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From the Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Address correspondence and reprint requests to Amanda A. Fox, MD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. Address e-mail to afox{at}partners.org.
Cardiovascular disease is the leading killer of women in the developed world.1 In the United States alone, approximately 220,000 women die annually from causes related to ischemic heart disease (IHD), whereas another 7.3 million women live chronically with this condition.2 Many of these women are likely to undergo cardiac or noncardiac surgeries that may alter systemic inflammatory and coagulation cascades, algesic pathways, and cardiovascular responses in ways that increase cardiovascular risk. Fortunately, as described in this issue’s thorough review by Matyal, there is an exciting and evolving body of research that is identifying gender-related differences in the manifestation and physiology of cardiovascular disease, particularly IHD.3 It is now the responsibility of anesthesiologists and other perioperative physicians to become increasingly aware of the research that is defining the pathophysiology of IHD in women and to use this awareness both to implement changes in current perioperative management practices and to motivate researchers along investigative tracks that can capitalize upon gender differences to identify new medical interventions that may benefit future perioperative management.
Based on presently available data, one way by which anesthesiologists are likely to have a significant impact on perioperative cardiovascular risk reduction is through better preoperative identification of women with probable IHD. Despite the fact that IHD is a leading health problem in women, many women perceive cancer and not IHD as their major health concern.1 Furthermore, women’s symptoms during myocardial ischemia or infarction (MI) often differ substantially from those observed in men.4 These factors may account at least in part for the fact that, despite having a IHD prevalence similar to men, women are generally less likely than men to undergo diagnostic and therapeutic procedures related to IHD.1 The combination of these variables suggests that a significant number of women presenting for preoperative assessments may have undiagnosed IHD that warrants further work-up, medical management, and possible coronary revascularization before they undergo their scheduled surgeries.
The fact that women often describe different symptoms with myocardial ischemia or MI when compared with men also has important implications for early identification of women who experience postoperative MI. In a retrospective survey of more than 500 ambulatory women who experienced an acute MI, 43% of women described no chest pain at all, whereas their most commonly reported symptom was shortness of breath.4 Therefore, it seems reasonable that myocardial ischemia or MI should be high on the differential when perioperative physicians evaluate women having increased shortness of breath pre- or postoperatively.
The American Heart Association (AHA)/American College of Cardiology’s (ACC) 2004 Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women provide anesthesiologists with a valuable resource for identifying women at high, intermediate, and low risk for IHD and for implementing medical therapies for related cardiovascular risk reduction.5 Anesthesiologists should adopt perioperative responsibility for adherence to these Guidelines, particularly with regards to recommendations for initiating indicated β-blockers, statins, and angiotensin-converting enzyme inhibitors. In studies assessing men and women together, it appears that perioperative β-blockade and statin therapy are significantly associated with reduced postoperative cardiovascular morbidity.6,7 Although these perioperative benefits have not been assessed specifically in women, we would expect that the cardiovascular risk reduction associated with recommended β-blocker or statin therapies in ambulatory women should translate to women undergoing surgery. This logic is indirectly corroborated by the AHA/ACC 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Non-Cardiac Surgery which state that patients should be continued on perioperative β-blockers if they are taking β-blockers for an AHA/ACC Class I indication and should be on perioperative statins if they already require statin therapy for a preoperative indication6; both of these drug classes have specific indications in ambulatory female patients as per the 2004 Guidelines for Cardiovascular Disease Prevention in Women.5 Future research specifically investigating the effects of such medications in female surgical patients should add to currently available management guidelines. For example, it would be important to assess the incidence of bradycardia and hypotension in women receiving perioperative β-blockade, particularly since women have a higher incidence of left ventricular hypertrophy and diastolic dysfunction than men.8
Gender differences in incidence of cardiovascular morbidity and mortality after surgery has perhaps been most extensively explored in IHD patients undergoing coronary artery bypass graft (CABG) surgery. Women tend to develop IHD 10 years later than their male counterparts and generally have more associated comorbidities including congestive heart failure, unstable angina, diabetes, and hypertension.9 When shorter and longer-term mortality are assessed without statistical adjustment for comorbidities, women appear to have worse outcomes than men.9,10 After adjusting for comorbidities, there is continuing debate whether women have inferior shorter and longer-term outcomes after CABG.11–14 The AHA/ACC 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Non-Cardiac Surgery do not give gender-specific perioperative management recommendations.6 Rather these Guidelines reiterate the point that older age and increased comorbidities explain much of womens’ increased morbidity and mortality after MI. However, these Guidelines also go on to say that, "Whether or not factors such as coronary artery size or different pathophysiology also contribute to increased risk in women is not yet fully understood.6" This statement begs the question of whether there is enough preliminary data regarding physiologic differences in IHD in women to warrant substantial research focus on how such physiologic differences can be leveraged to offset the increased morbidity that women with IHD experience after MI and surgery. Such research could certainly have a significant impact on future versions of these AHA/ACC Perioperative Guidelines.
There is some promising research regarding how changing intraoperative approaches and interventions may differentially affect IHD-related surgical outcomes. Large retrospective studies comparing outcomes in women undergoing CABG surgery with and without use of cardiopulmonary bypass revealed that the incidence of adverse cardiovascular events was significantly lower in women undergoing off-pump revascularization.15–17 Although these results should be interpreted with a recognition of the potential biases of retrospective study design and with the understanding that results of off-pump surgeries tend to be significantly better at institutions that perform them frequently,18 these findings warrant further consideration and are encouraging for exploring off-pump and other surgical techniques that could also improve perioperative outcomes in women with IHD.
The importance of research efforts that specifically look for gender differences in effects of perioperative medical therapies is illustrated by the results of prospective, multicenter, randomized, controlled trials conducted in high-risk cardiac surgical patients to assess the association between preoperative complement inhibition with soluble complement receptor 1 and the outcomes of complement activation, short-term postoperative MI and death. In this study, complement activation was significantly suppressed in both men and women, whereas the incidence of MI and mortality was significantly reduced only in men.19,20 These results suggest that the complement may have a greater role in postoperative MI after high-risk cardiac surgery in men than in women, but these findings also bring into question what physiology might drive this gender effect.
Finally, findings from the Women’s Ischemia Syndrome Evaluation study regarding somewhat unique relationships between myocardial ischemia and vascular smooth muscle and endothelial dysfunction have possibly the most intriguing implications for future advancements in perioperative cardiovascular risk reduction in women.21 Although many women who develop myocardial ischemia or MI have significant obstructive coronary artery disease (CAD), at least a subset of women without angiographically significant obstructive CAD experience decreased myocardial perfusion and adverse cardiovascular events.22 In one study, women hospitalized for chest pain who did not have angiographically significant CAD were evaluated after exercise with phosphorous-31 nuclear magnetic resonance spectroscopy, and a fifth of these women were found to experience myocardial ischemia.23 Another study of women undergoing angiography to exclude CAD found that less coronary vasodilation in response to administration of intracoronary acetylcholine predicted long-term adverse cardiovascular events independently from severity of CAD and other covariates such as age, smoking, and diabetes.24 What still needs to be determined is how vascular endothelial dysfunction relates to progression of atherosclerosis, how best to identify patients with significant endothelial dysfunction, and what treatments effectively reverse endovascular dysfunction and improve cardiovascular outcomes.
Although sex hormones and associated receptors may have important roles in mitigating coronary micro- and macrovascular endothelial and smooth muscle dysfunction and in improving availability of endothelial progenitor cells important for vascular endothelial repair,21,25,26 the excess of coronary events as well as increased incidence of invasive breast cancer observed in studies of ambulatory postmenopausal women on hormone replacement therapy warrants a deeper understanding and identification of the specific biologic pathways by which sex hormones could provide cardiovascular benefit.25 Rather than simply administering exogenous sex steroids, therapies may be developed for ambulatory and perioperative use that capitalize on specific hormonally mediated biologic pathways to provide beneficial cardiovascular effects without accompanying adverse thrombotic or carcinogenic effects. Endothelial nitric oxide synthesis21,26 or mediation of L-type voltage-gated calcium-activated potassium channel function21 are just two possible biologic targets for future research.
In conclusion, presently available data provide anesthesiologists, surgeons, and critical care physicians with improved ability to identify women surgical candidates who have IHD, thereby allowing more targeted monitoring and initiation of medical therapies to reduce cardiovascular morbidity. Currently available data also create a stepping stone from which researchers within our field and related specialties should build to translate gender differences in the physiology of IHD into new operative techniques and pharmacologic therapies that can reduce adverse cardiovascular events in women undergoing surgery. The 2004 AHA/ACC Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women5 were developed to provide an evidence-based approach to overall cardiovascular risk reduction in women. Now it is important to generate further hypotheses and studies that can bring this evidence-based approach more prominently into perioperative practice.
Footnotes
Accepted for publication February 13, 2008.
REFERENCES
This article has been cited by other articles:
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  K. Gelb and A. W. Gelb Sex and Gender in the Perioperative Period: Wake Up to Reality Anesth. Analg., July 1, 2008; 107(1): 1 - 3. [Full Text] [PDF]
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