Sex differences of angiotensin-converting enzyme inhibitors in blood pressure lowering and cardiac remodeling: a systematic review and meta-analysis

Main Article Content

Sophie A. J. S. Laven, MD Daniek A. M. Meijs, MD Zenab Mohseni-Alsalhi, MSc Eveline M. van Luik, BSc Maud A. M. Vesseur, MD Esmée W. P. Vaes, BSc Nick Wilmes, MD Sander de Haas, MSc, MD Marc E. A. Spaanderman, MD, PhD Chahinda Ghossein-Doha, MD, PhD

Abstract

Objectives: Hypertension is the leading risk factor for cardiovascular disease. While treatment of high blood pressure is essential in cardiovascular disease prevention or slowing it down once cardiovascular disease occurred, it is assumed that pharmacological effectiveness may be hampered by sex differences. The aim is to evaluate sex-stratified effects for angiotensin-converting-enzyme inhibitors (ACEIs) on blood pressure and cardiac function in hypertensive participants.


Methods: A systematic review and meta-analysis were performed for studies on ACEIs from 1945 to May 2020. Studies had to present both baseline and follow-up measurements of the interested outcome variables and present sex stratified data. Mean differences were calculated using a random-effects model. 45 studies with 976 participants were used in this review.


Results: In females as compared to males, systolic blood pressure decreased by 19.9 mmHg (95% CI, -26.8; -13.0) vs. 15.1 mmHg (95% CI, -19.5; -10.8), diastolic blood pressure by 14.5 mmHg (95% CI, -17.2; -11.8) vs. 8.5 mmHg (95% CI, -11.4; -5.7), heart rate by -3.5 bpm (95% CI, -6.1; -0.9) vs. -2.5 bpm (95% CI, -4.8; -0.2). Only diastolic blood pressure lowered significantly more in females as compared to males. Left ventricular ejection fraction increased by 2.3% (95% CI, 0.8; 3.7) vs. 1.5% (95% CI, 0.6; 2.3), but without reaching statistical significance.


Conclusion: Although hypertensive treatment effects of ACEIs are comparable between sexes, diastolic blood pressure response is stronger in females, which may guide treatment choices in systolic or diastolic hypertension. It may be that other pharmacological different antihypertensive compounds show sex-specific differences in effectiveness.

Keywords: hypertension, cardiovascular disease, antihypertensive drugs, angiotensin-converting-enzyme inhibitors, sex differences

Article Details

How to Cite
LAVEN, Sophie A. J. S. et al. Sex differences of angiotensin-converting enzyme inhibitors in blood pressure lowering and cardiac remodeling: a systematic review and meta-analysis. Medical Research Archives, [S.l.], v. 11, n. 10, nov. 2023. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4306>. Date accessed: 23 july 2024. doi: https://doi.org/10.18103/mra.v11i10.4306.
Section
Review Articles

References

1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease and stroke statistics--2010 update: a report from the American Heart Association. Circulation 2010; 121(7):948-54 doi:10.1161/CIRCULATIONAHA.109.192666published Online First: Epub Date]|.

2. WHO Global status report on noncommunicable diseases 2010

3. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001;104 (22):2746-53 doi: 10.1161/hc4601.099487 published Online First: Epub Date]|.

4. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33(13) :1635-701 doi:10.1093/eurheartj/ehs092 published Online First: Epub Date]|.

5. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association. Circulation 2011; 123(11):1243-62 doi:10.1161/CIR.0b013e 31820faaf8published Online First: Epub Date]|.

6. Mosca L, Barrett-Connor E, Wenger NK. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation 2011;124(19): 2145-54 doi: 10.1161/CIRCULATIONAHA. 110.968792published Online First: Epub Date]|.

7. Young L, Cho L. Unique cardiovascular risk factors in women. Heart 2019;105(21):1656-60 doi: 10.1136/heartjnl-2018-314268 published Online First: Epub Date]|.

8. Stock EO, Redberg R. Cardiovascular disease in women. Curr Probl Cardiol 2012;37(11):450-526 doi: 10.1016/j.cpcardiol. 2012.07.001published Online First: Epub Date]|.

9. Keteepe-Arachi T, Sharma S. Cardiovascular Disease in Women: Understanding Symptoms and Risk Factors. Eur Cardiol 2017;12(1):10-13 doi: 10.15420/ ecr.2016:32:1published Online First: Epub Date]|.

10. Mosca L, Linfante AH, Benjamin EJ, et al. National study of physician awareness and adherence to cardiovascular disease prevention guidelines. Circulation 2005;111 (4):499-510 doi: 10.1161/01.CIR.0000154568. 43333.82published Online First: Epub Date]|.

11. Messerli FH, Bangalore S, Bavishi C, Rimoldi SF. Angiotensin-Converting Enzyme Inhibitors in Hypertension: To Use or Not to Use? J Am Coll Cardiol 2018;71(13):1474-82 doi: 10.1016/j.jacc.2018.01.058 published Online First: Epub Date]|.

12. Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993;45 (2):205-51

13. Abramson BL, Melvin RG. Cardiovascular risk in women: focus on hypertension. Can J Cardiol 2014;30(5):553-9 doi: 10.1016/j.cjca. 2014.02.014published Online First: Epub Date]|.

14. Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL. Women's Participation in Cardiovascular Clinical Trials From 2010 to 2017. Circulation 2020;141(7):540-48 doi: 10.1161/CIRCULATIONAHA.119.043594published Online First: Epub Date]|.

15. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898 doi: 10.1136/bmj.l4898published Online First: Epub Date]|.

16. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928 doi: 10.1136/bmj.d5928 published Online First: Epub Date]|.

17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7(3):177-88 doi: 10.1016/0197-2456(86)90046-2 published Online First: Epub Date]|.

18. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109 ):629-34 doi: 10.1136/bmj.315.7109.629 published Online First: Epub Date]|.

19. Higgins JPT. Chapter 10: Analysing data and untertaking meta-analyses. Cochrane handbook for systematic reviews of interventions, 2019.

20. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions: Wiley, 2019.

21. Schwarzer G. Meta: An R package for meta-analysis.

22. Team RC. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. 2016.

23. Kaiser T, Heise T, Nosek L, Eckers U, Sawicki PT. Influence of nebivolol and enalapril on metabolic parameters and arterial stiffness in hypertensive type 2 diabetic patients. J Hypertens 2006;24(7):1397-403 doi: 10.1097/01.hjh.0000234121.48272.67 published Online First: Epub Date]|.

24. Cocco G, Kohn S, Jerie P. Effects of combined treatment with enalapril and losartan on myocardial function in heart failure. Heart 2002;88(2):185-6 doi: 10.1136/ heart.88.2.185published Online First: Epub Date]|.

25. Burggraaf J, Schoemaker RC, Kroon JM, Cohen AF. The influence of nifedipine and captopril on liver blood flow in healthy subjects. Br J Clin Pharmacol 1998;45(5):447-51 doi: 10.1046/j.1365-2125.1998.00709. xpublished Online First: Epub Date]|.

26. Arcidiacono G, Asmundo GO, Battaglia E, et al. Left ventricular performance after intravenous infusion of captopril in patients with congestive heart failure. Minerva Cardioangiol 1995;43(11-12):481-4

27. Ahmad S, Giles TD, Roffidal LE, Haney Y, Given MB, Sander GE. Intravenous captopril in congestive heart failure. J Clin Pharmacol 1990;30(7) :609-14 doi: 10.1002/j.1552-4604.1990.tb01863.xpublished Online First: Epub Date]|.

28. Capewell S, Taverner D, Hannan WJ, Muir AL. Acute and chronic arterial and venous effects of captopril in congestive cardiac failure. BMJ 1989;299(6705):942-5 doi: 10.1136/bmj.299.6705.942published Online First: Epub Date]|.

29. Kramer B, Topic N, Massie B. Acute and long-term effects of captopril on exercise cardiac performance and exercise capacity in congestive heart failure. Br J Clin Pharmacol 1982;14 Suppl 2:143S-51S doi: 10.1111/ j.1365-2125.1982.tb02071.xpublished Online First: Epub Date]|.

30. Komajda M, Eugene M, Evans J, Drobinski G, Laurenceau JL, Grosgogeat Y. Long-term treatment of congestive heart failure with captopril. Br J Clin Pharmacol 1982;14 Suppl 2:223S-29S doi: 10.1111/j.1365-2125.1982.tb 02081.xpublished Online First: Epub Date]|.

31. Brunner HR, Gavras H, Waeber B, Turini GA, Wauters JP. Captopril: an oral angiotension converting enzyme inhibitor active in man. Arch Int Pharmacodyn Ther 1980;Suppl:188-212

32. Spoelstra-de Man AM, van Ittersum FJ, Schram MT, et al. Aggressive antihypertensive strategies based on hydrochlorothiazide, candesartan or lisinopril decrease left ventricular mass and improve arterial compliance in patients with type II diabetes mellitus and hypertension. J Hum Hypertens 2006;20(8):599-611 doi: 10.1038/sj.jhh. 1002025published Online First: Epub Date]|.

33. Undas A, Brummel-Ziedins KE, Potaczek DP, et al. Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost 2006;4(11):2397-404 doi: 10.1111/j.1538-7836.2006.02165.xpublished Online First: Epub Date]|.

34. van den Heuvel AF, Dunselman PH, Kingma T, et al. Reduction of exercise-induced myocardial ischemia during add-on treatment with the angiotensin-converting enzyme inhibitor enalapril in patients with normal left ventricular function and optimal beta blockade. J Am Coll Cardiol 2001;37(2):470-4 doi: 10.1016/s0735-1097 (00)01111-6published Online First: Epub Date]|.

35. Nalbantgil S, Yilmaz H, Gurun C, Özerkan F, Nalbantgil I, Önder R. Effects of valsartan and enalapril on regression of left ventricular hypertrophy in patients with mild to moderate hypertension: A randomized, double-blind study. Current Therapeutic Research 2000;61(6):331-38 doi: 10.1016/s0011-393x (00)80002-8published Online First: Epub Date]|.

36. Gaudron P, Kugler L, Hu K, et al. Effect of quinapril initiated during progressive remodeling in asymptomatic patients with healed myocardial infarction. Am J Cardiol 2000;86(2):139-44 doi: 10.1016/s0002-9149 (00)00849-3published Online First: Epub Date]|.

37. Sasaguri M, Noda K, Tashiro E, et al. The regression of left ventricular hypertrophy by imidapril and the reduction of serum procollagen type III amino-terminal peptide in hypertensive patients. Hypertens Res 2000;23(4):317-22 doi: 10.1291/hypres. 23.317published Online First: Epub Date]|.

38. Vescovo G, Dalla Libera L, Serafini F, et al. Improved exercise tolerance after losartan and enalapril in heart failure: correlation with changes in skeletal muscle myosin heavy chain composition. Circulation 1998;98(17) :1742-9 doi: 10.1161/01.cir.98.17.1742 published Online First: Epub Date]|.

39. Oki T, Fukuda N, Iuchi A, et al. Effects of enalapril on left ventricular mass and diastolic function in essential hypertension: special reference to duration of hypertension. J Card Fail 1995;1(5):365-70 doi: 10.1016/s1071-9164 (05)80005-3published Online First: Epub Date]|.

40. Iriarte M, Caso R, Murga N, et al. Enalapril-induced regression of hypertensive left ventricular hypertrophy, regional ischemia, and microvascular angina. Am J Cardiol 1995;75(12):850-2 doi: 10.1016/s0002-9149 (99)80431-7published Online First: Epub Date]|.

41. Henderson RJ, Cranswick RW, Hunyor SN. Structural adaptation of the heart in borderline hypertensives in response to blood pressure lowering with captopril. J Hypertens 1994;12(1):65-72

42. Cleland JG, Shah D, Krikler S, et al. Effects of lisinopril on cardiorespiratory, neuroendocrine, and renal function in patients with asymptomatic left ventricular dysfunction. Br Heart J 1993;69(6):512-5 doi: 10.1136 /hrt.69.6.512published Online First: Epub Date]|.

43. Gupta RK, Kjeldsen SE, Krause L, et al. Hemodynamic effects of quinapril, a novel angiotensin-converting enzyme inhibitor. Clin Pharmacol Ther 1990;48(1):41-9 doi: 10.1038/ clpt.1990.116published Online First: Epub Date]|.

44. Marmor A, Green T, Krakuer J, Szucs T, Schneeweiss A. A single dose of cilazapril improves diastolic function in hypertensive patients. Am J Med 1989;87(6B):61S-63S doi: 10.1016/0002-9343(89)90095-8published Online First: Epub Date]|.

45. Graettinger WF, Lipson JL, Klein RC, Cheung DG, Weber MA. Comparison of antihypertensive therapies by noninvasive techniques. Chest 1989;96(1):74-9 doi: 10.1378/chest.96.1.74published Online First: Epub Date]|.

46. Sheiban I, Arcaro G, Covi G, Accardi R, Zenorini C, Lechi A. Regression of cardiac hypertrophy after antihypertensive therapy with nifedipine and captopril. J Cardiovasc Pharmacol 1987;10 Suppl 10:S187-91

47. Chrysant SG, Gollub S, Dunn MI, Bal IS, Dreiling R, Konijeti JR. Hemodynamic and metabolic effects of enalapril in patients with heart failure. Clin Cardiol 1985;8(11):585-90 doi: 10.1002/clc.4960081107published Online First: Epub Date]|.

48. Osadchuk. HEART REMODELING AND QUALITY OF LIFE IN PATIENTS WITH CHRONIC KIDNEY DISEASE ON RENAL REPLACEMENT THERAPY MEDICAL NEWS OF THE NORTH CAUCASUS 2019 doi: https://doi.org/10.14300/mnnc.2019.14109published Online First: Epub Date]|.

49. Buda V, Andor M, Cristescu C, et al. Thrombospondin-1 Serum Levels In Hypertensive Patients With Endothelial Dysfunction After One Year Of Treatment With Perindopril. Drug Des Devel Ther 2019;13:3515-26 doi: 10.2147/DDDT. S218428published Online First: Epub Date]|.

50. Marakas SA, Kyriakidis MK, Vourlioti AN, Petropoulakis PN, Toutouzas PK. Acute effect of captopril administration on baroreflex sensitivity in patients with acute myocardial infarction. Eur Heart J 1995;16(7):914-21 doi: 10.1093/oxfordjournals.eurheartj.a061025published Online First: Epub Date]|.

51. Naganuma F, Kubota S, Hirahara N, et al. Ventricular unloading and improvement in left ventricular function after angiotensin converting enzyme inhibition with enalapril in patients with chronic congestive heart failure. Jpn Circ J 1994;58(1):34-42 doi: 10.1253 /jcj.58.34published Online First: Epub Date]|.

52. Schanzenbacher P, Liebau G. Effect of captopril on left ventricular dynamics in patients with chronic left ventricular volume overload. Klin Wochenschr 1983;61(7):343-7 doi: 10.1007/BF01485025published Online First: Epub Date]|.

53. Wenting GJ, Man in't veld AJ, Woittiez AJ, et al. Effects of captopril in acute and chronic heart failure. Correlations with plasma levels of noradrenaline, renin, and aldosterone. Br Heart J 1983;49(1):65-76 doi: 10.1136/ hrt.49.1.65published Online First: Epub Date]|.

54. Levine TB, Franciosa JA, Cohn JN. Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure. Circulation 1980;62(1):35-41 doi: 10.1161/01.cir.62.1.35published Online First: Epub Date]|.

55. Demirel S, Erk O, Unal M, et al. Cilazapril treatment in a cohort of seven patients with congestive heart failure: a seven-year follow-up study. Curr Ther Res Clin Exp 2003;64(3):167-75 doi: 10.1016/S0011-393X (03)00026-2published Online First: Epub Date]|.

56. Bartels GL, van den Heuvel FM, van Veldhuisen DJ, van der Ent M, Remme WJ. Acute anti-ischemic effects of perindoprilat in men with coronary artery disease and their relation with left ventricular function. Am J Cardiol 1999;83(3):332-6 doi: 10.1016/s0002-9149(98)00863-7published Online First: Epub Date]|.

57. Anand IS, Kalra GS, Ferrari R, Wahi PL, Harris PC, Poole-Wilson PA. Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention. Int J Cardiol 1990;28(3):341-6 doi: 10.1016/0167-5273(90) 90317-xpublished Online First: Epub Date]|.

58. Mulligan IP, Fraser AG, Lewis MJ, Henderson AH. Effects of enalapril on myocardial noradrenaline overflow during exercise in patients with chronic heart failure. Br Heart J 1989;61(1):23-8 doi: 10.1136/ hrt.61.1.23published Online First: Epub Date]|.

59. Awan NA, Amsterdam EA, Hermanovich J, Bommer WJ, Needham KE, Mason DT. Long-term hemodynamic and clinical efficacy of captopril therapy in ambulatory management of severe chronic congestive heart failure. Am Heart J 1982;103(4 Pt 1):474-9 doi: 10.1016/0002-8703(82)90332-5published Online First: Epub Date]|.

60. Massie BM, Kramer BL, Topic N. Acute and long-term effects of captopril on left and right ventricular volumes and function in chronic heart failure. Am Heart J 1982;104(5 Pt 2):1197-203 doi: 10.1016/0002-8703(82) 90051-5published Online First: Epub Date]|.

61. McGrath BP, Denham IM, Johnston CI. Clinical improvement and hormonal changes in severe cardiac failure after captopril treatment. Aust N Z J Med 1981;11(6):639-44 doi: 10.1111/j.1445-5994.1981.tb03538. xpublished Online First: Epub Date]|.

62. Yuksek U, Cerit L, Eren NK, Ergene O. The effect of perindopril on echocardiographic parameters, NYHA functional class and serum NT-proBNP values in patients with diastolic heart failure. Cardiovasc J Afr 2019;30(4):222-27 doi: 10.5830/CVJA-2019-022published Online First: Epub Date]|.

63. Asker M, Timucin OB, Asker S, Karadag MF. Effect of ramipril therapy on abnormal left atrial appendage function. J Int Med Res 2011 ;39(6):2429-35 doi:10.1177/147323001103900644published Online First: Epub Date]|.

64. Cuocolo A, Storto G, Izzo R, et al. Effects of valsartan on left ventricular diastolic function in patients with mild or moderate essential hypertension: comparison with enalapril. J Hypertens 1999;17(12 Pt 1):1759-66 doi: 10.1097/00004872-199917120-00014 published Online First: Epub Date]|.

65. Toyama T, Aihara Y, Iwasaki T, et al. Cardiac sympathetic activity estimated by 123I-MIBG myocardial imaging in patients with dilated cardiomyopathy after beta-blocker or angiotensin-converting enzyme inhibitor therapy. J Nucl Med 1999;40(2):217-23

66. Palatini P, Bongiovi S, Mario L, Mormino P, Raule G, Pessina AC. Effects of ACE inhibition on endurance exercise haemodynamics in trained subjects with mild hypertension. Eur J Clin Pharmacol 1995;48(6):435-9 doi: 10.1007/BF00194331 published Online First: Epub Date]|.

67. Creager MA, Massie BM, Faxon DP, et al. Acute and long-term effects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure. J Am Coll Cardiol 1985;6(1):163-73 doi: 10.1016/s0735-1097(85)80269-2published Online First: Epub Date]|.

68. Osadchuk. Corrective effect of angiotensin-converting enzyme inhibitors on the daily profile of blood pressure and somnological characteristics in elderly patients with combined cardiac pathology. MEDICAL NEWS OF THE NORTH CAUCASUS 2019

69. Todd PA, Goa KL. Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension. Drugs 1992;43(3):346-81 doi:10.2165/00003495-199243030-00005 published Online First: Epub Date]|.

70. Nicolaou PA. Sex differences in heart failure medications targeting the renin-angiotensin-aldosterone system. Eur J Pharmacol 2021;897:173961 doi: 10.1016/ j.ejphar.2021.173961published Online First: Epub Date]|.

71. James GD, Sealey JE, Muller F, Alderman M, Madhavan S, Laragh JH. Renin relationship to sex, race and age in a normotensive population. J Hypertens Suppl 1986;4(5) : S387-9

72. Kaplan NM, Kem DC, Holland OB, Kramer NJ, Higgins J, Gomez-Sanchez C. The intravenous furosemide test: a simple way to evaluate renin responsiveness. Ann Intern Med 1976;84(6):639-45 doi: 10.7326/0003-4819-84-6-639published Online First: Epub Date]|.

73. Proudler AJ, Ahmed AI, Crook D, Fogelman I, Rymer JM, Stevenson JC. Hormone replacement therapy and serum angiotensin-converting-enzyme activity in postmenopausal women. Lancet 1995;346 (8967):89-90 doi: 10.1016/s0140-6736(95) 92114-1published Online First: Epub Date]|.

74. Nogawa N, Sumino H, Ichikawa S, et al. Effect of long-term hormone replacement therapy on angiotensin-converting enzyme activity and bradykinin in postmenopausal women with essential hypertension and normotensive postmenopausal women. Menopause 2001;8(3):210-5 doi: 10.1097/ 00042192-200105000-00011published Online First: Epub Date]|.

75. Affinito P, Palomba S, Bonifacio M, et al. Effects of hormonal replacement therapy in postmenopausal hypertensive patients. Maturitas 2001;40(1):75-83 doi: 10.1016/ s0378-5122(01)00196-7published Online First: Epub Date]|.

76. O'Donnell CJ, Lindpaintner K, Larson MG, et al. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not women in the Framingham Heart Study. Circulation 1998;97(18):1766-72 doi: 10.1161/01.cir.97.18.1766published Online First: Epub Date]|.

77. Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the Immune System in Hypertension. Physiol Rev 2017;97(3):1127-64 doi: 10.1152/ physrev.00031.2016published Online First: Epub Date]|.

78. Sandberg K, Ji H, Hay M. Sex-specific immune modulation of primary hypertension. Cell Immunol 2015;294(2):95-101 doi: 10.1016/j.cellimm.2014.12.001published Online First: Epub Date]|.

79. Medina D, Mehay D, Arnold AC. Sex differences in cardiovascular actions of the renin-angiotensin system. Clin Auton Res 2020;30(5):393-408 doi: 10.1007/s10286-020-00720-2published Online First: Epub Date]|.

80. White MC, Fleeman R, Arnold AC. Sex differences in the metabolic effects of the renin-angiotensin system. Biol Sex Differ 2019;10(1):31 doi: 10.1186/s13293-019-0247-5published Online First: Epub Date]|.

81. Al-Gburi S, Deussen A, Zatschler B, et al. Sex-difference in expression and function of beta-adrenoceptors in macrovessels: role of the endothelium. Basic Res Cardiol 2017;112(3):29 doi: 10.1007/s00395-017-0617-2published Online First: Epub Date]|.

82. Kneale BJ, Chowienczyk PJ, Cockcroft JR, Coltart DJ, Ritter JM. Vasoconstrictor sensitivity to noradrenaline and NG-monomethyl-L-arginine in men and women. Clin Sci (Lond) 1997;93(6):513-8 doi: 10.1042/cs0930513published Online First: Epub Date]|.

83. Loria AS, Brinson KN, Fox BM, Sullivan JC. Sex-specific alterations in NOS regulation of vascular function in aorta and mesenteric arteries from spontaneously hypertensive rats compared to Wistar Kyoto rats. Physiol Rep 2014;2(8) doi: 10.14814/phy2.12125 published Online First: Epub Date]|.

84. Song JJ, Ma Z, Wang J, Chen LX, Zhong JC. Gender Differences in Hypertension. J Cardiovasc Transl Res 2020;13(1):47-54 doi: 10.1007/s12265-019-09888-zpublished Online First: Epub Date]|.

85. Wilbert-Lampen U, Seliger C, Trapp A, Straube F, Plasse A. Female sex hormones decrease constitutive endothelin-1 release via endothelial sigma-1/cocaine receptors: an action independent of the steroid hormone receptors. Endothelium 2005;12(4):185-91 doi: 10.1080/10623320500227275published Online First: Epub Date]|.

86. Konstam MA, Rousseau MF, Kronenberg MW, et al. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators. Circulation 1992;86(2):431-8 doi: 10.1161/01.cir.86.2.431 published Online First: Epub Date]|.

87. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327(10):669-77 doi: 10.1056/ NEJM 199209033271001 published Online First: Epub Date]|.

88. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273(18):1450-6

89. Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov 2006;5(5):425-38 doi: 10.1038/nrd2032 published Online First: Epub Date]|.

90. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993;342 (8875):821-8

91. Heart Outcomes Prevention Evaluation Study I, Yusuf S, Sleight P, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342(3):145-53 doi:10.1056/NEJM200001203420301published Online First: Epub Date]|.

92. Mohseni-Alsalhi Z, Vesseur MAM, Wilmes N, et al. The Representation of Females in Studies on Antihypertensive Medication over the Years: A Scoping Review. Biomedicines 2023;11(5).doi:10.3390/biomedicines11051435published Online First: Epub Date]|.

93. Wilmes N, van Luik EM, Vaes EWP, et al. Exploring Sex Differences of Beta-Blockers in the Treatment of Hypertension: A Systematic Review and Meta-Analysis. Biomedicines 2023;11(5).doi:10.3390/biomedicines11051494published Online First: Epub Date]|.

94. van Luik EM, Vaes EWP, Vesseur MAM, et al. Sex Differences in the Anti-Hypertensive Effect of Calcium-Channel Blockers: A Systematic Review and Meta-Analysis. Biomedicines 2023;11(6) doi: 10.3390/ biomedicines11061622published Online First: Epub Date]|.

95. Carey RM, Muntner P, Bosworth HB, Whelton PK. Prevention and Control of Hypertension: JACC Health Promotion Series. J Am Coll Cardiol 2018;72(11):1278-93 doi: 10.1016/j.jacc.2018.07.008published Online First: Epub Date]|.

96. Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 2021;143(8):e254-e743.doi:10.1161/CIR.0000000000000950published Online First: Epub Date]|.

97. Orshal JM, Khalil RA. Gender, sex hormones, and vascular tone. Am J Physiol Regul Integr Comp Physiol 2004;286(2):R233-49.doi:10.1152/ajpregu.00338.2003published Online First: Epub Date]|.

98. Hudson M, Rahme E, Behlouli H, Sheppard R, Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure--a population study. Eur J Heart Fail 2007;9(6-7):602-9 doi:10.1016/j.ejheart.2007.02.001 published Online First: Epub Date]|.

99. Komukai K, Mochizuki S, Yoshimura M. Gender and the renin-angiotensin-aldosterone system. Fundam Clin Pharmacol 2010;24(6) :687-98 doi: 10.1111/j.1472-8206. Date]|.

100. Paz Ocaranza M, Riquelme JA, Garcia L, et al. Counter-regulatory renin-angiotensin system in cardiovascular disease. Nat Rev Cardiol 2020;17(2):116-29 doi: 10.1038/ s41569-019-0244-8published Online First: Epub Date]|.

101. Colafella KMM, Denton KM. Sex-specific differences in hypertension and associated cardiovascular disease. Nat Rev Nephrol 2018;14(3):185-201 doi:10.1038/nrneph. 2017.189published Online First: Epub Date]|.

102. Sullivan JC, Rodriguez-Miguelez P, Zimmerman MA, Harris RA. Differences in angiotensin (1-7) between men and women. Am J Physiol Heart Circ Physiol 2015;308(9):H1171-6 doi: 10.1152/ajpheart. 00897.2014published Online First: Epub Date]|.

103. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39(33):3021-104 doi: 10.1093/ eurheartj/ehy339 published Online First: Epub Date]|.

104. Unger T, Borghi C, Charchar F, et al. 2020 International Society of Hypertension global hypertension practice guidelines. J Hypertens 2020;38(6):982-1004 doi: 10.1097/ HJH.0000000000002453published Online First: Epub Date]|.

105. Barton M, Meyer MR. Postmenopausal hypertension: mechanisms and therapy. Hypertension 2009;54(1):11-8 doi: 10.1161/HYPERTENSIONAHA.108.120022published Online First: Epub Date]|.

106. Kompas F. Enalapril. Secondary Enalapril n.d. https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/e/enalapril.

107. Kompas F. Captopril. Secondary Captopril n.d. https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/c/captopril.

108. Kompas F. Lisinopril. Secondary Lisinopril n.d. https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/l/lisinopril.

109. UpToDate. Quinalapril. Secondary Quinalapril n.d. https://www.uptodate.com/contents/table-of-contents/drug-information/international-drug-information-concise.

110. UpToDate. Imidapril. Secondary Imidapril n.d. https://www.uptodate.com/contents/table-of-contents/drug-information/international-drug-information-concise.

111. UpToDate. Cilazapril. n.d.

112. Kompas F. Ramipril. Secondary Ramipril n.d. https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/r/ramipril.

113. Kompas F. Perindopril. Secondary Perindopril n.d. https://www.farmacotherapeutischkompas.nl/bladeren/preparaatteksten/p/perindopril