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European Heart Journal Advance Access originally published online on May 23, 2006
European Heart Journal 2006 27(12):1408-1415; doi:10.1093/eurheartj/ehl040
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women's Ischaemia Syndrome Evaluation (WISE) study

B. Delia Johnson1,*, Leslee J. Shaw2, Carl J. Pepine3, Steven E. Reis4, Sheryl F. Kelsey1, George Sopko5, William J. Rogers6, Sunil Mankad7, Barry L. Sharaf8, Vera Bittner6 and C. Noel Bairey Merz2

1 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
2 Division of Cardiology, Department of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
3 Division of Cardiovascular Medicine, University of Florida, Gainesville, FL, USA
4 Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
5 National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA
6 Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
7 Division of Cardiology, Department of Medicine, Allegheny University of the Health Sciences, Pittsburgh, PA, USA
8 Division of Cardiology, Rhode Island Hospital, RI, USA

Received 21 October 2005; revised 14 April 2006; accepted 4 May 2006; online publish-ahead-of-print 23 May 2006.

* Corresponding author. Tel: +1 412 624 7256; fax: +1 412 624 3775. E-mail address: djohnson{at}edc.pitt.edu

See page 1387 for the editorial comment on this article (doi:10.1093/eurheartj/ehi758)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims Women with chest pain but without obstructive coronary artery disease (CAD) are considered at low risk for cardiovascular (CV) events, but half continue to experience debilitating chest pain over many years. This study compared CV outcomes in women with persistent chest pain (PChP) vs. those without PChP.

Methods and results We studied 673 Women's Ischaemia Syndrome Evaluation (WISE) participants with chest pain undergoing coronary angiography for suspected myocardial ischaemia and at least 1 year of follow-up. PChP was defined as self-reported continuing chest pain after 1 year. Events occurring after that year were recorded for a median of 5.2 years. We compared CV event rates for women with and without PChP in subgroups with and without obstructive CAD. The median age was 58 years, 20% were racial minorities, 45% had PChP, 39% had obstructive CAD. Among women without CAD, those with PChP had more than twice the rate of composite CV events (P=0.03), that included non-fatal myocardial infarctions (P=0.11), strokes (P=0.03), congestive heart failure (P=0.38), and CV deaths (P=0.73), compared with those without PChP. In women with CAD, there was no difference in composite CV events in those with and without PChP (P=0.72).

Conclusion Among women undergoing coronary angiography for suspected myocardial ischaemia, PChP in women with no obstructive CAD predicted adverse CV outcomes. Such women might benefit from additional evaluation and aggressive risk factor modification therapy.

Key Words: Chest pain • Prognosis • Women • Myocardial ischaemia


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
In clinical practice, chest pain in the absence of obstructive coronary artery disease (CAD) remains a baffling problem that primarily affects women. More than half of women with chest pain undergoing coronary angiography in the U.S. are found to have normal or near-normal coronaries, as compared with only 15% of men.1–2 This high ‘false-positive’ rate for severe coronary artery stenosis among symptomatic women has not declined since it was first reported.3–4 Today, among the over half million angiograms performed annually in U.S. women, the cost related to lack of specific diagnosis in the presence of normal angiographic findings is estimated around $300 million.5

About 50% of women sent home with normal coronaries continue to experience disabling symptoms that are often unresponsive to conventional anti-ischaemic therapy4,6 and return for repeat evaluations, adding to the economic and human costs in terms of lost productivity and need for continuing evaluation and care. Although the constellation of angina and normal coronary angiograms may have multiple aetiologies, recent evidence suggests that an ischaemic mechanism may play a role due to coronary microvascular or macrovascular endothelial dysfunction7–11 that in many cases appears to be female-specific.11–14

The prognosis in women with chest pain and normal coronary angiograms is said to be excellent.15–18 However, in a recent study of women with chest pain and normal appearing coronaries, 59% who additionally displayed an abnormal vasomotor response to acetylcholine continued to experience chest pain and developed CAD at up to 10 years.19 The women with normal vasomotor response, by contrast, had a complete resolution of their symptoms at follow-up. Although the study was small (42 women), the findings suggest that persistent chest pain (PChP) in women with angiographically normal coronaries may forecast downstream development of obstructive CAD and cardiovascular (CV) events. The aims of the present study were (i) to evaluate systematically the clinical status and prognosis of women referred for coronary angiography who have PChP or symptoms suggestive of ischaemia and (ii) to evaluate the prognostic significance of PChP in women without obstructive CAD.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Study population
The study population consisted of 673 participants in the Women's Ischaemia Syndrome Evaluation (WISE) study who reported chest pain symptoms at baseline, who had at least 1 year of follow-up that included a symptom/chest pain assessment necessary for the definition of PChP, and for whom follow-up information was available beyond the 1 year follow-up. WISE is a National Heart, Lung, and Blood Institute-sponsored 4-center study of 936 women undergoing clinically ordered coronary angiography for suspected myocardial ischaemia.20 Exclusion criteria included emergency referral, pregnancy, cardiomyopathy (as defined in the patients' medical records), New York Heart Association class IV congestive heart failure (CHF), acute ischaemic syndrome (defined as acute myocardial infarction (MI) or unstable angina) within one month prior to study entry, coronary revascularization by either CABG or PTCA within 6 months prior to study entry, conditions other than ischaemic heart disease likely to be fatal or requiring frequent hospitalization within 4 years (such as severe lung, renal or hepatic disease, or surgically uncorrected significant congenital or valvular heart disease), any contraindication to provocative myocardial stress testing, and any condition likely to affect study retention (alcoholism, drug abuse, or severe psychiatric illness). Of the consecutive women screened and those who met the WISE eligibility criteria, 50% agreed to participate in the study. This study complies with the Declaration of Helsinki. All women provided signed informed consent for baseline evaluations and follow-up by using forms and procedures in accordance with institutional guidelines and approved by the institutional review board at each WISE clinical site.

Baseline evaluation
On enrolment, baseline evaluation by site physicians and study nurses included the collection of demographic information, risk factors for CAD, medication use, medical and reproductive history, detailed symptom history and psychosocial evaluation, a physical examination, activity status assessment, and sampling of blood. All WISE women also received an ECG that was evaluated by the WISE ECG core laboratory for rhythm, rate, LVH, conduction abnormalities, ST-T wave changes, and Q-Waves.

Quantitative angiographic assessment of CAD
In order to maintain uniformity of methodology and interpretation, all coronary angiograms obtained at enrolment were analysed quantitatively and qualitatively offline at the WISE angiographic core laboratory (Rhode Island Hospital, Providence, RI, USA) by investigators masked to all other WISE clinical data.21 Luminal diameter was measured at all stenoses with a cine projector-based ‘cross hairs electronic caliper’ method for all angiograms recorded onto cine film and with a computer-based edge detection method for all angiograms recorded onto CD-ROM. The inter-observer variability for this lab was 0.196 mm with a 6.3% coefficient of variation.21 The presence of obstructive CAD was defined as ≥50% stenosis in ≥1 major epicardial coronary artery. An angiographic CAD severity index was calculated based on the stenosis severity weighted by proximal lesion.21

Definition of chest pain and PChP
Both at baseline and 1 year follow-up, all WISE women were questioned by site physicians and nurses about their experience of pain or discomfort above the waist over the prior year. When asked, ‘In the last 12 months have you had pain or discomfort above the waist?’ 94% had experienced such symptoms at baseline. The 57 asymptomatic women were excluded from the current analysis. PChP was defined as symptoms at 1 year follow-up as assessed by the same question. Symptoms were considered not persistent (no PChP) if not present at the 1 year follow-up. Consistent with prior WISE findings,22 the characterization of symptoms was not limited to ‘pain’ or location in the chest but included other descriptors and locations (e.g. shortness of breath, discomfort, shoulder location).

At baseline and follow-up, all women also completed a brief symptom questionnaire to assess the presence of typical angina, defined as pain that is substernal, precipitated by exertion or emotional stress, and relieved within 10 min by rest or nitroglycerin.23 Additionally, at baseline, the women completed an extensive symptom checklist regarding specific symptom types (e.g. chest tightness, nausea), locations (e.g. chest, stomach, arm), severity, frequency, triggers (e.g. lower body exertion, during or after meals), and relievers (e.g. rest, heartburn medications), with instructions to check all the relevant items. In addition to specific items, we also assessed the number of items checked in the various categories (e.g. number of locations, triggers, etc.).

Follow-up procedures
Follow-up was conducted by site nurses and physicians through telephone and/or mail contact at 6 weeks and then yearly thereafter. Follow-up consisted of a scripted interview by an experienced nurse or physician. Each woman was queried about symptoms, medication use, CV events since last contact, hospitalizations, and diagnostic or revascularization procedures. In the event of death, a death certificate was obtained. Classification of deaths as CV was performed by WISE investigators masked to angiographic findings. Besides individual events, two composite outcomes were assessed: (i) CV death or MI and (ii) CV event (defined as CV death, MI, CHF, or stroke). As PChP was defined at the 1 year follow-up, only CV events occurring after the 1 year follow-up evaluation were included (Figure 1) in the present analysis in order to maintain the predictive nature of PChP.


Figure 0401
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  		Figure 1 Definition of follow-up period.

 
Statistical methods
Baseline data are reported as means ± SD. We compared four groups of women (no CAD/no PChP, no CAD/PChP, CAD/no PChP, CAD/PChP), and the major comparisons were between women with PChP vs. those without PChP within the CAD and no CAD subgroups. Because we found a strong relationship between PChP and age, and because age is also a major correlate in WISE of demographic characteristics and CAD risk factors, all P-values in Table 1 (with the exception of age and menopausal status) were adjusted for age using logistic regression.


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  		Table 1 Demographic and risk factor characteristics by presence/absence of obstructive CAD and presence/absence of PChP. Means ± SD for continuous variables, percentages for frequencies

 
Because of differing follow-up times due to censoring, we estimated the 6-year CV event rates, beginning after the first year, by using the Kaplan–Meier method. The statistical significance of differences in event rates between women with and without PChP was derived using the log rank statistic for subgroups of those with and without obstructive CAD. The Cox proportional hazards method was used to generate separate hazard ratios and 95% confidence intervals for women with and without CAD. We developed a multivariable Cox proportional hazards model based on the major risk factors for CV events (using Framingham risk criteria) in addition to PChP. We then added specific chest pain and diagnostic parameters, such as ECG results, that provided incremental predictive information. All analyses were performed using the SAS 8.12 software (Cary, NC, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Population characteristics
Overall, 673 out of the 936 (72%) women enrolled in WISE were included in this analysis. Not included were women who were asymptomatic at baseline (n=57) and women without a 1-year symptom assessment (n=206). Compared with the study population, the 57 asymptomatic women were much older (mean age 66 vs. 58 years, P<0.0001), and sicker (54 vs. 39% with obstructive CAD, P=0.01; CAD severity score 22.4 vs. 14.3, P=0.007). However, they were less depressed (P<0.0001), had less anxiety symptoms (P=0.04), and reported a better quality of life (QOL) than those with chest pain at baseline (P<0.0001). Most (60%) of these women listed an abnormal stress test as their primary reason for referral to coronary angiography.

Among the 206 women without a 1-year symptom assessment, 18 women died during the first year, 38 chose not to participate in any follow-up, 117 had a 6-week follow up only, and 33 did not receive their 1-year follow-up but were re-contacted for later follow-ups. These women were slightly but significantly younger (56 vs. 58 years, P=0.009) but did not differ significantly in any other baseline characteristics when compared with the study population.

The median age of the study population (N=673) was 58 years (range 21–86), and 20% were racial minorities, primarily black. Sixty-eight percent of the women had at least two CAD risk factors [including diabetes (24%), history of dyslipidemia (55%), history of hypertension (60%), current smoking (19%), and obesity (BMI≥30, 40%)]. Obstructive CAD was present in 39% of the women, and 45% had PChP. Notably, there was no difference in the prevalence of PChP (44 vs. 46%) comparing women with and without obstructive CAD.

Tabulation of demographic and risk factor variables by PChP within the CAD subgroups (Table 1) shows that women with PChP but no obstructive CAD were younger (P=0.0002), and had lower functional capacity as measured by the Duke Activity Status Index (DASI) (P=0.002). They had a slightly but statistically higher (P=0.05, age adjusted) mean angiographic CAD severity score (7.4 ± 3.9 vs. 7.0 ± 3.8) as compared with those without PChP. They rated their symptoms at baseline as more intense (P=0.01), more frequent (P=0.0004), and occurring in more body locations (P=0.0006), however, no differences were found for typical angina. They also had a higher prevalence of co-morbidities (P=0.01) and psychological problems, such as depression (P=0.001) and anxiety (P=0.04), were more likely to be using antidepressant or anti-anxiety medications (P=0.002), and rated their overall QOL as lower (P=0.003). No differences were found for ECG characteristics. Notably, 57% of the women without obstructive CAD were found to have angiographically normal coronary arteries (no lesions), but this did not differ by the presence or absence of PChP.

These differences were found to a lesser extent in women with obstructive CAD. PChP was not associated with CV risk factors, typical angina, baseline ECG characteristics, or baseline lipid-lowering or anti-hypertensive medication use. Change in the use of these therapies at 1 year did not differ by PChP. However, among women diagnosed with obstructive CAD who were not receiving lipid-lowering or anti-hypertensive therapies at baseline, 37 and 34% had initiated these respective therapies at 1 year follow-up. In contrast, among those diagnosed as having no CAD, only 9 and 14% initiated these therapies. No differences were observed between women with and without PChP. Interestingly, regardless of CAD, women with PChP were more likely at baseline to report chest, neck, back, shoulder, arm, hand, and throat pain but not jaw, oesophagus, or stomach pain, and the number of sites was highly associated with PChP (P=0.0006 and P=0.0004).

Prediction of CV events
The median follow-up period, beginning after the first year, among surviving patients was 5.2 years [ranging from 5.0 to 5.5 years (P=0.39) among the four groups]. Among the 673 women, 72 died of any cause, 53 died from CV causes, 24 suffered a non-fatal MI, 44 were hospitalized for CHF, and 33 had a stroke. A total of 189 women were hospitalized for chest pain not associated with any of the above events, and 196 underwent repeat angiography.

Women without obstructive CAD also experienced major CV events, although at a far lower rate than the subgroup with obstructive CAD (Figure 2). However, in the former, those with PChP had more than three times the 6-year rate of non-fatal MI (5.3 vs. 1.6%, P=0.11), more than three times the rate of strokes (7.5 vs. 2.0%, P=0.03), twice the rate of CHF events (7.5 vs. 3.7%, P=0.38), and 30% more CV deaths (P=0.73). No appreciable differences were observed for all-cause mortality. Women with obstructive CAD had about the same rate of MIs as those without obstructive CAD, and those with PChP had almost twice the rate of MIs (7.7 vs. 4.2%, P=0.34) and the same rates of CHF, stroke, CV deaths, and all-cause mortality. The 6-year incidence of all combined CV events was twice as high in women with PChP in the non-obstructive CAD subgroup (20.5 vs. 10.1%, P=0.03) but not in the obstructive CAD subgroup (38.2 vs. 36.8%, P=0.72). When predicting composite CV events, the hazard ratio for PChP was 1.89 (1.06, 3.39), P=0.03 in women without and 1.17 (0.76,1.80), P=0.49 in those with obstructive CAD (Figure 3).


Figure 0402
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  		Figure 2 Six-year CV event rates by CAD and PChP. CV events defined as CV death, MI, CHF, or stroke. Six-year event rates were estimated by Kaplan–Meier method.

 

Figure 0403
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  		Figure 3 Event-free survival from CV events by CAD and PChP. CV events defined as CV death, MI, CHF, or stroke.

 
In both subgroups of women, those with PChP underwent repeat coronary angiography at a higher rate than those without PChP (34.5 vs. 21.2%, P=0.01 in those without obstructive CAD; 64.3 vs. 39.8%, P=0.0006 in those with obstructive CAD). In women with obstructive CAD, 39.8% with and 23.2% without PChP underwent a revascularization procedure over 6 years (P=0.02) (not tabulated).

In order to evaluate the potential confounding role of minimal lesions in women without obstructive CAD, we repeated the same analyses in women with normal coronary angiograms (57% of the women without obstructive CAD). The same higher 6-year rates for MI, CHF, and stroke were observed in women with vs. without PChP (composite CV events 16.6 vs. 5.1%, P=0.03).

Multivariable prediction of CV outcomes
In order to determine whether PChP was an independent predictor of CV events, a multivariable Cox proportional hazards model was calculated for all women without obstructive CAD. Table 2 gives the multivariable risk model for predicting CV events in such women. Notably, smoking, CAD severity, diabetes, and increased QTc interval were significant independent predictors of CV events. PChP added to this model remained a statistically significant (P=0.049) predictor of CV events. In this group of women without obstructive CAD, age, history of hypertension or dyslipidemia, and use of anti-hypertension medications did not predict CV events.


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  		Table 2 Multivariable model of CV events among WISE women with no obstructive CAD (n=412, 47 eventsa)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
Women without obstructive CAD at coronary angiography have been considered a low risk population,4,17,24–31 and indeed, these women in our study had a lower overall CV event rate compared with women with obstructive CAD. However, our data suggest that PChP in the absence of obstructive CAD is not a benign condition. These women experienced major CV events such as MI and stroke at approximately double the rate found in women with neither PChP nor CAD. This association between PChP and adverse CV events was not found in women with obstructive CAD.

Although prior studies address the issue of chest pain in the absence of obstructive CAD,4,30,32,33 very little is known about chronic chest pain in such patients with regard to adverse CV outcomes. Prior work has demonstrated a high prevalence of PChP in patients without obstructive CAD, noting it as a typical outcome in about half of the patients.4,30,32,33 However, to our knowledge, PChP per se has not been studied as a predictor of CV outcome. The need for investigating the risk associated with chronic chest pain syndromes has recently been discussed in detail in an NHLBI/AHA/WISE workshop.34

One possible explanation for our findings may be that these women have atherosclerosis that is relatively diffuse and not apparent as focal stenosis by angiography (B. Sharaf, submitted for publication). In support of this possibility was the finding of a mildly elevated CAD severity score in those with vs. without PChP, and that severity score was an independent predictor of adverse events. Against this possibility, we found that PChP was predictive of adverse events even among the subgroup (57%) of women with completely normal coronary angiograms.

A major difference between women with and without PChP was that the former were experiencing a higher prevalence and severity of psychological symptoms, including depression, anxiety, and panic disorder. Ever since Freud's description of hysteria in women, ‘non-cardiac chest pain’ has often been ascribed to such psychological symptoms and the two are often shown to correlate.31,35 Moreover, psychological problems worsen the CV prognosis in women.36,37 However, such evidence does not necessarily prove the causal direction between unexplained PChP symptoms and psychological problems. It has been suggested that depression and anxiety may in fact be a normal and expected reaction to severe, debilitating, and persistent symptoms of undetermined aetiology,38,39 i.e. can also be considered an outcome of persistent and unexplained symptoms rather than vice versa. The current results support this, in that adjustment for psychosocial variables in our multivariable model did not significantly alter our results. More study is needed to resolve this issue.

Other evidence suggests that much of women's chest discomfort in the absence of obstructive CAD may be due to coronary macrovessel40 or microvessel25 dysfunction that limits the coronary microcirculation during stress.41–44 Recent work from the WISE study has demonstrated a high prevalence of abnormal microvascular coronary flow reserve and macrovascular endothelial dysfunction,12,14,45,46 and resultant abnormal metabolic responses to stress consistent with myocardial ischaemia.10,13 Additionally, a recent study47 on men and women has demonstrated that a dipyridamole echocardiography test, diagnostic for myocardial ischaemia, performed on patients with chest pain and no obstructive CAD can identify those at higher long-term risk for CV events. Other studies have indicated that such impairment may not just be functional but may also represent structural changes in the small coronary arteries,48,49 and appear to predict an adverse CV outcome.7,50,51

It is currently not known whether these structural and functional coronary abnormalities represent a distinct disease state or whether they are simply part of the spectrum of progressive atherosclerotic CAD. The recent results by Bugiardini,19 demonstrating that coronary endothelial dysfunction predicts the development of future obstructive CAD, imply the latter. Similarly, an older study52 reported that 27% of patients with mild disease (<50% diameter narrowing) and recurrent chest pain progressed to obstructive CAD over a mean of 42 months, whereas those patients with normal arteries did not. Our findings demonstrate an adverse association between persistent symptoms and CV outcome even in women with normal coronary arteries. While we did not evaluate repeat angiograms during the follow-up time and therefore cannot exclude the development of severe large vessel obstructive CAD as an explanation for the adverse CV events, plaque erosion with embolization in an already disordered microvasculature is also a plausible mechanism. The distribution of events in the no obstructive CAD group, relatively equal across CV death, MI, CHF, and stroke, are most consistent with a generalized atherosclerotic process potentially involving both the macro and microvascular systems.

The current results suggest that the presence of chest pain in the absence of obstructive CAD should raise concern that the patient may be at higher risk for adverse CV events. Thus, PChP may be considered a risk ‘marker.’ The finding of an adverse prognosis in these women may simply reflect the lack of clinical follow-up subsequent to an angiographic finding of normal or near-normal coronaries. Evidence is accumulating that women with angina and normal coronary arteries may be helped with a wide variety of therapies including nitrates, beta blockers, imipramine, statins, angiotensin-converting enzyme inhibitors, L-arginine, and exercise training.11 Our current results show that women with no obstructive CAD did not receive more aggressive risk factor reduction, while those with obstructive CAD were more likely to have lipid-lowering and anti-hypertensive therapies initiated during the follow-up period. Indeed, the women with no obstructive CAD were more likely to receive sedative or hypnotic medications that are unlikely to protect against adverse outcomes. Notably, most of the WISE women had a sufficient burden of CVD risk factors to warrant aggressive risk factor modification therapy.

The major implication of this study is that women with no obstructive CAD and chronic chest pain symptoms should likely undergo additional evaluations due to their relatively higher risk of adverse CV events. Such evaluation might include provocative coronary angiographic assessment for macro and microvascular dysfunction and documentation of atherosclerosis if not evident on the coronary angiogram. The presence of CV risk factors and/or evidence of atherosclerosis or endothelial dysfunction should be treated with risk factor modification. Moreover, these patients should be closely followed and monitored for the development of infarctions, strokes, and other vascular events rather than discharged from care as ‘non-cardiac.’ Future research should be aimed at developing risk stratification tools, ideally non-invasive, available to practicing physicians.

Study limitations
First, low statistical power likely reduced our ability to differentiate groups with regard to individual types of CV events. However, the results showed a consistent trend throughout as well as improved significance when combining these events. We believe that low power was also a partial explanation for the attenuation of the relationship between PChP and CV events in the no obstructive CAD women when adjusting for a significant risk model. It is clear that these findings need to be confirmed in a larger study over a longer observation period. Second, outcomes were primarily obtained from patients' information, although deaths were verified and we frequently verified other events against medical records as per our WISE protocol. However, we cannot exclude that knowledge of angiographic results and PChP may have influenced outcome reporting, choice of therapy, and actual outcomes. Moreover, we did not collect angiographic information for women undergoing repeat angiography. Third, because our study cohort was an angiographic referral population, these results may not be generalizable to the general population. However, the possible referral bias may be outweighed by the possibility that these women were already pre-screened by their referring physician for obvious non-cardiac causes such as gastro-oesophageal reflux and psychiatric disorders. Finally, even within the female angiographic population, only 50% of women eligible for WISE participation chose to enroll, and we have no further information on how the women who did not enroll differed from our study population. We further excluded 57 asymptomatic women from this analysis (who turned out to be older and sicker), thus further limiting the generalizability of our results.

Conclusions
Our findings suggest that, contrary to popular belief, PChP in the absence of obstructive CAD is not benign and is associated with adverse CV outcomes. Women without obstructive CAD but PChP had more than twice the number of CV events, including MIs, strokes, CHF, and CV deaths compared with those without PChP. Women with no obstructive CAD and PChP should have aggressive risk factor reduction therapy designed to reduce adverse CV events as well as follow-up monitoring. Ongoing efforts should be directed at understanding the underlying pathophysiology as well as developing risk stratification tools.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by contracts from the National Heart, Lung and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, a GCRC grant MO1-RR00425 from the National Center for Research Resources, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, New Jersey, USA, The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California, USA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania, USA, and QMED, Inc., Laurence Harbor, New Jersey, USA.

Conflict of interest disclosure: There are no conflicts of interest to disclose by any of the co-authors.

A preliminary analysis of earlier versions of these data was previously presented as a poster at the AHA 4th Scientific Forum on Quality of Care and Outcomes Research in CV Disease and Stroke, Washington, DC, USA, 13–14 October, 2002.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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