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1 Pulmonary and Critical Care Medicine, Nebraska Medical Center, Omaha, Nebraska
Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., Pulmonary and Critical Care Medicine, 985885 Nebraska Medical Center, Omaha, NE 68198-5885. E-mail: srennard{at}unmc.edu
ABSTRACT
Chronic obstructive pulmonary disease, heart disease, and lung cancer are the most common causes of mortality caused by cigarette smoking. However, these conditions are associated with each other more commonly than would be expected by chance, even when their relationship to smoking is considered. This suggests more fundamental relationships among these conditions. Exploration of those relationships promises to advance the understanding of all three diseases and holds the potential to advance the diagnosis and treatment of these common and devastating conditions.
Key Words: COPD • lung cancer • heart disease
The goal in any multidisciplinary conference is to achieve "cross-fertilization." This is based on the concept that insights gained in one area may be of relevance, either directly or methodologically, in other areas. With regard to "the Big Three,"—chronic obstructive pulmonary disease (COPD), lung cancer, and heart disease—there are a number of reasons to be particularly interested in a multidisciplinary approach. First, in addition to the generic benefits of any cross-disciplinary program, there is an increasing body of epidemiologic information that supports an association among these conditions, which appears to be stronger than what would be expected by chance or by a simple relationship to cigarette smoking. In addition, the "Big Three" are each major clinical problems. How a patient with multiple conditions should be managed, both diagnostically and therapeutically, therefore is a major clinical issue. Unfortunately, there is much needed in this regard; one of the strengths of a multidisciplinary approach is that it helps emphasize that this gap is, in part, due to the way medicine currently approaches these conditions. This article will not resolve these complex issues, but will help emphasize four key questions that the 9th Lund COPD Conference was designed to explore.
WHAT IS THE STRENGTH OF THE ASSOCIATIONS?
The Framingham Study identified the relationship between cardiac disease mortality and lung function (1). This relationship was still present when the data were adjusted for smoking. A number of subsequent studies have continued to find the relationship, and they have been reviewed in a meta-analysis (2). Importantly, the relationship of reduced lung function and cardiac risk is observed across all levels of lung function, even modest reductions having a significant effect. Similarly, several studies have demonstrated that COPD, per se, is associated with an increased risk of developing lung cancer (3–6). This relationship also persists when adjusted for smoking history.
Several reasons could account for these relationships. There is always the possibility of artifact. First, there may be a case ascertainment bias; that is, individuals with COPD who have interacted with the health care system may be more likely to be diagnosed with other conditions. Several of the epidemiologic studies cited above, however, were population based, and this source of bias should have been minimized. Second, as COPD worsens, it is likely that mortality from COPD per se increases. However, the diagnoses listed on death certificates frequently underrepresent COPD, even when the COPD is severe (7). In contrast, a default diagnosis of heart attack is often listed when someone dies suddenly at home. Thus some COPD deaths, which should be related to lung function, may be misdiagnosed as cardiac deaths, thus accounting for the relationship between lung function and cardiac mortality. It seems, however, that this is not likely to be a major effect, because the relationship between lung function is also present with acute nonfatal cardiac events (2), for which there is much more diagnostic certainty.
A second reason for the associations could be the shared etiologic risk factor of smoking. Although the epidemiologic studies are generally "adjusted" for smoking, the measures used are usually limited. The most commonly used measure is pack-years (one package smoked per day for 1 year is 1 pack-year). However, this captures only part of the burden of smoking. Smokers of the same number of cigarettes may smoke them very differently, resulting in markedly different toxin exposures (8, 9). In addition, cigarettes are not equivalent in their yield of toxins (10). Starting before growth is complete can compromise maximally attained lung function (11). Whether there are similar effects of the age of initiation on cardiac disease is unclear. However, it is clear that measures in addition to pack-years are needed to capture the variability of smoking behavior.
Twin studies have provided convincing evidence that there are genetic bases for smoking (12, 13). It is likely that many genes will be relevant and will influence smoking initiation, persistence, and smoking pattern (14). One of the candidate genes suggested is CYP2A6, which metabolizes nicotine to cotinine (15). Individuals who have genetic variants that result in slower metabolism are less likely to become smokers. If they smoke, however, they are likely to smoke less, presumably because they need less nicotine intake to sustain an addiction. When adjusted for smoking intensity (pack-years), individuals with CYP2A6 variants with slower metabolism have better lung function (16) and a lower risk for lung cancer (17, 18); CYP2A6 also can activate carcinogens, so there are other potential mechanisms for decreased risk in slow metabolizers (19).
COPD could also serve as a more accurate measure of smoke exposure, thus accounting for the association with lung cancer. It is possible that other genotypes and similar effects on smoking behavior could account for the associations among these diseases. For example, genome-wide association studies have identified a region of chromosome 15 that is associated with lung cancer and vascular disease (20–22). This region also contains several nicotinic receptor genes that have been associated with smoking behavior, and a behavioral effect could be the link among the disorders (12, 23, 24).
It is unlikely that all the associations are based on smoking behavior, however. The association between COPD and heart disease, for example, has been observed among nonsmokers in several studies (2). While passive smoking may be a mechanism, it seems highly likely that there are other mechanistic links. This raises the important point that COPD, because of its important link to smoking, has been most commonly studied in smokers. The natural history, risk factors, and disease associations of COPD in nonsmokers, who make up 20% of the COPD population in the United States (25–27), is largely unknown.
There are, therefore, a number of issues relating to the strength of the associations among the "Big Three." These include evaluation of the impact of smoking in studies that capture smoking behavior in a more detailed manner than has been done to date. In addition, it will be important to define the association in nonsmokers, as all of the "Big Three" occur at a much lower frequency in nonsmokers. Finally, as genetic susceptibilities become defined for various conditions, the impact of these on co-morbidities needs to be assessed. That there may be genotypes that lead to smoking patterns that alter risk for multiple conditions is an important direction for future research.
ARE THERE SHARED MECHANISMS OF DISEASE?
There is a wealth of data that suggest overlapping mechanisms between COPD, lung cancer, and heart disease. In part, this may be due to many pathologic processes acting on a highly integrated network of physiologic and cellular pathways. For example, inflammation is common to all three processes, and it should be no surprise that similar cells and mediators are involved in all three. There are, moreover, a number of other similarities. For example, both atherosclerosis and airways disease are characterized by the accumulation of mesenchymal cells, luminal compromise, and chronic accumulation of inflammatory cells (28, 29). Similarly, the destruction of lung tissue associated with emphysema is associated with proteolytic and oxidant stress (30), as is vascular aneurysm (31). The proliferative pathways that are activated in lung cancer are highly overlapping with those activated after lung epithelial injury that is believed to occur in COPD. The associations among the diseases, therefore, could be mechanistically related to susceptibility to toxins that are acting in parallel in different systems. Consistent with this, toxins that are believed to damage lung epithelial cells and contribute to the development of lung cancer also have toxic effects on vascular cells and may contribute to vascular disease (32). Abnormal peripheral vascular function appears to be common in COPD and may suggest shared vascular pathogenetic mechanism between COPD and cardiovascular disease (33). It is also possible that disease in one organ contributes to disease in others. In this context, it is appealing, at least to a pulmonologist, that inflammation in the lung "spills over" into the systemic circulation and contributes to systemic diseases, including heart disease (34). No doubt other models are possible. Nevertheless, inflammation appears to be associated with risk for several different conditions and may represent a mechanistic link.
However, in the context of cross-fertilization, there are a number of other opportunities. For example, the acquisition of somatic cell mutations is a mainstream concept in the development of lung cancer (35, 36). Several investigators have suggested that somatic cell mutations could also contribute to the development of COPD (37, 38), and the observation of increased microsatellite instability with COPD supports this concept (39). The ability of smoke to induce DNA damage while in epithelial cells while inhibiting the apoptosis that may serve to protect the integrity of the genome could contribute to both lung cancer and COPD (38). DNA damage of mesenchymal cells does not appear to result in sarcomas of the lung but could, nevertheless, contribute to risk for other diseases (40). Similarly, inflammation is recognized as an important feature of COPD and heart disease, and has some association with lung cancer. A key feature of inflammation in COPD is its abnormal persistence, even when the inciting stimulus (e.g., smoking) stops (28, 41, 42). To what degree vascular inflammation persists needs to be defined. Finally, all of the "Big Three" are diseases that progress with age. The role of the aging process on all three conditions needs to be defined, but the association of these conditions in patients with genetic diseases that resemble accelerated aging supports shared mechanisms (43).
Exploration of shared mechanisms can have a number of benefits. First, methodologic advances in one field may accelerate the progress in other areas. Second, if the diseases are linked, therapeutic targets identified in one disease may be appropriate for others. Similarly, biomarkers based on mechanistic features that measure disease risk, activity, or severity may be nonspecific. Far from being a disadvantage, such markers may be a much better overall assessment of a patient's clinical status. Finally, the features that are not shared may be the crucial ones to identify. Determining why inflammation does not persist in cardiac disease (if that is the case) may be the key to altering the natural history of COPD, for example.
WHAT ABOUT DISEASE MANAGEMENT?
That patients frequently have multiple co-morbid conditions is well recognized, both by clinicians and in the literature (44, 45). The GOLD guidelines recognize the importance of co-morbidities and recommend that they be identified and treated (46). Unfortunately, there are a number of difficulties for guidelines to provide specific guidance in this regard. Most guidelines have been prepared using evidence-based methods that value controlled clinical trials. The vast majority of such trials, and in the case of COPD almost all trials, are those performed by pharmaceutical companies either for the purpose of registering a treatment with regulatory authorities or for providing post-marketing support for specific products. While much useful information has come from such trials, the information also has serious limitations. Importantly, patients with serious co-morbidities are often excluded. Inclusion of such patients could confound outcomes that could be driven by conditions other than COPD. In addition, patients who are very ill from any condition are generally excluded, both for safety reasons and because subjects who are at a relatively high risk of death during a trial are unlikely to contribute data if they do not complete. As a result, the information available on which guidelines are largely based includes relatively healthy subjects who do not have serious co-morbidities.
Nevertheless, the management of a given patient may require detailed assessment of co-morbidities. Decisions on whether to treat with statins, for example, depend on a comprehensive assessment of risk (47, 48). Many factors are used to compute this risk. Inclusion of measures of lung function, which are easily and inexpensively obtained, could help refine these calculations. Conversely, patients with COPD, particularly those with mild disease, are most at risk for death from cardiac disease (2). A comprehensive approach to cardiac risk factors should be standard of care. COPD patients are also at increased risk for the development of lung cancer (3–6). Whether such individuals should be routinely assessed for lung cancer, for example with CT scanning, remains unclear (49, 50). However, whether measurement of spirometry can help inform such decisions would seem to be an important practical question.
Detection of subtle abnormalities may also improve patient care. For example, unsuspected 
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mismatching due to undiagnosed COPD could lead to exercise-induced oxygen desaturation and could exacerbate angina pectoris in cardiac patients. The presence of COPD in such patients is likely to be undiagnosed in the absence of a high index of suspicion. Dynamic hyperinflation compromises not only ventilation (51), but also cardiac output (52). To the extent that it occurs, it would compromise performance in individuals with congestive heart failure (CHF). As bronchodilators can improve dynamic hyperinflation (51), a careful determination of the presence of airflow limitation could help optimize treatment of all patients with CHF. Conversely, treatment of appropriate cardiac patients with β-blockers improves survival (53). Mortality also appears to be improved for cardiac patients with COPD (53–55). Finally, while the incidence of diastolic dysfunction in COPD has not been explored in large studies, it may be quite common (56, 57). Aggressive assessment of cardiac function in patients with COPD, therefore, is also necessary to optimize the care of individual patients.
In addition to diagnosis of co-morbid conditions improving the management of patients, the treatment of co-morbid conditions is likely to inform the treatment of allied conditions. For example, the retrospective analysis of the impact of treatment with cardiovascular disease risk modifiers including statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers on outcomes for patients with COPD by Mancini and colleagues has attracted considerable interest (58). This study demonstrated a reduction in hospitalization for both myocardial infarction and for COPD exacerbation. Because COPD events may have been misdiagnosed, these events were also assessed in patients at low risk for myocardial infarction (MI). Importantly, there was still a significant reduction in hospitalization for COPD exacerbation and death in those individuals, and in this group there was no effect on MI. The majority of the effect appeared to be due to statins. It is not surprising that these agents would have no effect on MIs in low-risk patients, as they had few MIs. Why these individuals were treated with the agents assessed is, of course, unanswered in this retrospective study. That there was a significant effect on COPD events is the startling point, and begs the question of mechanism. It also begs the question of to what degree are the benefits of these agents in patients at high risk for MI due to treatment of concurrent COPD.
The study by Mancini and coworkers has led to another retrospective analysis that has found similar results (59). While the mechanisms that could account for such an effect are unclear, an anti-inflammatory effect of statins has been demonstrated and could play a role in COPD. This carefully done retrospective clinical study has led to a number of prospective studies evaluating both basic mechanisms and clinical outcomes. It is an excellent example of the enriching effects of multidisciplinary cross-fertilization.
HOW DOES THIS AFFECT THE RESEARCH AGENDA?
Multidisciplinary approaches can inform the research agenda in many ways. Most superficially, methods developed to address problems in one discipline can often be used to great effect in others. Recognizing that there are shared risk factors that lead to clinical associations among common diseases can help define those risk factors. For example, cigarette smoking is a major risk factor for all the "Big Three." However, it accounts for only part of the risk. The impact of other risk factors has been best evaluated with respect to cardiac disease. In contrast, the reasons for the variable susceptibility of smokers to develop COPD and lung cancer remain a major area for investigation. The experience of studies evaluating other cardiac risks should help inform similar studies in COPD and lung cancer.
It is likely that some of the association among the "Big Three" is due to shared mechanisms. This leads directly to the possibility for new clinical approaches. Targeting a shared mechanism could treat multiple conditions. A biomarker that reflects a shared mechanism could be a robust measure of disease risk, activity, or severity. Exploitation of these opportunities, however, is likely to require a major shift in investigational and regulatory approach.
Current clinical study is characterized by a reductionist approach. Each condition is defined, as rigorously as possible, and then evaluated with instruments that are as specific as possible. That cardiac disease, lung disease, or lung cancer could represent different manifestations of the same pathophysiologic mechanisms suggests that an intervention targeting that mechanism should be evaluable by all of those outcomes. This is not the most commonly used approach in assessing clinical interventions, but integrative approaches assessing effects of multiple conditions are possible and have been used successfully.
FOOTNOTES
Conflict of Interest Statement: S.I.R. has participated as a speaker at programs organized by AstraZeneca (AZ), Boehringer-Ingelheim, GlaxoSmithKline (GSK), Otsuka, and Pfizer. He serves on advisory boards for Altana, AZ, Dey, GSK, Novartis, Schering-Plough, and Talecris. He has conducted clinical trials for Almirall, Altana, Astellas, Centocor, GSK, Nabi, Novartis, and Pfizer. He has served as a consultant for Adams, Almirall, Altana, AZ, Bend, Biolipox, Centocor, Critical Therapeutics, GSK, ICOS, Johnson & Johnson, Novartis, Ono, Parengenix, Pfizer, Roche, Sankyo, Sanofi, and Schering-Plough. A patent is pending on a method for stem cell differentiation; S.I.R. is a co-inventor of the patent owned by the University of Nebraska Medical Center.
(Received in original form July 1, 2008; accepted in final form August 5, 2008)
REFERENCES
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