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The association of chronic cough with the risk of myocardial infarction: the Framingham Heart Study
The Association of Chronic Cough with the Risk of Myocardial Infarction: The Framingham Heart Study Agha W. Haider, MD, PhD, Martin G. Larson, ScD, Christopher J. O’Donnell, MD, MPH, Jane C. Evans, MPH, Peter W. F. Wilson, MD, Daniel Levy, MD PURPOSE: A persistent inflammatory response accompanying chronic infections may contribute to the risk of coronary atherothrombosis. Recent studies have reported an association between chronic respiratory infections and an increased risk of coronary heart disease; however, these reports have not accounted for important confounders such as impaired lung function. METHODS: We considered chronic cough as an indicator of chronic lung infection or inflammation in the original Framingham Heart Study participants aged 47 to 89 years. Chronic cough was defined as a cough present for at least 3 months in the preceding year and was categorized as either nonproductive or productive. The association of chronic cough with myocardial infarction was examined for six consecutive examination cycles (1965 to 1979) among participants free of myocardial infarction at the baseline examination. In a secondary analysis, plasma fibrinogen levels were measured during examination cycle 10 (1965 to 1967) in a subgroup of the study sample (n 5 1,288). Multivariable logistic regression analysis was performed adjusting for age, gender, smoking status, forced vital capacity, and other known risk factors.
RESULTS: The cross-sectional pooling method yielded 15,656 person-examinations in 3,637 subjects. During follow-up, there were 291 incident myocardial infarctions. Chronic nonproductive cough (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.1 to 2.8) and chronic productive cough (OR 1.6, CI 1.1 to 2.4) were independent predictors of myocardial infarction. Results were unchanged when we further adjusted for a history of heart failure. Adjusted plasma fibrinogen levels (mean 6 SD) were greater in those with chronic nonproductive cough than among those without cough (3.2 6 0.6 g/L versus 2.9 6 0.6 g/dL, P 5 0.001). CONCLUSIONS: These findings provide evidence that chronic cough, a clinical manifestation of pulmonary infection or chronic inflammation, is associated with the risk of myocardial infarction. Acute phase reactants such as plasma fibrinogen may be implicated in this association. Prospective serologic studies of infections as predictors of coronary heart disease risk are warranted. Am J Med. 1999;106:279 –284. q1999 by Excerpta Medica, Inc.
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tion have been associated with the risk of adverse cardiovascular events, suggesting that chronic inflammation is implicated in coronary heart disease risk (3–9). Bacterial and viral infections have been proposed as risk factors in a variety of studies (10 –16), and investigators have reported an increased risk of coronary heart disease in association with Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus infections (7,15,17–21). However, it is not known whether chronic infections and inflammation cause coronary heart disease or merely reflect other underlying disease processes that are also associated with the risk of coronary disease (22). Chronic bronchitis is characterized by a chronic productive cough, inflammation of the airways, and impaired lung function. Recurrent respiratory infections can cause exacerbations and progression of chronic bronchitis (23). Respiratory infections also often precede the development of myocardial infarction (10,24). Recent studies have reported an association between chronic bronchitis and an increased risk for cardiovascular disease (25,26). These studies, however, have not accounted for important potential confounders such as impaired lung function. The Framingham Heart Study provided an opportu-
nflammation appears to play an important role in the initiation and progression of atherosclerosis (1). Several components of the inflammatory response, including mononuclear cells, cytokines, and growth factors, have been found in and near coronary atherosclerotic lesions, and the presence of these inflammatory components has, in general, reflected the severity of the disease (2). Furthermore, systemic markers of inflamma-
From the National Heart, Lung, and Blood Institute’s Framingham Heart Study (AWH, MGL, CJO, PWFW, DL), Framingham, Massachusetts; the Section of Epidemiology and Preventive Medicine (AWH, MGL, JCE, DL), Boston University School of Medicine, Boston, Massachusetts; the Massachusetts Veterans Epidemiology Research and Information Center, Preventive Cardiology Department, VAMC, West Roxbury, Massachusetts (AWH); the Cardiac Unit (CJO), Massachusetts General Hospital; and the Divisions of Cardiology and Clinical Epidemiology (DL), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Supported by NIH/NHLBI contract NO1-38038. Dr. Haider’s fellowship was supported in part by a grant from Astra Pharm, Wayne, Pennsylvania. Dr. Haider is a recipient of the Sue McCarthy travel award of the British Hyperlipidemia Association. Requests for reprints should be addressed to Daniel Levy, MD, Framingham Heart Study, 5 Thurber Street, Framingham, Massachusetts 01702-6334. Manuscript submitted April 27, 1998, and accepted in revised form November 4, 1998. q1999 by Excerpta Medica, Inc. All rights reserved.
0002-9343/99/$–see front matter 279 PII S0002-9343(99)00027-3
Infections/Inflammation and Myocardial Infarction/Haider et al
nity to investigate the association of chronic cough, an indicator of pulmonary infection and chronic inflammation, with the risk of coronary heart disease. Smoking status, symptoms of chronic cough, other risk factors, and serial respiratory function tests have been obtained routinely at serial clinic visits. In addition, plasma fibrinogen level, a marker of inflammation and a potential risk factor for myocardial infarction, was measured at a single examination in a subset of the study sample.
farction. All suspected events were evaluated by a panel of three physicians who reviewed relevant Framingham Heart Study clinic notes, 12-lead electrocardiograms, hospitalization records, and pathology reports. The diagnosis of myocardial infarction was confirmed when at least two of the following criteria were fulfilled: (1) symptoms consistent with myocardial infarction; (2) diagnostic electrocardiographic changes of acute myocardial infarction; and (3) diagnostic elevation of cardiac enzymes (28). To ensure precision in dating of infarctions, unrecognized myocardial infarctions were excluded.
METHODS
Statistical Analysis
Since 1948, the Framingham Heart Study has followed up participants at regular intervals as part of a prospective population-based investigation of cardiovascular disease (27). In 1948, 5,209 men and women 28 to 62 years of age were enrolled in the study. Biennial follow-up visits were conducted to collect a medical history, physical examination, 12-lead electrocardiogram, and laboratory tests. Data regarding age, gender, height, weight, cardiovascular risk factors, and antihypertensive medication use were obtained routinely (28). Participants were categorized as smokers if they currently smoked cigarettes or if they had quit within 1 year prior to the clinic examination. For current smokers, the number of cigarettes usually smoked each day was recorded. Serum cholesterol levels were measured by the Abell-Kendal method (29). Diabetes mellitus was defined on the basis of a fasting blood glucose level greater than 7.77 mmol/L, two random nonfasting levels greater than 11.10 mmol/L, or the use of insulin or an oral hypoglycemic agent. Left ventricular hypertrophy was considered to be present when increased voltage was associated with major ST-T repolarization changes (“strain” pattern) (28). In a secondary analysis, fibrinogen levels were measured at examination cycle 10 (1965 to 1967) in 1,288 participants (30). A standardized questionnaire regarding cough was administered at each visit by the examining physician. Subjects were asked if they had a chronic cough lasting at least 3 months in the preceding year. Chronic cough was further categorized as either productive or nonproductive. To measure vital capacity, participants were instructed to take the deepest breath possible and exhale to the fullest extent into a 13.5 L Collins Vitalometer (Warren Collins, Braintree, Massachusetts). The best of three efforts was taken as the vital capacity. Vital capacity in milliliters was divided by the subjects’ height in inches to obtain the forced vital capacity-height index (28). First fatal or nonfatal acute myocardial infarction was the endpoint for this study. At each clinic examination, a history of interim hospitalizations and symptoms of heart disease was obtained. Medical records of participants who did not attend an examination were obtained and evaluated for the evidence of interim myocardial in280
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A cross-sectional pooling method (31) was used to examine the association of chronic cough with myocardial infarction over Framingham Heart Study examination cycles 10 to 15 (1965 to 1979). At each biennial examination, subjects free of prevalent myocardial infarction were followed for the subsequent 2 years for the development of myocardial infarction. Multivariable logistic regression (32) was performed adjusting for age, gender, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy on electrocardiogram, angina pectoris or coronary insufficiency (prolonged angina with documented ischemic changes on the electrocardiogram), total cholesterol level, smoking, and forced vital capacity adjusted for height. Stepwise logistic regression analysis was used to determine interactions between variables. Interactions were considered between cough status (none, nonproductive, productive) and several variables including gender, former smoking, current smoking, and presence of angina pectoris or coronary insufficiency. The association of plasma fibrinogen levels with chronic cough was assessed by multivariable linear regression analysis adjusting for age, gender, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy on electrocardiogram, angina pectoris or coronary insufficiency, total cholesterol level, smoking, and forced vital capacity adjusted for height (33). Statistical analysis was performed using SAS software (34,35). Odds ratios (OR) and 95% confidence intervals (CI) were estimated.
RESULTS The cross-sectional pooling method yielded 15,656 person-examination from 1,437 men and 2,200 women (mean age 65, range 47 to 89). Chronic cough was more prevalent in men (Table 1). Not surprisingly, pack-years of cigarette smoking were greater and forced vital capacity (adjusted for height) was lower in subjects with chronic cough compared with those with no cough. Chronic cough was more common among current smokers than among never-smokers in both men and women (Table 2). During follow-up, 291 first myocardial infarctions
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Table 1. Characteristics of the Study Sample of 3,637 participants*
Age (years) Male (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Antihypertensive treatment (%) Total cholesterol level (mmol/L) Angina or coronary insufficiency (%) Diabetes mellitus (%) Body mass index (kg/m2) Left ventricular hypertrophy (%) Cigarette smoking (pack-years) FVC/height (mL/inch)
No Cough (n 5 13,888)
Nonproductive Cough (n 5 758)
Productive Cough (n 5 1,010)
65 6 8 37 139 6 22 79 6 11 24 6.2 6 1.1 9 7 26 6 4 2 16 6 22 41 6 11
65 6 8 41 139 6 21 78 6 12 22 6.1 6 1.1 10 6 26 6 5 2 28 6 28 38 6 11
65 6 8 54 142 6 21 80 6 12 22 6.0 6 1.2 9 7 26 6 4 4 37 6 29 37 6 11
* Numbers (n) refer to person-examinations. Plus-minus values are mean 6 SD. FVC 5 forced vital capacity.
were documented (163 in men, 128 in women). In models adjusting for age and gender, participants with chronic nonproductive cough (OR 1.9, CI 1.2 to 3.0) or chronic productive cough (OR 2.1, CI 1.4 to 3.0) had an increased risk of myocardial infarction compared with subjects with no cough. Inclusion of smoking in the model decreased the odds ratios to 1.8 (CI 1.1 to 2.8) in those with nonproductive cough and to 1.8 (CI 1.2 to 2.6) in those with productive cough. Further adjusting for forced vital capacity (adjusted for height) reduced these odds ratios to 1.6 (CI 1.0 to 2.6) and 1.5 (CI 1.0 to 2.2). In the fully adjusted multivariable model, the odds ratios for myocardial infarction were 1.8 (CI 1.1 to 2.8) in those with chronic nonproductive cough and 1.6 (CI 1.1 to 2.4) in those with chronic productive cough (Table 3). Since cough may be a manifestation of heart failure, we carried out an analysis that also adjusted for a history of heart failure; the results did not change. The associations of chronic nonproductive and productive cough with the risk of myocardial infarction were unchanged when participants with baseline evidence of angina pectoris or coronary insufficiency were excluded from the analysis. No significant interactions between cough status and gender, smoking, and angina pectoris or coronary insufficiency were observed. Among never-
smokers, the odds ratio for myocardial infarction associated with productive cough was 2.0 (CI 0.7 to 5.7); for nonproductive cough, it was 1.5 (CI 0.6 to 3.9). Plasma fibrinogen levels (mean 6 SD) were greater in participants with chronic nonproductive cough compared with those with no cough (3.2 6 0.6 g/L versus 2.9 6 0.6 g/dL, P 5 0.001). A similar, but nonsignificant trend in fibrinogen levels was seen in participants with chronic productive cough compared with those with no cough (3.1 6 0.6 g/dL versus 2.9 6 0.6 g/dL, P 5 0.15).
DISCUSSION In this large prospective population-based study, we found an association between chronic cough and the risk of myocardial infarction. This association persisted after adjustment for traditional cardiovascular disease risk factors and pulmonary function as well as a history of heart failure. As fibrinogen levels were greater in subjects with chronic cough, these findings are consistent with the hypothesis that chronic cough is associated with persistent infection or inflammation, which contributes to the risk of coronary heart disease. Recent studies have reported the association between
Table 2. Prevalence of Chronic Cough according to Smoking Status at Baseline* Men Smoking Status
Women Smoking Status
Cough Status
Never (n 5 1195)
Former (n 5 2951)
Current (n 5 1837)
Never (n 5 4878)
Former (n 5 2271)
Current (n 5 2524)
No cough Nonproductive cough Productive cough
94.8% 2.6% 2.6%
90.8% 3.5% 5.7%
71.4% 9.6% 19.0%
93.4% 4.0% 2.6%
93.3% 3.5% 3.2%
82.7% 6.8% 10.5%
* Numbers (n) refer to person-examinations among a total of 3,637 participants. March 1999
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Table 3. The Association between Chronic Cough and the Risk of Incident Myocardial Infarction Nonproductive Cough Model Adjusted For Age, gender Age, gender, smoking Age, gender, smoking, FVC Age, gender, smoking, and multiple risk factors†
Productive Cough
Odds Ratio (95% Confidence Interval)* 1.9 (1.2–3.0) 1.8 (1.1–2.8) 1.6 (1.0–2.6) 1.8 (1.1–2.8)
2.1 (1.4–3.0) 1.8 (1.2–2.6) 1.5 (1.0–2.2) 1.6 (1.1–2.4)
* Compared with those without cough. † Also adjusted for FVC, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy on electrocardiogram, angina pectoris or coronary insufficiency, and total cholesterol level. FVC 5 forced vital capacity (adjusted for height).
chronic respiratory infections or inflammation and an increased risk for cardiovascular disease (25,26). Jousilahti et al (25) reported that chronic bronchitis was an independent predictor of coronary heart disease. In a cross-sectional study, Grau et al (26) demonstrated that chronic bronchitis was significantly associated with acute cerebrovascular ischemia after accounting for smoking and other potential confounders. These studies, however, did not account for impaired lung function or angina pectoris (25,26). It is important to adjust for lung function because ventilatory impairment, a hallmark of chronic bronchitis, is a strong predictor of cardiovascular morbidity and mortality (36,37). Several mechanisms might explain the association between chronic cough and myocardial infarction. Even after adjustment for smoking history, the association of chronic cough and myocardial infarction may be confounded by smoking to the extent that exposure to cigarette smoke is inadequately measured (37). However, in the present study the association between cough and coronary disease persisted after accounting for measured lung function. Both coronary disease and chronic obstructive airway disease are believed to arise, at least in part, from a chronic inflammatory process. A common defect in the ability to modulate tissue injury from such chronic inflammation might underlay both conditions (38). Chronic cough may simply be a marker of underlying inflammation or infection. Infection can be involved in thrombosis, arterial wall damage, and the atherosclerotic process directly or through changes in other risk factors (39 – 41). Perturbations in the coagulation system by infections may be an important trigger in the development of thrombosis and myocardial infarction (16). Cytokine production due to a variety of stimuli, including infections, may lead to instability of preexisting coronary plaques (2,39). An unstable plaque is more likely to rupture when subjected to mechanical stress (16) such as 282
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tachycardia, fluctuations in blood pressure, increased intrathoracic pressure, or even barotrauma caused by bouts of cough. Chlamydia pneumoniae infection has been consistently shown to be associated with the risk of developing cardiovascular disease (17,18,20,42– 46). A recent study suggested that recurrent infection in those with chronic C pneumoniae infection may precipitate myocardial infarction (20). Recurrent chest infection is also a frequent complaint of patients with chronic bronchitis. Low levels of antioxidants are believed to increase the susceptibility to infections and may be risk factors for coronary heart disease (47,48). The pathophysiological mechanism linking antioxidants, infections, inflammation, and the hemostatic system with myocardial infarction may be that many procoagulant factors are also acute phase proteins (5). Additionally, the white blood cell count is directly related to the risk of coronary thrombosis (49,50). The association between chronic cough and elevated fibrinogen level is intriguing. Fibrinogen level is predictive of incident and recurrent cardiovascular events (5,30). Elevated fibrinogen levels appear to reflect a persistent low-grade inflammatory process that is integral to atherogenesis (1). Previous studies have reported an association between cigarette smoking and plasma fibrinogen levels (30,50,51). This association may reflect increases in fibrinogen levels due to smoking-induced infection or inflammation. In the present study, fibrinogen levels were greater in those with chronic cough, even after adjusting for major risk factors including smoking and pulmonary function. Other contributing mechanisms may be the influence of fibrinogen on plasma viscosity, platelet aggregability, and amount of fibrin produced during thrombosis (51). There are several potential limitations to this study. The diagnosis of chronic bronchitis was based on symptoms and respiratory function measurements. However, relevant information on radiographic findings, serological, bacteriological, and laboratory evidence of infection were not available. There also was potential for misclassification of chronic cough; however, both nonproductive and productive cough were associated with an increased risk of myocardial infarction. Incomplete accounting for potential confounders such as vitamin or alcohol consumption and use of antimicrobial or anti-inflammatory therapy are other potential limitations (3,43,48,52). Finally, although infections and inflammations may play a role in the development of myocardial infarction, evidence of causality is lacking. We have demonstrated an association between chronic productive and nonproductive cough, which may be manifestations of pulmonary infection and inflammation, and myocardial infarction that persists after adjust-
Infections/Inflammation and Myocardial Infarction/Haider et al
ing for traditional coronary risk factors and pulmonary function. Our findings are consistent with the hypothesis that chronic infections or inflammation lead to myocardial infarction, and that fibrinogen may be a mediator of this process. Whether the association is causal can only be answered by additional studies.
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RESULTS: The cross-sectional pooling method yielded 15,656 person-examinations in 3,637 subjects. During follow-up, there were 291 incident myocardial infarctions. Chronic nonproductive cough (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.1 to 2.8) and chronic productive cough (OR 1.6, CI 1.1 to 2.4) were independent predictors of myocardial infarction. Results were unchanged when we further adjusted for a history of heart failure. Adjusted plasma fibrinogen levels (mean 6 SD) were greater in those with chronic nonproductive cough than among those without cough (3.2 6 0.6 g/L versus 2.9 6 0.6 g/dL, P 5 0.001). CONCLUSIONS: These findings provide evidence that chronic cough, a clinical manifestation of pulmonary infection or chronic inflammation, is associated with the risk of myocardial infarction. Acute phase reactants such as plasma fibrinogen may be implicated in this association. Prospective serologic studies of infections as predictors of coronary heart disease risk are warranted. Am J Med. 1999;106:279 –284. q1999 by Excerpta Medica, Inc.
I
tion have been associated with the risk of adverse cardiovascular events, suggesting that chronic inflammation is implicated in coronary heart disease risk (3–9). Bacterial and viral infections have been proposed as risk factors in a variety of studies (10 –16), and investigators have reported an increased risk of coronary heart disease in association with Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus infections (7,15,17–21). However, it is not known whether chronic infections and inflammation cause coronary heart disease or merely reflect other underlying disease processes that are also associated with the risk of coronary disease (22). Chronic bronchitis is characterized by a chronic productive cough, inflammation of the airways, and impaired lung function. Recurrent respiratory infections can cause exacerbations and progression of chronic bronchitis (23). Respiratory infections also often precede the development of myocardial infarction (10,24). Recent studies have reported an association between chronic bronchitis and an increased risk for cardiovascular disease (25,26). These studies, however, have not accounted for important potential confounders such as impaired lung function. The Framingham Heart Study provided an opportu-
nflammation appears to play an important role in the initiation and progression of atherosclerosis (1). Several components of the inflammatory response, including mononuclear cells, cytokines, and growth factors, have been found in and near coronary atherosclerotic lesions, and the presence of these inflammatory components has, in general, reflected the severity of the disease (2). Furthermore, systemic markers of inflamma-
From the National Heart, Lung, and Blood Institute’s Framingham Heart Study (AWH, MGL, CJO, PWFW, DL), Framingham, Massachusetts; the Section of Epidemiology and Preventive Medicine (AWH, MGL, JCE, DL), Boston University School of Medicine, Boston, Massachusetts; the Massachusetts Veterans Epidemiology Research and Information Center, Preventive Cardiology Department, VAMC, West Roxbury, Massachusetts (AWH); the Cardiac Unit (CJO), Massachusetts General Hospital; and the Divisions of Cardiology and Clinical Epidemiology (DL), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Supported by NIH/NHLBI contract NO1-38038. Dr. Haider’s fellowship was supported in part by a grant from Astra Pharm, Wayne, Pennsylvania. Dr. Haider is a recipient of the Sue McCarthy travel award of the British Hyperlipidemia Association. Requests for reprints should be addressed to Daniel Levy, MD, Framingham Heart Study, 5 Thurber Street, Framingham, Massachusetts 01702-6334. Manuscript submitted April 27, 1998, and accepted in revised form November 4, 1998. q1999 by Excerpta Medica, Inc. All rights reserved.
0002-9343/99/$–see front matter 279 PII S0002-9343(99)00027-3
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nity to investigate the association of chronic cough, an indicator of pulmonary infection and chronic inflammation, with the risk of coronary heart disease. Smoking status, symptoms of chronic cough, other risk factors, and serial respiratory function tests have been obtained routinely at serial clinic visits. In addition, plasma fibrinogen level, a marker of inflammation and a potential risk factor for myocardial infarction, was measured at a single examination in a subset of the study sample.
farction. All suspected events were evaluated by a panel of three physicians who reviewed relevant Framingham Heart Study clinic notes, 12-lead electrocardiograms, hospitalization records, and pathology reports. The diagnosis of myocardial infarction was confirmed when at least two of the following criteria were fulfilled: (1) symptoms consistent with myocardial infarction; (2) diagnostic electrocardiographic changes of acute myocardial infarction; and (3) diagnostic elevation of cardiac enzymes (28). To ensure precision in dating of infarctions, unrecognized myocardial infarctions were excluded.
METHODS
Statistical Analysis
Since 1948, the Framingham Heart Study has followed up participants at regular intervals as part of a prospective population-based investigation of cardiovascular disease (27). In 1948, 5,209 men and women 28 to 62 years of age were enrolled in the study. Biennial follow-up visits were conducted to collect a medical history, physical examination, 12-lead electrocardiogram, and laboratory tests. Data regarding age, gender, height, weight, cardiovascular risk factors, and antihypertensive medication use were obtained routinely (28). Participants were categorized as smokers if they currently smoked cigarettes or if they had quit within 1 year prior to the clinic examination. For current smokers, the number of cigarettes usually smoked each day was recorded. Serum cholesterol levels were measured by the Abell-Kendal method (29). Diabetes mellitus was defined on the basis of a fasting blood glucose level greater than 7.77 mmol/L, two random nonfasting levels greater than 11.10 mmol/L, or the use of insulin or an oral hypoglycemic agent. Left ventricular hypertrophy was considered to be present when increased voltage was associated with major ST-T repolarization changes (“strain” pattern) (28). In a secondary analysis, fibrinogen levels were measured at examination cycle 10 (1965 to 1967) in 1,288 participants (30). A standardized questionnaire regarding cough was administered at each visit by the examining physician. Subjects were asked if they had a chronic cough lasting at least 3 months in the preceding year. Chronic cough was further categorized as either productive or nonproductive. To measure vital capacity, participants were instructed to take the deepest breath possible and exhale to the fullest extent into a 13.5 L Collins Vitalometer (Warren Collins, Braintree, Massachusetts). The best of three efforts was taken as the vital capacity. Vital capacity in milliliters was divided by the subjects’ height in inches to obtain the forced vital capacity-height index (28). First fatal or nonfatal acute myocardial infarction was the endpoint for this study. At each clinic examination, a history of interim hospitalizations and symptoms of heart disease was obtained. Medical records of participants who did not attend an examination were obtained and evaluated for the evidence of interim myocardial in280
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A cross-sectional pooling method (31) was used to examine the association of chronic cough with myocardial infarction over Framingham Heart Study examination cycles 10 to 15 (1965 to 1979). At each biennial examination, subjects free of prevalent myocardial infarction were followed for the subsequent 2 years for the development of myocardial infarction. Multivariable logistic regression (32) was performed adjusting for age, gender, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy on electrocardiogram, angina pectoris or coronary insufficiency (prolonged angina with documented ischemic changes on the electrocardiogram), total cholesterol level, smoking, and forced vital capacity adjusted for height. Stepwise logistic regression analysis was used to determine interactions between variables. Interactions were considered between cough status (none, nonproductive, productive) and several variables including gender, former smoking, current smoking, and presence of angina pectoris or coronary insufficiency. The association of plasma fibrinogen levels with chronic cough was assessed by multivariable linear regression analysis adjusting for age, gender, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy on electrocardiogram, angina pectoris or coronary insufficiency, total cholesterol level, smoking, and forced vital capacity adjusted for height (33). Statistical analysis was performed using SAS software (34,35). Odds ratios (OR) and 95% confidence intervals (CI) were estimated.
RESULTS The cross-sectional pooling method yielded 15,656 person-examination from 1,437 men and 2,200 women (mean age 65, range 47 to 89). Chronic cough was more prevalent in men (Table 1). Not surprisingly, pack-years of cigarette smoking were greater and forced vital capacity (adjusted for height) was lower in subjects with chronic cough compared with those with no cough. Chronic cough was more common among current smokers than among never-smokers in both men and women (Table 2). During follow-up, 291 first myocardial infarctions
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Table 1. Characteristics of the Study Sample of 3,637 participants*
Age (years) Male (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Antihypertensive treatment (%) Total cholesterol level (mmol/L) Angina or coronary insufficiency (%) Diabetes mellitus (%) Body mass index (kg/m2) Left ventricular hypertrophy (%) Cigarette smoking (pack-years) FVC/height (mL/inch)
No Cough (n 5 13,888)
Nonproductive Cough (n 5 758)
Productive Cough (n 5 1,010)
65 6 8 37 139 6 22 79 6 11 24 6.2 6 1.1 9 7 26 6 4 2 16 6 22 41 6 11
65 6 8 41 139 6 21 78 6 12 22 6.1 6 1.1 10 6 26 6 5 2 28 6 28 38 6 11
65 6 8 54 142 6 21 80 6 12 22 6.0 6 1.2 9 7 26 6 4 4 37 6 29 37 6 11
* Numbers (n) refer to person-examinations. Plus-minus values are mean 6 SD. FVC 5 forced vital capacity.
were documented (163 in men, 128 in women). In models adjusting for age and gender, participants with chronic nonproductive cough (OR 1.9, CI 1.2 to 3.0) or chronic productive cough (OR 2.1, CI 1.4 to 3.0) had an increased risk of myocardial infarction compared with subjects with no cough. Inclusion of smoking in the model decreased the odds ratios to 1.8 (CI 1.1 to 2.8) in those with nonproductive cough and to 1.8 (CI 1.2 to 2.6) in those with productive cough. Further adjusting for forced vital capacity (adjusted for height) reduced these odds ratios to 1.6 (CI 1.0 to 2.6) and 1.5 (CI 1.0 to 2.2). In the fully adjusted multivariable model, the odds ratios for myocardial infarction were 1.8 (CI 1.1 to 2.8) in those with chronic nonproductive cough and 1.6 (CI 1.1 to 2.4) in those with chronic productive cough (Table 3). Since cough may be a manifestation of heart failure, we carried out an analysis that also adjusted for a history of heart failure; the results did not change. The associations of chronic nonproductive and productive cough with the risk of myocardial infarction were unchanged when participants with baseline evidence of angina pectoris or coronary insufficiency were excluded from the analysis. No significant interactions between cough status and gender, smoking, and angina pectoris or coronary insufficiency were observed. Among never-
smokers, the odds ratio for myocardial infarction associated with productive cough was 2.0 (CI 0.7 to 5.7); for nonproductive cough, it was 1.5 (CI 0.6 to 3.9). Plasma fibrinogen levels (mean 6 SD) were greater in participants with chronic nonproductive cough compared with those with no cough (3.2 6 0.6 g/L versus 2.9 6 0.6 g/dL, P 5 0.001). A similar, but nonsignificant trend in fibrinogen levels was seen in participants with chronic productive cough compared with those with no cough (3.1 6 0.6 g/dL versus 2.9 6 0.6 g/dL, P 5 0.15).
DISCUSSION In this large prospective population-based study, we found an association between chronic cough and the risk of myocardial infarction. This association persisted after adjustment for traditional cardiovascular disease risk factors and pulmonary function as well as a history of heart failure. As fibrinogen levels were greater in subjects with chronic cough, these findings are consistent with the hypothesis that chronic cough is associated with persistent infection or inflammation, which contributes to the risk of coronary heart disease. Recent studies have reported the association between
Table 2. Prevalence of Chronic Cough according to Smoking Status at Baseline* Men Smoking Status
Women Smoking Status
Cough Status
Never (n 5 1195)
Former (n 5 2951)
Current (n 5 1837)
Never (n 5 4878)
Former (n 5 2271)
Current (n 5 2524)
No cough Nonproductive cough Productive cough
94.8% 2.6% 2.6%
90.8% 3.5% 5.7%
71.4% 9.6% 19.0%
93.4% 4.0% 2.6%
93.3% 3.5% 3.2%
82.7% 6.8% 10.5%
* Numbers (n) refer to person-examinations among a total of 3,637 participants. March 1999
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Table 3. The Association between Chronic Cough and the Risk of Incident Myocardial Infarction Nonproductive Cough Model Adjusted For Age, gender Age, gender, smoking Age, gender, smoking, FVC Age, gender, smoking, and multiple risk factors†
Productive Cough
Odds Ratio (95% Confidence Interval)* 1.9 (1.2–3.0) 1.8 (1.1–2.8) 1.6 (1.0–2.6) 1.8 (1.1–2.8)
2.1 (1.4–3.0) 1.8 (1.2–2.6) 1.5 (1.0–2.2) 1.6 (1.1–2.4)
* Compared with those without cough. † Also adjusted for FVC, diabetes mellitus, systolic blood pressure, left ventricular hypertrophy on electrocardiogram, angina pectoris or coronary insufficiency, and total cholesterol level. FVC 5 forced vital capacity (adjusted for height).
chronic respiratory infections or inflammation and an increased risk for cardiovascular disease (25,26). Jousilahti et al (25) reported that chronic bronchitis was an independent predictor of coronary heart disease. In a cross-sectional study, Grau et al (26) demonstrated that chronic bronchitis was significantly associated with acute cerebrovascular ischemia after accounting for smoking and other potential confounders. These studies, however, did not account for impaired lung function or angina pectoris (25,26). It is important to adjust for lung function because ventilatory impairment, a hallmark of chronic bronchitis, is a strong predictor of cardiovascular morbidity and mortality (36,37). Several mechanisms might explain the association between chronic cough and myocardial infarction. Even after adjustment for smoking history, the association of chronic cough and myocardial infarction may be confounded by smoking to the extent that exposure to cigarette smoke is inadequately measured (37). However, in the present study the association between cough and coronary disease persisted after accounting for measured lung function. Both coronary disease and chronic obstructive airway disease are believed to arise, at least in part, from a chronic inflammatory process. A common defect in the ability to modulate tissue injury from such chronic inflammation might underlay both conditions (38). Chronic cough may simply be a marker of underlying inflammation or infection. Infection can be involved in thrombosis, arterial wall damage, and the atherosclerotic process directly or through changes in other risk factors (39 – 41). Perturbations in the coagulation system by infections may be an important trigger in the development of thrombosis and myocardial infarction (16). Cytokine production due to a variety of stimuli, including infections, may lead to instability of preexisting coronary plaques (2,39). An unstable plaque is more likely to rupture when subjected to mechanical stress (16) such as 282
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tachycardia, fluctuations in blood pressure, increased intrathoracic pressure, or even barotrauma caused by bouts of cough. Chlamydia pneumoniae infection has been consistently shown to be associated with the risk of developing cardiovascular disease (17,18,20,42– 46). A recent study suggested that recurrent infection in those with chronic C pneumoniae infection may precipitate myocardial infarction (20). Recurrent chest infection is also a frequent complaint of patients with chronic bronchitis. Low levels of antioxidants are believed to increase the susceptibility to infections and may be risk factors for coronary heart disease (47,48). The pathophysiological mechanism linking antioxidants, infections, inflammation, and the hemostatic system with myocardial infarction may be that many procoagulant factors are also acute phase proteins (5). Additionally, the white blood cell count is directly related to the risk of coronary thrombosis (49,50). The association between chronic cough and elevated fibrinogen level is intriguing. Fibrinogen level is predictive of incident and recurrent cardiovascular events (5,30). Elevated fibrinogen levels appear to reflect a persistent low-grade inflammatory process that is integral to atherogenesis (1). Previous studies have reported an association between cigarette smoking and plasma fibrinogen levels (30,50,51). This association may reflect increases in fibrinogen levels due to smoking-induced infection or inflammation. In the present study, fibrinogen levels were greater in those with chronic cough, even after adjusting for major risk factors including smoking and pulmonary function. Other contributing mechanisms may be the influence of fibrinogen on plasma viscosity, platelet aggregability, and amount of fibrin produced during thrombosis (51). There are several potential limitations to this study. The diagnosis of chronic bronchitis was based on symptoms and respiratory function measurements. However, relevant information on radiographic findings, serological, bacteriological, and laboratory evidence of infection were not available. There also was potential for misclassification of chronic cough; however, both nonproductive and productive cough were associated with an increased risk of myocardial infarction. Incomplete accounting for potential confounders such as vitamin or alcohol consumption and use of antimicrobial or anti-inflammatory therapy are other potential limitations (3,43,48,52). Finally, although infections and inflammations may play a role in the development of myocardial infarction, evidence of causality is lacking. We have demonstrated an association between chronic productive and nonproductive cough, which may be manifestations of pulmonary infection and inflammation, and myocardial infarction that persists after adjust-
Infections/Inflammation and Myocardial Infarction/Haider et al
ing for traditional coronary risk factors and pulmonary function. Our findings are consistent with the hypothesis that chronic infections or inflammation lead to myocardial infarction, and that fibrinogen may be a mediator of this process. Whether the association is causal can only be answered by additional studies.
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