Medical Hypotheses 84 (2015) 40–43
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Transition from sinus rhythm to atrial fibrillation – A mechanism inducing or delaying pulmonary congestion and edema Guy Dori ⇑ Department of Internal Medicine E, HaEmek Medical Center, Afula, Israel
a r t i c l e
i n f o
Article history: Received 7 July 2014 Accepted 12 November 2014
a b s t r a c t Cardiogenic pulmonary edema (PEd) is a life-threatening condition where fluid accumulates in the lungs due to increasing hydrostatic pressure building up in the pulmonary vasculature (PV): veins, venules and capillaries. Atrial fibrillation (AF) is accepted as an arrhythmia which triggers and promotes the pathophysiological processes leading to pulmonary congestion and its final expression: PEd. We propose a different view, where AF is actually a physiological solution temporarily protecting from PEd. We hypothesize that the compliance of the left atrium (LA) increases with the onset of AF. Thus, it is possible that even if the volume of blood within the LA increases due to loss of atrial contraction, the pressure within the LA would still be lower than that prior to AF (because of the increased LA compliance during AF). Decreased LA pressure allows more blood to flow from the PV to the LA, abating the hydrostatic pressure buildup in the PV compartment. The ratio, R, between the LA volume gained from the transition to AF provided by the greater LA compliance, and the volume of blood retained in the LA due to loss of atrial contraction, determines the instant pressure in the LA, as AF begins. If R is >1, then the LA pressure will instantly decrease with the transition to AF and this may be beneficial in delaying PEd. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction This medical hypothesis focuses on the role of the left atrium (LA) when atrial fibrillation (AF) commences. Specifically, it is suggested that the transition from normal sinus rhythm (NSR) to AF may be beneficial in delaying the development of pulmonary congestion and edema. The general idea has recently been elegantly presented in the journal [1] however the present hypothesis differs and complements the idea. Whereas Tilman et al. base their hypothesis on ‘‘considering the heart as a hydrodynamic system’’ [1], we believe that hydrodynamics reflect the physical part of the events. It is the physiology of the system with the ability to change compliance of vascular compartments during AF which account for the suggested hypothesis. The conditions when this Abbreviations: AF, atrial fibrillation; CMR, cardiac magnetic resonance; CO, cardiac output; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; HR, heart rate; LA, left atrium; LA-C, left atrial compliance; LA-P, left atrial pressure; LA-V, left atrial volume; LA-Vmax, maximum LA-V; LA-Vmin, minimum LA-V; LV, left ventricle; LVOT, left ventricular outflow tract; MDCT, multi-detector computed tomography; NSR, normal sinus rhythm; PEd, pulmonary edema; PV, pulmonary vasculature; SV, stroke volume; TTE, trans thoracic echocardiography. ⇑ Address: Internal Medicine E, HaEmek Medical Center, Rabin Blvd, Afula 18101, Israel. Tel.: +972 4 6494241, mobile: +972 50 6265516; fax: +972 4 6495375. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.11.012 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
hypothesis holds and when it fails and the significance of heart rate are portrayed. Background Cardiac compartments The left side of the heart is composed of compartments connected in series. Starting at the systemic circulation (and going against the direction of blood flow), the aorta is connected to the left ventricle (LV) via the aortic valve. The LV is connected to the left atrium (LA) via the mitral valve. (Valves throughout this hypothesis are assumed to be competent and unidirectional.) The LA and the pulmonary vasculature (PV, i.e. pulmonary veins, venules, and capillaries) are distinct compartments connected in series without valves separating them. Consequently, change of pressure in either compartment affects the pressure in the other. Left atrium Since the LA plays a major role in this hypothesis, several fundamental points are emphasized. Evaluating LA area using echocardiography reveals three main phases during the cardiac cycle [2]. (1) LA filling phase, where the LA serves as a reservoir, starts when
G. Dori / Medical Hypotheses 84 (2015) 40–43
mitral valve closes and terminates when it opens. This period of time is equal to the duration of LV contraction (systole). The volume of the LA (LA-V) is lowest at the time mitral valve closes (LA-Vmin), whereas it is greatest just before mitral valve opens again (LA-Vmax). (2) LA emptying phase, where the LA serves as a conduit chamber, starts when mitral valve opens and terminates at a distinct LA-V before the onset of LA contraction. This LA-V is labeled here: LA-V75%, because approximately 75% of the LA stroke volume (SV, the volume transferred from the LA to the LV per beat) is transferred from the LA to the LV during this phase. (3) LA booster pump phase, where the LA muscle contracts and propels blood into the LV. At the end of this phase LA-V equals LA-Vmin. The duration of phases 2 and 3 is equal to the duration of the LV diastole (approximately 2/3 of the duration of the cardiac cycle at normal HR). It is noted that during phases 1 and 2 LA wall tension is determined by the volume of blood distending the LA. During phase 3 LA wall tension is assumed to be greater than it is during the former phases (1 and 2), due to LA muscle contraction. The latter adds to the wall tension already produced by distention of blood in phase 2. We did not find literature supporting this assumption; however, two points logically favor this assumption. Phase 3 always follows phase 2 in time (during NSR), and wall tension at the end of phase 2 serves as the starting point for further development of wall tension due to LA contraction in phase 3. (For further reading see ref. [3] an elegant investigation of the LA-V using cardiac magnetic resonance imaging in healthy young and elderly subjects. Figs. 3 and 4 show LA-V as a function of time). During atrial fibrillation (AF) booster pump phase (phase 3 above) is lost. Consequently, less blood is transferred from the LA to the LV per cardiac cycle, thus more blood is retained in the LA. LA-V varies during AF however the values of LA-Vmin and LA-Vmax are different from those obtained during NSR (see section evidence related to LA-V below). Left atrial compliance Compliance of an elastic component is defined by the change in pressure (DP) required to cause a change in volume (DV), C = DV/DP. When a large change in pressure is required to induce a small change in volume the compliance is low, and vice versa. LA compliance, LA-C, at a certain volume can be appreciated from the local derivative on the LA-V versus LA pressure (LA-P) plot (see Fig. 2 in Ref. [4]). Specifically, LA-C is greatest at low LA-V, and it decreases with the distention of LA walls. We claim, although it is not proven, that the LA-C during phase 3 is lower than that during phase 2. Pathophysiology of pulmonary congestion and edema In pulmonary congestion and edema fluid shifts from the PV (mainly pulmonary capillaries) into the surrounding supporting tissues (interstitium) and pulmonary alveoli, respectively. Two pathological forces account for the fluid shift: (a) increased hydrostatic pressure within the PV or (b) increased permeability of the pulmonary capillaries. This hypothesis relates to the former force only. Increased hydrostatic pressure within the PV is the result of various scenarios overloading the PV compartment with blood. For example, a sudden rise in the systemic blood pressure increases the resistance against which the LV must contract. This imposes a decrease in LV SV and therefore, more blood is retained in the LV at the end of contraction before the next filling. The excess of blood retained increases the LV pressure according to its compliance. Consequently, the LA-P required now for filling the LV must be greater than that required before systemic blood pressure had increased. The increased LA-P reflects backwards to the PV increasing the hydrostatic pressure [5].
41
Atrial fibrillation (AF) has 3 forms: paroxysmal (appears acutely and reverts to NSR spontaneously), persistent (appears acutely and does not revert to NSR spontaneously, but may be converted to NSR by medications or electric shock), and permanent (AF which cannot be converted to NSR) [6]. In this work we refer to the reversible forms only: paroxysmal and persistent. AF is another cause for pressure buildup in the PV. Briefly, as AF initiates atrial contraction is instantly lost, diminishing the LA SV by as much as 20% [7–8]. Consequently, blood accumulates in the LA, increasing LA pressure, and in turn also increases the pressure within the PV. This process promotes fluid shift from the intravascular space to the interstitium first and then to the alveoli, culminating in pulmonary congestion and edema, respectively [9]. Case vintage A 70 years old woman is admitted to the emergency room with progressive dyspnea which developed over the last few days, accompanied by palpitations. She also complains of leg edema and waking up at night with difficulty breathing over the last week. Medical history reveals 25 years for hypertension, 10 years of type II diabetes mellitus, and obesity. Her physical examination revealed: normal vital signs except for blood pressure 170/75, endinspiratory crackles over lung bases, and bilateral leg edema. Blood tests were normal, including troponin level. EKG demonstrated rapid AF, 130 beats per minute, and signs of LV hypertrophy. Her chest X-ray displayed signs of PEd. Patient was treated immediately with oxygen, morphine, and diuretics. After initial improvement heart rate (HR) lowering drugs (rate control), and anti-coagulation therapy was added. Standard trans-thoracic echocardiography (performed 3 days after patient improved and converted spontaneously to NSR) demonstrated: LA enlargement, thickened left ventricular walls with a small LV cavity (concentric hypertrophy), normal LV systolic function (ejection fraction 60%), transmitral flow velocity measurements demonstrated findings consistent with a ‘‘pseudonormalization’’ pattern (diastolic dysfunction grade II) [10]. This clinical case is commonly encountered in internal medicine departments. Hypothesis Before presenting the hypothesis several assumptions are made: (1) LA and PV are compliant compartments containing blood, connected in series with no valves separating them apart. (2) Blood is a non-compressible fluid. (3) As a result of (1) and (2), a change in pressure in the LA compartment will instantly affect the pressure in the PV compartment. (4) Mitral valve remains competent during the transition from NSR to AF. The following scenario may also explain the clinical case. Systemic blood pressure rises (for various common causes such as fluid, salt or medication indiscretion) forcing the LV to contract against a greater resistance at its outflow tract (LVOT). As the resistance increases less blood can be propelled from the LV to the circulation. (Consider the extreme case, where the LVOT is severely compromised, as in severe aortic stenosis. Then, the SV decreases significantly, clinically expressed by a weak palpated pulse, and events of fainting [11]). As SV diminishes, more blood per cardiac cycle accumulates in the compartments upstream to the LVOT that is in the LV, LA, and PV. As blood accumulates, it exerts pressure on the walls of the latter compartments, distending them. The walls of the LA are assumed here to be the ‘‘weakest part in the chain’’ because they are the thinnest. Data show that the risk for AF increases with LA-V [12]. Thus, at a certain point of LA distention AF initiates. In addition, the pressures within the LA, and PV compartments rise. This increase in hydrostatic pressure within the PV
42
G. Dori / Medical Hypotheses 84 (2015) 40–43
circulation promotes fluid shift from the intravascular space to the interstitium leading to pulmonary congestion and PEd. However, there is another component to this scenario which deserves attention and is the basis for the hypothesis. A fibrillating LA has a greater volume per cardiac cycle compared with a contracting LA [13]. On average, over a cardiac cycle, a fibrillating LA can accommodate more blood then a contracting LA, at similar LA pressures. Consider two distinct time intervals in the LA cycle. The first is the time when the LA contracts (phase 3 above), label this time tC. The second is the time of the rest of the cardiac cycle, label it tR (where tR + tC equals the duration of the cardiac cycle in seconds). The LA wall tension during tC is greater than that during tR because the LA muscle is contracted during tC, whereas during tR the LA is relaxed and distended passively by the blood flowing into the LA (see section left atrium above). Compliance can be considered roughly as the reciprocal of wall tension. When wall tension is high compliance is low and vice versa. In terms of compliance, during NSR the LA-C is a combination of LA-C during tR and tC. On the other hand, during AF, the component of LA-C affected by LA contraction is lost, and therefore depends only on LA-C during tR (although it is clear LA-V during NSR differs from that during AF). At any LA-V the LA-P is lower during AF than it is during NSR. This allows more blood to flow from the PV to the LA. If more blood leaves the PV compartment the hydrostatic pressure within it decreases, delaying the process that shifts blood to the interstitium causing pulmonary congestion and PEd. If during AF LA-P at any given LA-V remains the same as during NSR or even increases, the hypothesis described above fails. It is further suggested that the change in LA-P, as AF initiates, depends on two volumes: (A) the potential ‘‘LA-V gained’’ by the change in LA-C as AF begins, where ‘‘LA-V gained’’ is the difference between the LA-V during AF (at a given LA-P and LA-C) minus LA-V during NSR (at the same LA-P, but a lower LA-C). (B) The ‘‘LA SV lost’’ as AF begins [7,8]. Intuitively, if the LA can potentially accommodate a larger blood volume during AF than the volume of SV lost due to AF, than the LA-P will decrease on the transition to AF. Define the ratio between ‘‘LA-V gained’’ and ‘‘LA SV lost’’ as R, then if R > 1 on the transition to AF, then the hypothesis holds. It is also suggested that the palpitations accompanying the onset of AF serve as an alarm signal for the patient, stating clinically that ‘‘something is wrong’’. Palpitations during AF are sensed by approximately 25% of patients [14]. Since this percentage is relatively low, it is not a ‘‘trustworthy’’ mechanism to rely on. Left atrial volume during NSR and AF LA volume is normally evaluated when the LA is maximally full or distended, immediately before the mitral valve opens [15]. The range for normal LA-V is wide 22–52 and 18–58 ml, for healthy women and men, respectively. Normalized to body surface area LA-V is 22 ± 6 ml/m2 regardless of gender [15]. Bank et al. used cardiac magnetic resonance (CMR) to demonstrate that the LA-V was 81 ± 24 ml just before mitral valve opened, and it was 38 ± 15 ml when the LA was maximally contracted (that is in NSR) [13]. When the LA-V is normalized to body surface area (dividing by 1.7 m2) the maximal LA-V is approximately 47 ml/m2. These results are greater than those reported by Lang et al. Therkelsen et al. determined the LA-V in 19 normal subjects, 58 patients with persistent and 19 patients with permanent AF using MRI. The maximal mean atrial volumes were similar in the two groups with AF [77.4–82.1 ml/m2] and the latter differed significantly from that in healthy volunteers (62.3 ml/m2) [16]. These results are also greater than those reported by Lang et al. Agner et al. determined how measurements of LA-V obtained by transthoracic echocardiography (TTE), CMR, and 320-slice multi-detector computed tomography (MDCT) correlated in patients with
permanent AF. In 34 patients they showed that maximal LA-V was 80 ml/m2 by 320-slice MDCT, 73 ml/m2 by CMR, and 60 ml/m2 by TTE [17]. In a recent study, Zakeri et al. investigated the temporal relationship between AF and heart failure and preserved ejection fraction (HFPEF). They showed that mean LA-V indexed to body surface area was: 40.7 ± 12.4 ml/m2 in HFPEF patients with NSR, 47.0 ± 13.5 ml/m2 in HFPEF patients with concurrent AF (which initiated ±3 months relative to the diagnosis of HFEPF), and 54.7 ± 22.5 ml/m2 in HFPEF patients with prior AF (i.e. AF that was present >3 months prior to diagnosing HFPEF). This study shows that LA-V increases with the duration of AF in HFPEF patients [18]. The data above show that LA-V varies with the method of measurement and between studies, however, it is clear that LA-V during AF is greater than that during NSR. This fact alone is insufficient for substantiating the hypothesis. The important variable which determines whether pressure build up in the PV abates as AF commences is the instant LA-P which is determined by the instant LA-C during AF. Discussion The hypothesis presented suggests that AF, apart from being an arrhythmia and an independent potential cause for PEd [19], also has a ‘‘physiological role’’ in delaying the development of PEd [1]. A fundamental basis of the hypothesis is based on an assumption that LA-C increases during AF relative to the LA-C during NSR. Work considering this issue was sought but not found. Indirect, weak evidence supporting the hypothesis – ‘‘AF is not all bad’’ The following examples show that AF was not associated with increased risk (compared with NSR) suggesting that the transition to AF from NSR was ‘‘not bad’’ and perhaps is a physiological solution under certain conditions. In a very general sense, several seminal studies showed that a clinical approach of controlling HR in AF is not inferior to converting patients with AF to NSR. Clinical outcomes were similar when the so called rate control approach was compared with rhythm control [20]. Later, it was shown that lenient HR control was not inferior to a stringent approach [14]. From these studies it is possible to infer that AF is not a toxic condition calling for an immediate intervention. Rienstra et al. performed a post hoc analysis of patients with heart failure and reduced ejection fraction (HFREF, EF < 35%) and AF. These researchers showed that mortality was higher in the cohort of patients with lower HR during AF. One of their possible explanations for the unexpected outcome was that increased HR in AF provides a compensatory mechanism for preserving CO [21]. Anter et al. reviewed the relation between HFREF and AF, as both diseases are very common and related by at least mutual risk factors as hypertension, and diabetes. They concluded that ‘‘the prognostic significance of AF in patients with heart failure remains controversial because no consensus exists that AF is an independent risk factor of adverse outcome’’ [22]. Lechat et al. analyzed the effects of baseline HR, HR change after 2 months of bisoprolol treatment and nature of cardiac rhythm: NSR versus AF, on mortality and rehospitalization for HF. They showed that a low baseline HR and a significant HR change (decrease) at 2 months were associated with a better survival and lower rehospitalization rate. However, bisoprolol reduced mortality in HFREF patients in NSR where it did not in AF. These results may suggest that lower (versus higher) HR entails a better prognosis, regardless of whether the rhythm is NSR or AF [23]. Van Veldhuisen et al. analyzing HFREF patients in NSR or AF, receiving metoprolol versus placebo (in the MERIT-HF study), showed that the drug had no effect on mortality reducing all-cause
G. Dori / Medical Hypotheses 84 (2015) 40–43
or HF associated hospitalizations in the AF cohort [24]. Bohm et al. investigated the relationship between HR and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial. They showed that higher HR was associated with a significantly higher risk of all outcomes studied for patients in sinus rhythm, however no relationship between heart rate and outcomes was observed for patients in AF [25]. These studies do not prove a physiological mechanism, however they show that the attempt to restore NSR is not always beneficial. In our view this may suggest that AF could be a solution rather than a problem. Limitations It was assumed that HR remained approximately the same on the transition to AF, yet this is often not the case and HR may increase significantly on the transition to AF. Increased HR to the level where cardiac output increases as well, decompresses the LA by increasing the rate of pumping blood out of the LA. This mechanism also serves to delay the development of PEd and competes with the mechanism described in the hypothesis. The limitation of this mechanism lies in the fact that when HR increases right ventricular output to the pulmonary circulation increases as well. Whether increased HR is beneficial depends on the capacitance characteristics of the arterial part of the pulmonary vessels. It is stressed that the proposed mechanism is beneficial in delaying the development of PEd not preventing it. If the cause for increased hydrostatic pressure within the PV, be it increased systemic blood pressure or transient myocardial ischemia, or a spontaneous arrhythmia, is not treated, then pressure will continue building up, shifting fluid into the interstitium and alveoli, culminating in PEd. This hypothesis ignored an important issue – the time history of LA distention. It is reasonable to think that acute increase of afterload (as described in the case vintage) causing LA to distend within minutes or hours or even days would differ from mitral stenosis which evolves over years. The biological response (genetic, humoral, histological, etc.) to these triggers is expected to be different. Implications If this hypothesis were true there are some points that we as clinicians should consider especially in the settings where LA-V is increased acutely: (a) Converting AF to NSR during the acute setting in the emergency room may be hazardous. The preferred treatment should be to decrease afterload (blood pressure lowering agents administered intravenously), decrease preload as well (e.g. morphine) and remove excess of fluid from blood vessels by induction of urination (e.g. furosemide). (b) After treatment described in (a) has been administered, it may be expected that AF would revert spontaneously to NSR. Conflict of interest There is no conflict of interest. References [1] Tilman V. Atrial fibrillation and heart failure: is atrial fibrillation a disease?. Med Hypotheses 2014;83:299–301. http://dx.doi.org/10.1016/j.mehy.2014.05.024.
43
[2] Spencer KT, Mor-Avi V, Gorcsan III J, et al. Effects of aging on left atrium reservoir, conduit, and booster pump function: a multi-institutional acoustic quantification study. Heart 2001;85:272–7. [3] Ahtarovski KA, Iversen KK, Lønborg JT, Madsen PL, Engstrøm T, Vejlstrup N. Left atrial and ventricular function during dobutamine and glycopyrrolate stress in healthy young and elderly as evaluated by cardiac magnetic resonance. Am J Physiol Heart Circ Physiol 2012;303:H1469–73. [4] Rosca M, Lancellotti P, Popescu BA, Pierard LA. Left atrial function: pathophysiology, echocardiographic assessment, and clinical applications. Heart 2011;97:1982–9. [5] Schwammenthal E, Vered Z, Agranat O, Kaplinsky E, Rabinowitz B, Feinberg MS. Impact of atrioventricular compliance on pulmonary artery pressure in mitral stenosis: an exercise echocardiographic study. Circulation 2000;102:2378–84. [6] Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213–20. [7] Phan TT, Abozguia K, Shivu GN, et al. Increased atrial contribution to left ventricular filling compensates for impaired early filling during exercise in heart failure with preserved ejection fraction. J Card Fail 2009;15:890–7. [8] Alhogbani T, Strohm O, Friedrich MG. Evaluation of left atrial contraction contribution to left ventricular filling using cardiovascular magnetic resonance. J Magn Reson Imaging 2013;37:860–4. [9] Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation 2011;124:2264–74. [10] Nishimura RA, Tajik JA. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. [11] Fang JC, O’Gara PT. The history and physical examination: an evidence-based approach. In: Libby P, Bonow RO, Mann DL, Zipes DP, Braunwald E, editors. Braunwald’s heart disease: a textbook of cardiovascular medicine. Philadelphia: Saunders Elsevier; 2008. p. 133. [12] Zhuang J, Wang Y, Tang K, et al. Association between left atrial size and atrial fibrillation recurrence after single circumferential pulmonary vein isolation: a systematic review and meta-analysis of observational studies. Europace 2012;14:638–45. [13] Bank A, Wickstrom K, Handran C, Burkhoff D, Lesser JR, Schwartz RS. Modeling left atrial volume, shape and contraction patterns in normal subjects by cardiac magnetic resonance imaging. Int J Cardiol 2013;168:3348–50. [14] Van Gelder IC, Groenveld HF, Crijns HJGM, RACE II Investigators, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–73. [15] Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [16] Therkelsen SK, Groenning BA, Svendsen JH, Jensen GB. Atrial and ventricular volume and function in persistent atrial fibrillation, a magnetic resonance imaging study. J Cardiovasc Magn Reson 2005;7:465–73. [17] Agner BFR, Kuhl JT, Linde JJ, et al. Assessment of left atrial volume and function in patients with permanent atrial fibrillation: comparison of cardiac magnetic resonance imaging, 320-slice multi-detector computed tomography, and transthoracic echocardiography. Eur Heart J Cardiovasc Imaging 2014;15:532–40. [18] Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction. A community-based study. Circulation 2013;128:1085–93. [19] Teerlink JR. Diagnosis and management of acute heart failure. In: Libby P, Bonow RO, Mann DL, Zipes DP, Braunwald E, editors. Braunwald’s heart disease: a textbook of cardiovascular medicine. Philadelphia: Saunders Elsevier; 2008. p. 591. [20] Van Gelder IC, Hagens VE, Bosker HA, Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–40. [21] Rienstra M, Van Gelder IC, Van den Berg MP, Boomsma F, Hillege HL, Van Veldhuisen DJ. A comparison of low versus high heart rate in patients with atrial fibrillation and advanced chronic heart failure: effects on clinical profile, neurohormones and survival. Int J Cardiol 2006;109:95–100. [22] Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation 2009;119:2516–25. [23] Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation 2001;103:1428–33. [24] van Veldhuisen DJ, Aass H, El Allaf D, MERIT-HF Study Group, et al. Presence and development of atrial fibrillation in chronic heart failure: experiences from the MERIT-HF Study. Eur J Heart Fail 2006;8:539–46. [25] Bohm M, Perez AC, Jhund PS, I-Preserve Committees and Investigators, et al. Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve). Eur J Heart Fail 2014. http://dx.doi.org/10.1002/ejhf.85.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Transition from sinus rhythm to atrial fibrillation – A mechanism inducing or delaying pulmonary congestion and edema Guy Dori ⇑ Department of Internal Medicine E, HaEmek Medical Center, Afula, Israel
a r t i c l e
i n f o
Article history: Received 7 July 2014 Accepted 12 November 2014
a b s t r a c t Cardiogenic pulmonary edema (PEd) is a life-threatening condition where fluid accumulates in the lungs due to increasing hydrostatic pressure building up in the pulmonary vasculature (PV): veins, venules and capillaries. Atrial fibrillation (AF) is accepted as an arrhythmia which triggers and promotes the pathophysiological processes leading to pulmonary congestion and its final expression: PEd. We propose a different view, where AF is actually a physiological solution temporarily protecting from PEd. We hypothesize that the compliance of the left atrium (LA) increases with the onset of AF. Thus, it is possible that even if the volume of blood within the LA increases due to loss of atrial contraction, the pressure within the LA would still be lower than that prior to AF (because of the increased LA compliance during AF). Decreased LA pressure allows more blood to flow from the PV to the LA, abating the hydrostatic pressure buildup in the PV compartment. The ratio, R, between the LA volume gained from the transition to AF provided by the greater LA compliance, and the volume of blood retained in the LA due to loss of atrial contraction, determines the instant pressure in the LA, as AF begins. If R is >1, then the LA pressure will instantly decrease with the transition to AF and this may be beneficial in delaying PEd. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction This medical hypothesis focuses on the role of the left atrium (LA) when atrial fibrillation (AF) commences. Specifically, it is suggested that the transition from normal sinus rhythm (NSR) to AF may be beneficial in delaying the development of pulmonary congestion and edema. The general idea has recently been elegantly presented in the journal [1] however the present hypothesis differs and complements the idea. Whereas Tilman et al. base their hypothesis on ‘‘considering the heart as a hydrodynamic system’’ [1], we believe that hydrodynamics reflect the physical part of the events. It is the physiology of the system with the ability to change compliance of vascular compartments during AF which account for the suggested hypothesis. The conditions when this Abbreviations: AF, atrial fibrillation; CMR, cardiac magnetic resonance; CO, cardiac output; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; HR, heart rate; LA, left atrium; LA-C, left atrial compliance; LA-P, left atrial pressure; LA-V, left atrial volume; LA-Vmax, maximum LA-V; LA-Vmin, minimum LA-V; LV, left ventricle; LVOT, left ventricular outflow tract; MDCT, multi-detector computed tomography; NSR, normal sinus rhythm; PEd, pulmonary edema; PV, pulmonary vasculature; SV, stroke volume; TTE, trans thoracic echocardiography. ⇑ Address: Internal Medicine E, HaEmek Medical Center, Rabin Blvd, Afula 18101, Israel. Tel.: +972 4 6494241, mobile: +972 50 6265516; fax: +972 4 6495375. E-mail address: [email protected] http://dx.doi.org/10.1016/j.mehy.2014.11.012 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
hypothesis holds and when it fails and the significance of heart rate are portrayed. Background Cardiac compartments The left side of the heart is composed of compartments connected in series. Starting at the systemic circulation (and going against the direction of blood flow), the aorta is connected to the left ventricle (LV) via the aortic valve. The LV is connected to the left atrium (LA) via the mitral valve. (Valves throughout this hypothesis are assumed to be competent and unidirectional.) The LA and the pulmonary vasculature (PV, i.e. pulmonary veins, venules, and capillaries) are distinct compartments connected in series without valves separating them. Consequently, change of pressure in either compartment affects the pressure in the other. Left atrium Since the LA plays a major role in this hypothesis, several fundamental points are emphasized. Evaluating LA area using echocardiography reveals three main phases during the cardiac cycle [2]. (1) LA filling phase, where the LA serves as a reservoir, starts when
G. Dori / Medical Hypotheses 84 (2015) 40–43
mitral valve closes and terminates when it opens. This period of time is equal to the duration of LV contraction (systole). The volume of the LA (LA-V) is lowest at the time mitral valve closes (LA-Vmin), whereas it is greatest just before mitral valve opens again (LA-Vmax). (2) LA emptying phase, where the LA serves as a conduit chamber, starts when mitral valve opens and terminates at a distinct LA-V before the onset of LA contraction. This LA-V is labeled here: LA-V75%, because approximately 75% of the LA stroke volume (SV, the volume transferred from the LA to the LV per beat) is transferred from the LA to the LV during this phase. (3) LA booster pump phase, where the LA muscle contracts and propels blood into the LV. At the end of this phase LA-V equals LA-Vmin. The duration of phases 2 and 3 is equal to the duration of the LV diastole (approximately 2/3 of the duration of the cardiac cycle at normal HR). It is noted that during phases 1 and 2 LA wall tension is determined by the volume of blood distending the LA. During phase 3 LA wall tension is assumed to be greater than it is during the former phases (1 and 2), due to LA muscle contraction. The latter adds to the wall tension already produced by distention of blood in phase 2. We did not find literature supporting this assumption; however, two points logically favor this assumption. Phase 3 always follows phase 2 in time (during NSR), and wall tension at the end of phase 2 serves as the starting point for further development of wall tension due to LA contraction in phase 3. (For further reading see ref. [3] an elegant investigation of the LA-V using cardiac magnetic resonance imaging in healthy young and elderly subjects. Figs. 3 and 4 show LA-V as a function of time). During atrial fibrillation (AF) booster pump phase (phase 3 above) is lost. Consequently, less blood is transferred from the LA to the LV per cardiac cycle, thus more blood is retained in the LA. LA-V varies during AF however the values of LA-Vmin and LA-Vmax are different from those obtained during NSR (see section evidence related to LA-V below). Left atrial compliance Compliance of an elastic component is defined by the change in pressure (DP) required to cause a change in volume (DV), C = DV/DP. When a large change in pressure is required to induce a small change in volume the compliance is low, and vice versa. LA compliance, LA-C, at a certain volume can be appreciated from the local derivative on the LA-V versus LA pressure (LA-P) plot (see Fig. 2 in Ref. [4]). Specifically, LA-C is greatest at low LA-V, and it decreases with the distention of LA walls. We claim, although it is not proven, that the LA-C during phase 3 is lower than that during phase 2. Pathophysiology of pulmonary congestion and edema In pulmonary congestion and edema fluid shifts from the PV (mainly pulmonary capillaries) into the surrounding supporting tissues (interstitium) and pulmonary alveoli, respectively. Two pathological forces account for the fluid shift: (a) increased hydrostatic pressure within the PV or (b) increased permeability of the pulmonary capillaries. This hypothesis relates to the former force only. Increased hydrostatic pressure within the PV is the result of various scenarios overloading the PV compartment with blood. For example, a sudden rise in the systemic blood pressure increases the resistance against which the LV must contract. This imposes a decrease in LV SV and therefore, more blood is retained in the LV at the end of contraction before the next filling. The excess of blood retained increases the LV pressure according to its compliance. Consequently, the LA-P required now for filling the LV must be greater than that required before systemic blood pressure had increased. The increased LA-P reflects backwards to the PV increasing the hydrostatic pressure [5].
41
Atrial fibrillation (AF) has 3 forms: paroxysmal (appears acutely and reverts to NSR spontaneously), persistent (appears acutely and does not revert to NSR spontaneously, but may be converted to NSR by medications or electric shock), and permanent (AF which cannot be converted to NSR) [6]. In this work we refer to the reversible forms only: paroxysmal and persistent. AF is another cause for pressure buildup in the PV. Briefly, as AF initiates atrial contraction is instantly lost, diminishing the LA SV by as much as 20% [7–8]. Consequently, blood accumulates in the LA, increasing LA pressure, and in turn also increases the pressure within the PV. This process promotes fluid shift from the intravascular space to the interstitium first and then to the alveoli, culminating in pulmonary congestion and edema, respectively [9]. Case vintage A 70 years old woman is admitted to the emergency room with progressive dyspnea which developed over the last few days, accompanied by palpitations. She also complains of leg edema and waking up at night with difficulty breathing over the last week. Medical history reveals 25 years for hypertension, 10 years of type II diabetes mellitus, and obesity. Her physical examination revealed: normal vital signs except for blood pressure 170/75, endinspiratory crackles over lung bases, and bilateral leg edema. Blood tests were normal, including troponin level. EKG demonstrated rapid AF, 130 beats per minute, and signs of LV hypertrophy. Her chest X-ray displayed signs of PEd. Patient was treated immediately with oxygen, morphine, and diuretics. After initial improvement heart rate (HR) lowering drugs (rate control), and anti-coagulation therapy was added. Standard trans-thoracic echocardiography (performed 3 days after patient improved and converted spontaneously to NSR) demonstrated: LA enlargement, thickened left ventricular walls with a small LV cavity (concentric hypertrophy), normal LV systolic function (ejection fraction 60%), transmitral flow velocity measurements demonstrated findings consistent with a ‘‘pseudonormalization’’ pattern (diastolic dysfunction grade II) [10]. This clinical case is commonly encountered in internal medicine departments. Hypothesis Before presenting the hypothesis several assumptions are made: (1) LA and PV are compliant compartments containing blood, connected in series with no valves separating them apart. (2) Blood is a non-compressible fluid. (3) As a result of (1) and (2), a change in pressure in the LA compartment will instantly affect the pressure in the PV compartment. (4) Mitral valve remains competent during the transition from NSR to AF. The following scenario may also explain the clinical case. Systemic blood pressure rises (for various common causes such as fluid, salt or medication indiscretion) forcing the LV to contract against a greater resistance at its outflow tract (LVOT). As the resistance increases less blood can be propelled from the LV to the circulation. (Consider the extreme case, where the LVOT is severely compromised, as in severe aortic stenosis. Then, the SV decreases significantly, clinically expressed by a weak palpated pulse, and events of fainting [11]). As SV diminishes, more blood per cardiac cycle accumulates in the compartments upstream to the LVOT that is in the LV, LA, and PV. As blood accumulates, it exerts pressure on the walls of the latter compartments, distending them. The walls of the LA are assumed here to be the ‘‘weakest part in the chain’’ because they are the thinnest. Data show that the risk for AF increases with LA-V [12]. Thus, at a certain point of LA distention AF initiates. In addition, the pressures within the LA, and PV compartments rise. This increase in hydrostatic pressure within the PV
42
G. Dori / Medical Hypotheses 84 (2015) 40–43
circulation promotes fluid shift from the intravascular space to the interstitium leading to pulmonary congestion and PEd. However, there is another component to this scenario which deserves attention and is the basis for the hypothesis. A fibrillating LA has a greater volume per cardiac cycle compared with a contracting LA [13]. On average, over a cardiac cycle, a fibrillating LA can accommodate more blood then a contracting LA, at similar LA pressures. Consider two distinct time intervals in the LA cycle. The first is the time when the LA contracts (phase 3 above), label this time tC. The second is the time of the rest of the cardiac cycle, label it tR (where tR + tC equals the duration of the cardiac cycle in seconds). The LA wall tension during tC is greater than that during tR because the LA muscle is contracted during tC, whereas during tR the LA is relaxed and distended passively by the blood flowing into the LA (see section left atrium above). Compliance can be considered roughly as the reciprocal of wall tension. When wall tension is high compliance is low and vice versa. In terms of compliance, during NSR the LA-C is a combination of LA-C during tR and tC. On the other hand, during AF, the component of LA-C affected by LA contraction is lost, and therefore depends only on LA-C during tR (although it is clear LA-V during NSR differs from that during AF). At any LA-V the LA-P is lower during AF than it is during NSR. This allows more blood to flow from the PV to the LA. If more blood leaves the PV compartment the hydrostatic pressure within it decreases, delaying the process that shifts blood to the interstitium causing pulmonary congestion and PEd. If during AF LA-P at any given LA-V remains the same as during NSR or even increases, the hypothesis described above fails. It is further suggested that the change in LA-P, as AF initiates, depends on two volumes: (A) the potential ‘‘LA-V gained’’ by the change in LA-C as AF begins, where ‘‘LA-V gained’’ is the difference between the LA-V during AF (at a given LA-P and LA-C) minus LA-V during NSR (at the same LA-P, but a lower LA-C). (B) The ‘‘LA SV lost’’ as AF begins [7,8]. Intuitively, if the LA can potentially accommodate a larger blood volume during AF than the volume of SV lost due to AF, than the LA-P will decrease on the transition to AF. Define the ratio between ‘‘LA-V gained’’ and ‘‘LA SV lost’’ as R, then if R > 1 on the transition to AF, then the hypothesis holds. It is also suggested that the palpitations accompanying the onset of AF serve as an alarm signal for the patient, stating clinically that ‘‘something is wrong’’. Palpitations during AF are sensed by approximately 25% of patients [14]. Since this percentage is relatively low, it is not a ‘‘trustworthy’’ mechanism to rely on. Left atrial volume during NSR and AF LA volume is normally evaluated when the LA is maximally full or distended, immediately before the mitral valve opens [15]. The range for normal LA-V is wide 22–52 and 18–58 ml, for healthy women and men, respectively. Normalized to body surface area LA-V is 22 ± 6 ml/m2 regardless of gender [15]. Bank et al. used cardiac magnetic resonance (CMR) to demonstrate that the LA-V was 81 ± 24 ml just before mitral valve opened, and it was 38 ± 15 ml when the LA was maximally contracted (that is in NSR) [13]. When the LA-V is normalized to body surface area (dividing by 1.7 m2) the maximal LA-V is approximately 47 ml/m2. These results are greater than those reported by Lang et al. Therkelsen et al. determined the LA-V in 19 normal subjects, 58 patients with persistent and 19 patients with permanent AF using MRI. The maximal mean atrial volumes were similar in the two groups with AF [77.4–82.1 ml/m2] and the latter differed significantly from that in healthy volunteers (62.3 ml/m2) [16]. These results are also greater than those reported by Lang et al. Agner et al. determined how measurements of LA-V obtained by transthoracic echocardiography (TTE), CMR, and 320-slice multi-detector computed tomography (MDCT) correlated in patients with
permanent AF. In 34 patients they showed that maximal LA-V was 80 ml/m2 by 320-slice MDCT, 73 ml/m2 by CMR, and 60 ml/m2 by TTE [17]. In a recent study, Zakeri et al. investigated the temporal relationship between AF and heart failure and preserved ejection fraction (HFPEF). They showed that mean LA-V indexed to body surface area was: 40.7 ± 12.4 ml/m2 in HFPEF patients with NSR, 47.0 ± 13.5 ml/m2 in HFPEF patients with concurrent AF (which initiated ±3 months relative to the diagnosis of HFEPF), and 54.7 ± 22.5 ml/m2 in HFPEF patients with prior AF (i.e. AF that was present >3 months prior to diagnosing HFPEF). This study shows that LA-V increases with the duration of AF in HFPEF patients [18]. The data above show that LA-V varies with the method of measurement and between studies, however, it is clear that LA-V during AF is greater than that during NSR. This fact alone is insufficient for substantiating the hypothesis. The important variable which determines whether pressure build up in the PV abates as AF commences is the instant LA-P which is determined by the instant LA-C during AF. Discussion The hypothesis presented suggests that AF, apart from being an arrhythmia and an independent potential cause for PEd [19], also has a ‘‘physiological role’’ in delaying the development of PEd [1]. A fundamental basis of the hypothesis is based on an assumption that LA-C increases during AF relative to the LA-C during NSR. Work considering this issue was sought but not found. Indirect, weak evidence supporting the hypothesis – ‘‘AF is not all bad’’ The following examples show that AF was not associated with increased risk (compared with NSR) suggesting that the transition to AF from NSR was ‘‘not bad’’ and perhaps is a physiological solution under certain conditions. In a very general sense, several seminal studies showed that a clinical approach of controlling HR in AF is not inferior to converting patients with AF to NSR. Clinical outcomes were similar when the so called rate control approach was compared with rhythm control [20]. Later, it was shown that lenient HR control was not inferior to a stringent approach [14]. From these studies it is possible to infer that AF is not a toxic condition calling for an immediate intervention. Rienstra et al. performed a post hoc analysis of patients with heart failure and reduced ejection fraction (HFREF, EF < 35%) and AF. These researchers showed that mortality was higher in the cohort of patients with lower HR during AF. One of their possible explanations for the unexpected outcome was that increased HR in AF provides a compensatory mechanism for preserving CO [21]. Anter et al. reviewed the relation between HFREF and AF, as both diseases are very common and related by at least mutual risk factors as hypertension, and diabetes. They concluded that ‘‘the prognostic significance of AF in patients with heart failure remains controversial because no consensus exists that AF is an independent risk factor of adverse outcome’’ [22]. Lechat et al. analyzed the effects of baseline HR, HR change after 2 months of bisoprolol treatment and nature of cardiac rhythm: NSR versus AF, on mortality and rehospitalization for HF. They showed that a low baseline HR and a significant HR change (decrease) at 2 months were associated with a better survival and lower rehospitalization rate. However, bisoprolol reduced mortality in HFREF patients in NSR where it did not in AF. These results may suggest that lower (versus higher) HR entails a better prognosis, regardless of whether the rhythm is NSR or AF [23]. Van Veldhuisen et al. analyzing HFREF patients in NSR or AF, receiving metoprolol versus placebo (in the MERIT-HF study), showed that the drug had no effect on mortality reducing all-cause
G. Dori / Medical Hypotheses 84 (2015) 40–43
or HF associated hospitalizations in the AF cohort [24]. Bohm et al. investigated the relationship between HR and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial. They showed that higher HR was associated with a significantly higher risk of all outcomes studied for patients in sinus rhythm, however no relationship between heart rate and outcomes was observed for patients in AF [25]. These studies do not prove a physiological mechanism, however they show that the attempt to restore NSR is not always beneficial. In our view this may suggest that AF could be a solution rather than a problem. Limitations It was assumed that HR remained approximately the same on the transition to AF, yet this is often not the case and HR may increase significantly on the transition to AF. Increased HR to the level where cardiac output increases as well, decompresses the LA by increasing the rate of pumping blood out of the LA. This mechanism also serves to delay the development of PEd and competes with the mechanism described in the hypothesis. The limitation of this mechanism lies in the fact that when HR increases right ventricular output to the pulmonary circulation increases as well. Whether increased HR is beneficial depends on the capacitance characteristics of the arterial part of the pulmonary vessels. It is stressed that the proposed mechanism is beneficial in delaying the development of PEd not preventing it. If the cause for increased hydrostatic pressure within the PV, be it increased systemic blood pressure or transient myocardial ischemia, or a spontaneous arrhythmia, is not treated, then pressure will continue building up, shifting fluid into the interstitium and alveoli, culminating in PEd. This hypothesis ignored an important issue – the time history of LA distention. It is reasonable to think that acute increase of afterload (as described in the case vintage) causing LA to distend within minutes or hours or even days would differ from mitral stenosis which evolves over years. The biological response (genetic, humoral, histological, etc.) to these triggers is expected to be different. Implications If this hypothesis were true there are some points that we as clinicians should consider especially in the settings where LA-V is increased acutely: (a) Converting AF to NSR during the acute setting in the emergency room may be hazardous. The preferred treatment should be to decrease afterload (blood pressure lowering agents administered intravenously), decrease preload as well (e.g. morphine) and remove excess of fluid from blood vessels by induction of urination (e.g. furosemide). (b) After treatment described in (a) has been administered, it may be expected that AF would revert spontaneously to NSR. Conflict of interest There is no conflict of interest. References [1] Tilman V. Atrial fibrillation and heart failure: is atrial fibrillation a disease?. Med Hypotheses 2014;83:299–301. http://dx.doi.org/10.1016/j.mehy.2014.05.024.
43
[2] Spencer KT, Mor-Avi V, Gorcsan III J, et al. Effects of aging on left atrium reservoir, conduit, and booster pump function: a multi-institutional acoustic quantification study. Heart 2001;85:272–7. [3] Ahtarovski KA, Iversen KK, Lønborg JT, Madsen PL, Engstrøm T, Vejlstrup N. Left atrial and ventricular function during dobutamine and glycopyrrolate stress in healthy young and elderly as evaluated by cardiac magnetic resonance. Am J Physiol Heart Circ Physiol 2012;303:H1469–73. [4] Rosca M, Lancellotti P, Popescu BA, Pierard LA. Left atrial function: pathophysiology, echocardiographic assessment, and clinical applications. Heart 2011;97:1982–9. [5] Schwammenthal E, Vered Z, Agranat O, Kaplinsky E, Rabinowitz B, Feinberg MS. Impact of atrioventricular compliance on pulmonary artery pressure in mitral stenosis: an exercise echocardiographic study. Circulation 2000;102:2378–84. [6] Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213–20. [7] Phan TT, Abozguia K, Shivu GN, et al. Increased atrial contribution to left ventricular filling compensates for impaired early filling during exercise in heart failure with preserved ejection fraction. J Card Fail 2009;15:890–7. [8] Alhogbani T, Strohm O, Friedrich MG. Evaluation of left atrial contraction contribution to left ventricular filling using cardiovascular magnetic resonance. J Magn Reson Imaging 2013;37:860–4. [9] Iwasaki YK, Nishida K, Kato T, Nattel S. Atrial fibrillation pathophysiology: implications for management. Circulation 2011;124:2264–74. [10] Nishimura RA, Tajik JA. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician’s Rosetta stone. J Am Coll Cardiol 1997;30:8–18. [11] Fang JC, O’Gara PT. The history and physical examination: an evidence-based approach. In: Libby P, Bonow RO, Mann DL, Zipes DP, Braunwald E, editors. Braunwald’s heart disease: a textbook of cardiovascular medicine. Philadelphia: Saunders Elsevier; 2008. p. 133. [12] Zhuang J, Wang Y, Tang K, et al. Association between left atrial size and atrial fibrillation recurrence after single circumferential pulmonary vein isolation: a systematic review and meta-analysis of observational studies. Europace 2012;14:638–45. [13] Bank A, Wickstrom K, Handran C, Burkhoff D, Lesser JR, Schwartz RS. Modeling left atrial volume, shape and contraction patterns in normal subjects by cardiac magnetic resonance imaging. Int J Cardiol 2013;168:3348–50. [14] Van Gelder IC, Groenveld HF, Crijns HJGM, RACE II Investigators, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–73. [15] Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [16] Therkelsen SK, Groenning BA, Svendsen JH, Jensen GB. Atrial and ventricular volume and function in persistent atrial fibrillation, a magnetic resonance imaging study. J Cardiovasc Magn Reson 2005;7:465–73. [17] Agner BFR, Kuhl JT, Linde JJ, et al. Assessment of left atrial volume and function in patients with permanent atrial fibrillation: comparison of cardiac magnetic resonance imaging, 320-slice multi-detector computed tomography, and transthoracic echocardiography. Eur Heart J Cardiovasc Imaging 2014;15:532–40. [18] Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction. A community-based study. Circulation 2013;128:1085–93. [19] Teerlink JR. Diagnosis and management of acute heart failure. In: Libby P, Bonow RO, Mann DL, Zipes DP, Braunwald E, editors. Braunwald’s heart disease: a textbook of cardiovascular medicine. Philadelphia: Saunders Elsevier; 2008. p. 591. [20] Van Gelder IC, Hagens VE, Bosker HA, Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–40. [21] Rienstra M, Van Gelder IC, Van den Berg MP, Boomsma F, Hillege HL, Van Veldhuisen DJ. A comparison of low versus high heart rate in patients with atrial fibrillation and advanced chronic heart failure: effects on clinical profile, neurohormones and survival. Int J Cardiol 2006;109:95–100. [22] Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: treatment considerations for a dual epidemic. Circulation 2009;119:2516–25. [23] Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation 2001;103:1428–33. [24] van Veldhuisen DJ, Aass H, El Allaf D, MERIT-HF Study Group, et al. Presence and development of atrial fibrillation in chronic heart failure: experiences from the MERIT-HF Study. Eur J Heart Fail 2006;8:539–46. [25] Bohm M, Perez AC, Jhund PS, I-Preserve Committees and Investigators, et al. Relationship between heart rate and mortality and morbidity in the irbesartan patients with heart failure and preserved systolic function trial (I-Preserve). Eur J Heart Fail 2014. http://dx.doi.org/10.1002/ejhf.85.
