RESEARCH ARTICLE
Prognostic Importance of Dyspnea for Cardiovascular Outcomes and Mortality in Persons without Prevalent Cardiopulmonary Disease: The Atherosclerosis Risk in Communities Study a11111
Mario Santos1,2, Dalane W. Kitzman3, Kunihiro Matsushita4, Laura Loehr5, Carla A. Sueta5, Amil M. Shah1* 1 Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, United States of America, 2 Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Porto, Portugal, 3 Wake Forest Baptist Medical Center, Winston Salem, NC, United States of America, 4 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America, 5 University of North Carolina, Chapel Hill, NC, United States of America
OPEN ACCESS Citation: Santos M, Kitzman DW, Matsushita K, Loehr L, Sueta CA, Shah AM (2016) Prognostic Importance of Dyspnea for Cardiovascular Outcomes and Mortality in Persons without Prevalent Cardiopulmonary Disease: The Atherosclerosis Risk in Communities Study. PLoS ONE 11(10): e0165111. doi:10.1371/journal. pone.0165111 Editor: Katriina Aalto-Setala, University of Tampere, FINLAND Received: May 8, 2016 Accepted: October 6, 2016
* [email protected]
Abstract
Background The relationship between dyspnea and incident heart failure (HF) and myocardial infarction (MI) among patients without previously diagnosed cardiopulmonary disease is unclear. We studied the prognostic relevance of self-reported dyspnea for cardiovascular outcomes and all-cause mortality in persons without previously diagnosed cardiopulmonary disease.
Published: October 25, 2016 Copyright: © 2016 Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: Work for this manuscript was supported research grants from the Portuguese Foundation for Science and Technology (HMSP- ICJ/0013/ 2012; M.S.), the National Institutes of Health (grant 1K08HL116792-01A1; A.M.S.), and the American Heart Association (grant 14CRP20380422; A.M. S.). The sponsors had no role in the study design,
Methods and Results We studied 10 881 community-dwelling participants (mean age 57±6, 56% women, 25% black) who were free of prevalent cardiopulmonary disease from Atherosclerosis Risk in Communities Study. Dyspnea status at study entry using the modified Medical Research Council (mMRC) scale. The primary outcomes were time to HF, MI or all-cause death. Dyspnea prevalence was 22%, and was mild (mMRC grade 1 or 2) in 21% and moderate-tosevere (mMRC 3 or 4) in 1%. The main correlates of dyspnea were older age, female sex, higher BMI and active smoking. Over a follow-up of 19±5 years, greater self-reported dyspnea severity was associated with worse prognosis. Mild dyspnea was associated with significantly heightened risk of HF (adjusted Hazard Ratio, HR,1.30; 95% CI: 1.16–1.46), MI (adjusted HR 1.34; 95%CI: 1.20–1.50), and death (adjusted HR 1.16; 95%CI: 1.06–1.26), with moderate/severe dyspnea associated with an even greater risk (adjusted HR 2.14, 95%CI: 1.59–2.89; 1.93, 95%CI: 1.41–2.56; 1.96, 95%CI: 1.55–2.48, respectively).
PLOS ONE | DOI:10.1371/journal.pone.0165111 October 25, 2016
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Dyspnea and Risk of Cardiovascular Outcomes
data collection, data analysis, data interpretation, or writing of the manuscript. Competing Interests: Dr Shah reports receiving research support from Novartis, Actelion Pharmaceuticals Ltd, and Gilead. The other authors have no disclosures. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Conclusion In community-dwelling persons free of previously diagnosed cardiopulmonary disease, self-reported dyspnea is common and, even when of mild intensity, it is independently associated with a greater risk of incident HF, MI, and death. Our data emphasize the prognostic importance of even mild self-reported dyspnea for cardiovascular outcomes.
Introduction Dyspnea is a subjective experience of breathing discomfort that consists of distinct sensations of varying intensity[1]. In the general population, the overall prevalence of dyspnea is variable across studies,[2] related to differences in the distribution of known correlates of dyspnea such as age, gender, and smoking status, in the burden of comorbidities, and in the instrument used to measure dyspnea[3]. Despite variable prevalence estimates, dyspnea has been consistently associated with greater mortality in the general population[4, 5]. It is a more powerful predictor of clinical outcomes than objective physiologic measures such as pulmonary function testing[6, 7] in the general population, or angina in patients referred for cardiac evaluation[8]. However, little data is available regarding the prognostic relevance of self-reported dyspnea for non-fatal cardiovascular (CV) outcomes, such as incident myocardial infarction (MI) or heart failure (HF). In addition, scarce data is available regarding the prevalence and prognostic significance of dyspnea in African Americans, a population that carries a sizable proportion of the cardiovascular disease burden[9, 10]. We determined the prognostic relevance of self-reported dyspnea for CV outcomes in persons without previously diagnosed cardiopulmonary disease. We examined the correlates of self-reported dyspnea in a large biracial community-based cohort. We then defined the relationship between the presence and severity of dyspnea and all-cause mortality among participants with prevalent CV disease (MI, HF, stroke), pulmonary disease (COPD, asthma), or neither. Finally, among participants without previously diagnosed cardiopulmonary disease, we determined the prognostic relevance of dyspnea for incident MI and HF.
Methods Study population The Atherosclerosis Risk in Communities (ARIC) Study is an ongoing, prospective observational study. Detailed study rationale, design, and procedures have been previously published [11]. The original cohort included 15 792 persons aged 45 to 64 years recruited between 1987 and 1989 (Visit 1) from four communities in the United States: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Three subsequent follow-up visits occurred at 3-year intervals, with annual telephone interviews conducted between visits and currently ongoing. The ARIC study has been approved by Institutional Review Boards (IRB) at all participating institutions: University of North Carolina at Chapel Hill IRB, Johns Hopkins University IRB, University of Minnesota IRB, and University of Mississippi Medical Center IRB. Study participants provided written informed consent at all study visits. This analysis was restricted to ARIC participants who attended Visit 2 (1990–1992) and completed the dyspnea questionnaire (n = 13,425). We restricted our analyses to self-described black or white participants (40 exclusions due to other race). We analyzed a total of 13 385 U.S.
PLOS ONE | DOI:10.1371/journal.pone.0165111 October 25, 2016
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Dyspnea and Risk of Cardiovascular Outcomes
adults aged 46 to 70 year-old followed prospectively through 2011 (median follow-up of 19±5 years). From among this population, we identified participants free of prevalent cardiovascular and pulmonary disease (n = 10 881), defined as the absence of a previous history of HF, MI, stroke, COPD, and asthma.
Dyspnea Assessment The modified British Medical Research Council (mMRC) instrument is an activity-based dyspnea scale that describes five grades of dyspnea according to a positive response to the following questions (from the original MRC questionnaire[12]): dyspnea only with strenuous exercise (grade 0 or normal); dyspnea when hurrying on level ground or up a slight hill (grade 1); dyspnea when walking at one’s own pace on level ground (grade 2); dyspnea when walking 100 yards or for a few minutes (grade 3); and dyspnea at rest (grade 4). This questionnaire was administered to ARIC participants at Visit 2. We further arbitrarily grouped subjects as having no dyspnea (mMRC grade 0), mild dyspnea (mMRC grade 1 or 2), and moderate to severe dyspnea (mMRC grade 3 or 4).
Covariates Established definitions for hypertension, obesity, diabetes mellitus, HF, coronary heart disease (CHD), stroke, and smoking status were used as previously described in the ARIC study[13]. Briefly, sitting BP was measured. Recent use of antihypertensive medications, and smoking status were self-reported. Fasting plasma total cholesterol and Serum glucose were measured. Body mass index (kg/m2) was computed from measured weight and height. Preexisting heart failure was defined as: (1) self report of recent medications for heart failure, or (2) Stage 3 or “manifest heart failure” by Gothenburg criteria which rest on a physician’s judgment based on physical exam and history. Preexisting coronary heart disease at baseline was defined by selfreported prior physician diagnosis, or by evidence of MI by 12-lead ECG. Preexisting stroke was defined by any self-reported prior physician diagnosis of stroke. Self-reported COPD and asthma were assessed by the answer to the question “Has your doctor ever said you had: 1) chronic lung disease, such as chronic bronchitis, or emphysema; 2) asthma?”. Physical activity was expressed as the product of average metabolic equivalents by minutes during a week (METs min/week) of moderate-to-vigorous activity. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration (CKD-EPI) equation[14]. Medication history was obtained at Visit 2 by self-report of medication use during the previous two weeks and by reviewing medications brought by the participants to their visit. All covariates were ascertained at Visit 2 except for physical activity which was ascertained at Visit 1.
Clinical Events ARIC participants undergo surveillance for incident CHD events (fatal CHD, definite or probable MI, or coronary revascularization) and all-cause mortality as previously described in detail [15]. Briefly, incident CHD events were defined as the first occurrence of a fatal or non-fatal MI ascertained through surveillance, abstraction, and physician adjudication of hospitalizations with CHD-related ICD codes[15] and annual participant contact. Incident HF was based on HF hospitalization or HF death according to ICD codes (code 410 in any position) obtained by ARIC surveillance of hospital discharges[16]. Deaths were ascertained using National Death Index.
PLOS ONE | DOI:10.1371/journal.pone.0165111 October 25, 2016
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Dyspnea and Risk of Cardiovascular Outcomes
Statistical analysis Summary statistics were calculated as counts and percentages for categorical data and means and standard deviation for continuous data, by dyspnea category. Comparisons of baseline characteristics between groups were made using Pearson Chi-squared test and analysis of variance (ANOVA). To determine the cross-sectional correlates of dyspnea, we used linear regression (mMRC scale as dependent variable) and logistic regression (moderate-to-severe dyspnea as dependent variable); only covariates with a p
Prognostic Importance of Dyspnea for Cardiovascular Outcomes and Mortality in Persons without Prevalent Cardiopulmonary Disease: The Atherosclerosis Risk in Communities Study a11111
Mario Santos1,2, Dalane W. Kitzman3, Kunihiro Matsushita4, Laura Loehr5, Carla A. Sueta5, Amil M. Shah1* 1 Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, United States of America, 2 Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, University of Porto, Porto, Portugal, 3 Wake Forest Baptist Medical Center, Winston Salem, NC, United States of America, 4 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America, 5 University of North Carolina, Chapel Hill, NC, United States of America
OPEN ACCESS Citation: Santos M, Kitzman DW, Matsushita K, Loehr L, Sueta CA, Shah AM (2016) Prognostic Importance of Dyspnea for Cardiovascular Outcomes and Mortality in Persons without Prevalent Cardiopulmonary Disease: The Atherosclerosis Risk in Communities Study. PLoS ONE 11(10): e0165111. doi:10.1371/journal. pone.0165111 Editor: Katriina Aalto-Setala, University of Tampere, FINLAND Received: May 8, 2016 Accepted: October 6, 2016
* [email protected]
Abstract
Background The relationship between dyspnea and incident heart failure (HF) and myocardial infarction (MI) among patients without previously diagnosed cardiopulmonary disease is unclear. We studied the prognostic relevance of self-reported dyspnea for cardiovascular outcomes and all-cause mortality in persons without previously diagnosed cardiopulmonary disease.
Published: October 25, 2016 Copyright: © 2016 Santos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: Work for this manuscript was supported research grants from the Portuguese Foundation for Science and Technology (HMSP- ICJ/0013/ 2012; M.S.), the National Institutes of Health (grant 1K08HL116792-01A1; A.M.S.), and the American Heart Association (grant 14CRP20380422; A.M. S.). The sponsors had no role in the study design,
Methods and Results We studied 10 881 community-dwelling participants (mean age 57±6, 56% women, 25% black) who were free of prevalent cardiopulmonary disease from Atherosclerosis Risk in Communities Study. Dyspnea status at study entry using the modified Medical Research Council (mMRC) scale. The primary outcomes were time to HF, MI or all-cause death. Dyspnea prevalence was 22%, and was mild (mMRC grade 1 or 2) in 21% and moderate-tosevere (mMRC 3 or 4) in 1%. The main correlates of dyspnea were older age, female sex, higher BMI and active smoking. Over a follow-up of 19±5 years, greater self-reported dyspnea severity was associated with worse prognosis. Mild dyspnea was associated with significantly heightened risk of HF (adjusted Hazard Ratio, HR,1.30; 95% CI: 1.16–1.46), MI (adjusted HR 1.34; 95%CI: 1.20–1.50), and death (adjusted HR 1.16; 95%CI: 1.06–1.26), with moderate/severe dyspnea associated with an even greater risk (adjusted HR 2.14, 95%CI: 1.59–2.89; 1.93, 95%CI: 1.41–2.56; 1.96, 95%CI: 1.55–2.48, respectively).
PLOS ONE | DOI:10.1371/journal.pone.0165111 October 25, 2016
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Dyspnea and Risk of Cardiovascular Outcomes
data collection, data analysis, data interpretation, or writing of the manuscript. Competing Interests: Dr Shah reports receiving research support from Novartis, Actelion Pharmaceuticals Ltd, and Gilead. The other authors have no disclosures. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Conclusion In community-dwelling persons free of previously diagnosed cardiopulmonary disease, self-reported dyspnea is common and, even when of mild intensity, it is independently associated with a greater risk of incident HF, MI, and death. Our data emphasize the prognostic importance of even mild self-reported dyspnea for cardiovascular outcomes.
Introduction Dyspnea is a subjective experience of breathing discomfort that consists of distinct sensations of varying intensity[1]. In the general population, the overall prevalence of dyspnea is variable across studies,[2] related to differences in the distribution of known correlates of dyspnea such as age, gender, and smoking status, in the burden of comorbidities, and in the instrument used to measure dyspnea[3]. Despite variable prevalence estimates, dyspnea has been consistently associated with greater mortality in the general population[4, 5]. It is a more powerful predictor of clinical outcomes than objective physiologic measures such as pulmonary function testing[6, 7] in the general population, or angina in patients referred for cardiac evaluation[8]. However, little data is available regarding the prognostic relevance of self-reported dyspnea for non-fatal cardiovascular (CV) outcomes, such as incident myocardial infarction (MI) or heart failure (HF). In addition, scarce data is available regarding the prevalence and prognostic significance of dyspnea in African Americans, a population that carries a sizable proportion of the cardiovascular disease burden[9, 10]. We determined the prognostic relevance of self-reported dyspnea for CV outcomes in persons without previously diagnosed cardiopulmonary disease. We examined the correlates of self-reported dyspnea in a large biracial community-based cohort. We then defined the relationship between the presence and severity of dyspnea and all-cause mortality among participants with prevalent CV disease (MI, HF, stroke), pulmonary disease (COPD, asthma), or neither. Finally, among participants without previously diagnosed cardiopulmonary disease, we determined the prognostic relevance of dyspnea for incident MI and HF.
Methods Study population The Atherosclerosis Risk in Communities (ARIC) Study is an ongoing, prospective observational study. Detailed study rationale, design, and procedures have been previously published [11]. The original cohort included 15 792 persons aged 45 to 64 years recruited between 1987 and 1989 (Visit 1) from four communities in the United States: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Three subsequent follow-up visits occurred at 3-year intervals, with annual telephone interviews conducted between visits and currently ongoing. The ARIC study has been approved by Institutional Review Boards (IRB) at all participating institutions: University of North Carolina at Chapel Hill IRB, Johns Hopkins University IRB, University of Minnesota IRB, and University of Mississippi Medical Center IRB. Study participants provided written informed consent at all study visits. This analysis was restricted to ARIC participants who attended Visit 2 (1990–1992) and completed the dyspnea questionnaire (n = 13,425). We restricted our analyses to self-described black or white participants (40 exclusions due to other race). We analyzed a total of 13 385 U.S.
PLOS ONE | DOI:10.1371/journal.pone.0165111 October 25, 2016
2 / 15
Dyspnea and Risk of Cardiovascular Outcomes
adults aged 46 to 70 year-old followed prospectively through 2011 (median follow-up of 19±5 years). From among this population, we identified participants free of prevalent cardiovascular and pulmonary disease (n = 10 881), defined as the absence of a previous history of HF, MI, stroke, COPD, and asthma.
Dyspnea Assessment The modified British Medical Research Council (mMRC) instrument is an activity-based dyspnea scale that describes five grades of dyspnea according to a positive response to the following questions (from the original MRC questionnaire[12]): dyspnea only with strenuous exercise (grade 0 or normal); dyspnea when hurrying on level ground or up a slight hill (grade 1); dyspnea when walking at one’s own pace on level ground (grade 2); dyspnea when walking 100 yards or for a few minutes (grade 3); and dyspnea at rest (grade 4). This questionnaire was administered to ARIC participants at Visit 2. We further arbitrarily grouped subjects as having no dyspnea (mMRC grade 0), mild dyspnea (mMRC grade 1 or 2), and moderate to severe dyspnea (mMRC grade 3 or 4).
Covariates Established definitions for hypertension, obesity, diabetes mellitus, HF, coronary heart disease (CHD), stroke, and smoking status were used as previously described in the ARIC study[13]. Briefly, sitting BP was measured. Recent use of antihypertensive medications, and smoking status were self-reported. Fasting plasma total cholesterol and Serum glucose were measured. Body mass index (kg/m2) was computed from measured weight and height. Preexisting heart failure was defined as: (1) self report of recent medications for heart failure, or (2) Stage 3 or “manifest heart failure” by Gothenburg criteria which rest on a physician’s judgment based on physical exam and history. Preexisting coronary heart disease at baseline was defined by selfreported prior physician diagnosis, or by evidence of MI by 12-lead ECG. Preexisting stroke was defined by any self-reported prior physician diagnosis of stroke. Self-reported COPD and asthma were assessed by the answer to the question “Has your doctor ever said you had: 1) chronic lung disease, such as chronic bronchitis, or emphysema; 2) asthma?”. Physical activity was expressed as the product of average metabolic equivalents by minutes during a week (METs min/week) of moderate-to-vigorous activity. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration (CKD-EPI) equation[14]. Medication history was obtained at Visit 2 by self-report of medication use during the previous two weeks and by reviewing medications brought by the participants to their visit. All covariates were ascertained at Visit 2 except for physical activity which was ascertained at Visit 1.
Clinical Events ARIC participants undergo surveillance for incident CHD events (fatal CHD, definite or probable MI, or coronary revascularization) and all-cause mortality as previously described in detail [15]. Briefly, incident CHD events were defined as the first occurrence of a fatal or non-fatal MI ascertained through surveillance, abstraction, and physician adjudication of hospitalizations with CHD-related ICD codes[15] and annual participant contact. Incident HF was based on HF hospitalization or HF death according to ICD codes (code 410 in any position) obtained by ARIC surveillance of hospital discharges[16]. Deaths were ascertained using National Death Index.
PLOS ONE | DOI:10.1371/journal.pone.0165111 October 25, 2016
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Dyspnea and Risk of Cardiovascular Outcomes
Statistical analysis Summary statistics were calculated as counts and percentages for categorical data and means and standard deviation for continuous data, by dyspnea category. Comparisons of baseline characteristics between groups were made using Pearson Chi-squared test and analysis of variance (ANOVA). To determine the cross-sectional correlates of dyspnea, we used linear regression (mMRC scale as dependent variable) and logistic regression (moderate-to-severe dyspnea as dependent variable); only covariates with a p
