Effects of Hormone Therapy on Heart Fat and Coronary Artery Calcification Progression: Secondary Analysis From the KEEPS Trial

Samar R El Khoudary, Qian Zhao, Vidya Venugopal, JoAnn E Manson, Maria M Brooks, Nanette Santoro, Dennis M Black, S Mitchell Harman, Marcelle I Cedars, Paul N Hopkins, Ann E Kearns, Virginia M Miller, Hugh S Taylor, Matthew J Budoff, Samar R El Khoudary, Qian Zhao, Vidya Venugopal, JoAnn E Manson, Maria M Brooks, Nanette Santoro, Dennis M Black, S Mitchell Harman, Marcelle I Cedars, Paul N Hopkins, Ann E Kearns, Virginia M Miller, Hugh S Taylor, Matthew J Budoff

Abstract

Background Heart fats (epicardial and paracardial adipose tissue [PAT]) are greater after menopause. Endogenous estrogen may regulate these fat depots. We evaluated the differential effects of hormone therapy formulations on heart fat accumulations and their associations with coronary artery calcification (CAC) progression in recently menopausal women from KEEPS (Kronos Early Estrogen Prevention Study). Methods and Results KEEPS was a multicenter, randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens and 50 µg/d transdermal 17β-estradiol, compared with placebo, on 48-month progression of subclinical atherosclerosis among 727 early menopausal women. CAC progression was defined if baseline CAC score was 0 and 48-month CAC score was >0 or if baseline CAC score was >0 and <100 and annualized change in CAC score was ≥10. Of 727 KEEPS participants, 474 (mean age: 52.7 [SD: 2.6]; 78.1% white) had computed tomography-based heart fat and CAC measures at both baseline and 48 months. Compared with women on placebo, women on oral conjugated equine estrogens were less likely to have any increase in epicardial adipose tissue (odds ratio for oral conjugated equine estrogens versus placebo: 0.62 [95% CI, 0.40-0.97]; P=0.03). PAT did not change in any group. Changes in epicardial adipose tissue and PAT did not differ by treatment group. CAC increased in 14% of participants. The assigned treatment modified the association between PAT changes and CAC progression (P=0.02) such that PAT increases were associated with CAC increases only in the transdermal 17β-estradiol group. Conclusions In recently menopausal women, oral conjugated equine estrogens may slow epicardial adipose tissue accumulation, whereas transdermal 17β-estradiol may increase progression of CAC associated with PAT accumulation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00154180.

Keywords: coronary artery disease; epicardial fat; estrogen; menopause.

Figures

Figure 1
Figure 1
CONSORT flow diagram of the KEEPS (Kronos Early Estrogen Prevention Study) heart fat ancillary study. CONSORT indicates Consolidated Standards of Reporting Trials; o‐CEE, oral conjugated equine estrogens; t‐E2, transdermal β17‐estradiol.
Figure 2
Figure 2
Effect modification of assigned HT use on the association between the change in EAT (A) or PAT (B) and CAC progression. Odds ratio (95% CI) represents the increase in the risk of coronary artery calcification progression per 1‐SD increase in the change of heart fat. Models adjusted for age, race and study site, education, smoking, physical activity, alcohol consumption, lipids, systolic blood pressure, waist circumference, antihypertensive medication and treatment, and baseline heart fat volume. EAT indicates epicardial adipose tissue; HT, hormone therapy; o‐CEE, oral conjugated equine estrogens; PAT, paracardial adipose tissue; t‐E2, transdermal β17‐estradiol.

References

    1. El Khoudary SR, Shields KJ, Janssen I, Hanley C, Budoff MJ, Barinas‐Mitchell E, Everson‐Rose SA, Powell LH, Matthews KA. Cardiovascular fat, menopause, and sex hormones in women: the SWAN cardiovascular fat ancillary study. J Clin Endocrinol Metab. 2015;100:3304–3312.
    1. Iacobellis G, Willens HJ. Echocardiographic epicardial fat: a review of research and clinical applications. J Am Soc Echocardiogr. 2009; 22:1311–1319. quiz 1417–8.
    1. Kaushik M, Reddy YM. Distinction of “fat around the heart”. J Am Coll Cardiol. 2011;5:1640; author reply 1640‐1.
    1. Rosito GA, Massaro JM, Hoffmann U, Ruberg FL, Mahabadi AA, Vasan RS, O'Donnell CJ, Fox CS. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community‐based sample: the Framingham Heart Study. Circulation. 2008;117:605–613.
    1. Mahabadi AA, Lehmann N, Kälsch H, Robens T, Bauer M, Dykun I, Budde T, Moebus S, Jöckel KH, Erbel R, Möhlenkamp S. Association of epicardial adipose tissue with progression of coronary artery calcification is more pronounced in the early phase of atherosclerosis: results from the Heinz Nixdorf Recall Study. JACC Cardiovasc Imaging. 2014;7:909–916.
    1. Mahabadi AA, Massaro JM, Rosito GA, Levy D, Murabito JM, Wolf PA, O'Donnell CJ, Fox CS, Hoffmann U. Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study. Eur Heart J. 2009;30:850–856.
    1. Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky SB, Szklo M, Ouyang P, Espeland MA, Lohman KK, Criqui MH, Allison M, Bluemke DA, Carr JJ. The association of pericardial fat with incident coronary heart disease: the Multi‐Ethnic Study of Atherosclerosis (MESA). Am J Clin Nutr. 2009;90:499–504.
    1. Mahabadi AA, Berg MH, Lehmann N, Kälsch H, Bauer M, Kara K, Dragano N, Moebus S, Jöckel KH, Erbel R, Möhlenkamp S. Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf Recall Study. J Am Coll Cardiol. 2013;61:1388–1395.
    1. Larsen BA, Laughlin GA, Saad SD, Barrett‐Connor E, Allison MA, Wassel CL. Pericardial fat is associated with all‐cause mortality but not incident CVD: the Rancho Bernardo Study. Atherosclerosis. 2015;239:470–475.
    1. Cetin M, Cakici M, Polat M, Suner A, Zencir C, Ardic I. Relation of epicardial fat thickness with carotid intima‐media thickness in patients with type 2 diabetes mellitus. Int J Endocrinol. 2013;2013:769175.
    1. Abazid RM, Smettei OA, Kattea MO, Sayed S, Saqqah H, Widyan AM, Opolski MP. Relation between epicardial fat and subclinical atherosclerosis in asymptomatic individuals. J Thorac Imaging. 2017;32:378–382.
    1. Iacobellis G, Gao YJ, Sharma AM. Do cardiac and perivascular adipose tissue play a role in atherosclerosis? Curr Diab Rep. 2008;8:20–24.
    1. El Khoudary SR, Shields KJ, Janssen I, Budoff MJ, Everson‐Rose SA, Powell LH, Matthews KA. Postmenopausal women with greater paracardial fat have more coronary artery calcification than premenopausal women: the SWAN cardiovascular fat ancillary study. J Am Heart Assoc. 2017;6:e004545 DOI: 10.1161/JAHA.116.004545.
    1. Nkonde‐Price C, Bender JR. Menopause and the heart. Endocrinol Metab Clin North Am. 2015;44:559–564.
    1. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613.
    1. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women's Health Initiative Investigators . Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321–333.
    1. Naftolin F, Taylor HS, Karas R, Brinton E, Newman I, Clarkson TB, Mendelsohn M, Lobo RA, Judelson DR, Nachtigall LE, Heward CB, Hecht H, Jaff MR, Harman SM; Women's Health Initiative . The Women's Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition. Fertil Steril. 2004;81:1498–1501.
    1. Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski‐Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil‐Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013;310:1353–1368.
    1. Stuenkel CA, Gass ML, Manson JE, Lobo RA, Pal L, Rebar RW, Hall JE. A decade after the Women's Health Initiative—the experts do agree. J Clin Endocrinol Metab. 2012;97:2617–2618.
    1. Goodman MP. Are all estrogens created equal? A review of oral vs. transdermal therapy. J Womens Health (Larchmt). 2012;21:161–169.
    1. Harman SM, Brinton EA, Cedars M, Lobo R, Manson JE, Merriam GR, Miller VM, Naftolin F, Santoro N. KEEPS: the Kronos Early Estrogen Prevention Study. Climacteric. 2005;8:3–12.
    1. Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM, Neal‐Perry G, Santoro N, Taylor HS, Vittinghoff E, Yan M, Hodis HN. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Ann Intern Med. 2014;161:249–260.
    1. Nasir K, Raggi P, Rumberger JA, Braunstein JB, Post WS, Budoff MJ, Blumenthal RS. Coronary artery calcium volume scores on electron beam tomography in 12,936 asymptomatic adults. Am J Cardiol. 2004;93:1146–1149.
    1. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827–832.
    1. Berry JD, Liu K, Folsom AR, Lewis CE, Carr JJ, Polak JF, Shea S, Sidney S, O'Leary DH, Chan C, Lloyd‐Jones DM. Prevalence and progression of subclinical atherosclerosis in younger adults with low short‐term but high lifetime estimated risk for cardiovascular disease: the coronary artery risk development in young adults study and Multi‐Ethnic Study of Atherosclerosis. Circulation. 2009;119:382–389.
    1. Huang G, Wang D, Zeb I, Budoff MJ, Harman SM, Miller V, Brinton EA, El Khoudary SR, Manson JE, Sowers MR, Hodis HN, Merriam GR, Cedars MI, Taylor HS, Naftolin F, Lobo RA, Santoro N, Wildman RP. Intra‐thoracic fat, cardiometabolic risk factors, and subclinical cardiovascular disease in healthy, recently menopausal women screened for the Kronos Early Estrogen Prevention Study (KEEPS). Atherosclerosis. 2012;221:198–205.
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta‐cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419.
    1. Seaman SR, White IR. Review of inverse probability weighting for dealing with missing data. Stat Methods Med Res. 2013;22:278–295.
    1. Kristensen K, Pedersen SB, Vestergaard P, Mosekilde L, Richelsen B. Hormone replacement therapy affects body composition and leptin differently in obese and non‐obese postmenopausal women. J Endocrinol. 1999;163:55–62.
    1. Gambacciani M, Ciaponi M, Cappagli B, Piaggesi L, De Simone L, Orlandi R, Genazzani ARJ. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal women. J Clin Endocrinol Metab. 1997;82:414–417.
    1. Reubinoff BE, Wurtman J, Rojansky N, Adler D, Stein P, Schenker JG, Brzezinski A. Effects of hormone replacement therapy on weight, body composition, fat distribution, and food intake in early postmenopausal women: a prospective study. Fertil Steril. 1995;64:963–968.
    1. Mattiasson I, Rendell M, Törnquist C, Jeppsson S, Hulthén UL. Effects of estrogen replacement therapy on abdominal fat compartments as related to glucose and lipid metabolism in early postmenopausal women. Horm Metab Res. 2002;34:583–588.
    1. Sites CK, L'Hommedieu GD, Toth MJ, Brochu M, Cooper BC, Fairhurst PA. The effect of hormone replacement therapy on body composition, body fat distribution, and insulin sensitivity in menopausal women: a randomized, double‐blind, placebo‐controlled trial. J Clin Endocrinol Metab. 2005;90:2701–2707.
    1. Aloia JF, Vaswani A, Russo L, Sheehan M, Flaster E. The influence of menopause and hormonal replacement therapy on body cell mass and body fat mass. Am J Obstet Gynecol. 1995;172:896–900.
    1. Yuksel H. Effects of postmenopausal hormone replacement therapy on body fat composition. Gynecol Endocrinol. 2007;23:99–104.
    1. dos Reis CM, de Melo NR, Meirelles ES, Vezozzo DP, Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen. Maturitas. 2003;46:59–68.
    1. Hänggi W, Lippuner K, Jaeger P, Birkhäuser MH, Horber FF. Differential impact of conventional oral or transdermal hormone replacement therapy or tibolone on body composition in postmenopausal women. Clin Endocrinol (Oxf). 1998;48:691–699.
    1. Vinogradova Y, Coupland C, Hippisley‐Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case‐control studies using the QResearch and CPRD database. BMJ. 2019;364:k4810.
    1. Bhavnani BR, Stanczyk FZ. Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action. J Steroid Biochem Mol Biol. 2014;142:16–29.
    1. Washburn SA, Honoré EK, Cline JM, Helman M, Wagner JD, Adelman SJ, Clarkson TB. Effects of 17 alpha‐dihydroequilenin sulfate on atherosclerotic male and female rhesus monkeys. Am J Obstet Gynecol. 1996;175:341–349; discussion 349–51.
    1. Marseglia L, Manti S, D'Angelo G, Nicotera A, Parisi E, Di Rosa G, Gitto E, Arrigo T. Oxidative stress in obesity: a critical component in human diseases. Int J Mol Sci. 2014;16:378–400.
    1. Gao H, Dahlman‐Wright K. Implications of estrogen receptor alpha and estrogen receptor beta for adipose tissue functions and cardiometabolic complications. Horm Mol Biol Clin Investig. 2013;15:81–90.
    1. Barros RP, Gustafsson JA. Estrogen receptors and the metabolic network. Cell Metab. 2011;14:289–299.
    1. Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med (Maywood). 2004;229:1127–1135.
    1. Pallottini V, Bulzomi P, Galluzzo P, Martini C, Marino M. Estrogen regulation of adipose tissue functions: involvement of estrogen receptor isoforms. Infect Disord Drug Targets. 2008;8:52–60.
    1. Dieudonne MN, Leneveu MC, Giudicelli Y, Pecquery R. Evidence for functional estrogen receptors alpha and beta in human adipose cells: regional specificities and regulation by estrogens. Am J Physiol Cell Physiol. 2004;286:C655–C661.
    1. Rodriguez‐Cuenca S, Monjo M, Proenza AM, Roca P. Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu. Am J Physiol Endocrinol Metab. 2005;288:E200–E207.
    1. Davis KE, Neinast MD, Sun K, Skiles WM, Bills JD, Zehr JA, Zeve D, Hahner LD, Cox DW, Gent LM, Xu Y, Wang ZV, Khan SA, Clegg DJ. The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Mol Metab. 2013;2:227–242.
    1. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause. 2018;25:1362–1387.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel