Cholesterinhomöostase und kardiovaskuläres Risiko

Zusammenfassung

Hypercholesterinämie ist ein wesentlicher Risikofaktor für kardiovaskuläre Erkrankungen. Cholesterin wird enteral resorbiert und endogen synthetisiert. Statine hemmen die HMG-CoA-Reduktase, das geschwindigkeits-bestimmende Enzym der endogenen Cholesterinsynthese und senken Serumcholesterinspiegel und kardiovaskuläre Morbidität und Mortalität. Indirekte Evidenz aus kleineren Studien zeigt, dass Patienten mit hoher Baseline-Cholesterinresorption möglicherweise nur gering auf eine Statintherapie ansprechen. Darüber hinaus deuten aktuelle klinische Studien darauf hin, dass eine vermehrte Cholesterinresorption bei verringerter Cholesterinsynthese mit einem erhöhten kardiovaskulären Risiko assoziiert ist. Diese Übersichtsarbeit fasst die aktuelle Literatur zusammen und fordert prospektiv angelegte Studien, um zu klären, ob das Verhältnis von Cholesterin-Synthese zu Resorption zu einer individualisierten Lipidtherapie beitragen kann und ob bei selektionierten Patienten mit hoher Cholesterinresorptionsrate eine Hemmung der enteralen Cholesterinaufnahme kardiovaskuläre Ereignisse weiter vermindern kann.

Abstract

Hypercholesterolemia is a major risk factor for cardiovascular diseases. Serumcholesterol concentrations are regulated by enteral absorption and hepatic synthesis. Statins inhibit the rate-limiting enzyme of endogenous cholesterol synthesis, HMG-CoA-reductase and reduce serum cholesterol concentrations as well as cardiovascular morbidity. Indirect evidence from smaller studies shows, that patients with high baseline cholesterol absorption may show only a small response to statin treatment in terms of cholesterol lowering. Moreover, evidence from recent clinical studies suggests that increased cholesterol absorption and decreased hepatic cholesterol synthesis is associated with an increased cardiovascular risk. This article reviews the current literature on this issue and suggests prospective clinical studies to analyze whether determination of the baseline relation of cholesterol synthesis and absorption may facilitate an individualized lipid lowering therapy to further reduce cardiovascular risk.

Schlüsselwörter

Cholesterinhomöostase - kardiovaskuläres Risiko - Lathosterol - Phytosterole

Keywords

cholesterol homeostasis - cardiovascular risk - lathosterol - phytosterols

Literatur

• 1 Al-Jarallah A, Trigatti B L. A role for the scavenger receptor, Class B Type I in high density lipoprotein dependent activation of cellular signaling pathways.  Biochim Biophys Acta. 2010; 
• 2 Assmann G, Cullen P, Erbey J. et al . Plasma sitosterol elevations are associated with an increased incidence of coronary events in men.  Nutr Metab Cardiovasc Dis. 2006;  16 13-21
• 3 Baigent C, Keech A, Kearney P M. et al . Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.  Lancet. 2005;  366 1267-1278
• 4 Berneis K, Rizzo M, Berthold H K. et al . Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men.  Eur Heart J. 2010;  31 1633-1639
• 5 Buchwald H, Varco R L, Matts J P. et al . Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia.   N Engl J Med. 1990;  323 946-955
• 6 Calpe-Berdiel L, Escola-Gil J C, Blanco-Vaca F. New insights into the molecular actions of plant sterols and stanols in cholesterol metabolism.  Atherosclerosis. 2009;  203 18-31
• 7 Castelli W P. Epidemiology of coronary heart disease: the Framingham study.  Am J Med. 1984;  76 4-12
• 8 Davidson M H, Dillon M A, Gordon B. et al . Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects.  Arch Intern Med. 1999;  159 1893-1900
• 9 Dujovne C A, Ettinger M P, McNeer J F. et al . Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia.  Am J Cardiol. 2002;  90 1092-1097
• 10 Endo A. A gift from nature: the birth of the statins.  Nat Med. 2008;  14 1050-1052
• 11 Farnier M, Averna M, Missault L. et al . Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared with rosuvastatin 10 mg in high-risk hypercholesterolaemic patients inadequately controlled with prior statin monotherapy – The IN-CROSS study.  Int J Clin Pract. 2009;  63 547-559
• 12 Fassbender K, Lutjohann D, Dik M G. et al . Moderately elevated plant sterol levels are associated with reduced cardiovascular risk – the LASA study.  Atherosclerosis. 2008;  196 283-288
• 13 Goldstein M R, Mascitelli L, Pezzetta F. Point: Statins, plant sterol absorption, and increased coronary risk.  J Clin Lipidol. 2008;  2 306-308
• 14 Grundy S M, Cleeman J I, Merz C N. et al . Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.  J Am Coll Cardiol. 2004;  44 720-732
• 15 Gylling H, Miettinen T A. Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients.  Atherosclerosis. 2002;  160 477-481
• 16 Hendriks H F, Weststrate J A, van Vliet T, Meijer G W. Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects.  Eur J Clin Nutr. 1999;  53 319-327
• 17 Katan M B, Grundy S M, Jones P, Law M, Miettinen T, Paoletti R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels.  Mayo Clin Proc. 2003;  78 965-978
• 18 Matthan N R, Pencina M, Larocque J M. et al . Alterations in cholesterol absorption and synthesis characterize Framingham offspring study participants with coronary heart disease.  J Lipid Res. 2009;  1527-1535
• 19 Matthan N R, Resteghini N, Robertson M. et al . Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy.  J Lipid Res. 2010;  51 202-209
• 20 McNamara D J, Davidson N O, Samuel P, Ahrens Jr E H. Cholesterol absorption in man: effect of administration of clofibrate and/or cholestyramine.  J Lipid Res. 1980;  21 1058-1064
• 21 Miettinen T A. Detection of changes in human cholesterol metabolism.  Ann Clin Res. 1970;  2 300-320
• 22 Miettinen T A, Tilvis R S, Kesaniemi Y A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.  Am J Epidemiol. 1990;  131 20-31
• 23 Miettinen T A, Gylling H, Strandberg T, Sarna S. Baseline serum cholestanol as predictor of recurrent coronary events in subgroup of Scandinavian simvastatin survival study. Finnish 4S Investigators.  BMJ. 1998;  316 1127-1130
• 24 Miettinen T A, Strandberg T E, Gylling H. Noncholesterol sterols and cholesterol lowering by long-term simvastatin treatment in coronary patients: relation to basal serum cholestanol.  Arterioscler Thromb Vasc Biol. 2000;  20 1340-1346
• 25 Miettinen T A, Gylling H. Effect of statins on noncholesterol sterol levels: implications for use of plant stanols and sterols.  Am J Cardiol. 2005;  96 40D-6D
• 26 Miettinen T A, Puska P, Gylling H, Vanhanen H, Vartiainen E. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population.  N Engl J Med. 1995;  333 1308-1312
• 27 Natarajan P, Ray K K, Cannon C P. High-density lipoprotein and coronary heart disease: current and future therapies.  J Am Coll Cardiol. 2010;  55 1283-1299
• 28 Pinedo S, Vissers M N, von Bergmann K. et al . Plasma levels of plant sterols and the risk of coronary artery disease: the prospective EPIC-Norfolk Population Study.  J Lipid Res. 2007;  48 139-144
• 29 Pöss J, Böhm M, Laufs U. [HDL and CETP in atherogenesis].  Dtsch Med Wochenschr. 2010;  135 188-192
• 30 Rajaratnam R A, Gylling H, Miettinen T A. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women.  J Am Coll Cardiol. 2000;  35 1185-1191
• 31 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;  344 1383-1389
• 32 Rinninger F, Greten H. Neu entschlüsselte Mechanismen der Cholesterinhomöostase.  Dtsch Arztebl. 2005;  102 A 516-519
• 33 Sarwar R, Neuwirth C, Walji S. et al . Efficacy of ezetimibe and future role of refractory hyperlipidaemia in high-risk patients.  Br J Cardiol. 2008;  15 205-209
• 34 Schmitz G, Grandl M. The molecular mechanisms of HDL and associated vesicular trafficking mechanisms to mediate cellular lipid homeostasis.  Arterioscler Thromb Vasc Biol. 2009;  29 1718-1722
• 35 Shepherd J, Cobbe S M, Ford I. et al . Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.  N Engl J Med. 1995;  333 1301-1307
• 36 Silbernagel G, Fauler G, Renner W. et al . The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease.  J Lipid Res. 2009;  50 334-341
• 37 Silbernagel G, Fauler G, Hoffmann M M. et al . The associations of cholesterol metabolism and plasma plant sterols with all-cause- and cardiovascular mortality.  J Lipid Res. 2010; 
• 38 Sudhop T, von Bergmann K. Sitosterolemia – a rare disease. Are elevated plant sterols an additional risk factor?.  Z Kardiol. 2004;  93 921-928
• 39 Thuluva S C, Igel M, Giesa U. et al . Ratio of lathosterol to campesterol in serum predicts the cholesterol-lowering effect of sitostanol-supplemented margarine.  Int J Clin Pharmacol Ther. 2005;  43 305-310
• 40 Teoh H, Mendelsohn A A, Goodman S G. et al . Usefulness of statin-ezetimibe combination to reduce the care gap in dyslipidemia management in patients with a high risk of atherosclerotic disease.  Am J Cardiol. 2009;  104 798-804
• 41 Teupser D, Baber R, Ceglarek U. et al . Genetic regulation of serum phytosterol levels and risk of coronary artery disease.  Circ Cardiovasc Genet. 2010;  3 331-339
• 42 van Himbergen T M, Matthan N R, Resteghini N A. et al . Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers.  J Lipid Res. 2009;  50 730-739
• 43 Weingärtner O, Laufs U, Böhm M, Lütjohann D. An alternative pathway of reverse cholesterol transport: the oxysterol 27-hydroxycholesterol.  Atherosclerosis. 2010;  209 39-41
• 44 Weingärtner O, Böhm M, Laufs U. Controversial role of plant sterol esters in the management of hypercholesterolaemia.  Eur Heart J. 2009;  30 404-409
• 45 Weingärtner O, Böhm M, Laufs U. [Plant sterols as dietary supplements for the prevention of cardiovascular diseases].  Dtsch Med Wochenschr. 2008;  133 1201-1204
• 46 Weingärtner O, Lütjohann D, Ji S. et al . Vascular effects of diet supplementation with plant sterols.  J Am Coll Cardiol. 2008;  51 1553-1561
• 47 Weingärtner O, Weingärtner N, Scheller B. et al . Alterations in cholesterol homeostasis are associated with coronary heart disease in patients with aortic stenosis.  Coron Artery Dis. 2009;  20 376-382
• 48 Weingärtner O, Pinsdorf T, Rogacev K S. et al . The relationships of markers of cholesterol homeostasis with carotid intima-media thickness.   PLoS ONE. 2010;  5 (10) e13467 DOI: 10.1371/journal.pone.0013467
• 49 Westrate J A, Meijer G W. Plant sterol-enriched margarines amd reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolaemic and mildly hypercholesterolaemic subjects.  Eur J Clin Nutr. 1998;  52 334-343
• 50 Zhou L, Choi H Y, Li W -P, Xu F, Herz J. LRP1 Controls cPLA2 Phosphorylation, ABCA1 Expression and Cellular Cholesterol Export.  PLoS ONE. 2009;  4 (8) e6853 DOI: 10.1371/journal.pone.0006853
• 51 Wanner C, Krane V, März W. et al . Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis.  N Engl J Med. 2005;  353 238-248
• 52 Fellström B C, Jardine A G, Schmieder R E. et al . Rosuvastatin and cardiovascular events in patients undergoing hemodialysis.  N Engl J Med. 2009;  360 1395-1407