Review Article
Ischemic Heart Disease in Women
Abstract
Cardiovascular disease is the leading cause of death in women. Although overall mortality from coronary heart disease (CHD) has decreased, there are subsets of patients, particularly young women, in whom the mortality rate has increased. Underlying sex differences in CHD may be an explanation. Women have more frequent symptoms, more ischemia, and higher mortality than men, but less obstructive coronary artery disease (CAD). Despite this, traditional risk factor assessment has been ineffective in risk stratifying women, prompting the emergence of novel markers and prediction scores to identify a population at risk. Sex differences in manifestations and the pathophysiology of CHD also have led to differences in the selection of diagnostic testing and treatment options for women, having profound effects on outcomes. The frequent finding of nonobstructive CAD in women with ischemia suggests microvascular dysfunction as an underlying cause; therefore, coronary reactivity and endothelial function testing may add to diagnostic accuracy in female patients. In spite of evidence that women benefit from the same therapies as men, they continue to receive less-aggressive therapy, which is reflected in higher healthcare resource utilization and adverse outcomes. More sex-specific research is needed in the area of symptomatic nonobstructive CAD to define the optimal therapeutic approach.This content is limited to qualifying members.
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References
1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012; 125: e2–e220.
2. Mosca L, Mochari-Greenberger H, Dolor RJ, et al. Twelve-year follow-up of American women’s awareness of cardiovascular disease risk and barriers to heart health. Cardiovascular quality and outcomes. Circ Cardiovasc Qual Outcomes. 2010; 3: 120–127.
3. Mosca L, Linfante AH, Benjamin EJ, et al. National study of physician awareness and adherence to cardiovascular disease prevention guidelines. Circulation. 2005; 111: 499–510.
4. 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. 2006; 47: S21–S29.
5. 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. 2006; 47: S4–S20.
6. Shaw LJ, Shaw RE, Merz CN, et al. Impact of ethnicity and gender differences on angiographic coronary artery disease prevalence and in-hospital mortality in the American College of Cardiology-National Cardiovascular Data Registry. Circulation. 2008; 117: 1787–1801.
7. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. 2009; 54: 1561–1575.
8. Daly C, Clemens F, Lopez Sendon JL, et al. Gender differences in the management and clinical outcome of stable angina. Circulation. 2006; 113: 490–498.
9. Shaw LJ, Merz CN, Pepine CJ, et al. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health–National Heart, Lung, and Blood Institute–sponsored Women’s Ischemia Syndrome Evaluation. Circulation. 2006; 114: 894–904.
10. Gulati M, Shaw LJ, Bairey Merz CN. Myocardial ischemia in women: lessons from the NHLBI WISE study. Clin Cardiol. 2012; 35: 141–148.
11. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of overweight and obesity in the United States, 1999–2004. JAMA. 2006; 295: 1549–1555.
12. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003; 289: 76–79.
13. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002; 287: 356–359.
14. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007; 49: 403–414.
15. Kanaya AM, Grady D, Barrett-Connor E. Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med. 2002; 162: 1737–1745.
16. McTigue K, Larson JC, Valoski A, et al. Mortality and cardiac and vascular outcomes in extremely obese women. JAMA. 2006; 296: 79–86.
17. Spencer EA, Pirie KL, Stevens RJ, et al. Diabetes and modifiable risk factors for cardiovascular disease: the prospective Million Women Study. Eur J Epidemiol. 2008; 23: 793–799.
18. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106: 3143–3421.
19. Lakoski SG, Greenland P, Wong ND, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med. 2007; 167: 2437–2442.
20. Michos ED, Nasir K, Braunstein JB, et al. Framingham risk equation underestimates subclinical atherosclerosis risk in asymptomatic women. Atherosclerosis. 2006; 184: 201–206.
21. Pasternak RC, Abrams J, Greenland P, et al. 34th Bethesda Conference: task force #1—Identification of coronary heart disease risk: is there a detection gap? J Am Coll Cardiol. 2003; 41: 1863–1874.
22. Ridker PM, Buring JE, Cook NR, et al. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003; 107: 391–397.
23. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA. 2005; 294: 326–333.
24. Ridker PM, Buring JE, Rifai N, et al. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007; 297: 611–619.
25. Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med. 2008; 358: 2107–2116.
26. Bairey Merz CN, Johnson BD, Sharaf BL, et al. Hypoestrogenemia of hypothalamic origin and coronary artery disease in premenopausal women: a report from the NHLBI-sponsored WISE study. J Am Coll Cardiol. 2003; 41: 413–419.
27. Shaw LJ, Bairey Merz CN, Azziz R, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health–National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metab. 2008; 93: 1276–1284.
28. Bellamy L, Casas JP, Hingorani AD, et al. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007; 335: 974
29. Ratner RE. Prevention of type 2 diabetes in women with previous gestational diabetes. Diabetes Care. 2007; 30: S242–S245.
30. Jones LW, Haykowsky MJ, Swartz JJ, et al. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol. 2007; 50: 1435–1441.
31. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004; 291: 1701–1712.
32. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288: 321–333.
33. LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011; 305: 1305–1314.
34. Shufelt CL, Johnson BD, Berga SL, et al. Timing of hormone therapy, type of menopause, and coronary disease in women: data from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation. Menopause. 2011; 18: 943–950.
35. von Mering GO, Arant CB, Wessel TR, et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004; 109: 722–725.
36. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study. JAMA. 2002; 287: 1153–1159.
37. Burke AP, Farb A, Malcom GT, et al. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation. 1998; 97: 2110–2116.
38. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation. 2011; 124: 1414–1425.
39. Sun H, Mohri M, Shimokawa H, et al. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol. 2002; 39: 847–851.
40. Reis SE, Holubkov R, Conrad Smith AJ, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001; 141: 735–741.
41. Douglas PS, Ginsburg GS. The evaluation of chest pain in women. N Engl J Med. 1996; 334: 1311–1315.
42. Hemingway H, Langenberg C, Damant J, et al. Prevalence of angina in women versus men: a systematic review and meta-analysis of international variations across 31 countries. Circulation. 2008; 117: 1526–1536.
43. Canto JG, Goldberg RJ, Hand MM, et al. Symptom presentation of women with acute coronary syndromes: myth vs reality. Arch Intern Med. 2007; 167: 2405–2413.
44. Sharaf BL, Pepine CJ, Kerensky RA, et al. Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation [WISE] Study Angiographic Core Laboratory). Am J Cardiol. 2001; 87: 937–941.
45. 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. 2009; 169: 843–850.
46. Blomkalns AL, Chen AY, Hochman JS, et al. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative. J Am Coll Cardiol. 2005; 45: 832–837.
47. Humphries KH, Pu A, Gao M, et al. Angina with “normal” coronary arteries: sex differences in outcomes. Am Heart J. 2008; 155: 375–381.
48. Reynolds HR, Farkouh ME, Lincoff AM, et al. Impact of female sex on death and bleeding after fibrinolytic treatment of myocardial infarction in GUSTO V. Arch Intern Med. 2007; 167: 2054–2060.
49. Hemingway H, McCallum A, Shipley M, et al. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA. 2006; 295: 1404–1411.
50. Vaccarino V, Parsons L, Every NR, et al. Sex-based differences in early mortality after myocardial infarction. National Registry of Myocardial Infarction 2 Participants. N Engl J Med. 1999; 341: 217–225.
51. Kohli P, Gulati M. Exercise stress testing in women: going back to the basics. Circulation. 2010; 122: 2570–2580.
52. Kwok Y, Kim C, Grady D, et al. Meta-analysis of exercise testing to detect coronary artery disease in women. Am J Cardiol. 1999; 83: 660–666.
53. Alexander KP, Shaw LJ, Shaw LK, et al. Value of exercise treadmill testing in women. J Am Coll Cardiol. 1998; 32: 1657–1664.
54. Shaw LJ, Peterson ED, Shaw LK, et al. Use of a prognostic treadmill score in identifying diagnostic coronary disease subgroups. Circulation. 1998; 98: 1622–1630.
55. Gulati M, Black HR, Shaw LJ, et al. The prognostic value of a nomogram for exercise capacity in women. N Engl J Med. 2005; 353: 468–475.
56. Kavanagh T, Mertens DJ, Hamm LF, et al. Peak oxygen intake and cardiac mortality in women referred for cardiac rehabilitation. J Am Coll Cardiol. 2003; 42: 2139–2143.
57. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012; 60: e44–e164.
58. Mieres JH, Shaw LJ, Arai A, et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: consensus statement from the Cardiac Imaging Committee, Council on Clinical Cardiology, and the Cardiovascular Imaging and Intervention Committee, Council on Cardiovascular Radiology and Intervention, American Heart Association. Circulation. 2005; 111: 682–696.
59. Marwick TH, Shaw LJ, Lauer MS, et al. The noninvasive prediction of cardiac mortality in men and women with known or suspected coronary artery disease. Economics of Noninvasive Diagnosis (END) Study Group. Am J Med. 1999; 106: 172–178.
60. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiology. 2004; 11: 171–185.
61. Pianou N, Georgakopoulos A, Anagnostopoulos CD. Positron emission tomography for risk assessment of women investigated for coronary artery disease. Cardiology. 2011; 118: 164–167.
62. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med. 2002; 346: 1948–1953.
63. Vermeltfoort IA, Bondarenko O, Raijmakers PG, et al. Is subendocardial ischaemia present in patients with chest pain and normal coronary angiograms? A cardiovascular MR study. Eur Heart J. 2007; 28: 1554–1558.
64. Johnson BD, Shaw LJ, Buchthal SD, et al. Prognosis in women with myocardial ischemia in the absence of obstructive coronary disease: results from the National Institutes of Health-National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004; 109: 2993–2999.
65. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005; 111: 363–368.
66. Roman MJ, Naqvi TZ, Gardin JM, et al. American society of echocardiography report. Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology. Vasc Med. 2006; 11: 201–211.
67. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000; 101: 1899–1906.
68. Bonetti PO, Barsness GW, Keelan PC, et al. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J Am Coll Cardiol. 2003; 41: 1761–1768.
69. Modena MG, Bonetti L, Coppi F, et al. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002; 40: 505–510.
70. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007; 356: 1503–1516.
71. Novack V, Cutlip DE, Jotkowitz A, et al. Reduction in sex-based mortality difference with implementation of new cardiology guidelines. Am J Med. 2008; 121: 597–60.
72. Diver DJ, Bier JD, Ferreira PE, et al. Clinical and arteriographic characterization of patients with unstable angina without critical coronary arterial narrowing (from the TIMI-IIIA Trial). Am J Cardiol. 1994; 74: 531–537.
73. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011; 123: 1243–1262.
74. Alexander KP, Chen AY, Newby LK, et al. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative. Circulation. 2006; 114: 1380–1387.
75. Jneid H, Fonarow GC, Cannon CP, et al. Sex differences in medical care and early death after acute myocardial infarction. Circulation. 2008; 118: 2803–2810.
76. Healy B. The Yentl syndrome. N Engl J Med. 1991; 325: 274–276.
77. Roeters van Lennep JE, Zwinderman AH, Roeters van Lennep HW, et al. Gender differences in diagnosis and treatment of coronary artery disease from 1981 to 1997. No evidence for the Yentl syndrome. Eur Heart J. 2000; 21: 911–918.
78. O’Donoghue M, Boden WE, Braunwald E, et al. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: a meta-analysis. JAMA. 2008; 300: 71–80.
79. Lansky AJ. Outcomes of percutaneous and surgical revascularization in women. Prog Cardiovasc Dis. 2004; 46: 305–319.
80. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006; 354: 1477–1488.
81. Cho L, Topol EJ, Balog C, et al. Clinical benefit of glycoprotein IIb/IIIa blockade with Abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials. Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation in Percutaneous Transluminal Coronary Angioplasty to Improve Long-Term Outcome with Abciximab GP IIb/IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stent. J Am Coll Cardiol. 2000; 36: 381–386.
82. Abbott JD, Vlachos HA, Selzer F, et al. Gender-based outcomes in percutaneous coronary intervention with drug-eluting stents (from the National Heart, Lung, and Blood Institute Dynamic Registry). Am J Cardiol. 2007; 99: 626–631.
83. Farouque HM, Tremmel JA, Raissi Shabari F, et al. Risk factors for the development of retroperitoneal hematoma after percutaneous coronary intervention in the era of glycoprotein IIb/IIIa inhibitors and vascular closure devices. J Am Coll Cardiol. 2005; 45: 363–368.
84. Weintraub WS, Wenger NK, Kosinski AS, et al. Percutaneous transluminal coronary angioplasty in women compared with men. J Am Coll Cardiol. 1994; 24: 81–90.
85. Al-Fiadh AH, Andrianopoulos N, Farouque O, et al. Contemporary outcomes in women undergoing percutaneous coronary intervention for acute coronary syndromes. Int J Cardiol. 2011; 151: 195–199.
86. Kim C, Redberg RF, Pavlic T, et al. A systematic review of gender differences in mortality after coronary artery bypass graft surgery and percutaneous coronary interventions. Clin PubMed | CrossRef
87. Duvernoy CS, Smith DE, Manohar P, et al. Gender differences in adverse outcomes after contemporary percutaneous coronary intervention: an analysis from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2) percutaneous coronary intervention registry. Am Heart J. 2010; 159: 677–683.
88. BARI 2D Study Group, Frye RL, August P, et al. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009; 360: 2503–2515.
89. Bangalore S, Fonarow GC, Peterson ED, et al. Age and gender differences in quality of care and outcomes for patients with ST-segment elevation myocardial infarction. Am J Med. 2012; 125: 1000–1009.
90. Jackson EA, Moscucci M, Smith DE, et al. The association of sex with outcomes among patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction in the contemporary era: insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). Am Heart J. 2011; 161: 106–112.
91. Humphries KH, Gao M, Pu A, et al. Significant improvement in short-term mortality in women undergoing coronary artery bypass surgery (1991 to 2004). J Am Coll Cardiol. 2007; 49: 1552–1558.
92. Lanza GA, Colonna G, Pasceri V, et al. Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X. Am J Cardiol. 1999; 84: 854–856.
93. Sutsch G, Oechslin E, Mayer I, et al. Effect of diltiazem on coronary flow reserve in patients with microvascular angina. Int J Cardiol. 1995; 52: 135–143.
94. Chen JW, Hsu NW, Wu TC, et al. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol. 2002; 90: 974–982.
95. Kayikcioglu M, Payzin S, Yavuzgil O, et al. Benefits of statin treatment in cardiac syndrome-X1. Eur Heart J. 2003; 24: 1999–2005.
96. Pizzi C, Manfrini O, Fontana F, et al. Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cardiac syndrome X: role of superoxide dismutase activity. Circulation. 2004; 109: 53–58.
97. Eriksson BE, Tyni-Lenne R, Svedenhag J, et al. Physical training in syndrome X: physical training counteracts deconditioning and pain in syndrome X. J Am Coll Cardiol. 2000; 36: 1619–1625.
98. Mehta PK, Goykhman P, Thomson LE, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc Imag. 2011; 4: 514–522.
