Background
The authors hypothesized that in patients with heart failure with normal left ventricular (LV) ejection fraction (HFNEF), the same fibrotic processes that affect the subendocardial layer of the left ventricle could also alter the subendocardial fibers of the left atrium. Consequently, these fibrotic alterations, together with chronically elevated LV filling pressures, would lead to both systolic and diastolic subendocardial dysfunction of the left atrium (i.e., impaired left atrial [LA] longitudinal systolic and diastolic function) in patients with HFNEF.
Methods
Patients with HFNEF and a control group consisting of asymptomatic patients with LV diastolic dysfunction (LVDD) matched by age, gender, and LV ejection fraction were studied using two-dimensional speckle-tracking echocardiography.
Results
A total of 420 patients were included (119 with HFNEF and 301 with asymptomatic LVDD). LA longitudinal systolic (LA late diastolic strain rate) and diastolic (LA systolic strain and strain rate) function was significantly more impaired in patients with HFNEF (LA late diastolic strain rate, −1.17 ± 0.63 s −1 ; LA systolic strain, 19.9 ± 7.3%; LA systolic strain rate, 1.17 ± 0.46 s −1 ) compared with those with asymptomatic LVDD (−1.80 ± 0.70 s −1 , 30.8 ± 11.4%, and 1.67 ± 0.59 s −1 , respectively) (all P values < .0001). On multiple regression analysis, LV global longitudinal systolic strain and diastolic strain rate were the most important independent predictors of LA longitudinal systolic and diastolic function, in contrast to noninvasive LV filling pressures (i.e., mitral E/e′ average septal-lateral ratio), which were modestly related to LA longitudinal systolic and diastolic function. Furthermore, in patients with HFNEF, the subendocardial function of both the left atrium and the left ventricle was significantly impaired in high proportions. In that regard, in patients with HFNEF, the rate of LA longitudinal systolic and diastolic dysfunction was 65.5% and 28.5%, whereas the prevalence of LV longitudinal systolic and diastolic dysfunction was 81.5% and 58%, respectively. In addition, patients with both systolic and diastolic longitudinal dysfunction of the left atrium presented worse NYHA functional class as compared with those with normal LA longitudinal function.
Conclusions
In patients with HFNEF, LA subendocardial systolic and diastolic dysfunction is common and possibly associated with the same fibrotic processes that affect the subendocardial fibers of the left ventricle and to a lesser extent with elevated LV filling pressures. Furthermore, these findings suggest that LA longitudinal systolic and diastolic dysfunction could be related to reduced functional capacity during effort in patients with HFNEF.
Heart failure (HF) with normal left ventricular (LV) ejection fraction (HFNEF) is a highly prevalent pathology, with a significant increase of prevalence in patients aged ≥85 years. Unlike systolic HF, HFNEF is characterized by normal LV systolic function, often evaluated using the biplane Simpson’s method. However, with the development of new echocardiographic technologies (two-dimensional speckle tracking), recent studies have shown that despite having normal LV ejection fraction (LVEF), patients with HFNEF have significantly lower values of LV longitudinal systolic function both at rest and during submaximal exercise than healthy subjects, suggesting that in these patients, LV subendocardial systolic function is not preserved. Nevertheless, despite these recent studies, the role of left atrial (LA) subendocardial systolic and diastolic function (i.e., the longitudinal systolic and diastolic function of the left atrium) in the pathophysiology of HFNEF remains poorly understood.
HFNEF is a known cause of elevated LV filling pressures. An increase in LA afterload through the development of elevated LV filling pressures secondary to severe LV diastolic dysfunction (LVDD) has long been considered the main underlying mechanism of LA dysfunction. However, several and recent studies suggest that the degree of elevated LV filling pressures may not fully explain LA failure and that LA myocardial fibrosis may play a role in the systolic and diastolic dysfunction of the left atrium. It is well known that LV interstitial fibrosis as a consequence of comorbid conditions, such as type 2 diabetes, obesity, hypertension, and previous history of coronary artery disease (CAD), affects primarily the subendocardial systolic and diastolic function of the left ventricle (i.e., LV longitudinal systolic and diastolic function). In that regard, we hypothesized that in patients with HFNEF as a result of elevated prevalence of comorbidities (i.e., type 2 diabetes, obesity, hypertension, and history of CAD), the same fibrotic processes that affect the subendocardial layer of the left ventricle could also alter the subendocardial fibers of the left atrium. Consequently, these fibrotic alterations and to a lesser extent elevated LV filling pressures would lead to both systolic and diastolic longitudinal dysfunction of the left atrium in patients with HFNEF. With the aim of validating our hypothesis and elucidating the pathophysiologic mechanisms of HFNEF, we analyzed LA longitudinal systolic and diastolic function using two-dimensional speckle-tracking echocardiography in patients with HFNEF and in a control group consisting of asymptomatic patients with LVDD matched by age, gender, and LVEF.
Methods
Study Population
We enrolled consecutive patients aged ≥18 years with signs or symptoms of HF with LVEF > 50% by transthoracic echocardiography (according to the diagnostic criteria of the consensus of experts in HFNEF and in LV diastolic function of the European Society of Echocardiography and the American Society of Echocardiography) and a control group consisting of asymptomatic patients with LVDD without history of HFNEF (in accordance with the diagnostic criteria of the European Society of Echocardiography and the American Society of Echocardiography; i.e., septal e′ mitral annular peak velocity < 8 cm/s, lateral e′ mitral annular peak velocity < 10 cm/s, or maximal LA volume index ≥ 34 mL/m 2 ). These two groups were matched by age, gender, and LVEF (matching 1:2; i.e., two control subjects for each patient with HFNEF). Three conditions were necessary for the diagnosis of HFNEF: (1) presence of signs or symptoms of congestive HF (dyspnea [New York Heart Association (NYHA) class ≥ II], pulmonary rales, pulmonary edema, bilateral lower extremity edema, hepatomegaly, or fatigue), (2) presence of normal LV systolic function (LVEF > 50% by Simpson’s method), and (3) evidence of LVDD (septal e′ mitral annular peak velocity < 8 cm/s, lateral e′ mitral annular peak velocity < 10 cm/s, or maximal LA volume index ≥ 34 mL/m 2 ). We included consecutive inpatients and outpatients admitted to the Department of Cardiology (Campus Virchow-Klinikum) of Charité University Hospital (Berlin, Germany) from April 1, 2009, to April 1, 2010. The Charité institutional review board approved this research project, and informed consent was obtained from all subjects.
The selection of exclusion criteria in this study was based on the consensus of experts in HFNEF and in LV diastolic function. In that regard, to avoid reversible causes of myocardial dysfunction, patients with active CAD were excluded from this study (i.e., patients with unstable angina or non–ST-segment elevation myocardial infarction [NSTEMI] without revascularization or with revascularization in the past 72 hours, patients with ST-segment elevation myocardial infarction [STEMI] in the past 30 days, subjects awaiting coronary artery bypass grafting or within 90 days postoperatively, subjects with chronic stable angina, and patients with evidence of myocardial ischemia assessed by stress echocardiography). Moreover, with the purpose of excluding causes of dyspnea or myocardial dysfunction other than HFNEF, patients with pulmonary arterial hypertension (causes other than isolated LVDD or HFNEF), severe pulmonary disease (defined as pulmonary pathology with supplemental oxygen requirement), severe kidney disease (glomerular filtration rate < 30 mL/min/1.72 m 2 for ≥3 months, history of renal transplantation, or severe acute renal failure with dialysis requirement), severe chronic liver disease or history of liver transplantation, congenital heart disease, pericardial disease (moderate or severe pericardial effusion [echo-free space in diastole ≥ 10mm] or constrictive pericarditis), cardiomyopathy, and valvular heart disease (defined as mild, moderate, or severe mitral or aortic stenosis, moderate or severe nonfunctional mitral or tricuspid regurgitation, severe functional mitral or tricuspid regurgitation, and moderate or severe aortic regurgitation) were excluded from this study. In addition, to avoid underestimations of myocardial and mitral annular measurements, patients with valvular heart surgery, mitral annular calcification (≥5 mm), cardiac pacing or cardiac resynchronization therapy, and poor two-dimensional quality in ≥1 LV or LA myocardial segment (for analysis by two-dimensional and speckle-tracking echocardiography in the apical four-chamber, two-chamber, and long-axis views) were excluded from this study. Furthermore, to avoid an underestimation of LA systolic function by LA myocardial stunning, patients with atrial arrhythmias in the past 8 weeks or at the time of inclusion in the study were also excluded.
Two-Dimensional and Speckle-Tracking Echocardiography
LV Measurements
All patients were examined at rest in the left lateral decubitus position using a Vivid 7 ultrasound system (GE Vingmed Ultrasound AS, Horten, Norway). The echocardiographic measurements and analyses were performed by experienced echocardiographers blinded to each other’s results. LV diameters, LV volumes, LV mass and grading of LV hypertrophy, LVEF (Simpson’s method), LA volumes and remodeling (maximal LA volume index ≥ 34 mL/m 2 ), LV filling pressures, and LV diastolic function were assessed as recommended by the American Society of Echocardiography. LV filling pressures were noninvasively assessed by the mitral E/e′ average septal-lateral ratio (i.e., the ratio of early diastolic mitral inflow peak velocity by pulsed-wave Doppler to e′ mitral annular [average septal-lateral] peak velocity using spectral Doppler tissue imaging [DTI]). The analyses on two-dimensional speckle-tracking echocardiography (using EchoPAC version 6.1 workstation; GE Vingmed Ultrasound AS) were performed offline and blinded to the clinical characteristics of the patients. The measurements of LV longitudinal systolic strain and LV longitudinal early diastolic strain rate (SRe) were performed in the apical four-chamber, two-chamber, and long-axis views. The average values of peak longitudinal systolic strain and peak longitudinal early-diastolic SRe, obtained of all segments of the left ventricle, were denominated as LV global longitudinal systolic strain (LV-Strain) and LV global longitudinal early-diastolic SRe (LV-SRe), respectively. All echocardiographic measurements and analyses were performed in sinus rhythm and were the average of three consecutive cycles.
LA Measurements
In patients in sinus rhythm, quantitative assessments of the systolic and diastolic function of the left atrium were obtained. The volumetric parameters of LA systolic function were calculated as follows : LA total emptying fraction = (LA total emptying volume/maximal LA volume in ventricular systole just before mitral valve opening) × 100, and LA active emptying fraction = (LA active emptying volume/LA volume at the onset of the P wave on electrocardiography) × 100. LA total and active emptying fractions were derived in the apical four-chamber and two-chamber views using two-dimensional (Simpson’s method) echocardiography. LA total emptying volume was calculated as = (maximal LA volume in ventricular systole just before mitral valve opening − minimal LA volume after mitral valve closure), and LA active emptying volume derived as = (LA volume at the onset of the P wave on electrocardiography − minimal LA volume after mitral valve closure). Furthermore, LA longitudinal systolic and diastolic function was analyzed (offline and blinded to the clinical characteristics of the patients) in the apical four-chamber and two-chamber views using two-dimensional speckle-tracking echocardiography (using EchoPAC version 6.1 workstation; GE Vingmed Ultrasound AS). LA longitudinal systolic strain (LA-Strain) and LA longitudinal systolic strain rate (LA-SR) (parameters of the longitudinal relaxation or diastolic function of the left atrium) were derived as the average values of peak systolic strain and strain rate of all LA segments obtained in the four-chamber and two-chamber views during LV systole. LA longitudinal late-diastolic strain rate (LA-SRa) (a parameter of the longitudinal contraction or systolic function of the left atrium) was calculated as the average value of peak late diastolic strain rate of all LA segments obtained in the four-chamber and two-chamber views during LV late-diastole or atrial contraction. Furthermore, quantitative pulsed spectral DTI to assess LA systolic function was also performed (i.e., septal and/or lateral late diastolic [a′] mitral annular peak velocity on DTI). All echocardiographic measurements and analyses were the average of three consecutive cycles.
Echocardiographic Criteria
The criteria of LA and LV systolic and diastolic dysfunction were based on previously validated studies (i.e., values below the 95% confidence interval of healthy subjects). In that regard, LV and LA dysfunction was defined as follows: LV longitudinal systolic dysfunction = LV global longitudinal systolic strain > −16%, LV longitudinal diastolic dysfunction = LV global longitudinal early-diastolic SRe < 0.80 s −1 , LA longitudinal systolic dysfunction = LA-SRa > −1.32 s −1 , LA longitudinal diastolic dysfunction = LA-SR < 0.82 s −1 , and LA systolic dysfunction (by Simpson’s method) = LA total emptying fraction < 50% or LA active emptying fraction < 35%.
Statistical Analysis
Continuous data are presented as mean ± SD and dichotomous data as percentages. Differences in continuous variables between groups (comparisons of two groups) were assessed using unpaired Student’s t tests only, because all data were normally distributed (the Kolmogorov-Smirnov test was used to test for normal distribution). Categorical variables were compared using χ 2 tests and Fisher exact tests as appropriate. Comparisons between three or more groups were assessed using one-way analysis of variance. The relationships between continuous variables were analyzed using simple linear regression analysis. Selections of independent variables for the prediction of LA longitudinal systolic and diastolic function were performed using forward stepwise multivariate analysis. With the purpose of determining the intraobserver and interobserver variability of LA measurements, we analyzed the mean absolute differences and interclass correlation coefficients of LA longitudinal systolic and diastolic function in 22 randomly selected patients. All statistical analyses were performed using SAS version 9 (SAS Institute Inc., Cary, NC). Differences were considered statistically significant at P < .05.
Results
Patient Characteristics and LV Echocardiographic Measurements
A total of 654 patients met the eligibility criteria during the study period (218 with HFNEF and 436 with asymptomatic LVDD). However, 89 patients (17 with HFNEF and 72 with asymptomatic LVDD) could not be enrolled, because of poor two-dimensional quality in one or more LA and LV segments for analysis by speckle-tracking echocardiography and Simpson’s method ( n = 24), severe kidney disease ( n = 12), cardiac pacing ( n = 8), severe chronic liver disease ( n = 8), NSTEMI in the past 72 hours ( n = 7), STEMI in the past 30 days ( n = 15), coronary artery bypass grafting in the past 90 days ( n = 4), evidence of myocardial ischemia assessed by stress echocardiography ( n = 5), mild aortic stenosis ( n = 4), mild mitral stenosis ( n = 1), and moderate pericardial effusion ( n = 1). Moreover, to avoid an underestimation of LA systolic function by LA myocardial stunning, patients with atrial arrhythmias in the past 8 weeks or at the time of inclusion in the study were also excluded (82 with HFNEF and 63 with asymptomatic LVDD). Thus, 420 patients were ultimately studied and analyzed (119 with HFNEF and 301 with asymptomatic LVDD). Clinical and echocardiographic characteristics of these patients are summarized in Table 1 . The comorbidities in patients with HFNEF and those with asymptomatic LVDD were characterized by the presence of type 2 diabetes, hypertension, obesity, and previous history of CAD (92% NSTEMI and 8% STEMI in patients with HFNEF and 95% NSTEMI and 5% STEMI in those with asymptomatic LVDD; Table 1 ). Furthermore, we found that patients with HFNEF presented significantly more impaired LV global longitudinal systolic strain and early-diastolic SRe than those with asymptomatic LVDD ( Table 1 ). Nevertheless, there were no significant differences in LVEF or LV end-diastolic volume index between patients with HFNEF and those with asymptomatic LVDD, and moderate or severe functional mitral regurgitation was absent in both groups.
| Variable | HFNEF ( n = 119) | Asymptomatic LVDD ( n = 301) | P |
|---|---|---|---|
| Clinical characteristics | |||
| Age (y) | 70 ± 10 | 69 ± 9 | .151 |
| Women | 44% | 39% | .398 |
| Body mass index (kg/m 2 ) | 29 ± 5 | 27 ± 4 | .0019 |
| Hemoglobin (g/dL) | 13.3 ± 1.6 | 13.4 ± 1.6 | .282 |
| eGFR (mL/min/1.73 m 2 ) | 67.6 ± 22.6 | 75.9 ± 21 | .0006 |
| Hypertension | 100% | 82% | <.0001 |
| Type 2 diabetes | 34.5% | 22% | .0023 |
| Obesity | 35% | 11% | <.0001 |
| History of CAD | 62% | 33% | <.0001 |
| Systolic blood pressure (mm Hg) | 140 ± 22 | 133 ± 20 | .016 |
| Diastolic blood pressure (mm Hg) | 80 ± 11 | 79 ± 12 | .202 |
| LV conventional measurements | |||
| LVEF (%) | 59 ± 7 | 61 ± 6 | .078 |
| LVEDVI (mL/m 2 ) | 45 ± 13 | 42 ± 11 | .088 |
| LV mass index (g/m 2 ) | 122 ± 30 | 105 ± 23 | <.0001 |
| Septal e′ mitral annular peak velocity (cm/s) | 4.6 ± 1.4 | 6 ± 1.4 | <.0001 |
| Lateral e′ mitral annular peak velocity (cm/s) | 6.4 ± 1.4 | 8 ± 1.6 | <.0001 |
| Mitral E/e′ (average septal-lateral) ratio | 17.1 ± 5.9 | 10.6 ± 3.9 | <.0001 |
| LV measurements by speckle-tracking | |||
| LV global longitudinal systolic strain (%) | −14.09 ± 3.31 | −19.01 ± 2.63 | <.0001 |
| LV longitudinal systolic dysfunction (LV-Strain > −16%) | 81.5% | 15.5% | <.0001 |
| LV global longitudinal early-diastolic SRe (s −1 ) | 0.82 ± 0.26 | 1.03 ± 0.31 | <.0001 |
| LV longitudinal diastolic dysfunction (LV-SRe < 0.80 s −1 ) | 58% | 22% | <.0001 |
LA Systolic and Diastolic Function in Patients with HFNEF
The analyses of LA function showed that patients with HFNEF had significantly more impaired LA systolic and diastolic function compared to those with asymptomatic LVDD ( Tables 2 and 3 , Figures 1 and 2 ). Moreover, we found that patients in NYHA functional classes II, III, and IV had significantly lower values of LA longitudinal systolic and diastolic function than patients in NYHA functional class I ( Table 4 ). Furthermore, on multiple regression analysis, we found that LV global longitudinal systolic strain and early-diastolic SRe were the most important independent predictors of LA longitudinal systolic and diastolic function ( Table 5 , Figure 3 ), in contrast to noninvasive LV filling pressures (i.e., mitral E/e′ average septal-lateral ratio), which were modestly related to LA longitudinal systolic and diastolic function.
| Variable | HFNEF ( n = 119) | Asymptomatic LVDD ( n = 301) | P |
|---|---|---|---|
| LA volumes | |||
| LA Vol max (mL) | 64.8 ± 24 | 45 ± 16 | <.0001 |
| LA Vol min (mL) | 27.8 ± 18.3 | 15.3 ± 9.5 | <.0001 |
| LA Vol p (mL) | 48.8 ± 21.1 | 33.5 ± 12.9 | <.0001 |
| LA total emptying volume (mL) | 37 ± 11 | 29.7 ± 9.5 | .0006 |
| LA active emptying volume (mL) | 21 ± 7.5 | 18.2 ± 6.4 | .0885 |
| LA Doppler parameters | |||
| A mitral inflow peak velocity (cm/s) | 65.5 ± 26.8 | 76.6 ± 19.8 | <.0001 |
| Septal a′ mitral annular peak velocity (cm/s) | 6.8 ± 2.3 | 9.1 ± 2 | <.0001 |
| Lateral a′ mitral annular peak velocity (cm/s) | 8.3 ± 2.9 | 10.6 ± 2.4 | <.0001 |
| Septal-lateral a′ mitral annular peak velocity (cm/s) | 7.5 ± 2.4 | 9.8 ± 2 | <.0001 |
| LA remodeling | |||
| LA Vol max index (mL/m 2 ) | 32.5 ± 13 | 23.5 ± 8 | <.0001 |
| LA Vol max index ≥ 34 mL/m 2 | 78% | 19.6% | <.0001 |
| LA systolic function | |||
| LA total emptying fraction (%) | 57 ± 14.7 | 66 ± 10.6 | <.0001 |
| LA active emptying fraction (%) | 43 ± 16.2 | 54.3 ± 13 | <.0001 |
| LA systolic dysfunction | |||
| LA total emptying fraction < 50% | 31% | 5.6% | <.0001 |
| LA active emptying fraction < 35% | 26% | 9.3% | <.0001 |
| Variable | HFNEF ( n = 119) | Asymptomatic LVDD ( n = 301) | P |
|---|---|---|---|
| LA longitudinal diastolic function | |||
| LA-Strain (%) | 19.9 ± 7.3 | 30.8 ± 11.4 | <.0001 |
| LA-SR (s −1 ) | 1.17 ± 0.46 | 1.67 ± 0.59 | <.0001 |
| LA longitudinal systolic function | |||
| LA-SRa (s −1 ) | −1.17 ± 0.63 | −1.80 ± 0.70 | <.0001 |
| LA longitudinal diastolic dysfunction | |||
| LA-SR < 0.82 s −1 | 28.5% | 1.3% | <.0001 |
| LA longitudinal systolic dysfunction | |||
| LA-SRa > −1.32 s −1 | 65.5% | 30% | <.0001 |
| Variable | NYHA functional class | P (ANOVA) | |||
|---|---|---|---|---|---|
| I ( n = 301) | II ( n = 85) | III ( n = 21) | IV ( n = 13) | ||
| LA systolic function | |||||
| LA total emptying fraction (%) | 66 ± 10.6 | 59.1 ± 14.3 ∗ | 53.8 ± 15.4 † | 50.7 ± 14.4 ‡ | <.0001 |
| LA active emptying fraction (%) | 54.3 ± 13 | 45.7 ± 15.7 ∗ | 38.5 ± 16.4 † | 36.1 ± 16.9 ‡ | <.0001 |
| LA-SRa (s −1 ) | −1.80 ± 0.70 | −1.13 ± 0.59 ∗ | −1.40 ± 0.82 † | −0.88 ± 0.14 ‡ | <.0001 |
| LA diastolic function | |||||
| LA-Strain (%) | 30.8 ± 11.4 | 19.6 ± 7.1 ∗ | 22.1 ± 8.6 † | 17.0 ± 1.17 ‡ | <.0001 |
| LA-SR (s −1 ) | 1.67 ± 0.59 | 1.15 ± 0.44 ∗ | 1.33 ± 0.57 † | 0.83 ± 0.07 ‡ | <.0001 |
∗ P < .05, NYHA class II versus class I.
† P < .05, NYHA class III versus class I.
| Variable | LA late diastolic strain rate | LA systolic strain rate | LA systolic strain | |||
|---|---|---|---|---|---|---|
| R | P | R | P | R | P | |
| LV global longitudinal systolic strain | .41 | <.0001 ∗ | .44 | <.0001 † | .52 | <.0001 ‡ |
| LV global longitudinal early-diastolic SRe | .30 | <.0001 ∗ | .41 | <.0001 † | .43 | <.0001 ‡ |
| Mitral E/e′ (average septal-lateral) ratio | .27 | .0002 | .32 | <.0001 | .30 | <.0001 |
| E mitral inflow peak velocity | .29 | <.0001 | .25 | .0002 | .19 | .0054 |
| Septal-lateral e′ mitral annular peak velocity | .10 | .1155 | .16 | .0488 | .23 | .0014 |
| LV mass index | .27 | <.0001 | .22 | .0004 | .21 | .0009 |
| LV relative wall thickness | .05 | .3605 | .01 | .8379 | .10 | .2158 |
| Midwall fractional shortening | .25 | <.0001 | .24 | .0001 | .21 | .0008 |
| Body mass index | .20 | .0108 | .17 | .0458 | .22 | .0002 |
| Pulse pressure | .04 | .6473 | .12 | .1369 | .10 | .2160 |
| Systolic blood pressure | .03 | .7341 | .01 | .8998 | .06 | .4596 |
| Diastolic blood pressure | .07 | .175 | .17 | .0458 | .05 | .5276 |
| Age | .02 | .7403 | .08 | .2265 | .16 | .0116 |
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