Accepted Manuscript

Characteristics of among Patients with Atrial Fibrillation compared to Patients with Sinus Rhythm

Lukas J. Motloch, MD, PhD, Sara Reda, MD, Robert Larbig, MD, Ariane Wolff, MD, Karolina A. Motloch, MD, Bernhard Wernly, MD, Christina Granitz, MD, Michael Lichtenauer, MD, PhD, Martin Wolny, PhD, Uta C. Hoppe, MD PII: S1109-9666(16)30160-9 DOI: 10.1016/j.hjc.2017.03.001 Reference: HJC 145

To appear in: Hellenic Journal of Cardiology

Received Date: 22 August 2016 Revised Date: 24 February 2017 Accepted Date: 3 March 2017

Please cite this article as: Motloch LJ, Reda S, Larbig R, Wolff A, Motloch KA, Wernly B, Granitz C, Lichtenauer M, Wolny M, Hoppe UC, Characteristics of Coronary Artery Disease among Patients with Atrial Fibrillation compared to Patients with Sinus Rhythm, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2017.03.001.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 ACCEPTED MANUSCRIPT Characteristics of Coronary Artery Disease among Patients with Atrial

Fibrillation compared to Patients with Sinus Rhythm

Lukas J. Motloch, MD, PhD 1; Sara Reda, MD 1; Robert Larbig, MD 1, 2 ; Ariane Wolff, MD 1;

Karolina A. Motloch, MD 1, 3 ; Bernhard Wernly, MD 1; Christina Granitz, MD 1; Michael

Lichtenauer, MD, PhD 1; Martin Wolny, PhD 1; Uta C. Hoppe, MD 1

1Department of Internal Medicine II, Paracelsus Medical University Salzburg, Salzburg,

Austria

2Division of , Department of Cardiovascular Medicine, University

Hospital Muenster, Muenster, Germany

3Department of Ophthalmology, SALK/University Clinic, Paracelsus Medical University, Salzburg, Austria MANUSCRIPT

Brief title: Coronary artery disease in atrial fibrillation

Correspondence to:

Lukas J. Motloch, MD, PhD

Department of Internal Medicine II Paracelsus MedicalACCEPTED University Salzburg Muellner Hauptstr. 48

A-5020 Salzburg, Austria

Phone: +43 (0)662 4482-58870, Fax: +43 (0)662 4482-4111

E-Mail: [email protected] 2 ACCEPTED MANUSCRIPT Abstract

Background: With a high prevalence of coronary artery disease (CAD) among patients with atrial fibrillation (AF), CAD is one of the main risk factors for AF. However, little is known about the characteristics of CAD in AF patients. Especially, the question, whether a specific anatomical distribution of coronary artery stenoses might predispose to AF via atrial ischemia remains speculative. To address this issue, we evaluated potential associations between angiographic characteristics of CAD and AF.

Methods: In a single-center retrospective analysis 796 consecutive patients with confirmed

CAD and AF (CAD-AF), and 785 patients with CAD and sinus rhythm (CAD-SR) were enrolled. Clinical characteristics and angiographic findings were compared between both groups in stable CAD and during acute myocardial infarction (MI).

Results: In CAD-AF, mitral valve disease and chronic failure were significantly more common than in CAD-SR. Clinical condition in CAD-AF was significantly more severe, as indicated by NYHA/WHO functional class. Left MANUSCRIPTventricular was reduced in CAD-AF, reflecting the marked fraction of patients with ischemic cardiomyopathy. No association between anatomical characteristics of CAD and AF was found. However, CAD-

AF seemed to be associated with a higher degree of severity of CAD (p=0.06). Additionally,

CAD-AF with MI showed a significantly higher number of diseased coronary vessels.

Conclusion: The anatomical distribution of coronary artery stenoses does not contribute to

AF in CAD patients. However, AF is linked to a higher degree of severity of CAD which might predisposeACCEPTED to AF by driving ischemic heart disease and changes in left ventricular function.

Keywords: coronary artery disease, atrial fibrillation, heart failure, myocardial infarction, coronary artery stenoses

3 ACCEPTED MANUSCRIPT Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia and associated with a high risk of stroke, heart failure and hospitalization [1, 2]. AF is related to a variety of cardiovascular and other conditions, which have additive effects on the perpetuation of AF by promoting a substrate that maintains AF. Coronary artery disease (CAD) is present in over 20% of the AF population [3]. In contrast to the high prevalence of CAD in AF stands a relatively low prevalence of AF in the total population with CAD. In the Coronary Artery Surgical Study

(CASS) AF was present in only 0.6% of patients with angiographically documented CAD, though the prevalence of intermittent AF was presumably somewhat higher [4].

Furthermore, AF occurs transiently in 6 to 10 percent of patients with acute myocardial infarction (MI). These patients are known to have worse prognosis which is mostly due to comorbidities such as heart failure. Since patients with severe CAD are very likely to have a reduced left ventricular ejection fraction, heart failure is thought to be a cause of AF in patients with MI. However, also in this population MANUSCRIPT besides atrial stretching secondary to heart failure, atrial ischemia is suggested to drive AF [5-7].

Nevertheless, whether CAD per se predisposes to AF via atrial ischemia and how AF interacts with coronary artery perfusion are uncertain [8, 9]. Indeed, one might speculate, that coronary macroangiophathy drives atrial ischemia and therefore, triggers atrial arrhythmias. The sinus nodal artery arises from the proximal right coronary artery in about 60% of patients and from the proximal left circumflex artery in 40% of patients and supplies most of the right . The left atrial circumflexACCEPTED artery arises from the proximal left circumflex artery and supplies most of the left atrium [10]. Consequently, in patients with CAD and AF, angiographic localizations of coronary artery lesions might correspond to the coronary arteries supplying the atria.

However, in this population, the characteristics of coronary artery stenoses have not been systematically assessed, yet. Therefore, whether specific anatomical distributions of coronary 4 ACCEPTED MANUSCRIPT artery stenoses might promote AF remains speculative. To address this issue, we compared the angiographic characteristics of coronary artery lesions between CAD patients with AF and

CAD patients with sinus rhythm.

Methods

Study participants

A flow diagram outlining the total number of patient records screened and how the final numbers of patients who were included in the trial were obtained is presented in figure 1. To study a population who was investigated by similar clinical standards, all patients included in this study were admitted to the same university hospital due to acute MI, PCI or diagnostic coronary angiography in the same period of time between December 1999 and September

2008. The study cohort comprised of all eligible 796 consecutive patients with confirmed diagnosis of AF and stable CAD or acute MI (CAD-AF). To compare this group to a similar MANUSCRIPT number of patients who were studied in the same period of time, 785 patients were randomly chosen from the cohort of all eligible 3680 consecutive patients with confirmed sinus rhythm and stable CAD or MI (CAD-SR) using the PASW statistics 18 software (SPSS, Chicago,

USA; Figure 1). Furthermore, in both study groups, a subgroup analysis in the subpopulation with acute MI (MI-AF vs. MI-SR) was performed.

In all eligible patients, retrospectively classification of AF into one of the three groups (first diagnosed, paroxysmal, persistent/permanent) [9], and information about the clinical severity (NYHA/WHO functionalACCEPTED class), medication, concomitant diseases were obtained from the University Patient Database. Furthermore, results of coronary angiography evaluations were analyzed in all patients. Inclusion criteria were the presence of at least coronary one vessel disease on the coronary angiogram. Patients´ data was only analyzed if a complete data set including conclusive coronary angiogram of all three coronary vessels, information about the clinical severity (NYHA/WHO functional class), medication and concomitant diseases could 5 ACCEPTED MANUSCRIPT be obtained from the university database. Exclusion criteria were the history of a different supraventricular rhythm disorders than AF including sick sinus syndrome, atrial flutter, atrioventricular tachycardia and unclassified atrial tachycardia. If during the study period, more than one coronary angiogram was performed in one patient, only data from the first coronary evaluation was included.

[Figure 1 near here]

Definition of AF

AF was defined as the presence of AF on an electrocardiogram during the index hospitalization and/or as indicated by a diagnosis found in medical records, the hospitalization database, or outpatient databases. Electrocardiographic AF was defined as the presence of an irregular rhythm with fibrillatory waves and no defined P-waves. Diagnoses and classification of AF were based on physician-assigned diagnoses in the medical records and/or the presence of corresponding ICD-9-CM codes for AF (427.31) MANUSCRIPT in the hospital discharge or outpatient databases [1]. AF was sub-classified into newly diagnosed AF, paroxysmal AF or chronic AF

(persistent and permanent) [9].

Left heart catheterization

Left ventricular ejection fraction was estimated via biplane ventriculography as previously described [11]. Coronary angiography was carried out according to the technique of Judkins [12]. ACCEPTED

Definition of CAD

The degree of CAD was classified as one, two or three vessel disease. One, two or three vessel disease was diagnosed when coronary angiography presented a reduction of 70% or more of the internal diameter of the right coronary artery, left anterior descending or left 6 ACCEPTED MANUSCRIPT circumflex system. A stenosis of 50% or more of the left main artery was considered to be a two vessel disease [13]. Locations of coronary stenoses were established according to definitions of coronary artery segments as previously described [13]. More than one stenosis of one of the main coronary artery branches (right coronary artery, left anterior descending or left circumflex coronary artery) were defined as multiple stenoses. In this case, only the most proximal localization with an obstruction of at least 70% of the internal diameter was analyzed. A chronic total occlusion (CTO) was defined as TIMI 0 flow for more than three months [14]. MI and differentiation of ST-elevation myocardial infarction (STEMI) or non-

ST-elevation myocardial infarction (NSTEMI) were assessed according to the European guidelines [15].

Statistical analysis

Statistical analyses were performed using PASW statistics 18 software (SPSS, Chicago, USA). The results are given as mean ± standard MANUSCRIPTerror of mean (SEM). Differences between groups and subgroups were evaluated by chi-square-testing for discrete variables and student-t test for continuous variables. For ordinal data Mann-Whitney-U test was used. A p < 0.05 was considered as statistically significant.

Results

Baseline Characteristics A total of 796 ACCEPTED patients with CAD and AF were analyzed in this retrospective study and compared to 785 patients with CAD and absent AF (SR). The demographic variables of the individual groups with and without AF are shown in Table 1. Valve disease, chronic heart failure and previous were significantly more common in the CAD-AF group.

This observation was consistent for all causes of left heart failure. Furthermore, in case of valvular disease a strong association between mitral valve disease and AF was evident. 7 ACCEPTED MANUSCRIPT

Left ventricular function in patients with CAD and AF

Cardiac function data were evaluated by ventriculography. Expectedly, left ventricular ejection fraction was reduced in the CAD-AF group, reflecting the marked fraction of patients with ischemic cardiomyopathy (Table 1).

[Table 1 near here]

Results of coronary angiography in patients with CAD-AF and CAD-SR

CAD-AF showed a trend towards a higher degree of CAD without reaching statistical significance (p=0.06) indicating a more severe CAD in CAD-AF (Table 2). To assess the distribution and characteristics of coronary artery stenoses in patients with AF compared to

SR, we analyzed coronary angiographies. The results are presented in table 1. Distribution of stenoses, neither in RCA, LAD or RCX nor in the smaller branches of the coronary arteries showed any significant differences in CAD-AF compar MANUSCRIPTed to CAD-SR (Table 2). Furthermore, no significant difference in the percentage degree of coronary artery stenoses was found in patients with AF compared to SR (Figure 2).

[Table 2 and Figure 2 near here]

AF and MI

The demographic variables of the individual groups MI-AF and MI-SR are shown in table 3. The distributionACCEPTED of stenoses was similar in MI-AF compared to MI-SR. Notably CAD-AF with acute MI showed a significantly higher number of diseased coronary vessels (Table 3).

[Table 3 near here]

Discussion 8 ACCEPTED MANUSCRIPT In the present study, in CAD patients we systematically assessed the distribution and degree of coronary artery stenoses and their association with AF.

Distribution of small vessels in the atria varies. Since atrial branches divide either from the proximal RCA or the proximal RCX, one might speculate atrial ischemia caused by proximal stenoses of these vessels to be associated with AF. Indeed, in a cohort of 25 patients undergoing coronary artery bypass graft Kolvekar and colleagues described an association between atrial ischemia (sclerosis of SA nodal and AV nodal arteries) and postoperative AF

[16]. In dogs occlusion of an atrial coronary artery increased the duration of AF induced by burst pacing [17]. Furthermore, in a previous study stenosis of the RCA was shown to be a risk factor for postoperative AF in patients undergoing coronary bypass graft surgery [18]. Of note, the studies described above were performed in an experimental setting in animals or in a different population of patients who underwent cardiac surgery [16-18]. Nevertheless, by analyzing first time coronary angiographs in AF patients, compared to the cohort with clinically non relevant CAD, Kralev and colleagues MANUSCRIPT reported a higher prevalence of RCA occlusions in patients undergoing coronary intervention [19]. In our trial by performing a systematic analysis of coronary angiograms in a bigger study cohort, we did not observe any association between degree or localization of coronary stenoses and AF, indicating that a more complex mechanism might drive AF in CAD patients.

Davies and Pomerance, who carried out studies on from deceased patients with AF described cases with presumed atrial ischemia and no evidence of significant lesions of either the major coronaryACCEPTED arteries or the intraatrial vessels [20]. They suggested that, in patients with CAD, prior left ventricular failure is a major risk factor for AF [20]. Similar findings are also observed in our cohort with CAD and AF. In accordance with Davies and Pomerance, we did not observe any differences between CAD-AF and CAD-SR with regard to frequency or severity of coronary stenoses of neither the proximal RCA nor the proximal RCX.

Additionally, we did not find any significant differences in the locations of coronary artery 9 ACCEPTED MANUSCRIPT stenoses in AF regardless of any vessel compared to SR implicating that AF occurrence presumably might be independent of coronary macroangiopathy distribution. However, in accordance with speculations by Davies and Pomerance patients with CAD and AF presented a higher prevalence of chronic heart failure and mitral valve disease which was mainly caused by ischemic heart disease or/ and mitral ring dilatation due to ischemic heart failure.

Consequently, patients with AF presented a higher NYHA classification.

Given distinct cardiac pathomechanisms, we decided to further evaluate coronary angiograms in the subgroup of patients with acute MI. Indeed, AF is known to be an indicator of a severe prognosis after acute MI, both in short and long term follow-up [7, 21-23]. AF occurs transiently in 6 to 10 percent of patients with MI, presumably due to atrial ischemia or atrial stretching secondary to MI complications like heart failure [5, 24, 25]. Sakata and colleagues reported a higher incidence of RCA infarct related lesions in patients with acute MI and occurrence of AF in the first 24 hours after the incident. Furthermore, a decreased cardiac function was observed in AF patients [26]. Conseque MANUSCRIPTntly, GUSTO-1 patients with AF at entry or after admission presented more extensive CAD and more impaired left ventricular function.

However, GUSTO-1 only weakly implicated right coronary artery involvements (suggesting territories at risk - including the sinoatrial node, the atrioventricular node and the atria) in the pathogenesis of AF [5]. Moreover, AF occurred frequently secondary to infarct complications

[25]. Interestingly, similar findings were reported by Kinjo and colleagues [23]. In the present study, by performing a systematical analysis of the distribution of the acute coronary events, we were not ableACCEPTED to find any associations between the localizations of acute occlusions in neither the proximal RCA nor the proximal RCX. Furthermore, no additional differences were observed in the localizations of coronary artery stenoses when MI-AF was compared to MI-

SR suggesting, that the overall incidence of AF after MI might be independent of the anatomical distributions of acute coronary events. However, in accordance with GUSTO-3 and the observations obtained by Kinjo and colleagues [23, 25], patients in the MI-AF group 10 ACCEPTED MANUSCRIPT presented a significantly higher number of diseased coronary vessels indicating a more severe

CAD in this subgroup.

Of note, this trend was also detected in the total CAD-AF population in our trial (p=0.06).

This observation is consistent with previous studies which explored the severity of CAD in patients with AF [19, 27, 28]. Furthermore, our results are additionally supported by a previous observation in patients with AF on electrocardiograms obtained at the time of coronary angiography. In consistence with our results no differences in the distributions of coronary artery stenoses were reported. However, patients with AF presented also a more severe CAD which was associated with a higher prevalence of chronic heart failure and mitral valve insufficiency [28]. Interestingly, in CAD patients the severity of CAD is known be associated with a worth outcome [29, 30]. Indeed, CAD may induce chronic heart failure by among others promoting a decrease in LV performance [31] as well as an increase the incidence of moderate or severe mitral regurgitation [32]. All these mentioned cardiac pathologies are known to drive the incidence of AF. MANUSCRIPT In accordance, they were more frequently present in our CAD-AF population. Therefore, one might speculate that not atrial ischemia but rather secondary consequences of ischemic heart disease like reduced LV performance or mitral regurgitation might drive AF in CAD patients. However, this speculation should be applied with caution.

Our data might have also an impact on clinical practice. Since, in our study AF was linked to a higher number of diseased coronary vessels, one might suggest, that a closer rhythm monitoring shouldACCEPTED be applied in patients with severe CAD. Of note, early detection of AF in this population could have an impact on the prevention of AF associated complications like stroke, heart failure and hospitalization. On the other hand, since in our study prevalence of

AF was independent of the distribution of coronary stenoses, this observation might discount a higher risk for the incidence of AF when angiographic localizations of coronary lesions correspond to the coronary arteries supplying the atria. 11 ACCEPTED MANUSCRIPT

Limitations

Our study suffers also from several limitations. Generally, results obtained retrospectively in a single-center should be confirmed in a preferably multicenter, randomized prospective study.

However, our data represent a real-life scenario since they were obtained during daily clinical practice. In our population, functional flow reserve was not determined. This could promote inaccurate assessment of the functional significance of coronary stenosis. Therefore, to minimize this issue, in this study only a stenosis with a reduction of at least 70% was defined as significant [33]. In addition, in regard to the percentage degree of occlusion, no significant differences between CAD-SR and CAD-AF were observed in our trial (Figure 2).

Furthermore, our study did not explore the impact of cardiac ischemia, which is induced by coronary small vessel disease. Indeed, coronary plaque distribution and coronary microangiopathy were shown to occur independently of coronary large vessel occlusions [34, 35]. Of note, in the Rotterdam Study asymptomatic MANUSCRIPT atherosclerosis was shown to be associated with AF [36].

Conclusion

Our findings suggest that in patients with stable CAD or MI undergoing coronary angiography, AF is not associated with the localization of coronary artery stenoses. However, the severity of CAD could drive ischemic heart disease and promote changes in LV performance whichACCEPTED might induce AF. Further trials should investigate the impact of CAD in AF patients.

Conflict of interest

The authors have declared that no conflict of interest exists. 12 ACCEPTED MANUSCRIPT References

1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study.

JAMA. 2001;285:2370-2375.

2. Vardas P, Andrikopoulos G, Baroutsou B, Investigators O. A Greek Prospective

Observational Study of Cardiovascular Morbidity and Mortality in Patients with Atrial

Fibrillation. Hellenic J Cardiol. 2015;56:475-494.

3. Nieuwlaat R, Capucci A, Camm AJ, Olsson SB, Andresen D, Davies DW, et al. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart

Survey on Atrial Fibrillation. Eur Heart J. 2005;26:2422-2434.

4. Cameron A, Schwartz MJ, Kronmal RA, Kosinski AS. Prevalence and significance of atrial fibrillation in coronary artery disease (CASS Registry). Am J Cardiol. 1988;61:714-717. 5. Crenshaw BS, Ward SR, Granger CB, StebbinsMANUSCRIPT AL, Topol EJ, Califf RM. Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. Global

Utilization of Streptokinase and TPA for Occluded Coronary Arteries. J Am Coll Cardiol.

1997;30:406-413.

6. Liberthson RR, Salisbury KW, Hutter AM, Jr., DeSanctis RW. Atrial tachyarrhythmias in acute myocardial infarction. Am J Med. 1976;60:956-960.

7. Foussas S. Acute coronary syndromes and atrial fibrillation. Hellenic J Cardiol. 2016;57:141-142.ACCEPTED 8. Goette A, Bukowska A, Dobrev D, Pfeiffenberger J, Morawietz H, Strugala D, et al.

Acute atrial tachyarrhythmia induces angiotensin II type 1 receptor-mediated oxidative stress and microvascular flow abnormalities in the ventricles. Eur Heart J. 2009;30:1411-1420.

9. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of 13 ACCEPTED MANUSCRIPT the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33:2719-2747.

10. James TN. Anatomy of the coronary arteries in health and disease. Circulation.

1965;32:1020-1033.

11. Dodge HT, Sandler H, Ballew DW, Lord JD, Jr. The use of biplane angiocardigraphy for the measurement of left ventricular volume in man. Am Heart J. 1960;60:762-776.

12. Judkins MP. Percutaneous transfemoral selective coronary arteriography. Radiol Clin

North Am. 1968;6:467-492.

13. Ringqvist I, Fisher LD, Mock M, Davis KB, Wedel H, Chaitman BR, et al. Prognostic value of angiographic indices of coronary artery disease from the Coronary Artery Surgery

Study (CASS). J Clin Invest. 1983;71:1854-1866.

14. Suero JA, Marso SP, Jones PG, Laster SB, Huber KC, Giorgi LV, et al. Procedural outcomes and long-term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native MANUSCRIPT coronary arteries: a 20-year experience. J Am Coll Cardiol. 2001;38:409-414.

15. Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, Borger MA, et al. ESC

Guidelines for the management of acute myocardial infarction in patients presenting with ST- segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012.

16. Kolvekar S, D'Souza A, Akhtar P, Reek C, Garratt C, Spyt T. Role of atrial ischaemia in developmentACCEPTED of atrial fibrillation following coronary artery bypass surgery. Eur J Cardiothorac Surg. 1997;11:70-75.

17. Sinno H, Derakhchan K, Libersan D, Merhi Y, Leung TK, Nattel S. Atrial ischemia promotes atrial fibrillation in dogs. Circulation. 2003;107:1930-1936. 14 ACCEPTED MANUSCRIPT 18. Pehkonen E, Honkonen E, Makynen P, Kataja M, Tarkka M. Stenosis of the right coronary artery and retrograde predispose patients to atrial fibrillation after coronary artery bypass grafting. Thorac Cardiovasc Surg. 1998;46:115-120.

19. Kralev S, Schneider K, Lang S, Suselbeck T, Borggrefe M. Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography. PLoS One. 2011;6:e24964.

20. Davies MJ, Pomerance A. Pathology of atrial fibrillation in man. Br Heart J.

1972;34:520-525.

21. Mehta RH, Dabbous OH, Granger CB, Kuznetsova P, Kline-Rogers EM, Anderson

FA, Jr., et al. Comparison of outcomes of patients with acute coronary syndromes with and without atrial fibrillation. Am J Cardiol. 2003;92:1031-1036.

22. Pizzetti F, Turazza FM, Franzosi MG, Barlera S, Ledda A, Maggioni AP, et al.

Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data. Heart. 2001;86:527-532. MANUSCRIPT 23. Kinjo K, Sato H, Sato H, Ohnishi Y, Hishida E, Nakatani D, et al. Prognostic significance of atrial fibrillation/atrial flutter in patients with acute myocardial infarction treated with percutaneous coronary intervention. Am J Cardiol. 2003;92:1150-1154.

24. Eldar M, Canetti M, Rotstein Z, Boyko V, Gottlieb S, Kaplinsky E, et al. Significance of paroxysmal atrial fibrillation complicating acute myocardial infarction in the thrombolytic era. SPRINT and Thrombolytic Survey Groups. Circulation. 1998;97:965-970. 25. Wong CK,ACCEPTED White HD, Wilcox RG, Criger DA, Califf RM, Topol EJ, et al. New atrial fibrillation after acute myocardial infarction independently predicts death: the GUSTO-III experience. Am Heart J. 2000;140:878-885.

26. Sakata K, Kurihara H, Iwamori K, Maki A, Yoshino H, Yanagisawa A, et al. Clinical and prognostic significance of atrial fibrillation in acute myocardial infarction. Am J Cardiol.

1997;80:1522-1527. 15 ACCEPTED MANUSCRIPT 27. Nucifora G, Schuijf JD, Tops LF, van Werkhoven JM, Kajander S, Jukema JW, et al.

Prevalence of coronary artery disease assessed by multislice computed tomography coronary angiography in patients with paroxysmal or persistent atrial fibrillation. Circ Cardiovasc

Imaging. 2009;2:100-106.

28. Lokshyn S, Mewis C, Kuhlkamp V. Atrial fibrillation in coronary artery disease. Int J

Cardiol. 2000;72:133-136.

29. Hammermeister KE, DeRouen TA, Dodge HT. Variables predictive of survival in patients with coronary disease. Selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations. Circulation. 1979;59:421-430.

30. Nelson GR, Cohn PF, Gorlin R. Prognosis in medically-treated coronary artery disease: influence of ejection fraction compared to other parameters. Circulation.

1975;52:408-412. 31. Moraski RE, Russell RO, Jr., Smith MK, MANUSCRIPT Rackley CE. Left ventricular function in patients with and without myocardial infarction and one, two or three vessel coronary artery disease. Am J Cardiol. 1975;35:1-10.

32. Gahl K, Sutton R, Pearson M, Caspari P, Lairet A, McDonald L. Mitral regurgitation in coronary heart disease. Br Heart J. 1977;39:13-18.

33. Tonino PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, et al.

Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow ACCEPTED reserve versus angiography in multivessel evaluation. J Am Coll Cardiol. 2010;55:2816-2821.

34. Mosseri M, Yarom R, Gotsman MS, Hasin Y. Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries.

Circulation. 1986;74:964-972. 16 ACCEPTED MANUSCRIPT 35. Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol. 1998;31:126-133.

36. Heeringa J, van der Kuip DA, Hofman A, Kors JA, van Rooij FJ, Lip GY, et al.

Subclinical atherosclerosis and risk of atrial fibrillation: the rotterdam study. Arch Intern

Med. 2007;167:382-387.

MANUSCRIPT

ACCEPTED 17 ACCEPTED MANUSCRIPT Table 1. Patients‘ Characteristics

CAD-AF CAD-SR

(n = 796) (n = 785) % or Mean ±±± % or Mean ±±± Characteristic n n SEM SEM Age 796 70.2 ± 0.3 785 63.8 ± 0.4 * Male 578 72.6% 607 77.3% Female 218 27.4% 178 22.7% Atrial fibrillation Type of atrial fibrillation First diagnosed AF 167 21.0% Paroxysmal AF 406 51.0% Persistent or permanent AF 223 28.0% NYHA classification NYHA I 509 63.9% 621 79.1% § NYHA II 143 18.0% 135 17.2% § NYHA III 128 16.1% 27 3.4% § NYHA IV 16 2.0% 2 0.3% § Cardiac function LVEF 648 61.6 ± 0.7 575 67.4 ± 0.6 * Patients history Myocardial infarction 248 31.2% 245 31.2% Arterial hypertension 549 69.0% 568 72.4% Diabetes mellitus 218 27.4% 196 25.0% Hyperlipoproteinemia 388 MANUSCRIPT 48.7% 479 61.0% # History of coronary PTCA 205 25.8% 208 26.5% History of coronary stenting 133 16.7% 148 18.9% Mitral valve disease 111 13.9% 17 2.2% # Mitral valve regurgitation 86 10.8% 17 2.2% # Mitral valve stenosis 6 0.7% 0 0.0% # Combined mitral valve disease 11 1.4% 0 0.0% # History of mitral valve intervention 11 1.4% 0 0.0% # Other valvular disease 172 21.6% 56 7.1% # Pulmonary disease 93 11.7% 73 9.3% Chronic heart failure 164 20.6% 63 8.0% # Systolic heart failure 134 16.8% 58 7.4% # Diastolic heart failure 29 3.6% 8 1.0% # Dilatative cardiomyopathy 17 2.1% 4 0.5% # Ischemic cardiomyopathy 152 19.1% 109 13.9% # Hypertrophic cardiomyopathyACCEPTED 5 0.6% 3 0.4% Previous heart surgery 214 26.9% 111 14.1% # Pulmonary embolism 13 1.6% 9 1.1% Myocarditis 2 0.3% 1 0.1% Hyperthyroidism 53 6.7% 20 2.5% # Medication Cardioselective calciumantagonist 25 3.1% 3 0.4% # Non-cardioselective calciumantagonist 115 14.4% 94 12.0% Betablocker 688 86.4% 698 88.9% Digitalis 304 38.2% 19 2.4% # 18 ACCEPTED MANUSCRIPT Amiodarone 82 10.3% 9 1.1% # Sotalol 10 1.3% 0 0.0% # Class-I antiarrhythmics 2 0.3% 0 0.0% Diuretics 569 71.5% 469 59.7% # Aldosteron-antagonists 164 20.6% 56 7.1% # ACE-inhibitor / AT-1 antagonist 618 77.6% 572 72.9% Statins 544 68.3% 654 33.3% #

ACE = angiotensin converting enzyme; AT = angiotensin; PTCA = percutaneous transluminal

coronary angioplasty; LVEF = left ventricular ejection fraction obtained by cardiac

ventriculography. * p < 0.05 vs. CAD-AF student t-test; # p < 0.05 vs. CAD-AF chi-square

test; § p < 0.05 vs. CAD-AF Mann-Whitney-U-Test.

MANUSCRIPT

ACCEPTED 19 ACCEPTED MANUSCRIPT Table 2. Comparison of coronary angiography results in SR and AF

CAD-AF CAD-SR Coronary angiography n % n % Newly diagnosed CAD 356 44.7% 388 49.4% 1-vessel coronary artery disease 218 27.4% 239 30.4% (p=0.06 §) 2-vessel coronary artery disease 201 25.2% 209 26.6% (p=0.06 §) 3-vessel coronary artery disease 377 47.3% 337 42.9% (p=0.06 §) LCA Stenosis 81 10.2% 57 7.3% LAD Stenosis 416 52.3% 441 56.2% proximal LAD 252 31.7% 283 36.1% middle LAD 140 17.6% 137 17.5% distal LAD 24 3.0% 21 2.7% Chronic total occlusion 117 14.7% 116 14.8% proximal LAD 64 8.0% 59 7.5% middle LAD 37 4.6% 50 6.4% distal LAD 16 2.0% 7 0.9% RD-1 Stenosis 143 18.0% 152 19.4% Chronic total occlusion 12 1.5% 7 0.9% RD-2 Stenosis 8 1.0% 8 1.0% Chronic total occlusion 0 0.0% 0 0.0% RIMA Stenosis 44MANUSCRIPT 5.5% 29 3.7% Chronic total occlusion 5 0.6% 6 0.8% RCX Stenosis 294 36.9% 283 36.1% proximal RCX 196 24.6% 180 22.9% middle RCX 73 9.2% 88 11.2% distal RCX 25 3.1% 15 1.9% Chronic total occlusion 80 10.1% 54 6.9% proximal RCX 59 7.4% 37 4.7% middle RCX 11 1.4% 13 1.7% distal RCX 8 1.0% 4 0.5% OB Marg-1 Stenosis 20 2.5% 35 4.5% Chronic total occlusion 14 1.8% 8 1.0% OB Marg-2 Stenosis ACCEPTED79 9.9% 60 7.6% Chronic total occlusion 8 1.0% 9 1.1% RCA Stenosis 359 45.1% 344 43.8% proximal RCA 221 27.8% 226 28.8% middle RCA 92 11.6% 81 10.3% distal RCA 46 5.8% 37 4.7% Chronic total occlusion 123 15.5% 126 16.1% proximal RCA 97 12.2% 93 11.8% middle RCA 19 2.4% 23 2.9% 20 ACCEPTED MANUSCRIPT distal RCA 7 0.9% 10 1.3% RPLS Stenosis 13 1.6% 16 2.0% Chronic total occlusion 5 0.6% 3 0.4% RPDA Stenosis 23 2.9% 26 3.3% Chronic total occlusion 2 0.3% 2 0.3%

LCA = left coronary artery; RCA = right coronary artery; LAD = left anterior descending;

RCX = circumflex coronary artery; RPLS = right posterolateral segment; RPDA = artery of

the posterior interventricular groove; RIMA = Ramus intermedius; RD-1 = first diagonal

branch; RD-2 = second diagonal branch; OB Marg-1 = first obtuse marginal; OB Marg-2 =

second obtuse marginal. § vs. CAD-AF Mann-Whitney-U-Test.

MANUSCRIPT

ACCEPTED 21 ACCEPTED MANUSCRIPT Table 3. AF in patients with acute myocardial infarction

MI-AF MI-SR Myocardial infarction n % or Mean ±±± n % or Mean ±±± SEM SEM Age 99 70.7 ± 0.9 148 60.2 ± 1.0 * Male 70 70.7% 119 80.4% Female 29 29.3% 29 19.6% STEMI 49 49.5% 80 54.1% NSTEMI 50 50.5% 68 45.9% Cardiac function n Mean ± SEM n Mean ± SEM LVEF 43 55.6 ± 1.0 47 59.9 ± 2.2 Coronary angiography n % n % 1-vessel coronary artery disease 23 23.3% 58 39.2% § 2-vessel coronary artery disease 35 35.4% 39 26.4% § 3-vessel coronary artery disease 41 41.4% 51 34.5% § LCA Stenosis 8 8.1% 5 3.4% LAD Stenosis 65 65.7% 92 62.2% proximal LAD 43 MANUSCRIPT43.4% 58 39.2% middle LAD 20 20.2% 32 21.3% distal LAD 2 2.0% 2 1.4% RCX Stenosis 42 42.4% 62 41.9% proximal RCX 26 26.3% 35 23.6% middle RCX 15 15.2% 26 17.6% distal RCX 1 1.0% 1 0.7% RCA Stenosis 55 55.6% 71 48.0% proximal RCA 38 38.4% 51 34.5% middle RCAACCEPTED 12 12.1% 17 11.5% distal RCA 5 5.1% 3 2.0%

LCA = left coronary artery; RCA = right coronary artery; LAD = left anterior descending;

RCX = circumflex coronary artery; LVEF = left ventricular ejection fraction obtained by 22 ACCEPTED MANUSCRIPT cardiac ventriculography. * p < 0.05 vs. MI-AF student t-test, § p < 0.05 vs. MI-AF Mann-

Whitney-U-Test.

MANUSCRIPT

ACCEPTED 23 ACCEPTED MANUSCRIPT Figure legends

Figure 1. Flow diagram of patients’ screening protocol.

The flow diagram presents the total number of patient records screened and how the final numbers of patients who were studied were obtained

Figure 2. Degree of stenoses in AF compared to SR. Comparison of the percentage degree of stenoses of coronary arteries in CAD-AF and CAD-SR. A) Branches of LCA and LAD. B)

Branches of RCX. C) Branches of RCA. LCA = left coronary artery, RCA = right coronary artery, LAD = left anterior descending, RCX = circumflex coronary artery, RPLS = right posterolateral segment, RPDA = artery of the posterior interventricular groove, RIMA =

Ramus intermedius, RD-1 = first diagonal branch, RD-2 = second diagonal branch, OB Marg-

1 = first obtuse marginal, OB Marg-2 = second obtuse marginal. * p < 0.05 vs. CAD-AF student t-test. MANUSCRIPT

ACCEPTED ACCEPTED MANUSCRIPT

MANUSCRIPT

ACCEPTED ACCEPTED MANUSCRIPT

MANUSCRIPT

ACCEPTED