Gender and cardiovascular disease: Are sex-biased microRNA networks a driving force behind heart failure with preserved ejection fraction in women?

Cardiovascular Research

Volumn 114, Issue 2, 2018, Pages 210-225

  Florijn, Barend W ^a   Bijkerk, Roel ^a   Van Der Veer, Eric P ^a   Van Zonneveld, Anton Jan ^a  

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

HFpEF; Microvascular injury; Sex biased miRNAs; Women

Indexed keywords

BIOLOGICAL MARKER; ESTROGEN; MICRORNA; ESTRADIOL;

AUTOPHAGY; CARDIAC MUSCLE CELL; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; COMORBIDITY; GENDER; GENE EXPRESSION; GENE LOCUS; HEART FAILURE WITH PRESERVED EJECTION FRACTION; HEART MUSCLE FIBROSIS; HEART MUSCLE INJURY; HEMODYNAMICS; HUMAN; HYPERGLYCEMIA; MICROVASCULATURE; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SEX CHROMOSOME MOSAICISM; VASCULITIS; X CHROMOSOME INACTIVATION; AGE; ANIMAL; FEMALE; GENE EXPRESSION REGULATION; GENETICS; HEALTH DISPARITY; HEART FAILURE; HEART LEFT VENTRICLE FUNCTION; HEART STROKE VOLUME; HEART VENTRICLE REMODELING; MALE; MENOPAUSE; METABOLISM; PATHOLOGY; PREVALENCE; RISK ASSESSMENT; RISK FACTOR; SEX FACTOR; X CHROMOSOME;

AGE FACTORS; ANIMALS; CHROMOSOMES, HUMAN, X; COMORBIDITY; ESTRADIOL; FEMALE; GENE EXPRESSION REGULATION; HEALTH STATUS DISPARITIES; HEART FAILURE; HUMANS; MALE; MENOPAUSE; MICRORNAS; MYOCYTES, CARDIAC; PREVALENCE; RISK ASSESSMENT; RISK FACTORS; SEX FACTORS; STROKE VOLUME; VENTRICULAR FUNCTION, LEFT; VENTRICULAR REMODELING; X CHROMOSOME INACTIVATION;

EID: 85041398861     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvx223     Document Type: Review

References (199)

1. Garcia M, Mulvagh SL, Bairey Merz CN, Buring JE, Manson JE. Cardiovascular disease in women: clinical perspectives. Circ Res 2016;118:1273-1293.
2. Appelman Y, van Rijn BB, Ten Haaf ME, Boersma E, Peters SA. Sex differences in cardiovascular risk factors and disease prevention. Atherosclerosis 2015;241:211-218.
3. Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon CP, Hernandez AF, Fonarow GC. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes. Circulation 2012;126:65-75.
4. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 2006;355:260-269.
5. Devereux RB, Roman MJ, Liu JE, Welty TK, Lee ET, Rodeheffer R, Fabsitz RR, Howard BV. Congestive heart failure despite normal left ventricular systolic function in a population-based sample: the Strong Heart Study. Am J Cardiol 2000;86: 1090-1096.
6. Abebe TB, Gebreyohannes EA, Tefera YG, Abegaz TM. Patients with HFpEF and HFrEF have different clinical characteristics but similar prognosis: a retrospective cohort study. BMC Cardiovasc Disord 2016;16:232.
7. O'Neal WT, Sandesara P, Hammadah M, Venkatesh S, Samman-Tahhan A, Kelli HM, Soliman EZ. Gender differences in the risk of adverse outcomes in patients with atrial fibrillation and heart failure with preserved ejection fraction. Am J Cardiol 2017;119:1785-1790.
8. Edelmann F, Stahrenberg R, Gelbrich G, Durstewitz K, Angermann CE, Dungen HD, Scheffold T, Zugck C, Maisch B, Regitz-Zagrosek V, Hasenfuss G, Pieske BM, Wachter R. Contribution of comorbidities to functional impairment is higher in heart failure with preserved than with reduced ejection fraction. Clin Res Cardiol 2011;100:755-764.
9. Deswal A, Bozkurt B. Comparison of morbidity in women versus men with heart failure and preserved ejection fraction. Am J Cardiol 2006;97:1228-1231.
10. Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, Kajstura J, Anversa P. Myocyte death in the failing human heart is gender dependent. Circ Res 1999;85: 856-866.
11. Loffredo FS, Nikolova AP, Pancoast JR, Lee RT. Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res 2014;115: 97-107.
12. De Simone G, Devereux RB, Chinali M, Roman MJ, Barac A, Panza JA, Lee ET, Howard BV. Sex differences in obesity-related changes in left ventricular morphology: the Strong Heart Study. J Hypertens 2011;29:1431-1438.
13. Meyer S, van der Meer P, Massie BM, O'Connor CM, Metra M, Ponikowski P, Teerlink JR, Cotter G, Davison BA, Cleland JG, Givertz MM, Bloomfield DM, Fiuzat M, Dittrich HC, Hillege HL, Voors AA. Sex-specific acute heart failure phenotypes and outcomes from PROTECT. Eur J Heart Fail 2013;15:1374-1381.
14. Ghossein-Doha C, van Neer J, Wissink B, Breetveld NM, de Windt LJ, van Dijk AP, van der Vlugt MJ, Janssen MC, Heidema WM, Scholten RR, Spaanderman ME. Preeclampsia: an important risk factor for asymptomatic heart failure. Ultrasound Obstet Gynecol 2017;49:143-149.
15. Dhingra A, Garg A, Kaur S, Chopra S, Batra JS, Pandey A, Chaanine AH, Agarwal SK. Epidemiology of heart failure with preserved ejection fraction. Curr Heart Fail Rep 2014;11:354-365.
16. Gori M, Senni M, Gupta DK, Charytan DM, Kraigher-Krainer E, Pieske B, Claggett B, Shah AM, Santos AB, Zile MR, Voors AA, McMurray JJ, Packer M, Bransford T, Lefkowitz M, Solomon SD. Association between renal function and cardiovascular structure and function in heart failure with preserved ejection fraction. Eur Heart J 2014;35:3442-3451.
17. Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschope C, Leite-Moreira AF, Musters R, Niessen HW, Linke WA, Paulus WJ, Hamdani N. Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart Fail 2016;4:312-324.
18. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 2015;131:550-559.
19. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschope C. Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail 2011;4:44-52.
20. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kuhl U, Schultheiss HP, Tschope C. Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction. J Am Coll Cardiol 2011;57:977-985.
21. van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, van der Velden J, Stienen GJ, Laarman GJ, Somsen A, Verheugt FW, Niessen HW, Paulus WJ. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012;126:830-839.
22. Borbely A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, Leite-Moreira AF, Bronzwaer JG, Papp Z, van der Velden J, Stienen GJ, Paulus WJ. Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res 2009;104:780-786.
23. Borbely A, van der Velden J, Papp Z, Bronzwaer JG, Edes I, Stienen GJ, Paulus WJ. Cardiomyocyte stiffness in diastolic heart failure. Circulation 2005;111:774-781.
24. van Heerebeek L, Borbely A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 2006;113:1966-1973.
25. van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbely A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 2008;117:43-51.
26. Gori M, Lam CS, Gupta DK, Santos AB, Cheng S, Shah AM, Claggett B, Zile MR, Kraigher-Krainer E, Pieske B, Voors AA, Packer M, Bransford T, Lefkowitz M, McMurray JJ, Solomon SD. Sex-specific cardiovascular structure and function in heart failure with preserved ejection fraction. Eur J Heart Fail 2014;16:535-542.
27. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62:263-271.
28. Srivaratharajah K, Coutinho T, deKemp R, Liu P, Haddad H, Stadnick E, Davies RA, Chih S, Dwivedi G, Guo A, Wells GA, Bernick J, Beanlands R, Mielniczuk LM. Reduced myocardial flow in heart failure patients with preserved ejection fraction. Circ Heart Fail 2016;9:pii: e002562.
29. Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H, Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol 2012;60: 1778-1786.
30. Regitz-Zagrosek V, Kararigas G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol Rev 2017;97:1-37.
31. Fliegner D, Schubert C, Penkalla A, Witt H, Kararigas G, Kararigas G, Dworatzek E, Staub E, Martus P, Ruiz Noppinger P, Kintscher U, Gustafsson J-A, Regitz-Zagrosek V. Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload. Am J Physiol Regul Integr Comp Physiol 2010;298: R1597-R1606.
32. Weinberg EO, Thienelt CD, Katz SE, Bartunek J, Tajima M, Rohrbach S, Douglas PS, Lorell BH. Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol 1999;34:264-273.
33. Scantlebury DC, Borlaug BA. Why are women more likely than men to develop heart failure with preserved ejection fraction? Curr Opin Cardiol 2011;26:562-568.
34. Hayward CS, Kelly RP. Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol 1997;30:1863-1871.
35. Krumholz HM, Larson M, Levy D. Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993;72:310-313.
36. Carroll JD, Carroll EP, Feldman T, Ward DM, Lang RM, McGaughey D, Karp RB. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 1992;86:1099-1107.
37. Villar AV, Llano M, Cobo M, Expo sito V, Merino R, Martin-Duran R, Hurle MA, Nistal JF. Gender differences of echocardiographic and gene expression patterns in human pressure overload left ventricular hypertrophy. J Mol Cell Cardiol 2009;46: 526-535.
38. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011;12:861-874.
39. de Bruin RG, Rabelink TJ, van Zonneveld AJ, van der Veer EP. Emerging roles for RNA-binding proteins as effectors and regulators of cardiovascular disease. Eur Heart J 2017;38:1380-1388.
40. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004;5:522-531.
41. Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, Wang Q, Bekiranov S, Sementchenko V, Fox EA, Silver PA, Gingeras TR, Liu XS, Brown M. Genome-wide analysis of estrogen receptor binding sites. Nat Genet 2006;38:1289-1297.
42. Klinge CM. miRNAs regulated by estrogens, tamoxifen, and endocrine disruptors and their downstream gene targets. Mol Cell Endocrinol 2015;418(pt. 3):273-297.
43. Guo X, Su B, Zhou Z, Sha J. Rapid evolution of mammalian X-linked testis microRNAs. BMC Genomics 2009;10:97.
44. Song R, Ro S, Michaels JD, Park C, McCarrey JR, Yan W. Many X-linked microRNAs escape meiotic sex chromosome inactivation. Nat Genet 2009;41: 488-493.
45. Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 2005;434:400-404.
46. Evangelista AM, Deschamps AM, Liu D, Raghavachari N, Murphy E. miR-222 contributes to sex-dimorphic cardiac eNOS expression via ets-1. Physiol Genomics 2013; 45:493-498.
47. Bernardo BC, Ooi JY, Matsumoto A, Tham YK, Singla S, Kiriazis H, Patterson NL, Sadoshima J, Obad S, Lin RC, McMullen JR. Sex differences in response to miRNA-34a therapy in mouse models of cardiac disease: identification of sex-, disease-and treatment-regulated miRNAs. J Physiol 2016;594:5959-5974.
48. van Zonneveld AJ, Rabelink TJ, Bijkerk R. miRNA-coordinated networks as promising therapeutic targets for acute kidney injury. Am J Pathol 2017;187:20-24.
49. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136: 215-233.
50. Vitale C, Fini M, Speziale G, Chierchia S. Gender differences in the cardiovascular effects of sex hormones. Fundam Clin Pharmacol 2010;24:675-685.
51. Murphy E. Estrogen signaling and cardiovascular disease. Circ Res 2011;109:687-696.
52. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583-1587.
53. Mendelsohn ME. Protective effects of estrogen on the cardiovascular system. Am J Cardiol 2002;89:12E-17E; discussion 17E-18E.
54. Wagner AH, Schroeter MR, Hecker M. 17beta-estradiol inhibition of NADPH oxidase expression in human endothelial cells. FASEB J 2001;15:2121-2130.
55. Nofer JR. Estrogens and atherosclerosis: insights from animal models and cell systems. J Mol Endocrinol 2012;48:R13-R29.
56. Ueda K, Lu Q, Baur W, Aronovitz MJ, Karas RH. Rapid estrogen receptor signaling mediates estrogen-induced inhibition of vascular smooth muscle cell proliferation. Arterioscler Thromb Vasc Biol 2013;33:1837-1843.
57. Ma Y, Qiao X, Falone AE, Reslan OM, Sheppard SJ, Khalil RA. Gender-specific reduction in contraction is associated with increased estrogen receptor expression in single vascular smooth muscle cells of female rat. Cell Physiol Biochem 2010;26: 457-470.
58. Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E, Kajstura J, Anversa P, Sussman MA. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res 2001;88:1020-1027.
59. Patten RD, Pourati I, Aronovitz MJ, Baur J, Celestin F, Chen X, Michael A, Haq S, Nuedling S, Grohe C, Force T, Mendelsohn ME, Karas RH. 17beta-estradiol reduces cardiomyocyte apoptosis in vivo and in vitro via activation of phospho-inositide-3 kinase/Akt signaling. Circ Res 2004;95:692-699.
60. Skavdahl M, Steenbergen C, Clark J, Myers P, Demianenko T, Mao L, Rockman HA, Korach KS, Murphy E. Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy. Am J Physiol Heart Circ Physiol 2005;288:H469-H476.
61. Iorga A, Li J, Sharma S, Umar S, Bopassa JC, Nadadur RD, Centala A, Ren S, Saito T, Toro L, Wang Y, Stefani E, Eghbali M. Rescue of pressure overload-induced heart failure by estrogen therapy. J Am Heart Assoc 2016;5:e002482.
62. O'Donnell E, Floras JS, Harvey PJ. Estrogen status and the renin angiotensin aldosterone system. Am J Physiol Regul Integr Comp Physiol 2014;307:R498-R500.
63. Zimmerman MA, Sullivan JC. Hypertension: what's sex got to do with it? Physiology (Bethesda) 2013;28:234-244.
64. Hernandez Schulman I, Raij L. Salt sensitivity and hypertension after menopause: role of nitric oxide and angiotensin II. Am J Nephrol 2006;26:170-180.
65. Sandberg K, Ji H. Sex differences in primary hypertension. Biol Sex Differ 2012;3:7.
66. Knopp RH, Paramsothy P, Retzlaff BM, Fish B, Walden C, Dowdy A, Tsunehara C, Aikawa K, Cheung MC. Sex differences in lipoprotein metabolism and dietary response: basis in hormonal differences and implications for cardiovascular disease. Curr Cardiol Rep 2006;8:452-459.
67. Gardner G, Banka CL, Roberts KA, Mullick AE, Rutledge JC. Modified LDLmediated increases in endothelial layer permeability are attenuated with 17 betaestradiol. Arterioscler Thromb Vasc Biol 1999;19:854-861.
68. Sulistiyani, St Clair RW. Effect of 17 beta-estradiol on metabolism of acetylated low-density lipoprotein by THP-1 macrophages in culture. Arterioscler Thromb Vasc Biol 1997;17:1691-1700.
69. Herrington DM, Howard TD, Hawkins GA, Reboussin DM, Xu J, Zheng SL, Brosnihan KB, Meyers DA, Bleecker ER. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002;346:967-974.
70. Badeau RM, Metso J, Wahala K, Tikkanen MJ, Jauhiainen M. Human macrophage cholesterol efflux potential is enhanced by HDL-associated 17beta-estradiol fatty acyl esters. J Steroid Biochem Mol Biol 2009;116:44-49.
71. Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, Dahlman-Wright K, Nilsson S, Gustafsson JA, Efendic S, Khan A. Evidence that oestrogen receptoralpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 2006;49:588-597.
72. Lundholm L, Bryzgalova G, Gao H, Portwood N, Falt S, Berndt KD, Dicker A, Galuska D, Zierath JR, Gustafsson JA, Efendic S, Dahlman-Wright K, Khan A. The estrogen receptor {alpha}-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms. J Endocrinol 2008;199: 275-286.
73. Lindheim SR, Buchanan TA, Duffy DM, Vijod MA, Kojima T, Stanczyk FZ, Lobo RA. Comparison of estimates of insulin sensitivity in pre-and postmenopausal women using the insulin tolerance test and the frequently sampled intravenous glucose tolerance test. J Soc Gynecol Investig 1994;1:150-154.
74. Walton C, Godsland IF, Proudler AJ, Wynn V, Stevenson JC. The effects of the menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. Eur J Clin Invest 1993;23:466-473.
75. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. 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.
76. 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.
77. Karim R, Mack WJ, Hodis HN, Roy S, Stanczyk FZ. Influence of age and obesity on serum estradiol, estrone, and sex hormone binding globulin concentrations following oral estrogen administration in postmenopausal women. J Clin Endocrinol Metab 2009;94:4136-4143.
78. Ying SY, Lin SL. Current perspectives in intronic micro RNAs (miRNAs). J Biomed Sci 2006;13:5-15.
79. Castellano L, Giamas G, Jacob J, Coombes RC, Lucchesi W, Thiruchelvam P, Barton G, Jiao LR, Wait R, Waxman J, Hannon GJ, Stebbing J. The estrogen receptor-alphainduced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci U S A 2009;106:15732-15737.
80. Maillot G, Lacroix-Triki M, Pierredon S, Gratadou L, Schmidt S, Benes V, Roche H, Dalenc F, Auboeuf D, Millevoi S, Vagner S. Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer Res 2009;69: 8332-8340.
81. Bhat-Nakshatri P, Wang G, Collins NR, Thomson MJ, Geistlinger TR, Carroll JS, Brown M, Hammond S, Srour EF, Liu Y, Nakshatri H. Estradiol-regulated microRNAs control estradiol response in breast cancer cells. Nucleic Acids Res 2009; 37:4850-4861.
82. Manavalan TT, Teng Y, Appana SN, Datta S, Kalbfleisch TS, Li Y, Klinge CM. Differential expression of microRNA expression in tamoxifen-sensitive MCF-7 versus tamoxifen-resistant LY2 human breast cancer cells. Cancer Lett 2011;313:26-43.
83. Lin CY, Vega VB, Thomsen JS, Zhang T, Kong SL, Xie M, Chiu KP, Lipovich L, Barnett DH, Stossi F, Yeo A, George J, Kuznetsov VA, Lee YK, Charn TH, Palanisamy N, Miller LD, Cheung E, Katzenellenbogen BS, Ruan Y, Bourque G, Wei CL, Liu ET. Whole-genome cartography of estrogen receptor alpha binding sites. PLoS Genet 2007;3:e87.
84. Adams BD, Claffey KP, White BA. Argonaute-2 expression is regulated by epidermal growth factor receptor and mitogen-activated protein kinase signaling and correlates with a transformed phenotype in breast cancer cells. Endocrinology 2009; 150:14-23.
85. Li P, Wei J, Li X, Cheng Y, Chen W, Cui Y, Simoncini T, Gu Z, Yang J, Fu X. 17betaestradiol enhances vascular endothelial Ets-1/miR-126-3p expression: the possible mechanism for attenuation of atherosclerosis. J Clin Endocrinol Metab 2017;102: 594-603.
86. Schweisgut J, Schutt C, Wust S, Wietelmann A, Ghesquiere B, Carmeliet P, Drose S, Korach KS, Braun T, Boettger T. Sex-specific, reciprocal regulation of ERalpha and miR-22 controls muscle lipid metabolism in male mice. EMBO J 2017;36: 1199-1214.
87. Olivieri F, Ahtiainen M, Lazzarini R, Pollanen E, Capri M, Lorenzi M, Fulgenzi G, Albertini MC, Salvioli S, Alen MJ, Kujala UM, Borghetti G, Babini L, Kaprio J, Sipila S, Franceschi C, Kovanen V, Procopio AD. Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions: a study on postmenopausal monozygotic twin pairs. Aging Cell 2014;13:850-861.
88. Shi Z, Zhao C, Guo X, Ding H, Cui Y, Shen R, Liu J. Differential expression of microRNAs in omental adipose tissue from gestational diabetes mellitus subjects reveals miR-222 as a regulator of ERalpha expression in estrogen-induced insulin resistance. Endocrinology 2014;155:1982-1990.
89. Arnal JF, Fontaine C, Billon-Gales A, Favre J, Laurell H, Lenfant F, Gourdy P. Estrogen receptors and endothelium. Arterioscler Thromb Vasc Biol 2010;30: 1506-1512.
90. Hahn C, Schwartz MA. Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 2009;10:53-62.
91. Lin Z, Kumar A, SenBanerjee S, Staniszewski K, Parmar K, Vaughan DE, Gimbrone MA Jr, Balasubramanian V, Garcia-Cardena G, Jain MK. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function. Circ Res 2005;96:e48-e57.
92. Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK. Kruppel-like factor 4 regulates endothelial inflammation. J Biol Chem 2007;282:13769-13779.
93. Cleaver O, Melton DA. Endothelial signaling during development. Nat Med 2003;9: 661-668.
94. Seferovic PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J 2015;36:1718-1727.
95. van Empel VP, Mariani J, Borlaug BA, Kaye DM. Impaired myocardial oxygen availability contributes to abnormal exercise hemodynamics in heart failure with preserved ejection fraction. J Am Heart Assoc 2014;3:e001293.
96. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 2004;84:767-801.
97. Trochu JN, Bouhour JB, Kaley G, Hintze TH. Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease. Circ Res 2000;87:1108-1117.
98. Seddon M, Shah AM, Casadei B. Cardiomyocytes as effectors of nitric oxide signalling. Cardiovasc Res 2007;75:315-326.
99. Kazakov A, Hall R, Jagoda P, Bachelier K, Müller-Best P, Semenov A, Lammert F, Böhm M, Laufs U. Inhibition of endothelial nitric oxide synthase induces and enhances myocardial fibrosis. Cardiovasc Res 2013;100:211-221.
100. Brutsaert DL. Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicity. Physiol Rev 2003;83:59-115.
101. Zhao J, Imbrie GA, Baur WE, Iyer LK, Aronovitz MJ, Kershaw TB, Haselmann GM, Lu Q, Karas RH. Estrogen receptor-mediated regulation of microRNA inhibits proliferation of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2013;33: 257-265.
102. Queiros AM, Eschen C, Fliegner D, Kararigas G, Dworatzek E, Westphal C, Sanchez Ruderisch H, Regitz-Zagrosek V. Sex-and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart. Int J Cardiol 2013;169: 331-338.
103. Kararigas G, Dworatzek E, Petrov G, Summer H, Schulze TM, Baczko I, Knosalla C, Golz S, Hetzer R, Regitz-Zagrosek V. Sex-dependent regulation of fibrosis and inflammation in human left ventricular remodelling under pressure overload. Eur J Heart Fail 2014;16:1160-1167.
104. Wang N, Sun LY, Zhang SC, Wei R, Xie F, Liu J, Yan Y, Duan MJ, Sun LL, Sun YH, Niu HF, Zhang R, Ai J. MicroRNA-23a participates in estrogen deficiency induced gap junction remodeling of rats by targeting GJA1. Int J Biol Sci 2015;11:390-403.
105. Sun LY, Wang N, Ban T, Sun YH, Han Y, Sun LL, Yan Y, Kang XH, Chen S, Sun LH, Zhang R, Zhao YJ, Zhang H, Ai J, Yang BF. MicroRNA-23a mediates mitochondrial compromise in estrogen deficiency-induced concentric remodeling via targeting PGC-1alpha. J Mol Cell Cardiol 2014;75:1-11.
106. Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci U S A 1986;83:2496-2500.
107. Rosano GM, Vitale C, Marazzi G, Volterrani M. Menopause and cardiovascular disease: the evidence. Climacteric 2007;10(Suppl. 1):19-24.
108. Nguyen DK, Disteche CM. Dosage compensation of the active X chromosome in mammals. Nat Genet 2006;38:47-53.
109. Augui S, Nora EP, Heard E. Regulation of X-chromosome inactivation by the Xinactivation centre. Nat Rev Genet 2011;12:429-442.
110. Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell 2013;152:1308-1323.
111. Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 2010;10:594-604.
112. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016; 16:626-638.
113. van Zonneveld AJ, de Boer HC, van der Veer EP, Rabelink TJ. Inflammation, vascular injury and repair in rheumatoid arthritis. Ann Rheum Dis 2010;69(Suppl. 1):i57-i60.
114. Gianturco L, Bodini BD, Atzeni F, Colombo C, Stella D, Sarzi-Puttini P, Drago L, Galaverna S, Turiel M. Cardiovascular and autoimmune diseases in females: the role of microvasculature and dysfunctional endothelium. Atherosclerosis 2015;241: 259-263.
115. Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, Stampfer MJ, Curhan GC. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107:1303-1307.
116. Arnold AP, Chen X. What does the "four core genotypes" mouse model tell us about sex differences in the brain and other tissues? Front Neuroendocrinol 2009;30: 1-9.
117. Ji H, Zheng W, Wu X, Liu J, Ecelbarger CM, Watkins R, Arnold AP, Sandberg K. Sex chromosome effects unmasked in angiotensin II-induced hypertension. Hypertension 2010;55:1275-1282.
118. Li J, Chen X, McClusky R, Ruiz-Sundstrom M, Itoh Y, Umar S, Arnold AP, Eghbali M. The number of X chromosomes influences protection from cardiac ischaemia/ reperfusion injury in mice: one X is better than two. Cardiovasc Res 2014;102: 375-384.
119. Chen X, McClusky R, Itoh Y, Reue K, Arnold AP. X and Y chromosome complement influence adiposity and metabolism in mice. Endocrinology 2013;154: 1092-1104.
120. Meunier J, Lemoine F, Soumillon M, Liechti A, Weier M, Guschanski K, Hu H, Khaitovich P, Kaessmann H. Birth and expression evolution of mammalian microRNA genes. Genome Res 2013;23:34-45.
121. Boonman-de Winter LJ, Rutten FH, Cramer MJ, Landman MJ, Liem AH, Rutten GE, Hoes AW. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia 2012;55: 2154-2162.
122. Eaton CB, Pettinger M, Rossouw J, Martin LW, Foraker R, Quddus A, Liu S, Wampler NS, Hank Wu WC, Manson JE, Margolis K, Johnson KC, Allison M, Corbie-Smith G, Rosamond W, Breathett K, Klein L. Risk factors for incident hospitalized heart failure with preserved versus reduced ejection fraction in a multiracial cohort of postmenopausal women. Circ Heart Fail 2016;9:e002883.
123. Li Y, Song YH, Li F, Yang T, Lu YW, Geng YJ. MicroRNA-221 regulates high glucose-induced endothelial dysfunction. Biochem Biophys Res Commun 2009;381: 81-83.
124. Li XX, Liu YM, Li YJ, Xie N, Yan YF, Chi YL, Zhou L, Xie SY, Wang PY. High glucose concentration induces endothelial cell proliferation by regulating cyclin-D2-related miR-98. J Cell Mol Med 2016;20:1159-1169.
125. Caporali A, Meloni M, Vollenkle C, Bonci D, Sala-Newby GB, Addis R, Spinetti G, Losa S, Masson R, Baker AH, Agami R, Le Sage C, Condorelli G, Madeddu P, Martelli F, Emanueli C. Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation 2011;123:282-291.
126. Caporali A, Meloni M, Nailor A, Mitic T, Shantikumar S, Riu F, Sala-Newby GB, Rose L, Besnier M, Katare R, Voellenkle C, Verkade P, Martelli F, Madeddu P, Emanueli C. p75(NTR)-dependent activation of NF-kappaB regulates microRNA-503 transcription and pericyte-endothelial crosstalk in diabetes after limb ischaemia. Nat Commun 2015;6:8024.
127. Coleman CB, Lightell DJ Jr, Moss SC, Bates M, Parrino PE, Woods TC. Elevation of miR-221 and-222 in the internal mammary arteries of diabetic subjects and normalization with metformin. Mol Cell Endocrinol 2013;374:125-129.
128. Reddy MA, Das S, Zhuo C, Jin W, Wang M, Lanting L, Natarajan R. Regulation of vascular smooth muscle cell dysfunction under diabetic conditions by miR-504. Arterioscler Thromb Vasc Biol 2016;36:864-873.
129. Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG, Liu Y, Hoffmann U, Bauer DC, Newman AB, Kritchevsky SB, Harris TB, Butler J. Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol 2010;55: 2129-2137.
130. Fang Y, Davies PF. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler Thromb Vasc Biol 2012;32: 979-987.
131. Loyer X, Potteaux S, Vion AC, Guerin CL, Boulkroun S, Rautou PE, Ramkhelawon B, Esposito B, Dalloz M, Paul JL, Julia P, Maccario J, Boulanger CM, Mallat Z, Tedgui A. Inhibition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice. Circ Res 2014;114:434-443.
132. Chen Z, Wen L, Martin M, Hsu CY, Fang L, Lin FM, Lin TY, Geary MJ, Geary GG, Zhao Y, Johnson DA, Chen JW, Lin SJ, Chien S, Huang HD, Miller YI, Huang PH, Shyy JY. Oxidative stress activates endothelial innate immunity via sterol regulatory element binding protein 2 (SREBP2) transactivation of microRNA-92a. Circulation 2015;131:805-814.
133. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 2011;13:423-433.
134. Tabet F, Vickers KC, Cuesta Torres LF, Wiese CB, Shoucri BM, Lambert G, Catherinet C, Prado-Lourenco L, Levin MG, Thacker S, Sethupathy P, Barter PJ, Remaley AT, Rye KA. HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells. Nat Commun 2014;5:3292.
135. Li S, Chen H, Ren J, Geng Q, Song J, Lee C, Cao C, Zhang J, Xu N. MicroRNA-223 inhibits tissue factor expression in vascular endothelial cells. Atherosclerosis 2014; 237:514-520.
136. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011;473:298-307.
137. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669-676.
138. Ushio-Fukai M. Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 2006;71:226-235.
139. Jeansson M, Gawlik A, Anderson G, Li C, Kerjaschki D, Henkelman M, Quaggin SE. Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest 2011;21:2278-2289.
140. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 2006;12:235-239.
141. Boodhwani M, Sodha NR, Mieno S, Xu SH, Feng J, Ramlawi B, Clements RT, Sellke FW. Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes. Circulation 2007;116:I31-I37.
142. Mohammed SF, Majure DT, Redfield MM. Zooming in on the Microvasculature in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail 2016;9:e003272.
143. Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 2007;101:59-68.
144. Ghosh G, Subramanian IV, Adhikari N, Zhang X, Joshi HP, Basi D, Chandrashekhar YS, Hall JL, Roy S, Zeng Y, Ramakrishnan S. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis. J Clin Invest 2010;120:4141-4154.
145. Chamorro-Jorganes A, Araldi E, Penalva LO, Sandhu D, Fernandez-Hernando C, Suarez Y. MicroRNA-16 and microRNA-424 regulate cell-autonomous angiogenic functions in endothelial cells via targeting vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1. Arterioscler Thromb Vasc Biol 2011;31:2595-2606.
146. Shi L, Fisslthaler B, Zippel N, Fromel T, Hu J, Elgheznawy A, Heide H, Popp R, Fleming I. MicroRNA-223 antagonizes angiogenesis by targeting beta1 integrin and preventing growth factor signaling in endothelial cells. Circ Res 2013;113:1320-1330.
147. Yang Q, Jia C, Wang P, Xiong M, Cui J, Li L, Wang W, Wu Q, Chen Y, Zhang T. MicroRNA-505 identified from patients with essential hypertension impairs endothelial cell migration and tube formation. Int J Cardiol 2014;177:925-934.
148. Dentelli P, Rosso A, Orso F, Olgasi C, Taverna D, Brizzi MF. microRNA-222 controls neovascularization by regulating signal transducer and activator of transcription 5A expression. Arterioscler Thromb Vasc Biol 2010;30:1562-1568.
149. Chen CF, Huang J, Li H, Zhang C, Huang X, Tong G, Xu YZ. MicroRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1. Gene 2015;565:246-251.
150. Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 2007;100:1164-1173.
151. Rippe C, Blimline M, Magerko KA, Lawson BR, LaRocca TJ, Donato AJ, Seals DR. MicroRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp Gerontol 2012;47:45-51.
152. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res 2008;79:581-588.
153. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G. MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006;108:3068-3071.
154. Chen Y, Banda M, Speyer CL, Smith JS, Rabson AB, Gorski DH. Regulation of the expression and activity of the antiangiogenic homeobox gene GAX/MEOX2 by ZEB2 and microRNA-221. Mol Cell Biol 2010;30:3902-3913.
155. Hinkel R, Penzkofer D, Zuhlke S, Fischer A, Husada W, Xu QF, Baloch E, van Rooij E, Zeiher AM, Kupatt C, Dimmeler S. Inhibition of microRNA-92a protects against ischemia/reperfusion injury in a large-animal model. Circulation 2013;128:1066-1075.
156. Huss JM, Kelly DP. Mitochondrial energy metabolism in heart failure: a question of balance. J Clin Invest 2005;115:547-555.
157. Chen Y, Liu Y, Dorn GW. Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 2011;109:1327-1331.
158. Shenouda SM, Widlansky ME, Chen K, Xu G, Holbrook M, Tabit CE, Hamburg NM, Frame AA, Caiano TL, Kluge MA, Duess MA, Levit A, Kim B, Hartman ML, Joseph L, Shirihai OS, Vita JA. Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus. Circulation 2011;124:444-453.
159. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787-790.
160. Falcao-Pires I, Hamdani N, Borbely A, Gavina C, Schalkwijk CG, van der Velden J, van Heerebeek L, Stienen GJ, Niessen HW, Leite-Moreira AF, Paulus WJ. Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. Circulation 2011;124: 1151-1159.
161. Wang K, Liu CY, Zhang XJ, Feng C, Zhou LY, Zhao Y, Li PF. miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury. Cell Death Differ 2015;22:1058-1068.
162. Wang K, Zhou LY, Wang JX, Wang Y, Sun T, Zhao B, Yang YJ, An T, Long B, Li N, Liu CY, Gong Y, Gao JN, Dong YH, Zhang J, Li PF. E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1. Nat Commun 2015;6:7619.
163. Palomer X,A lvarez-Guardia D, Davidson MM, Chan TO, Feldman AM, Vazquez-Carrera M, Eltzschig HK. The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells. PLoS One 2011;6:e19724.
164. Lagranha CJ, Deschamps A, Aponte A, Steenbergen C, Murphy E. Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females. Circ Res 2010;106:1681-1691.
165. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011; 147:728-741.
166. Kobayashi S, Liang Q. Autophagy and mitophagy in diabetic cardiomyopathy. Biochim Biophys Acta 2015;1852:252-261.
167. Shirakabe A, Ikeda Y, Sciarretta S, Zablocki DK, Sadoshima J. Aging and autophagy in the heart. Circ Res 2016;118:1563-1576.
168. Wang K, Liu CY, Zhou LY, Wang JX, Wang M, Zhao B, Zhao WK, Xu SJ, Fan LH, Zhang XJ, Feng C, Wang CQ, Zhao YF, Li PF. APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p. Nat Commun 2015;6:6779.
169. Bo L, Su-Ling D, Fang L, Lu-Yu Z, Tao A, Stefan D, Kun W, Pei-Feng L. Autophagic program is regulated by miR-325. Cell Death Differ 2014;21:967-977.
170. Su M, Wang J, Wang C, Wang X, Dong W, Qiu W, Wang Y, Zhao X, Zou Y, Song L, Zhang L, Hui R. MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis. Cell Death Differ 2015;22:986-999.
171. Melenovsky V, Hwang SJ, Redfield MM, Zakeri R, Lin G, Borlaug BA. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction. Circ Heart Fail 2015;8:295-303.
172. Shah AM, Shah SJ, Anand IS, Sweitzer NK, O'Meara E, Heitner JF, Sopko G, Li G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail 2014;7:104-115.
173. Melenovsky V, Borlaug BA, Rosen B, Hay I, Ferruci L, Morell CH, Lakatta EG, Najjar SS, Kass DA. Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community: the role of atrial remodeling/dysfunction. J Am Coll Cardiol 2007;49:198-207.
174. Bernardo BC, Nguyen SS, Winbanks CE, Gao XM, Boey EJ, Tham YK, Kiriazis H, Ooi JY, Porrello ER, Igoor S, Thomas CJ, Gregorevic P, Lin RC, Du XJ, McMullen JR. Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy. FASEB J 2014;28: 5097-5110.
175. Wang YS, Zhou J, Hong K, Cheng XS, Li YG. MicroRNA-223 displays a protective role against cardiomyocyte hypertrophy by targeting cardiac troponin I-interacting kinase. Cell Physiol Biochem 2015;35:1546-1556.
176. Wang C, Wang S, Zhao P, Wang X, Wang J, Wang Y, Song L, Zou Y, Hui R. MiR-221 promotes cardiac hypertrophy in vitro through the modulation of p27 expression. J Cell Biochem 2012;113:2040-2046.
177. Yang Y, Ago T, Zhai P, Abdellatif M, Sadoshima J. Thioredoxin 1 negatively regulates angiotensin II-induced cardiac hypertrophy through upregulation of miR-98/let-7. Circ Res 2011;108:305-313.
178. Tschope C, Paulus WJ. Is echocardiographic evaluation of diastolic function useful in determining clinical care? Doppler echocardiography yields dubious estimates of left ventricular diastolic pressures. Circulation 2009;120:810-820; discussion 820.
179. Franssen C, Paulus WJ. The future diagnosis of heart failure with normal ejection fraction: less imaging, more biomarkers? Eur J Heart Fail 2011;13:1043-1045.
180. Mottram PM, Leano R, Marwick TH. Usefulness of B-type natriuretic peptide in hypertensive patients with exertional dyspnea and normal left ventricular ejection fraction and correlation with new echocardiographic indexes of systolic and diastolic function. Am J Cardiol 2003;92:1434-1438.
181. Meyer S, van der Meer P, van Deursen VM, Jaarsma T, van Veldhuisen DJ, van der Wal MH, Hillege HL, Voors AA. Neurohormonal and clinical sex differences in heart failure. Eur Heart J 2013;34:2538-2547.
182. Wong LL, Armugam A, Sepramaniam S, Karolina DS, Lim KY, Lim JY, Chong JP, Ng JY, Chen YT, Chan MM, Chen Z, Yeo PS, Ng TP, Ling LH, Sim D, Leong KT, Ong HY, Jaufeerally F, Wong R, Chai P, Low AF, Lam CS, Jeyaseelan K, Richards AM. Circulating microRNAs in heart failure with reduced and preserved left ventricular ejection fraction. Eur J Heart Fail 2015;17:393-404.
183. Watson CJ, Gupta SK, O'Connell E, Thum S, Glezeva N, Fendrich J, Gallagher J, Ledwidge M, Grote-Levi L, McDonald K, Thum T. MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure. Eur J Heart Fail 2015;17: 405-415.
184. Schmitter D, Voors AA, van der Harst P. HFpEF vs. HFrEF: can microRNAs advance the diagnosis? Eur J Heart Fail 2015;17:351-354.
185. Nair N, Kumar S, Gongora E, Gupta S. Circulating miRNA as novel markers for diastolic dysfunction. Mol Cell Biochem 2013;376:33-40.
186. van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG, Paulus WJ, Voors AA, Hillege HL. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013; 61:1498-1506.
187. Nakada Y, Kawakami R, Nakano T, Takitsume A, Nakagawa H, Ueda T, Nishida T, Onoue K, Soeda T, Okayama S, Takeda Y, Watanabe M, Kawata H, Okura H, Saito Y. Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction. Am J Physiol Heart Circ Physiol 2016;310:H813-H820.
188. Wang YT, Tsai PC, Liao YC, Hsu CY, Juo SH. Circulating microRNAs have a sexspecific association with metabolic syndrome. J Biomed Sci 2013;20:72.
189. Carreras-Badosa G, Bonmati A, Ortega F-J, Mercader J-M, Guindo-Martinez M, Torrents D, Prats-Puig A, Martinez-Calcerrada J-M, Platero-Gutierrez E, De Zegher F, Ibanez L, Fernandez-Real J-M, Lopez-Bermejo A, Bassols J. Altered circulating miRNA expression profile in pregestational and gestational obesity. J Clin Endocrinol Metab 2015;100:E1446-E1456.
190. Hromadnikova I, Kotlabova K, Hympanova L, Krofta L. Gestational hypertension, preeclampsia and intrauterine growth restriction induce dysregulation of cardiovascular and cerebrovascular disease associated microRNAs in maternal whole peripheral blood. Thromb Res 2016;137:126-140.
191. Zeng Y, Zhang X, Kang K, Chen J, Wu Z, Huang J, Lu W, Chen Y, Zhang J, Wang Z, Zhai Y, Qu J, Ramchandran R, Raj JU, Wang J, Gou D. MicroRNA-223 attenuates hypoxia-induced vascular remodeling by targeting RhoB/MLC2 in pulmonary arterial smooth muscle cells. Sci Rep 2016;6:24900.
192. Tsai PC, Liao YC, Wang YS, Lin HF, Lin RT, Juo SH. Serum microRNA-21 and microRNA-221 as potential biomarkers for cerebrovascular disease. J Vasc Res 2013;50:346-354.
193. Jiang Y, Wang HY, Cao HM, Wang CY, Zhang L, Wang H, Liu L, Li Y, Cai JH. Peripheral blood miRNAs as a biomarker for chronic cardiovascular diseases. Sci Rep 2015;4:5026.
194. Ortega FJ, Mercader JM, Moreno-Navarrete JM, Rovira O, Guerra E, Esteve E, Xifra G, Martinez C, Ricart W, Rieusset J, Rome S, Karczewska-Kupczewska M, Straczkowski M, Fernandez-Real JM. Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. Diabetes Care 2014;37:1375-1383.
195. Zampetaki A, Kiechl S, Drozdov I, Willeit P, Mayr U, Prokopi M, Mayr A, Weger S, Oberhollenzer F, Bonora E, Shah A, Willeit J, Mayr M. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 2010;107:810-817.
196. Zampetaki A, Willeit P, Tilling L, Drozdov I, Prokopi M, Renard JM, Mayr A, Weger S, Schett G, Shah A, Boulanger CM, Willeit J, Chowienczyk PJ, Kiechl S, Mayr M. Prospective study on circulating MicroRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012;60:290-299.
197. Zhang YY, Zhou X, Ji WJ, Shi R, Lu RY, Li JL, Yang GH, Luo T, Zhang JQ, Zhao JH, Jiang TM, Li YM. Decreased circulating microRNA-223 level predicts high ontreatment platelet reactivity in patients with troponin-negative non-ST elevation acute coronary syndrome. J Thromb Thrombolysis 2014;38:65-72.
198. Bijkerk R, Duijs JM, Khairoun M, Ter Horst CJ, van der Pol P, Mallat MJ, Rotmans JI, de Vries AP, de Koning EJ, de Fijter JW, Rabelink TJ, van Zonneveld AJ, Reinders ME. Circulating microRNAs associate with diabetic nephropathy and systemic microvascular damage and normalize after simultaneous pancreas-kidney transplantation. Am J Transplant 2015;15:1081-1090.
199. Ventura-Clapier R, Dworatzek E, Seeland U, Kararigas G, Arnal J-F, Brunelleschi S, Carpenter TC, Erdmann J, Franconi F, Giannetta E, Glezerman M, Hofmann SM, Junien C, Katai M, Kublickiene K, Kö nig IR, Majdic G, Malorni W, Mieth C, Miller VM, Reynolds RM, Shimokawa H, Tannenbaum C, D'Ursi AM, Regitz-Zagrosek V. Sex in basic research: concepts in the cardiovascular field. Cardiovasc Res 2017;113: 711-724.