The Proceedings of the American Thoracic Society 2:44-49 (2005)
© 2005 The American Thoracic Society
Cardiovascular Disease in Chronic Obstructive Pulmonary Disease
Donald B. Hunninghake
AstraZeneca LP, Wilmington, Delaware
Correspondence and requests for reprints should be addressed to Donald B. Hunninghake, M.D., U.S. Medical Affairs, Field Medical, AstraZeneca LP, 1800 Concord Pike, Wilmington, DE 19850. E-mail: donald.hunninghake{at}astrazeneca.com
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ABSTRACT
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Smoking is a major cause of chronic obstructive pulmonary disease (COPD) and cardiovascular disorders, including coronary heart disease (CHD) and peripheral arterial disease. Smoking-induced inflammation and other risk factors like dyslipidemia cause vascular endothelial damage via oxidative stress, and a vicious cycle with the characteristics of atherosclerosis ensues. Inflammatory cytokines stimulate hepatic acute-phase protein production, and C-reactive protein is now used widely to assess inflammation in the arterial wall. Smoking is associated with many alterations in lipids and lipoproteins, and is also prothrombotic. Global risk assessment, which determines the absolute risk for developing CHD in 10 years, is used widely to determine who should receive lipid-lowering therapy. Major CHD risk factors include age, sex, smoking, blood pressure, lipoproteins, and cholesterol, but COPD is not among them. Future studies should determine the absolute risk for developing CHD in patients with COPD. The 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are used widely to treat and prevent cardiovascular disease. The statins may also produce other beneficial pleiotropic effects, including increased nitric oxide and prostacyclin, antithrombosis, and decreased inflammation, perhaps indicating utility in the therapy for COPD. Efforts are currently underway to determine if such antiinflammatory effects are independent of or in addition to simply lowering low-density lipoprotein cholesterol.
Key Words: cardiovascular disease • cholesterol • COPD • statin • therapy
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INFLAMMATION
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The original concept of atherosclerosis as a disorder of lipid metabolism and deposition into the arterial wall was widely accepted. However, it is now recognized that the pathophysiology is more complex, and atherosclerosis is now considered an inflammatory disease (1–4). Inflammation is also a major etiologic factor in chronic obstructive pulmonary disease (COPD) (5, 6). Smoking is the initiating factor of the inflammatory response in many susceptible individuals who develop COPD, and is also a major risk factor for the development of cardiovascular disease (CVD). Multiple other risk factors may also contribute to the development of the atherosclerotic process through a common pathway involving oxidative stress. The roles of local and systemic inflammation in COPD are discussed extensively by others in this issue.
A clearer understanding of the mechanisms involved in the development of the atherosclerotic plaque has evolved in the past decade. Libby and coworkers have conducted much of the research leading to the proposed schema for atheroma formation presented in Figure 1 (2). Lipoproteins enter the intima through the vascular endothelium, which may become more permeable from a variety of factors. Oxidative stress and the modified lipoproteins can induce various cytokines and cell adhesion molecules, such as intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Cytokines can induce the expression of ICAM-1 and VCAM-1, increasing inflammatory cell attachment to endothelial cells, and chemoattractants, which direct their migration into the vascular intima. This environment augments the expression of scavenger receptors on monocytes/macrophages, which avidly ingest the modified lipoprotein particles and promote the development of foam cells (Figure 1). Vascular smooth muscle proliferates and additional smooth muscle cells may migrate into the intima from the media. Smooth muscle cells produce extracellular matrix, which accumulates in the plaque with the formation of fibrofatty lesions. Vessel wall fibrosis continues, and smooth muscle cell death and calcification may occur, resulting in a fibrous cap surrounding a lipid-rich core.
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Figure 1. Evolution of atherosclerotic plaque. A schematic represention of the sequence and role of lipoproteins, inflammatory cells, and cytokines in the development of foam cells and atherosclerotic plaque. IL-1 = interleukin 1; LDL = low-density lipoprotein. Reproduced with permission from Reference 2.
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An increasing number of cytokines and other proinflammatory stimulants are being recognized. The effects of several of these in the atherosclerotic process are illustrated in Figure 2. Activated T lymphocytes and macrophages stimulate the release of multiple cytokines producing endothelial cell activation, increased plasminogen activator inhibitor type 1 (PAI-1), and decreased tissue-type plasminogen activator (tPA), thereby producing a prothrombotic state. (The effects of smoking on PAI-1, tPA, and blood coagulation are discussed in more detail by MacCallum [pp. 34–43] and Tapson [pp. 71–77] in this issue.) The activated endothelial cells increase the expression of adhesion molecules, including ICAM-1, VCAM-1, and selectins, as well as cytokines, such interleukins 1 (IL-1) and IL-6, and tumor necrosis factor 
, which facilitate lipid deposition and the other components of atheroma and plaque formation (Figure 2). Two types of plaques occur (see also article by MacCallum [pp. 34–43] in this issue). First, the stable plaque is characterized by a thick fibrous cap and relatively little lipid accumulation. This type of plaque progresses slowly and occludes the vessel lumen, leading to clinical symptoms of ischemia. Second, the generally termed vulnerable plaque has a thin fibrous cap and contains large amounts of lipids and inflammatory cells. It is prone to rupture. When plaques rupture, the lipids are extruded into the arterial lumen, inducing vasospasm and thrombus formation. Depending on the amount of thrombus formation, the clinical manifestations are unstable angina or myocardial infarction.
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Figure 2. Key cytokines marking inflammatory activity. The role of inflammatory cells and major cytokines acting on the endothelium to promote the prothrombotic state and atherosclerotic plaque as well as the hepatic production of C-reactive protein (CRP). ICAM = intracellular adhesion molecule; PAI-1 = plasminogen activator inhibitor type 1; SAA = serum amyloid A; tPA = tissue-type plasminogen activator; VCAM = vascular cell adhesion molecule. Reproduced with permission from Reference 4.
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Statin Therapy
The proposed mechanisms underlying the clinical benefits of therapy with statin drugs, which inhibit 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, include depletion of plaque lipid, decreased inflammation, and increased nitric oxide (NO) production. NO has antithrombotic and vasodilator effects and produces many effects similar to other antioxidants. A thicker fibrous cap is formed and there is overall plaque stabilization. The proinflammatory cytokines also stimulate the liver with increased release of C-reactive protein (CRP) and serum amyloid A into the systemic circulation (Figure 2). Statin therapy is associated with reductions in CRP levels. Elevated CRP levels increase the risk prediction for CVD at all levels of low-density lipoprotein cholesterol (LDL-C) and the Framingham Risk Score, as illustrated in Figure 3 (7). Measurement of CRP is now recommended for individuals in the Framingham Risk Score range of 10 to 20% to more accurately determine the intensity of therapy. Also, recent evidence indicates that when CRP is added to either pulmonary function testing or the Global Initiative for Obstructive Lung Disease (GOLD) criteria, the combination of the two more reliably predicts risk for CVD than either single assessment (8, 9; see also article by Sin and Man [pp. 8–11] in this issue).
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Figure 3. CRP improves risk prediction at all levels of LDL cholesterol and at all levels of the Framingham Risk Score. Reproduced with permission from Reference 7.
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RISK FACTORS FOR CVD
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Lipids and Lipoproteins
The primary focus in the lipid area is in controlling LDL-C levels for reducing CVD risk (10). The guidelines for the United States are cited, but similar guidelines have been published for many countries and regions of the world. LDL-C reduction is associated with a reduced risk for CVD death, myocardial infarction, need for revascularization, hospitalization for unstable angina, and stroke. The prevalence of both CVD and COPD increases with age and the likelihood of detecting CVD or modifiable risk factors for CVD in patients with COPD is increased. There have been multiple studies in controlled, randomized clinical event trials involving approximately 100,000 participants, which have demonstrated the efficacy and safety of HMG-CoA reductase inhibitor (statin) therapy for reducing risk for CVD. A few selected statin trials are included in Table 1. The overall assessment of these trials is that CVD risk over a 3- to 5-year period is reduced 25 to 35% with LDL-C reduction/statin therapy. Greater reductions will likely be seen in the future with more aggressive therapy. Specifically, risk was reduced in smokers, but COPD was not specifically identified in these trials.
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TABLE 1. Selected clinical trials with statins (hmg-coa reductase inhibitor) for reducing risk for cardiovascular disease
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These trials have provided some important milestones in our current recommendations for lipid management (Table 1). The West of Scotland Coronary Prevention Study demonstrated that LDL-C reduction was associated with a reduction in CVD risk in 6,596 men without CVD at baseline (11). A subgroup analysis was done comparing smokers and nonsmokers. Both had a 31% reduction in relative risk. However, the total number of events prevented in smokers was greater than in nonsmokers per 1,000 participants treated, because their baseline risk was greater. This finding continues to be seen in subsequent studies. For the same degree of LDL-C reduction, the reduction in relative risk tends to be similar, but the total number of events prevented is increased as baseline risk increases. Thus, it is more cost-effective to treat higher risk patients, and they should be treated more aggressively. Smoking cessation should occur, but such efforts often fail.
The Scandinavian Simvastatin Survival Study was important because it demonstrated that total mortality could be reduced with statin therapy (12). This was the final hurdle that had to be cleared for some of the nonbelievers in the benefits of LDL-C reduction. The Medical Research Council/British Heart Foundation Heart Protection Study has provided much of the information that underlies the current recommendations for lipid management (13). This large study involved 20,536 participants and demonstrated that LDL-C reduction was beneficial in all participants regardless of baseline disease, lipid status, or risk factors. Similar benefit in the 5,963 subjects with diabetes in this trial was also demonstrated (14). The results of these studies have led to recommendations that all high-risk subjects for developing either first or recurrent cardiovascular events should receive statin therapy (10, 15).
Now that there is evidence that all high-risk patients should be treated, the focus is on how low to go with LDL-C levels. The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial demonstrated that a median LDL-C level of 62 mg/dl (1.6 mmol/L) obtained with 80 mg of atorvastatin resulted in greater benefit than a median LDL-C level of 95 mg/dl (2.6 mmol/L) observed with 40 mg of pravastatin in 4,162 participants with acute coronary syndromes (16). That finding has led to an interim revision in the Adult Treatment Panel III guidelines to an optional LDL-C target goal of less than 70 mg (1.8 mmol/L) in high-risk patients with CVD (15).
Another recent trial of interest is the Anglo-Scandinavian Cardiac Outcome Trial–Lipid Lowering Arm (17). This trial involved 19,342 hypertensive patients with excellent control of their blood pressure. A substudy in 10,305 patients with total cholesterol of 251 mg/dl or less (6.5 mmol/L) were randomized to placebo or 10 mg of atorvastatin. LDL-C levels were reduced from a mean of 132 to 90 mg/dL. The study was stopped early after 3.3 years because of a 36% reduction in nonfatal myocardial infarction and fatal coronary heart disease. There was also a 27% reduction in stroke. Studies such as the Anglo-Scandinavian Cardiac Outcome Trial indicate that we should strive for lower LDL-C levels in patients with risk factors for, but without, clinically evident CVD than current guidelines recommend.
A brief synopsis of the current U.S. guidelines for management of LDL-C is included in Table 2 (15). A new category of very high-risk patients has been added, and includes patients with CVD and one or more of the following conditions: current cigarette smokers, diabetes mellitus, and two or more risk factors or low levels of high-density lipoprotein cholesterol (HDL-C) plus elevated triglycerides. Sufficient epidemiologic and clinical trial data are not yet available, but it is likely that patients with more severe forms of COPD and CVD would fit into this category. Coronary heart disease risk equivalents include any clinical manifestations of noncoronary atherosclerosis, diabetes mellitus, or 10-year risk for developing coronary heart disease of more than 20%. Note that patients with peripheral artery disease fit into this category. Peripheral artery disease is especially common in smokers, and risk for developing CVD is very high in individuals with claudication or ankle-brachial systolic pressure indices of less than 0.9. An optional goal of an LDL-C of less than 100 mg/dl was added for patients whose 10-year risk is calculated at 10 to 20%. The group with 0 to 1 risk factor was not changed. However, more aggressive therapy may be indicated in patients with familial hypercholesterolemia, a very strong family history, or very abnormal values for certain risk factors, such as a very low HDL-C.
Additional recommendations were that a minimum reduction in LDL-C of 30 to 40% should be the goal of drug therapy. Non–HDL-C (total HDL-C) is recommended as a secondary target if triglyceride levels are more than 200 mg/dl (2.25 mmol/L). The target level is 30 mg/dl higher than the LDL-C goal. Isolated low HDL-C levels may also warrant therapy.
Smoking
Smoking has been known to be associated with decreased FVC, decreased FEV1, and increased risk for mortality, including cardiovascular death, for many decades (18). The GOLD criteria, which incorporate pulmonary function and respiratory symptoms, were used in the analysis of the National Health and Nutrition Examination Survey (NHANES) follow-up study (19). Smoking was associated with increased mortality in both univariate and multivariate analyses. When smoking and other risk factors were included in the multivariate model, increasing severity of COPD was associated with increased mortality. Increased levels of high-sensitivity CRP, a systemic marker for inflammation, are associated with the presence of the known risk factors for CVD, including age, smoking, obesity, hypertension, and dyslipidemia (3, 20) (see Man and Sin [pp. 78–82] in this issue). Recent studies have indicated that when the presence of inflammatory proteins is added to pulmonary function, an increased risk for CVD is noted (8, 9). Additional studies are required, but it is likely that CRP levels will also predict the presence of significant COPD or severity of COPD.
Smoking produces a number of effects that are known to increase cardiovascular risk. In addition to stimulating all the processes involved in atheroma and plaque formation illustrated in Figures 1 and 2, smoking increases platelet activation, increases PAI-1, decreases tPA, and produces a prothrombotic state (21, 22). Smoking decreases HDL-C levels (23) and may also increase LDL-C, triglyceride, and very-low-density lipoprotein cholesterol levels (22). It may also have an adverse effect on the arterial wall and negatively influences endothelial function. Other risk factors for CVD should also be considered and managed in patients with COPD, but are discussed elsewhere (24–26).
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RECOMMENDATIONS
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Increased Awareness
There should be an attempt to increase awareness of the association of COPD, not just cigarette smoking, and risk for CVD. Effective measures will only be developed when there is more recognition of the problem. For example, the current management of risk factors for preventing CVD is improving in the general population, but is still less than desirable. Risk factors for CVD should also be aggressively controlled in patients with COPD. There may be tendency to focus on the short-term management of symptoms and ignore longer term goals of preventing CVD. There are innumerable examples in the cardiovascular area where a "call to action" has been successful. Peripheral artery disease was infrequently diagnosed in the past. It was viewed primarily in terms of risk for amputation, but the significance of the very high risk for cardiovascular morbidity and mortality was generally not recognized. The Vascular Medicine Society has been influential in the development and conduct of clinical trials to evaluate various therapies in patients with peripheral artery disease. Routine screening for this disease by simple, noninvasive procedures (ankle-brachial systolic pressure indices) in high-risk and older patients is now recommended. Management of risk factors (lipids) as aggressively as in patients with clinical evidence of CHD is now recommended in national guidelines (10). Various organizations have assisted in increasing the recognition that CVD is the number-one killer in women. Specific guidelines for the management of CVD risk in women have now been developed (24).
Improved Collaboration between Investigators in Pulmonary and Cardiovascular Diseases
There are several desirable goals:
- Define more precisely the risk for developing the complications of CVD in patients with COPD and the relationship of risk factors to the development of CVD in patients with COPD.
- Develop information from clinical trials of the benefits and risks of therapy for preventing CVD, especially pharmacotherapy, in patients with COPD and, conversely, the benefits and risks of therapies for COPD in terms of cardiovascular outcomes. Although there are few drug therapies for COPD at present, many more approaches are being developed. It would seem appropriate to also assess the effect of these therapies on cardiovascular morbidity and mortality. Quality of life is commonly assessed in trials of new therapies.
The number of subjects in trials that have recently been completed or that are still in progress to assess the effect of risk-factor management for CVD is staggering. In the lipid area alone, more than 50,000 subjects have completed long-term intervention trials with statin therapy since the National Cholesterol Education Program published the guidelines in 2001 (10), and the results in another 30,000 subjects should be available in the next year. An interim revision of the guidelines based on these newer trials was just published (15). Many other trials are in progress or planned. In addition, the guidelines for management of hypertension (25) and diabetes mellitus (26) have recently been revised to incorporate the latest information.
The number of participants in these lipid intervention trials who also have COPD must be extensive, especially in the secondary prevention trials. The effect in the subgroup of smokers is always defined, but there is no attempt to routinely define COPD at baseline, to assess progression during the study, or to monitor pulmonary function or symptoms. Even if pulmonary status could be assessed at the end of some of the ongoing randomized trials, useful information might be obtained. High-sensitivity CRP is now routinely measured in many trials assessing the benefits of risk-factor management for CVD. The epidemiologic evaluation in NHANES indicated that the combination of CRP and FEV1 significantly predicted future cardiovascular events (8, 9). I believe that it would be highly desirable to develop a diagnostic algorithm for COPD and assessment of pulmonary function in the cardiovascular trials. They could be incorporated with a modest increase in time and cost, but the benefits could be quite extensive.
Guideline Development
The amount of information related to the importance of risk factors for developing CVD is extensive, and there is some information specific to patients with COPD. As is discussed in the articles in this issue, the evidence for COPD as a risk factor for developing CVD is extensive. It would be helpful to summarize all the data in a central repository. Attention could also be drawn to future research needs. The National Heart Lung Blood Institute recently conducted a workshop regarding needs in clinical research in COPD (27). Recommendations for the diagnosis of COPD and the monitoring of pulmonary function and symptoms for use in clinical trials could also be made.
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FOOTNOTES
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Conflict of Interest Statement: D.B.H. is an employee of AstraZeneca, which sponsored the symposium and paid for his travel expenses, and his compensation from AstraZeneca also includes stock.
(Received in original form October 15, 2004; accepted in final form January 22, 2005)
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ABSTRACT
INFLAMMATION
