DISCUSSION
This study showed normal ranges of atrial S/SR in two large
population-based studies. Furthermore, it demonstrated that reduced PACS
and ATS were related to high NT-proBNP levels and these parameters had
incremental value in the detection of elevated NT-proBNP in the general
population.
Normal Ranges for atrial strain and SR
Several previous studies have reported normal values and ranges for
atrial S/SR; however, only a few publications have referred to larger
population-based studies with more than 1000 healthy subjects (14, 15).
Apart from the inclusion of participants with diabetes in the present
study, the exclusion criteria were similar in all the three studies. In
accordance with these two large previous studies, our data confirmed
higher ACS, ATS, and SRE in the younger population and in females.
Nielsen et al. reported an increase in PACS with age, whereas our
results showed the same but not a significant tendency. The absence of
age dependence in SR S and SR A reflects previous findings (14).
Compared with the population-based studies of Nielsen et al. (15) and
Liao et al. (14) (1641 and 2812 healthy participants, respectively), the
mean atrial strain values in the present study were generally higher.
They were also generally higher than those in the meta-analysis by
Pathan et al. :23% vs. 21%, 27% vs. 23%, and 47.5% vs. 39% for
PACS, ACS, and ATS, respectively. The meta-analysis showed high
variations between the underlying studies, with a range of ATS between
28% and 60%, illustrating the challenges of defining normalcy in
thin-walled atria. The high range may be due to difficulties in defining
the atrial wall, which must be defined at the longest distance from the
probe, leading to a low lateral resolution of the atrial walls. Small
changes in the ROI position and the definition of atrial wall thickness
(as necessary in EchoPac) can significantly affect the outcomes of
atrial S/SR measurements. Large differences between studies and the
significance of relatively small differences within each study indicate
systematic errors between different laboratories.
For clinicians, the most important values for defining normalcy are the
lower limits. Interestingly, compared with the study by Nielsen et al.
(15), our study showed that PACS and ATS were similar, whereas the lower
limits for ACS were lower, with higher variations than those for PACS.
Similarly, the lower limits may be explained by the higher values in the
present study, with higher data variability. Comparing SR S, SR E and SR
A between the present study and the one by Liao et al. (14), we found
similar mean values for SR S and SR A (2.5 vs. 2.6; 2.3 vs. 3.0 and 3.0
vs 2.9 /s, respectively), while SR E was lower (2.3 vs. 3.0,
respectively). For the SR, the SD was larger (0.9/s) than that of the
study by Liao et al. (0.5/s). The higher SD may reflect a higher
variability between the Norwegian and Russian populations, apart from
the lower population size and lower imaging or reading quality. Higher
values of atrial strain may be due to a more central position of the ROI
which might also explain the higher variability of the measurements.
Normal EF
Several studies have confirmed the usefulness of NT-proBNP as a marker
of elevated filling pressure, indicating the presence of subclinical
heart-failure in asymptomatic patients (16, 23, 24). Other studies have
shown a relationship between adverse outcomes and HFpEF and heart
failure with reduced EF (HFrEF) (25, 26). The cut-off value for a normal
NT-proBNP in the present study has been chosen by averaging the 99
percentile of recently published age- and sex-adjusted normal-ranges of
the Tromsø Study (22).
A recent population-based study of 620 individuals with normal EFs
investigated LA S/SR and LASI in relation to elevated NT-proBNP levels
(27) and showed weak but significant correlations between S/SR
parameters and elevated NT-proBNP levels. In accordance with the study
by Liu et al., all three groups with normal EF, low EF, and AF showed
significantly lower atrial S/SR at elevated NT-proBNP levels, confirming
the previous numbers with three times as much participants.
Based on the 2016 recommendations for hearts with preserved EF, E/e, ’
septal e, ’ lateral e´, TR velocity, and LA volume should be used to
assess elevated filling pressures. In the normal EF group of the present
study, E/e’ and MV DT, in addition to ATS, were independently associated
with elevated NT-proBNP levels. However, these differing results cannot
be regarded as a contradiction since larger studies on diastolic
function have so far not been able to show sufficient test accuracies
for single parameters, with the highest AUCs of around 0.7. Given the
small effect sizes of each possible indicator, multiple regression
analyses in different studies always favor different parameters. Liu et
al. showed that LASI is a good marker of high NT-proBNP levels, which
was confirmed in the present study. However, LASI was not a better
indicator than the other atrial S/SR parameters.
Reduced EF
Participants with reduced EF and normal NT-proBNP are a diverse group,
where either systolic or diastolic heart function is within the
low-normal range, echocardiographic pathology precedes an increase in
NT-proBNP, and participants may present at the stage of compensated
heart failure. Thus, this study population cannot be compared with
clinical studies, in which extreme values render higher test accuracies.
However, because the 2016 recommendations for the assessment of
diastolic dysfunction suggest a different approach for the assessment of
diastolic filling pressures in hearts with reduced EFs (19), we chose to
investigate the subpopulation with reduced EF separately.
Although the group with reduced EF comprised only 173 participants and
12 pathological cases, atrial S/SR revealed similar results to the
normal EF group. As in the high EF group, independent conventional
indicators for high NT-proBNP such as LV SV and LV ESV were different
from the recommended parameters (E/A ratio, MV E, E/e´, TR velocity, and
LAVI) from the 2016 guidelines (19). According to the multiple
regression, PACS was an “independent” indicator for elevated
NT-proBNP, supporting previous reports, that atrial S/SR are valuable
indicators for high filling pressures and diastolic dysfunction (6-8).
Accordingly, ROC curve analysis revealed a significant effect of adding
these parameters to the combination of two conventional parameters, LVSV
and LVESV. Interestingly, PACS was the only independent diastolic
functional indicator of high NT-proBNP levels, indicating the usefulness
of adding atrial S/SR parameters to the assessment of diastolic
dysfunction.
AF
Previous studies demonstrated that LA S/SR is a useful predictor of the
incidence of recurrent AF (3, 4, 28), LA reverse remodeling after
radiofrequency catheter ablation (29), and future embolic events (30) in
patients with known AF. However, this population-based study included
only a small group of participants with AF, and unexpectedly, the number
of participants with elevated NT-proBNP levels was low. In addition,
this group was highly inhomogeneous, comprising participants with sinus
rhythm, a history of AF, and presenting with AF during echocardiographic
examination. The small group size and differences between registrations
with sinus rhythm or AF were the most likely causes of the insignificant
outcomes of the multiple regression analysis. However, a significant
indirect comparison of groups and univariate regression analysis
revealed the highest number of possible predictors of increased filling
pressures, including atrial S/SR parameters, especially PACS and atrial
SR, which is in accordance with previous studies confirming the
importance of LA S/SR in assessing cardiac function and outcomes.
Clinical application
Invasive catheter-based studies have shown that the atrial S/SR is a
valuable indicator of high filling pressures (5, 31). However, this was
a population study based on healthy or asymptomatic participants to
ascertain whether echocardiographic screening for elevated filling
pressures or heart failure could be improved by adding LA S/SR
parameters as previous studies have shown that high clinical values of
atrial S/SR and LASI may predict outcomes in patients with previous AF
(3, 4, 29, 30).
Assessing elevated filling pressures without an invasive approach
remains challenging. Although the European Association of Cardiovascular
Imaging (EACVI)- recommendations suggest a limited number of parameters,
modern echocardiography provides over 40 Doppler, tissue Doppler and
speckle tracking-based parameters that may be used to evaluate LV
filling pressures. Pandey et al. introduced a deep-learning AI-based
approach that included LA S/SR, 13 echocardiographic measures, and
clinical parameters(17). All current approaches indicate that a single
key parameter cannot accurately assess diastolic dysfunction, especially
in asymptomatic patients. Furthermore, AI-based assessment and a
clinician visually assessing the echocardiograms will still both be
needed to assess many accessible parameters for optimal reading results,
especially in large areas of inconclusive or contradictory measurements
as the present study showed that LA strain adds incremental information;
therefore, these parameters should be integrated into the assessment of
LV filling pressure.
Limitations
This study has several limitations. According to previous meta-analyses
and reviews (13, 32), LA strain measurements and variability differed
significantly between the study groups. Furthermore, this was a
single-reader study with low intra-reader variability. Multiple readers
should be involved to test for a screening situation. General
population-based studies have limitations in reproducing the test
accuracies observed in selected patients with symptoms or a high-risk
profile. However, this study was able to answer the question of the
incremental value of LA S/SR compared with conventional
echocardiographic parameters. Averina et al. (22) demonstrated that
NT-proBNP has low sensitivity and specificity for detecting cardiac
disease in the general population, reflecting the challenge of
evaluating the test accuracy within only low pathological deviations.
Furthermore, the chosen NT-proBNP cutoff value plays a crucial role in
test accuracy. Cardiac disease can be present at high or low filling
pressures; therefore, the question remains whether NT-proBNP is a
sufficient indicator of filling pressures in the general population.