REVIEW URRENT C OPINION
Left atrial function in heart failure with impaired and preserved ejection fraction Fang Fang, Alex Pui-Wai Lee, and Cheuk-Man Yu
Purpose of review Left atrial structural and functional changes in heart failure are relatively ignored parts of cardiac assessment. This review illustrates the pathophysiological and functional changes in left atrium in heart failure as well as their prognostic value. Recent findings Heart failure can be divided into those with systolic dysfunction and heart failure with preserved ejection fraction (HFPEF). Left atrial enlargement and dysfunction commonly occur in systolic heart failure, in particular, in idiopathic dilated cardiomyopathy. Atrial enlargement and dysfunction also carry important prognostic value in systolic heart failure, independently of known parameters such as left ventricular ejection fraction. In HFPEF, there is evidence of left atrial enlargement, impaired atrial compliance, and reduction of atrial pump function. This occurs not only at rest but also during exercise, indicating significant impairment of atrial contractile reserve. Furthermore, atrial dyssynchrony is common in HFPEF. These factors further contribute to the development of new onset or progression of atrial arrhythmias, in particular, atrial fibrillation. Summary Left atrial function is an integral part of cardiac function and its structural and functional changes in heart failure are common. As changes of left atrial structure and function have different clinical implications in systolic heart failure and HFPEF, routine assessment is warranted. Keywords atrial function, echocardiography, heart failure, heart failure with preserved ejection fraction, systolic dysfunction
INTRODUCTION The left atrium has three primary functions: as a reservoir for pulmonary venous return during ventricular systole; as a conduit for rapid left ventricular (LV) filling during early ventricular diastole; and as a booster pump during late ventricular diastole, contributing further to the LV filling and forward stroke volume. Left atrial function is an integral part of LV function. In heart failure, left atrial function is also altered, affected by the change of either ventricular structure or function, or develops secondary changes both compensatory and decompensatory in nature. As heart failure can further be divided into heart failure with systolic dysfunction and heart failure with preserved ejection fraction (HFPEF), the changes of left atrial function can be totally different. This review will summarize the changes of left atrial function in these two types of heart failure. www.co-cardiology.com
ATRIAL FUNCTION IN HEART FAILURE WITH SYSTOLIC DYSFUNCTION The left atrial emptying function seems to be particularly important when LV systolic function is already impaired. In patients with LV systolic dysfunction, atrial contribution tends to be less effective in augmenting cardiac output when filling
Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, and Institute of Vascular Medicine, The Chinese University of Hong Kong, Hong Kong Correspondence to Professor Cheuk-Man Yu, Division of Cardiology and Heart Education and Research Training (HEART) Centre, Department of Medicine and Therapeutics, Prince of Wales Hospital and Institute of Vascular Medicine, The Chinese University of Hong Kong, Hong Kong. Tel: +852 2632 3132; fax: +852 2647 5643; e-mail:
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Left atrial function in heart failure Fang et al.
KEY POINTS • Left atrial enlargement and dysfunction occur commonly in systolic heart failure, which also carry important prognostic value.
response to left atrial pressure and volume overload, which is a compensatory mechanism to maintain left atrial contribution to LV filling at the expense of increased atrial mechanical work [5].
• In HFPEF, there is evidence of left atrial enlargement, impaired atrial compliance, and reduction of atrial pump function.
PROGNOSTIC VALUE OF ATRIAL SIZE AND FUNCTION IN HEART FAILURE WITH SYSTOLIC DYSFUNCTION
• In HFPEF, there is also impairment of atrial contractile reserve as illustrated during exercise.
The prognostic implication of left atrial size was initially demonstrated in patients with LV dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry and Trials, where echocardiographic measurements of LV mass, left atrial size, and ejection fraction were significantly associated with mortality and rate of cardiovascular hospitalizations [6]. In patients with DCM, left atrial enlargement represents a strong predictive marker, presumably because examining the atrial chamber allows comprehensive evaluation of several factors associated with a poor prognosis, which are often difficult to examine separately. These adverse prognostic factors include the presence of atrial fibrillation, LV remodeling, diastolic dysfunction, and the degree of mitral regurgitation, which are all determinants of the left atrial size. The maximal volume of the left atrium has an independent and incremental prognostic value when compared with all its determinants. Patients with a left atrial maximal volume greater than 68.5 ml/m2 had a risk ratio for death of 3.8 over a follow-up period of 41 months [7]. Although left atrium remodeling is often more severe in patients with systolic heart failure than in those with HFPEF [8], the prognostic
• Atrial dyssynchrony is common in HFPEF, which will further contribute to the development of new onset or progression of atrial arrhythmias, in particular, atrial fibrillation.
pressure is already elevated [1] (Fig. 1). Moreover, increased left atrial size and depressed left atrial contractile performance are associated with increased neurohormonal activation in patients with idiopathic dilated cardiomyopathy (DCM) [2]. The impaired left atrial emptying function may be the result both of left atrial dilatation secondary to the increased preload seen in LV systolic dysfunction and of atrial involvement in the myopathic process associated with DCM [3]. Myopathic involvement of the left atrium may explain why left atrial active emptying fraction is depressed in idiopathic DCM but preserved in ischemic cardiomyopathy despite similar left atrial loading conditions [3,4]. In an animal model of pacing-induced heart failure, there is an isoform switch from the fast to slow myosin heavy chain predominantly in the left atrial body in
FIGURE 1. Severely impaired left atrial function in a patient with dilated cardiomyopathy. Atrial contractile function can be assessed with tissue Doppler echocardiography by measuring the atrial velocity (a’) of the mitral annulus. In this patient with dilated cardiomyopathy, ejection fraction was 16%, and mitral inflow shows restrictive filling with a E and A wave ratio greater than 2, indicative of severely elevated left ventricular filling pressure. The markedly reduced a’ of 1.8 cm/s is consistent with significantly impaired left atrial contraction.
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Imaging and echocardiography
impact of increased left atrial size and decreased left atrial emptying function can be observed in heart failure patients, elderly and younger patients, with both depressed and preserved ejection fraction [8,9]. In fact, left atrial volume has been shown to have comparable predictability to left ventricular ejection fraction (LVEF) for heart failure hospitalization and mortality [8,10,11]. In a study of 935 ambulatory adults with coronary artery disease, the unadjusted odds ratio for heart failure hospitalization was 4.4 for left atrial volume index greater than 50 ml/m2 and 5.3 for LVEF less than 45% [10]. Measurement of left atrial volume using 3-D echocardiography (Fig. 2) appears to be more accurate than the 2-D biplane area–length method, which tends to underestimate true left atrial volume. Left atrial volume measured by 3-D echocardiography is a major predictor of adverse clinical outcomes in patients with severe LV dysfunction and in sinus rhythm. The clinical value of 3-D left atrial volume seems to be superior to its 2-D counterpart [12]. The prognostic role of evaluating left atrial performance in addition to left atrial size was recently studied in 243 chronic heart failure patients, among whom over 70% have depressed ejection fraction. The left atrial work can be calculated from the following formula: 0.5 m A2, where m is the product of the left atrial stroke volume and blood density, and A is the transmitral Doppler peak atrial velocity. In these patients, left atrial work has an incremental prognostic value over
(a)
left atrial size, suggesting the importance of a precise evaluation of left atrial function beyond left atrial volume [13 ]. High levels of left atrial work imply the activation of critical compensatory mechanisms, indicating a higher risk of cardiovascular death or hospitalization for heart failure. &
CHANGES OF LEFT ATRIAL FUNCTION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION About 40% of patients with heart failure have a relatively normal LVEF but presence of LV diastolic dysfunction. These patients were being described as diastolic heart failure or HFPEF [14]. HFPEF, a disease with increasing prevalence, carries a mortality similar to that of systolic heart failure and a high healthcare burden. However, the pathophysiologic mechanism underlying the development of HFPEF is not entirely clear. HFPEF commonly occurs in the elderly population, both of which are common contributors to the elevation of LV filling pressure. Furthermore, these two factors are closely related to the alteration of atrial function. For example, atrial pump function contributes up to 30% of total LV diastolic filling in aging populations, in contrast to about 20% in young adulthood [15]. In contrast to the role of left atrial function in systolic heart failure, little is known about the impact of HFPEF on left atrial structure and function. In recent years, with the advancement of new
(b)
FIGURE 2. Measurement of left atrial volume by 3-D echocardiography. (a) In the same patient depicted in Fig. 1 having heart failure with severe systolic left ventricular dysfunction due to dilated cardiomyopathy, the volumetric data set of the left atrium can be obtained from the apical window, which was analyzed for contour detection of the left atrial chamber to allow volumetric measurement without geometric assumption. (b) Time–left atrial volume curve is generated showing significantly dilated left atrium (maximum left atrial volume ¼ 136 ml; minimum left atrial volume ¼ 122 ml) but a reduced total left atrial stroke volume (136 122 ¼ 14 ml).
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Left atrial function in heart failure Fang et al.
LVDD é LV filling pressure
é LA pressure
LVH
LA enlargement and remodeling
ê LA compliance
Compensatory é in atrial pump function
LA histological and electrical remodeling
Atrial failure
Inter-atrial dyssynchrony
Atrial fibrillation
Asymptomatic
Symptoms of SOB
HFPEF
FIGURE 3. Progression of atrial remodeling, atrial dysfunction, and atrial fibrillation in heart failure with preserved ejection fraction. HFPEF, heart failure with preserved ejection fraction; LA, left atrial; LV DD, left ventricular diastolic dysfunction; LVH, left ventricular hypertrophy; SOB, short of breath.
echocardiographic technologies, there were studies that illustrated subclinical LV systolic abnormalities in patients with HFPEF, including myocardial velocity [16,17], deformation [18], rotation [19], and untwisting, that were demonstrated at rest and during exercise, despite the apparently preserved global ejection fraction. The alteration of LV diastolic function, and, to a lesser extent, systolic function, in HFPEF leads to reduced LV recoil and suction during diastole. As a result, these patients are more dependent on atrial pump function in late diastole to maintain normal ventricular filling. Furthermore, with the use of advanced echocardiographic technologies, in particular, tissue Doppler imaging and speckle tracking imaging, the relationship between HFPEF and atrial remodeling as well as atrial electrical abnormalities is better described.
DIAGNOSTIC AND PROGNOSTIC VALUE OF LEFT ATRIAL VOLUME IN HEART FAILURE WITH PRESERVED EJECTION FRACTION As a thin-walled chamber, the left atrium is prone to be stretched in HFPEF because of the chronic elevation of both LV filling pressure and left atrial pressure, resulting in left atrial remodeling. Therefore, atrial size is always increased in HFPEF, which not only has become a diagnostic criterion but also is useful as a prognosticator. Although LV diastolic dysfunction is the fundamental pathophysiological change in HFPEF, this condition is difficult to ascertain by the occurrence of this diastolic dysfunction alone. In fact, left atrial dilation was
recommended to be included as the additional structural abnormality for the diagnosis of HFPEF in the European Society of Cardiology guideline [20]. Previous studies have shown that patients with HFPEF had larger left atrial size than hypertensive patients with LV hypertrophy. In fact, LV hypertrophy is also a common precursor of HFPEF [21] and an indicator of elevated left atrial pressure leading to atrial remodeling [19] (Fig. 3). Moreover, left atrial dilatation also contributes to clinical symptoms, worsening of LV diastolic function, and adverse outcome in HFPEF. A previous study found that left atrial enlargement was associated with the presence of dyspnea in HFPEF. Patel et al. [22] showed that left atrial enlargement was related to more severe diastolic dysfunction and higher LV filling pressure, and independently predicted allcause mortality regardless of LV geometry in HFPEF. Further analysis with stratification of left atrial volume index showed that increasing tertile of left atrial size was associated with progressively higher mortality. Of note, mortality in patients with severely enlarged left atrial volume was nearly threefold when compared with those having normal left atrial volume [22].
LEFT ATRIAL MECHANICAL FUNCTION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION AT REST AND DURING EXERCISE Normally, left atrial pump function accounts for about 20% of LV stroke volume as a booster to augment diastolic filling, although it becomes
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Imaging and echocardiography (a)
(b)
FIGURE 4. Left atrial dyssynchrony in a patient with heart failure with preserved ejection fraction. (a) Normal patient without atrial dyssynchrony. Left atrial contraction velocity measured by tissue Doppler imaging at apical four and two-chamber views showing simultaneous contraction of the opposite walls (arrows). (b) Left atrial dyssynchrony in a patient with heart failure with preserved ejection fraction. Note that atrial contraction velocity of opposite walls showed delay in lateral and anterior atrial walls (arrows).
more significant during exercise [22]. When LV diastolic dysfunction develops, LV compliance reduces with decrease in early diastolic filling, leading to a compensatory increase in atrial pump function [23,24]. This phenomenon is particularly obvious in hypertensive patients with LV hypertrophy. However, with progressive elevation of LV filling pressure and atrial remodeling, such a compensatory mechanism will gradually impair because of the reduction of atrial contractile function or even atrial failure. In a study including African American patients, it was demonstrated that left atrial dilatation and atrial failure were the two main pathological differences between patients with hypertensive LV hypertrophy and HFPEF [21]. By using tissue Doppler strain and speckle tracking strain assessment, it was shown that left atrial strain was reduced in HFPEF but remained unchanged in those with LV hypertrophy, although both conditions share similar abnormalities including increased LV mass and left atrial volume [25]. Given the fact that most patients with HFPEF have exercise-related symptoms, it is, therefore, pivotal to investigate the changes of left atrial 434
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function during exercise or stress in HFPEF. A study using resting and exercise radionuclide ventriculography found that patients with HFPEF had increased left atrial contribution to LV filling as a compensatory response to impaired early LV filling during submaximal exercise [26]. However, in the recent few years, the use of more advanced echocardiographic analysis consistently confirmed that, during exercise, left atrial function failed to increase, resulting in insufficient compensation during late diastolic filling [24]. Melenovsky et al. [21] found that, in isometric handgrip, atrial emptying fraction was reduced and late mitral annulus velocity was unchanged in HFPEF. In contrast, this was increased in hypertensive patients [21]. By using the leg lifting test in patients with HFPEF, left atrial strain was found to be blunted when compared with those with hypertension [27 ]. Furthermore, Tan et al. [19] and Kusunose et al. [28] demonstrated that atrial contractile reserve failed to increase in patients with HFPEF. These findings illustrated that progressive atrial mechanical failure may act as part of the pathophysiological mechanism underlying the &
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Left atrial function in heart failure Fang et al.
progression from LV hypertrophy to HFPEF, while reduction of left atrial contractile reserve during exercise plays a role in the symptom of breathlessness.
ATRIAL DYSSYNCHRONY AND ATRIAL FIBRILLATION IN HEART FAILURE WITH PRESERVED EJECTION FRACTION It has been observed that, in mitral stenosis, atrial conduction delay was present in the dilated left atrium, since electrical impulse propagates along a larger area of atrial myocardium within the atrial chamber [29]. On top of change in size, the histological burden of myocardial fibrosis, especially in the chronically dilated left atrium, will further hinder conduction [30]. Intriguingly, there is a link among atrial remodeling, atrial function, and atrial dyssynchrony, which, in turn, plays a potential role in the occurrence of atrial arrhythmias [31]. When timing of atrial function was assessed by tissue Doppler imaging, it was shown that interatrial dyssynchrony and atrial dysfunction were contributing factors to both new-onset atrial fibrillation and progress from paroxysmal to persistent atrial fibrillation in HFPEF [32,33]. There are two potential contributing factors for the development of atrial fibrillation in HFPEF. The elevated LV filling pressure leads to increased left atrial afterload that results in left atrial enlargement and increased atrial chamber tension. Furthermore, atrial dyssynchrony develops as a result of atrial dilatation and mechanical dysfunction. In a recent study, more than half of patients with HFPEF had significant interatrial dyssynchrony, in contrast to the absence of this phenomenon in normal patients [34] (Fig. 4). Further studies will be helpful to elucidate the role of atrial dyssynchrony in atrial electrical and histological remodeling in the development of atrial arrhythmias in HFPEF.
CONCLUSION In summary, left atrial enlargement and dysfunction are common consequences of heart failure with systolic dysfunction, in particular, in DCM. Atrial enlargement and dysfunction also carry important prognostic value in systolic heart failure, and are independent of known parameters such as LVEF. In HFPEF, there is evidence of left atrial enlargement, impaired atrial compliance, and reduction of atrial pump function. This is not only observed in the resting condition but also, importantly, during exercise, indicating the significant impairment of atrial contractile reserve. Furthermore, atrial dyssynchrony is common in HFPEF. These factors will further contribute to the
development of new onset or progression of atrial arrhythmias, in particular, atrial fibrillation. Acknowledgements This work was supported in part by the Collaborative Research Fund – RGC Collaborative Research Fund 2010/11: CUHK9/CRF/10. We appreciate Prof. John Elsby Sanderson for his kindly help with the paper. Conflicts of interest There are no conflicts of interest.
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