Symptoms, myocardial ischaemia and quality of life in women:

Results from the NHLBI-sponsored WISE Study

Marian B. Olsona,*, Sheryl F. Kelseya, Karen Matthewsa, Leslee J. Shawb, Barry L. Sharafc, Gerald M. Pohostd, Carol E. Cornelle, Susan P. McGorrayf, Diane Vidog and C.Noel Bairey Merzh

a Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
b Atlanta Cardiovascular Research Institute, Atlanta, Georgia, USA
c Division of Cardiology, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
d Division of Cardiovascular Medicine, University of Southern California, Los Angeles, USA
e Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
f Division of Cardiology, Department of Medicine, University of Florida, Gainesville, Florida, USA
g Division of Cardiology, Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
h Division of Cardiology, Department of Medicine, Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

* Corresponding author: Marian B. Olson, MS, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA. 15261, USA. Tel.: +1-412-624-5526; fax: +1-412-624-3775
E-mail address: olson{at}edc.gsph.pitt.edu

Received 13 December 2002; revised 12 February 2003; accepted 30 April 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Aims Our goal was to evaluate health-related quality of life (QOL) in women undergoing angiography for suspected ischaemia.

Methods and results QOL measurements were obtained in 406 women with chest pain symptoms in the Women’s Ischemia Syndrome Evaluation (WISE). QOL measures included a general rating (GR), Duke Activity Status Index (DASI), and the Beck Depression Inventory (BDI). Higher scores on the GR and DASI are indicative of better QOL and functioning. Higher scores on the BDI indicate more symptoms of depression. Women were stratified by the presence and absence of obstructive angiographic coronary artery disease (CAD) and by the presence and absence of myocardial ischaemia. Women with angiographic obstructive CAD had lower DASI and higher BDI scores compared to women without obstructive CAD (both P<0.05). Stratification by the presence and absence of ischaemia demonstrated that women with ischaemia had better QOL, evidenced by higher GR QOL scores and lower BDI scores (both P<0.05) than women without ischaemia. Symptoms of angina were significant independent predictors of QOL scores (P<0.001).

Conclusions Chest pain symptoms have a significant impact on health-related QOL in women undergoing coronary angiography for suspected myocardial ischaemia andare more important determinants of QOL than the underlying conditions of CAD or ischaemia.

Key Words: Quality of life • Coronary artery disease • Myocardial ischaemia • Women


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Improvements in disease prevention and treatment have effected a 35%–50% reduction in cardiovascular mortality in recent decades.1As patients achieve substantial gains in life years, there is increasing interest in improving the quality of life (QOL) during the extended survival time period.2An array of standardized questionnaires has been developed in order to quantify changes in QOL for both the general population and patient groups. These instruments assess the individual’s perception of performance or functioning, rather than the practitioner’s view of a technical success or measured physiological outcome.3–5

Previous studies have shown that patients with anginal chest pain have lower QOL as compared with those without angina, even if their symptoms were mild.5,6Investigations into reasons for poorer QOL have focused on the frequency,7number, severity of symptoms8and the degree of impairment.9,10Prior work has not specifically examined angina symptoms and QOL in women, who have a disproportionately higher burden of angina symptoms compared to men.11

We undertook an analysis of health-related QOL in women. We started by examining two groups: women with obstructive angiographic coronary artery disease (≥50% stenosis in one or more epicardial coronary artery) (coronary artery disease (CAD)) and those without CAD. We further subdivided these two groups into those with myocardial ischaemia and those without ischaemia, indicated by a positive response during noninvasive stress testing. We hypothesized that women with CAD would have the lowest quality of life and that women with myocardial ischaemia would have QOL ratings that were worse than those without myocardial ischaemia. Women with myocardial ischaemia, we hypothesized, would have more functional impairment and more symptoms ofdepression than those without ischaemia.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
The Women’s Ischemia Syndrome Evaluation (WISE) study is a National Heart, Lung and Blood Institute (NHLBI)-sponsored four-centre study that aims to improve diagnostic testing in the evaluation of ischaemic heart disease in women, as well as improve understanding of the pathophysiology of myocardial ischaemia in women with and without obstructive CAD. Specifically, the WISE study sought to document the prevalence and significance of myocardial ischaemia in the absence of obstructive CAD, as prior evidence suggests that women disproportionately suffer from this condition compared to men.11

Each centre obtained institutional review board approval and participant consent before the initiation of testing. Women with chest pain symptoms of suspected ischaemia referred for coronary angiography underwent an initial evaluation that included the collection of demographic, medical history, psychosocial and symptom data. Women also underwent a physical examination that included height, weight, blood pressure, and lipid determination followed by quantitative coronary angiography. Determination of waist circumference and a waist-hip ratio involved measurement of the waist at the natural waistline and the hip at the widest part across the buttocks. Questions on the frequency of chest pain covered the six weeks prior to the physical exam and included the following categories: never, 1–3 times, 1–3 times per week, almost every day, 1–3 times a day and four or more times per day. The complete study design and methodology of the WISE study are described elsewhere.12

2.1. Quality of Life measures
Three QOL measures were collected in the full WISE cohort: a general rating, the Duke Activity Status Index, and the Beck Depression Inventory. This paper focuses on these three measures since they cover both the physical and psychological domains.

General QOL rating is collected at baseline in answer to the question ‘Overall, how would the patient rate her quality of life?’ The possible responses fall along an interval scale from zero (worst) to 10 (best). This summary measure has been used to assess health-related QOL in the Health Care Cost and Utilization Study.13

Duke Activity Status Index (DASI) is a 12-item, self-administered questionnaire that assesses functional capacity by determining the patient’s ability to perform a range of specific daily activities. The DASI has been shown to correlate well with functional capacity measured by maximum oxygen uptake,14exercise stress testing in women,15and to vary appropriately among patients according to clinical characteristics.14The DASI has been used in large cross-sectional studies of coronary patients.3Scores on the DASI range from 0–58.2 with higher scores indicating greater functional capacity.

Beck Depression Inventory (BDI) is a 21-item instrument designed to measure the existence and severity of depression symptoms in both adolescents and adults. By design, the items represent cognitive rather than somatic affective symptoms of depression, and include items that describe the manifestation of depression in relation to general life satisfaction, mood, relations with others, self-esteem, appetite, sleep and libido. The items are rated on a 4-point scale range from 0–3 in terms of severity;16the range of scores is from 0–63. Higher scores are indicative of more symptoms of depression.

2.2. Chest pain symptoms
Symptom history forms were used to collect information on angina and associated symptoms. The list of symptoms is included in the Appendix. We chose to use a broad number of symptoms in addition to the traditional designations of typical angina, atypical angina and non-anginal chest pain because the traditional designation is a less accurate correlate of CAD in women compared to men17and because we were interested in exploring the pathophysiology of ischaemia in the absence of obstructive CAD. The intensity of chest pain symptoms is reported on a 5-point interval scale that ranges from ‘tolerable, no relief needed’ to ‘not tolerable, not relieved with usual measures’. Length of time sensations lasted are rated as less than 1min, 1–5min, 5–15min, 15–30min, 30–60min and more than 60min.

Social ties are defined from the Cohen Social Network Diversity Index. The index assesses participation in 12 types of social relationships in which the respondent speaks with someone in the relationship every two weeks. Higher scores are indicative of a more diverse social network.18

2.3. Myocardial ischaemia classification
We defined myocardial ischaemia as a positive response on any of three non-invasive stress tests used in WISE and readily available in the community. These included exercise electrocardiography (ECG) (n=129), dobutamine stress echocardiography (n=77) and exercise (n=103) or pharmacologic (n=201) myocardial perfusion SPECT. About one-quarter (n=104) of the women had more than one test. Each individual test was evaluated for a positive response. On an exercise ECG, a positive reading was defined as exercise-induced ST-segment depression of ≥1mm in at least two contiguous leads.

2.4. Echocardiographic procedures
Echocardiographic procedures have been previously described.19In brief, for dobutamine stress echocardiography, the leftventricle was divided into sixteen segments, each of which was scored for evidence of hypokinetic, akinetic or dyskinetic wall motion abnormalities. A new or worsening wall motion abnormality was defined by comparing each of the 16-segment myocardial model at baseline and during peak dobutamine infusion. For rest and peak infusion, a total of wall motion abnormalities was scored from each of the 16 myocardial segments. If the peak dobutamine score was greater than the baseline score in one or more of the segments, the test was scored as positive, reflecting new or worsening wall motion abnormalities, suggestive of myocardial ischaemia.

2.5. SPECT imaging procedures
Protocols for acquisition, processing and imaging interpretation for the single photon emission computed tomographic imaging are those commonly employed and have been previouslydescribed.20However, imaging included the use of a 1 or 2-day protocol for tomographic imaging. The radioisotope used for SPECT imaging was Tc-99m sestamibi with doses averaging 8 and 22mCi injected at rest and approximately 1-min prior to the termination of exercise testing.

Tomographic imaging was performed at rest and immediately following exercise using a gamma camera interfaced with a computer; image acquisition was performed over a 180° semicircular orbit. Tomographic data was acquired in a 64x64 matrix for 64 projections in a step-and-shoot format. Image processing was accomplished using a ramp back-projection filter where each set of horizontal and vertical long axis and short axis images were normalized to maximal myocardial activity. Interpretation was performed by experienced readers who were blinded to clinical, exercise, and angiographic data. For the SPECT scan, the myocardium was divided into 6 segments: anterior, inferior, septal, apex, lateral and posterior walls. Evidence of inducible ischaemia with exercise was defined when new or worsening perfusion abnormalities were noted on the SPECT scan.

All exercise electrocardiographic, echocardiographic, and SPECT imaging results were interpreted locally but with investigators blinded to clinical, angiographic, and noninvasive imaging test results.

2.6. Quantitative angiographic core laboratory
Coronary angiograms were analysed by the core laboratory at Brown University (PI:BLS). Measurements included quantitative assessment as to the presence, severity and complexity of epicardial artery stenoses, using previously published methods.21Obstructive coronary artery disease (CAD) is defined as ≥50% stenosis in ≥one epicardial coronary artery.

2.7. WISE classifications
Women were classified into four groups: (1) women with obstructive CAD with evidence of myocardial ischaemia (CAD/ischaemia group); (2) women with obstructive CAD and no evidence of myocardial ischaemia (CAD/no ischaemia group); (3) women with no obstructive CAD with evidence of myocardial ischaemia (no CAD/ischaemia group); and (4) women with no obstructive CAD and no evidence of myocardial ischaemia (no CAD/no ischaemia group).

2.8. Statistical methods
Data are presented as means and the standard deviation for continuous variables and frequencies for categorical variables. Pearson correlation coefficients were used to assess bivariate associations of age with QOL measures. Differences across CAD, ischaemia and WISE categories were assessed using a general linear model with adjustments for age and education. Categorical variables such as education, ethnic groups, frequency of chest pain, duration and intensity of symptoms, presence/absence of risk factors and presence of co-morbid conditions were assessed using chi square. Stepwise linear regression analyses were used to model the three QOL measures (GR, DASI, BDI) separately as a function of CAD risk factors (including a history of hypertension, diabetes and dyslipidemia, current smoking, stress, waist circumference), demographic characteristics (age, education, social ties), current use of HRT, number of symptoms (continuous), duration, intensity, and frequency of chest pain (daily vs less). Both extent of obstructive angiographic CAD (yes/no) and classification of ischaemia (yes/no) were entered as dichotomous predictors. Variables were chosen for entry into the model based upon prior univariate and multivariate associations with QOL. Initial modelling showed chest pain symptoms were the dominant predictors of QOL scores. Models were run without symptoms to assess other associations. There was little change in the independent predictors of QOL with symptoms deleted from the model, except a decrease in the R square value. The final model presented is that with the largest R square with both CAD and ischaemia fixed as predictors. Criterion for entry into the initial model was P=0.15. Probability values <0.05 were considered statistically significant. Analyses were performed using SAS software release 6.12 (Cary, NC).


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Table 1presents the baseline characteristics of this population of women presenting with anginal chest pain. The women were primarily a postmenopausal group and had a history of hypertension and dyslipidemia as dominant risk factors.


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Table 1 Baseline characteristics by WISE categories

 
Of the 406 WISE women, 68 (17%) were classified as having CAD/ischaemia, 52 (13%) as CAD/no ischaemia, 105 (26%) as no CAD/ischaemia, and 181 (44%) as no CAD/no ischaemia. When we examined the demographic and risk factors by these WISE categories, there were differences in age, race, and some risk factors by the WISE groupings. As expected, women with CAD were older than women without disease, with the youngest women in the group no CAD/ischaemia. This latter group also had the smallest waist circumference and fewest women with a history of hypertension and dyslipidemia.

3.1. QOL and demographic/risk factors
The general QOL rating was positively associated with age (r=0.14, P<0.01) while the BDI was negatively associated (r=–0.16, P<0.01). Both of these measures show QOL scores were better for older women. Associations between age and DASI were not statistically significant. Women with a greater than high school education rated their QOL higher than those with less, across all three measures (age-adjusted P<0.01). Stratification by ethnic group (Caucasian vs. African-American) showed that Caucasian women had higher general rating thanAfrican-American (7.3±2.1 vs 6.6±2.1) (P<0.05, adjusted for education), respectively and better BDI scores (10.5±8.2 vs 13.3±8.8) (P<0.05, adjusted for education), respectively, but there was no statistically significant difference in the DASI.

Women with a history of hypertension, history of dyslipidemia and current smokers rated their GR QOL, DASI and BDI (all P<0.05) worse than women without these risk factors. While current hormone replacement therapy (HRT) was associated with higher QOL scores for the DASI (23.2±15.9 vs 20.2±14.8, P<0.05) in comparison to those not on HRT, there was no difference in GR and BDI scores for this subgroup.

3.2. QOL and obstructive CAD
Initial results demonstrate that there was no difference in the general QOL rating (7.2±2.2 vs 7.1±2.1) but DASI scores are lower (18.6±13.0 vs 22.9±15.7, P=0.01) and BDI scores were higher (11.8±8.7 vs 10.7±8.3, P<0.05) in women with obstructive CAD, compared to women without obstructive CAD.

3.3. QOL and myocardial ischaemia
Overall, women with myocardial ischaemia had better QOL, evidenced by higher GR QOL scores (7.4±2.0 vs 7.0±2.2, P=0.04), higher DASI (22.9±14.9 vs 20.6±15.2, P=0.14) and lower BDI scores (9.9±7.5 vs 11.9±8.9, P=0.01) compared to women without ischaemia.

3.4. QOL and obstructive CAD/myocardial ischaemia
In the overall group, women rate their life toward the positive (best) end of the GR scale, but there was some limitation in ability to do everyday tasks (DASI) and an indication of mild depressive symptoms (BDI). The worst GR, DASI and BDI scores were observed in women with CAD/no ischaemia.

Of the four groups, women with CAD/no ischaemia also reported the most symptoms (Fig. 1). There was, however, no difference in the frequency or the duration of the anginal symptoms across the four groups. A higher proportion of women (29%) with CAD/no ischaemia indicate that the intensity of the pain as ‘not tolerable’ compared to CAD/ischaemia (16%), no CAD/ischaemia (13%) and no CAD/no ischaemia (Table 2) (12%), P=0.03.



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Fig. 1 Box and whisker plots of anginal symptoms by WISE categories: coronary artery disease (CAD)/ischaemia, CAD/no ischaemia, No CAD/ischaemia and no CAD/no ischaemia. Maximum and minimum values are indicated on the end of the whisker, quartile (25th percentile—bottom, 75th percentile—top) values are shown on the edge of the box.

 

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Table 2 Comparison of Quality of Life measures by WISE categories

 
3.5. Predictors of QOL
Factors predictive of QOL are presented in Table 3. The number of anginal symptoms, as well as the intensity and duration of symptoms were associated with lower QOL. Education (beyond high school) was associated with higher QOL for the GR and the DASI. Diversity of social ties was also a positive influence on all three QOL measures. Forcing CAD and ischaemia into the model did not change the outcome as shown in Table 3. Repeat modelling without including the symptoms, demonstrated that the explanatory variables remained the same, although ischaemia entered the model for the BDI at the last step (P=0.049) as a positive predictor. The multivariate results were consistent with our univariate findings, and demonstrate that after controlling for age, risk factors, environmental stress, race and social ties, women with ischaemia had better BDI scores.


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Table 3 Significant independent predictors of QOL measures based on linear regression modelsa

 
3.6. QOL and co-morbidity
Because the QOL scores, number of symptoms and frequency of anginal chest pain in women with no CAD/no ischaemia were similar to those of women with obstructive CAD, and worse than the women with no CAD/ischaemia, we investigated what other conditions might adversely impact QOL in this group without evidence of cardiac disease. The women without ischaemia may be so functionally impaired, so decompensated with symptoms, and heavier that they cannot provoke ischaemia through conventional testing. The women with no CAD/no ischaemia had larger waist-hip ratios (0.86±0.10 vs 0.82±0.10, P<0.01), more migraine headaches (33% vs 21%, P<0.03), and oesophageal reflux (54% vs 38%, P<0.01) compared to the no CAD/ischaemia women. However, compared to the CAD group, there was no significant difference in these conditions.

We additionally evaluated the ability to exercise during the treadmill testing as a comorbidity marker and possible explanation for the more adverse QOL in the no CAD/no ischaemia women. Of the no CAD/no ischaemia women, 39/181 (22%) compared with 69/105 (66%) of the no CAD/ischaemia women underwent exercise stress testing (P<0.01). Among the 108 women from both groups with exercise ECG testing data, the group with no CAD/no ischaemia also had lower achieved MET values (5.8 vs 7.1, age adjusted P<0.01) than those women with no CAD/ischaemia.

We also examined the association of QOL with each of the individual tests (exercise ECG, dobutamine stress echocardiography and exercise or pharmacologic myocardial perfusion SPECT). Women with a nonischaemic response rated their QOL lower than those with evidence of ischaemia, regardless of obstructive CAD status.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
4.1. Obstructive CAD
Our results demonstrate that among women undergoing coronary angiography for suspected myocardial ischaemia, while obstructive CAD is associated with reduced QOL, evidence of myocardial ischaemia, paradoxically, is not. The number and severity of symptoms, conversely were independent predictors of QOL scores in our population of women. These findings were consistent across all three subjective measures of health-related QOL: (1) general rating QOL (2) functional capacity, measured by the DASI and (3) depressive symptoms, measured by the BDI. Our findings suggest that chest pain symptoms are primary QOL determinants among women compared to the underlying potential causes of symptoms, e.g. obstructive CAD and myocardial ischaemia.

Prior work demonstrates that patients with CAD have a reduced QOL. In the RITA trial, while the majority (70–80%) of patients did not have angina 2 years after revascularization, patients with persistent angina following revascularization had greater QOL impairment than angina-free patients, even if their anginal symptoms were only mild.5In a recent study of 41 women with CAD, QOL was measured with the Seattle Angina Questionnaire and the ability to perform everyday tasks was measured by the Household Activities Scale. The women perceived that cardiac symptoms limited their ability to perform household tasks.10These data are consistent with the current analyses that demonstrate that symptoms per se rather than CAD are primary determinants of QOL.

Our findings confirm prior studies concerning the negative association of the number, severity and frequency of symptoms on QOL in both patients with and without obstructive CAD. In a cross-sectional study of 170 coronary patients (79% male), QOL was assessed using both the short form SF-36 and the Angina Pectoris Quality of Life Questionnaire (APQLQ). Asymptomatic patients reported a better QOL profile than symptomatic patients. QOL profile scores declined as the severity of the chest pain reported increased. This impact was seen in the major QOL domains: physical, social and mental.7In a study of 66 patients (83% female) with normal angiograms and chest pain, QOL scores were inversely related to the number and severity of chest pain episodes and the overall severity of anginal chest pain.8In a study by Greene and colleagues of 212 patients (61% male), reporting chest discomfort and referred for coronary angiographic evaluation, more symptoms were reported by patients with no significant CAD, regardless of age or gender.22The current results extend these observations to a large cohort of women with and without obstructive CAD.

4.2. Myocardial ischaemia
Our results that women with ischaemia rated their QOL higher than women without ischaemia seem paradoxical. When we investigated women that underwent exercise testing, women with ischaemia achieved higher METS than those without ischaemia, suggesting that they were in fact less functionally impaired than women without ischaemia. A study by Mattera and colleagues23of 238 patients (32% women) referred for exercise ECG with myocardial perfusion imaging and an evaluation of QOL found similar results. Patients with ischaemia by exercise ECG testing and myocardial perfusion had the same or better QOL scores than patients with normal test results. Additionally, patients with ischaemia by ECG testing achieved the highest METS compared with patients with normal or nondiagnostic test results.23These data combined with the current study results indicate that patients able to exercise to a sufficient workload to elicit an ischaemic response may have better QOL because they are less functionally impaired.

4.3. Beneficial associations
Factors that were associated with better QOL scores in our group of women included current use of HRT and greater social ties (e.g. more social roles). Higher DASI scores were found among users of HRT. This finding is consistent with the work of Adamson et al. who recently reported the beneficial effect of esterified estrogens combined with methyltestosterone on emotional well-being in postmenopausal women with chest pain and normal coronary arteries.24Alternatively, it has been demonstrated that women who chose to take HRT have better lifestyle habits and higher SES,25important contributions to QOL. Further work is needed to determine if these beneficial associations are causative.

4.4. Study limitations
The current study results are limited by the cross-sectional design, which precludes inferences regarding causality between our variables and the QOL measures. Grouping the noninvasive stress tests under the one heading of ‘ischaemia’ could be viewed as a limitation. However, when we examined QOL for each of the individual stress tests, the results were similar, e.g. women with no evidence of ischaemia rated their QOL lower than those with evidence of ischaemia. The lack of a core laboratory for the evaluation of the noninvasive tests may be considered a limitation; however, while all exercise, electrocardiographic, echocardiographic and SPECT imaging results were interpreted locally, the investigators were blinded to clinical and angiographic results.

4.5. Relevance
The current and prior study results have relevance to understanding QOL in women with suspected ischaemic heart disease. From the current study results and prior work, it is evident that physiologic and anatomic variables may have an impact on QOL but do not solely determine it in the setting of ischaemic heart disease.26Chest pain symptoms, regardless of underlying cause are the most important QOL determinants in these and prior study results. Prior WISE results by Rutledge et al.27found that a history of anxiety disorders was associated with a lower probability of obstructive angiographic CAD, confirming again a negative association between psychologic attributes, symptoms and disease in this population of women. Women with no CAD/no ischaemia may benefit from diagnostic and therapeutic strategies that address a variety of aetiologies, including anxiety and depression. While our population of women had a relatively high prevalence of noncardiac comorbidity (migraine headaches, oesophageal reflux), it was unclear if these associations represent cause or effect of symptoms in the no CAD/no ischaemia women. Clearly research aimed at linking mechanisms to chest pain symptoms is needed to develop effective therapeutic options for these women.


    Appendix A
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Symptoms from the WISE Symptom History Form
Symptoms Symptoms

Abdominal pain Heartburn/indigestion/stomach problems
Arm pain or shoulder pain Impending doom
Back pain Jaw pain
Chest pain Loss of consciousness/fainting
Chest pressure Nausea/vomiting
Chest tightness Neck pain
Chest discomfort (heaviness, burning, tenderness) Numbness/tingling in arm or hand
Cough Palpitations/rapid heart rate
Dizziness, lightheadedness Shortness of breath/difficulty breathing
Feel lousy Sweating
Headache Weakness/fatigue/faintness


    Acknowledgments
 
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, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, New Jersey, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, California, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, Pennsylvania, and QMED, Inc., Laurence Harbor, New Jersey.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Appendix A
 References
 

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