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Circulation. 2004;109:e47-e49
doi: 10.1161/01.CIR.0000116207.38349.FF
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(Circulation. 2004;109:e47-e49.)
© 2004 American Heart Association, Inc.

AHA/NHLBI Conference Proceedings

Women’s Ischemic Syndrome Evaluation

Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2–4, 2002: Section 2: Stable Ischemia: Pathophysiology and Gender Differences

Rita F. Redberg, MD, Chair; Richard O. Cannon, III, MD, Cochair; Noel Bairey Merz, MD; Amir Lerman, MD; Steven E. Reis, MD; David S. Sheps, MD, Endorsed by the American College of Cardiology Foundation


Key Words: AHA Scientific Statements • women • ischemia • cardiovascular diseases

The WISE workshop was convened to review results from the Women’s Ischemic Syndrome Evaluation (WISE) study and other studies of ischemic heart disease to examine the nature and scope of gender differences in both chronic and acute cardiac ischemia, in terms of clinical manifestations, detection, and treatment. This section addresses research needs in understanding the pathophysiology of chronic myocardial ischemic syndromes in women and mechanisms for gender differences.

Pathology and Pathophysiology

Flow-limiting stenoses within epicardial coronary arteries (obstructive coronary artery disease [CAD]) may cause myocardial ischemia, which is sensed as angina pectoris or dyspnea and is associated with characteristic electrocardiographic, perfusion, or left ventricular functional abnormalities, on conventional testing in women with CAD, as in men. The issue of contention for several decades has been whether women who do not have obstructive CAD experience myocardial ischemia by a pathophysiology different from that of the majority of men with CAD. In this regard, several large cohort studies, including the Coronary Artery Surgery Study sponsored by the National Heart, Lung and Blood Institute,1 documented that women (mean age of 54 years) presenting with chest pain are less likely to have obstructive CAD at diagnostic coronary angiography than are men. In the WISE cohort, the majority of women (mean age of 59±12 years) were not found to have obstructive CAD at catheterization.2 Some of this disparity may be explained by the Bayes theorem, where the prevalence of age-predicted obstructive CAD in women is lower than in men. Possible explanations for chest pain in this setting include (1) underestimation of the extent and severity of obstructive CAD by visual assessment of coronary angiograms; (2) functional abnormalities of endothelium or smooth muscle at the macrovascular or microvascular level that cause dynamic alterations in coronary blood flow at rest or during stress; and (3) nonischemic pain. Evidence for underestimation of the extent and severity of coronary atherosclerosis is currently forthcoming from studies using intravascular ultrasound, but the frequency and scope of this finding remains to be determined in a large series of women with chest pain symptoms who are undergoing diagnostic coronary angiography. Although several groups, including the WISE investigators, have reported evidence for endothelial dysfunction3–5 and for limited coronary blood flow responses to intracoronary vasodilator agonists primarily active at the microvascular level,6 relevance of these findings to the etiology of chest pain symptoms experienced in daily life remains unclear. Furthermore, associations between coronary flow abnormalities detected in the catheterization laboratory and confirmatory evidence of myocardial ischemia with conventional stress testing have been inconsistent. Countering the "ischemia hypothesis" are many reports of altered visceral pain sensitivity (including in the heart) with nonischemic stimuli,7–11 and of psychiatric morbidity,11–13 such as anxiety or panic disorders that may amplify nonischemic chest sensations and are generally unappreciated or ignored by healthy individuals.

Clinical Application and Evidence

Progress in resolving the dilemma of chest pain in the absence of obstructive CAD in women has largely been achieved on two fronts. The ischemia front has been approached with magnetic resonance technology, including nuclear magnetic resonance spectroscopy (MRS) that provides spectra from high-energy phosphates vital to maintaining normal cardiac function during stress, and magnetic resonance imaging (MRI) with sufficient resolution to demonstrate blood flow patterns in the endocardium versus the epicardium at rest and during stress. WISE investigators reported changes in high-energy phosphate signals by MRS in a subset of women who had chest pain without significant epicardial obstruction, with reductions in signals from phosphocreatine relative to adenosine 5'-triphosphate during hand-grip exercise that were more than 2 standard deviations below the mean value for control women without chest pain.14 In a recent study, MRI demonstrated limited increase in subendocardial flow relative to subepicardial flow in patients (men and women) with chest pain and normal coronary angiograms (designated as Syndrome X) after flow stimulation with intravenous adenosine, as compared with control subjects.15 What remains unclear, however, is whether endothelial dysfunction and coronary flow limitation, determined by infusion of agonists, occur in routine daily life and cause myocardial ischemia.

On the second front, other investigations have considered the possibility that central neural processing of sensory input from viscera may be important in understanding symptoms in men and women with Syndrome X.16 They measured regional cerebral blood flow by positron emission tomography as an index of neuronal activity at rest and during dobutamine stress. Dobutamine precipitated severe chest pain and ST-segment depression in all patients, although echocardiography showed increased left ventricular contractility. Patients and controls showed similar increases in blood flow in most regions of the cerebrum. However, in patients, but not controls, increased blood flow was also noted in right anterior insula/frontal operculum junction. In a previous study of identical design but with CAD patients who had flow-limiting stenoses, dobutamine infusion provoked chest pain and echocardiographic evidence of myocardial ischemia, but no increased blood flow in the right insula was noted in these patients.17 Thus, patients with chest pain despite normal coronary angiograms may have an altered pattern of cortical activation by visceral afferent signals, causing abnormal pain perception during cardiac stress, either in the absence of ischemia or with ischemia sufficiently mild or diffuse as to not be reliably detectable by conventional cardiac testing modalities. There is a paucity of randomized intervention trial data for this condition. One trial suggests that exercise may be a successful therapy for this condition.18

Session 2 Recommendations

  1. Novel methodology for evaluating ischemia is needed. MRS should be validated (reproducibility and variability data with higher-strength magnets [>1.5 T]) by use of stronger stressors and compared with tests of atherosclerosis distribution and extent by intravascular ultrasound, endothelial function, and coronary flow reserve.
  2. New methods of evaluating coronary flow reserve should be explored. These could include gadolinium MRI with adenosine or dipyridamole and could be compared with coronary epicardial and microvascular endothelial responsiveness.
  3. Ongoing National Institutes of Health–sponsored outcome studies of endothelial dysfunction should be carefully stratified by gender. Several large studies that include endothelial function measurement exist and should be reported stratified by gender. Other ongoing studies can be examined with regard to how therapy affects symptoms and mortality rate by gender.
  4. Additional research is needed in women with chest pain but no obstructive CAD. This should be targeted at improving mechanistic understanding of the syndrome and may include investigation of increased pain sensitivity, functional brain imaging, and psychosocial evaluation. Randomized outcome trials evaluating interventions such as exercise, L-arginine, and imipramine on the outcomes of morbidity and mortality are needed.
  5. Research to determine if improved diagnosis of ischemic heart disease in women leads to improved outcomes should be undertaken.

Footnotes

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This paper represents a summary of a scientific conference sponsored by the National Heart, Lung and Blood Institute on October 2–4, 2002. The opinions expressed in this paper are those of the authors and do not necessarily represent those of the editor or the American Heart Association.

The publication of this statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 5, 2003. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0277. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-528-4121, fax 410-528-4264, or e-mail kgray@lww.com. To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.

References

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  3. Egashira K, Inou T, Hirooka Y, et al. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med. 1993; 328: 1659–1664.[Abstract/Free Full Text]
  4. Zeiher AM, Krause T, Schachinger V, et al. Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation. 1995; 91: 2345–2352.[Abstract/Free Full Text]
  5. Hasdai D, Gibbons RJ, Holmes DR Jr, et al. Coronary endothelial dysfunction in humans is associated with myocardial perfusion defects. Circulation. 1997; 96: 3390–3395.[Abstract/Free Full Text]
  6. 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.[CrossRef][Medline] [Order article via Infotrieve]
  7. Cannon RO3rd, Quyyumi AA, Schenke WH, et al. Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries. J Am Coll Cardiol. 1990; 16: 1359–1366.[Abstract]
  8. Lagerqvist B, Sylven C, Waldenstrom A. Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary angiograms. Br Heart J. 1992; 68: 282–285.
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  11. Cannon RO3rd, Quyyumi AA, Mincemoyer R, et al. Imipramine in patients with chest pain despite normal coronary angiograms. N Engl J Med. 1994; 330: 1411–1417.[Abstract/Free Full Text]
  12. Bass C, Wade C, Hand D, et al. Patients with angina with normal and near normal coronary arteries: clinical and psychosocial state 12 months after angiography. Br Med J (Clin Res Ed). 1983; 287: 1505–1508.[Medline] [Order article via Infotrieve]
  13. Beitman BD, Mukerji V, Lamberti JW, et al. Panic disorder in patients with chest pain and angiographically normal coronary arteries. Am J Cardiol. 1989; 63: 1399–1403.[CrossRef][Medline] [Order article via Infotrieve]
  14. Buchthal SD, den Hollander JA, Merz CN, et al. Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms. N Engl J Med. 2000; 342: 829–835.[Abstract/Free Full Text]
  15. 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.[Abstract/Free Full Text]
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