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Background Although dyspnea is a common symptom, there has been only limited investigation of its prognostic significance among patients referred for cardiac evaluation.
Methods We studied 17,991 patients undergoing myocardial-perfusion single-photon-emission computed tomography during stress and at rest. Patients were divided into five categories on the basis of symptoms at presentation (none, nonanginal chest pain, atypical angina, typical angina, and dyspnea). Multivariable analysis was used to assess the incremental prognostic value of symptom categories in predicting the risk of death from cardiac causes and from any cause. In addition, the prognosis associated with various symptoms at presentation was compared in subgroups selected on the basis of propensity analysis.
Results After a mean (±SD) follow-up of 2.7±1.7 years, the rate of death from cardiac causes and from any cause was significantly higher among patients with dyspnea (both those previously known to have coronary artery disease and those with no known history of coronary artery disease) than among patients with other or no symptoms at presentation. Among patients with no known history of coronary artery disease, those with dyspnea had four times the risk of sudden death from cardiac causes of asymptomatic patients and more than twice the risk of patients with typical angina. Dyspnea was associated with a significant increase in the risk of death among each clinically relevant subgroup and remained an independent predictor of the risk of death from cardiac causes (P<0.001) and from any cause (P<0.001) after adjustment for other significant factors by multivariable and propensity analysis.
Conclusions In a large series of patients, self-reported dyspnea identified a subgroup of otherwise asymptomatic patients at increased risk for death from cardiac causes and from any cause. Our results suggest that an assessment of dyspnea should be incorporated into the clinical evaluation of patients referred for cardiac stress testing.
For years, we have included a single questionnaire item concerning dyspnea in the assessment of all patients undergoing myocardial-perfusion single-photon-emission computed tomography (SPECT) at rest and during stress. Follow-up survival data have been obtained in a large cohort of these patients. We analyzed the value of dyspnea as a predictor of death from cardiac causes and from any cause.
Methods
Study Design
We evaluated consecutive patients free of known cardiomyopathy or valvular disease who underwent separate-acquisition dual-isotope myocardial-perfusion SPECT at rest with the use of thallium-201 as a tracer and during exercise-induced or vasodilator-induced stress with the use of technetium-99m (sestamibi) between January 1991 and May 2000. All patients were prospectively enrolled in a registry, and follow-up data were obtained for at least one year after testing. Each patient provided written informed consent (including consent to participate in our registry) at the time of exercise testing. The study was approved by the institutional review board of Cedars–Sinai Medical Center in Los Angeles. Funding for the follow-up aspects of this study was provided by grants from Bristol-Myers Squibb Medical Imaging and Fujisawa Healthcare. The sponsors had no role in the conception and design of the study, the collection, analysis, and interpretation of the data, and the drafting and revision of the manuscript.
Patients were divided into five categories according to their self-reported symptoms of chest pain and dyspnea at the time of testing. Typical angina was defined as chest pain that was substernal, occurred during stress, and resolved within 10 minutes after rest or the receipt of nitroglycerin.8 Chest pain was classified as atypical angina if two of these features were present and as nonanginal if one or none of these features were present. Among patients without chest discomfort, those who responded affirmatively to the question "Do you experience shortness of breath?" were classified as having dyspnea; the remainder were classified as asymptomatic. Dyspnea was not coded in patients with chest pain.
Stress Testing
Patients underwent resting and stress myocardial-perfusion SPECT as previously described9,10 with the use of symptom-limited stress induced by exercise on a treadmill or by a vasodilator.9,10 The response of the heart rate to stress was considered abnormal if the heart-rate reserve — calculated as follows: (the peak heart rate – the resting heart rate) ÷ ([220 – age] – the resting heart rate) — was less than 80 percent during exercise-induced stress11 or if the ratio of the peak heart rate to the resting heart rate during vasodilator-induced stress was 1.12 or less.10
Myocardial-Perfusion Spect
Myocardial-perfusion SPECT was performed with the use of 180-degree acquisition and standard energy windows.9 Projection data were reconstructed into transaxial tomograms and automatically reoriented into short-axis images. In patients studied after 1994, eight-frame gated myocardial-perfusion SPECT was performed to assess the left ventricular ejection fraction and end-diastolic volume after stress with the use of an automatic program.12
Experienced observers used a five-point scoring system to evaluate 20 segments of each myocardial-perfusion SPECT.9,13 An abnormal result was defined as one in which at least 5 percent of myocardium was abnormal during stress. Ischemia was defined by the presence of reversible defects in at least 5 percent of myocardium,13 and a fixed defect was defined by the finding that at least 5 percent of myocardium was abnormal at rest.
Follow-up
Deaths were identified through our hospital-based patient-information system (WebVS) and the Social Security Death Index. To ascertain the cause of death, the information provided by WebVS and the death certificates obtained for all who died in Los Angeles County were reviewed consensually in a blinded fashion by two experienced cardiologists. Death from any cause was defined as any death during follow-up. Death from cardiac causes was defined as death from any cardiac cause (e.g., lethal arrhythmia, myocardial infarction, or pump failure). Follow-up in the remaining patients was sought through a mailed questionnaire or a scripted telephone interview performed in a blinded fashion with patients who did not respond to the questionnaire, followed by the use of WebVS. Patients who were not confirmed to have died and who had no follow-up information (obtained by means of the mailed questionnaire or telephone interview or at least one year of data in WebVS) were considered to be lost to follow-up.
Statistical Analysis
We compared available clinical, historical, myocardial-perfusion SPECT, and outcome data among the patients in each of the five symptom categories. Unadjusted means for continuous variables were compared with use of Student's t-test. Categorical variables were compared with use of a chi-square test. We used Bonferroni's test for adjusted pairwise comparisons by multiplying the ordinary, unadjusted pairwise P values by the number of comparisons in the family.14 All reported P values are two-sided.
A Cox proportional-hazards regression model15 was used to evaluate adjusted and unadjusted predictive values for death from cardiac causes and death from any cause according to the symptom category and to assess the incremental prognostic value of dyspnea over other clinical information. Survival was measured from the time of the original stress test. We used the date of last contact for patients who were not known to be deceased to calculate survival in the Cox survival analysis. For the Cox analysis of death from cardiac causes, we regarded deaths from other or unknown causes as censored observations. A significant increase in the global chi-square value after the addition of a variable indicated incremental prognostic value. Kaplan–Meier analysis was used to depict risk-adjusted cumulative survival curves comparing patients with symptoms with those who were asymptomatic at the time of testing.
Study end points were also analyzed in subgroups matched for propensity scores according to methods described elsewhere.16,17,18 We defined one subgroup that compared asymptomatic patients with patients with dyspnea and another that compared asymptomatic patients with those with typical angina. Logistic-regression modeling was used to generate a propensity score for having either dyspnea or angina. For this purpose, we used a nonparsimonious model, including all the available clinical variables, demographic variables, and variables associated with myocardial-perfusion SPECT. We applied Cox analysis to compare survival within these propensity-matched subgroups.
Results
A total of 20,572 patients were evaluated for inclusion in the study. The 1735 patients who underwent coronary revascularization within 60 days after testing were excluded, as were 846 patients (4.4 percent) lost to follow-up, resulting in a study population of 17,991 patients, of whom 11,888 (66.1 percent) underwent myocardial-perfusion SPECT with exercise-induced stress and 6103 (33.9 percent) underwent myocardial-perfusion SPECT with vasodilator-induced stress. In 5804 patients studied after 1994, eight-frame gated myocardial-perfusion SPECT was used to assess the left ventricular ejection fraction and end-diastolic volume after stress, as noted above.12
Table 1 shows the patients' clinical characteristics and the results of myocardial-perfusion SPECT, according to the symptoms at presentation. The distribution of symptoms at presentation and the distribution of results of myocardial-perfusion SPECT among the patients who were lost to follow-up were very similar to those among patients who were included in the analysis. Among those known to have coronary artery disease, as well as among those not known to have coronary artery disease, patients with dyspnea were older and had a higher rate of left ventricular enlargement on myocardial-perfusion SPECT than did the other four groups of patients. Patients with dyspnea also had higher rates of atrial fibrillation and left ventricular hypertrophy on electrocardiography (P<0.05) (data not shown). Patients with dyspnea had significantly higher rates of diabetes and hypertension than did asymptomatic patients, patients with nonanginal chest pain, and patients with atypical angina. As compared with asymptomatic patients, patients with dyspnea had similar levels of inducible ischemia in the absence of known coronary artery disease and slightly higher levels in the presence of known heart disease. But in both patients with and those without known heart disease, the level of inducible ischemia among patients with dyspnea was substantially less than that among patients with typical angina.
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In our study, patients with dyspnea, both those with and those without known coronary artery disease, had increased rates of death from cardiac causes and death from any cause. Among the latter, patients with dyspnea had four times the risk of death from cardiac causes of asymptomatic patients and more than twice the risk of patients with typical angina.
One potential explanation for these findings is that dyspnea reflects underlying cardiovascular disease. Along these lines, it is widely assumed that dyspnea can represent ischemia (an anginal equivalent).3 However, in our study, the level of inducible ischemia was similar among patients with dyspnea and asymptomatic patients without known coronary artery disease. Moreover, although patients with known coronary artery disease who reported dyspnea had a higher level of inducible ischemia than asymptomatic patients, the magnitude of the increase was substantially less than that among patients with typical angina. Nevertheless, patients with dyspnea had higher event rates than did patients with angina. Thus, our results do not provide objective evidence that dyspnea was associated with increased risk because it is an anginal equivalent. We cannot rule out the possibility, however, that patients with dyspnea had an increased event rate in part because they had "balanced" ischemia undetected by SPECT.
Left ventricular systolic dysfunction is another cardiac abnormality that could explain the association between dyspnea and mortality. We used three separate scintigraphic variables to rule out various relevant cardiac abnormalities: perfusion defects at rest, left ventricular enlargement at rest, and gated left ventricular ejection fraction. Among patients with no abnormalities on each of these assessments (normal function, normal left ventricular volume, or no scarring), there was still a tripling of cardiac event rates among those with dyspnea. The added prognostic value of dyspnea was most apparent in patients without a perfusion defect and those with a normal left ventricular ejection fraction on myocardial-perfusion SPECT.
We did not have data to assess diastolic function in our patients. Diastolic dysfunction may be an important contributor to heart failure, even in the presence of normal systolic function.19,20 Although patients with dyspnea had a greater incidence of both hypertension and left ventricular hypertrophy than other patients, dyspnea was still a significant determinant of outcome after adjustment for these variables.
Among noncardiac disorders, pulmonary disease would be a leading candidate to explain our findings. We did not have information in our database regarding the presence or absence of a history of chronic lung disease, but the relationship between dyspnea and clinical events was nearly identical among our 2282 smokers and 15,709 nonsmokers. Anemia and psychogenic causes of dyspnea were not evaluated.
It is not readily apparent why dyspnea is associated with a poorer prognosis among patients without underlying left ventricular systolic dysfunction after adjustment for the extent of myocardial ischemia, but recent data indicate several possible explanations. Many patients with coronary artery disease have paradoxical peripheral vasoconstriction during exercise rather than the vasodilation that constitutes the normal peripheral thermoregulatory vascular response to exercise.21,22 Could impaired heat regulation in patients with peripheral vasoconstriction cause impaired exercise tolerance and sensations of dyspnea? Alternatively, the development of coronary artery disease is associated with inflammatory proteins that can potentially induce somatic symptoms, such as malaise and fatigue.23 Perhaps a subjective sense of dyspnea can sometimes accompany such somatic symptoms.
There is only a sparse literature concerning the prognostic significance of dyspnea in patients with known or suspected cardiac disease. A few older studies are supportive of the findings of our study.4,5,6,7 By contrast, in one recent study,18 the differences in outcome between asymptomatic patients and patients with dyspnea disappeared after propensity analysis was applied to adjust for differences in patients' characteristics. Comparison of this study to our own is difficult because of differences in exclusion criteria between the two studies, differences in the designation of dyspnea (reported by the patient or identified by the referring physician), and differences in the variables used for propensity analysis, such as our inclusion of covariates based on myocardial-perfusion SPECT that reflect the percentage of ischemic and scarred myocardium. In addition, experience has demonstrated that differences in "pretest referral biases" (i.e., differences in the clinical characteristics of referral populations)24,25 can markedly influence the perceived prognostic accuracy of clinical variables among studies. Accordingly, there is a need to assess the extent to which the prognostic significance of dyspnea is influenced by pretest referral bias across various patient populations.
Our study has a number of limitations. Ventricular function was not assessed in all the patients, since gated myocardial-perfusion SPECT, required for its assessment, was not routinely performed until 1995. We used only a single dichotomous question concerning dyspnea, which did not grade the severity or precipitants of the symptom. By comparison, the American Thoracic Society uses a five-point scale for dyspnea.26 Paradoxically, this limitation underscores the strength of our data, since dichotomously evaluated test variables generally convey less inherent information than variables that are classified in more strata.27 Since we only coded dyspnea among patients without chest pain, we could not evaluate the potential interaction between dyspnea and symptoms of chest pain. We also did not evaluate the reproducibility of the self-reported symptoms. Historical or testing information regarding lung disease would have been useful. In addition, since our study patients represent a referral population for myocardial-perfusion SPECT, caution should be exercised in extrapolating our findings to the general population.
The most important limitation of our study is that, because dyspnea is closely associated with a variety of both cardiovascular and noncardiovascular disorders, it may not have been possible to account for all of the important resulting interactions. However, given the fact that the association between dyspnea and the outcome persisted after extensive assessment of the effect of other factors, it is an important observation that dyspnea as a presenting symptom in patients undergoing noninvasive testing is associated with an increased risk of death from any cause and from cardiac causes, perhaps for other reasons in addition to those commonly recognized.
In our population, asymptomatic patients without dyspnea had a rate of adverse events that was similar to the rate among those with chest pain. Similar findings have been noted by Christopher Jones et al.18 These observations may be due in part to the tendency to designate as "asymptomatic" patients with known or suspected cardiac disease who have symptoms other than chest pain that have been noted to be associated with an increased incidence of adverse events, such as a sense of exhaustion,28 difficulty in relaxing,29 depressive symptoms,30 and sleeplessness.31 For instance, in a follow-up of 5053 male college alumni, those responding "frequently" to the question "how often do you experience exhaustion (except after exercise)" had twice the rate of death from cardiac causes as did other respondents over a 12-year follow-up.28 Given our findings regarding dyspnea, these other somatic symptoms may also deserve further study relative to their prognostic significance in cardiac populations.
Our results indicate that dyspnea is an important symptom among patients with suspected and known coronary artery disease and imply that when dyspnea is present, the likelihood of death from cardiac causes and from any cause is increased. On the basis of our results, it may be appropriate to include an evaluation of dyspnea in the clinical assessment of patients referred for cardiac stress testing. It may also be appropriate to include an evaluation of dyspnea in future efforts to refine algorithms (such as the Duke Treadmill Score) that are used to assess the prognosis of coronary artery disease.
Presented in part at the annual American Heart Association Scientific Sessions, New Orleans, November 7–10, 2004.
Dr. Rozanski reports having received lecture fees from Bristol-Myers Squibb and Pfizer. Dr. Hachamovitch reports having served as a consultant to King Pharmaceuticals, Bristol-Myers Squibb Medical Imaging, and Fujisawa Healthcare and having received lecture fees from Bristol-Myers Squibb Medical Imaging and Fujisawa Healthcare. Dr. Germano reports having received lecture fees from Bristol-Myers Squibb. Dr. Berman reports having received grant support from Bristol-Myers Squibb Medical Imaging and Medtronic and lecture fees from Fujisawa Healthcare and Bristol-Myers Squibb Medical Imaging. The software used to measure ejection fractions and volumes is owned by Cedars–Sinai Medical Center, which receives royalties from its licensing. A minority portion of those royalties is shared by Drs. Berman and Germano. Dr. Abidov was a Save-A-Heart Foundation Research Fellow in Cardiac Imaging at the Cedars–Sinai Medical Center during the data collection and analysis.
We are indebted to the nurse practitioners, nuclear technicians, members of the Artificial Intelligence in Medicine group, research coordinators, and follow-up team in the Cardiac Imaging Department, Cedars–Sinai Medical Center; to Dr. Xingping Kang for technical assistance in the preparation and submission of the manuscript; and to Mrs. Heidi Gransar for statistical assistance.
Source Information
From the Department of Imaging, Division of Nuclear Medicine, and the Department of Medicine, Division of Cardiology, Cedars–Sinai Medical Center, Los Angeles (A.A., S.W.H., F.A.-E., I.C., J.D.F., G.G., D.S.B.); the Department of Medicine, St. Joseph Mercy Oakland Medical Center, Pontiac, Mich. (A.A.); the Division of Cardiology, St. Luke's–Roosevelt Hospital Center, New York (A.R.); the Cardiovascular Division, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles (R.H.); and the Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles (J.D.F., G.G., D.S.B.).
Address reprint requests to Dr. Berman at the Department of Imaging, Cedars–Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, or at bermand{at}cshs.org.
References
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Related Letters:
Dyspnea and Stress Testing
Haji S. A., Cuculi F., Erne P., Piérard L. A., Lancellotti P., Takagi H., Kato T., Matsuno Y., Stern S., Abidov A., Rozanski A., Berman D. S.
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N Engl J Med 2006;
354:871-873, Feb 23, 2006.
Correspondence
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