DOI: 10.1161/CIRCULATIONAHA.115.016595
Does Myocardial Infarction Beget Atrial Fibrillation and Atrial Fibrillation Beget Myocardial Infarction?
Running title: Vermond et al.; AF and MI
Rob A. Vermond, MD1; Isabelle C. Van Gelder, MD, PhD1; Harry J. Crijns, MD, PhD2; Michiel Rienstra, MD, PhD1
1
Dept of Cardiology, University of Groningen, Universityy Medical Center Groningen, Groningen, Groningen thee Netherlands; th Neth Ne t errla land n s; 2Maastricht University Me Medi Medical d cal Center, Maastric di Maastricht, icht ic h , the Netherlands
Address A ddress for Correspondence: C rr Co rresp ponden ncee: Michiel Mich chie ch iell Rienstra, ie Rieenstra Ri ra, MD, ra MD PhD Ph University of Groningen, University Medical Center Groningen Department of Cardiology P.O. Box 30.001 9700 RB Groningen, the Netherlands Tel: +31 50 3612355 Fax: +31 50 3614391 E-mail: [email protected]
Journal Subject Codes: Atherosclerosis:[134] Pathophysiology, Etiology:[4] Acute myocardial infarction, Etiology:[5] Arrhythmias, clinical electrophysiology, drugs, Etiology:[8] Epidemiology Key words: inflammation, endothelial dysfunction, Editorial, atrial fibrillation, myocardial infarction, epidemiology, risk factor
1 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on April 29, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016595
Atrial fibrillation (AF) affects millions of people worldwide.1 It is already known several decades that AF is not a benign condition, and it’s associated with a 5-fold increased risk of stroke, 3-fold increased risk of heart failure, and doubling of risk of dementia and death.2-4 Myocardial infarction, and coronary heart disease, are traditional risk factors of AF,5 however, whether myocardial infarction is a consequence of AF, has not been studied in great detail yet. The focus of current treatment for AF is pointed towards prevention of stroke. This is of utmost importance; however the other cardiovascular morbidities and mortality should not be overseen. An analysis of patients originally diagnosed with idiopathic AF, demonstrated that these patients develop frequently cardiovascular disease, including myocardial infarction and coronary artery disease.6 An analysis of Medicare data emphasized d the importance of cardiovascu cardiovascular ula larr ev even events ents en ts beyond stroke, such as heart failure, myocardial infarction and death in older adults with AF.7 In the the current currreent issue of Circulation, Solima Soliman mann et al. describe the as ma association sso sociation of AF with m myocardial yoocardial inf infarction. nfar arcttio ar on.8 Similar Sim imillar ffindings indi in dinggs in 2 oother di therr ccohorts ohhor ortts ts by the he ssame amee le am lead ead aauthor utho ut horr ha ho hhave ve bbeen eenn ee 9,10 10 published pu ubl blis i hed inn the is the h la last ast months. monthss.9,1 mo First, Firrst s , tthe hee an analysis nallys y iss ooff 23, 223,928 3,928 ,9 8 U US S re resi residents side d ntss wi with without hout co coron coronary narry hea heart eart
dise di seas se asee included as incl in clud cl uded ded in in the the Reasons Reas Re ason as onss for on for Geographic Geog Ge ogra og raph ra phic ph ic and and Racial Raci Ra cial ci al Differences Dif iffe fere fe renc re nces nc es in Stroke Str trok okee (REGARDS) ok (REG (R EGAR EG ARDS AR DS)) DS disease cohort demonstrated that prevalent AF was associated with a 2-fold higher incidence of myocardial infarction.9 Risk of myocardial infarction was significantly higher in women and blacks. Second, the analysis from the Cardiovascular Health Study (CHS) showed similar associations.10 Third, 8 Soliman and colleagues present an analysis of 14,462 participants who were free of coronary heart disease at baseline, included in the Atherosclerosis Risk in Communities (ARIC) study. The authors investigated the association of AF as a time-varying variable (n=1545) with overall incident myocardial infarction, and by type of myocardial infarction (ST elevation myocardial infarction [STEMI] or non-ST elevation myocardial
2 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on April 29, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016595
infarction [NSTEMI]). Atrial fibrillation was associated with a 63% increase in risk of myocardial infarction after multivariable adjustments. The association was limited to NSTEMI; no association with STEMI was found. In accordance with REGARDS, women had higher risks of developing myocardial infarction, than men. Racial differences did not reach statistical significance here. How can we explain the recent findings in several independent cohorts? Is it because the prevalence of both AF and myocardial infarction are increasing, and is it a matter of time until both conditions happen in the same individual? Or is it because the high-sensitive troponin assays enhance the detection of minimal myocardial damage, and the diagnosis of myocardial infarction, nfarction, especially NSTEMI, is made more often than in the old days, and mayy ev even en rrepresent epre ep rese re sent se myocardial damage as result of AF itself rather than result of atherosclerosis?11 However, there also so oother ther th er po ossi ossi s ble explanations. are al possible Firstly, bboth otth AF AF aand nd m myocardial yocard yoc card rdia ial infa ia infarction farcction fa n sshare hare re m many anyy ca an card cardiovascular diova iova vasccular ar rrisk isk fa isk fact factors tor ors including ncl c ud uding ag age, ge, e hyp hypertension yperteenssion an yp andd di diabetes iab abettess m mellitus. elllitus. li 122 Pos Possibly osssibl os blly the th he association assoociiattionn of AF asso F and and my m yoc ocar oc ardi ar dial di al infarction inf nfar arct ar ctio ct ionn reflects io refl re flec fl ects ec ts a final fin inal al ccommon ommo om monn pa mo path thwa th way a of underlying und nder nd erly er lyin ingg vascular in vaasc vasc scul ular lar disease. dis isea ease ea se. se myocardial pathway Extrapolating ideas from the relation of AF and stroke to the relation of AF and myocardial infarction may be of value to support this notion. There has always been a strong belief that AF, clot formation and stroke are temporally linked, especially since this fits Virchov’s triad with low flow, increased plasma clotting factors and vessel wall, i.e. atrial wall abnormalities. However, the Asymptomatic AF and Stroke Evaluation in pacemaker patients and the AF Reduction atrial pacing (ASSERT) Trial has recently shown that there is a temporal disconnect between stroke and continuously monitored occurrence of AF.13 This suggests that stroke, and probably also myocardial infarction, and AF have pathophysiological mechanisms in common.
3 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on April 29, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016595
This is also reflected by the CHA2DS2-VASc score, the risk of stroke depends on the number of cardiovascular conditions present in patients with a diagnosis of AF, and not on the number of AF recurrences after the initial diagnosis.2,3 However, the explanation of shared risk factors, and common pathways, negates the complex relations between AF and myocardial infarction. Myocardial infarction, and transient ischemia, may beget AF.14 Myocardial infarction, and coronary heart disease, are well-established risk factors for incident AF,12 and subclinical coronary artery disease also increases AF risk, potentially via atrial remodeling or transient ventricular ischemia with atrial diastolic overload.5,15 Studies investigating oral anticoagulants in AF suggested an increased risk of myocardial infarction in patients with AF,16,17 and it has been suggested uggested that there are differences between the diverse oral anticoagulants in red reducing duc ucin ingg ri in risk sk ooff myocardial infarction.18,19 The opposite, AF may beget myocardial infarction also seems true, as conv nvin nv inci in cing ci n ly y ddemonstrated emonstrated by the studies aauthored utho ut hored by Soliman.8-100 A ho Atrial trial fibrillation may wass co convincingly lead ead d to myocardial myocardi diall infarction di inf nfarrct nf ctio ionn through io thro th ro oug ughh increased i creaaseed heart in heeart rate rate and and thus thu huss increased incr incr crea e sedd oxygen ea oxyg ox ygen yg en ddemand, eman em and, an d sympathetic endothelial pro-inflammatory and ymp mpatheticc aactivation, ctiva vationn, endo va oth thel e iall ddysfunction, yssfu uncctioon, aand ndd pr ro-in nflaamm mmaator ory an or nd ppro-thrombotic roo-thro rom ro mbootiic effe ef effects fect fe ctss ((Figure ct Figu Fi gure re 11). ).14 The The finding fin indi ding di ng that tha hatt NSTEMI, NSTE NS TEMI TE MI, bu MI bbut utt no nott STEMI STEM ST EMII was EM waas as asso associated soci so ciat ci ated at ed wit with ithh AF it AF, su ssupports upp ppor pp orts or tss the notion that recurrent ischemia is more frequently associated with NSTEMI compared to STEMI. However, coronary angiograms, which might substantiate this, were not routinely done in present community-based studies.8-10 Also, coronary stenosis or occlusion on coronary angiograms or performed percutaneous coronary interventions were not essential for the diagnosis of myocardial infarction in these cohorts. The authors are congratulated for their contribution to the literature. Their findings once again underscore the need for a detailed search for underlying causes and risk factors of AF, and also strict follow up to determine risk of cardiovascular events, beyond stroke. Previously, strict
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DOI: 10.1161/CIRCULATIONAHA.115.016595
implementation of AF guidelines using nurse-led care has shown to improve overall AF-related outcomes, including cardiovascular events beyond stroke.20 Currently, the IntegRAted CarE for Atrial Fibrillation (RACE-4) study, a randomized multicenter study in the Netherlands, is recruiting up to 1716 patients to further study whether strict evaluation and follow-up of individuals with AF by specialized nurses can improve AF-related outcomes. It is also a call for more research to better understand the causality of both conditions, and the underlying pathophysiology. This cannot be established from present community-based cohort studies.
Funding Sources: Dr. M. Rienstra is supported by grants from the Netherlands Organization for Scientific Research (Veni grant 016.136.055) and from the EHRA Academic Fellow ow wsh s ip Fellowship programme. We acknowledge the support from the Netherlands Cardiovascular R esea es earc ea rchh rc Research nitiative: an initiative with h support of the Dutch Heart Foundation, Foundation, CVON 2014-9: Reappraisal Initiative: of Atrial Atr tria iall Fi ia Fibr brillaati br tioon: interaction between hyperC rC Coa oagulability, Electrica al re rremodeling, modeling, and Fibrillation: hyperCoagulability, Electrical Vas V ascular sc desstabiili lisa s tiion in in the t e progression th prog pr ogreess og ssio ionn of AF io AF (RACE (R RAC CE V). V). Vascular destabilisation
Co onf nfli lict li ct of of Interest I teere In rest s Disclosures: st Disscl c osur ures ur es:: N es onne. e Conflict None.
References: 1. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillum RF, Kim YH, McAnulty JH,Jr, Zheng ZJ, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJ. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129:837-847. 2. January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC,Jr, Cigarroa JE, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-2104. 3. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH. Guidelines for the management of atrial fibrillation: the Task Force
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for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31:2369-2429. 4. Magnani JW, Rienstra M, Lin H, Sinner MF, Lubitz SA, McManus DD, Dupuis J, Ellinor PT, Benjamin EJ. Atrial fibrillation: current knowledge and future directions in epidemiology and genomics. Circulation. 2011;124:1982-1993. 5. Weijs B, Pisters R, Haest RJ, Kragten JA, Joosen IA, Versteylen M, Timmermans CC, Pison L, Blaauw Y, Hofstra L, Nieuwlaat R, Wildberger J, Crijns HJ. Patients originally diagnosed with idiopathic atrial fibrillation more often suffer from insidious coronary artery disease compared to healthy sinus rhythm controls. Heart Rhythm. 2012;9:1923-1929. 6. Weijs B, de Vos CB, Tieleman RG, Peeters FE, Limantoro I, Kroon AA, Cheriex EC, Pisters R, Crijns HJ. The occurrence of cardiovascular disease during 5-year follow-up in patients with idiopathic atrial fibrillation. Europace. 2013;15:18-23. 7. Piccini JP, Hammill BG, Sinner MF, Hernandez AF, Walkey AJ, Benjamin EJ, Curtis LH, Heckbert SR. Clinical course of atrial fibrillation in older adults: the importance of cardiovascular events beyond stroke. Eur Heart J. 2014;35:250-256. 8. Soliman EZ, Lopez F, O’Neal WT, Chen LY, Bengtson L, Zhang ZM, Zhang ZM, Loehr LR, Cushman M, Alonso A. Atrial Fibrillation and Risk of ST-Segment Elevation versus Non-ST Segment Atherosclerosis Communities Segm gmen gm entt Elevation en Elev El evatio ev ionn Myocardial Infarction: The A io theerosclerosis Risk in th nC ommunities (ARIC) Study. Circulation. St tud udyy. Circul ulation. 2015;131:XX-XXX. ul 99. Soliman Soliman EZ, Safford Safforrd MM, MM M, Muntner Muntner P, P, Khodneva Khhoddneva vaa Y, Dawood Dawo Da wood FZ, wo FZ Z, Zakai Zaakaai NA, NA, Thacker Thhac hacker ck r EL, EL, Judd Howard VJ, Howard Herrington Cushman M.. A Atrial fibrillation Ju udd S, Howa ward V wa J, H owardd G, Her erring er ngto ng t n DM DM, Cu ushhmann M trria iall fibr brillaati t on and nd thee rrisk isk of of myocardial infarction. Med. myoc car ardi dial di al infar arct ctio ion. io n JAMA JAM IIntern nter nt ern Me er ed. 2014; 2014 20 14; 174: 14 174: 17 4: 107-114. 107-114 114 14. 10. O'Neal WT, Sangal K, Zhang ZM, Soliman EZ. Atrial fibrillation and incident myocardial infarction in the elderly. Clin Cardiol. 2014;37:750-755. 11. Hussein AA, Bartz TM, Gottdiener JS, Sotoodehnia N, Heckbert SR, Lloyd-Jones D, Kizer JR, Christenson R, Wazni O, deFilippi C. Serial measures of cardiac troponin T levels by a highly sensitive assay and incident atrial fibrillation in a prospective cohort of ambulatory older adults. Heart Rhythm. 2015;12:879-885. 12. Kirchhof P, Lip GY, Van Gelder IC, Bax J, Hylek E, Kaab S, Schotten U, Wegscheider K, Boriani G, Brandes A, Ezekowitz M, Diener H, Haegeli L, Heidbuchel H, Lane D, Mont L, Willems S, Dorian P, Aunes-Jansson M, Blomstrom-Lundqvist C, Borentain M, Breitenstein S, Brueckmann M, Cater N, Clemens A, Dobrev D, Dubner S, Edvardsson NG, Friberg L, Goette A, Gulizia M, Hatala R, Horwood J, Szumowski L, Kappenberger L, Kautzner J, Leute A, Lobban T, Meyer R, Millerhagen J, Morgan J, Muenzel F, Nabauer M, Baertels C, Oeff M, Paar D, Polifka J, Ravens U, Rosin L, Stegink W, Steinbeck G, Vardas P, Vincent A, Walter M, Breithardt G, Camm AJ. Comprehensive risk reduction in patients with atrial fibrillation: emerging diagnostic and therapeutic options--a report from the 3rd Atrial Fibrillation
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Competence NETwork/European Heart Rhythm Association consensus conference. Europace. 2012;14:8-27. 13. Brambatti M, Connolly SJ, Gold MR, Morillo CA, Capucci A, Muto C, Lau CP, Van Gelder IC, Hohnloser SH, Carlson M, Fain E, Nakamya J, Mairesse GH, Halytska M, Deng WQ, Israel CW, Healey JS, ASSERT Investigators. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation. 2014;129:2094-2099. 14. Schoonderwoerd BA, Van Gelder IC, Crijns HJ. Left ventricular ischemia due to coronary stenosis as an unexpected treatable cause of paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 1999;10:224-228. 15. Skalidis EI, Hamilos MI, Karalis IK, Chlouverakis G, Kochiadakis GE, Vardas PE. Isolated atrial microvascular dysfunction in patients with lone recurrent atrial fibrillation. J Am Coll Cardiol. 2008;51:2053-2057. 16. Weijs B, Blaauw Y, Rennenberg RJ, Schurgers LJ, Timmermans CC, Pison L, Nieuwlaat R, Hofstra L, Kroon AA, Wildberger J, Crijns HJ. Patients using vitamin K antagonists show increased ncreased levels of coronary calcification: an observational study in low-risk atrial al ffibrillation ibri ib rill ri llat ll atio at ionn io patients. Eur Heart J. 2011;32:2555-2562. 17. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis controlled 2012;172:397-402. meta taa-a -ana naly na lysi ly siss off noninferiority si non o inferiority y randomized cont tro roll lled trials. Arch Intern ll Interrn Med. 2012;172:397-402 18. 18. Hohnloser SH, SH, Oldgren Oldg Ol dgre dg renn J, Yang re Yan angg S, S Wallentin Wallle lenntin L, Ezekowitz Eze zeko ze kowi ko witz wi t M, tz M, Reilly Reil Re illly il ly P, Eikelboom Eike Ei kelb ke lbooom lb oom J,, Brueckmann Yusuf Connolly SJ. Myocardial ischemic events with B ueckmann M, Y Br usuuf S, Con onnolly SJ on J. M yoocaardial ische hemi he mic even mi entts in pa en ppatients atieentts wit th aatrial triiall fibrillation with dabigatran warfarin (Randomized Evaluation fiibril illa il l tion treated tre reated ed wit th dabi iga gatr tran oorr wa tr warfar arrin n in th thee RE RE-LY Y (R (Ra ando domi do m zed Ev Eval a uattioon of of LongLonng-Term Anticoagulation Therapy) trial. mA ntic nt icoagu ic gula gu lati tion ti on T h rapyy) tr he tri ial. Circulation. Circ Ci rcul rc ulat ul atiion at ion. 2012;125:669-676. 2012 20 2;1 ;125 25:6 25 :669-6 :6 676 76. 19. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM, ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891. 20. Hendriks JM, de Wit R, Crijns HJ, Vrijhoef HJ, Prins MH, Pisters R, Pison LA, Blaauw Y, Tieleman RG. Nurse-led care vs. usual care for patients with atrial fibrillation: results of a randomized trial of integrated chronic care vs. routine clinical care in ambulatory patients with atrial fibrillation. Eur Heart J. 2012;33:2692-2699.
Figure Legend:
Figure 1. Conceptual figure of the bidirectional relation between atrial fibrillation and myocardial infarction.
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Shared cardiovascular risk factors
Vascular d disease
Sympathetic activation Ischemia
Atrial fibrillation Endothelial dysfunction
Fibrosis Myocardial Myo ocard dial remodeling
Myocardial infarction Increased heart rate Increased oxygen demand Pro-inflammatory Pro-thrombotic factors
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Does Myocardial Infarction Beget Atrial Fibrillation and Atrial Fibrillation Beget Myocardial Infarction? Rob A. Vermond, Isabelle C. Van Gelder, Harry J. Crijns and Michiel Rienstra Circulation. published online April 27, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2015/04/27/CIRCULATIONAHA.115.016595
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Does Myocardial Infarction Beget Atrial Fibrillation and Atrial Fibrillation Beget Myocardial Infarction?
Running title: Vermond et al.; AF and MI
Rob A. Vermond, MD1; Isabelle C. Van Gelder, MD, PhD1; Harry J. Crijns, MD, PhD2; Michiel Rienstra, MD, PhD1
1
Dept of Cardiology, University of Groningen, Universityy Medical Center Groningen, Groningen, Groningen thee Netherlands; th Neth Ne t errla land n s; 2Maastricht University Me Medi Medical d cal Center, Maastric di Maastricht, icht ic h , the Netherlands
Address A ddress for Correspondence: C rr Co rresp ponden ncee: Michiel Mich chie ch iell Rienstra, ie Rieenstra Ri ra, MD, ra MD PhD Ph University of Groningen, University Medical Center Groningen Department of Cardiology P.O. Box 30.001 9700 RB Groningen, the Netherlands Tel: +31 50 3612355 Fax: +31 50 3614391 E-mail: [email protected]
Journal Subject Codes: Atherosclerosis:[134] Pathophysiology, Etiology:[4] Acute myocardial infarction, Etiology:[5] Arrhythmias, clinical electrophysiology, drugs, Etiology:[8] Epidemiology Key words: inflammation, endothelial dysfunction, Editorial, atrial fibrillation, myocardial infarction, epidemiology, risk factor
1 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on April 29, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016595
Atrial fibrillation (AF) affects millions of people worldwide.1 It is already known several decades that AF is not a benign condition, and it’s associated with a 5-fold increased risk of stroke, 3-fold increased risk of heart failure, and doubling of risk of dementia and death.2-4 Myocardial infarction, and coronary heart disease, are traditional risk factors of AF,5 however, whether myocardial infarction is a consequence of AF, has not been studied in great detail yet. The focus of current treatment for AF is pointed towards prevention of stroke. This is of utmost importance; however the other cardiovascular morbidities and mortality should not be overseen. An analysis of patients originally diagnosed with idiopathic AF, demonstrated that these patients develop frequently cardiovascular disease, including myocardial infarction and coronary artery disease.6 An analysis of Medicare data emphasized d the importance of cardiovascu cardiovascular ula larr ev even events ents en ts beyond stroke, such as heart failure, myocardial infarction and death in older adults with AF.7 In the the current currreent issue of Circulation, Solima Soliman mann et al. describe the as ma association sso sociation of AF with m myocardial yoocardial inf infarction. nfar arcttio ar on.8 Similar Sim imillar ffindings indi in dinggs in 2 oother di therr ccohorts ohhor ortts ts by the he ssame amee le am lead ead aauthor utho ut horr ha ho hhave ve bbeen eenn ee 9,10 10 published pu ubl blis i hed inn the is the h la last ast months. monthss.9,1 mo First, Firrst s , tthe hee an analysis nallys y iss ooff 23, 223,928 3,928 ,9 8 U US S re resi residents side d ntss wi with without hout co coron coronary narry hea heart eart
dise di seas se asee included as incl in clud cl uded ded in in the the Reasons Reas Re ason as onss for on for Geographic Geog Ge ogra og raph ra phic ph ic and and Racial Raci Ra cial ci al Differences Dif iffe fere fe renc re nces nc es in Stroke Str trok okee (REGARDS) ok (REG (R EGAR EG ARDS AR DS)) DS disease cohort demonstrated that prevalent AF was associated with a 2-fold higher incidence of myocardial infarction.9 Risk of myocardial infarction was significantly higher in women and blacks. Second, the analysis from the Cardiovascular Health Study (CHS) showed similar associations.10 Third, 8 Soliman and colleagues present an analysis of 14,462 participants who were free of coronary heart disease at baseline, included in the Atherosclerosis Risk in Communities (ARIC) study. The authors investigated the association of AF as a time-varying variable (n=1545) with overall incident myocardial infarction, and by type of myocardial infarction (ST elevation myocardial infarction [STEMI] or non-ST elevation myocardial
2 Downloaded from http://circ.ahajournals.org/ at CONS CALIFORNIA DIG LIB on April 29, 2015
DOI: 10.1161/CIRCULATIONAHA.115.016595
infarction [NSTEMI]). Atrial fibrillation was associated with a 63% increase in risk of myocardial infarction after multivariable adjustments. The association was limited to NSTEMI; no association with STEMI was found. In accordance with REGARDS, women had higher risks of developing myocardial infarction, than men. Racial differences did not reach statistical significance here. How can we explain the recent findings in several independent cohorts? Is it because the prevalence of both AF and myocardial infarction are increasing, and is it a matter of time until both conditions happen in the same individual? Or is it because the high-sensitive troponin assays enhance the detection of minimal myocardial damage, and the diagnosis of myocardial infarction, nfarction, especially NSTEMI, is made more often than in the old days, and mayy ev even en rrepresent epre ep rese re sent se myocardial damage as result of AF itself rather than result of atherosclerosis?11 However, there also so oother ther th er po ossi ossi s ble explanations. are al possible Firstly, bboth otth AF AF aand nd m myocardial yocard yoc card rdia ial infa ia infarction farcction fa n sshare hare re m many anyy ca an card cardiovascular diova iova vasccular ar rrisk isk fa isk fact factors tor ors including ncl c ud uding ag age, ge, e hyp hypertension yperteenssion an yp andd di diabetes iab abettess m mellitus. elllitus. li 122 Pos Possibly osssibl os blly the th he association assoociiattionn of AF asso F and and my m yoc ocar oc ardi ar dial di al infarction inf nfar arct ar ctio ct ionn reflects io refl re flec fl ects ec ts a final fin inal al ccommon ommo om monn pa mo path thwa th way a of underlying und nder nd erly er lyin ingg vascular in vaasc vasc scul ular lar disease. dis isea ease ea se. se myocardial pathway Extrapolating ideas from the relation of AF and stroke to the relation of AF and myocardial infarction may be of value to support this notion. There has always been a strong belief that AF, clot formation and stroke are temporally linked, especially since this fits Virchov’s triad with low flow, increased plasma clotting factors and vessel wall, i.e. atrial wall abnormalities. However, the Asymptomatic AF and Stroke Evaluation in pacemaker patients and the AF Reduction atrial pacing (ASSERT) Trial has recently shown that there is a temporal disconnect between stroke and continuously monitored occurrence of AF.13 This suggests that stroke, and probably also myocardial infarction, and AF have pathophysiological mechanisms in common.
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DOI: 10.1161/CIRCULATIONAHA.115.016595
This is also reflected by the CHA2DS2-VASc score, the risk of stroke depends on the number of cardiovascular conditions present in patients with a diagnosis of AF, and not on the number of AF recurrences after the initial diagnosis.2,3 However, the explanation of shared risk factors, and common pathways, negates the complex relations between AF and myocardial infarction. Myocardial infarction, and transient ischemia, may beget AF.14 Myocardial infarction, and coronary heart disease, are well-established risk factors for incident AF,12 and subclinical coronary artery disease also increases AF risk, potentially via atrial remodeling or transient ventricular ischemia with atrial diastolic overload.5,15 Studies investigating oral anticoagulants in AF suggested an increased risk of myocardial infarction in patients with AF,16,17 and it has been suggested uggested that there are differences between the diverse oral anticoagulants in red reducing duc ucin ingg ri in risk sk ooff myocardial infarction.18,19 The opposite, AF may beget myocardial infarction also seems true, as conv nvin nv inci in cing ci n ly y ddemonstrated emonstrated by the studies aauthored utho ut hored by Soliman.8-100 A ho Atrial trial fibrillation may wass co convincingly lead ead d to myocardial myocardi diall infarction di inf nfarrct nf ctio ionn through io thro th ro oug ughh increased i creaaseed heart in heeart rate rate and and thus thu huss increased incr incr crea e sedd oxygen ea oxyg ox ygen yg en ddemand, eman em and, an d sympathetic endothelial pro-inflammatory and ymp mpatheticc aactivation, ctiva vationn, endo va oth thel e iall ddysfunction, yssfu uncctioon, aand ndd pr ro-in nflaamm mmaator ory an or nd ppro-thrombotic roo-thro rom ro mbootiic effe ef effects fect fe ctss ((Figure ct Figu Fi gure re 11). ).14 The The finding fin indi ding di ng that tha hatt NSTEMI, NSTE NS TEMI TE MI, bu MI bbut utt no nott STEMI STEM ST EMII was EM waas as asso associated soci so ciat ci ated at ed wit with ithh AF it AF, su ssupports upp ppor pp orts or tss the notion that recurrent ischemia is more frequently associated with NSTEMI compared to STEMI. However, coronary angiograms, which might substantiate this, were not routinely done in present community-based studies.8-10 Also, coronary stenosis or occlusion on coronary angiograms or performed percutaneous coronary interventions were not essential for the diagnosis of myocardial infarction in these cohorts. The authors are congratulated for their contribution to the literature. Their findings once again underscore the need for a detailed search for underlying causes and risk factors of AF, and also strict follow up to determine risk of cardiovascular events, beyond stroke. Previously, strict
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DOI: 10.1161/CIRCULATIONAHA.115.016595
implementation of AF guidelines using nurse-led care has shown to improve overall AF-related outcomes, including cardiovascular events beyond stroke.20 Currently, the IntegRAted CarE for Atrial Fibrillation (RACE-4) study, a randomized multicenter study in the Netherlands, is recruiting up to 1716 patients to further study whether strict evaluation and follow-up of individuals with AF by specialized nurses can improve AF-related outcomes. It is also a call for more research to better understand the causality of both conditions, and the underlying pathophysiology. This cannot be established from present community-based cohort studies.
Funding Sources: Dr. M. Rienstra is supported by grants from the Netherlands Organization for Scientific Research (Veni grant 016.136.055) and from the EHRA Academic Fellow ow wsh s ip Fellowship programme. We acknowledge the support from the Netherlands Cardiovascular R esea es earc ea rchh rc Research nitiative: an initiative with h support of the Dutch Heart Foundation, Foundation, CVON 2014-9: Reappraisal Initiative: of Atrial Atr tria iall Fi ia Fibr brillaati br tioon: interaction between hyperC rC Coa oagulability, Electrica al re rremodeling, modeling, and Fibrillation: hyperCoagulability, Electrical Vas V ascular sc desstabiili lisa s tiion in in the t e progression th prog pr ogreess og ssio ionn of AF io AF (RACE (R RAC CE V). V). Vascular destabilisation
Co onf nfli lict li ct of of Interest I teere In rest s Disclosures: st Disscl c osur ures ur es:: N es onne. e Conflict None.
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Figure Legend:
Figure 1. Conceptual figure of the bidirectional relation between atrial fibrillation and myocardial infarction.
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Shared cardiovascular risk factors
Vascular d disease
Sympathetic activation Ischemia
Atrial fibrillation Endothelial dysfunction
Fibrosis Myocardial Myo ocard dial remodeling
Myocardial infarction Increased heart rate Increased oxygen demand Pro-inflammatory Pro-thrombotic factors
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Does Myocardial Infarction Beget Atrial Fibrillation and Atrial Fibrillation Beget Myocardial Infarction? Rob A. Vermond, Isabelle C. Van Gelder, Harry J. Crijns and Michiel Rienstra Circulation. published online April 27, 2015; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2015 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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