Left Atrial Ejection Force as a Marker for the Diagnosis of Heart Failure with Preserved Ejection Fraction.

INTRODUCTION: Several echocardiographic techniques are used to diagnose heart failure with preserved ejection fraction (HFPEF). Left atrial ejection force (LAEF) is a measure of left atrial (LA) systolic function. The aim of this study was to examine the use of LAEF as a measure for the diagnosis of HFPEF.
METHODS: A prospective study including 100 patients with HFPEF and 100 healthy controls. Heart failure association algorithm score for the diagnosis of HFPEF (HFA-PEFF score) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) were assessed. Transthoracic echocardiography measured indexed left ventricular mass index (LVMI), left ventricular (LV) ejection fraction, LA volume index (LAVI), global longitudinal strain (GLS), trans-mitral Doppler velocities, E/A ratio, E/e' ratio, and estimation of LAEF.
RESULTS: Patients in the HFPEF group were more frequently hypertensive, diabetic, and had a history of ischemic heart disease. NT-pro-BNP was higher in the HFPEF group (P < 0.0001). LVMI, relative wall thickness, and LAVI were all significantly higher in the HFpEF group (P < 0.0001 for all). LV-GLS was significantly lower in the HFPEF (P < 0.0001). LAEF was significantly higher in the study group 142.14 ± 24.27 versus 92.18% ±13.99% (P < 0.0001). A sub-group of 18 patients in the study group with a borderline HFA-PEF score of 4 had a LAEF that was significantly higher than the control group (P < 0.0001) but did not differ from the rest of the HFPEFF group patients.
CONCLUSION: LAEF was significantly higher in patients with HFPEF compared to healthy controls. Patients with a borderline HFA-PEFF score of 4 had a significantly higher LAEF as compared to controls. Copyright:

INTRODUCTION

Nearly half of all patients suffering from heart failure have a normal or near normal ejection fraction referred to as heart failure with preserved ejection fraction (HFPEF). The prevalence of HFPEF remains on the rise. This has been attributed to improved diagnosis caused by the availability of advanced cardiac imaging modalities, an aging population, and the constant rise in related risk factors such as obesity, hypertension, metabolic syndrome, and renal impairment.[123]

HFPEF is associated with increased left ventricular (LV) diastolic pressures despite essentially normal LV end diastolic volumes. Patient with HFPEF usually have LV wall hypertrophy with increased interstitial collagen deposition and cellular infiltration of the myocardium. Such histological changes cause the LV to be stiff and lose part of its distensibility and elasticity. LV stiffness causes an increase in left atrial (LA) pressure which eventually increases pulmonary venous pressure.[45]

Guidelines published by both the European Society of Cardiology (ESC) and the American Heart Association have defined specific clinical, echocardiographic, and biomarker criteria for a diagnosis of HFPEF to be established.[678] Recently, the Heart Failure Association of the ESC presented a consensus document with a proposed diagnostic algorithm specifically designed to aid clinicians with the diagnosis of HFPEF by using a scoring system.[9]

LA ejection force (LAEF) has been used as a measure of LA systolic function. It refers to the force exerted by the LA to force blood into the LV at the end of ventricular diastole. Based on the Newton's second law, LAEF is calculated as the product of the mass and acceleration of blood from the LA during atrial systole. It has been previously studied in patients with myocardial infarction, heart failure, hypertrophic cardiomyopathy (HCM), and to assess LA function following successful catheter ablation for atrial fibrillation.[10111213]

The aim of this study was to examine the use of LAEF as measure for the diagnosis of HFPEF.

Methods

This was a prospective study performed on 100 consecutive patients with HFPEF and 100 age- and sex-matched healthy controls with normal LV diastolic function during the period from May 2019 to June 2020. Approval of Institutional Ethical Committee was obtained for the study protocol. Informed consents were obtained from all participating subjects.

Patients in the study group had an established diagnosis of HFPEF based on the definition given by the ESC in the form of having symptoms and signs of heart failure, an N-terminal pro-brain natriuretic peptide (NT-pro-BNP) more than 125 pg/ml, in addition to, documented echocardiographic findings such as a LA volume index (LAVI) more than 34 ml/m2, a LV mass index (LVMI) more than 115 g/m2 for males and 95 g/m2 for females, or an E/e' ratio more than 13 with septal and lateral e` <9 cm/s.[6]

Patients were excluded from this study if they had any of the following: LV ejection fraction (LVEF) <50%; HCM; having no signs or symptoms of HFPEF; more than mild valvular stenosis or regurgitation; atrial fibrillation; rhythm other than sinus; recent (<1 month) myocardial infarction or acute coronary syndrome; recent (<1 month) hospitalization for decompensated heart failure; history of coronary artery bypass grafting or valve replacement; age <18 years old.

Baseline clinical and laboratory assessment

Patients were interviewed for history of smoking, hypertension, diabetes mellitus, ischemic heart disease, and heart failure and were examined thoroughly. Body mass index (BMI) was calculated using the following formula: BMI in kg/m2 = weight in kilograms divided by height in meters squared.[14] Body surface area (BSA) was calculated using the Mosteller formula where BSA = square root of the height in centimeters multiplied by the weight in kilograms divided by 3600.[15]

A 12-lead surface ECG was performed to confirm sinus rhythm. A trans-cubital venous blood sample was withdrawn from all participants to measure the plasma NT-pro-BNP using an enzyme-linked immunosorbent assay technique.

Trans-thoracic echocardiography

Standard trans-thoracic echocardiography was performed by an experienced echocardiographer blinded to the groups using a Vivid E9 commercial ultrasound scanner (GE Vingmed Ultrasound AS, Horten, Norway) with a 3S matrix array probe having a frequency range of 1.7/3.4 MHz. The following measurements were assessed following recommendations of the American Society of Echocardiography and European Association of Cardiovascular Imaging: [16]

Left ventricular mass and systolic functions

LVEF was measured using the modified biplane Simpson method from the apical 4- and 2-chamber views.

From the parasternal short-axis view at the level of papillary muscles, m-mode echocardiography was used to measure internal LV end diastolic diameter (LVEDD), LV posterior wall thickness at end diastole (PWTD), and interventricular septum thickness at end diastole (IVSTD).

LV mass in grams was calculated using the following formula: [17] LV mass = 0.8× (1.04× [(LVEDD + PWTD + IVSTD)3−(LVEDD)3]) +0.6. This was then divided by BSA to estimate LVMI in g/m2.

Relative wall thickness (RWT) was then calculated by dividing 2 × PWTD by the LVEDD.[16]

Doppler imaging

From the apical 4-chamber view, trans-mitral pulsed wave Doppler at the mitral valve leaflet tips was used to estimate peak early diastolic filling (E-wave) and late diastolic filling (A-wave) velocities and the E/A ratio.

Tissue Doppler imaging

Color-coded tissue Doppler imaging was applied to a gray-scale apical 4-chamber view. Pulsed-wave Doppler was then applied to the lateral and medial aspects of the mitral annulus. Lateral and septal e' wave velocities for early diastolic myocardial relaxation were recorded. These were then averaged to estimate mean E/e' ratio.

Left atrial volume and left atrial ejection fraction

LA volume was measured using the area-length method from the apical 2- and 4-chamber views at ventricular end systole. This was then divided by BSA to obtain LAVI.[18]

LAEF was calculated using the formula: LAEF in Kdynes = 1/3 × MVA × square of trans-mitral A wave velocity[19] Where MVA in the mitral valve area assessed by 2-D planimetry. This was obtained by tracing the narrowest mitral orifice from the short-axis parasternal ensuring to be tangential to the mitral annulus [Figure 1].[16]

Figure 1

Calculating the left atrial ejection force requires measurement of the trans-mitral A wave velocity (left image) and the mitral valve area by 2-D planimetry (right image).

Corrected LAEF to age (% LAEF) was calculated using the formula:

%LAEF = (Calculated LAEF divided by the normal LAEF according to age) ×100. Where the normal LAEF according to age was estimated as (0.098 × age) – 0.74.[20]

Left ventricular strain measurement

Two-dimensional speckle tracking echocardiography was performed by offline analysis of he acquired LV images using EchoPAC v 2.2 software (GE Vingmed Ultrasound AS, Horten, Norway). Mean global longitudinal strain (GLS) was calculated as the average of the GLS in the apical 4-, 3-, and 2-chamber.[9]

Assessment of the heart failure association algorithm score for the diagnosis of heart failure with preserved ejection fraction (HFA–PEFF score)

HFA-PEFF score was calculated for all study group patients. This score uses functional echocardiographic parameters (septal e', lateral e', average E/e' ratio, or GLS), morphological echocardiographic parameters (LAVI, LVMI, and RWT), in addition to, biomarkers (NT-pro-BNP) to diagnose HFPEF where a score of more than equal to 5 is diagnostic of HFPEF. Those with a score of 2–4 would require additional diastolic stress testing to establish the diagnosis of HFPEF according to this diagnostic algorithm.[9]

Statistical analysis

Data were collected, coded, tabulated, and then statistically analyzed using the IBM SPSS Statistics software version 25 (IBM corporation, Armonk, NY, USA). Categorical variables were expressed as number and percentage and analyzed using the Chi-square test. Continuous variables were expressed as mean ± standard deviation and analyzed using student's t-test for the variables that passed normality tests and Mann–Whitney U-test for those that did not pass normality. Correlations were analyzed using Pearson's correlation coefficient ®. Eta-squared was used to correlate to continuous variables to nominal ones. A probability value P < 0.05 was considered statistically significant.

RESULTS

Clinical characteristics

There was no difference between study and control groups regarding age, gender distribution, the percentage of smokers, and BMI. As would be expected, there was a higher percentage of hypertensives, diabetics, and those with a history of ischemic heart disease in the study group [Table 1].

Table 1

Baseline clinical characteristics and laboratory findings

Variable	Study (n=100)	Control (n=1000)	P
Clinical characteristics
Age (years)	60.88±7.21	60.47±6.12	0.665
Male gender, n (%)	32 (32)	33 (33)	0.302
Current smoker, n (%)	18 (18)	12 (12)	0.322
Hypertension, n (%)	47 (47)	0	<0.0001
Diabetes, n (%)	65 (65)	0	<0.0001
History of ischemic heart disease, n (%)	13 (13)	0	0.0002
BMI (kg/m2)	33.86±3.81	26.68±3.42	0.665
Laboratory findings
NT-pro-BNP (pg/ml)	233.67±32.05	59.3±22.79	<0.0001

Continuous variables are expressed as mean and SD whereas categorical variables are expressed as n (%). NT-pro-BNP=N-terminal pro-brain natriuretic peptide, BMI=Body mass index, BNP=Brain natriuretic peptide, NT=N-terminal, SD=Standard deviation

Plasma N-terminal pro-brain natriuretic peptide

Plasma NT-pro-BNP was significantly higher in the study group 233.67 ± 32.05 versus 59.3 ± 22.79 pg/ml (P < 0.0001) [Table 1].

Echocardiographic findings

LVEF was normal in both groups but was lower in the study group. Patients with HFPEF had a larger LVMI and a larger RWT compared to the control group (P < 0.0001 for all) [Table 2].

Table 2

Echocardiographic variables in both groups

Variable	Study (n=100)	Control (n=100)	P
Left ventricular mass and systolic functions
LVEF (%)	63.59±3.31	65.37±3.06	0.0001
LVMI (kg/m2)	190.01±48.63	69.71±11.14	<0.0001
Relative wall thickness	0.647±0.13	0.293±0.07	<0.0001
Left ventricular diastolic function and Doppler measurements
Trans-mitral E wave (m/s)	0.739±0.134	1.02±0.26	<0.0001
Trans-mitral A wave (m/s)	1.13±0.124	1.1±0.112	0.796
Trans-mitral E/A ratio	0.721±0.198	1.003±0.262	<0.0001
Lateral e’ velocity (cm/s)	7.37±1.08	12±0.84	<0.0001
Septal e’ velocity (cm/s)	5.68±0.95	8.54±0.52	<0.0001
Average E/e’ ratio	12.82±2.86	6.27±0.72	<0.0001
Left atrial volume and ejection force
LAVI (ml/m2)	36.05±2.5	26.86±2.64	<0.0001
% LAEF (%)	142.14±24.27	92.18±13.99	<0.0001
Left ventricular strain
LV-GLS (%)	16.88±9.11	20.19±2.81	<0.0001

Continuous data were expressed as mean and standard deviation. LVEF=Left ventricular ejection fraction; LVMI=Left ventricular mass index, LAVI=Left atrial volume index, % LAEF=Percent left atrial ejection force, LV-GLS=Left ventricular global longitudinal strain

Left ventricular diastolic function and Doppler measurements

As would be expected, trans-mitral E wave velocity, E/A ratio, septal e' velocity, and lateral e' velocity were all significantly lower in the study group (P < 0.0001 for all). Average E/e` ratio was significantly higher in the study group (P < 0.0001). LAVI was significantly higher in the study group 36.05 ± 2.5 versus 26.86 ± 2.64 ml/m2 (P < 0.0001). There was no difference between both groups regarding trans-mitral A wave velocity [Table 2].

Left ventricular global longitudinal strain

LV-GLS was significantly lower in the study group 16.88 ± 9.11 versus 20.19 ± 2.81% (P < 0.0001).

Left atrial ejection force

LAEF (corrected to age) was significantly higher in the study group 142.14 ± 24.27 versus 92.18 ± 13.99% (P < 0.0001).

LAEF had a negative correlation with age (r =-0.27, P = 0.05) and a positive correlation with the HFA-PEFF score (r = 0.256, P = 0.01) and a positive correlation with a diagnosis of HFPEF according to the ESC definition (eta-squared = 0.616).

Sub-group analysis of patients in the study group with an HFA-PEFF score of 4

In the study group, 18 patients had an established diagnosis of HFPEF according to the ESC definition yet had a borderline HFA-PEFF score of 4. For this sub-group, LAEF was significantly higher than that of the control group 137.00 ± 23.55 (P < 0.0001). However, it was not significantly different than the rest of the study group with an HFA-PEFF score more than or equal to 5 who had a mean LAEF of 143.27 ± 24.42 (P = 0.06).

DISCUSSION

The left atrium plays a major role in LV filling particularly in patients with HFPEF who have an elevated LV end diastolic pressure. The various methods used to assess LA function remain underrepresented in studies on HFPEF patients. LAEF is a measure of the force exerted by the LA during LV filling. It remains scarcely studied in the literature with the LA ejection fraction being was more extensively studied.[212223] In this study, we aimed to examine LAEF as a possible additional measure for the diagnosis of HFPEF.

The main findings of this study were as follows: (1) LAEF was significantly higher in patients with HFPEF compared to healthy controls; (2) Patients with an HFA-PEFF score of 4 (who should undergo diastolic stress testing to validate the diagnosis according to the algorithm) had a significantly higher LAEF as compared to healthy controls.

Secondary findings included that patients with HFPEF had a lower LV GLS and higher plasma NT-pro-BNP levels.

The LA performs several functions: A reservoir function, a contractile (booster) function, and a conduit function. It is difficult to have a single measure that can assess all atrial functions collectively. The LA contractile function is more complex than would be presumed as LA contraction is affected by the force with which the LA propels blood across the mitral valve, LV end-diastolic pressure, and atrial pre-load. Different methods have been proposed to assess the so-called “true” or “total” atrial function.[2425]

The concept of measuring LAEF to assess LA systole was first introduced by Manning et al. in 1993. They based their research on the concept that the contribution of atrial systole to LA filling and hence diastolic function was neglected. The formula they devised is based on classic Newton laws using area (mitral valve area) and velocity (trans-mitral A wave) to measure force. They concluded that LAEF is a physiological measure of atrial systolic function and is a useful index for assessing the contribution of the left atrium to diastolic function.[19]

A study assessed LAEF and kinetic energy in 58 heart failure patients with an average LVEF of 47% ±17.3% compared to 48 healthy controls. The authors concluded that LAEF was increased in patients with chronic heart failure[20] Another study examined LAEF in neonates who are generally known to have slower ventricular relaxation compared to adults and found that LAEF is increased in newborn infants compared to adults.[26]

LAEF is occasionally referred to in the literature as LA systolic force (LASF) and in a population-based study on 2808 patients of the Strong Heart Study which included patients without valvular abnormalities or prior cardiac events, it was found that LASF was associated with geometric changes to the heart and increased cardiac morbidity and mortality.[27]

LAEF was also found to be elevated in patients with HCM in a study on 30 patients compared to 15 healthy controls. In this study, mitral valve area was assessed using three-dimensional echocardiography to improve the accuracy of measurement of the mitral orifice. LAEF was found to be even higher in those with obstructive HCM as compared to nonobstructive HCM.[10] Similarly, LAEF was elevated in a study examining 17 patients with noncompaction cardiomyopathy as compared to healthy controls.[28]

A study on 58 patients with ST-segment elevation myocardial infarction (STEMI) managed by primary percutaneous coronary intervention aimed to assess expected changes in diastolic function in such patients compared to healthy controls. The authors assessed LAEF and NT-pro-BNP and found that LAEF is elevated in patients with STEMI and correlates with NT-pro-BNP levels. They concluded that increased LAEF in their study population is a manifestation of impaired diastolic function and recommended considering LAEF as a diagnostic tool in the diagnosis of HFPEF.[11]

Several studies have found that patients with paroxysmal atrial fibrillation and sick sinus syndrome have impaired LA systolic function compared to normal individuals as assessed by reduced LAEF in such patients when they are in sinus rhythm.[29]

The validity of LAEF was also examined in a study on 34 healthy individuals where three-dimensional speckle tracking echocardiography was used to assess global LA peak circumferential, area, and longitudinal strain. All of which were found to correlate with LAEF. In addition, LAEF correlated with total atrial stroke volume, total atrial emptying fraction, and global LA 3D strain.[30]

Another study examined 120 patients with different grades of LV diastolic dysfunction with the aim of comparing LAEF to different echocardiographic measures of LV diastolic function and found that LAEF is elevated in patients with HFPEF. However, patients with restrictive type of diastolic function were found to have a significantly lower LAEF compared to those with Grade 1 and 2 diastolic function.[31]

Study limitations

Limitations of the current study are that it comes from a single medical center with a relatively small number of patients. Advanced cardiac imaging modalities such as three-dimensional echocardiography and cardiac magnetic resonance imaging were not used. The normal LAEF for age is yet to be confirmed. Patients with an HFA-PEFF score of 2–3 were not included in this study. The mitral orifice does not remain constant during normal cardiac contractility but variations in its size are minimal and should not significantly influence results.[32] The formula for estimating LAEF considers the mitral valve to be circular while it is actually elliptical. This should not have an impact on our findings as the same method was obtained for patients and controls.

CONCLUSION

LAEF was significantly higher in patients with HFPEF as compared to healthy controls. Patients with a borderline HFA-PEFF score of 4 had a significantly higher LAEF as compared to controls.

Ethical clearance

Research protocol was approved by institutional ethical committee.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.