Sex-Based Differences in Risk Determinants and Management of Heart Failure

  • Ahmed Almomani
  • Satish KenchaiahEmail author


In the United States, more than 40% of heart failure (HF) patients are women, and among the elderly the prevalence of HF is greater in women than in men. Generally, HF affects women at a more advanced age with better global left ventricular systolic function, compared with men. The risk factors associated with HF and its underlying pathophysiology partially differ by sex. Hypertension and diabetes mellitus impose a greater risk of HF in women than in men, who are more likely to have coronary artery disease as an etiology. Most large HF trials have under-represented women in their enrollment numbers, and this has narrowed our understanding of sex-related differences in HF pathophysiology, diagnosis, and treatment. Among patients with HF, survival seems to be better in women than men, with the likely exception of patients with HF due to ischemic heart disease where prognosis is similar in both sexes. Current treatment guidelines are not sex-specific because sufficient data is not available, however, as the therapeutic options for HF expand, sex-based modifications to HF management may be considered in future revisions.


Heart failure Risk factors Sex-specific treatment 



Dr. Kenchaiah was partly supported by the intramural research program of the National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health (NIH), grant number Z99 HL999999, and the Translational Research Institute, grant numbers UL1TR000039 and KL2TR000063 through the NIH National Center for Research Resources and National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conflicts of Interest: None.


  1. 1.
    Mastroianni ACFR, Federman D. Women and health research: ethical and legal issues of including women in clinical studies: volume I. Washington, DC: National Academies Press; 1994.Google Scholar
  2. 2.
    Kimmelstiel CD, Konstam MA. Heart failure in women. Cardiology. 1995;86:304–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129:e28–e292.CrossRefPubMedGoogle Scholar
  4. 4.
    Hsich EM, Piña IL. Heart failure in women: a need for prospective data. J Am Coll Cardiol. 2009;54:491–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068–72.CrossRefPubMedGoogle Scholar
  6. 6.
    Kenchaiah S, Vasan RS. Heart failure in women—insights from the Framingham Heart Study. Cardiovasc Drugs Ther. 2015;29:377–90.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Taylor AL, Lindenfeld J, Ziesche S, et al. Outcomes by gender in the African-American Heart Failure Trial. J Am Coll Cardiol. 2006;48:2263–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Galvao M, Kalman J, DeMarco T, et al. Gender differences in in-hospital management and outcomes in patients with decompensated heart failure: analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Card Fail. 2006;12:100–7.CrossRefPubMedGoogle Scholar
  9. 9.
    He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK. Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001;161:996–1002.CrossRefPubMedGoogle Scholar
  10. 10.
    Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced cardiotoxicity. Maedica (Buchar). 2013;8:59–67.Google Scholar
  11. 11.
    Geiger S, Lange V, Suhl P, Heinemann V, Stemmler HJ. Anticancer therapy induced cardiotoxicity: review of the literature. Anti-Cancer Drugs. 2010;21:578–90.CrossRefPubMedGoogle Scholar
  12. 12.
    Shaikh AY, Shih JA. Chemotherapy-induced cardiotoxicity. Curr Heart Fail Rep. 2012;9:117–27.CrossRefPubMedGoogle Scholar
  13. 13.
    Arany Z, Elkayam U. Peripartum cardiomyopathy. Circulation. 2016;133:1397–409.CrossRefPubMedGoogle Scholar
  14. 14.
    Ritchie C. Clinical contribution to the pathology, diagnosis, and treatment of certain chronic diseases of the heart. Edinburgh Med Surg J. 1849;185:333–42.Google Scholar
  15. 15.
    Porak C. De. L’influence reciproque de la grossesse et del maladies du Coeur [thesis]. Medical Faculty of Paris, France; 1880.Google Scholar
  16. 16.
    Rigolli M, Whalley GA. Heart failure with preserved ejection fraction. J Geriatr Cardiol. 2013;10:369–76.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Deswal A, Bozkurt B. Comparison of morbidity in women versus men with heart failure and preserved ejection fraction. Am J Cardiol. 2006;97:1228–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Johnstone D, Limacher M, Rousseau M, et al. Clinical characteristics of patients in studies of left ventricular dysfunction (SOLVD). Am J Cardiol. 1992;70:894–900.CrossRefPubMedGoogle Scholar
  19. 19.
    Latini R, Masson S. NT-proBNP: a guide to improve the management of patients with heart failure. EJIFCC. 2013;24:78–84.PubMedGoogle Scholar
  20. 20.
    Wang TJ, Larson MG, Levy D, et al. Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol. 2002;90:254–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350:655–63.CrossRefPubMedGoogle Scholar
  22. 22.
    Christ M, Laule-Kilian K, Hochholzer W, et al. Gender-specific risk stratification with B-type natriuretic peptide levels in patients with acute dyspnea: insights from the B-type natriuretic peptide for acute shortness of breath evaluation study. J Am Coll Cardiol. 2006;48:1808–12.CrossRefPubMedGoogle Scholar
  23. 23.
    Meyer S, van der Meer P, van Deursen VM, et al. Neurohormonal and clinical sex differences in heart failure. Eur Heart J. 2013;34:2538–47.CrossRefPubMedGoogle Scholar
  24. 24.
    Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339:900–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.CrossRefPubMedGoogle Scholar
  26. 26.
    Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369:29–36.CrossRefPubMedGoogle Scholar
  27. 27.
    Zuppinger C, Suter TM. Cancer therapy-associated cardiotoxicity and signaling in the myocardium. J Cardiovasc Pharmacol. 2010;56:141–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Ntusi NB, Mayosi BM. Aetiology and risk factors of peripartum cardiomyopathy: a systematic review. Int J Cardiol. 2009;131:168–79.CrossRefPubMedGoogle Scholar
  29. 29.
    Scantlebury DC, Borlaug BA. Why are women more likely than men to develop heart failure with preserved ejection fraction? Curr Opin Cardiol. 2011;26:562–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–55.CrossRefGoogle Scholar
  31. 31.
    Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–8.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation. 2001;103:375–80.CrossRefPubMedGoogle Scholar
  33. 33.
    Ghali JK, Piña IL, Gottlieb SS, Deedwania PC, Wikstrand JC. Group M-HS. Metoprolol CR/XL in female patients with heart failure: analysis of the experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation. 2002;105:1585–91.CrossRefPubMedGoogle Scholar
  34. 34.
    Shekelle PG, Rich MW, Morton SC, et al. Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials. J Am Coll Cardiol. 2003;41:1529–38.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yakoob MY, Bateman BT, Ho E, et al. The risk of congenital malformations associated with exposure to β-blockers early in pregnancy: a meta-analysis. Hypertension. 2013;62:375–81.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Magee LA, Abalos E, von Dadelszen P, et al. How to manage hypertension in pregnancy effectively. Br J Clin Pharmacol. 2011;72:394–401.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Group CTS. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–35.CrossRefGoogle Scholar
  38. 38.
    Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN, Investigators S. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.CrossRefPubMedGoogle Scholar
  39. 39.
    Packer M, Poole-Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100:2312–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Pfeffer MA, Braunwald E, Moyé 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;327:669–77.CrossRefPubMedGoogle Scholar
  41. 41.
    The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821–8.Google Scholar
  42. 42.
    Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med. 1995;333:1670–6.CrossRefPubMedGoogle Scholar
  43. 43.
    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;273:1450–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/aha guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;136(6):e137–61.Google Scholar
  45. 45.
    O'Meara E, Clayton T, McEntegart MB, et al. Sex differences in clinical characteristics and prognosis in a broad spectrum of patients with heart failure: results of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation. 2007;115:3111–20.CrossRefPubMedGoogle Scholar
  46. 46.
    Cohn JN, Tognoni G, Investigators VHFT. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hubers SA, Brown NJ. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Circulation. 2016;133:1115–24.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986;314:1547–52.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303–10.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Group DI. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525–33.CrossRefGoogle Scholar
  54. 54.
    Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347:1403–11.CrossRefPubMedGoogle Scholar
  55. 55.
    Adams KF, Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. J Am Coll Cardiol. 2005;46:497–504.CrossRefPubMedGoogle Scholar
  56. 56.
    Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–37.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140–50.CrossRefPubMedGoogle Scholar
  58. 58.
    Zareba W, Moss AJ, Jackson Hall W, et al. Clinical course and implantable cardioverter defibrillator therapy in postinfarction women with severe left ventricular dysfunction. J Cardiovasc Electrophysiol. 2005;16:1265–70.CrossRefPubMedGoogle Scholar
  59. 59.
    Bardy GH, Lee KL, Mark DB, et al. Sudden cardiac death-heart failure trial (SCD-HeFT). In: Woosley RL, Singh SN, editors. Ar rhythmia treatment and therapy: evaluation of clinical trial evidence. New York: Marcel Dekker; 2000. p. 323–42.Google Scholar
  60. 60.
    Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877–83.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Al-Khatib SM, Hellkamp AS, Hernandez AF, et al. Trends in use of implantable cardioverter-defibrillator therapy among patients hospitalized for heart failure: have the previously observed sex and racial disparities changed over time? Circulation. 2012;125:1094–101.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Arshad A, Moss AJ, Foster E, et al. Cardiac resynchronization therapy is more effective in women than in men: the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy) trial. J Am Coll Cardiol. 2011;57:813–20.CrossRefPubMedGoogle Scholar
  63. 63.
    Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–49.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med. 2007;357:885–96.CrossRefPubMedGoogle Scholar
  65. 65.
    Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345:1435–43.CrossRefPubMedGoogle Scholar
  66. 66.
    Bogaev RC, Pamboukian SV, Moore SA, et al. Comparison of outcomes in women versus men using a continuous-flow left ventricular assist device as a bridge to transplantation. J Heart Lung Transplant. 2011;30:515–22.CrossRefPubMedGoogle Scholar
  67. 67.
    Heatley G, Sood P, Goldstein D, et al. Clinical trial design and rationale of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 (MOMENTUM 3) investigational device exemption clinical study protocol. J Heart Lung Transplant. 2016;35:528–36.CrossRefPubMedGoogle Scholar
  68. 68.
    Hsich EM, Naftel DC, Myers SL, et al. Should women receive left ventricular assist device support?: findings from INTERMACS. Circ Heart Fail. 2012;5:234–40.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Weymann A, Patil NP, Sabashnikov A, et al. Gender differences in continuous-flow left ventricular assist device therapy as a bridge to transplantation: a risk-adjusted comparison using a propensity score-matching analysis. Artif Organs. 2015;39:212–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Stehlik J, Edwards LB, Rowe A, et al. ISHLT international registry for heart and lung transplantation—three decades of scientific contributions. Transplant Rev (Orlando). 2013;27:38–42.CrossRefGoogle Scholar
  71. 71.
    Regitz-Zagrosek V, Petrov G, Lehmkuhl E, et al. Heart transplantation in women with dilated cardiomyopathy. Transplantation. 2010;89:236–44.CrossRefPubMedGoogle Scholar
  72. 72.
    Shin JJ, Hamad E, Murthy S, Piña IL. Heart failure in women. Clin Cardiol. 2012;35:172–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Stevenson WG, Stevenson LW, Middlekauff HR, et al. Improving survival for patients with advanced heart failure: a study of 737 consecutive patients. J Am Coll Cardiol. 1995;26:1417–23.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Division of Cardiovascular Medicine, Department of Internal Medicine, College of MedicineUniversity of Arkansas for Medical SciencesLittle RockUSA
  2. 2.Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai HospitalIcahn School of Medicine at Mount SinaiNew YorkUSA

Personalised recommendations