kebaldwin
Tue, Jun-19-07, 18:56
Chronic Obstructive Pulmonary Disease And Premature Aging
American Journal of Respiratory and Critical Care Medicine
06-15-07
The 2004 American Thoracic Society/European Respiratory Society task force position paper (1) presented the first set of guidelines that defined chronic obstructive pulmonary disease (COPD) as a lung disease that also produces significant systemic consequences. In the revised 2006 version of the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, weight loss, nutritional abnormalities, and skeletal muscle dysfunction are mentioned as well-recognized extrapulmonary effects. In addition, it is stated that patients with COPD are at increased risk for-among others-depression, diabetes, sleep disorders, anemia, glaucoma, osteoporosis, and myocardial infarction (2). From epidemiologic studies, it is known that a large percentage of deaths in patients with COPD arise from cardiovascular diseases (3). In addition, COPD is one of the most important comorbidities in patients with myocardial infarction (4). Moreover, patients with myocardial infarction and COPD have a higher mortality than those without lung disease (5).
We do not know for sure how cardiovascular diseases are related to COPD: Are they just a consequence of the same bad habit (i.e., cigarette smoking), or is there a cause-effect relationship in the sense that COPD induces the development of cardiovascular disorders? The article by Sabit and colleagues (6) in this issue of the Journal (pp. 1259-1265) gives important and new information concerning this issue.
The authors assumed thatCOPDleads to alterations in vascular structure. To evaluate this hypothesis, they analyzed arterial stiffness by measuring aortic pulse wave velocity. Increased arterial stiffness has been shown to predict cardiovascular outcomes in various populations (7). Aortic pulse wave velocity is considered the most clinically relevant measure of arterial stiffness and independently predicts cardiovascular risk (8). Sabit and colleagues included patients with stable COPD representing GOLD stages I-IV. Healthy smokers and ex-smokers were used as control subjects. Mean aortic pulse wave velocity was greater in patients than in control subjects. Furthermore, pulse wave velocity was correlated to the GOLD stage-the more severe the flow limitation, the higher the pulse wave velocity values. Thus, COPD may induce increased arterial stiffness, which in turn may promote vascular remodeling, thickening of arterial walls, and plaque formation. This process may start in the early stages of COPD and worsen with decline of lung function. These results are supported by data from Eickhoff and coworkers (9) who analyzed endothelial function in the brachial artery of patients with COPD by measuring endothelium-dependent flow-mediated dilution. In that study, this parameter was lower in patients with COPD compared with healthy smokers and much lower compared with nonsmokers, suggesting the presence of significant endothelial dysfunction in COPD.
The second focus of the article by Sabit and colleagues was osteoporosis. The authors found that bone mineral density was lower in patients with COPD than in control subjects. Among the patients with COPD, 32% had osteoporosis and this was not restricted to those with severe COPD. The presence of osteoporosis associated with COPD is not a novel finding (10). Interestingly, patients with osteoporosis also had the greatest arterial stiffness. This observation is novel and in agreement with the findings by Schulz and coworkers (11). In a longitudinal study in postmenopausal women, Schultz and colleagues found that the decrease in bone mineral density was accompanied by an increase in aortic calcification.
COPD is associated with an airflow-dependent loss of elasticity in large arteries and osteoporosis. The question remains: What is the link? The authors evaluated several markers of systemic inflammation and found elevated levels of circulating IL-6 as well as tumor necrosis factor (TNF)-α soluble receptor types I and II in patients with COPD. In addition, these parameters were correlated to aortic pulse wave velocity. The mechanism linking systemic inflammation and arterial stiffening is unknown, but it has been shown that inflammatory processes are involved in all stages of atherosclerosis from initiation to evolution of lesions and even to acute thrombotic complications (12). In osteoporosis, the balance between osteoclast (causing bone resorption) and osteoblast (causing bone formation) activity is disturbed. Osteoclast function is regulated by osteoprotegerin, a receptor linked to activation of nuclear factor-κB (RANK), and its ligand (13). It has been shown that T cells and pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, may induce expression of the RANK ligand, thereby producing osteoporosis (14). Thus, the systemic inflammation inCOPDmay cause osteoporosis via vascular calcification and/or activation of osteoclasts.
The study by Sabit and colleagues suffers from several limitations: it is of cross-sectional nature with asymmetric populations. A proper case-control study with age and sex matching would have been preferable. In addition, the power of the study is limited and the patients have comorbidities, such as hypertension, that may impact on the results. Therefore, clear-cut causal relationships cannot be inferred.
Nevertheless, the common theme of all the reported findings could be that COPD is characterized by an inflammatory state that induces premature aging of the lung and other organs. Several publications lead in the same direction: Teramoto and coworkers (15) found that a senescence-prone mouse strain is more susceptible to tobacco smoke exposure than a resistant strain. Holz and colleagues (16) demonstrated that lung fibroblasts from patients with emphysema have a reduced proliferation rate. They subsequently found that these cells carried markers of senescence. These results were confirmed and extended by Tsuji and associates (17), who described that senescence of alveolar epithelial and endothelial cells is accelerated in patients with COPD. Of note, Patel and colleagues (18) showed that facial wrinkling is associated with a substantially increased risk of COPD and that FEV^sub 1^ is significantly lower in patients with wrinkles than in those without.
In summary, the article by Sabit and colleagues is the first to report a relationship among arterial stiffness, severity of airflow limitation, osteoporosis, and systemic inflammation. As always, more data are mandatory. In particular, we need to learn more about the acceleration of aging and how it can be stopped. In an ideal world "wrinkles should merely indicate where smiles have been" (Mark Twain).
American Journal of Respiratory and Critical Care Medicine
06-15-07
The 2004 American Thoracic Society/European Respiratory Society task force position paper (1) presented the first set of guidelines that defined chronic obstructive pulmonary disease (COPD) as a lung disease that also produces significant systemic consequences. In the revised 2006 version of the GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, weight loss, nutritional abnormalities, and skeletal muscle dysfunction are mentioned as well-recognized extrapulmonary effects. In addition, it is stated that patients with COPD are at increased risk for-among others-depression, diabetes, sleep disorders, anemia, glaucoma, osteoporosis, and myocardial infarction (2). From epidemiologic studies, it is known that a large percentage of deaths in patients with COPD arise from cardiovascular diseases (3). In addition, COPD is one of the most important comorbidities in patients with myocardial infarction (4). Moreover, patients with myocardial infarction and COPD have a higher mortality than those without lung disease (5).
We do not know for sure how cardiovascular diseases are related to COPD: Are they just a consequence of the same bad habit (i.e., cigarette smoking), or is there a cause-effect relationship in the sense that COPD induces the development of cardiovascular disorders? The article by Sabit and colleagues (6) in this issue of the Journal (pp. 1259-1265) gives important and new information concerning this issue.
The authors assumed thatCOPDleads to alterations in vascular structure. To evaluate this hypothesis, they analyzed arterial stiffness by measuring aortic pulse wave velocity. Increased arterial stiffness has been shown to predict cardiovascular outcomes in various populations (7). Aortic pulse wave velocity is considered the most clinically relevant measure of arterial stiffness and independently predicts cardiovascular risk (8). Sabit and colleagues included patients with stable COPD representing GOLD stages I-IV. Healthy smokers and ex-smokers were used as control subjects. Mean aortic pulse wave velocity was greater in patients than in control subjects. Furthermore, pulse wave velocity was correlated to the GOLD stage-the more severe the flow limitation, the higher the pulse wave velocity values. Thus, COPD may induce increased arterial stiffness, which in turn may promote vascular remodeling, thickening of arterial walls, and plaque formation. This process may start in the early stages of COPD and worsen with decline of lung function. These results are supported by data from Eickhoff and coworkers (9) who analyzed endothelial function in the brachial artery of patients with COPD by measuring endothelium-dependent flow-mediated dilution. In that study, this parameter was lower in patients with COPD compared with healthy smokers and much lower compared with nonsmokers, suggesting the presence of significant endothelial dysfunction in COPD.
The second focus of the article by Sabit and colleagues was osteoporosis. The authors found that bone mineral density was lower in patients with COPD than in control subjects. Among the patients with COPD, 32% had osteoporosis and this was not restricted to those with severe COPD. The presence of osteoporosis associated with COPD is not a novel finding (10). Interestingly, patients with osteoporosis also had the greatest arterial stiffness. This observation is novel and in agreement with the findings by Schulz and coworkers (11). In a longitudinal study in postmenopausal women, Schultz and colleagues found that the decrease in bone mineral density was accompanied by an increase in aortic calcification.
COPD is associated with an airflow-dependent loss of elasticity in large arteries and osteoporosis. The question remains: What is the link? The authors evaluated several markers of systemic inflammation and found elevated levels of circulating IL-6 as well as tumor necrosis factor (TNF)-α soluble receptor types I and II in patients with COPD. In addition, these parameters were correlated to aortic pulse wave velocity. The mechanism linking systemic inflammation and arterial stiffening is unknown, but it has been shown that inflammatory processes are involved in all stages of atherosclerosis from initiation to evolution of lesions and even to acute thrombotic complications (12). In osteoporosis, the balance between osteoclast (causing bone resorption) and osteoblast (causing bone formation) activity is disturbed. Osteoclast function is regulated by osteoprotegerin, a receptor linked to activation of nuclear factor-κB (RANK), and its ligand (13). It has been shown that T cells and pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, may induce expression of the RANK ligand, thereby producing osteoporosis (14). Thus, the systemic inflammation inCOPDmay cause osteoporosis via vascular calcification and/or activation of osteoclasts.
The study by Sabit and colleagues suffers from several limitations: it is of cross-sectional nature with asymmetric populations. A proper case-control study with age and sex matching would have been preferable. In addition, the power of the study is limited and the patients have comorbidities, such as hypertension, that may impact on the results. Therefore, clear-cut causal relationships cannot be inferred.
Nevertheless, the common theme of all the reported findings could be that COPD is characterized by an inflammatory state that induces premature aging of the lung and other organs. Several publications lead in the same direction: Teramoto and coworkers (15) found that a senescence-prone mouse strain is more susceptible to tobacco smoke exposure than a resistant strain. Holz and colleagues (16) demonstrated that lung fibroblasts from patients with emphysema have a reduced proliferation rate. They subsequently found that these cells carried markers of senescence. These results were confirmed and extended by Tsuji and associates (17), who described that senescence of alveolar epithelial and endothelial cells is accelerated in patients with COPD. Of note, Patel and colleagues (18) showed that facial wrinkling is associated with a substantially increased risk of COPD and that FEV^sub 1^ is significantly lower in patients with wrinkles than in those without.
In summary, the article by Sabit and colleagues is the first to report a relationship among arterial stiffness, severity of airflow limitation, osteoporosis, and systemic inflammation. As always, more data are mandatory. In particular, we need to learn more about the acceleration of aging and how it can be stopped. In an ideal world "wrinkles should merely indicate where smiles have been" (Mark Twain).