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Original Article
Prognostic Relevance of Left Atrial Dysfunction in Heart
Failure With Preserved Ejection Fraction
Angela B.S. Santos, MD; Gabriela Querejeta Roca, MD; Brian Claggett, PhD;
Nancy K. Sweitzer, MD; Sanjiv J. Shah, MD; Inder S. Anand, MD, PhD;
James C. Fang, MD; Michael R. Zile, MD; Bertram Pitt, MD; Scott D. Solomon, MD;
Amil M. Shah, MD, MPH
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Background—Left atrial (LA) size is an established marker of risk for adverse outcomes in heart failure with preserved
ejection fraction (HFpEF). However, the independent prognostic importance of LA function in HFpEF is not known.
Methods and Results—We assessed LA function measured by speckle-tracking echocardiography in 357 patients with
HFpEF enrolled in the Treatment Of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)
trial who were in sinus rhythm at the time of echocardiography. Lower peak LA strain, indicating LA dysfunction, was
associated with older age, higher prevalence of atrial fibrillation and left ventricular (LV) hypertrophy, worse LV and
right ventricular systolic function, and worse LV diastolic function. At a mean follow-up of 31 months (interquartile
range, 18–43months), 91 patients (25.5%) experienced the primary composite end point of cardiovascular death, HF
hospitalization, and aborted sudden death. Lower peak LA strain was associated with a higher risk of the composite
end point (hazard ratio, 0.96 per unit of reduction in strain; 95% confidence interval, 0.94–0.99; P=0.009) and of HF
hospitalization alone (hazard ratio, 0.95 per unit of reduction in strain; 95% confidence interval, 0.92–0.98; P=0.003). The
association of LA strain with incident HF hospitalization remained significant after adjustment for clinical confounders,
but not after further adjustment for LV global longitudinal strain and the E/E′ ratio, parameters of LV systolic and
diastolic function, respectively.
Conclusions—LA dysfunction in HFpEF is associated with a higher risk of HF hospitalization independent of potential
clinical confounders, but not independent of LV strain and filling pressure. Impairment in LV systolic and diastolic
function largely explains the association between impaired LA function and higher risk of HF hospitalization in HFpEF.
Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302. (Circ Heart Fail. 2016;9:e002763. DOI: 10.1161/CIRCHEARTFAILURE.115.002763.)
Key Words: atrial strain
■
diastolic heart failure
H
eart failure with preserved ejection fraction (HFpEF) is
common, accounting for up to half of patients with heart
failure (HF),1,2 and for an increasing proportion of patients hospitalized with acute decompensated HF.3,4 Although the pathophysiologic mechanisms underlying HFpEF remain unclear,
these patients are more likely to have left ventricular (LV)
hypertrophy or concentric remodeling, LV diastolic dysfunction, and left atrial (LA) enlargement.5 LA size is independently
associated with increased risk of morbidity and mortality in
HFpEF.6,7 Previous studies have demonstrated impairment of
LA function in HFpEF,8–10 with LA reservoir function measured by peak LA strain emerging as a particularly robust
■
echocardiography
■
prognosis
measure of LA dysfunction in these patients.11 However, data
on the prognostic relevance of LA dysfunction in HFpEF is
limited,12 and the prognostic value of LA dysfunction beyond
measures of LV function is not known.
See Clinical Perspective
We used baseline data from the echocardiographic study
of the Treatment Of Preserved Cardiac Function Heart Failure
With an Aldosterone Antagonist (TOPCAT) trial5 to determine the correlates of LA dysfunction measured by peak LA
strain in patients with HFpEF and to define the prognostic
importance of LA dysfunction for the composite end point of
Received October 20, 2015; accepted March 4, 2016.
From the Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (A.B.S.S., G.Q.R., B.C., S.D.S., A.M.S.); Cardiology Division, Hospital
de Clínicas de Porto Alegre, Universidade Federal of Rio Grande do Sul, Porto Alegre, Brazil (A.B.S.S.); Division of Cardiovascular Medicine, Sarver
Heart Center, University of Arizona College of Medicine, Tucson (N.K.S.); Cardiology Division, Northwestern University Feinberg School of Medicine,
Chicago, IL (S.J.S.); Cardiovascular Division, VA Medical Center, Minneapolis, MN (I.S.A.); Cardiology Division, University of Utah School of Medicine,
Salt Lake City (J.F.); RHJ Department of Veterans Affairs Medical Center, Medical University of South Carolina, Charleston (M.R.Z.); and Cardiology
Division, University of Michigan School of Medicine, Ann Arbor (B.P.).
Guest Editor for this article was Gregg C. Fonarow, MD.
The Data Supplement is available at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.115.002763/-/DC1.
Correspondence to Amil M. Shah, MD, MPH, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02445.
E-mail [email protected]
© 2016 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.115.002763
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2 Santos et al LA Dysfunction and HFpEF
cardiovascular death, HF hospitalization and aborted sudden
death, and its individual components.
Methods
Patient Population
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The TOPCAT trial was designed to determine the efficacy of the aldosterone antagonist spironolactone to reduce cardiovascular morbidity
and mortality in patients with HFpEF.13 A total of 3445 adults at least
50 years of age with symptomatic HF, a left ventricular ejection fraction
(LVEF) ≥45% per local site reading, controlled systolic blood pressure,
and a serum potassium level of <5 mmol/L were enrolled. Eligible patients had at least 1 hospitalization in the past 12 months for which HF
was a major component or, if no qualifying hospitalization, a B-type
natriuretic peptide (BNP) in the past 60 days ≥100 pg/mL or N-terminal
pro-BNP ≥360 pg/mL. Baseline demographics and clinical characteristics of the trial population were previously described in detail.14
For quality control purposes, each enrolling site was required to
submit echocardiographic images obtained within 6 months before
enrollment from at least the first 2 randomized patients to the echocardiographic core laboratory for verification of LVEF as previously
described in detail.5 At 27 sites, patients consenting to participation
in the overall TOPCAT trial were separately consented for participation in the echocardiographic substudy. The current analysis pooled
all baseline echocardiograms with quality suitable for quantitative
analysis from the echo substudy and the quality assurance studies.
All patients provided written informed consent, and the study was
approved by the local Institutional Review Board at each site.
Echocardiographic Methods
Standard echocardiographic and Doppler parameters were analyzed using an offline analysis workstation at a dedicated core laboratory blinded to clinical information as previously described.5 All measurements
were made in accordance with the recommendations of the American
Society of Echocardiography15,16 and included LV and LA dimensions
and volumes, right ventricular (RV) areas, LV wall thickness, LV mass,
LVEF, RV fractional area change, mitral inflow propagation and mitral
annular relaxation velocities, and tricuspid regurgitation jet velocity.
LV wall thickness was defined as the average between interventricular septal wall and posterior wall thickness, and relative wall thickness
(RWT) was calculated as 2×(posterior wall thickness)/LV end-diastolic
diameter. LV hypertrophy (LVH) was defined as LV mass indexed to
body surface area >95 g/m2 in women and >115 g/m2 in men. Normal
geometry was defined as RWT ≤0.42 and no LVH; concentric remodeling as RWT >0.42 and no LVH; concentric hypertrophy as RWT >0.42
and LVH; and eccentric hypertrophy as RWT ≤0.42 and LVH.
LA and LV deformation were measured using a B-mode speckletracking vendor-independent software with algorithms designed for
the LV (TomTec Imaging Systems, Unterschleissheim, Germany).
This software is angle independent and identifies cardiac motion by
tracking multiple reference points over time.17,18 The LA and LV endocardial borders were traced at the end-diastolic frame of 2-dimensional images acquired from the apical 2- and 4-chamber views.17 End
diastole was defined by the QRS complex or as the frame after mitral
valve closure. Speckles were tracked by the software frame by frame
during the course of 1 cardiac cycle. Semiquantitative segment tracking was carefully inspected for each image and manually adjusted as
needed. For patients in atrial fibrillation (Data Supplement), strain
values were averaged over 3 cardiac cycles.11
For LV deformation, global longitudinal strain (GLS) was calculated as the average LV longitudinal strain across the 12 segments obtained using apical 4- and 2-chamber views as previously described.19
Because LV myocardial contraction results in ventricular shortening
in systole, GLS results in a negative strain value. From LA speckletracking analysis, LA phasic function was measured using volumes and
strain indices calculated as the average of the 12 segments obtained using apical 4- and 2-chamber views. LA time-volume curves were generated by calculating LA volume at each phase of the cardiac cycle (LA
maximal, LA pre-A, and LA minimum volumes) using the Simpson
method. From these LA volumes, LA phasic function was estimated as:
LA emptying fraction (reservoir function)=([LA maximum
volume−LA minimal volume]/LA maximum volume)×100
LA passive emptying fraction (conduit function)=([LA maximum
volume−LA pre-A volume]/LA maximum volume)×100
LA active emptying fraction (pump function)=([LA pre-A
volume−LA minimal volume]/LA pre-A volume]×100
From LA strain analysis, LA reservoir function was estimated
using peak strain during ventricular systole (peak LA strain), which
represents LA filling during LV systole (Figure 1). Because the LA
expands during ventricular systole, peak LA strain is a positive strain
value. If >2 segments could not be tracked or there was a lack of
a full cardiac cycle, missing view, non-DICOM images, or significant foreshortening of the cavity, the measurements were considered
unreliable and the patient was excluded from the analysis. Because
Figure 1. Two-dimensional speckle-tracking imaging in the apical 4-chamber view in a heart failure with preserved ejection fraction
patient with impairment of left atrial (LA) function (decreased peak LA strain).
3 Santos et al LA Dysfunction and HFpEF
dedicated software for LA strain analysis has not yet been released,
we used the current software for LV analysis to study the LA strain.
Of the 935 studies suitable for conventional echocardiographic measures, images were not in DICOM format in 278 patients and image
quality was inadequate in another 191 patients, leaving 466 patients
with image quality sufficient for LA speckle tracking. Because atrial
fibrillation has been strongly associated with LA dysfunction,20 the
main analysis was performed restricted to patients in sinus rhythm
at the time of echocardiography (357 patients; Figure I in the Data
Supplement). All LV strain analysis was performed by a single investigator, as was LA strain analysis. Intraobserver variability for peak
LA strain was assessed in a sample of 20 randomly selected TOPCAT
studies. The coefficient of variation was 7.7% and the intraclass correlation coefficient was 0.96 (95% confidence interval, 0.93–0.99).
Reproducibility measures for conventional echocardiographic measures and for the LV strain have been previously published.5,19
Outcomes
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The primary outcome for this analysis was the same as for the overall
TOPCAT trial, the composite of cardiovascular death, HF hospitalization, and aborted sudden death. HF hospitalization alone and cardiovascular death alone were secondary outcomes. All events were
reported by the primary site investigator and independently adjudicated by the Clinical End points Center as previously described.13
Statistical Analysis
All normally distributed data were presented as mean and SD (continuous data) or as count and proportion (categorical data). To compare
patients in the TOPCAT trial not included in this LA strain analysis
with patients included (Table I in the Data Supplement), and to compare patients in the TOPCAT echo study who were included in this
analysis with those not included (Table II in the Data Supplement),
we performed χ2 tests for categorical variables and 2-sided t test with
unequal variance for continuous variables. The prevalence of impaired LA deformation was based on thresholds obtained from data
in a healthy population with similar age.11 Smaller numeric values of
peak LA strain denote worse LA reservoir function. Values of peak LA
strain <26% represented 2 SD below the mean value for this healthy
group and were considered abnormal. Analysis was performed for the
population overall and stratified by LA size (normal versus enlarged
based on the threshold of 34 mL/m2).16 To assess the association between LA dysfunction and demographics, clinical characteristics, and
echocardiographic measures of cardiac structure and function, patients with HFpEF were categorized according to quartiles of peak LA
strain with trend tests across ordered groups, using linear regression.
Because the available natriuretic peptide levels in TOPCAT were a
mixture of BNP and N-terminal pro-BNP, to assess the association of
peak LA strain with natriuretic peptide level, we combined these data
by calculating the Z score of the log-transformed BNP or N-terminal
pro-BNP level for each patient with available data (n=197).
The association of peak LA strain with the outcome variables of
interest was assessed using a time to event analysis with univariate and
multivariable Cox proportional hazards models, adjusting for prognostic demographic and clinical prognostic covariates (age, sex, race,
randomization strata, enrollment region [Americas versus Russia/
Georgia], randomized treatment assignment, history of atrial fibrillation, heart rate, New York Heart Association class, history of stroke,
creatinine, and hematocrit) as previously described,7 as well as LA
volume and core laboratory LVEF. The proportional hazards assumption was tested for all analyses, and there was no evidence of violation
of the proportional-hazards assumption by LA strain. Similar analyses were performed for LA phasic volumes (reservoir, conduit, and
pump function). In addition, we investigated whether prognostic characteristics of the LV in HFpEF,6,21 including LVH, LV systolic function measured by GLS, and filling pressure measured by E/E′ ratio,
may explain the association of LA functional measures with clinical
outcomes because of shared physiological mechanisms. To evaluate if
the rhythm at the time of echocardiography may affect the prognostic
use of LA strain, we repeated the analysis including all participants
with adequate image quality for LA speckle tracking (n=466), including 109 patients in atrial fibrillation at the time of echocardiography.
We also tested for effect modification of rhythm at the time of echocardiography on the relationship between LA strain and clinical outcomes. Finally, we performed 2 sensitivity analyses: (1) restricted to
patients with normal LA size as LA enlargement has been associated
with LA dysfunction10 and (2) restricted to patients enrolled in the
Americas as marked differences in patient characteristics and outcomes were noted by enrollment region in TOPCAT.22
All statistical analyses were performed with STATA 12.0 (Stata
Corp, College Station, TX). All tests were 2-sided and P values of
<0.05 were considered statistically significant.
Results
Among the 357 HFpEF patients with measurable peak LA strain,
the mean value was 25.9±7.7% and 52% had abnormal peak LA
strain based on data in a healthy population with similar age.11
The LA strain was abnormal in 47% in patients with normal LA
size and 71% patients with LA enlargement (Figure 2). Compared with the 3088 patients in the TOPCAT trial not included
in this LA strain analysis, patients included in this analysis were
more frequently female, less frequently white, less frequently
enrolled in Russia or Georgia, and less frequently in the previous hospitalization randomization stratum. Diabetes mellitus was
Figure 2. Distribution of peak left atrial (LA) strain in the heart failure with preserved ejection fraction (HFpEF) study population (A) overall
and (B) by LA size.
4 Santos et al LA Dysfunction and HFpEF
more prevalent and, partially by design, a clinical history of atrial
fibrillation was less prevalent in the included patients (Table I in
the Data Supplement). Similarly, several differences in clinical
and echocardiographic measures were noted between patients
in the TOPCAT echo study who were included, compared with
those not included (n=578) in this analysis (Table II in the Data
Supplement), most notably younger age, greater proportion of
women and nonwhite patients, lower heart rate and hematocrit,
greater LV volumes, higher LVEF, and smaller LA size.
Baseline Correlates of LA Strain
Patients with lower peak LA strain were older and had a
higher prevalence of atrial fibrillation when compared with
patients with higher peak LA strain (Table 1). LA strain
was not associated with New York Heart Association class.
Lower peak LA strain was associated with greater LA size,
greater LV and RV systolic dimensions, greater LV mass
index, LV wall thickness, and prevalence of hypertrophy
(Table 2; Figure II in the Data Supplement). Lower peak LA
Table 1. Baseline Clinical Characterstics in the Study Population Overall and by Quartile of Left Atrial Strain
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Peak LA Strain
Overall (n=357)
Quartile 1
<20.7
16.3±3.3 (n=90)
Quartile 2
20.7–25.5
23.3±1.5 (n=89)
Quartile 3
25.5–30.9
28.2±1.4 (n=89)
Quartile 4
30.9–48.6
35.8±4.2 (n=89)
P for Trend
Age, y
68.9±9.7
70.6±10.0
69.8±9.4
68.3±9.9
67.1±9.1
0.008
Female
202 (56.6%)
52 (57.8%)
52 (58.4%)
48 (53.9%)
50 (56.2%)
0.69
White
272 (76.2%)
69 (76.7%)
70 (78.7%)
67 (75.3%)
66 (74.2%)
0.59
187 (52%)
51 (57%)
46 (52%)
48 (54%)
42 (47%)
0.27
Enrollment in Russia/Georgia
101 (28.3%)
19 (21.1%)
32 (36.0%)
27 (30.3%)
23 (25.8%)
0.68
Enrollment strata: previous
hospitalization
233 (65.3%)
46 (51.1%)
65 (73.0%)
61 (68.5%)
61 (68.5%)
0.033
Hypertension
331(93.0%)
81 (90.0%)
82 (92.1%)
83 (93.3%)
85 (96.6%)
0.09
Randomized treatment assignment
Co-morbidities
Myocardial infarction
108 (30.3%)
31 (34.4%)
31 (34.8%)
23 (25.8%)
23 (26.1%)
0.12
Coronary revascularization
52 (14.6%)
17 (18.9%)
13 (14.6%)
6 (6.7%)
16 (18.2%)
0.54
Stroke
36 (10.1%)
10 (11.1%)
10 (11.2%)
5 (5.6%)
11 (12.5%)
0.91
Atrial fibrillation
77 (21.6%)
27 (30.0%)
21 (23.6%)
16 (18.0%)
13 (14.8%)
0.009
Diabetes mellitus
148 (41.6%)
44 (48.9%)
29 (32.6%)
38 (42.7%)
37 (42.1%)
0.65
Obesity
213 (59.8%)
47 (52.2%)
55 (61.8%)
51 (57.3%)
60 (68.2%)
0.06
0.09
NYHA functional class
1
27 (7.6%)
4 (4.5%)
3 (3.4%)
9 (10.1%)
11 (12.6%)
2
198 (55.9%)
54 (60.7%)
46 (51.7%)
48 (53.9%)
50 (57.5%)
3
126 (35.6%)
31 (34.8%)
38 (42.7%)
32 (36.0%)
25 (28.7%)
4
3 (0.9%)
0 (0.0%)
2 (2.2%)
0 (0.0%)
1 (1.2%)
32.9±7.1
32.2±7.4
32.8±6.8
32.1±6.4
34.6±7.7
0.05
Heart rate, beats per minute
67±11
68±12
67±11
67±10
65±9
0.06
Systolic blood pressure, mm Hg
129±15
127±16
129±16
129±15
129±14
0.37
Diastolic blood pressure, mm Hg
73±11
72±11
73±11
73±11
73±9
0.41
67±21
67±21
69±22
70±22
65±21
0.63
Creatinine, mg/dL
1.11±0.33
1.11±0.30
1.10±0.30
1.10±0.38
1.17±0.35
0.22
Hematocrit, %
38.6±4.8
38.9±4.6
38.4±5.1
38.8±4.7
38.4±4.8
0.67
91 (25.5%)
31 (34.4%)
19 (21.4%)
27 (30.3%)
14 (15.7%)
0.022
Physical characteristics
BMI, kg/m2
Laboratory values
eGFR, mL/min per 1.73 m2
Incident cardiovascular events
Cardiovascular composite
Cardiovascular death
43 (12.0%)
14 (15.6%)
12 (13.5%)
10 (11.2%)
7 (7.9%)
0.101
HF hospitalization
62 (17.4%)
23 (25.6%)
14 (15.7%)
18 (20.2%)
7 (7.9%)
0.007
Numbers represent mean±SD for continuous variables and n (%) for categorical variables. BMI indicates body mass index; eGFR, estimated Glomerular Filtration Rate;
HF, heart failure; and NYHA, New York Heart Association.
5 Santos et al LA Dysfunction and HFpEF
Table 2. Echocardiographic Measurements in the Study Population Overall and by Quartile of LA Strain
n
Peak LA Strain
Overall (n=357)
Quartile 1
<20.7
16.3±3.3 (n=90)
Quartile 2
20.7–25.5
23.3±1.5 (n=89)
Quartile 3
25.5–30.9
28.2±1.4 (n=89)
Quartile 4
30.9–48.6
35.8±4.2 (n=89)
P for
Trend
LVEDVi, mL/m2
352
52.0±16.2
54.7±19.6
52.3±16.7
52.4±14.0
48.7±13.5
0.022
LVESVi, mL/m
LV structure
352
21.3±10.4
24.7±13.5
21.7±10.8
20.8±8.0
18.0±7.3
<0.001
Mean wall thickness, cm
354
1.16±0.19
1.22±0.25
1.14±0.16
1.15±0.16
1.14±0.16
0.023
LV mass index, mg/m
2
353
109±30
119±32
109±30
107±26
100±28
<0.001
Relative wall thickness
354
0.48±0.10
0.51±0.16
0.46±0.07
0.47±0.07
0.49±0.09
0.40
LV hypertrophy
353
176 (49.9%)
55 (61.8%)
50 (56.2%)
41 (46.6%)
30 (34.5%)
<0.001
LV geometry
353
2
0.004
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Normal
56 (15.9%)
15 (16.9%)
13 (14.6%)
13 (14.8%)
15 (17.2%)
Concentric remodeling
121 (34.3%)
19 (21.4%)
26 (29.2%)
34 (38.6%)
42 (48.3%)
Eccentric hypertrophy
33 (9.3%)
10 (11.2%)
12 (13.5%)
6 (6.8%)
5 (5.8%)
Concentric hypertrophy
143 (40.5%)
45 (50.6%)
38 (42.7%)
35 (39.8%)
25 (28.7%)
LV systolic function
LVEF, %
353
60.4±7.7
56.7±9.1
59.9±7.3
61.2±6.3
63.9±6.3
<0.001
LV GLS, %
307
−16.4±3.4
−13.7±3.5
−16.5±3.0
−17.1±2.7
−18.3±2.6
<0.001
E/A ratio
332
1.2±0.6
1.5±0.8
1.2±0.5
1.1±0.5
1.0±0.5
<0.001
DT, ms
334
211±57
198±59
215±57
217±59
215±53
0.06
TDI E′ (septal), cm/s
269
5.6±1.9
4.8±1.4
5.4±1.8
5.7±2.1
6.5±1.9
<0.001
E/E′ (septal)
267
15.7±6.7
18.9±6.8
16.4±7.5
14.1±5.6
13.5±5.3
<0.001
LAV, mL
349
55.8±23.3
64.5±35.2
55.0±17.1
51.3±15.6
52.0±17.2
<0.001
LAVi, mL/m2
348
28.4±11.4
33.6±16.9
28.3±8.8
26.1±7.6
25.5±7.6
<0.001
LA diameter, cm
354
4.19±0.59
4.40±0.63
4.18±0.51
4.11±0.57
4.06±0.61
<0.001
Diastolic dysfunction grade (Olmsted)
277
28 (10.1%)
1 (1.6%)
8 (10.4%)
8 (11.9%)
11 (15.5%)
LV diastolic function
Normal
<0.001
Mild
82 (29.6%)
16 (25.8%)
17 (22.1%)
27 (40.3%)
22 (31.0%)
Moderate
116 (41.9%)
23 (37.1%)
39 (50.7%)
23 (34.3%)
31 (43.7%)
Severe
51 (18.4%)
22 (35.5%)
13 (16.9%)
9 (13.4%)
7 (9.9%)
Pulmonary vascular and RV
TR jet velocity, m/s
185
2.81±0.46
2.89±0.51
2.82±0.42
2.82±0.44
2.64±0.46
0.024
RVFAC
281
0.50±0.08
0.47±0.08
0.51±0.08
0.50±0.07
0.51±0.07
0.020
2
281
19.7±5.9
20.3±6.4
19.7±6.6
19.8±5.1
18.8±5.5
0.16
RVESA, cm2
281
9.9±3.5
10.8±3.8
9.6±3.7
10.0±3.4
9.2±3.0
0.027
≥Moderate mitral regurgitation
281
33 (11.7%)
8 (10.7%)
15 (21.7%)
5 (7.3%)
5 (7.3%)
0.17
Aortic valve peak velocity, m/s
283
1.51±0.46
1.47±0.52
1.59±0.46
1.50±0.41
1.51±0.47
0.87
Valve disease
342
44 (12.9%)
13 (14.8%)
16 (18.6%)
7 (8.3%)
8 (9.5%)
0.11
357
27.3±10.3
21.4±8.0
25.1±8.3
28.4±9.1
34.5±10.7
<0.001
357
36.6±13.2
24.9±10.0
35.4±9.7
41.0±11.7
45.1±11.5
<0.001
RVEDA, cm
Valvular disease
LA function
LA conduit function
LA passive emptying fraction
LA pump function
LA active emptying fraction
Numbers represent mean±SD for continuous variables and n (%) for categorical variables. DT indicates deceleration time; GLS, global longitudinal strain; LA, left
artery; LAVi, left atrial volume index; LVEDVi, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVi, left ventricular end-systolic
volume index; RV, right ventricle; RVEDA, right ventricular end-diastolic area; RVESA, right ventricular end-systolic area; RVFAC, right ventricular fractional area change;
TDI, tissue doppler imaging; and TR, tricuspid regurgitation.
6 Santos et al LA Dysfunction and HFpEF
Figure 3. Scatter plot and Pearson correlation of peak left atrial (LA) strain and (A) global longitudinal strain and (B) E/E′ in the study
population overall.
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strain was also associated with worse LV systolic function,
measured by LVEF and LV GLS, and higher LV diastolic
filling pressure (Figure 3). Worse LA strain was also associated with worse RV systolic function by RVFAC and higher
pulmonary artery systolic pressure by the tricuspid regurgitation jet velocity. Among the 197 patients with natriuretic
peptide levels measured, worse LA strain was associated
with higher natriuretic peptide levels (Table III in the Data
Supplement).
Peak LA Strain and Incident Cardiovascular Events
During a median follow-up of 31 (25th and 75th percentile
limits 18–43) months, 91 patients (25.5%) experienced the
primary composite end point, including 43 (12.0%) cardiovascular deaths and 62 (17.4%) patients with HF hospitalization. Lower peak LA strain was associated with a heightened
risk for the primary composite end point (P=0.009) and HF
hospitalization alone (P=0.003) in the unadjusted analysis
(Table 3). This association was independent of demographic
and clinical characteristics, LVEF, and LA size for HF hospitalization, but not for the composite outcome. The association of peak LA strain with incident HF hospitalization
remained significant after additional adjustment for LVH,
but not after further adjustment for LV GLS or E/E′ (Table
4). Similar results were observed in analysis including
patients in atrial fibrillation at the time of echocardiography
(Tables IV and V in the Data Supplement). No significant
interaction was noted between LA strain and rhythm at the
time of echocardiography for the composite end point, cardiovascular death, or HF hospitalization (all P for interaction
>0.05). In contrast, these associations were only observed
in unadjusted analysis when the analysis was restricted to
patients with normal LA size (Table Vi in the Data Supplement). Among patients enrolled in the Americas, peak LA
strain remained associated with the primary composite end
point and HF hospitalization alone in multivariable analysis adjusting for demographic and clinical characteristics,
LVEF, LA size, and LVH, although these associations were
not independent of LV GLS and E/E′ (Tables VII and VIII in
the Data Supplement).
LA Phasic Volumes and Incident Cardiovascular
Events
Lower LA strain was associated with worse measures of LA
conduit and pump function (Table 1). Concordant with our
findings with peak LA strain, LA emptying fraction—also
a measure of LA reservoir function—was associated with a
heightened risk for the primary composite end point in unadjusted analysis and for HF hospitalization alone in unadjusted
and adjusted analyses (Figure 4). Worse LA pump function,
measured by the LA active emptying fraction, was also associated with higher risk of the primary composite end point
and HF alone, and remained significantly associated with HF
hospitalization in adjusted analysis. LA conduit function,
reflected in the LA passive emptying fraction, was not prognostic of outcomes.
Discussion
Our study is the largest, to our knowledge, to assess the prognostic implications of LA dysfunction in HFpEF and the
Table 3. Association of Peak Left Atrial Strain With Cardiovascular Outcomes in Univariate and Multivariate Analysis
Unadjusted
Adjusted*
n
Events/PersonTime at Risk
HR (95% CI)
P Value
n
Events/PersonTime at Risk
HR (95% CI)
P Value
Composite end point
357
91/11 510
0.96 (0.94–0.99)
0.009
335
87/10 773
0.97 (0.94–1.00)
0.07
Cardiovascular death
357
43/12 487
0.97 (0.93–1.01)
0.13
335
41/11 749
0.98 (0.93–1.03)
0.50
HF hospitalization
357
62/11 510
0.95 (0.92–0.98)
0.003
335
59/10 773
0.95 (0.91–0.99)
0.009
Hazard ratios (HRs) are per unit reduction in peak left atrial strain. ACA indicates aborted cardiac arrest; CI, confidence interval; and HF, heart failure.
*Adjusted for age, sex, race, randomization strata, enrollment region (Americas versus Russia/Georgia), randomized treatment assignment, history of atrial fibrillation,
heart rate, New York Heart Association class, history of stroke, creatinine, hematocrit, left ventricular ejection fraction, left atrial volume index
7 Santos et al LA Dysfunction and HFpEF
Table 4. Potential Contributors to the Association of Peak Left Atrial Strain With Cardiovascular Outcomes
n
Events/Person-Time at Risk
HR (95% CI)
P Value
Model 1
335
87/10 773
0.97 (0.94–1.00)
0.07
Model 1+LVMi
332
87/10 676
0.97(0.94–1.00)
0.10
Model 1+GLS
289
73/9300
1.00 (0.96–1.04)
0.81
Model 1+E/E′
250
67/7927
0.99 (0.95–1.04)
0.69
Model 1
335
41/11 749
0.98 (0.93–1.03)
0.50
Model 1+LVMi
332
41/11 653
0.98 (0.93–1.04)
0.52
Model 1+GLS
289
34/10 081
1.03 (0.97–1.10)
0.40
Model 1+E/E′
250
32/8735
1.00 (0.94–1.07)
0.87
Model 1
335
59/10 773
0.95 (0.91–0.99)
0.009
Model 1+LVMi
332
59/10 676
0.95 (0.91–0.99)
0.015
Model 1+GLS
289
49/9300
0.98 (0.93–1.03)
0.39
Model 1+E/E′
250
44/7927
0.96 (0.91–1.02)
0.19
Composite end point
Cardiovascular death
HF hospitalization
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Hazard ratios (HRs) are per unit reduction in peak left atrial strain. ACA indicates aborted cardiac arrest; GLS, global longitudinal strain; HF, heart failure; and LVMi,
left ventricular mass index.
*Model 1: age, sex, race, randomization strata, enrollment region (Americas versus Russia/Georgia), randomized treatment assignment, history of atrial fibrillation,
heart rate, New York Heart Association class, history of stroke, creatinine, hematocrit, left ventricular ejection fraction, left atrial volume index.
first to evaluate the association of LA dysfunction with clinical outcomes beyond clinical predictors and LV features in
HFpEF. Worse LA strain was associated with a higher risk
of HF hospitalization independent of potential clinical confounders, but not after adjusting for LV systolic deformation
and filling pressure. These findings suggest that impairments
in LV systolic and diastolic function largely explain the association between impaired LA function and worse outcomes
in HFpEF.
LA function by strain analysis using speckle tracking
is a direct measurement of intrinsic LA myocardial deformation. Although not load independent, LA strain seems
to be less dependent on loading conditions and geometric
assumptions than traditional parameters23,24 and has high
feasibility and reproducibility.17 However, this measure
still lacks clear standardization and validation. The presence of LA dysfunction by speckle tracking in HFpEF has
been demonstrated in relatively small populations, and the
reported prevalence of LA reservoir dysfunction was around
30%.9–11 We found a high prevalence of LA reservoir dysfunction, independent of LA dilation. Patients with worse
LA strain were older and the association between lower LA
strain and older age may be related to the age-related loss or
hypertrophy of myocytes, interstitial fibrosis, and impaired
cellular calcium uptake that occurs in the LV25,26 and may
affect the LA in parallel.27 Indeed, we found that lower LA
strain was related to more LVH and greater impairment of
LV systolic and diastolic function. This association may,
therefore, be because of shared risk factors impairing LV
and LA function in parallel. Alternatively, or concomitantly,
primary impairments in LV performance may result in
abnormal LA performance. Worse LV longitudinal systolic
function may contribute to LA dysfunction because of the
influence of downward motion of the mitral plane during
ventricular systole, leading to reduced systolic expansion of
the LA.28 Indeed, LA strain was highly correlated with LV
longitudinal strain in our population (Figure 3). In addition,
diastolic dysfunction with resulting elevation in LV filling
pressure may contribute to LA dysfunction through increasing LA afterload and wall tension.29–31 We noted significant
associations of worse LA strain with higher E/E′ ratio and
E/A ratio and lower E′. However, we cannot exclude the
possibility that a primary abnormality of LA function, with
reduced LA compliance, may result in a higher LA pressure
for any given LV diastolic pressure, with resulting higher
E-wave velocity and E/E′ ratio. The low prevalence of significative mitral regurgitation (12%) in our population may
indicate that mitral valvular disease is not an major factor
responsible for LA dysfunction in patients with HFpEF
included in this analysis.
LA reservoir dysfunction is a predictor of cardiovascular outcomes in population-based studies,32,33 in patients
with HF with reduced ejection fraction34 and in patients
with stable coronary heart disease and preserved ejection
fraction.35 Two studies have demonstrated the prognostic value of LA strain after acute myocardial infarction,
but the larger of these studies (n=843 patients) showed
that this association was not independent of GLS and LA
size.36,37 There is little data on the prognostic relevance of
LA dysfunction in HFpEF. A recent study of 101 highly
symptomatic patients with HFpEF who were followed for
a median of 350 days (31 events) demonstrated an association between reduced LA reservoir function (measuring by
volumes) and increased risk of death after adjusting for age
8 Santos et al LA Dysfunction and HFpEF
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Figure 4. Forest plot graph demonstrating the association of left atrial (LA) function (reservoir, conduit, and pump) with (A) the primary end point and (B) heart failure hospitalization. *Multivariable analysis is adjusted for age, sex, race, enrollment region (Americas versus Russia/Georgia), randomization strata, history of atrial fibrillation, heart rate, New York Heart Association class, history
of stroke, creatinine, hematocrit, left ventricular ejection fraction, LA volume index, and randomized treatment assignment. Hazard
ratios are standardized and expressed per SD of the predictor variable.
and sex. A similar trend was also seen for LA active function (P=0.05).12
In our study, we found that peak LA strain is associated
with a risk of the composite end point and of HF hospitalization, but not cardiovascular mortality, after adjusting for
clinical variables, LA size, LVEF, and LV mass. HF hospitalization may be more sensitive to changes in LA strain than
cardiovascular mortality. Impaired LA function may contribute to clinical symptoms and decompensation in HFpEF
through elevated pulmonary venous pressure and associated
right heart dysfunction.12 Indeed, we observed a significant
association of impaired LA strain with LV filling pressure
(E/E′ ratio), pulmonary pressure (tricuspid regurgitation
velocity), and RV systolic function (RVFAC). In contrast
to a recent study by Melenovsky et al,12 we did not find LA
dysfunction to be a predictor of mortality in HFpEF. This
discrepancy may be because of differences in severity of illness of the study populations, with HFpEF patients in our
study at a less advanced stage of the syndrome (56% patients
New York Heart Association II) than the previous studied
group (74% patients New York Heart Association III and
IV). Importantly, peak LA strain no longer predicted adverse
events after adjusting for LV GLS or LV filling pressure.
Given the coupling of LA strain with LV longitudinal function because of the downward motion of the mitral plane in
systole, and with LV filling pressure because of impact on
LA wall tension, this finding suggests that LV systolic and
diastolic dysfunction largely explain the association of LA
dysfunction with adverse events in HFpEF. Atrial fibrillation
is common in HFpEF and is associated with adverse outcomes.38 Atrial fibrillation is also associated with worse LA
function.39 Importantly, however, LA strain was prognostic
among patients in sinus rhythm, suggesting that impaired LA
strain is not simply a marker of risk associated with atrial
fibrillation. In contrast, we did not observe the same prognostic value of LA function in patients with normal LA size. We
9 Santos et al LA Dysfunction and HFpEF
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are unable to conclusively determine whether this is a consequence of the lower prevalence of LA dysfunction in patients
with normal LA size compared with the overall population or
if impaired LA function is a weaker predictor among patients
with less advanced disease.
We observed an association of worse LA pump function
with heightened risk of the composite end point and of HF
alone. The prognostic importance of LA pump function in
HFpEF is not well known. LA pump function is associated with
risk of atrial fibrillation in patients with aortic stenosis40 and
in the general population,41 but has also been associated with
adverse cardiovascular events in hypertensive populations.42,43
Impaired LA contractile reserve secondary to progressive
elevation of LV filling pressure may contribute to HFpEF
symptoms, particularly during exercise.44 Concomitantly,
reduced LV longitudinal function, with associated impairment
in LA systolic expansion and reservoir function, may result
in increased reliance on late-diastolic LA pump function for
adequate LV filling.
Several limitations of this analysis should be noted. We
analyzed only a subset of the patients enrolled in the overall TOPCAT trial, with some notable differences between
the patients included and excluded from this analysis. The
generalizability of these findings to the overall TOPCAT
population, and to the HFpEF syndrome more broadly, may
therefore be limited. Significant differences in patient characteristics, event rates, and treatment response have been
noted by region of enrollment (Americas versus Russia/
Georgia) in TOPCAT.22 However, we found similar findings
in a sensitivity analysis restricted to the patients enrolled
in the Americas (Tables V and VI in the Data Supplement).
Although the analysis of 3D images may be a more accurate measurement of LA function, such images were not
acquired in the TOPCAT trial.45 Limited data are available
on the stability of LA strain measures over time. In a subset
of patients in this study, echocardiography was performed
≤6 months before randomization, possibly resulting in
misclassification. In addition, the generalizability of these
findings to patients with HFpEF in the community may be
limited because of the inclusion and exclusion criteria of the
TOPCAT trial.
In summary, LA dysfunction is associated with a higher
risk of HF hospitalization in HFpEF, independent of potential
clinical confounders, but not independent of LV systolic deformation and diastolic filling pressure. Concomitant impairments in LV systolic and diastolic function largely explain the
association of LA dysfunction with adverse clinical outcomes
in HFpEF. Our data suggested that the assessment of LA function does not have additional clinical use beyond the assessment of LV function in the prognostic evaluation of patients
with HFpEF. Future studies are indicated to investigate the
mechanisms responsible for coupled LA and LV dysfunction
in HFpEF.
Sources of Funding
Treatment of Preserved Cardiac Function Heart Failure With an
Aldosterone Antagonist (TOPCAT) was funded by National Heart,
Lung, and Blood Institute (NHLBI), National Institutes of Health,
contract number HHSN268200425207C. The content of this article
does not necessarily represent the views of the sponsor or of the
Department of Health and Human Services. The work for this article
was also supported by NHLBI grant 1K08HL116792 (Dr Shah) and
AHA grant 14CRP20380422 (Dr Shah).
Disclosures
Dr A.M. Shah reports receiving research support from Novartis,
Gilead, and Actelion. Dr S.J. Shah reports receiving consulting fees
from the American Board of Internal Medicine, AstraZeneca, DC
Devices, Novartis, Bayer, and Alnylam; and speaker fees from the
Pulmonary Hypertension Association and the American Society
of Echocardiography. Dr Pitt reports serving as a consultant for
Pfizer, Bayer, Elli-Lilly, Novartis, and DaVinci therapeutics, and
has a patent pending on site-specific delivery of Eplerenone to the
myocardium.
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CLINICAL PERSPECTIVE
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Heart failure with preserved ejection fraction (HFpEF) is common, accounting for an increasing proportion of patients hospitalized with acute decompensated heart failure. Left atrial size is an established marker of risk for adverse outcomes in
HFpEF. However, the independent prognostic importance of LA function in HFpEF is not known. We assessed LA function
measured by speckle-tracking echocardiography in 357 patients with HFpEF enrolled in the Treatment Of Preserved Cardiac
Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. At a mean follow-up of 31 months, 91 patients
(25.5%) experienced the primary composite end point of cardiovascular death, HF hospitalization, and aborted sudden death.
Lower peak LA strain, indicating LA dysfunction, was associated with a higher risk of the composite end point (hazard ratio,
0.96 per unit of reduction in strain; 95% confidence interval, 0.94–0.99; P=0.009) and of HF hospitalization alone (hazard
ratio, 0.95 per unit of reduction in strain; 95% confidence interval, 0.92–0.98; P=0.003). The association of LA strain with
incident HF hospitalization remained significant after adjustment for clinical confounders, but not after further adjustment
for LV global longitudinal strain and the E/E′ ratio, parameters of LV systolic and diastolic function, respectively. Our findings suggest that quantification of LA function does not provide additional clinical use beyond the assessment of LV function
in the prognostic evaluation of patients with HFpEF. Future studies are indicated to investigate the mechanisms responsible
for coupled LA and LV dysfunction in HFpEF.
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Prognostic Relevance of Left Atrial Dysfunction in Heart Failure With Preserved Ejection
Fraction
Angela B.S. Santos, Gabriela Querejeta Roca, Brian Claggett, Nancy K. Sweitzer, Sanjiv J.
Shah, Inder S. Anand, James C. Fang, Michael R. Zile, Bertram Pitt, Scott D. Solomon and
Amil M. Shah
Circ Heart Fail. 2016;9:
doi: 10.1161/CIRCHEARTFAILURE.115.002763
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