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European Heart Journal 2001 22(6):465-471; doi:10.1053/euhj.2000.2408
Copyright © 2001 by the European Society of Cardiology.
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Importance of HDL cholesterol levels and the total/ HDL cholesterol ratio as a risk factor for coronary heart disease in molecularly defined heterozygous familial hypercholesterolaemia

J.T Reala, F.J Chavesb, I Martínez-Usóa, A.B García-Garcíab, J.F Ascasoa and R Carmenaa,f1

a Service of Endocrinology and Nutrition, Department of Medicine, Hospital Clinico Universitario, University of Valencia, Valencia, Spain
b Instituto de Investigaciones Citológicas, Valencia, Spain

revised August 1, 2000; accepted August 2, 2000

Abstract

Aims To assess the relationship of the lipid profile to coronary heart disease in a group of heterozygous familial hypercholesterolaemic subjects with similar age, sex, body mass index, prevalence of angiotensin converting enzyme DD genotype and type of low density lipoprotein receptor mutation.

Methods and Results A total of 66 molecularly defined heterozygous familial hypercholesterolaemic subjects, 33 of whom had coronary heart disease, were studied. Clinical features, cardiovascular risk factors and lipid parameters were compared in both groups. Familial hypercholesterolaemic patients with coronary heart disease showed significantly lower values of mean plasma HDL cholesterol and a higher total/HDL cholesterol ratio as compared with familial hypercholesterolaemic subjects free of coronary heart disease. Total and LDL cholesterol concentrations were higher in patients with coronary heart disease, without reaching statistical significance. No differences in plasma lipoprotein(a) levels on absolute and log-transformed values were observed between the two groups. In the whole familial hypercholesterolaemia group, plasma HDL cholesterol levels were related to plasma triglyceride values and to LDL receptor gene ‘null mutations’.

Conclusions In familial hypercholesterolaemic subjects of similar age, gender, body mass index, systolic and diastolic blood pressure, and genetic factors that could influence coronary heart disease risk, plasma HDL cholesterol values and total/HDL cholesterol ratios are two important coronary risk factors. Hence, treatment of familial hypercholesterolaemia should focus not only on lowering total and LDL cholesterol levels, but also on increasing HDL cholesterol values for coronary heart disease prevention. More prospective and intervention trials should be conducted to establish the relationship of HDL cholesterol levels and coronary heart disease in familial hypercholesterolaemia.

Key Words: Heterozygous familial hypercholesterolaemia, HDL cholesterol levels, coronary heart disease, angiotensin converting enzyme DD genotype, low density lipoprotein receptor mutations

f1 Correspondence: Dr Rafael Carmena, Department of Medicine, Hospital Clínico Universitario, Avda. Blasco Ibáñez 17, E-46010 Valencia, Spain.

References

  1. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34–47[Free Full Text]
  2. Hobbs H, Brown MS, Goldstein JL. Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1992;1:445–466[CrossRef][Medline]
  3. Hoeg JM. Homozygous familial hypercholesterolemia: a paradigm for phenotypic variation. Am J Cardiol. 1993;72:11D–14D[CrossRef][Medline]
  4. Ferrières J, Lambert J, Lussier-Cacan S, Davignon J. Coronary artery disease in heterozygous familial hypercholesterolemia patients with the same LDL receptor gene mutation. Circulation. 1995;92:290–295[Abstract/Free Full Text]
  5. Utermann G, Hoppichler F, Dieplinger H, Seed M, Thompson G, Boerwinkle E. Defects in the low density lipoprotein receptor gene affect lipoprotein(a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis. Proc Natl Acad Sci USA. 1989;86:4171–4174[Abstract/Free Full Text]
  6. Gaudet D, Vohl MC, Perron P. Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation. 1998;97:871–877[Abstract/Free Full Text]
  7. Vohl MC, Gaudet D, Moorjani S. Comparison of the effect of two low-density lipoprotein receptor class mutations on coronary heart disease among French-Canadian patients heterozygous for familial hypercholesterolemia. Eur J Clin Invest. 1997;27:366–373[CrossRef][Web of Science][Medline]
  8. O'Malley, Maslen CL, Illinworth DR. Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia. Circulation. 1998;97:1780–1783[Abstract/Free Full Text]
  9. Nielsen L, Stender S, Kjeldsen K, Nordestgaard B. Effect of angiotensin and enalapril on transfer of low density lipoprotein into aortic intima in rabbits. Circ Res. 1994;75:63–69[Abstract/Free Full Text]
  10. Kotze MJ, de Villiers WJS, Stein K. Phenotypic variation among familial hypercholesterolemic heterozygous for either one of two Afrikaner founder LDL receptor mutations. Arterioscler Thromb. 1993;13:1460–1468[Abstract/Free Full Text]
  11. Gudnason V, Day INM, Humphries SE. Effect on plasma lipid levels of different classes of mutations in the low-density lipoprotein receptor gene in patients with familial hypercholesterolemia. Arterioscler Thromb. 1994;17:1717–1722
  12. Vuorio, AF, Ojala, JP, Sarna, S, Turtola, H, Tikkanen, MJ, Kontula, K, Heterozygous familial hypercholesterolaemia: the influence of the mutation type of the low-density-lipoprotein receptor gene and PvuII polymorphism of the normal allele on serum lipid levels and response to lovastatin treatment, J Intern Med, 237, 1, 43, 8
  13. Leren TP, Hjermann I. Is responsiveness to lovastatin in familial hypercholesterolaemia influenced by the specific mutation in the low density lipoprotein receptor gene? Eur J Clin Invest. 1995;25:967–973[Web of Science][Medline]
  14. Diabetes Care. 1997;20:1183–1197[Web of Science][Medline]
  15. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470–475[Abstract]
  16. Ter Welle HF, Baartscheer T, Fiolet JWT. Influence of free glycerol on enzymatic evaluation of triglycerides. Clin Chem. 1984;30:1102–1103[Medline]
  17. Burstein M, Scholnick HR, Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res. 1970;11:583–595[Abstract]
  18. Havel RJ, Eder HJ, Bragdon JH. The distribution and chemical composition of centrifugally separated lipoproteins in human serum. Eur J Clin Invest. 1995;34:1345–1354
  19. Rosseneu M, Vercaemst R, Steinberg KK, Cooper GR. Some considerations of methodology and standarization of apolipoprotein B immunoassays. Clin Chem. 1983;29:427–433[Abstract/Free Full Text]
  20. Lombardi P, Sijbrands EJC, van de Giessen K. Mutations in the low density lipoprotein receptor gene of familial hypercholesterolemic patients detected by denaturing gel electrophoresis and direct sequencing. J Lipid Res. 1995;36:860–865[Abstract]
  21. Leren, TP, Solberg, K, Kodningen, OK, Ose, L, Tondstad, S, Berg, K, Evaluation of running conditions for SSCP for detection of point mutations in the LDL receptor gene. PCR Methods and Applications, 1993, 3, 159, 62
  22. Day, I, The low density lipoprotein receptor (LDL receptor) gene in familial hypercholesterolemia, http:\\www. ucl.ac.uk\FH\Ian Day
  23. Redon J, Chaves FJ, Liao Y. Influence of I/D polymorphism of the angiotensin converting enzyme gene on the outcome of microalbuminuria in essential hypertension. Hypertension. 2000;35:490–495[Abstract/Free Full Text]
  24. SPSS version 9.1.3. SPSS inc. 1999
  25. Carmena R, Lussier-Cacan S, Roy M. Lp(a) levels and hypercholesterolemia sharing the same gene defect. Arterioscler Throm Vasc Biol. 1996;16:129–136[Abstract/Free Full Text]
  26. Seed M, Hoppichler F, Reaveley D. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med. 1990;322:1494–1499[Abstract]
  27. Hausmann D, Johnson JA, Sudhir K. Angiographically silent atherosclerosis detected by intravascular ultrasound in patients with familial hypercholesterolemia and familial combined hyperlipidemia: correlation with high density lipoproteins. J Am Coll Cardiol. 1996;27:1562–1570[Abstract]
  28. Sudhir K, Ports TA, Amidon TM. Increased prevalence of coronary ectasia in heterozygous familial hypercholesterolemia. Circulation. 1995;91:1375–1380[Abstract/Free Full Text]
  29. Gordon DJ, Rifklind BM. High density lipoprotein—the clinical implications of recent studies. N Engl J Med. 1989;321:1311–1316[Web of Science][Medline]
  30. Goldbourt U, Yaari S, Medalie JH. Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality: a 21-year follow up of 8000 men. Arterioscler Thromb Vasc Biol. 1997;17:107–113[Abstract/Free Full Text]
  31. Rubins HB, Robins SJ, Iwane MK. Rationale and desing of the Department of Veterans Affairs High Density lipoprotein cholesterol intervention trial (HIT) for secondary prevention of coronary artery disease in men with low high density lipoprotein cholesterol and desirable low density lipoprotein cholesterol. Am J Cardiol. 1993;71:45–52[CrossRef][Web of Science][Medline]
  32. Nakamura T, Kobayashi H, Yanagi K. Importance of intra-abdominal visceral fat accumulation to coronary atherosclerosis in heterozygous familial hypercholesterolemia. Int J Obes Relat Metab Disord. 1997;21:580–586[CrossRef][Web of Science][Medline]
  33. Bowler A, Redgrave TG, Mano JCL. Chylomicron remnants clearance in homozygote and heterozygote Watanabe hereditable hyperlipidemic rabbits is defective. Lack of evidence for an independent chylomicron remnant receptor. Biochem J. 1991;276:381–386
  34. Kita T, Goldstein JL, Brown MS, Watanabe Y, Hornick CA, Havel RJ. Hepatic up take of chylomicrons remnants in WHHL rabbits: a mechanism genetically distinct from the LDL receptor. Proc Natl Acad Sci USA. 1982;79:3623–3627[Abstract/Free Full Text]
  35. Rubinsztein DC, Cohen JC, Berger GM, van der Westhuyzen DR, Coetzee GA, Gevers W. Chylomicron remnants clearance from the plasma is normal in familial hypercholesterolemic homozygous with defined receptor defects. J Clin Invest. 1990;86:1306–1312[Web of Science][Medline]
  36. Mano JCL, Smith D, Yu JCW. Accumulation of chylomicron remnants in homozygous subjects with familial hypercholesterolemia. Eur J Clin Invest. 1998;28:379–384[CrossRef][Web of Science][Medline]
  37. Castro-Cabezas H, De Bruin TWA, Westerveld KE. Delayed chylomicron remnants clearance in subjects with heterozygous familial hypercholesterolemia. J Int Med. 1998;244:299–307[CrossRef][Web of Science][Medline]
  38. Krieger M, Kozarsky K. Influence of the HDL receptor SB-RI on atherosclerosis. Curr Opin Lipidol. 1999;10:491–497[CrossRef][Web of Science][Medline]
  39. Rust S, Rosier M, Funke H. Tangier disease is caused by mutations in the encoding ATP-binding cassette transporter 1. Nature Genet. 1999;22:352–355[CrossRef][Web of Science][Medline]
  40. Pimstone SN, Gagne SE, Gagne C. Mutations in the gene for lipoprotein lipase. A cause for low cholesterol levels in individuals with heterozygous familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995;15:1704–1712[Abstract/Free Full Text]
  41. Rubins HB, Robins SJ, Collins D. Gemfibrozil for secondary prevention of coronary heart disease in men with low levels of high density lipoprotein cholesterol. Veterans Affairs High-density lipoprotein cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410–418[Abstract/Free Full Text]

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