Matarese, Alessandro

Santulli, Gaetano

Sardu, Celestino

Shu, Jun

Alessandro Matarese

Celestino Sardu

Jun Shu

Gaetano Santulli

Archivio della ricerca - Università degli studi di Napoli Federico II

International Journal of Cardiology xxx (xxxx) xxx–xxxIJCA-27116; No of Pages 3Contents lists available at ScienceDirectInternational Journal of Cardiologyj ourna l homepage: www.e lsev ie r .com/ locate / i j ca rdWhy is chronic obstructive pulmonary disease linked to atrialﬁbrillation? A systematic overview of the underlying mechanismsAlessandro Matarese a, Celestino Sardu b, Jun Shu c, Gaetano Santulli c,d,⁎a Department of Pneumology and Oncology, AORN “Ospedale dei Colli”, Naples, Italyb Department of Medical, Surgical, Neurological, Metabolic and Aging Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italyc Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, Monteﬁore University Hospital, New York, NY, USAd Department of Biomedical Advanced Sciences, “Federico II” University, Naples, ItalyDOI of original article: https://doi.org/10.1016/j.ijc⁎ Corresponding author E-mail address: gsantulli001@gmail.com (G. Santulli).https://doi.org/10.1016/j.ijcard.2018.10.0750167-5273/© 2018 Elsevier B.V. All rights reserved.Please cite this article as: A. Matarese, et al.,the underlying mechanisms, Int J Cardiol (20a r t i c l e i n f o 17.9 millions in Europe by 2060. AFib is classiﬁed into the followingArticle history:Received 19 October 2018Accepted 22 October 2018Available online xxxx1. Deﬁnitions and epidemiologythree types:-Paroxysmal: recurrent (N1 episode ≥30 s) AFib that terminatesspontaneously within 7 days;-Persistent: lasts b7 days but necessitates pharmacologic or electro-cardioversion or is sustained N7 days (deﬁned LongstandingwhenN1 year);-Permanent: refractory to cardioversion or accepted as a ﬁnal1.1. Chronic obstructive pulmonary disease (COPD)COPD is a progressive life-threatening obstructive lung disease, char-acterized by long-term breathing problems and overall poor airﬂow.The key symptoms include cough with sputum production and short-ness of breath. With its rising incidence and a prevalence of 251 millioncases globally, COPD represents a major public health problem. The pri-mary cause of COPD is exposure to tobacco smoke (either active or sec-ond-hand!); other risk factors include frequent lower respiratoryinfections during childhood, indoor and/or outdoor air pollution, andexposure to occupational dusts, fumes, irritants, and vapors. Notably,exposure to indoor air pollution can also affect the unborn child andrepresents a serious risk factor for developing COPD later in life [1].Moreover, COPD predisposes to exacerbations and severe illness, in-cluding cardiac disorders. In fact, the main cause of death in COPD pa-tients is given by cardiovascular disease rather than respiratory failure.1.2. Atrial ﬁbrillation (AFib)AFib is a supraventricular arrhythmia characterized by uncoordi-nated atrial activity. AFib is themost commonly occurring sustained ar-rhythmia, and its incidence and prevalence is increasing worldwide [2]:~9% of people ≥65-year-old and ~2% of people b65-year-old have AFib;AFib is predicted to affect 6–12 million people in the US by 2050 andard.2018.09.056.Why is chronic obstructive pu18), https://doi.org/10.1016/rhythm.2. COPD and AFib: evidence of an intimate association from clinicalstudiesThe main parameters to determine the severity of COPD are theforced expiratory volume in 1 s (FEV1, deﬁned as the maximal volumeof air exhaled in the ﬁrst second of a forced expiration from a positionof full inspiration) and the forced vital capacity (FVC, deﬁned as themaximal volume of air exhaled with maximally forced effort from amaximal inspiration).Interestingly, both FEV1 and FVC have been shown to be inverselyrelated to the incidence of AFib, in the Copenhagen City Heart Study[3] and in the Multi-Ethnic Study of Atherosclerosis-Lung Study [4],respectively. Furthermore, the risk for AFib hospitalization is higheramong patients with low FEV1. A prospective, population-based co-hort study (Rotterdam Study) demonstrated that COPD is associatedwith a 28% increased risk of developing AFib, and that having fre-quent COPD exacerbations increases the AFib risk approximately 2-fold [5].3. Clinical scores and scales useful for risk stratiﬁcationThe following scales are used to quantify the respiratory disabilityand provide a prognostic evaluation:-The Medical Research Council (MRC) dyspnea scale comprises ﬁvestatements that describe almost the entire range of respiratory dis-ability fromnone (Grade 1) to almost complete incapacity (Grade 5).-The Dyspnea, Eosinopenia, Consolidation, Acidemia and AFib(DECAF) score was introduced as a predictor of mortality inlmonary disease linked to atrial ﬁbrillation? A systematic overview ofj.ijcard.2018.10.075Fig. 1. Potential mechanisms linking COPD and AFib. Several pathogenic mechanisms present in COPD can lead to Aﬁb, including some drugs used to treat COPD. Abbreviations: HIF-1:Hypoxia-inducible factor 1; LV: left ventricle; MMP: Matrix metalloproteinase; QTc: corrected QT interval; TGF-β1: Transforming growth factor β1; VEGF: Vascular endothelial growthfactor.2hospitalized patients with COPD exacerbations. The DECAF score in-cludes in its acronym the 5 strongest predictors of mortality.-The CURB65 includes the following criteria: Confusion; Blood UreaN19mg/dL, Respiratory rate ≥ 30 bpm, Blood pressure ≤ 60/90 mmHg, Age ≥ 65-years-old.-The BODE index is a multidimensional 10-point scale which inte-grates body mass index, degree of airﬂow obstruction and dyspnea,and exercise capacity. Patientswith higher BODE index scores have asigniﬁcantly greater prevalence of supraventricular arrhythmias in-cluding AFib. The score is also directly proportional with mortality.-The HATCH (Hypertension, Age N 75-year-old, previous TransientIschemic Attack or stroke, COPD, Heart failure) score was generatedperforming a subgroup analysis studying AFib progression from par-oxysmal to persistent within the European Heart Survey (EHS); re-markably, all the HATCH criteria are independent predictors ofAFib progression.In addition to the above-mentioned scores, a left atrial diameter ofN45 mm and heart failure are among the strongest independent predic-tors of AFib [6].4. COPD in AFib patients: a two-way relationship?Alongside the increased risk of developing AFib observed in COPDpatients, mounting evidence indicates that also the opposite associationoccurs. Indeed, the presence of COPD in AFib patients is associated withAFib progression, recurrence of AFib after catheter ablation, augmentedrisk of stroke, and increased cardiovascular mortality. Additionally,COPD contributes most to the increased all-cause mortality of AFib,whereas the absence of COPD represents also an independent predictorfor a successful electro-cardioversion at 1-year follow-up [6].Please cite this article as: A. Matarese, et al., Why is chronic obstructive puthe underlying mechanisms, Int J Cardiol (2018), https://doi.org/10.1016/5. The association of COPD with AFib: the potential underlyingmechanismsThe potential mechanisms underlying the ominous association be-tween COPD and AFib are depicted in Fig. 1. Hypoxia is deﬁnitely akey tenet of COPD that can lead to atrial remodeling and eventually toAFib via an augmented vascular tonewhich elicits pulmonary hyperten-sion. Several molecular pathways triggered by COPD-related hypoxiacan mediate the pro-ﬁbrotic remodeling of the atrial tissue, includinghypoxia-inducible factor 1 (HIF-1), transforming growth factor β1(TGF-β1); vascular endothelial growth factor (VEGF), andmatrixmetal-loproteinases (MMP). Equally important, chronic respiratory acidosiscan prolong atrial depolarization and augment its refractoriness. In-creased oxidation (includingmitochondrial oxidative stress [7]) and in-ﬂammation are fundamental features of both COPD and AFib [8], andhave been mechanistically linked to ventricular dysfunction, affectingdiastolic function and causing ECG abnormalities. Supporting thisview, the above-mentioned RotterdamStudy actually indicates that sys-temic inﬂammation in COPD seems to be crucial in driving the risk of in-cident AFib [5]. Some of thesemechanisms could also help to enlight therecently reported relation between obstructive sleep apnea syndrome(OSAS) and AFib: in fact, OSAS has been shown not only to promote ini-tiation of AFib but also to have a signiﬁcant negative impact on itstreatment.Drugs commonly used to treat COPD have been independently asso-ciated with phenomena that can initiate AFib, including suppression ofthe parasympathetic system (anticholinergic drugs), chronotropic ef-fects (β-adrenergic agonists, especially if not-β2-selective [9]), electro-lyte depletion, such as increased excretion of potassium andmagnesium (methylxanthines). Moreover, oral glucocorticoids, espe-cially high-dose steroids, are associated with an increased risk of devel-oping AFib. Other potential mechanisms not fully studied includeexosomes andmicroRNAs [10], which canmediate a cross-talk betweenlungs and atrial cells.lmonary disease linked to atrial ﬁbrillation? A systematic overview ofj.ijcard.2018.10.0753AcknowledgementsGS is supported by the NIH, US, DK107895.Conﬂict of interestNone.References[1] N.N. Hansel, M.C. McCormack, V. Kim, The effects of air pollution and temperatureon COPD, COPD 13 (2016) 372–379.[2] M.R. Patel, K.W. Mahaffey, J. Garg, G. Pan, D.E. Singer, W. Hacke, G. Breithardt, J.L.Halperin, G.J. Hankey, J.P. Piccini, R.C. Becker, C.C. Nessel, J.F. Paolini, S.D.Berkowitz, K.A. Fox, R.M. Califf, R.A. Investigators, Rivaroxaban versus warfarin innonvalvular atrial ﬁbrillation, N. Engl. J. Med. 365 (2011) 883–891.[3] P. Buch, J. Friberg, H. Scharling, P. Lange, E. Prescott, Reduced lung function and riskof atrial ﬁbrillation in the Copenhagen City Heart Study, Eur. Respir. J. 21 (2003)1012–1016.Please cite this article as: A. Matarese, et al., Why is chronic obstructive puthe underlying mechanisms, Int J Cardiol (2018), https://doi.org/10.1016/[4] H. Chahal, S.R. Heckbert, R.G. Barr, D.A. Bluemke, A. Jain, M. Habibi, A. Alonso, R.Kronmal, D.R. Jacobs Jr., J.A. Lima, K.E. Watson, K. Liu, L.J. Smith, P. Greenland, Abilityof reduced lung function to predict development of atrial ﬁbrillation in persons aged45 to 84 years (from the multi-ethnic study of atherosclerosis-lung study), Am. J.Cardiol. 115 (2015) 1700–1704.[5] M. Grymonprez, V. Vakaet, M. Kavousi, B.H. Stricker, M.A. Ikram, J. Heeringa, O.H.Franco, G.G. Brusselle, L. Lahousse, Chronic obstructive pulmonary disease and thedevelopment of atrial ﬁbrillation, Int. J. Cardiol. (2018) In press.[6] S. Kochhauser, D.G. Dechering, K. Trought, P. Hache, T. Haig-Carter, Y. Khaykin, Z.Wulffhart, A. Pantano, B. Tsang, L. Eckardt, A. Verma, Predictors for progression ofatrial ﬁbrillation in patients awaiting atrial ﬁbrillation ablation, Can. J. Cardiol. 32(2016) 1348–1354.[7] W. Xie, G. Santulli, S.R. Reiken, Q. Yuan, B.W. Osborne, B.X. Chen, A.R. Marks, Mito-chondrial oxidative stress promotes atrial ﬁbrillation, Sci. Rep. 5 (2015), 11427.[8] A. Matarese, G. Santulli, Angiogenesis in chronic obstructive pulmonary disease: atranslational appraisal, Transl. Med. UniSa. 3 (2012) 49–56.[9] M. Ciccarelli, D. Sorriento, E. Coscioni, G. Iaccarino, G. Santulli, Adrenergic receptors,in: J. Schisler, C. Lang, M. Willis (Eds.), Endocrinology of the Heart in Health and Dis-ease, Academic Press, London, UK 2017, pp. 285–315.[10] G. Santulli, G. Iaccarino, N. De Luca, B. Trimarco, G. Condorelli, Atrial ﬁbrillation andmicroRNAs, Front. Physiol. 5 (2014) 15.lmonary disease linked to atrial ﬁbrillation? A systematic overview ofj.ijcard.2018.10.075

Why is Chronic Obstructive Pulmonary Disease linked to Atrial Fibrillation? A systematic overview of the underlying mechanisms.

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Why is Chronic Obstructive Pulmonary Disease linked to Atrial Fibrillation? A systematic overview of the underlying mechanisms.

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