Preview

New St. Petersburg Medical Records

Advanced search

Dyslipidemia as a cause of aortic stenosis. Review of literature and own experience of monitoring patients with familial hypercholesterolemia

https://doi.org/10.24884/1609-2201-2025-104-1-32-43

Abstract

Introduction. Aortic stenosis (AS) is the third leading cause of death from cardiovascular disease. AS is a multifactorial disease, and dyslipidemia is one of the possible etiopathogenetic mechanisms of its development. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated total cholesterol and low-density lipoprotein cholesterol levels from birth.
Aim: to analyze the contribution of dyslipidemia and elevated Lp(a) levels to the formation of AS in patients with FH.
Materials and methods: 134 patients with heterozygous FH were examined (mean age 52.9±3.2 years, 85 (63.4%) men), of which 10 (7.46%) patients were diagnosed with AS. FH was diagnosed according to the Dutch Lipid Clinic Network criteria. Lipoprotein(a) (Lp(a)) concentration was measured using the turbometric method.
Results. In patients with FH and AS, higher levels of total cholesterol were detected (11.88±1.83 mmol/l compared with 9.85±1.47 mmol/l without AS, p<0.01); higher levels of LDL cholesterol (9.24±1.2 mmol/l compared with 7.23±1.34 mmol/l without AS, p<0.001). An increase in Lp(a) by 1 unit of measurement (1 g/l) leads to a 10.6-fold increase in the OR for AS (OR = 10.5 [5.0; 21.9] p=0.0017).
Conclusions: Increased levels of total cholesterol and LDL cholesterol, Lp(a) are associated with the development of AS in patients with FH.. The role of extraoral TAS2Rs and mechanisms of its regulation remain uncertain, that requires further research, including the field of respiratory pathology.

About the Authors

V. A. Korneva
Petrozavodsk State University
Russian Federation

Victoria A. Korneva, Cand. of Sci. (Med.), assistant professor, assistant professor of the Department of Faculty Therapy, Phthisiology, Infectious Diseases and Epidemiology, Institute of Medicine named after prof. Anatoly P. Zilber

33, Lenin str., Petrozavodsk, 185035



T. Yu. Kuznetsova
Petrozavodsk State University
Russian Federation

Tatiana Yu. Kuznetsova, Dr. of Sci. (Med.), head of the Department of Faculty Therapy, Phthisiology, Infectious Diseases and Epidemiology, Institute of Medicine named after prof. Anatoly P. Zilber

33, Lenin str., Petrozavodsk, 185035



References

1. Bockeria L.A., Gudkova R.G. Cardiovascular surgery – 2008. Diseases and congenital anomalies of the circulatory system. M., 2009. (In Russ.).

2. Mursalimova A. I., Gendlin G. E., Storozhakov G. I. Features of the course and diagnosis of aortic stenosis. Atmosphere. Cardiology news. 2013;1. URL: https://cyberleninka.ru/article/n/osobennosti-techeniya-i-diagnostikiaortalnogo-stenoza (date of access: 01/05/2025). (In Russ.).

3. Baumgartner H., Falk V., Bax J. J. et al. ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;8(36):2739–2791. https://doi.org/10.1093/eurheartj/ehx391.

4. Mathieu P., Boulanger M. C., Bouchareb R. Molecular biology of calcific aortic valve disease: towards new pharmacological therapies. Expert Rev Cardiovasc Ther. 2014;12(7):851–862. https://doi.org/10.1586/147.

5. Hjortnaes J., Aikawa E. Calcific Aortic Valve Disease. URL: http://cdn.intechopen.com/pdfs/24205/InTechCalcific_aortic_valve_disease.pdf (дата обращения: 05.01.2025).

6. Freeman R. V., Otto C. M. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005;111(24):3316–26. https://doi.org/10.1161/CIRCULATIONAHA.104.486738.

7. Burdeynaya A. L., Afanasyeva O. I., Ezhov M. V. B et al. Genotype, phenotype and lipoprotein(a) level in patients with aortic stenosis depending on the presence of coronary heart disease. Atherosclerosis and dyslipidemia. 2020;4:35–43. (In Russ.). https://doi.org/10.34687/2219-8202.JAD.2020.04.0005.

8. Hulin A., Hego A., Lancellotti P. et al. Advances in pathophysiology of calcific aortic valve disease propose novel molecular therapeutic targets. Front Cardiovasc Med. 2018;5:21. https://doi.org/10.3389/fcvm.2018.00021.

9. Rajamannan N. M., Moura L. The lipid hypothesis in calcific aortic valve disease: the role of the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2016;36:774–6. https://doi.org/10.1161/ATVBAHA.116.307435.

10. Pawade T., Newby D., Dweck M. Calcification in Aortic Stenosis. The Skeleton Key. J Am Coll Cardiol. 2015;66:561–77. https://doi.org/10.1016/j.jacc.2015.05.066.

11. Rajamannan N. M. Oxidative-mechanical stress signals stem cell niche mediated Lrp5osteogenesis in eNOS(-/-) null mice. J Cell Biochem. 2012;113(5):1623–34. https://doi.org/10.1002/jcb.24031.

12. Bonetti A., Marchini M., Ortolani F. Ectopic mineralization in heart valves: new insights from in vivo and in vitro procalcific models and promising perspectives on noncalcifiable bioengineered valves. J Thorac Dis. 2019;11(5):2126–43. https://doi.org/10.21037/jtd.2019.04.78.

13. New S. E., Aikawa E. Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circ Res. 2011;108:1381–91. https://doi.org/10.1161/circresaha.110.234146.

14. Kim K. M. Calcification of matrix vesicles in human aortic valve and aortic media. Fed Proc. 1976;35:156–62.

15. Mohler E. R., Gannon F., Reynolds C. et al. Bone formation and inflammation in cardiac valves. Circulation. 2001;103:1522–30. https://doi.org/10.1161/01. CIR.103.11.1522.

16. El Accaoui R. N., Gould S. T., Hajj G. P. et al. Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase. Am J Physiol Heart Circ Physiol. 2014;306:H1302–13. https://doi.org/10.1152/ajpheart.00392.2013.

17. Tomita H., Egashira K., Ohara Y. et al. Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension. 1998;32:273–279. https://doi.org/10.1161/01.hyp.32.2.273.

18. Peltonen T., Napankangas J., Ohtonen P. et al. (Pro)renin receptors and angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in human aortic valve stenosis. Atherosclerosis. 2011;216:35–43. https://doi.org/10.1016/j.atherosclerosis.2011.01.018.

19. Capoulade R., Clavel M. A., Mathieu P. et al. Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis. Eur J Clin Invest. 2013;43:1262–72. https://doi.org/10.1111/eci.12169.

20. Qua X., Huanga X., Jin F. Bone mineral density and all-cause, cardiovascular and stroke mortality: A meta-analysis of prospective cohort studies. Int J Cardiol. 2013;166(2):385–93. https://doi.org/10.1016/j.ijcard.2011.10.114.

21. Lee S):Understanding the Natural History of Bicuspid Aortic Valve: Are We Close to Understanding It? J Cardiovasc Imaging. 2019;27(2):119–21. https://doi.org/10.4250/jcvi.2019.27.e21.

22. Sathyamurthy I., Alex S. Calcific aortic valve disease: is it another face of atherosclerosis? Indian heart journal. 2015;67(5):503–6. https://doi.org/10.1016/j.ihj.2015.07.033.

23. Ferreira-González I., Pinar-Sopena J., Ribera A. et al. Prevalence of calcific aortic valve disease in the elderly and associated risk factors: a populationbased study in a Mediterranean area. Eur J Prev Cardiol. 2013;20(6):1022–30. https://doi.org/10.1177/2047487312451238.

24. Smith J.G., Luk K., Schulz C-A, et al. Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. JAMA. 2014;312:1764–1771. https://doi.org/10.1001/jama.2014.13959.

25. Tsimikas S., Fazio S., Ferdinand K.C., et al. NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol. 2018;71:177–192. https:// doi.org/10.1016/j.jacc.2017.11.014.

26. Vuorio A., Watts G. F., Schneider W. J. et al. Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities. J Intern Med. 2020;287:2–18. https://doi.org/10.1111/joim.12981.

27. Ye C., Xu M., Wang S. et al. Decreased Bone Mineral Density Is an Independent Predictor for the Development of Atherosclerosis: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(5):e0154740. https://doi.org/10.1371/journal.pone.0154740.

28. Rajamannan N. M. Oxidative-mechanical stress signals stem cell niche mediated Lrp5 osteogenesis in eNOS(-/-) null mice. J Cell Biochem. 2012;113(5):1623–34. https://doi.org/10.1002/jcb.24031.

29. Smith J., Luk G. K., Schulz C. A. et al. Cohorts for heart and aging research in genetic epidemiology (CHARGE) extracoronary calcium working group. Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis. J Am Med Assoc. 2014;312:1764–71. https://doi.org/10.1001/jama.2014.13959.

30. Olgun Küçük H., Küçük U., Demirtaş C., Özdemir M. Role of serum high density lipoprotein levels and functions in calcific aortic valve stenosis progression. Int J Clin Exp Med. 2015;8(12):22543–9.

31. Lommi J. I., Kovanen T., Jauhiainen M. High-density lipoproteins (HDL) are present in stenotic aortic valves and may interfere with the mechanisms of valvular calcification. Atherosclerosis. 2011;219(2):538–44. https://doi. org/10.1016/j.atherosclerosis.2011.08.027.20.

32. Audet A., Cote N., Couture C. et al. Amyloid substance within stenotic aortic valves promotes mineralization. Histopathology. 2012;61:610–9. https://doi.org/10.1111/j.1365-2559.2012.04265.x.

33. Trapeaux J., Busseuil D., Shi Y. et al. Improvement of aortic valve stenosis by ApoA-mimetic therapy is associated with decreased aortic root and valve remodelling in mice. Br. J. Pharmacol. 2013;169(7):1587–99. https://doi.org/10.1111/bph.12236.

34. Allara E., Morani G., Carter P. et al. Genetic determinants of lipids and cardiovascular disease outcomes: a wide-angled mendelian randomization investigation. Circ Genomic Precis Med. 2019;12:543–551.

35. Storozhakov G. I., Gendlin G. E., Miller O. A. Diseases of the heart valves. M., 2015. (In Russ.).

36. Karpova N. Yu., Shostak N. A. The state of bone metabolism in patients with calcified aortic stenosis of degenerative origin. The clinician. 2006;(1). URL: https://cyberleninka.ru/article/n/sostoyanie-kostnogo-metabolizmau-bolnyh-kaltsinirovannym-aortalnym-stenozom-degenerativnogo-geneza (date of request: 06.01.2025). (In Russ.).

37. Capoulade R., Chan K. L., Yeang C. et al. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. J Am Coll Cardiol. 2015;66(11):1236–1246. https://doi.org/ 10.1016/j.jacc.2015.07.020.

38. Dweck M. R., Boon N. A., Newby D. E. Calcific aortic stenosis: a disease of the valve and the myocardium. J Am Coll Cardiol. 2012;60:1854–1863. https://doi.org/10.1016/j.jacc.2012.02.093.

39. Chen J. H., Simmons C. A. Cell-matrix interactions in the pathobiology of calcific aortic valve disease: critical roles for matricellular, matricrine, and matrix mechanics cues. Circ Res. 2011;108:1510–1524. https://doi.org/10.1161/CIRCRESAHA.110.234237.

40. Stewart B. F., Siscovick D., Lind B. K. et al. Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study. J Am Coll Cardiol. 1997;29(3):630–634. https://doi.org/10.1016/s0735–1097(96)00563–3.

41. Arsenault B. J., Boekholdt S. M., Dubé M. P., Rhéaume E. et al. Lipoprotein(a)levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication ina casecontrol cohort. Circ Cardiovasc Genet. 2014;7(3):304–310. https://doi.org/10.1161/CIRCGENETICS.113.000400.

42. Kronenberg F., Mora S., Stroes E. S. G. et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43(39):3925–46. https:// doi.org/10.1093/eurheartj/ehac361.

43. Tasdighi E., Adhikari R., Almaadawy O. et al. LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics. Annu Rev Pharmacol Toxicol. 2024;64:135–57. https://doi.org/10.1146/annurevpharmtox-031023-100609.

44. Kenet G., Lutkhoff L. K., Albisetti M. et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children:a systematic review and meta-analysis of observational studies. Circulation. 2010;121(16):1838–47. https://doi.org/10.1161/CIRCULATIONAHA.109.913673.

45. Manikpurage H. D., Paulin A., Girard A. et al. Contribution of Lipoprotein(a) to Polygenic Risk Prediction of Coronary Artery Disease: A Prospective UK Biobank Analysis. Circ Genom Precis Med. 2023;16(5):470–7. https:// doi.org/10.1161/CIRCGEN.123.004137.

46. Yezhov M. V., Kukharchuk V. V., Sergienko I. V. and others. Disorders of lipid metabolism. Clinical Recommendations 2023. Russian Journal of Cardiology. 2023;28(5):5471. (In Russ.). https://doi.org/10.15829/1560-4071-2023-5471.

47. Polyakova E. A., Khalimov Yu. Sh., Bazhenova E. A., Bahar T. M. Lipoprotein(a), atherosclerosis and cardiovascular risk. Rational Pharmacotherapy in Cardiology. 2024;20(5):559–565. (In Russ.). https:// doi.org/10.20996/1819-6446-2024-3080.

48. Deshmukh H. A., Colhoun H. M., Johnson T. et al. Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a). J Lipid Res. 2012;53(5):1000–11. https:// doi.org/10.1194/jlr.P021113.

49. Dimitrow P. P. Aortic stenosis: new pathophysiological mechanisms and their therapeutic implications. Pol Arch Med Wewn. 2014;124(12):723–30. https://doi.org/10.20452/pamw.2562.

50. Ardehali R., Leeper N. J., Wilson A. M. et al. The effect of angiotensinconverting enzyme inhibitors and statins on the progression of aortic sclerosis and mortality. J Heart Valve Dis. 2012;21(3):337–43.

51. De Vecchis R., Di Biase G., Esposito C. et al. Statin use for nonrheumatic calcific aortic valvestenosis: a review with meta-analysis. J Cardiovasc Med (Hagerstown). 2013;14(8):559–67. https://doi.org/10.2459/JCM.0b013e3283587267.

52. Chan K. L., Teo K., Dumesnil J. G. et al. 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;121:306–14. https://doi.org/10.1161/circulationaha.109.900027.

53. Tsimikas S., Gordts P. L. S. M., Nora C. et al. Statins and increases in Lp(a): an inconvenient truth that needs attention. Eur Heart J. 2020;41:192–193.

54. O’Donoghue M. L., Fazio S., Giugliano R. P. et al. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019;139(12):1483–92. https://doi.org/10.1161/CIRCULATIONAHA.118.037184.

55. Szarek M., Bittner V. A., Aylward P. et al. Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. Eur Heart J. 2020;41(44):4245–55. https://doi.org/10.1093/eurheartj/ehaa649.

56. Frampton J. E. Inclisiran: A Review in Hypercholesterolemia. Am J Cardiovasc Drugs. 2023;23(2):219–30. https://doi.org/10.1007/s40256-023-00568-7.

57. Perrot N., Valerio V., Moschetta D. et al. Genetic and in vitro inhibition ofPCSK9 and calcific aortic valve stenosis. JACC Basic Transl Sci. 2020;5:649–661.

58. Nicholls S. J., Nissen S. E., Fleming C. et al. Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial. JAMA. 2023;330(11):1042–53. https://doi.org/10.1001/jama.2023.16503.

59. LafÏn L. J., Nissen S. E. Lp(a) — an overlooked risk factor. Trends Cardiovasc Med. 2024;34(3):193–9. https://doi.org/10.1016/j.tcm.2023.01.003.

60. Julius U., Tselmin S., Korneva V.A. Is it possible to reverse the development of atherosclerotic lesions with long-term treatment with lipoprotein apheresis? Russian Journal of Cardiology. 2024;29(8):6069. (In Russ.). https://doi.org/10.15829/1560-4071-2024-6069.

61. Tsimikas S., Karwatowska-Prokopczuk E., Gouni-Berthold I. et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382:244–255. https://doi.org/10.1056/NEJMoa1905239.

62. Pe´rez De Isla L., Alonso R, Mata N. et al. Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation. 2017;135:2133–2144. https://doi.org/10.1161/CIRCULATIONAHA.116.024541.

63. Kamstrup P. R., Tybjærg-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. https://doi.org/10.1016/j.jacc.2013.09.038.

64. Chuang Y. W., Yu M. C., Lin C. L. et al. Risk of peripheral arterial occlusive disease inpatients with rheumatoid arthritis. A nationwide population-based cohort study. Thromb Haemost. 2016;115:439–45. https://doi.org/10.1160/TH15-07-0600.

65. Benn M., Watts G. F., Tybjærg-Hansen A., Nordestgaard B. G. Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217. European Heart Journal. 2016;37(17):1384–1394.https://doi.org/10.1093/eurheartj/ehw028.

66. Sjouke B., Kusters D. M., Kindt I. et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotypephenotype relationship,and clinical outcome. European Heart Journal. 2015;36(9):560–565. https://doi.org/org/10.1093/eurheartj/ehu05.

67. Zafiraki V. K., Kosmacheva E. D., Zakharova I. N. et al. Homozygous familial hypercholesterolemia: modern aspects of pathogenesis, diagnosis and therapy. Medical Council. 2018;17:253–260. (In Russ.). https://doi.org/10.21518/2079-701X-2018-17-253-259.

68. France M. Rees A., Datta D. et al. for HEART UK Medical Scientific and Research Committee.HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom. Atherosclerosis. 2016;255:128–139.

69. Fahed A.C., Shibbani K., Andary R.R et al. Premature valvular heart disease in homozygous familial hypercholesterolemia. Cholesterol. 2017:3685265. https://doi.org/10.1155/2017/3685265.

70. Hoeg J. M., Feuerstein I. M., Tucker E. E. Detection and quantitation of calcific atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia. Arteriosclerosis and Thrombosis. 1994;14(7):1066–1074. https://doi.org/10.1161/01.atv.14.7.1066.

71. Awan Z., Alrasadi K., Francis G. A. et al. Vascular calcifications in homozygote familial hypercholesterolemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28(4):777–785. https://doi.org/10.1161/ATVBAHA.107.160408.

72. Beheshti S. O., Madsen C. M., Varbo A., Nordestgaard B. G. Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects. Journal of the American College of Cardiology. 2020;75(20):2553–2566. https://doi.org/10.1016/j.jacc.2020.03.057.

73. Мeshkov A. N., Ershova A. I., Kiseleva A. V. et al. On Behalf Of The Fh-Esse-Rf Investigators. The Prevalence of Heterozygous Familial Hypercholesterolemia in Selected Regions of the Russian Federation: The FH-ESSE-RF Study. Journal of Personalized Medicine. 2021;11(6):464. https://doi.org/10.3390/jpm11060464.

74. Yezhov M. V., Bazhan S. S., Ershova A. I. and others. Clinical guidelines for familial hypercholesterolemia. Atherosclerosis. 2019;15(1):58–98. (In Russ.).

75. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Russian Journal of Cardiology. 2022;27(7):5160. (In Russ.). https://doi.org/10.15829/1560-4071-2022-5160.

76. Mata P., Alonso R., Pérez de Isla L., Badimón L. Dyslipidemia and aortic valve disease. Curr Opin Lipidol. 2021;32(6):349–354. https://doi.org/10.1097/MOL.0000000000000794.


Review

For citations:


Korneva V.A., Kuznetsova T.Yu. Dyslipidemia as a cause of aortic stenosis. Review of literature and own experience of monitoring patients with familial hypercholesterolemia. New St. Petersburg Medical Records. 2025;(1):32-43. (In Russ.) https://doi.org/10.24884/1609-2201-2025-104-1-32-43

Views: 13


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1609-2201 (Print)