Joining the Crowd
2013; Elsevier BV; Volume: 143; Issue: 4 Linguagem: Inglês
10.1378/chest.12-2444
ISSN1931-3543
AutoresCarroll E. Cross, Elizabeth J. Reverri, Brian M. Morrissey,
Tópico(s)Psoriasis: Treatment and Pathogenesis
ResumoNumerous chronic inflammatory diseases that activate systemic inflammatory biomarkers, such as peridontitis,1Tonetti MS D'Aiuto F Nibali L et al.Treatment of periodontitis and endothelial function.N Engl J Med. 2007; 356: 911-920Crossref PubMed Scopus (918) Google Scholar HIV,2Subramanian S Tawakol A Burdo TH et al.Arterial inflammation in patients with HIV.JAMA. 2012; 308: 379-386Crossref PubMed Scopus (338) Google Scholar inflammatory bowel disease,3Sappati Biyyani RS Fahmy NM Baum E Nelson KM King JF Inflammatory bowel disease and coronary artery disease.Indian J Gastroenterol. 2009; 28: 28-30Crossref PubMed Scopus (17) Google Scholar rheumatoid arthritis,4Holmes MV Jiang B McNeill K et al.Paradoxical association of C-reactive protein with endothelial function in rheumatoid arthritis.PLoS ONE. 2010; 5: e10242Crossref PubMed Scopus (12) Google Scholar and even psoriasis,5Mehta NN Yu Y Pinnelas R et al.Attributable risk estimate of severe psoriasis on major cardiovascular events.Am J Med. 2011; 124: 775.e1-775.e6Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar are reported to be associated with an increased incidence of cardiovascular disease (CVD). Respiratory tract (RT) diseases are among this roster of chronic inflammatory diseases. These include COPD,6Divo M Cote C de Torres JP BODE Collaborative Group et al.Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2012; 186: 155-161Crossref PubMed Scopus (753) Google Scholar α1-antitrypsin deficiency,7Duckers JM Shale DJ Stockley RA et al.Cardiovascular and musculskeletal co-morbidities in patients with alpha 1 antitrypsin deficiency.Respir Res. 2010; 11: 173Crossref PubMed Scopus (44) Google Scholar and possibly adult-onset asthma.8Onufrak SJ Abramson JL Austin HD Holguin F McClellan WM Vaccarino LV Relation of adult-onset asthma to coronary heart disease and stroke.Am J Cardiol. 2008; 101: 1247-1252Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 9Lee HM Truong ST Wong ND Association of adult-onset asthma with specific cardiovascular conditions.Respir Med. 2012; 106: 948-953Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar Might cystic fibrosis (CF) join the crowd? Despite the intense RT inflammation and activation of systemic markers of inflammation,10Hartl D Gaggar A Bruscia E et al.Innate immunity in cystic fibrosis lung disease.J Cyst Fibros. 2012; 11: 363-382Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar there has been little attention focused on the incidence of CVD in patients with CF. It is now increasingly important to examine the risk and incidence of age-related comorbidities, including CVD, in patients with CF who are now living into middle age and beyond. Risk factors suggesting that older patients with CF may be predisposed to CVD include pancreatic insufficiencies that render these patients susceptible to deficiencies in fat-soluble antioxidant vitamins and lipids in spite of supplementation.11Lezo A, Biasi F, Massarenti P, et al. Oxidative stress in stable cystic fibrosis patients: Do we need higher antioxidant plasma levels [published online ahead of print July 9, 2012]? J Cyst Fibros. doi:10.1016/j.jcf.2012.06.002.Google Scholar, 12Cantin AM White TB Cross CE Forman HJ Sokol RJ Borowitz D Antioxidants in cystic fibrosis. Conclusions from the CF antioxidant workshop, Bethesda, Maryland, November 11-12, 2003.Free Radic Biol Med. 2007; 42: 15-31Crossref PubMed Scopus (107) Google Scholar Additionally, a variety of multifaceted lipid abnormalities, some of which could potentially impact CVD risk, are recognized in CF.13Rhodes B Nash EF Tullis E et al.Prevalence of dyslipidemia in adults with cystic fibrosis.J Cyst Fibros. 2010; 9: 24-28Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar These include reduced high-density lipoprotein; reduced antiinflammatory ω-3 fatty acids, including eicosapentaenoic (20:5) and docosahexaenoic (22:6); increased proinflammatory arachidonic acid (20:4) metabolic processes; and abnormal cholesterol metabolism (ie, altered cellular distribution and trafficking).14White NM Jiang D Burgess JD Bederman IR Previs SF Kelley TJ Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis.Am J Physiol Lung Cell Mol Physiol. 2007; 292: L476-L486Crossref PubMed Scopus (68) Google Scholar, 15Gentzsch M Choudhury A Chang XB Pagano RE Riordan JR Misassembled mutant DeltaF508 CFTR in the distal secretory pathway alters cellular lipid trafficking.J Cell Sci. 2007; 120: 447-455Crossref PubMed Scopus (55) Google Scholar, 16Fang D West RH Manson ME et al.Increased plasma membrane cholesterol in cystic fibrosis cells correlates with CFTR genotype and depends on de novo cholesterol synthesis.Respir Res. 2010; 11: 61Crossref PubMed Scopus (26) Google Scholar Although the cumulative dyslipidemias' impact on atherosclerotic processes remains to be fully determined, several studies implicating CF in vascular pathobiology are beginning to accumulate.17Romano M Collura M Lapichino L et al.Endothelial perturbation in cystic fibrosis.Thromb Haemost. 2001; 86: 1363-1367PubMed Google Scholar, 18Hull JH Garrod R Ho TB et al.Increased augmentation index in patients with cystic fibrosis.Eur Respir J. 2009; 34: 1322-1328Crossref PubMed Scopus (50) Google Scholar, 19Henno P Maurey C Danel C et al.Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-kappaB and endothelin-1.Eur Respir J. 2009; 34: 1329-1337Crossref PubMed Scopus (28) Google Scholar, 20Buehler T Steinmann M Singer F et al.Increased arterial stiffness in children with cystic fibrosis.Eur Respir J. 2012; 39: 1536-1537Crossref PubMed Scopus (26) Google Scholar In this issue of CHEST (see page 939), Poore and colleagues21Poore S Berry B Eidson D McKie KT Harris RA Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis.Chest. 2013; 143: 939-945Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar report an association between CF and endothelial dysfunction in a cohort of 15 young patients with CF (aged 7–18 years). The patients with CF were fairly healthy, with relatively mild pulmonary function impairment (FEV1 %predicted, 88% ±22% [SD]), absence of overt CF-related diabetes, and elevated high-sensitivity C-reactive protein values (approximately four times the value of the demographically matched control subjects).21Poore S Berry B Eidson D McKie KT Harris RA Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis.Chest. 2013; 143: 939-945Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar Endothelial dysfunction is recognized as an early step in the development of atherosclerotic CVD. This study used a commonly used measure of endothelial dysfunction, brachial artery flow-mediated dilation (FMD), as measured by ultrasound. The demonstration of endothelial dysfunction in this young CF population is analogous to what has been recently reported in young patients with inflammatory bowel diseases who also have evidence of systemic inflammation.22Aloi M, Tromba L, Di Nardo G, et al. Premature subclinical atherosclerosis in pediatric inflammatory bowel disease. J Pediatr. 2012;161(4):589-594Google Scholar To what degree might the decreased FMD represent an intrinsic (CF transmembrane conductance regulator) or acquired (inflammatory) phenomenon? It would seem most likely that the mechanistic decrements of FMD would be similar to that of other inflammatory RT diseases (eg, “spillover” of inflammation and immune activation mediators from the RT into the systemic circulation).23Van Eeden S Leipsic J Paul Man SF Sin DD The relationship between lung inflammation and cardiovascular disease.Am J Respir Crit Care Med. 2012; 186: 11-16Crossref PubMed Scopus (143) Google Scholar However, in the current study, correlations between FMD decrements and high-sensitivity C-reactive protein levels, the only biomarker of activated systemic inflammatory-immune processes interrogated, did not reach significance. The authors hypothesize that the FMD abnormality may relate to abnormal vascular tissue nitric oxide (NO) generation in CF per se; this concept is perhaps supported by abnormal NO synthase activity known to be present in the CF RT24Grasemann H Ratjen F Nitric oxide and L-arginine deficiency in cystic fibrosis.Curr Pharm Des. 2012; 18: 726-736Crossref PubMed Scopus (43) Google Scholar and by the known expression of CF transmembrane conductance regulator protein in both endothelium and smooth muscle of vascular tissues.21Poore S Berry B Eidson D McKie KT Harris RA Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis.Chest. 2013; 143: 939-945Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The study findings, which correlated FMD decrements with pulmonary function decreases (perhaps a surrogate for the degree of airway and systemic inflammation) and maximal exercise capacity (hypothesized to reflect the degree of NO-related vasodilation muscle blood flow during exercise), are compatible with this concept. Significant correlations were found between the percent decrease in FMD and the decrease in airflow, and between the FMD absolute change and the maximal work (peak ventilation and workload during exercise). It remains unclear how accumulated structural lung disease, active airway inflammation, and dynamic airflow function might alter exercise capacity. The authors raise the intriguing possibility that the degree of reduced FMD could relate to a relative decrement in muscle blood flow that would be reflected in a reduced maximal exercise performance. This is a provocative concept. It is known that endothelial NO release contributes to the increase in muscle blood flow during exercise. This also represents an important circulatory adaption to exercise training effects,25Hirai DM Copp SW Ferguson SK et al.Exercise training and muscle microvascular oxygenation: functional role of nitric oxide.J Appl Physiol. 2012; 113: 557-565Crossref PubMed Scopus (34) Google Scholar thus adding to theoretical constructs supporting the importance of exercise conditioning in cardiopulmonary rehabilitation. As with other RT diseases with strong inflammatory components and an increased CVD risk, longitudinal studies of CF-related risk factors, including endothelial dysfunction, may yield better understanding of the mechanisms of CVD and potential therapeutic approaches. As mentioned by Poore and colleagues,21Poore S Berry B Eidson D McKie KT Harris RA Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis.Chest. 2013; 143: 939-945Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar it will be illuminating to further document possible CF-related decrements in NO production by vascular tissue and its influence on exercise-related muscle function. Since aging contributes to endothelial dysfunction and ultimately to CVD,26Seals DR Jablonski KL Donato AJ Aging and vascular endothelial function in humans.Clin Sci (Lond). 2011; 120: 357-375Crossref PubMed Scopus (411) Google Scholar it will be particularly important to perform longitudinal studies, including older patients with CF, and to design feasible interventions that could ameliorate this risk factor for CVD. As NO bioavailability in vascular tissues appears to be influenced by other inflammatory RT diseases, this concept has implications in RT diseases beyond CF in which muscle function appears impaired (eg, COPD). It is also tempting to continue to build on this emerging evidence—albeit inconclusive to date—that therapeutic strategies to reduce inflammation and immune activations and their accompanying “oxidative stress” may reduce CVD risk.27Quon BS Aitken ML Cystic fibrosis: What to expect now in the early adult years.Paediatr Respir Rev. 2012; 13: 206-214Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Finally, it is encouraging that patients with CF are now experiencing an increased life expectancy. As such, in addition to the enlarging spectrum of nonpulmonary CF-related diseases facing the adult patients with CF,28Lönn ME Dennis JM Stocker R Actions of “antioxidants” in the protection against atherosclerosis.Free Radic Biol Med. 2012; 53: 863-884Crossref PubMed Scopus (93) Google Scholar the usual adult diseases causing morbidity and mortality can be expected to become an increasing concern. This is perhaps punctuated by the almost 50% prevalence of CF-related diabetes, a well-recognized strong risk factor for atherosclerotic and microvascular CVD, in this population.29Schwarzenberg SJ Thomas W Olsen TW et al.Microvascular complications in cystic fibrosis-related diabetes.Diabetes Care. 2007; 30: 1056-1061Crossref PubMed Scopus (126) Google Scholar
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