Commentary

The Yentl syndrome and gender inequality in ischemic HD

C. Noel Bairey Merz, MD
C. Noel Bairey Merz

More women than men die annually of ischemic heart disease, which represents a reversal of fortune from prior decades and places women firmly as the new majority now affected. The adverse ischemic heart disease (HD) gender gap is the widest in relatively young women, where MI mortality is twofold higher in women younger than 50 years compared with age-matched men. Although it is clear that there are many gender differences in ischemic HD outcomes, including more frequent angina diagnosis, more office visits, more avoidable hospitalizations, higher MI mortality, and higher rates of HF in women compared with men, the contributing etiologies to these differences are unclear.

Gender differences highlighted

A number of contradictory findings are evident with regard to sex differences in ischemic HD: Women have a higher prevalence of angina compared with men, yet have an overall lower prevalence of obstructive CAD; symptomatic women undergoing coronary angiography have less extensive and severe obstructive CAD, despite being older with higher risk factor burden compared with men; and despite relatively less obstructive CAD, women have a more adverse prognosis compared with men. We have hypothesized an alternative, female-specific pattern of ischemic HD due to the relatively high frequency of microvascular coronary dysfunction in symptomatic women with and without obstructive CAD, which we have linked with symptoms, ischemia and adverse outcomes. This alternative “female-pattern” of ischemic HD is not easily recognized, given our male-pattern strategies aimed at detection and treatment of obstructive CAD.

What relevance does this have to the adverse gender gaps for ischemic HD in women? The literature suggests that when women look like men (with “male-pattern” obstructive CAD), they are more likely to be diagnosed and treated as men are treated. As characterized by the “Yentl” syndrome, depicted in the Barbra Streisand movie of the same name, Bernadine Healy, MD, used this term in 2001 to call attention to the paradox of adverse outcomes of women with ischemic HD, as well as the under-diagnosis and under-treatment of women.

Ten years later, recent analyses published in the European Heart Journal suggest that Yentl syndrome remains evident in 2011. Johnson and colleagues compared diagnostic coronary angiography, medication usage, and outcomes in 12,200 women and men with stable signs and symptoms of ischemic HD and 2-year outcomes in Sweden between 2006 and 2008. Bugiardini and colleagues summarized medication usage and outcomes in 6,558 women and men with ACS with 1-year outcomes from the Canadian ACS Registry I and II between 1999 and 2003. Both studies demonstrate under-treatment of women with medication, including lower rates of aspirin and ACE inhibitor use in stable women compared with men, as well lower rates of ACE inhibitor, beta-blocker and statin medication in ACS women compared with men. Both studies also show gender differences in use of procedures, where interestingly, stable women undergo more repeat angiography, whereas ACS women undergo fewer index angiograms, percutaneous coronary interventions and CABG compared with their male counterparts. The adverse outcomes described in these new works are consistent with prior literature. Both studies demonstrate adverse gender differences for women; Stable women have more MIs while ACS women have higher death rates compared with men.

Women remain undertreated

The Swedish data report equivalent use of the four life-saving medication strategies (ACE inhibitors, beta-blockers, aspirin and statins) among stable women and men after angiographic diagnosis of obstructive CAD. Importantly, appropriate medication utilization was accompanied by equivalent mortality between the sexes, although event rates were predictably lower in this stable lower-risk population. Prior work has shown an improvement of ischemic HD prognosis in women over time. Nevertheless, other contemporary data demonstrate persistently more adverse outcomes for women compared with men. The Canadian Registry analysis adds to the accumulated literature that women with ACS remain less likely than men to receive indicated diagnostic tests, guideline-indicated medication and procedures and subsequently suffer predictable higher rates of adverse outcomes.

Given the emphasis on guidelines therapy, why are women still undertreated with appropriate ischemic HD guidelines therapy? Both of these new studies provide similar clues. The Canadian Registry data demonstrate that female sex, despite adjustment for multiple associated variables, independently remains associated with under-utilization of guidelines therapy for ACS patients. The Swedish data demonstrate that the relatively large differences in medication between women and men before coronary angiography vanished following demonstration of obstructive CAD at angiography. These findings, which are consistent with prior literature, argue against cultural, “gender-based” factors, including misogyny and sexism, as a driving force for drug under-utilization in women, and suggest alternatively that biological, “sex-based” differences are key contributors. We can conclude from these studies and the prior literature that the presence or absence of obstructive CAD (eg, “male-pattern” ischemic HD) remains a key decision point in medication prescription for practicing physicians. Because higher proportions of women with ischemic HD present without obstructive CAD or undergo less coronary angiography, relatively fewer women will be treated, including those with evident ACS (for which guideline medication is not linked to angiography).

Toward improved outcomes

We have estimated the prevalence of signs and symptoms of ischemic HD in the absence of obstructive CAD using the NCDR database to be between 2 and 3 million women, placing it as a larger health care threat to women than breast cancer, and comparable to the highly prevalent 6 million women with clinically documented obstructive CAD in the US alone. Accordingly, two guidelines now specify strategies for women, including the AHA/ACC Prevention of Cardiovascular Disease in Women, and the AHA/ACC Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. Moreover, ischemic HD strategies that provide guideline-driven infrastructure support to physicians such as the AHA Get with the Guidelines and the ACC Guidelines Applied in Practice initiatives appear to have the largest impact on closing therapeutic gender-gaps that disadvantage women.

While increasing knowledge exists regarding pathophysiological mechanistic pathways for “female-pattern” ischemic HD, translational studies aimed at developing practical diagnosis and therapeutics with both traditional and novel treatments are needed. Further closure of knowledge gaps related to the paradox and the pathophysiology of ischemic HD in women is one of our highest priorities to improve the health of the 51% of the population that is female and who currently represent the majority of deaths.

C. Noel Bairey Merz, MD, is director of the Women’s Heart Center at Cedars Sinai Medical Center in Los Angeles and a member of the Cardiology Today Editorial Board.

For more information:

  • Bairey Merz CN, Kelsey SF, Pepine CJ, et al. The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. J Am Coll Cardiol. May 1999;33(6):1453-1461.
  • Bairey Merz CN, Shaw LJ, Reis SE, et al. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol. Feb 7 2006;47(3 Suppl):S21-29.
  • Berger JS, Bairey-Merz CN, Redberg RF, Douglas PS. Improving the quality of care for women with cardiovascular disease: report of a DCRI Think Tank, March 8 to 9, 2007. Am Heart J. Nov 2008;156(5):816-825, 825 e811.
  • Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries: a changing philosophy. JAMA. Jan 26 2005;293(4):477-484.
  • Bugiardini R, Yan A, Yan R, et al. Factors Influencing Underutilisation of Evidence Based Therapies in Women. European Heart Journal. in press.
  • Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med. May 11 2009;169(9):843-850.
  • Healy B. The Yentl syndrome. N Engl J Med. Jul 25 1991;325(4):274-276.
  • Johnston N, Schenck-Gustafsson K, Lagerqvist B. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? European Heart Journal. in press.
  • Kushner FG, Hand M, Smith SC, Jr., et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Dec 1 2009;54(23):2205-2241.
  • LaBresh KAeA. Get With The Guidelines Improves Cardiovascular Care in Hospitalized Patients with CAD. Circulation. 2003;107:IV-722 (abstract).
  • Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. Mar 20 2007;115(11):1481-1501.
  • Novack V, Cutlip DE, Jotkowitz A, Lieberman N, Porath A. Reduction in sex-based mortality difference with implementation of new cardiology guidelines. Am J Med. Jul 2008;121(7):597-603 e591.
  • Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. Jun 22 2010;55(25):2825-2832.
  • Reis SE, Holubkov R, Lee JS, et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. May 1999;33(6):1469-1475.
  • Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. Feb 6 2007;115(5):e69-171.
  • Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. Feb 7 2006;47(3 Suppl):S4-S20.
  • Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. Oct 20 2009;54(17):1561-1575.
  • Wessel TR, Arant CB, McGorray SP, et al. Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women’s Ischemia Syndrome Evaluation (WISE). Clin Cardiol. Feb 2007;30(2):69-74.

Disclosure: Dr. Bairey Merz reports no relevant financial disclosures.

C. Noel Bairey Merz, MD
C. Noel Bairey Merz

More women than men die annually of ischemic heart disease, which represents a reversal of fortune from prior decades and places women firmly as the new majority now affected. The adverse ischemic heart disease (HD) gender gap is the widest in relatively young women, where MI mortality is twofold higher in women younger than 50 years compared with age-matched men. Although it is clear that there are many gender differences in ischemic HD outcomes, including more frequent angina diagnosis, more office visits, more avoidable hospitalizations, higher MI mortality, and higher rates of HF in women compared with men, the contributing etiologies to these differences are unclear.

Gender differences highlighted

A number of contradictory findings are evident with regard to sex differences in ischemic HD: Women have a higher prevalence of angina compared with men, yet have an overall lower prevalence of obstructive CAD; symptomatic women undergoing coronary angiography have less extensive and severe obstructive CAD, despite being older with higher risk factor burden compared with men; and despite relatively less obstructive CAD, women have a more adverse prognosis compared with men. We have hypothesized an alternative, female-specific pattern of ischemic HD due to the relatively high frequency of microvascular coronary dysfunction in symptomatic women with and without obstructive CAD, which we have linked with symptoms, ischemia and adverse outcomes. This alternative “female-pattern” of ischemic HD is not easily recognized, given our male-pattern strategies aimed at detection and treatment of obstructive CAD.

What relevance does this have to the adverse gender gaps for ischemic HD in women? The literature suggests that when women look like men (with “male-pattern” obstructive CAD), they are more likely to be diagnosed and treated as men are treated. As characterized by the “Yentl” syndrome, depicted in the Barbra Streisand movie of the same name, Bernadine Healy, MD, used this term in 2001 to call attention to the paradox of adverse outcomes of women with ischemic HD, as well as the under-diagnosis and under-treatment of women.

Ten years later, recent analyses published in the European Heart Journal suggest that Yentl syndrome remains evident in 2011. Johnson and colleagues compared diagnostic coronary angiography, medication usage, and outcomes in 12,200 women and men with stable signs and symptoms of ischemic HD and 2-year outcomes in Sweden between 2006 and 2008. Bugiardini and colleagues summarized medication usage and outcomes in 6,558 women and men with ACS with 1-year outcomes from the Canadian ACS Registry I and II between 1999 and 2003. Both studies demonstrate under-treatment of women with medication, including lower rates of aspirin and ACE inhibitor use in stable women compared with men, as well lower rates of ACE inhibitor, beta-blocker and statin medication in ACS women compared with men. Both studies also show gender differences in use of procedures, where interestingly, stable women undergo more repeat angiography, whereas ACS women undergo fewer index angiograms, percutaneous coronary interventions and CABG compared with their male counterparts. The adverse outcomes described in these new works are consistent with prior literature. Both studies demonstrate adverse gender differences for women; Stable women have more MIs while ACS women have higher death rates compared with men.

Women remain undertreated

The Swedish data report equivalent use of the four life-saving medication strategies (ACE inhibitors, beta-blockers, aspirin and statins) among stable women and men after angiographic diagnosis of obstructive CAD. Importantly, appropriate medication utilization was accompanied by equivalent mortality between the sexes, although event rates were predictably lower in this stable lower-risk population. Prior work has shown an improvement of ischemic HD prognosis in women over time. Nevertheless, other contemporary data demonstrate persistently more adverse outcomes for women compared with men. The Canadian Registry analysis adds to the accumulated literature that women with ACS remain less likely than men to receive indicated diagnostic tests, guideline-indicated medication and procedures and subsequently suffer predictable higher rates of adverse outcomes.

Given the emphasis on guidelines therapy, why are women still undertreated with appropriate ischemic HD guidelines therapy? Both of these new studies provide similar clues. The Canadian Registry data demonstrate that female sex, despite adjustment for multiple associated variables, independently remains associated with under-utilization of guidelines therapy for ACS patients. The Swedish data demonstrate that the relatively large differences in medication between women and men before coronary angiography vanished following demonstration of obstructive CAD at angiography. These findings, which are consistent with prior literature, argue against cultural, “gender-based” factors, including misogyny and sexism, as a driving force for drug under-utilization in women, and suggest alternatively that biological, “sex-based” differences are key contributors. We can conclude from these studies and the prior literature that the presence or absence of obstructive CAD (eg, “male-pattern” ischemic HD) remains a key decision point in medication prescription for practicing physicians. Because higher proportions of women with ischemic HD present without obstructive CAD or undergo less coronary angiography, relatively fewer women will be treated, including those with evident ACS (for which guideline medication is not linked to angiography).

Toward improved outcomes

We have estimated the prevalence of signs and symptoms of ischemic HD in the absence of obstructive CAD using the NCDR database to be between 2 and 3 million women, placing it as a larger health care threat to women than breast cancer, and comparable to the highly prevalent 6 million women with clinically documented obstructive CAD in the US alone. Accordingly, two guidelines now specify strategies for women, including the AHA/ACC Prevention of Cardiovascular Disease in Women, and the AHA/ACC Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. Moreover, ischemic HD strategies that provide guideline-driven infrastructure support to physicians such as the AHA Get with the Guidelines and the ACC Guidelines Applied in Practice initiatives appear to have the largest impact on closing therapeutic gender-gaps that disadvantage women.

While increasing knowledge exists regarding pathophysiological mechanistic pathways for “female-pattern” ischemic HD, translational studies aimed at developing practical diagnosis and therapeutics with both traditional and novel treatments are needed. Further closure of knowledge gaps related to the paradox and the pathophysiology of ischemic HD in women is one of our highest priorities to improve the health of the 51% of the population that is female and who currently represent the majority of deaths.

C. Noel Bairey Merz, MD, is director of the Women’s Heart Center at Cedars Sinai Medical Center in Los Angeles and a member of the Cardiology Today Editorial Board.

For more information:

  • Bairey Merz CN, Kelsey SF, Pepine CJ, et al. The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. J Am Coll Cardiol. May 1999;33(6):1453-1461.
  • Bairey Merz CN, Shaw LJ, Reis SE, et al. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol. Feb 7 2006;47(3 Suppl):S21-29.
  • Berger JS, Bairey-Merz CN, Redberg RF, Douglas PS. Improving the quality of care for women with cardiovascular disease: report of a DCRI Think Tank, March 8 to 9, 2007. Am Heart J. Nov 2008;156(5):816-825, 825 e811.
  • Bugiardini R, Bairey Merz CN. Angina with “normal” coronary arteries: a changing philosophy. JAMA. Jan 26 2005;293(4):477-484.
  • Bugiardini R, Yan A, Yan R, et al. Factors Influencing Underutilisation of Evidence Based Therapies in Women. European Heart Journal. in press.
  • Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women’s Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med. May 11 2009;169(9):843-850.
  • Healy B. The Yentl syndrome. N Engl J Med. Jul 25 1991;325(4):274-276.
  • Johnston N, Schenck-Gustafsson K, Lagerqvist B. Are we using cardiovascular medications and coronary angiography appropriately in men and women with chest pain? European Heart Journal. in press.
  • Kushner FG, Hand M, Smith SC, Jr., et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Dec 1 2009;54(23):2205-2241.
  • LaBresh KAeA. Get With The Guidelines Improves Cardiovascular Care in Hospitalized Patients with CAD. Circulation. 2003;107:IV-722 (abstract).
  • Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. Mar 20 2007;115(11):1481-1501.
  • Novack V, Cutlip DE, Jotkowitz A, Lieberman N, Porath A. Reduction in sex-based mortality difference with implementation of new cardiology guidelines. Am J Med. Jul 2008;121(7):597-603 e591.
  • Pepine CJ, Anderson RD, Sharaf BL, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. Jun 22 2010;55(25):2825-2832.
  • Reis SE, Holubkov R, Lee JS, et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. May 1999;33(6):1469-1475.
  • Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. Feb 6 2007;115(5):e69-171.
  • Shaw LJ, Bairey Merz CN, Pepine CJ, et al. Insights from the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies. J Am Coll Cardiol. Feb 7 2006;47(3 Suppl):S4-S20.
  • Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. Oct 20 2009;54(17):1561-1575.
  • Wessel TR, Arant CB, McGorray SP, et al. Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women’s Ischemia Syndrome Evaluation (WISE). Clin Cardiol. Feb 2007;30(2):69-74.

Disclosure: Dr. Bairey Merz reports no relevant financial disclosures.