This Article Free upon publication Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Maseri, A. Search for Related Content PubMed PubMed Citation Articles by Maseri, A. Related Collections Health policy and outcome research Ischemic biology - basic studies CV surgery: coronary artery disease Chronic ischemic heart disease

(Circulation. 2004;109:e62-e63.)
© 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: Perspective: New Frontiers in Detection of Ischemic Heart Disease in Women

Attilio Maseri, MD, Endorsed by the American College of Cardiology Foundation

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

The prognostic implications of the diagnosis of ischemia vary dramatically in different clinical ischemic syndromes. At one extreme end, in unstable angina, the detection of ischemia indicates the persistence or recurrence of instability and hence carries much more severe prognostic implications than in chronic stable angina. At the other extreme, in patients with microvascular angina, the detection of ischemia does not indicate an increased risk of infarction or sudden cardiac death and becomes clinically relevant only if its causes can be understood and effectively treated.

A typical condition in which the diagnosis of myocardial ischemia is difficult is the so-called cardiac syndrome X. This syndrome, which includes 60% to 70% of women (about 60% postmenopausal and 40% premenopausal) but also 30% to 40% of men, is characterized by angina pectoris and normal coronary angiography. Its incidence may vary from 10% to 50% of patients submitted to coronary arteriography.

Such broad inclusion criteria confuse the issue because of the likely inclusion of heterogeneous patients with and without a cardiac origin of pain. The selection of patients who present with specific patterns of clinical symptoms and with transient ischemic ECG changes during chest pain would lead to more homogeneous subgroups, inasmuch as the association of anginal pain with transient ECG changes indicates a cardiac, although not necessarily ischemic, origin of pain. Moreover, distinct patterns of clinical presentation might correspond with different specific pathogenetic mechanisms.¹

Several studies focusing on this specific subgroup of patients have shown findings consistent with a patchily distributed coronary microvascular dysfunction—sufficient to cause chest pain, ECG changes, and in some cases, perfusion abnormalities during effort tests, but not confluent and severe enough to cause detectable contractile dysfunction or lactate production.² Characteristics include the following:

• reproduction of typical pain with the dipyridamole test, usually with typical ischemic changes but no myocardial contraction abnormality³;
  
• worsening of exercise test result after sublingual nitrates,⁴ consistent with the frequent clinical report of a poor response to sublingual nitrates;
  
• ischemic myocardial metabolic changes by magnetic resonance spectroscopy⁵; and
  
• release of lipid peroxidation products in the coronary sinus at the end of pacing-induced ischemic changes.⁶
  

The causes of this coronary microvascular dysfunction may be multiple, as suggested by the total absence of iobenguane ¹²³I sulfate cardiac uptake in >50% of the cases, by a regional defect corresponding to the site of thallium defects in about 25%, and by totally normal uptake in the remaining 25%.⁷ In spite of the absence of increased risk of infarction and cardiac death, these patients may be crippled by pain. The inconsistent response to nitrates and antianginal drugs indicates the need for research on the various potential causes of coronary vascular dysfunction to facilitate development of rational forms of therapy.

The New Avenues of Research

We are engaged in a program of outcome research on all patients presenting to our department with their very first manifestation of ischemic heart disease (IHD). After they have given informed consent, they are administered a computerized, standardized questionnaire that focuses on possible differences in symptoms and presentation for each of the various ischemic syndromes. A blood sample is obtained for proteomic studies and for analysis of traditional risk factors, mRNA from leukocytes and platelets, and genomic DNA; the blood sample is stored in biological banks. Within each clinically defined homogeneous subgroup, all patients undergo tests and interventions as clinically required, and selected patients are also involved in special pathogenetic studies. All enter in a regular follow-up program that will identify patients with different outcomes. Correlations between outcomes and blood tests on admission will allow us to obtain novel information on pathogenetic mechanisms and on predisposing and protective factors, which will be useful for developing novel, rational treatment strategies.

Future Clinical Research Directions

1. The main thrust of research in the field of IHD has been the identification of common mechanisms of disease and average prognostic determinants for combined, mixed events.
   
2. Even within such a broad research framework, epidemiological, postmortem, and clinical data revealed remarkable gender differences in the incidence, manifestations, and diagnosis of the various syndromes that compose IHD (ie, sudden ischemic cardiac death; unheralded acute infarction; acute infarction preceded by unstable angina; as well as infarction in stable, unstable, variant, and microvascular angina). In particular, epidemiological studies consistently show that, in contrast to infarction, the age-related incidence and prevalence of angina are similar in both genders and that the very first clinical manifestation of IHD is more often infarction in men and angina in women.
   
3. The new frontier of research in the multiple syndromes that compose IHD is the identification of the actual causes for gender differences in:
   

   (a) the incidence of the various ischemic syndromes and their relation to the extent and features of coronary atherosclerosis; and
   

   (b) the prevalence of different ischemic triggers within each syndrome.
   

   
   

A Multidimensional Problem

In this general scenario, the detection of myocardial ischemia in women represents a rather marginal aspect, which becomes relevant only when ischemia is not sufficiently extensive and severe to be clearly recognized by currently available techniques—a problem that, under similar circumstances, also applies to men. In such cases, it is not sufficient to diagnose the presence of ischemia, but, once detected, it is also necessary to identify its actual causes, together with its prognosis and rational treatment strategies. A much more intriguing and complex problem is the detection of IHD in women. This issue requires a precise definition of each of the various syndromes that compose IHD, as indicated in the introduction.

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

1. Maseri A. Chapter 18: Syndrome X and Microvascular Angina. In: Ischemic Heart Disease: A Rational Basis for Clinical Practise and Clinical Research. New York: Churchill Livingstone; 1995: 507–532.
   
2. Maseri A, Crea F, Kaski JC, et al. Mechanisms of angina pectoris in syndrome X. J Am Coll Cardiol. 1991; 17: 499–506.[Medline] [Order article via Infotrieve]
   
3. Picano E, Lattanzi F, Masini M, et al. Usefulness of a high-dose dipyridamole-echocardiography test for diagnosis of syndrome X. Am J Cardiol. 1987; 60: 508–512.[CrossRef][Medline] [Order article via Infotrieve]
   
4. Lanza GA, Manzoli A, Bia E, et al. Acute effects of nitrates on exercise testing in patients with syndrome X: clinical and pathophysiological implications. Circulation. 1994; 90: 2695–2700.[Abstract/Free Full Text]
   
5. 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]
   
6. Buffon A, Rigattieri S, Santini SA, et al. Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac Syndrome X. Am J Physiol (Heart Circ Physiol). 2000; 279: 2627–2633.
   
7. Lanza GA, Giordano A, Pristipino C, et al. Abnormal cardiac adrenergic nerve function in patients with syndrome X detected by [123I]metaiodobenzylguanidine myocardial scintigraphy. Circulation. 1997; 96: 821–826.[Abstract/Free Full Text]
   

This Article Free upon publication Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Maseri, A. Search for Related Content PubMed PubMed Citation Articles by Maseri, A. Related Collections Health policy and outcome research Ischemic biology - basic studies CV surgery: coronary artery disease Chronic ischemic heart disease