DOI: 10.1111/eci.12181
REVIEW Coronary artery disease concomitant with chronic obstructive pulmonary disease Sara Roversi*, Pietro Roversi†, Giuseppe Spadafora*, Rosario Rossi* and Leonardo M. Fabbri† *Section of Cardiology, Department of Medicine and Emergency Medicine, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy, †Section of Respiratory Diseases, Department of Oncology Haematology and Respiratory Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy
ABSTRACT Background Numerous epidemiologic studies have linked the presence of chronic obstructive pulmonary disease (COPD) to coronary artery disease (CAD). However, prevalence, pathological processes, clinical manifestations and therapy are still debated, as progress towards uncovering the link between these two disorders has been hindered by the complex nature of multimorbidity. Methods Articles targeting CAD in patients with COPD were identified from the searches of MEDLINE and EMBASE databases in July 2013. Three authors reviewed available evidence, focusing on the latest development on disease prevalence, pathogenesis, clinical manifestations and therapeutic strategies. Both clinical trial and previous reviews have been included in this work. Results The most accredited hypothesis asserts that the main common risk factors, that is, cigarette smoke and ageing, elicit a chronic low-grade systemic inflammatory response, which affects both cardiovascular endothelial cells and airways/lung parenchyma. The development of CAD in patients with COPD potentiates the morbidity of COPD, leading to increased hospitalizations, mortality and health costs. Moreover, correct diagnosis is challenging and therapies are not clearly defined. Conclusions Evidence from recently published articles highlights the importance of multimorbidity in patient management and future research. Moreover, many authors emphasize the importance of low-grade systemic inflammation as a common pathological mechanism and a possible future therapeutic target. Keywords Ageing, chronic bronchitis, ischaemic heart disease, multimorbidity, respiratory system, smoking. Eur J Clin Invest 2014; 44 (1): 93–102
Introduction Chronic obstructive pulmonary disease (COPD) is currently defined as a preventable and treatable respiratory disease characterized by chronic respiratory symptoms and persistent airflow limitation (AL) that are usually progressive and that are due to an abnormal inflammatory response to irritants, particularly cigarette smoking [1]. Compelling epidemiologic data reveal that patients with COPD have various concomitant diseases [including cardiovascular disease (CVD), skeletal muscle dysfunction, depression and lung cancer], with coronary artery disease (CAD) making up a large share of them [1,2]. Although many explanations have been suggested, the most accredited hypothesis asserts that systemic inflammation, most likely a result of common noxious stimuli (e.g. cigarette smoke) and ageing, might sustain both COPD and CAD [3–5]. The association of these disorders is important mostly for its nega-
tive effect on the course of the disease (i.e. increased hospitalization, increased risk of acute severe exacerbation and increased mortality) [6] and for the enhanced social and economic burden. Recently, awareness of multimorbidity and its clinical implications has been rising, even though a few guidelines and therapeutic indications target this subject [3,5]. Here, we give a broad review of the prevalence of both COPD and CAD, report the latest findings on possible pathogenic mechanisms and describe the symptoms and therapeutic strategies.
Prevalence and association of COPD and CAD Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality worldwide and results in a substantial
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and increasing economic and social burden [1,7]. Defining COPD prevalence is no easy task, because definition, survey methods and analytic approaches are not uniform across published studies [1,8]. Recent data suggest a population-based prevalence of approximately 9–10% in subjects aged 40 years and older, rising steeply with age and exceeding 20% in subjects older than 70 years [9]. Further, COPD prevalence among heavy smokers (> 20 pack-years) reached 31% in a survey addressing general adult population in Norway in the years 2003–2005 [1,10]. Ischaemic heart disease (IHD) or CAD, defined by the World Health Organization [11] as a disease of the blood vessels supplying the heart muscle, is also a substantial problem [12]. CAD alone accounted for about half of all cardiovascularrelated deaths in the United States in 2009; it caused more than 116 per 100 000 deaths (Table 1) [12], and it was the first leading disease contributing to premature death in 2010 [7,8]. Additionally, one American has a coronary event approximately every 34 s, and an American will die of CAD every minute. As with COPD, the prevalence of CAD increases with age, rising from 35 to 40% of subjects aged 40–59 years, to almost 70% for those aged 60–79 years [12,13]. Epidemiologic data indicate a strong association between AL and CAD, suggesting that patients with COPD might have a higher risk of developing IHD and patients with IHD might have a higher risk of developing COPD [14]. The prevalence of IHD (i.e. myocardial infarction, angina and coronary stenosis) in patients with COPD varies between studies, ranging from 47% to 60% [15]. In a population-based survey, CAD was reported in 7–13% of patients diagnosed with COPD, and COPD was reported in 26–35% of patients with IHD [14,16]. IHD prevalence increases with COPD severity, reaching rates as high as 60% of the patients affected by advanced COPD, who are undergoing transplant evaluation [17]. Moreover, COPD and IHD rates increase with advancing age, and thus, multimorbidity rates as high as 951% have been reported in patients aged 85 years (COPD and IHD, respectively, 159% and 63%)
Table 1 Cardiovascular disease (CVD), ischaemic heart disease (IHD) and myocardial infarction (MI) prevalence and mortality in the United States (National Health and Nutrition Examination Survey 2007–2010) [12] Men CVD prevalence% (age > 20 years) CVD death per 100 000 per year IHD prevalence % (age > 20 years) IHD death per 100 000 per year MI prevalence % (age > 20 years)
94
Women
Total
367
34
353
2814
1904
2361
79
51
64
1559
849
1161
42
17
29
[18]. Table 2 reviews some of the studies reporting IHD prevalence in COPD. Patient prognosis is influenced by comorbidities, and not surprisingly, the association of these two chronic conditions results in a worse prognosis. COPD seems to be an independent predictor of mortality in patients suffering from CAD [28]. For example, patients with myocardial infarction or patients who are receiving hospital treatment for IHD have a 50% increased risk of death at 3 years if affected by COPD, as compared with similar patients without COPD [29]. The risk increases fourfold in those who develop a COPD exacerbation during the 3-year follow-up [29]. On the other hand, CVDs are among the leading causes of death in patients with mild-to-moderate COPD, and the presence of manifest CAD is associated with an increased risk of death for these patients [21]. Furthermore, a significantly increased risk of myocardial infarction has been shown to follow COPD exacerbations [30], and associated ischaemic comorbidities confer greater long-term mortality in hospitalized COPD elderly patients (≥ 65 years) [23]. Individual diseases have dominated medical research for many years, but the latest epidemiologic data clearly reveal that comorbidities are often the rule, not the exception. Thus, future research should have a broader approach and focus on multimorbidities.
Pathogenesis Although prevalent data confirm an important association between COPD and IHD [14], the common underlying pathogenic mechanism is far from being fully explained. It seems that shared risk factors elicit a chronic low-grade systemic inflammatory response [31], which affects both cardiovascular endothelial cells and airways/lung parenchyma [32]. Additionally, pathophysiological changes associated with COPD could directly affect heart function, unmasking an underlying coronary disease [33]. However, disease development is a complex process, stemming from gene–environment interactions. Most likely, multifactorial biological processes interact on a complex background of genetic determinants, age-related tissue modification and noxious environmental stimuli, resulting in clinical manifestations [34] of COPD and CAD (Fig. 1).
Putative shared risk factors that sustain low-grade systemic inflammation Of the shared risk factors that could trigger systemic inflammation, cigarette smoking is probably the most common. Each puff on a cigarette contains more than 2000 xenobiotic compounds and 10 free radicals [35]. Damage from lung epithelial cells and vascular endothelial cells is proportionate to their concentration, and for most adverse outcomes, risk increases with the number of
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Table 2 List of studies reporting CAD prevalence in patients with COPD. The first four columns describe population characteristics (i.e. total number of patients, rates of male patients, mean age and COPD severity). The following columns report the rates of concomitant CAD. Where indicated in the cited works, CAD subtype (i.e. myocardial infarction and angina pectoris) and relative rates have been specified in the table Patients with COPD (N) 3183
Mean age 71
Men (%) 70
COPD definition and severity
CAD type
NS
CAD
Prevalence (%) 85
References [19]
527
68
849
GOLD stage I–IV
CAD
122–181
[20]
1659
66
89
GOLD stage I–IV
CAD
302
[21]
†
351
58
42
Severe COPD*
CAD
59
[17]
958
60
464
NS
CAD MI AP
161 148 11
[4]
25 281
> 35
62
NS
CAD MI
17 140
76
98
NS
MI AP
295 282
[23]
897
71
492
NS
MI
277
[24]
313 958
68
55
NS
MI
3–4
[25]
> 65
54
ICD-9 codes (491–4928)
MI AP
23 66
[26]
213
64
59
GOLD stage II–IV
MI
9
[2]
1003
61
42
NS
AP
22
[27]
11 493
920 481
[22]
CAD, coronary artery disease; MI, myocardial infarction; AP, angina pectoris; NS, not stated; COPD, chronic obstructive pulmonary disease. *Patients with a diagnosis of COPD referred for lung transplant evaluation. † CAD diagnosed by coronary angiography.
pack-years [35] Smoking-related effects are both local (by means of tissue injury from direct chemical exposure) and systemic (stimulating a low-grade inflammatory response that involves the whole organism) [36].Overall, current data suggest that chronic exposure to chemicals and free radicals of cigarette smoke affects a number of homeostatic mechanisms, for example, (i) it causes depletion of endogenous antioxidants and disturbs the physiological oxidative–antioxidative balance [36], (ii) it stimulates the haematopoietic system, with increased numbers of circulating leucocytes and platelets [36], (iii) it aggravates low-density lipoprotein (LDL) oxidation because of a higher concentration of reactive oxygen species, and (iv) it plays a role in enhanced platelet/monocyte aggregation and over expression of endothelial adhesion molecules [36]. Smoking is a relevant risk factor for all types of IHD, but its importance has been reported particularly in the setting of premature atherosclerosis [37]. In a population of almost 1000 patients (≤ 50 years) with clinically significant manifestations of atherosclerosis, cigarette smoking was the most common preventable risk factor [37]. However, data are scarce on COPD prevalence in this setting.
Along with smoking, other risk factors, such as sedentary lifestyle, obesity and insulin resistance, have been related to low-grade systemic inflammation and oxidative stress. Their causative role is well documented in CVD and atherosclerosis [38], but evidence is conflicting in the case of COPD. Abdominal obesity has been associated with impairment in lung function in population-based studies, and insulin resistance and diabetes have a high prevalence in patients with COPD [39]. The debate about these associations with COPD is ongoing [40].
Consequences of systemic inflammation on heart vessels and lung Ensuing oxidative stress, tissue damage and abnormal immune activation could be the common pathway causing persistent low-grade systemic inflammation and linking atherosclerosis and airflow obstruction [6]. Many investigators have described immune cells and inflammatory mediators at work in atheroma, implicating inflammation in plaque initiation, development and rupture [13]. The atherosclerotic process starts with damage to the endothelium, caused by a variety of noxious stimuli, including
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Figure 1 Common pathogenic mechanisms of chronic obstructive pulmonary disease and coronary artery disease, centred on chronic systemic inflammation, leading to tissue injury and repair, with subsequent parenchymal damage and clinical manifestations. ROS: reactive oxygen species; LDL-Ox: oxidized low-density lipoproteins.
hypercholesterolaemia, cigarette smoking, hypertension, diabetes mellitus, free oxygen radicals and many others [13,41]. Subsequent endothelial dysfunction alters the homeostatic properties of the endothelial barrier; endothelium begins to over-express surface adhesion molecules and promotes the entrance of white blood cells and oxidized LDL particles within the arterial walls [34]. Cytokines, growth factors and other mediators produced in the inflamed intima induce monocytes to enter the plaque and differentiate first into macrophages and then into foam cells [34]. Next, components of plasma lipoproteins, oxidized LDL, certain heat-shock proteins [42] and other particles serve as antigens, stimulating further recruitment of inflammatory cells such as T cells. The clones of the activated
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T cells proliferate and amplify the immune response, triggering inflammation even further [13]. This combined immune response within atheroma is a key event in the atherosclerosis progression and might ultimately lead to plaque disruption [13]. As in atherosclerosis, it seems that remodelling of the airways and destruction of the lung parenchyma may be due to both local and systemic inflammatory mechanisms [43]. Upon the release of numerous cytokines – for example, tumour necrosis factor-alpha and interleukins – macrophages, neutrophils and dendritic cells gather at the damaged site and orchestrate the initial innate immune response [43]. Later, the inflammatory response triggers the release of different proteolytic enzymes and reactive oxygen species, thus damaging
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tissues even further [35]. Particles released from necrotic or apoptotic cells and foreign material might serve as antigens and be presented to naive T cells, thus activating the adaptive response [43]. This complex process, sustained by both the innate and adaptive host response, is associated with local increased production of mucus, emphysematous parenchymal destruction, peribronchiolar fibrosis, thickening and remodelling of the airway wall, defective mucociliary clearance and disruption of the epithelial barrier [35,43,44]. Late-stage airway and pulmonary changes, such as proteolysis and degradation of extracellular matrix, present some shared features with atherosclerosis. In the lung, proteolysis induces parenchymal disruption and consequent emphysema; whereas in arteries, degradation of the fibrous cap of the atherosclerotic lesion induces plaque rupture. Matrix metalloproteinases could be potential common mediators [43]. Therefore, structural changes sustained by chronic inflammation and repeated tissue injury and repair have been described both in heart vessels and lung parenchyma. This process will result in plaque formation, development and rupture in IHD [13] and AL and chronic bronchitis in COPD [1].
Circulating markers of inflammation in CAD and COPD To sustain the hypothesis of a common pathological background, elevated plasma levels of acute-phase proteins and inflammatory markers (e.g. blood leucocytes, C-reactive protein, interleukins 6, 7 and 8 and fibrinogen) have been reported in both the diseases [31,42]. In atherosclerosis, increased presence of inflammatory mediators (especially C-reactive protein) has been extensively described [45], and it is related to increased cardiovascular risk and worse long-term outcomes [42]. In patients with COPD, discussion is still ongoing: it seems that elevated inflammatory markers might identify a subgroup of patients with significantly increased all-cause mortality and frequency of exacerbations [46].
Other common pathogenic mechanisms of CAD and COPD Although systemic inflammation seems to be the main common pathway between CAD and COPD, other possible mechanisms have been described. Imbalance of thrombotic/antithrombotic mechanisms, with increased procoagulant activity, has been postulated in COPD [34]. Accordingly, comorbidities related to altered thrombotic status, such as cardiovascular disorders, myocardial infarction and pulmonary embolism, are fairly common in patients with COPD [47]. Accelerated ageing, resulting from low-grade inflammation and chronic oxidative stress, has been described in both COPD and IHD [34]. Its effects manifest in an excessive loss of lung
elastic recoil, increased arterial stiffness, endothelial dysfunction and vascular calcification [34,48]. Autoimmunity (e.g. antibodies against elastin) has been postulated as a possible common mechanism [35], but debate is still ongoing [34]. In summary, the latest studies have highlighted the importance of investigating the association of COPD and ischaemic comorbidities and have shed light on the role of chronic inflammation and altered immune response in the development of CAD in patients with COPD. Why some patients develop both diseases and others do not is a matter of debate. However, it is clear that many patients with COPD will also have some degree of cardiac involvement, and many of those with heart disease will have respiratory problems as well.
Clinical manifestations According to Global Initiative for Chronic Obstructive Lung Disease (GOLD), a clinical diagnosis of COPD should be considered in any patient who has chronic respiratory symptoms (e.g. dyspnoea with or without chronic cough and sputum) and a history of exposure to risk factors for the disease [1]. As previously discussed, the anatomical and functional relationship that exists between heart and lungs is such that any dysfunction in one organ is likely to have consequences for the other. It is useful to keep in mind that almost one half of all people aged 65 years or older will have at least 3 chronic medical conditions, and IHD and COPD are likely to coexist [1,2,32,40]. However, diagnosis can be difficult, as the concomitant presence of other conditions can hinder the diagnostic workup, and clinical manifestations can be misleading, particularly during exacerbations [49]. The clinical diagnosis of IHD is difficult when there are masked and undefined symptoms that mimic those of lung disease. Exacerbation of CAD in patients with COPD may present clinically with organ-nonspecific symptoms, such as dyspnoea and loss of exercise capacity, and thus, a correct diagnosis may be delayed. Moreover, symptoms such as dyspnoea, chest tightness and occasionally chest pain are common during COPD exacerbations and may be interpreted as COPD related even when they are of cardiac origin [24,49]. Thus, sudden onset of myocardial ischaemia, which usually appears as angina pectoris, may manifest as a syndrome of painless dyspnoea, confounding the clinician. On the other hand, exercise capacity may be limited by impaired lung function and misinterpreted as coronary symptoms; or shortness of breath may be misinterpreted as manifestations of congestive heart failure, and underlying lung disease in cardiac patients may be missed [6]. Furthermore, noninvasive diagnostic modalities in advanced lung disease are hindered by limitations to exercise poor tolerance of pharmacologic agents for stress testing and poor
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echocardiographic ‘windows’ [17]. Thus, underdiagnosis or misdiagnosis of IHD in patients with COPD is fairly common. Some investigators have observed that 20–30% of patients with COPD present electrocardiographic evidence of a previous myocardial infarction, whereas only half of them have ever been diagnosed with one [24]. The prevalence of angiographically proven CAD is even harder to define. For example, in a population of severely ill patients with COPD being evaluated for lung transplantation, occult CAD was found in 53% of them [17]. The opposite is also true: there is substantial underdiagnosis of AL in subjects affected by CAD. Some investigators report that AL was not recognized in 60–87% of subjects with IHD; there were even higher rates of underdiagnosis in former smokers, less symptomatic individuals and patients with mild AL [50]. However, both conditions should be diagnosed, because there are important prognostic implications: patients with COPD with cardiovascular comorbidities experience more episodes of COPD exacerbation, more hospital admissions and higher cardiovascular mortality and are the cause of a notable increase in the cost of medical care [19]. COPD has been determined to be a strong predictor of mortality, recurrent infarction, cardiovascular shock and bleeding complications in patients suffering from myocardial infarction [29]. In summary, the strong message of these clinical data is that each patient presenting with COPD should be carefully and actively investigated for concomitant ischaemic comorbidities; likewise, patients with IHD should be investigated for respiratory comorbidities.
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Gender-related differences Sex-related differences have been investigated in most chronic diseases, including COPD and IHD [12,51]. Disparity between men and women is mostly a result of behavioural and environmental factors, coupled with biological and gender-based genetic factors [52]. The role of gender in COPD development and progression is still controversial: historically, COPD was considered a disease of men, but the past few decades have seen a shift in this paradigm [53]. Thus, from 1980 to 2000, concurrent with an increase in the prevalence of COPD in women, the estimated annual number of COPD deaths grew for women while it declined for men [53,54]. According to the recent statistics, in 2007, US ageadjusted COPD death rates per 100 000 were 635 for men vs. 468 for women [54]. On the contrary, CAD death rates are steadily declining for both men and women (Fig. 2) [12]. Although sex-related differences in lung disease are not as well studied as in the cardiovascular realm, there has been a steady increase in the recent years [53,55]. Many explanations have been offered for the observed gender differences in COPD. First of all, the gender trends in COPD prevalence might be a reflection of the secular trends in smoking habits (e.g. increased cigarette consumption during the 1980s among women) [53]. Moreover, women seem to have greater susceptibility to the lung-damaging effects of smoking and a higher predisposition to COPD development [56]. Accordingly, women typically develop symptoms at a younger age and with
Figure 2 Trend for age-adjusted death rate by gender in the US population in 1980–2010 for ischaemic heart disease and chronic lower respiratory disease (mainly chronic obstructive pulmonary disease). Death rates are per 100 000.
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substantially smaller pack-year smoking history [52]. When normalized for pack-years smoked, the rate of lung function decline in women is faster, with women losing 10 mL/packyear and men losing 8 mL/pack-year [56]. Most likely, sex hormones are partly responsible for these differences between genders [55]. Oestrogen and oestradiol have been implicated in a variety of processes, including lung maturation and mucus hypersecretion [55,56], cytochrome P450 up-regulation [56] and increased inflammatory response to irritants (e.g. cigarette smoke) [53]. Some authors postulate that women might be more susceptible to the damaging effect of smoke because of the anatomically smaller luminal area of the airways [55,56]. These authors have proposed the concept of ‘dysanapsis’ (meaning unequal growth and physiological variation in the geometry of the tracheobronchial tree and lung parenchyma) [55]. Although sex-related variability in CAD has been extensively reported as well [57], gender differences in comorbidities are relatively understudied. There are observations that suggest that cardiovascular comorbidity seems to be less prevalent in women [51,53]. Higher rates of IHD in men have been reported in a different setting of patients with COPD, including over 8000 patients in a long-term oxygen therapy [58] and 2164 clinically stable patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study [59]. Despite these findings, many questions remain unanswered. Data on gender and comorbidities are scarce and warrant further research.
Therapeutic consequences and future directions Despite having similar disease mechanisms, there are substantial differences between atherosclerosis and COPD in their current treatment strategies. Patients with CAD benefit from antithrombotic therapy, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and statins [60]. Current COPD treatment relies on beta2-agonists, anticholinergics, inhaled corticosteroids and phosphodiesterase-4 inhibitors [1]. The most striking difference in these treatment strategies is the use of beta-agonists in COPD and beta blockers in heart disease. This has led to contrasting indications and subsequent underuse, particularly of beta blockers, of some classes of drug [61]. Recent data, such as the Towards a Revolution in COPD Health (TORCH) trial [62], suggest that drugs used to treat COPD, such as long-acting beta2-agonists, are tolerated and have an acceptable safety cardiovascular profile [63]. Beta blockers, on the other hand, are a cornerstone of CAD treatment, but their use in patients with COPD remains uncertain. The main concern is that these drugs might induce broncho-
spasm and worsen lung function [64]. However, data have shown that beta blockers, especially if cardioselective, may also be beneficial and lower mortality in patients with COPD [61,62,64], with the only exception in the most severe requiring long-term oxygen treatment [65]. Antiplatelets seemed to decreased mortality in patients aged 45 years or older, who started long-term oxygen therapy for physician-diagnosed COPD [65], but research in this field is just beginning. Statins, widely used in IHD, may have pleiotropic antiinflammatory actions, useful in patients with COPD as well. A number of observational studies suggest that patients with COPD who take statins have reduced hospitalization and lower mortality for COPD exacerbations, as well as lower overall cardiovascular mortality [65]. Data from randomized control trials are still scarce, but a large nested case–control study part of the Rotterdam Study (a large prospective population-based cohort study among 7983 subjects ≥ 55 years) showed that statin therapy is associated with a reduced mortality in patients with COPD [66]. Other therapeutic agents used in IHD might be beneficial in patients with COPD, but no conclusive data are yet available [61]. From this perspective, some trials are exploring the role of anti-inflammatory [67] drugs in COPD, and results will be available in the near future: the ongoing Study to Understand Mortality and Morbidity in COPD (SUMMIT) study [68] aims to assess the effect of COPD medications on the survival of patients with moderate COPD and a history of, or the increased risk for, CVD. An ongoing US randomized clinical trial aims to determine the effect of simvastatin on the frequency of exacerbations of COPD in patients with moderate-to-severe COPD [69]. Clinicians whose patients have comorbidities such as COPD and CAD often struggle to balance the risks and benefits of multiple recommended treatments, and further studies are required.
Conclusions A common background of the low-grade systemic inflammation links COPD and IHD. Enhanced inflammatory activity is most likely triggered by noxious environmental stimuli, such as cigarette smoke, and damages both lung epithelium and vascular endothelium. The clinical manifestations of COPD and IHD are similar, with overlapping symptoms and consequent underestimation of these diseases. Despite the robust body of evidence supporting the connection between COPD and IHD, therapeutic options targeting both diseases are still being evaluated and no randomized clinical trial has yet been conducted in patients with both IHD and COPD.
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We believe that these patients need to be investigated and subjected to new and comprehensive treatment [70]. From this perspective, the ongoing Study to Understand Mortality and Morbidity in COPD (SUMMIT) study [68] is particularly timely.
Source of funding This study was supported in part by the Chiesi Foundation and the Italian Ministry of Health (CCM grant). Address Section of Cardiology, Department of Medicine and Emergency Medicine, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo 71, 44124 Modena, Italy (S. Roversi, G. Spadafora, R. Rossi); Section of Respiratory Diseases, Department of Oncology Haematology and Respiratory Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo 71, 44124 Modena, Italy (P. Roversi, L. M. Fabbri). Correspondence to: Leonardo M. Fabbri, Department of Oncology Haematology and Respiratory Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo 71, 44124 Modena, Italy. Tel.: +39 059 4222198; fax +39 059 4224231; e-mail: [email protected] Received 5 August 2013; accepted 19 September 2013 References 1 Vestbo J, Hurd SS, Agustı AG, Jones PW, Vogelmeier C, Anzueto A et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–65. 2 Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:728–35. 3 Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012;380:37–43. 4 Finkelstein J, Cha E, Scharf SM. Chronic obstructive pulmonary disease as an independent risk factor for cardiovascular morbidity. Int J Chron Obstruct Pulmon Dis 2009;4:337–49. 5 Guthrie B, Payne K, Alderson P, McMurdo ME, Mercer SW. Adapting clinical guidelines to take account of multimorbidity. BMJ 2012;345:e6341. 6 Boschetto P, Beghe B, Fabbri LM, Ceconi C. Link between chronic obstructive pulmonary disease and coronary artery disease: implication for clinical practice. Respirology 2012;17:422–31. 7 US Burden of Disease Collaborators. The state of US health, 1990– 2010: burden of diseases, injuries, and risk factors. JAMA 2013;310:591–608.
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8 Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013;369:448–57. 9 Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007;370:741–50. 10 Waatevik M, Skorge TD, Omenaas E, Bakke PS, Gulsvik A, Johannessen A. Increased prevalence of chronic obstructive pulmonary disease in a general population. Respir Med 2013;107:1037–45. 11 WHO, Media, centre. Fact sheet No 317. Secondary Fact sheet No 317 2013. 12 Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB et al. Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation 2013;127:e6–245. 13 Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation 2012;125:1147–56. 14 Schnell K, Weiss CO, Lee T, Krishnan JA, Leff B, Wolff JL et al. The prevalence of clinically-relevant comorbid conditions in patients with physician-diagnosed COPD: a cross-sectional study using data from NHANES 1999-2008. BMC Pulm Med 2012;12:26. 15 Mullerova H, Agusti A, Erqou S, Mapel DW. Cardiovascular comorbidity in chronic obstructive pulmonary disease: systematic literature review. Chest 2013;144:1163–78. 16 Eriksson B, Lindberg A, Mullerova H, Ronmark E, Lundback B. Association of heart diseases with COPD and restrictive lung function–results from a population survey. Respir Med 2013;107:98– 106. 17 Reed RM, Eberlein M, Girgis RE, Hashmi S, Iacono A, Jones S et al. Coronary artery disease is under-diagnosed and under-treated in advanced lung disease. Am J Med 2012;125:1228 e13–28 e22. 18 Formiga F, Ferrer A, Sanz H, Marengoni A, Alburquerque J, Pujol R. Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study. Eur J Intern Med 2013;24:40–4. 19 Garcıa-Olmos L, Alberquilla A, Ayala V, Garcıa-Sagredo P, Morales L, Carmona M et al. Comorbidity in patients with chronic obstructive pulmonary disease in family practice: a cross sectional study. BMC Fam Pract 2013;14:11. 20 de Lucas-Ramos P, Izquierdo-Alonso JL, Rodrıguez-Gonzalez Moro JM, Bell on-Cano JM, Ancochea-Berm udez J, Calle-Rubio M et al. [Cardiovascular risk factors in chronic obstructive pulmonary disease: results of the ARCE study]. Arch Bronconeumol 2008;44: 233–8. 21 Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:155–61. 22 Cazzola M, Calzetta L, Bettoncelli G, Cricelli C, Romeo F, Matera MG et al. Cardiovascular disease in asthma and COPD: a population-based retrospective cross-sectional study. Respir Med 2012;106:249–56. 23 Sibila O, Mortensen EM, Anzueto A, Laserna E, Restrepo MI. Prior cardiovascular disease increases long-term mortality in COPD patients with pneumonia. Eur Respir J 2013. doi: 10.1183/09031936. 00117312. [Epub ahead of print]. 24 Brekke PH, Omland T, Smith P, Soyseth V. Underdiagnosis of myocardial infarction in COPD - Cardiac Infarction Injury Score (CIIS) in patients hospitalised for COPD exacerbation. Respir Med 2008;102:1243–7. 25 Sode BF, Dahl M, Nordestgaard BG. Myocardial infarction and other co-morbidities in patients with chronic obstructive pulmonary
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disease: a Danish nationwide study of 7.4 million individuals. Eur Heart J 2011;32:2365–75. Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, Goehring E Jr et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16:63–70. Barr RG, Celli BR, Mannino DM, Petty T, Rennard SI, Sciurba FC et al. Comorbidities, patient knowledge, and disease management in a national sample of patients with COPD. Am J Med 2009;122:348–55. Nishiyama K, Morimoto T, Furukawa Y, Nakagawa Y, Ehara N, Taniguchi R et al. Chronic obstructive pulmonary disease–an independent risk factor for long-term cardiac and cardiovascular mortality in patients with ischemic heart disease. Int J Cardiol 2010;143:178–83. Campo G, Guastaroba P, Marzocchi A, Santarelli A, Varani E, Vignali L et al. Impact of COPD on long-term outcome after St-segment elevation myocardial infarction receiving primary percutaneous coronary intervention. Chest 2013;144:750–7. McAllister DA, Maclay JD, Mills NL, Leitch A, Reid P, Carruthers R et al. Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD. Eur Respir J 2012;39:1097–103. Man SF, Van Eeden S, Sin DD. Vascular risk in chronic obstructive pulmonary disease: role of inflammation and other mediators. Can J Cardiol 2012;28:653–61. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007;370:797–9. Kawut SM. COPD: CardiOPulmonary disease? Eur Respir J 2013;41:1241–3. Maclay JD, Macnee W. Cardiovascular disease in COPD: mechanisms. Chest 2013;143:798–807. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2009;360:2445–54. Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic effects of smoking. Chest 2007;131:1557–66. Radak D, Babic S, Peric M, Popov P, Tanaskovic S, Babic D et al. Distribution of risk factors in patients with premature coronary, supra-aortic branches and peripheral atherosclerotic disease. Med Princ Pract 2012;21:228–33. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WM et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635–701. Watz H, Waschki B, Kirsten A, M€ uller KC, Kretschmar G, Meyer T et al. The metabolic syndrome in patients with chronic bronchitis and COPD: frequency and associated consequences for systemic inflammation and physical inactivity. Chest 2009;136:1039–46. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–12. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95. Kaptoge S, DiAngelantonio E, Pennells L, Wood AM, White IR, Gao P et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012;367:1310–20. Decramer M, Janssens W, Miravitlles M. Chronic obstructive pulmonary disease. Lancet 2012;379:1341–51. Soriano JB, Rodriguez-Roisin R. Chronic obstructive pulmonary disease overview: epidemiology, risk factors, and clinical presentation. Proc Am Thorac Soc 2011;8:363–7.
45 Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009;54:2129– 38. 46 Agustı A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 2012;7: e37483. 47 Bertoletti L, Quenet S, Mismetti P, Hernandez L, Martın-Villasclaras JJ, Tolosa C et al. Clinical presentation and outcome of venous thromboembolism in COPD. Eur Respir J 2012;39:862–8. 48 Lee HY, Oh BH. Aging and arterial stiffness. Circ J 2010;74:2257–62. 49 Roca M, Verduri A, Corbetta L, Clini E, Fabbri LM, Beghe B. Mechanisms of acute exacerbation of respiratory symptoms in chronic obstructive pulmonary disease. Eur J Clin Invest 2013;43:510– 21. 50 Soriano JB, Rigo F, Guerrero D, Ya~ nez A, Forteza JF, Frontera G et al. High prevalence of undiagnosed airflow limitation in patients with cardiovascular disease. Chest 2010;137:333–40. 51 Almagro P, L opez Garcıa F, Cabrera F, Montero L, Morch on D, Dıez J et al. Comorbidity and gender-related differences in patients hospitalized for COPD. The ECCO study. Respir Med 2010;104: 253–9. 52 Camp PG, O’Donnell DE, Postma DS. Chronic obstructive pulmonary disease in men and women: myths and reality. Proc Am Thorac Soc 2009;6:535–8. 53 Aryal S, Diaz-Guzman E, Mannino DM. COPD and gender differences: an update. Transl Res 2013;162:208–18. 54 Health, United States. 2012: With Special Feature on Emergency Care. Hyattsville, MD: Health, United States; 2013. 55 Tam A, Sin DD. Why are women more vulnerable to chronic obstructive pulmonary disease? Expert Rev Respir Med 2013;7:197–9. 56 Townsend EA, Miller VM, Prakash YS. Sex differences and sex steroids in lung health and disease. Endocr Rev 2012;33:1–47. 57 Papakonstantinou NA, Stamou MI, Baikoussis NG, Goudevenos J, Apostolakis E. Sex differentiation with regard to coronary artery disease. J Cardiol 2013;62:4–11. 58 Ekstrom MP, Jogreus C, Strom KE. Comorbidity and sex-related differences in mortality in oxygen-dependent chronic obstructive pulmonary disease. PLoS ONE 2012;7:e35806. 59 Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122. 60 Steg PG, James SK, Atar D, Badano LP, Bl€ omstrom-Lundqvist C, Borger MA et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. 61 Matera MG, Calzetta L, Rinaldi B, Cazzola M. Treatment of COPD: moving beyond the lungs. Curr Opin Pharmacol 2012;12:315–22. 62 Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax 2010;65:719–25. 63 Decramer ML, Hanania NA, Lotvall JO, Yawn BP. The safety of long-acting beta2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013;8:53–64. 64 Etminan M, Jafari S, Carleton B, FitzGerald JM. Beta-blocker use and COPD mortality: a systematic review and meta-analysis. BMC Pulm Med 2012;12:48. 65 Ekstrom MP, Hermansson AB, Strom KE. Effects of cardiovascular drugs on mortality in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:715–20.
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66 Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HG, Brusselle GG et al. Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulm Pharmacol Ther 2013;26:212–7. 67 Gross NJ. Novel antiinflammatory therapies for COPD. Chest 2012;142:1300–7. 68 Vestbo J, Anderson J, Brook RD, Calverley PM, Celli BR, Crim C et al. The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol. Eur Respir J 2013;41:1017–22.
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69 Connet JA, Scharf SM, Dransfield M, Washko G, Albert LK, Casaburi R et al. Simvastatin Therapy for Moderate and Severe COPD (STATCOPE). NCT01061671 Available at: http://www. clinicaltrials.gov. Accessed on 22 June 2013. 70 Nozzoli C, Beghe B, Boschetto P, Fabbri LM. Identifying and treating COPD in cardiac patients. Chest 2013;144:723–6.
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REVIEW Coronary artery disease concomitant with chronic obstructive pulmonary disease Sara Roversi*, Pietro Roversi†, Giuseppe Spadafora*, Rosario Rossi* and Leonardo M. Fabbri† *Section of Cardiology, Department of Medicine and Emergency Medicine, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy, †Section of Respiratory Diseases, Department of Oncology Haematology and Respiratory Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Modena, Italy
ABSTRACT Background Numerous epidemiologic studies have linked the presence of chronic obstructive pulmonary disease (COPD) to coronary artery disease (CAD). However, prevalence, pathological processes, clinical manifestations and therapy are still debated, as progress towards uncovering the link between these two disorders has been hindered by the complex nature of multimorbidity. Methods Articles targeting CAD in patients with COPD were identified from the searches of MEDLINE and EMBASE databases in July 2013. Three authors reviewed available evidence, focusing on the latest development on disease prevalence, pathogenesis, clinical manifestations and therapeutic strategies. Both clinical trial and previous reviews have been included in this work. Results The most accredited hypothesis asserts that the main common risk factors, that is, cigarette smoke and ageing, elicit a chronic low-grade systemic inflammatory response, which affects both cardiovascular endothelial cells and airways/lung parenchyma. The development of CAD in patients with COPD potentiates the morbidity of COPD, leading to increased hospitalizations, mortality and health costs. Moreover, correct diagnosis is challenging and therapies are not clearly defined. Conclusions Evidence from recently published articles highlights the importance of multimorbidity in patient management and future research. Moreover, many authors emphasize the importance of low-grade systemic inflammation as a common pathological mechanism and a possible future therapeutic target. Keywords Ageing, chronic bronchitis, ischaemic heart disease, multimorbidity, respiratory system, smoking. Eur J Clin Invest 2014; 44 (1): 93–102
Introduction Chronic obstructive pulmonary disease (COPD) is currently defined as a preventable and treatable respiratory disease characterized by chronic respiratory symptoms and persistent airflow limitation (AL) that are usually progressive and that are due to an abnormal inflammatory response to irritants, particularly cigarette smoking [1]. Compelling epidemiologic data reveal that patients with COPD have various concomitant diseases [including cardiovascular disease (CVD), skeletal muscle dysfunction, depression and lung cancer], with coronary artery disease (CAD) making up a large share of them [1,2]. Although many explanations have been suggested, the most accredited hypothesis asserts that systemic inflammation, most likely a result of common noxious stimuli (e.g. cigarette smoke) and ageing, might sustain both COPD and CAD [3–5]. The association of these disorders is important mostly for its nega-
tive effect on the course of the disease (i.e. increased hospitalization, increased risk of acute severe exacerbation and increased mortality) [6] and for the enhanced social and economic burden. Recently, awareness of multimorbidity and its clinical implications has been rising, even though a few guidelines and therapeutic indications target this subject [3,5]. Here, we give a broad review of the prevalence of both COPD and CAD, report the latest findings on possible pathogenic mechanisms and describe the symptoms and therapeutic strategies.
Prevalence and association of COPD and CAD Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality worldwide and results in a substantial
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and increasing economic and social burden [1,7]. Defining COPD prevalence is no easy task, because definition, survey methods and analytic approaches are not uniform across published studies [1,8]. Recent data suggest a population-based prevalence of approximately 9–10% in subjects aged 40 years and older, rising steeply with age and exceeding 20% in subjects older than 70 years [9]. Further, COPD prevalence among heavy smokers (> 20 pack-years) reached 31% in a survey addressing general adult population in Norway in the years 2003–2005 [1,10]. Ischaemic heart disease (IHD) or CAD, defined by the World Health Organization [11] as a disease of the blood vessels supplying the heart muscle, is also a substantial problem [12]. CAD alone accounted for about half of all cardiovascularrelated deaths in the United States in 2009; it caused more than 116 per 100 000 deaths (Table 1) [12], and it was the first leading disease contributing to premature death in 2010 [7,8]. Additionally, one American has a coronary event approximately every 34 s, and an American will die of CAD every minute. As with COPD, the prevalence of CAD increases with age, rising from 35 to 40% of subjects aged 40–59 years, to almost 70% for those aged 60–79 years [12,13]. Epidemiologic data indicate a strong association between AL and CAD, suggesting that patients with COPD might have a higher risk of developing IHD and patients with IHD might have a higher risk of developing COPD [14]. The prevalence of IHD (i.e. myocardial infarction, angina and coronary stenosis) in patients with COPD varies between studies, ranging from 47% to 60% [15]. In a population-based survey, CAD was reported in 7–13% of patients diagnosed with COPD, and COPD was reported in 26–35% of patients with IHD [14,16]. IHD prevalence increases with COPD severity, reaching rates as high as 60% of the patients affected by advanced COPD, who are undergoing transplant evaluation [17]. Moreover, COPD and IHD rates increase with advancing age, and thus, multimorbidity rates as high as 951% have been reported in patients aged 85 years (COPD and IHD, respectively, 159% and 63%)
Table 1 Cardiovascular disease (CVD), ischaemic heart disease (IHD) and myocardial infarction (MI) prevalence and mortality in the United States (National Health and Nutrition Examination Survey 2007–2010) [12] Men CVD prevalence% (age > 20 years) CVD death per 100 000 per year IHD prevalence % (age > 20 years) IHD death per 100 000 per year MI prevalence % (age > 20 years)
94
Women
Total
367
34
353
2814
1904
2361
79
51
64
1559
849
1161
42
17
29
[18]. Table 2 reviews some of the studies reporting IHD prevalence in COPD. Patient prognosis is influenced by comorbidities, and not surprisingly, the association of these two chronic conditions results in a worse prognosis. COPD seems to be an independent predictor of mortality in patients suffering from CAD [28]. For example, patients with myocardial infarction or patients who are receiving hospital treatment for IHD have a 50% increased risk of death at 3 years if affected by COPD, as compared with similar patients without COPD [29]. The risk increases fourfold in those who develop a COPD exacerbation during the 3-year follow-up [29]. On the other hand, CVDs are among the leading causes of death in patients with mild-to-moderate COPD, and the presence of manifest CAD is associated with an increased risk of death for these patients [21]. Furthermore, a significantly increased risk of myocardial infarction has been shown to follow COPD exacerbations [30], and associated ischaemic comorbidities confer greater long-term mortality in hospitalized COPD elderly patients (≥ 65 years) [23]. Individual diseases have dominated medical research for many years, but the latest epidemiologic data clearly reveal that comorbidities are often the rule, not the exception. Thus, future research should have a broader approach and focus on multimorbidities.
Pathogenesis Although prevalent data confirm an important association between COPD and IHD [14], the common underlying pathogenic mechanism is far from being fully explained. It seems that shared risk factors elicit a chronic low-grade systemic inflammatory response [31], which affects both cardiovascular endothelial cells and airways/lung parenchyma [32]. Additionally, pathophysiological changes associated with COPD could directly affect heart function, unmasking an underlying coronary disease [33]. However, disease development is a complex process, stemming from gene–environment interactions. Most likely, multifactorial biological processes interact on a complex background of genetic determinants, age-related tissue modification and noxious environmental stimuli, resulting in clinical manifestations [34] of COPD and CAD (Fig. 1).
Putative shared risk factors that sustain low-grade systemic inflammation Of the shared risk factors that could trigger systemic inflammation, cigarette smoking is probably the most common. Each puff on a cigarette contains more than 2000 xenobiotic compounds and 10 free radicals [35]. Damage from lung epithelial cells and vascular endothelial cells is proportionate to their concentration, and for most adverse outcomes, risk increases with the number of
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Table 2 List of studies reporting CAD prevalence in patients with COPD. The first four columns describe population characteristics (i.e. total number of patients, rates of male patients, mean age and COPD severity). The following columns report the rates of concomitant CAD. Where indicated in the cited works, CAD subtype (i.e. myocardial infarction and angina pectoris) and relative rates have been specified in the table Patients with COPD (N) 3183
Mean age 71
Men (%) 70
COPD definition and severity
CAD type
NS
CAD
Prevalence (%) 85
References [19]
527
68
849
GOLD stage I–IV
CAD
122–181
[20]
1659
66
89
GOLD stage I–IV
CAD
302
[21]
†
351
58
42
Severe COPD*
CAD
59
[17]
958
60
464
NS
CAD MI AP
161 148 11
[4]
25 281
> 35
62
NS
CAD MI
17 140
76
98
NS
MI AP
295 282
[23]
897
71
492
NS
MI
277
[24]
313 958
68
55
NS
MI
3–4
[25]
> 65
54
ICD-9 codes (491–4928)
MI AP
23 66
[26]
213
64
59
GOLD stage II–IV
MI
9
[2]
1003
61
42
NS
AP
22
[27]
11 493
920 481
[22]
CAD, coronary artery disease; MI, myocardial infarction; AP, angina pectoris; NS, not stated; COPD, chronic obstructive pulmonary disease. *Patients with a diagnosis of COPD referred for lung transplant evaluation. † CAD diagnosed by coronary angiography.
pack-years [35] Smoking-related effects are both local (by means of tissue injury from direct chemical exposure) and systemic (stimulating a low-grade inflammatory response that involves the whole organism) [36].Overall, current data suggest that chronic exposure to chemicals and free radicals of cigarette smoke affects a number of homeostatic mechanisms, for example, (i) it causes depletion of endogenous antioxidants and disturbs the physiological oxidative–antioxidative balance [36], (ii) it stimulates the haematopoietic system, with increased numbers of circulating leucocytes and platelets [36], (iii) it aggravates low-density lipoprotein (LDL) oxidation because of a higher concentration of reactive oxygen species, and (iv) it plays a role in enhanced platelet/monocyte aggregation and over expression of endothelial adhesion molecules [36]. Smoking is a relevant risk factor for all types of IHD, but its importance has been reported particularly in the setting of premature atherosclerosis [37]. In a population of almost 1000 patients (≤ 50 years) with clinically significant manifestations of atherosclerosis, cigarette smoking was the most common preventable risk factor [37]. However, data are scarce on COPD prevalence in this setting.
Along with smoking, other risk factors, such as sedentary lifestyle, obesity and insulin resistance, have been related to low-grade systemic inflammation and oxidative stress. Their causative role is well documented in CVD and atherosclerosis [38], but evidence is conflicting in the case of COPD. Abdominal obesity has been associated with impairment in lung function in population-based studies, and insulin resistance and diabetes have a high prevalence in patients with COPD [39]. The debate about these associations with COPD is ongoing [40].
Consequences of systemic inflammation on heart vessels and lung Ensuing oxidative stress, tissue damage and abnormal immune activation could be the common pathway causing persistent low-grade systemic inflammation and linking atherosclerosis and airflow obstruction [6]. Many investigators have described immune cells and inflammatory mediators at work in atheroma, implicating inflammation in plaque initiation, development and rupture [13]. The atherosclerotic process starts with damage to the endothelium, caused by a variety of noxious stimuli, including
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Figure 1 Common pathogenic mechanisms of chronic obstructive pulmonary disease and coronary artery disease, centred on chronic systemic inflammation, leading to tissue injury and repair, with subsequent parenchymal damage and clinical manifestations. ROS: reactive oxygen species; LDL-Ox: oxidized low-density lipoproteins.
hypercholesterolaemia, cigarette smoking, hypertension, diabetes mellitus, free oxygen radicals and many others [13,41]. Subsequent endothelial dysfunction alters the homeostatic properties of the endothelial barrier; endothelium begins to over-express surface adhesion molecules and promotes the entrance of white blood cells and oxidized LDL particles within the arterial walls [34]. Cytokines, growth factors and other mediators produced in the inflamed intima induce monocytes to enter the plaque and differentiate first into macrophages and then into foam cells [34]. Next, components of plasma lipoproteins, oxidized LDL, certain heat-shock proteins [42] and other particles serve as antigens, stimulating further recruitment of inflammatory cells such as T cells. The clones of the activated
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T cells proliferate and amplify the immune response, triggering inflammation even further [13]. This combined immune response within atheroma is a key event in the atherosclerosis progression and might ultimately lead to plaque disruption [13]. As in atherosclerosis, it seems that remodelling of the airways and destruction of the lung parenchyma may be due to both local and systemic inflammatory mechanisms [43]. Upon the release of numerous cytokines – for example, tumour necrosis factor-alpha and interleukins – macrophages, neutrophils and dendritic cells gather at the damaged site and orchestrate the initial innate immune response [43]. Later, the inflammatory response triggers the release of different proteolytic enzymes and reactive oxygen species, thus damaging
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tissues even further [35]. Particles released from necrotic or apoptotic cells and foreign material might serve as antigens and be presented to naive T cells, thus activating the adaptive response [43]. This complex process, sustained by both the innate and adaptive host response, is associated with local increased production of mucus, emphysematous parenchymal destruction, peribronchiolar fibrosis, thickening and remodelling of the airway wall, defective mucociliary clearance and disruption of the epithelial barrier [35,43,44]. Late-stage airway and pulmonary changes, such as proteolysis and degradation of extracellular matrix, present some shared features with atherosclerosis. In the lung, proteolysis induces parenchymal disruption and consequent emphysema; whereas in arteries, degradation of the fibrous cap of the atherosclerotic lesion induces plaque rupture. Matrix metalloproteinases could be potential common mediators [43]. Therefore, structural changes sustained by chronic inflammation and repeated tissue injury and repair have been described both in heart vessels and lung parenchyma. This process will result in plaque formation, development and rupture in IHD [13] and AL and chronic bronchitis in COPD [1].
Circulating markers of inflammation in CAD and COPD To sustain the hypothesis of a common pathological background, elevated plasma levels of acute-phase proteins and inflammatory markers (e.g. blood leucocytes, C-reactive protein, interleukins 6, 7 and 8 and fibrinogen) have been reported in both the diseases [31,42]. In atherosclerosis, increased presence of inflammatory mediators (especially C-reactive protein) has been extensively described [45], and it is related to increased cardiovascular risk and worse long-term outcomes [42]. In patients with COPD, discussion is still ongoing: it seems that elevated inflammatory markers might identify a subgroup of patients with significantly increased all-cause mortality and frequency of exacerbations [46].
Other common pathogenic mechanisms of CAD and COPD Although systemic inflammation seems to be the main common pathway between CAD and COPD, other possible mechanisms have been described. Imbalance of thrombotic/antithrombotic mechanisms, with increased procoagulant activity, has been postulated in COPD [34]. Accordingly, comorbidities related to altered thrombotic status, such as cardiovascular disorders, myocardial infarction and pulmonary embolism, are fairly common in patients with COPD [47]. Accelerated ageing, resulting from low-grade inflammation and chronic oxidative stress, has been described in both COPD and IHD [34]. Its effects manifest in an excessive loss of lung
elastic recoil, increased arterial stiffness, endothelial dysfunction and vascular calcification [34,48]. Autoimmunity (e.g. antibodies against elastin) has been postulated as a possible common mechanism [35], but debate is still ongoing [34]. In summary, the latest studies have highlighted the importance of investigating the association of COPD and ischaemic comorbidities and have shed light on the role of chronic inflammation and altered immune response in the development of CAD in patients with COPD. Why some patients develop both diseases and others do not is a matter of debate. However, it is clear that many patients with COPD will also have some degree of cardiac involvement, and many of those with heart disease will have respiratory problems as well.
Clinical manifestations According to Global Initiative for Chronic Obstructive Lung Disease (GOLD), a clinical diagnosis of COPD should be considered in any patient who has chronic respiratory symptoms (e.g. dyspnoea with or without chronic cough and sputum) and a history of exposure to risk factors for the disease [1]. As previously discussed, the anatomical and functional relationship that exists between heart and lungs is such that any dysfunction in one organ is likely to have consequences for the other. It is useful to keep in mind that almost one half of all people aged 65 years or older will have at least 3 chronic medical conditions, and IHD and COPD are likely to coexist [1,2,32,40]. However, diagnosis can be difficult, as the concomitant presence of other conditions can hinder the diagnostic workup, and clinical manifestations can be misleading, particularly during exacerbations [49]. The clinical diagnosis of IHD is difficult when there are masked and undefined symptoms that mimic those of lung disease. Exacerbation of CAD in patients with COPD may present clinically with organ-nonspecific symptoms, such as dyspnoea and loss of exercise capacity, and thus, a correct diagnosis may be delayed. Moreover, symptoms such as dyspnoea, chest tightness and occasionally chest pain are common during COPD exacerbations and may be interpreted as COPD related even when they are of cardiac origin [24,49]. Thus, sudden onset of myocardial ischaemia, which usually appears as angina pectoris, may manifest as a syndrome of painless dyspnoea, confounding the clinician. On the other hand, exercise capacity may be limited by impaired lung function and misinterpreted as coronary symptoms; or shortness of breath may be misinterpreted as manifestations of congestive heart failure, and underlying lung disease in cardiac patients may be missed [6]. Furthermore, noninvasive diagnostic modalities in advanced lung disease are hindered by limitations to exercise poor tolerance of pharmacologic agents for stress testing and poor
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echocardiographic ‘windows’ [17]. Thus, underdiagnosis or misdiagnosis of IHD in patients with COPD is fairly common. Some investigators have observed that 20–30% of patients with COPD present electrocardiographic evidence of a previous myocardial infarction, whereas only half of them have ever been diagnosed with one [24]. The prevalence of angiographically proven CAD is even harder to define. For example, in a population of severely ill patients with COPD being evaluated for lung transplantation, occult CAD was found in 53% of them [17]. The opposite is also true: there is substantial underdiagnosis of AL in subjects affected by CAD. Some investigators report that AL was not recognized in 60–87% of subjects with IHD; there were even higher rates of underdiagnosis in former smokers, less symptomatic individuals and patients with mild AL [50]. However, both conditions should be diagnosed, because there are important prognostic implications: patients with COPD with cardiovascular comorbidities experience more episodes of COPD exacerbation, more hospital admissions and higher cardiovascular mortality and are the cause of a notable increase in the cost of medical care [19]. COPD has been determined to be a strong predictor of mortality, recurrent infarction, cardiovascular shock and bleeding complications in patients suffering from myocardial infarction [29]. In summary, the strong message of these clinical data is that each patient presenting with COPD should be carefully and actively investigated for concomitant ischaemic comorbidities; likewise, patients with IHD should be investigated for respiratory comorbidities.
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Gender-related differences Sex-related differences have been investigated in most chronic diseases, including COPD and IHD [12,51]. Disparity between men and women is mostly a result of behavioural and environmental factors, coupled with biological and gender-based genetic factors [52]. The role of gender in COPD development and progression is still controversial: historically, COPD was considered a disease of men, but the past few decades have seen a shift in this paradigm [53]. Thus, from 1980 to 2000, concurrent with an increase in the prevalence of COPD in women, the estimated annual number of COPD deaths grew for women while it declined for men [53,54]. According to the recent statistics, in 2007, US ageadjusted COPD death rates per 100 000 were 635 for men vs. 468 for women [54]. On the contrary, CAD death rates are steadily declining for both men and women (Fig. 2) [12]. Although sex-related differences in lung disease are not as well studied as in the cardiovascular realm, there has been a steady increase in the recent years [53,55]. Many explanations have been offered for the observed gender differences in COPD. First of all, the gender trends in COPD prevalence might be a reflection of the secular trends in smoking habits (e.g. increased cigarette consumption during the 1980s among women) [53]. Moreover, women seem to have greater susceptibility to the lung-damaging effects of smoking and a higher predisposition to COPD development [56]. Accordingly, women typically develop symptoms at a younger age and with
Figure 2 Trend for age-adjusted death rate by gender in the US population in 1980–2010 for ischaemic heart disease and chronic lower respiratory disease (mainly chronic obstructive pulmonary disease). Death rates are per 100 000.
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substantially smaller pack-year smoking history [52]. When normalized for pack-years smoked, the rate of lung function decline in women is faster, with women losing 10 mL/packyear and men losing 8 mL/pack-year [56]. Most likely, sex hormones are partly responsible for these differences between genders [55]. Oestrogen and oestradiol have been implicated in a variety of processes, including lung maturation and mucus hypersecretion [55,56], cytochrome P450 up-regulation [56] and increased inflammatory response to irritants (e.g. cigarette smoke) [53]. Some authors postulate that women might be more susceptible to the damaging effect of smoke because of the anatomically smaller luminal area of the airways [55,56]. These authors have proposed the concept of ‘dysanapsis’ (meaning unequal growth and physiological variation in the geometry of the tracheobronchial tree and lung parenchyma) [55]. Although sex-related variability in CAD has been extensively reported as well [57], gender differences in comorbidities are relatively understudied. There are observations that suggest that cardiovascular comorbidity seems to be less prevalent in women [51,53]. Higher rates of IHD in men have been reported in a different setting of patients with COPD, including over 8000 patients in a long-term oxygen therapy [58] and 2164 clinically stable patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study [59]. Despite these findings, many questions remain unanswered. Data on gender and comorbidities are scarce and warrant further research.
Therapeutic consequences and future directions Despite having similar disease mechanisms, there are substantial differences between atherosclerosis and COPD in their current treatment strategies. Patients with CAD benefit from antithrombotic therapy, beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and statins [60]. Current COPD treatment relies on beta2-agonists, anticholinergics, inhaled corticosteroids and phosphodiesterase-4 inhibitors [1]. The most striking difference in these treatment strategies is the use of beta-agonists in COPD and beta blockers in heart disease. This has led to contrasting indications and subsequent underuse, particularly of beta blockers, of some classes of drug [61]. Recent data, such as the Towards a Revolution in COPD Health (TORCH) trial [62], suggest that drugs used to treat COPD, such as long-acting beta2-agonists, are tolerated and have an acceptable safety cardiovascular profile [63]. Beta blockers, on the other hand, are a cornerstone of CAD treatment, but their use in patients with COPD remains uncertain. The main concern is that these drugs might induce broncho-
spasm and worsen lung function [64]. However, data have shown that beta blockers, especially if cardioselective, may also be beneficial and lower mortality in patients with COPD [61,62,64], with the only exception in the most severe requiring long-term oxygen treatment [65]. Antiplatelets seemed to decreased mortality in patients aged 45 years or older, who started long-term oxygen therapy for physician-diagnosed COPD [65], but research in this field is just beginning. Statins, widely used in IHD, may have pleiotropic antiinflammatory actions, useful in patients with COPD as well. A number of observational studies suggest that patients with COPD who take statins have reduced hospitalization and lower mortality for COPD exacerbations, as well as lower overall cardiovascular mortality [65]. Data from randomized control trials are still scarce, but a large nested case–control study part of the Rotterdam Study (a large prospective population-based cohort study among 7983 subjects ≥ 55 years) showed that statin therapy is associated with a reduced mortality in patients with COPD [66]. Other therapeutic agents used in IHD might be beneficial in patients with COPD, but no conclusive data are yet available [61]. From this perspective, some trials are exploring the role of anti-inflammatory [67] drugs in COPD, and results will be available in the near future: the ongoing Study to Understand Mortality and Morbidity in COPD (SUMMIT) study [68] aims to assess the effect of COPD medications on the survival of patients with moderate COPD and a history of, or the increased risk for, CVD. An ongoing US randomized clinical trial aims to determine the effect of simvastatin on the frequency of exacerbations of COPD in patients with moderate-to-severe COPD [69]. Clinicians whose patients have comorbidities such as COPD and CAD often struggle to balance the risks and benefits of multiple recommended treatments, and further studies are required.
Conclusions A common background of the low-grade systemic inflammation links COPD and IHD. Enhanced inflammatory activity is most likely triggered by noxious environmental stimuli, such as cigarette smoke, and damages both lung epithelium and vascular endothelium. The clinical manifestations of COPD and IHD are similar, with overlapping symptoms and consequent underestimation of these diseases. Despite the robust body of evidence supporting the connection between COPD and IHD, therapeutic options targeting both diseases are still being evaluated and no randomized clinical trial has yet been conducted in patients with both IHD and COPD.
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We believe that these patients need to be investigated and subjected to new and comprehensive treatment [70]. From this perspective, the ongoing Study to Understand Mortality and Morbidity in COPD (SUMMIT) study [68] is particularly timely.
Source of funding This study was supported in part by the Chiesi Foundation and the Italian Ministry of Health (CCM grant). Address Section of Cardiology, Department of Medicine and Emergency Medicine, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo 71, 44124 Modena, Italy (S. Roversi, G. Spadafora, R. Rossi); Section of Respiratory Diseases, Department of Oncology Haematology and Respiratory Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo 71, 44124 Modena, Italy (P. Roversi, L. M. Fabbri). Correspondence to: Leonardo M. Fabbri, Department of Oncology Haematology and Respiratory Diseases, University of Modena and Reggio Emilia, Policlinico di Modena, Largo del Pozzo 71, 44124 Modena, Italy. Tel.: +39 059 4222198; fax +39 059 4224231; e-mail: [email protected] Received 5 August 2013; accepted 19 September 2013 References 1 Vestbo J, Hurd SS, Agustı AG, Jones PW, Vogelmeier C, Anzueto A et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–65. 2 Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:728–35. 3 Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012;380:37–43. 4 Finkelstein J, Cha E, Scharf SM. Chronic obstructive pulmonary disease as an independent risk factor for cardiovascular morbidity. Int J Chron Obstruct Pulmon Dis 2009;4:337–49. 5 Guthrie B, Payne K, Alderson P, McMurdo ME, Mercer SW. Adapting clinical guidelines to take account of multimorbidity. BMJ 2012;345:e6341. 6 Boschetto P, Beghe B, Fabbri LM, Ceconi C. Link between chronic obstructive pulmonary disease and coronary artery disease: implication for clinical practice. Respirology 2012;17:422–31. 7 US Burden of Disease Collaborators. The state of US health, 1990– 2010: burden of diseases, injuries, and risk factors. JAMA 2013;310:591–608.
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8 Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med 2013;369:448–57. 9 Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM et al. International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study. Lancet 2007;370:741–50. 10 Waatevik M, Skorge TD, Omenaas E, Bakke PS, Gulsvik A, Johannessen A. Increased prevalence of chronic obstructive pulmonary disease in a general population. Respir Med 2013;107:1037–45. 11 WHO, Media, centre. Fact sheet No 317. Secondary Fact sheet No 317 2013. 12 Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB et al. Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation 2013;127:e6–245. 13 Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation 2012;125:1147–56. 14 Schnell K, Weiss CO, Lee T, Krishnan JA, Leff B, Wolff JL et al. The prevalence of clinically-relevant comorbid conditions in patients with physician-diagnosed COPD: a cross-sectional study using data from NHANES 1999-2008. BMC Pulm Med 2012;12:26. 15 Mullerova H, Agusti A, Erqou S, Mapel DW. Cardiovascular comorbidity in chronic obstructive pulmonary disease: systematic literature review. Chest 2013;144:1163–78. 16 Eriksson B, Lindberg A, Mullerova H, Ronmark E, Lundback B. Association of heart diseases with COPD and restrictive lung function–results from a population survey. Respir Med 2013;107:98– 106. 17 Reed RM, Eberlein M, Girgis RE, Hashmi S, Iacono A, Jones S et al. Coronary artery disease is under-diagnosed and under-treated in advanced lung disease. Am J Med 2012;125:1228 e13–28 e22. 18 Formiga F, Ferrer A, Sanz H, Marengoni A, Alburquerque J, Pujol R. Patterns of comorbidity and multimorbidity in the oldest old: the Octabaix study. Eur J Intern Med 2013;24:40–4. 19 Garcıa-Olmos L, Alberquilla A, Ayala V, Garcıa-Sagredo P, Morales L, Carmona M et al. Comorbidity in patients with chronic obstructive pulmonary disease in family practice: a cross sectional study. BMC Fam Pract 2013;14:11. 20 de Lucas-Ramos P, Izquierdo-Alonso JL, Rodrıguez-Gonzalez Moro JM, Bell on-Cano JM, Ancochea-Berm udez J, Calle-Rubio M et al. [Cardiovascular risk factors in chronic obstructive pulmonary disease: results of the ARCE study]. Arch Bronconeumol 2008;44: 233–8. 21 Divo M, Cote C, de Torres JP, Casanova C, Marin JM, Pinto-Plata V et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;186:155–61. 22 Cazzola M, Calzetta L, Bettoncelli G, Cricelli C, Romeo F, Matera MG et al. Cardiovascular disease in asthma and COPD: a population-based retrospective cross-sectional study. Respir Med 2012;106:249–56. 23 Sibila O, Mortensen EM, Anzueto A, Laserna E, Restrepo MI. Prior cardiovascular disease increases long-term mortality in COPD patients with pneumonia. Eur Respir J 2013. doi: 10.1183/09031936. 00117312. [Epub ahead of print]. 24 Brekke PH, Omland T, Smith P, Soyseth V. Underdiagnosis of myocardial infarction in COPD - Cardiac Infarction Injury Score (CIIS) in patients hospitalised for COPD exacerbation. Respir Med 2008;102:1243–7. 25 Sode BF, Dahl M, Nordestgaard BG. Myocardial infarction and other co-morbidities in patients with chronic obstructive pulmonary
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26
27
28
29
30
31
32 33 34 35 36 37
38
39
40 41 42
43 44
disease: a Danish nationwide study of 7.4 million individuals. Eur Heart J 2011;32:2365–75. Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, Goehring E Jr et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol 2006;16:63–70. Barr RG, Celli BR, Mannino DM, Petty T, Rennard SI, Sciurba FC et al. Comorbidities, patient knowledge, and disease management in a national sample of patients with COPD. Am J Med 2009;122:348–55. Nishiyama K, Morimoto T, Furukawa Y, Nakagawa Y, Ehara N, Taniguchi R et al. Chronic obstructive pulmonary disease–an independent risk factor for long-term cardiac and cardiovascular mortality in patients with ischemic heart disease. Int J Cardiol 2010;143:178–83. Campo G, Guastaroba P, Marzocchi A, Santarelli A, Varani E, Vignali L et al. Impact of COPD on long-term outcome after St-segment elevation myocardial infarction receiving primary percutaneous coronary intervention. Chest 2013;144:750–7. McAllister DA, Maclay JD, Mills NL, Leitch A, Reid P, Carruthers R et al. Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD. Eur Respir J 2012;39:1097–103. Man SF, Van Eeden S, Sin DD. Vascular risk in chronic obstructive pulmonary disease: role of inflammation and other mediators. Can J Cardiol 2012;28:653–61. Fabbri LM, Rabe KF. From COPD to chronic systemic inflammatory syndrome? Lancet 2007;370:797–9. Kawut SM. COPD: CardiOPulmonary disease? Eur Respir J 2013;41:1241–3. Maclay JD, Macnee W. Cardiovascular disease in COPD: mechanisms. Chest 2013;143:798–807. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2009;360:2445–54. Yanbaeva DG, Dentener MA, Creutzberg EC, Wesseling G, Wouters EF. Systemic effects of smoking. Chest 2007;131:1557–66. Radak D, Babic S, Peric M, Popov P, Tanaskovic S, Babic D et al. Distribution of risk factors in patients with premature coronary, supra-aortic branches and peripheral atherosclerotic disease. Med Princ Pract 2012;21:228–33. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WM et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2012;33:1635–701. Watz H, Waschki B, Kirsten A, M€ uller KC, Kretschmar G, Meyer T et al. The metabolic syndrome in patients with chronic bronchitis and COPD: frequency and associated consequences for systemic inflammation and physical inactivity. Chest 2009;136:1039–46. Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–12. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685–95. Kaptoge S, DiAngelantonio E, Pennells L, Wood AM, White IR, Gao P et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med 2012;367:1310–20. Decramer M, Janssens W, Miravitlles M. Chronic obstructive pulmonary disease. Lancet 2012;379:1341–51. Soriano JB, Rodriguez-Roisin R. Chronic obstructive pulmonary disease overview: epidemiology, risk factors, and clinical presentation. Proc Am Thorac Soc 2011;8:363–7.
45 Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009;54:2129– 38. 46 Agustı A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 2012;7: e37483. 47 Bertoletti L, Quenet S, Mismetti P, Hernandez L, Martın-Villasclaras JJ, Tolosa C et al. Clinical presentation and outcome of venous thromboembolism in COPD. Eur Respir J 2012;39:862–8. 48 Lee HY, Oh BH. Aging and arterial stiffness. Circ J 2010;74:2257–62. 49 Roca M, Verduri A, Corbetta L, Clini E, Fabbri LM, Beghe B. Mechanisms of acute exacerbation of respiratory symptoms in chronic obstructive pulmonary disease. Eur J Clin Invest 2013;43:510– 21. 50 Soriano JB, Rigo F, Guerrero D, Ya~ nez A, Forteza JF, Frontera G et al. High prevalence of undiagnosed airflow limitation in patients with cardiovascular disease. Chest 2010;137:333–40. 51 Almagro P, L opez Garcıa F, Cabrera F, Montero L, Morch on D, Dıez J et al. Comorbidity and gender-related differences in patients hospitalized for COPD. The ECCO study. Respir Med 2010;104: 253–9. 52 Camp PG, O’Donnell DE, Postma DS. Chronic obstructive pulmonary disease in men and women: myths and reality. Proc Am Thorac Soc 2009;6:535–8. 53 Aryal S, Diaz-Guzman E, Mannino DM. COPD and gender differences: an update. Transl Res 2013;162:208–18. 54 Health, United States. 2012: With Special Feature on Emergency Care. Hyattsville, MD: Health, United States; 2013. 55 Tam A, Sin DD. Why are women more vulnerable to chronic obstructive pulmonary disease? Expert Rev Respir Med 2013;7:197–9. 56 Townsend EA, Miller VM, Prakash YS. Sex differences and sex steroids in lung health and disease. Endocr Rev 2012;33:1–47. 57 Papakonstantinou NA, Stamou MI, Baikoussis NG, Goudevenos J, Apostolakis E. Sex differentiation with regard to coronary artery disease. J Cardiol 2013;62:4–11. 58 Ekstrom MP, Jogreus C, Strom KE. Comorbidity and sex-related differences in mortality in oxygen-dependent chronic obstructive pulmonary disease. PLoS ONE 2012;7:e35806. 59 Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122. 60 Steg PG, James SK, Atar D, Badano LP, Bl€ omstrom-Lundqvist C, Borger MA et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569–619. 61 Matera MG, Calzetta L, Rinaldi B, Cazzola M. Treatment of COPD: moving beyond the lungs. Curr Opin Pharmacol 2012;12:315–22. 62 Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax 2010;65:719–25. 63 Decramer ML, Hanania NA, Lotvall JO, Yawn BP. The safety of long-acting beta2-agonists in the treatment of stable chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2013;8:53–64. 64 Etminan M, Jafari S, Carleton B, FitzGerald JM. Beta-blocker use and COPD mortality: a systematic review and meta-analysis. BMC Pulm Med 2012;12:48. 65 Ekstrom MP, Hermansson AB, Strom KE. Effects of cardiovascular drugs on mortality in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:715–20.
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S. ROVERSI ET AL.
66 Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HG, Brusselle GG et al. Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulm Pharmacol Ther 2013;26:212–7. 67 Gross NJ. Novel antiinflammatory therapies for COPD. Chest 2012;142:1300–7. 68 Vestbo J, Anderson J, Brook RD, Calverley PM, Celli BR, Crim C et al. The Study to Understand Mortality and Morbidity in COPD (SUMMIT) study protocol. Eur Respir J 2013;41:1017–22.
102
www.ejci-online.com
69 Connet JA, Scharf SM, Dransfield M, Washko G, Albert LK, Casaburi R et al. Simvastatin Therapy for Moderate and Severe COPD (STATCOPE). NCT01061671 Available at: http://www. clinicaltrials.gov. Accessed on 22 June 2013. 70 Nozzoli C, Beghe B, Boschetto P, Fabbri LM. Identifying and treating COPD in cardiac patients. Chest 2013;144:723–6.
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