Women and Coronary Heart Disease: A Century After Herrick
2012; Lippincott Williams & Wilkins; Volume: 126; Issue: 5 Linguagem: Inglês
10.1161/circulationaha.111.086892
ISSN1524-4539
Autores Tópico(s)Cardiovascular Issues in Pregnancy
ResumoHomeCirculationVol. 126, No. 5Women and Coronary Heart Disease: A Century After Herrick Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBWomen and Coronary Heart Disease: A Century After HerrickUnderstudied, Underdiagnosed, and Undertreated Nanette K. Wenger, MD, MACC, MACP, FAHA Nanette K. WengerNanette K. Wenger From the Emory University School of Medicine, Emory Heart and Vascular Center, Atlanta, GA. Originally published31 Jul 2012https://doi.org/10.1161/CIRCULATIONAHA.111.086892Circulation. 2012;126:604–611Among the accolades most valued by a clinical cardiologist is to be selected to deliver the annual James B. Herrick Lecture. This lecture honors the legacy of James Herrick as an icon for the cardiac clinician/scientist. I am enormously grateful to the Council on Clinical Cardiology for this singular recognition.My choice to address "Women and Coronary Heart Disease: A Century after Herrick" will show that this problem remains understudied, underdiagnosed, and undertreated.James HerrickFirst, to James Herrick and his landmark contributions. As we know, in the 1900s, myocardial infarction was considered a uniformly fatal event, and its etiology was largely unknown. Herrick's scholarly 1912 presentation to the Association of American Physicians, subsequently published in the Journal of the American Medical Association, highlighted that survival could occur after myocardial infarction, albeit often for only a few days. Buttressed by meticulous autopsy data, he documented coronary artery thrombosis as the mechanism for myocardial infarction.1 Although dismayed by lack of response from colleagues to this carefully detailed scenario, Herrick continued to study and to publish, advocating treatment with digitalis to enhance myocardial contractility and maintain blood pressure, rather than use of nitroglycerin, which did not perform satisfactorily. Always a mentor, he encouraged Dr Fred Smith to explore the diagnostic potential of the newly available precordial ECG for recognition of myocardial infarction in a living patient,2 and the rest is history. Herrick's precise case presentations (incidentally all of male patients) and autopsy confirmation established thrombogenesis as pivotal in myocardial infarction and paved the way for antithrombotic therapy, coronary thrombolysis, and percutaneous coronary interventions later in the 20th century.Teaching and Applying KnowledgeIn his 1926 article, "The Clinician of the Future," in the Journal of the American Medical Association, Herrick cited the usefulness of physicians to society as a whole as the physicians' reason for existence. He advocated improved training of both general practitioners and specialists and cited need for their mutually helpful relationships. Herrick emphasized that there was no substitute for physical examination and careful documentation of a patient's medical history, reiterating that clinical medicine should be presented to medical students by a clinician, a practicing doctor. He deplored the overestimation of the value of the instrumental and laboratory components of medicine, indicating that laboratory tests should only be incorporated into the history, symptoms, physical examination, and other scientific data for each patient.3 Exquisitely relevant today is Herrick's emphasis on the medical history and physical examination; he urged caution in the reliance on the technology of the day, for him the chest x-ray and the ECG. He challenged dependence on laboratory data, identifying its foibles and urging its use as supplementary.The following quote, cited by a number of previous Herrick lecturers, is noteworthy. It should serve as a guidepost for the contemporary clinician/scientist: "The true physician must possess a dual personality, the scientific toward disease, the human and humane toward the patient."Now, a century after Herrick's publication, what of women and coronary heart disease (CHD)? Remember that Herrick's prototype patient was a man past the middle period of life.A wonderful cartoon from the early 1990s is a fitting introduction to this presentation. The physician, seated across the consultation desk from his female patient, says, "We have studies of fruit flies, mice, hamsters, frogs, monkeys, and men with this condition – but medical research using women as subjects just never occurred to anybody." Fortunately, the ensuing years have witnessed salutary changes in the research landscape. This article reviews the status of CHD in women at the end of 2011; some milestones, stepping stones, and obstructing boulders on the learning journey; the landmark 2010 Institute of Medicine (IOM) Report on Women's Health Research; what to do when disease discriminates; the question of whether the woman's heart beats to the tune of a different drummer; awareness/perceptions among women and physicians of women's CHD risk; and finally our challenges and opportunities.Status of CHD in Women 2011Recent decades have witnessed emerging interest in and consequent research studies of CHD in women, with striking salutary results. Once viewed as a man's disease, CHD remains the leading cause of mortality for women worldwide, in both industrialized nations and developing economies.4 However, changes in US data show major promise.The striking improvement in cardiovascular disease (CVD) survival documented between 2000 and 2007,5 with a more prominent decline in cardiovascular mortality for women than men (Figure), was equally attributable to the application of evidence-based therapies of established CVD and to preventive interventions for coronary risk factors. These advances were based on research data and advocacy/awareness initiatives, many generated by the cardiac clinician/scientists in attendance this evening. Nonetheless, since 1984, more cardiovascular deaths continue to occur annually among women than men; coronary deaths in women exceed deaths in women from all forms of cancer combined.Download figureDownload PowerPointFigure. Cardiovascular disease mortality trends for males and females (United States: 1979–2007). The overall comparability for cardiovascular disease between the International Classification of Diseases, 9th Revision (1979–1998) is 0.9962. No comparability ratios were applied. Source: National Center for Health Statistics, Heart Disease and Stroke Statistics–2011 Update.5.Based on research studies responding to this challenge, emerging data have highlighted important sex differences in the pathophysiology and clinical presentation of CHD in women and sex disparities in preventive interventions and diagnostic strategies, in management of acute coronary syndromes, and in the response to therapies, with consequent adverse outcomes of CHD in women.6 Underuse of guideline-based preventive and therapeutic strategies for women substantially contributes to their less favorable CHD outcomes, but the spectrum of sex-based differences likely reflects both biology and bias.Milestones, Stepping Stones, and Obstructing BouldersIn a review of CHD in women some years ago, I described the journey to explore the state of the science as characterized by "milestones, stepping stones, and obstructing boulders."7 Let me enumerate, update, and expand on several of these by using the same construct (Table 1).8–21 Among the milestones were the 1992 National Heart, Lung, and Blood Institute (NHLBI) Conference on Cardiovascular Health and Disease in Women; the 2001 IOM Report Exploring the Biological Contributions to Human Health: Does Sex Matter; the Heart and Estrogen/Progestin Replacement Study (HERS); the Women's Health Initiative (WHI); the Agency for Healthcare Research and Quality Report on Diagnosis and Treatment of Coronary Heart Disease in Women; the Women's Health Study; and the NHLBI Women's Ischemia Syndrome Evaluation (WISE) Study.Table 1. Women and Coronary Heart Disease Milestones and Stepping Stones1992NHLBI Conference: CV Health and Disease in Women8*New information → clinical applicationKnowledge gaps1998HERS9*Menopausal hormone therapy ↛ secondary prevention2001/2004WHI10,11*Menopausal hormone therapy ↛ primary prevention2001IOM Report12*Evaluate sex differences in human disease, medical research2003AHRQ: CHD in Women13,14*Dx, Rx, CHD in women extrapolated from studies in middle-aged menKnowledge gaps2005WHS15*Aspirin prevents stroke, not MI, in women <65 years of age2005AHA: Noninvasive Testing in Women16†Characteristics informing test choice2005CRUSADE: Women with NSTE-ACS17†ACS prognosis worse in women↓ Coronary intervention, guideline-based Rx in women2006NHLBI WISE18*Importance of microvascular disease in women2007/2008WACS/WAFACS cited in21†Vitamin E, C, beta carotene ↛ CVD prevention in womenFolic acid, vitamin B supplements ↛ CVD prevention in women2008Get with the Guidelines CAD Database19†↑ STEMI mortality initial 24 h in women↓ Timely reperfusion, guideline-based Rx2010IOM Report: Women's Health Research20*Progress in↓CV mortality↑ Attention needed to QOL issuesDisparities in subgroups of womenNeed sex-stratified research analysesTranslate research → clinical practice, public policy2011AHA Women's CVD Prevention Guidelines21†Pregnancy complications →↑ CV riskSystemic autoimmune disease →↑CVD risk2012→See future directionsTable 2NHLBI indicates National Heart, Lung, and Blood Institute; HERS, Heart and Estrogen/Progestin Replacement Study; WHI, Women's Health Initiative; IOM, Institute of Medicine; AHRQ, Agency for Healthcare Research and Quality; WISE, Women's Ischemia Syndrome Evaluation; WHS, Women's Health Study; AHA, American Heart Association; 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; WACS, Women's Antioxidant Cardiovascular Study; WAFACS, Women's Antioxidant and Folic Acid Cardiovascular Study; CV, cardiovascular; CVD, cardiovascular disease; CHD, coronary heart disease; NSTE-ACS, non–ST-elevation acute coronary syndrome; STEMI, ST-elevation myocardial infarction; MI, myocardial infarction; Dx, diagnosis; Rx, treatment; QOL, quality of life; ↑, indicates increased; ↓, decreased; and ↛, do not provide.*Milestone.†Stepping stone.It was my privilege to chair the initial milestone, the 1992 NHLBI Conference on cardiovascular health and disease in women.8 It derived from a 1986 NHLBI Workshop that first focused attention on this topic, presenting its challenges to the scientific community. The goals of the conference were to highlight new information appropriate for clinical application and to identify knowledge gaps that impeded optimal cardiovascular care for women.The next milestone was the 2001 IOM report, "Exploring the Biological Contributions to Human Health. Does Sex Matter?"12 that advocated for sex/gender explorations in all aspects of human health from basic science to clinical applications. This landmark report persuasively argued for evaluation of sex-based differences in human disease and in medical research, with translation of these differences into clinical practice.12Shortly thereafter, the results of 2 randomized clinical trials transformed clinical care for women: the HERS9 and the WHI hormone trials,10,11 which documented that menopausal hormone therapy did not prevent incident or recurrent CVD in women and increased their risk of stroke. HERS and WHI displaced menopausal hormone therapy as the ubiquitous solution to women's cardiovascular problems, refocusing attention on established cardiovascular preventive therapies.In 2003, the Agency for Healthcare Research and Quality Report on the Diagnosis and Treatment of CHD in women, a systematic review of relevant research, concluded that most contemporary recommendations for prevention, diagnostic testing, and medical and surgical treatments of CHD in women were extrapolated from studies conducted predominantly in middle-aged men, with resultant fundamental knowledge gaps regarding the biology, clinical manifestations, and optimal management strategies for women.13,14The Women's Health Study15 documented lack of aspirin benefit in preventing myocardial infarction (MI) in women 2 million people uniformly showed a 25% increased coronary risk among women smokers than men smokers.29 The disproportionately increased coronary risk for diabetic women versus diabetic men is well known. However, the proportion of women enrolled in prevention clinical trials inadequately reflects their representation in the US population, raising the potential for bias.Women constituted only 30% of all patients in the clinical trials used to support the 2007 AHA guidelines for the prevention of CVD in women. Representation of women was higher in primary prevention trials and in international (versus United States only) trials. During a comparable time period, the proportion of women enrolled in European randomized controlled trials of coronary prevention varied from 16% to 25%, despite a female prevalence of CHD similar to that of males in the general population.30 Although women account for 46% of the US population with CHD, they constituted 25% of participants in CHD prevention trials; sex-specific data were cited in only 31% of primary trial publications.31In numerous clinical settings, women with CHD have more unfavorable outcomes than men. Angina is the major initial and subsequent presentation of CHD among women. In comparison with their male counterparts, women with angina have a doubled morbidity and mortality. Anginal equivalents, the nonchest pain symptoms encountered in both sexes but predominating in women, remain underrecognized and understudied. Women with CHD, and, in particular, women <50 years of age, have a doubled mortality after MI,32 although in recent years younger women have had larger improvements in hospital mortality after MI than did younger men, narrowing the sex gap.33 The absolute reduction was 3 times greater in women than in men <55 years of age, suggesting a decrease in treatment-related sex bias.Despite their greater symptom burden of angina and its consequent morbidity and mortality, and despite their older age and higher risk factor burden, women paradoxically have less severe obstructive coronary disease at elective angiography than do men,34 a biological difference. Yet the male model of coronary disease, ie, obstructive atherosclerosis of the epicardial coronary arteries, constitutes the basis for most diagnostic and therapeutic strategies for both sexes.Women with stable ischemic heart disease have more MIs than men do.35,36 In a Swedish cohort (2006–2008), women with stable ischemic heart disease had lower rates of aspirin and ACE inhibitor use. More women with stable ischemic heart disease had repeat angiography, whereas fewer women than men had angiography in the setting of ACS and, consequently, less percutaneous coronary intervention and coronary artery bypass grafting (CABG) in comparison with their male counterparts; this is illustrative of gender bias. The absence of obstructive coronary disease appears to account for much of the therapeutic underutilization; the Swedish report36 documents equivalent ACE inhibitor, β-blocker, aspirin, and statin use in women and men with stable ischemic heart disease once there is an angiographic diagnosis of obstructive coronary disease.Myocardial ischemia with adverse outcomes, in the absence of obstructive coronary disease, is an emerging paradigm for women.18 Data derived from the NHLBI WISE study add microvascular disease to the spectrum of myocardial ischemia in women. Insights are needed into the underlying biological mechanism(s) and optimal recognition and therapies for microvascular disease. A recent report addressing mechanisms of MI in women without angiographically obstructive coronary artery disease37 defined occult plaque disruption with distal embolization of atherosclerotic debris or platelet aggregates and/or vasospasm as potentially etiologic. Plaque rupture and ulceration were common in women with MI in the absence of angiographically demonstrable obstructive coronary disease. Intravascular ultrasound and cardiac MRI may permit the categorization of these mechanisms in women. Women in the MERLIN-TIMI 36 trial of non–ST-elevation ACS were more likely than men to report angina, despite having less obstructive coronary artery disease. They had more ischemic periods recorded on continuous ECG.38 ECG ischemia was predictive of an unfavorable outcome.Additional research is mandatory to define the etiologic features in women with nonobstructive ischemic heart disease, which is likely present in almost half as many women with signs and symptoms of myocardial ischemia as obstructive coronary artery disease is likely to present. Guideline-based therapies of ACS must be instituted irrespective of angiographic anatomy. Comparative effectiveness research is requisite to select optimal strategies to evaluate symptoms of suspected myocardial ischemia in women, addressing both obstructive coronary disease and microvascular etiologies.Women with MI are more likely than men to have recurrent MI and to be subsequently disabled by heart failure.39 The Canadian Acute Coronary Syndrome Registry assessed the factors influencing the underutilization of evidence-based therapies in women.35 Canadian women in this 1999–2003 ACS cohort had higher death rates than men. There were lower rates of ACE inhibitor, β-blocker, and statin use among women, which correlated with older age; the consequences of the disease, particularly congestive heart failure; and physician assessment of the patient's risk as evidenced by the decision for cardiac catheterization. Despite adjustment for these biasing confounders, female sex remained associated with underutilization of ACS guideline-based therapy with lipid-modifying agents and with ACE inhibitors.Does the woman's heart beat to the tune of a different drummer? As noted, women with MI are more likely than men to incur heart failure,39 but women with heart failure far more frequently than men have intact ventricular systolic function. Effective treatments for this diastolic heart failure syndrome remain elusive, likely accounting for its unchanged prognosis, in contrast to the decrease in hospitalizations and improved survival encountered with systolic heart failure.40,41 Women with systolic heart failure and ventricular dyssynchrony preferentially benefit from cardiac resynchronization therapy,42 yet these procedures are underutilized in women.The safety and efficacy of cardiovascular devices may differ by sex. Lack of sex-specific data for high-risk cardiovascular devices before their Food and Drug Administration approval is widespread, despite a recent IOM recommendation that all medical products evaluated by the Food and Drug Administration present safety and efficacy data separately for women and men.43 Women comprised only about one-third of participants in 78 clinical trials of cardiovascular devices between 2000 and 2007, with the proportion of women enrolled unchanged over time. Women have not achieved levels of enrollment in premarket studies adequate to ensure evidence-based sex-specific recommendations. The Heart Disease Education, Analysis and Research, and Treatment for Women Act (HEART for Women Act), currently introduced in Congress, would mandate sex-specific data reporting, ending these disparities.Women have a doubled operative mortality after CABG surgery, particularly women 6 million US women with known CHD, a disproportionate number of women do not highlight CHD as their major health concern. Although serial surveys have documented increased awareness of CHD as a health threat among women, from 30% to 54%, a substantial proportion of all women surveyed remain unaware of their CVD risk. Lack of awareness is most persistent among the highest-risk populations, women of racial and ethnic minorities.Furthermore, physicians and other healthcare providers continue to underestimate women's cardiovascular risk, with consequent underutilization of preventive therapies.52,53 A 2004 AHA study of physician awareness and adherence to
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