EDITORIAL COMMENTARY

Atrial supply–demand mismatch in atrial fibrillation: The missing link between rapid rate and atrial remodeling? Rohan Wijesurendra, MB, BChir, Barbara Casadei, MD, DPhil From the Division of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. Atrial fibrillation (AF) is the most common clinical arrhythmia and an increasing public health burden because of its unrelenting increase in prevalence worldwide.1 The pathophysiology of AF is only partially understood,2 and the need for interventions that impact on the natural history of the disease (eg, progression from paroxysmal to persistent AF) and improve patient outcome is pressing.3 To this end, the relationship between AF and vascular dysfunction, affecting both the coronary circulation4 and systemic macrovascular and endothelial function,5 is particularly intriguing. Reduced vasodilatory reserve has been previously reported in the dog right atrium during AF6; however, regulation of atrial coronary blood flow in sinus rhythm has been relatively underinvestigated, and the precise mechanism by which paroxysmal AF affects atrial perfusion has remained unclear. In this issue of HeartRhythm, van Bragt et al7 shed new light on this aspect of AF pathophysiology. A series of experiments were conducted in anesthetized open-chest adult pigs, using Doppler probes to simultaneously measure flow in the atrial and ventricular branches of the left circumflex coronary artery. Measurements were undertaken in normal sinus rhythm, during rapid right atrial pacing, and before, during, and after AF (which was induced and maintained by continuous rapid burst pacing). Detailed physiologic measurements, including chamber-specific pressures and volumes, were recorded. This allowed accurate calculation of coronary vascular conductance (ie, flow divided by the pressure difference across the coronary bed) and chamberspecific work indices. Intracoronary infusion of acetylcholine was used to reduce atrial contractility and workload. The primary finding is clear evidence of a significant decrease in atrial flow during atrial contraction, such that 98% of atrial coronary flow occurs during atrial diastole (compared with 77% of ventricular coronary flow occurring in ventricular diastole in this model). The possibility that this phenomenon is due to increased atrial pressure (rather than atrial contraction per se) is excluded by examination of traces during 2:1 AV block. Left atrial pressure is much higher when the atrium contracts against a closed rather than open Address reprint requests and correspondence: Dr. Barbara Casadei, Division of Cardiovascular Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom. E-mail address: [email protected].

1547-5271/$-see front matter B 2015 Heart Rhythm Society. All rights reserved.

mitral valve, but there is little variation in the reduction in atrial coronary flow during each type of contraction. Atrial pacing shows that, although atrial and ventricular coronary flow both increase with increasing pacing rate, the response of atrial flow to both the onset and cessation of pacing is slower than that of ventricular flow. The increase in left atrial conductance is correlated with left atrial work index, suggesting (at least partial) matching of supply and demand. Finally, the effect of AF on atrial conductance also was examined. Average atrial conductance increases during the first few minutes of AF. After cessation of AF, average left atrial vascular conductance remains transiently elevated above baseline values, reflecting a hyperemic phase not present in the ventricle. These findings are closely related to those of a previous study by the same investigators (with a subset of the animals contributing data to both studies),8 providing evidence that, notwithstanding the lack of coordinated atrial contraction, AF leads to atrial supply–demand ischemia, resulting in increased lactate production despite a compensatory rise in both atrial coronary conduction and oxygen extraction. The present study adds to this work by demonstrating that atrial coronary flow is critically dependent on atrial diastole during regular contraction.7 Although the concept of phasic atrial diastole and systole is lost during AF, local atrial contraction may compress atrial vasculature and limit the magnitude of the compensatory increase in overall atrial coronary conduction. This might lead to a perfusion “debt” that is repaid by the period of hyperemia, evident after cessation of AF. Thus, repeated or prolonged episodes of AF could lead to a situation of chronic atrial ischemia, which may explain previous reports of impaired atrial energetic status in experimental (goat)9 and human10 AF. van Bragt et al have elegantly explored determinants of atrial coronary flow in health and disease in anesthetized pigs, but a note of caution should be sounded. Stability of AF is low in the pig,11 and in the present study it could only be maintained by continuous rapid (20-Hz) right atrial pacing; thus, the extent to which these findings would translate to human AF remains to be established. In summary, increasing data support the notion of a supply–demand mismatch during AF. Further studies are http://dx.doi.org/10.1016/j.hrthm.2015.01.036

1002 needed to establish whether such mismatch is a determinant of atrial remodeling in AF and, thus, a novel player in the process leading to self-perpetuation of the arrhythmia (“AF begets AF”).12 Most importantly, coronary flow may prove to be a viable target for therapeutic intervention to moderate the adverse effects of AF13,14 and potentially prevent AFinduced atrial remodeling.

References 1. Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014;129: 837–847. 2. Andrade J, Khairy P, Dobrev D, Nattel S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ Res 2014;114:1453–1468. 3. Kirchhof P, Breithardt G, Aliot E, et al. Personalized management of atrial fibrillation: proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference. Europace 2013;15:1540–1556. 4. Range FT, Schafers M, Acil T, et al. Impaired myocardial perfusion and perfusion reserve associated with increased coronary resistance in persistent idiopathic atrial fibrillation. Eur Heart J 2007;28:2223–2230.

Heart Rhythm, Vol 12, No 5, May 2015 5. Skalidis EI, Zacharis EA, Tsetis DK, et al. Endothelial cell function during atrial fibrillation and after restoration of sinus rhythm. Am J Cardiol 2007;99: 1258–1262. 6. White CW, Holida MD, Marcus ML. Effects of acute atrial fibrillation on the vasodilator reserve of the canine atrium. Cardiovasc Res 1986;20:683–689. 7. van Bragt KA, Nasrallah HM, Kuiper M, et al. Dynamic regulation of atrial coronary blood flow in healthy adult pigs. Heart Rhythm 2015;12:991–1000. 8. van Bragt KA, Nasrallah HM, Kuiper M, Luiken JJ, Schotten U, Verheule S. Atrial supply-demand balance in healthy adult pigs: coronary blood flow, oxygen extraction, and lactate production during acute atrial fibrillation. Cardiovasc Res 2014;101:9–19. 9. Ausma J, Coumans WA, Duimel H, Van der Vusse GJ, Allessie MA, Borgers M. Atrial high energy phosphate content and mitochondrial enzyme activity during chronic atrial fibrillation. Cardiovasc Res 2000;47:788–796. 10. Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidative injury during human atrial fibrillation. Circulation 2001;104:174–180. 11. Dosdall DJ, Ranjan R, Higuchi K, et al. Chronic atrial fibrillation causes left ventricular dysfunction in dogs but not goats: experience with dogs, goats, and pigs. Am J Physiol Heart Circ Physiol 2013;305:H725–H731. 12. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995;92:1954–1968. 13. Prystowsky EN, Fry ET. Atrial fibrillation and incident myocardial infarction. JAMA 2014;312:1049–1050. 14. Dukes JW, Marcus GM. Atrial fibrillation begets myocardial infarction. JAMA Intern Med 2014;174:5–7.

Atrial supply-demand mismatch in atrial fibrillation: The missing link between rapid rate and atrial remodeling?

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