Advertisement

Sex Differences in Heart Failure

Published:November 09, 2021DOI:https://doi.org/10.1016/j.cardfail.2021.10.006

      Highlights

      • Important sex-based differences exist in heart failure, including risk factors, pathophysiology, and response to therapy, yet significant gaps in knowledge remain.
      • Traditional risk factors such as hypertension, diabetes mellitus, tobacco, and obesity predispose women to heart failure to a greater extent than men.
      • Sex-based risk factors unique to women include breast cancer-related therapy, stress-induced cardiomyopathy, autoimmune disease, and pregnancy.
      • Women present with the heart failure syndrome with more severe symptoms and on the backdrop of a higher left ventricular ejection fraction.
      • Guideline-directed medical therapy, device-based therapies, and advanced therapies are underused in women.
      • Calls to action include the broader inclusion of women in clinical and basic science studies, editorial boards, clinical trial leadership, and grant funding agencies to promote sex-specific research and care.

      Abstract

      Heart failure (HF) continues to be a major contributor of morbidity and mortality for men and women alike, yet how the predisposition for, course and management of HF differ between men and women remains underexplored. Sex differences in traditional risk factors as well as sex-specific risk factors influence the prevalence and manifestation of HF in unique ways. The pathophysiology of HF differs between men and women and may explain sex-specific differences in clinical presentation and diagnosis. This in turn, contributes to variation in response to both pharmacologic and device/surgical therapy. This review examines sex-specific differences in HF spanning prevalence, risk factors, pathophysiology, presentation, and therapies with a specific focus on highlighting gaps in knowledge with calls to action for future research efforts.

      Key Words

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Journal of Cardiac Failure
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • 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: e254-e743
        • Ho KK
        • Pinsky JL
        • Kannel WB
        • Levy D.
        The epidemiology of heart failure: the Framingham Study.
        J Am Coll Cardiol. 1993; 22: 6A-13A
        • Sotomi Y
        • Hikoso S
        • Nakatani D
        • et al.
        Sex differences in heart failure with preserved ejection fraction.
        J Am Heart Assoc. 2021; 10e018574
        • Lloyd-Jones DM
        • Larson MG
        • Leip EP
        • et al.
        Lifetime risk for developing congestive heart failure: the Framingham Heart Study.
        Circulation. 2002; 106: 3068-3072
        • Bleumink GS
        • Knetsch AM
        • Sturkenboom MC
        • et al.
        Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure: The Rotterdam Study.
        Eur Heart J. 2004; 25: 1614-1619
        • Holloway SM
        • Wilcox DE
        • Wilcox A
        • et al.
        Life expectancy and death from cardiomyopathy amongst carriers of Duchenne and Becker muscular dystrophy in Scotland.
        Heart. 2008; 94: 633-636
        • Kannel WB
        • McGee DL.
        Diabetes and cardiovascular disease. The Framingham study.
        JAMA. 1979; 241: 2035-2038
        • Regensteiner JG
        • Golden S
        • Huebschmann AG
        • et al.
        Sex differences in the cardiovascular consequences of diabetes mellitus: a scientific statement from the American Heart Association.
        Circulation. 2015; 132: 2424-2447
        • Henry RM
        • Kamp O
        • Kostense PJ
        • et al.
        Left ventricular mass increases with deteriorating glucose tolerance, especially in women: independence of increased arterial stiffness or decreased flow-mediated dilation: the Hoorn study.
        Diabetes Care. 2004; 27: 522-529
        • Rutter MK
        • Parise H
        • Benjamin EJ
        • et al.
        Impact of glucose intolerance and insulin resistance on cardiac structure and function: sex-related differences in the Framingham Heart Study.
        Circulation. 2003; 107: 448-454
        • Bibbins-Domingo K
        • Lin F
        • Vittinghoff E
        • et al.
        Predictors of heart failure among women with coronary disease.
        Circulation. 2004; 110: 1424-1430
        • Levy D
        • Larson MG
        • Vasan RS
        • Kannel WB
        • Ho KK.
        The progression from hypertension to congestive heart failure.
        JAMA. 1996; 275: 1557-1562
        • Hussey LC
        • Hardin S.
        Comparison of characteristics of heart failure by race and gender.
        Dimens Crit Care Nurs. 2005; 24: 41-46
        • 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
        • Cesaroni G
        • Mureddu GF
        • Agabiti N
        • et al.
        Sex differences in factors associated with heart failure and diastolic left ventricular dysfunction: a cross-sectional population-based study.
        BMC Public Health. 2021; 21: 415
        • Joyce E
        • Lala A
        • Stevens SR
        • et al.
        Prevalence, profile, and prognosis of severe obesity in contemporary hospitalized heart failure trial populations.
        JACC Heart Fail. 2016; 4: 923-931
        • Packer M
        • Kitzman DW.
        Obesity-related heart failure with a preserved ejection fraction: the mechanistic rationale for combining inhibitors of aldosterone, neprilysin, and sodium-glucose cotransporter-2.
        JACC Heart Fail. 2018; 6: 633-639
        • Hales CM
        • Carroll MD
        • Fryar CD
        • Ogden CL.
        Prevalence of obesity and severe obesity among adults: United States, 2017-2018.
        NCHS Data Brief. 2020; : 1-8
        • Savji N
        • Meijers WC
        • Bartz TM
        • et al.
        The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF.
        JACC Heart Fail. 2018; 6: 701-709
        • 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
        • Selvaraj S
        • Martinez EE
        • Aguilar FG
        • et al.
        Association of central adiposity with adverse cardiac mechanics: findings from the Hypertension Genetic Epidemiology Network Study.
        Circ Cardiovasc Imaging. 2016; 9: 1161
        • ST Higgins
        • Kurti AN
        • Redner R
        • et al.
        A literature review on prevalence of gender differences and intersections with other vulnerabilities to tobacco use in the United States, 2004-2014.
        Prev Med. 2015; 80: 89-100
        • Folsom AR
        • Shah AM
        • Lutsey PL
        • et al.
        American Heart Association's Life's Simple 7: avoiding heart failure and preserving cardiac structure and function.
        Am J Med. 2015; 128 (e2): 970-976
        • Lara KM
        • Levitan EB
        • Gutierrez OM
        • et al.
        Dietary patterns and incident heart failure in U.S. adults without known coronary disease.
        J Am Coll Cardiol. 2019; 73: 2036-2045
        • Mostofsky E
        • Levitan EB
        • Wolk A
        • Mittleman MA.
        Chocolate intake and incidence of heart failure: a population-based prospective study of middle-aged and elderly women.
        Circ Heart Fail. 2010; 3: 612-616
        • Djousse L
        • Driver JA
        • Gaziano JM.
        Relation between modifiable lifestyle factors and lifetime risk of heart failure.
        JAMA. 2009; 302: 394-400
        • Fauchier L
        • Babuty D
        • Poret P
        • et al.
        Comparison of long-term outcome of alcoholic and idiopathic dilated cardiomyopathy.
        Eur Heart J. 2000; 21: 306-314
        • Lazarevic AM
        • Nakatani S
        • Neskovic AN
        • et al.
        Early changes in left ventricular function in chronic asymptomatic alcoholics: relation to the duration of heavy drinking.
        J Am Coll Cardiol. 2000; 35: 1599-1606
        • Walsh CR
        • Larson MG
        • Evans JC
        • et al.
        Alcohol consumption and risk for congestive heart failure in the Framingham Heart Study.
        Ann Intern Med. 2002; 136: 181-191
        • Rorth R
        • Wong C
        • Kragholm K
        • et al.
        Return to the workforce after first hospitalization for heart failure: a Danish nationwide cohort study.
        Circulation. 2016; 134: 999-1009
        • Hsich EM
        • Grau-Sepulveda MV
        • Hernandez AF
        • et al.
        Sex differences in in-hospital mortality in acute decompensated heart failure with reduced and preserved ejection fraction.
        Am Heart J. 2012; 163 (437 e1–3): 430-437
        • Moore TH
        • Kapur N
        • Hawton K
        • Richards A
        • Metcalfe C
        • Gunnell D.
        Interventions to reduce the impact of unemployment and economic hardship on mental health in the general population: a systematic review.
        Psychol Med. 2017; 47: 1062-1084
        • Murphy MO
        • Cohn DM
        • Loria AS.
        Developmental origins of cardiovascular disease: Impact of early life stress in humans and rodents.
        Neurosci Biobehav Rev. 2017; 74: 453-465
        • Schmaltz HN
        • Southern D
        • Ghali WA
        • et al.
        Living alone, patient sex and mortality after acute myocardial infarction.
        J Gen Intern Med. 2007; 22: 572-578
        • Wang Y
        • Jiao Y
        • Nie J
        • et al.
        Sex differences in the association between marital status and the risk of cardiovascular, cancer, and all-cause mortality: a systematic review and meta-analysis of 7,881,040 individuals.
        Glob Health Res Policy. 2020; 5: 4
        • Stansfeld SA.
        Social support and social cohesion.
        in: Marmot M Wilkinson R Social determinants of health. 2nd ed. Oxford University Press, Oxford, UK2005: 155-174
        • Adiyaman A
        • Verhoeff R
        • Lenders JW
        • Deinum J
        • Thien T.
        The position of the arm during blood pressure measurement in sitting position.
        Blood Press Monit. 2006; 11: 309-313
        • Sinha A
        • Ning H
        • Carnethon MR
        • et al.
        Race- and sex-specific population attributable fractions of incident heart failure: a population-based cohort study from the Lifetime Risk Pooling Project.
        Circ Heart Fail. 2021; 14e008113
        • Creanga AA
        • Syverson C
        • Seed K
        • Callaghan WM.
        Pregnancy-related mortality in the United States, 2011-2013.
        Obstet Gynecol. 2017; 130: 366-373
        • Echouffo-Tcheugui JB
        • Guan J
        • Retnakaran R
        • Shah BR.
        Gestational diabetes and incident heart failure: a cohort study.
        Diabetes Care. 2021; 12cd210552
        • Damp J
        • Givertz MM
        • Semigran M
        • et al.
        Relaxin-2 and soluble flt1 levels in peripartum cardiomyopathy: results of the multicenter IPAC study.
        JACC Heart Fail. 2016; 4: 380-388
        • Countouris ME VF
        • Berlacher KL
        • et al.
        Association of hypertensive disorders of pregnancy with left ventricular remodeling later in life.
        J Am Coll Cardiol. 2020; 77: 1057-1068
        • Melchiorre K
        • Sutherland GR
        • Baltabaeva A
        • Liberati M
        • Thilaganathan B.
        Maternal cardiac dysfunction and remodeling in women with preeclampsia at term.
        Hypertension. 2011; 57: 85-93
        • Alma LJ
        • Bokslag A
        • Maas A
        • Franx A
        • Paulus WJ
        • de Groot CJM.
        Shared biomarkers between female diastolic heart failure and pre-eclampsia: a systematic review and meta-analysis.
        ESC Heart Fail. 2017; 4: 88-98
        • Davis MB
        • Arany Z
        • McNamara DM
        • Goland S
        • Elkayam U.
        Peripartum cardiomyopathy: JACC state-of-the-art review.
        J Am Coll Cardiol. 2020; 75: 207-221
        • McNamara DM
        • Elkayam U
        • Alharethi R
        • et al.
        Clinical outcomes for peripartum cardiomyopathy in North America: results of the IPAC study (Investigations of Pregnancy-Associated Cardiomyopathy).
        J Am Coll Cardiol. 2015; 66: 905-914
        • Rasmusson K
        • Brunisholz K
        • Budge D
        • et al.
        Peripartum cardiomyopathy: post-transplant outcomes from the United Network for Organ Sharing Database.
        J Heart Lung Transplant. 2012; 31: 180-186
        • Elkayam U.
        Risk of subsequent pregnancy in women with a history of peripartum cardiomyopathy.
        J Am Coll Cardiol. 2014; 64: 1629-1636
        • Hilfiker-Kleiner D
        • Haghikia A
        • Masuko D
        • et al.
        Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy.
        Eur J Heart Fail. 2017; 19: 1723-1728
        • Sliwa K
        • Petrie MC
        • Hilfiker-Kleiner D
        • et al.
        Long-term prognosis, subsequent pregnancy, contraception and overall management of peripartum cardiomyopathy: practical guidance paper from the Heart Failure Association of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy.
        Eur J Heart Fail. 2018; 20: 951-962
        • Ware JS
        • Li J
        • Mazaika E
        • et al.
        Shared genetic predisposition in peripartum and dilated cardiomyopathies.
        N Engl J Med. 2016; 374: 233-241
        • Ky B
        • Putt M
        • Sawaya H
        • et al.
        Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab.
        J Am Coll Cardiol. 2014; 63: 809-816
        • Elbl L
        • Vasova I
        • Tomaskova I
        • et al.
        Cardiac function and cardiopulmonary performance in patients after treatment for non-Hodgkin's lymphoma.
        Neoplasma. 2006; 53: 174-181
        • Hershman DL
        • McBride RB
        • Eisenberger A
        • Tsai WY
        • Grann VR
        • Jacobson JS.
        Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin's lymphoma.
        J Clin Oncol. 2008; 26: 3159-3165
        • Neilan TG
        • Coelho-Filho OR
        • Pena-Herrera D
        • et al.
        Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines.
        Am J Cardiol. 2012; 110: 1679-1686
        • Wang L
        • Tan TC
        • Halpern EF
        • et al.
        Major cardiac events and the value of echocardiographic evaluation in patients receiving anthracycline-based chemotherapy.
        Am J Cardiol. 2015; 116: 442-446
        • Szmit S
        • Jurczak W
        • Zaucha JM
        • et al.
        Pre-existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following (R)-CHOP chemotherapy in patients with lymphoma.
        J Am Soc Hypertens. 2014; 8: 791-799
        • Armenian SH
        • Lacchetti C
        • Barac A
        • et al.
        Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline.
        J Clin Oncol. 2017; 35: 893-911
        • Bozkurt B
        • Colvin M
        • Cook J
        • et al.
        Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association.
        Circulation. 2016; 134: e579-e646
        • Amir E
        • Seruga B
        • Niraula S
        • Carlsson L
        • Ocana A.
        Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.
        J Natl Cancer Inst. 2011; 103: 1299-1309
        • Khosrow-Khavar F
        • Filion KB
        • Bouganim N
        • Suissa S
        • Azoulay L.
        Aromatase inhibitors and the risk of cardiovascular outcomes in women with breast cancer: a population-based cohort study.
        Circulation. 2020; 141: 549-559
        • Bowles EJ
        • Wellman R
        • Feigelson HS
        • et al.
        Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study.
        J Natl Cancer Inst. 2012; 104: 1293-1305
        • Dang CT
        • Yu AF
        • Jones LW
        • et al.
        Cardiac surveillance guidelines for trastuzumab-containing therapy in early-stage breast cancer: getting to the heart of the matter.
        J Clin Oncol. 2016; 34: 1030-1033
        • Saiki H
        • Petersen IA
        • Scott CG
        • et al.
        Risk of heart failure with preserved ejection fraction in older women after contemporary radiotherapy for breast cancer.
        Circulation. 2017; 135: 1388-1396
        • Iwata M
        • Yoshikawa T
        • Baba A
        • Anzai T
        • Mitamura H
        • Ogawa S.
        Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy.
        J Am Coll Cardiol. 2001; 37: 418-424
        • Sharkey SW
        • Windenburg DC
        • Lesser JR
        • et al.
        Natural history and expansive clinical profile of stress (Tako-Tsubo) cardiomyopathy.
        J Am Coll Cardiol. 2010; 55: 333-341
        • Medina de Chazal H
        • Del Buono MG
        • Keyser-Marcus L
        • et al.
        Stress cardiomyopathy diagnosis and treatment: JACC state-of-the-art review.
        J Am Coll Cardiol. 2018; 72: 1955-1971
        • Templin C
        • Ghadri JR
        • Diekmann J
        • et al.
        Clinical features and outcomes of Takotsubo (stress) cardiomyopathy.
        N Engl J Med. 2015; 373: 929-938
        • Schneider B
        • Athanasiadis A
        • Stollberger C
        • et al.
        Gender differences in the manifestation of Tako-Tsubo cardiomyopathy.
        Int J Cardiol. 2013; 166: 584-588
        • Citro R
        • Rigo F
        • Previtali M
        • et al.
        Differences in clinical features and in-hospital outcomes of older adults with Tako-Tsubo cardiomyopathy.
        J Am Geriatr Soc. 2012; 60: 93-98
        • Vitale C
        • Mendelsohn ME
        • Rosano GM.
        Gender differences in the cardiovascular effect of sex hormones.
        Nat Rev Cardiol. 2009; 6: 532-542
        • Pelliccia F
        • Kaski JC
        • Crea F
        • Camici PG.
        Pathophysiology of Takotsubo syndrome.
        Circulation. 2017; 135: 2426-2441
        • Kegai S
        • Sato K
        • Goto K
        • et al.
        Coexistence of spontaneous coronary artery dissection, Takotsubo cardiomyopathy, and myocardial bridge.
        JACC Case Rep. 2021; 3: 250-254
        • Jogani S
        • Timmermans Sr., P
        • Desmet W
        • Koopman P
        • Timmermans Jr., P
        Dynamic Takotsubo syndrome: when SCAD hides in a pot.
        JACC Case Rep. 2020; 2: 1923-1931
        • Krittanawong C
        • Yue B
        • Mahtta D
        • et al.
        Hospital readmission in patients with spontaneous coronary artery dissection.
        Am J Cardiol. 2021; 151: 39-44
        • Klein SL
        • Flanagan KL.
        Sex differences in immune responses.
        Nat Rev Immunol. 2016; 16: 626-638
        • Beale AL
        • Meyer P
        • Marwick TH
        • Lam CSP
        • Kaye DM.
        Sex differences in cardiovascular pathophysiology: why women are overrepresented in heart failure with preserved ejection fraction.
        Circulation. 2018; 138: 198-205
        • Stolfo D
        • Uijl A
        • Vedin O
        • et al.
        Sex-based differences in heart failure across the ejection fraction spectrum: phenotyping, and prognostic and therapeutic implications.
        JACC Heart Fail. 2019; 7: 505-515
        • Bachmann KN
        • Huang S
        • Lee H
        • et al.
        Effect of testosterone on natriuretic peptide levels.
        J Am Coll Cardiol. 2019; 73: 1288-1296
        • Adamo L
        • Yu J
        • Rocha-Resende C
        • Javaheri A
        • Head RD
        • Mann DL.
        Proteomic signatures of heart failure in relation to left ventricular ejection fraction.
        J Am Coll Cardiol. 2020; 76: 1982-1994
        • Stienen S
        • Ferreira JP
        • Kobayashi M
        • et al.
        Sex differences in circulating proteins in heart failure with preserved ejection fraction.
        Biol Sex Differ. 2020; 11: 47
        • Owan TE
        • Hodge DO
        • Herges RM
        • Jacobsen SJ
        • Roger VL
        • Redfield MM.
        Trends in prevalence and outcome of heart failure with preserved ejection fraction.
        N Engl J Med. 2006; 355: 251-259
        • Ho JE
        • Enserro D
        • Brouwers FP
        • et al.
        Predicting heart failure with preserved and reduced ejection fraction: the International Collaboration on Heart Failure Subtypes.
        Circ Heart Fail. 2016; 9: 10.1161
        • Krumholz HM
        • Larson M
        • Levy D.
        Sex differences in cardiac adaptation to isolated systolic hypertension.
        Am J Cardiol. 1993; 72: 310-313
        • Sotomi Y
        • Hikoso S
        • Nakatani D
        • et al.
        Sex differences in heart failure with preserved ejection fraction.
        J Am Heart Assoc. 2021; 10e018574
        • Gori M
        • Lam CS
        • Gupta DK
        • et al.
        Sex-specific cardiovascular structure and function in heart failure with preserved ejection fraction.
        Eur J Heart Fail. 2014; 16: 535-542
        • Lau ES
        • Cunningham T
        • Hardin KM
        • et al.
        Sex differences in cardiometabolic traits and determinants of exercise capacity in heart failure with preserved ejection fraction.
        JAMA Cardiol. 2020; 5: 30-37
        • Tayal U
        • Newsome S
        • Buchan R
        • et al.
        Phenotype and clinical outcomes of titin cardiomyopathy.
        J Am Coll Cardiol. 2017; 70: 2264-2274
        • Merlo M
        • Cannata A
        • Pio Loco C
        • et al.
        Contemporary survival trends and aetiological characterization in non-ischaemic dilated cardiomyopathy.
        Eur J Heart Fail. 2020; 22: 1111-1121
        • Kumar S
        • Baldinger SH
        • Gandjbakhch E
        • et al.
        Long-term arrhythmic and nonarrhythmic outcomes of lamin A/C mutation carriers.
        J Am Coll Cardiol. 2016; 68: 2299-2307
        • Herman DS
        • Lam L
        • Taylor MR
        • et al.
        Truncations of titin causing dilated cardiomyopathy.
        N Engl J Med. 2012; 366: 619-628
        • Franaszczyk M
        • Chmielewski P
        • Truszkowska G
        • et al.
        Titin truncating variants in dilated cardiomyopathy - prevalence and genotype-phenotype correlations.
        PLoS One. 2017; 12e0169007
        • Tayal U
        • Prasad S
        • Cook SA.
        Genetics and genomics of dilated cardiomyopathy and systolic heart failure.
        Genome Med. 2017; 9: 20
        • Denfeld QE
        • Winters-Stone K
        • Mudd JO
        • Gelow JM
        • Kurdi S
        • Lee CS.
        The prevalence of frailty in heart failure: a systematic review and meta-analysis.
        Int J Cardiol. 2017; 236: 283-289
        • Denfeld QE
        • Habecker BA
        • Camacho SA
        • et al.
        Characterizing sex differences in physical frailty phenotypes in heart failure.
        Circ Heart Fail. 2021; 14e008076
        • Blumer V
        • Greene SJ
        • Wu A
        • et al.
        Sex differences in clinical course and patient-reported outcomes among patients hospitalized for heart failure.
        JACC Heart Failure. 2021; 9: 336-345
        • Kolte D
        • Khera S
        • Aronow WS
        • et al.
        Trends in incidence, management, and outcomes of cardiogenic shock complicating ST-elevation myocardial infarction in the United States.
        J Am Heart Assoc. 2014; 3e000590
        • Stolfo D
        • Uijl A
        • Vedin O
        • et al.
        Sex-based differences in heart failure across the ejection fraction spectrum: phenotyping, and prognostic and therapeutic implications.
        JACC Heart Failure. 2019; 7: 505-515
        • Dewan P
        • Rorth R
        • Raparelli V
        • et al.
        Sex-related differences in heart failure with preserved ejection fraction.
        Circ Heart Fail. 2019; 12e006539
        • Lichtman JH
        • Leifheit EC
        • Safdar B
        • et al.
        Sex differences in the presentation and perception of symptoms among young patients with myocardial infarction: evidence from the VIRGO Study (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients).
        Circulation. 2018; 137: 781-790
        • Lew J
        • Sanghavi M
        • Ayers CR
        • et al.
        Sex-based differences in cardiometabolic biomarkers.
        Circulation. 2017; 135: 544-555
        • Lau ES
        • Paniagua SM
        • Guseh JS
        • et al.
        Sex differences in circulating biomarkers of cardiovascular disease.
        J Am Coll Cardiol. 2019; 74: 1543-1553
        • Daniels LB
        • Maisel AS.
        Cardiovascular biomarkers and sex: the case for women.
        Nat Rev Cardiol. 2015; 12: 588-596
        • Suthahar N
        • Meems LMG
        • Ho JE
        • de Boer RA.
        Sex-related differences in contemporary biomarkers for heart failure: a review.
        Eur J Heart Fail. 2020; 22: 775-788
        • Suthahar N
        • Lau ES
        • Blaha MJ
        • et al.
        Sex-specific associations of cardiovascular risk factors and biomarkers with incident heart failure.
        J Am Coll Cardiol. 2020; 76: 1455-1465
        • Chung AK
        • Das SR
        • Leonard D
        • et al.
        Women have higher left ventricular ejection fractions than men independent of differences in left ventricular volume: the Dallas Heart Study.
        Circulation. 2006; 113: 1597-1604
        • McMurray JJV
        • Jackson AM
        • Lam CSP
        • et al.
        Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction: insights from PARAGON-HF.
        Circulation. 2020; 141: 338-351
        • Solomon SD
        • Mc MJ.
        Making the case for an expanded indication for sacubitril/valsartan in heart failure.
        J Card Fail. 2021; 27: 693-695
        • Ibrahim NE
        • Pina IL
        • Camacho A
        • et al.
        Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan.
        Eur J Heart Fail. 2020; 22: 2018-2025
        • Kenigsberg BB
        • Majure DT
        • Sheikh FH
        • et al.
        Sex-associated differences in cardiac reverse remodeling in patients supported by contemporary left ventricular assist devices.
        J Card Fail. 2020; 26: 494-504
        • Yin FH
        • Fan CL
        • Guo YY
        • Zhu H
        • Wang ZL.
        The impact of gender difference on clinical and echocardiographic outcomes in patients with heart failure after cardiac resynchronization therapy: a systematic review and meta-analysis.
        PloS One. 2017; 12e0176248
        • Chatterjee NA
        • Borgquist R
        • Chang Y
        • et al.
        Increasing sex differences in the use of cardiac resynchronization therapy with or without implantable cardioverter-defibrillator.
        Eur Heart J. 2017; 38: 1485-1494
        • Maddox TM
        • Januzzi Jr., JL
        • Allen LA
        • et al.
        2021 update to the 2017 ACC Expert Consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee.
        J Am Coll Cardiol. 2021; 77: 772-810
        • Zhao M
        • Woodward M
        • Vaartjes I
        • et al.
        Sex differences in cardiovascular medication prescription in primary care: a systematic review and meta-analysis.
        J Am Heart Assoc. 2020; 9e014742
        • Mauvais-Jarvis F
        • Berthold HK
        • Campesi I
        • et al.
        Sex- and gender-based pharmacological response to drugs.
        Pharmacol Rev. 2021; 73: 730-762
        • Santema BT
        • Ouwerkerk W
        • Tromp J
        • et al.
        Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study.
        Lancet. 2019; 394: 1254-1263
        • White-Williams C
        • Rossi LP
        • Bittner VA
        • et al.
        Addressing social determinants of health in the care of patients with heart failure: a scientific statement from the American Heart Association.
        Circulation. 2020; 141: e841-e863
        • Bots SH
        • Groepenhoff F
        • Eikendal ALM
        • et al.
        Adverse drug reactions to guideline-recommended heart failure drugs in women: a systematic review of the literature.
        JACC Heart Fail. 2019; 7: 258-266
        • 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: 303-310
        • Taylor AL
        • Lindenfeld J
        • Ziesche S
        • et al.
        Outcomes by gender in the African-American Heart Failure Trial.
        J Am Coll Cardiol. 2006; 48: 2263-2267
      1. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
        Lancet. 1999; 353: 9-13
        • Ghali JK
        • Piña IL
        • Gottlieb SS
        • Deedwania PC
        • Wikstrand JC.
        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: 1585-1591
        • Regitz-Zagrosek V.
        Therapeutic implications of the gender-specific aspects of cardiovascular disease.
        Nat Rev Drug Discov. 2006; 5: 425-438
        • 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: 821-828
        • Yusuf S
        • Sleight P
        • Pogue J
        • Bosch J
        • Davies R
        • Dagenais G.
        Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
        N Engl J Med. 2000; 342: 145-153
        • Do TP
        • Seetasith A
        • Belleli R
        • et al.
        A database cohort study to assess the risk of angioedema among patients with heart failure initiating angiotensin-converting enzyme inhibitors in the USA.
        Am J Cardiovasc Drugs. 2018; 18: 205-211
        • Kostis JB
        • Shelton B
        • Gosselin G
        • et al.
        Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators.
        Am Heart J. 1996; 131: 350-355
      2. The effect of digoxin on mortality and morbidity in patients with heart failure.
        N Engl J Med. 1997; 336: 525-533
        • 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: 1403-1411
        • McMurray JJ
        • Packer M
        • Desai AS
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • Vicent L
        • Ayesta A
        • Esteban-Fernández A
        • et al.
        Sex influence on the efficacy and safety of sacubitril/valsartan.
        Cardiology. 2019; 142: 73-78
        • McMurray JJV
        • Solomon SD
        • Inzucchi SE
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Packer M
        • Anker SD
        • Butler J
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • Teerlink JR
        • Diaz R
        • Felker GM
        • et al.
        Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.
        N Engl J Med. 2021; 384: 105-116
        • Packer M
        • Anker SD
        • Butler J
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • Armstrong PW
        • Pieske B
        • Anstrom KJ
        • et al.
        Vericiguat in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2020; 382: 1883-1893
        • Swedberg K
        • Komajda M
        • Bohm M
        • et al.
        Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
        Lancet. 2010; 376: 875-885
        • Merrill M
        • Sweitzer NK
        • Lindenfeld J
        • Kao DP.
        Sex differences in outcomes and responses to spironolactone in heart failure with preserved ejection fraction: a secondary analysis of TOPCAT trial.
        JACC Heart Fail. 2019; 7: 228-238
        • Solomon SD
        • McMurray JJV
        • Anand IS
        • et al.
        Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction.
        N Engl J Med. 2019; 381: 1609-1620
        • Anker SD
        • Butler J
        • Filippatos G
        • et al.
        Empagliflozin in heart failure with a preserved ejection fraction.
        N Engl J Med. 2021; 385: 1451-1461
        • Bardy GH
        • Lee KL
        • Mark DB
        • et al.
        Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.
        N Engl J Med. 2005; 352: 225-237
        • 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: 877-883
        • Gillis AM.
        Atrial fibrillation and ventricular arrhythmias: sex differences in electrophysiology, epidemiology, clinical presentation, and clinical outcomes.
        Circulation. 2017; 135: 593-608
        • Hsich EM.
        Sex differences in advanced heart failure therapies.
        Circulation. 2019; 139: 1080-1093
        • Rho RW
        • Patton KK
        • Poole JE
        • et al.
        Important differences in mode of death between men and women with heart failure who would qualify for a primary prevention implantable cardioverter-defibrillator.
        Circulation. 2012; 126: 2402-2407
        • Santangeli P
        • Pelargonio G
        • Dello Russo A
        • et al.
        Gender differences in clinical outcome and primary prevention defibrillator benefit in patients with severe left ventricular dysfunction: a systematic review and meta-analysis.
        Heart Rhythm. 2010; 7: 876-882
        • Zeitler EP
        • Hellkamp AS
        • Fonarow GC
        • et al.
        Primary prevention implantable cardioverter-defibrillators and survival in older women.
        JACC Heart Fail. 2015; 3: 159-167
        • Zeitler EP
        • Hellkamp AS
        • Schulte PJ
        • et al.
        Comparative effectiveness of implantable cardioverter defibrillators for primary prevention in women.
        Circ Heart Fail. 2016; 9e002630
        • Curtis LH
        • Al-Khatib SM
        • Shea AM
        • Hammill BG
        • Hernandez AF
        • Schulman KA.
        Sex differences in the use of implantable cardioverter-defibrillators for primary and secondary prevention of sudden cardiac death.
        JAMA. 2007; 298: 1517-1524
        • Hernandez AF
        • Fonarow GC
        • Liang L
        • et al.
        Sex and racial differences in the use of implantable cardioverter-defibrillators among patients hospitalized with heart failure.
        JAMA. 2007; 298: 1525-1532
        • 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: 1094-1101
        • Hess PL
        • Hernandez AF
        • Bhatt DL
        • et al.
        Sex and race/ethnicity differences in implantable cardioverter-defibrillator counseling and use among patients hospitalized with heart failure: findings from the Get With The Guidelines-Heart Failure program.
        Circulation. 2016; 134: 517-526
        • M Writing Group
        • Tracy CM
        • Epstein AE
        • et al.
        2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
        J Thorac Cardiovasc Surg. 2012; 144: e127-e145
        • 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: 813-820
        • Zusterzeel R
        • Selzman KA
        • Sanders WE
        • et al.
        Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data.
        JAMA Intern Med. 2014; 174: 1340-1348
        • Randolph TC
        • Hellkamp AS
        • Zeitler EP
        • et al.
        Utilization of cardiac resynchronization therapy in eligible patients hospitalized for heart failure and its association with patient outcomes.
        Am Heart J. 2017; 189: 48-58
        • Sridhar AR
        • Yarlagadda V
        • Parasa S
        • et al.
        Cardiac resynchronization therapy: US trends and disparities in utilization and outcomes.
        Circ Arrhythm Electrophysiol. 2016; 9e003108
        • Fonarow GC
        • Albert NM
        • Curtis AB
        • et al.
        Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF).
        Circulation. 2010; 122: 585-596
        • Nishimura RA
        • Otto CM
        • Bonow RO
        • et al.
        2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        J Am Coll Cardiol. 2017; 70: 252-289
        • Chan V
        • Chen L
        • Messika-Zeitoun D
        • Elmistekawy E
        • Ruel M
        • Mesana T.
        Is late left ventricle remodeling after repair of degenerative mitral regurgitation worse in women?.
        Ann Thorac Surg. 2019; 108: 1189-1193
        • Badhwar V
        • Peterson ED
        • Jacobs JP
        • et al.
        Longitudinal outcome of isolated mitral repair in older patients: results from 14,604 procedures performed from 1991 to 2007.
        Ann Thorac Surg. 2012; 94 (discussion 1877–9): 1870-1877
        • Vassileva CM
        • Stelle LM
        • Markwell S
        • Boley T
        • Hazelrigg S.
        Sex differences in procedure selection and outcomes of patients undergoing mitral valve surgery.
        Heart Surg Forum. 2011; 14: E276-E282
        • Lindenfeld J
        • Abraham WT
        • Grayburn PA
        • et al.
        Association of effective regurgitation orifice area to left ventricular end-diastolic volume ratio with transcatheter mitral valve repair outcomes: a secondary analysis of the COAPT trial.
        JAMA Cardiol. 2021; 6: 427-436
        • Estévez-Loureiro R
        • Settergren M
        • Winter R
        • et al.
        Effect of gender on results of percutaneous edge-to-edge mitral valve repair with MitraClip system.
        Am J Cardiol. 2015; 116: 275-279
        • Attizzani GF
        • Ohno Y
        • Capodanno D
        • et al.
        Gender-related clinical and echocardiographic outcomes at 30-day and 12-month follow up after MitraClip implantation in the GRASP registry.
        Catheter Cardiovasc Interv. 2015; 85: 889-897
        • Chan V
        • Messika-Zeitoun D
        • Labinaz M
        • et al.
        Impact of sex on outcomes after percutaneous repair of functional mitral valve regurgitation.
        J Card Surg. 2021; 36: 1900-1903
        • Werner N
        • Puls M
        • Baldus S
        • et al.
        Gender-related differences in patients undergoing transcatheter mitral valve interventions in clinical practice: 1-year results from the German TRAMI registry.
        Catheter Cardiovasc Interv. 2020; 95: 819-829
        • Paulus MG
        • Meindl C
        • Böhm L
        • et al.
        Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation.
        PLoS One. 2020; 15e0232817
        • Obadia JF
        • Messika-Zeitoun D
        • Leurent G
        • et al.
        Percutaneous repair or medical treatment for secondary mitral regurgitation.
        N Engl J Med. 2018; 379: 2297-2306
        • Stone GW
        • Lindenfeld J
        • Abraham WT
        • et al.
        Transcatheter mitral-valve repair in patients with heart failure.
        N Engl J Med. 2018; 379: 2307-2318
        • Kosmidou I
        • Lindenfeld J
        • Abraham WT
        • et al.
        Sex-specific outcomes of transcatheter mitral-valve repair and medical therapy for mitral regurgitation in heart failure.
        JACC Heart Fail. 2021; 9: 674-683
        • Grayburn PA
        • Sannino A
        • Cohen DJ
        • et al.
        Predictors of clinical response to transcatheter reduction of secondary mitral regurgitation: the COAPT trial.
        J Am Coll Cardiol. 2020; 76: 1007-1014
        • Park SD
        • Orban M
        • Karam N
        • et al.
        Sex-related clinical characteristics and outcomes of patients undergoing transcatheter edge-to-edge repair for secondary mitral regurgitation.
        JACC Cardiovasc Interv. 2021; 14: 819-827
        • Blumer V
        • Mendirichaga R
        • Hernandez GA
        • Zablah G
        • Chaparro SV.
        Sex-specific outcome disparities in patients receiving continuous-flow left ventricular assist devices: a systematic review and meta-analysis.
        ASAIO J. 2018; 64: 440-449
        • Imamura T
        • Combs P
        • Siddiqi U
        • et al.
        Sex difference in the impact of smoking on left ventricular assist device outcomes.
        J Card Surg. 2020; 35: 2913-2919
        • Imamura T.
        Implication of cardiac reverse remodeling during left ventricular assist device support in women.
        J Card Fail. 2020; 26: 640
        • Kanwar MK
        • Stehlik J.
        Sex-related differences in heart disease: another piece of the puzzle.
        J Card Fail. 2020; 26: 505-506
        • 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: 1435-1443
        • Slaughter MS
        • Pagani FD
        • McGee EC
        • et al.
        HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial.
        J Heart Lung Transplant. 2013; 32: 675-683
        • Slaughter MS
        • Rogers JG
        • Milano CA
        • et al.
        Advanced heart failure treated with continuous-flow left ventricular assist device.
        N Engl J Med. 2009; 361: 2241-2251
        • Mehra MR
        • Uriel N
        • Naka Y
        • et al.
        A fully magnetically levitated left ventricular assist device - final report.
        N Engl J Med. 2019; 380: 1618-1627
        • Gruen J
        • Caraballo C
        • Miller PE
        • et al.
        Sex differences in patients receiving left ventricular assist devices for end-stage heart failure.
        JACC Heart Fail. 2020; 8: 770-779
        • DeFilippis EM
        • Truby LK
        • Garan AR
        • et al.
        Sex-related differences in use and outcomes of left ventricular assist devices as bridge to transplantation.
        JACC Heart Fail. 2019; 7: 250-257
        • Huckaby LV
        • Seese LM
        • Aranda-Michel E
        • et al.
        Sex-based heart transplant outcomes after bridging with centrifugal left ventricular assist devices.
        Ann Thorac Surg. 2020; 110: 2026-2033
        • Mariani S
        • Li T
        • Bounader K
        • et al.
        Sex differences in outcomes following less-invasive left ventricular assist device implantation.
        Ann Cardiothorac Surg. 2021; 10: 255-267
        • Joshi AA
        • Lerman JB
        • Sajja AP
        • et al.
        Sex-based differences in left ventricular assist device utilization: insights from the Nationwide Inpatient Sample 2004 to 2016.
        Circ Heart Fail. 2019; 12e006082
        • Ahmed A
        • Adegbala O
        • Akintoye E
        • et al.
        Gender differences in outcomes after implantation of left ventricular assist devices.
        Ann Thorac Surg. 2020; 109: 780-786
        • Levy WC
        • Mozaffarian D
        • Linker DT
        • et al.
        The Seattle Heart Failure Model: prediction of survival in heart failure.
        Circulation. 2006; 113: 1424-1433
        • Pocock SJ
        • Ariti CA
        • McMurray JJ
        • et al.
        Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies.
        Eur Heart J. 2013; 34: 1404-1413
        • Wehbe RM
        • Anderson AS.
        Sex differences in outcomes of LVAD patients bridged to transplant: the problem of selection bias.
        JACC Heart Fail. 2019; 7: 731
        • DeFilippis EM
        • Farr MA
        • Topkara VK.
        Reply: sex differences in outcomes of LVAD patients bridged to transplant: the problem of selection bias.
        JACC Heart Fail. 2019; 7: 732
        • Nayak A
        • Hu Y
        • Ko YA
        • et al.
        Gender differences in mortality after left ventricular assist device implant: a causal mediation analysis approach.
        ASAIO J. 2021; 67: 614-621
        • Nayak A
        • Hu Y
        • Ko YA
        • et al.
        Creation and validation of a novel sex-specific mortality risk score in LVAD recipients.
        J Am Heart Assoc. 2021; 10e020019
        • Mullan CW
        • Chouairi F
        • Sen S
        • et al.
        Changes in use of left ventricular assist devices as bridge to transplantation with new heart allocation policy.
        JACC Heart Fail. 2021; 9: 420-429
        • Colvin M
        • Smith JM
        • Hadley N
        • et al.
        OPTN/SRTR 2018 annual data report: heart.
        Am J Transplant. 2020; 20 Suppl s1: 340-426
        • Hsich E
        • Chadalavada S
        • Krishnaswamy G
        • et al.
        Long-term prognostic value of peak oxygen consumption in women versus men with heart failure and severely impaired left ventricular systolic function.
        Am J Cardiol. 2007; 100: 291-295
        • Varshney AS
        • Berg DD
        • Katz JN
        • et al.
        Use of temporary mechanical circulatory support for management of cardiogenic shock before and after the United Network for Organ Sharing donor heart allocation system changes.
        JAMA Cardiol. 2020; 5: 703-708
        • Hanff TC
        • Harhay MO
        • Kimmel SE
        • et al.
        Trends in mechanical support use as a bridge to adult heart transplant under new allocation rules.
        JAMA Cardiol. 2020; 5: 728-729
        • Moayedi Y
        • Fan CPS
        • Cherikh WS
        • et al.
        Survival outcomes after heart transplantation: does recipient sex matter?.
        Circ Heart Fail. 2019; 12e006218
        • Cook JL
        • Grady KL
        • Colvin M
        • et al.
        Sex differences in the care of patients with advanced heart failure.
        Circ Cardiovasc Qual Outcomes. 2015; 8: S56-S59
        • Kaczmarek I
        • Meiser B
        • Beiras-Fernandez A
        • et al.
        Gender does matter: gender-specific outcome analysis of 67,855 heart transplants.
        Thorac Cardiovasc Surg. 2013; 61: 29-36
        • Van Spall HGC
        • Lala A
        • Deering TF
        • et al.
        Ending gender inequality in cardiovascular clinical trial leadership: JACC review topic of the week.
        J Am Coll Cardiol. 2021; 77: 2960-2972
        • Chuzi S
        • Reza N.
        Cultivating interest in heart failure careers: can we reverse the current trend? Cultivating interest in heart failure careers.
        J Card Fail. 2021; 27: 819-821