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Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease
Medical Hypotheses 84 (2015) 155–158
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease A. Vukic Dugac a,1, A. Ruzic b,c,⇑,1, M. Samarzija a,d, S. Badovinac a, T. Kehler e, M. Jakopovic a,d a
University Hospital Centre Zagreb, Zagreb, Croatia University Hospital Centre Rijeka, Rijeka, Croatia School of Medicine, University of Rijeka, Rijeka, Croatia d School of Medicine, University of Zagreb, Zagreb, Croatia e Hospital Thalassotherapia Opatija, Opatija, Croatia b c
a r t i c l e
i n f o
Article history: Received 30 June 2014 Accepted 22 November 2014
a b s t r a c t Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in developed countries of the world, while the main cause of mortality and morbidity in COPD patients are acute exacerbations and cardiovascular diseases. With regard to the frequency of exacerbations the phenotype «frequent exacerbators» has been defined, which, besides a more severe clinical course and a significantly higher total mortality, is also characterised by an elevated risk of cardiovascular mortality, as some indicators show us. It is notable that during the exacerbation of COPD, next to other changes, a significant aggravation of endothelial function occurs while the ED and COPD relationship seems very complex and is still in greater part unknown. Making the pathophysiological link between the frequency of exacerbations of COPD and ED could change our understanding of the character of this type of pulmonary disease. We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with ancillary systemic effects. Our opinion is that differences in COPD phenotype do not only determine the clinical picture but could also be of key importance in defining the progressivity of the disease. ED, which in these patients persists between frequent exacerbations, could be the main cause of the progression of pulmonary disease, and not only of the high cardiovascular risk of these patients. Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms, could contemporaneously induce new exacerbations of COPD, the progression of pulmonary changes and the development of systemic atherosclerosis as a main extrapulmonary manifestation in these patients. Such a model defines endothelium as a common soil of progressive pulmonary and cardiovascular changes in FE COPD. It can fully explain all the elements of the clinical course and co-morbidity in FE COPD, for which we still do not have adequate explanation. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Chronic obstructive pulmonary disease (COPD) is now regarded as multicomponent disease characterised by a complex effect on the lungs and other organs, while its mechanism is in a great part still unknown. The classic pathophysiology of the disease underlines
⇑ Corresponding author at: Department of Cardiology, Clinic of Internal Medicine, University Hospital Centre Rijeka, T. Strizˇic´a 3, 51 000 Rijeka, Croatia. Tel.: +358 51 407 225; fax: +385 51 407 149. E-mail address: [email protected] (A. Ruzic). 1 The first two authors contributed equally to the paper. http://dx.doi.org/10.1016/j.mehy.2014.11.017 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
bronchoobstruction and local pulmonary inflammation as the primary mechanism, while a great frequency of co-morbidity is generally ascribed to smoking as a common cause of changes [1]. The World Health Organisation (WHO) predicts that by the year 2020 COPD will have become the third leading cause of death in the world due to the steady increase in prevalence and mortality [2]. Co-morbidities such as cardiovascular disease (CVD), metabolic syndrome and carcinoma, significantly contribute to the mortality of these patients [3–5]. According to the latest research, COPD outcome depends more on the frequency of exacerbations than on the degree of respiratory dysfunction during the insult [6,7]. This is why the phenotype «frequent exacerbator» – FE COPD [6,7] has been set
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A. Vukic Dugac et al. / Medical Hypotheses 84 (2015) 155–158
apart as a significant distinct entity. These patients are characterised by a malignant clinical course, that is, progressive impairment of pulmonary function, additionally increased risk of cardiovascular disease, as well as the significantly higher total mortality as compared to other COPD patients [4,6,7]. As there has been a prevailing opinion that the FE COPD group of patients regards those with the same clinical characteristics of a probably different aetiology and pathophysiology, the concept of «phenotype» has become usual for their designation. Presently, there are gaps in the knowledge of COPD’s natural history regarding the exact pathogenesis underlying the different clusters of co-morbidities as well as the extent to which these clusters affect patient outcomes [1]. It is important to note that during the COPD exacerbation, next to other changes, a significant impairment of endothelial function also occurs [4,8,9]. Hypoxia and a more intense oxidative stress induce local inflammation in respiratory airways, next to the systemic inflammatory response, which could be in connection with the development of endothelial dysfunction (ED), being specific for CVD, but also described in COPD [10,11]. ED is well known as a concurrent, generalised/systemic disorder of all functions of the interior vascular layer, involving its pro-inflammatory, proliferating and prothrombotic state. It has a specific dynamic and can thus occur as acute dysfunction with prior normal functioning or be of a chronic, smouldering character, with tendency for occasional sudden aggravations. It is unquestionable that the generalised ED has a key role in the development of different cardiovascular diseases, being of significance in the occurrence and progression of arterial hypertension, atherosclerosis, coronary artery disease and heart failure [12,13]. In COPD, ED is linked with a more severe degree of disease, lower values of forced expiratory volume in 1 s (FEV1), and also with worse overall prognosis of pulmonary disease [14–16]. The systemic inflammatory process together with the activation of inflammatory cells and the increase of pro-inflammatory cytokines can be leading causes of endothelial dysfunction in COPD [14]. The relationship between ED and COPD seems very complex and is still in great part unknown [8–10]. A recently published research by Seung Jun Lee et al. opens the possibility that ED is more closely linked with the frequency of exacerbations than with the severity of COPD [17]. In its basic interpretation, this can offer the explanation for the high risk of CVD in FE COPD patients [1,4,17] However, if the relations are considered more widely, the link between ED and the frequency of exacerbations could be much more comprehensive. It could explain a range of specificities of the clinical course of FE COPD patients, which are hard to explain with the existing insights. Making the pathophysiological link between the frequency of exacerbations of COPD and ED, could change our understanding of the character of this type of pulmonary disease.
systemic atherosclerosis as the major extrapulmonary manifestation in these patients. The proposal of this pathophysiological model places ED in the centre of a vicious circle, namely, when due to frequent COPD exacerbations persistent ED develops, it induces new lung injuries, which again aggravate ED and lead to an overall progressive disorder. Such a model defines endothelium as a common soil of progressive lung and cardiovascular changes in FE COPD. It can explain in its entirety all the elements of clinical course and co-morbidity in FE COPD, for which we so far do not have an adequate explanation. Due to the intermittent establishment of endothelial function, patients with more severe but less frequent exacerbations could in this model, despite occasional serious respiratory dysfunction, be spared of the permanent presence of ED as a smouldering mechanism as shown in Fig. 1. They have a «window» in which the normalisation of endothelial function is achieved, which makes the main difference with regard to FE COPD, slowing down the clinical course of pulmonary disease and leading to a lower incidence of CVD and an overall better outcome. The confirmation of this theory could change the understanding of the character of FE COPD significantly and induce new approaches to the treatment, primarily that of the disorder of endothelial function.
Evaluation of hypothesis To confirm this hypothesis it is necessary to research endothelial function in patients with infrequent and in patients with frequent exacerbations of COPD. Endothelial function should be measured with the help of a few selected yet different diagnostic methods simultaneously, namely methods that according to the existing research describe endothelial function reliably. It would be worthwhile to follow some of the following: plasma markers such as endothelin 1 (ET1), von Willebrand factor (vWF), plasminogen activator inhibitor 1 (PAI-1), vascular endothelial growth factor (VEFG) or circulating endothelial microparticles (EMPs), also
Hypothesis We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with side systemic effects. If the frequency of exacerbations of COPD has been underlined as a predictive factor that is more important than the severity of the attack itself, the frequent aggravation of hypoxia and distinct oxidative stress could in these patients cross the threshold necessary for ED to be permanently present, with endothelial function failing to normalise between COPD attacks. In that case, ED would be a permanent state showing only a slight variability, but without achieving normal endothelial function during a significant time period. Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms could induce new COPD exacerbations, the progression of pulmonary changes and development of
Fig. 1. Curves of the assumed fluctuation of endothelial function. FE COPD has frequent exacerbations of endothelial function that follow the exacerbation of pulmonary disease – frequent acute attacks. Due to the high frequency of occurrence, endothelial function does not fully normalise between the attacks. The nonFE COPD curve has less frequent and milder attacks between which normal endothelial function is established. There is a dashed line between the fields endothelial dysfunction and normal endothelial function, presenting the general and symbolic borderline between normal and disordered endothelial function for different parameters and diagnostic methods employed in the testing of ED. Abbreviations: FE COPD, frequent exacerbator COPD; nonFE COPD, non frequent exacerbator COPD.
A. Vukic Dugac et al. / Medical Hypotheses 84 (2015) 155–158
employ flow mediated dilatation test (FMD) or MRI-based evaluation of endothelial reactivity. Invasive tests of systemic ED do not seem necessary, neither are they ethically acceptable in patients without manifest CVD [12,18]. However, what remains open is the issue of the assessment of endothelial function in pulmonary circulation, for which the employment of endovascular procedures should be considered. In order to confirm the hypothesis, all the measurements of ED should be carried out repeatedly and in short time intervals in both groups of patients, as well as in control subjects, by all means between and during the exacerbations of COPD. All subjects involved in the research should undergo long-term prospective follow-up, while significant clinical outcomes should be defined and recorded. What should be monitored during the entire research are parameters of pulmonary function, functional cardiovascular indicators, number of hospitalizations and selfevaluation of the quality of life as surrogate outcomes, while the development of major cardiovascular events (fatal and nonfatal myocardial infarction) and death as final outcomes. Both groups of patients involved in the research should receive all standard therapy, while, with regard to the proven effects of some groups of medications on ED, also according to this criteria, it would be necessary to secure the highest possible compatibility of both groups with COPD. In addition to this, it would be necessary to eliminate the factors that can affect ED itself as well as the link between COPD and ED, such as present smoking, acute infectious and non infectious inflammatory states that are not connected with COPD, other significant acute diseases, women in the generative age and the age above 80 years [19]. Consequences of the hypothesis and discussion It is endothelial dysfunction that could explain the character of the disease itself and its distinction with regard to other forms of COPD that have a better clinical course and fewer complications, often aggravating during the attack in a specific and very severe FE COPD while failing to achieve a more permanent normal state between the attacks, becoming a constant part of this specific clinical phenotype. A similar model of persistent ED with frequent acute exacerbations has been described in some progressive CVDs, such as some forms of ischaemic heart disease and chronic heart failure, in which a strong predictive value of the tests of endothelial function has been evidenced [20]. Persistent ED in FE COPD can account for local pulmonary changes and their progressivity. The link between the decreased expression of VEGF and its receptor VEGRFII with apoptosis of lung endothelial cells has been proved by clinical trials and laboratory models [21]. Patients with COPD have increased arterial stiffness that is independent of cigarette smoke exposure, however, it has not been explained by systemic endothelial dysfunction. The studies that analysed this connection involved a small group of subjects, follow-ups were short, while the assessment did not include the severity of COPD, neither the criteria for the frequency of exacerbations, the consideration of which could have thrown light upon this relationship [16]. Our hypothesis could contribute to the elucidation of the complex and insufficiently defined relationship between COPD and pulmonary hypertension. In spite of numerous researches, a many questions still remain open in this significant field. It is known that pulmonary hypertension does not depend on the severity of respiratory dysfunction and that it is not caused by hypoxia [22], however, what has been established is its connection with IL-6 levels that are regularly raised in the very ED, as it represents the generalised proinflammatory state [23]. The role of statins in COPD treatment has not been established as a standard one, despite a great number of studies and positive effects on all-cause mortality and reduced lung function decline [24]. Although it has been proven that statins lower pulmonary arterial pressure, it is unknown which is the
157
mechanism through which this effect has been mediated [22]. The research of our theory, accompanied by additional analyses and the follow-up of pulmonary pressure, could contribute to the elucidation of the mechanism of the effect of statins, as well as help us come to valuable conclusions for their further use in COPD. In case our hypothesis proves to be correct, we can expect that it is the specific groups of patients, namely those with FE COPD and raised pulmonary pressure in COPD that could avail most of such a therapy. Naturally, such promising assumptions will require additional, double blind randomized prospective studies, next to those the need of which to be performed we have already pointed out. Recently, high levels of E-selectin EMPs in stable patients with COPD have been proved to be predictive of rapid FEV1 decline [25]. As what is discussed is the link between endothelial factor and the progressivity of the disease, the above mentioned clearly states that it is necessary to research this relationship, also with regard to the frequency of exacerbations, and thus confirm our theory. The significant negative correlation of ET-1 and FEV1 has been proved in different stages of COPD, though the same relationship has not been proved for the tumour necrosis factor a (TNF-a) and FEV1. Despite the fact that according to its definition ED involves pro-inflammatory state, these interesting data lead to a possible distinction in endothelial and inflammatory mechanisms of development and progress of COPD, emphasising the significance of ED and underlining the relationship presented in our hypothesis [26]. According to the available data, permanently present ED could be a very significant part of the overall pathology of FE COPD, so that a confirmation of this could significantly contribute to the further development of the approach to treatment, with possible impact on the very course of disease, the development of co-morbidity as well as the overall outcome. If we draw a parallel with the field of cardiovascular diseases and consider the amount of progress in their treatment marked by the life saving drugs, primarily statins and ACE-inhibitors in atherosclerosis, ACE-inhibitors and mineralocorticoid receptor blockers in heart failure [27], we can only assume what change in the preservation of quality of life and in the survival of patients with COPD such a treatment could bring, affecting the pathophysiological mechanism responsible for the progression of disease. Within COPD as a significant disease with increasing prevalence, public health and social implications, it is FE COPD that stands out due to its exceptional severity, thus presenting also a special priority in future researches. We hope that our hypothesis and the presented opinion will prompt further research in this undoubtedly significant and promising area. Conflict of interest We, as the authors of this manuscript, disclose any financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work in respect of employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants of other funding. References [1] Aryal S, Diaz-Guzman E, Mannino DM. Epidemiology of comorbidities in chronic obstructive pulmonary disease: clusters, phenotypes and outcomes. Ital J Med 2012;6:276–84. [2] Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095–128. [3] Decramer M, Janssens W. Chronic obstructive pulmonary disease and comorbidities. Lancet Respir Med 2013;1:73–83. [4] Patel AR, Kowlessar BS, Donaldson GC, et al. Cardiovascular risk, myocardial injury, and exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1091–9.
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[5] Fabbri LM, Luppi F, Beghe B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204–12. [6] Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122. [7] Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010;182:598–604. [8] Takahashi T, Kobayashi S, Fujino N, et al. Increased circulating endothelial microparticles in COPD patients: a potential biomarker for COPD exacerbation susceptibility. Thorax 2012;67:1067–74. [9] Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847–52. [10] Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J 2007;29:527–34. [11] Chang C, Yao W. Time course of inflammation resolution in patients with frequent exacerbations of chronic obstructive pulmonary disease. Med Sci Monit 2014;20:311–20. [12] Brunner H, Cockcroft JR, Deanfield J, et al. Working group on endothelins and endothelial factors of the european society of hypertension. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the working group on endothelins and endothelial factors of the european society of hypertension. J Hypertens 2005;23:233–46. [13] Galiè N, Ghofrani AH. New horizons in pulmonary arterial hypertension therapies. Eur Respir Rev 2013;22:503–14. [14] Eickhoff P, Valipour A, Kiss D, et al. Determinants of systemic vascular function in patients with stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;178:1211–8. [15] Barr RG, Mesia-Vela S, Austin JH, et al. Impaired flow-mediated dilation is associated with low pulmonary function and emphysema in ex-smokers: the
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Emphysema and Cancer Action Project (EMCAP) Study. Am J Respir Crit Care Med 2007;176:1200–7. Maclay JD, McAllister DA, Mills NL, et al. Vascular dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:513–20. Lee SJ, Lee SH, Kim YE. Clinical features according to the frequency of acute exacerbation in COPD. Tuberc Respir Dis 2012;72:367–73. Balen S, Ruzic A, Mirat J, Persic V. Exercise induced von Willebrand factor release – new model for routine endothelial testing. Med Hypotheses 2007;69:1320–2. Celermajer DS, Sorensen KE, Gooch VM, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–5. Takishima I, Nakamura T, Hirano M, et al. Predictive value of serial assessment of endothelial function in chronic heart failure. Int J Cardiol 2012;158(3):417–22. Voelkel NF, Cool CD. Pulmonary vascular involvement in chronic obstructive pulmonary disease. Eur Respir J Suppl 2003;22:28S–32S. Young RP, Hopkins R, Eaton TE. Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev 2009;18:222–32. Chaouat A, Savale L, Chaouaid C. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 2009;136:678–87. Young RP, Hopkins R. Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities. Expert Rev Respir Med 2013;7:533–44. Takahashi T, Kobayashi S, Fujino N. Annual FEV1 changes and numbers of circulating endothelial microparticles in patients with COPD: a prospective study. BMJ Open 2014;4:e004571. Samy N, El-Maksoud A, Khayyal AE, Imam A. Clinical utility of biomarkers as predictors of lung function in chronic obstructive pulmonary disease. New York Sci J 2012;3:25–9. Braunwald E. Heart failure. JACC Heart Fail 2013;1:1–20.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease A. Vukic Dugac a,1, A. Ruzic b,c,⇑,1, M. Samarzija a,d, S. Badovinac a, T. Kehler e, M. Jakopovic a,d a
University Hospital Centre Zagreb, Zagreb, Croatia University Hospital Centre Rijeka, Rijeka, Croatia School of Medicine, University of Rijeka, Rijeka, Croatia d School of Medicine, University of Zagreb, Zagreb, Croatia e Hospital Thalassotherapia Opatija, Opatija, Croatia b c
a r t i c l e
i n f o
Article history: Received 30 June 2014 Accepted 22 November 2014
a b s t r a c t Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in developed countries of the world, while the main cause of mortality and morbidity in COPD patients are acute exacerbations and cardiovascular diseases. With regard to the frequency of exacerbations the phenotype «frequent exacerbators» has been defined, which, besides a more severe clinical course and a significantly higher total mortality, is also characterised by an elevated risk of cardiovascular mortality, as some indicators show us. It is notable that during the exacerbation of COPD, next to other changes, a significant aggravation of endothelial function occurs while the ED and COPD relationship seems very complex and is still in greater part unknown. Making the pathophysiological link between the frequency of exacerbations of COPD and ED could change our understanding of the character of this type of pulmonary disease. We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with ancillary systemic effects. Our opinion is that differences in COPD phenotype do not only determine the clinical picture but could also be of key importance in defining the progressivity of the disease. ED, which in these patients persists between frequent exacerbations, could be the main cause of the progression of pulmonary disease, and not only of the high cardiovascular risk of these patients. Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms, could contemporaneously induce new exacerbations of COPD, the progression of pulmonary changes and the development of systemic atherosclerosis as a main extrapulmonary manifestation in these patients. Such a model defines endothelium as a common soil of progressive pulmonary and cardiovascular changes in FE COPD. It can fully explain all the elements of the clinical course and co-morbidity in FE COPD, for which we still do not have adequate explanation. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction Chronic obstructive pulmonary disease (COPD) is now regarded as multicomponent disease characterised by a complex effect on the lungs and other organs, while its mechanism is in a great part still unknown. The classic pathophysiology of the disease underlines
⇑ Corresponding author at: Department of Cardiology, Clinic of Internal Medicine, University Hospital Centre Rijeka, T. Strizˇic´a 3, 51 000 Rijeka, Croatia. Tel.: +358 51 407 225; fax: +385 51 407 149. E-mail address: [email protected] (A. Ruzic). 1 The first two authors contributed equally to the paper. http://dx.doi.org/10.1016/j.mehy.2014.11.017 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
bronchoobstruction and local pulmonary inflammation as the primary mechanism, while a great frequency of co-morbidity is generally ascribed to smoking as a common cause of changes [1]. The World Health Organisation (WHO) predicts that by the year 2020 COPD will have become the third leading cause of death in the world due to the steady increase in prevalence and mortality [2]. Co-morbidities such as cardiovascular disease (CVD), metabolic syndrome and carcinoma, significantly contribute to the mortality of these patients [3–5]. According to the latest research, COPD outcome depends more on the frequency of exacerbations than on the degree of respiratory dysfunction during the insult [6,7]. This is why the phenotype «frequent exacerbator» – FE COPD [6,7] has been set
156
A. Vukic Dugac et al. / Medical Hypotheses 84 (2015) 155–158
apart as a significant distinct entity. These patients are characterised by a malignant clinical course, that is, progressive impairment of pulmonary function, additionally increased risk of cardiovascular disease, as well as the significantly higher total mortality as compared to other COPD patients [4,6,7]. As there has been a prevailing opinion that the FE COPD group of patients regards those with the same clinical characteristics of a probably different aetiology and pathophysiology, the concept of «phenotype» has become usual for their designation. Presently, there are gaps in the knowledge of COPD’s natural history regarding the exact pathogenesis underlying the different clusters of co-morbidities as well as the extent to which these clusters affect patient outcomes [1]. It is important to note that during the COPD exacerbation, next to other changes, a significant impairment of endothelial function also occurs [4,8,9]. Hypoxia and a more intense oxidative stress induce local inflammation in respiratory airways, next to the systemic inflammatory response, which could be in connection with the development of endothelial dysfunction (ED), being specific for CVD, but also described in COPD [10,11]. ED is well known as a concurrent, generalised/systemic disorder of all functions of the interior vascular layer, involving its pro-inflammatory, proliferating and prothrombotic state. It has a specific dynamic and can thus occur as acute dysfunction with prior normal functioning or be of a chronic, smouldering character, with tendency for occasional sudden aggravations. It is unquestionable that the generalised ED has a key role in the development of different cardiovascular diseases, being of significance in the occurrence and progression of arterial hypertension, atherosclerosis, coronary artery disease and heart failure [12,13]. In COPD, ED is linked with a more severe degree of disease, lower values of forced expiratory volume in 1 s (FEV1), and also with worse overall prognosis of pulmonary disease [14–16]. The systemic inflammatory process together with the activation of inflammatory cells and the increase of pro-inflammatory cytokines can be leading causes of endothelial dysfunction in COPD [14]. The relationship between ED and COPD seems very complex and is still in great part unknown [8–10]. A recently published research by Seung Jun Lee et al. opens the possibility that ED is more closely linked with the frequency of exacerbations than with the severity of COPD [17]. In its basic interpretation, this can offer the explanation for the high risk of CVD in FE COPD patients [1,4,17] However, if the relations are considered more widely, the link between ED and the frequency of exacerbations could be much more comprehensive. It could explain a range of specificities of the clinical course of FE COPD patients, which are hard to explain with the existing insights. Making the pathophysiological link between the frequency of exacerbations of COPD and ED, could change our understanding of the character of this type of pulmonary disease.
systemic atherosclerosis as the major extrapulmonary manifestation in these patients. The proposal of this pathophysiological model places ED in the centre of a vicious circle, namely, when due to frequent COPD exacerbations persistent ED develops, it induces new lung injuries, which again aggravate ED and lead to an overall progressive disorder. Such a model defines endothelium as a common soil of progressive lung and cardiovascular changes in FE COPD. It can explain in its entirety all the elements of clinical course and co-morbidity in FE COPD, for which we so far do not have an adequate explanation. Due to the intermittent establishment of endothelial function, patients with more severe but less frequent exacerbations could in this model, despite occasional serious respiratory dysfunction, be spared of the permanent presence of ED as a smouldering mechanism as shown in Fig. 1. They have a «window» in which the normalisation of endothelial function is achieved, which makes the main difference with regard to FE COPD, slowing down the clinical course of pulmonary disease and leading to a lower incidence of CVD and an overall better outcome. The confirmation of this theory could change the understanding of the character of FE COPD significantly and induce new approaches to the treatment, primarily that of the disorder of endothelial function.
Evaluation of hypothesis To confirm this hypothesis it is necessary to research endothelial function in patients with infrequent and in patients with frequent exacerbations of COPD. Endothelial function should be measured with the help of a few selected yet different diagnostic methods simultaneously, namely methods that according to the existing research describe endothelial function reliably. It would be worthwhile to follow some of the following: plasma markers such as endothelin 1 (ET1), von Willebrand factor (vWF), plasminogen activator inhibitor 1 (PAI-1), vascular endothelial growth factor (VEFG) or circulating endothelial microparticles (EMPs), also
Hypothesis We hypothesize that frequent exacerbator COPD is a progressive and generalised vascular disease, not only an isolated respiratory disorder with side systemic effects. If the frequency of exacerbations of COPD has been underlined as a predictive factor that is more important than the severity of the attack itself, the frequent aggravation of hypoxia and distinct oxidative stress could in these patients cross the threshold necessary for ED to be permanently present, with endothelial function failing to normalise between COPD attacks. In that case, ED would be a permanent state showing only a slight variability, but without achieving normal endothelial function during a significant time period. Such a persistent ED in FE COPD, with its pro-inflammatory, vasoconstrictory and prothrombotic mechanisms could induce new COPD exacerbations, the progression of pulmonary changes and development of
Fig. 1. Curves of the assumed fluctuation of endothelial function. FE COPD has frequent exacerbations of endothelial function that follow the exacerbation of pulmonary disease – frequent acute attacks. Due to the high frequency of occurrence, endothelial function does not fully normalise between the attacks. The nonFE COPD curve has less frequent and milder attacks between which normal endothelial function is established. There is a dashed line between the fields endothelial dysfunction and normal endothelial function, presenting the general and symbolic borderline between normal and disordered endothelial function for different parameters and diagnostic methods employed in the testing of ED. Abbreviations: FE COPD, frequent exacerbator COPD; nonFE COPD, non frequent exacerbator COPD.
A. Vukic Dugac et al. / Medical Hypotheses 84 (2015) 155–158
employ flow mediated dilatation test (FMD) or MRI-based evaluation of endothelial reactivity. Invasive tests of systemic ED do not seem necessary, neither are they ethically acceptable in patients without manifest CVD [12,18]. However, what remains open is the issue of the assessment of endothelial function in pulmonary circulation, for which the employment of endovascular procedures should be considered. In order to confirm the hypothesis, all the measurements of ED should be carried out repeatedly and in short time intervals in both groups of patients, as well as in control subjects, by all means between and during the exacerbations of COPD. All subjects involved in the research should undergo long-term prospective follow-up, while significant clinical outcomes should be defined and recorded. What should be monitored during the entire research are parameters of pulmonary function, functional cardiovascular indicators, number of hospitalizations and selfevaluation of the quality of life as surrogate outcomes, while the development of major cardiovascular events (fatal and nonfatal myocardial infarction) and death as final outcomes. Both groups of patients involved in the research should receive all standard therapy, while, with regard to the proven effects of some groups of medications on ED, also according to this criteria, it would be necessary to secure the highest possible compatibility of both groups with COPD. In addition to this, it would be necessary to eliminate the factors that can affect ED itself as well as the link between COPD and ED, such as present smoking, acute infectious and non infectious inflammatory states that are not connected with COPD, other significant acute diseases, women in the generative age and the age above 80 years [19]. Consequences of the hypothesis and discussion It is endothelial dysfunction that could explain the character of the disease itself and its distinction with regard to other forms of COPD that have a better clinical course and fewer complications, often aggravating during the attack in a specific and very severe FE COPD while failing to achieve a more permanent normal state between the attacks, becoming a constant part of this specific clinical phenotype. A similar model of persistent ED with frequent acute exacerbations has been described in some progressive CVDs, such as some forms of ischaemic heart disease and chronic heart failure, in which a strong predictive value of the tests of endothelial function has been evidenced [20]. Persistent ED in FE COPD can account for local pulmonary changes and their progressivity. The link between the decreased expression of VEGF and its receptor VEGRFII with apoptosis of lung endothelial cells has been proved by clinical trials and laboratory models [21]. Patients with COPD have increased arterial stiffness that is independent of cigarette smoke exposure, however, it has not been explained by systemic endothelial dysfunction. The studies that analysed this connection involved a small group of subjects, follow-ups were short, while the assessment did not include the severity of COPD, neither the criteria for the frequency of exacerbations, the consideration of which could have thrown light upon this relationship [16]. Our hypothesis could contribute to the elucidation of the complex and insufficiently defined relationship between COPD and pulmonary hypertension. In spite of numerous researches, a many questions still remain open in this significant field. It is known that pulmonary hypertension does not depend on the severity of respiratory dysfunction and that it is not caused by hypoxia [22], however, what has been established is its connection with IL-6 levels that are regularly raised in the very ED, as it represents the generalised proinflammatory state [23]. The role of statins in COPD treatment has not been established as a standard one, despite a great number of studies and positive effects on all-cause mortality and reduced lung function decline [24]. Although it has been proven that statins lower pulmonary arterial pressure, it is unknown which is the
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mechanism through which this effect has been mediated [22]. The research of our theory, accompanied by additional analyses and the follow-up of pulmonary pressure, could contribute to the elucidation of the mechanism of the effect of statins, as well as help us come to valuable conclusions for their further use in COPD. In case our hypothesis proves to be correct, we can expect that it is the specific groups of patients, namely those with FE COPD and raised pulmonary pressure in COPD that could avail most of such a therapy. Naturally, such promising assumptions will require additional, double blind randomized prospective studies, next to those the need of which to be performed we have already pointed out. Recently, high levels of E-selectin EMPs in stable patients with COPD have been proved to be predictive of rapid FEV1 decline [25]. As what is discussed is the link between endothelial factor and the progressivity of the disease, the above mentioned clearly states that it is necessary to research this relationship, also with regard to the frequency of exacerbations, and thus confirm our theory. The significant negative correlation of ET-1 and FEV1 has been proved in different stages of COPD, though the same relationship has not been proved for the tumour necrosis factor a (TNF-a) and FEV1. Despite the fact that according to its definition ED involves pro-inflammatory state, these interesting data lead to a possible distinction in endothelial and inflammatory mechanisms of development and progress of COPD, emphasising the significance of ED and underlining the relationship presented in our hypothesis [26]. According to the available data, permanently present ED could be a very significant part of the overall pathology of FE COPD, so that a confirmation of this could significantly contribute to the further development of the approach to treatment, with possible impact on the very course of disease, the development of co-morbidity as well as the overall outcome. If we draw a parallel with the field of cardiovascular diseases and consider the amount of progress in their treatment marked by the life saving drugs, primarily statins and ACE-inhibitors in atherosclerosis, ACE-inhibitors and mineralocorticoid receptor blockers in heart failure [27], we can only assume what change in the preservation of quality of life and in the survival of patients with COPD such a treatment could bring, affecting the pathophysiological mechanism responsible for the progression of disease. Within COPD as a significant disease with increasing prevalence, public health and social implications, it is FE COPD that stands out due to its exceptional severity, thus presenting also a special priority in future researches. We hope that our hypothesis and the presented opinion will prompt further research in this undoubtedly significant and promising area. Conflict of interest We, as the authors of this manuscript, disclose any financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work in respect of employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants of other funding. References [1] Aryal S, Diaz-Guzman E, Mannino DM. Epidemiology of comorbidities in chronic obstructive pulmonary disease: clusters, phenotypes and outcomes. Ital J Med 2012;6:276–84. [2] Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095–128. [3] Decramer M, Janssens W. Chronic obstructive pulmonary disease and comorbidities. Lancet Respir Med 2013;1:73–83. [4] Patel AR, Kowlessar BS, Donaldson GC, et al. Cardiovascular risk, myocardial injury, and exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1091–9.
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