Sex-specific differences in the predictive value of cholesterol homeostasis markers and 10-year cardiovascular disease event rate in Framingham Offspring Study participants

Nirupa R Matthan, Lei Zhu, Michael Pencina, Ralph B D'Agostino, Ernst J Schaefer, Alice H Lichtenstein, Nirupa R Matthan, Lei Zhu, Michael Pencina, Ralph B D'Agostino, Ernst J Schaefer, Alice H Lichtenstein

Abstract

Background: Available data are inconsistent regarding factors influencing plasma cholesterol homeostasis marker concentrations and their value in predicting subsequent cardiovascular disease (CVD) events.

Methods and results: To address this issue, the relationship between markers of cholesterol absorption (campesterol, sitosterol, cholestanol) and synthesis (squalene, desmosterol, lathosterol) and 10-year CVD incidence was assessed in Framingham Offspring Study participants (cycle 6) who were without CVD at baseline and not taking lipid-lowering medications (N=2616). The primary end point was "hard" coronary heart disease (HCHD; coronary death and myocardial infarction), and the secondary end point was full CVD (HCHD plus stroke, coronary insufficiency, angina pectoris, peripheral artery disease, and congestive heart failure). In cross-sectional analysis, significant differences by sex, age, body mass index, blood pressure, and smoking status were observed. In both women and men, lower cholesterol absorption was associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol concentrations, whereas lower cholesterol synthesis was associated with higher low-density lipoprotein (LDL) cholesterol concentrations (P for trend <0.05). In women only, lower cholesterol synthesis and absorption were associated with higher non-HDL cholesterol concentrations. Using Cox proportional hazards model adjusting for standard CVD risk factors, squalene concentrations were associated with lower HCHD in women (hazard ratio=0.70 [0.5 to 0.9]). In contrast, squalene (hazard ratio=1.40 [1.1 to 1.8]) concentrations were associated with higher HCHD in men (P<0.0001 for interaction). The cholesterol absorption markers were not predictive of HCHD or full CVD in either women or men.

Conclusions: These data suggest significant sex differences in the 10-year prognostic value of cholesterol synthesis markers and HCHD, specifically coronary death and incidence of myocardial infarction.

Clinical trial registration: URL:http://ClinicalTrials.gov. Unique identifier: NCT00074464.

Figures

Figure 1.
Figure 1.
Multivariable‐adjusted hazard ratios for cholesterol synthesis markers (A), cholesterol absorption markers (B), cholesterol synthesis:absorption ratios (C), and “hard” coronary heart disease (coronary death and myocardial infarction) based on Cox proportional hazards model. Error bars represent 95% CIs.
Figure 2.
Figure 2.
Multivariable‐adjusted hazard ratios for cholesterol synthesis markers (A), cholesterol absorption markers (B), cholesterol synthesis:absorption ratios (C), and full cardiovascular disease (“hard” coronary heart disease plus stroke, coronary insufficiency, angina pectoris, peripheral artery disease, and congestive heart failure) based on Cox proportional hazards model. Error bars represent 95% CIs.
Figure 3.
Figure 3.
Cholesterol biosynthetic pathway highlighting the formation of squalene, an early intermediate, as well as desmosterol (Bloch pathway) and lathosterol (Kandutsch–Russell pathway) formed from squalene later in the biosynthetic pathway. HMG‐CoA indicates 3‐hydroxy‐3‐methylglutaryl–coenzyme A.

References

    1. National Cholesterol Education Program (NCEP) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106:3143-3421
    1. Matthan NR, Lichtenstein AH. Approaches to measuring cholesterol absorption in humans. Atherosclerosis. 2004; 174:197-205
    1. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham Offspring Study. Am J Epidemiol. 1979; 110:281-290
    1. Ulbricht TL, Southgate DA. Coronary heart disease: seven dietary factors. Lancet. 1991; 338:985-992
    1. Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high‐risk individuals: a randomised placebo‐controlled trial. Lancet. 2002; 360:23-33
    1. Long‐term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998; 339:1349-1357
    1. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM., Jr Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. J Am Med Assoc. 1998; 279:1615-1622
    1. Garland M, Sacks FM, Colditz GA, Rimm EB, Sampson LA, Willett WC, Hunter DJ. The relation between dietary intake and adipose tissue composition of selected fatty acids in US women. Am J Clin Nutr. 1998; 67:25-30
    1. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. 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
    1. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344:1383-1389
    1. Cuchel M, Schaefer EJ, Millar JS, Jones PJ, Dolnikowski GG, Vergani C, Lichtenstein AH. Lovastatin decreases de novo cholesterol synthesis and LDL Apo B‐100 production rates in combined‐hyperlipidemic males. Arterioscler Thromb Vasc Biol. 1997; 17:1910-1917
    1. Miettinen TA. Cholesterol absorption inhibition: a strategy for cholesterol‐lowering therapy. Int J Clin Pract. 2001; 55:710-716
    1. Kesaniemi YA, Ehnholm C, Miettinen TA. Intestinal cholesterol absorption efficiency in man is related to apoprotein E phenotype. J Clin Invest. 1987; 80:578-581
    1. Miettinen TA, Tilvis RS, Kesaniemi YA. 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
    1. Kuksis A. Plasma non‐cholesterol sterols. J Chromatogr A. 2001; 935:203-236
    1. Matthan NR, Giovanni A, Schaefer EJ, Brown BG, Lichtenstein AH. Impact of simvastatin, niacin, and/or antioxidants on cholesterol metabolism in CAD patients with low HDL. J Lipid Res. 2003; 44:800-806
    1. Miettinen TA, Gylling H. Cholesterol absorption efficiency and sterol metabolism in obesity. Atherosclerosis. 2000; 153:241-248
    1. Matthan NR, Pencina M, LaRocque JM, Jacques PF, D'Agostino RB, Schaefer EJ, Lichtenstein AH. Alterations in cholesterol absorption/synthesis markers characterize Framingham Offspring Study participants with CHD. J Lipid Res. 2009; 50:1927-1935
    1. Weingartner O, Pinsdorf T, Rogacev KS, Blomer L, Grenner Y, Graber S, Ulrich C, Girndt M, Fliser D, Laufs U, Lutjohann D, Heine GH. The relationships of markers of cholesterol homeostasis with carotid intima‐media thickness. PLoS ONE. 2010; 5:e13467.
    1. Sibernagel G, Fauler G, Hoffmann MM, Lutjohann D, Winkelmann BR, Marz W. The associations of cholesterol metabolism and plasma plant sterols with all‐cause and cardiovascular mortality. J Lipid Res. 2010; 51:2384-2393
    1. Gylling H, Hallikainen M, Rajaratnam RA, Simonen P, Pihlajamaki J, Laakso M, Miettinen TA. The metabolism of plant sterols is disturbed in postmenopausal women with coronary artery disease. Metabolism. 2009; 58:401-407
    1. Assmann G, Cullen P, Erbey J, Ramey DR, Kannenberg F, Schulte H. Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case–control analysis of the Prospective Cardiovascular Munster (PROCAM) study. Nutr Metab Cardiovasc Dis. 2005; 16:13-21
    1. Rajaratnam RA, Gylling H, Miettinen TA. Serum squalene in postmenopausal women without and with coronary artery disease. Atherosclerosis. 1999; 146:61-64
    1. Rajaratnam RA, Gylling H, Miettinen TA. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol. 2000; 35:1185-1191
    1. Sudhop T, Gottwald BM, von Bergmann K. Serum plant sterols as a potential risk factor for coronary heart disease. Metabolism. 2002; 51:1519-1521
    1. Escurriol V, Cofan M, Moreno‐Iribas C, Larranaga N, Martinez C, Navarro C, Rodriguez L, Gonzalez CA, Corella D, Ros E. Phytosterol plasma concentrations and coronary heart disease in the prospective Spanish EPIC cohort. J Lipid Res. 2010; 51:618-624
    1. Fassbender K, Lutjohann D, Dik MG, Bremmer M, Konig J, Walter S, Liu Y, Letiembre M, von Bergmann K, Jonker C. Moderately elevated plant sterol levels are associated with reduced cardiovascular risk—the LASA study. Atherosclerosis. 2008; 196:283-288
    1. Pinedo S, Vissers MN, von Bergmann K, Elharchaoui K, Lutjohann D, Luben R, Wareham NJ, Kastelein JJ, Khaw KT, Boekholdt SM. 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
    1. Wilund KR, Yu L, Xu F, Vega GL, Grundy SM, Cohen JC, Hobbs HH. No association between plasma levels of plant sterols and atherosclerosis in mice and men. Arterioscler Thromb Vasc Biol. 2004; 24:2326-2332
    1. Windler E, Zyriax BC, Kuipers F, Linseisen J, Boeing H. Association of phytosterol concentrations with incident coronary heart diease. Data from the CORA study, a case–control study of coronary artery disease in women. Atherosclerosis. 2009; 203:284-290
    1. Dawber TR, Meadors GF, Moore F. Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health. 1951; 41:279-286
    1. Pencina MJ, D'Agostino RB, Larson MG, Massaro JM, Vasan RS. Predicting 30‐year risk of cardiovascular disease. The Framingham Heart Study. Circulation. 2009; 119:3078-3084
    1. McNamara JR, Schaefer EJ. Automated enzymatic standardized lipid analyses for plasma and lipoprotein fractions. Clin Chim Acta. 1987; 166:1-8
    1. Warnick GR, Benderson J, Albers JJ. Dextran sulfate‐Mg2+ precipitation procedure for quantitation of high‐density‐lipoprotein cholesterol. Clin Chem. 1982; 28:1379-1388
    1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low‐density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972; 18:499-502
    1. Matthan NR, Raeini‐Sarjaz M, Lichtenstein AH, Ausman LM, Jones PJ. Deuterium uptake and plasma cholesterol precursor levels correspond as methods for measurement of endogenous cholesterol synthesis in hypercholesterolemic women. Lipids. 2000; 35:1037-1044
    1. Nissinen MJ, Gylling H, Miettinen TA. Responses of surrogate markers of cholesterol absorption and synthesis to changes in cholesterol metabolism during various amounts of fat and cholesterol feeding among healthy men. Br J Nutr. 2008; 99:370-378
    1. Clayton PT. Disorders of cholesterol biosynthesis. Arch Dis Child. 1998; 78:185-189
    1. Strandberg TE, Tilvis RS, Pitkala KH, Miettinen TA. Cholesterol and glucose metabolism and recurrent cardiovascular events among the elderly. J Am Coll Cardiol. 2006; 48:708-714
    1. Tilvis RS, Valvanne JN, Stranberg TE, Miettinen TA. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17 year population study. Ann Med. 2011; 43:292-301
    1. Strandberg TE, Gylling H, Tilvis RS, Miettinen H. Serum plant and other noncholesterol sterols, cholesterol metabolism and 22 year mortality among middle‐aged men. Atherosclerosis. 2010; 210:282-287
    1. Silbernagel G, Fauler G, Renner W, Landl EM, Hoffmann MM, Winkelmann BR, Boehm BO, Marz W. The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease. J Lipid Res. 2009; 50:334-341
    1. Kempen HJ, de Knijff P, Boomsma DI, van der Voort HA, Gevers Leuven JA, Havekes L. Plasma levels of lathosterol and phytosterols in relation to age, sex, anthropometric parameters, plasma lipids, and apolipoprotein E phenotype, in 160 Dutch families. Metabolism. 1991; 40:604-611
    1. Buffa R, Floris GU, Putzu PF, Marini E. Body composition variations in ageing. Coll Antropol. 2011; 35:259-265
    1. Paramsothy P, Knoop RH, Kahn SE, Tretzlaff BM, Fish B, Ma L, Ostlund RE., Jr Plasma sterol evidence for decreased absorption and increased synthesis of cholesterol in insulin resistance and obesity. Am J Clin Nutr. 2011; 94:1182-1188
    1. Peltola P, Pihlajamaki J, Koutnikova H, Ruotsalainen E, Salmenniemi U, Vauhkonen I, Kainulainen S, Gylling H, Miettinen TA, Auwerx J, Laakso M. Visceral obesity is associated with high levels of serum squalene. Obesity. 2006; 14:1155-1163
    1. Simonen P, Gylling H, Howard AN, Miettinen T. Introducing a new component of the metabolic syndrome: low cholesterol absorption. Am J Clin Nutr. 2000; 72:82-88
    1. Chan DC, Watts GF, Barrett HR, O'Neill FH, Thompson GR. Plasma markers of cholesterol homeostasis and apolipoprotein B‐100 kinetics in the metabolic syndrome. Obes Res. 2003; 11:591-596
    1. Assmann G, Cullen P, Kannenberg F, Schulte H. Relationship between phytosterol levels and components of the metabolic syndrome in the PROCAM study. Eur J Cardiovasc Prev Rehabil. 2007; 2:208-214
    1. Briones ER, Steiger DL, Palumbo PJ, O'Fallon WM, Langworthy AL, Zimmerman BR, Kottke BA. Sterol excretion and cholesterol absorption in diabetics and nondiabetics with and without hyperlipidemia. Am J Clin Nutr. 1986; 44:353-361
    1. Gylling H, Miettinen TA. Cholesterol absorption and lipoprotein metabolism in type II diabetes mellitus with and without coronary artery disease. Atherosclerosis. 1996; 126:325-332
    1. Pihlajamaki J, Gylling H, Miettinen T, Laakso M. Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men. J Lipid Res. 2004; 45:507-512
    1. Simonen PP, Gylling HK, Miettinen TA. Diabetes contributes to cholesterol metabolism regardless of obesity. Diabetes Care. 2002; 25:1511-1515
    1. Lagor WR, Millar JS. Overview of the LDL receptor. Relevance to cholesterol metabolism and future approaches for the treatment of coronary heart disease. J Receptor Ligand Channel Res. 2010; 3:1-14
    1. Blaha MJ, Blumenthal RS, Brinton EA, Jacobson TANational Lipid Association Taskforce on Non‐HDL Cholesterol The importance of non‐HDL cholesterol reporting in lipid management. J Clin Lipidol. 2008; 4:267-273
    1. Gardner CD, Winkelby M, Fortman SP. Population frequency distribution of non‐high‐density lipoprotein cholesterol (Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994). Am J Cardiol. 2000; 86:299-304
    1. De Marinis E, Martini C, Trentalance A, Pallottini V. Sex differences in hepatic regulation of cholesterol homeostasis. J Endocrinol. 2008; 198:635-643
    1. Bjorkhem I, Miettinen T, Reihner E, Ewerth S, Angelin B, Einarsson K. Correlation between serum levels of some cholesterol precursors and activity of HMG‐CoA reductase in human liver. J Lipid Res. 1987; 28:1137-1143

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