ApoC-III is a novel inducer of calcification in human aortic valves

Abstract

Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein–lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker. Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein–lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker. Calcific aortic valve disease (CAVD) is a chronic disorder with increasing prevalence in the Western world but lacks pharmacological therapies. Valvular interstitial cells (VICs) maintain a quiescent fibroblast phenotype in healthy heart valves (1Aikawa E. Libby P. A rock and a hard place: chiseling away at the multiple mechanisms of aortic stenosis.Circulation. 2017; 135: 1951-1955Crossref PubMed Scopus (23) Google Scholar), which when challenged by pathologic stimuli, undergo myofibroblastic or osteoblastic differentiation, promoting tissue fibrosis and calcification leading to CAVD and aortic stenosis (AS) (1Aikawa E. Libby P. A rock and a hard place: chiseling away at the multiple mechanisms of aortic stenosis.Circulation. 2017; 135: 1951-1955Crossref PubMed Scopus (23) Google Scholar). Multiple aspects that regulate these processes have been identified, with lipoproteins and associated proinflammatory factors (2Bouchareb R. Mahmut A. Nsaibia M.J. Boulanger M.C. Dahou A. Lepine J.L. Laflamme M.H. Hadji F. Couture C. Trahan S. Page S. Bosse Y. Pibarot P. Scipione C.A. Romagnuolo R. et al.Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve.Circulation. 2015; 132: 677-690Crossref PubMed Scopus (153) Google Scholar) suggested to play a major role in CAVD pathogenesis. However, the assessment of the role of apolipoproteins and proteins involved in the formation of lipoproteins, in CAVD, remains scant. Apolipoproteins form a special class of proteins that can associate with lipids, serve as essential structural and functional components in lipoproteins, and have well-established roles in regulating atherosclerosis (3Sacks F.M. The apolipoprotein story.Atheroscler. Suppl. 2006; 7: 23-27Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). The knowledge of specific effects of apolipoproteins on aortic valve (AV) disease pathogenesis is largely limited to studies on apolipoprotein B (apoB)–containing lipoproteins that serve as carriers for oxidized phospholipids (4López-Armada M.J. Riveiro-Naveira R.R. Vaamonde-García C. Valcárcel-Ares M.N. Mitochondrial dysfunction and the inflammatory response.Mitochondrion. 2013; 13: 106-118Crossref PubMed Scopus (305) Google Scholar), angiotensin-converting enzyme (5Zheng 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. Aikawa E. Arsenault B.J. Witztum J.L. Newby D.E. Koschinsky M.L. et al.Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis.J. Am. Coll. Cardiol. 2019; 73: 2150-2162Crossref PubMed Scopus (130) Google Scholar), as well as lipoprotein(a) [lp(a)] that carries proinflammatory lipids and promotes CAVD (2Bouchareb R. Mahmut A. Nsaibia M.J. Boulanger M.C. Dahou A. Lepine J.L. Laflamme M.H. Hadji F. Couture C. Trahan S. Page S. Bosse Y. Pibarot P. Scipione C.A. Romagnuolo R. et al.Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve.Circulation. 2015; 132: 677-690Crossref PubMed Scopus (153) Google Scholar). Genetically, LPA is the only lipoprotein gene that has been associated with AV calcification (6Thanassoulis 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. Malhotra R. O'Brien K.D. Kamstrup P.R. Nordestgaard B.G. Tybjaerg-Hansen A. et al.Genetic associations with valvular calcification and aortic stenosis.N. Engl. J. Med. 2013; 368: 503-512Crossref PubMed Scopus (626) Google Scholar). At the epidemiological level, apoB (7Wang Y.-T. Li Y. Ma Y.-T. Yang Y.-N. Ma X. Li X.-M. Liu F. Chen B.-D. Association between apolipoprotein B genetic polymorphism and the risk of calcific aortic stenosis in Chinese subjects, in Xinjiang, China.Lipids Health Dis. 2018; 17: 40Crossref PubMed Scopus (8) Google Scholar), lp(a) (8Capoulade R. Yeang C. Chan K.L. Pibarot P. Tsimikas S. Association of mild to moderate aortic valve stenosis progression with higher lipoprotein(a) and oxidized phospholipid levels: secondary analysis of a randomized clinical trial.JAMA Cardiol. 2018; 3: 1212-1217Crossref PubMed Scopus (52) Google Scholar, 9Capoulade R. Chan K.L. Yeang C. Mathieu P. Bossé Y. Dumesnil J.G. Tam J.W. Teo K.K. Mahmut A. Yang X. Witztum J.L. Arsenault B.J. Després J.-P. Pibarot P. Tsimikas S. Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis.J. Am. Coll. Cardiol. 2015; 66: 1236-1246Crossref PubMed Scopus (239) Google Scholar), and apoC-III (10Gerber Y. Goldbourt U. Feinberg M.S. Segev S. Harats D. Are triglyceride-rich lipoproteins associated with aortic valve sclerosis?: a preliminary report.Atherosclerosis. 2003; 170: 301-305Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 11Capoulade R. Torzewski M. Mayr M. Chan K.-L. Mathieu P. Bossé Y. Dumesnil J.G. Tam J. Teo K.K. Burnap S.A. Schmid J. Gobel N. Franke U.F.W. Sanchez A. Witztum J.L. et al.ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis.Heart. 2020; 106: 738Crossref PubMed Scopus (21) Google Scholar) are associated with CAVD, and apoA-I has demonstrated an inverse relationship to risk for AS incidence (12Zheng 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; 8e013020Crossref PubMed Scopus (11) Google Scholar) and its hemodynamic progression (13Tastet L. Capoulade R. Shen M. Clavel M.-A. Côté N. Mathieu P. Arsenault M. Bédard É. Tremblay A. Samson M. Bossé Y. Dumesnil J.G. Arsenault B.J. Beaudoin J. Bernier M. et al.ApoB/ApoA-I ratio is associated with faster hemodynamic progression of aortic stenosis: results from the PROGRESSA (metabolic determinants of the progression of aortic stenosis) study.J. Am. Heart Assoc. 2018; 7e007980Crossref PubMed Scopus (11) Google Scholar). Low-density lipoprotein cholesterol (LDL-C), oxidized phospholipids, and triglycerides are associated with onset of CAVD (10Gerber Y. Goldbourt U. Feinberg M.S. Segev S. Harats D. Are triglyceride-rich lipoproteins associated with aortic valve sclerosis?: a preliminary report.Atherosclerosis. 2003; 170: 301-305Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 14Speidl W.S. Cimmino G. Ibanez B. Elmariah S. Hutter R. Garcia M.J. Fuster V. Goldman M.E. Badimon J.J. Recombinant apolipoprotein A-I milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model.Eur. Heart J. 2010; 31: 2049-2057Crossref PubMed Scopus (52) Google Scholar, 15Kaltoft M. Langsted A. Nordestgaard B.G. Triglycerides and remnant cholesterol associated with risk of aortic valve stenosis: mendelian randomization in the Copenhagen General Population Study.Eur. Heart J. 2020; 41: 2288-2299Crossref PubMed Scopus (41) Google Scholar) and are introduced into the valvular matrix as components of lipoproteins. In a large Mendelian randomization study, plasma LDL-C was related to the presence of AV calcium, and a LDL-C genetic risk score was associated with increased incidence of AS (16Smith J.G. Luk K. Schulz C.-A. Engert J.C. Do R. Hindy G. Rukh G. Dufresne L. Almgren P. Owens D.S. Harris T.B. Peloso G.M. Kerr K.F. Wong Q. Smith A.V. et al.Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis.JAMA. 2014; 312: 1764-1771Crossref PubMed Scopus (152) Google Scholar). In vitro evidence suggests that autotaxin derived from circulating lp(a) particles promotes inflammation and mineralization of AV (2Bouchareb R. Mahmut A. Nsaibia M.J. Boulanger M.C. Dahou A. Lepine J.L. Laflamme M.H. Hadji F. Couture C. Trahan S. Page S. Bosse Y. Pibarot P. Scipione C.A. Romagnuolo R. et al.Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve.Circulation. 2015; 132: 677-690Crossref PubMed Scopus (153) Google Scholar) and participates in the metabolism of oxidized phospholipids that induce osteogenic changes in VICs (5Zheng 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. Aikawa E. Arsenault B.J. Witztum J.L. Newby D.E. Koschinsky M.L. et al.Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis.J. Am. Coll. Cardiol. 2019; 73: 2150-2162Crossref PubMed Scopus (130) Google Scholar). Oxidized high-density lipoprotein (HDL) promotes VIC calcification (17Sun J.T. Chen Y.Y. Mao J.Y. Wang Y.P. Chen Y.F. Hu X. Yang K. Liu Y. Oxidized HDL, as a novel biomarker for calcific aortic valve disease, promotes the calcification of aortic valve interstitial cells.J. Cardiovasc. Transl. Res. 2019; 12: 560-568Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). In vivo, apolipoprotein E–deficient and LDL-receptor deficient mice, and LDL receptor–deficient apo B-100 are to In addition, of an apoA-I to and to a in fibrosis and calcification W.S. Cimmino G. Ibanez B. Elmariah S. Hutter R. Garcia M.J. Fuster V. Goldman M.E. Badimon J.J. Recombinant apolipoprotein A-I milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model.Eur. Heart J. 2010; 31: 2049-2057Crossref PubMed Scopus (52) Google Scholar, J. D. Y. S. D. M. M. R. E. J.C. of aortic valve stenosis by is associated with aortic and valve in J. 2013; PubMed Scopus (23) Google Scholar, M. M. M. S. lipoproteins (HDL) are in aortic valves and with the mechanisms of valvular Full Text Full Text PDF PubMed Scopus Google Scholar, D. Y. M. G. E. J.G. E. J.C. of aortic valve stenosis by in J. PubMed Scopus Google Scholar). of these aspects of CAVD to K.L. M.C. C.A. of calcific aortic valve J. Google Scholar). these metabolism to CAVD, randomized pharmacological LDL with have failed to effects on CAVD progression K. P. K. E. C. C.A. S. T. K. et with and in aortic stenosis.N. Engl. J. Med. PubMed Scopus Google Scholar, Newby D.E. P. J. A randomized of in calcific aortic stenosis.N. Engl. J. Med. PubMed Scopus Google Scholar, L. Teo K. Dumesnil G. A. Tam J. of with on progression of aortic stenosis.Circulation. 2010; PubMed Scopus Google Scholar). apolipoproteins and have been in studies of CAVD, there has been an study of apolipoprotein prevalence in human CAVD, and roles of apolipoproteins in CAVD are we to whether apolipoproteins to CAVD pathogenesis by apolipoproteins CAVD tissues that disease progression and calcification effects of available human apolipoproteins as an in vitro of To the human AV apolipoprotein CAVD tissues, we the of CAVD proteomics F. A. S. M.C. P. T. Rogers M.A. A. J. et a of the aortic valve and 2018; PubMed Scopus Google Scholar) to analysis on were by major CAVD nonfibrotic/noncalcific fibrotic and calcific We the prevalence of apolipoproteins in calcific CAVD tissue as apoA-II, apoC-III, and apoB We apolipoproteins P. of apolipoproteins for and of plasma PubMed Google Scholar) from the and were (1) apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific CAVD tissue to the and also to the fibrotic CAVD tissue and apolipoproteins apoE, and no CAVD tissues We on these by a of to the of between to for these 12 apolipoproteins in the in AV from We first a F. A. S. M.C. P. T. Rogers M.A. A. J. et a of the aortic valve and 2018; PubMed Scopus Google Scholar, S.A. B. F.M. Aikawa M. Multiple apolipoprotein in human by Res. Full Text Full Text PDF PubMed Scopus Google Scholar) on human S.A. B. F.M. Aikawa M. Multiple apolipoprotein in human by Res. Full Text Full Text PDF PubMed Scopus Google Scholar) apolipoproteins in from the CAVD and the demonstrated by proteomics analysis We also from CAVD F. A. S. M.C. P. T. Rogers M.A. A. J. et a of the aortic valve and 2018; PubMed Scopus Google Scholar) to whether prevalence of apolipoproteins in calcific CAVD tissue to in apolipoprotein to in the calcific CAVD only was The gene that apoJ was in calcific CAVD tissue This between valvular and proteomics of apolipoproteins is with that we demonstrated F. A. S. M.C. P. T. Rogers M.A. A. J. et a of the aortic valve and 2018; PubMed Scopus Google Scholar). In to CAVD tissue proteomics analysis of of apolipoproteins disease progression, we immunohistochemistry to the of apolipoproteins the AV and with matrix and calcification. apoB, and to a apoJ and a and in matrix of the disease-prone fibrosa layer fibrosa In addition, these apolipoproteins were around calcific regions calcification the tissue of and apoJ and limited to calcification. apoA-II, apoA-IV, apoD, and colocalized with calcification in the fibrosa layer but were enriched in the matrix of the fibrosa demonstrated and in with in and around cells and by VICs cells were largely within AV colocalized with a limited of cell these from a aortic cells were for and only cells were for We an population of of which of cells were for apoJ and of cells were for with for and for evidence that apoC-III promote of lipoproteins and lipids as LDL or triglycerides (17Sun J.T. Chen Y.Y. Mao J.Y. Wang Y.P. Chen Y.F. Hu X. Yang K. Liu Y. Oxidized HDL, as a novel biomarker for calcific aortic valve disease, promotes the calcification of aortic valve interstitial cells.J. Cardiovasc. Transl. Res. 2019; 12: 560-568Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). is currently in clinical as a for J. D. Y. S. D. M. M. R. E. J.C. of aortic valve stenosis by is associated with aortic and valve in J. 2013; PubMed Scopus (23) Google Scholar, K. P. K. E. C. C.A. S. T. K. et with and in aortic stenosis.N. Engl. J. Med. PubMed Scopus Google Scholar). In of these and that apoC-III was enriched in calcific CAVD in the disease-prone fibrosa and around calcific we on whether apoC-III can promote AV calcification as an in vitro of of the we with proteomics and apolipoprotein CAVD apoC-III in fibrotic and calcific AV regions In addition, apoC-III was found in and around calcific of human AV and that apoC-III to AV calcification, of its in lipoprotein In to that apoC-III can promote calcification, we primary human VICs with human apoC-III and calcification at multiple an in vitro calcification S. Rogers M.A. M.C. F. Aikawa M. S.A. Aikawa E. of human calcific aortic valve disease in vitro Cardiovasc. Med. 2019; PubMed Scopus Google Scholar). Calcific was in to at of VIC calcification apoA-I calcification that this was a specific of apoC-III To mechanisms by which apoC-III VIC calcification, we the in vitro of analysis suggested a major of the on the VIC on a of proteins and for proteins with a between proteins detected the apoC-III a involved in of mitochondrial was of the proteins apoC-III to and and mitochondrial dysfunction in apoC-III VICs apoC-III increased mitochondrial and proteins and and of inflammation and to and We enriched for enriched proteins apoC-III to and and detected a in and in enriched in In addition, the with inflammation Wang J. determinants of calcification and J. 2020; PubMed Scopus Google Scholar), calcification Wang J. determinants of calcification and J. 2020; PubMed Scopus Google Scholar), and CAVD F. A. S. M.C. P. T. Rogers M.A. A. J. et a of the aortic valve and 2018; PubMed Scopus Google Scholar) on the and Mitochondrial dysfunction and inflammation (4López-Armada M.J. Riveiro-Naveira R.R. Vaamonde-García C. Valcárcel-Ares M.N. Mitochondrial dysfunction and the inflammatory response.Mitochondrion. 2013; 13: 106-118Crossref PubMed Scopus (305) Google Scholar). The was enriched apoC-III In with of the by proteomics and gene was apoC-III have been to VIC calcification (2Bouchareb R. Mahmut A. Nsaibia M.J. Boulanger M.C. Dahou A. Lepine J.L. Laflamme M.H. Hadji F. Couture C. Trahan S. Page S. Bosse Y. Pibarot P. Scipione C.A. Romagnuolo R. et al.Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve.Circulation. 2015; 132: 677-690Crossref PubMed Scopus (153) Google we assessed a that apoC-III calcification potential via increased in human VICs an of a mitochondrial dysfunction/inflammation-mediated calcification by apoC-III in human VICs In this study, we demonstrated the in the (1) apolipoproteins of disease pathogenesis apolipoprotein tissue in matrix of a of pathogenic apoC-III promotes calcification in primary human and apoC-III induced a mitochondrial dysfunction/inflammation-mediated calcification pathway. We the of AV for disease progression F. A. S. M.C. P. T. Rogers M.A. A. J. et a of the aortic valve and 2018; PubMed Scopus Google Scholar). from calcified the disease progression to and as well as the CAVD of fibrotic and calcific tissues from the by We the of this to the of the In the study, of proteomics with the analysis to the presence of a broad of apolipoproteins in CAVD tissues and tissue the presence of apolipoproteins in AV tissue that is limited to the lipoproteins and low-density as well as major apoB, and apoC-III, localized apolipoproteins in AV evidence that a of apolipoproteins play roles in disease and progression, with cells and matrix or is well that to valvular as a first to and of factors into the valvular interstitial of VICs to these factors disease and pathologic The role of apolipoproteins on these processes in VICs remains of an of apolipoproteins within the matrix and the of in calcific AV tissue the of a apolipoprotein and in In addition, that of the apolipoprotein to for the large in apolipoprotein that apolipoprotein of this In the of the of on and CAVD, the of an between by proteomics and disease in this study was but can by that we were to is of the which are in Newby D.E. P. J. A randomized of in calcific aortic stenosis.N. Engl. J. Med. PubMed Scopus Google Scholar), and for within a tissue are To no for in large of the has also been suggested that at of secondary to its to at of in the of AV B.G. Langsted A. lipoprotein(a) aortic valve Am. Coll. Cardiol. 2015; 66: PubMed Scopus (11) Google Scholar), the in To a limited of apolipoproteins have been to play a role in the pathogenesis of CAVD, S. S. Koschinsky M.L. S.M. G. G. Witztum J.L. S. M. et to risk of disease and aortic stenosis.J. Am. Coll. Cardiol. 2018; PubMed Scopus Google Scholar) and apoB (5Zheng 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. Aikawa E. Arsenault B.J. Witztum J.L. Newby D.E. Koschinsky M.L. et al.Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis.J. Am. Coll. Cardiol. 2019; 73: 2150-2162Crossref PubMed Scopus (130) Google Scholar). We available human which associated with disease progression in tissue proteomics and large structural components of the major lipoprotein of and low-density In to that apoC-III VIC calcification in observed in plasma (4López-Armada M.J. Riveiro-Naveira R.R. Vaamonde-García C. Valcárcel-Ares M.N. Mitochondrial dysfunction and the inflammatory response.Mitochondrion. 2013; 13: 106-118Crossref PubMed Scopus (305) Google Scholar), we found that apoC-III valvular calcification via a mitochondrial inflammatory an a demonstrated as a major of VIC calcification (2Bouchareb R. Mahmut A. Nsaibia M.J. Boulanger M.C. Dahou A. Lepine J.L. Laflamme M.H. Hadji F. Couture C. Trahan S. Page S. Bosse Y. Pibarot P. Scipione C.A. Romagnuolo R. et al.Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve.Circulation. 2015; 132: 677-690Crossref PubMed Scopus (153) Google Scholar, 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; 8e013020Crossref PubMed Scopus (11) Google Scholar). analysis of the with inflammation Wang J. determinants of calcification and J. 2020; PubMed Scopus Google Scholar), calcification Wang J. determinants of calcification and J. 2020; PubMed Scopus Google Scholar), and F. A. S. M.C. P. T. Rogers M.A. A. J. et a of the aortic valve and 2018; PubMed Scopus Google Scholar) and results are in with that proinflammatory a of and 2015; PubMed Scopus Google Scholar, C. V. Aikawa E. K. F.M. Aikawa M. apolipoprotein cell and Heart J. 2013; PubMed Scopus Google Scholar). novel are also in with epidemiological of an between circulating plasma apoC-III and AV (10Gerber Y. Goldbourt U. Feinberg M.S. Segev S. Harats D. Are triglyceride-rich lipoproteins associated with aortic valve sclerosis?: a preliminary report.Atherosclerosis. 2003; 170: 301-305Abstract Full Text Full Text PDF PubMed Scopus (14) Google valvular that occurs to the onset of valvular calcification. However, a novel of apoC-III with valvular calcification beyond an epidemiological as a available human apolipoprotein that we for effects on calcification. The of in vitro calcification is with apoA-I an inverse relationship to risk for AS incidence (12Zheng 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; 8e013020Crossref PubMed Scopus (11) Google Scholar) and hemodynamic AS progression (13Tastet L. Capoulade R. Shen M. Clavel M.-A. Côté N. Mathieu P. Arsenault M. Bédard É. Tremblay A. Samson M. Bossé Y. Dumesnil J.G. Arsenault B.J. Beaudoin J. Bernier M. et al.ApoB/ApoA-I ratio is associated with faster hemodynamic progression of aortic stenosis: results from the PROGRESSA (metabolic determinants of the progression of aortic stenosis) study.J. Am. Heart Assoc. 2018; 7e007980Crossref PubMed Scopus (11) Google Scholar). in suggested that of an apoA-I to and to a in fibrosis and calcification W.S. Cimmino G. Ibanez B. Elmariah S. Hutter R. Garcia M.J. Fuster V. Goldman M.E. Badimon J.J. Recombinant apolipoprotein A-I milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model.Eur. Heart J. 2010; 31: 2049-2057Crossref PubMed Scopus (52) Google Scholar, J. D. Y. S. D. M. M. R. E. J.C. of aortic valve stenosis by is associated with aortic and valve in J. 2013; PubMed Scopus (23) Google Scholar, M. M. M. S. lipoproteins (HDL) are in aortic valves and with the mechanisms of valvular Full Text Full Text PDF PubMed Scopus Google Scholar, D. Y. M. G. E. J.G. E. J.C. of aortic valve stenosis by in J. PubMed Scopus Google Scholar). was to induce and in VICs M. M. M. S. lipoproteins (HDL) are in aortic valves and with the mechanisms of valvular Full Text Full Text PDF PubMed Scopus Google Scholar), which VIC However, this is the first to that apoA-I calcification effects are in in primary human valvular interstitial study the for on a broad of apolipoproteins in CAVD and a to whether of specific in clinical for CAVD also CAVD results a of human valvular to study the between apolipoproteins and CAVD, and apoC-III as an active and modifiable to human valvular calcification.

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