting cardiovascular disease and cardiovascular events. Biomark. Med. 2011, 5, 673–694. [Google Scholar] [CrossRef]
- Capoulade, R.; Chan, K.L.; Yeang, C.; Mathieu, P.; Bosse, Y.; Dumesnil, J.G.; Tam, J.W.; Teo, K.K.; Mahmut, A.; Yang, X.; et al. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. J. Am. Coll. Cardiol. 2015, 66, 1236–1246. [Google Scholar] [CrossRef]
- Dweck, M.R.; Jenkins, W.S.A.; Vesey, A.T.; Pringle, M.A.H.; Chin, C.W.L.; Malley, T.S.; Cowie, W.J.A.; Tsampasian, V.; Richardson, H.; Fletcher, A.; et al. 18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis. Circ. Cardiovasc. Imaging 2014, 7, 371–378. [Google Scholar] [CrossRef]
- Zheng, K.H.; Tsimikas, S.; Pawade, T.; Kroon, J.; Jenkins, W.S.A.; Doris, M.K.; White, A.C.; Timmers, N.K.L.M.; Hjortnaes, J.; Rogers, M.A.; et al. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. J. Am. Coll. Cardiol. 2019, 73, 2150–2162. [Google Scholar] [CrossRef] [PubMed]
- New, S.E.P.; Aikawa, E. Molecular Imaging Insights Into Early Inflammatory Stages of Arterial and Aortic Valve Calcification. Circ. Res. 2011, 108, 1381–1391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Otto, C.M.; Kuusisto, J.; Reichenbach, D.D.; Gown, A.M.; O’brien, K.D. Characterization of the Early Lesion of “Degenerative” Valvular Aortic Stenosis. Histological and Immunohistochemical Studies. Circulation 1994, 90, 844–853. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, B.; Li, W.; Li, X.; Zhou, H. Inflammation: A Novel Therapeutic Target/Direction in Atherosclerosis. Bentham Sci. 2017, 23, 1216–1227. [Google Scholar] [CrossRef]
- Tuttolomondo, A.; Di Raimondo, D.; Pecoraro, R.; Arnao, V.; Pinto, A.; Licata, G. Atherosclerosis as an inflammatory disease. Curr. Pharm. Des. 2012, 18, 4266–4288. [Google Scholar] [CrossRef]
- Gimbrone, M.A.; García-Cardeña, G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ. Res. 2016, 118, 620–636. [Google Scholar] [CrossRef] [Green Version]
- Hadi, H.A.R.; Carr, C.S.; Suwaidi, J. Al Endothelial dysfunction: Cardiovascular risk factors, therapy, and outcome. Vasc. Health Risk Manag. 2005, 1, 183–198. [Google Scholar]
- Demer, L.L.; Tintut, Y. Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 715–723. [Google Scholar] [CrossRef] [Green Version]
- Zhong, S.; Li, L.; Shen, X.; Li, Q.; Xu, W.; Wang, X.; Tao, Y.; Yin, H. An update on lipid oxidation and inflammation in cardiovascular diseases. Free Radic. Biol. Med. 2019, 144, 266–278. [Google Scholar] [CrossRef]
- Peeters, F.E.C.M.; Meex, S.J.R.; Dweck, M.R.; Aikawa, E.; Crijns, H.J.G.M.; Schurgers, L.J.; Kietselaer, B.L.J.H. Calcific aortic valve stenosis: Hard disease in the heart: A biomolecular approach towards diagnosis and treatment. Eur. Heart J. 2018, 39, 2618–2624. [Google Scholar] [CrossRef] [Green Version]
- Hjortnaes, J.; Butcher, J.; Figueiredo, J.-L.; Riccio, M.; Kohler, R.H.; Kozloff, K.M.; Weissleder, R.; Aikawa, E. Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: A role for inflammation. Eur. Heart J. 2010, 31, 1975–1984. [Google Scholar] [CrossRef] [PubMed]
- Hutcheson, J.D.; Goettsch, C.; Bertazzo, S.; Maldonado, N.; Ruiz, J.L.; Goh, W.; Yabusaki, K.; Faits, T.; Bouten, C.; Franck, G.; et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat. Mater. 2016, 15, 335–343. [Google Scholar] [CrossRef] [PubMed]
- Demer, L.L.; Tintut, Y. Vascular calcification: Pathobiology of a multifaceted disease. Circulation 2008, 117, 2938–2948. [Google Scholar] [CrossRef] [PubMed]
- Leopold, J.A. Cellular mechanisms of aortic valve calcification. Circ. Cardiovasc. Interv. 2012, 5, 605–614. [Google Scholar] [CrossRef] [Green Version]
- Dweck, M.R.; Khaw, H.J.; Sng, G.K.Z.; Luo, E.L.C.; Baird, A.; Williams, M.C.; Makiello, P.; Mirsadraee, S.; Joshi, N.V.; van Beek, E.J.R.; et al. Aortic stenosis, atherosclerosis, and skeletal bone: Is there a common link with calcification and inflammation? Eur. Heart J. 2013, 34, 1567–1574. [Google Scholar] [CrossRef] [Green Version]
- Hjortnaes, J.; Shapero, K.; Goettsch, C.; Hutcheson, J.D.; Keegan, J.; Kluin, J.; Mayer, J.E.; Bischoff, J.; Aikawa, E. Valvular interstitial cells suppress calcification of valvular endothelial cells. Atherosclerosis 2015, 242, 251–260. [Google Scholar] [CrossRef] [Green Version]
- Bouchareb, R.; Mahmut, A.; Nsaibia, M.J.; Boulanger, M.-C.; Dahou, A.; Lepine, J.-L.; Laflamme, M.-H.; Hadji, F.; Couture, C.; Trahan, S.; et al. Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve. Circulation 2015, 132, 677–690. [Google Scholar] [CrossRef]
- Salles, J.P.; Laurencin-Dalicieux, S.; Conte-Auriol, F.; Briand-Mesange, F.; Gennero, I. Bone defects in LPA receptor genetically modified mice. Biochim. Biophys. Acta 2013, 1831, 93–98. [Google Scholar] [CrossRef]
- Brasier, A.R. The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation. Cardiovasc. Res. 2010, 86, 211–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El Husseini, D.; Boulanger, M.-C.; Mahmut, A.; Bouchareb, R.; Laflamme, M.-H.; Fournier, D.; Pibarot, P.; Bosse, Y.; Mathieu, P. P2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt: Implication for calcific aortic valve disease. J. Mol. Cell. Cardiol. 2014, 72, 146–156. [Google Scholar] [CrossRef]
- Rawadi, G.; Vayssiere, B.; Dunn, F.; Baron, R.; Roman-Roman, S. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J. Bone Miner. Res. 2003, 18, 1842–1853. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Meng, X.; Su, X.; Mauchley, D.C.; Ao, L.; Cleveland, J.C.J.; Fullerton, D.A. Bone morphogenic protein 2 induces Runx2 and osteopontin expression in human aortic valve interstitial cells: Role of Smad1 and extracellular signal-regulated kinase 1/2. J. Thorac. Cardiovasc. Surg. 2009, 138, 1008–1015. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Song, R.; Zeng, Q.; Ao, L.; Yu, J.A.; Cleveland, J.C.; Zhao, K.-S.; Fullerton, D.A.; Meng, X. Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor-2. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 2711–2720. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pawade, T.A.; Newby, D.E.; Dweck, M.R. Calcification in aortic stenosis: The skeleton key. J. Am. Coll. Cardiol. 2015, 66, 561–577. [Google Scholar] [CrossRef] [Green Version]
- Garg, V.; Muth, A.N.; Ransom, J.F.; Schluterman, M.K.; Barnes, R.; King, I.N.; Grossfeld, P.D.; Srivastava, D. Mutations in NOTCH1 cause aortic valve disease. Nature 2005, 437, 270–274. [Google Scholar] [CrossRef] [PubMed]
- Kaden, J.J.; Bickelhaupt, S.; Grobholz, R.; Vahl, C.F.; Hagl, S.; Brueckmann, M.; Haase, K.K.; Dempfle, C.; Borggrefe, M. Expression of Bone Sialoprotein and Bone Morphogenetic Protein-2 in Calcific Aortic Stenosis. J. Heart Valve Dis. 2004, 13, 560–566. [Google Scholar]
- Nigam, V.; Srivastava, D. Notch1 represses osteogenic pathways in aortic valve cells. J. Mol. Cell. Cardiol. 2009, 47, 828–834. [Google Scholar] [CrossRef] [Green Version]
- Ducy, P. Cbfa1: A molecular switch in osteoblast biology. Dev. Dyn. 2000, 219, 461–471. [Google Scholar] [CrossRef]
- Rajamannan, N.M.; Evans, F.J.; Aikawa, E.; Grande-Allen, K.J.; Demer, L.L.; Heistad, D.D.; Simmons, C.A.; Masters, K.S.; Mathieu, P.; O’Brien, K.D.; et al. Calcific aortic valve disease: Not simply a degenerative process: A review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2011 update. Circulation 2011, 124, 1783–1791. [Google Scholar] [CrossRef] [Green Version]
- Gu, G.-J.; Chen, T.; Zhou, H.-M.; Sun, K.-X.; Li, J. Role of Wnt/β-catenin Signaling Pathway in the Mechanism of Calcification of Aortic Valve. J. Huazhong Univ. Sci. Technol. 2014, 34, 33–36. [Google Scholar] [CrossRef]
- Bostrom, K.I.; Rajamannan, N.M.; Towler, D.A. The regulation of valvular and vascular sclerosis by osteogenic morphogens. Circ. Res. 2011, 109, 564–577. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Y.; Li, J.; Zhou, K.; Liao, X.; Zhou, X.; Shen, K. The methylation of Notch1 promoter mediates the osteogenesis differentiation in human aortic valve interstitial cells through Wnt/β-catenin signaling. J. Cell. Physiol. 2019, 234, 20366–20376. [Google Scholar] [CrossRef] [PubMed]
- Demer, L.L.; Tintut, Y. Return to Ectopia: Stem Cells in the Artery Wall. Arterioscler. Thromb. Vasc. Biol. 2005, 25, 1307–1308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, Q.; Liao, J.K. Pleiotropic effects of statins: Basic research and clinical perspectives. Circ. J. 2010, 74, 818–826. [Google Scholar] [CrossRef] [Green Version]
- Tsimikas, S.; Gordts, P.L.S.M.; Nora, C.; Yeang, C.; Witztum, J.L. Statin therapy increases lipoprotein(a) levels. Eur. Heart J. 2019. [Google Scholar] [CrossRef]
- Poggio, P.; Songia, P.; Cavallotti, L.; Barbieri, S.S.; Zanotti, I.; Arsenault, B.J.; Valerio, V.; Ferri, N.; Capoulade, R.; Camera, M. PCSK9 Involvement in Aortic Valve Calcification. J. Am. Coll. Cardiol. 2018, 72, 3225–3227. [Google Scholar] [CrossRef]
- Stiekema, L.C.A.; Stroes, E.S.G.; Verweij, S.L.; Kassahun, H.; Chen, L.; Wasserman, S.M.; Sabatine, M.S.; Mani, V.; Fayad, Z.A. Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. Eur. Heart J. 2019, 40, 2775–2781. [Google Scholar] [CrossRef] [Green Version]
- Viney, N.J.; van Capelleveen, J.C.; Geary, R.S.; Xia, S.; Tami, J.A.; Yu, R.Z.; Marcovina, S.M.; Hughes, S.G.; Graham, M.J.; Crooke, R.M.; et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): Two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet (Lond. Engl.) 2016, 388, 2239–2253. [Google Scholar] [CrossRef]
- Sexton, T.; Alkhasova, M.; de Beer, M.; Lynch, D.; Smyth, S. Changes in thromboinflammatory profiles across the generations of transcatheter aortic heart valves. J. Thromb. Thrombolysis 2019, 47, 174–178. [Google Scholar] [CrossRef]
- Karkhur, S.; Hasanreisoglu, M.; Vigil, E.; Halim, M.S.; Hassan, M.; Plaza, C.; Nguyen, N.V.; Afridi, R.; Tran, A.T.; Do, D.V.; et al. Interleukin-6 inhibition in the management of non-infectious uveitis and beyond. J. Ophthalmic Inflamm. Infect. 2019, 9, 17. [Google Scholar] [CrossRef] [Green Version]
- Callegari, A.; Coons, M.L.; Ricks, J.L.; Rosenfeld, M.E.; Scatena, M. Increased calcification in osteoprotegerin-deficient smooth muscle cells: Dependence on receptor activator of NF-kappaB ligand and interleukin 6. J. Vasc. Res. 2014, 51, 118–131. [Google Scholar] [CrossRef] [PubMed]
- Palmer, S.M.; Snyder, L.; Todd, J.L.; Soule, B.; Christian, R.; Anstrom, K.; Luo, Y.; Gagnon, R.; Rosen, G. Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial of BMS-986020, a Lysophosphatidic Acid Receptor Antagonist for the Treatment of Idiopathic Pulmonary Fibrosis. Chest 2018, 154, 1061–1069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Schnitzler, J.G.; Ali, L.; Groenen, A.G.; Kaiser, Y.; Kroon, J. Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis. Biomolecules 2019, 9, 760. https://doi.org/10.3390/biom9120760
Schnitzler JG, Ali L, Groenen AG, Kaiser Y, Kroon J. Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis. Biomolecules. 2019; 9(12):760. https://doi.org/10.3390/biom9120760
Chicago/Turabian StyleSchnitzler, Johan G., Lubna Ali, Anouk G. Groenen, Yannick Kaiser, and Jeffrey Kroon. 2019. "Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis" Biomolecules 9, no. 12: 760. https://doi.org/10.3390/biom9120760