[en] Aims: Palmitic acid (PA) and oleic acid (OA) are two main dietary fatty acids. Dietary intake of PA has been associated with cardiovascular disease risk, and the effect of OA remains uncertain. Our study aimed to assess the effect of a short-term intake of lard, as source of PA and OA, on aorta and aortic valve. Methods and Results: Rabbits were fed with two lard-enriched diets, containing either elevated levels of PA or of both PA and OA as compared to chow diet. After 16 weeks of each diet, calcification was observed in the aortic intima and in the aortic valve. The extent of calcification did not differ between the two diets. In contrast, rabbits fed chow diet did not develop any calcification. In blood, PA enrichment resulted in decreased lymphocyte and monocyte counts and increased levels of hemoglobin and haematocrit. Levels of the calcification inhibitor fetuin-A were also diminished, whereas creatinine levels were raised. Of note, none of the diets changed cholesterol levels in LDL or HDL. Comprehensive quantitative lipidomics analysis identified diet-related changes in plasma lipids. Dietary PA enrichment led to a drop of polyunsaturated fatty acids (PUFA), in particular of linoleic acid in cholesteryl esters, triglycerides and diacylglycerols (DAG). Ratios of PA to 18-carbon PUFA in DAG were positively correlated with the extent of aortic valve calcification, and inversely with monocyte counts. PA content in blood correlated with aorta calcification. Conclusions: Regular dietary PA intake induces vascular and valvular calcification independently of traditional risk factors. Our findings raise awareness about PA-rich food consumption and its potential deleterious effect on cardiovascular health.
Ference BA Graham I Tokgozoglu L Catapano AL. Impact of lipids on cardiovascular health: JACC health promotion series. J Am Coll Cardiol. (2018) 72:1141–56. 10.1016/j.jacc.2018.06.04630522632
Afshin A Sur PJ Fay KA Cornaby L Ferrara G Salama JS et al. Health effects of dietary risks in 195 countries, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. (2019) 393:1958–72. 10.1016/S0140-6736(19)30041-830954305
Stegemann C Pechlaner R Willeit P Langley SR Mangino M Mayr U et al. Lipidomics profiling and risk of cardiovascular disease in the prospective population-based bruneck study. Circulation. (2014) 129:1821–31. 10.1161/CIRCULATIONAHA.113.00250024622385
DiNicolantonio JJ O'Keefe JH. Effects of dietary fats on blood lipids: a review of direct comparison trials. Open Hear. (2018) 5:1–5. 10.1136/openhrt-2018-00087130094038
Praagman J Beulens JWJ Alssema M Zock PL Wanders AJ Sluijs I et al. The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European prospective investigation into cancer and nutrition-Netherlands cohort. Am J Clin Nutr. (2016) 103:356–65. 10.3945/ajcn.115.12267126791181
De Oliveira Otto MC Mozaffarian D Kromhout D Bertoni AG Sibley CT Jacobs DR et al. Erratum: dietary intake of saturated fat by food source and incident cardiovascular disease: the multi-ethnic study of atherosclerosis. Am J Clin Nutr. (2012) 96:397–404. 10.3945/ajcn.112.037770
Praagman J De Jonge EAL Kiefte-De Jong JC Beulens JWJ Sluijs I Schoufour JD et al. Dietary saturated fatty acids and coronary heart disease risk in a Dutch middle-aged and elderly population. Arterioscler Thromb Vasc Biol. (2016) 36:2011–8. 10.1161/ATVBAHA.116.30757827417581
Jin J Lu Z Li Y Cowart LA Lopes-Virella MF Huang Y. Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on lPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis. PLoS ONE. (2018) 13:1–18. 10.1371/journal.pone.019334329474492
Hellmann J Zhang MJ Tang Y Rane M Bhatnagar A Spite M. Increased saturated fatty acids in obesity alter resolution of inflammation in part by stimulating prostaglandin production. J Immunol. (2013) 191:1383–92. 10.4049/jimmunol.120336923785121
Wang Y Qian Y Fang Q Zhong P Li W Wang L et al. Saturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2. Nat Commun. (2017) 8:13997. 10.1038/ncomms1399729553572
Harvey KA Walker CL Pavlina TM Xu Z Zaloga GP Siddiqui RA. Long-chain saturated fatty acids induce pro-inflammatory responses and impact endothelial cell growth. Clin Nutr. (2010) 29:492–500. 10.1016/j.clnu.2009.10.00819926177
Kageyama A Matsui H Ohta M Sambuichi K Kawano H Notsu T et al. Palmitic acid induces osteoblastic differentiation in vascular smooth muscle cells through ACSL3 and NF-κB, novel targets of eicosapentaenoic acid. PLoS ONE. (2013) 8:e68197. 10.1371/journal.pone.006819723840832
Brodeur MR Bouvet C Barrette M Moreau P. Palmitic acid increases medial calcification by inducing oxidative stress. J Vasc Res. (2013) 50:430–41. 10.1159/00035423524080574
Zong G Li Y Sampson L Dougherty LW Willett WC Wanders AJ et al. Monounsaturated fats from plant and animal sources in relation to risk of coronary heart disease among US men and women. Am J Clin Nutr. (2018) 107:445–53. 10.1093/ajcn/nqx00429566185
Steffen BT Duprez D Szklo M Guan W Tsai MY. Circulating oleic acid levels are related to greater risks of cardiovascular events and all cause mortality: the multi-ethnic study of atherosclerosis. J Clin Lipidol. (2018) 12:1404–12. 10.1016/j.jacl.2018.08.00430201531
Ma J Folsom AR Shahar E Eckfeldt JH. Plasma fatty acid composition as an indicator of habitual dietary fat intake in middle-aged adults. Am J Clin Nutr. (1995) 62:564–71. 10.1093/ajcn/62.3.5647661118
Bankhead P Loughrey MB Fernández JA Dombrowski Y McArt DG Dunne PD et al. QuPath: open source software for digital pathology image analysis. Sci Rep. (2017) 7:1–7. 10.1038/s41598-017-17204-529203879
Ubhi BK. Direct infusion-tandem mass spectrometry (DI-MS/MS) analysis of complex lipids in human plasma and serum using the lipidyzerTM platform. Methods Mol Biol. (2018) 1730:227–36. 10.1007/978-1-4939-7592-1_15
Alarcon-Barrera JC von Hegedus JH Brouwers H Steenvoorden E Ioan-Facsinay A Mayboroda OA et al. Lipid metabolism of leukocytes in the unstimulated and activated states. Anal Bioanal Chem. (2020) 412:2353–63. 10.1007/s00216-020-02460-832055910
Contrepois K Mahmoudi S Ubhi BK Papsdorf K Hornburg D Brunet A et al. Cross-platform comparison of untargeted and targeted lipidomics approaches on aging mouse plasma. Sci Rep. (2018) 8:1–9. 10.1038/s41598-018-35807-430532037
Cao Z Schmitt TC Varma V Sloper D Beger RD Sun J. Evaluation of the performance of lipidyzer platform and its application in the lipidomics analysis in mouse heart and liver. J Proteome Res. (2020) 19:2742–9. 10.1021/acs.jproteome.9b0028931310547
Lintonen TPI Baker PRS Suoniemi M Ubhi BK Koistinen KM Duchoslav E et al. Differential mobility spectrometry-driven shotgun lipidomics. Anal Chem. (2014) 86:9662–9. 10.1021/ac502174425160652
Piccinin E Cariello M De Santis S Ducheix S Sabbà C Ntambi JM et al. Role of oleic acid in the gut-liver axis: from diet to the regulation of its synthesis via stearoyl-CoA desaturase 1 (SCD1). Nutrients. (2019) 11:1–22. 10.3390/nu1110228331554181
Bhatt DL Steg PG Miller M Brinton EA Jacobson TA Ketchum SB et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. (2019) 380:11–22. 10.1056/NEJMoa181279230415628
Farvid MS Ding M Pan A Sun Q Chiuve SE Steffen LM et al. Dietary linoleic acid and risk of coronary heart disease: a systematic review and meta-analysis of prospective cohort studies. Circulation. (2014) 130:1568–78. 10.1161/CIRCULATIONAHA.114.01023625161045
Yang WS Chen YY Chen PC Hsu HC Su TC Lin HJ et al. Association between plasma n-6 polyunsaturated fatty acids levels and the risk of cardiovascular disease in a community-based cohort study. Sci Rep. (2019) 9:1–9. 10.1038/s41598-019-55686-731848413
Fernández-Friera L Fuster V López-Melgar B Oliva B García-Ruiz JM Mendiguren J et al. Normal lDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol. (2017) 70:2979–91. 10.1016/j.jacc.2017.10.02429241485
Sachdeva A Cannon CP Deedwania PC LaBresh KA Smith SC Dai D et al. Lipid levels in patients hospitalized with coronary artery disease: an analysis of 136,905 hospitalizations in get with the guidelines. Am Heart J. (2009) 157:111–7.e2. 10.1016/j.ahj.2008.08.01019081406
Ding M Rexrode KM. A review of lipidomics of cardiovascular disease highlights the importance of isolating lipoproteins. Metabolites. (2020) 10:1–13. 10.3390/metabo1004016332340170
Mitchell JD Paisley R Moon P Novak E Villines TC. Coronary artery calcium and long-term risk of death, myocardial infarction, and stroke: the walter reed cohort study. JACC Cardiovasc Imaging. (2018) 11:1799–806. 10.1016/j.jcmg.2017.09.00329153576
Clavel MA Pibarot P Messika-Zeitoun D Capoulade R Malouf J Aggarval S et al. Impact of aortic valve calcification, as measured by MDCT, on survival in patients with aortic stenosis: results of an international registry study. J Am Coll Cardiol. (2014) 64:1202–13. 10.1016/j.jacc.2014.05.06625236511
Torzewski M Ravandi A Yeang C Edel A Bhindi R Kath S et al. Lipoprotein(a)-associated molecules are prominent components in plasma and valve leaflets in calcific aortic valve stenosis. JACC Basic Transl Sci. (2017) 2:229–40. 10.1016/j.jacbts.2017.02.00429147686
Roijers RB Debernardi N Cleutjens JPM Schurgers LJ Mutsaers PHA Van Der Vusse GJ. Microcalcifications in early intimal lesions of atherosclerotic human coronary arteries. Am J Pathol. (2011) 178:2879–87. 10.1016/j.ajpath.2011.02.00421531376
Lindman BR Clavel M-A Mathieu P Iung B Lancellotti P Otto CM et al. Calcific aortic stenosis. Nat Rev Dis Prim. (2016) 2:16006. 10.1038/nrdp.2016.6
Koenig W. Low-grade inflammation modifies cardiovascular risk even at very low lDL-C levels are we aiming for a dual target concept? Circulation. (2018) 138:150–3. 10.1161/CIRCULATIONAHA.118.03510729986958
Håversen L Danielsson KN Fogelstrand L Wiklund O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis. (2009) 202:382–93. 10.1016/j.atherosclerosis.2008.05.03318599066
L'Homme L Sermikli BP Staels B Piette J Legrand-Poels S Dombrowicz D. Saturated fatty acids promote GDF15 expression in human macrophages through the PERK/eIF2/CHOP signaling pathway. Nutrients. (2020) 12:3771. 10.3390/nu1212377133302552
Wang X Chen LL Zhang Q. Increased serum level of growth differentiation factor 15 (GDF-15) is associated with coronary artery disease. Cardiovasc Ther. (2016) 34:138–43. 10.1111/1755-5922.1218426996787
Kim JB Kobayashi Y Moneghetti KJ Brenner DA O'Malley R Schnittger I et al. GDF-15 (growth differentiation factor 15) is associated with lack of ventricular recovery and mortality after transcatheter aortic valve replacement. Circ Cardiovasc Interv. (2017) 10:1–9. 10.1161/CIRCINTERVENTIONS.117.00559429222133
Li Y Sun Z Zhang L Yan J Shao C Jing L et al. Role of macrophages in the progression and regression of vascular calcification. Front Pharmacol. (2020) 11:661. 10.3389/fphar.2020.0066132457633
Davanso MR Crisma AR Murata G Newsholme P Curi R. Impact of dietary fatty acids on macrophage lipid metabolism, signaling and function. Immunometabolism. (2020) 2:1–41. 10.20900/immunometab20200008
Artiach G Carracedo M Plunde O Wheelock CE Thul S Sjövall P et al. Omega-3 polyunsaturated fatty acids decrease aortic valve disease through the resolvin E1 and chemR23 axis. Circulation. (2020) 142:776–789. 10.1161/CIRCULATIONAHA.119.04186832506925
Irace C Ciamei M Crivaro A Fiaschi E Madia A Cortese C et al. Hematocrit is associated with carotid atherosclerosis in men but not in women. Coron Artery Dis. (2003) 14:279–84. 10.1097/01.mca.0000071769.74379.4912826926
Carallo C Pujia A Irace C De Franceschi MS Motti C Gnasso A. Whole blood viscosity and haematocrit are associated with internal carotid atherosclerosis in men. Coron Artery Dis. (1998) 9:113–7. 10.1097/00019501-199802000-000089647412
Gagnon DR Zhang TJ Brand FN Kannel WB. Hematocrit and the risk of cardiovascular disease-the framingham study: a 34-year follow-up. Am Heart J. (1994) 127:674–82. 10.1016/0002-8703(94)90679-38122618
Danesh J Collins R Peto R Lowe GDO. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J. (2000) 21:515–20. 10.1053/euhj.1999.169910775006
Cho YI Cho DJ Rosenson RS. Endothelial shear stress and blood viscosity in peripheral arterial disease. Curr Atheroscler Rep. (2014) 16:404. 10.1007/s11883-014-0404-624519415